Assessment of surveillance of human West Nile virus infection in Quebec, 2003.
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Adult↗
Biomedical subjects
L Lambert
Publications and source records attributed to L Lambert.
Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV.
We examined the effects of human immunodeficiency virus infection on the turnover of CD4 and CD8 T lymphocytes in 17 HIV-infected patients by 30 min in vivo pulse labeling with bromodeoxyuridine (BrdU). The percentage of labeled CD4 and CD8 T lymphocytes was initially higher in lymph nodes than in blood. Labeled cells equilibrated between the two compartments within 24 h. Based on mathematical modeling of the dynamics of BrdU-labeled cells in the blood, we identified rapidly and slowly proliferating subpopulations of CD4 and CD8 T lymphocytes. The percentage, but not the decay rate, of labeled CD4 or CD8 cells in the rapidly proliferating pool correlated significantly with plasma HIV RNA levels for both CD4 (r = 0.77, P < 0.001) and CD8 (r = 0.81, P < 0.001) T cells. In six patients there was a geometric mean decrease of greater than 2 logs in HIV levels within 2 to 6 mo after the initiation of highly active antiretroviral therapy; this was associated with a significant decrease in the percentage (but not the decay rate) of labeled cells in the rapidly proliferating pool for both CD4 (P = 0.03) and CD8 (P < 0.001) T lymphocytes. Neither plasma viral levels nor therapy had an effect on the decay rate constants or the percentage of labeled cells in the slowly proliferating pool. Monocyte production was inversely related to viral load (r = -0.56, P = 0.003) and increased with therapy (P = 0.01). These findings demonstrate that HIV does not impair CD4 T cell production but does increase CD4 and CD8 lymphocyte proliferation and death by inducing entry into a rapidly proliferating subpopulation of cells.
Adult↗
Coordinate control of sphingolipid biosynthesis and multidrug resistance in Saccharomyces cerevisiae.
Multiple or pleiotropic drug resistance often occurs in the yeast Saccharomyces cerevisiae through genetic activation of the Cys(6)-Zn(II) transcription factors Pdr1p and Pdr3p. Hyperactive alleles of these proteins cause overproduction of target genes that include drug efflux pumps, which in turn confer high level drug resistance. Here we provide evidence that both Pdr1p and Pdr3p act to regulate production of an enzyme involved in sphingolipid biosynthesis in S. cerevisiae. The last step in formation of the major sphingolipid in the yeast plasma membrane, mannosyldiinositol phosphorylceramide, is catalyzed by the product of the IPT1 gene, inositol phosphotransferase (Ipt1p). Transcription of the IPT1 gene is responsive to changes in activity of Pdr1p and Pdr3p. A single Pdr1p/Pdr3p response element is present in the IPT1 promoter and is required for regulation by these factors. Loss of IPT1 has complex effects on drug resistance of the resulting strain, consistent with an important role for mannosyldiinositol phosphorylceramide in normal plasma membrane function. Direct assay for lipid contents of cells demonstrates that changes in sphingolipid composition correlate with changes in the activity of Pdr3p. These data suggest that Pdr1p and Pdr3p may act to modulate the lipid composition of membranes in S. cerevisiae through activation of sphingolipid biosynthesis along with other target genes.
DNA, Fungal↗
Annealing of RNA editing substrates facilitated by guide RNA-binding protein gBP21.
RNA editing within the mitochondria of African trypanosomes is characterized by the insertion and deletion of uridylate residues into otherwise incomplete primary transcripts. The reaction takes place in a high molecular mass ribonucleoprotein (RNP) complex of uncertain composition. Furthermore, factors that interact with the RNP complex during the reaction are by and large unknown. Here we present evidence for an editing-related biochemical activity of the gRNA-binding protein gBP21. Using recombinant gBP21 preparations, we show that the protein stimulates the annealing of gRNAs to cognate pre-mRNAs in vitro. This represents the presumed first step of the editing reaction. Kinetic data establish an enhancement of the second order rate constant for the gRNA- pre-mRNA interaction. gBP21-mediated annealing is not exclusive for RNA editing substrates since complementary RNAs, unrelated to the editing process, can also be hybridized. The gBP21-dependent RNA annealing activity was identified in mitochondrial extracts of trypanosomes and can be inhibited by immunoprecipitation of the polypeptide. The data suggest a factor-like contribution of gBP21 to the RNA editing process by accelerating the rate of gRNA-pre-mRNA anchor formation.
Animals↗
Interleukin-2 induced immune effects in human immunodeficiency virus-infected patients receiving intermittent interleukin-2 immunotherapy.
To characterize the immunological effects of intermittent IL-2 therapy, which leads to selective increases in CD4+ T lymphocytes in HIV-infected patients, 11 patients underwent extensive immunological evaluation. While IL-2 induced changes in both CD4+ and CD8+ cell number acutely, only CD4+ cells showed sustained increases following discontinuation of IL-2. Transient increases in expression of the activation markers CD38 and HLA-DR were seen on both CD4+ and CD8+ cells, but CD25 (a chain of the IL-2 receptor) increased exclusively on CD4+ cells. This increase in CD25 expression was sustained for months following discontinuation of IL-2, and was seen in naive as well as memory cells. IL-2 induced cell proliferation, but tachyphylaxis to these proliferative effects developed after 1 week despite continued IL-2 administration. It thus appears that sustained CD25 expression selectively on CD4+ cells is a critical component of the immunological response to IL-2, and that intermittent administration of IL-2 is necessary to overcome the tachyphylaxis to IL-2-induced proliferation.
ADP-ribosyl Cyclase↗
Falls risk factors in the hospital setting: a systematic review.
The objective of this systematic review was to summarize the best available evidence on the factors that increase the risk of patients falling during hospitalization. Studies included in the review were those that involved adult patients in hospital, that attempted to identify risk factors for falling, and used a cohort or case-control research design. The search strategy covered all major databases and including MEDLINE, CINAHL, Current Contents, Psyclit, Embase and the Cochrane Library. Results were summarized by a narrative discussion, identifying risk factors that were commonly identified in a range of practice settings. Eighteen papers met the review inclusion criteria and are reported in this paper. Factors associated with an increased risk of falling include impaired mental status, special toileting needs, impaired mobility, and a history of falling. While findings are contradictory, it appears that both medications and advanced age will also influence a patient's risk of falling.
Accidental Falls↗
Legislation will benefit dietitians, patients in pre-dialysis, post-transplant setting.
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Diabetes Mellitus↗
Longitudinal changes in CD4+ T cell antigen receptor diversity and naive/memory cell phenotype during 9 to 26 months of antiretroviral therapy of HIV-infected patients.
Although skewing of the CD4+ TCR repertoire in advanced HIV infection is well documented, increases in polyclonality during antiretroviral therapy have been less consistently observed. Ten patients, each with documented abnormalities within the CD4+ TCR repertoire, were studied by CDR3 spectratyping, semiquantitative PCR, and SSCP during 9-26 months of therapy. Naive and memory cell phenotypes were analyzed by flow cytometry. Six of 10 patients showed increased polyclonality of their TCR repertoires, 1 showed no change, and 3 showed increased TCR skewing, despite suppressed viral replication. Overall, there was no significant change in the percentage of abnormal BV subfamilies (from a mean of 25.5 to 17.1%) or the percentage of naive CD4+ T cells (from a mean of 18 to 25%). Further, progression of TCR repertoire disruptions was observed in some patients even with suppression of plasma viral RNA below 500 copies/ml. Although a spectrum of changes may be seen within the CD4+ TCR repertoire in the setting of antiretroviral therapy, increases in polyclonality are observed in some patients.
Anti-HIV Agents↗
Effects of intermittent interleukin-2 therapy on plasma and tissue human immunodeficiency virus levels and quasi-species expression.
To characterize the effects of intermittent interleukin (IL)-2 therapy on human immunodeficiency virus (HIV), 11 patients underwent detailed virological evaluation during a year of IL-2 therapy. Six patients showed a >0.5 log increase in plasma HIV during at least 1 IL-2 cycle, with 2 experiencing an increase in >50% of cycles. Three of the remaining 5 patients had a >0.5 log decrease during at least 1 IL-2 cycle, and the remaining patients exhibited <0.5 log changes. No changes in lymphoid (tonsil) levels of HIV were seen during the year. Quasi-species analysis in a separate cohort demonstrated that the virus induced by IL-2 most commonly resembled pre-IL-2 plasma quasi species. Thus, intermittent IL-2 does not result in sustained increases in either plasma or tissue levels of HIV and does not result in sustained expression of a previously silent quasi species.
Adult↗
Maintenance of large numbers of virus-specific CD8+ T cells in HIV-infected progressors and long-term nonprogressors.
The virus-specific CD8+ T cell responses of 21 HIV-infected patients were studied including a unique cohort of long-term nonprogressors with low levels of plasma viral RNA and strong proliferative responses to HIV Ags. HIV-specific CD8+ T cell responses were studied by a combination of standard cytotoxic T cell (CTL) assays, MHC tetramers, and TCR repertoire analysis. The frequencies of CD8+ T cells specific to the majority of HIV gene products were measured by flow cytometric detection of intracellular IFN-gamma in response to HIV-vaccinia recombinant-infected autologous B cells. Very high frequencies (0.8-18.0%) of circulating CD8+ T cells were found to be HIV specific. High frequencies of HIV-specific CD8+ T cells were not limited to long-term nonprogressors with restriction of plasma virus. No correlation was found between the frequency of HIV-specific CD8+ T cells and levels of plasma viremia. In each case, the vast majority of cells (up to 17.2%) responded to gag-pol. Repertoire analysis showed these large numbers of Ag-specific cells were scattered throughout the repertoire and in the majority of cases not contained within large monoclonal expansions. These data demonstrate that high numbers of HIV-specific CD8+ T cells exist even in patients with high-level viremia and progressive disease. Further, they suggest that other qualitative parameters of the CD8+ T cell response may differentiate some patients with very low levels of plasma virus and nonprogressive disease.
Adult↗
The involvement of gRNA-binding protein gBP21 in RNA editing-an in vitro and in vivo analysis.
RNA editing in the parasitic organism Trypanosoma brucei is characterised by the insertion and deletion of uridylate residues into otherwise incomplete primary transcripts. The processing reaction is a required pathway for the expression of most mitochondrial genes and proceeds by a cascade of enzyme-catalysed steps. RNA editing involves one or more macromolecular ribonucleoprotein complexes which are likely to interact with additional components as the reaction proceeds. Here we examined the involvement of the gRNA-binding polypeptide gBP21, a protein which has been demonstrated to be associated with active RNA editing complexes. We show that in vitro RNA editing can be suppressed by the addition of a gBP21-specific antibody or by immunodepletion of the protein. By creating a gBP21 knockout mutant we analysed the requirement for the protein in vivo. gBP21(-) trypanosomes are viable as bloodstream stage cells and contain edited mRNAs. However, the knockout mutant is not capable of differentiating from the bloodstream to the insect life cycle stage in vitro. Moreover, mutant cells are characterised by a low mitochondrial transcript abundance. Together, these data establish that gBP21 contributes a non-essential function to the RNA editing reaction and further suggest that the protein is involved in additional mitochondrial processes which impact a larger pool of mitochondrial transcripts.
Animals↗
DEAD-box protein HEL64 from Trypanosoma brucei: subcellular localization and gene knockout analysis.
RNA helicases are molecules that play a central role in the control of ribonucleic acid metabolism. Only two putative RNA helicase genes of the DEAD-box family have been identified in the protozoan parasite Trypanosoma brucei brucei. One of these genes is HEL64, a single-copy gene of unknown function. In this study we conducted targeted gene-disruption experiments of the HEL64 locus with the aim of identifying a phenotype that would suggest a function for the encoded protein. It is likely that HEL64 is an essential gene in insect-stage trypanosomes, since all attempts to create a HEL64 double-allele knockout cell line failed. Instead, we obtained a mutant derived from an unusual recombination event that nonetheless contained a functional copy of the gene. One allele of HEL64 is sufficient for the survival of the parasite. Single-allele knockout mutants showed no gross change in cell morphology and multiplied with a cell-doubling time identical to that of wild-type trypanosomes. Though HEL64 has high sequence homology with the nuclear DEAD-box protein p68, it is localized in the cytosol of trypanosomes and, thus, cannot be a homologue of p68 as previously suggested. Since the protein did not cross-hybridize with an anti-eIF-4A antibody, we excluded the possibility that HEL64 might be a homologue of the translation initiation factor eIF-4A. Although the function of HEL64 remains unknown, the present data indicate that the encoded DEAD-box protein plays an important role during the insect life-cycle stage of the parasite.
Alleles↗
Can lowering homocysteine levels reduce the incidence of stroke?
Hyperhomocysteinaemia has been identified as an independent risk factor for atherosclerotic and thromboembolic diseases such as cerebro-vascular diseases, coronary artery disease and venous thrombosis. This review will discuss the role of high levels of plasma homocysteine in stroke disease.
Animals↗
Expression analysis of two gene subfamilies encoding the plasma membrane H+-ATPase in Nicotiana plumbaginifolia reveals the major transport functions of this enzyme.
The plasma membrane H+-ATPase couples ATP hydrolysis to proton transport, thereby establishing the driving force for solute transport across the plasma membrane. In Nicotiana plumbaginifolia, this enzyme is encoded by at least nine pma (plasma membrane H+-ATPase) genes. Four of these are classified into two gene subfamilies, pma1-2-3 and pma4, which are the most highly expressed in plant species. We have isolated genomic clones for pma2 and pma4. Mapping of their transcript 5' end revealed the presence of a long leader that contained small open reading frames, regulatory features typical of other pma genes. The gusA reporter gene was then used to determine the expression of pma2, pma3 and pma4 in N. tabacum. These data, together with those obtained previously for pma1, led to the following conclusions. (i) The four pma-gusA genes were all expressed in root, stem, leaf and flower organs, but each in a cell-type specific manner. Expression in these organs was confirmed at the protein level, using subfamily-specific antibodies. (ii) pma4-gusA was expressed in many cell types and notably in root hair and epidermis, in companion cells, and in guard cells, indicating that in N. plumbaginifolia the same H+-ATPase isoform might be involved in mineral nutrition, phloem loading and control of stomata aperture. (iii) The second gene subfamily is composed, in N. plumbaginifolia, of a single gene (pma4) with a wide expression pattern and, in Arabidopsis thaliana, of three genes (aha1, aha2, aha3), at least two of them having a more restrictive expression pattern. (iv) Some cell types expressed pma2 and pma4 at the same time, which encode H+-ATPases with different enzymatic properties.
Amino Acid Sequence↗
Do simple prudent health behaviours protect men from myocardial infarction?
BACKGROUND: We tested whether behaviours such as discarding obvious fat on meat, cessation of smoking, avoidance of passive smoking, habitual use of reduced fat milk, prudent consumption of alcohol and regular but moderate physical exercise are associated with a reduction of cardiovascular risk. METHODS: This was a population-based case-control study done in Perth, Western Australia. The cases (n = 336) were men aged 27-64 years with a first-ever acute myocardial infarction (AMI) during the period 1992-1993, and who survived at least 28 days. The controls (n = 735) were participants in a population-based survey of cardiovascular risk factors conducted during May-November 1994. Both groups completed the same questionnaire and the data were analysed with multiple logistic regression using backward elimination technique. RESULTS: Among men aged 27-64 years simple measures such as participation in nonvigorous exercise (odds ratio [OR] = 0.5, 95% CI: 0.4-0.7), and avoidance of added salt (OR = 0.6, 95% CI: 0.4-0.9) are associated with significant and important protection from AMI. CONCLUSION: After 25 years of falling mortality in Australia, lifestyles can still be significantly improved to reduce heart disease even further.
Adult↗
Sleep disturbances in children with human immunodeficiency virus infection.
OBJECTIVE: To describe the sleep patterns and level of fatigue in children and adolescents (6-18 years of age) with HIV infection, compared with ethnic-, gender-, and age-matched healthy children in the home setting. DESIGN: Descriptive, comparative. SETTING: Conducted in each child's home environment. STUDY PARTICIPANTS: Eighteen HIV-infected and 15 noninfected children completed the study. The Centers for Disease Control and Prevention HIV classifications for the 18 HIV-infected children were: A (n = 7), B (n = 6), and C (n = 5). METHODS: A symptom diary was developed using a previously validated fatigue assessment scale, modified for use with children. Content validity of the diary was established with a panel of 5 experts in child development and pediatric HIV disease. Children were asked to complete the diary each morning and evening for 3 days. Each child wore a wrist actigraph during the same period. RESULTS: The HIV-infected children had significantly more wake time after sleep onset, compared with noninfected children (13.55% vs 7. 47%). The HIV-infected children had more awakenings (25.33 vs 16.71) and were awake for longer periods (3.01 vs 1.01 minutes), compared with noninfected children. By parent report, 7 HIV-infected children napped and 2 noninfected children napped, indicating greater daytime fatigue in the HIV-infected children. HIV-infected children also reported a greater level of evening tiredness (2.47 vs 1.8). CONCLUSIONS: The findings from this study suggest that sleep disturbances occur in HIV-infected children, similar to findings previously described in HIV-infected adults. Additional research is necessary to characterize the nature and patterns of sleep disturbance and fatigue related to pediatric HIV-infection, to assess the impact these may have on daily activities, and to develop strategies to improve sleep for these children.
Adolescent↗
Critical pathways for postoperative care after simple congenital heart surgery.
OBJECTIVE: To evaluate the clinical, financial, and parent/patient satisfaction impact of critical pathways on the postoperative care of pediatric cardiothoracic patients with simple congenital heart lesions. STUDY DESIGN: Critical pathways were developed by pediatric intensive care nurses and implemented under the direction of pediatric cardiothoracic surgeons. PATIENTS AND METHODS: Critical pathways were used during a 12-month study on 46 postoperative patients with simple repair of atrial septal defect (ASD), coarctation of the aorta (CoA), and patent ductus arteriosus (PDA). Using the study criteria, a control group of 58 patients was chosen from 1993. Prospective and control group data collected included postoperative intubation time, total laboratory tests, arterial blood gas utilization, morphine utilization, time in the pediatric intensive care unit, total hospital stay, total hospital charges, total hospital cost, and complications. Variances from the critical pathway and satisfaction data were also recorded for study patients. RESULTS: Resource utilization was reduced after implementation of critical pathways. Significant reductions were seen in total hours in the pediatric intensive care unit, total number of laboratory tests, postoperative intubation times, arterial blood gas utilization, morphine utilization, length of hospitalization (ASD, 4.9 to 3.1 days; CoA, 5.2 to 3.2 days; and PDA, 4.1 to 1.4 days; all P < 0.05), total hospital charges (ASD, $16,633 to $13,627; CoA, $14,292 to $8319; and PDA, $8249 to $4216; all P < 0.05), and total hospital costs. There was no increase in respiratory complications or other complications. Patients and families were generally satisfied with their hospital experience, including analgesia and length of hospitalization. CONCLUSIONS: Implementation of critical pathways reduced resource utilization and costs after repair of three simple congenital heart lesions, without obvious complications or patient dissatisfaction.
Aortic Coarctation↗
Trypanosoma brucei TBRGG1, a mitochondrial oligo(U)-binding protein that co-localizes with an in vitro RNA editing activity.
We report the characterization of a Trypanosoma brucei 75-kDa protein of the RGG (Arg-Gly-Gly) type, termed TBRGG1. Dicistronic and monocistronic transcripts of the TBRGG1 gene were produced by both alternative splicing and polyadenylation. TBRGG1 was found in two or three forms that differ in their electrophoretic mobility on SDS-polyacrylamide gel electrophoresis gels, one of which was more abundant in the procyclic form of the parasite. TBRGG1 was localized to the mitochondrion and appeared to be more abundant in bloodstream intermediate and stumpy forms in which the mitochondrion reactivates and during the procyclic stage, which possesses a fully functional mitochondrion. This protein was characterized to display oligo(U) binding characteristics and was found to co-localize with an in vitro RNA editing activity in a sedimentation analysis. TBRGG1 most likely corresponds to the 83-kDa oligo(U)-binding protein previously identified by UV cross-linking of guide RNA to mitochondrial lysates (Leegwater, P., Speijer, D., and Benne, R. (1995) Eur. J. Biochem. 227, 780-786).
Alternative Splicing↗