Community paediatrics and public health: taking stock for the next millennium.
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Child↗
Biomedical subjects
D Hall
Publications and source records attributed to D Hall.
Lip-reading ability and patterns of cortical activation studied using fMRI.
Lip-reading is a complex cognitive skill with large individual differences in performance. The basis of these individual differences remains poorly understood. Functional magnetic resonance imaging (fMRI) techniques allows brain activation accompanying complex cognitive activities to be studied noninvasively. In the present paper, fMRI was used to study the patterns of cortical activation that occur during the silent lip-reading of connected speech and to investigate whether there are detectable differences in activation between subjects with widely differing lip-reading abilities. From a cohort of 26 volunteers, nine subjects who fell into three distinct lip-reading ability groups were selected. Brain activation was measured in two conditions: an experimental condition where subjects attempted to lip-read sentences; and a baseline condition where subjects passively viewed a static image of a talker's face. Relative to the baseline condition, lip-reading induced activation in several cortical areas, including the auditory cortices, despite the lack of an auditory component to the task. In comparison to the better two groups of lip-readers, subjects in the poorest group displayed significantly less activation in superior and middle temporal gyrus, but not inferior temporal gyrus. These preliminary results justify more extensive investigations of the cortical basis of individual differences in lip-reading.
Adult↗
The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells.
Protease inhibitors are very effective in treating patients infected with HIV. However, many drugs in this class penetrate poorly into the central nervous system (CNS) and may permit this site to be a sanctuary from which resistant virus can emerge. Previous studies have shown that the protease inhibitor saquinavir (SQV) interacts with the multidrug transport system, P-glycoprotein (P-gp), expressed in epithelial cells in the gut mucosa and at the blood-brain barrier, and thus might affect both the oral absorption and the penetration of SQV into the CNS. To determine whether SQV is a substrate for P-gp, its uptake was determined in cancer cells, which do (Dx5) and do not (MES-SA) express P-gp. The distribution of SQV between brain tissue and plasma was also investigated in rats and in normal and P-gp-deficient mdr1a(-/-) mice. The distribution ratio of SQV in plasma:brain:cerebrospinal fluid was approximately 100:10:0.2 in rats. The accumulation of SQV was enhanced in MES-SA cells (P-gp-negative) versus Dx5 cells (P-gp-positive). Bolus i.v. injection of [(14)C]SQV (2 and 5 mg/kg) into mdr1a(-/-) and normal mice (n = 3 or 4) resulted in 3-fold higher radioactivity in brains from mdr1a(-/-) mice. Similarly, oral administration of [(14)C]SQV (500 mg/kg) resulted in a 5-fold increase in systemic exposure and a 10-fold increase in brain levels in mdr1a(-/-) mice. These data demonstrate that saquinavir is a substrate for P-gp and that this transport system may play a role in limiting oral absorption and CNS exposure to this protease inhibitor.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
CD4+ CD45RB low-density cells from untreated mice prevent acute allograft rejection.
In the absence of therapy that suppresses the action of the immune system, the immune response to transplantation Ags results in rapid rejection of the transplant. The most successful mechanism so far described that achieves organ-specific immunological tolerance is that which controls peripheral tolerance to self-tissue. Until now, no similarities have been documented between the peripheral response to self-Ags and the response to transplantation Ags. CD4+ cells that express a high density of CD45RB (in the mouse) and CD45RC (in the rat) on their surface have been shown to cause a number of autoimmune disorders. In contrast, autoimmunity caused by the CD45RB high-density cells is inhibited by CD4+ CD45RB cells that express a low density of CD45RB (CD45RC in the rat). In this paper we show that CD4+ CD45RB high-density cells are sufficient to cause rejection of a MHC-mismatched pancreas allograft, whereas CD4+ CD45RB low-density cells are not. Unexpectedly, the CD45RB low-density cells prevent the CD45RBhigh expressing cells from causing rejection. These data suggest that the response to foreign tissue can be controlled in the same way as the response to self-tissue.
Acute Disease↗
Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin.
Iron chelators are pluripotent neuronal antiapoptotic agents that have been shown to enhance metabolic recovery in cerebral ischemia models. The precise mechanism(s) by which these agents exert their effects remains unclear. Recent studies have demonstrated that iron chelators activate a hypoxia signal transduction pathway in non-neuronal cells that culminates in the stabilization of the transcriptional activator hypoxia-inducible factor-1 (HIF-1) and increased expression of gene products that mediate hypoxic adaptation. We examined the hypothesis that iron chelators prevent oxidative stress-induced death in cortical neuronal cultures by inducing expression of HIF-1 and its target genes. We report that the structurally distinct iron chelators deferoxamine mesylate and mimosine prevent apoptosis induced by glutathione depletion and oxidative stress in embryonic cortical neuronal cultures. The protective effects of iron chelators are correlated with their ability to enhance DNA binding of HIF-1 and activating transcription factor 1(ATF-1)/cAMP response element-binding protein (CREB) to the hypoxia response element in cortical cultures and the H19-7 hippocampal neuronal cell line. We show that mRNA, protein, and/or activity levels for genes whose expression is known to be regulated by HIF-1, including glycolytic enzymes, p21(waf1/cip1), and erythropoietin, are increased in cortical neuronal cultures in response to iron chelator treatment. Finally, we demonstrate that cobalt chloride, which also activates HIF-1 and ATF-1/CREB in cortical cultures, also prevents oxidative stress-induced death in these cells. Altogether, these results suggest that iron chelators exert their neuroprotective effects, in part, by activating a signal transduction pathway leading to increased expression of genes known to compensate for hypoxic or oxidative stress.
Activating Transcription Factor 1↗
Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group.
BACKGROUND: Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS: Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS: Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. CONCLUSIONS: Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.
Adult↗
Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism.
BACKGROUND: Hepatic uridine diphosphate glucuronosyltransferase (UGT) isoform 1A1 (UGT1A1) is primarily responsible for the glucuronidation of SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of the anticancer agent irinotecan. UGT1A1, also catalyzing the glucuronidation of bilirubin, has been shown to have reduced activity in Gilbert's syndrome. The presence of an additional TA repeat [(TA)7TAA] in the TATA sequence of UGT1A1 has been associated with Gilbert's syndrome. OBJECTIVE: To evaluate the relationship between UGT1A1 phenotypic activity and UGT1A1 promoter polymorphism. METHODS: Phenotypic measurements included in vitro SN-38 and bilirubin glucuronidation in human liver microsomes (n = 44). A recently developed genotyping test was used to determine TATA sequence polymorphisms in UGT1A1. Genotypes were assigned as follows: 7/7, homozygous for the (TA)7TAA allele; 6/6, homozygous for the (TA)6TAA allele; and 6/7, heterozygous with 1 of each allele. RESULTS: Nine percent of screened liver samples were found to be homozygous for allele 7 (7/7), 43% were homozygous for allele 6 (6/6), and 48% were heterozygous (6/7). Frequencies of (TA)7TAA and (TA)6TAA alleles were 0.33 and 0.67, respectively. A significant trend toward a decrease in SN-38 and bilirubin glucuronidation rates was found as the number of TA repeats increased (6/6 > 6/7 > 7/7). Glucuronidation rates of both substrates were significantly lower in the 7/7 and 6/7 groups compared with the 6/6 group. CONCLUSIONS: The results indicate a significant association of UGT1A1 phenotype and genotype based on in vitro phenotypic measurements. The clinical significance of our finding remains to be established.
Antineoplastic Agents, Phytogenic↗
Comparison of the effects of two low fat diets with different alpha-linolenic:linoleic acid ratios on coagulation and fibrinolysis.
Fish oils rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been demonstrated to alter coagulation and fibrinolysis variables. This study compared the effects of a traditional cholesterol-lowering diet and a similar diet, which had 50% of the linoleic acid (LA) replaced with the 18 carbon n-3 fatty acid, alpha-linolenic acid (ALA), on selected hemostatic variables. After a 2-week run-in diet with 39.5% total energy (en) from fat, 29 healthy male subjects consumed a 31.5% en fat diet with approximately 7% en from polyunsaturated fat and an ALA:LA ratio of either 1:1.2 (ALA-rich, n=15) or 1:21 (LA-rich, n=14) for 6 weeks. Blood was collected at the beginning, middle and end of test diets for analysis of Factor VIIc and VIIIc, fibrinogen, von Willebrand factor, activated protein C resistance (APC resistance), tissue plasminogen activator and plasminogen activator inhibitor type-1 activities and/or protein concentrations and platelet fatty acids. The ALA-rich diet tripled the percentage of platelet EPA, (P < 0.0005) but had little effect on coagulation and fibrinolysis. The APC ratio demonstrated increased anticoagulant activity on the ALA-rich diet (P < 0.001) only. Studies in patients with vascular pathologies are indicated to corroborate the current findings. Greater ratios of ALA:LA, achievable only with greater amounts of polyunsaturated fat, may be necessary to produce the effects demonstrated after feeding fish oils.
Adolescent↗
Receptor dimerization and Hill coefficients.
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Animals↗
Potential downregulation of HMG-CoA reductase after prolonged administration of P-407 in C57BL/6 mice.
This study investigated the potential alteration in the amount of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase messenger RNA (mRNA) and lipoprotein lipase (LPL) mRNA in the livers of C57BL/6 mice after long-term (200 days) treatment with the nonionic surfactant called poloxamer 407 (P-407). Previously, P-407 has been used to produce a dose-controlled hyperlipidemic state in C57BL/6 mice with subsequent formation of atherosclerotic lesions. Five groups of mice were studied; controls (C); mice fed a standard chow diet enriched with only cholic acid (CH); mice fed the high-cholesterol, high-fat Paigen diet (HF); mice treated with 0.5 g/kg P-407 every third day (P); and mice administered 0.5 g/kg P-407 every third day while consuming a diet identical to that of mice in group CH (PC). Neither a significant (p < 0.05) weight loss nor alteration in liver enzymes (AST and ALT) were observed for any group throughout the study when compared with the control mice. Total plasma cholesterol (CHOL) was significantly elevated compared with controls for mice in groups HF, P, and PC, whereas total plasma triglycerides (TG) were significantly increased for mice in only groups P and PC. Long-term ingestion of a high-fat diet or a diet enriched in cholic acid resulted in a significant (p < 0.05) reduction in HDL-CHOL when compared with controls. Plasma samples assayed at 200 days for mice in groups HF and P showed a shift in the lipoprotein fraction distribution primarily to VLDL-CHOL as compared with mice in group C in which, as expected, most of the CHOL was contained in the HDL fraction. The biologic activity of HMG-CoA reductase assayed in hepatic microsomal homogenates was significantly reduced for mice in groups CH (p < 0.01), HF (p < 0.01), and PC (p < 0.05), but not for mice in group P, when compared with control. A statistical analysis of the data demonstrated significant (p < 0.05) reductions in the HMG-CoA reductase mRNA levels in hepatic tissue for all treatment groups relative to mRNA levels determined for mice in group C. In contrast, no treatment group demonstrated a significant difference in hepatic LPL mRNA levels when compared with mRNA levels determined for control animals. These data demonstrate that P-407 administration to C57BL/6 mice significantly decreased the amount of HMG-CoA reductase mRNA detected in liver.
Animals↗
Rib biopsy technique for cortical bone evaluation in rhesus monkeys (Macaca mulatta).
Old World primates are often studied to model human skeletal physiology. An important advantage of monkeys over other animal models (i.e., rodents) is the presence of cortical bone Haversian remodeling. Seventy-five female rhesus monkeys (Macaca mulatta) were subjected to bone biopsy. With monkeys in lateral decubitus position, the tenth rib was surgically exposed and freed from periosteum by use of careful sharp and blunt dissection. The rib section was resected, using bone cutters, and the surgical wound was closed. This procedure was repeated for the contralateral rib at a later time point in 65 monkeys. There was no mortality or appreciable morbidity. The bone specimens were (mean +/- SD) 2.50 +/- 0.25 cm long, with 5.5 +/- 1.0 mm2 total cross-sectional area. They were adequate for histologic, immunohistochemical, and quantitative histomorphometric examinations. Prevalence of pneumothorax was approximately 8.0% for the 140 procedures. This complication was immediately and successfully corrected by insertion of a small thoracic tube, evacuation of pneumothorax, and closure of the incision. This well-tolerated, repeatable procedure yields excellent specimens for performance of cortical bone histologic examination without euthanasia, allowing longitudinal evaluation.
Animals↗
Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates.
Variation at the UDP-glucuronosyltransferase (UGT) 1A1 gene promoter is present in humans. Variable numbers of TA repeats in the TATA box of this gene are found which are inversely related to levels of gene expression. We investigated this polymorphism in 658 individuals from a worldwide sample of 15 aboriginal and two admixed human populations. This study shows that there is a great deal of variability across ethnic groups with regard to UGT1A1 allele frequencies, with the most common allele varying in frequency from 33% to 91%. Populations of African origin harbor four different alleles while non-African populations appear to have only two alleles. In addition, alleles associated with lower gene expression levels reach the highest frequencies in populations of African origin and lowest among Asians and Amerindians. Thus, more variability in the metabolism of drugs eliminated by UGT1A1 glucuronidation should be expected in populations of Sub-Saharan African origin. The sequence analysis of nine primate species shows that the number of TA repeats has increased during primate evolution achieving the largest number in humans. We suggest that the UGT1A1 promoter variability does not reflect historical relationships between populations and that it may be maintained by natural selection. Our findings are consistent with the proposal that the TA repeat variation is a balanced polymorphism.
Africa↗
Estimates of the virological benefit of antiretroviral therapy are both assay- and analysis-dependent.
OBJECTIVE: To assess the potential discrepancies in reported changes in plasma viral load (PVL) depending on how values below the detection limit of the assay are handled in the data analysis phase of a randomized controlled clinical trial. DESIGN: Data from a recently completed clinical trial comparing combinations of zidovudine, didanosine and nevirapine were analysed. In this trial, PVL was measured using an assay with a lower quantification limit of 400 HIV-1 RNA copies/ml initially. All PVL values less than 500 copies/ml were retested with a more sensitive assay with a lower quantification limit of 20 copies/ml. METHODS: Several summary measures for assessing change in PVL were calculated using three different methods to adjust for PVL values less than the quantification limit of the assay. The differences between these measures were evaluated. RESULTS: We found that the magnitude of the discrepancy between summary measures used to report changes in PVL depended on the proportion of subjects with PVL less than the quantification limit of the assay, how those observations were handled in the data analysis, and the relative difference between the quantification limits of the conventional and more sensitive assay. CONCLUSION: The lack of consensus in reporting of PVL data in the literature makes the interpretation of published trial results difficult. In the absence of agreement on the most appropriate summary measure of PVL data, we recommend that all summaries include information on the quantification limit of the assay used, the proportion of observations at or below the quantification limit and how these observations were handled in the data analysis.
Analysis of Variance↗
Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy.
BACKGROUND: Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/ml. METHODS: Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 x 10(6) cells/l who were naive to antiretroviral therapy and AIDS-free at enrolment. RESULTS: One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir < or = (>) 20 copies/ml (P = 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P = 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02-0.12] and 0.37 (95% CI, 0.23-0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir < or = 20 copies/ml were at a significantly lower risk of virologic failure than individuals with a pVL nadir of between 21 and 400 copies/ml (P = 0.0001). CONCLUSIONS: Our results demonstrate that suppression of pVL below 20 copies/ml is necessary to achieve a long-term antiretroviral response. Our data support the need for a revision of current therapeutic guidelines for the management of HIV infection.
Anti-HIV Agents↗
Violence begins at home. Domestic strife has lifelong effects on children.
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Child↗
A simple, whole blood method for assessment of platelet function: application to dietary intervention.
The propensity to thrombosis in an individual or population represents a significant risk factor in coronary heart disease, that ultimately may result in acute myocardial infarction or unstable angina. A variety of currently available tests assess the relative potential for platelets to be activated and then aggregate, including agonist-dependent platelet aggregation or flow cytometric analysis of platelet activation. However, all of these methods have certain limitations, ranging from being poorly quantifiable with limited sensitivity, to the necessity for specialized equipment. In the present study, we describe the development of a simple whole blood, radiolabel assay that measures the surface expression of the alpha-granule protein, P-selectin, by activated platelets. This assay is performed in the presence of GP IIb-IIIa blockade to allow quantitation without interference by platelet aggregate formation, and thus directly measures agonist dose-response without complications arising from secondary activation mediated by GP IIb-IIIa. The sensitivity of this assay method to dietary manipulation was investigated by administration of fish oil capsules at a dose known to decrease platelet aggregation.
Adolescent↗
A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study.
CONTEXT: Current guidelines recommend that individuals infected with the human immunodeficiency virus type 1 (HIV-1) be treated using combinations of antiretroviral agents to achieve sustained suppression of viral replication as measured by the plasma HIV-1 RNA assay, in the hopes of achieving prolonged remission of the disease. However, until recently, many drug combinations have not led to sustained suppression of HIV-1 RNA. OBJECTIVE: To compare the virologic effects of various combinations of nevirapine, didanosine, and zidovudine. DESIGN: Double-blind, controlled, randomized trial. SETTING: University-affiliated ambulatory research clinics in Italy, the Netherlands, Canada and Australia (INCAS). PATIENTS: Antiretroviral therapy-naive adults free of the acquired immunodeficiency syndrome with CD4 cell counts between 0.20 and 0.60x10(9)/L (200-600/microL). INTERVENTION: Patients received zidovudine plus nevirapine (plus didanosine placebo), zidovudine plus didanosine (plus nevirapine placebo), or zidovudine plus didanosine plus nevirapine. MAIN OUTCOME MEASURE: Plasma HIV-1 RNA. RESULTS: Of the 153 enrolled patients, 151 were evaluable. At week 8, plasma HIV-1 RNA levels had decreased by log 2.18, 1.55, and 0.90 in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.05). The proportions of patients with plasma HIV-1 RNA levels below 20 copies per milliliter at week 52 were 51%, 12%, and 0% in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.001). Viral amplification was attempted in 59 patients at 6 months. Viral isolation was unsuccessful in 19 (79%) of 24, 10 (53%) of 19, and 5 (31%) of 16 patients in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively. Among patients from whom virus could be amplified, resistance to nevirapine was found in all 11 patients receiving zidovudine plus nevirapine and in all 5 patients receiving triple drug therapy. Rates of disease progression or death were 23% (11/47), 25% (13/53), and 12% (6/51) for the zidovudine plus nevirapine, zidovudine plus didanosine, and triple drug therapy groups, respectively (P=.08). CONCLUSIONS: Triple drug therapy with zidovudine, didanosine, and nevirapine led to a substantially greater and sustained decrease in plasma viral load than the 2-drug regimens studied. Our results also suggest that suppression of viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load below the level of quantitation of the most sensitive test available, may at least forestall the development of resistance.
Adult↗