Search PubMed⌕ Search

Biomedical subjects

J Allison

Publications and source records attributed to J Allison.

At least 37 records · Page 2Linked to original sources
PubMed1999

Can data-driven benchmarks be used to set the goals of healthy people 2010?

OBJECTIVES: Expert panels determined the public health goals of Healthy People 2000 subjectively. The present study examined whether data-driven benchmarks provide a better alternative. METHODS: We developed the "pared-mean" method to define from data the best achievable health care practices. We calculated the pared-mean benchmark for screening mammography from the 1994 National Health Interview Survey, using the metropolitan statistical area as the "provider" unit. Beginning with the best-performing provider and adding providers in descending sequence, we established the minimum provider subset that included at least 10% of all women surveyed on this question. The pared-mean benchmark is then the proportion of women in this subset who received mammography. RESULTS: The pared-mean benchmark for screening mammography was 71%, compared with the Healthy People 2000 goal of 60%. CONCLUSIONS: For Healthy People 2010, benchmarks derived from data reflecting the best available care provide viable alternatives to consensus-derived targets. We are currently pursuing additional refinements to the data-driven pared-mean benchmark approach.

Benchmarking↗
PubMed1999

A quantitative comparison of dibenzo[a,l]pyrene-DNA adduct formation by recombinant human cytochrome P450 microsomes.

Dibenzo[a,l]pyrene (DB[a,l]P), an extremely potent environmental carcinogen, is metabolically activated in mammalian cells and microsomes through the fjord-region dihydrodiol, trans-DB[a,l]P-11, 12-diol, to syn- and anti-DB[a,l]P-11,12-diol-13,14-epoxides (syn- and anti-DB[a,l]PDEs). The role of seven individual recombinant human cytochrome P450s (1A1, 1A2, 1B1, 2B6, 2C9, 2E1, and 3A4) in the metabolic activation of DB[a,l]P and formation of DNA adducts was examined by using (32)P postlabeling, thin-layer chromatography, and high-pressure liquid chromatography. We found that, in the presence of epoxide hydrolase, only P450 1A1 and P450 1B1 catalyzed the formation of DB[a,l]PDE-DNA adducts and several unidentified polar adducts. Human P450 1A1 catalyzed the formation of DB[a, l]PDE-DNA adducts and unidentified polar adducts at rates threefold and 17-fold greater than did human P450 1B1 (256 fmol/h/nmol P450 versus 90 fmol/h/nmol P450 and 132 fmol/h/nmol P450 versus 8 fmol/h/nmol P450, respectively). P450 1A1 DNA adducts were derived from both anti- and syn-DB[a,l]PDE at rates of 73 fmol/h/nmol P450 and 51 fmol/h/nmol P450, respectively. P450 1B1 produced adducts derived from anti-DB[a,l]PDE at a rate of 82 fmol/h/nmol, whereas only a small number of adducts were derived from syn-DB[a,l]PDE (0.4 fmol/h/nmol). These results demonstrated the potential of human P450 1A1 and P450 1B1 to contribute to the metabolic activation and carcinogenicity of DB[a,l]P and provided additional evidence that human P450 1A1 and 1B1 differ in their stereospecific activation of DB[a,l]P. Mol. Carcinog. 26:74-82, 1999. Published 1999 Wiley-Liss, Inc.

Animals↗
PubMed1998

Mechanisms of beta cell death in diabetes: a minor role for CD95.

Insulin-dependent diabetes mellitus is an autoimmune disease, under polygenic control, manifested only when >90% of the insulin-producing beta cells are destroyed. Although the disease is T cell mediated, the demise of the beta cell results from a number of different insults from the immune system. It has been proposed that foremost amongst these effector mechanisms is CD95 ligand-induced beta cell death. Using the nonobese diabetic lpr mouse as a model system, we have found, to the contrary, that CD95 plays only a minor role in the death of beta cells. Islet grafts from nonobese diabetic mice that carry the lpr mutation and therefore lack CD95 were protected only marginally from immune attack when grafted into diabetic mice. An explanation to reconcile these differing results is provided.

Animals↗
PubMed1998

The threshold for autoimmune T cell killing is influenced by B7-1.

The concept that naive CD4+ and CD8+ T cells require co-stimulatory signals for activation and proliferation is well documented. Less clear is the need for co-stimulation during the effector phase of the T cell response. Here we examined the influence of B7-1 (CD80) during the effector phase of an autoimmune response to pancreatic islets using transgenic mouse lines which expressed B7-1 in either all or only some of their beta cells ("confluent" or "patchy" RIP-B7-1 mice). Transgenic expression of B7-1 in normal mouse islets that co-expressed the pro-inflammatory cytokine, IL-2, resulted in early spontaneous autoimmunity. Islets with IL-2 and "confluent" B7-1 expression were destroyed whereas islets with IL-2 and "patchy" B7-1 expression showed selective killing of the B7-1+ beta cells. Islet-reactive T cells, circulating in the RIP-B7-1/IL-2 mice, rejected syngeneic islet grafts, but only if these expressed B7-1. Introduction of the B7-1 transgene into the nonobese diabetic (NOD) genetic background likewise resulted in early spontaneous autoimmunity, but splenocytes from the diabetic animals could only transfer diabetes to NOD scid recipients that expressed B7-1 on their beta cells. In both these transgenic models, therefore, islet destruction required continuous B7-1 expression by target beta cells. Thus, although the normal repertoire contains T cells with potential islet reactivity, these T cells remain harmless because parenchymal cells like the beta cell cannot normally express B7-1. Our results also have implications for tumor immunotherapy in that the ability of T cells to kill poorly immunogenic targets may be dependent upon B7-1 expression by the target cell itself.

Animals↗
PubMed1998

Apoptosis and beta-cell destruction in pancreatic islets of NOD mice with spontaneous and cyclophosphamide-accelerated diabetes.

Autoimmune-mediated destruction of pancreatic islet beta cells leads to insulin-dependent diabetes in non-obese diabetic (NOD) mice. Although both direct cytotoxic T cell- and indirect cytokine-, nitric oxide- or free radical-mediated mechanisms induce beta-cell apoptosis in vitro, beta-cell death in vivo in spontaneous autoimmune diabetes is not well-characterized. Furthermore, whether beta cells die gradually, or rapidly in the late pre-clinical stage, is a question of current interest. To investigate beta-cell death in vivo, we measured the frequency and intra-islet localisation of apoptosis, defined as DNA strand breaks by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) technique, during spontaneous and cyclophosphamide-accelerated diabetes in NOD mice. In spontaneous diabetes, the frequency of apoptosis in islets correlated with the progression of beta-cell destruction with age. Although apoptosis was detected at low frequency within the reduced insulin-positive islet area of pre-diabetic mice at 90 days of age, it was rarely co-localised to beta cells. After acceleration of beta-cell destruction with cyclophosphamide, the frequency of apoptosis reached maximum at 12 days, at which time 3.2 % of apoptotic cells were beta cells. Apoptosis was most frequent in the insulin-negative islet area comprised of mononuclear cell infiltrate and was localized to CD8+ T cells. The rarity of detectable apoptotic beta cells in spontaneous pre-diabetic mice with pronounced insulitis and reduced insulin-positive islet areas most likely reflects the rapid clearance of apoptotic beta cells. Our findings are more consistent with gradual destruction of non-renewable beta-cells in spontaneous diabetes, than with their rapid, accelerated destruction (as after cyclophosphamide) in the late pre-clinical stage.

Aging↗
PubMed1998

Visceral adipose tissue and cardiovascular risk factors in obese children.

OBJECTIVE: In adults visceral adipose tissue (VAT) has been shown to be more highly correlated with cardiovascular (CV) risk factors than are other measures of adiposity such as subcutaneous abdominal adipose tissue (SAAT), percent body fat (%BF), or total body fat mass (TFM). We examined the relations between these measures of fatness and CV risk factors in obese children. STUDY DESIGN: Subjects were 64 obese (27% to 61% BF) children (24 black girls, 19 white girls, 11 black boys, 10 white boys) aged 7 to 11 years. VAT and SAAT were measured with magnetic resonance imaging. TFM and %BF were determined with dual x-ray absorptiometry. Hierarchical stepwise multiple regression analyses were used to determine the proportions of variance in CV risk factors explained by the demographic and adiposity measures. RESULTS: VAT but not SAAT, %BF, or TFM explained a significant proportion of the variance (r2 range = 0.10 to 0.21) in several lipid/lipoprotein risk factors including triacylglycerols, high-density lipoprotein cholesterol, the ratio of total cholesterol to high-density lipoprotein cholesterol, and low-density lipoprotein particle size. CONCLUSION: Many of the deleterious relations between VAT and lipid/lipoprotein risk factors seen in adults were already present in this sample of obese children.

Abdomen↗
PubMed1998

Metabolic activation of racemic and enantiomeric trans-8, 9-dihydroxy-8,9-dihydrodibenzo[a,l]pyrene (dibenzo[def,p]chrysene) to dibenzo[a,l]pyrene-bis-dihydrodiols by induced rat liver microsomes and a recombinant human P450 1A1 system: the role of the K-region-derived metabolic intermediates in the formation of dibenzo[a,l]pyrene-DNA adducts.

Metabolic activation studies of dibenzo[a,l]pyrene (DB[a,l]P) (dibenzo[def,p]chrysene), an extremely potent environmental carcinogen, have been focused on metabolism at the fjord region, a region associated with high mutagenic and carcinogenic activities of the corresponding fjord-region DB[a,l]P-11,12-diol-13,14-epoxides. DB[a,l]P is metabolized by beta-naphthoflavone (BNF)- and 3-methylcholanthrene-induced rat liver microsomes and a recombinant human P450 1A1 system to two major dihydrodiols, the K-region dihydrodiol, DB[a,l]P-8,9-dihydrodiol (DB[a,l]P-8,9-diol), and the fjord-region dihydrodiol, DB[a,l]P-11,12-dihydrodiol. We have investigated the further metabolic activation of DB[a,l]P-8,9-diol by BNF-induced rat liver microsomes and a recombinant human P450 1A1 system with epoxide hydrolase to DB[a,l]P-bis-diols and to DNA adducts. (+/-)-trans-DB[a,l]P-8,9-diol was synthesized and resolved into its enantiomers. Racemic trans-DB[a,l]P-8,9-diol was metabolized by BNF-induced rat liver microsomes to six metabolites: two diastereomers of trans,trans-DB[a,l]P-8,9:11,12-bis-diol, two diastereomers of trans,cis-DB[a,l]P-8,9:11,12-bis-diol, and two diastereomers of trans-DB[a,l]P-8,9:13,14-bis-diol as characterized by NMR, MS, and UV spectroscopy. Metabolic studies using both enantiomeric (-)- and (+)-trans-DB[a,l]P-8,9-diol further demonstrated that each diastereomer of trans,trans-DB[a,l]P-8,9:11, 12-bis-diol and trans-DB[a,l]P-8,9:13,14-bis-diol was comprised of two enantiomers. Similarly, incubations of enantiomeric or racemic trans-DB[a,l]P-8,9-diol with a recombinant human P450 1A1 system and epoxide hydrolase also gave the same two enantiomeric mixtures of diastereomers of trans,trans-DB[a,l]P-8,9:11,12-bis-diol and the same two enantiomeric mixtures of diastereomers of trans-DB[a,l]P-8, 9:13,14-bis-diol. This suggested that the microsomal oxidations of (-)- and (+)-trans-DB[a,l]P-8,9-diol were stereospecific. The stereospecific formation of enantiomers of trans-DB[a,l]P-8,9-diol from DB[a,l]P was examined using both BNF-induced rat liver microsomes and a recombinant human P450 1A1 system with epoxide hydrolase. Stereospecificity was observed as both metabolic systems favored the formation of (-)-trans-DB[a,l]P-8,9-diol by 8-9-fold. DNA adduct studies were undertaken using TLC/HPLC 32P-postlabeling techniques. In the presence of a recombinant human P450 1A1 system with epoxide hydrolase, DB[a,l]P gave two groups of calf thymus DNA adducts. The group of later-eluting adducts were identified as arising from syn- and anti-DB[a,l]P-11,12-diol-13,14-epoxides, while the more polar early-eluting adducts were derived, in part, from the further activation of trans-DB[a,l]P-8,9-diol. Our data indicate that, in P450 1A1-mediated microsomal incubations, DB[a,l]P is metabolized to trans-DB[a,l]P-8,9-diol which is further metabolized to DB[a,l]P-bis-diols. trans-DB[a,l]P-8,9-diol is metabolically activated to intermediates that can bind to DNA and give DNA adducts similar to those observed with DB[a,l]P. These results indicate that DB[a,l]P can be metabolically activated by both fjord-region and K-region pathways.

Animals↗
PubMed1998

Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements.

We describe the generation of ovalbumin (OVA)-specific, MHC class II-restricted alpha beta T cell receptor (TCR) transgenic mice. Initial attempts at generating these transgenic mice utilized heterologous regulatory elements to drive the expression of cDNA genes encoding the separate alpha- and beta-chains of the TCR. Unexpectedly, T cells bearing the transgenic alpha beta TCR failed to emerge from the thymus in these mice, although the transgenes did modify endogenous TCR expression. However, subsequent modification of the approach which enabled expression of the TCR beta-chain under the control of its natural regulatory elements generated mice whose peripheral T cells expressed the transgenic TCR and were capable of antigen-dependent proliferation. These results show that successful generation of MHC class II-restricted, OVA-specific alpha beta TCR transgenic mice was dependent upon combining cDNA- and genomic DNA-based constructs for expression of the respective alpha- and beta-chains of the TCR.

Animals↗
PubMed1998

Fat distribution and hemostatic measures in obese children.

We examined the relation of general and visceral adiposity to plasma hemostatic factors [fibrinogen, D-dimer, and plasminogen activator inhibitor 1 (PAI-1)] in obese boys and girls 7-11 y of age (n = 41). Boys had significantly greater fibrinogen and D-dimer concentrations than girls (P < 0.05). whereas blacks had significantly greater fibrinogen and D-dimer concentrations than whites (P < 0.05). Univariate analyses revealed that fibrinogen was positively associated with percentage body fat (%BF) (r = 0.42, P < 0.01), subcutaneous abdominal adipose tissue (SAAT) (r = 0.40, P < 0.01), total fat mass (r = 0.42, P < 0.01), and body mass index (r = 0.41, P < 0.01). PAI-1 was positively associated with visceral adipose tissue (VAT) (r = 0.49, P < 0.01), SAAT (r = 0.32, P < 0.05), fat-free mass (r = 0.50, P < 0.01), and insulin (r = 0.61, P < 0.001). D-Dimer was positively associated with %BF (r = 0.40, P < 0.01), SAAT (r = 0.37, P < 0.05), total fat mass (r = 0.40, P < 0.01), and body mass index (r = 0.43, P < 0.01). Multiple regression analysis revealed that for fibrinogen, sex and higher %BF explained significant independent portions of the variance. For PAI-1, higher amounts of VAT and fat-free mass were significant predictors. For D-dimer, ethnicity was a significant predictor. These results suggest that general adiposity and VAT may play a role in regulating plasma hemostatic factors in obese children. Even early in childhood, adiposity is associated with unfavorable concentrations of hemostatic factors that are in turn implicated in cardiovascular morbidity and mortality later in life.

Adipose Tissue↗
PubMed1998

Induction of peripheral CD8+ T-cell tolerance by cross-presentation of self antigens.

There is now convincing evidence that CD8+ T cells can be activated by professional antigen-presenting cells which present antigens derived from non-lymphoid tissues in association with MHC class I molecules in the draining lymph nodes. This mechanism, referred to as cross-presentation, enables the immune system to respond to those microorganisms that infect only non-lymphoid tissues. Consistent with this view, cross-presentation was found to focus on antigens expressed in high concentrations and those released from dying cells, which can be expected to result from viral infections. Recent evidence, however, demonstrates that high dose self antigens can be cross-presented constitutively, resulting in the activation of autoreactive CD8+ T cells. This does not lead to auto immunity under physiologic conditions, but to CD95-mediated deletion of the T cells. Cross-presentation can thus engage a well-defined pathway of antigen-induced T-cell death and purge the immune system of autoreactive CD8+ T cells. Low dose self antigens are not cross-presented and are consequently ignored. The immune system therefore uses two strategies to avoid CD8+ T-cell-mediated autoimmunity in the periphery: deletion of autoreactive CD8+ T cells responding to high dose self antigens and ignorance of self antigens expressed at low concentrations.

Animals↗
PubMed1998

Increased susceptibility of diabetic mice to influenza virus infection: compromise of collectin-mediated host defense of the lung by glucose?

The influence of diabetes on susceptibility to influenza virus infection was examined in a mouse model in which RIP-Kb transgenic mice and their nontransgenic littermates were used as the diabetic and nondiabetic hosts, respectively. Influenza virus A/Phil/82 (H3N2) grew to significantly higher titers in the lungs of diabetic than nondiabetic mice. The extent of viral replication in the lungs was proportional to blood glucose levels in the mice at the time of infection, and the enhanced susceptibility of diabetic mice was reversed with insulin. Growth of A/HKx31 (H3N2) virus was also enhanced in diabetic mice, whereas the highly virulent strain A/PR/8/34 (H1N1) showed no difference in virus yields in diabetic and nondiabetic mice, even with low inocula. A/Phil/82 and A/HKx31 are sensitive to neutralization in vitro by the pulmonary collectin surfactant protein D (SP-D), whereas A/PR/8/34 is essentially resistant. Glucose is a ligand for SP-D, and neutralization of A/Phil/82 virus by SP-D was abolished in the presence of glucose at levels commonly found in diabetic mice. These findings suggest that in mice, and perhaps in humans, diabetes predisposes to influenza virus infection through compromise of collectin-mediated host defense of the lung by glucose.

Animals↗
PubMed1998

Functional MR imaging in patients with epilepsy.

Recent advances in MR imaging have significantly enhanced the diagnosis and management of epilepsy. This article focuses on the expanding role of functional MR imaging in our imaging armamentarium. Diffusion, perfusion, and BOLD functional MR imaging techniques are discussed in detail with emphasis on epilepsy applications. Functional MR imaging seizure focus localization, eloquent cortex mapping, and the potential for functional MR imaging to replace Wada testing are explored. With anticipated future developments, functional MR imaging holds great promise for epilepsy patients.

Brain↗
PubMed1998

Beta-cell apoptosis in an accelerated model of autoimmune diabetes.

BACKGROUND: The non-obese diabetic (NOD) mouse is a model of human type 1 diabetes in which autoreactive T cells mediate destruction of pancreatic islet beta cells. Although known to be triggered by cytotoxic T cells, apoptosis has not been unequivocally localized to beta cells in spontaneously diabetic NOD mice. We created a model of accelerated beta-cell destruction mediated by T cells from spontaneously diabetic NOD mice to facilitate the direct detection of apoptosis in beta cells. MATERIALS AND METHODS: NOD.scid (severe combined immunodeficiency) mice were crossed with bm1 mice transgenically expressing the costimulatory molecule B7-1 (CD80) in their beta cells, to generate B7-1 NOD.scid mice. Apoptosis in islet cells was measured as DNA strand breakage by the TdT-mediated-dUTP-nick end labeling (TUNEL) technique. RESULTS: Adoptive transfer of splenocytes from spontaneously diabetic NOD mice into B7-1 NOD.scid mice caused diabetes in recipients within 12-16 days. Mononuclear cell infiltration and apoptosis were significantly greater in the islets of B7-1 NOD.scid mice than in nontransgenic NOD.scid mice. Dual immunolabeling for TUNEL and either B-7 or insulin, or the T cell markers CD4 and CD8, and colocalization by confocal microscopy clearly demonstrated apoptosis in beta cells as well in a relatively larger number of infiltrating T cells. The clearance time of apoptotic beta cells was estimated to be less than 6 min. CONCLUSIONS: B7-1 transgenic beta cells undergo apoptosis during their accelerated destruction in response to NOD mouse effector T cells. Rapid clearance implies that beta cells undergoing apoptosis would be detected only rarely during more protracted disease in spontaneously diabetic NOD mice.

Adoptive Transfer↗
PubMed1997

CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity.

Self-antigens expressed in extrathymic tissues such as the pancreas can be transported to draining lymph nodes and presented in a class I-restricted manner by bone marrow-derived antigen-presenting cells. Such cross-presentation of self-antigens leads to CD8+ T cell tolerance induction via deletion. In this report, we investigate the influence of CD4+ T cell help on this process. Small numbers of autoreactive OVA-specific CD8+ T cells were unable to cause diabetes when adoptively transferred into mice expressing ovalbumin in the pancreatic beta cells. Coinjection of OVA-specific CD4+ helper T cells, however, led to diabetes in a large proportion of mice (68%), suggesting that provision of help favored induction of autoimmunity. Analysis of the fate of CD8+ T cells indicated that CD4(+) T cell help impaired their deletion. These data indicate that control of such help is critical for the maintenance of CD8+ T cell tolerance induced by cross-presentation.

Adoptive Transfer↗
PubMed1997

Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts.

Binding of CD95 (Fas/APO-1) by its ligand (CD95L) commonly induces apoptosis. Apoptosis of activated T cells, induced by CD95L expressed in the rodent testis, has been proposed to be the mechanism of immune privilege [Bellgrau, D., Gold, D., Selawry, H., Moore, J., Franzusoff, A. & Duke, R. C. (1995) Nature (London) 377, 630-632]. To test whether CD95L could protect pancreatic islet grafts from rejection, we made transgenic mice expressing murine CD95L on their islet beta cells and transplanted fetal pancreata under the kidney capsules of allogeneic animals. Expression of CD95L failed to protect the grafts from rejection. However, transgenic mice developed a granulocytic infiltration in their pancreata. These results demonstrate a pro-inflammatory function of CD95L and suggest that expression of CD95L may not be sufficient to protect organ allografts.

Animals↗