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Biomedical subjects

C Deng

Publications and source records attributed to C Deng.

At least 55 records · Page 3Linked to original sources
PubMed2000

Disability case management: an impact assessment in an automotive manufacturing organization.

A multifaceted disability management program was instituted at an automotive manufacturing organization to control rising workers' compensation costs. A pilot program showed major cost savings over a 9-month period. When total and component disability leave rates were calculated as a percentage of the available workforce and tracked on a weekly basis over the subsequent 3 years, total disability leave rates fell by nearly 50%. This was largely attributable to an approximately 50% decrease in the extended (> 1-year) disability leave rate and a 75% decrease in the workers' compensation leave rate. A novel approach to biostatistical analysis showed a good fit of weekly disability leave rates to a Poisson random variable distribution with an identifiable break point at about 1 1/2 years after observation for extended disability leaves and at 2 years for workers' compensation leaves. This biostatistical approach may prove generalizable to tracking leave rates in other organizations.

Adult↗
PubMed2000

Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity.

The presence of two families of seven distinct mammalian cyclin-dependent kinase (CDK) inhibitor genes is thought to mediate the complexity of connecting a variety of cellular processes to the cell cycle control pathway. The distinct pattern of tissue expression of CDK inhibitor genes suggests that they may function as tumor suppressors with different tissue specificities. To test this hypothesis, we have characterized two strains of double mutant mice lacking either p18(INK4c) and p27(KIP1) or p18(INK4c) and p21(CIP1/WAF1). Loss of both p18 and p27 function resulted in the spontaneous development by 3 months of age of at least eight different types of hyperplastic tissues and/or tumors in the pituitary, adrenals, thyroid, parathyroid, testes, pancreas, duodenum, and stomach. Six of these hyperplastic tissues and tumors were in endocrine organs, and several types of tumors routinely developed within the same animal, a phenotype reminiscent of that seen in combined human multiple endocrine neoplasia syndromes. The p18-p21 double null mice, on the other hand, developed pituitary adenomas, multifocal gastric neuroendocrine hyperplasia, and lung bronchioalveolar tumors later in life. G(1) CDK2 and CDK4 kinase activities were increased in both normal and neoplastic tissues derived from mice lacking individual CDK inhibitors and were synergistically stimulated by the simultaneous loss of two CDK inhibitors. This indicates that an increase in G(1) CDK kinase activity is a critical step during but is not sufficient for tumor growth. Our results suggest that functional collaborations between distinct CDK inhibitor genes are tissue specific and confer yet another level of regulation in cell growth control and tumor suppression.

Animals↗
PubMed2000

Generation and phenotype of mice harboring a nonsense mutation in the V2 vasopressin receptor gene.

The V2 vasopressin receptor (V2R) plays a key role in the maintenance of a normal body water balance. To generate an in vivo model that allows the physiological and molecular analysis of the role of V2Rs in kidney function, we have created mouse lines that lack functional V2Rs by using targeted mutagenesis in mouse embryonic stem cells. Specifically, we introduced a nonsense mutation known to cause X-linked nephrogenic diabetes insipidus (XNDI) in humans (Glu242stop) into the mouse genome. V2R-deficient hemizygous male pups showed a decrease in basal urine osmolalities and were unable to concentrate their urine. These pups also exhibited an enlargement of renal pelvic space, failed to thrive, and died within the first week after birth due to hypernatremic dehydration. Interestingly, female mice heterozygous for the V2R mutation showed normal growth but displayed an XNDI-like phenotype, characterized by reduced urine concentrating ability of the kidney, polyuria, and polydipsia. Western blot analysis and immunoelectron microscopic studies showed that the loss of functional V2Rs had no significant effect on the basal expression levels of aquaporin-2 and the bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1). The V2R mutant mice described here should serve as highly useful tools for the development of novel therapeutic strategies for the treatment of XNDI.

Animals↗
PubMed2000

Detecting hormesis using a non-parametric rank test.

When a dose-response experiment is conducted, the enhanced responses can be observed at low doses. This phenomenon is often called hormesis. The enhanced responses at low doses does not necessarily mean the existence of hormesis. It is important to conduct statistical analyses to determine whether a departure from monotonic relationships is significantly different from the chance occurrence. This paper introduces a non-parametric rank test to detect hormesis. To illustrate the use of this method, we apply it to the data from a Whole Effluent Toxicity test. We demonstrate that the occurrence of hormesis can be statistically evaluated by using this non-parametric rank test.

Animals↗
PubMed2000

DNA methylation in the regulation of T cell LFA-1 expression.

Inducing T cell LFA-1 overexpression by transfection, or by treatment with DNA methylation inhibitors including 5-azacytidine, procainamide and hydralazine, causes MHC-specific T cell autoreactivity in vitro and autoimmunity in vivo. How DNA methylation inhibitors increase LFA-1 expression is unknown. In this report we identify a mechanism by which DNA methylation affects LFA-1 expression. Nuclear run-on assays demonstrated that inhibiting DNA methylation increased transcription of CD11a but not CD18 or beta-actin mRNA. CD11a mRNA stability was not affected. Transfection of hypomethylated cells with reporter constructs containing the CD11a promoter showed no role for overexpression of transcription factors. However, the CD11a promoter demethylated following treatment with DNA methyltransferase inhibitors, and in vitro methylation of the construct suppressed its expression. Together, these results indicate that DNA methylation inhibitors can cause LFA-1 overexpression directly by demethylating the CD11a promoter. This mechanism could contribute to T cell autoreactivity, and potentially to autoimmunity.

Azacitidine↗
PubMed2000

[Clinical study on interferon treatment of chronic idiopathic thrombocytopenic purpura].

The efficacy and mechanism of interferon alpha-2a (IFN alpha-2a) were assessed in the treatment of chronic idiopathic thrombocytopenic purpura (cITP). 20 patients with cITP (treatment group) were treated with IFN alpha-2a 3MIU i.m. once a week for 8 weeks; 28 patients with cITP (control group) were treated with prednisone 1 mg/(kg.d) for 4 weeks. Blood platelet counts (BPC), megakaryocyte number, immunnological parameters, percent and absolute counts of reticulated platelets (RPs) and megakaryocyte colony formation units were observed before and after therapy. The results showed that the efficacy of IFN alpha-2a was better than that of corticosteroid, P < 0.05. The RPs% decreased and the platelet-producing megakaryocyte percentage increased from 11.43% to 33.19% significantly after IFN alpha-2a therapy, but there were no significant changes in immunnological parameters. These indicate that IFN alpha-2a is effective in treating cITP, the mechanism may be based on promoting the megakaryocyte development and activating the production of platelets.

Adolescent↗
PubMed1999

Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice.

Muscarinic acetylcholine receptors (M(1)-M(5)) regulate many key functions of the central and peripheral nervous system. Primarily because of the lack of receptor subtype-selective ligands, the precise physiological roles of the individual muscarinic receptor subtypes remain to be elucidated. Interestingly, the M(4) receptor subtype is expressed abundantly in the striatum and various other forebrain regions. To study its potential role in the regulation of locomotor activity and other central functions, we used gene-targeting technology to create mice that lack functional M(4) receptors. Pharmacologic analysis of M(4) receptor-deficient mice indicated that M(4) receptors are not required for muscarinic receptor-mediated analgesia, tremor, hypothermia, and salivation. Strikingly, M(4) receptor-deficient mice showed an increase in basal locomotor activity and greatly enhanced locomotor responses (as compared with their wild-type littermates) after activation of D1 dopamine receptors. These results indicate that M(4) receptors exert inhibitory control on D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are coexpressed at high levels. Our findings offer new perspectives for the treatment of Parkinson's disease and other movement disorders that are characterized by an imbalance between muscarinic cholinergic and dopaminergic neurotransmission.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1999

A vital role for glycosphingolipid synthesis during development and differentiation.

Glycosphingolipids (GSLs) are believed to be integral for the dynamics of many cell membrane events, including cellular interactions, signaling, and trafficking. We have investigated their roles in development and differentiation by eliminating the major synthesis pathway of GSLs through targeted disruption of the Ugcg gene encoding glucosylceramide synthase. In the absence of GSL synthesis, embryogenesis proceeded well into gastrulation with differentiation into primitive germ layers and patterning of the embryo but was abruptly halted by a major apoptotic process. In vivo, embryonic stem cells deficient in GSL synthesis were again able to differentiate into endodermal, mesodermal, and ectodermal derivatives but were strikingly deficient in their ability to form well differentiated tissues. In vitro, however, hematopoietic and neuronal differentiation could be induced. The results demonstrate that the synthesis of GSL structures is essential for embryonic development and for the differentiation of some tissues and support the concept that GSLs are involved in crucial cell interactions mediating these processes.

Animals↗
PubMed1999

Analysis of human peripheral blood T cells and single-cell-derived T cell clones uncovers extensive clonal CpG island methylation heterogeneity throughout the genome.

Methylation of cytosine residues in CpG dinucleotides is generally associated with silencing of gene expression. DNA methylation, as a somatic event, has the potential of diversifying gene expression in individual cells of the same lineage. There is little quantitative data available concerning the extent of methylation heterogeneity in individual cells across the genome. T cells from the peripheral blood can be grown as single-cell-derived clones and can be analyzed with respect to their DNA methylation patterns by restriction landmark genomic scanning. The use of the methylation-sensitive enzyme NotI to cut and end-label DNA fragments before their separation in two dimensions provides a quantitative assessment of methylation at NotI sites that characteristically occur in CpG islands. We have undertaken quantitative analysis of two-dimensional DNA patterns to determine the extent of methylation heterogeneity at NotI sites between peripheral blood single-cell-derived T cell clones from the same individual. A total of 1,068 NotI-tagged fragments were analyzed. A subset of 156 fragments exhibited marked methylation heterogeneity at NotI sites between clones. Their average intensity among clones correlated with their intensity in uncultured, whole-blood-derived T cells, indicating that the methylation heterogeneity observed in clones was largely attributable to methylation heterogeneity between the individual cells from which the clones were derived. We have cloned one fragment that exhibited variable NotI-site methylation between clones. This fragment contained a novel CpG island for a gene that we mapped to chromosome 4. The methylation status of the NotI site of this fragment correlated with expression of the corresponding gene. Our data suggest extensive diversity in vivo in the methylation and expression profiles of individual T cells at multiple unrelated loci across the genome.

Base Composition↗
PubMed1999

Differential sensitivities of the two visual pathways of the chick to labelling by fluorescent retrograde tracers.

This study investigates the neurone structure-specific differences of sensitivities of fluorescent tracers. The tracers were used for retrograde labelling of contralateral projections in the two visual pathways of the chick. Rhodamine B Isothiocyanate (RITC), Fluorogold (FG) and True blue (TB) were injected into either the visual Wulst (thalamofugal pathway) or the nucleus rotundus (Rt; tectofugal pathway) and the retrogradely labelled neurones in the nucleus geniculatus lateralis pars dorsalis (GLd) or the optic tectum, respectively, were counted. Differential retrograde labelling in the two pathways was observed. In the thalamofugal pathway, both the contralateral and ipsilateral GLd cells were labelled by all three tracers (RITC, FG and TB). However, in the tectofugal pathway, whereas RITC labelled both the ipsilateral and contralateral tectal neurones, FG or TB labelled effectively only the ipsilateral tectal neurones. It was clear that FG and TB were taken up by the nerve endings and transported part-way along the axon but failed to be transported to the cell bodies of the contralateral tectal neurones. In addition, red beads and green beads were also injected into Rt and the differential labelling was also observed. Red beads labelled both ipsilateral and contralateral tectal neurones but green beads labelled only the ipsilateral tectal neurones. Since the contralateral tectal projections consist of divergent axon collaterals, the present study suggests that various retrograde tracers are not transported in these axon collaterals to label cell bodies. The contralaterally projecting neurones in the thalamofugal pathway are not axon collaterals and they were labelled by all of the tracers used.

Animals↗
PubMed1999

Genetic deletion of p21WAF1 enhances papilloma formation but not malignant conversion in experimental mouse skin carcinogenesis.

Tumor suppression by p53 is believed to reside in its ability to regulate gene transcription, including up-regulation of p21WAF1. In p53(-/-) mice, chemical- or oncogene-induced skin tumors undergo accelerated malignant conversion. To determine the contribution of the p21WAF1 gene product to epidermal carcinogenesis, animals +/+, +/-, and -/- for a null mutation in the p21WAF1 gene were treated once with 25 nmol 7,12-dimethylbenz[a]anthracene, followed by 5 microg of TPA two times/week for 20 weeks. Papilloma frequency was higher in the p21WAF1-deficient mice. However, the frequency of malignant conversion was similar among all three genotypes. After TPA treatment, all genotypes developed epidermal hyperplasia, although the labeling index was lower in p21WAF1 (-/-) epidermis compared with p21WAF1 (+/+). Furthermore, the expression of differentiation markers was the same across genotypes in untreated or TPA-treated epidermis. Similar frequencies of malignant conversion were also observed in an in vitro assay. Thus, p21WAF1 suppresses early stages of papilloma formation but not malignant progression in mouse skin carcinogenesis, and decreased levels of p21WAF1 do not account for the enhanced malignant conversion of p53 null epidermal tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

[HLA-DQA1 genes involved in the genetic susceptibility to duodenal ulcer in Wuhan Hans]

OBJECTIVE: To study the genetic susceptibility of HLA-DQA1 alleles to duodenal ulcer in Chinese Hans from Wuhan and its nearby regions. METHODS: Seventy patients with duodenal ulcer and fifty healthy controls were examined for HLA-DQA1 genotypes. HLA-DQA1 typing was carried out by digesting the locus specific polymerase chain reaction amplified products with alleles specific restriction enzymes (PCR-RFLP), Apal I, Basj I, Hph I, Fok I, Mbo II and Mnl I. RESULTS: The allele frequency of DQA1 0301 in patients with duodenal ulcer (64.3%) was significantly higher than that in healthy controls (36%). In contrast, the allele frequency of DQA1 0102 in patients with duodenal ulcer (8.6%) was significantly lower than that in healthy controls (26%). CONCLUSION: These findings suggest that DQA1 0301 is a susceptible gene for duodenal ulcer in Wuhan Hans while DQA1 0102 is its resistant gene, and there are immunogenetic differences in HLA-DQA1 locus between duodenal ulcer patients and healthy controls.

Journal Article↗
PubMed1999

Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta.

SMAD3 is one of the intracellular mediators that transduces signals from transforming growth factor-beta (TGF-beta) and activin receptors. We show that SMAD3 mutant mice generated by gene targeting die between 1 and 8 months due to a primary defect in immune function. Symptomatic mice exhibit thymic involution, enlarged lymph nodes, and formation of bacterial abscesses adjacent to mucosal surfaces. Mutant T cells exhibit an activated phenotype in vivo, and are not inhibited by TGF-beta1 in vitro. Mutant neutrophils are also impaired in their chemotactic response toward TGF-beta. Chronic intestinal inflammation is infrequently associated with colonic adenocarcinoma in mice older than 6 months of age. These data suggest that SMAD3 has an important role in TGF-beta-mediated regulation of T cell activation and mucosal immunity, and that the loss of these functions is responsible for chronic infection and the lethality of Smad3-null mice.

Animals↗
PubMed1999

Light experience and lateralization of the two visual pathways in the chick.

Using retrograde labelling with the fluorescent tracer rhodamine B isocyanate (RITC), we have examined the organisation of the thalamofugal and tectofugal visual projections to the forebrain of the young chick. In addition, we have investigated the influence of light exposure prior to hatching on the development of the tectofugal visual projections. Our results for the thalamofugal projections confirm those found previously; viz., that there are more projections from the left side of the thalamus to the right hyperstriatum of the forebrain than from the right side of the thalamus to the left hyperstriatum in males and females. The organisation of the tectofugal visual projections to the rotundal nuclei was more symmetrical (males only examined) although there was a trend towards a greater number of projections from the left optic tectum to its ipsilateral nucleus rotundus than from the right optic tectum to its ipsilateral nucleus rotundus. There are numerous projections from the optic tecta to their contralateral rotundal nuclei but, in contrast to reports for the pigeon, no marked asymmetry was present in these. The ratio of contralateral to ipsilateral projections revealed significant asymmetry for projections from the ventral regions of the optic tecta and symmetry from the dorsal regions. Thus both visual pathways of the chick have asymmetrical organisation but the asymmetry is much greater in the thalamofugal pathway. The slight asymmetry in the tectofugal projections may be determined by exposing the embryo to light just before hatching, as known to be the case for thalamofugal projections.

Animals↗
PubMed1999

Role of decay-accelerating factor in regulating complement activation on the erythrocyte surface as revealed by gene targeting.

Decay-accelerating factor (DAF) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that inhibits both the classical and the alternative pathways of complement activation. DAF has been studied extensively in humans under two clinical settings: when absent from the erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) patients, who suffer from complement-mediated hemolytic anemia, and in transgenic pigs expressing human DAF, which have been developed to help overcome complement-mediated hyperacute rejection in xenotransplantation. Nevertheless, the exact role of DAF in regulating complement activation in vivo on the cell surface and the species specificity of this molecule remain to be fully characterized. To address these issues, we have used gene targeting to produce mice lacking GPI-anchored DAF. We found that erythrocytes from mice deficient in GPI-anchored DAF showed no increase in spontaneous complement activation in vivo but exhibited impaired regulation of zymosan-initiated bystander and antibody-triggered classical pathway complement activation in vitro, resulting in enhanced complement deposition. Despite a high level of C3 fixation, no homologous hemolysis occurred. It is noteworthy that GPI-linked DAF knockout erythrocytes, when tested with human and guinea pig sera, were more susceptible to heterologous complement lysis than were normal erythrocytes. These results suggest that DAF is capable of regulating homologous as well as heterologous complement activation via the alternative or the classical pathway. They also indicate that DAF deficiency alone is not sufficient to cause homologous hemolysis. In contrast, when the assembly of the membrane-attack complex is not properly regulated, as in the case of heterologous complement activation or in PNH patients, impaired erythrocyte DAF activity and enhanced C3 deposition could lead to increased hemolytic reaction.

Animals↗
PubMed1999

Fibroblast growth factor receptors (FGFRs) and their roles in limb development.

Fibroblast growth factor (FGF) receptors constitute a family of four membrane-spanning tyrosine kinases (FGFR1-4) which serve as high-affinity receptors for 17 growth factors (FGF1-17). To study functions of FGF/ FGFR signals in development, mice that carry mutations in each receptor have been created by gene targeting. Analysis of these mutant mice revealed essential functions of FGF receptors in multiple biological processes, including mesoderm induction and patterning, cell growth and migration, organ formation and bone growth. In this review we discuss recent work with FGF receptors to illustrate mechanisms, through which the FGF/FGFR signals specify vertebrate limb initiation, outgrowth and patterning.

Animals↗
PubMed1999

Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response.

The generation of animals lacking SMAD proteins, which transduce signals from transforming growth factor-beta (TGF-beta), has made it possible to explore the contribution of the SMAD proteins to TGF-beta activity in vivo. Here we report that, in contrast to predictions made on the basis of the ability of exogenous TGF-beta to improve wound healing, Smad3-null (Smad3ex8/ex8) mice paradoxically show accelerated cutaneous wound healing compared with wild-type mice, characterized by an increased rate of re-epithelialization and significantly reduced local infiltration of monocytes. Smad3ex8/ex8 keratinocytes show altered patterns of growth and migration, and Smad3ex8/ex8 monocytes exhibit a selectively blunted chemotactic response to TGF-beta. These data are, to our knowledge, the first to implicate Smad3 in specific pathways of tissue repair and in the modulation of keratinocyte and monocyte function in vivo.

Animals↗