Biomedical subjects

M L Tang

Publications and source records attributed to M L Tang.

At least 19 recordsLinked to original sources

PubMed2001

Important roles for L-selectin and ICAM-1 in the development of allergic airway inflammation in asthma.

Airway inflammation and airway hyperresponsiveness (AHR) are fundamental features of asthma. Migration of inflammatory cells from the circulation into the lungs is dependent upon adhesion molecule interactions. The cell surface adhesion molecules L-selectin and intercellular adhesion molecule (ICAM)-1 have been demonstrated to mediate leukocyte rolling on inflamed pulmonary endothelium, and ICAM-1 has also been shown to mediate capillary sequestration in inflamed lung. However, their roles in the development of airway inflammation and AHR in asthma have not been directly examined. We have characterised the roles of L-selectin and ICAM-1 in the recruitment of inflammatory cells to the lung and in the development of airway hyperresponsiveness using an ovalbumin (OVA)-induced allergic airway disease model of asthma and adhesion molecule-deficient mice. OVA-sensitized/challenged ICAM-1-deficient mice have dramatically reduced inflammatory influx into the airway/lung and a corresponding attenuation of AHR as compared to wild-type controls. OVA-sensitized/challenged L-selectin-deficient mice demonstrate significantly reduced numbers of CD3(+)lymphocytes and increased numbers of B220(+)lymphocytes in BAL as compared to wild-type mice (P< 0.05). However, other parameters of airway/lung inflammation in OVA-sensitized/challenged L-selectin-deficient mice were equivalent to wild-type control mice. Remarkably, despite a fulminant inflammatory response in the airway/lung, AHR was completely abrogated in OVA-sensitized/challenged L-selectin-deficient mice. These findings suggest a crucial role for ICAM-1 in the development of airway inflammation and AHR in asthma. In contrast, L-selectin plays a more selective role in the development of airway hyperresponsiveness but not allergic inflammation in this animal model of asthma. Thus, L-selectin and ICAM-1 represent potential targets for novel asthma therapies specifically aimed at controlling airway inflammation and/or airway hyperresponsiveness.

Airway Resistance↗

PubMed2001

Applied anatomy of the V-shaped fibular osteomyocutaneous flap in reconstruction of the hindfoot.

To establish the applied anatomy of the V-shaped fibular osteomyocutaneous flap pedicled on the peroneal vessels, cadaver dissections were made in 60 lower limbs and 40 calcanei were examined to sum up the features of calcaneal biomechanics on the stability of the foot and the blood supply of the fibular osteomyocutaneous flap. There were four anastomoses and large communicating branches between the lower segment of the peroneal artery and the anterior and posterior tibial arteries. The flap was well supplied by a retrograde circulation through these anastomoses. A suitable length of pedicle was 20 cm. In the sagittal section of the calcaneus passing through the center of the articular surface for the cuboid bone, the arrangement of the trabeculae formed a triangular zone. The V-shaped flap corresponds nicely with the calculated lines of stress evoked by the weight of the body. The procedure may provide a new method for hindfoot reconstruction. This flap meets the criteria outlined for composite tissue reconstruction of defects of the extremities and biomechanics of the hindfoot, especially for calcaneal and cuboid defects.

Adult↗

PubMed2001

Childhood asthma as an allergic disease: rationale for the development of future treatment.

UNLABELLED: The fundamental abnormality in asthma is inflammation of the airways. T-helper 2 (Th2) lymphocytes are the key orchestrators of this inflammation, initiating and propagating inflammation through the release of Th2 cytokines. Interleukins(IL)-4, IL-5 and IL-13. IL-4 and IL-13 promote IgE production by B-cells, mast cell growth and differentiation, and upregulate adhesion molecule expression on vascular endothelium. IL-4 also promotes differentiation of uncommitted Th0 lymphocytes into Th2 lymphocytes. IL-5 promotes differentiation and recruitment of eosinophils and activates them to degranulate within tissues, resulting in damage to the respiratory epithelium. Current treatment of childhood asthma relies predominantly on corticosteroids that have nonspecific anti-inflammatory activity and are associated with potential side-effects. Novel therapies that selectively target the underlying immunopathogenesis hold great promise. Disruption of the Th2 lymphocyte induced allergic inflammatory response represents a novel approach to selectively inhibiting allergic inflammation at its origin. Possible therapeutic interventions include inhibition of Th2 response (CpG oligonucleotides, vaccination, CTLA4Ig fusion protein, IL-12, IL-10), inhibition of IgE (the anti-IgE antibody rhuMAb-E25 omalizumab, which is undergoing clinical trials), inhibition of mediator activity (leukotriene modifiers, which are approved for use in childhood asthma), and targeting Th2 cytokines (soluble IL-4 receptors, IL-5 antibody, IL-13). Other therapeutic approaches targeting downstream events in the allergic inflammatory cascade are also currently under investigation (chemokine receptors CCR3, tryptase inhibitors, and inhibitors of cyclic AMP-specific phosphodiesterase 4). CONCLUSION: As we further understand the pathophysiology of asthma, the potential to develop novel treatments increases. This paper addresses current possible new treatments for the future.

Anti-Allergic Agents↗

PubMed2001

L-selectin and intercellular adhesion molecule 1 mediate lymphocyte migration to the inflamed airway/lung during an allergic inflammatory response in an animal model of asthma.

T lymphocytes play a critical role in the development of allergic inflammation in asthma. Early in the allergic response, T lymphocytes migrate from the circulation into the lung to initiate and propagate airway inflammation. The adhesion molecules that mediate lymphocyte entry into inflamed lung have not been defined. This study directly examined the roles of L-selectin and intercellular adhesion molecule 1 (ICAM-1) in lymphocyte migration to the lung during an allergic inflammatory response in an animal model of asthma. Short-term (1 hour) in vivo migration assays and various combinations of adhesion molecule-deficient and wild-type mice were used. Migration of in vivo activated lymphocytes into inflamed lung was significantly greater than entry of resting lymphocytes into noninflamed lung (24.5% +/- 2.7% vs 9.5% +/- 1.3%, P =.001). Migration of activated lymphocytes into inflamed lung was inhibited by 30% in the absence of L-selectin (17.3% +/- 1.3%, P =.04), 47% in the absence of cell surface ICAM-1 (13.0% +/- 2.5%, P =.01), and 47% in the absence of endothelial ICAM-1 (13.0% +/- 2.5%, P =.01). Loss of ICAM-1 on both lymphocytes and lung endothelium inhibited lymphocyte migration by 60% (9.8% +/- 1.8%, P =.002). These findings demonstrate clear roles for both L-selectin and ICAM-1 in lymphocyte migration to the lung during an allergic inflammatory response, with ICAM-1 playing a greater role.

Animals↗

PubMed2001

L-Selectin is required for the development of airway hyperresponsiveness but not airway inflammation in a murine model of asthma.

BACKGROUND: Airway inflammation and airway hyperresponsiveness (AHR) are fundamental features of asthma. Migration of inflammatory cells from the circulation into the lungs is dependent on adhesion molecule interactions. The cell surface adhesion molecule L-selectin has been demonstrated to mediate leukocyte rolling on inflamed and noninflamed pulmonary endothelium. However, its role in the development of airway inflammation and AHR in asthma has not been examined. OBJECTIVE: We sought to characterize the role of L-selectin in the recruitment of inflammatory cells to the airway-lung and the development of AHR in a murine model of asthma. METHODS: An ovalbumin (OVA)-induced allergic airway disease model of asthma was applied to L-selectin-deficient (LKO) mice and C57BL/6 wild-type (WT) control mice. The development of airway inflammation was assessed by examining leukocyte influx into bronchoalveolar lavage (BAL) fluid and the lung. Total and differential BAL leukocyte counts were determined, and the immunophenotype of BAL lymphocytes was assessed by means of flow cytometry. The development of AHR was assessed by means of whole-body plethysmography. RESULTS: Airway-lung inflammation was equivalent in LKO and WT mice sensitized-challenged with OVA, as measured by total and differential BAL cell counts and histologic analysis of lung tissue. Numbers of eosinophils, neutrophils, lymphocytes, and monocytes in BAL fluid were equivalent in LKO and WT mice. However, phenotypic analysis of BAL lymphocytes demonstrated significantly reduced CD3(+) populations and increased B220(+) populations in LKO compared with WT mice (P <.05). Remarkably, despite a fulminant inflammatory response in the airway-lung in LKO mice sensitized-challenged with OVA, AHR was completely abrogated. CONCLUSION: L-selectin plays a crucial role in the development of AHR but not allergic inflammation in an animal model of asthma. L-selectin represents a potential target for novel asthma therapies specifically aimed at controlling AHR.

Animals↗

PubMed2001

[Clinical application of the serial flap pedicled with posterior interosseous artery and its recurrent branch].

OBJECTIVE: To explore a new surgical approach to repair skin and soft tissue defect of hands. METHODS: Based on the anatomical study of the origin, course, branch, distribution, and anastomosis of the posterior interosseous artery and its recurrent branches in 40 upper limbs of cadavers, the posterior forearm serial flap, pedicled with the posterior interosseous artery and its recurrent branches, was designed and applied clinically in 17 cases to repair the skin and soft tissue defect of hands from August 1998 to July 2000. The size of flaps ranged from 7 cm x 5 cm to 15 cm x 10 cm. All of the cases were followed up for 3 weeks to 6 months. RESULTS: The anatomy study showed that the posterior forearm serial flap had long vascular pedicle, suitable thickness and large skin area. The clinical application indicated that the flaps survived in 16 cases. But flap necrosis at the distal end, sized 2 cm x 3 cm, was observed in one case, in which the defect was repaired by delayed skin grafting, CONCLUSION: The posterior forearm serial flap pedicled with the posterior interosseous artery and its recurrent branch have the character of avoidance of sacrificing the major arteries of the extremity, longer vascular pedicle, larger area and suitable thickness. The posterior forearm serial flap is a safe and easily manipulated surgical approach to repair the skin and soft tissue defect of the hands, especially of the thumb, palm, and proximal part of the fingers.

Adolescent↗

PubMed1999

Leukocyte entry into sites of inflammation requires overlapping interactions between the L-selectin and ICAM-1 pathways.

Leukocyte interactions with vascular endothelium during inflammation depend on cascades of adhesion molecule engagement, particularly during selectin-mediated leukocyte rolling. Leukocyte rolling is also facilitated by members of the integrin and Ig families. Specifically, leukocyte rolling velocities during inflammation are significantly increased in ICAM-1-deficient mice, with ICAM-1 expression required for optimal P- and L-selectin-mediated rolling. Elimination of ICAM-1 expression in L-selectin-deficient mice significantly reduces leukocyte rolling. Whether disrupted leukocyte rolling in L-selectin and ICAM-1 double-deficient (L-selectin/ICAM-1-/-) mice affects leukocyte entry into sites of inflammation in vivo was assessed in the current study by using experimental models of inflammation; thioglycollate-induced peritonitis, chemokine-induced neutrophil migration to the skin, delayed-type hypersensitivity responses, rejection of allogeneic skin grafts, and septic shock. In many cases, the loss of both L-selectin and ICAM-1 expression dramatically reduced leukocyte migration into sites of inflammation beyond what was observed with loss of either receptor alone. In fact, the effects from loss of both L-selectin and ICAM-1 effectively eliminated multiple chronic inflammatory responses in L-selectin/ICAM-1-/- mice. By contrast, the combined loss of L-selectin and ICAM-1 expression had minimal effects on the generation of Ag-specific T cell responses or humoral immunity. Thus, members of the selectin and Ig families function synergistically to mediate optimal leukocyte rolling and entry into tissues, which is essential for the generation of effective inflammatory responses in vivo.

Animals↗

PubMed1998

Efficient lymphocyte migration across high endothelial venules of mouse Peyer's patches requires overlapping expression of L-selectin and beta7 integrin.

Lymphocyte migration into lymphoid organs is regulated by adhesion molecules including L-selectin and the beta7 integrins. L-selectin and alpha4beta7 are predominantly hypothesized to direct the selective migration of lymphocytes to peripheral lymph nodes and the gut-associated lymphoid tissues, respectively. To further characterize interactions between L-selectin and beta7 integrins during lymphocyte recirculation, mice deficient in both receptors (L-selectin/beta7 integrin-/-) were generated. The simultaneous loss of L-selectin and beta7 integrin expression prevented the majority of lymphocytes (>95% inhibition) from attaching to high endothelial venules (HEV) of Peyer's patches and other lymphoid tissues during in vitro binding assays. Moreover, the inability to bind HEV eliminated the vast majority of L-selectin/beta7 integrin-/- lymphocyte migration into Peyer's patches during short-term and long-term in vivo migration assays (>99% inhibition,p < 0.01). The lack of lymphocyte migration into Peyer's patches correlated directly with the dramatically reduced size and cellularity (99% reduced) of this tissue in L-selectin/beta7 integrin-/- mice. High numbers of injected L-selectin/beta7 integrin-/- lymphocytes remaining in the blood of wild-type mice correlated with markedly increased numbers of circulating lymphocytes in L-selectin/beta7 integrin-/- mice. Loss of either L-selectin or the beta7 integrins alone resulted in significant but incomplete inhibition of Peyer's patch migration. Collectively, the phenotype of L-selectin/beta7 integrin-/- mice demonstrates that these two receptors primarily interact along the same adhesion pathway that is required for the vast majority of lymphocyte migration into Peyer's patches.

Animals↗

PubMed1998

Regulation of L-selectin-mediated rolling through receptor dimerization.

L-selectin binding activity for its ligand expressed by vascular endothelium is rapidly and transiently increased after leukocyte activation. To identify mechanisms for upregulation and assess how this influences leukocyte/endothelial cell interactions, cell-surface dimers of L-selectin were induced using the coumermycin-GyrB dimerization strategy for cross-linking L-selectin cytoplasmic domains in L-selectin cDNA-transfected lymphoblastoid cells. Coumermycin- induced L-selectin dimerization resulted in an approximately fourfold increase in binding of phosphomanan monoester core complex (PPME), a natural mimic of an L-selectin ligand, comparable to that observed after leukocyte activation. Moreover, L-selectin dimerization significantly increased (by approximately 700%) the number of lymphocytes rolling on vascular endothelium under a broad range of physiological shear stresses, and significantly slowed their rolling velocities. Therefore, L-selectin dimerization may explain the rapid increase in ligand binding activity that occurs after leukocyte activation and may directly influence leukocyte migration to peripheral lymphoid tissues or to sites of inflammation. Inducible oligomerization may also be a common mechanism for rapidly upregulating the adhesive or ligand-binding function of other cell-surface receptors.

Cells, Cultured↗

PubMed1998

Intrinsic differences in L-selectin expression levels affect T and B lymphocyte subset-specific recirculation pathways.

Lymphocyte migration into lymphoid organs is regulated by tissue-specific adhesion molecules such as L-selectin and the alpha4beta7 integrin. Whether L-selectin also regulates lymphocyte subset-specific migration into specific lymphoid tissues was examined in this study by comparing the migration of CD4+ T cells, CD8+ T cells, and B cells from L-selectin-deficient and wild-type mice. T cells were the predominant lymphocyte subset entering PLN, MLN, Peyer's patches, and spleen during short term (1-h) migration assays. However, both B cell and CD4+ and CD8+ T cell entries into PLN, MLN, and Peyer's patches were dramatically impaired (73-98%) by loss of L-selectin. Lymphocyte expression of alpha4beta7 integrin did not compensate for the loss of L-selectin, since both B and T cells predominantly migrated into the spleen in the absence of L-selectin. The more efficient migration of T cells into peripheral lymphoid tissues relative to that of B cells was partly explained by the finding that T cells expressed L-selectin at 50 to 100% higher levels than B cells. In addition, a 50% reduction in L-selectin expression by lymphocytes from hemizygous L-selectin(+/-) mice resulted in a 50 to 70% decrease in short term lymphocyte migration into peripheral lymphoid tissues relative to that of wild-type lymphocytes. Thus, the differential migration of T and B lymphocyte subsets to lymphoid tissues is regulated in part by subset-specific differences in L-selectin expression levels.

Animals↗

PubMed1998

Pneumatosis intestinale in children with primary combined immunodeficiency.

We report six episodes of pneumatosis intestinale (PI) in children with primary combined immunodeficiency. PI was generally benign and responded to conservative therapy. Increased risk of infection or disruption of gastrointestinal mucosa are probable predisposing factors. A diagnosis of PI should be considered in children with primary combined immunodeficiency who experience otherwise unexplained gastrointestinal symptoms, particularly in the early post-transplant period.

Anti-Bacterial Agents↗

PubMed1997

L-selectin is involved in lymphocyte migration to sites of inflammation in the skin: delayed rejection of allografts in L-selectin-deficient mice.

Adhesion of leukocytes to vascular endothelium is crucial for leukocyte migration into tissues. The contributions of L-selectin, P-selectin, and ICAM-1 to interactions between lymphocytes and endothelium was examined using allogeneic skin graft rejection as a model of cutaneous inflammation. L-selectin-deficient (L-selectin(-/-)) mice rejected both primary and secondary allogeneic (BALB/c) skin grafts significantly more slowly than L-selectin(+/+) littermates. Furthermore, skin graft rejection remained significantly delayed in L-selectin(-/-) mice, despite placement of grafts 7 days after i.p. immunization with allogeneic cells, when CTL responses in L-selectin(-/-) mice and L-selectin(+/+) littermates were confirmed to be equivalent. Indeed, specific CTL responses to BALB/c splenocytes were normal or elevated in L-selectin(-/-) mice following either skin grafts or immunization. However, the number of T lymphocytes within allogeneic grafts was lower in L-selectin(-/-) mice as compared with L-selectin(+/+) littermates. Therefore, delayed rejection of skin grafts by L-selectin(-/-) mice reflects impaired migration of effector cells into the graft rather than delayed or impaired generation of a CTL response. In contrast to L-selectin(-/-) mice, P-selectin-deficient and ICAM-1-deficient mice rejected allogeneic skin grafts normally. These findings delineate an important role for L-selectin in lymphocyte recruitment to cutaneous sites of inflammation.

Animals↗

PubMed1997

Maximum likelihood estimation in covariance structure analysis with truncated data.

We study an estimation procedure for maximum likelihood estimation in covariance structure analysis with truncated data, and obtain the statistical properties of the estimator as well as a test of the model structure. Truncated data with and without knowledge about the number of unmeasured observations are both considered. The Broyden-Fletcher-Goldfarb-Shanno (BFGS) algorithm, which requires only first derivatives, is proposed to obtain the maximum likelihood estimates. We illustrate the statistics and parameter estimates by a fictitious example. The maximum likelihood method is compared to an alternative two-stage method.

Algorithms↗

PubMed1996

CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: altered signaling in CD22-deficient mice.

B cell activation following antigen receptor cross-linking can be augmented in vitro by ligation of cell surface CD22, which associates with the SHP1 protein tyrosine phosphatase. The targeted deletion of CD22 in mice demonstrated that CD22 differentially regulates antigen receptor signaling in resting and antigen-stimulated B lymphocytes. B cells from CD22-deficient mice exhibited the cell surface phenotype and augmented intracellular calcium responses characteristic of chronically stimulated B cells, as occurs in SHP1-defective mice. Thus, CD22 negatively regulates antigen receptor signaling in the absence of antigen. However, activation of CD22-deficient B lymphocytes by prolonged IgM cross-linking resulted in modest B cell proliferation, demonstrating that CD22 positively regulates antigen receptor signaling in the presence of antigen.

Animals↗

PubMed1996

Identification of immune system and response genes, and novel mutations causing melanotic tumor formation in Drosophila melanogaster.

We are using Drosophila as a model system for analysis of immunity and tumor formation and have conducted two types of screens using enhancer detector strains to find genes related to these processes; genes expressed in the immune system (type A; hemocytes, lymph glands and fat body) and genes increased in expression by bacterial infection (type B). For type A, tissue-specific reporter gene activity was determined. For type B, a variation of enhancer detection was devised in which beta-galactosidase is assayed spectrophotometrically with and without bacterial infection. Because of immune system involvement in melanotic tumor formation, a third type was hypothesized to be found among types A and B; genes that, when mutated, have a melanotic tumor phenotype. Enhancer detector strains (2800) were screened for type A, 900 for B, and 11 retained for further analysis. Complementation tests, cytological mapping, P-element mobilization, and determination of lethal phase and mutant phenotype have identified six novel genes, Dorothy, wizard, toto, viking, Thor and dappled, and one previously identified gene, Collagen IV. All are associated with reporter gene expression in at least one immune system tissue. Thor has increased expression upon infection. Mutations of wizard and dappled have a melanotic tumor phenotype.

Animals↗

PubMed1995

Exact power computation for dose-response studies.

The toxicity of an agent or the therapeutic effect of a drug may be assessed by a dose-response study. We present a method for computing the exact power of exact and large sample statistical tests employed for binary response data from such a study. This method, based on recursive polynomial multiplications, enables fast computation of exact power for studies with up to a moderately large sample size. We demonstrate the efficiency of our method using three examples. The method is suitable for the design and power analysis of dose-response studies in which the usual asymptotic approximations are suspect.

Adenoma↗

PubMed1995

Interleukin-4 and interferon-gamma production in atopic and non-atopic children with asthma.

Previous studies have demonstrated increased production of interleukin-4 (IL-4) and reduced production of interferon (IFN)-gamma in stimulated peripheral blood mononuclear cell cultures from children and adults with atopic dermatitis, however, it is unclear whether such an imbalance of cytokine production relates to other childhood atopic diseases such as asthma, and in particular to the presence of the atopic state per se. The production of IL-4 and IFN gamma in phytohaemagglutin- (PHA)-stimulated peripheral blood mononuclear cell (PBMC) cultures from atopic and non-atopic children with moderately severe chronic persistent asthma, and a group of age-matched non-atopic controls who did not have asthma was examined. Atopic children with asthma produced significantly more IL-4 and less IFN gamma than non-atopic children with asthma and non-atopic controls who did not have asthma. There was no significant difference in IL-4 or IFN gamma production between non-atopic children with asthma and controls. These findings demonstrate that an imbalance of IL-4 and IFN gamma production is present in atopic asthma as previously documented in atopic dermatitis, therefore suggesting that it is a feature of the atopic state per se.

Asthma↗

PubMed1995

Ontogeny of IL4 production.

There is evidence to suggest that the production of some cytokines in childhood is different to that in adults. The production of IL4 in PHA-stimulated PBMC cultures was examined in healthy neonates, children and adults to determine the ontogeny of IL4 production throughout childhood. In vitro IL4 production was found to be significantly reduced in neonates and children under 10 years of age as compared to adults, and to increase progressively with age. The mechanisms leading to reduced IL4 production in neonates were shown to be different to those in children, with a defect in signal transduction demonstrated for lymphocytes from neonates but not children < 10 years. The presence of an inhibitory factor in cord blood plasma was also noted. These age-dependent variations in IL4 production and response to stimulation with PMA/Ca may reflect differences in naive and memory T cell populations.

Adolescent↗