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At least 1,279 records · Page 71Linked to original sources
PubMed2005

Aortic root replacement with a novel decellularized cryopreserved aortic homograft: postoperative immunoreactivity and early results.

OBJECTIVE: Novel antigen-reduction SynerGraft technology (CryoLife Inc, Kennesaw, Ga) reduces the cellular components of a cadaver homograft with an enzymatic and washing process, leaving the extracellular matrix intact. We report the immunoreactivity (positive panel reactive antibody assay) and early operative results of the CryoLife SynerGraft aortic valve conduit homograft. METHODS: Twenty-two patients (age 53 +/- 14 years, range 31-80 years) from April 2002 to July 2003 underwent aortic root replacement with a CryoLife SynerGraft aortic valve conduit homograft (CryoLife Inc, Kennesaw, Ga) for congenital or acquired aortic valve disease, aortic aneurysm with aortic valve disease, or native or prosthetic aortic valve endocarditis. Baseline percentage positive panel reactive antibody results were negative (<10%) for all and were assessed at 1 month, 3 months, and 1-year. Homograft function was evaluated by echocardiography. RESULTS: Early mortality was 0%. Two late deaths at 1 postoperative year were unrelated to homograft function. At 1 postoperative month, panel reactive antibody results were negative in 20 patients (91%). At 3 months, 19 of 22 patients (86%) had negative results, including 1 with previous positive results. At 1 year, 19 of 20 patients (95%) had negative results, including 2 of the 3 with previous positive results. The mean aortic valve gradients were 12 +/- 8 mm Hg (n = 21) at discharge and 11 +/- 7 mm Hg (n = 18) at 1 year. At a mean follow-up of 30.3 +/- 5.2 months, the mean gradient was 8.8 +/- 6.3 mm Hg. CONCLUSION: The SynerGraft decellularization technology successfully removed antigens from an aortic valve homograft conduit. Aortic root reconstruction with the CryoLife SynerGraft aortic valve homograft resulted in low transvalvular gradients, similar to those seen with standard cryopreserved homografts. These early results suggest an advancement in homograft technology. The low panel reactive antibody response may enhance durability by eliminating immune complex-mediated reaction against the homograft. The lack of allosensitization in patients who may require organ transplantation in the future is an added benefit.

Adult↗
PubMed2004

Targeting estrogen responsive elements (EREs): design of potent transactivators for ERE-containing genes.

The estrogen hormone (E2) plays an important role in the physiology and pathophysiology of target tissues. The effects of E2 are conveyed by the estrogen receptors (ER) alpha and beta. The E2-ER complex mediates an array of genomic and non-genomic events that orchestrate the expression of a number of genes involved in the regulation of cell proliferation and differentiation. The interaction of with the regulatory DNA sequence, estrogen responsive element (ERE), of each responsive gene constitutes a critical genomic signaling pathway. However, the relative importance of ERE-dependent E2-ER signaling in cell proliferation remains to be elucidated. To address this issue, we engineered ERE-binding activators (EBAs) that specifically and potently regulate ERE-containing genes. The modular nature of ER allowed us to initially design a monomeric ERE-binding module by genetically joining two DNA-binding domains with the hinge domain. Integration of strong activation domains from other transcription factors into this module generated constitutively active EBAs. These transactivators robustly induced the expression of only ERE-containing promoter constructs in transfected cells independent of ligand, dimerization, ER-subtype and -status. Moreover, EBAs altered cell cycle progression in breast cancer cell lines in a manner similar to E2-ER. These results demonstrate the importance of ERE-containing genes in the regulation of cell proliferation. These novel ERE-binding transregulators could also be a basis for the targeted regulation of ERE-containing genes, the identification of estrogen responsive gene networks, and the development of alternative/complementary therapeutic approaches for estrogen target tissue cancers.

Animals↗
PubMed2006

New roles for beta-arrestins in cell signaling: not just for seven-transmembrane receptors.

beta-arrestins, originally discovered as molecules that bind to and desensitize the activated and phosphorylated form of the G protein-coupled beta2-adrenergic receptor (beta2-AR), have recently emerged as multifunctional adaptor/scaffold proteins that dynamically assemble a wide range of multiprotein complexes in response to stimulation of most seven-transmembrane receptors (7TMRs). These complexes mediate receptor signaling, trafficking, and degradation. Moreover, beta-arrestins are increasingly found to perform analogous functions for receptors from structurally diverse classes, including atypical 7TMRs such as frizzled and smoothened, the nicotinic cholinergic receptors, receptor tyrosine kinases, and cytokine receptors, thereby regulating a growing list of cellular processes such as chemotaxis, apoptosis, and metastasis.

Animals↗
PubMed1980

Tubular basement membrane antibody-induced interstitial nephritis in systemic lupus erythematosus.

Interstitial nephritis characterized by linear staining for human immunoglobulin G (IgG) along the tubular basement membrane of proximal renal tubules is described in a child with systemic lupus erythematosus (SLE). Autoantibodies reacting with the tubular basement membrane of the proximal renal tubules and Bowman capsule of glomeruli were present in serum. The autoantibodies were specific and could be absorbed with a normal human renal cortical fraction. The findings suggest that in addition to the well-known, immune complex-mediated injury, autoantibody-induced interstitial nephritis can also rarely occur in SLE.

Antibody Specificity↗
PubMed2003

Peripheral keratitis associated with erythema elevatum diutinum.

PURPOSE: To describe a case of peripheral keratitis associated with erythema elevatum diutinum (EED), an unusual immune-complex-mediated cutaneous vasculitis. DESIGN: Observational case report. METHODS: A 25-year-old man who was diagnosed 15 months previously with erythema elevatum diutinum presented with an inflammatory peripheral keratitis of the left eye. RESULTS: Serologic investigations for systemic disorders associated with vasculitic peripheral ulcerative keratitis were unremarkable. As the sclerokeratitis was thought to represent an ocular extension of the patient's cutaneous vasculitis, dapsone therapy was initiated and resulted in a rapid response of both the cutaneous and the ocular inflammation. CONCLUSIONS: Erythema elevatum diutinum should be included in the differential diagnosis of vasculitic peripheral keratitis.

Adult↗
PubMed2004

Loss of LFA-1, but not Mac-1, protects MRL/MpJ-Fas(lpr) mice from autoimmune disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune complex-mediated tissue injury. Many different adhesion molecules are thought to participate in the development of SLE; however, few studies have directly examined the contributions of these proteins. Here we demonstrate that LFA-1 plays an essential role in the development of lupus in MRL/MpJ-Fas(lpr) mice. Mice deficient in LFA-1, but not Mac-1, showed significantly increased survival, decreased anti-DNA autoantibody formation, and reduced glomerulonephritis. The phenotype of the LFA-1-deficient mice was similar to that observed in beta(2) integrin-deficient (CD18-null) MRL/MpJ-Fas(lpr) mice, suggesting a lack of redundancy among the beta(2) integrin family members and other adhesion molecules. These studies identify LFA-1 as a key contributor in the pathogenesis of autoimmune disease in this model, and further suggest that therapeutic strategies targeting this adhesion molecule may be beneficial for the treatment of SLE.

Animals↗
PubMed2002

Development of a high-throughput fluorescence polarization assay for Bcl-x(L).

Antiapoptotic protein Bcl-x(L) has been demonstrated to play a very important role in a variety of diseases such as cancer. Its biological function can be inhibited by proapoptotic proteins such Bak, Bad, and Bax by forming complexes mediated primarily by the Bcl-2 homology 3 (BH3) domain. To facilitate drug discovery for Bcl-x(L) inhibitors, we have developed and optimized a fluorescence polarization assay based on the interaction between Bcl-x(L) and BH3 domain peptides. We observed that the fluorescein-labeled Bad BH3 peptide [NLWAAQRYGRELRRMSDK(fluorescein)FVD or fluorescent Bad peptide] generates best overall results. Fluorescent Bad peptide interacts strongly with Bcl-x(L) with a K(d) of 21.48nM. The assay is stable over a 24-h period and can tolerate the presence of dimethyl sulfoxide up to 8%. By using a competition assay, several peptides derived from the BH3 region of Bak, Bad, Bax, and Bcl-2 were investigated. Bad and Bak BH3 peptides compete efficiently with IC(50) values of 0.048 and 1.14 microM, respectively, while the peptides from the BH3 region of Bcl-2 and Bax compete weakly. A mutated Bak peptide, which has been shown to be inactive for binding to Bcl-x(L), did not compete. The relative binding order of the peptides (Bad>Bak>Bcl-2>Bax>mutated Bak) correlates well with previously published results. When tested in high-throughput formats, the assay has a signal-to-noise ratio of 15.37 and a Z(') factor of at least 0.73. The plate-to-plate variability for free peptide control and bound peptide control is minimal. This validates the assay not only for investigating the nature of Bcl-x(L)-peptide interaction, but also for high-throughput screening of Bcl-x(L) inhibitors.

Binding, Competitive↗
PubMed2002

Interaction of Btk and Akt in B cell signaling.

Reactive oxygen species (ROS) or reactive oxygen intermediates (ROIs) mediate complex signaling involving multiple pathways. In this report, we demonstrate for the first time that endogenous Bruton's tyrosine kinase (Btk) and Akt can interact with each other in DT40 chicken B cells and human Nalm6 B cells and that this interaction is inducible following H2O2 stimulation. This interaction is supported by visualizing the co-localization of Btk and Akt in the perinuclear region and membrane ruffles in COS-7 cells. We have also shown the involvement of phosphatidylinositol 3-kinase (PI 3-K) and Btk in the phosphorylation of Akt following stimulation by hydrogen peroxide (H2O2). Interestingly, Akt phosphorylation was found in the presence of Btk even in the absence of oxidative stress. In addition, we have investigated the involvement of PI 3-K in the MAPKs and ERK and JNK phosphorylation, in the presence or absence of Btk. Phosphorylation of both ERK and JNK increased when the PI 3-K pathway was inhibited and both pathways were modulated positively by Btk. Taken together, based on the study of endogenous conditions, we show the novel interaction of Btk and Akt in H2O2 signaling in B cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1986

System analysis of Phycomyces light-growth response. Photoreceptor and hypertropic mutants.

The light-growth responses of Phycomyces behavioral mutants, defective in genes madB, madC, and madH, were studied with the sum-of-sinusoids method of system identification. Modified phototropic action spectra of these mutants have indicated that they have altered photoreceptors (P. Galland and E.D. Lipson, 1985, Photochem. Photobiol. 41:331). In the two preceding papers, a kinetic model of the light-growth response system was developed and applied to wild-type frequency kernels at several wavelengths and temperatures. The present mutant studies were conducted at wavelength 477 nm. The log-mean intensity was 6 X 10(-2)W m-2 for the madB and madC night-blind mutants, and 10(-4)W m-2 for the madH hypertropic mutant. The prolonged light-growth responses of the madB and madC mutants are reflected in the reduced dynamic order of their frequency kernels. The linear response of the hypertropic mutant is essentially normal, but its nonlinear behavior shows modified dynamics. The behavior of these mutants can be accounted for by suitable modifications of the parametric model of the system. These modifications together support the hypothesis that an integrated complex mediates sensory transduction in the light responses and other responses of the sporangiophore.

Kinetics↗
PubMed1998

Drug-associated acute-onset vanishing bile duct and Stevens-Johnson syndromes in a child.

Acute vanishing bile duct syndrome is a rare but established cause of progressive cholestasis in adults, is most often drug or toxin related, and is of unknown pathogenesis. It has not been reported previously in children. Stevens-Johnson syndrome is a well-recognized immune complex-mediated hypersensitivity reaction that affects all age groups, is drug or infection induced, and has classic systemic, mucosal, and dermatologic manifestations. A previously healthy child who developed acute, severe, rapidly progressive vanishing bile duct syndrome shortly after Stevens-Johnson syndrome is described; this was temporally associated with ibuprofen use. Despite therapy with ursodeoxycholic acid, prednisone, and then tacrolimus, her cholestatic disease was unrelenting, with cirrhosis shown by biopsy 6 months after presentation. This case documents acute drug-related vanishing bile duct syndrome in the pediatric age group and suggests shared immune mechanisms in the pathogenesis of both Stevens-Johnson syndrome and vanishing bile duct syndrome.

Acute Disease↗
PubMed1994

Partial albinism with immunodeficiency (Griscelli syndrome).

Partial albinism with immunodeficiency is a rare and fatal immunologic disorder characterized by pigmentary dilution and variable cellular immunodeficiency. To define the phenotype, therapy, and outcome, we retrospectively analyzed seven consecutive patients. Primary abnormalities included a silvery-grayish sheen to the hair, large pigment agglomerations in hair shafts, and an abundance of mature melanosomes in melanocytes, with reduced pigmentation of adjacent keratinocytes. Clinical onset occurred between the ages of 4 months and 4 years and was characterized by accelerated phases (lymphohistiocytic infiltration of multiple organs, including the brain and the meninges), triggered by viral and bacterial infections. Characteristic laboratory features included pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hypoproteinemia. Consistent immunologic abnormalities were characterized by absent delayed-type cutaneous hypersensitivity and impaired natural killer cell function. Some patients had secondary hypogammaglobulinemia, impaired major histocompatibility complex-mediated cytotoxic effects, a decreased capacity of lymphocytes to trigger a mixed lymphocyte reaction, or various functional granulocytic abnormalities. The disease seems to be invariably lethal without bone marrow transplantation; the mean age at the time of death was 5 years. Bone marrow transplantation has been performed in three cases; two patients died in the immediate posttransplantation period of infectious complications, but one patient is cured after a follow-up of 5 years. We conclude that partial albinism with immunodeficiency (Griscelli syndrome) can be differentiated from Chédiak-Higashi syndrome by pathognomonic histologic features. One of the underlying immunologic defects may be a defective function of natural killer cells, predisposing the patient to virus-associated hemophagocytic syndrome or accelerated phases. The prognosis is very poor unless early bone marrow transplantation is carried out.

Adrenal Cortex Hormones↗
PubMed2003

Osteoprotegerin and its correlations with new markers of bone formation and bone resorption in kidney transplant recipients.

Osteoprotegerin (OPG), a natural decoy receptor for osteoclast differentiation factor, is produced by osteoblasts in response to PTH. OPG and its ligand RANKL constitute a complex mediator system involved in the regulation of bone resorption, probably playing an important role in the homeostasis of bone turnover. At present, little is known about the effects of OPG on uremic bone. Successful kidney transplantation reverses many abnormalities of bone metabolism; however, the improvement is often incomplete. The aim of the study was to assess OPG and RANKL concentrations in long-term kidney allograft recipients and their correlations with biochemical markers of bone resorption and formation. The present studies on 48 kidney transplant recipients and 25 healthy volunteers included concentrations of parathormone, osteocalcin, bone-specific alkaline phosphatase, serum CrossLaps, calcidiol, calcitriol, ICTP, PICP, tartrate-resistant acid phosphatase, beta2 microglobulin, IGF-1, IFGBP-1, IGFBP-3, OPG, and RANKL using commercially available kits for measurements. Among kidney transplant recipients OPG and RANKL did not differ between transplant patients and healthy volunteers, whereas other markers of bone formation and resorption were significantly higher in the former group. OPD was related to age, time on dialysis prior transplantation, urea, platelet count, CSA dose, azathioprine dose, 25(OH)D(3), TRAP, IGF-1, IGFBP-3, whereas RANKL was related to leukocyte count, CSA concentration and dose, urine DPD, and beta2 microglobulin content. In healthy volunteers OPG correlated only with CrossLaps, whereas RANKL correlated only with osteocalcin and TRAP. Correlations between OPG, IGF system components, and some markers of bone metabolism may indicate the role of OPG/RANKL system in the pathogenesis of bone metabolism disturbances following renal transplantation.

Adult↗
PubMed1985

Segmental subepithelial deposits in primary glomerulonephritis: scanning electron microscopic examination of acellular glomeruli.

More accurate perception of the structural alterations in glomerular basement membrane (GBM) produced by subepithelial immune complex deposits is possible with a recently adapted technique that uses scanning electron microscopy of acellular material. With this procedure frozen tissue is treated sequentially by osmotic lysis, detergents, and DNase to solubilize both cellular components and immune complex deposits. Four patients with glomerulonephritis (acute postinfectious glomerulonephritis [one patient], segmental membranous glomerulonephritis [two patients], membranoproliferative glomerulonephritis, type III [one patient]) in whom segmental subepithelial deposits were found were studied by this technique; the resulting observations were correlated with the results of routine morphologic studies and a previous study of minimal change disease and diffuse membranous glomerulonephritis. Four types of structural alterations of the subepithelial GBM surface were observed. The differences in lesions observed in the various forms of glomerulonephritis are believed to be related to temporal, quantitative, and qualitative differences in immune complex-mediated glomerular injury.

Basement Membrane↗
PubMed1996

Factors affecting the cytokine production of human T cells stimulated by different modes of activation.

According to the widely accepted classification, human TH cell clones can be divided into two mutually exclusive subsets, TH1 and TH2, based on their profile of cytokine production. The intracellular difference between these clones is not clear. To characterize the biochemical nature of T-cell receptor (TCR)/CD3 complex-mediated signal transduction pathways, we introduced several human TH cell clones of THO- or TH1-like phenotype and analyzed the effects of various drugs and antibodies on cytokine production or proliferation of these clones. The tyrosine kinase inhibitor herbimycin inhibited the production of interferon-gamma (IFN-gamma) by THO-like clone, after stimulation with anti-CD3 monoclonal antibody alpha CD3-mAb) or with phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore A23187. However, whereas herbimycin strongly inhibited the production of IL-4 and IL-5 by alpha CD3 mAb stimulated T cells, it did not affect the production of these cytokines after PMA/A23187 stimulation. Cyclosporin A inhibited the proliferation as well as the production of the cytokines, including that of IL-2, IL-4, IL-5, and IFN-gamma, irrespective of the mode of stimulation. A23187, which synergizes with PMA in the induction of IL-4 and IFN-gamma, inhibited PMA-induced IL-10 production in a dose-dependent manner. Transforming growth factor-beta and anti-IL-2 receptor monoclonal antibody partially inhibited alpha CD3 mAb-mediated T-cell proliferation, but had no effect on the proliferation induced by PMA and A23187. Cyclic adenosine monophosphate (cAMP)-elevating drugs, like prostaglandin E2 and dibutyryl cAMP, inhibited the TCR-mediated cytokine production but shifted the cytokine production profile from a TH0 to a TH2 type after stimulation with PMA and A23187. Finally, we analyzed the induction of activity of two transcription factors, nuclear factor-kappa B (NF-kappa B) and nuclear factor of activated T cells, involved in the regulation of cytokine gene expression, after a different mode of activation. The induction of NF-kappa B (p50/p65 heterodimer) by using alpha CD3-mAb stimulation but not by using PMA/A23187 stimulation was found to be inhibited by using cAMP-elevating drugs.

Antibodies, Monoclonal↗
PubMed2002

The RNA polymerase II machinery: structure illuminates function.

Essential components of the eukaryotic transcription apparatus include RNA polymerase II, a common set of initiation factors, and a Mediator complex that transmits regulatory information to the enzyme. Insights into mechanisms of transcription have been gained by three-dimensional structures for many of these factors and their complexes, especially for yeast RNA polymerase II at atomic resolution.

Animals↗
PubMed1985

Atheroembolic renal disease causes hypocomplementaemia.

7 patients with atheroembolic renal disease were found to have hypocomplementaemia. Evidence obtained in an experimental model of atheroembolic disease shows that the hypocomplementaemia is the result of complement activation by the atheromatous material in vivo. In addition to hypocomplementaemia, 6 patients had thrombocytopenia and 5 had eosinophilia. These observations indicate that atheroembolic disease should now be included in the differential diagnosis of hypocomplementaemia. In addition, atheroembolic disease should be considered in patients presenting with a combination of multisystem disease, hypocomplementaemia, thrombocytopenia, and eosinophilia--a syndrome which previously would have been regarded as diagnostic of immune-complex-mediated vasculitis.

Aged↗
PubMed2001

Corticotropin-releasing hormone (CRH) as a regulator of waking.

Corticotropin-releasing hormone (CRH), expressed in widely distributed regions of the central nervous system (CNS), mediates the hypothalamic-pituitary-adrenal (HPA) axis and autonomic components of responses to stressors. Sleep, a fundamental CNS process, is altered in response to a variety of stressors. Although there is an extensive literature on the role of CRH in responses to stressors, there is relatively little information on the role of CRH in normal, spontaneous behavior. We hypothesize that CRH is involved in the regulation of waking in the absence of overt stressors. Some of the early evidence supporting this hypothesis was indirect. We summarize in this review studies from our laboratory and others that provide direct evidence that CRH is involved in the regulation of spontaneous waking. We also suggest on the basis of recent studies that some effects of CRH on waking and sleep may be mediated by actions within the CNS of the immunomodulatory cytokine interleukin (IL)-1. Collectively, these observations suggest that CRH contributes to the regulation of spontaneous waking in the absence of stressors, and also indicate a potential mechanism mediating complex alterations in sleep that occur in response to immune challenge.

Animals↗
PubMed1996

The SHIP phosphatase becomes associated with Fc gammaRIIB1 and is tyrosine phosphorylated during 'negative' signaling.

Immune-complex mediated co-ligation of antigen and Fc receptors on B-cells leads to abortive antigen receptor (BCR) signaling and provides a mechanism for feedback regulation of the immune response. A phosphotyrosine-containing 13 amino acid sequence (ITIM) found in the FcgammaRIIB1 cytoplasmic tail mediates this inhibition and specifically associates with the phosphotyrosine phosphatase SHP1. In vitro binding studies demonstrate that the phosphorylated ITIM binds unidentified proteins of 70 and 160 kD in addition to SHP1. Here we report the identification of p70 as SHP2 and p160 as the SH2 containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase SHIP. SHIP is inducibly tyrosine phosphorylated following BCR-FcgammaRIIB1 co-ligation. Further, we observe SHIP association with tyrosine phosphorylated FcgammaRIIB1 in intact cells following BCR-FcgammaRIIB1 co-ligation. To a much lesser but significant degree, tyrosine phosphorylation of SHIP is also observed upon BCR ligation. These observations suggest that SHIP may play an important role in FcgammaRIIB1 dependent and independent regulation of BCR signaling.

Animals↗