Thrombosing umbilical vein varix.
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Adult↗
Biomedical subjects
A B Roberts
Publications and source records attributed to A B Roberts.
Does renal failure influence infrainguinal bypass graft outcome?
The purpose of this study is to determine the role of renal failure (RF) in infrainguinal bypass graft outcome. From 1990 through 1996, 206 patients underwent 241 infrainguinal bypass grafts at two institutions. Thirty-three RF patients (42 bypasses) had a mean follow-up of 14.0 months and a mean age of 67.7 years, and 21 (64%) were male. Risk factors included hypertension (100%), diabetes (81.8%), and cardiac disease (75.8%). RF patients included 20 with end-stage renal disease (ESRD) and 14 with renal insufficiency (RI). One patient had RI during his first bypass and ESRD for his subsequent bypass. The major operative indication was limb salvage (90.5%). Total perioperative morbidity for ESRD was significantly higher than for RI and non-RF groups (P = 0.019). Early mortalities occurred in three ESRD, no RI, and seven non-RF patients. Life table analysis demonstrated no significant difference between primary patency (P = 0.56), secondary patency (P = 0.96), and limb salvage (P = 0.69) between ESRD and non-RF groups. However, there was an overall decreased survival rate in the ESRD group (P < 0.01). In conclusion, infrainguinal vein bypass grafting can be successfully performed in RF patients with comparable patency and limb salvage rates and therefore improve quality of life. However, perioperative morbidity was higher in ESRD and survival was significantly shorter for RF than for non-RF patients.
Aged↗
TGF-beta1 up-regulates the mRNA for the Na+/Ca2+ exchanger in neonatal rat cardiac myocytes.
Northern analyses of neonatal cardiac myocytes demonstrated that TGF-beta1 (5 ng/ml) stimulates and IL-1beta (5 ng/ml) decreases the steady-state levels of the mRNA coding for the Na+/Ca2+ exchanger. This is in agreement with the effects of TGF-beta1 and IL-1beta on beating rate and calcium uptake, suggesting that such effects might be mediated, at least partially, through up-regulation of the Na+/Ca2+ exchanger. Basal and TGF-beta1 stimulated mRNA levels were inhibited by the PKC inhibitors H7 (10 microM) and GF109203X (250 nM). In addition, apigenin (12.5 microM), a MAP kinase inhibitor, was able to inhibit basal mRNA levels for the exchanger. Cycloheximide (35.5 microM) had no effect on basal mRNA levels for the exchanger but steady-state levels were diminished in cells treated with TGF-beta1. Finally, actinomycin D (10 microM) inhibited both basal and TGF-beta1 stimulated mRNA levels, though with a more pronounced effect in the presence of TGF-beta1. These results suggest that a complex mechanism of regulation exists for the exchanger and that PKC and possibly MAP kinases might be involved. The up-regulation of this important protein for calcium extrusion, induced by TGF-beta1, might prepare cells to better overcome the calcium overload which occurs under cellular stress and might explain some of the cytoprotective effects of TGF-beta1.
Animals↗
Characterization of functional domains within Smad4/DPC4.
Smad proteins are a family of highly conserved, intracellular proteins that signal cellular responses downstream of transforming growth factor-beta (TGF-beta) family serine/threonine kinase receptors. One of these molecules, Smad4, originally identified as the candidate tumor suppressor gene dpc-4, reconstitutes TGF-beta- and activin-dependent transcriptional responses in Smad4 null cell lines and interacts in a ligand-dependent manner with other Smad family members in both TGF-beta, activin, and bone morphogenetic protein-2/-4 pathways. Here, we used an assay based on the restoration of ligand-dependent transcriptional responses in a Smad4 null cell line to characterize functional domain structures within Smad4. We showed that restoration of TGF-beta-induced transcriptional responses by Smad4 was inhibited by co-transfection with a kinase dead TGF-beta type II receptor and that constitutive activation was blocked with TGF-beta neutralizing antibodies, confirming the essential role of Smad4 in TGF-beta signaling. Using a series of Smad4 mutation, deletion, and Smad1/Smad4 chimera constructs we identified a 47-amino acid deletion within the middle-linker region of Smad4 that is essential for the mediation of signaling responses. In addition, we showed that the NH2-terminal domain of Smad4 augments ligand-dependent activation associated with the middle-linker region, indicating that there is a distinct ligand-response domain within the N terminus of this molecule.
Binding Sites↗
TGF-beta: a critical modulator of immune cell function.
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Adjuvants, Immunologic↗
Toe amputation in the diabetic patient.
BACKGROUND: We considered whether it is more practical to amputate the toe of a diabetic patient with osteomyelitis and good circulation or to treat the patient with antibiotics for a prolonged period. METHODS: We undertook a retrospective study of 141 diabetic patients who had undergone a toe-ray amputation for proven or documented osteomyelitis. RESULTS: The mean ankle/brachial index of all patients was 0.81 (range, 0.68 to 1.14); the mean functional days lost on antibiotic therapy was 39 (range, 7 to 84 days). The cost of 6 to 8 weeks of preoperative antibiotic therapy was $900 to $2240 (mean, $1440). CONCLUSIONS: Diabetic patients with good circulation and osteomyelitis of the toe may benefit from prompt toe amputation.
Amputation, Surgical↗
Carotid plaque typing by multiple-parameter ultrasonic tissue characterization.
We evaluated the ability of ultrasonic tissue characterization (UTC), based on backscattered echo signals, to distinguish among the components of advanced carotid plaques. We performed spectral analysis of echo signals acquired from human carotid endarterectomy specimens in vitro to calculate three parameters of the calibrated power spectrum: slope, intercept and total power for fibrous, lipid pool and thrombus constituents of plaque. Plaque constituents were identified histologically. We evaluated classification efficacy by discriminant function analysis. Slope and intercept parameters alone provided correct classification in 92.5%, 57.6% and 72.4% of fibrous, lipid pool and thrombus plaque components, respectively. Slope, intercept and total power used in combination improved classification of the three tissue types to 93.0%, 69.7% and 81.0%. The overall proportion of correctly classified tissue regions increased from 84.5% to 88.0% by the combined use of the three parameters. The improvement in classification that occurred when we included total power as a third parameter suggests that ultrasound plaque components may not consist solely of small, randomly distributed isotropic scatterers. Our ability to identify plaque thrombi provides motivation for future studies of parameter-based imaging methods for identifying such plaque that presents an increased risk of embolic neurologic ischemic events.
Arteriosclerosis↗
Biology of TGF-beta in knockout and transgenic mouse models.
This paper reviews the basic biology and biochemistry of the TGF-beta isoforms including their unique serine-threonine receptors and signaling intermediates. Dysregulation of TGF-beta expression and/or receptor/signaling function have been implicated in a wide variety of pathologies. We will discuss mechanisms underlying some of these disease processes as gained from study of transgenic mice in which expression of TGF-beta 1 has either been lost by targeted deletion of its gene, is overexpressed in a tissue-specific manner, or blocked by its latency associated peptide.
Albumins↗
Fetal liver length in twin-twin transfusion syndrome.
Fetal liver length was measured by ultrasound in 14 pregnancies with twin-twin transfusion syndrome. The liver size was increased above normal values in both the donor (small) and recipient (large) twin. The liver length was significantly greater than in a control group of dichorionic twin pregnancies with discordant growth. Measurement of liver length may be useful in diagnosing twin-twin transfusion syndrome.
Female↗
Regional variability in the time course of TGF-beta 1 expression, cellular proliferation and extracellular matrix expansion following arterial injury.
Transforming growth factor-beta 1 (TGF-beta 1) has been variably associated with the regulation of cellular proliferation and extracellular matrix expansion after arterial injury. We tested these associations in vivo in the rat carotid injury model. At 0, 3, 7, 14 and 28 days following arterial balloon injury, regional expression of TGF-beta 1 mRNA was assessed using in situ hybridization and the results compared to measures of cellular proliferation and extracellular matrix expansion. Both the TGF-beta 1 concentration measured in culture media of explanted carotid arteries and the quantitative in situ hybridization signal for TGF-beta 1 arterial media and neointima were maximal at 14 days after balloon injury. However, medial cellular proliferation was maximal at 3 days whereas neointimal proliferation was maximal at 14 days and significantly greater than medial proliferation. Neointimal cell density declined significantly between 7 and 14 days, indicating the expansion of extracellular matrix; however, medial cell density was unchanged between 3 and 28 days after balloon injury. Thus, differences in the regional arterial wall relationships between the time course of cellular proliferation, extracellular matrix expansion and the level of TGF-beta 1 expression demonstrate in vivo variability in the response to TGF-beta 1.
Angioplasty, Balloon, Coronary↗
Binding affinity of transforming growth factor-beta for its type II receptor is determined by the C-terminal region of the molecule.
Transforming growth factor-beta (TGF-beta) isoforms have differential binding affinities for the TGF-beta type II receptor (TbetaRII). In most cells, TGF-beta1 and TGF-beta3 bind to TbetaRII with much higher affinity than TGF-beta2. Here, we report an analysis of the effect of TGF-beta structure on its binding to TbetaRII by using TGF-beta mutants with domain deletions, amino acid replacements, and isoform chimeras. Examination of the binding of TGF-beta mutants to the recombinant extracellular domain of TbetaRII by a solid-phase TGF-beta/TbetaRII assay demonstrated that only those TGF-beta mutants containing the C terminus of TGF-beta1 (TGF-beta1-(Delta69-73), TGF-beta1-(Trp71), and TGF-beta2/beta1-(83-112)) bind with high affinity to TbetaRII, similar to native TGF-beta1. Moreover, replacement of only 6 amino acids in the C terminus of TGF-beta1 with the corresponding sequence of TGF-beta2 (TGF-beta1/beta2-(91-96)) completely eliminated the high affinity binding of TGF-beta1. Proliferation of fetal bovine heart endothelial (FBHE) cells was inhibited to a similar degree by all of the TGF-beta mutants. However, recombinant soluble TbetaRII blocked the inhibition of FBHE cell proliferation induced by TGF-beta mutants retaining the C terminus of TGF-beta1, consistent with the high binding affinity between these TGF-beta molecules and TbetaRII. It was further confirmed that the TGF-beta2 mutant with its C terminus replaced by that of TGF-beta1 (TGF-beta2/beta1-(83-112)) competed as effectively as TGF-beta1 with 125I-TGF-beta1 for binding to membrane TbetaRI and TbetaRII on FBHE cells. These observations clearly indicate that the domain in TGF-beta1 responsible for its high affinity binding to TbetaRII, both the soluble and membrane-bound forms, is located at C terminus of the molecule.
Amino Acid Sequence↗
Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression.
The progressive inflammatory process found in transforming growth factor beta1 (TGF-beta1)-deficient mice is associated with several manifestations of autoimmunity, including circulating antibodies to nuclear antigens, immune complex deposition, and increased expression of both class I and class II major histocompatibility complex (MHC) antigens. The contribution of MHC class II antigens to the genesis of this phenotype has been determined by crossing the TGF-beta1-null [TGF-beta1(-/-)] genotype into the MHC class II-deficient [MHC-II(-/-)] background. Mice homozygous for both the TGF-beta1 null allele and the class II null allele [TGF-beta1(-/-);MHC-II(-/-)] are without evidence of inflammatory infiltrates, circulating autoantibodies, or glomerular immune complex deposits. Instead, these animals exhibit extensive extramedullary hematopoiesis with progressive splenomegaly and adenopathy, surviving only slightly longer than TGF-beta1(-/-);MHC-II(+/+) mice. The role of CD4+ T cells, which are also absent in MHC class II-deficient mice, is directly demonstrated through the administration of anti-CD4 monoclonal antibodies in class II-positive, TGF-beta1(-/-) mice. The observed reduction in inflammation and improved survival emphasize the significance of CD4+ cells in the pathogenesis of the autoimmune process and suggest that the additional absence of class II antigens in TGF-beta1(-/-);MHC-II(-/-) mice may contribute to their extreme myeloid metaplasia. Thus, MHC class II antigens are essential for the expression of autoimmunity in TGF-beta1-deficient mice, and normally may cooperate with TGF-beta1 to regulate hematopoiesis.
Animals↗
Nomenclature: vertebrate mediators of TGFbeta family signals.
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Animals↗
Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease.
In Alzheimer's disease (AD), affected neurons accumulate beta amyloid protein, components of which can induce mouse microglia to express the high-output isoform of nitric oxide synthase (NOS2) in vitro. Products of NOS2 can be neurotoxic. In mice, NOS2 is normally suppressed by transforming growth factor beta 1 (TGF-beta 1). Expression of TGF-beta 1 is decreased in brains from AD patients, a situation that might be permissive for accumulation of NOS2. Accordingly, we investigated the expression of NOS2 in patients with AD, using three monospecific antibodies: a previously described polyclonal and two new monoclonal antibodies. Neurofibrillary tangle-bearing neurons and neuropil threads contained NOS2 in brains from each of 11 AD patients ranging in age from 47 to 81 years. NOS2 was undetectable in brains from 6 control subjects aged 23-72 years, but was expressed in small amounts in 3 control subjects aged 77-87 years. Thus, human neurons can express NOS2 in vivo. The high-output pathway of NO production may contribute to pathogenesis in AD.
Adult↗
Serine phosphorylation, chromosomal localization, and transforming growth factor-beta signal transduction by human bsp-1.
The transforming growth factor-beta (TGF-beta) superfamily regulates a multitude of cellular and developmental events. TGF-beta family ligands signal through transmembrane serine/threonine kinase receptors whose downstream effectors are largely unknown. Using genetic data from the fruit fly, we have identified a downstream effector of TGF-beta-induced signaling. TGF-beta signaling protein-1 (BSP-1) is rapidly phosphorylated in response to TGF-beta. Localization of bsp-1 to chromosome 4q28 suggests a role in carcinogenesis. These data suggest that BSP-1 is the prototype of a new class of signaling molecules.
Amino Acid Sequence↗
Transforming growth factor beta 1: three-dimensional structure in solution and comparison with the X-ray structure of transforming growth factor beta 2.
The three-dimensional solution structure of human transforming growth factor beta 1 (TGF-beta 1) has been determined using multinuclear magnetic resonance spectroscopy and a hybrid distance geometry/ simulated annealing algorithm. It represents one of the first examples of a mammalian protein structure that has been solved by isotopic labeling of the protein in a eukaryotic cell line and multinuclear NMR spectroscopy. The solution structure of the 25 kDa disulfide-linked TGF-beta 1 homodimer was calculated from over 3200 distance and dihedral angle restraints. The final ensemble of 33 accepted structures had no NOE or dihedral angle violations greater than 0.30 A and 5.0 degrees, respectively. The RMSD of backbone atoms for the ensemble of 33 structures relative to their mean structure was 1.1 A when all residues were used in the alignment and 0.7 A when loop regions were omitted. The solution structure of TGF-beta 1 follows two independently determined crystal structures of TGF-beta 2 (Daopin et al., 1992, 1993; Schlunegger & Grütter, 1992, 1993), providing the first opportunity to examine structural differences between the two isoforms at the molecular level. Although the structures are very similar, with an RMSD in backbone atom positions of 1.4 A when loop regions are omitted in the alignment and 1.9 A when all residues are considered, there are several notable differences in structure and flexibility which may be related to function. The clearest example of these is in the beta-turn from residues 69-72: the turn type found in the solution structure of TGF-beta 1 falls into the category of type II, whereas that present in the X-ray crystal structure of TGF-beta 2 is more consistent with a type I turn conformation. This may be of functional significance as studies using TGF-beta chimeras and deletion mutants indicate that this portion of the molecule may be important in receptor binding.
Amides↗
The recombinant proregion of transforming growth factor beta1 (latency-associated peptide) inhibits active transforming growth factor beta1 in transgenic mice.
All three isoforms of transforming growth factors beta (TGF-betal, TGF-beta2, and TGF-beta3) are secreted as latent complexes and activated extracellularly, leading to the release of the mature cytokines from their noncovalently associated proregions, also known as latency-associated peptides (LAPs). The LAP region of TGF-beta1 was expressed in a baculovirus expression system and purified to homogeneity. In vitro assays of growth inhibition and gene induction mediated by TGF-beta3 demonstrate that recombinant TGF-beta1 LAP is a potent inhibitor of the activities of TGF-betal, -beta2, and -beta3. Effective dosages of LAP for 50% neutralization of TGF-beta activities range from 4.7- to 80-fold molar excess depending on the TGF-beta isoform and activity examined. Using 125I-labeled LAP, we show that the intraperitoneal application route is effective for systemic administration of LAP. Comparison of concentrations of LAP in tissues shows a homogenous pattern in most organs with the exception of heart and muscle, in which levels of LAP are 4- to 8-fold lower. In transgenic mice with elevated hepatic levels of bioactive TGF-betal, treatment with recombinant LAP completely reverses suppression of the early proliferative response induced by TGF-beta1 in remnant livers after partial hepatectomy. The results suggest that recombinant LAP is a potent inhibitor of bioactive TGF-beta both in vitro and in vivo, after intraperitoneal administration. Recombinant LAP should be a useful tool for novel approaches to study and therapeutically modulate pathophysiological processes mediated by TGF-beta3.
Animals↗
Spontaneously increased production of nitric oxide and aberrant expression of the inducible nitric oxide synthase in vivo in the transforming growth factor beta 1 null mouse.
Transforming growth factor beta 1 null mice (TGF-beta 1-/-) suffer from multifocal inflammation and die by 3-4 wk of age. In these mice, levels of nitric oxide (NO) reaction products in serum are elevated approximately fourfold over levels in controls, peaking at 15-17 d of life. Shortterm treatment of TGF-beta 1-/- mice with NG-monomethyl-L-arginine suppressed this elevated production of NO. Expression of inducible NO synthase (iNOS) mRNA and protein is increased in the kidney and heart of TGF-beta 1-/- mice. These findings demonstrate that TGF-beta 1 negatively regulates iNOS expression in vivo, as had been inferred from mechanistic studies on the control of iNOS expression by TGF-beta 1 in vitro.
Amino Acid Sequence↗