Biomedical subjects

A B Roberts

Publications and source records attributed to A B Roberts.

At least 37 records · Page 2Linked to original sources

PubMed2000

Effects of steroids and retinoids on wound healing.

HYPOTHESIS: Anti-inflammatory corticosteroids significantly impair wound healing. Retinoids partially, but significantly, reverse this effect. Little is known about the mechanism of steroid retardation or retinoid reversal. We hypothesized that corticosteroids lower transforming growth factor-beta (TGF-beta) and insulin-like growth factor-I (IGF-I) levels and tissue deposition in wounds and that retinoids stimulate corticosteroid-impaired TGF-beta and IGF-I release and collagen production. DESIGN: Randomized controlled trial. SETTING: Wound healing research laboratory. PARTICIPANTS: Animal study. INTERVENTIONS: Four wire mesh wound cylinders were implanted subcutaneously into the backs of 72 male Sprague-Dawley rats. Wound healing was impaired by a single subcutaneous injection of 6 mg of methylprednisolone acetate (Depo-Medrol). Two preparations of retinoids were used in separate experiments: all-trans-retinoic acid and 9-cis-retinoic acid that were fed orally. MAIN OUTCOME MEASURES: Hydroxyproline content was measured in the healing tissue and TGF-beta and IGF-I levels were analyzed in the wound fluid. RESULTS: Methylprednisolone treatment significantly decreased TGF-beta and IGF-I levels in the wound fluid and hydroxyproline content in the tissue (P<.05). Oral all-trans- and 9-cis-retinoic acid partially reversed the TGF-beta and IGF-I decrease and significantly increased hydroxyproline content toward normal levels (P<.05). Oral all-trans-retinoic acid enhanced collagen deposition, TGF-beta and IGF-I levels over normal chow fed control animals (P<.05). CONCLUSIONS: Steroids and retinoids have antagonistic effects on growth factors and collagen deposition in wound healing. These effects can be relevant for treatment options in a clinical setting.

Alitretinoin↗

PubMed2000

Zebrafish nma is involved in TGFbeta family signaling.

Bone morphogenetic proteins (BMP) are members of the TGFbeta superfamily of secreted factors with important regulatory functions during embryogenesis. We have isolated the zebrafish gene, nma, that encodes a protein with high sequence similarity to human NMA and Xenopus Bambi. It is also similar to TGFbeta type I serine/theronine kinase receptors in the extracellular ligand-binding domain but lacks a cytoplasmic kinase domain. During development, nma expression is similar to that of bmp2b and bmp4, and analysis in the dorsalized and ventralized zebrafish mutants swirl and chordino indicates that nma is regulated by BMP signaling. Overexpression of nma during zebrafish and Xenopus development resulted in phenotypes that appear to be based on inhibition of BMP signaling. Biochemically, NMA can associate with TGFbeta type II receptors and bind to TGFbeta ligand. We propose that nma is a BMP-regulated gene whose function is to attenuate BMP signaling during development through interactions with type II receptors and ligands.

Activin Receptors, Type I↗

PubMed2000

A pilot randomized controlled trial of two regimens of fetal surveillance for small-for-gestational-age fetuses with normal results of umbilical artery doppler velocimetry.

OBJECTIVE: This study was undertaken to determine whether the frequency of fetal surveillance could be safely reduced from twice weekly to fortnightly in the case of small-for-gestational-age fetuses with normal results of umbilical artery Doppler velocimetry studies. STUDY DESIGN: Pregnant women between 24 and 36 weeks' gestation (n = 167) with small-for-gestational-age fetuses and normal results of umbilical artery Doppler velocimetry studies were randomly allocated to undergo twice-weekly or fortnightly fetal surveillance. Statistical analysis was carried out according to intention to treat. RESULTS: Eighty-five women were randomly assigned to undergo twice-weekly fetal surveillance and 82 were randomly assigned to undergo fortnightly fetal surveillance. Those randomly assigned to twice-weekly surveillance were delivered 4 days earlier (264 vs 268 days; P =.04) and were more likely to have labor induced (n = 70, 82%, vs n = 54, 66%; P =.02) than those randomly assigned to fortnightly surveillance. Fifty-four babies (23%) were admitted to the neonatal nursery, but there were no differences in neonatal morbidity between the groups. CONCLUSIONS: Maternal intervention (induction) was more common in the twice-weekly group. No differences in neonatal outcomes were detected. A much larger trial is required to determine the safety and potential benefits of less frequent surveillance of small-for gestational-age fetuses with normal results of umbilical artery Doppler velocimetry studies.

Female↗

PubMed2000

Kinaesthetic judgements and refinement of striking action.

Little is known about the developmental course of striking action. This cross-sectional study explored the refinement of striking in 28 children aged between 4 and 12 years and investigated how well they could use kinaesthesis to gauge the length of an unseen bat. The kinematic data (including smoothness of movement) showed quantitative differences between the age groups. In contrast, no differences were found in the children's ability to judge the length of the unseen bat: within three strikes all of the children had made a clean hit, indicating that they had successfully judged bat length. The children then appeared to memorize the bat with which they had accurately hit the target and made: (1) minimal errors when using this bat in later trials and (2) predictable errors when using two other bats of different sizes. The results show that the striking action becomes optimized over childhood, with smoothness of movement providing an index of this refinement. The findings also suggest that young children have a higher level of kinaesthetic sensitivity than has been assumed previously on the basis of static limb positioning tasks. The results suggest that the striking task used in this study might be a useful tool for investigating the development of movement skills in children with developmental disorders.

Age Factors↗

PubMed2000

A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.

Here we describe a protein product of the human septin H5/PNUTL2/CDCrel2b gene, which we call ARTS (for apoptosis-related protein in the TGF-beta signalling pathway). ARTS is expressed in many cells and acts to enhance cell death induced by TGF-beta or, to a lesser extent, by other apoptotic agents. Unlike related septin gene products, ARTS is localized to mitochondria and translocates to the nucleus when apoptosis occurs. Mutation of the P-loop of ARTS abrogates its competence to activate caspase 3 and to induce apoptosis. Taken together, these observations expand the functional attributes of septins previously described as having roles in cytokinesis and cellular morphogenesis.

Amino Acid Motifs↗

PubMed2000

Perinatal mortality in Type 2 diabetes mellitus.

AIMS: In many parts of the world the number of pregnancies in women with Type 2 diabetes mellitus (DM) now exceeds that in women with Type 1 DM, but there are few data published on perinatal mortality in Type 2 DM. This study reports observational data on perinatal mortality in Type 2 DM from a population with a high background rate of this disorder. METHODS: Over a 12-year period (1985-1997) at the Diabetes Clinic at National Women's Hospital, Auckland, there were 434 pregnancies in women with Type 2 DM (256 known and 178 diagnosed with gestational diabetes mellitus (GDM), but confirmed to have Type 2 DM early post-partum), 160 pregnancies in women with Type 1 DM and 932 in women with GDM. Perinatal mortality was classified as either intermediate fetal death (20-28 weeks' gestation), late fetal death (28 weeks' gestation to term) or early neonatal death (up to 1 month post-partum). RESULTS: The perinatal mortality in Type 2DM was 46.1/1,000, significantly higher than the rates for the general population (12.5), Type 1 DM (12.5) and GDM (8.9) (P < 0.0001). Congenital malformations accounted for only 10% of the perinatal mortality. There was a seven-fold increase in the rate of late fetal death and 2.5-fold increase in the rates of intermediate fetal and late neonatal death. Subjects with Type 2 DM were significantly older and more obese than subjects with Type 1 DM, and presented later to the diabetes service. CONCLUSIONS: Perinatal mortality in Type 2 DM is significantly increased, mainly owing to an excess of late fetal death. Maternal factors such as obesity may be important contributors to the high perinatal mortality. Women diagnosed with GDM who have unrecognized Type 2 DM are also at high risk, but perinatal mortality is low in women with milder degrees of glucose intolerance in pregnancy.

Adult↗

PubMed2000

Gender does not impact infrainguinal vein bypass graft outcome.

BACKGROUND: The percentage of women requiring infrainguinal bypass graft operations continues to increase, whereas the effect of gender on postoperative outcome remains unclear. The purpose of this study was to assess the influence of gender on patient selection and outcome in patients requiring infrainguinal vein bypass grafting procedures. METHODS: This retrospective study reviewed 217 infrainguinal vein bypass grafts performed over an 8-year period. Medical records and patient interviews were used to determine study measures and outcomes. Gender and multiple covariables affecting patient survival were analyzed; postoperative complications and graft patencies were examined. Bivariate and life-table analyses were conducted, followed by multivariate analysis with the Cox proportional hazards model. RESULTS: No statistical differences existed between men and women for age, diabetes, cardiac disease, tobacco use, hypertension, stroke, renal disease, or prior contralateral bypass or major amputation. Women were more likely to be black (P =.014) and have a spliced vein graft (P =.035). No differences were noted between the 2 groups for 30-day morbidity rates-except women had more incisional complications (P =.01)-or for survival (P =.45), primary-patency (P =.57), secondary-patency (P =. 79), or limb-salvage rates (P =.40). Multivariate analysis showed that gender had no role in affecting survival rates. CONCLUSIONS: Gender does not affect graft patency, limb salvage, or survival rates. There should be no introduction of a gender bias into management of infrainguinal occlusive disease.

Adult↗

PubMed2000

Selective loss of the transforming growth factor-beta apoptotic signaling pathway in mutant NRP-154 rat prostatic epithelial cells.

Retroviral insertional mutagenesis was used to select mutant NRP-154 rat prostate carcinoma cells resistant to transforming growth factor (TGF)-beta-induced cell death. Similar to the parental cells, a mutant clone, M-NRP1, expressed TGF-beta receptors and was still responsive to induction both of direct target genes by TGF-beta and of apoptosis by staurosporine or okadaic acid. In contrast, indicators of cell growth, strongly suppressed by TGF-beta in the parental cells, were unaffected in M-NRP1 cells. M-NRP1 cells overexpress the antiapoptotic protein, Bcl-xL, and show dysregulated expression and localization of a protein related to a novel human septin, ARTS (designation of apoptotic response to TGF-beta signals), cloned by homology to an exonic sequence flanked by the viral long terminal repeats in M-NRP1 cells and shown to make cells competent to undergo apoptosis in response to TGF-beta. We propose that ARTS might operate within the same apoptotic pathway as Bcl-xL and that M-NRP1 cells could serve as a useful model for characterization of this pathway.

Animals↗

PubMed1999

Beta 2-microglobulin-deficient background ameliorates lethal phenotype of the TGF-beta 1 null mouse.

TGF-beta 1 null (TGF-beta1-/-) mice die at 3-4 wk of age and show an autoimmune inflammatory phenotype associated with enhanced expression of both class I and II MHC molecules. To determine the role of MHC class I Ags in the autoimmune manifestations and the inflammation observed in TGF-beta 1-/- mice, we generated TGF-beta 1-/- mice in the genetic background of beta 2-microglobulin deficiency (beta 2M-/-). TGF-beta 1-/-;beta 2M-/- mice had improved survival compared with TGF-beta 1-/- mice. Histopathological examination showed less severe inflammation, especially in the heart, where Mac-2 reactive macrophages were significantly decreased as compared with TGF-beta 1-/- mice. In vivo depletion of CD8+ T cells in TGF-beta 1-/- mice confirmed suppression of inflammation and reduction in the severity of the wasting syndrome. MHC class II mRNA expression in TGF-beta 1-/-;beta 2M-/- mice was also lower than that in TGF-beta 1-/- mice, suggesting reduced systemic inflammation. Autoimmune response as judged by serum Ab titers to ssDNA and 16/6 Id and by immune complex deposits in kidney was reduced in TGF-beta 1-/-;beta 2M-/- mice, when compared with that in TGF-beta 1-/- mice. Our data thus indicate that MHC class I molecules influence the development of the autoimmunity and the inflammation seen in TGF-beta 1-/- mice and CD8+ T cells may have a contribution to the inflammation in TGF-beta 1-/- mice.

Animals↗

PubMed1999

Heterotopic endochondrial ossification with mixed tumor formation in C3(1)/Tag transgenic mice is associated with elevated TGF-beta1 and BMP-2 expression.

Transgenic mice which express the simian virus 40 large T-antigen (Tag) under the regulatory control of the hormone responsive rat C3(1) gene develop unusual lesions of heterotopic bone growth associated with mixed tumor formation arising from eccrine sweat glands found only in the foot pads of mice, ischiocavernosus muscle adjacent to bulbourethral glands and occasionally the salivary and mammary glands. These lesions are very similar to mixed tumors arising in several types of human cancers. Based upon electron microscopic examination and immunocytochemical analyses of cellular differentiation markers, the mixed proliferative lesions in this transgenic mouse model begin with the Tag-induced proliferation of epithelial and myoepithelial cells. The proliferation of these two types of cells results in hyperplasia and adenomatous transformation of the epithelial component, whereas the proliferating myoepithelial cells undergo metaplasia to form chondrocytes which deposit extracellular matrix, including collagen fibers. Cartilage develops focally between areas of epithelial proliferation and subsequently ossifies through a process of endochondrial bone formation. The metaplasia of myoepithelial cells to chondrocytes appears to require the inductive interaction of factors produced by the closely associated proliferating epithelial cells, including members of the TGF-beta superfamily. We demonstrate that TGF-beta1 protein accumulates in the extracellular matrix of the lesions, whereas RNA in situ hybridization reveals that BMP-2, another strong inducer of heterotopic bone formation, is overexpressed by the proliferating epithelial cells during the development of ectopic bone. The formation of sarcomatous tumors within the mixed tumors appears to be androgen-dependent and more frequent in mice lacking a normal allele of p53. This process of cartilage and bone induction may mimic epithelial-mesenchymal interactions which occur during embryonic bone formation. These transgenic mice may provide new insights into the processes of ectopic endochondrial bone formation associated with mixed tumor formation and serve as a useful model for human heterotopic bone disease.

Actins↗

PubMed1999

Functional analysis of human Smad1: role of the amino-terminal domain.

The signals originating from transforming growth factor beta/activin/bone morphogenetic proteins (BMPs) are transduced by a set of evolutionarily conserved family of Smad proteins which, upon activation, directly translocate to the nucleus where they may activate transcription. Smad proteins of different species contain conserved amino- (N) and carboxy- (C) terminal domains separated by a proline-rich linker. Human, Drosophila, and Xenopus Smad1 all have been shown to mediate the biological effects of BMP-4 in Xenopus embryos. We have investigated the functional domains of human Smad1 (hSmad1) using the Xenopus embryo system. Dorsal injection of hSmad1 RNA into the 4-cell-stage embryos results in embryonic ventralization. Since the C-terminus of Smads has been shown to mediate the transcriptional activity, whereas this activity is masked by the presence of the N-terminus, we tested the effect of a hSmad1 construct lacking the C-terminal domain [hSmad1(N)] in the Xenopus embryo system. Surprisingly, we found that hSmad1(N) not only synergizes with hSmad1 in embryonic ventralization, but induces ventralization by itself. Ectopic expression of a dominant negative BMP receptor (DN-BR) as well as neural inducers noggin and chordin induce neurogenesis in the animal cap, which is inhibited by co-expression of either hSmad1 or hSmad1(N). Ventral expression of DN-BR induces formation of a second body axis at tailbud stage, which is also prevented by hSmad1 and hSmad1(N). It has recently been reported that calmodulin interacts with the N-terminal domain of Smad proteins. We demonstrate that the ventralizing activity of hSmad1 and hSmad1(N) is markedly inhibited by calmodulin. Thus, calmodulin acts as a Smad1 inhibitor. A model is proposed to accomodate these findings.

Animals↗

PubMed1999

Regulation of transforming growth factor beta1 by nitric oxide.

Many tumor cells or their secreted products suppress the function of tumor-infiltrating macrophages. Tumor cells often produce abundant transforming growth factor beta1 (TGF-beta1), which in addition to other immunosuppressive actions suppresses the inducible isoform of NO synthase. TGF-beta1 is secreted in a latent form, which consists of TGF-beta1 noncovalently associated with latency-associated peptide (LAP) and which can be activated efficiently by exposure to reactive oxygen species. Coculture of the human lung adenocarcinoma cell line A549 and ANA-1 macrophages activated with IFN-gamma plus lipopolysaccharide resulted in increased synthesis and activation of latent TGF-beta1 protein by both A549 and ANA-1 cells, whereas unstimulated cultures of either cell type alone expressed only latent TGF-beta1. We investigated whether exposure of tumor cells to NO influences the production, activation, or activity of TGF-beta1.A549 human lung adenocarcinoma cells exposed to the chemical NO donor diethylamine-NONOate showed increased immunoreactivity of cell-associated latent and active TGF-beta1 in a time- and dose-dependent fashion at 24-48 h after treatment. Exposure of latent TGF-beta1 to solution sources of NO neither led to recombinant latent TGF-beta1 activation nor modified recombinant TGF-beta1 activity. A novel mechanism was observed, however: treatment of recombinant LAP with NO resulted in its nitrosylation and interfered with its ability to neutralize active TGF-beta1. These results provide the first evidence that nitrosative stress influences the regulation of TGF-beta1 and raise the possibility that NO production may augment TGF-beta1 activity by modifying a naturally occurring neutralizing peptide.

Adenocarcinoma↗

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

A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity.

The new synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a potent, multifunctional molecule. It induces monocytic differentiation of human myeloid leukemia cells and adipogenic differentiation of mouse 3T3-L1 fibroblasts and enhances the neuronal differentiation of rat PC12 pheochromocytoma cells caused by nerve growth factor. CDDO inhibits proliferation of many human tumor cell lines, including those derived from estrogen receptor-positive and -negative breast carcinomas, myeloid leukemias, and several carcinomas bearing a Smad4 mutation. Furthermore, it suppresses the abilities of various inflammatory cytokines, such as IFN-gamma, interleukin-1, and tumor necrosis factor-alpha, to induce de novo formation of the enzymes inducible nitric oxide synthase (iNos) and inducible cyclooxygenase (COX-2) in mouse peritoneal macrophages, rat brain microglia, and human colon fibroblasts. CDDO will also protect rat brain hippocampal neurons from cell death induced by beta-amyloid. The above activities have been found at concentrations ranging from 10(-6) to 10(-9) M in cell culture, and these results suggest that CDDO needs further study in vivo, for either chemoprevention or chemotherapy of malignancy as well as for neuroprotection.

3T3 Cells↗

PubMed1999

Influence of incisional complications on infrainguinal vein bypass graft outcome.

Incisional complications following infrainguinal vein bypass remain a formidable challenge to the vascular surgeon. A retrospective analysis of 250 infrainguinal vein bypass grafts (214 patients) was undertaken to identify risk factors for the development of incisional complications and determine the impact of incisional complications on outcome. Incisional complications occurred in 47 (19%) of the bypasses. The mean age was 67.8 years and 155 (62%) of the bypasses were performed in men. The patients were divided into two groups based on the presence or absence of an incisional complication. By univariate analysis, the contributing factors for an incisional complication were: veteran hospital status, dialysis dependence, anemia, obesity, leukocytosis, and hypoalbuminemia (p < 0.05). By multivariate analysis, veteran hospital status, female gender, leukocytosis, and prior ipsilateral bypass were independent risk factors for incisional complications (p < 0.05). The increased incidence of incisional complications in the veteran's hospital group was associated with anemia, leukocytosis, decreased lymphocyte count, and increased incidence of tissue loss (p < 0.05). By life-table analysis, incisional complications did not influence primary patency (p = 0.73), secondary patency (p = 0.91), limb salvage (p = 0.69), or survival (p = 0.92). However, a significant suppurative soft-tissue infection ultimately resulted in a high rate of major amputation.

Aged↗

PubMed1999

Ultrasonographic measurement of liver length in the small-for-gestational-age fetus.

OBJECTIVE: Our purpose was to measure fetal liver size in small-for-gestational-age fetuses diagnosed by ultrasonography and to determine whether the small abdominal circumference used to diagnose small for gestational age is the result of a small liver. STUDY DESIGN: Ninety-eight pregnant women who were diagnosed as having a fetus that was small for gestational age were included. All had a fetal ultrasonographic measurement of abdominal circumference <10th percentile for gestational age. Measurements were made of the length of the right lobe of the fetal liver within 2 weeks of delivery. The liver length measurements were compared with data collected from a normal population that had been previously published by the authors. The group of fetuses with liver length measurements <10th percentile for gestational age were compared with those with liver length measurements within normal limits. RESULTS: Liver length measurements were >10th percentile in 80 fetuses (82%). Eighteen fetuses (18%) had small liver lengths, and this group had significantly smaller antenatal ultrasonographic measurements of head, abdomen, and femur. They were smaller at birth with smaller placentas and they had a higher perinatal mortality rate. CONCLUSION: The small abdominal circumference measurement that is the mainstay of ultrasonographic diagnosis of small for gestational age is thought to be a reflection of fetal liver size. This study questions that assumption. The majority of small-for-gestational-age fetuses in this small study did not have small liver lengths. The small abdominal circumference measurement may reflect a reduction in size of other intra-abdominal organs, reduced amounts of fat, or possibly an elevated diaphragm because of poor lung growth.

Case-Control Studies↗

PubMed1999

TGF-beta signaling from receptors to the nucleus.

In the past three years, a novel signal transduction pathway downstream of the transforming growth factor-beta (TGF-beta) superfamily receptor serine-threonine kinases has been shown to be mediated by a family of latent transcription factors called 'Smads'. These proteins mediate a short-circuited pathway in which a set of receptor-activated Smads are phosphorylated directly by the receptor kinase and then translocate to the nucleus complexed to the common mediator, Smad4, to participate in transcriptional complexes. Smads 2 and 3 mediate signals predominantly from the TGF-beta receptors. Of these, specific roles have been ascribed to Smad3 in control of chemotaxis of neutrophils and macrophages and the inhibition of Smad3 activity by the oncogene Evi-1 suggests that it may play a role in leukemogenesis. Other data, such as the induction by the inflammatory cytokine interferon-gamma of an inhibitory Smad, Smad7, which blocks the actions of Smad3, suggest that identification of the specific gene targets of Smad proteins in immune cells will provide new insight into the mechanisms of TGF-beta action on these cells.

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↗