Antiphospholipid antibody syndrome associated with primary angiitis of the central nervous system: report of two biopsy proven cases.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
M Quintero
Publications and source records attributed to M Quintero.
Hypoxia-inducible factor 1alpha in oral cancer.
BACKGROUND: Hypoxia is a common feature of many cancers. It contributes to local and systemic tumour progression as well as potentially compromising radiotherapy and chemotherapy. Hypoxia-inducible factor 1alpha (HIF-1alpha) is an essential component in changing the transcriptional response of tumours under hypoxia. It targets the transcription of over 60 genes involved in many aspects of cancer biology including cell survival, glucose metabolism, cell invasion and angiogenesis. METHODS: In this review, we discuss the relevant literature on HIF-1alpha with specific emphasis on oral cancer. We also present some of our preliminary data on HIF-1alpha in oral cancer. RESULTS: Although there are a few conflicting reports of its prognostic significance, over expression of HIF-1alpha seems to play an adverse role in the malignant progression of head and neck cancer by facilitating the adaptation of cells to hypoxia as well as contributing to the invasive properties and angiogenesis in these tumours. CONCLUSIONS: HIF-1alpha has an important role to play in pathophysiology of oral cancer, both under normal and hypoxic conditions. The pharmacological manipulation of HIF-1alpha has marked effects on tumour growth, and it could prove to be an important target for drug therapy, both in oral cancer and in other hypoxia-dependent disease states.
Cell Hypoxia↗
Hunterian Lecture. Regulation of hypoxia-inducible factor 1 (HIF-1) by nitric oxide in oral squamous cell carcinoma.
INTRODUCTION: Hypoxia is a common feature of many cancers, contributing to tumour progression as well as potentially compromising radiotherapy and chemotherapy. Hypoxia-inducible factor 1 (HIF-1) is an essential component in changing the transcriptional response of tumours under hypoxia and it targets the transcription of many genes involved in cancer biology. Over-expression of HIF-1 has been associated with increased patient mortality in several cancer types. Regulation of HIF-1 by the signalling molecule nitric oxide (NO) is becoming increasingly recognised. METHOD: Three oral cancer cell lines were used to investigate the effects of NO synthase enzymes (NOS) on HIF-1alpha expression under both normal oxygen and hypoxic conditions. The effect of NOS inhibition was evaluated with the drug L-NMMA. Protein expression was determined with Western blotting. RESULTS & CONCLUSIONS: HIF-1alpha expression occurred following exposure of cells to 3% oxygen for 8 h in all three cell lines, and its expression was found to be dependent on NOS activity, being reduced or inhibited by L-NMMA. Although the mechanism remains to be established, NO appears to play a role in the expression of HIF-1alpha in oral cancer. The possible clinical implications of targeting HIF-1 in cancer are discussed.
Carcinoma, Squamous Cell↗
Hypoxia-inducible factor 1 (HIF-1) in cancer.
Hypoxia is a common feature of many cancers. It contributes to local and systemic tumour progression as well as potentially compromising radiotherapy and chemotherapy. Hypoxia-inducible factor 1 (HIF-1) is an essential component in changing the transcriptional response of tumours under hypoxia. It targets the transcription of over 60 genes involved in many aspects of cancer biology including cell survival, glucose metabolism, cell invasion and angiogenesis. Over-expression of HIF-1 has been associated with increased patient mortality in several cancer types including breast, stomach, cervical, endometrial and ovarian cancers. The pharmacological manipulation of HIF-1 has marked effects on tumour growth, and it could prove to be an important target for drug therapy, both in cancer and in other hypoxia-dependent disease states.
Cell Hypoxia↗
Opposite effects of low and high doses of arginine on glutamate-induced nitric oxide formation in rat substantia nigra.
L-arginine is a very versatile amino acid that is involved in many important physiological processes such as protein, nitric oxide (NO), agmatine, putrescine, urea, L-ornithine or creatine synthesis and is essential for posttranslational arginylation of protein. The present study was designed to evaluate in vivo the effect of L-arginine on NO production in substantia nigra. In vivo spectroscopic and voltammetric studies were addressed in rats to record modifications in methemoglobin and NO levels under glutamate stimulation. Results showed that, under physiological L-arginine extracellular concentration, the intranigral infusion of glutamate produced an increase in NO levels. When a low dose of L-arginine was co-infused with glutamate, a persistent and higher increase in NO levels was observed. The co-infusion of glutamate with a moderate dose of L-arginine induced drastic and persistent NO production. It was also observed that high doses of either L-arginine or D-arginine inhibit NO production. Subsequently, these data show that L-arginine and D-arginine are involved in a mechanism that inhibits NO production.
Animals↗
Prostaglandin E(2) regulates the level and stability of cyclooxygenase-2 mRNA through activation of p38 mitogen-activated protein kinase in interleukin-1 beta-treated human synovial fibroblasts.
The p38 MAPK mediates transcriptional and post-transcriptional control of cyclooxygenase-2 (COX-2) mRNA following interleukin-1(IL-1)/lipopolysaccharide cellular activation. We explored a positive feedback, prostaglandin E(2) (PGE(2))-dependent stabilization of COX-2 mRNA mediated by the p38 MAPK cascade in IL-1 beta-stimulated human synovial fibroblasts. We observed a rapid (5 min), massive (>30-fold), and sustained (>48 h) increase in COX-2 mRNA, protein, and PGE(2) release following a recombinant human (rh) IL-1 beta signal that was inhibited by NS-398, a COX-2 inhibitor, and SB202190, a selective, cell-permeable p38 MAPK inhibitor. PGE(2) completely reversed NS-398-mediated inhibition but not SB202190-dependent inhibition. The eicosanoid didn't potentiate IL-1 beta-induced COX-2 expression nor did it activate COX-2 gene expression in quiescent cells. Transfection experiments with a human COX-2 promoter construct revealed a minor element of p38 MAPK-dependent transcriptional control after IL-1 beta stimulation. p38 MAPK synergized with the cAMP/cAMP-dependent protein kinase cascade to transactivate the COX-2 promoter. When human synovial fibroblasts were activated with rhIL-1 beta for 3-4 h (steady state) followed by washout, the elevated levels of COX-2 mRNA declined rapidly (<2 h) to control levels. If PGE(2), unlike EP2/3 agonists butaprost and sulprostone, was added to fresh medium, COX-2 mRNA levels remained elevated for up to 16 h. SB202190 or anti-PGE(2) monoclonal antibody compromised the stabilization of COX-2 mRNA by PGE(2). Deletion analysis using transfected chimeric luciferase-COX-2 mRNA 3'-untranslated region reporter constructs revealed that IL-1 beta increased reporter gene mRNA stability and translation via AU-containing distal regions of the untranslated region. This response was mediated entirely by a PGE(2)/p38 MAPK-dependent process. We conclude that the magnitude and duration of the induction of COX-2 mRNA, protein, and PGE(2) release by rhIL-1 beta is primarily the result of PGE(2)-dependent stabilization of COX-2 mRNA and stimulation of translation, a process involving a positive feedback loop mediated by the EP4 receptor and the downstream kinases p38 MAPK and, perhaps, cAMP-dependent protein kinase.
Base Sequence↗
[Doppler ultrasound in type I diabetes: preliminary results].
PURPOSE: To study the differences of blood flow in type I diabetes patients using a color Doppler ultrasound. MATERIAL AND METHODS: We measured the systolic peak velocity (Vmax), diastolic velocity (Vmin) as well as the resistance index in the central retinal artery (CRA) and in the ophthalmic artery (OA) using a color Doppler ultrasound in 40 diabetic patients. We classified the patients according to the duration of diabetes, which ranged from 1 to 28 years. and whether retinopathy was present. We compared the results against those obtained in the 40 control subjects without vascular pathology. RESULTS: When the results of the two groups were compared, we found that no decrease was observed in the CRA flow rate in diabetics without retinopathy, however there was a significant decrease in flow velocity in patients with initial (p<0.05), moderate (p<0.001) or proliferative retinopathy (p<0.05). The ophthalmic artery presents an increase in the vascular resistance in diabetics with proliferative retinopathy. As the time of diabetes increases, there is a decrease in the blood flow in CRA and an increase in resistance in the OA. CONCLUSIONS: The Doppler ultrasound is a non-invasive technique which allows us to perform a hemodynamic study of the orbital vessels. It is essential to understand the correlation between blood flow velocity and the severity of retinopathy in diabetes patients as it manifests the relationship between the velocity of the blood flow with the severity of the retinopathy and that there is a direct relationship with the evolution of the diabetes and the flood flow velocity.
Adolescent↗
Granulocyte-macrophage colony stimulating factor activates proteoglycan, type II collagen, and cAMP production by rat articular chondrocytes through specific binding sites.
OBJECTIVE: To evaluate the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on rat articular chondrocyte (AC) with respect to DNA synthesis, collagen type II and proteoglycan (PG) synthesis and expression, and cAMP production; to examine these cells for the presence of GM-CSF-specific binding sites; and to study their regulation by growth factors and cytokines. METHODS: First passage monolayers of rat AC were incubated with various concentrations of recombinant human GM-CSF, and then [3H]-thymidine, [3H]-proline, and [35S]SO4 incorporation and cAMP production were measured. The density of GM-CSF-specific binding sites, the effects of growth factors and cytokines on receptor density, and the activation of certain post-receptor signaling pathways were also examined by labeling the cell monolayers with [125I]-GM-CSF. RESULTS: GM-CSF (6-100 U/ml) inhibited (30%) [3H]-thymidine incorporation into DNA, and, in contrast, stimulated up to 3.6- and 2-fold [35S]SO4 and [3H]-proline incorporation into glycosaminoglycan side chains and collagen molecules, respectively. GM-CSF also increased aggrecan and type II collagen (Coll II) transcripts by 2- to 3-fold, respectively. These effects were associated with a concentration-dependent increase in cAMP production. A single class of high affinity (Kd = 98 pM; Bmax = 7.08 pM/microg DNA) binding sites of about 220 kDa were found. The [125I]-GM-CSF binding to the cells was slightly increased with phorbol 12-myristate 13-acetate (PMA), insulin-like growth factor-I, platelet derived growth factor, basic fibroblast growth factor, and tumor necrosis factor-alpha, and decreased with pertussis toxin, cholera toxin, and interleukin-1beta. CONCLUSION: These results suggest that GM-CSF may play a role in the regulation of chondrocyte metabolism as an anabolic agent and may stimulate cartilage healing under pathological conditions.
Animals↗
Action of antidepressant drugs on maternal stress-induced hypoactivity in female rats.
It has been reported that rats forced to swim in a restricted space assume, after initial frenzied attempts to escape, an immobile posture. Porsolt et al. referred to this phenomenon as "behavioral despair", an animal model of depression. Prenatal stress induces an increase of behavioral depression in adult female offspring. This study presents new evidence supporting the hypothesis that maternal stress during gestation increases the risk of depression in the offspring since immobility time was modified by antidepressant drugs (tricyclics and an atypical antidepressant). In rats, amitriptyline (5 mg/kg), imipramine (5 mg/kg) and nomifensine (1 mg/kg) decreased the immobility time in Porsolt test in offspring of mothers stressed during gestation. Moreover, increasing doses of amitriptyline (1, 5, 25 and 40 mg/kg) reduced depression in the forced swimming test in dose-dependent manner.
Amitriptyline↗
[Cytogenetic findings in ductal carcinoma of the breast].
Breast cancer in women is an important medical problem with public health and social implications. In spite of its great clinical importance, little is known about the cytogenetic features of breast carcinomas. Chromosomal abnormalities in some malignant tumors have been used for diagnosis and prognosis or for localizing genes involved in the pathology malignancies. In this report, we present the chromosomal abnormalities found in 32 primary breast ductal carcinomas. The tumor samples were studied using the technique for short-term culturing and cytogenetic analysis with G-banding. Only one tumor with normal karyotype was observed. Thirty one (99%) of the tumors had chromosomal abnormalities including 21 (65.6%) in which chromosome 1 was involved (trisomy, monosomy or structural abnormalities of the type t(1q;2p) and del(1q42). Other recurrent anomalies such as del(12p); del 4(p); +7; +8; -7; -3; were observed. The significance of these findings and their role in tumorogenesis will become more evident with close follow-up of women who have tumors with an abnormal karyotype.
Adult↗
Interferon-alpha in patients with chronic hepatitis C and normal transaminase levels.
OBJECTIVE: to assess the response to interferon-alpha therapy in patients with chronic hepatitis C and normal alanine transferase levels. METHODS: 16 patients with normal transaminases (group A) and 36 patients with elevated ALT levels (group B) were treated with interferon-alpha-2b at a dose of 3 MU for 6 months. The biochemical, virological (HCV RNA in serum, liver and peripheral blood mononuclear cells) and histological responses were analyzed. RESULTS: no significant differences were observed between the two groups in age, sex, parenteral or sporadic transmission, hepatic lesion, Knodell index or HCV genotype, except for the higher proportion of women in group A. We found no significant differences between the groups in rates of patients with normal ALT in the follow-up period (6 months post-interferon, group A 44%, group B 17%) or in post-therapy negativization of HCV RNA levels (group A 31%, group B 17%). In 7 patients (44%) in group A, ALT remained normal throughout the study, whereas in the rest of the patients we observed some elevation during or after interferon treatment. Post-therapy mean Knodell index was 6 +/- 3 in group A versus 9 +/- 4 in group B (p < 0.05). CONCLUSIONS: the response to interferon was similar in patients with normal or elevated transaminases.
Adult↗
Basal and induced nitric oxide and cGMP productions are decreased in senescent cultured rat articular chondrocytes.
The effects of interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and lipopolysaccharide (LPS) on the productions of nitric oxide (NO) and cGMP by cultured articular chondrocyte (AC) monolayers from 1-, 8- and 18-month old male Wistar rats were studied. It was found that basal NO and cGMP productions decrease with the age of animals. The productions were more than 2-fold greater in cells from 1-month old rats then in cells from older animals. IL-1, TNF-alpha, and LPS stimulated all three types of cells to produce NO and cGMP in a time- and concentration-dependent manner. Although the cells from young animals produced more NO per microg DNA, the older counterparts were more sensitive to these agents since they produced more NO upon stimulation then the corresponding non-stimulated controls. At the concentration of 10(-3) M, the nitric oxide synthase (NOS) inhibitor, Ng-monomethyl-L-arginine (L-NMA), blocked, although incompletely, both the basal and stimulated NO and cGMP productions in cells from the 1 and 8-month old rats and only induced productions in 18-month old counterparts. These results show a decreased capacity of unstimulated- and stimulated-AC from old rats to produce NO and cGMP in culture, which may affect the ageing cells in some yet unknown way.
Aging↗
[Prenatal diagnosis. I: Prenatal diagnosis program at the Medical Genetics Unit of the Universidad de Zulia, Maracaibo, Venezuela].
The Prenatal Diagnosis Program of the Medical Genetic Unit of University of Zulia has the following objectives: Identification of Genetic Risk Factors (GRF) in those couples who attend to the Prenatal Genetic Clinic, application of different prenatal diagnostic procedures (PDP), and providing adequate genetic counseling. The goal of this paper is to show preliminary results obtained between January 1993 and December 1996. Three hundred and twenty one pregnant women were analyzed by determining the GRF and taking into account the genetic clinical history. The GRF analyzed were: Advanced maternal age (AMA), congenital malformation history (CMH), previous child with chromosomic anomalies (PCCA), defects of neural tube history (DNTH), congenital heart disease history (CHDH), any parent carrier of chromosomic anomaly (PCA), habitual abortion (HA), abnormal fetal echography (AFE), altered maternal serum levels of alpha-feto-protein (AMSAFP) and OTHERS: exposure to teratogenic agents, history of Mendelian diseases, maternal systemic diseases and anxiety in the mother or in her partner. The PDP was designed according to the GRF, which included fetal echography (FE), fetal echocardiography (FEc), amniocentesis (AMN), chordocentesis (CCT) and AMSAFP. Results showed that 58.4% of the expectant mothers asked for counseling during the 2nd trimester, 70% of the total showed only one GRF, and AMA was the most frequent GRF found (40.3%), followed by PCCA, AFE, CHDH, HA, DNTH, PCA, and OTHERS in that order. The specific PDP applied to the identified GRF allowed a health evaluation of the fetus. The GRF identification gave the opportunity of establishing a Prenatal Diagnostic Program producing a response to the couple's needs and showed the utility of an integral and multidisciplinary management directed to any expecting mother in order to identify any high GRF.
Abortion, Habitual↗
[Prenatal diagnosis. II. Importance of ultrasonographic markers in prenatal diagnosis of chromosome abnormalities].
The Medical Genetic Unit of the University of Zulia (MGUUZ) has developed a Prenatal Diagnosis Program (PDP) since January-1993, in which Genetic Risk Factors are determined in couples who request prenatal genetic counseling. In this program, different prenatal diagnostic procedures are performed to detect congenital defects during intrauterine life. One of these procedures is the Fetal Sonogram (FS). FS is a non invasive technique which permits the prenatal diagnosis of many genetic dysmorphic syndromes. Through the search of abnormal specific characteristics in the fetus, chromosomopathies may be suspected. These findings are named "Echosonographic Markers of Chromosomal Abnormalities" (EMCA). During three years (January-1993 to December-1996), patients attended in the PDP included 321 pregnant women in which 312 FS were performed. Abnormal outcomes were 22 (17 with isolated congenital malformations and 5 with EMCA). Only one fetus with chromosome abnormality (46,XX21q-) could not be detected by FS. The goals of this paper are: 1) to report 5 patients with sonographic markers suggestive of chromosomal abnormalities and 2) to show the FS usefulness in prenatal diagnosis of chromosompathies. We conclude that, in the search of the EMCA the FS should be offered systematically to all pregnant women without recognizable genetic risk. They are the main group with optimal reproductive age and in consequence, with the possibility of having a relatively major number of conception outcomes with congenital defects, with or without chromosomic etiology. The majority of those defects can be detected by FS and could allow us to select the patients in which the use of an invasive prenatal diagnostic procedure could be justified.
Adolescent↗
The mechanism of inhibition of endothelin-1-induced stimulation of DNA synthesis in rat articular chondrocytes.
Endothelin-1 (ET-1) is a potent mitogen for rat articular chondrocytes (AC) in short term culture (24 h). Prolonged incubation (72 h) of AC with ET-1 resulted in inhibition of [3H]thymidine incorporation. This inhibition seemed to be mediated by prostaglandins (PGs) released in response to ET-1, since indomethacin (INDO) enhanced ET-1-induced [3H]thymidine incorporation. In agreement with this hypothesis, exogenous prostaglandins (PGE2, PGF2alpha and TxB2) blocked all basal, ET-1-induced and ET-1 induced-INDO-enhanced [3H]thymidine incorporation and ET-1 stimulated PGE2 release in a time and concentration-dependent manner. INDO also blocked cGMP production and 6-anilino-5,8-quinolinedione, a relatively specific inhibitor of cGMP formation, enhanced the stimulation and suppressed the inhibition of ET-1-induced DNA synthesis. In addition, 8-bromo-cGMP, an analogue of cGMP, blocked at all time periods studied, both basal and ET-1-induced incorporations of [3H]thymidine. Thus, PGs produced in response to ET-1 counteract the ET-1-induced stimulation of [3H]thymidine incorporation into rat AC by increasing cGMP production.
Aminoquinolines↗
The mechanism of inhibition of DNA synthesis in articular chondrocytes from young and old rats by nitric oxide.
The mechanism by which nitric oxide inhibits the incorporation of [3H]thymidine into rat articular chondrocytes (AC) in culture was studied. First-passage articular chondrocytes, isolated by collagenase digestion of cartilage fragments from humeral and femoral heads of 1- and 18-month-old rats, were used in all experiments. NO-generating compounds, isosorbide dinitrate or sodium nitoprusside, inhibited the incorporation of [3H]thymidine and the release of prostaglandin E2 (PGE2) and stimulated cyclic guanosine monophosphate (cGMP) production by rat AC monolayers in a concentration-dependent manner. The cells from old rats were much less sensitive to NO donors and also produced less PGE2 and cGMP. Blocking the production of endogenous NO with NG-monomethyl-L-arginine (L-NMA), an inhibitor of NO synthase, stimulated DNA synthesis. cGMP was found to be a key mediator of the inhibition of DNA synthesis by NO donors in rat AC. 6-Anilino-5,8-quinolinedione (LY83583), an inhibitor of NO-dependent cGMP release, stimulated [3H]-thymidine incorporation, whereas the cGMP analog, 8- bromo-cGMP, inhibited L-NMA-induced or LY83583-induced stimulation of [3H]thymidine incorporation. NO donors blocked the stimulation of DNA synthesis induced by L-NMA and only marginally blocked that of LY83583. Indomethacin had no effect on the inhibition of DNA synthesis by NO or 8-bromo-cGMP. These results show that NO donors induce inhibition of DNA synthesis probably by elevating cGMP. The relative insensitivity of senescent cells to NO donors may be due, at least in part, to their decreased capacity to produce cGMP.
Aging↗
Ultrastructural study of chondrocytes from fibrillated and non-fibrillated human osteoarthritic cartilage.
Knee articular cartilage samples obtained by arthroscopy from ten patients with well defined knee osteoarthritis (OA) were studied by light and transmission electron microscopy. The morphological phenotype of cells from fibrillated and non-fibrillated regions of OA cartilage was characterized. Three different cell sub-populations were identified. Type 1 cells were found in the superficial and upper middle zones and comprised single chondrocytes and cells organized in aggregates or "clones' that showed a typical chondrocyte phenotype. Type 2 cells displayed a secretory phenotype. Type 3 cells comprised chondrocytes undergoing a degenerative process and were distributed throughout all zones of the cartilage. Changes in the cytoskeletal arrangement, presence of abundant filopodia, peripheral localization of centrioles, and presence of primary cilia were found in many chondrocytes suggesting that they are active motile cells. No mitotic figures were found in this study. Morphometrical analysis was performed to determine the total number of cells and the number of chondrocytes per lacuna in the superficial and upper middle zones of fibrillated and non-fibrillated OA cartilage. There were no statistically significant differences in the total number of cells. In contrast, fibrillated OA cartilage contained a statistically significantly higher percentage of lacunae containing four of more chondrocytes than non-fibrillated OA cartilage samples. The absence of mitotic figures and the presence of motile elements in many chondrocytes raise the possibility that cell aggregates or "clones' in damaged OA cartilage originate by an active process of cell migration rather than by cellular division.
Aged↗
Variability in the cell phenotype of aggregates or "clones" of human osteoarthritic cartilage. A case report.
Human samples of articular cartilage from the knee of a clinically classified osteoarthritic patient, assessed by arthroscopy as part of the surgical treatment was studied by light and transmission electron microscopy. This particular case differed from others already reported in the variability of cell phenotype within the aggregates or "clones" frequently present in the osteoarthritic cartilage. The most common morphology of "clonal" cells forming the aggregates were large and rounded with an euchromatic nucleus. The cytoplasm was characterized by the presence of alternately clear and dense sites. At the ultrastructural level it was seen that the clear sites were formed by disrupted intermediates filaments and small particles, and that the dense sites were constituted by the segregation of different organelles of the chondrocytes. In addition, there were atypical aggregates composed only by secretory cells or by degenerating chondrocytes. Furthermore, a complex structure consisting of a very large cell inside a giant lacunae delimited by electron-dense material with small vesicles is described as a novel finding. The variability in the chondrocyte phenotype of the aggregates described here could be an indication of a better prognosis; nevertheless, the follow-up of the evolution of this patient is needed in order to know the final outcome.
Cartilage, Articular↗