PubMed Health⌕ Search

Biomedical subjects

Sergio A Jimenez

Publications and source records attributed to Sergio A Jimenez.

At least 19 recordsLinked to original sources
PubMed2006

A cohort study of cancer incidence in systemic sclerosis.

OBJECTIVE: To describe the incidence of cancer in a large cohort of patients with systemic sclerosis (SSc) and compare it to the Surveillance Epidemiology and End Results (SEER) cancer registries. METHODS: Cancer risk in a large cohort of patients with SSc followed at our institution was assessed. A total of 769 patients with SSc who were followed between 1987 and 2002 were screened for the development of cancer. Standardized incidence ratios (SIR) for malignancies identified after diagnosis of SSc were calculated using the SEER cancer registries and stratified by sex. RESULTS: Ninety malignancies were diagnosed in 769 patients followed at our institution between 1987 and 2002. Sixty-two malignancies were diagnosed after diagnosis of SSc in a total of 3,775 patient years of followup. Twenty-eight malignancies were diagnosed prior to diagnosis of SSc. The SIR for all cancers diagnosed after diagnosis of SSc was 1.55 (1.16-1.93). The SIR for esophageal cancer was 15.9 (4.2-27.6) while that of oropharyngeal cancer was 9.63 (2.97-16.29). CONCLUSION: We identified an overall increase in the incidence of cancer in a cohort of patients with SSc compared to the general population, with statistically significant differences in the incidence of esophageal and oropharyngeal cancers.

Cohort Studies↗
PubMed2006

Acute myocardial infarction in systemic sclerosis patients: a case series.

To characterize the clinical manifestations of patients with systemic sclerosis who develop a myocardial infarction (MI), a retrospective review of the medical records of all patients who were admitted to our institution between 1982 and 2002 and had the dual diagnosis of systemic sclerosis and an acute MI was done. From 1,009 systemic sclerosis hospital admissions, 11 (1.09%) were for an acute MI. Three of these patients had normal coronaries, and instead of wall motion abnormalities, left ventricular hypertrophy was the predominant finding of an echocardiography. The odds ratio of finding normal coronaries in systemic sclerosis vs the general population who develops an acute MI is 33.89 (14.08-81.39). Seven of our patients had an elevated creatinine level on presentation. Acute MI is an uncommon manifestation in systemic sclerosis patients. Normal coronaries are seen more commonly in these patients as compared to the general population, while vascular, gastrointestinal, and renal involvement is prevalent in these patients.

Coronary Artery Disease↗
PubMed2006

Morbidity and mortality of patients diagnosed with systemic sclerosis after the age of 75: a nested case-control study.

This study aims to characterize the clinical features of a cohort of patients diagnosed with systemic sclerosis (SSc) after the age of 75 and compare them to a group diagnosed at a younger age. We record the review of 769 patients diagnosed with SSc over the past 16 years. Utilizing a nested case-control model, we compare demographics, disease severity, morbidity, and mortality data of all patients diagnosed after the age of 75 to sex- and disease-type-matched, randomly selected group of patients diagnosed with SSc before the age of 60. Twelve patients were diagnosed with SSc after the age of 75, seven with the diffuse, and five with the limited form. It took longer to diagnose SSc in the older patients, and comparison of disease severity revealed a worse pulmonary picture and a more frequent development of malignancy in the older patients as compared with the younger ones. During a mean follow-up of 36.2 months, our cohort of patients did not have worsening in their disease severity, though 6 months after the last follow-up, six patients died. We conclude that a diagnosis of SSc at an older age appears to be a poor prognostic indicator related to both disease severity and comorbidities. A higher clinical suspicion will lead to an earlier diagnosis and a potential decrease in morbidity and mortality.

Aged↗
PubMed2006

Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.

OBJECTIVES: To review the clinical and laboratory features of 12 cases of nephrogenic fibrosing dermopathy (NFD) studied at our institution and of 70 previously described cases in the literature. METHODS: Clinical evaluation and laboratory studies of 12 patients with NFD associated with chronic hemodialysis or peritoneal dialysis for end-stage renal disease and a review of 23 previous publications describing 70 patients with this disease. RESULTS: Eleven patients undergoing chronic hemodialysis and 1 patient undergoing chronic peritoneal dialysis for end-stage renal failure developed a severe and progressive cutaneous fibrotic process with woody induration of legs, thighs, hands, and forearms, and severe loss of motion and flexion contractures in multiple joints. Several patients displayed systemic involvement including fibrosis of muscles, myocardium, and lungs and marked elevations of the erythrocyte sedimentation rate and/or C-reactive protein. Three patients died within 2 years of symptom onset. A review of previously published reports of this disorder confirmed the presence of systemic involvement and a poor prognosis with a high mortality rate. CONCLUSIONS: NFD is a severe and usually progressive systemic fibrotic disease affecting the dermis, subcutaneous fascia, and striated muscles. It also appears that the disease can cause fibrosis of lungs, myocardium, and other organs.

Adult↗
PubMed2006

The role of allograft inflammatory factor 1 in systemic sclerosis.

PURPOSE OF REVIEW: The aim of this article is to review studies which support the hypothesis that allograft inflammatory factor-1, a protein initially identified in chronically rejected cardiac allografts, may be involved in the pathogenesis of the progressive fibroproliferative vasculopathy which is a hallmark of systemic sclerosis. RECENT FINDINGS: Recent findings demonstrated elevated allograft inflammatory factor-1 expression both in systemic sclerosis affected tissues and peripheral blood mononuclear cells. A detailed immunohistopathologic study examined the tissue and cellular localization of the protein in affected systemic sclerosis tissues and demonstrated its expression in the endothelium of dermal and pulmonary vessels, in the pulmonary parenchyma, and in relevant inflammatory cells including T cells and macrophages. Furthermore, functional studies showed specific allograft inflammatory factor-1 isoform expression stimulation by transforming growth factor-beta. SUMMARY: This review summarizes recent findings suggesting that allograft inflammatory factor-1 may play an important role in systemic sclerosis vasculopathy and provides supporting evidence to consider the molecule as a novel therapeutic target.

Biomarkers↗
PubMed2005

Single amino acid substitutions in the C-terminus of collagen II alter its affinity for collagen IX.

The structural integrity of cartilage depends on the presence of extracellular matrices (ECM) formed by heterotypic fibrils composed of collagen II, collagen IX, and collagen XI. The formation of these fibrils depends on the site-specific binding between relatively small regions of interacting collagen molecules. Single amino acid substitutions in collagen II change the physicochemical and structural characteristics of those sites, thereby leading to an alteration of intermolecular collagen II/collagen IX interaction. Employing a biosensor to study interactions between R75C, R789C or G853E collagen II mutants and collagen IX, we demonstrated significant changes in the binding affinities. Moreover, analyses of computer models representing mutation sites defined exact changes in physicochemical characteristics of collagen II mutants. Our study shows that changes in collagen II/collagen IX affinity could represent one of the steps in a cascade of changes occurring in the ECM of cartilage as a result of single amino acid substitutions in collagen II.

Amino Acid Substitution↗
PubMed2005

Statins and the vasculopathy of systemic sclerosis: potential therapeutic agents?

It has been postulated that endothelial cell injury is the initiating event in the pathogenesis of systemic sclerosis, causing attraction, attachment, migration and infiltration of activated T-cells and subsequent production of cytokines and growth factors. As a result of the action of these cytokines and growth factors, chemoattraction of fibroblasts into the vessel wall and transdifferentiation of resident fibroblasts and smooth muscle cells into myofibroblasts occur leading to fibrosis and exaggerated collagen deposition in the vessel wall. To date, the therapeutic options for the vasculopathy of systemic sclerosis have been limited to drugs that cause vasodilation and inhibit platelet aggregation and only a few agents have shown vascular remodeling effects. Therapeutic agents that could potentially modify the course of this vasculopathy may have a disease-modifying effect, particularly, if instituted in the early stages of the disease. Extensive recent studies have shown that statins display numerous effects independent of their well-established lipid-lowering effect that may be of potential benefit in preventing vascular injury and ischemic vascular events. Here, we review the current literature, which suggests that statins may have a modifying effect on the vasculopathy of systemic sclerosis.

Animals↗
PubMed2005

Demonstration of autoimmunity in the tight skin-2 mouse: a model for scleroderma.

The tight skin-2 (Tsk2/+) mouse has been proposed as an animal model of systemic sclerosis (SSc) because this animal exhibits increased collagen synthesis and accumulation in the dermis. The Tsk2/+ mouse also has been reported to have a mononuclear cell infiltrate in the dermis; however, to date no evidence of autoimmunity has been described in this animal model. We report here that Tsk2/+ mice harbor numerous autoantibodies in their plasma including some, which are similar to those, present in SSc patients. Immunofluorescence with HEp-2 cells revealed the presence of anti-nuclear Abs (ANAs) in the plasma of 92% of the Tsk2/+ mice. In contrast, <5% of cage-mated CAST/ei mice had a positive ANA and none of the C3H/HeJ age-matched controls were positive. Homogenous, speckled, rim, nucleolar, centromere as well as combinations of these patterns were observed. The proportion of Tsk2/+ animals with a positive ANA increased slightly with age. ELISAs showed that 93% of the Tsk2/+ animals were positive for anti-Scl70, 82% for anti-centromere, 5% for anti-RNP/Sm, and none were positive for anti-RNA-polymerase II Abs. Indirect immunofluorescence with Crithidia luciliae and ELISA for anti-dsDNA Abs showed that 76% of Tsk2/+ mice were positive for this autoantibody. The high frequency of anti-Scl70 and anti-centromere autoantibodies indicates that Tsk2/+ mice display some humoral immune alterations which are similar to those found in patients with SSc. However, the Tsk2/+ mice also develop autoantibodies to dsDNA and a majority of the mice develop multiple autoantibody specificities (anti-Scl70, anti-CENP-B, and anti-dsDNA) indicating that the mouse may be a useful model to study autoimmunity in a wider spectrum of connective tissue diseases.

Age Factors↗
PubMed2005

Regulation of the human Sox9 promoter by the CCAAT-binding factor.

Sox9 is an essential transcriptional regulator of chondrogenesis and chondrocyte-specific gene expression; however, the identity and function of transcription factors that regulate Sox9 gene expression are not well understood. Here, we have undertaken an analysis of the human Sox9 proximal promoter region in an effort to elucidate the function and identity of transcriptional regulators that are important for controlling Sox9 gene transcription. By transfection analysis, we show that elements residing between -256 bp and +67 bp are important for the overall level of Sox9 promoter activity. Previously, two CCAAT boxes were identified in the Sox9 mouse and human promoters (position -60 bp and -100 bp) by sequence analysis (Kanai, Y., Koopman, P., 1999. Structural and functional characterization of the mouse Sox9 promoter: implications for campomelic dysplasia. Hum. Mol. Genet., 8: 691-696). We demonstrate by electrophoretic mobility shift (EMSA) competition and supershift assays that the CCAAT-binding factor (CBF) can form a complex with both Sox9 CCAAT boxes in nuclear extracts from multiple cell lines. Transfection of human Sox9 promoter-luciferase constructs containing mutated or deleted CCAAT boxes demonstrated that both CCAAT boxes are important for Sox9 promoter activity in chondrogenic cell lines and primary chondrocytes. Chromatin immunoprecipitation (ChIP) experiments demonstrated that CBF interacts with the Sox9 promoter in vivo. Together, these studies show that the Sox9 promoter is regulated by CBF through its interaction with two functional CCAAT boxes.

Animals↗
PubMed2005

Microchimerism and systemic sclerosis.

PURPOSE OF REVIEW: Although 6 years have elapsed since the initial report describing the presence of microchimeric cells in affected tissues from patients with systemic sclerosis, a mechanism by which these cells might contribute to the pathogenesis of the disease is still unknown. This article reviews the published literature related to the possible role of microchimeric cells in the pathogenesis of systemic sclerosis. RECENT FINDINGS: Numerous studies have reported the identification or quantification of microchimeric cells in the peripheral blood or tissues from systemic sclerosis patients; however, only one study to date has investigated their function. Recent investigations have demonstrated microchimeric cells in the clinically uninvolved tissues from patients with systemic sclerosis, suggesting that these cells are present in early disease. However, after the identification of microchimeric cells in blood and tissues of patients with systemic sclerosis, these cells have been found in organs affected by nonautoimmune conditions. These cells are also commonly detected in the peripheral blood of healthy people. SUMMARY: These observations have raised questions about whether microchimeric cells are responsible for the pathologic events in systemic sclerosis or are merely remnants of a pregnancy remote in time, and it has been suggested that they might also have beneficial effects for the host.

Adult↗
PubMed2005

Increased incidence of carcinoma of the tongue in patients with systemic sclerosis.

OBJECTIVE: To describe the incidence of carcinoma of the tongue in a large cohort of patients with systemic sclerosis (SSc). METHODS: In total, 769 patients with SSc were prospectively followed over 16 years for the development of cancer. Patients with a diagnosis of carcinoma of the tongue were identified to determine the incidence of this cancer in SSc. The results were compared to the incidence of tongue cancer in the SEER cancer registries. RESULTS: A total of 3775 patient-years of followup of 769 patients with SSc (392 diffuse cutaneous, 377 limited cutaneous) prospectively evaluated for the occurrence of cancer disclosed 9 patients who were diagnosed with oral cavity and pharyngeal carcinomas. Six of these patients had squamous cell carcinoma of the tongue. One of these had both pharyngeal and tongue squamous cell carcinomas within a 4-year period, and another had 3 separate squamous cell carcinomas of the tongue. The standardized incidence ratio of squamous cell carcinoma of the tongue observed in this cohort of patients with SSc was 25-fold higher than that expected in an age adjusted population from the SEER cancer registries. All patients with SSc identified within this cohort with oral cavity carcinomas had the diffuse subset of the disease. CONCLUSION: There is a highly significant increase in the incidence of squamous cell carcinoma of the tongue in patients with SSc. A remarkable observation was that all patients within this cohort who developed oral cancer had the diffuse subset of SSc. This suggests a relationship between the etiology or pathogenesis of the diffuse form of SSc and development of squamous cell carcinoma of the tongue in this group of patients.

Aged↗
PubMed2004

Thermostability gradient in the collagen triple helix reveals its multi-domain structure.

A triple-helical conformation and stability at physiological temperature are critical for the mechanical and biological functions of the fibril-forming collagens. Here, we characterized the role of consecutive domains of collagen II in stabilizing the triple helix. Analysis of melting temperatures of genetically engineered collagen-like proteins consisting of tandem repeats of the D1, D2, D3 or D4 collagen II periods revealed the presence of a gradient of thermostability along the collagen molecule with thermolabile N-terminal domains and thermostable C-terminal domains. These results imply a multi-domain character of the collagen triple helix. Assays of thermostabilities of the Arg75Cys and Arg789Cys collagen II mutants suggest that, in contrast to the thermostable domains, the thermolabile domains are able to accommodate amino acid substitutions without altering the thermostability of the entire collagen molecule.

Blotting, Western↗
PubMed2004

B-Myb acts as a repressor of human COL1A1 collagen gene expression by interacting with Sp1 and CBF factors in scleroderma fibroblasts.

We investigated the role of B-Myb, a cell-cycle-regulated transcription factor, in the expression of the alpha1 (I) pro-collagen gene (COL1A1) in scleroderma fibroblasts. Scleroderma or SSc (systemic sclerosis) is a fibrotic disease characterized by excessive production of extracellular matrix components, especially type I collagen. Northern-blot analysis showed an inverse relationship between COL1A1 mRNA expression and that of B-Myb during exponential cell growth and during quiescence in human SSc fibroblasts. Overexpression of B-Myb in SSc fibroblasts was correlated with decreased COL1A1 mRNA expression. Transient transfections localized the down-regulatory effect of B-Myb to a region containing the proximal 174 bp of the COL1A1 promoter that does not contain B-Myb consensus binding sites. Gel-shift analysis, using nuclear extracts from normal and SSc fibroblasts transfected with B-Myb, showed no differences in DNA-protein complex formation when compared with the nuclear extracts from mock-transfected cells. However, we found that B-Myb decreases Sp1 (specificity protein 1) and CBF (CCAAT-binding factor) binding for their specific sites localized in the 174 bp COL1A1 proximal promoter. These results were also confirmed using B-Myb-immunodepleted nuclear extracts. Furthermore, immunoprecipitation assays using SSc nuclear extracts demonstrated a physical interaction of B-Myb with Sp1 and CBF transcription factors, and also an interaction between Sp1 and CBF. In addition, by employing full-length or deleted B-Myb cDNA construct, we found that B-Myb down-regulates the COL1A1 proximal promoter through its C-terminal domain. Thus these results suggest that B-Myb may be an important factor in the pathway(s) regulating collagen production in SSc fibroblasts.

Binding Sites↗
PubMed2004

Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy).

Nephrogenic fibrosing dermopathy (NFD), a newly recognized scleroderma-like disease, was originally described as a purely cutaneous disorder. More widespread involvement, including fibrosis of pulmonary and cardiac tissues, has been documented only recently, and it has been suggested that a more appropriate designation is dialysis-associated systemic fibrosis. We report five cases of this novel disorder, spanning a spectrum of primarily skin to primarily muscle involvement. Clinical, radiological, electrophysiological, and pathological studies revealed moderate to severe fibrosis of striated muscles. All patients had end-stage renal failure on chronic dialysis, subacute to chronic hardening of the skin and muscles, restriction of limb movements with joint contractures, but normal to only mildly weak muscle strength. Limitation of movements was caused predominantly by skin tightness and induration, and by joint contractures rather than muscle weakness. Computerized tomography showed fibrosis of the fascia and muscles in the most severely affected patients, and electromyography showed mild to severe myopathic changes. Histopathology of affected muscles revealed a spectrum of mild to severe fibrosis, degenerating fibers, and chronic inflammatory cells. These results further support the contention that NFD is not a purely cutaneous disease, but is part of a larger systemic fibrotic process that may involve muscles.

Adult↗
PubMed2004

Hypoxia inducible factor-1 alpha expression in human normal and osteoarthritic chondrocytes.

BACKGROUND: Articular cartilage is a unique tissue in that it is avascular with its nutrition and oxygen supply being dependent on the diffusion of solutes through the synovial fluid and to and from the subchondral bone. The oxygen levels in articular cartilage, therefore, are assumed to be low. Oxygen is an important modulator of gene expression and this regulation occurs largely through the activation of the transcriptional complex hypoxia-inducible factor-1 (HIF-1). However, little is known about how articular cartilage regulates genes in response to O(2)tension and whether this regulation occurs through HIF-1. AIM: The aim of this study was to investigate the expression profile of HIF-1alpha in normal and osteoarthritic (OA) chondrocytes under normoxic and hypoxic conditions, and in response to treatment with tumor necrosis factor alpha (TNFalpha). METHODS: Articular chondrocytes from human normal and OA knee cartilage were isolated and cultured in suspension under normoxic (21% O(2)) or hypoxic conditions (1% O(2)). Chondrocytes were also treated with TNF-alpha under normoxic conditions. Nuclear extracts and total RNA were prepared and HIF-1alpha protein and mRNA levels were assayed by immunoblotting and Northern hybridization. Localization of HIF-1alpha by immunofluorescence was performed on frozen sections of cartilage tissue by confocal microscopy. RESULTS: HIF-1alpha expression was detectable in human normal and OA chondrocytes and cartilage by Northern analysis, immunoblotting and immunofluorescence under normoxic conditions. Culture of OA or normal chondrocytes under hypoxic conditions for up to 16h resulted in a modest stabilization and/or increase of HIF-1alpha expression. Treatment of articular chondrocytes with TNFalpha resulted in an increase in HIF-1alpha protein steady state levels under normoxic conditions. The increase in HIF-1alpha expression induced by TNFalpha was partially blocked by pretreatment of the chondrocytes with inhibitors of NFkappaB or p38 MAP kinase. We also observed the expression of HIF-2alpha mRNA in human chondrocytes. CONCLUSION: HIF-1alpha is expressed in human normal and OA articular chondrocytes cultured under normoxic conditions. HIF-1alpha can be further induced or stabilized in articular chondrocytes by hypoxia or by treatment with TNFalpha. The relatively high constitutive expression of HIF-1alpha by chondrocytes may be an important adaptation to survival in the avascular-hypoxic environment of cartilage. Modulation of HIF-1alpha levels by TNF-alpha may have important implications for chondrocyte metabolism during degenerative joint disease. In addition, we detected for the first time the expression of HIF-2alpha mRNA in chondrocytes.

Cartilage, Articular↗