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Biomedical subjects

Jacob George

Publications and source records attributed to Jacob George.

At least 19 recordsLinked to original sources
PubMed2024

Exportin 4 DNA promoter methylation in liver fibrosis.

A role for exportin 4 (XPO4) in the pathogenesis of liver fibrosis was recently identified. We sought to determine changes in hepatic XPO4 promoter methylation levels during liver fibrosis. The quantitative real-time RT-PCR technique was used to quantify the mRNA level of XPO4. Additionally, pyrosequencing was utilized to assess the promoter methylation status of XPO4. The methylation rate of the XPO4 promoter was significantly increased with fibrosis in human and mouse models, while XPO4 mRNA expression negatively correlated with methylation of its promoter. DNA methyltransferases (DNMTs) levels (enzymes that drive DNA methylation) were upregulated in patients with liver fibrosis compared to healthy controls and in hepatic stellate cells upon transforming growth factor beta (TGFβ) stimulation. The DNA methylation inhibitor 5-Aza or specific siRNAs for these DNMTs led to restoration of XPO4 expression. The process of DNA methylation plays a crucial role in the repression of XPO4 transcription in the context of liver fibrosis development.

Animals↗
PubMed2006

Circulating endothelial progenitor cells in patients with cardiac syndrome X.

BACKGROUND: Cardiac syndrome X (CSX) encompasses the constellation of anginal chest pain in the presence of a pathological functional test and a normal coronary angiogram. Endothelial progenitor cells (EPCs) in the peripheral circulation contribute to tissue vascularisation. OBJECTIVE: To investigate the number and functional properties of circulating EPCs in patients with CSX. METHODS: 17 patients with CSX and a referent population (n = 20) were matched for age, atherosclerotic risk factors and use of drugs. Numbers of EPCs were studied by FACS, and their functional properties, including their proliferative capacity, adherence to matrix and mature endothelial cells as well as their ability to support in vitro tube formation, were investigated. Levels of soluble markers that associate with peripheral mobilisation and homing were studied in the serum samples of all subjects. RESULTS: Patients with CSX had significantly increased numbers of circulating EPCs as compared with the referent population (both CD34+/KDR and CD34+/CD133+). The proliferative capacity of EPCs and their ability to support in vitro tube formation were significantly impaired in patients with CSX as compared with the referent population. However, adhesiveness of EPCs from patients with CSX to fibronectin and cultured mature endothelial cells was enhanced as compared with the referent population. Serum vascular endothelial growth factor correlated with peripheral CD34+/KDR cell numbers, whereas serum concentration of erythropoietin correlated with the number of circulating CD34+/CD133+ cells CONCLUSION: Patients with CSX have a significantly altered circulating EPC phenotype that could potentially aid in understanding the complex pathogenesis of the syndrome.

Adiponectin↗
PubMed2006

High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid.

BACKGROUND: Allopurinol has been shown to improve endothelial function in chronic heart failure. This study aimed to establish its mechanism of action and to construct a dose-response curve for the effect of allopurinol. METHODS AND RESULTS: Two randomized, placebo-controlled, double-blind, crossover studies were performed for 1 month on patients with New York Heart Association Class II-III chronic heart failure, comparing 300 mg allopurinol, 600 mg allopurinol, and placebo for the first study and 1000 mg probenecid versus placebo in the second study. Endothelial function was assessed by standard forearm venous occlusion plethysmography. Allopurinol 600 mg/d significantly increased forearm blood flow response to acetylcholine compared with both allopurinol 300 mg/d and placebo (% change in forearm blood flow [mean+/-SEM]: 240.31+/-38.19% versus 152.10+/-18.21% versus 73.96+/-10.29%, P<0.001). For similar levels of urate lowering, the uricosuric agent probenecid had no effect on endothelial function. Sodium nitroprusside response was unchanged by all treatments. Vitamin C and acetylcholine coinfusion data showed that 600 mg/d allopurinol completely abolished the oxidative stress that was sensitive to high-dose vitamin C. CONCLUSIONS: For the first time, we have shown that a steep dose-response relationship exists between allopurinol and its effect on endothelial function. We also showed that the mechanism of improvement in endothelial function with allopurinol lies in its ability to reduce vascular oxidative stress and not in urate reduction. The reduction in vascular oxidative stress was profound because high-dose allopurinol totally abolished the oxidative stress that was sensitive to the high-dose vitamin C that was used in this study.

Acetylcholine↗
PubMed2006

Role of ethanol in the regulation of hepatic stellate cell function.

Evidence has accumulated to suggest an important role of ethanol and/or its metabolites in the pathogenesis of alcohol-related liver disease. In this review, the fibrogenic effects of ethanol and its metabolites on hepatic stellate cells (HSCs) are discussed. In brief, ethanol interferes with retinoid metabolism and its signaling, induces the release of fibrogenic cytokines such as transforming growth factor beta-1 (TGFbeta-1) from HSCs, up-regulates the gene expression of collagen I and enhances type I collagen protein production by HSCs. Ethanol further perpetuates an activated HSC phenotype through extracellular matrix remodeling. The underlying pathophysiologic mechanisms by which ethanol exerts these pro-fibrogenic effects on HSCs are reviewed.

Animals↗
PubMed2006

Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes.

AIMS: Considerable evidence supports the role of innate and adaptive immunity in the progression and destabilization of the atheromatous plaque. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are a subpopulation of lymphocytes that are capable of suppressing the progression of experimental autoimmune disorders. We have hypothesized that peripheral numbers and function of Tregs would be deranged in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: Peripheral numbers of Tregs were evaluated by FACS employing labelled antibodies to CD4 and CD25. Functional suppressive properties of Tregs were assayed by establishing a triple-cell culture in which purified Tregs were incubated with irradiated antigen-presenting cells and anti-CD3-activated responder T cells. Proliferation in the presence or absence of oxidized LDL (oxLDL) was evaluated by thymidine incorporation. mRNA and protein content of foxp3, a master transcriptional regulator of Tregs, were determined for all subjects. Patients with ACS exhibited significantly reduced numbers of peripheral Tregs as compared with patients with stable angina and normal coronary artery subjects. Moreover, oxLDL induced a more profound reduction in Treg numbers in patients with ACS. Tregs in ACS patients were significantly compromised as their ability to suppress responder CD4(+)CD25(-) T-cell proliferation was attenuated. mRNA and protein content of foxp3 were significantly reduced in purified Tregs obtained from patients with ACS. CONCLUSION: In patients with ACS, naturally occurring CD4(+)CD25(+) Treg numbers are reduced and their functional properties compromised. These findings may aid in understanding the mechanisms leading to culprit plaque associated T-cell activation in patients with ACS.

Acute Disease↗
PubMed2006

Effect of anti-TNFalpha treatment on circulating endothelial progenitor cells (EPCs) in rheumatoid arthritis.

UNLABELLED: Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, which may be attenuated by anti-inflammatory treatment. Endothelial progenitor cells (EPCs) have the ability to differentiate into mature endothelium and have a potentially reparative role protecting against ischemia and atherosclerosis. OBJECTIVE: To investigate the effect of treatment with infliximab on the number and functional capacity of endothelial progenitor cells (EPCs) in patients with RA, as a possible mechanism for reducing cardiovascular morbidity in this disorder. METHODS PATIENTS: Active seropositive RA patients (N = 14) considered candidates for starting infliximab treatment, were recruited. Assessment, based on DAS-28, was performed before treatment and 14 days later. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by the colony-forming unit (CFU) method. Endothelial phenotyping of CFU was performed by immunofluorescence employing antibodies to Tie-2 VEGF-receptor 2, and CD31. EPC Functional properties were evaluated by fibronectin adherance. RESULTS: A significant 33.4% increase (p < 0.001) in EPC levels was observed after infliximab. A 60% increase was noted in the EPC differentiation scale, (p < 0.002) while a 37.6% increase was observed in mean EPC adhesion (p < 0.001). These changes were associated with a 17.5% decrease in the DAS-28 (p < 0.0001). A significant correlation was observed between the clinical response, reflected by changes in DAS-28 and the degree of increase in EPC CFUs. CONCLUSION: A single dose of infliximab improved the number and functional properties of EPCs, in parallel with an early clinical effect, suggesting a possible mechanism by which anti-inflammatory treatment may reduce cardiovascular risk in RA patients.

Antibodies, Monoclonal↗
PubMed2006

Autoantibodies to cardiac troponin I in patients with idiopathic dilated and ischemic cardiomyopathy.

BACKGROUND: Progressive dilatation and functional compromise of heart function is attributed to a variety of pathogenic mechanisms. Experimental data suggests that autoantibodies could promote myocardial damage by inducing either inflammation or alternatively, augmentation of Ca2+ currents or activation of surface receptors on cardiomyocytes. Cardiac troponin I (cTpnI) is an essential protein component of the contractile heart. Herein, we studied the presence and functional properties of autoantibodies to cTpnI in patients with idiopathic dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM). METHODS AND RESULTS: Anti-cTpnI antibody ELISA was established for assessment of sera obtained from 33 patients with ICM, 32 with DCM and 42 healthy subjects. Binding specificity of purified cTpnI-reactive IgG fractions from patients with ICM and DCM was confirmed by competitive inhibition studies employing fluid-phase cTpnI. The effect of IgG preparations on intracellular Ca2+ ([Ca2+]i) transients was tested in cultured neonatal rat ventricular myocytes (NRVM). Six of the 33 ICM patients (18.2%) and 5 of the 32 DCM patients (15.6%) had positive anti-cTpnI antibody titer as compared to none in the healthy subjects. Purified IgG from positive patients appeared specific to cTpnI. IgG preparations reactive with cTpnI did not exhibit measurable effects on [Ca2+]i transients in cultured NRVM nor did they bind the respective cells by direct immunofluorescence. CONCLUSION: IgG antibodies to TpnI are increased in a significant number of patients with both ICM and idiopathic DCM, yet it appears that these autoantibodies cannot bind heart muscle cells or influence [Ca2+]i transients.

Adult↗
PubMed2006

Erythropoietin improves myocardial performance in doxorubicin-induced cardiomyopathy.

AIMS: Doxorubicin (Dox) is a potent chemotherapeutic agent associated with severe cardiotoxicity. Erythropoietin (Epo) has recently been shown to exhibit proangiogenic properties related to endothelial progenitor cell (EPC) mobilization. We tested the hypothesis that EPC are compromised in rats with Dox-induced cardiotoxicity and correction of this functional impairment by treatment with Epo could result in attenuation of myocardial dysfunction. METHODS AND RESULTS: Wistar rats were either treated with two different doses of Epo (20U or 200U) or PBS (n = 40 in each group) for four consecutive weeks, followed by Dox administration. In a second study, EPC obtained from healthy rats were transfused intravenously (n = 20/group) prior to induction of Dox cardiomyopathy. EPC from healthy subjects were evaluated for their proliferative and migratory properties in the presence or absence of Dox and Epo pre-treatment. Echocardiography demonstrated an improvement in fractional shortening (FS) in Epo-treated rats. Epo treatment was associated with a reduced mortality in both Epo-treated groups. Circulating EPC numbers were three times higher in Epo-treated compared with non-treated animals. Adhesive properties, migration, and tube formation capacity in matrigel of EPCs from both Epo-treated groups as compared with controls were significantly enhanced. EPC transfer to Dox-treated rats led to functional myocardial improvement equivalent to the protection afforded by treatment with Epo. In EPC obtained from humans, pre-incubation with Epo significantly attenuated the anti-proliferative and anti-migratory effects of treatment with Dox. CONCLUSION: Epo treatment is potentially protective against myocardial dysfunction induced by Dox. These effects are partially mediated by enhancement in the number of EPC and their functional properties.

Animals↗
PubMed2006

Cellular autoimmunity to cardiac myosin in patients with a recent myocardial infarction.

After a large myocardial infarction (MI) a progressive remodeling process can occur that results in a severe mechanical dysfunction of the heart. Among the determinants of remodeling, immune mediated inflammation has been suggested as an important contributor. However, the role of autoimmunity to cardiac antigens that are released to the circulation has not been sufficiently addressed. Cardiac myosin is a contractile protein that is unique to the myocardium and has been shown to induce a humoral immune response in patients after MI, and to trigger an autoimmune myocarditis in experimental rats and mice. In the current study, we evaluated humoral and cellular immune responses to myosin in patients with and without a history of recent MI. Eighteen patients with MI, 2 weeks to 4 months prior to initiation of the study, and eighteen control subjects were enrolled. Peripheral blood mononuclear cells (PMBC) were obtained and subjected to priming with different concentrations of cardiac myosin. Interferon-gamma and TNF-alpha were measured in conditioned medium obtained from the cultured PMBC upon priming with cardiac myosin. Humoral immune responses were also assessed by evaluating IgG anti-myosin antibodies. We have found that a third of the patients with the recent history of MI and none of the control subjects had a proliferative response to cardiac myosin evident by stimulation indices greater than 1.5. No differences were detected between the patients and controls with regard to IFN-gamma and TNF-alpha secreted by their PMBC, nor were there differences in the serum levels of IgG anti-myosin antibodies. Thus, in patients with a recent history of MI, cellular autoimmunity to cardiac myosin is present as compared with controls. It remains to be determined whether this autoimmune response is associated with an adverse outcome.

Autoimmunity↗
PubMed2006

Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: Role of insulin resistance and hepatic steatosis.

Hepatic steatosis has been associated with fibrosis, but it is unknown whether the latter is independent of the etiology of fat infiltration. We analyzed the relationship between clinical characteristics, insulin resistance (HOMA-R) and histological parameters in 132 patients with "viral" steatosis caused by genotype 3 chronic hepatitis C (CHC-3) and 132 patients with "metabolic" steatosis caused by nonalcoholic fatty liver disease (NAFLD), matched by age, BMI, and degree of liver fat accumulation. Tests of liver function were comparable in the two study populations. The prevalence of features of insulin resistance was higher in NAFLD, as was HOMA-R (P = .008). Logistic regression analysis confirmed that steatosis was associated with a high viral load and low serum cholesterol in CHC-3, and with high aminotransferase, glucose, ferritin and hypertriglyceridemia in NAFLD. At univariate analysis, advanced fibrosis was associated with steatosis in NAFLD, but not in CHC-3. Other parameters related to fibrosis severity were HOMA-R and a low platelet count in CHC-3, and high aminotransferases, HOMA-R, ferritin and low HDL-cholesterol in NAFLD. On multivariate analysis, only low platelet count (OR = 0.78; 95% CI, 0.67-0.92) and HOMA-R (OR = 2.98; 1.13-7.89) were independent predictors of advanced fibrosis in CHC-3. In NAFLD, severe fibrosis was predicted by fat grading (OR = 3.03; 1.41-6.53), ferritin (OR = 1.13; 1.03-1.25) and HOMA-R (OR = 1.16; 1.02-1.31). In conclusion, insulin resistance is an independent predictor of advanced fibrosis in both NAFLD and CHC-3, but the extent of steatosis contributes to advanced disease only in NAFLD. Virus-induced hepatic steatosis as seen in CHC-3 does not contribute significantly to liver fibrosis.

Adult↗
PubMed2006

Renal involvement in multicentric Castleman disease with glomeruloid hemangioma of skin and plasmacytoma.

A 47-year-old man presented with fever of unknown origin, generalized weakness, edema, and renal failure. He had left-sided pleural effusion, generalized lymphadenopathy, multiple nontender cutaneous nodules, hepatomegaly, renal failure, and hypergammaglobulinemia. Axillary lymph node biopsy showed findings consistent with Castleman disease of the hyaline vascular type associated with interfollicular plasmacytosis. A renal biopsy performed in view of proteinuria and acute renal failure showed hypercellular glomeruli with capillary loop thickening and double contours consistent with membranoproliferative glomerulonephritis. Skin nodule biopsy showed a glomeruloid hemangioma characterized by dermal proliferation of capillary loops in a nodular manner resembling a glomerulus. He experienced clinical and biochemical remission with steroids. Discontinuation of steroid therapy was associated with recurrence of renal failure, reappearance of nodules, lymphadenopathy, and appearance of bony lytic lesions. Biopsy of bony lytic lesions showed plasmacytoma. The patient achieved complete remission on treatment with steroids and cyclophosphamide and is free of symptoms at the end of 40 months of follow-up. To our knowledge, this is the first case report of the occurrence of membranoproliferative glomerulonephritis, glomeruloid hemangioma of the skin, and plasmacytoma in a patient with multicentric Castleman disease without human immunodeficiency virus infection.

Biopsy↗
PubMed2006

Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data.

BACKGROUND & AIMS: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. METHODS: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. RESULTS: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. CONCLUSIONS: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.

Adult↗
PubMed2006

Serum levels of anti heat shock protein 70 antibodies in patients with stable and unstable angina pectoris.

BACKGROUND: The heat shock protein (HSP) family comprises approximately 24 proteins displaying a high degree of sequence homology between different species. The induction of self-HSP immune reactivity is thought to be involved in the pathogenesis of several diseases. Antibodies to HSP60/65 have been demonstrated in the sera of patients with coronary artery disease. Moreover, the target antigens of the antibodies HSP60 and HSP70 are both expressed in smooth muscle cells and macrophages within atherosclerotic lesions. In this retrospective, case control study, we investigated whether patients with established atherosclerosis, with either stable or unstable angina have high levels of antibodies to HSP70. METHODS AND RESULTS: Patients with stable angina (n = 40) were from the outpatient clinic whereas patients with unstable angina (n = 91) were recruited upon admission and prior to performance of coronary angiography. Control patients (n = 18) were healthy subjects with no evidence of coronary artery disease. Serum levels of anti-HSP70 antibodies were assayed by ELISA. Patients with stable and unstable angina exhibited lower serum levels of antibodies to HSP70 (0.202+/-0.113 and 0.201+/-0.115, respectively) in comparison to control subjects (0.364+/-0.199, P = 0.0001 for both comparisons). Serum levels of antibodies to HSP70 did not differ significantly between patients with stable and unstable angina. No differences in serum levels of antibodies to HSP70 were evident between baseline and follow up in the patients with unstable angina. CONCLUSIONS: Patients with coronary atherosclerosis possess lower levels of anti-HSP70 antibody levels. Further research is required to explore whether higher levels of anti-HSP70 antibodies have a predictive value in coronary atherosclerosis.

Aged↗
PubMed2006

Comparative analysis of methods for assessment of circulating endothelial progenitor cells.

The number and properties of endothelial progenitor cells (EPC) in disease states is of considerable interest due to the importance attributed to this distinct cell population. However, there has been no study comparing each of the methods employed in the same sampled individuals. Herein, we performed an analysis of several methods used for circulating EPC assessment and correlated them with humoral factors known to influence their numbers. Thirty-eight individuals (mean age of 34 +/- 9 years) were tested. Peripheral blood mononuclear cells were obtained and stained for FACS analysis with antibodies to CD34, CD45, CD133, and KDR and the remaining cells grown under endothelial cell conditions for assessment of colony-forming unit (CFU) numbers and adhesive properties. Levels of circulating vascular endothelial growth factor (VEGF), erythropoietin (EPO), and C-reactive protein (CRP) were determined and correlated with each of the EPC markers. CFU numbers did not correlate with CD34/KDR or CD34/CD133/KDR and negatively correlated with CD34/ CD133 numbers. CD34/KDR numbers correlated with CD34/CD133/KDR, but not with CD34/ CD133. Only CD34/KDR and CD34/CD133/KDR correlated with VEGF serum levels. The number of EPC adhering to fibronectin and endothelial cells correlated with CFU numbers and not with either of the EPC membrane markers. Current methods for quantitatively assessing numbers of circulating EPC are not correlated. VEGF serum levels are associated only with CD34/KDR and CD34/ CD133/KDR, whereas CFU numbers correlate with EPC functional properties. These findings may suggest that CD34/KDR is more appropriate for the definition of circulating EPC, whereas CFU numbers are more likely to reflect their ability to proliferate.

Adult↗
PubMed2006

The role of erythropoietin in myocardial protection: potential mechanisms and applications.

The glycoprotein erythropoietin was originally discovered as a principal regulator that promotes the survival, proliferation and differentiation of erythroid progenitor cells. Despite potentially detrimental effects, such as increased blood pressure and hyperviscosity, recombinant human erythropoietin has been demonstrated to be a safe drug, as millions of anemia sufferers have received it over the last decade as a form of treatment. Recently, erythropoietin receptors have been discovered in a variety of tissues, including the cardiovascular system, and erythropoietin has been demonstrated to have a beneficial effect in congestive heart failure patients with anemia. The purpose of this review is to summarize the pleiotropic cardioprotective effects of erythropoietin in the cardiovascular system and to evaluate its potential role as a biomarker in these disorders.

Animals↗
PubMed2006

[Endothelial progenitor cells (EPCs)--new tools for diagnosis and therapy].

Accumulating evidence suggests that postnatal bone marrow is a source of cells that can participate in postnatal neovascularization and vascular homeostasis. Among these cells, a scarce population of endothelial progenitor cells (EPCs) have the capacity to migrate to the peripheral circulation, proliferate and differentiate into mature endothelial cells in response to stimulating signals emanating from vascular injuries or during tumor growth. Questions persist, however, regarding the precise panel of cell surface markers that defined EPCs, as well as the different mechanisms stimulating or inhibiting their mobilization and differentiation. In the last decade, EPCs number and function have been correlated with risk factors for cardiovascular and peripheral vascular diseases. The authors review experimental results obtained from both animal studies and recent clinical trials, which point to the importance of EPCs potential as diagnostic markers and therapeutic tools in ischemic diseases. Furthermore, the article discusses the risk of potentially harmful side effects of altered EPCs number and functional properties, a critical barrier to overcome while bringing progenitor cell therapy to the clinical arena.

Endothelium, Vascular↗
PubMed2006

[Erythropoietin as a protective agent in myocardial ischemia].

Erythropoietin and its receptor, a cytokine hormone long-known for its pro-erythropoietic effect, has been found to be expressed on a variety of tissues, including the cardiovascular system. Recent experimental studies in the ischemia-reperfusion model have demonstrated that erythropoietin has a significant cardioprotective and pro-angiogenic effect. This effect is quantified by a reduction in the relative infarct and apoptosis area and improved recovery of mechanical function. Despite potentially detrimental effects, erythropoietin has been used extensively in the last decade for treatment of anemia associated with chronic renal failure, and it has been found to be a safe drug in humans. The potential role of erythropoietin in the treatment of ischemic heart disease in humans has yet to be demonstrated in preliminary clinical trials.

Anemia↗