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Biomedical subjects

Jacob George

Publications and source records attributed to Jacob George.

At least 55 records · Page 3Linked to original sources
PubMed2005

Antioxidant levels in peripheral blood, disease activity and fibrotic stage in chronic hepatitis C.

BACKGROUND: This study addressed the suggested association between levels of the antioxidants glutathione (GSH), vitamin C and vitamin E in peripheral blood and the histological activity and fibrosis stage in chronic hepatitis C (CHC). We then determined whether regular antioxidant supplementation influenced these antioxidant levels or disease severity. METHODS: Clinical, biochemical, histological and demographic data were collected from 247 CHC patients at the time of liver biopsy. Whole blood total GSH, plasma vitamin C and E were assessed by high-performance liquid chromatography. Statistical analyses were performed to test for associations between the variables and to identify independent predictors for hepatic necroinflammatory and fibrosis scores. RESULTS: GSH and vitamin C, but not vitamin E correlated with both portal/periportal activity (r = -0.19, P = 0.004; r = -0.19, P = 0.009 respectively) and fibrosis stage (r = -0.18, P = 0.007; r = -0.18, P = 0.009 respectively). GSH was an independent negative predictor of portal/periportal inflammation (P = 0.02) and fibrosis (P = 0.01). Vitamin C was an independent negative predictor of fibrosis stage (P = 0.02). Antioxidant intake was associated with higher vitamin C (P < 0.0001) and vitamin E (P = 0.005) levels, but not GSH. CONCLUSIONS: Whole blood GSH and plasma vitamin C are negatively associated with hepatic portal/periportal inflammation and fibrosis stage in CHC. Controlled intervention studies with vitamin C and agents that boost endogenous GSH levels are warranted.

Adolescent↗
PubMed2005

Non-alcoholic fatty liver disease.

This article reviews the nomenclature, clinical and histological basis for a diagnosis of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, its natural history, pathophysiology and an approach to clinical management.

Biopsy↗
PubMed2004

Temporal association between circulating proteolytic, inflammatory and neurohormonal markers in patients with coronary ectasia.

BACKGROUND: The prevalence of coronary ectasia (CE) appears to rise in recent years. However, the pathogenetic mechanisms that underlie this entity are not understood. We hypothesized that dysregulation of circulating matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) contributes to ectasia formation. We also evaluated the association of MMP with inflammatory or the neurohormonal markers. METHODS: We screened coronary angiographic procedures conducted in our hospital. Thirty-four patients with CEs were identified; 17 with a single ectasia and 17 with generalized ectasias. Two control groups; patients with atherosclerotic coronary disease (n=26) and patients with normal coronary arteries (n=27) were chosen randomly. Serum levels of MMP-2, MMP-3 and TIMP-1 were determined by ELISA. Pro B-type natriuretic peptide (proBNP) and high sensitivity C-reactive protein (hsCRP) serum levels were also measured. RESULTS: Serum levels of MMP-2, MMP-3, TIMP-1, proBNP and hsCRP did not differ between the three groups of patients. However, subgroup analysis demonstrated that MMP-3 level is significantly lower in patients with generalized CEs compared to those with single vessel ectasia. We also found a statistically significant correlation between proBNP and MMP-2/TIMP-1 (for MMP-2: r(2)=0.3, p=0.003 and for TIMP-1 r(2)=0.42, p<0.000l). By performing subgroup analysis we found that this correlation is only demonstrated in patients with CEs. No correlation was demonstrated between hsCRP and MMPs/TIMP. CONCLUSIONS: These observations suggest that MMP/TIMP imbalance is present in patients with generalized CE and may contribute to ectasia formation. This imbalance could be mediated by BNP.

Aged↗
PubMed2004

Suppression of early atherosclerosis in LDL-receptor deficient mice by oral tolerance with beta 2-glycoprotein I.

BACKGROUND: Atherosclerosis is considered analogous to chronic inflammatory diseases. Beta 2-glycoprotein I (beta 2GPI) is a phospholipid binding protein shown to serve as a target for prothrombotic antiphospholipid antibodies. It has recently been demonstrated to drive an immune mediated reaction and enhance murine atherosclerosis. Oral tolerance is a method in which feeding a given antigen, downregulates the respective immune responses towards it, and attenuates concomitant organ specific disorders. Herein, we tested the hypothesis, that inhibiting cellular immunity to beta 2GPI would result in suppression of fatty streak formation in mice. METHODS AND RESULTS: LDL receptor deficient mice were fed different doses of human or bovine beta 2GPI or BSA and than switched to an atherogenic diet. To determine the effect of feeding on lymph node proliferative indices, separate groups of mice were fed beta 2GPI and then immunized with the respective antigen. Feeding either human or bovine beta 2GPI was effective in attenuating atherosclerosis as compared to control fed animals. Oral feeding with of beta 2GPI inhibited lymph node cell reactivity to beta 2GPI in mice immunized against the human protein. Oral tolerance was also capable of reducing reactivity to oxidized LDL in mice immunized against oxLDL. IL-4 and IL-10 production was upregulated in lymph node cells of beta 2GPI-tolerant mice immunized against beta 2GPI, upon priming with the respective protein. CONCLUSION: Thus, oral administration of beta 2GPI is an effective means of suppressing atherogenesis in mice and should further be investigated.

Administration, Oral↗
PubMed2004

Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index.

We sought to develop a clinically useful index comprising standard and physiologically relevant variables to predict the probability of significant hepatic fibrosis in subjects with chronic hepatitis C virus (HCV) infection. Fibrosis was graded as mild (stages F0 or F1) or significant (stages F2-F4). Thirty-five clinical and laboratory parameters were analyzed initially in 176 patients with detectable HCV RNA to derive a fibrosis probability index (FPI) to predict significant fibrosis. This index then was validated in a second group of 126 subjects. Among 18 variables associated with severe fibrosis on univariate analysis, multiple logistic regression analysis identified age, aspartate aminotransferase (AST), total cholesterol level, insulin resistance (by homeostasis model), and past alcohol intake as independent predictors of significant fibrosis. The area under the receiver operating characteristic (ROC) curves was 0.84 for the initial cohort and 0.77 for the validation cohort. In the initial cohort, the sensitivity of the FPI based on these five predictors was 96%, and the negative predictive value was 93% at a score of >/=0.2. At scores >/=0.8, the FPI was 94% specific and had a positive predictive value of 87%. In conclusion, an FPI using routinely assessed markers and incorporating a measure of insulin resistance can reliably predict the probability of significant hepatic fibrosis in most patients with chronic HCV infection. Such an index should prove useful to guide decision making regarding the need for liver biopsy, and potentially for avoiding or deferring biopsy in a large proportion of patients with mild liver disease.

Adult↗
PubMed2004

Beyond insulin resistance in NASH: TNF-alpha or adiponectin?

Adiponectin has antilipogenic and anti-inflammatory effects, while tumor necrosis factor alpha (TNF-alpha) reduces insulin sensitivity and has proinflammatory effects. We examined (1) the extent to which hypoadiponectinemia and TNF-alpha activation are features of nonalcoholic steatohepatitis (NASH) and (2) whether serum levels of these markers correlate with the severity of histological changes in 109 subjects with nonalcoholic fatty liver disease (NAFLD), including 80 with NASH and 29 with simple steatosis. By multivariate analysis, subjects with NASH had reduced adiponectin level and increased TNF-alpha and soluble TNF receptor 2 (sTNFR2)-but not leptin levels, compared with controls matched by age, sex, and body mass index; these differences were independent of the increased insulin resistance (by homeostasis model [HOMA-IR]) in NASH. When compared with simple steatosis, NASH was associated with lower adiponectin levels and higher HOMA-IR, but there were no significant differences in the levels of TNF-alpha and sTNFR2. The majority of subjects with steatohepatitis (77%) had adiponectin levels less than 10 microg/mL and HOMA-IR greater than 3 units, but only 33% of those with pure steatosis had these findings. HOMA-IR and low serum adiponectin were also independently associated with increased grades of hepatic necroinflammation. In conclusion, hypoadiponectinemia is a feature of NASH independent of insulin resistance. Reduced adiponectin level is associated with more extensive necroinflammation and may contribute to the development of necroinflammatory forms of NAFLD.

Adiponectin↗
PubMed2004

L-arginine attenuates lymphocyte activation and anti-oxidized LDL antibody levels in patients undergoing angioplasty.

BACKGROUND: Patients with acute coronary syndromes exhibit evidence of peripheral T lymphocyte activation, elevated acute phase proteins and enhanced oxidative stress. Nitric oxide (NO) has been recognized as one of the relaxant factors synthesized and released by normal endothelium, and acts as a double-edged sword on the immune system. L-arginine ameliorates experimental atherosclerosis and restenosis as well as endothelial dysfunction. We sought to investigate the effect of L-arginine administration on the extent of lymphocyte activation and anti-oxLDL antibodies in patients with unstable angina undergoing PCI with stent placement. METHODS: Patients with unstable angina were randomized to treatment with L-arginine (6g per day; n = 13) or none (n = 16) for 1 month starting immediately on the day of stent deployment. Lymphocyte activation was assayed by FACS employing double staining with a common lymphocyte marker (CD3) and an activation marker HLA-DR, on the day of the procedure and 1 month later. Anti-oxLDL antibodies were assayed by ELISA. RESULTS: Patients with unstable angina not receiving L-arginine exhibited a significant 43% rise in the percentage of activated peripheral T lymphocytes, 1 month after stent deployment. Patients treated with L-arginine exhibited a fall albeit not significant in the fraction of peripheral lymphocytes bearing the activation marker. Antibodies to anti-oxLDL rose significantly between baseline and 1 month follow-up. L-arginine treatment significantly attenuated the rise in anti-oxLDL antibody levels. CONCLUSION: L-arginine attenuates the systemic rise in peripheral lymphocyte activation and oxidative stress markers induced by vessel wall injury following PCI. These effects may contribute to a favorable effect of the drug in patients with acute coronary syndromes undergoing PCI.

Aged↗
PubMed2004

Zinc reduces intimal hyperplasia in the rat carotid injury model.

BACKGROUND: The response to arterial injury following balloon dilatation is known to involve proliferative and inflammatory processes. The current widespread use of stents to maintain arterial patency not only does not eliminate but possibly exaggerates the proliferative and inflammatory phenotype and although drug-eluting stents are available, their long-term safety is yet to be determined. Zinc is a trace element that serves as a cofactor of many enzymes. Interestingly, it has been shown to have anti-inflammatory and anti-proliferative properties. We thus sought to investigate its effect on smooth muscle cell proliferation and intimal thickening in the rat carotid artery injury model. METHODS AND RESULTS: Smooth muscle cells (SMC) were cultured from carotid arteries of rats and proliferation was assessed by thymidine incorporation after exposure to different concentrations of zinc. Next, carotid artery injury was induced in rats by balloon dilatation and they were either treated with I.P injections of zinc or PBS for 2 weeks until sacrifice for assessment of neointimal formation and lumen area. Zinc inhibited in vitro SMC proliferation in a dose-dependent manner. In vivo, zinc treatment resulted in a 50% reduction in neointimal area and a significant decrease in neointimal/media ratio with no significant change in lumen area. CONCLUSION: Thus, zinc appears to reduce neointimal growth and should be tested by local delivery systems including stent coatings.

Animals↗
PubMed2004

Circulating endothelial progenitor cells in patients with unstable angina: association with systemic inflammation.

BACKGROUND: Endothelial progenitor cells (EPC) are present in peripheral blood and can develop a functional endothelial phenotype. The number and function of circulating EPCs are altered in atherosclerosis, diabetes, and after myocardial infarction and EPCs have been shown to promote postnatal angiogenesis and vasculogenesis. We investigated the number and adhesive properties of EPCs from patients with unstable angina and no evidence of cardiac necrosis. METHODS AND RESULTS: Patients were selected with unstable angina (n=29) and no evidence of cardiac necrosis, and controls with stable angina (n=12) and atherosclerotic risk factors, medication use, and coronary vessel involvement similar to patients. Circulating EPC numbers were determined by colony-forming unit assay and their adhesive properties were evaluated by EPC capacity to bind immobilised fibronectin. High-sensitivity C-reactive protein (hsCRP) was determined in all patients. Circulating EPCs were significantly increased in patients with unstable as compared with stable angina (24.5+/-2.6 vs. 13.3+/-2.9, respectively). Seven unstable angina patients followed up for 3 months after clinical stabilisation exhibited a reduction of close to 50% in circulating EPC numbers. The adhesive capacity of EPCs from patients with unstable and stable angina did not differ. A positive correlation was found between systemic CRP levels and circulating EPC numbers, but not their adhesive capacity. CONCLUSION: Patients with unstable angina and no evidence of cardiac necrosis exhibited increased circulating EPCs. Systemic inflammation, in addition to recognised growth factors, could play a role in the peripheral mobilisation of EPCs in patients with anginal syndromes.

Angina, Unstable↗
PubMed2004

Evidence for the involvement of T cell costimulation through the B-7/CD28 pathway in atherosclerotic plaques from apolipoprotein E knockout mice.

Antigen-specific T cell activation is thought to influence the initiation and progression of the atherosclerotic plaque. For the T cell activation program to be functional, it is essential not only to facilitate T cell receptor engagement by antigen-presenting cells (APC), but also to deliver requisite costimulatory signals. The most widely comprehended costimulatory pathway involves the ligation of CD28 expressed on T cells by CD80 and CD86 upregulated on APCs. We hypothesized that signals of costimulation should be localized to plaque areas that correspond to the presence of the provoking autoantigen. Atherosclerotic plaques from apoE knockout (KO) mice at different stages of maturation were studied immunohistochemically by monoclonal antibodies to respective markers of primary and secondary lymphocyte activation. Subsequently, flow cytometry studies were conducted in spleen cells from C57BL/6 and apoE KO mice aiming to determine whether the presence of plaques is associated with increased expression of costimulatory signals. We found that regardless of the maturation stage, CD80 and CD86 were evident within the plaques, and colocalized with the presence of markers of dendritic cells and with expression of the extensively investigated autoantigen-oxidized LDL. FACS analysis studies showed that splenocytes from aged atherosclerotic apoE KO mice exhibited increased expression on B cells (which represent APCs) of CD80 and CD86 as compared to their young apoE or naïve C57BL/6 litters that have no plaques. These results suggest that primary T cell activation may assume a functional proinflammatory program within the plaque by involvement of CD28/B7 costimulatory pathway.

Animals↗
PubMed2004

The effect of early and late treatment with the tyrphostin AG-556 on the progression of experimental autoimmune myocarditis.

Experimental autoimmune myocarditis (EAM) in rats is a T-cell-mediated disorder; the involvement of TNF-alpha in this disorder has been demonstrated. EAM represents a model for human autoimmune myocarditis, a condition for which no optimal treatment is currently available. Tyrphostins AG-126 and AG-556 were previously shown to reduce TNF-alpha production and its end-organ cytotoxicity, thus proving beneficial in animal models of septic shock and experimental autoimmune encephalomyelitis. To study the effects of AG-126 and AG-556 on EAM, we induced the disorder in male Lewis rats through immunization against myosin and subsequently treated the rats with both agents or the control DMSO both before and after the appearance of myocardial inflammation. AG-556 administered daily for 21 days from the day of EAM induction, significantly reduced the severity of myocarditis. Similarly, AG-556 administered for an additional 10 days after myosin immunization (when signs of inflammation are already present) attenuated the progression of myocarditis, though AG-126 did not. TNF-alpha and IFN-gamma production by in vitro sensitized splenocytes from AG-556-treated rats was significantly diminished as compared with control cells from EAM animals. Thus, AG-556 may represent a novel strategy of ameliorating the progression of myocarditis without non-selectively compromising the immune system.

Animals↗
PubMed2004

Stent thrombosis in patients treated with thienopyridines: clinical description of 10 cases.

Subacute stent thrombosis (SAST) is a major thrombotic complication of coronary stenting. Its occurrence has been substantially reduced by thienopyridine treatment. However, information on clinical profile of patients with SAST in clopidogrel era is limited. In order to define the incidence and factors predisposing to stent thrombosis, we analyzed the computerized angiographic database of three interventional cardiology centers. Out of a total number of 5903 percutaneous coronary interventions (PCIs) with stent implantation, we found 10 patients with SAST (0.17%). The indication for PCI was usually an early invasive approach (90%) during an acute coronary syndrome. All patients were treated with an apparently optimal antithrombotic regimen (90% received heparin or LMWH and 70% received IIb/IIIa receptor inhibitors and all given aspirin). In each of the patients, we could identify high-risk angiographic findings. SAST presentation was always clinically significant with definite myocardial infarction in 100% of cases. 80% of cases occurred during the first six days post PCI. Two patients had a recurrent event. Finally, despite earlier reports of atorvastatin-mediated inhibition of clopidogrel activation we did not find any patient with SAST taking both drugs. Thus, patients with stent thrombosis during thienopyridine treatment usually exhibit high-risk angiographic features. Prospective studies should be performed to elucidate drug interactions that may reduce clopidogrel efficacy and contribute to stent thrombosis.

Aged↗
PubMed2004

Eptifibatide does not influence lymphocyte activation and CRP levels in patients with undergoing coronary angioplasty.

Inhibitors of the IIB-IIIA integrin are widely used to prevent stent thrombosis. Abciximab has been shown to attenuate the inflammatory response in patients undergoing PCI. Herein, we tested the effect of eptifibatide infused during PCI on peripheral lymphocyte activation and CRP levels before, and one month after the procedure showing no noticeable effect. These results may explain the differences in clinical outcome following PCI by use of different IIB-IIIA agents.

Aged↗
PubMed2004

Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock?

Clinicians in both the developed and also the newer industrial economies in the Asia-Pacific region will encounter non-alcoholic fatty liver disease (NAFLD) with increasing frequency. Although the region has been a significant contributor to the current state of knowledge, the spectrum of NAFLD, its severity and the potential for significant future morbidity and health costs are not widely recognized. Lifestyle changes, the epidemic of childhood and adult obesity and type 2 diabetes sweeping the Asia-Pacific represent the key substrates for the rising prevalence of NAFLD. Physicians in all disciplines need to be aware of clinical clues to the presence of NAFLD in the absence of other liver disease and in those with chronic viral hepatitis and they should be able to identify subsets at risk for liver-related morbidity. Given the scope of the problem, efforts should focus primarily on preventing or ameliorating the impact of risk factors; the key one is insulin resistance and its associates of diabetes and central obesity. Pharmacotherapy may play a role in selected individuals. A regional agenda for case definition, future study and public health initiatives is urgently required.

Age Distribution↗
PubMed2004

Effects of interferon treatment response on liver complications of chronic hepatitis C: 9-year follow-up study.

OBJECTIVES: Fibrotic severity, biochemical indices of poor liver function, and sporadic transmission are independent predictors of liver complications among people with chronic hepatitis C. After accounting for these factors, we tested whether interferon treatment or the treatment response reduces the rate of liver cancer, liver-related death or transplantation, and other liver complications during extended follow-up. METHODS: Liver clinic cohort of 455 patients with histologically proven chronic hepatitis C was followed prospectively for median 9 yr (IQ 6, 11 yr); 384 received interferon, 343 completed a treatment course. Liver complications were assessed in relation to treatment and treatment response in univariate and multivariate models, and survival to onset of liver-related complications was determined. RESULTS: The annual incidence of total liver complications was 1.5% in treated and 2.9% in untreated patients and appeared quasilinear throughout 9-yr follow-up. Interferon treatment did not influence the rate of liver complications. However, the rate of complications increased exponentially with transition of the treatment response from sustained viral response (SVR), through response-relapse to nonresponse (or no treatment). By univariate analysis, response to interferon treatment was a significant predictor of complications. After adjustment for fibrosis score, serum albumin concentration and mode of transmission in a multivariate model, treatment response just failed to reach significance (p= 0.058) as a predictor of outcome. CONCLUSIONS: Response to antiviral therapy, and particularly SVR, appears to reduce liver complications in chronic hepatitis C. However, in the absence of an antiviral treatment response, a course of interferon does not reduce risks of liver cancer or liver failure.

Adult↗
PubMed2004

Antigen-tailored therapy based on the inflammatory theory of atherosclerosis.

In recent years, considerable data has been provided to support the role of the immune system in atherosclerosis. These reports came from studies involving knockout murine models of atherosclerosis and human subjects. The notion that inflammatory mechanisms are operable in atherogenesis has fueled a series of studies demonstrating that autoimmune responses are also evident in the atherosclerotic lesions and appear to influence the initiation and progression of the plaque. The principal autoantigens that have been suggested as potential triggers of autoimmune responses in atherosclerosis are modified forms of low-density lipoproteins, heat shock proteins and beta2 glycoprotein I. Immunization against these antigens influenced the generation of lesions and adoptive transfer studies of lymphocytes reactive to some of these antigens have also been demonstrated to enhance the growth of the plaques. The realization that autoimmune-like responses may play a role in the progression of atherosclerotic lesions has paved the way for exciting modes of manipulating lesions, irrespective of the effect on the lipid profile. Thus, recent studies indicate that oral tolerance with antigens or derivatives could suppress the respective immune responses and reduce the extent of the lesions in transgenic atherosclerosis-prone mice. These observations should be further explored and if validated, could represent novel modalities for influencing atherogenessis in humans.

Administration, Oral↗