Abstract: Renal function and urea are frequently abnormal in patients with heart failure (HF) and are predictive of increased mortality. The relative importance of each parameter is less clear. We prospectively compared the predictive value of renal function and serum urea on clinical outcome in patients with HF. Patients hospitalized with definite clinical diagnosis of HF (n = 355) were followed for short-term (1 yr) and long-term (mean, 6.5 yr) survival and HF rehospitalization. Increasing tertiles of discharge estimated glomerular filtration rate (eGFR) were an independent predictor of increased long-term survival (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.47-0.91; p = 0.01) but not short-term survival. Admission and discharge serum urea and blood urea nitrogen (BUN)/creatinine ratio were predictors of reduced short-and long-term survival on multivariate Cox regression analysis. Increasing tertiles of discharge urea were a predictor of reduced 1-year survival (HR, 2.13; 95% CI, 1.21-3.73; p = 0.009) and long-term survival (HR, 1.93; 95% CI, 1.37-2.71; p < 0.0001). Multivariate analysis including discharge eGFR and serum urea demonstrated that only serum urea remained a significant predictor of long-term survival; however, eGFR and BUN/creatinine ratio were both independently predictive of survival. Urea was more discriminative than eGFR in predicting long-term survival by area under the receiver operating characteristic curve (0.803 vs. 0.787; p = 0.01). Increasing tertiles of discharge serum urea and BUN/creatinine were independent predictors of HF rehospitalization and combined death and HF rehospitalization. This study suggests that serum urea is a more powerful predictor of survival than eGFR in patients with HF. This may be due to urea's relation to key biological parameters including renal, hemodynamic, and neurohormonal parameters pertaining to the overall clinical status of the patient with chronic HF.
Abstract: Background: Percutaneous interventions for aorto-ostial narrowing of native coronary arteries are challenging because of early elastic recoil after the procedure and the high restenosis rate. Cutting balloon angioplasty may reduce this complication. Hypothesis: The purpose of the study was to evaluate the clinical outcomes of cutting balloon angioplasty and stent implantation for aorto-ostial lesions with a 1-year clinical follow-up. Methods: All patients with aorto-ostial lesions in our laboratory underwent cutting balloon angioplasty and were followed for approximately 1 year. Results: Forty-eight patients underwent balloon angioplasty; 36 of whom had lesions in the ostial right coronary artery, and 12 of whom had lesions in the left main coronary artery (LMCA). Thirty-five patients (73%) had a stent implanted. Procedural success was achieved in all patients. The in-hospital rate of major adverse cardiac events (MACEs) was 2.1% because of the death of 1 patient following urgent bypass surgery. Mean clinical follow-up was 11.6 +/- 7 month. Twelve patients (27%) required repeat coronary angiography, and restenosis was found in 7 patients (16%). Six patients (13.6%) had MACEs. Conclusions: Cutting balloon angioplasty in combination with bare metal stent (BMS) implantation has a good clinical outcome. This technique should be compared with implantation of drug-eluting stents (DESs) in a controlled study.
Abstract: Adipose tissue (AT) can accumulate macrophages and secrete several inflammatory mediators. Despite its pivotal role in the progression of chronic inflammatory processes such as atherosclerosis, the adaptive role of immunity in obesity remains poorly explored. Visceral AT of diet-induced obese C57BL/6 mice had higher numbers of both CD4(+) and CD8(+) T cells than lean controls, monitored by flow cytometry. When stimulated in vitro, T cells from obese AT produced more interferon (IFN)gamma than those from controls. AT from obese animals also had more cells expressing I-Ab, a mouse class II histocompatibility marker implicated in antigen presentation, as determined by immunostaining. Differentiated 3T3-L1 cells stimulated with recombinant IFN gamma or T-helper 1-derived supernatant produced several chemokines and their mRNAs. Obese IFN gamma-deficient animals had significantly reduced AT expression of mRNA-encoding inflammatory genes such as tumor necrosis factor-alpha and monocyte chemoattractant protein-1, decreased AT inflammatory cell accumulation, and better glucose tolerance than control animals consuming the same diet. Obese mice doubly deficient for IFN gamma receptor and apolipoprotein (Apo) E on a mixed 129SvEv/C57BL/6 (129/B6) genetic background, despite exhibiting similar AT mRNA levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 as 129/B6-ApoE(-/-) controls, had decreased expression of important T cell-related genes, such as IFN gamma-inducible protein-10 and I-A(b), and lower plasma triglycerides and glucose. These results indicate a role for T cells and IFN gamma, a prototypical T-helper 1 cytokine, in regulation of the inflammatory response that accompanies obesity. (Circ Res. 2008; 103: 467-476.)
Abstract: Evidence from many human and rodent studies has established that T lymphocytes enhance inflammation in atherosclerotic plaques and contribute to lesion progression and remodeling. Recent work also indicates that regulatory T cells are important in limiting proatherogenic T-cell responses. Given the important role of T cells in atherosclerosis, there is a need to fully understand how proatherogenic T cells are activated and regulated. Antigen-dependent activation of nave T cells, leading to clonal expansion and effector T-cell differentiation, and effector and memory T cells, is enhanced by signals provided by costimulatory molecules expressed by antigen presenting cells, which bind to receptors on the T cells. In addition, T-cell responses to antigen are negatively regulated by coinhibitory molecules expressed by antigen-presenting cells, which bind to receptors on T cells. Two major families of costimulatory molecules include the B7 and the tumor necrosis factor (TNF) families. These molecules bind to receptors on T cells belonging to the CD28 or TNF receptor families, respectively. The best-defined coinhibitors and their receptors belong to the B7 and CD28 families. Recent work has begun to define how these T-cell costimulatory and coinhibitory pathways influence atherosclerosis, largely in mouse models of the disease. Profound effects are attributable to molecules in both the B7/CD28 (B7-1/2, ICOS, and PDL-1/2) and the TNF/TNF receptor (CD40, OX40, and CD137) families. One emerging theme is that both pathogenic effector T-cell responses and regulatory T cells are influenced by overlapping sets of costimulators and coinhibitors. These complexities must be considered as immunotherapeutic approaches for atherosclerotic disease are developed. (Circ Res. 2008; 103: 1220-1231.)
Abstract: Recent reports suggest dyslipidemia impairs dendritic cell (DC) function and adaptive immunity. This study aimed to characterize the effect of hypercholesterolemia on antigen-presenting cell function of DCs and DC-dependent CD4(+) T-cell responses. DCs incubated in vitro with acetylated low-density lipoprotein cholesterol with or without an acyl-coenzyme A: cholesterol acyl-transferase inhibitor maintained their ability to prime CD4(+) T cells. Analysis of T-cell proliferation and interferon-gamma and tumor necrosis factor-alpha production after ex vivo coculture of naive CD4(+) T cells with splenic, inguinal, or iliac DCs from low-density lipoprotein receptor-deficient (LDLR-/-) or apolipoprotein E-deficient (ApoE(-/-)) mice fed an atherogenic diet highlighted DC efficacy in effector T-cell generation under hypercholesterolemic conditions. Adoptive transfer of carboxyfluorescein diacetate, succinimidyl ester (CFSE)-labeled naive CD4(+) T cells in LDLR-/- recipients and subsequent immunization demonstrated effective priming of naive T cells in hypercholesterolemic mice. CFSE dilution analyses revealed that hypercholesterolemic DCs were equipotent in naive CD4(+) T-cell priming efficacy with normocholesterolemic DCs. Quantitative real-time PCR and flow cytometric analyses demonstrated that DC expression of multiple molecules involved in antigen processing, presentation, and T-cell stimulation remained unaltered by dyslipidemia. Finally, endogenous antigen-primed CD4(+) T cells responded equivalently to a secondary ex vivo antigenic challenge, regardless of whether they were primed in vivo under hypercholesterolemic or control conditions, demonstrating that all essential steps in CD4(+) T-cell responses remain intact under atherogenic conditions. This study affirms that the adaptive immune response prevails under the hypercholesterolemic conditions present in atherosclerosis. In particular, DCs remain functional antigen-presenting cells and maintain their ability to prime CD4(+) T cells even when cholesterol-loaded. (Circ Res. 2008; 103:965-973.)
Abstract: Background: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers improve prognosis in congestive heart failure and are the treatment of choice in these patients. Despite this, the rates of ACE-1 usage in heart failure patients remain low in clinical practice, Objectives: To evaluate the rate of ACE-1/ARB treatment in hospitalized patients with CHF, and analyze the reasons for non-treatment. Methods: We prospectively evaluated 362 consecutive patients hospitalized with CHF. Patients were evaluated for ACE-1/ARB usage at discharge and were followed for 1 year. Results: At hospital discharge 70% of the patients were prescribed ACE-1/ARB treatment. Only 69% received recommended target or sub-target dosages, proven to improve prognosis. This decreased to 63% and 59% at 6 months and 12 months of follow-up respectively, due to a shift from sub-target levels to low dosages. Justified reasons for under-treatment were apparent in only 25% not optimally treated discharged patients and this decreased to 12% and 4% at 6 and 12 months follow-up, respectively. Common reasons for non-treatment at discharge were hyperkalemia and elevation in serum creatinine, while hypotension and cough were more prominent at follow-up. Clinical parameters associated with increased treatment rates were ischemic heart disease and the absence of chronic renal failure. Patients receiving treatment had lower hospitalization and mortality rates. Conclusions: ACE-1/ARB treatment is still underutilized in patients discharged from hospital with a diagnosis of CHF Increasing the awareness of the importance of these drugs may increase the number of patients treated.
Abstract: BACKGROUND: Patients with heart failure have a poor prognosis. However, it has been presumed that patients with heart failure and preserved left ventricular function (LVF) may have a more benign prognosis. OBJECTIVES: We evaluated the clinical outcome of patients with heart failure and preserved LVF compared with patients with reduced function and the factors affecting prognosis. METHODS: We prospectively evaluated 289 consecutive patients hospitalized with a definite clinical diagnosis of heart failure based on typical symptoms and signs. They were divided into 2 subsets based on echocardiographic LVF. Patients were followed clinically for a period of 1 year. RESULTS: Echocardiography showed that more than one third (36%) of the patients had preserved systolic LVF. These patients were more likely to be older and female and have less ischemic heart disease. The survival at 1 year in this group was poor and not significantly different from patients with reduced LVF (75% vs 71%, respectively). The adjusted survival by Cox regression analysis was not significantly different (P =. 25). However, patients with preserved LVF had fewer rehospitalizations for heart failure (25% vs 35%, P <. 05). Predictors of mortality in the whole group by multivariate analysis were age, diabetes, chronic renal failure, atrial fibrillation, residence in a nursing home, and serum sodium <= 135 mEq/L. CONCLUSION: The prognosis of patients with clinical heart failure with or without preserved LVF is poor. Better treatment modalities are needed in both subsets. (C) 2008 Elsevier Inc. All rights reserved.
Abstract: Background: Atherosclerosis is a chronic inflammatory process resulting in coronary artery disease. Objectives: To determine the relationship between inflammatory markers and the angiographic severity of CAD. Methods: We measured inflammatory markers in sequential patients undergoing coronary angiography. This included C-reactive protein, fibrinogen, serum cytokines (interleukin-1 beta, IL-1 receptor antagonist, IL-6, IL-8, IL-10) and tumor necrosis factor-alpha), all measured by high sensitivity enzyme-linked immunoabsorbent assay. Results: There was a significant correlation between TNF alpha and the severity of CAD as assessed by the number of obstructed coronary vessels and the Gensini severity score, which is based on the proximity and severity of the lesions. Patients had more coronary vessel disease (> 70% stenosis) with increasing tertiles of serum TNF alpha; the mean number of vessels affected was 1.15, 1.33, and 2.00 respectively (P< 0.001). IL-6 correlated with the Gensini severity score and coronary vessel disease (> 70% stenosis). A weaker correlation was present with IL-1 receptor antagonist. A significant correlation was not found with the other inflammatory markers. After adjustment for major risk factors, multivariate analyses showed that significant independent predictors of CAD vessel disease were TNF alpha (P< 0.05) and combined levels of TNF alpha and IL-6 (P< 0.05). IL-6 levels were independently predictive of Gensini coronary score (P < 0.05). Conclusion: TNF alpha and IL-6 are significant predictors of the severity of coronary artery disease. This association is likely an indicator of the chronic inflammatory burden and an important marker of increased atherosclerosis risk.
Abstract: Background - PD-L1 and PD-L2 are ligands for the inhibitory receptor programmed death-1 (PD-1), which is an important regulator of immune responses. PD-L1 is induced on cardiac endothelial cells under inflammatory conditions, but little is known about its role in regulating immune injury in the heart. Methods and Results - Cytotoxic T-lymphocyte - mediated myocarditis was induced in mice, and the influence of PD-L1 signaling was studied with PD-L1/L2 - deficient mice and blocking antibodies. During cytotoxic T-lymphocyte-induced myocarditis, the upregulation of PD-L1 on cardiac endothelia was dependent on T-cell- derived interferon-gamma, and blocking of interferon-gamma signaling worsened disease. Genetic deletion of both PD-1 ligands [PD-L1/2((-/-))], as well as treatment with PD-L1 blocking antibody, transformed transient myocarditis to lethal disease, in association with widespread polymorphonuclear leukocyte-rich microabscesses but without change in cytotoxic T-lymphocyte recruitment. PD-L1/2((-/-)) mice reconstituted with bone marrow from wild- type mice remained susceptible to severe disease, which demonstrates that PD-L1 on non-bone marrow-derived cells confers the protective effect. Finally, depletion of polymorphonuclear leukocytes reversed the enhanced susceptibility to lethal myocarditis attributable to PD-L1 deficiency. Conclusions - Myocardial PD-L1, mainly localized on endothelium, is critical for control of immune- mediated cardiac injury and polymorphonuclear leukocyte inflammation.
Abstract: T lymphocyte responses promote proatherogenic inflammatory events, which are influenced by costimulatory molecules of the B7 family. Effects of negative regulatory members of the B7 family on atherosclerosis have not been described. Programmed death-ligand 1 (PD-L1) and PD-L2 are B7 family members expressed on several cell types, which inhibit T cell activation via binding to programmed death-1 (PD-1) on T cells. In order to test whether the PD-1/PD-L pathway regulates proatherogenic T cell responses, we compared atherosclerotic lesion burden and phenotype in hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice and LDLR-/- controls. PD-1/2 deficiency led to significantly increased atherosclerotic burden throughout the aorta and increased numbers of lesional CD4+ and CD8+ T cells. Compared with controls, PD-L1/2(-/-)LDLR(-/-) mice had iliac lymphadenopathy and increased numbers of activated CD4+ T cells. Serum levels of TNF-alpha were higher in PD-L1/2(-/-)LDLR(-/-) mice than in controls. PD-L1/2-deficient APCs were more effective than control APCs in activating CD4+ T cells in vitro, with or without cholesterol loading. Freshly isolated APCs from hypercholesterolemic PD-L1/2(-/-)LDLR(-/-) mice stimulated greater T cell responses than did APCs from hypercholesterolemic controls. Our findings indicate that the PD-1/PD-L pathway has an important role in downregulating proatherogenic T cell response and atherosclerosis by limiting APC-dependent T cell activation.
Abstract: Background: Infective endocarditis is a common disease with significant morbidity mortality. Objectives: To define clinical and echocardiographic parameters predicting morbidity and in-hospital mortality in patients with infective endocarditis hospitalized in a tertiary hospital from 1991 to 2000. Methods: All patients with definite infective endocarditis diagnosed according to the Duke criteria were included. We examined relevant clinical features that might influence outcome. Results: The study group comprised 100 consecutive patients, 77 with native value and 23 with prosthetic valve endocarditis. The overall in-hospital mortality rate was 8%. There was a higher mortality in the PVE group compared to the NVE group (13% vs. 7%, P = 0.07) The mortality rate in each group, with or without surgery, was not significantly different. Clinical predictors of mortality were older age and hospital-acquired endocarditis. The presence of vegetations and their size were significant predictors of major embolic events and mortality. Staphylococcus aereus was a predictor of mortality (25% vs 5%, P < 0.005) and abscess formation. Multivariate logistic analysis identified vegetation size and S. aureus as independent predictors of mortality. Conclusions: Mortality is higher in older hospitalized patients. S. aureus is associated with a poor outcome. Vegetation size is an independent predictor of embolic events and of a higher mortality.
Abstract: Background: Coronary artery disease (CAD) is a highly prevalent disease with significant morbidity and mortality. Periodontal disease has been suggested to influence this disease and has been associated with CAD in some epidemiologic studies. However, this relation is still controversial. This study aimed to determine the relationship between periodontal disease measures and CAD and acute coronary syndromes (ACSs). Methods: Two hundred one patients presenting with stable angina or ACS referred for coronary angiography underwent a periodontal assessment including evaluation of periodontal pathogens. Severity of CAD was determined by the number of obstructed coronary arteries. Results: Patients with severe CAD defined by multiple vessel disease had significantly more periodontal destruction than those with mild CAD, as shown by mean clinical attachment level, a measure of chronic periodontal disease (CAL; 5.43 +/- 1.8 versus 4.85 +/- 1.6; P = 0.02), percentage of teeth with CAL; 5 mm (82.1 +/- 23.4 versus 70.4 +/- 26.9; P= 0.002), and number of missing teeth (8.75 +/- 6.6 versus 6.76 +/- 6.6; P= 0.03). Logistic regression analysis showed that percentage of teeth with CAL >= 5 mm was significantly associated with CAD severity. Patients with ACS had significantly higher plaque scores, gingival index, and Porphyromonas gingivalis counts than stable patients. Logistic regression analysis showed that either plaque score or percentage of P. gingivalis was significantly associated with ACS. Conclusion: Periodontal destruction measures are significantly correlated with CAD severity, whereas periodontal infectious measures are significantly associated with clinical cardiac status.
Abstract: Background - T-cell-mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule ( ICOS) on atherosclerosis and associated immune responses. Methods and Results - Bone morrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor-deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4(+) T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4(+) T cells from ICOS-deficient chimeras proliferated more and secreted more interferon-gamma and tumor necrosis factor-alpha than T cells from control mice, which suggests a lack of regulation. FoxP3(+) regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS- deficient mice had decreased numbers of FoxP3(+) Treg and impaired in vitro Treg suppressive function compared with control mice. Conclusions - ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.
Abstract: Chronic graft versus host disease (cGVHD) is the result of an immune-mediated attack by transplanted donor lymphocytes, entailing inflammatory damage to host target organs. Clinically, the post-bone marrow transplantation (BMT) graft versus leukemia (GVL) effect may be associated with GVHD. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of cGVHD in a murine model. To evaluate whether amelioration of cGVHD in mice by induction of oral immune regulation in donors toward recipient pretransplant lymphocyte antigens is associated with attenuation of the GVL effect donor B10.D2 mice were fed with Balb/c splenocytes, B10.D2 splenocytes, bovine serum albumin (BSA), or regular chow, every other day for 10 days. Subsequently, transplantation of 2 X 107 splenocytes from donor B10.D2 mice to recipient Balb/c mice was undertaken, followed by inoculation of 3 X 103 BCL-1 leukemia on the day of BMT. Control groups were fed identically without leukemia inoculation. Mice were followed for survival and leukemia progression. Induction of tolerance was assessed by a mixed lymphocyte reaction (MLR). Cutaneous GVHD was assessed macroscopically. To elucidate the mechanism of any observed effect, serum interferon (IFN), interleukin (IL-2), IL-12, IL-4, and IL-10 were determined by enzyme-linked immuncisorbent assay and flow cytometry analysis for CD4+, CD8+, and NK 1.1 + lymphocyte subpopulations was performed. There was no significant difference in leukemia progression manifested by survival or white blood cell counts of orally immune-regulated mice compared with control animals. Cutaneous cGVHD was significantly ameliorated in Balb/c mice transplanted from tolerized B10.D2 mice. This effect was associated with a significant reduction in the mixed lymphocyte response of effector splenocytes from tolerized B10.D2 mice against Balb/c target splenocytes; significantly decreased serum IFN-gamma and IL-2; increased serum IL-12 levels; increased peripheral NK1.1 + cells; and CD4+/CD8+ lymphocyte ratio. Oral tolerization of BMT donors toward recipient antigens ameliorates cGVHD without hampering the GVL effect. (c) American Society for Histocompatibility and Immunogenetics, 2005. Published by Elsevier Inc.
Abstract: Background: Pyoderma gangrenosum is an uncommon ulcerative cutaneous condition associated with inflammatory bowel disease. PG occurs rarely in IBD patients and there are insufficient data on the clinical manifestations of this disease with IBD. Objective: To determine the incidence, clinical manifestations and treatment of PG in patients with IBD and the connection to IBD, its activity and extent. Methods: All patients hospitalized with IBD at a university hospital during a 20 year period were evaluated for the occurrence of PG. Results: Of 986 patients hospitalized for IBD 6 suffered from PG (0.6% incidence). Their average age was 37 with equal sex distribution and equal distribution of Crohn's disease and ulcerative colitis. PG appeared 6.5 years on average after diagnosis of IBD in all patients. The development of PG correlated with significant clinical exacerbation of IBD, the majority having active colitis at the onset of the PG. Extra-intestinal manifestations of IBD occurred in half the patients (sacroiliitis, peripheral arthritis and erythema nodosum). Pathergy was not elicited in any patients. Four patients had multiple skin lesions, frequently on the lower extremities. Diagnosis was made by skin biopsy in four patients. There was little correlation between amelioration of IBD and the skin lesions. Treatment consisted of high dose steroids and immunomodulatory drugs (cyclosporine, azathioprine and dapsone) in conjunction with topical treatment. Conclusions: PG is a rare extra-intestinal manifestation of IBD that coincides with the exacerbation of the intestinal disease but does not always respond to treatment of the bowel disease.
Abstract: Background: Acute myocardial infarction is rare in people under the age of 30. Objective: To determine the clinical features and outcome in young patients presenting with AMI. Methods: All patients aged 30 years and younger hospitalized with AMI during a period of 8 years (1993-2000) were evaluated for clinical features and outcome. Results: Of the 3,758 patients with AMI, 15 were 30 years old or younger (0.4%). The mean age was 28 (range 21-30 years) and all were male. Eight had normal coronary arteries on angiogram; seven had obstructive coronary artery disease. Patients with OCA had more classical risk factors for coronary disease. A complete diagnostic workup was abnormal in four patients with NCA: thrombophilia in two patients, spasm due to alcohol withdrawal and hyperthyroidism in one patient each. All patients presented with typical new-onset chest pain. None had a previous history of angina. All patients with OCA received reperfusion therapy as compared to one patient with NCA. Peak creatine phosphokinase in NCA and OCA was 504 +/- 547 and 1,328 +/- 440 respectively (P < 0.01). All patients with NCA had good left ventricular function on follow-up echocardiography, compared to only three in the OCA group (P = 0.02). There was one death due to cardiogenic shock in a patient with OCA. Follow-up of 4 +/- 2 years demonstrated recurrent acute coronary syndromes in four of seven patients with OCA versus none in the NCA patients (P = 0.02). Conclusions: AMI is rare in very young patients, and more than half have NCA. A thrombophilic tendency or spasm should be considered. Young patients with NCA have an excellent prognosis.
Abstract: BACKGROUND, Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) expresses hepatitis B surface antigen (HBsAg) on its cell surface, and this may serve as a tumor-associated antigen. It was shown previously that adoptive transfer of immunity against HBsAg facilitates the suppression of experimental human HCC-expressing HBsAg in athymic mice. The authors recently showed that it was possible to augment the anti-HBV immune response through induction of oral immune regulation for HBV-associated antigens. The objective of this study was to evaluate the effect of oral immune regulation for HBV antigens on the growth of HBsAg-expressing HCC. METHODS. Recipient athymic Balb/c mice were irradiated sublethally and injected with 10(7) human hepatoma cells followed by the adoptive transfer of 2 x 10(6) splenocytes from donor mice. Four groups of donor Balb/c mice were studied: Two groups were immune modulated through oral administration of HBV antigens (HBsAg, PreS1, and PreS2) or bovine serum albumin (BSA). Two control groups were immunized for HBsAg and fed HBV antigens or BSA. Recipient mice were followed for tumor volume and serum alpha-fetoprotein (alphaFP) levels. The humoral immune response was determined by measuring serum HBs antibodies, HBV specific T-cell immune modulation was assessed in vitro by HBV specific T-cell proliferation and interferon gamma (IFNgamma) ELISPOT assays as well as cytokine expression by reverse transcriptase-polymerse chain reaction assays. RESULTS. The adoptive transfer of orally immune modulated HBV splenocytes induced complete tumor suppression in recipient mice compared with control mice transplanted with nonimmune modulated cells (BSA), which showed significant tumor growth (serum aFP levels were 3.5 ng/mL and 2320.0 ng/mL, respectively). Control mice transplanted with anti-HBs immunized cells (with or without oral immune modulation) manifested similar tumor suppression (3,5 ng/mL and 0.5 ng/mL, respectively). Immunoregulation for HBV antigens augmented the HBV specific T-cell immune response, as manifested by ail increase in HBV specific T-cell proliferation and IFNgamma ELISPOT assays in mice orally immune regulated with HBV proteins compared with naive mice. Tumor suppression was mediated through increased IFNgamma production in immune regulated and immunized mice. CONCLUSIONS, The induction of oral immune regulation for HBV antigens modulated the antitumor immune response, thus suppressing the growth of HCC in mice. This effect was mediated by the enhancement of anti-HBV specific T-cell immunity. (C) 2002 American Cancer Society.
Abstract: Adoptive transfer of immunity against hepatitis B surface antigen (HBsAg) was previously shown to facilitate suppression of experimental human hepatocellular carcinoma (HCC) expressing HBsAg in athymic mice. We have shown that oral tolerance induces antigen-specific immune suppression of HBsAg by feeding hepatitis B virus (HBV) antigens. In the present study we evaluated the effect of oral tolerance induction toward HBV or HCC antigens on the growth of experimental HCC-expressing HBsAg in mice. Tolerance induction was induced in mice by 5 oral feedings of 1 mug HBV antigens or HCC-extracted proteins (50 jig protein) before vaccination with recombinant HBsAg. Splenocytes (2 X 10(6)) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 10(7) human hepatoma Hep3B cells. Adoptive transfer of splenocytes immunized toward HBsAg prevented tumor growth. At 4 weeks after splenocyte transplantation, tumor volume and serum alpha-fetoprotein (AFP) levels in athymic mice transplanted with splenocytes immunized to HBsAg were undetectable as compared with 1,048 +/- 738 mm(3) and 2,500 +/- 1,431 ng/ml in recipients of naive splenocytes (p < 0.0001). Mice receiving splenocytes tolerized toward Hep3B cells, as manifested by reduced serum HBs antibody levels, reduced HBV-specific stimulation index and reduced HBV-specific-IFN gamma spot-forming cells, had early tumor growth evident by elevated AFP serum levels, weight loss and mortality, which were suppressed at 6 weeks. Mice transplanted with splenocytes tolerized toward HBV antigens did not have direct evidence of tumor growth. Induction of oral tolerance toward HCC-extracted proteins enabled transient tumor growth in this model. This effect was mediated through downregulation of the anti-HBV immune response. (C) 2002 Wiley-Liss, Inc.
Abstract: Background and Aim: In glucose-6-phosphate dehydrogenase (G6PD) deficiency, the enzyme is deficient in liver cells as well as in erythrocytes. It has been suggested that this may be associated with a more severe clinical presentation of acute viral hepatitis A. The aim of this study is to determine the severity of liver disease in patients with viral hepatitis and G6PD deficiency. Methods: Eighteen patients with diagnosed G6PD deficiency and acute hepatitis A were compared with 18 matched control patients with hepatitis A in a university hospital for liver disease severity and clinical outcome. Results: Two of 18 patients with G6PD deficiency had neurological deterioration. Patients with G6PD deficiency had a mean peak prothrombin time (PT) that was significantly prolonged as compared with the control group (15.5 +/- 3.7 vs 12.9 +/- 2.0 s, respectively, P < 0.02), and a significantly higher proportion had an abnormal PT (PT > 13.3 s): 61 versus 11% (P < 0.0001). Hemolysis occurred in 44% of the G6PD deficiency patients. Total and direct bilirubin were significantly higher in all patients with G6PD deficiency, including patients without hemolysis. There was no significant difference in liver enzyme levels between the two groups. Patients with G6PD deficiency had a longer average hospital stay (9.5 +/- 4.8 vs 3.4 +/- 0.8 days, respectively, P < 0.001). There was no difference in the final clinical outcome between the two groups, and recovery of liver function was seen in all patients. Conclusions: Glucose-6-phosphate dehydrogenase deficiency in patients with hepatitis A causes a more severe initial clinical presentation, but does not alter the final clinical outcome. (C) 2001 Blackwell Science Asia Pty Ltd.
Abstract: The association of hepatitis C virus (HCV) with neoplasia is not completely understood. Hepatitis C virus is hepatolymphotrophic. It is considered an inducing factor of hepatocellular carcinoma (HCC) and is associated with various types of lymphomas. We describe a patient with HCV cirrhosis who developed gastric lymphoma and HCC, and we review the current data and theories about the oncogenesis of HCV.
Abstract: The imbalance between Th1 pro-inflammatory and Th2 anti-inflammatory cytokine-producing cells plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Induction of oral tolerance to colitis-extracted proteins was previously shown to down-regulate the anti-colon immune response, thereby alleviating experimental colitis. Immune bystander effect and liver-associated lymphocytes expressing the NK1.1 marker (NK1.1(+) LAL) have been suggested as being important in tolerance induction. The aims of the present study were to determine whether oral administration of inflammatory and non-inflammatory colon-extracted proteins of different species can induce peripheral immune tolerance and alleviate experimental colitis; and to examine the role of NK1.1(+) LAL in oral tolerance induction. Colitis was induced in C57/136 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted from TNBS-colitis colonic wall, or normal colonic wall, from four different species. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFN gamma) and interleukin 10 (IL10) levels were measured by ELISA. To evaluate the role of NK1.1(+) LAL in maintaining the balance between immunogenic and tolerogenic subsets of cells, their cytotoxicity functions were tested in tolerized and non-tolerized-mice. The administration of mouse-derived colitis-extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or human inflammatory colons, was found to alleviate experimental colitis. Tolerized mice had less diarrhoea; showed a marked reduction of colonic ulceration, intestinal and peritoneal adhesions, wall thickness, and oedema; and demonstrated a significant improvement of all microscopic parameters for colitis. Induction of tolerance led to an increase in IL10 and a decrease in IFN gamma serum levels. NK1.1(+) LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from normal rat, rabbit, and human colon, or from rabbit inflammatory colon, developed severe colitis, with a marked increase in IFN gamma and a decrease in IL10 serum levels, and down-regulation of NK1.1(+) LAL function. This study has shown that oral tolerance can be induced in experimental colitis by means of the feeding of surrogate antigens; this alleviates experimental colitis. NK1.1(+) LAL cytotoxicity function is associated with peripheral tolerance induction and may help to maintain the Th1/Th2 immune balance. Copyright (C) 2001 John Wiley & Sons, Ltd.
Abstract: The mechanism by which hepatocellular carcinoma (HCC) develops and the role of the hepatitis B virus (HBV) in inducing tumors, are not yet well understood. Patients persistently infected with HBV tend to have a defective immune response against the virus, which fails to dear the virus and also induces liver injury. This defective response may also have an inducible effect on the virus and on cells that express HBV antigens, as well as play a role in the growth of neoplasm. It is possible that one of the mechanisms of tumor growth is related to a deviant immune response towards viral or tumor associated antigens. We describe two responses against the tumor. A 'good' response that would suppress the tumor and a 'bad' response that would promote it and theorize that the net balance between 'bad' and 'good' responses of the immune system towards a cancerous cell and/or antigen will predict whether a tumor grows or is suppressed. Oral tolerance involves the induction of immunological hyporesponsiveness towards specific antigens, It was shown that oral tolerance induces antigen-specific immune suppression towards tumor-associated-antigens by feeding of HBV or other tumor proteins. We hypothesize that induction of immune tolerance towards tumor-associated antigens will suppress the immune response towards these antigens, thus reducing the 'bad' response. The proposed new treatment strategy would redirect the focus from augmenting anti-tumor immune responses to inducing host tolerance towards the tumor. (C) 2001 Harcourt Publishers Ltd.
Abstract: Oral tolerance is a recognized procedure for induction of antigen-specific peripheral immune hyporesponsiveness. Recently, it has been shown that oral tolerance can be used to prevent experimental colitis. The aim of this study was to test whether induction of oral tolerance toward proteins extracted from inflammatory and noninflammatory colons can alleviate preexisting experimental colitis. Colitis was induced in BALB/c mice by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS-induced colitis or normal colons, before, or 7 days after colitis was induced. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFN gamma) and interleukin (IL)4 levels were measured by enzyme-linked immunosorbent assay. Feeding of colitis- or normal colon-extracted proteins before, or following colitis induction, ameliorated colonic inflammation as shown by decreased diarrhea, increased body weight, reduction of colonic ulcerations, intestinal and peritoneal adhesions, wall thickness, and edema. Histological parameters for colitis were markedly improved in tolerized animals, and there was a significant reduction in inflammatory response and mucosal ulcerations. Tolerized mice developed an increase in IL4 and a decrease in IFN gamma serum levels. The results show that induction of oral tolerance to colitis- or normal colon-extracted proteins down-regulated preexisting anticolon immune response, thereby ameliorating experimental colitis. Tolerance induction was mediated via a shift from a proinflammatory T helper (Th)1 to an anti-inflammatory Th2 immune response.
Abstract: OBJECTIVE:To report a case of complete atrioventricular (AV) block and QTc prolongation following coadministration of high-dose verapamil and erythromycin. SUMMARY: A 79-year-old white woman was admitted to the hospital due to extreme fatigue and dizziness. On admission, heart 40 beats/min and blood pressure was 80/40 mmHg. An electrocardiogram showed complete atrioventricular (AV) block, escape rhythm of 50 beats/min, and QTc prolongation 583 msec. This event was attributed to concomitant treatment with verapamil 480 mg/d and erythromycin 2000 mg/d, which was prescribed one week before admission. DISCUSSION: This is the first case published describing complete AV block and prolongation of QTc following coadministration of erythromycin and verapamil. CYP3A4 is the main isoenzyme responsible for metabolism of erythromycin and verapamil. Both drugs are potent inhibitors of CYP3A4 and of P-glycoprotein this may be the basis for the pharmacokinetic interaction between erythromycin and verapamil. In addition to being a woman, our patient had other risk factors for QT prolongation: slow baseline heart rate (probably induced by verapamil), left ventricular hypertrophy, and possibly ischemic heart disease. CONCLUSIONS: This life-threatening arrhythmia was probably the result of a pharmacokinetic and/or pharmacodynamic interaction of high dose verapamil and erythromycin.
Abstract: We report a case of chronic mesenteric ischemia that caused abdominal angina and weight loss in an 80-year-old woman. A mesenteric angiogram revealed total occlusion of the superior mesenteric artery and 90% stenosis of the celiac and inferior mesenteric arteries. Balloon angioplasty of the celiac artery failed because of elastic recoil. A 15-mm Palmaz-Schatz stent was dilated to 6 mm in the proximal celiac artery with an excellent angiographic result and complete resolution of symptoms. A clinical, I-year follow-up demonstrated success with no recurrence of pain. This case report illustrates the value of balloon dilatation and stent implantation in a patient with atherosclerotic narrowing of multiple abdominal visceral arteries.
Abstract: PURPOSE: To determine the causes of pleural effusions in patients with heart failure, and the association of the characteristics of these statistics with the use of diuretics. SUBJECTS AND METHODS: Eighty-one patients with a definite diagnosis of heart failure who underwent thoracentesis were evaluated. Fluids were classified as transudates or exudates using Light's criteria. RESULTS: Forty-one effusions (in 34 patients) were transudates, and 54 (in 47 patients) were exudates. A specific cause was found for 32 of the exudates (27 patients); except for heart failure, no obvious cause was found for the remaining 22 fluids (20 patients). Euxdates with a specific cause for an exudate were more likely to have at least two of Light's criteria (18 of 27 [67%]) than did exudates without a known cause (2 of 21 [10%]). Intravenous diuretic therapy in the 24 hours before thoracentesis was significantly more common among patients with exudates without a specific cause. CONCLUSIONS: Patients with heart failure may have exudative pleural effusions without an obvious cause except heart failure. (C) 2001 by Excerpta Medica, Inc.
Abstract: Chronic graft versus host disease (cGVHD) is a major complication that can develop after bone marrow transplantation. It involves an immune-mediated attack by transplanted donor lymphocytes, and often results in inflammatory damage of host target organs. immune hyporesponsiveness induced by oral antigen administration has been recently shown to prevent the development of cGVHD in a murine model. The aim of this study was to evaluate whether tolerance induction in bone marrow transplant (BMT) recipients after transplantation, toward their pretransplant antigens, can alleviate preexisting cGVHD in a mouse model. cGVHD was generated by infusing 2.5 x 10(7) splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ by minor histocompatibility antigens. Transplantation resulted in cGVHD, with characteristic scleroderma-like cutaneous fibrosis, increased skin collagen content, decreased body weight, and hepatic and small bowel inflammation. Oral tolerance was induced by feeding recipient BALB/c mice with proteins extracted from BALB/c splenocytes for 11 days after B10.D2 splenocyte transplantation. Tolerance induction was evidenced by a significant reduction in mixed lymphocyte response of effector splenocytes from tolerant BALB/c mice transplanted with B10.D2 splenocytes against BALB/c target splenocytes. Oral tolerance decreased skin collagen deposits. Reduction of collagen (alpha 1(1)) gene expression and skin collagen were shown by in situ hybridization and histochemistry, respectively. Liver and bowel biopsy specimens revealed less inflammation. Serum IL-10 levels were higher in tolerant mice than in controls, whereas IFN gamma was significantly reduced. Oral tolerance of BMT recipients toward their pretransplant antigens after splenocyte transplantation down-regulated the immune attack by transplanted cells, thus ameliorating cGVHD. (Blood. 2000;95: 3613-3619) (C) 2000 by The American Society of Hematology.
Abstract: Background Sarcoidosis is a chronic multisystem disorder characterized by an exaggerated cellular immune response to antigens with the production of various antibodies including rheumatoid factor and antinuclear antibodies (ANA). The prevalence and significance of antibodies to double-stranded DNA (anti-dsDNA) in sarcoid patients is unknown. The occurrence of anti-dsDNA antibodies is known to be a specific marker of systemic lupus erythematosus (SLE), Sarcoidosis can occur with SLE. It is unclear if anti-dsDNA antibodies in patients with sarcoidosis signify the eventual development of SLE. Objectives: To determine the prevalence of anti-dsDNA antibodies in patients with sarcoidosis in a university hospital and their significance in predicting the diagnosis of associated SLE. Methods: In a retrospective study, 34 patient files with diagnosed sarcoidosis in a university hospital during a period of 15 years were reviewed for serological markers, including ANA, anti-dsDNA, and immunoglobulin and C3 levels. The occurrence of SLE in these patients also was evaluated. Results:ANA were positive in 10 of 34 of the patients screened. Two patients with sarcoidosis had antibodies to dsDNA. C3 levels in these 34 patients were an average of 87.7 +/- 25.3 mg/100 mt, which is within the normal range. IgG immunoglobulin levels were an average of 2,206 +/- 999 mg/100 mt, which was above normal limits. The 2 patients who were positive for anti-dsDNA had normal C3 levels and SLE did not develop during a follow-up period of 10 to 15 years. Conclusions: Anti-dsDNA antibodies may occur in patients with sarcoidosis, but their presence does not predict the subsequent development of SLE. Copyright (C) 2000 by W.B. Saunders Company.
Abstract: Mefloquine is an effective drug for prophylaxis and treatment of malaria caused by Plasmodium falciparum. It is generally well tolerated with few side effects. Minimal elevation of liver function tests has been reported after exposure to mefloquine, especially in susceptible individuals with prior abnormal liver function tests. Our patient, who had had elevated liver function tests attributed to heart failure, experienced an acute elevation of liver transaminases 6 weeks after exposure to mefloquine 250 mg/week. Cessation of the drug caused test results to return to normal. Mefloquine should be prescribed cautiously in patients with liver disease.
Abstract: Background: Hepatitis B virus (HBV) is a non-cytopathic virus, and the hepatocellular injury that occurs as a consequence of HBV infection is mediated by the host antiviral immune response. Subjects with natural tolerance to HBV have minimal or no liver injury despite chronic viremia. We have shown that immune tolerance towards viruses call be induced by oral administration of viral proteins. aims: To test whether oral induction of tolerance can be induced towards HBV antigens, and whether oral tolerance induction downregulates preexisting anti-HBV immune response. Methods: Oral tolerance was induced via feeding of five low oral doses of HBV proteins (HBsAg + preS1 + preS2, BioHepB). This was followed by two inoculations with the BioHepB vaccine. Humoral immune tolerance was evaluated by measuring serum levels of anti-HBs antibody titers at monthly intervals. To determine if oral tolerance induction downregulates pie-existing anti-HBs immunity, mice were inoculated twice with the BioHepB vaccine, Followed by feeding of BioHepB-HBV proteins. Results: Feeding of HBV proteins markedly inhibited production of anti-HBs antibodies in naive mice. Anti-HBs titers were 45 versus 135 mIU/ml, in tolerized versus non-tolerized controls (P<0.005). Moreover, oral tolerance induction effectively down-regulated pr e-existing immunity and reduced the anti-HBs titers in previously immunized mice to 112 versus 223 mIU/ml, in tolerized compared with non-tolerized controls: (P < 0.01). Conclusions: Induction of oral tolerance towards HBV proteins downregulates the antiviral humoral immune response in naive mice, and in the presence of preexisting anti-HBV immunity. This approach should be further investigated as a method for alleviation of antiviral-mediated liver injury in chronic HBV hepatitis. (C) 2000 Elsevier Science B.V. All rights reserved.
Abstract: Oral tolerance is the induction of immunological hyporesponsiveness towards orally administered antigens. Tolerance initiation involves induction of anti-inflammatory (Th2) lymphocytes, with downregulation of pro-inflammatory (Th1) lymphocytes, The liver was previously shown to play a critical role in oral tolerance induction. The aim of the present study was to test whether liver-associated-lymphocytes expressing the NK1.1 marker (NK1.1+ LAL) are substantial for induction of oral tolerance in an experimental colitis model. Colitis was induced in C57 mice by intracolonic instillation of trinitrobenzensulfonic acid (TNBS), Mice received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall. Anti-NK1.1 monoclonal antibodies were injected before tolerance induction. Colitis was assessed by standard clinical, macroscopic, and microscopic scores. Serum IFN-gamma, TGF-beta 1, and IL4 levels were measured by enzyme-linked immunosorbent assay. To evaluate the role of NK1.1+ LAL in keeping the balance between immunogenic and tolerogenic subsets of cells, we tested whether peripheral lymphocytes harvested from tolerized and NK1.1-depleted nontolerized mice can adoptively transfer the tolerance into naive irradiated rats. Depletion of NK1.1+ LAL prevented immune tolerance induction in the experimental colitis model. NK1.1+ LAL-depleted nontolerized mice, disclosed severe clinical, macroscopic, and microscopic parameters of colitis. These mice had significantly lower TGF-beta 1, IL4, and higher IFN-gamma serum levels, and their lymphocytes failed to transfer the tolerance into naive animals. In contrast, the feeding of colitis-extracted proteins, without NK1.1+ LAL depletion, markedly alleviated the disease. Tolerized mice had higher IL4 and TGF-beta 1 and lower IFN-gamma serum levels, and adoptive transfer of their suppressor splenocytes markedly alleviated colitis in naive recipients. NK1.1+ LAL plays a critical role in oral tolerance induction. Depletion of this subset of LAL prevents a shift from Th1 to a Th2 type of immune response, hindering the ability to induce immune tolerance.
