Sex-matched Healthy Blood Donors Research Articles

Imbalance of Follicular Helper and Follicular Regulatory T Cells in Chronic Rhinosinusitis with Nasal Polyps.

Data regarding the imbalance in follicular helper T (Tfh) and follicular regulatory T (Tfr) cell responses in patients having chronic rhinosinusitis with nasal polyps (CRSwNP) is so far limited. Thus, we aimed to assess the changes in circulating Tfh and Tfr in CRSwNP patients. This case-control study included 21 patients having CRSwNP and 20 age and sex-matched healthy blood donors as a control group. Lund-Mackay staging system was used for radiologic scoring of chronic rhinosinusitis. Two milliliters of peripheral blood samples were collected from all participants into EDTA-containing vacutainer tubes to assess the levels of Tfh and Tfr cells using flow cytometry. Patients having CRSwNP did not show significant differences in the percentages of CD4+ T cells and total CD4+CXCR5+ T cells from healthy controls. Meanwhile, levels of both activated circulating Tfh and Tfr showed a marked rise in patients than controls. In addition, a positive correlation was observed between the levels of both activated Tfh and Tfr cells. An imbalance in circulating Tfh/Tfr levels was detected in patients having CRSwNP. A significant rise in the levels of Tfh and Tfr was detected in patients proposing a possible role of this imbalance in disease pathogenesis.

Interleukin-6 plasma levels are elevated in patients with acute myocardial infarction and predict death or recurrent infarction within 1 year - a case-control study

Abstract Background Acute myocardial infarction (AMI) harbours marked inflammatory components. While cytokines of the same family have been causally related to patient outcome, the role of interleukin (IL)-6 in AMI remains incompletely understood. Recent trials suggest benefits of inhibiting IL-6 in patients with ST-segment elevation myocardial infarction (STEMI). In patients at high atherosclerotic risk, IL-6 blockade reduces markers of inflammation and thrombosis. Purpose This study aimed to assess the levels of IL-6 in AMI patients and their predictive value. Methods 160 cases (recurrent AMI or death within 1 year) and 160 matched controls were selected from the prospective, multicentric SPUM-ACS Cohort. All patients had an AMI (STEMI or NSTEMI) as initial event and underwent percutaneous coronary intervention (PCI) within 24h of symptom onset. Blood samples were drawn before PCI and biomarker plasma levels were assessed (mesoscale). Comparisons were made with age- and sex-matched healthy blood donors (HD). IL-6 levels are presented as medians and interquartile ranges. Cases, controls and HD were compared using the Kruskal-Wallis test. Correlations of baseline variables to IL-6 levels within cases and controls were assessed by linear regression analyses. Patients were divided into those with higher or lower IL-6 levels according to the median IL-6 level. Kaplan-Meier (KM) analyses for the combined endpoint of death or recurrent AMI were performed. Results The overall median IL-6 level was 21.3pg/ml. Patients with higher IL-6 had more previous AMI (n=22, 14%) than patients with lower IL-6 (n=12, 7%, p=0.045). Patients with increased IL-6 had more previous PCI (n=30, 20%) than patients with lower IL6 (n=19, 11%, p=0.045). Both cases and controls showed higher levels of IL-6 than HD (cases: 25.7pg/ml [14.8–81.6], controls: 20.0pg/ml [11.3–40.1], HD: 5.9pg/ml [3.6–9.9]; cases/controls vs. HD: p<0.0001). Among AMI patients, cases showed higher IL-6 levels than controls (p=0.030) (Figure 1). Within cases and controls, IL-6 was related to IL-1beta (r=0.628, p<0.001), IL-1alpha (r=0.174, p=0.002) and IL-1 receptor antagonist (r=0.422, p<0.001). IL-6 was related to neutrophil/lymphocyte ratio (r=0.147, p=0.016), but not to high-sensitivity C-reactive protein (r=0.087, p=0.142) or N-terminal pro B-type natriuretic peptide (r=0.091, p=0.118). IL-6 was related to Killip Class upon presentation (r=0.190, p<0.001). KM analyses showed significantly higher rates of death or recurrent AMI within 1 year for patients with higher IL-6 (log-rank p=0.006, Figure 2), with early divergence of the curves. Conclusions IL-6 is markedly higher in patients with AMI compared to healthy controls and predicts death or recurrent AMI within 1 year. IL-6 might be a valuable target for early anti-inflammatory therapy to patients with AMI. A deeper understanding of factors influencing IL-6 levels may help select those patients that will benefit most from such treatment.Figure 1:Cases vs. Controls vs. HDFigure 1:Kaplan-Meier Analysis

The relation between clinical and objective gait scores in clubfoot patients with and without a relapse

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with complex genetic inheritance. Many reports have provided evidence that signal transducer and activator of transcription-4 (STAT4) may participate in the pathogenesis of SLE.The aim was to investigate the clinical significance and possible association of STAT4 (G/T) genetic polymorphism and the susceptibility to SLE in a cohort of Egyptian female patients.Sixty-five Egyptian SLE female patients and 100 age and sex-matched unrelated female healthy blood donors who served as controls, were included in the study. STAT4 genotyping was performed by real time PCR-allelic discrimination technique.STAT4 genotyping in patients revealed that 63.1% had GG, 32.3% GT and 6.15% wild (TT) genotype. There was a non-significant difference in the distribution of STAT4 genotypes between patients and controls. Vasculitis, photosensitivity and lupus nephritis were significantly increased in patients with the homomutant (GG and TT) compared to heteromutant (GT) genotype (p = 0.01, p = 0.04 and p < 0.01 respectively). Patients with a TT genotype had a significantly consumed C3 and C4 levels and higher anti-dsDNA positivity compared to those with GG and GT genotypes. Promoter polymorphism tended to be higher in juvenile-onset SLE cases.STAT4 (G/T) polymorphism was not associated with an increased risk of SLE in Egyptian females. However, vasculitis, photosensitivity and renal involvement were significantly higher among patients harboring the homomutant genotypes. Genetic polymorphism may be an important determinant affecting disease progression and is associated with DNA positivity and younger age of onset.

MiRNA 126 as a New Predictor Biomarker in Venous Thromboembolism of Persistent Residual Vein Obstruction: A Review of the Literature Plus a Pilot Study.

Venous thromboembolism (VTE) is the third most common cardiovascular disease. Interleukins (ILs) and micro-ribonucleic acids (miRNAs) have been proposed as molecules able to modulate endothelial inflammation and platelet hyperactivity. At present, no early biomarkers are available to predict the outcome of VTE. We investigated in a pilot study a selected number of miRNAs and ILs as prognostic VTE biomarkers and reviewed literature in this setting. Twenty-three patients (aged 18-65) with a new diagnosis of non-oncological VTE and free from chronic inflammatory diseases were enrolled. Twenty-three age- and sex-matched healthy blood donors were evaluated as control subjects. Serum miRNAs (MiRNA 126, 155, 17.92, 195), inflammatory cytokines (IL-6, tumor necrosis factor-α, IL-8), and lymphocyte subsets were evaluated in patients at enrolment (T0) and in controls. In VTE patients, clinical and instrumental follow-up were performed assessing residual vein obstruction, miRNA and ILs evaluation at 3 months' follow-up (T1). At T0, IL-8, activated T lymphocytes, Treg lymphocytes, and monocytes were higher in patients compared with healthy controls, as were miRNA 126 levels. Moreover, miRNA 126 and IL-6 were significantly increased at T0 compared with T1 evaluation in VTE patients. Higher levels of MiR126 at T0 correlated with a significant overall thrombotic residual at follow-up. In recent years an increasing number of studies (case-control studies, in vivo studies in animal models, in vitro studies) have suggested the potential role of miRNAs in modulating the cellular and biohumoral responses involved in VTE. In the frame of epidemiological evidence, this pilot study with a novel observational approach supports the notion that miRNA can be diagnostic biomarkers of VTE and first identifies miRNA 126 as a predictor of outcome, being associated with poor early recanalization.

A Systemic Protein Deviation Score Linked to PD-1+ CD8+ T Cell Expansion That Predicts Overall Survival in Diffuse Large B Cell Lymphoma

Current prognostic variables can only partly explain the large outcome heterogeneity in diffuse large B cell lymphoma (DLBCL). We aimed to investigate the utility of systems-level protein and immune repertoire profiling for outcome prognostication in DLBCL. In this retrospective study, we used proximity extension assay technology to quantify 81 immune-related proteins in serum or plasma in 2 independent cohorts in a total 111 DLBCL patients. Protein levels were assessed before and after treatment with rituximab and chemotherapy, and the patients were compared with 19 age- and sex-matched healthy blood donors. In a subset of the patients, we performed a broad mass cytometric characterization of immune cell repertoires in peripheral blood. Patients displayed large deviations in protein profiles compared with healthy controls. Development of a systemic protein deviation (SPD) score provided a 4-protein-based metric that reflected the overall degree of protein deviations compared with age- and sex-matched healthy blood donors. The SPD score identified patients with very poor overall survival in both cohorts and correlated with increased frequencies of peripheral blood PD-1+ CD8+ Tcells, and expansion of myeloid-derived suppressor cells. Our results show that a simple metric based on measurement of a small set of serum or plasma proteins can be used to probe systemic immune changes associated with poor survival in DLBCL. This finding warrants further investigation in larger, prospective studies to establish a clinical prognostic biomarker.

Methotrexate therapy is not associated with increased liver stiffness and significant liver fibrosis in rheumatoid arthritis patients: A cross-sectional controlled study with real-time two-dimensional shear wave elastography

ObjectiveTo explore the significance of the association between treatment with methotrexate (MTX) and liver stiffness in rheumatoid arthritis (RA) patients. MethodsWe enrolled 140 consecutive RA patients under MTX treatment (MTX-treated RA; mean treatment duration: 6.2 years; mean MTX cumulative dose: 4.67 g), 33 RA patients naive to MTX (MTX-naive RA) and 100 age and sex-matched healthy blood donors (HD). Liver stiffness was assessed by real time two-dimensional shear wave elastography, with values ≥7.1 Kilopascals (kPa) defining significant liver fibrosis. ResultskPa values in HD (4.32 ± 0.7) were lower than that in MTX-naive RA (4.92 ± 0.8) and MTX-treated RA (4.85 ± 0.9, p < .0005 for trend). On the contrary, the difference in kPa between MTX-naive and MTX-treated RA was not significant (p = .89). Similarly, liver stiffness was not significantly different across strata of cumulative MTX dose (4.95 ± 0.7 kPa in MTX <1 g, 4.90 ± 1.1 kPa in MTX 1–3 g and 4.80 ± 0.9 in MTX >3 g, p = .610). Significant liver fibrosis was diagnosed in 4 patients in the MTX-treated RA (highest kPa value = 7.6; no liver function test abnormalities or clinical signs of hepatic failure) and in none in both the MTX-naive RA and HD groups (p = .145). ConclusionLiver stiffness values, although within the normal range, are significantly higher in RA patients vs. controls, irrespective of MTX treatment. RA patients taking MTX do not have a higher prevalence of significant liver fibrosis when compared to MTX naive RA patients and the general population.

Detection of systemic inflammation in severely impaired chronic pain patients and effects of a multimodal pain rehabilitation program.

Background and aims Recent research indicates a previously unknown low-grade systemic or neurogenic inflammation in groups of chronic pain (CP) patients. Low-grade inflammation may have an important role in symptoms that have previously not been well depicted: widespread pain, tiredness and cognitive dysfunctions frequently seen in severely impaired CP patients. This study aimed to investigate the plasma inflammatory profile in a group of very complex CP patients at baseline and at a 1-year follow-up after participation in a cognitive behavior therapy (CBT)-based multimodal pain rehabilitation program (PRP). Methods Blood samples were collected from 52 well-characterized CP patients. Age- and sex-matched healthy blood donors served as controls. The samples were analyzed with a multiple Proximal Extension Analysis allowing a simultaneous analysis of 92 inflammation-related proteins consisting mainly of cytokines, chemokines and growth-factors. At follow-up, 1-year after participation in the RPR samples from 28 patients were analyzed. The results were confirmed by a multi-array technology that allows quantitative estimation. Results Clear signs of increased inflammatory activity were detected in the CP patients. Accepting a false discovery rate (FDR) of 5%, there were significant differences in 43/92 inflammatory biomarkers compared with the controls. In three biomarkers (CXCL5, SIRT2, AXIN1) the expression levels were elevated more than eight times. One year after the PRP, with the patients serving as their own controls, a significant decrease in overall inflammatory activity was found. Conclusions Our results indicate that the most impaired CP patients suffer from low-grade chronic systemic inflammation not described earlier with this level of detail. The results may have implications for a better understanding of the cluster of co-morbid symptoms described as the "sickness-syndrome" and the wide-spread pain seen in this group of patients. The decrease in inflammatory biomarkers noted at the follow-up after participation in the PRP may reflect the positive effects obtained on somatic and psycho-social mechanisms involved in the inflammatory process by a rehabilitation program. Besides the PRP, no major changes in medication or lifestyle factors were implemented during the same period. To our knowledge, this is the first study reporting that a PRP may induce inflammatory-reducing effects. Further studies are needed to verify the objective findings in CP patients and address the question of causality that remains to be solved. Implications The findings offer a new insight into the complicated biological processes underlying CP. It may have implications for the understanding of symptoms collectively described as the "sickness-syndrome" - frequently seen in this group of patients. The lowering of cytokines after the participation in a PRP indicate a new way to evaluate this treatment; by measuring inflammatory biomarkers.

Signal transducer and activator of transcription 4 (STAT4) G/T gene polymorphism in Egyptian systemic lupus erythematosus female patients

BackgroundSystemic lupus erythematosus (SLE) is a systemic autoimmune disease with complex genetic inheritance. Many reports have provided evidence that signal transducer and activator of transcription-4 (STAT4) may participate in the pathogenesis of SLE. Aim of the workThe aim was to investigate the clinical significance and possible association of STAT4 (G/T) genetic polymorphism and the susceptibility to SLE in a cohort of Egyptian female patients. Patients and methodsSixty-five Egyptian SLE female patients and 100 age and sex-matched unrelated female healthy blood donors who served as controls, were included in the study. STAT4 genotyping was performed by real time PCR-allelic discrimination technique. ResultsSTAT4 genotyping in patients revealed that 63.1% had GG, 32.3% GT and 6.15% wild (TT) genotype. There was a non-significant difference in the distribution of STAT4 genotypes between patients and controls. Vasculitis, photosensitivity and lupus nephritis were significantly increased in patients with the homomutant (GG and TT) compared to heteromutant (GT) genotype (p=0.01, p=0.04 and p<0.01 respectively). Patients with a TT genotype had a significantly consumed C3 and C4 levels and higher anti-dsDNA positivity compared to those with GG and GT genotypes. Promoter polymorphism tended to be higher in juvenile-onset SLE cases. ConclusionsSTAT4 (G/T) polymorphism was not associated with an increased risk of SLE in Egyptian females. However, vasculitis, photosensitivity and renal involvement were significantly higher among patients harboring the homomutant genotypes. Genetic polymorphism may be an important determinant affecting disease progression and is associated with DNA positivity and younger age of onset.

Vitamin D status in primary hyperparathyroidism: a Southern European perspective

Vitamin D deficiency (VDD) is common in patients with primary hyperparathyroidism (pHPT), and this could affect the clinical expression of the disease. However, few North American or North European studies have addressed this issue, showing vitamin D repletion in only about one-third of the patients. Vitamin D status was evaluated both in an observational study in a series of 206 consecutive patients with pHPT at diagnosis and in a case-control analysis with 113 age- and sex-matched healthy blood donors. Vitamin D status was assessed by measuring plasma 25-hydroxy-vitamin D (25OHD) levels and was defined as VDD or severe VDD if 25OHD was <20 ng/ml (<50 nm) and <10 ng/ml (<25 nm), respectively. No seasonal variability was observed in 25OHD levels. VDD was observed in 75 of 206 patients (36·4%). The VDD was severe in 24 of 75 patients (11·7%). There was no difference in prevalence of VDD between men and women nor between asymptomatic and 'bone and stone' symptomatic patients. 25OHD levels was negatively correlated with parathyroid hormone, ionized calcium, and bone turnover markers, and positively correlated with phosphate. 25OHD levels were also positively correlated with bone mineral density at all sites measured. In the case-control study, the overall prevalence of VDD and severe VDD was higher in patients with pHPT compared with controls (33·6% vs 10·6%, P < 0·0001, and 8·8% vs 1·8%, P = 0·0337, respectively). Our study shows that VDD occurs in about one-third of patients with pHPT resident in a Southern European area, a lower figure than previously reported. Moreover, VDD is related to a more severe bone disease, and its prevalence is higher in patients with pHPT than in healthy matched subjects.

Association of a Novel Adipokine with Insulin Resistance and Disease Severity in HCV Infected Patients

Retinol-binding protein 4 (RBP4) has been identified as a protein contributing to insulin resistance (IR). As insulin resistance is present in nearly all patients with liver cirrhosis, we evaluated RBP4 in patients with chronic hepatitis C virus infected patients (CHC). This study aimed to evaluate the role of serum retinol binding protein 4 (RBP-4) as a predictor for early detection of insulin resistance (IR) in patients with CHC infection. Research Design and Methods: Serum RBP4 was measured in 60 non diabetic CHC Patients classified according to Child- Pugh classification (Child A, Child B, Child C), 20 diabetic CHC patients and 20 age- and sex-matched healthy blood donors served as control subjects. RBP-4 correlation with the homeostasis model assessment of insulin resistance index (HOMA-IR) and metabolic factors was investigated. Results: Serum RBP-4 levels were significantly lower in HCV infected patients and HCV diabetic patients compared with controls (HCV 16545.17± 10633.16, Diabetic HCV 10310 ± 4371.31, Control 27820.0 ± 9316.46, P< 0.001). In addition, serum levels of RBP-4 significantly decreased between all stages of cirrhosis, with the lowest level in Child C. HOMA-IR not significantly higher in HCV infected patients compared to control (HCV 5.54 ± 3.67, and Control 4.11 ± 2.42). RBP-4 levels correlate positively with GGT (P<0.01), CHOL (P<0.05) and TG (P<0.05) in HCV Child C, additionally, it shows significant positive correlation with TG (P< 0.05) in HCV Child B. Conclusions: Disease severity may limit the role of RBP4 as a predictor of IR in CHC. These data demonstrate that RBP4 in CHC patients decreased due to reduced hepatic production, and it is not associated with insulin resistance. Keywords: HCV, RBP4, Insulin Resistance Abbreviations: RBP4: Retinol-binding protein 4, IR: insulin resistance, HOMA-IR: homeostasis model assessment of insulin resistance index, CHC: Chronic Hepatitis C Virus.

Use of serum VEGF (SVEGF) levels to predict outcome of esophageal cancer (EC) patients undergoing preoperative chemoradiation (CRT).

4140 Background: Increased sVEGF concentrations have been correlated with outcome in many solid tumors, including EC. 72 pts with untreated locally advanced EC undergoing CRT were evaluated to elucidate the association of sVEGF levels with clinico-pathologic parameters andoutcome. Methods: Blood samples were obtained from pts before and after CRT. Fifty age- and sex-matched healthy blood donors were used for determination of normal sVEGF levels. sVEGF levels were determined using an ELISA kit. Results: Pretreatment sVEGF levels were significantly higher in pts than in the control group (455.2 ± 108 vs. 85.1 ± 21 pg/mL; p < 0.001). sVEGF levels were significantly higher in EUS stage III than EUS stage II disease (655.7 ± 87.3 vs. 381.2 ± 48.7 pg/mL; p = 0.0025). Preoperative sVEGF levels were not correlated with age, gender, PS, histology, grading, tumor location and platelets. All pts were evaluable for CRT response: basal sVEGF levels in responding group (pCR + pPR: 49 pts) were significantly lower than those of non-responding group (SD + PD:23 pts): 315.3 ± 95.3 vs. 689.58 ± 132.1 pg/mL; p = 0.0010). The mean follow up time was 31.2 ± 15.3 months. The 3-years OS for all pts was 37%: pts with VEGF levels higher than 455.2 pg/mL had a lower 3-year OS rate than pts with lower VEGF levels (61% vs. 17%; p < 0.001). The 3-years DFS rate for all pts was 32%: pts with VEGF levels higher than 455.2 pg/mL had a lower 3-year DFS rate than pts with lower VEGF levels (70% vs. 19%; p < 0.0014). Conclusions: Our results suggest that sVEGF levels correlate with tumor burden and are useful in predicting the outcome of EC patients undergoing preoperative CRT. No significant financial relationships to disclose.

Insulin Resistance in Liver Cirrhosis Is Not Associated With Circulating Retinol-Binding Protein 4

Retinol-binding protein 4 (RBP4) has been identified as a novel adipokine mediating systemic insulin resistance, and elevated serum RBP4 indicates overt or impending insulin resistance in lean, obese, and type 2 diabetic subjects. As insulin resistance is present in nearly all patients with liver cirrhosis, we evaluated RBP4 in patients with chronic liver disease (CLD). Serum RBP4 was measured in 111 CLD patients. Ninety-nine age- and sex-matched healthy blood donors served as control subjects. RBP4 gene expression was also quantified in normal and cirrhotic rat liver. In CLD patients, serum RBP4 was significantly reduced compared with healthy control subjects and closely correlated with the stage of liver cirrhosis. CLD patients without cirrhosis showed normal RBP4 concentrations, which correlated with serum glucose and insulin secretion and inversely correlated with insulin sensitivity. In patients with Child A-C liver cirrhosis, however, RBP4 was not correlated with glucose metabolism or other adipokines, such as adiponectin or resistin, but closely linked to the hepatic biosynthetic capacity, fibrotic changes in liver histology, or clinical complications such as portal hypertension. In an animal model of experimental cirrhosis, hepatic RBP4 gene expression decreased in cirrhotic liver. RBP4 appears, unlike in obesity or type 2 diabetes, not to be a relevant systemic factor in the pathogenesis of insulin resistance in liver cirrhosis. Liver function has a tremendous impact on RBP4 levels, and future studies will need to take liver function into account when examining serum RBP4 levels.

Haplotype association of IL‐8 gene with Behcet’s disease

Interleukin-8 (IL-8), a CXC chemokine that recruits and activates inflammatory cells, plays a critical role in the pathogenesis of Behcet's disease (BD). To investigate the association of the genetic polymorphism of IL-8 and BD, we genotyped IL-8 -845 T/C, -738 T/A, -353 A/T, -251 A/T, +293 G/T, +678 T/C and receptors CXCR-1 +2607 G/C and CXCR-2 +785 C/T polymorphisms in 119 Korean patients with BD and 119 age- and sex-matched healthy blood donors. Then, single nucleotide polymorphisms (SNPs) and haplotypes were analyzed between patients and controls. There were no SNPs associated with BD. However, the frequency of haplotype TAT inferred from SNPs, IL-8 -353 A/T, -251 A/T and +678 T/C, was significantly higher in patients with BD than controls (5.9 vs 0.0%, P = 0.0001), as was haplotype ATC (6.7 vs 0.0%, P < 0.0001). The haplotype difference was still valid in human leukocyte antigen-B51-negative subjects. In conclusion, we found a significant difference in the distribution of IL-8 gene haplotypes between patients with BD and healthy controls. These results suggest that the genetic polymorphisms of proinflammatory chemokine IL-8 can contribute to the pathogenesis of BD.

Insulin resistance in liver cirrhosis is not associated with circulating Retinol Binding Protein 4

OBJECTIVE—Retinol-binding protein 4 (RBP4) has been identified as a novel adipokine mediating systemic insulin resistance, and elevated serum RBP4 indicates overt or impending insulin resistance in lean, obese, and type 2 diabetic subjects. As insulin resistance is present in nearly all patients with liver cirrhosis, we evaluated RBP4 in patients with chronic liver disease (CLD). RESEARCH DESIGN AND METHODS—Serum RBP4 was measured in 111 CLD patients. Ninety-nine age- and sex-matched healthy blood donors served as control subjects. RBP4 gene expression was also quantified in normal and cirrhotic rat liver. RESULTS—In CLD patients, serum RBP4 was significantly reduced compared with healthy control subjects and closely correlated with the stage of liver cirrhosis. CLD patients without cirrhosis showed normal RBP4 concentrations, which correlated with serum glucose and insulin secretion and inversely correlated with insulin sensitivity. In patients with Child A-C liver cirrhosis, however, RBP4 was not correlated with glucose metabolism or other adipokines, such as adiponectin or resistin, but closely linked to the hepatic biosynthetic capacity, fibrotic changes in liver histology, or clinical complications such as portal hypertension. In an animal model of experimental cirrhosis, hepatic RBP4 gene expression decreased in cirrhotic liver. CONCLUSIONS—RBP4 appears, unlike in obesity or type 2 diabetes, not to be a relevant systemic factor in the pathogenesis of insulin resistance in liver cirrhosis. Liver function has a tremendous impact on RBP4 levels, and future studies will need to take liver function into account when examining serum RBP4 levels.

Effect of zoledronic acid on markers of bone turnover and mineral density in osteoporotic patients with beta-thalassaemia

Osteoporosis has emerged as an important cause of morbidity in patients with thalassemia major. Studies regarding the efficacy of bisphosphonates in thalassemia-induced osteoporosis have yielded conflicting results. We performed this prospective study to evaluate the efficacy of zoledronic acid in osteoporotic patients with thalassemia major. Patients, 29, were given 1 mg zoledronic acid intravenously every 3 months for a total of four doses. Twenty age- and sex-matched healthy blood donors served as controls. Before each infusion and 3 months after the last infusion, we determined serum levels of osteoprotegerin (OPG), N-terminal cross-linking telopeptide of type I collagen (NTX), osteocalcin (OC) and insulin-like growth factor 1 (IGF-1). Bone mineral density (BMD) of the lumbar spine was measured at baseline and after the treatment's completion. At baseline, OPG did not differ significantly between patients and controls (p=0.2), NTX were higher in patients although not significantly (p=0.139), whereas, OC levels were significantly higher and IGF-1 levels significantly lower in patients than in controls (p<0.001 and p<0.006, respectively). Zoledronic acid administration resulted in a significant decrease in NTX, OC and IGF-1 (p<0.05, p<0.001 and p<0.05, respectively) and in a significant increase in OPG and BMD (p<0.05 for both comparisons). The change in NTX, osteocalcin and IGF-1 became significant as early as 3 months after the first administration of zoledronic acid, while the change in OPG reached significance only after three infusions. Our study supports the effectiveness of bisphosphonates in the treatment of thalassemia-induced osteoporosis.

Interleukin-10−1082 GG polymorphism influences the occurrence and the clinical characteristics of hepatitis C virus infection

In this study, we determined the genotypic and allelic frequencies of the Interleukin (IL)-10(-1082G/A) IL-10(-592A/C), and IL-10(-819C/T) polymorphisms, and their association with the risk to develop B cell Non Hodgkin Lymphoma (NHL) in hepatitis virus C (HCV) carriers. Genetic polymorphisms in the IL-10 gene promoter were studied in 250 consecutive patients with B-cell NHL with no clinical and/or laboratory findings of cryoglobulinemia, 142 NHL/HCV- and 108 NHL/HCV+ with chronic hepatitis (CH), 120 consecutive subjects with HCV-related CH, and 110 age, sex-matched healthy blood donors. The frequency of the IL-10(-1082GG) genotype vs remaining genotypes (IL-10(-1082GA/AA)) was higher in NHL/HCV+ patients than HCV-related CH patients (P=0.0002, OR=2.89, CI: 1.62-5.15) and in NHL/HCV+ than NHL/HCV- patients (P=0.0001, OR=2.99, CI: 1.72-5.19). Moreover, the IL-10(-1082GG) genotype was more prevalent in indolent NHL/HCV+ cases than aggressive NHL/HCV+ (P=0.0004, OR=4.97, CI: 2.10-11.79). Finally, we confirmed that IL-10(-1082GG) genotype is associated with higher IL-10 production compared to AA homozygous (P=0.037). The high IL-10 production, due to IL-10(-1082GG) genotype, influences the clinical expression of the HCV infection by increasing susceptibility to develop NHL and might contribute to the indolent form of the disease.

Plasma N-Terminal Pro-Brain Natriuretic Peptide as a Marker of Right Ventricular Dysfunction in Patients With Tetralogy of Fallot After Surgical Repair

Chronic heart failure is associated with neurohormonal activation that is not only related to outcome but is also a therapeutic target. We have attempted to demonstrate whether a similar pattern of neurohormonal activation exists in adult congenital heart disease (ACHD) and, if so, whether it relates to disease severity determined by cardiopulmonary exercise testing. Concentrations of N-terminal pro-atrial natriuretic peptide, N-terminal pro-brain natriuretic peptide (NT-proBNP), endothelin (ET)-1, renin, aldosterone, adrenalin, and noradrenalin were determined in 50 adults (mean age, 27.8 +/- 1.7 years [+/- SEM]; 26 women) with tetralogy of Fallot (TOF) after surgical repair (New York Heart Association functional class 1.1 +/- 0.1). One hundred age- and sex-matched healthy blood donors served as a control group for NT-proBNP determination. Dimensions of ventricles, left ventricular pump function, and estimated right ventricular (RV) systolic pressure were determined by echocardiography. Maximum oxygen uptake (V(O2max) was measured in all patients using spiroergometry. TOF patients had elevated levels of NT-proBNP compared with healthy individuals: NT-proBNP (women: 180 pg/mL vs 43 pg/mL, and men: 147 pg/mL vs 32 pg/mL; p < 0.0001) and ET-1 (2.5 fmol/L vs 0.7 fmol/L). There was a significant correlation of NT-proBNP to dimension and estimated peak systolic pressure of the RV as well as impairment of V(O2max). RV dysfunction detected by echocardiography and plasma NT-proBNP determination in asymptomatic or minimally symptomatic TOF patients correlates well with their cardiopulmonary exercise capacity. Thus, these simple and noninvasive screening methods can be used additionally to stratify ACHD patients with impaired cardiac function before they become clinically symptomatic.

Detection of TT Virus in Patients with Idiopathic Inflammatory Myopathies

The TT virus, a recently identified single-stranded DNA virus with unknown pathogenicity, has been shown to commonly infect humans. Viruses have been considered to contribute to disease pathogenesis in autoimmune disorders including idiopathic inflammatory myopathies (IIMs) and rheumatoid arthritis (RA). We assessed the prevalence of TTV infection in IIM compared with that in patients with RA and healthy blood donors. Detection of TTV was conducted by nested PCR and real-time PCR in the sera of 94 patients with IIM, 95 RA patients. and 95 age- and sex-matched healthy blood donors. Identity of the PCR products was confirmed by sequencing. TTV DNA was detected in 61 of 94 (64.9%) patients with IIM, in 64 of 95 (67.4%) patients with RA, and in 62 of 95 (65.3%; P > 0.05) healthy individuals. Age, sex, activity, or duration of disease had no influence on TTV positivity in either group. However, patients with severe IIM (n = 36) had a significantly higher rate of TTV infection (31/36, 86.1%) than patients with mild disease (30/58, 51.7%, P < 0.05, chi(2) = 10.0). Disease was considered severe in IIM when immunosuppressive treatment was necessary because of continuous high activity and/or serious inner-organ involvement despite corticosteroid treatment. In conclusion, although we found the detection rate of TTV similar in patients with idiopathic inflammatory myopathies and rheumatoid arthritis and comparable to that in healthy controls, our data suggest that infection with TT virus may result in a more severe disease in patients with idiopathic inflammatory myopathies.

Hepatitis E virus superinfection in patients with chronic liver disease

Infection with hepatitis A virus (HAV) can cause severe illness in adult patients with chronic liver disease (CLD) caused by hepatitis C. In endemic areas such as South Asia, however, most adult patients already have been exposed to HAV but could still be susceptible to hepatitis E virus (HEV) infection. We document that HEV superinfection in 4 of our CLD patients caused severe liver decompensation. We then determined the seroprevalence of HAV and HEV in 233 patients with stable CLD, with the goal of defining the need for protection against these viruses in these patients. Overall, 41 (17.5%) of 233 CLD patients were HEV antibody immunoglobulin G (IgG)–positive, and 228 of 233 (97.8%) were HAV IgG–positive. As controls, we tested 90 age- and sex-matched healthy volunteer blood donors for HAV and HEV antibodies IgG. There was no difference in the percentage of CLD patients and blood donors positive for HEV antibody IgG (17.7% vs. 17.5%) or for HAV IgG (97.8% vs. 94%). No differences were observed in the severity of liver disease between previously HEV-exposed and -nonexposed patients. In conclusion, superinfection with HEV in patients with underlying CLD can cause severe hepatic decompensation leading to increased morbidity and mortality. The large majority of adult CLD patients in endemic countries are vulnerable to infection with HEV, but are protected against hepatitis A, and are ideal candidates for an HEV vaccine. (H EPATOLOGY 2002;36:474-478.)

Serum S100B Levels in Patients with Lupus Erythematosus: Preliminary Observation

S100B is an astrocytic calcium-binding protein which has been proposed as a biochemical marker of brain damage or dysfunction in acute and chronic diseases. We investigated whether serum S100B levels could be related to systemic lupus erythematosus (SLE) activity. Patients were grouped as having inactive SLE (ISLE), active SLE without central nervous system (CNS) involvement (ASLE), or active SLE with unequivocal neurologic or psychiatric manifestation (NPSLE). The control group consisted of age- and sex-matched healthy blood donors. S100B levels were determined using a luminescence immunoassay. All SLE groups had higher levels of serum S100B than the control group. Among the SLE groups, significantly higher levels of serum S100B protein were found in the NPSLE group than in the ISLE and ASLE groups, and there was no significant difference in S100B levels between the ISLE and ASLE groups. These preliminary results point to a putative relevance of serum S100B protein levels in SLE patients, specifically concerning CNS involvement present in this disease.