Early post-transplant neopterin associated with one year survival and bacteremia in liver transplant recipients

Bacterial infections are the most common complications, and the major cause of mortality after liver transplantation (Tx). Neopterin, a marker of immune activation, is produced in monocyte/macrophages in response to inflammation. The aim of our study was to investigate whether early post-operation serum levels of neopterin were associated with post-transplant bacteremia and mortality in liver transplant recipients. We studied 162 of 262 liver Tx patients between January 2008 and February 2011 of whom pre- and early post-Tx sera samples were available.Pre- and early post-operative risk factors of infection and mortality were evaluated in 45 bacteremic patients and 117 non-bacteremic patients. During one-year follow-up, 28 of 262 patients died because of graft failure, septicemia and other diseases.Post-Tx serum neopterin on day 10 (p < 0.001) were significantly higher in bacteriemic patients than in patients without bacteremia. Logistic regression analyses showed that day 10 post-Tx neopterin serum level ⩾40 nmol/l has a predictive value (OR = 6.86: p < 0.001) for bacteremia and mortality (OR = 3.47: p = 0.021).Our results suggest that early post-Tx neopterin serum levels are very sensitive predictive markers of one-year post-Tx bacteremia and mortality in liver Tx recipients.     

Usefulness of microvolt T-wave alternans testing in the assessment of all-cause mortality and life-threatening ventricular arrhythmia risk in patients with left ventricular dysfunction

Introduction

Patients with left ventricular ejection fraction (LVEF) ≤ 35% are eligible for implantable cardioverter-defibrillator (ICD) placement in the primary prevention of sudden cardiac death. Nevertheless, other risk factors facilitating the selection of individuals with highest mortality are still sought. The aim of the study was to verify the usefulness of microvolt T-wave alternans (MTWA) testing in the assessment of all-cause mortality and life-threatening ventricular arrhythmias (EVENTs) in these patients. Previous data from the literature are inconclusive.

Material and methods

Patients with LVEF ≤ 35% were eligible if they did not have a history of sustained ventricular arrhythmias, and were treated with β-blockers. Participants underwent MTWA testing and were subsequently followed.

Results

The group consisted of 139 patients. MTWA results were classified as non-negative (MTWA_non-neg) in 93 and negative (MTWA_neg) in 46 patients. During the 14.3 ±8.6 months of follow-up, EVENTs were observed in 21 patients. The 1-year EVENT rate was 16.4% among MTWA_non-neg patients, and 2.6% among MTWA_neg patients (p = 0.006). The sensitivity of the MTWA test was 95.24%, the specificity – 38.14%, the positive predictive value – 21.51% and the negative predictive value – 97.83%.

Conclusions

In the group of patients with left ventricular systolic dysfunction, with the exclusion of patients with the history of life-threatening ventricular arrhythmia and individuals not being on chronic β-adrenolytic therapy, the abnormal result of MTWA testing is associated with significantly increased risk of all-cause mortality and life-threatening ventricular arrhythmia during 1 year of follow-up, thus identifying the individuals at the highest risk.     

Impact of diabetes on mortality and complications after coronary artery by-pass graft operation in patients with left main coronary artery disease

PurposeLeft main disease (LMD) is a severe form of coronary artery disease (CAD). Fifty percent of patients with LMD treated conservatively die within 3–5 years of diagnosis. The aim of the study was to assess the influence of type 2 diabetes on early and late (2-year) prognosis and the risk of complications after coronary artery by-pass graft (CABG) surgery in patients with LMD.Material/methodsWe enrolled 257 patients diagnosed with LMD. 169 (67%) underwent CABG, 19 (8%) percutaneous coronary intervention (PCI) without left main stem protection. 30 (12%) patients had CABG previously. Patients treated with CABG were divided into two groups – with and without diabetes. There were 43 (25.4%) patients with diabetes and 126 (74.6%) without diabetes.ResultsWe observed more complications with wound healing (40.5% vs. 12.8%, p < 0.001) and sternal dehiscence (23.8% vs. 4.0%, p < 0.001) after CABG in patients with diabetes. There were no differences in 7-day, 30-day, 3-month and 1-year mortality. 2-Year mortality was also similar in both groups (11.6% vs. 11.1%, p = 0.928). Patients with diabetes were more frequently hospitalized due to other reasons than angina (39.5% vs. 20.6%, p = 0.014).ConclusionsPatients with diabetes and LMD had more often complications with wound healing and sternal dehiscence after CABG than patients without diabetes. Type 2 diabetes did not influence early and late mortality in patients with LMD treated with cardiac surgery, but the presence of diabetes was associated with more frequent hospitalizations.     

Early coupled up-regulation of interleukin-12 receptor beta-1 in CD8+ central memory and effector T cells for better clinical outcomes in liver transplant recipients

This study aimed to investigate the role of initial priming of interleukin (IL)-12 receptor beta-1 in CD8⁺central memory T cells (initial IL-12RT_CM priming) and CCR7-negative subsets (CNS) in effector cell expansion and clinical outcome after living donor liver transplantation (LDLT). One hundred and six patients who underwent LDLT were classified into the following three groups according to hierarchical clustering of CD8⁺CD45 isoforms before LDLT: I, naive-dominant; II, effector memory-dominant; and III, effector-dominant. The pre-existing CD8⁺effector cells (T_E) and activated immune status increased progressively from group I to group II to group III. Groups I, II and III received tacrolimus (Tac)/glucocorticoid (GC) regimens. Eighteen group III recipients received Tac/mycophenolate mofetil (MMF) and were defined as group IV. Initial IL-12RT_CM priming was slightly, moderately and markedly decreased in droups I, II, and III, respectively. Initial priming of IL-12Rβ1 in CNS was decreased markedly in the three groups with marked decreases of T_E, perforin and interferon (IFN)-γ; all parameters were restored by up-regulation of IL-12Rβ1⁺T_CM through the self-renewal of T_CM. The lag time required until coupled up-regulation of IL-12Rβ1 of T_CM and CNS to above baseline was 12, 20 and 32 days in groups I, II and III, respectively. Inferior clinical outcomes were associated with increasing lag time. In contrast, the initial priming of IL-12Rβ1 in T_CM and CNS remained above baseline in group IV due to MMF-mediated increase of IL-12Rβ1. Early coupled up-regulation of T_CM and CNS leads to efficient T_E differentiation and optimal clinical outcomes.     

Asymmetrical dimethylarginine and severity of erectile dysfunction and their impact on cardiovascular events in patients with acute coronary syndrome

Introduction

Coronary artery disease (CAD) and vascular erectile dysfunction (ED) are related to endothelial dysfunction. Elevated asymmetrical dimethylarginine (ADMA) levels and ED are common in patients with increased cardiovascular risk. Our aim was to investigate whether ADMA has a predictive role for major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS). The secondary aim of this study was to investigate whether severity of ED predicts MACE in these patients.

Material and methods

Follow-up data were available for severity of ED in 71 patients with ACS. Plasma ADMA levels were determined by ELISA in 57 patients. Erectile dysfunction was assessed by the International Index of Erectile Function-6 (IIEF-6) score. Major adverse cardiovascular events (reinfarction, all-cause hospitalisation, stroke and all-cause death) was evaluated after a median of 10 months.

Results

Severe ED had no significantly increased hazard ratio for cardiovascular events compared with mild, mild to moderate, and moderate ED (0.259 [95% CI 0.041–1.6], p = 0.147; 0.605 [95% CI 0.095–3.8], p = 0.594; 0.980 [95% CI 0.233–4.1], p = 0.978; and 0.473 [95% CI 0.052–1.3], p = 0.508). The patients who had ADMA levels ≥ 0.32 µmol/l had no significantly increased hazard ratio for cardiovascular events compared with patients who had ADMA levels < 0.32 µmol/l (2.018 [95% CI 0.615–6.6], p = 0.247).

Conclusions

Severity of ED and ADMA did not increase the risk of cardiovascular events in follow-up patients with ACS in our study. Larger prospective studies are necessary to evaluate whether ADMA predicts cardiovascular events in patients with ACS.     

Appearance of large scavenger receptor A-positive cells and increased small scavenger receptor A positive cells in peripheral blood is associated with mortality in systemic inflammatory response syndrome and multiple organ dysfunction syndrome

We investigated the association of scavenger receptor A-positive (SRA(+) ) cells in peripheral blood (PB) with mortality in subjects with systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). A total of 467 subjects with SIRS (62 of 467 satisfied the diagnostic criteria of MODS) were prospectively examined. The subjects were classified into three groups according to the SRA index (number of small SRA(+) cells in 10 high power field, normal upper limit < 30) and the appearance of large SRA(+) cells as follows: group A, large SRA(+) cells were not detected; group B, large SRA(+) cells were detected but SRA index did not exceed 30; group C, the two factors (appearance of large SRA(+) cells and SRA index > 30) coincided. The duration from the diagnosis of SIRS to death in groups A and B was significantly shorter than in group C. The mortality rate in group C was significantly higher than in groups A and B. Kaplan-Meier curves of group C showed significantly worse survival than groups A and B. These results indicate that the coincidence of two factors (appearance of large SRA(+) cells and SRA index > 30) may be useful to predict the outcome in patients with SIRS or MODS.     

Coupled regulation of interleukin-12 receptor beta-1 of CD8+ central memory and CCR7-negative memory T cells in an early alloimmunity in liver transplant recipients

This study investigated how CD8⁺ T cell subsets respond to allo‐ and infectious immunity after living donor liver transplantation (LDLT). Early alloimmunity: 56 recipients were classified into three types according to the post‐transplant course; type I demonstrated uneventful post‐transplant course, type II developed severe sepsis leading to multiple organ dysfunction syndrome or retransplantation and type III with acute rejection. In 23 type I recipients, the interleukin (IL)‐12 receptor beta‐1 (Rβ1)⁺ cells of central memory T cells (Il‐12Rβ1⁺ T_CM) were increased above the pretransplant level. In 16 type II recipients, IL‐12Rβ1⁺ T_CM was decreased markedly below the pretransplant level on postoperative day (POD) 5. In 17 type III recipients, IL‐12Rβ1⁺ T_CM was decreased for a more prolonged period until POD 10. Along with down‐regulation of IL‐12Rβ1⁺ T_CM, the IL‐12Rβ1⁺ cells of CCR7‐negative subsets (CNS) as well as perforin, interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α decreased gradually, resulting in the down‐regulation of effectors and cytotoxicity. The down‐regulation of IL‐12Rβ1⁺ T_CM was suggested to be due to the recruitment of alloantigen‐primed T cells into the graft, and then their entry into the secondary lymphoid organ, resulting in graft destruction. Infectious immunity: immunocompetent memory T cells with the capacity to enhance effectors and cytotoxicity were generated in response to post‐transplant infection along with both up‐regulation of the IL‐12Rβ1⁺ T_CM and an increase in the CNS showing the highest level of IL‐12Rβ1⁺ cells. In conclusion, this work demonstrated that the IL‐12Rβ1⁺ cells of T_CM and CNS are regulated in a tightly coupled manner and that expression levels of IL‐12Rβ1⁺ T_CM play a crucial role in controlling allo‐ and infectious immunity.     

血清IL-6、CRP和PCT水平对严重多发伤后MODS的预测价值

目的探讨多发伤患者外周血血清白细胞介素-6(IL-6)、C反应蛋白(CRP)和降钙素原(PCT)对多器官功能障碍综合征(MODS)的预测价值。方法 87例多发伤患者按治疗过程中有无发生MODS分为MODS组和非MODS组。采用ELISA法测定患者伤后第1、2、3、5、和7天血清IL-6和PCT的含量,采用免疫比浊法测定血清CRP的水平,并与20例健康对照比较,应用受试者工作特征曲线(ROC曲线)进行统计学分析。结果与健康对照组相比,多发伤患者血清IL-6、CRP和PCT水平伤后早期均出现不同程度的升高(P<0.01),其中PCT水平升高最早;与非MODS组比较,MODS组各项指标均有显著差异(P<0.01)。IL-6、CRP和PCT的ROC曲线下面积分别为0.686、0.854和0.914。PCT对严重多发伤后发生MODS的诊断价值高于IL-6和CRP。结论 PCT是严重多发伤后预测MODS发生的较好辅助诊断指标,其诊断价值优于IL-6和CRP。     

Eye tracking dysfunction is a putative phenotypic susceptibility marker of schizophrenia and maps to a locus on chromosome 6p in families with multiple occurrence of the disease

The difficulties in defining the borders of the schizophrenia spectrum is one major source of variance in linkage studies of schizophrenia. The employment of biological markers may prove advantageous. Due to empirical evidence, eye tracking dysfunction (ETD) has been discussed to be the most promising marker for genetic liability to schizophrenia. With respect to the recent progress in genomic scans, which have pointed to the short arm of chromosome 6, we carried out a scan of the 6p21–23 region with 16 microsatellite markers to test for linkage between chromosomal markers and ETD as well as schizophrenia. We tested 5 models of inheritance of ETD and found maximum two-point lod scores of 3.51 for D6S271 and 3.44 for D6S282. By including these markers in a multipoint analysis, a lod score of 4.02 was obtained. In the case of schizophrenia, 7 models were tested; however, with non-significant results. Our findings, together with another recent linkage report, point to the possibility of a second susceptibility locus for schizophrenia which may be located centromeric to the HLA region. Also, the evidence of ETD being a susceptibility marker for schizophrenia receives further support.     

Gender and ethnic differences in the post-liver transplant outcomes of patients with autoimmune hepatitis with acute liver failure at initial presentation: a case-control study

Introduction

Autoimmune hepatitis (AIH) may initially present as acute liver failure (ALF). The outcome of liver transplantation (LT) in patients with AIH and ALF is not very well defined. We determined the outcome of LT in UNOS (United Network for Organ Sharing) status 1 adult patients with and without AIH using post-MELD (Model for End-Stage Liver Disease) UNOS data.

Material and methods

For each AIH patient, 3 patients with non-AIH, matched for age ±5 years and donor risk index (DRI) ±5 years, were identified; 200 patients (50 AIH, 150 non-AIH) were found eligible for the study.

Results

Patients with AIH were more likely to be female (p = 0.003), non-Caucasian (p = 0.009), have higher bilirubin (p = 0.003), longer waiting time (p = 0.01), and lower creatinine (p = 0.019). African American patients with AIH were younger (p = 0.003), had lower bilirubin (p = 0.037), and were more likely to have had a prior LT compared to Caucasians (p = 0.02). Kaplan-Meier analysis showed that 5-year post-LT survival was similar in those with and without AIH (p = 0.3). African American with AIH showed a trend for lower 5-year survival compared to Caucasians (55% vs. 80%, p = NS). Women had a better outcome, especially in those with non-AIH (p = 0.002).

Conclusions

Patients with AIH transplanted as status 1 have similar outcomes to those without AIH. Women with non-AIH-related ALF have better survival than their male counterparts.     

The refit model for end-stage liver disease-Na is not a better predictor of mortality than the refit model for end-stage liver disease in patients with cirrhosis and ascites

Background/Aims

The modification of the Model for End-Stage Liver Disease (MELD) scoring system (Refit MELD) and the modification of MELD-Na (Refit MELDNa), which optimized the MELD coefficients, were published in 2011. We aimed to validate the superiority of the Refit MELDNa over the Refit MELD for the prediction of 3-month mortality in Korean patients with cirrhosis and ascites.

Methods

We reviewed the medical records of patients admitted with hepatic cirrhosis and ascites to the Konkuk University Hospital between January 2006 and December 2011. The Refit MELD and Refit MELDNa were compared using the predictive value of the 3-month mortality, as assessed by the Child-Pugh score.

Results

In total, 530 patients were enrolled, 87 of whom died within 3 months. Alcohol was the most common etiology of their cirrhosis (n=271, 51.1%), and the most common cause of death was variceal bleeding (n=20, 23%). The areas under the receiver operating curve (AUROCs) for the Child-Pugh, Refit MELD, and Refit MELDNa scores were 0.754, 0.791, and 0.764 respectively; the corresponding values when the analysis was performed only in patients with persistent ascites (n=115) were 0.725, 0.804, and 0.796, respectively. The significant difference found among the Child-Pugh, Refit MELD, and Refit MELDNa scores was between the Child-Pugh score and Refit MELD in patients with persistent ascites (P=0.039).

Conclusions

Refit MELD and Refit MELDNa exhibited good predictability for 3-month mortality in patients with cirrhosis and ascites. However, Refit MELDNa was not found to be a better predictor than Refit MELD, despite the known relationship between hyponatremia and mortality in cirrhotic patients with ascites.     

Early anemia and rapid virological response improve the predictive efficiency of IL28B-genotype for treatment outcome to antiviral combination therapy in patients infected with chronic HCV genotype 1

IL28B genotypes and virological response within 4 weeks are predictors of sustained virological response in patients infected with chronic hepatitis C virus (HCV) genotype 1 treated with antiviral dual combination therapy. The predictive value of “early” anemia (within 4 weeks) alone or in combination with the two other predictors has not been studied yet. A total of 305 pegylated interferon‐α and ribavirin‐treated patients with HCV genotype 1 were included in this study. Hemoglobin values at week 0, 4, 8, and 12 as well as the predictive efficiency of early anemia (hemoglobin value below the gender‐specific lower limit: female < 11.5; male < 13.5 g/dl) during therapy were assessed with IL28B genotypes and rapid virological response. Forty‐eight percent of treated patients developed early anemia. In both females and males (64%), a decrease of hemoglobin concentration of 3 g/dl (female: 14.7 ± 1.1 to 11.4 ± 1.3; male: 15.2 ± 1.2 to 12.2 ± 1.5) significantly correlated with sustained virological response. 64% of IL28B‐CC patients showed a sustained virological response. Seventy‐eight percent of patients with rapid virological response definitively eliminated the virus. Early anemia (81:48:41%) and rapid virological response (83:91:92%) increased the predictive efficiency of IL28B rs12979860 genotype distribution (CC:CT:TT). IL28B‐CC and early anemia as well as IL28B‐CC and rapid virological response had an Odds ratio of 42.4 or 75 to achieve a sustained virological response compared to TT without early anemia or rapid virological response. This finding may help to early identify responders to standard PEG‐IFN‐α and ribavirin treatment even within those with unfavorable IL28B genotype. J. Med. Virol. 84: 1208–1216, 2012. © 2012 Wiley Periodicals, Inc.     

Regulation of the neutralizing anti-hepatitis B surface (HBs) antibody response in vitro in HBs vaccine recipients and patients with acute or chronic hepatitis B virus (HBV) infection

Antibodies directed to the HBs antigen indicate viral clearance and the development of life-long immunity in patients that recovered from HBV infection. In HBs antigen vaccine recipients anti-HBs antibodies provide protective immunity. However, little is known about the regulation of this HBs-specific antibody response. The existence of anti-HBs-secreting B cells was demonstrated using the highly sensitive ELISPOT technique compared with conventional ELISA in serum and cell culture supernatants. In the peripheral blood of patients with acute self-limited hepatitis B, HBs-specific B cells were demonstrated with a high frequency despite undetectable anti-HBs serum antibodies. HBV-immunized patients that had recovered from infection and vaccine recipients had significantly lower frequencies, whereas chronic HBV carriers and negative controls showed no anti-HBs-secreting B cells. Coculture experiments of isolated B and T cells revealed that the anti-HBs antibody response was restricted to the presence of T helper cells, but not to identical HLA class II molecules. Allogeneic T cells derived from vaccine recipients or chronic HBV carriers stimulated the HBs-specific B cell response in HBs vaccine recipients. Otherwise, isolated T helper cells could never provide sufficient help to induce the HBs-specific B cell response in chronic HBV carriers. Furthermore, peripheral blood mononuclear cells (PBMC) of six out of 10 vaccine recipients, one out of five HBV-immunized patients, but of no chronic HBV carrier showed a proliferative response to different HBs antigen preparations. This study demonstrated a high frequency of circulating anti-HBs-producing B cells in the early phase of acute HBV infection, but a lower frequency of HBs-specific B cells years after resolution of HBV infection. In chronic HBV carriers, however, deficient HBs-specific T and B cell responses were observed.     

Soluble donor HLA class I and β2m-free heavy chain in serum of lung transplant recipients: steady-state levels and increases in patients with recurrent CMV infection, acute rejection episodes, and poor outcome

We determined the concentration of donor sHLA/β₂m and total β₂m-free heavy chain (HC) in the serum of lung transplant recipients with ELISA assays. While we were unable to detect specific donor β₂m-free HCs due to a lack of available antibodies, we could determine if events that led to an increase in the release of β₂m-free HC also led to an increase in the release of donor sHLA/β₂m, particularly the 36 kDa, proteolytically cleaved form. We found that lung transplants constituitively release donor sHLA/β₂m at ng/ml levels. The levels (both of donor sHLA/β₂m and total β₂m-free HC) were significantly increased in CMV-sero-negative recipients (but not in CMV-sero-positive recipients) at the onset of post-transplant CMV disease. Acute rejection episodes were also associated with an increased release of donor sHLA/β₂m, but not of β₂m-free HC. However, in patients with particularly poor outcome (i.e., graft loss within 1 year) there was a significant release of β₂m-free HC. Analysis of one such patient showed a predominance of 36 kDa forms of donor-sHLA/β₂m. Our data are consistent with the hypothesis that the metalloproteinase that cleaves β₂m-free HC is active during uncontrolled CMV infection and acute rejection. However, recall responses to CMV and controlled immune responses to donor may result in little or no activation of sHLA class I release.