New insights into the mechanisms involved in B-type natriuretic peptide elevation and its prognostic value in septic patients

Introduction

Elevated plasma B-type natriuretic peptide (BNP) levels in patients with critical sepsis (severe sepsis and septic shock) may indicate septic cardiomyopathy. However, multiple heterogeneous conditions may also be involved in increased BNP level. In addition, the prognostic value of BNP in sepsis remains debatable. In this study, we sought to discover potential independent determinants of BNP elevation in critical sepsis. The prognostic value of BNP was also evaluated.

Methods

In this observational study, we enrolled mechanically ventilated, critically septic patients requiring hemodynamic monitoring through a pulmonary artery catheter. All clinical, laboratory and survival data were prospectively collected. Plasma BNP concentrations were measured daily for five consecutive days. Septic cardiomyopathy was assessed on day 1 on the basis of left and right ventricular ejection fractions (EF) derived from echocardiography and thermodilution, respectively. Mortality was recorded at day 28.

Results

A total of 42 patients with severe sepsis (N = 12) and septic shock (N = 30) were ultimately enrolled. Daily BNP levels were significantly elevated in septic shock patients compared with those with severe sepsis (P ≤0.002). Critical illness severity (assessed by Acute Physiology and Chronic Health Evaluation II and maximum Sequential Organ Failure Assessment scores), and peak noradrenaline dose on day 1 were independent determinants of BNP elevation (P <0.05). Biventricular EFs were inversely correlated with longitudinal BNP measurements (P <0.05), but not independently. Pulmonary capillary wedge pressures (PCWP) and volume expansion showed no correlation with BNP. In septic shock, increased central venous pressure (CVP) and CVP/PCWP ratio were independently associated with early BNP values (P <0.05).Twenty-eight-day mortality was 47.6% (20 of 42 patients). Daily BNP values poorly predicted outcome; BNP on day 1 > 800 pg/ml (the best cutoff point) fairly predicted mortality, with a sensitivity%, specificity% and area under the curve values of 65, 64 and 0.70, respectively (95% confidence interval = 0.54 to 0.86; P = 0.03). Plasma BNP levels declined faster in survivors than in nonsurvivors in both critical sepsis and septic shock (P ≤0.002). In septic shock, a BNP/CVP ratio >126 pg/mmHg/ml on day 2 and inability to reduce BNP <500 pg/ml implied increased mortality (P ≤0.036).

Conclusions

The severity of critical illness, rather than septic cardiomyopathy, is probably the major determinant of BNP elevation in patients with critical sepsis. Daily BNP values are of limited prognostic value in predicting 28-day mortality; however, fast BNP decline over time and a decrease in BNP <500 pg/ml may imply a favorable outcome.     

Cerebral metastases of malignant melanoma: contemporary treatment modalities and survival outcome

The aim of our study was to analyze prognostic factors, effect of treatment and survival outcome of a contemporary cohort of melanoma patients with cerebral metastases and eventually propose new recommendations regarding therapy. Sixty four patients with melanoma brain metastases were treated in our department within a 15-year period. We performed a retrospective analysis of their survival with respect to the type of treatment instituted. Four groups were formed according to treatment: Group A patients treated with surgery followed by radiotherapy; group B temozolomide as first-line treatment and radiotherapy after cerebral disease progression; group C radiotherapy alone; group D supportive care only. Patients* characteristics influenced the selection of treatment modality: Group A (7.8%) patients with a single brain metastasis (p=0.001) and controlled extra-cranial disease (p<0.0001), while Group D (21.8%) patients with ulcerated primary lesions (p=0.010) and uncontrolled extra-cranial disease (p<0.0001). Only group B (26.6%) and C (43.7%) patients with similar characteristics including more than one brain lesion. Median overall survival was 3 months. In univariate analysis, median survival for groups A, B, C and D was 12, 5, 3 and 2 months, respectively (p<0.0001). The survival difference between the surgery and non-surgery groups was statistically significant (p=0.0011). Patients treated with supportive care had the worse prognosis (p<0.0001). A survival benefit for patients receiving first-line treatment with temozolomide, as compared to those receiving radiotherapy alone was noted (p=0.0267). In multivariate survival analysis, the number of brain lesions (p=0.0138), the absence of uncontrolled extra-cranial disease (p=0.00221) and the type of treatment for the cerebral disease (p=0.0053) remained significant independent survival predictors. Patients' characteristics remain a critical factor for treatment selection. The number of brain metastases, the extent of disease and the type of treatment represent independent survival predictors. Melanoma patients with a single brain metastasis and controlled extra-cranial disease gain a survival benefit, if surgically treated. Including temozolomide in the first-line treatment of melanoma patients with brain metastases who would have been treated with radiotherapy alone, might present a promising future direction affecting the length of survival.     

Immunohistochemical localization of glutathione S-transferase-pi in human colorectal polyps

AIM： To investigate the distribution of the placental form of glutathione-S-transferase （GST） in colon polyps in order to evaluate the role of GST-pi in these tissues. METHODS： Sixteen polyp tissues removed at colon- oscopy were examined. Tissues were investigated his- tologically and ultrastructurally. GST-pi expression was also analysed immunohistochemically, using peroxidase anti-peroxidase （PAP） method and immunogold label- ling method, for light and electron microscope respec- tively. RESULTS： All polyp tissues examined were adenoma of low, mild and high- grade dysplasia as shown in the histopathological reports. Nevertheless, the examina- tion of the above specimens with electron microscope revealed that 3 of 9 adenoma of mild dysplasia had ultrastuctural features similar to high-grade dysplasia adenoma. GST-pi was variably expressed in adenoma, with the lowest relative levels occurring in low-grade adenoma and the highest levels found in high-grade adenoma. GST-pi was located mainly in undifferentiat- ed epithelial cells. GST-pi positive particles were found in the cytoplasm and especially in the nucleus adjacent to the nuclear membrane of these cells. CONCLUSION： The overexpression of GST-pi in mild- grade adenomas with significant subcellular changes and in the majority of high-grade dysplasia adenoma suggests that this might be related to the carcinogenetic proceeding. Immunohistochemical localization of GST-pi in combination with ultrastructural changes indicate that GST-pi might be a sensitive agent for the detection of preneoplastic transformations in adenoma.     

Monoclonal gammopathy of undetermined significance (MGUS) in patients with solid tumors: effects of chemotherapy on the monoclonal protein

The aim of this study was to assess the effect of systemic chemotherapy on the monoclonal protein levels of patients with solid tumors who also have a monoclonal gammopathy of undetermined significance (MGUS). All patients with solid tumors who were referred to our department for consideration of systemic chemotherapy were evaluated with serum protein electrophoresis (SPEP) for the presence of MGUS. When MGUS was confirmed with immunofixation, serial SPEP was performed during and after completion of chemotherapy. Over a 6-year period, 21 patients with solid tumors and MGUS were prospectively identified and assessed. At least 50% reduction of serum monoclonal protein was noted in 4 of 11 patients treated with paclitaxel or docetaxel with a platinum analogue and in 5 of 7 patients who received an irinotecan-containing regimen. Our data indicate that in MGUS patients treated with irinotecan-containing chemotherapy regimens, a high incidence of reduction in their monoclonal protein levels is observed. Since topotecan, another topoisomerase I inhibitor, has some activity in multiple myeloma, further evaluation of irinotecan may be warranted. Evaluation of larger numbers of MGUS patients treated with chemotherapy for their underlying malignancy may help identify in vivo potentially active agents and regimens for patients with overt myeloma.     

One-year non-invasive ventilation in chronic hypercapnic COPD: effect on quality of life

The data on long-term application of non-invasive ventilation (NIV) in patients with chronic respiratory failure due to COPD are contradictory. We evaluated the effect of the addition of NIV to optimal treatment for 1 year on the quality of life of stable hypercapnic COPD patients. NIV was offered to 49 of 58 initially enrolled consecutive patients, of whom 22 refused NIV and comprised the standard treatment group whereas 27 received NIV. Quality of life was assessed with the SF-36 questionnaire. Additional measurements included blood gases, pulmonary function tests, dyspnea, daytime sleepiness, exacerbations and hospitalizations. The NIV group showed a significant improvement in quality of life in the third month, both in the Physical (31+/-4 to 38+/-8, p<0.0001) and the Mental Component Summary Score (28+/-7 to 40+/-10, p=0.009), that was maintained until the twelfth month. PaCO2 decreased by the first month in the NIV group (54+/-4.5 to 44.6+/-5.6 mmHg, p<0.0001), and PaO2 rose during the sixth month (58.9+/-5.7 to 64.4+/-6.5 mmHg, p=0.004). Dyspnea and diurnal sleepiness improved significantly. No significant improvements were observed in the control group. Patients on NIV spent less days in the hospital compared to controls. NIV when added to optimal medical treatment has beneficial effects on quality of life in stable hypercapnic COPD patients, with additional improvements in arterial blood gases, dyspnea and daytime sleepiness.     

Interleukin-18: interleukin-10 ratio and in-hospital adverse events in patients with acute coronary syndrome

INTRODUCTION: Inflammatory mechanisms contribute to the development of acute coronary syndromes (ACS), and it has been suggested that an imbalance between pro- and anti-inflammatory responses may be an important determinant of recurrent cardiac events in this setting. Both increased serum levels of interleukin (IL)-18 and reduced concentrations of IL-10 have been shown to have prognostic significance in ACS. We sought to assess whether the ratio of serum IL-18/IL-10 levels has higher positive predictive value than the individual measurement of IL-10 and IL-18 in patients admitted to hospital with ACS. METHODS: We recruited 107 consecutive patients (79 men, mean age 65+/-12 years) with ACS (41 STEMI, 39 NSTEMI and 27 UA). The composite of cardiac death, recurrence of unstable angina, re-infarction, life threatening arrhythmias, and urgent revascularization during hospitalization was the pre-specified study end-point. We assessed independent predictors of the combined end-point using multiple logistic regression analysis. Serum IL-10 and IL-18 levels were measured at study entry using commercially available ELISAs. RESULTS: During hospitalization 44 patients (41%) had events and 63 (59%) had no events. Significantly higher odd ratios were found for IL-18/IL-10 ratio (1.74 95% CI 1.09-2.78) compared to individual IL-18 (1.46 95% CI 0.93-2.27) and 1/IL-10 (1.63 95% CI 1.04-2.56) measurements. CONCLUSION: Serum IL-18/IL-10 ratio is an independent predictor of in-hospital adverse events in patients with ACS. Our study strongly endorses the notion that an imbalance between pro and anti-inflammatory forces predisposes to plaque disruption and recurrent cardiovascular events.     

The molecular heterogeneity of beta-thalassemia in Greece

β-thalassemia is the most predominant genetic defect in Greece. In this study, we investigated the heterogeneity and the frequency of β-thalassemia mutations among 3796 heterozygotes detected in the course of DNA based diagnoses. The diagnostic strategy included Denaturing Gradient Gel Electrophoresis (DGGE), Allele Specific Oligonucleotide Hybridization (ASO), GAP PCR, Restriction Enzyme (RE) analysis and direct sequencing and led to 100% identification of the underlying molecular lesion. Six out of 33 different β-globin defects identified accounted for more than 91.4% of the total β-thalassemia chromosomes in Greece. The β-globin gene mutations cd29 C→T, IVS-I-2 T→C, IVS-I-5 G→T, cd37 G→A and poly A Kurdish AATAAA→AATAAG are for the first time reported in Greece, whereas cd7 GAG→TAG is a new β⁰-thalassemia mutation detected in an adult man from Albania residing in Greece. Three DNA single nucleotide polymorphisms (IVS-I-85 T→C, IVS-I-91 C→T and IVS-I-108 T→C) were also revealed; among these, IVS-I-85 T→C and IVS-I-91 C→T are new and described for the first time worldwide.     

CD8(+) T cells with parasite-specific cytotoxic activity and a Tc1 profile of cytokine and chemokine secretion develop in experimental visceral leishmaniasis

Recently, a prominent role for CD8(+) T cells in immunity against pathogens has emerged. The mode of action of CD8(+) T cells in murine visceral leishmaniasis and their contribution to the clearance of the parasite has been addressed in the present study. We showed that during the course of experimental infection cytotoxic clones specific for Leishmania infantum antigens developed in the spleen of susceptible BALB/c mice, showed an activated phenotype and became susceptible to apoptotic cell death late in the course of the disease. CD8(+) T cells exhibited considerable cytotoxic activity against cells expressing Leishmania antigens. This activity was mediated by both the perforin and the Fas/FasL pathway, as judged from in vitro and in vivo assays. The CD8(+) T cells also up-regulated mRNAs for cytokines (IFN-gamma and TNF-alpha) and C-C chemokines (RANTES and MIP-1alpha), which have a major role in immunity against the pathogen. CD8(+) T-cells thus displayed a Tc1 pattern of differentiation. In conclusion, CD8(+) T cells appear to play multiple roles in an experimental model of visceral leishmaniasis comprising both cytotoxic activity and secretion of cytokines and chemokines.     

Role of angiogenesis and vascular remodeling in chronic obstructive pulmonary disease

Recently, angiogenesis and pulmonary vascular remodeling in COPD has been investigated. It has been hypothesized that endothelial dysfunction might be an initiating event that promotes vessel remodeling in COPD.Inflammatory tissue- a pivotal pathological feature of COPD- often hypoxic, can induce angiogenesis through upregulation of factors such as VEGF or FGF and regulators of angiogenesis such as chemokines (CXC family), acting either as angiogenic or angiostatic. Angiopoietins are distinct molecules that act in association with VEGF at different stages of angiogenic process. The regulation of angiogenesis is determined by a dual, yet opposing balance of angiogenic and angiostatic factors that promote or inhibit neovascularization, respectively, not yet elucidated in detail in COPD.Recent studies suggested an increased expression of VEGF in pulmonary muscular arteries of patients with moderate COPD and also in smokers with normal lung function. This was also associated with enlargement of the arterial wall. However, in patients with severe emphysema, the expression of VEGF tended to be low, despite intense vascular remodelling. Furthermore, it has been suggested that VEGF might be involved in the pathogenesis of emphysema through apoptotic mechanisms. Experimental studies showed that the lung microvascular endothelial cells (including the alveolar septal capillary cells) are particularly vulnerable and dependent on VEGF for their survival. Apoptosis of endothelial, leading to the loss of capillaries may well be a central mechanism in patients with emphysema and muscle wasting.This review article summarizes the current knowledge regarding the contribution of vascular remodeling, as well as the pathogenetic and therapeutic implications of pivotal angiogenic mediators, in COPD.     

Smoking cessation in clinical practice: predictors of six-month continuous abstinence in a sample of Greek smokers.

AIM: To identify the predictors of six-month continuous abstinence among Greek smokers treated in a Smoking Cessation Clinic, emphasising the role of sleep disturbance on the outcome. METHODS: A nested case-control design was used. Patients who attended the Smoking Cessation Clinic between November 2004 and October 2005, and who completed six months of follow-up, constituted the final study population (N=285). The patients were separated into two groups - those who managed to quit smoking and those who didn't. The cessation method included pharmacotherapy, one-to- one behavioral counselling, and follow-up by telephone communication. RESULTS: Among various baseline characteristics examined, multivariate regression analysis indicated that the time to first cigarette after awakening, and use of bupropion, independently predicted abstinence, while awakening during the night was negatively associated with abstinence. CONCLUSION: These multivariate factors, which can positively or negatively affect the outcome, should be taken into account so that smoking cessation treatment can be individualised.