Polymorphisms of the NRAMP1 gene: distribution and susceptibility to the development of pulmonary tuberculosis in the Greek population.

BACKGROUND: Ample evidence suggests that host genetic factors affect human susceptibility to tuberculosis. The natural resistance-associated macrophage protein 1 (NRAMP1) gene seems to play a role in the pathophysiology of a number of intracellular infections, including mycobacteria. A case-control study was conducted in the Greek population to determine whether NRAMP1 polymorphisms affect the susceptibility to development of overt pulmonary tuberculosis. MATERIAL/METHODS: NRAMP1 polymorphisms (3'UTR, D543N, INT4) were evaluated among 142 patients with culture-positive pulmonary tuberculosis and 144 ethnically matched healthy controls having latent M. tuberculosis infection. Patients with human immunodeficiency virus infection were excluded. RESULTS: Out of the 3 NRAMP1 polymorphisms, a trend of increased incidence of INT4 polymorphism was found in the patients' group compared to the control group. A lack of association was observed between the 2 groups as far as the other 2 polymorphisms (D543N, 3'UTR) are concerned. INT4-CC homozygotes were found to have a higher risk to develop pulmonary tuberculosis compared to GG homozygotes (p=0.022). An increased incidence G/TGTG/C genotype combination was found in the patients' group as compared to controls. G/TGTG/C genotype combination was associated with a 36% higher risk of developing pulmonary tuberculosis (p=0.004) compared to the baseline expression of G/TGTG/G combination. CONCLUSIONS: INT4-NRAMP1 polymorphism may have a role in the development of culture-positive pulmonary tuberculosis after an initial M. tuberculosis latent infection. The possible role of INT4-NRAMP1 polymorphism in the development of active pulmonary tuberculosis needs further investigation.

Tumor necrosis factor-alpha promotes malignant pleural effusion.

Tumor necrosis factor (TNF)-alpha is present in the microenvironment of human tumors, including malignant pleural effusion (MPE). Although the cytokine is produced in the pleural cavity by both tumor and host cells, its effects on MPE formation are unknown. In these studies, we sought to determine the role of TNF-alpha in the pathogenesis of MPE and to assess the therapeutic effects of its neutralization in a preclinical model. For this, MPEs were generated in immunocompetent mice using intrapleural injection of mouse lung adenocarcinoma cells. The roles of tumor- and host-derived TNF-alpha were assessed using combined experimentation with TNF-alpha gene-deficient mice and in vivo TNF-alpha neutralization. To expand the scope of preclinical data, TNF-alpha and vascular endothelial growth factor (VEGF) expression were determined in human cancer cell lines and human MPE. In the MPE model, TNF-alpha of host and tumor origin was present. TNF-alpha neutralization significantly limited tumor dissemination, effusion formation, vascular hyperpermeability, TNF-alpha and VEGF expression, and angiogenesis, thereby improving survival. In contrast, these variables were not different between TNF-alpha gene-sufficient and TNF-alpha gene-deficient mice. In mouse cancer cells, TNF-alpha functioned via nuclear factor-kappaB- and neutral sphingomyelinase-dependent pathways to induce TNF-alpha and VEGF, respectively. These results were recapitulated in human cancer cells, and a correlation was detected between TNF-alpha and VEGF content of human MPE. We conclude that tumor-derived TNF-alpha is important in the development of MPE in mice, and provide preclinical evidence supporting the efficacy of TNF-alpha blockade against malignant pleural disease.

Serological diagnosis of Chlamydophila pneumoniae infection in Greek COPD patients by microimmunofluorescence and ELISA.

BACKGROUND: The possible role of Chlamydophila pneumoniae infection in episodes of acute exacerbation of COPD (AECOPD) was described in 4-34% of COPD patients, but never in Greece. The possible association of chronic C. pneumoniae infection with disease severity is under study, with a diversity of results reported. MATERIAL/METHODS: Seventy-five Greek patients with AECOPD were tested for serum C. pneumoniae antibodies using the microimmunofluorescence (MIF) test and ELISA during the first day of their hospitalization and 30 days after enrollment. Serological diagnosis of acute and past C. pneumoniae infection was determined and the sensitivities, specificities, and predictive values of both methods were evaluated. Chronic C. pneumoniae infection was also estimated in both the patient group and a control group. RESULTS: Seven patients (9.3%) had serological evidence of acute C. pneumoniae infection. Although ELISA and MIF produced equal results for the diagnosis of acute C. pneumoniae infection, the sensitivity and negative predictive value of ELISA for the diagnosis of past C. pneumoniae infection was low when MIF was used as the gold-standard method. Chronic C. pneumoniae infection was more common in COPD patients than in the control group and was even more common in patients with FEV(1)<50%. CONCLUSIONS: Acute C. pneumoniae infection is associated with AECOPD in Greece. ELISA may currently be a valuable diagnostic tool for the diagnosis of acute C. pneumoniae infection, but not for the diagnosis of past infection. The possible role of chronic C. pneumoniae infection in COPD progression needs further investigation.

Leukotriene B4 in exhaled breath condensate and sputum supernatant in patients with COPD and asthma.

STUDY OBJECTIVES: Some patients with COPD present with significant reversibility of airflow limitation after receiving bronchodilation therapy. Leukotriene B(4) (LTB(4)) has been implicated in the pathophysiology of both COPD and asthma. We tested the hypothesis that COPD patients with airflow reversibility and asthmatic patients who smoke might have similar levels of LTB(4) in exhaled breath condensate (EBC) and sputum supernatant. The repeatability and stability of LTB(4) measurements were additionally studied. DESIGN: Prospective, cross-sectional study. PATIENTS OR PARTICIPANTS: We studied 30 patients with COPD (15 smokers [FEV(1), 56% predicted; SD, 6% predicted]; 15 patients with significant reversibility in airway obstruction after bronchodilation [FEV(1), 14% predicted; SD, 2% predicted]). Fifteen asthmatic patients who smoked, with similar FEV(1) and reversibility were also studied. Ten healthy smokers served as control subjects. SETTING: A hospital research laboratory. INTERVENTIONS: Spirometry and reversibility testing were performed on the first visit. On the following day, EBC was collected for the measurement of LTB(4), and induced sputum was collected for differential cell counts and LTB(4) measurement in the sputum supernatant. MEASUREMENTS AND RESULTS: LTB(4) levels in EBC [mean (SD)] were increased in COPD patients (mean, 86.7 pg/mL; SD, 19 pg/mL) and asthmatic patients (mean, 97.5 pg/mL; SD, 15 pg/mL) compared to control subjects (mean, 32.3 pg/mL; SD, 10 pg/mL; p < 0.0001 for both groups). COPD patients with airflow reversibility (mean, 99.8 pg/mL; SD, 12 pg/mL) had values similar to those of asthmatic patients (mean, 97.5 pg/mL; SD, 15 pg/mL; p = 0.2) and higher than those of COPD patients without airflow reversibility (mean, 73.7 pg/mL; SD, 17 pg/mL; p = 0.002). Similar results were observed in the sputum supernatant. Measurements of LTB(4) in EBC and sputum were repeatable on two consecutive days, but measurements in the frozen samples of EBC and sputum were not stable after 3 weeks. CONCLUSIONS: Patients with asthma and reversible COPD presented with higher LTB(4) values compared to patients with nonreversible COPD and healthy smokers. This difference may be mainly attributed to the presence of reversibility in airway obstruction, probably as part of a common underlying inflammatory process.

Thiazolidinediones and type 2 diabetes: from cellular targets to cardiovascular benefit.

The prevalence of type 2 diabetes is evolving globally at an alarming rate. This fact is mainly the result of our global lifestyle "modernization" that has resulted in overweight and obesity. Dysfunction of peroxisome proliferator activated receptor-gamma (PPAR-gamma) has been implicated in the development of insulin resistance, while a reduce expression of many PPAR-gamma regulated genes has been observed in an obese diabetic state. Thiazolidinediones (TZDs) are potent exogenous agonists of PPAR-gamma, which augment the effects of insulin to its cellular targets and mainly at the level of adipose tissue. Preclinical and clinical studies have demonstrated that apart from their glucose-lowering activity, these drugs also regulate the production of inflammatory mediators by cells that play a pivotal role in the pathogenesis of atherosclerosis. This paper summarizes the evolving changes observed in an enlarged adipose tissue and examines the activity of TZDs in their main cellular targets. It also discusses whether these cellular pleiotropic effects can result in a clinically meaningful outcome, in terms of cardiovascular benefit, in this population.

Chlamydophila pneumoniae infection and COPD: more evidence for lack of evidence?

Chlamydophila pneumoniae has been recognized as a common cause of respiratory tract infections affecting all age groups. The organism has been implicated as an infectious trigger for acute exacerbations of COPD. Moreover, the intracellular existence of this pathogen and the ability to cause chronic respiratory infections have led to a number of studies that investigated its possible association with disease development. The present paper examines and discusses the possible association of acute C. pneumoniae infection in episodes of acute exacerbation of COPD. It also reviews the existing evidence of chronic C. pneumoniae infection with disease pathogenesis and severity. The significant interstudy variation of the choice of diagnostic methods and criteria applied is most likely responsible for the great diversity of results observed. The use of well-standardized, commercially available diagnostic tools, as well as the adoption of a more unified diagnostic approach is probably the key element missing in order to clarify the exact role of C. pneumoniae in COPD.

Asymptomatic stage I sarcoidosis complicated by pulmonary tuberculosis: a case report.

INTRODUCTION: Sarcoidosis is a multisystem granulomatous disorder characterized pathologically by the presence of non-caseating granulomas in involved tissues. Depressed cellular immunity predisposes patients to infections with certain intracellular organisms, mostly fungi, Mycobacterium tuberculosis and Nocardia species. As these infections are mainly insidious and difficult to differentiate from the underlying disease, a possible misdiagnosis may lead to fatal complications for the patient. CASE PRESENTATION: We present a case of a 67-year-old woman with undiagnosed asymptomatic stage I sarcoidosis for at least 8 years before her admission and a 1-month history of fever, exertional dyspnea and dry cough, in whom pulmonary tuberculosis was documented. CONCLUSION: This case highlights the need for great vigilance among physicians in order to rule out any possible infection before establishing the diagnosis of sarcoidosis.

Sleep apnea-related cognitive deficits and intelligence: an implication of cognitive reserve theory.

Cognitive deficits in patients with obstructive sleep apnea syndrome (OSAS) are well demonstrated, but the pathophysiology of these deficits is still controversial, as the relationship between OSA severity and cognitive deficits is usually weak. Our study considers the possible relationship between OSA-related cognitive deficits and the overall intellectual function of OSA patients. Forty-seven OSA patients and 36 normal individuals underwent a neuropsychological battery test assessing attention and alertness. According to the resulting IQ score, patients and controls were divided into a high-intelligence group (IQ > or = 90th percentile) and a normal-intelligence group (50 < or = IQ < 90%ile). Between the two patient groups there were no significant differences noticed, regarding OSA severity or sleepiness. High-intelligence patients showed the same attention/alertness performance compared with the high-intelligence controls. On the contrary, patients with normal-intelligence showed attention/alertness decline compared with the normal-intelligence control group. The two patient groups were re-examined with the same battery test after at least 1 year of CPAP treatment. At re-examination neither patient group showed any differences regarding attention and alertness compared with the control groups. We assume that high-intelligence may have a protective effect against OSA-related cognitive decline, perhaps due to increased cognitive reserve.

Sarcoidosis associated with interferon-alpha therapy for chronic hepatitis C.

BACKGROUND: Recombinant interferon-alpha (IFN-alpha ) is widely used for the treatment of chronic hepatitis C. Pulmonary side effects of IFN-alpha therapy seem to be rare. So far, only a few cases of sarcoidosis in association with IFN-alpha treatment of chronic hepatitis C have been CASE REPORT: A 52-year-old woman with chronic hepatitis C developed sarcoidosis during treatment with IFN-alpha. Diagnosis of sarcoidosis was based on chest imaging studies, the increased serum angiotensin converting enzyme levels, and the histology of a biopsied cervical lymph node. Spontaneous remission was observed following IFN-alpha withdrawal. CONCLUSIONS: Use of recombinant IFN-alpha in patients with chronic hepatitis C may trigger or contribute to the development of sarcoidosis in susceptible individuals. Patients should be monitored during and following IFN-alpha therapy for the occurrence of manifestations suggesting sarcoidosis.

Sputum carcinoembryonic antigen, neuron-specific enolase and cytokeratin fragment 19 levels in lung cancer diagnosis.

OBJECTIVE: The aim of the present study was to examine the impact of sputum carcinoembryonic antigen (CEA), neuron-specific enolase (NSE) and cytokeratin fragment 19 (CYFRA 21-1) levels in lung cancer diagnosis and to compare the diagnostic usefulness of sputum assays with that of serum assays. METHODOLOGY: Forty-seven patients with lung cancer and 62 with benign lung disease were studied. Tumour marker levels in sputum (sp.) and serum (ser) were measured by immunoradiometric assays. RESULTS: Sputum and serum tumour marker levels were significantly higher in lung cancer than in benign disease. When the specificity was 95%, the sensitivity was 57%, 43%, 36%, 30%, 28% and 19%, for spCEA, serCYFRA 21-1, spCYFRA 21-1, serCEA, serNSE, and spNSE, respectively. Bayesian analysis showed that the best predictive values correspond to spCEA and serCYFRA 21-1. The maximum overall gain was obtained in pretest probability of 0.35 for both spCEA and serCYFRA 21-1, with predictive values of 84% and 80% for spCEA and serCYFRA 21-1, respectively. CONCLUSION: Sputum tumour marker levels were no more useful than the serum levels in lung cancer diagnosis. SpCEA offered the best predictive values but these were still not sufficiently satisfactory for spCEA to be proposed for routine use.