In silico studies and the design of novel agents for the treatment of systemic tuberculosis.

Tuberculosis (TB) is an ancient infectious disease, which re-emerged with the appearance of multidrug-resistant strains and acquired immune deficiency syndrome. Enoyl-acyl-carrier protein reductase (InhA) has emerged as a promising target for the development of anti-tuberculosis therapeutics. This study aims to develop quantitative structure-activity relationship (QSAR) models for a series of arylcarboxamides as InhA inhibitors. The QSAR models were calculated on the basis of optimal molecular descriptors based on the simplified molecular-input line-entry system (SMILES) notation with the Monte Carlo method as a model developer. The molecular docking study was used for the final assessment of the developed QSAR model and designed novel inhibitors. Methods used for the validation indicated that the predictability of the developed model was good. Structural indicators defined as molecular fragments responsible for increases and decreases of the studied activity were defined. The computer-aided design of new compounds as potential InhA inhibitors was presented. The Monte Carlo optimization was capable of being an efficient in silico tool for developing a model of good statistical quality. The predictive potential of the applied approach was tested and the robustness of the model was proven using different methods. The results obtained from molecular docking studies were in excellent correlation with the results from QSAR studies. This study can be useful in the search for novel anti-tuberculosis therapeutics based on InhA inhibition. Communicated by Ramaswamy H. Sarma.

Changes in respiratory function impairment following the treatment of severe pulmonary tuberculosis - limitations for the underlying COPD detection.

BACKGROUND: During the treatment phase of active pulmonary tuberculosis (PTB), respiratory function impairment is usually restrictive. This may become obstructive, as a PTB-associated airflow obstruction (AFO) or as a later manifestation of underlying COPD. PURPOSE: The aim of the study was to examine the potential causes and risks for AFO development in PTB by exploring the aspects of spirometry limitations and clinical implications for the underlying COPD detection, taking into account various confounding factors. PATIENTS AND METHODS: Prospective, nest case-control study on 40 new cases of PTB with initial restrictive respiratory function impairment, diagnosed and treated according to the directly observed treatment short course (DOTS) strategy. RESULTS: From all observed patients, 37.5% of them developed AFO upon the completion of PTB treatment, with significantly increased average of forced vital capacity (%) (P<0.01). Their changes in forced expiratory volume in the first second (%) during the PTB treatment were strongly associated with the air pollution exposure in living (0.474%-20.971% for 95% confidence interval [CI]; P=0.041) and working environments (3.928%-20.379% for 95% CI; P=0.005), initial radiological extent of PTB lesions (0.018%-0.700% for 95% CI; P=0.047), leukocyte count (0.020%-1.328% for 95% CI; P=0.043), and C-reactive protein serum level (0.046%-0.205% for 95% CI; P=0.003) compared to the other patients. The multivariate logistic regression analysis model shows initial radiological extent of pulmonary tuberculosis lesions (OR 1.01-1.05 for 95% CI; P=0.02) and sputum conversion rate on culture (OR 1.02-1.68 for 95% CI; P=0.04) as the most significant predictors for the risk of AFO development. CONCLUSION: AFO upon PTB treatment is a common manifestation of underlying COPD, which mostly occurs later, during the reparative processes in active PTB, even in the absence of major risk factors, such as cigarette smoking and biomass fuel dust exposure. Initial spirometry testing in patients with active PTB is not a sufficient and accurate approach in the detection of underlying COPD, which may lead to their further potential health deterioration.

Role of D-dimer in predicting mortality in patients with community-acquired pneumonia.

AIM: To determine whether D-dimer in patients with communityacquired pneumonia (CAP) can predict mortality risk better than standard biomarkers. METHODS: White blood cell (WBC), C-reactive protein (CRP) and D-dimer in 129 patients with CAP were analyzed. The recommended Pneumonia Severity Index (PSI) score was used to classify CAP patients into five groups according to the severity of disease (Group PSI I-V), and for predicting mortality. Additionally, the patients were divided in surviving and non-surviving group. RESULTS: White blood cell and CRP were not in correlation with the severity of CAP and the risk of mortality. The correlation between plasma D-dimer and severity of CAP was found (r=0.4993; p less than 0.001). The level of D-dimer was significantly higher in nonsurviving (2498.38 ± 1248.83 ng/mL) than in surviving patients (966.44 ± 968.73 ng/mL) (p less than 0.001). In predicting mortality risk, D-dimer showed sensitivity of 0.84 (cut of >1538 mg/mL), specificity 0.86 and AUC 0.859 (95%CI; 0.787-0.914). Pneumonia Severity Index in predicting of mortality risk for cut of > PSI III showed sensitivity of 0.92, specificity 0.62 and AUC 0.868 (95%CI; 0.797-0.921). There was no statistical difference between AUC of PSI and D-dimer (delta AUC= 0.00895) (p=0.9005). CONCLUSION: Coagulation abnormalities were presented in older patients with severe infections and comorbidity. Plasma D-dimer correlated better than standard inflammatory markers with severity of disease and risk of mortality in patients with CAP. In predicting mortality risk, D-dimer did not show difference among the PSI score.

Pulmonary function parameters as prognostic factors in advanced non-small cell lung cancer.

AIM: To investigate the impact of some parameters of lung function (forced expiratory volumen in 1 second - FEV1, forced vital capacity - FVC and ratio FEV1/FVC%) on survival in patients with advanced non-small cell lung cancer (NSCLC). METHODS: It retrospectively analyzed data of 155 patients with NSCLC receiving second-line treatment in the Clinic for Lung Diseases, Clinical Center Nis, Serbia, from October 2009 to December 2012. Fifteen potential prognostic variables were subjected to univariate and multivariate analysis to investigate prognostic impact to survival. RESULTS: Among the total of 155 patients, 124 (80%) were males. The most frequent was squamous carcinoma, 86 (55,5%). Mean FEV1 was 1.89 ± 0.71 L (61.8%), mean FVC 2.95 ± 0.8 L (77.2%) and mean FEV1/FVC% was 63.6%. In a multivariate analysis using Cox regression hazard model (hazard ratio, HR), independent prognostic factors for overall survival (OS) were: FEV1 less than 50% of predicted HR= 4.513, 95% confidence interval (CI): 1.433-14.216 (p=0.010), performance status 2 (HR= 0.090, CI= 0.035-0.230 (p=0.000) and weight loss more than 5 % (HR= 0.162, CI= 0.068-0.382 (p=0.000). CONCLUSION: FEV1 in patients with advanced NSCLC receiving chemotherapy is an important independent factor that can predict survival. There was close relationship between impaired lung function and lung cancer patients survival.

Challenges in the diagnosis and treatment of recurrent non-resolving pneumonia - the case of foreign body aspiration in adult mimicking lung neoplasm.

Foreign-body tracheobronchial aspiration in adults is fairly rare, and it is caused mostly by the failure of airway protective mechanisms. The symptoms of this clinical entity can mimic many other respiratory diseases, such as recurrent or non-resolving pneumonia, asthma, lung neoplasm etc. Flexible bronchoscopy was indicated in this situation, both for diagnostic and therapeutic purposes. We are reporting on a case of a fiftythree- year old women with recurrent, non-resolving pneumonia, recurrent hemoptysis, dyspnea, fiver, chest pain and radiological presentation of middle lobe neoplasm caused by aspirated chicken neck bone.

Pulmonary embolism in chronic hypoxemic patients with and without secondary polycythemia--analysis of risk factors in prospective clinical study.

AIM: Prospectively evaluate the incidence of pulmonary embolism and risk factors for this life-threatening disease on chronic hypoxemic patients treated in intensive respiratory care unit. METHODS: The study enrolled 842 consecutive patients with severe exacerbation of chronic obstructive pulmonary disease or respiratory failure. The initial assessment included clinical history collection, physical examination, hematological and biochemical analysis, gas analysis, chest X ray, 12 lead electrocardiography and determination of value of D-dimer. Of all enrolled patients, 211 met the exclusion criteria. Of 631 included patients, 269 (42.6%) had normal D-dimer. D-dimer level ≥ 500 µg/L was found in 362 (57.5%) patients who were referred to Doppler echocardiography, lower limb color Doppler ultrasonography and thoracic multidetector helical computed tomography. According the value of hematocrit, all patients were divided in two groups: group I (100 patients) with polycythema and group II (262 patients) without polycythemia. RESULTS: The first outcome of the study was the significantly higher incidence of pulmonary embolism in group I of patients than in group II, 39 (39%) and 29 (11.06%), respectively. Patients in group I had significantly worse disturbance of pulmonary function and higher degree of pulmonary hypertension (58.4 ± 3.66 vs. 30.3 ± 9.41). Apart from polycythemia in group I, the most common risk factors were arrhythmia, absolute and varicose veins. CONCLUSION: Polycythemia is a single most significant risk factor for pulmonary embolism in chronic hypoxemic patients. Value of D-dimer ≥ 500 µg /L, as well as presence of comorbidity, particularly vein varicose, in these patients should raise clinical suspicion of PE. Key words: chronic obstructive pulmonary disease, multidetector computed tomography, arrhythmia, varicose veins, pulmonary hypertension.

Nutrition disorder and systemic inflammation in patients with chronic obstructive pulmonary disease.

AIM: To detect nutrition disorders (underweight and obesity) in patients with chronic obstructive disease (COPD) and presence of systemic inflammation by determination of inflammatory mediators serum values C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α) and leptin. METHODS: The examination involved 85 patients with COPD. Nutrition categories were defined by body mass index (BMI). Fat free mass (FFM) was evaluated by mid upper-arm circumference (MUAC) and fat mass (FM) by tricipital skin-fold thickness (TFS). Values of TNF-α and leptin were measured by standardized ELISA kits and, CRP by latex turbidimetry. RESULTS: There were 14 (16.5%) underweight patients, 28 (32.9%) normal, 28 (32.9%) pre-obese and 15 (17.6%) obese. Values of MUAC and TSF were significantly different among the nutrition categories (p=0.000). The lowest MUAC and TSF values were in the underweight, and the highest in the obese. There was no significant difference of CRP and TNF-α among nutrition categories. Leptin of the underweight and normal nutrition was significantly different from leptin of the pre-obese and obese (p=0.000). The highest CRP and the lowest TNF-α and leptin were in the underweight patients. The obese had the lowest CRP (although increased as compared to normal values) and the highest leptin, while the pre-obese had the highest TNF-α. CONCLUSION: Two basic nutrition disorders (underweight and obesity) were manifested in COPD patients. The inflammatory profile differs between underweight COPD patients and obese. Probably that happens due to systemic inflammation, and in part due to dysfunction of adipose tissue.

Osteoporosis in patients with chronic obstructive pulmonary disease.

UNLABELLED: One of the extrapulmonary effects of chronic obstructive pulmonary disease (COPD) is osteoporosis. Osteoporosis is characterized by a low bone mineral density (BMD). THE AIM: The aim of this study was to determine relationship between bone mineral density and severity of COPD and body mass index (BMI). PATIENTS AND METHODS: in this study 85 COPD patients were recruited. Diagnosis and severity of COPD was made according to the GOLD guidelines. Height and weight were measured, and BMI was calculated. BMD (at the lumbar spine and at the femoral neck) were performed using Dual energy X-ray absorptiometry (DXA). BMD was expressed in g/cm2 and standardized T-score. RESULTS: The increase of COPD severity leads to the decrease of average values of BMD (femoral neck p = 0.005; lumbar spine p = 0.026), as well as T score (femoral neck p = 0.026; lumbar spine = 0.156). Also, the decrease of BMI leads to the decrease of average values of BMD (femoral neck p = 0.034; lumbar spine p = 0.269) and T score (femoral neck p = 0.001; lumbar spine p = 0.105), as well as to the increase of total osteoporosis (p = 0.009). CONCLUSION: patients with severe COPD and lowe BMI have lower BMD and T score and more frequently have osteoporosis.

Chronic airflow obstruction syndrome due to pulmonary tuberculosis treated with directly observed therapy--a serious changes in lung function.

UNLABELLED: The origin of Chronic airflow obstruction (CAO) syndrome in active Tuberculosis (TB), despite significant similarities with chronic obstructive pulmonary disease (COPD), still remains unknown. The aim of the study was to examine the potential causes and risks for the development of CAO syndrome in new cases of pulmonary TB. DESIGN: Prospective, nest case-control study. PATIENTS: 40 patients with newly detected cavitary pulmonary TB and initial normal respiratory function, diagnosed and treated according to DOTS strategy. MEASUREMENTS AND RESULTS: The average values of Snider's radiological score during TB treatment were significantly reduced (p < 0.001), as well as average values of non-specific systemic serum markers of inflammation. The average values of FEV1 (%), both before, during and at the end of completion of TB treatment were significantly decreased (p < 0.05;). Linear regression analysis confirmed a statistically significant association between changes in the values of FEV1 (%), resulting in TB treatment completion, and the value of Snider's radiological score and the sputum culture conversion rate. From the initial findings of normal pulmonary ventilation tests, upon the completion of TB treatment 35.0% of observed patients developed the CAO syndrome. Logistic regression analysis confirmed a positive familiar burden for COPD, Snider's radiological score at the beginning of TB treatment and sputum conversion rate on culture, as statistically significant predictors, while multivariate logistic regression analysis confirmed Snider's radiological score at the beginning of TB treatment and sputum conversion rate on culture as most significant risk factors for CAO syndrome occurrence and development. CONCLUSION: The CAO syndrome is often a consequence and significant functional impairment of the respiratory system, during the reparative processes in active TB, even in the absence of risk factors for COPD. Only microbiological cure of TB patients with underlying risks for disorders of lung function, is not sufficient and effective approach for prevention of their further potential health deterioration.

[Prognostic factors of mortality in elderly with community acquired pneumonia].

BACKGROUND/AIM: Community acquired pneumonia in elderly has specific clinical aspect and higher mortality in relation to younger patients. According to specific pneumonia severity assessment on admission and its importance in proper prediction of clinical course and outcome, the aim of this study was defining prognostic factors of mortality. METHODS: This study included 240 patients aged > or = 65 years with community acquired pneumonia. On admission, demographic characteristics, underlying diseases, physical symptoms and findings, laboratory values, chest radiography and oxygen blood saturation (SaO2) were analyzed. Multivariate analysis was used to identify characteristic prognostic factors which showed a statistical significance in relation to mortality. RESULTS: Altered mental status, respiratory frequency > or = 23/min and the presence of bilateral pneumonic infiltrates were defined as the most important prognostic factors of mortality (p < 0.001). These factors displayed 57.89% sensitivity, 100% specificity and 93.33% accuracy. CONCLUSION: The presence of identified characteristic prognostic factors on admission pointed out an adverse clinical course and outcome of community acquired pneumonia in elderly. Age and sex were not significantly associated with mortality.

[Pulmonary rehabilitation in patients with chronic obstructive pulmonary disease].

BACKGROUND/AIM: Chronic obstructive pulmonary disease (COPD) irreversibly damages pulmonary function leading to disorder of arterial bloodgases, arterialpartial prescure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2), appearance of dyspnea, and decrease of physical condition. The aim of this study was to establish if medical treatment and respiratory rehabilitation in COPD used simultaneously lead to the greater improvement of PaO2, PaCO2 and physical condition and decreaseing dyspnea than medical treatment alone. METHODS: A total of 60 patients divided into three groups according to the severity of obstruction (mild--I, severe--II, very severe--III) weretested. Each group had the two subgroups of patients--first one with those treated both with medical treatment and respiratory rehabilitation (A) and the second one with the patients treated only with medical treatment (B). The treatment took 21 days. The measurements of PaO2 and PaCO2) intensity of dyspnea at rest and exercise (10--point Borg Category Scale), and physical capacity (Six-Minute Walk Test--6MWT) were done on the first and on the last day of testing. RESULTS: The results showed that all of the patients who were treated with the combination of medical treatment and respiratory rehabilitation had significantly higher increase in the values of PaO2 (I--p < 0.01; II--p < 0.05; III--p < 0.01), score of Borg's scale (I--p < 0.05, p < 0.001; II--p < 0.05, p < 0.001; III--p < 0.001, p < 0.001) and 6MWT (I--p < 0.001; II--p < 0.001; III--p < 0.001), and that statistically significant increase of the values of PaCO2 (p < 0.05) had only the patients with very severe COPD treated with the combination of drugs and respiratory rehabilitation. CONCLUSION: Based on the obtained results we conclude that using respiratory rehabilitation in combination with pharmacological treatment of COPD gives statistically higher improvement of values of PaO2 and PaCO2, and physical condition, and also leads to decrease of intensity of dyspnea than using just drug therapy.