L-Arginine Pathway in COPD Patients with Acute Exacerbation: A New Potential Biomarker.

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remains a major cause of mortality. Clinical criteria of AECOPD are subjective. Biomarkers for AECOPD may aid in the initiation of early treatment. Increased production of asymmetric and symmetric dimethylarginine (ADMA, SDMA) is related to hypoxia. In COPD, a rise in ADMA results in a shift of L-arginine breakdown, contributing to airway obstruction. We aimed to compare serum levels of ADMA, SDMA and L-arginine in patients with and without AECOPD. METHODS: L-arginine metabolites quantified by high-performance liquid chromatography in venous blood samples and partial capillary oxygen pressure were prospectively investigated in 32 patients with COPD, 12 with AECOPD and 30 healthy subjects. RESULTS: Both ADMA and SDMA were significantly higher in AECOPD compared to stable COPD (p = 0.004 and p < 0.001, respectively). Oxygen content in capillaries correlated with serum ADMA concentration. However, the concentration of L-arginine was not different between AECOPD and stable COPD. Both ADMA and SDMA separated AECOPD with high sensitivity and specificity (AUC: 0.81, p = 0.001; AUC: 0.91, p < 0.001, respectively). A cut-off value ≥0.57 for SDMA was an independent variable to confirm AECOPD in a regression model (OR: 1.632, p = 0.001). All markers were significantly higher in the sera of both patient groups compared to the controls (p < 0.05, respectively). CONCLUSIONS: COPD is associated with elevated L-arginine, ADMA and SDMA serum levels. In patients with AECOPD, production of ADMA and SDMA are more pronounced presumably due to more severe hypoxic insult. Methylated arginine derivatives in the sera may help early recognition of AECOPD.

Noninvasive ventilation improves the outcome in patients with pneumonia-associated respiratory failure: Systematic review and meta-analysis.

BACKGROUND: Noninvasive ventilation (NIV) is beneficial in exacerbations of chronic obstructive pulmonary disease (COPD), but its effectiveness in pneumonia-associated respiratory failure is still controversial. In the current meta-analysis, we aimed to investigate whether the use of NIV before intubation in pneumonia improves the mortality and intubation rates of respiratory failure as compared to no use of NIV in adults. METHODS: We searched three databases from inception to December 2019. We included studies, in which pneumonia patients were randomized initially into either NIV-treated or non-NIV-treated groups. Five full-text publications, including 121 patients, reported eligible data for statistical analysis. RESULTS: With NIV the overall hospital mortality rate seemed lower in patients with pneumonia-associated respiratory failure, but this was not significant [odds ratio (OR) = 0.39; 95% confidence interval (CI): 0.13-1.14; P = 0.085]. In the intensive care unit, the mortality was significantly lower when NIV was applied compared to no NIV treatment (OR = 0.22; 95% CI: 0.07-0.75; P = 0.015). NIV also decreased mortality compared to no NIV in patient groups, which did not exclude patients with COPD (OR = 0.25; 95% CI: 0.08-0.74; P = 0.013). The need for intubation was significantly reduced in NIV-treated patients (OR = 0.22; 95% CI: 0.09-0.53; P = 0.001), which effect was more prominent in pneumonia patient groups not excluding patients with pre-existing COPD (OR = 0.13; 95% CI: 0.03-0.46; P = 0.002). CONCLUSION: NIV markedly decreases the death rate in the intensive care unit and reduces the need for intubation in patients with pneumonia-associated respiratory failure. The beneficial effects of NIV seem more pronounced in populations that include patients with COPD. Our findings suggest that NIV should be considered in the therapeutic guidelines of pneumonia, given that future clinical trials confirm the results of our meta-analysis. AVAILABILITY OF DATA AND MATERIALS: All data and materials generated during the current study are available from the corresponding author on reasonable request.

Double Stenting for Malignant Biliary and Duodenal Obstruction: A Systematic Review and Meta-Analysis.

INTRODUCTION: Data about the efficacy of palliative double stenting for malignant duodenal and biliary obstruction are limited. METHODS: A systematic literature search was performed to assess the feasibility and optimal method of double stenting for malignant duodenobiliary obstruction compared with surgical double bypass in terms of technical and clinical success, adverse events, reinterventions, and survival. Event rates with 95% confidence intervals were calculated. RESULTS: Seventy-two retrospective and 8 prospective studies published until July 2018 were included. Technical and clinical success rates of double stenting were 97% (95%-99%) and 92% (89%-95%), respectively. Clinical success of endoscopic biliary stenting was higher than that of surgery (97% [94%-99%] vs 86% [78%-92%]). Double stenting was associated with less adverse events (13% [8%-19%] vs 28% [19%-38%]) but more frequent need for reintervention (21% [16%-27%] vs 10% [4%-19%]) than double bypass. No significant difference was found between technical and clinical success and reintervention rate of endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic drainage, and endoscopic ultrasound-guided biliary drainage. ERCP was associated with the least adverse events (3% [1%-6%]), followed by percutaneous transhepatic drainage (10% [0%-37%]) and endoscopic ultrasound-guided biliary drainage (23% [15%-33%]). DISCUSSION: Substantially high technical and clinical success can be achieved with double stenting. Based on the adverse event profile, ERCP can be recommended as the first choice for biliary stenting as part of double stenting, if feasible. Prospective comparative studies with well-defined outcomes and cohorts are needed.

Role of microparticles derived from monocytes, endothelial cells and platelets in the exacerbation of COPD.

BACKGROUND: Microparticles (MPs) are shedding membrane vesicles released from activated blood and endothelial cells under inflammatory conditions. The role of endothelial MPs (EMPs) in pathophysiology of COPD is relatively well known. However, the release and function of MPs of other cellular origins, eg, platelets, red blood cells and leukocytes, are not clearly evaluated in COPD. PURPOSE: The aim of this study was to measure EMPs and other cell-derived circulating MPs in stable and exacerbated COPD patients. PATIENTS AND METHODS: A total of 50 patients with COPD and 19 healthy volunteers were enrolled in the study. EMPs (CD31+, CD62E+) and platelet-derived (CD61+, CD41+, CD42a+, PAC1+), red blood cell-derived (GlyA+) and leukocyte-derived (CD45+, CD13+, CD14+, CD56+) MPs were measured. Flow cytometry (FC) was performed on Beckman Coulter FC500 analyzer. MP reference gate was set using 0.3-0.5-0.9 µm microbeads with MP size gates of 0.5-1.0 µm. RESULTS: All the measured MPs were significantly (P<0.001) higher in COPD patients than in the controls. Furthermore, CD62E+, CD41+, CD42a+ and CD14+ MP values were significantly (P<0.001) increased in exacerbated COPD compared to stable COPD. These MPs showed significant (P<0.001) inverse correlation with FEV1/FVC, as well. CONCLUSION: In this study, we describe a reliable flow cytometric assay for MP analysis that was successfully applied in COPD. Besides EMPs, COPD is accompanied by an increased concentration of various MPs in the systemic circulation; particularly, platelet- and monocyte-derived MPs seem to be important in exacerbation.

Cigarette Smoke-Induced Pulmonary Inflammation Becomes Systemic by Circulating Extracellular Vesicles Containing Wnt5a and Inflammatory Cytokines.

Chronic obstructive pulmonary disease (COPD) is a devastating, irreversible pathology affecting millions of people worldwide. Clinical studies show that currently available therapies are insufficient, have no or little effect on elevated comorbidities and on systemic inflammation. To develop alternative therapeutic options, a better understanding of the molecular background of COPD is essential. In the present study, we show that non-canonical and pro-inflammatory Wnt5a is up-regulated by cigarette smoking with parallel up-regulation of pro-inflammatory cytokines in both mouse and human model systems. Wnt5a is not only a pro-inflammatory Wnt ligand but can also inhibit the anti-inflammatory peroxisome proliferator-activated receptor gamma transcription and affect M1/M2 macrophage polarization. Both Wnt5a and pro-inflammatory cytokines can be transported in lipid bilayer sealed extracellular vesicles that reach and deliver their contents to every organ measured in the blood of COPD patients, therefore, demonstrating a potential mechanism for the systemic nature of this crippling disease.

[Assessment of suicidal behaviour in general practice]. / Az öngyilkos viselkedés gyakorisága és jellegzetességei a családorvosi gyakorlatban.

AIM: To assess the prevalence of suicidal behavior (wish to die, suicidal thoughts, suicide attempts) and to determine the characteristics of suicide attempters in primary care, including screening for major mental disorders. METHOD: A Hungarian urban general practitioner's district with 1248 inhabitants was screened for suicidal behavior as well as for major mental disorders. All the patients (n=382) who visited their general practitioner within a two-week period were asked to participate. 277 patients completed the Prime-MD questionnaire, an easy-to-use diagnostic instrument developed for general practitioners to recognize the most common psychiatric disorders, like depressive (major depressive disorder, minor depressive disorder), anxiety (panic disorder, generalized anxiety disorder), somatoform, eating and alcohol related disorders. Detailed data about suicidal thoughts and attempts were also collected by the structured questions of MINI-Plus diagnostic interview. RESULTS: Prevalence of suicide attempts in primary care was 2.9%. 9% of the patients had either suicidal thoughts or suicide attempts in the previous month. Suicidal patients were more ready to use psychotropic drugs, they assessed their health status more poorly, and had more mental symptoms than the control group (non-suicidal patients). 60% of suicidal patients and 11.5% of the investigated population had a current depressive episode. Beside depressive symptoms, anxiety disorders and alcohol problems were also more common among suicidal patients. The rate of previous psychiatric treatments was also higher in suicidal patients, who generally visited their general practitioners less frequently than non-suicidal patients. According to multivariate logistic regression, suicidal patients are more ready to take antidepressants, they tend to have more previous psychiatric treatments and suicidal attempts, and they visit their general practitioners less frequently and have a current depressive episode. CONCLUSION: Suicidal behavior and mental disorders are frequent in primary care. Since almost every tenth patient visiting their general practitioner has suicidal thoughts or depressive or anxiety disorder, the recognition of suicide risk and mental disorders is very important in primary care. As for preventing suicides, the diagnosing and treating of mental disorders -especially affective disorders- are very important for general practitioners. In addition to pharmacotherapy, psychotherapies are also important in treating patients in crisis situations, or with suicidal thoughts or depressive disorder. The modified Prime-MD questionnaire can be an effective, easy-to-use method in the hand of the general practitioners to identify suicidal risk and to recognize the most common mental disorders in the average population.

The Frequency of EGFR Mutation in Lung Adenocarcinoma and the Efficacy of Tyrosine Kinase Inhibitor Therapy in a Hungarian Cohort of Patients.

In the last decades new therapeutic drugs have been developed for the treatment of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) significantly increase the progression free survival (PFS) of patients with NSCLC carrying epidermal growth factor receptor (EGFR) mutations. This type of lung cancer occurs mainly among non-smoking women and Asian origin. However, the new ESMO guideline recommends EGFR mutation analysis in every patient with NSCLC, because in patients with activating EGFR mutation, TKIs should be considered as first line therapy. In our recent work, we analyzed data of patients with EGFR-mutant adenocarcinoma from January 2009. The number of patients investigated was 446, among them 44 cases were positive for EGFR mutation. The ratio of positive cases was 9.86 % that is lower than the average mutation rate in Europe and much lower than that found in Asia. The exon 19 deletion was detected in 61.4 % of the patients, while L858R point mutation in exon 21 was observed in 34.1 % of them. In one subject, both exon 19 and 21 mutations were present simultaneously. A rare mutation located in exon 21 was found in another patient. TKI therapy was conducted in 38 patients. The disease control rate by TKI therapy was 85.7 %; primary resistance was documented in five subjects. Non-smoking patients with EGFR mutant adenocarcinoma had the highest benefit from TKI treatment. Our data support the recommendation that EGFR mutation status should be defined in all cases of locally advanced or metastatic lung adenocarcinoma.