By deflating the lungs pulmonologists help the cardiologists. A literature review.

In this review, we present the effects of lung hyperinflation on the cardiovascular system (CVS) and the beneficial outcomes of different deflation treatment modalities. We discuss the effects of long-acting bronchodilator drugs, medical and surgical lung volume reduction on the performance of the CVS. Although there is a small number of studies investigating lung deflation and the CVS, the short-term improvement in heart function was clearly demonstrated. However, more studies, with longer duration, are needed to verify these significant beneficial effects of deflation of the lungs on the CVS. Dynamic hyperinflation during exercise could be a research model to investigate further the effects of lung hyperinflation and/or deflation on the CVS.

Asthma and stroke: a narrative review.

Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation, bronchial reversible obstruction and hyperresponsiveness to direct or indirect stimuli. It is a severe disease causing approximately half a million deaths every year and thus possessing a significant public health burden. Stroke is the second leading cause of death and a major cause of disability worldwide. Asthma and asthma medications may be a risk factors for developing stroke. Nevertheless, since asthma is associated with a variety of comorbidities, such as cardiovascular, metabolic and respiratory, the increased incidence of stroke in asthma patients may be due to a confounding effect. The purpose of this review is to analyze the complex relationship between asthma and stroke.

Small airways' function in Obstructive Sleep Apnea-Hypopnea Syndrome.

INTRODUCTION AND OBJECTIVES: Most of the studies of the pathophysiology of Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) focus on the collapsibility and obstruction of the upper airways. The aim of our study was the investigation of small airways' function in patients with OSAHS. MATERIALS AND METHODS: We studied 23 patients (mean age, 51.6 years) diagnosed with mild to severe OSAHS, without comorbidities and 8 controls (mean age, 45.9 years). All subjects underwent full polysomnography sleep study; spirometry and maximum flow/volume curves while breathing room air and a mixture of 80%He-20%O2. The volume of equal flows (VisoV⋅) of the two curves and the difference of flows at 50% of FVC (ΔV˙max50) were calculated, as indicates of small airways' function. RESULTS: The results showed that VisoV⋅ was significantly increased in patients with OSAHS compared with controls (18.79±9.39 vs. 4.72±4.68, p=0.004). No statistically significantly difference was found in ΔV˙max50% (p=0.551); or the maximum Expiratory flow at 25-75% of FVC (p=0.067) and the maximum expiratory flow at 50% of FVC (p=0.174) breathing air. CONCLUSIONS: We conclude that at the time of the diagnosis of OSAHS, the function of the small airways is affected. This could be due to breathing at low lung volumes and the cyclic closure/opening of the small airways and may affect the natural history of OSAHS. The findings could lead to new therapeutic implications, targeting directly the small airways.

miRNAs and their role in the correlation between schizophrenia and cancer (Review).

Schizophrenia (SZ) and cancer (Ca) have a broad spectrum of clinical phenotypes and a complex biological background, implicating a large number of genetic and epigenetic factors. SZ is a chronic neurodevelopmental disorder signified by an increase in the expression of apoptotic molecular signals, whereas Ca is conversely characterized by an increase in appropriate molecular signaling that stimulates uncontrolled cell proliferation. The rather low risk of developing Ca in patients suffering from SZ is a hypothesis that is still under debate. Recent evidence has indicated that microRNAs (miRNAs or miRs), a large group of small non­coding oligonoucleotides, may play a significant role in the development of Ca and major psychiatric disorders, such as SZ, bipolar disorder, autism spectrum disorders, suicidality and depression, through their interference with the expression of multiple genes. For instance, the possible role of let­7, miR­98 and miR­183 as biomarkers for Ca and SZ was investigated in our previous research studies. Therefore, further investigations on the expression profiles of these regulatory, small RNA molecules and the molecular pathways through which they exert their control may provide a plausible explanation as to whether there is a correlation between psychiatric disorders and low risk of developing Ca.

Combined Pulmonary Fibrosis and Emphysema in Scleroderma-Related Lung Disease Has a Major Confounding Effect on Lung Physiology and Screening for Pulmonary Hypertension.

OBJECTIVE: To assess the prevalence of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD) and the effect of CPFE on the pulmonary function tests used to evaluate the severity of SSc-related ILD and the likelihood of pulmonary hypertension (PH). METHODS: High-resolution computed tomography (HRCT) scans were obtained in 333 patients with SSc-related ILD and were evaluated for the presence of emphysema and the extent of ILD. The effects of emphysema on the associations between pulmonary function variables and the extent of SSc-related ILD as visualized on HRCT and echocardiographic evidence of PH were quantified. RESULTS: Emphysema was present in 41 (12.3%) of the 333 patients with SSc-related ILD, in 26 (19.7%) of 132 smokers, and in 15 (7.5%) of 201 lifelong nonsmokers. When the extent of fibrosis was taken into account, emphysema was associated with significant additional differences from the expected values for diffusing capacity for carbon monoxide (DLco) (average reduction of 24.1%; P < 0.0005), and the forced vital capacity (FVC)/DLco ratio (average increase of 34.8%; P < 0.0005) but not FVC. These effects were identical in smokers and nonsmokers. Multivariate analysis showed that the presence of emphysema had a greater effect than echocardiographically determined PH on the FVC/DLco ratio, regardless of whether it was analyzed as a continuous variable or using a threshold value of 1.6 or 2.0. CONCLUSION: Among patients with SSc-related ILD, emphysema is sporadically present in nonsmokers and is associated with a low pack-year history in smokers. The confounding effect of CPFE on measures of gas exchange has major implications for the construction of screening algorithms for PH in patients with SSc-related ILD.

Treatment of Experimental Candida Sepsis with a Janus Kinase Inhibitor Controls Inflammation and Prolongs Survival.

Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) levels and IL-10/TNF-α ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-α ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.

Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma.

BACKGROUND: Although asthma is characterized by variable airways obstruction, most studies of asthma phenotypes are cross-sectional. The stability of phenotypes defined either by biomarkers or by physiological variables was assessed by repeated measures over 1 year in the Pan-European BIOAIR cohort of adult asthmatics. METHODS: A total of 169 patients, 93 with severe asthma (SA) and 76 with mild-to-moderate asthma (MA), were examined at six or more visits during 1 year. Asthma phenotype clusters were defined by physiological variables (lung function, reversibility and age of onset of the disease) or by biomarkers (eosinophils and neutrophils in induced sputum). RESULTS: After 1 year of follow-up, the allocation to clusters was changed in 23.6% of all asthma patients when defined by physiological phenotypes and, remarkably, in 42.3% of the patients when stratified according to sputum cellularity (P = 0.034). In the SA cohort, 30% and 48.6% of the patients changed allocation according to physiological and biomarker clustering, respectively. Variability of phenotypes was not influenced by change in oral or inhaled corticosteroid dose, nor by the number of exacerbations. Lower stability of single and repeated measure was found for all evaluated biomarkers (eosinophils, neutrophils and FeNO) in contrast to good stability of physiological variables (FEV1 ), quality of life and asthma control. CONCLUSION: Phenotypes determined by biomarkers are less stable than those defined by physiological variables, especially in severe asthmatics. The data also imply that definition of asthma phenotypes is improved by repeated measures to account for fluctuations in lung function, biomarkers and asthma control.

[Chronic obstructive pulmonary disease: sense of coherence and family support versus anxiety and depression].

Chronic Obstructive Pulmonary Disease (COPD) is mainly related to smoking habit and is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Worldwide and in Greece, COPD constitutes a major epidemiological issue. Incidence of depression and anxiety is high in the COPD population. Most studies on depression and anxiety in COPD deal with factors that are positively correlated with both of these comorbidities. The aim of our study was to assess whether two variables, sense of coherence (SOC) and perception of family support (FS), are negatively correlated with depressive and anxiety symptoms in outpatients with COPD. According to Aaron Antonovsky, sense of coherence refers to the ability of individuals to make sense of and manage events. Studies in other diseases suggest that sense of family support has a significant impact on the course and outcome of the disease, yet a limited number of reports across literature addresses the role of family support in COPD patients. In our present study one hundred twenty two (98 men and 24 women) outpatients with pure COPD were included. Age and years of education were recorded. Severity of COPD was assessed with spirometry before and after bronchodilation. All patients replied to self- administered questionnaires on depression (Beck Depression Inventory, BDI), anxiety (Spielberger State-Trait Anxiety Scale, STAI), family support (Family Support Scale, FSS-13) and sense of coherence (Sense of Coherence Scale, SOC). According to our results the mean BDI depression score was 11.65 (SD 7.35), mean trait anxiety score was 40.69 (SD 11.19), mean SOC score was 54.62 (SD 7.40) and mean FS score was 64.58 (SD 11.63). Women patients had higher anxiety scores and lower sense of family support compared to men. Significant negative correlations were evidenced between depression and sense of coherence as well as between anxiety and family support. Step-wise multiple linear regression analysis verified the results and quantified the aforementioned correlations. Notably, raising scores in sense of family support by one point reduces anxiety scores by 0.14 points, and increasing sense of coherence scores by one point reduces depression scores by 0.21 points. In sum, our study confirms the presence of high levels of anxiety and depressive symptoms in COPD patients, with females being in a more disadvantaged position as they tend to have higher levels of both. Sense of coherence and family support are both protective psychological factors against the risk of developing anxiety and depressive symptoms in these patients.

Differential telomerase expression in idiopathic pulmonary fibrosis and non-small cell lung cancer.

Telomerase is a reverse transcriptase ribonucleo-protein (h-TERT) that synthesizes telomeric repeats using its RNA component (h-TERC) as a template. Telomerase dysfunction has been associated with both fibrogenesis and carcinogenesis. In this study, we aimed to evaluate the telomerase mRNA expression levels of both subunits (h-TERT and h-TERC) in lung tissue and bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) and non-small cell lung cancer (NSCLC), since there are indications of common pathogenetic pathways in these diseases. We prospectively examined lung tissue samples from 29 patients with IPF, 10 patients with NSCLC and 21 controls. Furthermore, we examined BALF samples from 31 patients with NSCLC, 23 patients with IPF and 12 control subjects. The mRNA expression for both h-TERT and h-TERC was measured by real-time RT-PCR. In the lung tissue samples, both h-TERT and h-TERC mRNA expression levels varied among the 3 groups (p=0.036 and p=0.002, respectively). h-TERT mRNA levels in the patients with IPF were lower compared with those in the controls (p=0.009) and patients with NSCLC (p=0.004). h-TERC mRNA levels in the patients with IPF were lower compared with those in the controls (p=0.0005) and patients with NSCLC (p=0.0004). In the BALF samples, h-TERT mRNA expression levels varied among the groups (p=0.012). More specifically, h-TERT mRNA levels in the patients with IPF were higher compared with those in the controls (p=0.03) and patients with NSCLC (p=0.007). The attenuation of telomerase gene expression in IPF in comparison to lung cancer suggests a differential role of this regulatory gene in fibrogenesis and carcinogenesis. Further functional studies are required in order to further elucidate the role of telomerase in these devastating diseases.

An update on idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic disease with a median survival of 3-5 years. Despite recent advances the pathophysiology of the disease remains not fully understood. However, injury of type II alveolar epithelial cells is considered the key event for the initiation of the development of fibrosis. An accurate diagnosis is imperative because commencing treatment at an early stage may reduce disease progression. In this regard, the multidisciplinary disease meeting between pulmonologists, radiologists and pathologists has definitely improved the diagnostic confidence. Importantly, a milestone has been recently reached as the first IPF-specific drug namely pirfenidone has been licensed in Europe, Japan and Asia.

The presence of Merkel cell polyomavirus is associated with deregulated expression of BRAF and Bcl-2 genes in non-small cell lung cancer.

Polyomaviruses such as BK virus (BKV), JC virus (JCV) and Merkel cell polyomavirus (MCPyV) are typically nononcogenic, although they have been detected in a variety of human neoplasms. The aim of our study was to determine the frequency of the most common polyomaviruses MCPyV, BKV and JCV as well as the gene expression profile of genes involved in oncogenesis including K-ras, BRAF, RKIP, Bax, Bcl-2, p53 and RB1 in a cohort of non-small cell lung cancer (NSCLC) patients. Real-time and nested polymerase chain reaction (PCR) were used to assess the presence of polyomaviruses DNA in tissue biopsies from 110 patients with primary NSCLC and 14 tissue specimens from macroscopically healthy sites of their lung. Real-time PCR was also used to determine the mRNA expression of K-ras, BRAF, RKIP, Bax, Bcl-2, p53 and RB1 in selected samples. Results showed that ten NSCLC specimens were positive for the presence of MCPyV DNA (10/110, 9.1%), whereas no control sample was tested positive for the virus. The MCPyV-positive samples were predominantly obtained from male smokers (9/10). BKV and JCV DNA were not detected either in lung tissues biopsies or the control specimens. Interestingly, gene expression analysis revealed increased mRNA and protein expression of BRAF gene in association with BRAF phosphorylation in the MCPyV-positive samples, whereas Bcl-2 gene expression was downregulated in the same type of samples. The detected MCPyV prevalence in NSCLC in combination with the deregulated expression of BRAF and Bcl-2 genes suggests that these events are likely to contribute to the pathogenesis of NSCLC.

miR-183 as a molecular and protective biomarker for cancer in schizophrenic subjects.

Previous studies have suggested that schizophrenia is associ-ated with a reduced risk of cancer. Genes that are involved in cell cycle regulation seem to have additional functions in post-mitotic neurons involved in neuronal migration and synaptic plasticity. MicroRNAs (miRNAs) play a dominant role in the regulation of gene expression in the central nervous system (CNS). Due to their involvement in a large number of CNS pathways, miRNAs pose as appealing molecules for further investigation, with potential diagnostic, prognostic and therapeutic value. In the present study, we investigated the potential association between cancer and schizophrenia in 2 patient sample groups. We analyzed a large number of miRNAs in a control group of 6 schizophrenic patients and a study group of 8 schizophrenic patients with a solid tumor. A comparison between the control and study groups showed that only miR-183 was differentially expressed. Specifically, a significant downregulation of miR-183 in the samples of the study group was observed. Although a larger sample size is required to validate this result for the general patient population, our findings provide a first indication that miR-183 may play a role in regulating the expression of other genes with onco-suppressor activity. Our results are in agreement with the theory that patients with schizophrenia may have a tumor suppressor gene or enhanced neuronal apoptotic activities. Further studies are required in order to shed light on the role of miRNAs and particularly, on the suppressive role of miR-183 in the neurobiological pathways involved in schizophrenia.

Recent advances in the pathogenesis and clinical evaluation of pulmonary fibrosis.

Interstitial lung diseases (ILDs) are a group of heterogeneous disorders, either idiopathic or associated with injurious or inflammatory causes, in which the major site of damage is the lung interstitium. For a long time, knowledge regarding pathogenesis was trivial and there were difficulties in diagnosing and subsequently treating these diseases. During the past decade, however, there has been an impressive development in the field of ILDs. Idiopathic pulmonary fibrosis, the most common and fatal form of ILD, was initially believed to be due to an inflammatory response to unknown lung injury, whereas nowadays it is believed to be the result of multiple injuries at different sites of the lung followed by aberrant repair. The integration of clinical, radiological and histological data, namely a multidisciplinary team (MDT) approach, has provided grounds for a more accurate diagnosis of ILDs, and helped the identification of different entities and development of different therapeutic approaches. However, because of the complexity of ILDs, even this approach may fail to establish a confident diagnosis. How should the clinician behave in this case and what are the pitfalls of the MDT approach? In addition, since diagnosis is the major predictor of prognosis, are there any other tools available to predict prognosis?

Apoptosis and cell proliferation correlated with tumor grade in patients with lung adenocarcinoma.

BACKGROUND: Apoptosis and cell proliferation in patients with adenocarcinoma of the lung have not been well described with relation to fine-needle aspiration biopsies (FNABs). To investigate the contribution of apoptosis to the growth of adenocarcinoma of the lung, both apoptosis and cell proliferation were analysed for correlation with the grade of the tumor. PATIENTS AND METHODS: Fifty tumors from 50 patients with adenocarcinoma of the lung were studied. Twelve tumors were well-differentiated, 22 were moderately differentiated and 16 were poorly differentiated. The detection of DNA fragments in situ using the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay was applied to investigate active cell death (apoptosis) and the MIB-1 antigen was used to investigate cell proliferation. RESULTS: The TUNEL indices were 0.55±0.09, 0.90±0.33 and 3.1±0.99 in well-, moderately and poorly differentiated adenocarcinoma of the lung respectively. The MIB-1 antigen labeling indices were 7.1±0.12, 14.3±3.5 and 28.7±6.9, respectively, in the same order of tumor differentiation. The differences in both TUNEL and MIB-1 labeling indices were significant between well-, moderately and poorly differentiated adenocarcinoma of the lung and a positive correlation was found between the TUNEL indices and the MIB-1 indices. CONCLUSION: Apoptosis (cell death) and cell proliferation increases as the grade of differentiation decreases in adenocarcinoma of the lung, suggesting a rapid turn over of the tumor cells in tumors with a lower grade of differentiation.

A one-year trial of tiotropium Respimat plus usual therapy in COPD patients.

In this randomised double-blind study, patients >or=40 years old with COPD, a smoking history of >or=10 pack-years, a pre-bronchodilator FEV(1) of

Association of serum brain-derived neurotrophic factor and duration of untreated psychosis in first-episode patients with schizophrenia.

BACKGROUND/AIMS: The brain-derived neurotrophic factor (BDNF) levels in serum and the central nervous system are altered in patients with schizophrenia, suggesting that changes in the expression of BDNF might contribute to the disease pathophysiology. Long duration of untreated psychosis (DUP) has been associated with poorer prognosis in patients with schizophrenia. Such a relationship of untreated psychosis to outcome may indicate a neurodegenerative process and may have important implications for understanding the pathophysiology of schizophrenia. METHODS: In this study, we investigated the association between serum BDNF levels and DUP in a sample of drug-naïve patients in their first episode of schizophrenia (FEP). We investigated serum BDNF levels in a sample of 37 drug-naïve FEP patients and 21 matched healthy subjects. RESULTS: The serum BDNF level in the sample of FEP was significantly reduced compared to the healthy subjects (18.87 +/- 8.23 vs. 29.2 +/- 7.73 ng/ml, t = 4.76, d.f. = 57, p = 0.01). A negative correlation was found between serum BDNF levels and DUP in the group of patients (r = -0.346, p = 0.036). CONCLUSIONS: Our findings indicate that low serum BDNF levels at the onset of schizophrenia were associated with a long DUP and this could reflect an acute neurodegenerative reaction during the untreated phase of psychosis.