Kiriakos Karkoulias

Pulmonary complications in diabetes mellitus

Clear decrements in lung function have been reported in patients with diabetes over the past two decades, and many reports have suggested plausible pathophysiological mechanisms. However, there are no reports of functional limitations of activities of daily living ascribable to pulmonary disease in patients with diabetes. This review attempts to summarize the available information from the present literature, to describe the nature of the lung dysfunction in diabetes and the emerging clinical implications of such dysfunction.

DNA sequence variations of metalloproteinases: their role in asthma and COPD

Asthma and chronic obstructive pulmonary disease (COPD) are complex genetic diseases that cause considerable morbidity and mortality worldwide. Genetic variability interacting with environmental and ethnic factors is presumed to cause tobacco smoke susceptibility and to influence asthma severity. A disintegrin and metalloproteinase 33 (ADAM33) and matrix metalloproteinase-9 (MMP9) appear to have important roles in asthma and COPD pathogenesis. ADAM33 and MMP9 genetic alterations could possibly contribute to the establishment and progression of these multifactorial diseases, although their association with the clinical phenotypes has not yet been elucidated. However, the occurrence of these alterations does not always result in clear disease, implying that either they are an epiphenomenon or they are in proximity to the true causative alteration. This review summarises the most recent literature dealing with the genetic variations of metalloproteinases and outlines their potential pathogenetic outcome.

Role and Pharmacogenomics of TNF-α in Asthma

Asthma is a chronic heterogeneous inflammatory disease of the respiratory system in which numerous cytokines play a significant role. Among them TNF-α (tumour necrosis factor α), a proinflammatory cytokine, has a predominant role in orchestrating airway inflammation and affecting treatment outcome. In this review we attempt to summarize the involvement of TNF-α in the pathogenesis of asthma, illustrate variations of TNF-α gene that potentially influence asthma phenotype and highlight promising therapies by blocking the production of TNF-α or inhibiting its action. A cytokine specific target therapy seems to be very promising since agents that block TNF-α slow disease progression, suppress inflammation and in some cases induce remission of chronic inflammation.

Targeting Leukotrienes for the Treatment of COPD

New drugs and new approaches of the treatment of chronic obstructive pulmonary disease (COPD) are needed. Despite recent advances in medical therapeutics, treatment of patients with COPD remains largely symptomatic. Although inhaled corticosteroids are currently the drug of choice for anti-inflammatory therapy, the inflammatory process in COPD is essentially steroid resistant. By now, COPD has been increasingly recognized as an inflammatory disease characterized by sputum neutrophilia and, in some cases, eosinophilia. Moreover other cell types thought to play the predominant role in COPD, are cytotoxic T lymphocytes (CD8+ T) cells and macrophages. Leukotriene B4, (LTB 4), a neutrophil and T cell chemoattractant which is produced by macrophages, neurophils and epithelial cells, is a potent inflammatory mediator. Also cysteinyl leukotrienes (LTC4, LTD4 and LTE4) are known to induce mucus secretion, inflammatory cell infiltration, increase vascular permeability and tissue edema, damage ciliary clirens, and cause severe bronchoconstriction. These are derivatives of arachidonic acid, metabolized via 5-lypoxygenase (5-LO) pathway. There are several sites along this pathway that antileukotriene agents exert their action and at the end-organ receptors. They are classified into two major categories: receptor antagonists and synthesis inhibitors. Beneficial effects on therapy of patients with COPD have already derived from studies, while they seem well tolerated. More studies are underway.

Derived Arterial Stiffness is Increased in Patients with Obstructive Sleep Apnea and Periodic Limb Movements during Sleep.

STUDY OBJECTIVES Both periodic limb movements during sleep (PLMS) and obstructive sleep apnea (OSA) have been associated with increased risk of cardiovascular disease (CVD). OSA has also been linked to increased large arterial stiffness, which is considered an independent risk factor for CVD. We utilized a previously validated index of large artery stiffness (SIDVP) derived from the digital volume pulse (DVP) to seek comparison in patients with PLMS and OSA. METHODS Forty-nine adult male subjects, without known comorbidities that could affect arterial stiffness or on vasoactive medication, were retrospectively identified and categorized into controls (n = 8), PLMS (n = 13), OSA (n = 17), and OSA/PLMS (n = 11). The cutoff for PLMS was a periodic limb movement index (PLMI) > 15 events/h, and for OSA an apnea-hypopnea index (AHI) > 10 events/h. SIDVP was derived from the raw data of photoplethysmography of the nocturnal polysomnography, averaged for 2 min prior to sleep study initiation (baseline), after completion in the morning, and every half hour after sleep onset. RESULTS The groups were age/body mass index-matched. Controls showed lower baseline, morning, and overall SIDVP compared to the other groups (p < 0.01). Patients with PLMS (PLMI: 50.69 ± 9.7 events/h) and the OSA group (AHI: 29.7 ± 2 events/h) demonstrated similar overall SIDVP (6.78 ± 0.08 versus 6.94 ± 0.04, respectively, p = 0.5), whereas the OSA/PLMS (AHI: 29.35 ± 8, PLMI: 50.63 ± 7.2) group demonstrated the highest (7.40 ± 0.06, p < 0.001). CONCLUSIONS Based on an easily reproducible and applicable marker of large arterial stiffness, patients with significant PLMS had higher SIDVP when compared to controls and comparable to those with moderate/severe OSA. The OSA/PLMS group had the highest SIDVP, implying a possible additive effect of OSA and PLMS on arterial stiffness.

Pulmonary Arterial Hypertension: Need to Treat

Pulmonary Arterial Hypertension (PAH) is defined by a persistent elevation in pulmonary artery pressure with normal left-sided pressures. It is characterized by increased pulmonary vascular resistance due to increased vascular tone and structural remodeling of pulmonary vessels. PAH is a quite rare condition, thus considering the rarity, subtle presentation, and diagnostic dilemma commonly posed by this disease, underdiagnosis and underreporting are probably widespread. In order to reach a diagnosis the use of echocardiography, right-heart catheterization and the six-minute walk test is essential. As far as therapy is concerned, the patient should be supported by oxygen, diuretics, anticoagulants, digoxin and suggest life-style changes. After diagnosing the condition ca-blockers should be administered to those who respond positively in acute vasodilation test. Other agents used, target the endothelin pathway (ET-1 blockers such as bosentan), the NO pathway (sildenafil, inhaled NO, L-arginine) and the prostacyclin pathway (prostacyclin analogues). In some cases surgical treatment is essential (atrial septestomy, pulmonary endarterectomy, lung and heart transplantation). Finally, future therapies include administration of VIP and SSRIs. The goals of evaluating pulmonary hypertension are detection, definition of severity and the nature of the hemodynamic lesion and its consequences, diagnosis of causal or associated conditions, and determination of optimal therapy.

EBUS: Faster, cheaper and most effective in lung cancer staging

The use of endobronchial ultrasound trans‐bronchial needle aspiration (EBUS‐TBNA) as the initial diagnostic and staging procedure in patients with suspected, non‐metastatic lung cancer has gained substantial support, and is now recommended by numerous guidelines. Whereas considerable attention has been pointed to the reductions in costs achieved by EBUS‐TBNA, that has not been the case for some of its more significant benefits, namely the reduction of the diagnostic work‐up time and its ability to accurately assess and restage lymph nodes, which were previously stated incorrectly by CT or PET scan. Both these benefits translate into improved outcomes for patients, as delays are reduced, futile surgeries are prevented and curable operations can be performed on patients previously excluded by CT or PET scan. Indeed, the use of EBUS as the initial diagnostic and staging procedure has been proven to significantly increase survival, compared with conventional diagnostic and staging procedures, in a pragmatic, randomised controlled trial (Navani N. et al, 2015). The instalment of EBUS will have the greatest effect on overwhelmed, suboptimally functioning national healthcare systems, by decreasing the number of required diagnostic and staging procedures, therefore reducing both treatment delays and costs. The improved selection of surgical candidates by EBUS will result in improved patient outcomes. The latest findings regarding the benefits of EBUS are outlined in this review, which, to the best of our knowledge, is the first to emphasise the impact of the procedure, both on timing and costs of lung cancer staging, as well as on survival.

Physical Exercise in Patients With Inflammatory Bowel Disease

Inflammatory bowel diseases [IBD] have an impact on the general patients’ well-being. Exercise training in patients with a chronic disease enhances their functional capacity and allows them to overcome the detrimental physiological effects of bed rest and previous sedentary living.1 The rate of regular exercise in patients with Crohn’s disease has been reported to range from 30% to 42%.2 Low-intensity activity of moderate duration is enough to elicit improvements in fitness, decrease stress, and ameliorate symptoms.2 Physical activity may induce the desirable effects of enhancing fitness and general well-being.3 In our centre, 18 patients with IBD underwent full cardiopulmonary exercise testing [CPET] using a treadmill. Participants were divided into two categories: 10 patients with inactive disease and eight patients with active disease. Participants in the two groups had similar characteristics in terms of age, gender, and body mass index [BMI]. The following pulmonary function tests were performed: spirometry, lung diffusion capacity, and full cardiopulmonary exercise test [CPET]. In addition, we measured maximum usage of oxygen [VO2max], maximum CO2 production [VCO2max], and total ventilation in anaerobic threshold [VEAT]. The analysis of our data showed that between the two groups with inactive and active IBD the spirometry and lung diffusion test results did not have statistically significant differences: (FEV1 [% predicted], 104.3 ± 2.3 vs 99.2 ± 9.1, FEV1/FVC [ratio], 83.8 ± 1.5 vs 80.0 ± 2.9, TLCO [% predicted], 105.0 ± 6.2 vs 118.2 ± 10.6, and KCO [% predicted], 99.4 ± 7.3 vs 112.4 ± 7.6, respectively, p = not significant). In addition, CPET results did not differ significantly between the above-mentioned groups (VO2max [l/min], 1.75 ± 0.20 vs 1.92 ± 0.26, VCO2max [l/min], 1.60 ± 0.20 vs 1.96 ± 0.35, and VEAT [l/min], 29.8 ± 4.1 vs 33.5 ± 3.2, respectively, p = not significant), yet remaining within normal values, suggesting that patients with inflammatory bowel disease have a competitive physical exercise potential. Regular mild exercise programmes can improve physical functioning and well-being of patients with IBD and reduce stress.4 Stress is known to orchestrate immunological and neuroendocrine changes that enhance vulnerability to auto-immune diseases, such as inflammatory bowel diseases. It has been reported that stress may play a role in the exacerbation of IBD.4 Stress has been significantly related to illness in patients with a low level of physical activity; thus physical activity has a beneficial effect on immune status and disease control.4 To date, employees with physically demanding jobs have lower prevalence of IBD.5 In conclusion, patients with IBD should not avoid exercise and they can be motivated to perform moderate exercise on a regular basis.

Gene Therapy Perspectives Against Diseases of the Respiratory System

Gene therapy uses a variety of techniques as the introduction of a normal allele of a gene in cases where the cell does not express the gene or in other cases where the gene is underexpressed. In order to achieve effective gene therapy for a specific gene in a certain type of cells a lot of work is needed. More specifically the following steps are essential: 1. Isolation of target gene, 2. Development of a specific gene vector, 3. Specification of the target cell, 4. Definition of route of administration, and 5. Identification of other potential uses of the gene.

Mediators of inflammation in pulmonary diseases

Inflammation is supposed to play a great role in the pathogenesis of the most common diseases of the respiratory system. In Chronic Obstructive Pulmonary Disease (COPD), which is a major cause of morbidity and mortality all around the world, smoking mainly causes the initiation of the inflammatory process that leads to an impaired respiratory function. Moreover, in bronchial asthma there are numerous proinflammatory mediators that are responsible for the onset and the progression of the disease. Finally, pulmonary infections and especially tuberculosis result in the orchestration of an inflammatory process that targets the causative agent in order to protect the host. L. M. O. Caram et al. have evaluated the levels of vitamin A in the serum and sputum and attempted to correlate it with known inflammatory markers, such as tumor necrosis factor alpha (TNF-α), interleukin- (IL-) 6, IL-8, and C-reactive protein (CRP) in 50 COPD patients and 50 individuals without COPD. The authors concluded that serum concentration of vitamin A is negatively associated with the presence of COPD and that it is positively associated with smoking status. Although COPD patients exhibited increased inflammation, these inflammatory markers were not associated with serum retinol concentrations. The manuscript of W. Zhang et al. tested the effect of a novel γ-secretase inhibitor to promote Th17 cell differentiation in a mouse model of allergic asthma. Their findings suggest that the inhibitor directly regulates Th17 responses in the mouse model of allergic asthma that they used, making it potentially efficacious. In their study, R. Rajajendram et al. tried a synthetic chalcone analogue in a murine model of asthma. Their results demonstrate a potential role of the substance in asthma, as the treatment with it inhibited eosinophilia, goblet cell hyperplasia, peripheral blood total IgE, and airway hyperresponsiveness in ovalbumin-sensitized and challenged mice. However, the tested nonsteroid potentially anti-inflammatory substance is far away from clinical use. In the manuscript entitled “Binding of CXCL8/IL-8 to Mycobacterium tuberculosis Modulates the Innate Immune Response,” A. Krupa et al. illustrate the role of IL-8 in the pathogenesis of tuberculosis (TB). The authors investigated the contribution of IL-8 in the inflammatory processes that are typically elicited in patients with TB. Their findings show that IL-8 seems to be the major chemokine responsible for recruiting T lymphocytes (CD3+, CD4+, and CD8+ T cells) and plays important role in the innate immunity against Mycobacterium tuberculosis. Last but not least, the study of R. Baumann et al. investigated the IgA and IgG responses to mycobacterial protein antigens in subjects with latent tuberculosis, active tuberculosis, and healthy individuals. In their conclusions they present a new biomarker for the diagnosis of active pulmonary tuberculosis.