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Tumor necrosis factor (TNF)-α 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-α 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-α were assessed using combined experimentation with TNF-α gene–deficient mice and in vivo TNF-α neutralization. To expand the scope of preclinical data, TNF-α and vascular endothelial growth factor (VEGF) expression were determined in human cancer cell lines and human MPE. In the MPE model, TNF-α of host and tumor origin was present. TNF-α neutralization significantly limited tumor dissemination, effusion formation, vascular hyperpermeability, TNF-α and VEGF expression, and angiogenesis, thereby improving survival. In contrast, these variables were not different between TNF-α gene–sufficient and TNF-α gene–deficient mice. In mouse cancer cells, TNF-α functioned via nuclear factor-κB– and neutral sphingomyelinase–dependent pathways to induce TNF-α and VEGF, respectively. These results were recapitulated in human cancer cells, and a correlation was detected between TNF-α and VEGF content of human MPE. We conclude that tumor-derived TNF-α is important in the development of MPE in mice, and provide preclinical evidence supporting the efficacy of TNF-α blockade against malignant pleural disease. [Cancer Res 2007;67(20):9825–34]

Supplementary Figure Legend from Tumor Necrosis Factor-α Promotes Malignant Pleural Effusion

Supplementary Figure 1 from Tumor Necrosis Factor-α Promotes Malignant Pleural Effusion

Dizziness is one of the most common symptoms encountered by physicians daily. It is divided into four categories: vertigo, disequilibrium, presyncope, and psychogenic dizziness. It is essential to distinguish these four symptoms because the causes, prognosis, and treatment differ. Vertigo constitutes a disease of the central or peripheral nervous system. Central origin vertigo may be a life-threatening situation and must be detected as soon as possible because it includes diseases such as stroke, hemorrhage, tumors, and multiple sclerosis. Peripheral origin vertigo includes benign diseases, which may be fully treatable such as vestibular migraine, benign paroxysmal positional vertigo, vestibular neuritis, Ménière's disease, and cervical vertigo. The HINTS (head impulse, nystagmus, test of skew) examination is essential to distinguish central from peripheral causes. A detailed history including the duration of vertigo (episodic or continuous), its trigger, and a clinical examination step by step following the appropriate protocol could help to make a definite and accurate diagnosis and treatment. Due to a lack of expertise in dizziness and inappropriate treatment, many patients are admitted to dizziness clinics with long-standing dizziness. A holistic treatment combining medications, vestibular rehabilitation, physiotherapy, and psychotherapy should be initiated to improve the quality of life of these patients. So, this review aims to recommend a clinical protocol for approaching a dizzy patient with vertigo and to present in detail the epidemiology, pathophysiology, symptoms, diagnosis, and contemporary treatments of all causes of vertigo.

Infection with SARS-COV-2 may result in severe pneumonia potentially leading to mechanical ventilation and intensive care treatment. The aim of the present study was to analyze the immune responses in critically ill coronavirus 2019 (COVID-19) patients requiring mechanical ventilation and assess their potential use as markers of clinical progression and outcome. Confirmed COVID-19 patients were grouped into those requiring mechanical ventilation (intubated) and non-intubated. Immune phenotyping was performed and cytokine levels were determined. A novel ratio of CD8+:B cells was significantly lower in intubated versus non-intubated (p = 0.015) and intubated non-survivors (NSV) versus survivors (SV) (p = 0.015). The same ratio correlated with outcome, CRP, IL-6 levels and neutrophil count. Receiving operating curve (ROC) analysis for prediction of requirement of mechanical ventilation by the CD8+:B cells ratio revealed an AUC of 0.747 and a p = 0.007. The ratio of CD8+:B cells may serve as a useful prognostic marker for disease severity and outcome., Graphical abstract Image 1

We hypothesized that severe COPD patients who present with the disadvantageous phenomenon of Expiratory Flow Limitation (EFL) may benefit as COPD patients without EFL do after implementation of a Pulmonary Rehabilitation (PR) program. Forty-two stable COPD patients were studied at rest and during exercise. EFL and dynamic hyperinflation (DH) were documented using the negative expiratory pressure (NEP) technique and inspiratory capacity (IC) maneuvers, respectively. Patient centered outcomes were evaluated by the Saint-George's Respiratory Questionnaire (SGRQ) and the mMRC dyspnea scale. Before PR, 16 patients presented with EFL at rest and/or during exercise. After PR, EFL was abolished in 15 out of those 16 EFL patients who exhibited a significant increase in IC values. These were mainly accomplished through a modification of the breathing pattern. In the 26 NFL patients no increase was noted in their IC or a modification of their breathing pattern. However, both NFL and EFL COPD patients improved exercise capacity and patients centered outcomes undergoing the same PR program.

Introduction: We wondered whether anthropometric, lung function, arterial blood gas (ABG), tidal volume (VT), and Negative Expiratory Pressure (NEP) Technique data could be utilized alone or collectively for predicting the presence of obstructive sleep apnea syndrome (OSAS). Methods: Thirty-eight consecutive subjects (29% females) were referred for symptoms suggestive of OSAS. They had no respiratory or any other system failure. Anthropometric data, VT and lung function measurements were obtained. All subjects underwent overnight polysomnogaphy (PSG). They were also subjected to the NEP technique (-5 cm H2O) in seated and supine positions, specifically investigating the usefulness of known NEP-acquired indices (EFL %, ΔV %, V, NEP 0.5, V0.2%). PSG classified subjects according to Apnea/Hypopnea Index (AHI). Results: Eleven patients had AHI

The involvement of complement activation in various forms of cardiovascular disease renders it an important factor for disease progression and therapeutic intervention. The protective effect of resveratrol against cardiovascular disease via moderate red wine consumption has been established but the exact mechanisms are still under investigation. The current study utilised human coronary artery endothelial cells (HCAECs) in order to assess the extent to which the protective effect of resveratrol, at concentrations present in red wine, can be attributed to the upregulation of complement regulatory proteins through heme-oxygenase (HO)-1 induction. Resveratrol at concentrations as low as 0.001 μΜ increased HO-1 expression as well as membrane cofactor protein (MCP, CD46) and decay-accelerating factor (DAF, CD55) expression with no-effect on CD59. Silencing of HO-1 expression by HO-1 siRNAs abrogated both DAF and MCP protein expression with no effect on CD59. Resveratrol-mediated induction of DAF and MCP reduced C3b deposition following incubation of HCAECs with 10% normal human serum or normal rat serum as a source of complement. Incubation of HCAECs, with either a DAF blocking antibody or following transfection with HO-1 siRNAs, in the presence of 10% normal rat serum increased C3b deposition, indicating that both DAF and HO-1 are required for C3b reduction. These observations support a novel mechanism for the protective effect of resveratrol against cardiovascular disease and confirm the important role of HO-1 in the regulation of the complement cascade., Graphical abstract Image 1, Highlights • Resveratrol upregulated HO-1 protein in human coronary artery endothelial cells (HCAECs). • Resveratrol upregulated complement control proteins DAF and MCP in HCAECs. • HCAECs treatment with siHO-1 abolished HO-1 expression and reduced expression of both DAF and MCP. • HCAECs resveratrol treatment in the presence of a source of complement reduced C3 deposition.

Niki Gianniou,1 Charilena Giannakopoulou,2 Efrossini Dima,2 Matina Kardara,3 Paraskevi Katsaounou,1 Alexandros Tsakatikas,4 Charis Roussos,1–3 Nikolaos Koulouris,2 Nikoletta Rovina2 1Pulmonary and Critical Care Department, Evangelismos Hospital, 21st Department of Pulmonary Medicine, “Sotiria” Hospital; Athens Medical School, 3“M.Simos” Laboratories, Department of Critical Care and Pulmonary Services, National and Kapodistrian University of Athens, Athens, 4Medical Department, Hellenic Fireforce, Athens, Greece Introduction: The aim of this study was to assess respiratory health and airway and systemic inflammation in professional forest firefighters post firefighting. Methods: A total of 60 firefighters who participated in forest firefighting operations in Greece during 2008 were included in the study. A questionnaire consisting of symptoms and exposure, pulmonary function, atopy, bronchial hyperresponsiveness, and markers of inflammation in induced sputum, serum, and bronchoalveolar lavage (BAL) fluid was assessed. Results: A measurable eosinophilic and neutrophilic inflammation was shown to be induced in the bronchial airways after acute exposure during forest firefighting. This was associated with increased respiratory symptoms from the upper and lower respiratory tract and pulmonary function impairment. Additionally, a measurable systemic inflammatory response was demonstrated. This study showed that acute exposure during forest firefighting significantly augments the intensity of airway and systemic inflammation in relation to the baseline inflammatory background due to chronic exposure. Conclusion: The repeated acute exposures during firefighting augment the burden of chronic airway and systemic inflammation and may eventually lead to allergic sensitization of the airways and increased incidence of rhinitis and asthma after prolonged exposure.Keywords: firefighters, acute exposure, airway inflammation, systemic inflammation, allergic sensitization

Pulmonary endothelium is a major metabolic organ affecting pulmonary and systemic vascular homeostasis. Brain death (BD)-induced physiologic and metabolic derangements in donors' lungs, in the absence of overt lung pathology, may cause pulmonary dysfunction and compromise post-transplant graft function. To explore the impact of BD on pulmonary endothelium, we estimated pulmonary capillary endothelium-bound (PCEB)-angiotensin converting enzyme (ACE) activity, a direct and quantifiable index of pulmonary endothelial function, in eight brain-dead patients and ten brain-injured mechanically ventilated controls. No subject suffered from acute lung injury or any other overt lung pathology. Applying indicator-dilution type techniques, we measured single-pass transpulmonary percent metabolism (%M) and hydrolysis (v) of the synthetic, biologically inactive, and highly specific for ACE substrate (3)H-benzoyl-Phe-Ala-Pro, under first order reaction conditions, and calculated lung functional capillary surface area (FCSA). Substrate %M (35 ± 6.8%) and v (0.49 ± 0.13) in BD patients were decreased as compared to controls (55.9 ± 4.9, P = 0.033 and 0.9 ± 0.15, P = 0.033, respectively), denoting decreased pulmonary endothelial enzyme activity at the capillary level; FCSA, a reflection of endothelial enzyme activity per vascular bed, was also decreased (BD patients: 1,563 ± 562 mL/min vs 4,235 ± 559 in controls; P = 0.003). We conclude that BD is associated with subtle pulmonary endothelial injury, expressed by decreased PCEB-ACE activity. The applied indicator-dilution type technique provides direct and quantifiable indices of pulmonary endothelial function at the bedside that may reveal the existence of preclinical lung pathology in potential lung donors.

The inspiratory muscles are the diaphragm, external intercostals and parasternal internal intercostal muscles. The internal intercostals and abdominal muscles are expiratory. The ability of a subject to take one breath depends on the balance between the load faced by the inspiratory muscles and their neuromuscular competence. The ability of a subject to sustain the respiratory load over time (endurance) depends on the balance between energy supplied to the inspiratory muscles and their energy demands. Hyperinflation puts the diaphragm at a great mechanical disadvantage, decreasing its force-generating capacity. In response to acute increases in load the inspiratory muscles become fatigued and inflammed. In response to reduction in load by the use of mechanical ventilation they develop atrophy and dysfunction. Global respiratory muscle function can be tested using maximum static inspiratory and expiratory mouth pressures, and sniff pressure. Diaphragm function can be tested by measuring the transdiaphragmatic and twitch pressures developed upon electrical or magnetic stimulation of the phrenic nerve.

Background and objectives Little data exist on short- and long-term effects of occupational exposure on airway and systemic inflammation in professional firefighters. We aimed to characterize airway and systemic inflammation in training firefighters with a maximum occupational exposure of 1 year compared to the long-term exposure of professional firefighters. Methods A questionnaire for symptoms and exposure, pulmonary function, atopy, bronchial hyper-responsiveness, and markers of inflammation in induced sputum, serum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies were assessed in a total of 92 firefighters (63 full-time professionals and 29 trainees). Results Professional firefighters showed allergic bronchial sensitization documented by the presence of atopy, and eosinophilia in induced sputum, BAL and bronchial biopsies. IL-8, ECP, VEGF, and TNF-α levels were statistically significantly higher in the sputum supernatants of professional firefighters compared to the trainees (p = 0.04, p = 0.02, p = 0.04, and p = 0.02, respectively). Serum IL-8 and TNF-α levels were also statistically significantly higher in the group of professional firefighters (p = 0.04, p = 0.03, respectively). Finally, there was a linear correlation between the duration of the occupation in Service and the degree of airway and systemic inflammation. Conclusions These results indicate a “dose-response” effect of chronic exposure to a polluted environment on bronchial and systemic inflammation in professional firefighters.

Background Pulmonary tuberculosis remains the single deadliest infectious disease causing high mortality in humans leading to 1.4 million deaths annually. Inherited genetic factors may explain why some people resist infection more successfully than others. Methods The polymorphisms of HLA-class I (-A, -B) and class II (-DRB1, -DQB1) genes have been evaluated using DNA-based typing in a population of 86 non-immunosuppressed, unrelated Greek patients with PTb and 46 healthy unrelated people without a history of PTb, who were all tested purified protein derivative positive (>14 mm). Results The HLA-A R 114 and HLA-DRβN 37 residues are associated with susceptibility. They operate independently from each other and their effect is detected when the population is evaluated for their concurrent presence (A R 114 positive or DRβN 37 positive or A R 114 and DRβN 37 positive). Furthermore the HLA-A S 77 appears to have a protective role, however in the presence of the DRβN 37 , the A-S 77 does not exert its protective effect. Conclusion The HLA residues A-S 77 , A-R 114 and DRβN 37 in combination with PTb antigenic elements possibly modulate T-cell responses against MTb that lead to either protection or susceptibility. The HLA-A and -DRB1-dependent T-cell networks may interact among themselves and influence each other resulting in different PTb phenotypes.

In healthy humans, cerebral oxygen desaturation during exercise affects motor unit recruitment, while oxygen supplementation enhances cerebral oxygenation and work capacity. It remains unknown whether in patients with chronic obstructive pulmonary disease (COPD), the well-documented improvement in exercise tolerance with oxygen supplementation may also be partly due to the increase in cerebral oxygenation. Using near infrared spectroscopy, we measured both frontal cerebral cortex blood flow (CBF) using indocyanine green dye and cerebrovascular oxygen saturation (S(t,O(2))) in 12 COPD patients during constant-load exercise to exhaustion at 75% of peak capacity. Subjects exercised while breathing air, 100% oxygen or normoxic heliox, the latter two in balanced order. Time to exhaustion while breathing air was less than for either oxygen or heliox (mean±sem 394±35 versus 670±43 and 637±46 s, respectively). Under each condition, CBF increased from rest to exhaustion. At exhaustion, CBF was higher while breathing air and heliox than oxygen (30.9±2.3 and 31.3±3.5 versus 26.6±3.2 mL·min(-1) per 100 g, respectively), compensating for the lower arterial oxygen content (C(a,O(2))) in air and heliox, and leading to similar cerebral cortex oxygen delivery (CQ(O(2)) for air was 5.3±0.4, for oxygen was 5.5±0.6 and for heliox was 5.6±1.0 mL O(2) per min per 100 g). In contrast, end-exercise S(t,O(2)) was greater while breathing oxygen compared with air or heliox (67±4 versus 57±3 and 53±3%, respectively), reflecting C(a,O(2)) rather than CQ(O(2)). Prolonged time to exhaustion by breathing oxygen and heliox, despite these having a similar CQ(O(2)) to air, a lower S(t,O(2)) with heliox than oxygen, and yet similar endurance time and similar S(t,O(2)) in air and heliox despite greater endurance with heliox, do not support the hypothesis that an improvement in cerebral cortex oxygen availability plays a contributing role in increasing exercise capacity with oxygen or heliox in patients with COPD.

Tumor necrosis factor (TNF) has been implicated in inflammation-associated tumor progression. Although multiple reports identified a role for TNF signaling in established cancers, few studies have assessed the impact of TNF blockade on early tumor formation promotion. We aimed at exploring the effects of TNF neutralization in a preclinical mouse model of lung carcinogenesis. For this, Balb/c mice (n = 42) received four weekly intraperitoneal urethane injections (1 g/kg) and twice-weekly intraperitoneal soluble TNF receptor (etanercept; 10 mg/kg) administered during tumor initiation/promotion, tumor progression, or continuously (months 1, 6, and 1-8 after urethane start, respectively). Lung oncogenesis was assessed after 8 months. In separate short-term studies, Balb/c mice (n = 21) received a single control or urethane injection followed by twice-weekly intraperitoneal control or sTNFR:Fc injections. Lung inflammation was assessed after 1 week. We found that sTNFR:Fc treatment during tumor initiation/promotion resulted in a significant reduction of tumor number but not dimensions. However, sTNFR:Fc administered during tumor progression did not impact tumor multiplicity but significantly decreased tumor diameter. Continued sTNFR:Fc administration was effective in halting both respiratory tumor formation and progression in response to urethane. This favorable impact was associated with impaired cellular proliferation and new vessel formation in lung tumors. In addition, TNF neutralization altered the lung inflammatory response to urethane, evidenced by reductions in TNF and macrophage and increases in interferon γ and interleukin 10 content of the air spaces. sTNFR:Fc treatment of RAW264.7 macrophages downregulated TNF and enhanced interferon γ and interleukin 10 expression. In conclusion, TNF neutralization is effective against urethane-induced lung oncogenesis in mice and could present a lung chemoprevention strategy worth testing clinically.

During maximal hypoxic exercise, a reduction in cerebral oxygen delivery may constitute a signal to the central nervous system to terminate exercise. We investigated whether the rate of increase in frontal cerebral cortex oxygen delivery is limited in hypoxic compared to normoxic exercise. We assessed frontal cerebral cortex blood flow using near-infrared spectroscopy and the light-absorbing tracer indocyanine green dye, as well as frontal cortex oxygen saturation (S(tO2)%) in 11 trained cyclists during graded incremental exercise to the limit of tolerance (maximal work rate, WRmax) in normoxia and acute hypoxia (inspired O2 fraction (F(IO2)), 0.12). In normoxia, frontal cortex blood flow and oxygen delivery increased (P < 0.05) from baseline to sub-maximal exercise, reaching peak values at near-maximal exercise (80% WRmax: 287 ± 9 W; 81 ± 23% and 75 ± 22% increase relative to baseline, respectively), both leveling off thereafter up to WRmax (382 ± 10 W). Frontal cortex S(tO2)% did not change from baseline (66 ± 3%) throughout graded exercise. During hypoxic exercise, frontal cortex blood flow increased (P = 0.016) from baseline to sub-maximal exercise, peaking at 80% WRmax (213 ± 6 W; 60 ± 15% relative increase) before declining towards baseline at WRmax (289 ± 5 W). Despite this, frontal cortex oxygen delivery remained unchanged from baseline throughout graded exercise, being at WRmax lower than at comparable loads (287 ± 9 W) in normoxia (by 58 ± 12%; P = 0.01). Frontal cortex S(tO2)% fell from baseline (58 ± 2%) on light and moderate exercise in parallel with arterial oxygen saturation, but then remained unchanged to exhaustion (47 ± 1%). Thus, during maximal, but not light to moderate, exercise frontal cortex oxygen delivery is limited in hypoxia compared to normoxia. This limitation could potentially constitute the signal to limit maximal exercise capacity in hypoxia.

Background: Exercise training confers beneficial effects on vascular reactivity in patients with chronic heart failure (CHF). This randomized study compares the effects of interval cycle training combined with strength training versus interval training alone on vascular reactivity in CHF patients. Methods: Twenty-eight consecutive stable CHF patients (23 males, 53 6 10 years, 28.4 6 4.1 kg/m 2 , left ventricular ejection fraction of 37 6 12%) were randomly assigned to 3 times’ weekly training sessions for 3 months, consisting of a) 40 minutes of interval cycle training (n 5 14), versus b) 20 minutes of similar interval training plus 20 minutes of strength training of the quadriceps, hamstrings, muscles of the shoulder and biceps brachialis (n 5 14). The work/recovery ratio of each session was 30/60 seconds. The intensity of interval training was set at 50% of the peak workload achieved at the steep ramp test (consisted of a 25-Watt increase on a cycle ergometer every 10 seconds until exhaustion). All patients underwent maximal, symptom-limited cardiopulmonary exercise testing and ultrasound evaluation of vascular reactivity by flow-mediated vasodilation (FMD) before and after the program. Results: A significant improvement in FMD was observed in the combined training group (P 5 0.002), in contrast to the interval training alone group (P 5 NS); the improvement was significantly greater in the combined training than in the interval training alone group (P ! .05). Peak oxygen uptake increased significantly and similarly in both groups, in the interval training group (P 5 .03), and in the combined training group (P 5 .006). No significant correlation was found between FMD improvement and cardiopulmonary exercise parameters. Conclusions: A combined high-intensity, interval cycle exercise with strength training induces a greater beneficial effect on vascular reactivity rather than interval exercise training alone in CHF patients. (J Cardiac Fail 2011;17:585e591)

Background The inflammatory influence of prolonged mechanical ventilation in uninjured lungs remains a matter of controversy and largely unexplored in humans. The authors investigated pulmonary inflammation by using exhaled breath condensate (EBC) in mechanically ventilated, brain-injured patients in the absence of acute lung injury or sepsis and explored the potential influence of positive end-expiratory pressure (PEEP). Methods Inflammatory EBC markers were assessed in 27 mechanically ventilated, brain-injured patients with neither acute lung injury nor sepsis and in 12 healthy and 8 brain-injured control subjects. Patients were ventilated with 8 ml/kg during zero end-expiratory pressure (ZEEP group, n = 12) or 8 cm H(2)O PEEP (PEEP group, n = 15). EBC was collected on days 1, 3, and 5 of mechanical ventilation to measure pH; interleukins (IL)-10, 1β, 6, 8, and 12p70; and tumor necrosis factor-α. Results EBC pH was lower, whereas IL-1β and tumor necrosis factor-α were greater in both patient groups compared with either control group; IL-6 was higher, whereas IL-10 and IL-12p70 were sporadically higher than in healthy control subjects; no differences were noted between the two patient groups, except for IL-10, which decreased by day 5 during PEEP. Leukocytes, soluble IL-6, and soluble triggering receptor expressed on myeloid cells-1 in blood were constantly higher during zero end-expiratory pressure; EBC cytokines appeared mostly related to soluble IL-8 and inversely related to soluble triggering receptor expressed on myeloid cells-1. Conclusions In brain-injured, mechanically ventilated patients with neither acute lung injury nor sepsis, EBC markers appear to indicate the presence of subtle pulmonary inflammation that is mostly unaffected by PEEP. There is evidence for a systemic inflammatory response, especially in patients during zero end-expiratory pressure.

Introduction The initial management of suspected pulmonary embolism (PE) is commonly done in respiratory departments, but is based on clinical prediction rules developed in other settings. Objective To determine the accuracy of established prediction rules for PE in patients with respiratory emergencies. Design A prospective study Materials and Methods Patients presenting to respiratory emergency department with acute symptoms and signs suggestive of PE (n = 183) and subsequently admitted to hospital were prospectively enrolled. Wells’ rule, original and revised Geneva scores, their components separately, and other common clinical parameters were recorded during admission. PE was diagnosed by perfusion lung scanning, computed tomographic pulmonary angiography, lower limb venous ultrasonography, magnetic resonance pulmonary angiography, and/or pulmonary angiography. Results PE was confirmed in 52 and ruled out in 131 patients. Tachycardia, atelectasis, elevated hemidiaphragm, clinical signs of deep-venous thrombosis, physician perception that PE is the likeliest diagnosis, previous thromboembolism, chest pain, and absence of chronic obstructive pulmonary disease or cough were associated with the presence of PE. These significant parameters could be combined for accurate pre-test PE prediction, with a newly devised combinatorial tool exhibiting the highest area under curve [0.92 (95% CI: 0.87-0.97)], followed by Wells’ rule [0.86 (95% CI 0.79-0.92)], the revised Geneva score [0.83 (95% CI 0.77-0.90)], and the original Geneva score [0.75 (95% CI 0.68-0.83)]. Conclusion Wells’ rule and the revised Geneva score are more useful in diagnosing PE in respiratory emergencies. A newly devised prediction tool can be of even greater accuracy in this patient population.

Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-κB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF-κB (BAY-11–7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-κB, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-α, IL-10, IL-2, IL-1β) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF-κB. Inhibition of NF-κB and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-κB/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-κB/p65 phosphorylation. In conclusion, IRB-induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-κB. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-κB independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm.

In acute respiratory distress syndrome (ARDS), combined high frequency oscillation (HFO) and tracheal gas insufflation (TGI) improves oxygenation versus standard HFO, likely through TGI-induced lung recruitment. Experimental data suggest that steady flows such as TGI favor the filling of the lower (i.e., subcarinal) lung. We used whole-lung computerized tomography (CT) to determine whether HFO-TGI versus HFO improves the recruitment of the lower lung, and especially of its dependent region, where loss of aeration is maximized in ARDS.We enrolled 15 patients who had ARDS for 96 h or less, and pulmonary infiltrates in at least three chest X-ray quadrants. Patients were subjected to whole-lung CT after lung-protective conventional mechanical ventilation (CMV) and after 45 min of HFO and 45 min of HFO-TGI. HFO/HFO-TGI were employed in random order. CT scans were obtained at a continuous positive airways pressure equal to the mean tracheal pressure (P (tr)) of CMV. During HFO/HFO-TGI, mean airway pressure was titrated to the CMV P (tr) level. Gas exchange and intra-arterial pressure/heart rate were determined for each ventilatory technique.Regarding total lung parenchyma, HFO-TGI versus HFO and CMV resulted in a lower percentage of nonaerated lung tissue (mean ± SD, 51.4 ± 5.1% vs. 60.0 ± 2.5%, and 62.1 ± 9.0%, respectively; P≤0.04); this was due to HFO-TGI-induced recruitment of nonaerated tissue in the dependent and nondependent lower lung. HFO-TGI increased normally aerated tissue versus CMV (P=0.04) and poorly aerated tissue versus HFO and CMV (P≤0.04), and improved oxygenation versus HFO and CMV (P≤0.04).HFO-TGI improves oxygenation versus HFO and CMV through the recruitment of previously nonaerated lower lung units.

To determine the epidemiology, risk factors for and outcome of candidaemia in critically ill patients, a matched case-control study was performed in a 25-bed intensive care unit (ICU) from August 2004 to January 2006. Candidaemia occurred in 33 patients; each patient was matched to four controls according to admission illness severity, diagnostic category and length of ICU stay. Candida non-albicans species predominated (67.7%). The presence of acute respiratory distress syndrome (ARDS) was the only independent risk factor for candidaemia development (OR, 2.93; 95% CI 1.09-7.81, P = 0.032). Mortality was 60.6% among patients with candidaemia and 22% among controls (P < 0.001). The presence of candidaemia (OR, 9.37; 95% CI 3.48-25.26, P < 0.001) and the illness severity on admission (acute physiologic and chronic health evaluation II score, OR, 1.17; 95% CI 1.12-1.24, P < 0.001) were independently associated with mortality. Among candidaemic patients, risk factors for mortality were the severity of organ dysfunction (sequential organ failure assessment score, OR, 1.57; 95% CI 1.00-2.46, P = 0.05) and a low serum albumin level (OR, 0.74; 95% CI 0.59-0.94, P = 0.012) both of them occurred on candidaemia onset. We conclude that in critically ill patients matched for illness severity and length of ICU stay, the only independent risk factor for candidaemia was the presence of ARDS. Mortality was independently associated with acquisition of candidaemia and with the illness severity at candidaemia onset.

Background Systemic inflammation may represent a possible cause of anemia. Previous data support that anemic patients with COPD present high erythropoietin (EPO) levels, suggestive of EPO resistance, possibly mediated through inflammatory mechanisms. Objectives We aimed to determine whether systemic inflammation, which is usually up-regulated during exacerbations of COPD (ECOPD) is associated with low hemoglobin levels expressing erythropoietin resistance. Methods Hemoglobin (Hb), EPO and serum biomarkers of systemic inflammation [CRP, TNF-α, fibrinogen and IL-6] were assessed at three time points (admission, resolution and stable phases) in a selected cohort of 93 COPD patients. Results Hemoglobin levels were significantly lower on admission compared to resolution and stable phases (median 12.1 g/dl [interquartile ranges 11.2–12.7], vs 13.5 [12.4–14.3] vs 13.4 [12.7–14.08], respectively p = 0.002), whereas EPO was significantly higher on admission compared to resolution and stable phases. A negative association between Hb and IL-6 and a positive association between EPO and IL-6 were observed only during the acute phase of exacerbation. EPO and Hb were negatively associated during the acute phase, whereas they were positively associated during discharge and stable phase. Conclusions In this observational study we have shown that during admission for ECOPD Hb levels are decreased and EPO levels are increased. We have also identified a negative association between Hb and EPO. The above association is mainly related to increased IL-6 levels, indicating a possible EPO resistance through the mechanism of increased systemic inflammatory process.

Congenital central hypoventilation syndrome (CCHS) is an uncommon disorder characterized by the absence of adequate autonomic control of respiration, which results in alveolar hypoventilation and decreased sensitivity to hypercarbia and hypoxemia, especially during sleep.1 Patients with CCHS need lifelong ventilatory support. The treatment options for CCHS include intermittent positive pressure ventilation administered via tracheostomy, noninvasive positive pressure ventilation, negative-pressure ventilation by body chamber or cuirass, and phrenic nerve pacing.2 However, it may be necessary to alter the mode of ventilation according to age, psychosocial reasons, complications of therapy, and emergence of new modes of ventilation.3 We present a case of a 16-year-old girl with CCHS who was mechanically ventilated via tracheostomy for 16 years and was successfully transitioned to a new modality of noninvasive ventilation (average volume-assured pressure support [AVAPS]) that automatically adjusts the pressure support level in order to provide a consistent tidal volume. Citation: Vagiakis E; Koutsourelakis I; Perraki E; Roussos C; Mastora Z; Zakynthinos S; Kotanidou A. Average volume-assured pressure support in a 16-year-old girl with central congenital hypoventilation syndrome. J Clin Sleep Med 2010;6(6):609-612.

IL-5 is a T helper 2 cytokine important in the trafficking and survival of eosinophils. Because eosinophils can be found in malignant pleural effusions (MPE) from mice and humans, we asked whether IL-5 is involved in the pathogenesis of MPE.To determine the role of IL-5 in MPE formation.The effects of IL-5 on experimental MPE induced in C57BL/6 mice by intrapleural injection of syngeneic lung (Lewis lung cancer [LLC]) or colon (MC38) adenocarcinoma cells were determined using wild-type (il5(+/+)) and IL-5-deficient (il5⁻(/)⁻) mice, exogenous administration of recombinant mouse (rm) IL-5, and in vivo antibody-mediated neutralization of endogenous IL-5. The direct effects of rmIL-5 on LLC cell proliferation and gene expression in vitro were determined by substrate reduction and microarray.Eosinophils and IL-5 were present in human and mouse MPE, but the cytokine was not detected in mouse (LLC) or human (A549) lung and mouse colon (MC38) adenocarcinoma-conditioned medium, suggesting production by host cells in MPE. Compared with il5(+/+) mice, il5⁻(/)⁻ mice showed markedly diminished MPE formation in response to both LLC and MC38 cells. Exogenous IL-5 promoted MPE formation in il5(+/+) and il5⁻(/)⁻ mice, whereas anti-IL-5 antibody treatment limited experimental MPE in il5(+/+) mice. Exogenous IL-5 had no effects on LLC cell proliferation and gene expression; however, IL-5 was found to be responsible for recruitment of eosinophils and tumor-promoting myeloid suppressor cells to MPE in vivo.Host-derived IL-5 promotes experimental MPE and may be involved in the pathogenesis of human MPE.

Resistive breathing is associated with large negative intrathoracic pressures. Increased mechanical stress induces high-permeability pulmonary edema and lung inflammation.To determine the effects of resistive breathing on the healthy lung.Anesthetized rats breathed through a two-way nonrebreathing valve. The inspiratory line was connected to a resistance setting peak inspiratory tracheal pressure at 50% of maximum (inspiratory resistive breathing), while 100% oxygen was supplied to prevent hypoxemia. Quietly breathing animals (100% oxygen) served as controls. Lung injury was evaluated after 3 and 6 hours of resistive breathing.After both 3 and 6 hours of resistive breathing, lung permeability was increased, as assessed by (99m)Tc-diethylenetriaminepentaacetic acid scintigraphy and Evans blue dye extravasation. Tissue elasticity, measured on the basis of static pressure-volume curves and by the low-frequency forced oscillation technique, was also increased. After both 3 and 6 hours of resistive breathing, gravimetric measurements revealed the presence of pulmonary edema and analysis of bronchoalveolar lavage showed increased total protein content, whereas the total cell count was elevated only after 6 hours of resistive breathing. Cytokine levels were assessed in bronchoalveolar lavage fluid and lung tissue by ELISA and were increased after 6 hours compared with controls. Western blot analysis showed early activation of Src kinase via phosphorylation (at 30 min), and Erk1/2 and IκBα (nuclear factor-κB inhibitor) were phosphorylated at 3 and 6 hours. Pathology revealed the presence of lung injury after resistive breathing.Resistive breathing induces acute lung injury and inflammation.

Eur J Clin Invest 2010; 41 (1): 30–38 Abstract Background Obesity and asthma are characterized by the presence of inflammation. Leptin and adiponectin are circulating hormones produced by adipose tissue that regulate several metabolic and inflammatory functions. We aimed to determine whether obesity influences asthmatic inflammation as well as the contribution of leptin or/and adiponectin to a possible linkage between asthmatic and obesity-related inflammation. Materials and methods One hundred patients with asthma and 60 healthy controls were studied. Subjects who had a comorbid illness that could interfere with the proposed tests were excluded. All subjects were divided into three groups (normal range, pre-obese, obese) according to the criteria of the current WHO international classification for body mass index (BMI). Possible associations between variables expressing airway inflammation, bronchial hyper-responsiveness, systemic inflammation and obesity, as assessed by BMI, were evaluated. Leptin and adiponectin were also measured and were associated with asthma airway and systemic inflammatory variables to elucidate possible associations. Results Obese patients had significant higher values of LTE4/creatinine in urine compared with pre-obese and normal range ones. In a linear regression model, the only significant associations were those between BMI and LTE4/creatinine in urine. Using the same model, log leptin and log adiponectin presented positive and negative associations, respectively with LTE4/creatinine in urine. No other significant associations were observed in both patients and healthy subjects. Conclusions In a selected cohort of asthmatic patients, obesity is significantly associated with increased urinary leukotriene levels. Alterations of leptin/adiponectin balance may be related to the presence of leukotriene inflammation in obese asthmatic patients.

We investigated whether expiratory muscle loading induced by the application of expiratory flow limitation (EFL) during exercise in healthy subjects causes a reduction in quadriceps muscle blood flow in favor of the blood flow to the intercostal muscles. We hypothesized that, during exercise with EFL quadriceps muscle blood flow would be reduced, whereas intercostal muscle blood flow would be increased compared with exercise without EFL. We initially performed an incremental exercise test on eight healthy male subjects with a Starling resistor in the expiratory line limiting expiratory flow to ∼ 1 l/s to determine peak EFL exercise workload. On a different day, two constant-load exercise trials were performed in a balanced ordering sequence, during which subjects exercised with or without EFL at peak EFL exercise workload for 6 min. Intercostal (probe over the 7th intercostal space) and vastus lateralis muscle blood flow index (BFI) was calculated by near-infrared spectroscopy using indocyanine green, whereas cardiac output (CO) was measured by an impedance cardiography technique. At exercise termination, CO and stroke volume were not significantly different during exercise, with or without EFL (CO: 16.5 vs. 15.2 l/min, stroke volume: 104 vs. 107 ml/beat). Quadriceps muscle BFI during exercise with EFL (5.4 nM/s) was significantly ( P = 0.043) lower compared with exercise without EFL (7.6 nM/s), whereas intercostal muscle BFI during exercise with EFL (3.5 nM/s) was significantly ( P = 0.021) greater compared with that recorded during control exercise (0.4 nM/s). In conclusion, increased respiratory muscle loading during exercise in healthy humans causes an increase in blood flow to the intercostal muscles and a concomitant decrease in quadriceps muscle blood flow.

Sarcoidosis is a complex disease with autoimmune basis and still unknown etiology. We have screened for mutations in the cystic fibrosis conductance regulator (CFTR) gene and genotyped single-nucleotide polymorphisms in the tumor necrosis factor (TNF), interferon alpha-10 (IFNA10), IFNA17, and interferon gamma (IFNG) genes in 89 Greek patients with sarcoidosis and 212 control subjects to detect possible association between them and the risk for developing sarcoidosis. We have found a statistically significant increase (p = 6.1 x 10(-8)) of CFTR mutation carriers in the population of patients with sarcoidosis versus the control population. A difference was also noted within the group of patients with sarcoidosis where the ones with CFTR mutations suffered more frequently from dyspnea than those without (p = 5 x 10(-6)). Our study did not reproduce the associations previously noted with the TNF, IFNA10, IFNA17, and IFNG genes, which highlights the genetic complexity of the disorder and is in agreement with previous studies showing that CFTR might be an important factor in the clinical course of the disease.

Background: Distinct infl ammatory cellular phenotypes of severe refractory asthma (SRA) have been reported. Fractional exhaled nitric oxide (F e NO) primarily is related to eosinophilic infl ammation. Exhaled breath condensate (EBC) pH has been suggested as a noninvasive tool in the assessment of patients with asthma. We sought to determine whether F e NO and EBC pH could identify the presence and type of the underlying cellular infl ammation in patients with SRA. Methods: Twenty-nine patients with SRA, 27 patients with moderate asthma, and 17 healthy subjects underwent F e NO measurement, EBC collection for pH measurement, and sputum induction for cell count identifi cation. Results: F e NO was signifi cantly higher and pH signifi cantly lower in patients with SRA than in the other groups. In SRA, F e NO levels of . 19 parts per billion were associated with a sensitivity of 0.78 and a specifi city of 0.73 for sputum eosinophilia, whereas F e NO levels of , 19 parts per billion were associated with a sensitivity of 0.63 and a specifi city of 0.9 for sputum neutrophilia irrespective of the presence of eosinophils. The pH failed to predict the cellular profi le in SRA, but a cutoff value of , 7.37 could predict sputum eosinophilia in moderate asthma. Conclusions: In patients with SRA, different F e NO threshold values can identify those with predominant eosinophilia as well as those with neutrophilia. F e NO levels were reduced in patients with predominant neutrophilia regardless of the concomitant presence of eosinophilia. Although pH could not identify the cellular profi le in SRA, it seemed to be a better index for predicting eosinophilia in moderate asthma.

OBJECTIVE We hypothesized that pretreatment with atorvastatin improves alveolar capillary permeability and hemodynamics and, thus, confers protection against lung injury caused by high-stretch mechanical ventilation. METHODS Twenty-four isolated sets of normal rabbit lungs were utilized. Treated animals received atorvastatin (20 mg/kg body weight/day by mouth) for 3 days before surgery. Lungs were perfused constantly (300 mL/min) and ventilated for 1 hr with pressure-control ventilation at either 23 (high pressure; resulting in tidal volume approximately 22 mL/kg) or 11 (low pressure; tidal volume approximately 10 mL/kg) cm H2O peak inspiratory pressure and positive end-expiratory pressure of 3 cm H2O. Four groups were examined: high pressure-no statin, high pressure-statin pretreatment, low pressure-no statin, and low pressure-statin pretreatment. RESULTS The high-pressure-no statin group sustained more damage than the low-pressure groups. In high-pressure groups, lungs of statin-pretreated vs. no statin-pretreated animals sustained a significantly lower increase in ultrafiltration coefficient (an accurate marker of alveolar capillary permeability; high-pressure-statin pretreatment vs. high-pressure-no statin, -0.013 +/- 0.017 g/min/mm Hg/100g vs. 1.723 +/- 0.495 g/min/mm Hg/100g; p < .001), lower weight gain (i.e., less edema formation; 4.62 +/- 1.50 grams vs. 17.75 +/- 4.71 grams; p = .005), improved hemodynamics (i.e., lower increase in mean pulmonary artery pressure; 0.56 +/- 0.51 mm Hg vs. 5.62 +/- 1.52 mm Hg; p = .04), lower protein concentration in bronchoalveolar lavage fluid (p < .001), and fewer histologic lesions (p = .013). Apoptosis of lung parenchyma cells was not different (p = .97). There was no difference between low-pressure-statin pretreatment and low-pressure-no statin groups regarding these outcomes. CONCLUSION In this model, atorvastatin improves alveolar capillary permeability and hemodynamics and, thus, attenuates lung injury caused by high-stretch mechanical ventilation.

Strenuous exercise leads to the up-regulation of interleukin-6 (IL-6) production and enhanced nitric oxide (NO) release within the contracting skeletal muscles. In this study, we investigated whether NO regulates IL-6 production in C2C12 myotubes. These cells exhibited a concentration-dependent increase in IL-6 production upon stimulation with NO donors (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate), (Z)-1-[N-(3-aminopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA-NONOate), and sodium nitroprusside (SNP). This treatment did not alter cGMP levels nor did the soluble guanylyl cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one(ODQ), alter this response. The NO-independent sGC activator 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY41-2272) and cyclic guanosine monophosphate (cGMP) analog 8Br-cGMP failed to induce IL-6 production. Upon exposure to NO donors, we observed an increase in Erk1/2 and p38 MAPK phosphorylation but not in SAPK/JNK. In addition, NO-induced IL-6 release was inhibited in a concentration-dependent fashion by the MEK1/2 inhibitor PD98059 and the p38 MAPK inhibitor SB203580 but not by the SAPK/JNK inhibitor SP600125. We conclude that NO-stimulated IL-6 production in differentiated C2C12 myotubes is cGMP-independent and mediated by activation of MAPK pathways.

Near-infrared spectroscopy (NIRS) with the tracer indocyanine green (ICG) may be used for measuring muscle blood flow (MBF) during exercise, if arterial ICG concentration is measured simultaneously. Although pulse dye densitometry allows for noninvasive measurement of arterial dye concentration, this technique is sensitive to motion and may not be applicable during exercise. The aim of this study was to evaluate a noninvasive blood flow index (BFI), which is derived solely from the muscle ICG concentration curve. In 10 male cyclists 5 mg ICG were injected into an antecubital vein at rest and during cycling at 30, 60, 70, 80, 90, and 100% of previously determined maximal work load. Simultaneously blood was withdrawn through a photodensitometer at 20 ml/min from the radial artery to measure arterial ICG concentration. To measure muscle tissue ICG concentrations, two sets of NIRS optodes were positioned on the skin, one over the left seventh intercostal space and the other over the left vastus lateralis muscle. MBF was calculated from the arterial and muscle concentration data according to Fick's principle. BFI was calculated solely from the muscle concentration curve as ICG concentration difference divided by rise time between 10 and 90% of peak. During exercise mean BFI values changed similarly to MBF in both intercostal and quadriceps muscles and showed excellent correlations with MBF: r = 0.98 and 0.96, respectively. Individual data showed some scattering among BFI and MBF values but still reasonable correlations of BFI with MBF: r = 0.73 and 0.72 for intercostal and quadriceps muscles, respectively. Interobserver variability, as analyzed by Bland-Altman plots, was considerably less for BFI than MBF. These data suggest that BFI can be used for measuring changes in muscle perfusion from rest to maximal exercise. Although absolute blood flow cannot be determined, BFI has the advantages of being essentially noninvasive and having low interobserver variability.

Morbidelli L, Pyriochou A, Filippi S, Vasileiadis I, Roussos C, Zhou Z, Loutrari H, Waltenberger J, Stossel A, Giannis A, Ziche M, Papapetropoulos A. The soluble guanylyl cyclase inhibitor NS-2028 reduces vascular endothelial growth factor-induced angiogenesis and permeability. Am J Physiol Regul Integr Comp Physiol 298: R824-R832, 2010. First published December 23, 2009; doi:10.1152/ajpregu.00222.2009.-Nitric oxide (NO) is known to promote vascular endothelial growth factor (VEGF)stimulated permeability and angiogenesis. However, effector molecules that operate downstream of NO in this pathway remain poorly characterized. Herein, we determined the effect of soluble guanylyl cyclase (sGC) inhibition on VEGF responses in vitro and in vivo. Treatment of endothelial cells (EC) with VEGF stimulated eNOS phosphorylation and cGMP accumulation; pretreatment with the sGC inhibitor 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS-2028) blunted cGMP levels without affecting VEGF-receptor phosphorylation. Incubation of cells with NS-2028 blocked the mitogenic effects of VEGF. In addition, cells in which sGC was inhibited exhibited no migration and sprouting in response to VEGF. To study the mechanisms through which NS-2028 inhibits EC migration, we determined the effects of alterations in cGMP levels on p38 MAPK. Initially, we observed that inhibition of sGC attenuated VEGF-stimulated activation of p38. In contrast, the addition of 8-Br-cGMP to EC stimulated p38 phosphorylation. The addition of cGMP elevating agents (BAY 41-2272, DETA NO and YC-1) enhanced EC migration. To test whether sGC also mediated the angiogenic effects of VEGF in vivo, we used the rabbit cornea assay. Animals receiving NS-2028 orally displayed a reduced angiogenic response to VEGF. As increased vascular permeability occurs prior to new blood vessel formation, we determined the effect of NS-2028 in vascular leakage. Using a modified Miles assay, we observed that NS-2028 attenuated VEGF-induced permeability. Overall, we provide evidence that sGC mediates the angiogenic and permeability-promoting activities of VEGF, indicating the significance of sGC as a downstream effector of VEGF-triggered responses.

Interleukin 18 (IL-18) is a pro-inflammatory cytokine, which has been shown to be implicated in the induction of airway hyperresponsiveness (AHR) in murine asthma models. The association of IL-18 with AHR in human bronchial asthma is not clear as yet. As cigarette smoking modifies airway inflammation we aimed to assess the relationship of IL-18 with airway hyperresponsiveness (AHR) in non-smoking versus smoking asthmatics. IL-18 was measured in sputum supernatants obtained from asthmatic (24 smokers and 22 non-smokers) and healthy subjects (16 smokers and 17 non-smokers). All subjects were assessed by spirometry, skin-prick tests to common aeroallergens and bronchial provocation to methacholine (Mch). There was no significant difference in IL-18 levels between healthy and asthmatic smokers and between healthy and asthmatic non-smokers. IL-18 levels in sputum were significantly lower in healthy smokers compared to non-smokers (p=0.048); similarly, in asthmatic smokers as compared to non-smokers (p=0.037). An inverse correlation was found between IL-18 levels, FEV(1) (% pred) (r=-0.495, p=0.043), and PD(20)Mc(h) in non-smoking asthmatics (r=-0.621, p=0.024). A positive correlation was found in smoking asthmatics between IL-18 levels in sputum and FEV(1) (% pred) (r=0.627, p=0.002), FVC (% pred) (r=0.460, p=0.031), and PD(20)Mc(h) (r=0.809, p=0.005). Cigarette smoking reduced IL-18 levels in induced sputum in healthy and asthmatic smokers. IL-18 levels were correlated with airway obstruction and AHR in an inverse way in smoking and non-smoking asthmatics. These results suggest the implication of IL-18 in airway hyperresponsiveness characterizing bronchial asthma, which is modified by smoking.

Background Chronotropic response to exercise (CR) and heart rate recovery (HRR) immediately after exercise are indirect indices of sympathetic and parasympathetic activity, respectively. The aim of this study was to evaluate CR and HRR in patients with pulmonary arterial hypertension (PAH) in relation to disease severity. Methods and Results Ten PAH patients (6 females/4 males, mean age: 48 ± 12 years) and 10 control subjects matched for age, gender, and body mass index (6 females/4 males, mean age: 46 ± 6 years) performed a ramp incremental symptom-limited cardiopulmonary exercise test on a cycle ergometer. Main measurements included heart rate at rest (HR), CR = [(peak HR-resting HR/220-age-resting HR) × 100, %], HRR1 = HR difference from peak exercise to 1 minute after, ventilatory efficiency during exercise (VE/VCO2 slope), peak oxygen uptake (VO2p), and the first-degree slope of VO2 for the first minute of the recovery period (VO2/t-slope). PAH patients had a significantly decreased CR (58 ± 31 vs 92 ± 13, %, P < .001) and HRR1 (10 ± 5 vs 29 ± 6, beats/min, P < .001) as well as VO2p (11.9 ± 3.5 vs 26.9 ± 6.6, mL·kg·min) and VO2/t-slope (0.2 ± 0.1 vs. 0.9 ± 0.2, mL·kg·min2) compared with controls. CR and HRR1 correlated well with VO2p (r = 0.7; P < .001 and r = 0.85; P < .001, respectively) and VO2/t-slope (r = 0.66; P < .001 and r = 0.85; P < .001, respectively) and had a significant inverse correlation with VE/VCO2 slope (r = –0.47; P < .01 and r = –0.77; P < .001, respectively). Conclusions PAH patients present a significant impairment of CR and HRR1 in relation to disease severity, indicating profound autonomic nervous system abnormalities.

BACKGROUND AND OBJECTIVE Although sputum culture in patients with an acute exacerbation of COPD is of uncertain value, it is routinely done. The ability to clinically identify patients likely or unlikely to yield bacterial sputum isolates would potentially reduce unnecessary tests. The objective of this study was to identify the clinical predictors of positive sputum cultures in this patient population. METHODS Consecutive patients with a COPD exacerbation requiring an emergency visit were prospectively enrolled. Quantitative sputum culture was performed on-site. Data on current smoking, sputum purulence, FEV(1), Medical Research Council chronic dyspnoea scale, BMI, severe exacerbations in the preceding year requiring hospitalization, PaO(2), PaCO(2), Acute Physiology and Chronic Health Evaluation (APACHE) II score, and oral and inhaled steroid use were recorded. RESULTS Of the 94 patients enrolled, sputum from 36 yielded bacterial pathogens. These patients were characterized by a higher frequency of purulent sputum, lower FEV(1), BMI and PaO(2,) higher APACHE II score and more frequent use of inhaled steroids (P < 0.05). On multivariate regression, purulent sputum, FEV(1) and BMI were independent determinants of a positive sputum culture. Using receiver-operator-optimized thresholds for these variables (purulent sputum, FEV(1) < 35% predicted and BMI < or = 22 kg/m(2)), we proposed a regression coefficient-weighted prediction model that accurately determined the likelihood of sputum bacterial isolation. CONCLUSIONS A prediction model based on the variables of purulent sputum, FEV(1) and BMI predicted sputum culture result with about 90% accuracy. Pending further validation, this model may save valuable healthcare resources.

We studied in 10 healthy subjects the effect of chronic enteral supplementation of antioxidants (vitamins E, C, A, allopurinol, and N-acetylcysteine) on cytokine production by monocytes at rest, end exercise (60-min cycling at 60% of maximum oxygen consumption), and 60 min post-exercise (recovery). The percentage and the mean fluorescent intensity (MFI) of both unstimulated and lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6-producing monocytes were detected using flow cytometry. Antioxidants decreased the percentage of unstimulated IL-6-producing monocytes following exercise, while their MFI increased at rest. The percentage of LPS-stimulated monocytes increased after exercise and they produced more IL-6 both at rest and following exercise. The percentage of unstimulated and LPS-stimulated IL-1beta-producing monocytes was not affected by antioxidants. The MFI of IL-1beta-produced unstimulated monocytes was increased after antioxidants both at rest and following exercise. After antioxidants, LPS-stimulated monocytes produced more IL-1beta following exercise. Antioxidants decreased the percentage of TNF-alpha spontaneously-produced monocytes following exercise, which produced more TNF-alpha at recovery. Antioxidants did not affect the percentage of LPS-stimulated monocytes producing TNF-alpha, while LPS-stimulated production of TNF-alpha increased both at rest and following exercise. Antioxidants differentially affect TNF-alpha, IL-1beta, and IL-6 production by monocytes, with a general tendency of augmenting cytokine production.

Mastic oil from Pistacia lentiscus variation chia, a traditionally used dietary flavoring agent with medicinal properties, has been shown to exert in vitro antitumor activities, but no study has addressed in vivo efficacy and mechanisms of action. Presently, we demonstrated that treatment of immunocompetent mice with mastic oil (45 mg/kg body weight, intraperitoneally, 3 times a wk for approximately 3 wk) significantly inhibited tumor growth (56.4% +/- 5.7 maximum reduction in tumor volumes) without toxicity. Analysis of tumors by immunohistochemistry and ELISA indicated that this effect is associated with increased apoptosis, reduced neovascularization, and inhibition of chemokine expression. Likewise mastic oil reduced vascular endothelial growth factor and chemokine release by Lewis lung carcinoma (LLC) cells. Furthermore, mastic oil administration decreased small guanosine triphosphatases (GTPases) Ras, RhoA and nuclear factor-kappa-B-dependent reporter gene expression in vivo and in vitro, indicating a mechanistic link between mastic oil activities and blocking of relevant signaling and transcription pathways. A dose-response comparison with perillyl alcohol and alpha-pinene, two of its components, revealed a higher efficacy of mastic oil, pointing to a beneficial collective interaction among its ingredients. Conclusively, our results provide novel in vivo evidence of mastic oil inhibitory effects on tumor growth and set a rational basis for its future application in cancer prevention.

The BODE index is frequently used to assess functional capacity in patients with COPD. The aim of this study was to investigate the effectiveness of interval-load training (ILT) to improve the BODE index in comparison to the commonly implemented constant-load training (CLT). Forty-two patients with COPD [FEV(1): (mean+/-SEM) 42+/-3% predicted] were randomly allocated to either ILT (n=21) or CLT (n=21). The training program consisted of cycling exercise 3 days/week for 10 weeks. Patients assigned to ILT exercised at a mean intensity of 126+/-4% of baseline peak work rate (Wpeak) with 30-s work periods alternated with 30-s rest periods for 45 min per day, whereas patients allocated to CLT exercised at a mean intensity of 76+/-5% of baseline Wpeak for 30 min per day. The BODE index and its components: body mass index, FEV(1), MMRC dyspnea score and the 6-min walk test (6-MWT) as well as cycling Wpeak were assessed before and after both exercise training regimes. Both ILT and CLT significantly (p

The outcome after hospitalization for an exacerbation of chronic obstructive pulmonary disease (COPD) is unfavorable and uncertainty exists about factors predicting short and long-term prognosis.To identify clinical predictors of length of hospital stay (LOS) and three-year mortality after COPD exacerbations requiring hospitalization.Retrospective analysis of prospectively collected data.All consecutive patients hospitalized with COPD exacerbation were enrolled. Disease severity was estimated by FEV(1,) body mass index (BMI), Medical Research Council (MRC) chronic dyspnoea scale, previous hospitalizations, need for long-term oxygen treatment (LTOT), arterial oxygen and carbon dioxide partial pressures (PaO(2) and PaCO(2)), pH and respiratory rate. Outcome was assessed by LOS and three-year mortality.Out of 81 patients enrolled, three-year mortality data were available for 61. LOS was related to BMI, MRC scale and respiratory rate. Three-year mortality was related to FEV(1), BMI, MRC scale, LTOT, and PaCO(2). Multiple logistic regression analysis demonstrated that MRC scale was the only independent determinant of LOS, [p = 0.001, odds ratio (OR) 7.67 (95% CI 2.50-23.41)], whereas MRC scale and BMI predicted three-year mortality, [p = 0.001, OR 8.28 (95% CI 2.25-30.47) and p = 0.006, OR 6.91 (95% CI 1.74-27.48), respectively]. Cox regression analysis demonstrated identical results. Using receiver-operator-optimized thresholds for these variables (MRC2 and BMI25 kg/m(2)), we propose a prediction model that accurately determines three-year mortality risk.In this study, MRC scale and BMI predicted outcome after COPD hospitalization. Pending further validation, this predictive model may contribute to identify patients with poor outcome even when spirometric data are unavailable.