A fluorophore-conjugated reagent enabling rapid detection, isolation and live tracking of senescent cells.

Cellular senescence is a stress-response mechanism implicated in various physiological processes, diseases, and aging. Current detection approaches have partially addressed the issue of senescent cell identification in clinical specimens. Effective methodologies enabling precise isolation or live tracking of senescent cells are still lacking. In-depth analysis of truly senescent cells is, therefore, an extremely challenging task. We report (1) the synthesis and validation of a fluorophore-conjugated, Sudan Black-B analog (GLF16), suitable for in vivo and in vitro analysis of senescence by fluorescence microscopy and flow cytometry and (2) the development and application of a GLF16-carrying micelle vector facilitating GLF16 uptake by living senescent cells in vivo and in vitro. The compound and the applied methodology render isolation of senescent cells an easy, rapid, and precise process. Straightforward nanocarrier-mediated GLF16 delivery in live senescent cells comprises a unique tool for characterization of senescence at an unprecedented depth.

A Systematic Review of the Interventions for Management of Pain in Patients After Spinal Cord Injury.

Chronic pain is a very common problem in patients with spinal cord injury (SCI) as it affects 80% of these patients, which negatively affects their quality of life. Despite many advantages that exist in the management of any type of pain (neuropathic, nociceptive, mixed) in these patients, there is no cure, and the analgesic effect of some treatments is inadequate. This study aims to conduct an evidence-based systematic review regarding the various interventions used for the management of pain after SCI. The PubMed, Physiotherapy Evidence Database (PEDro), and Cochrane Library databases were searched from 1969 to 2023. The risk of bias was assessed using the PEDro scoring system. A total of 57 studies met the inclusion criteria and were included in this systematic review. Among the different interventions at present, 18 studies examined the role of oral medications, 11 studies examined the role of minimally invasive methods (injection and infusion), 16 studies investigated physiotherapy and alternative treatments, and 12 studies examined the role of repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and cranial electrotherapy stimulation (CES) in the management of pain in patients after SCI. Gabapentin and pregabalin are very effective in managing chronic neuropathic pain after SCI, and pregabalin also seems to reduce anxiety and sleep disturbances in the patients. It is noteworthy that lamotrigine, valproate, and carbamazepine do not have an analgesic effect, but mirogabalin is a novel and promising drug. Antidepressants (selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors) did not reduce the pain of the patients, although some studies showed an efficacy of amitriptyline especially in depressed patients and tramadol should be considered short-term with caution. Also, tDCS and rTMS reduced pain. Moreover, botulinum toxin type A, lidocaine, ketamine, and intrathecal baclofen significantly reduced pain intensity, although the sample of the studies was small. Physiotherapy and alternative treatments seem to relieve pain, and transcutaneous electrical nerve stimulation had the greatest reduction of pain intensity. In conclusion, several pharmaceutical and non-pharmaceutical methods exist, which can reduce pain in patients after SCI. The type of intervention can be considered by the physician depending on the patients' preference, age, medical history, type of pain, and associated symptoms. However, more studies with greater samples and with better methodological quality should be conducted.

A Holistic Approach to a Dizzy Patient: A Practical Update.

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.

A novel ratio of CD8+:B-cells as a prognostic marker of coronavirus disease 2019 patient progression and outcome.

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.

The influence of biphasic positive airway pressure vs. sham biphasic positive airway pressure on pulmonary function in morbidly obese patients after bariatric surgery.

BACKGROUND: The effect of biphasic positive airway pressure (BPAP) at individualized pressures on the postoperative pulmonary recovery of morbidly obese patients (MOP) undergoing open bariatric surgery (OBS) and possible placebo device-related effects (sham BPAP) were investigated. METHODS: Forty-eight MOP scheduled for OBS were initially enrolled. Subjects were randomly assigned to: A) the BPAP group in which BPAP, at individualized inspiratory positive airway pressure/expiratory positive airway pressure (IPAP/EPAP), was applied for 3 days postoperatively and B) the sham BPAP group in which sham BPAP was applied for the same time. Pulmonary function was assessed by spirometry 24 h prior to surgery and at 24, 48 and 72 h postoperatively and respiratory complications were recorded. RESULTS: Thirty-five subjects, 21 in the BPAP group and 14 in the sham BPAP group, completed the study. Baseline characteristics and pulmonary function were similar between groups preoperatively. Subjects in the BPAP group showed in general better spirometric performance and SpO2 values postoperatively and expedited pulmonary recovery. Atelectasis combined with respiratory distress syndrome (RDS) symptoms was observed in 21% of subjects in the sham BPAP group and one of these subjects developed lower respiratory tract infection. No respiratory complications were recorded in the BPAP group. Use of higher BPAP pressures was not associated with anastomosis leakage or disruption in any patient. CONCLUSION: Use of BPAP, at individualized pressures, expedites postoperative pulmonary recovery and eliminates respiratory complications in MOP who have undergone OBS.

Induction of decay accelerating factor and membrane cofactor protein by resveratrol attenuates complement deposition in human coronary artery endothelial cells.

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.

Acute effects of smoke exposure on airway and systemic inflammation in forest firefighters.

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.

Effect of pulmonary rehabilitation on tidal expiratory flow limitation at rest and during exercise in COPD patients.

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.

Prolonged occupational exposure leads to allergic airway sensitization and chronic airway and systemic inflammation in professional firefighters.

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.

BTNL2 gene SNPs as a contributing factor to sarcoidosis pathogenesis in a cohort of Greek patients.

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology that primarily affects adults between the ages of 20 and 40 years old. It is characterized by the activation of Th1 lymphocytes resulting in the production of inflammatory cytokines and the formation of noncaseating epithelioid cell granulomas in affected tissues. The lungs and lymphatic system are the ones most frequently affected. The disease usually presents spontaneous remission in the first two years and, in a few patients, the disease progresses to pulmonary fibrosis or other fatal complications depending on the affected organ. The pathogenesis of sarcoidosis is still not clearly defined, and is considered an interaction between the environment and risk alleles in many genes. The present case control study consisted of 146 Greek patients with sarcoidosis and 90 healthy volunteers from the same ethnic group. The coding and neighboring intronic regions of the BTNL2 gene were sequenced and risk alleles were compared amongst the two groups. Thirty-seven different variants were detected from which 12 were synonymous substitutions and 25 non-synonymous. With the help of in silico tools (SIFT, PolyPhen, PROVEAN, PMut and EX_SKIP), 13 variants were classified as possible pathological risk variants including 4 novel ones. The most common risk variants contributing to phenotypic modulation of sarcoidosis were p.S360G and p.S334L, with the latter contributing to a more severe disease stage with extra-pulmonary manifestations such as skin granulomas and relapses being more common.

Induced expression and functional effects of aquaporin-1 in human leukocytes in sepsis.

INTRODUCTION: Gene expression profiling was performed via DNA microarrays in leukocytes from critically ill trauma patients nonseptic upon admission to the ICU, who subsequently developed either sepsis (n = 2) or severe sepsis and acute respiratory distress syndrome (n = 3). By comparing our results with published expression profiling studies in animal models of sepsis and lung injury, we found aquaporin-1 to be differentially expressed across all studies. Our aim was to determine how the water channel aquaporin-1 is involved in regulating the immune response in critically ill patients during infection acquired in the ICU. METHODS: Following the results of the initial genetic screening study, we prospectively followed aquaporin-1 leukocyte expression patterns in patients with ICU-acquired sepsis who subsequently developed septic shock (n = 16) versus critically ill patients who were discharged without developing sepsis (n = 13). We additionally determined aquaporin-1 expression upon lipopolysaccharide (LPS) exposure and explored functional effects of aquaporin-1 induction in polymorphonuclear granulocytes (PMNs). RESULTS: Leukocyte aquaporin-1 expression was induced at the onset of sepsis (median 1.71-fold increase; interquartile range: 0.99 to 2.42, P = 0.012 from baseline) and was further increased upon septic shock (median 3.00-fold increase; interquartile range: 1.20 to 5.40, P = 0.023 from sepsis, Wilcoxon signed-rank test); no difference was observed between baseline and discharge in patients who did not develop sepsis. Stimulation of PMNs by LPS led to increased expression of aquaporin-1 in vitro, which could be abrogated by the NF-κB inhibitor EF-24. PMN hypotonic challenge resulted in a transient increase of the relative cell volume, which returned to baseline after 600 seconds, while incubation in the presence of LPS resulted in persistently increased cell volume. The latter could be abolished by blocking aquaporin-1 with mercury and restored by incubation in ß-mercaptoethanol, which abrogated the action of mercury inhibition. CONCLUSIONS: Aquaporin-1 is induced in leukocytes of patients with ICU-acquired sepsis and exhibits higher expression in septic shock. This phenomenon may be due to LPS-triggered NF-κB activation that can also lead to alterations in plasma membrane permeability.

Preclinical pulmonary capillary endothelial dysfunction is present in brain dead subjects.

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.

Risk factors for carbapenem-resistant Gram-negative bacteremia in intensive care unit patients.

PURPOSE: Carbapenem-resistant (CR) Gram-negative pathogens have increased substantially. This study was performed to identify the risk factors for development of CR Gram-negative bacteremia (GNB) in intensive care unit (ICU) patients. METHODS: Prospective study; risk factors for development of CR-GNB were investigated using two groups of case patients: the first group consisted of patients who acquired carbapenem susceptible (CS) GNB and the second group included patients with CR-GNB. Both case groups were compared to a shared control group defined as patients without bacteremia, hospitalized in the ICU during the same period. RESULTS: Eighty-five patients with CR- and 84 patients with CS-GNB were compared to 630 control patients, without bacteremia. Presence of VAP (OR 7.59, 95 % CI 4.54-12.69, p < 0.001) and additional intravascular devices (OR 3.69, 95 % CI 2.20-6.20, p < 0.001) were independently associated with CR-GNB. Presence of VAP (OR 2.93, 95 % CI 1.74-4.93, p < 0.001), presence of additional intravascular devices (OR 2.10, 95 % CI 1.23-3.60, p = 0.007) and SOFA score on ICU admission (OR 1.11, 95 % CI 1.03-1.20, p = 0.006) were independently associated with CS-GNB. The duration of exposure to carbapenems (OR 1.079, 95 % CI 1.022-1.139, p = 0.006) and colistin (OR 1.113, 95 % CI 1.046-1.184, p = 0.001) were independent risk factors for acquisition of CR-GNB. When the source of bacteremia was other than VAP, previous administration of carbapenems was the only factor related with the development of CR-GNB (OR 1.086, 95 % CI 1.003-1.177, p = 0.042). CONCLUSIONS: Among ICU patients, VAP development and the presence of additional intravascular devices were the major risk factors for CR-GNB. In the absence of VAP, prior use of carbapenems was the only factor independently related to carbapenem resistance.

Cerebral cortex oxygen delivery and exercise limitation in patients with COPD.

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.

Nitric oxide regulates cytokine induction in the diaphragm in response to inspiratory resistive breathing.

Resistive breathing (encountered in chronic obstructive pulmonary disease and asthma) results in cytokine upregulation and decreased nitric oxide (NO) levels in the strenuously contracting diaphragm. NO can regulate gene expression. We hypothesized that endogenously produced NO downregulates cytokine production triggered by strenuous diaphragmatic contraction. Wistar rats treated with vehicle, the nonselective NO synthase inhibitor NG-nitro-l-arginine-methylester (l-NAME), or the NO donor diethylenetriamine-NONOate (DETA) were subjected to inspiratory resistive breathing (IRB; 50% of maximal inspiratory pressure) for 6 h or sham operation. Additional groups of rats were subjected to IRB for 6 h with concurrent administration of l-NAME and inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), or P38 (SB203580). Inhibition of NO production (with l-NAME) resulted in upregulation of IRB-induced diaphragmatic IL-6, IL-10, IL-2, TNF-α, and IL-1ß levels by 50%, 53%, 60%, 47%, and 45%, respectively. In contrast, the NO donor (DETA) attenuated the IRB-induced cytokine upregulation to levels characteristic of quietly breathing animals. l-NAME augmented IRB-induced activation of MAPKs (P38 and ERK1/2) and NF-κB, whereas DETA triggered the opposite effect. NF-κB and ERK1/2 inhibition in l-NAME-treated animals blunted the l-NAME-induced cytokine upregulation except IL-6, whereas P38 inhibition blunted all (including IL-6) cytokine upregulation. NO downregulates IRB-induced cytokine production in the strenuously contracting diaphragm through its action on MAPKs and NF-κB.

Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma.

Mitochondrial glucocorticoid (mtGR) and estrogen (mtER) receptors participate in the coordination of the cell's energy requirement and in the mitochondrial oxidative phosphorylation enzyme (OXPHOS) biosynthesis, affecting reactive oxygen species (ROS) generation and induction of apoptosis. Although activation of mtGR and mtER is known to trigger anti-inflammatory signals, little information exists on the presence of these receptors in lung tissue and their role in respiratory physiology and disease. Using a mouse model of allergic airway inflammation disease and applying confocal microscopy, subcellular fractionation, and Western blot analysis we showed mitochondrial localization of GRα and ERß in lung tissue. Allergic airway inflammation caused reduction in mtGRα, mtERß, and OXPHOS enzyme biosynthesis in lung cells mitochondria and particularly in bronchial epithelial cells mitochondria, which was accompanied by decrease in lung mitochondrial mass and induction of apoptosis. Confirmation and validation of the reduction of the mitochondrial receptors in lung epithelial cells in human asthma was achieved by analyzing autopsies from fatal asthma cases. The presence of the mitochondrial GRα and ERß in lung tissue cells and especially their reduction in bronchial epithelial cells during allergic airway inflammation suggests a crucial role of these receptors in the regulation of mitochondrial function in asthma, implicating their involvement in the pathophysiology of the disease.

Metformin attenuates ventilator-induced lung injury.

INTRODUCTION: Diabetic patients may develop acute lung injury less often than non-diabetics; a fact that could be partially ascribed to the usage of antidiabetic drugs, including metformin. Metformin exhibits pleiotropic properties which make it potentially beneficial against lung injury. We hypothesized that pretreatment with metformin preserves alveolar capillary permeability and, thus, prevents ventilator-induced lung injury. METHODS: Twenty-four rabbits were randomly assigned to pretreatment with metformin (250 mg/Kg body weight/day per os) or no medication for two days. Explanted lungs were perfused at constant flow rate (300 mL/min) and ventilated with injurious (peak airway pressure 23 cmH2O, tidal volume ≈17 mL/Kg) or protective (peak airway pressure 11 cmH2O, tidal volume ≈7 mL/Kg) settings for 1 hour. Alveolar capillary permeability was assessed by ultrafiltration coefficient, total protein concentration in bronchoalveolar lavage fluid (BALF) and angiotensin-converting enzyme (ACE) activity in BALF. RESULTS: High-pressure ventilation of the ex-vivo lung preparation resulted in increased microvascular permeability, edema formation and microhemorrhage compared to protective ventilation. Compared to no medication, pretreatment with metformin was associated with a 2.9-fold reduction in ultrafiltration coefficient, a 2.5-fold reduction in pulmonary edema formation, lower protein concentration in BALF, lower ACE activity in BALF, and fewer histological lesions upon challenge of the lung preparation with injurious ventilation. In contrast, no differences regarding pulmonary artery pressure and BALF total cell number were noted. Administration of metformin did not impact on outcomes of lungs subjected to protective ventilation. CONCLUSIONS: Pretreatment with metformin preserves alveolar capillary permeability and, thus, decreases the severity of ventilator-induced lung injury in this model.

Serial changes in adiponectin and resistin in critically ill patients with sepsis: associations with sepsis phase, severity, and circulating cytokine levels.

PURPOSE: The aim of the present study was to describe the variation in adiponectin and resistin levels, 2 adipokines with opposing effects on metabolism, in mechanically ventilated patients with sepsis and their relationships to disease severity and cytokine levels. MATERIALS AND METHODS: An observational prospective study was conducted in a secondary/tertiary unit. Forty-one mechanically ventilated patients diagnosed as having sepsis were included in the study. The Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were estimated. Adiponectin, resistin, and cytokines were measured upon sepsis diagnosis and every 3 to 4 days thereafter until day 30. Adiponectin and resistin were also measured in 40 controls. RESULTS: The patients had higher adiponectin (10.9 ± 6.1 µg/mL vs 6.0 ± 2.9 µg/mL, P < .001) and resistin (24.7 ng/mL vs 3.8 ng/mL, P < .001) levels compared with the controls. Adiponectin increased and resistin decreased significantly over time in the entire cohort. Resistin correlated with Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, interleukin (IL)-6, IL-8, and IL-10 and was significantly higher in severe sepsis/septic shock compared with sepsis. No correlations between adiponectin and clinical scores were noted. CONCLUSIONS: Adiponectin and resistin change reciprocally during the course of sepsis. Resistin relates to the severity of sepsis and the degree of inflammatory response. Adiponectin and resistin may play a critical role in the metabolic adaptations observed in sepsis.

Cardiopulmonary rehabilitation enhances heart rate recovery in patients with COPD.

BACKGROUND: Autonomic dysfunction is present early in the course of COPD, and is associated with adverse outcomes. We utilized heart rate recovery, a simple and validated index of autonomic balance, to investigate the effects of exercise training on autonomic dysfunction in patients with COPD. METHODS: We evaluated 45 stable subjects with COPD who participated in a 36-session exercise-based cardiopulmonary rehabilitation program. Subjects underwent maximal cardiopulmonary exercise testing at baseline and after completion of the rehabilitation program. We recorded exercise testing parameters and heart rate during rest, exercise, and recovery. Heart rate recovery was calculated as heart rate at peak exercise minus heart rate at the first minute of recovery. RESULTS: Thirty-nine subjects (age 66.3 ± 7.8 y, 90% male, body mass index 27.1 ± 4.1 kg/m(2), FEV(1) 45.7 ± 18.7%) completed the program. In these subjects, heart rate recovery increased from 16.2 ± 8.0 beats/min to 18.4 ± 8.4 beats/min (P = .01), resting heart rate decreased from 88.0 ± 10.7 beats/min to 83.3 ± 10.5 beats/min (P = .004), and heart rate at anaerobic threshold decreased from 109.0 ± 12.5 beats/min to 105.5 ± 11.7 beats/min (P = .040). In addition, oxygen consumption (V(O(2))) increased from 14.3 ± 3.7 mL/kg/min to 15.2 ± 3.8 mL/kg/min at peak exercise, and from 9.7 ± 2.4 mL/kg/min to 10.4 ± 2.6 mL/kg/min at anaerobic threshold (both P = .02), while the V(O(2))/t slope increased from -0.32 ± 0.16 mL/kg/min(2) to -0.38 ± 0.19 mL/kg/min(2) (P = .003). Parameters of ventilatory performance improved also. CONCLUSIONS: In subjects with COPD, exercise-based rehabilitation improves heart rate recovery, modestly though, which indicates a degree of attenuated autonomic dysfunction. Exercise and muscular oxidative capacity, as expressed by V(O(2))/t slope, is also improved.

HLA-A and HLA-DRB1 amino acid polymorphisms are associated with susceptibility and protection to pulmonary tuberculosis in a Greek population.

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-DRßN(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 DRßN(37) positive or A R(114) and DRßN(37) positive). Furthermore the HLA-A S(77) appears to have a protective role, however in the presence of the DRßN(37), the A-S(77) does not exert its protective effect. CONCLUSION: The HLA residues A-S(77), A-R(114) and DRßN(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.