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Water is a key component of atmospheric aerosol, affecting many aerosol processes including gas-to-particle partitioning of semi-volatile compounds. Water related to secondary organic aerosol (SOAW) is often neglected in atmospheric chemical transport models and is not considered in gas-to-particle partitioning calculations for inorganic species. We use a new inorganic aerosol thermodynamics model, ISORROPIA-lite, which considers the effects of SOAW, to perform chemical transport model simulations for 1 year over the continental United States to quantify its effects on aerosol mass concentration and composition. SOAW can increase average fine aerosol water levels by up to a factor of 2 when secondary organic aerosol (SOA) is a major PM1 component. This is often the case in the south-eastern US, where SOA concentrations are higher. Although the annual average impact of this added water on total dry PM1 concentrations due to increased partitioning of nitrate and ammonium is small (up to 0.1 µg m−3), total dry PM1 increases of up to 2 µg m−3 (with nitrate levels increases of up to 200 %) can occur when RH levels and PM1 concentrations are high.

The dependence of aerosol acidity on particle size, location, and altitude over Europe during a summertime period is investigated using the hybrid version of aerosol dynamics in the chemical transport model PMCAMx. The pH changes more with particle size in northern and southern Europe owing to the enhanced presence of non-volatile cations (Na, Ca, K, Mg) in the larger particles. Differences of up to 1–4 pH units are predicted between sub- and supermicron particles, while the average pH of PM1−2.5 can be as much as 1 unit higher than that of PM1. Most aerosol water over continental Europe is associated with PM1, while coarse particles dominate the water content in the marine and coastal areas due to the relatively higher levels of hygroscopic sea salt. Particles of all sizes become increasingly acidic with altitude (0.5–2.5 units pH decrease over 2.5 km) primarily because of the decrease in aerosol liquid water content (driven by humidity changes) with height. Inorganic nitrate is strongly affected by aerosol pH with the highest average nitrate levels predicted for the PM1−5 range and over locations where the pH exceeds 3. Dust tends to increase aerosol pH for all particle sizes and nitrate concentrations for supermicron range particles. This effect of dust is quite sensitive to its calcium content. The size-dependent pH differences carry important implications for pH-sensitive processes in the aerosol.

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Myasthenia Gravis (MG) patients often report an affected quality of life (QoL). The aim of the current study was to evaluate the QoL of patients with MG in Greece using a specific tool. A cross-sectional online survey was performed. Adult patients were invited to participate. A questionnaire incorporating the MG-QOL15r scale was distributed, following its translation and cultural adaptation into Greek. Overall, 99 valid responses were submitted. The median age (interquartile range) of the participants was 48.50 (13.50) years and 76.80% were females. One third of the patients mentioned that they could not work/changed jobs after their diagnosis (28.30%) and that they face severe restriction of their everyday activities (26.30%). The mean MG-QOL15r score was 13.50 ± 7.70. Patients with important restriction of everyday activities ( p < 0.01), patients with more pronounced need of emotional support ( p < 0.01), patients with generalized MG ( p < 0.01) and patients with myasthenic crises ( p < 0.01) reported lower QoL. This study is the first to report on the affected QoL of the Greek population with MG using the MG-QoL15r scale. Further work should be done to incorporate the routine evaluation of QoL in the care of patients with MG.

Ventilation in a prone position (PP) for 12 to 16 h per day improves survival in ARDS. However, the optimal duration of the intervention is unknown. We performed a prospective observational study to compare the efficacy and safety of a prolonged PP protocol with conventional prone ventilation in COVID-19-associated ARDS. Prone position was undertaken if P/F < 150 with FiO 2 > 0.6 and PEEP > 10 cm H 2 O. Oxygenation parameters and respiratory mechanics were recorded before the first PP cycle, at the end of the PP cycle and 4 h after supination. We included 63 consecutive intubated patients with a mean age of 63.5 years. Of them, 37 (58.7%) underwent prolonged prone position (PPP group) and 26 (41.3%) standard prone position (SPP group). The median cycle duration for the SPP group was 20 h and for the PPP group 46 h ( p < 0.001). No significant differences in oxygenation, respiratory mechanics, number of PP cycles and rate of complications were observed between groups. The 28-day survival was 78.4% in the PPP group versus 65.4% in the SPP group ( p = 0.253). Extending the duration of PP was as safe and efficacious as conventional PP, but did not confer any survival benefit in a cohort of patients with severe ARDS due to COVID-19.

Globally, chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality, having a significant socioeconomic effect. Several molecular mechanisms have been related to COPD including chronic inflammation, telomere shortening, and epigenetic modifications. Nowadays, there is an increasing need for novel therapeutic approaches for the management of COPD. These treatment strategies should be based on finding the source of acute exacerbation of COPD episodes and estimating the patient's own risk. The use of biomarkers and the measurement of their levels in conjunction with COPD exacerbation risk and disease prognosis is considered an encouraging approach. Many types of COPD biomarkers have been identified which include blood protein biomarkers, cellular biomarkers, and protease enzymes. They have been isolated from different sources including peripheral blood, sputum, bronchoalveolar fluid, exhaled air, and genetic material. However, there is still not an exclusive biomarker that is used for the evaluation of COPD but rather a combination of them, and this is attributed to disease complexity. In this review, we summarize the clinical significance of COPD-related biomarkers, their association with disease outcomes, and COPD patients' management. Finally, we depict the various samples that are used for identifying and measuring these biomarkers.

The outbreak of the new coronavirus strain SARS-CoV-2 (COVID-19) highlighted the need for appropriate feeding practices among critically ill patients admitted to the intensive care unit (ICU). This study aimed to describe feeding practices of intubated COVID-19 patients during their second week of hospitalization in the First Department of Critical Care Medicine, Evaggelismos General Hospital, and evaluate potential associations with all cause 30-day mortality, length of hospital stay, and duration of mechanical ventilation. We enrolled adult intubated COVID-19 patients admitted to the ICU between September 2020 and July 2021 and prospectively monitored until their hospital discharge. Of the 162 patients analyzed (52.8% men, 51.6% overweight/obese, mean age 63.2 ± 11.9 years), 27.2% of patients used parenteral nutrition, while the rest were fed enterally. By 30 days, 34.2% of the patients in the parenteral group had died compared to 32.7% of the patients in the enteral group (relative risk (RR) for the group receiving enteral nutrition = 0.97, 95% confidence interval = 0.88-1.06, p = 0.120). Those in the enteral group demonstrated a lower duration of hospital stay (RR = 0.91, 95% CI = 0.85-0.97, p = 0.036) as well as mechanical ventilation support (RR = 0.94, 95% CI = 0.89-0.99, p = 0.043). Enteral feeding during second week of ICU hospitalization may be associated with a shorter duration of hospitalization and stay in mechanical ventilation support among critically ill intubated patients with COVID-19.

Background & Aims: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Nutritional and functional status derangement is a commonly seen in COPD patients, and this is associated with a higher disease severity and mortality. To assess body composition analysis - measured by segmental multi-frequency bioelectrical impedance analysis (BIA)- and functional status and investigate their relationship with the COPD acute exacerbation risk., Methods: Eighty COPD patients admitted to hospital for COPD acute exacerbation were prospectively followed-up for one year after discharge, focusing on a new incidence of COPD acute exacerbation. Following discharge, participants' body composition was assessed with the use of segmental multi-frequency BIA, whereas physical function by performing 5-repetitions and 30 s sit-to-stand (STS) tests. Unadjusted and multivariate logistic regression analyses were performed to evaluate the ability of the various measures to predict incidence of future COPD acute exacerbation in one-year period., Results: Seventy-six out of 80 participants completed the study and were analyzed. Fifty-one [24 male (47.1%)] out of 76 participants (67.1%), mean aged of 69.3 ± 8.9 years, developed at least one new COPD acute exacerbation during the one year follow-up. The probability of COPD acute exacerbation in one year was significantly related to BMI (OR = 0.75, 95% CI; 0.61-0.91, p = 0.004) and Fat Free Mass (OR = 0.88, 95% CI; 0.79-0.97, p = 0.012) after adjustment for sex, age and smoking index (pack × years). Both 5-repetitions and 30 s STS tests had a good predictive ability for the incidence of COPD acute exacerbation in one year (AUC = 0.80, 95% CI; 0.65-0.95, p = 0.009 and AUC = 0.83, 95% CI; 0.70-0.96, p = 0.004, respectively)., Conclusion: In an observational study among patients admitted with COPD acute exacerbation, body composition analysis parameters and functional status are related to acute exacerbation risk incidence., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

There is an ongoing need for new therapeutic modalities against SARS-CoV-2 infection. Mast cell histamine has been implicated in the pathophysiology of COVID-19 as a regulator of proinflammatory, fibrotic, and thrombogenic processes. Consequently, mast cell histamine and its receptors represent promising pharmacological targets. At the same time, nutritional modulation of immune system function has been proposed and is being investigated for the prevention of COVID-19 or as an adjunctive strategy combined with conventional therapy. Several studies indicate that several immunonutrients can regulate mast cell activity to reduce the de novo synthesis and/or release of histamine and other mediators that are considered to mediate, at least in part, the complex pathophysiology present in COVID-19. This review summarizes the effects on mast cell histamine of common immunonutrients that have been investigated for use in COVID-19.

Chronic obstructive pulmonary disease (COPD) management remains challenging due to the high heterogeneity of clinical symptoms and the complex pathophysiological basis of the disease. Airflow limitation, diagnosed by spirometry, remains the cornerstone of the diagnosis. However, the calculation of the forced expiratory volume in the first second (FEV1) alone, has limitations in uncovering the underlying complexity of the disease. Incorporating additional pulmonary function tests (PFTs) in the everyday clinical evaluation of COPD patients, like resting volume, capacity and airway resistance measurements, diffusion capacity measurements, forced oscillation technique, field and cardiopulmonary exercise testing and muscle strength evaluation, may prove essential in tailoring medical management to meet the needs of such a heterogeneous patient population. We aimed to provide a comprehensive overview of the available PFTs, which can be incorporated into the primary care physician's practice to enhance the efficiency of COPD management.

Although several studies have reported an association between malnutrition and the risk of severe complications after abdominal surgery, there have been no studies evaluating the use of Global Leadership Initiative on Malnutrition (GLIM) criteria for predicting postoperative pulmonary complications (PPCs) following major abdominal surgery in cancer patients. This study aimed to investigate the association among the diagnosis of malnutrition by GLIM criteria, PPCs risk and 90-day all-cause mortality rate following major abdominal surgery in cancer patients. We prospectively analyzed 218 patients (45% male, mean age 70.6 ± 11.2 years) with gastrointestinal cancer who underwent major abdominal surgery at our hospital between October 2018 and December 2019. Patients were assessed preoperatively using GLIM criteria of malnutrition, and 90-day all-cause mortality and PPCs were recorded. In total, 70 patients (32.1%) were identified as malnourished according to GLIM criteria, of whom 41.1% fulfilled the criteria for moderate and 12.6% for severe malnutrition. PPCs were detected in 48 of 218 patients (22%) who underwent major abdominal surgery. Univariate logistic regression analysis revealed that the diagnosis of malnutrition was significantly associated with the risk of PPCs. Furthermore, in multivariate model analysis adjusted for other clinical confounding factors, malnutrition remained an independent factor associated with the risk of PPCs (RR = 1.82; CI = 1.21-2.73) and 90-day all-cause mortality (RR = 1.97; CI = 1.28-2.63, for severely malnourished patients). In conclusion, preoperative presence of malnutrition, diagnosed by the use of GLIM criteria, is associated with the risk of PPCs and 90-day mortality rate in cancer patients undergoing major abdominal surgery.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) ABCD classification tool has been used to assess the symptom burden and exacerbation risk of patients with chronic obstructive pulmonary disease (COPD). An area requiring further exploration is the relationship between the GOLD classification's basic components and the measurements acquired by Sit-to-Stand tests (STST). We aimed to study the relationship between STST and the component of the GOLD classification tool. This study was conducted on a sample of 42 COPD subjects with patient history, COPD assessment test (CAT) and spirometry. 5STST performance time and the number 30s-STST repetitions showed differences of statistical significance in COPD subjects considered to be more symptomatic and in subjects with high risk of future exacerbations. Both STSTs correlated significantly with forced expiratory volume in one second % predicted (FEV1%), CAT, number of acute exacerbations in the past year and number of hospitalized exacerbations in the past year. STST performance correlates significantly with items of the CAT questionnaire that assess breathlessness, limitation of activities, confidence and lack of energy. Using multivariate analysis, age, FEV1% and CAT score manifested the strongest negative association with STST performance. 5STST performance time and the number 30s-STST repetitions in COPD patients correlates with the level of symptoms and the risk of future exacerbations that define groups A-D based on GOLD 2018 classification tool (at the time of data acquisition). The correlation of STST performance with CAT score involves specific items of the questionnaire that assess breathlessness, limitation of activities, confidence and lack of energy.

Parenchymal lung infections occasionally present with clinical symptoms and radiological findings similar to lung malignancy. Pulmonary actinomycosis is a rare condition of its own right, let alone in coexistence with tuberculosis. We report a case of a man presenting with hemoptysis alongside a chest computed tomography compatible with lung cancer. The diagnosis, after removal of a large endobronchial mass with flexible bronchoscopy and cryon, was a concomitant infection with Mycobacterium tuberculosis and Actinomyces odontoliticus. In the literature, there are few reported cases with concomitant tuberculosis and actinomycosis. To our knowledge, such radical treatment without surgical intervention has not been reported in the past.

Background: During the past few years, the use of criteria introduced by Global Initiative for Chronic Obstructive Lung Disease (GOLD) is recommended for the diagnosis and classification of Chronic Obstructive Pulmonary Disease(COPD),taking into account the values of a Forced Expiratory Volume In 1 second (FEV1) and a Forced Expiratory Volume In 1 second (FEV1) to Forced Vital Capacity (FVC) ratio. In Europe, the reference values of the European Coal and Steel Community (ECSC), that were originally developed in 1993 are still used., Aim of the Study: The study aimed to carry out measurement of spirometric values in a healthy, non smoking Greek population, development of local equations and comparison with ECSC and Global Lung Initiative(GLI) equations, in order to see if there is a need for separate ones in everyday use., Methods: Normal predicted values for FEV1 and FEV1/FVC% were obtained from a group of 500 healthy subjects, aged 18-89 years. In addition, a group of 124 COPD patients, with no other comorbidities was studied. Patients were classified according to GOLD criteria in four groups with ECSC, GLI predicted values or with our own predicted values., Results: The statistical analysis has revealed that there is no significant difference among the three sets of predicted values and no statistical difference was detected among the classification of COPD patients., Conclusion: It is shown that the 3 sets of predicted values are almost identical, despite the fact that they have been collected from different study populations.Αccording to the study, there is no need in recalculating values for Greek population.

Background: Observational studies examining the association between body mass index (BMI) and the outcome of cardiac arrest (CA) shows controversial results., Methods: We reviewed literature for studies assessing the impact of BMI on survival and neurological outcome following CA. Eligible studies were subsequently meta-analyzed and pooled odds ratios and their corresponding 95% confidence intervals for post CA survival and neurological status were derived., Results: A total of 7 studies with 24,651 patients were evaluable for this meta-analysis. The studies were also categorized by location of the CA and the use of therapeutic hypothermia. Our results suggested that BMI between 25 and 29.9 kgr/m 2 had a favorable impact on survival after CA (OR = 1.172, 95% CI, 1.109-1.236) in comparison to normal weight subjects. Likewise, overweight patients presented increased odds for a favorable neurological outcome after CA (OR = 1.112, 95% CI, 1.020-1.213). On the contrary, underweight subjects presented decreased odds of surviving after CA as compared to normal BMI subjects (OR = 0.781, 95% CI, 0.652-0.935). Finally, BMI >30 kgr/m 2 was not associated with improved survival or neurological outcome as compared to BMI 18.5-24.9 kgr/m 2 ., Conclusions: Overweight patients have a favorable prognosis after CA in terms of both survival and neurological outcome. This effect was amplified when the analysis is restricted in in-hospital cardiac arrest and in patients non-treated with therapeutic hypothermia., (Copyright © 2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

IL-36 cytokines signal through the IL-36 receptor (IL-36R) and a shared subunit, IL-1RAcP (IL-1 receptor accessory protein). The activation mechanism for the IL-36 pathway is proposed to be similar to that of IL-1 in that an IL-36R agonist (IL-36α, IL-36β, or IL-36γ) forms a binary complex with IL-36R, which then recruits IL-1RAcP. Recent studies have shown that IL-36R interacts with IL-1RAcP even in the absence of an agonist. To elucidate the IL-36 activation mechanism, we considered all possible binding events for IL-36 ligands/receptors and examined these events in direct binding assays. Our results indicated that the agonists bind the IL-36R extracellular domain with micromolar affinity but do not detectably bind IL-1RAcP. Using surface plasmon resonance (SPR), we found that IL-1RAcP also does not bind IL-36R when no agonist is present. In the presence of IL-36α, however, IL-1RAcP bound IL-36R strongly. These results suggested that the main pathway to the IL-36R·IL-36α·IL-1RAcP ternary complex is through the IL-36R·IL-36α binary complex, which recruits IL-1RAcP. We could not measure the binding affinity of IL-36R to IL-1RAcP directly, so we engineered a fragment crystallizable-linked construct to induce IL-36R·IL-1RAcP heterodimerization and predicted the binding affinity during a complete thermodynamic cycle to be 74 μm The SPR analysis also indicated that the IL-36R antagonist IL-36Ra binds IL-36R with higher affinity and a much slower off rate than the IL-36R agonists, shedding light on IL-36 pathway inhibition. Our results reveal the landscape of IL-36 ligand and receptor interactions, improving our understanding of IL-36 pathway activation and inhibition., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Our aim was to prospectively assess the prognostic value of beta2-microglobulin (b2-M) in patients with acute pulmonary embolism (PE). We conducted a prospective study of 109 patients admitted in a pulmonary clinic due to acute PE. A panel of inflammatory markers including b2-M white blood cell (WBC) count and C-reactive protein (CRP) was determined for each patient. In this preliminary study, baseline b2-M levels significantly correlated with the impairment of oxygenation and with all the parameters that are used for the early risk stratification of patients. In multivariate analysis, patients' age and baseline b2-M levels were significantly associated with an increased risk of death. These findings require further prospective validation.

Early-onset pneumonia (EOP) is a common complication after successful cardiopulmonary resuscitation. Currently, EOP diagnosis is difficult because usual diagnostic tools are blunted by the features of post-cardiac arrest syndrome and therapeutic hypothermia itself. When the diagnosis of EOP is suspected, empiric antimicrobial therapy should be considered following bronchopulmonary sampling. The onset of EOP increases the length of mechanical ventilation duration and intensive care unit stay, but its influence on survival and neurological outcome seems marginal. Therapeutic hypothermia has been recognized as an independent risk factor for this infectious complication. All together, these observations underline the need for future prospective clinical trials to better delineate pathogens and risk factors associated with EOP. In addition, there is a need for diagnostic approaches serving the accurate diagnosis of EOP., (Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: Carboxyhemoglobin (COHb) and methemoglobin (MetHb) levels have been associated with a poor outcome in patients with various pathological conditions including cardiovascular diseases. Our aim was to retrospectively assess the prognostic value of arterial COHb and MetHb in patients with acute pulmonary embolism (PE)., Methods: We conducted a retrospective study of 156 patients admitted in a pulmonary clinic due to acute PE. Measured variables during emergency department evaluation that were retrospectively analyzed included the ratio of the partial pressure of oxygen in arterial blood to the fraction of oxygen in inspired gas, Acute Physiology and Chronic Health Evaluation II score, risk stratification indices, and arterial blood gases. The association between arterial COHb and MetHb levels and disease severity or mortality was evaluated using bivariate tests and logistic regression analysis., Results: Arterial COHb and MetHb levels correlated with Acute Physiology and Chronic Health Evaluation II and pulmonary severity index scores. Furthermore, arterial COHb and MetHb levels were associated with troponin T and N-terminal pro-B-type natriuretic peptide levels. In univariate logistic regression analysis, COHb and MetHb levels were both significantly associated with an increased risk of death. However, in multivariate analysis, only COHb remained significant as an independent predictor of in-hospital mortality., Conclusion: Our preliminary data suggest that arterial COHb and MetHb levels reflect the severity of acute PE, whereas COHb levels are independent predictors of in hospital death in patients in this clinical setting. These findings require further prospective validation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Although poorly understood, interstitial lung disease has been reported as a possible complication of tumor necrosis factor alpha inhibitors. We report a case of interstitial lung disease in a 64-year-old man with psoriasis 3 weeks after the initiation of infliximab treatment. The patient had received two fortnightly infusions of infliximab following a short course of methotrexate. Thoracic computed tomography showed bilateral ground glass and interstitial infiltrates, while the results of microbiology and immunologic workup were negative. Likewise, bronchoalveolar lavage detected neither typical nor atypical pathogens. Infliximab-induced interstitial lung injury was suspected and corticosteroid therapy was administered which resulted in rapid clinical and radiological improvement. This is one of the few reported cases of interstitial lung disease due to infliximab in the psoriasis population. The patient had no pre-existing lung pathology, while his previous exposure to methotrexate was minimal and was not temporally associated with the induction of interstitial lung disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This case report concerns the diagnosis of two independent chronic diseases in a patient hospitalized for stroke, myasthenia gravis (MG) and giant cell arteritis (GCA). MG has been found to be associated with several diseases, but there are very few cases documenting its coexistence with GCA. We report the case of a 79-year-old woman initially hospitalized for stroke. Patient's concurrent symptoms of blepharoptosis, dysphagia, and proximal muscle weakness were strongly suggestive of myasthenia gravis. The persistent low-grade fever and elevated inflammatory markers in combination with the visual deterioration that developed also raised the suspicion of GCA. Histological examination confirmed GCA, while muscle acetylcholine receptor antibodies were also present. Even though in medicine one strives to interpret a patient's symptoms with one diagnosis, when one entity cannot fully interpret the clinical and laboratory findings, clinicians must consider the possibility of a second coexisting illness.

As a critical component of post-resuscitation care, prompt optimization of hemodynamic status by means of targeted interventions is vital in order to maximize the likelihood of good outcome. Vasoactive agents play an essential role in the supportive care of post cardiac arrest patients. The administration of these agents is associated with serious side-effects and therefore they should be used in the minimal dose necessary to achieve low-normal mean arterial pressure and adequate systematic perfusion. Careful and frequent serial evaluation of the patient is important primarily to assess volume status and adequacy of circulatory support. Continuous monitoring of blood pressure and laboratory parameters is essential both to accurately titrate therapy and because inotropes and vasopressors have the potential to induce life-threatening side-effects. The clinical efficacy of inotropes and vasopressors has been largely investigated through examination of their impact on hemodynamic end points, and clinical practice has been driven in part by expert opinion, extrapolation from animal studies, and physician preference. Clearly these agents should all be considered as supportive measures to stabilize the patient prior to some form of definitive therapy., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Sudden cardiac arrest is a leading cause of death worldwide with survival rates still remaining suboptimal. Unfortunately, most cardiac arrest patients, who achieve return of spontaneous circulation (ROSC), develop a multi-faceted post-cardiac arrest syndrome, including post-cardiac arrest brain injury, myocardial dysfunction, and systemic ischemia/reperfusion response. Erythropoietin (EPO), the principal hematopoietic hormone regulating erythropoiesis, exhibits diverse cellular effects in nonhematopoietic tissues. Due to its anti-apoptotic, anti-inflammatory, and anti-oxidant properties, as well as its angiogenic action, EPO plays a role in neuroprotection and cardioprotection. In this regard, EPO represents a promising agent in the cardiac arrest setting, based on a therapeutic strategy that focuses on the post-resuscitation phase. This review aims to provide a comprehensive account of EPO's role in the treatment of each individual component of post-cardiac arrest syndrome.

Current pharmacotherapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is not optimal, and the biological and physiological complexity of these severe lung injury syndromes requires consideration of combined-agent treatments or agents with pleiotropic action. In this regard, exogenous erythropoietin (EPO) represents a possible candidate since a number of preclinical studies have revealed beneficial effects of EPO administration in various experimental models of ALI. Taken together, this treatment strategy is not a single mediator approach, but it rather provides protection by modulating multiple levels of early signaling pathways involved in apoptosis, inflammation, and peroxidation, potentially restoring overall homeostasis. Furthermore, EPO appears to confer vascular protection by promoting angiogenesis. However, only preliminary studies exist and more experimental and clinical studies are necessary to clarify the efficacy and potentially cytoprotective mechanisms of EPO action. In addition to the attempts to optimize the dose and timing of EPO administration, it would be of great value to minimize any potential toxicity, which is essential for EPO to fulfill its role as a potential candidate for the treatment of ALI in routine clinical practice. The present article reviews recent advances that have elucidated biological and biochemical activities of EPO that may be potentially applicable for ALI/ARDS management.

We report the discovery and characterization of a novel ribosome inhibitor (NRI) class that exhibits selective and broad-spectrum antibacterial activity. Compounds in this class inhibit growth of many gram-positive and gram-negative bacteria, including the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis, and are nontoxic to human cell lines. The first NRI was discovered in a high-throughput screen designed to identify inhibitors of cell-free translation in extracts from S. pneumoniae. The chemical structure of the NRI class is related to antibacterial quinolones, but, interestingly, the differences in structure are sufficient to completely alter the biochemical and intracellular mechanisms of action. Expression array studies and analysis of NRI-resistant mutants confirm this difference in intracellular mechanism and provide evidence that the NRIs inhibit bacterial protein synthesis by inhibiting ribosomes. Furthermore, compounds in the NRI series appear to inhibit bacterial ribosomes by a new mechanism, because NRI-resistant strains are not cross-resistant to other ribosome inhibitors, such as macrolides, chloramphenicol, tetracycline, aminoglycosides, or oxazolidinones. The NRIs are a promising new antibacterial class with activity against all major drug-resistant respiratory pathogens.

The methylmalonyl coenzyme A (methylmalonyl-CoA)-specific acyltransferase (AT) domains of modules 1 and 2 of the 6-deoxyerythronolide B synthase (DEBS1) of Saccharopolyspora erythraea ER720 were replaced with three heterologous AT domains that are believed, based on sequence comparisons, to be specific for malonyl-CoA. The three substituted AT domains were "Hyg" AT2 from module 2 of a type I polyketide synthase (PKS)-like gene cluster isolated from the rapamycin producer Streptomyces hygroscopicus ATCC 29253, "Ven" AT isolated from a PKS-like gene cluster of the pikromycin producer Streptomyces venezuelae ATCC 15439, and RAPS AT14 from module 14 of the rapamycin PKS gene cluster of S. hygroscopicus ATCC 29253. These changes led to the production of novel erythromycin derivatives by the engineered strains of S. erythraea ER720. Specifically, 12-desmethyl-12-deoxyerythromycin A, which lacks the methyl group at C-12 of the macrolactone ring, was produced by the strains in which the resident AT1 domain was replaced, and 10-desmethylerythromycin A and 10-desmethyl-12-deoxyerythromycin A, both of which lack the methyl group at C-10 of the macrolactone ring, were produced by the recombinant strains in which the resident AT2 domain was replaced. All of the novel erythromycin derivatives exhibited antibiotic activity against Staphylococcus aureus. The production of the erythromycin derivatives through AT replacements confirms the computer predicted substrate specificities of "Hyg" AT2 and "Ven" AT and the substrate specificity of RAPS AT14 deduced from the structure of rapamycin. Moreover, these experiments demonstrate that at least some AT domains of the complete 6-deoxyerythronolide B synthase of S. erythraea can be replaced by functionally related domains from different organisms to make novel, bioactive compounds.