Assessment of pathogenic protozoa in a drinking water treatment plant with UV treatment.

Controlling drinking water treatment processes is essential to address water contamination and the adaptability of certain pathogenic protozoa. Sometimes, standard treatment methods and chlorine disinfection may prove insufficient in eliminating pathogenic protozoa. However, ultraviolet (UV) radiation has proved to be more effective than chlorine. This study aims to characterize the eukaryotic community of a drinking water treatment plant that applies a final UV disinfection treatment, focusing on pathogenic protozoa. Fifty water samples (raw water, before and after UV treatment) were evaluated to comply with regulation parameters and identify relevant protozoa. Despite physicochemical and microbiological parameters meeting the regulation, some potentially pathogenic protozoa, such as Blastocystis or Cryptosporidium, were still detected in very low relative abundances in treated water. It was found for the first time in Spain the pathogenic amoebae Naegleria fowleri in one river water, which was not found after the treatment. Moreover, Blastocystis subtypes ST1-ST6 were detected in this study in raw, before and after UV water samples. Blastocystis was only found in 2 two samples after UV treatment, with a very low abundance (≤0.02%). Obtained results demonstrate the effectiveness of water treatment in reducing the prevalence of pathogenic protozoa.

First report of in vitro resistance of Psoroptes ovis to ivermectin in Argentina.

Sheep scab, or psoroptic mange, a disease caused by the mite Psoroptes ovis, is commonly treated with ivermectin (IVM) and other macrocyclic lactones. In Argentina, in vivo trials have shown a decrease in IVM effectiveness to treat both sheep and bovine scab. In this work, we used an in vitro technique to establish the efficacy of IVM and two other macrocyclic lactones, doramectin (DRM) and moxidectin (MXD), against P. ovis in sheep. Mites were exposed to plates with culture medium and either ethanol or each of the acaricides, and mite mortality at a diagnostic concentration of IVM was assessed. Total survival in one of the strains studied demonstrated the presence of resistance, associated with control failures previously described by the authors. These resistant mites also presented larger LC50 values for both DRM and MXD than expected. Since, in in vivo trials, we had also previously observed a decrease in DRM effectiveness, cross-resistance may exist between DRM and IVM. We propose the use of in vitro tests to evaluate the efficacy of acaricides, considering their practicality, low cost and proven usefulness in detecting resistance in cases of low effectiveness against sheep scab.

Doramectin efficacy against Psoroptes ovis in sheep: Evaluation of pharmacological strategies.

The aims of this study were to evaluate the efficacy of two injectable formulations of doramectin (DRM) against Psoroptes ovis in sheep infested under controlled experimental conditions and to characterize the DRM plasma disposition kinetics in the infested animals. To this end, sheep were experimentally infested with a P. ovis strain from a farm with a history of treatment failure, and then treated either with DRM 1% (traditional preparation) on days 0 and 7 or with DRM 3.15% (long-acting formulation) on day 0. The efficacy of each treatment was calculated by counting live mites in skin scrapings. Plasma samples were obtained from each animal and DRM concentrations were measured by HPLC. After the two doses of DRM 1%, the maximum efficacy (98.8%) was reached on day 28, whereas after the single dose of DRM 3.15%, the maximum efficacy (100%) was reached on day 35 and ratified on day 42. The long-acting formulation allowed obtaining higher exposure and more sustained concentrations of DRM than the traditional preparation. Although both DRM formulations studied were effective according to international protocols, they did not reach 100% effectiveness in the time required for approved pharmaceutical products against sheep scab, according to Argentine regulations.

Noninvasive hemoglobin monitoring in critically ill pediatric patients at risk of bleeding. / Monitorización no invasiva transcutánea de la concentración de hemoglobina en pacientes críticos pediátricos con riesgo de sangrado.

OBJECTIVE: To determine the accuracy and usefulness of noninvasive continuous hemoglobin (Hb) monitoring in critically ill patients at risk of bleeding. DESIGN: An observational prospective study was made, comparing core laboratory Hb measurement (LabHb) as the gold standard versus transcutaneous hemoglobin monitoring (SpHb). SETTING: Pediatric Intensive Care Unit of a tertiary University Hospital. PATIENTS: Patients weighing >3kg at risk of bleeding. INTERVENTIONS: SpHb was measured using the Radical7 pulse co-oximeter (Masimo Corp., Irvine, CA, USA) each time a blood sample was drawn for core laboratory analysis (Siemens ADVIA 2120i). VARIABLES: Sociodemographic characteristics, perfusion index (PI), pleth variability index, heart rate, SaO2, rectal temperature, low signal quality and other events that can interfere with measurement. RESULTS: A total of 284 measurements were made (80 patients). Mean LabHb was 11.7±2.05g/dl. Mean SpHb was 12.32±2g/dl (Pearson 0.72, R2 0.52). The intra-class correlation coefficient was 0.69 (95%CI 0.55-0.78)(p<0.001). Bland-Altman analysis showed a mean difference of 0.07 ±1.46g/dl. A lower PI and higher temperature independently increased the risk of low signal quality (OR 0.531 [95%CI 0.32-0.88] and 0.529 [95%CI 0.33-0.85], respectively). CONCLUSIONS: SpHb shows a good overall correlation to LabHb, though with wide limits of agreement. Its main advantage is continuous monitoring of patients at risk of bleeding. The reliability of the method is limited in cases with poor peripheral perfusion.

Large number of imported chikungunya cases in mainland France, 2014: a challenge for surveillance and response.

During the summer of 2014, all the pre-requisites for autochthonous transmission of chikungunya virus are present in southern France: a competent vector, Aedes albopictus, and a large number of travellers returning from the French Caribbean islands where an outbreak is occurring. We describe the system implemented for the surveillance of chikungunya and dengue in mainland France. From 2 May to 4 July 2014, there were 126 laboratory-confirmed imported chikungunya cases in mainland France.

Effects of androgen deprivation therapy on elderly men with high-risk prostate cancer: PROSARC observational study.

INTRODUCTION: Prostatic carcinoma (PC) is a frequent neoplasm in elderly patients. Although androgen deprivation is associated with survival benefits, it is also related to adverse effects such as osteoporosis, frailty, or sarcopenia, which can negatively affect the patient's quality of life. This study aims to quantify and evaluate the prevalence of osteoporosis, frailty, or sarcopenia in elderly PC patients before and after androgen deprivation. We present data from an interim analysis. MATERIALS AND METHODS: PROSARC is a national (Spain) prospective observational study (May-2022-May-2025) still in progress in 2 hospitals. It includes patients with high-risk PC, aged ≥70 years, non-candidates for local treatment and scheduled to start androgen deprivation therapy. The following variables are analyzed: comorbidity, frailty (Fried frailty phenotype criteria), osteoporosis, sarcopenia (EWGSOP2), fat mass and muscle mass, before treatment and after 6 months of follow-up. RESULTS: A 6-month follow-up was completed by 12/25 included patients (mean age, 84 years), with a high baseline prevalence of pre-frailty/frailty (67.7%), sarcopenia (66.7%) and osteoporosis (25%). Treatment did not significantly alter these variables or comorbidity. We observed changes in body mass index (p=0.666), decreased mean value of appendicular muscle mass (p=0.01) and increased percentage of fat mass (p=0.012). CONCLUSION: In patients with high-risk PC, advanced age and a considerable prevalence of osteoporosis, frailty and sarcopenia, androgen deprivation (ADT; 6 months) produces decreased muscle mass without impact on the incidence of the known adverse effects of androgen deprivation.

[Influence of the COVID-19 pandemia on the ophthalmologic emergency department in the Toulouse University Hospital during the first lockdown from March the 17th to May the 10th of 2020]. / Impact de la pandémie de COVID-19 sur les urgences ophtalmologiques du CHU de Toulouse lors du premier confinement du 17 mars au 10 mai 2020.

INTRODUCTION: We conducted this study to assess the impact of the COVID-19 pandemic and the lockdown in France from March 17, 2020 to May 10, 2020, on the ophthalmic emergency department at Toulouse University Hospital, compared to the period from March 2 to March 16, 2020. MATERIALS AND METHODS: This was a retrospective observational study, conducted in the ophthalmic emergency department of Toulouse University Hospital. We included the patients presenting to the emergency department from March 2 to May 10, 2020. We recorded age, sex, day of visit, time until care was received, past ocular history, outpatient or inpatient status, final diagnosis and its severity, outpatient or inpatient disposition, and medical or surgical treatment after the emergency department visit. RESULTS: We found a substantial decrease in the number of patients per day, mostly during the first month of the lockdown: 44 patients per day before the lockdown compared to 23 patients per day during the first month, followed by 38 patients per day for the second month of lockdown; more patients visiting promptly; and elderly patients represented a higher proportion of patients. CONCLUSION: The first lockdown in France due to the COVID-19 pandemic had an impact on the Toulouse ophthalmic emergency department, especially concerning the number of patients per day; this study helps to assess individual behavior in this context of a public health crisis.

Development and implementation of an immunotherapy unit in a urology department.

INTRODUCTION: Immunotherapy is revolutionizing cancer treatment, with monoclonal antibodies directed against checkpoint regulatory molecules currently being the most widely used therapy. A total of six immune checkpoint inhibitor (CPI) drugs have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in various solid tumors of the genitourinary tract. MATERIAL AND METHODS: The literature is reviewed and the methodology, as well as our own experience, are analyzed to establish treatment with CPIs in a urology department. RESULTS: The requirements recommended in terms of training, logistics and procedure are described in order to safely offer expert treatment with CPIs to patients with genitourinary tumors. CONCLUSIONS: Compliance with the proposed program ensures safe administration of immune checkpoint inhibitors in a hospital setting.

[Transurethral resection (TUR) in saline plasma vaporization of the prostate versus standard TUR of the prostate: an economic evaluation]. / Étude comparant les coûts hospitaliers de la résection monopolaire et de la vaporisation bipolaire de la prostate.

OBJECTIVE: To evaluate and compare the hospital costs of the transurethral resection in saline plasma vaporization of the prostate (TURis-PVP) and the standard TUR of the prostate (TURP). BACKGROUND: their efficiency and short terms outcomes are similar. PATIENTS AND METHODS: In an observational retrospective and monocentric study, 86 consecutive patients with benign prostatic enlargement (BPE) secondary to benign prostatic hyperplasia (BPH) were enrolled in two non randomized groups. TURP was performed in 44 cases and TURis-PVP in 42 cases. Patients with prostate cancer, urethral stenosis or bladder neck stenosis were not included. Hospital costs with a 3-month follow-up were measured using the database and hospital cost accounting system of the Medical Information Department. RESULTS: Patients from both series had similar preoperative characteristics concerning the age, ASA score, urologic history, and antithrombosis treatments. Catheterization period, complications and rehospitalisation rates were similar. With TURis-PVP, prostatic volume was larger (60±24mL vs. 42±16mL; P<0.05), hospital stay was shorter (4.0±2.8days vs. 4.4±2.1days; P<0.05), single-used materials costs were higher (332±64€ vs. 40±18€; P<0.05). The costs of the first hospitalization were 3721±843€ with TURis-PVP and were 3712±880€ with TURP (P=0.14). Global costs with a 3-month follow-up were 3867±1104€ with TURis-PVP and were 4074±1624€ with TURP (P=0.53). CONCLUSION: In this study, the costs for the hospital are lightly higher in TURis-PVP, due to single use systems, but there is no significant difference for global costs between TURP and TURis-PVP with a 3-month follow-up difference for the health care system.

[Analysis of the evolution of surgery for the treatment of primary renal tumors during the period 2006-2010: report of 458 consecutive surgeries]. / Analyse de l'évolution des pratiques chirurgicales pour la prise en charge des tumeurs primitives du rein dans la période 2006-2010: à propos d'une série de 458 chirurgies consécutives.

OBJECTIVE: Most of small renal masses are accessible to conservative surgery, which has proved to maintain carcinological outcome, with a lower cardiovascular morbidity, hospital stay and mortality. Current international guidelines for the management of renal tumours recommend that partial nephrectomy be the new standard of treatment of T1 tumours. In this study, the authors assessed evolutive trends in the surgical management of renal tumours in the period 2006 to 2010 in a university hospital. PATIENTS AND METHODS: Retrospective analysis of a cohort of 446 consecutive patients treated for renal tumour between 2006 and 2010. RESULTS: Overall, 458 surgeries were performed, divided in 184 (40.2%) partial nephrectomy and 274 (49.8%) radical nephrectomy. During the study period, the number of partial nephrectomy increased significantly, with a mean annual increase rate of 10% in T1a tumours (P=0.002). We also observed a non significant increasing trend for conservative surgery in T1b tumours. Furthermore, the number of laparoscopic partial nephrectomy increased significantly, with a mean annual increase rate of 8% (P=0.02). At the end of the study period, one in two patients, whatever the stage, was treated by partial nephrectomy. This change in practice occurred without any increase in per- and postoperative morbidity (P=0.39). CONCLUSION: Analysis of this cohort of patients operated for renal tumour between 2006 and 2010 in our university hospital did not highlight underuse of conservative surgery, taking into account the current international guidelines. This trend for more partial nephrectomy did not underscore an increase in surgical morbidity or decrease in carcinological outcome. However, the higher rate of positive surgical margins in the laparoscopic partial nephrectomy group should incite to caution.

Specificity and sensibility of the Spanish version of the COMFORT Behaviour Scale for assessing pain, grade of sedation and withdrawal syndrome in the critically ill paediatric patient. Multicentre COSAIP study (Phase 1).

AIM: The main aim of this investigation was to analyse the specificity and sensibility of the COMFORT Behaviour Scale (CBS-S) in assessing grade of pain, sedation, and withdrawal syndrome in paediatric critical care patients. METHOD: An observational, analytical, cross-sectional and multicentre study conducted in Level III Intensive Care Areas of 5 children's university hospitals. Grade of sedation was assessed using the Spanish version of the CBS-S and the Bispectral Index on sedation, once per shift over one day. Grade of withdrawal was determined using the CBS-S and the Withdrawal Assessment Tool-1, once per shift over three days. RESULTS: A total of 261 critically ill paediatric patients with a median age of 5.07 years (P25:0.9-P75:11.7) were included in this study. In terms of the predictive capacity of the CBS-S, it obtained a Receiver Operation Curve of .84 (sensitivity of 81% and specificity of 76%) in relation to pain; .62 (sensitivity of 21% and specificity of 78%) in relation to sedation grade, and .73% (sensitivity of 40% and specificity of 74%) in determining withdrawal syndrome. CONCLUSIONS: The Spanish version of the COMFORT Behaviour Scale could be a useful, sensible and easy scale to assess the degree of pain, sedation and pharmacological withdrawal of critically ill paediatric patients.

Grade of sedation in the critically ill pediatric patient and its correlation with sociodemographic and clinical variables. Multicentre COSAIP study.

AIMS: To determine the grade of sedation in the critically ill paediatric patient using Biespectral Index Sensor (BIS) and to analyse its relationship with sociodemographic and clinical patient variables. METHODS: Observational, analytical, cross-sectional and multicentre study performed from May 2018 to January 2020 in 5 Spanish paediatric critical care units. Sex, age, reason for admission, presence of a chronic pathology, type and number of drugs and length of stay were the sociodemographic and clinical variables registered. Furthermore, the grade of sedation was assessed using BIS, once per shift over 24 h. RESULTS: A total of 261 paediatric patients, 53.64% of whom were male, with a median age of 1.61 years (0.35-6.55), were included in the study. Of the patients, 70.11% (n = 183) were under analgosedation and monitored using the BIS sensor. A median of BIS values of 51.24 ±â€¯14.96 during the morning and 50.75 ±â€¯15.55 during the night were observed. When comparing BIS values and sociodemographic and clinical paediatric variables no statistical significance was detected. CONCLUSIONS: Despite the limitations of the BIS, investigations and the present study show that BIS could be a useful instrument to assess grade of sedation in critically ill paediatric patients. However, further investigations which determine the sociodemographic and clinical variables involved in the grade of paediatric analgosedation, as well as studies that contrast the efficacy of clinical scales like the COMFORT Behaviour Scale-Spanish version, are required.

Specificity and sensibility of the Spanish version of the COMFORT Behaviour Scale for assessing pain, grade of sedation and withdrawal syndrome in the critically ill paediatric patient. Multicentre COSAIP study (Phase 1). / Especificidad y sensibilidad de la COMFORT Behavior Scale-Versión española para valorar el dolor, el grado de sedación y síndrome de abstinencia en el paciente crítico pediátrico. Estudio multicéntrico COSAIP (Fase 1).

AIM: The main aim of this investigation was to analyse the specificity and sensibility of the COMFORT Behaviour Scale (CBS-S) in assessing grade of pain, sedation, and withdrawal syndrome in paediatric critical care patients. METHOD: An observational, analytical, cross-sectional and multicentre study conducted in Level III Intensive Care Areas of 5 children's university hospitals. Grade of sedation was assessed using the Spanish version of the CBS-S and the Bispectral Index on sedation, once per shift over one day. Grade of withdrawal was determined using the CBS-S and the Withdrawal Assessment Tool-1, once per shift over three days. RESULTS: A total of 261 critically ill paediatric patients with a median age of 5.07 years (P25:0.9-P75:11.7) were included in this study. In terms of the predictive capacity of the CBS-S, it obtained a Receiver Operation Curve of .84 (sensitivity of 81% and specificity of 76%) in relation to pain; .62 (sensitivity of 21% and specificity of 78%) in relation to sedation grade, and .73% (sensitivity of 40% and specificity of 74%) in determining withdrawal syndrome. CONCLUSIONS: The Spanish version of the COMFORT Behaviour Scale could be a useful, sensible and easy scale to assess the degree of pain, sedation and pharmacological withdrawal of critically ill paediatric patients.

Grade of sedation in the critically ill paediatric patient and its correlation with sociodemographic and clinical variables. Multicentre COSAIP study. / Grado de sedación del paciente crítico pediátrico y variables sociodemográficas y clínicas correlacionadas. Estudio multicéntrico COSAIP.

AIMS: To determine the grade of sedation in the critically ill paediatric patient using Biespectral Index Sensor (BIS) and to analyse its relationship with sociodemographic and clinical patient variables. METHODS: Observational, analytical, cross-sectional and multicentre study performed from May 2018 to January 2020 in 5 Spanish paediatric critical care units. Sex, age, reason for admission, presence of a chronic pathology, type and number of drugs and length of stay were the sociodemographic and clinical variables registered. Furthermore, the grade of sedation was assessed using BIS, 11per shift over 24hours. RESULTS: A total of 261 paediatric patients, 53.64% of whom were male, with a median age of 1.61 years (0.35-6.55), were included in the study. Of the patients, 70.11% (n=183) were under analgosedation and monitored using the BIS sensor. A median of BIS values of 51.24±14.96 during the morning and 50.75±15.55 during the night were observed. When comparing BIS values and sociodemographic and clinical paediatric variables no statistical significance was detected. CONCLUSIONS: Despite the limitations of the BIS, investigations and the present study show that BIS could be a useful instrument to assess grade of sedation in critically ill paediatric patients. However, further investigations which determine the sociodemographic and clinical variables involved in the grade of paediatric analgosedation, as well as studies that contrast the efficacy of clinical scales like the COMFORT Behaviour Scale-Spanish version, are required.

Alveolar fibroblasts in acute lung injury: biological behaviour and clinical relevance.

Although fibroblasts are key cells in the lung repair/fibrosis process, their characteristics are poorly studied in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The aims of our study were to: 1) determine the biological behaviour of alveolar fibroblasts during ALI; and 2) to evaluate the clinical relevance of positive alveolar fibroblast culture from patients with ALI/ARDS. Cells were cultured from bronchoalveolar lavage (BAL) obtained from 68 critically ill, ventilated patients: ALI n = 17; ARDS n = 31; and ventilated controls n = 20. Patients were followed for 28 days and clinical data was recorded. We studied proliferation, migration and collagen-1 synthesis capacities of fibroblasts. Cells expressing fibroblast markers were cultured from BAL obtained in six (35%) ALI patients and six (19%) ARDS patients, but never from ventilated controls. Alveolar fibroblasts exhibited a persistent activated phenotype with enhanced migratory and collagen-1 production capacities, with hyporesponsiveness to prostaglandin E(2) compared to normal lung fibroblasts (p< or =0.04). Positive fibroblast culture was associated with both an increased collagen-1 concentration and monocyte/macrophage percentage in BAL fluid (p< or =0.01), and with a reduced duration of mechanical ventilation (p<0.001). We conclude that activated alveolar fibroblasts can be cultured either in ALI or ARDS and that their presence might reflect the initiation of the organising phase of ALI.

Nationwide outbreak of Salmonella serotype Kedougou associated with infant formula, Spain, 2008.

On 5 August 2008, the National Centre of Microbiology in Madrid, Spain, notified an increase in Salmonella Kedougou isolations compared to 2007, with 21 cases including 19 children under one year of age. Active case finding and a matched case-control study were carried out to confirm this increase, identify source, transmission mode and risk factors in order to implement control measures. Cases were defined as any child under one year of age with S. Kedougou isolated since 1 January 2008, and were matched for age, sex, medical practitioner and diagnosis week with controls who were selected among patients of the cases' medical practitioners. An ad hoc questionnaire was completed for cases and controls and a univariate analysis was conducted to identify risk factors. We found 42 isolates from 11 of the 19 Spanish Regions. Completed questionnaires were available for 39 of 42 patients identified; 31 were children under one year of age and fulfilled the case definition. The median age of the 31 cases was 4.3 months and 13 were male. Main symptoms were diarrhoea (n=31) and fever (n=13). Ten cases required hospitalisation. All 31 cases had consumed infant formula milk of Brand A which was associated with illness in the univariate analysis (exact matched odds ratio: 74.92; 95% confidence interval: 12.89-infinity). All patient isolates showed indistinguishable pulsed-field gel electrophoresis and antimicrobial susceptibility patterns. Five milk samples from three cases' households were negative for Salmonella. Our results suggest that Brand A was the transmission vehicle of S. Kedougou in the outbreak that occurred in Spain between January and August 2008. Food safety authorities recalled five batches of Brand A milk on 26 August 2008. No further cases have been detected as of 15 September 2009.

Activation of somatostatin receptors attenuates pulmonary fibrosis.

BACKGROUND AND AIM: Somatostatin analogues may have antifibrotic properties in the lung. The aim of this study was to evaluate the expression of the five somatostatin receptors sst1 to sst5 in normal and fibrotic mouse lung and the action of SOM230 (pasireotide), a new somatostatin analogue with a long half-life, in bleomycin induced lung fibrosis and in human lung fibroblasts in vitro. METHODS: After intratracheal injection of bleomycin, C57Bl6 male mice received one daily subcutaneous injection of SOM230 or saline. The lungs were evaluated on days 3, 7 and 14 after administration of bleomycin. RESULTS: We found that all somatostatin receptors were expressed in the normal mouse lung. The sst2 receptor mRNA expression was increased after bleomycin. SOM230 improved mice survival (69% vs 44%; p = 0.024), reduced lung collagen content at day 14 and decreased lung collagen-1 mRNA at day 7. SOM230 reduced bronchoalveolar lavage inflammatory cell influx at day 3, decreased lung connective tissue growth factor mRNA and transforming growth factor (TGF) beta mRNA and increased lung hepatocyte growth factor and keratinocyte growth factor mRNA. The sst2 receptor was strongly expressed in the human lung (normal or fibrotic), particularly by fibroblasts. In vitro, SOM230 reduced BrdU incorporation by control human lung fibroblasts cultured under basal conditions or with TGFbeta, and reduced alpha-1 collagen-1 mRNA expression in TGFbeta stimulated fibroblasts. CONCLUSION: We conclude that SOM230 attenuates bleomycin induced pulmonary fibrosis in mice and human lung fibroblasts activation. This study points to a potential new approach for treating pulmonary fibrotic disorders.

Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema.

BACKGROUND: Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, plays a role in the pathophysiology of smoking-related pulmonary emphysema. Expression of several antioxidant proteins, such as heme oxygenase-1 (HO-1), glutathione peroxidase 2 (GPX2) and NAD(P)H:quinone oxidoreductase 1 (NQO1), results from an equilibrium created by positive or negative regulation by the transcription factors Nrf2, Keap1 and Bach1, respectively. However, whether the expression of these transcription factors is altered in emphysema and could account for decreased expression of antioxidant proteins is not known. A study was undertaken to investigate the expression and subcellular localisation of Nrf2, Keap1 and Bach1 as potential regulators of HO-1, GPX2 and NQO1 in alveolar macrophages, a key cell in oxidative stress, in lung surgical specimens from non-smokers without emphysema and smokers with and without emphysema. METHODS AND RESULTS: Western blot, immunohistochemical and laser scanning confocal analysis revealed that the Nrf2 protein level decreased significantly in whole lung tissue and alveolar macrophages (cytosol and nucleus) in patients with emphysema compared with those without emphysema. Conversely, Bach1 and Keap1 levels were increased in patients with emphysema. These modifications were associated with a parallel decrease in the expression of HO-1, GPX2 and NQO1 at the cellular level, which was inversely correlated with airway obstruction and distension indexes, and increased macrophage expression of the lipid peroxidation product 4-hydroxy-2-nonenal. Silencing RNA experiments in vitro in THP-1 cells were performed to confirm the cause-effect relation between the loss of Nrf2 and the decrease in HO-1, NQO1 and GPX2 expression. Nrf2/Keap1-Bach1 equilibrium was altered in alveolar macrophages in pulmonary emphysema, which points to a decreased stress response phenotype. CONCLUSIONS: This finding opens a new view of the pathophysiology of emphysema and could provide the basis for new therapeutic approaches based on preservation and/or restoration of such equilibrium.

Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice.

Serotonin (5-hydroxytryptamine; 5-HT) is known to increase proliferation and collagen synthesis by fibroblasts. Two receptor subtypes, 5-HT2A and 5-HT2B, have been shown to play the most important roles in the lung. In the present study, the role of serotonin in lung fibrosis was investigated using the bleomycin mouse model. Serotonin concentrations in lung homogenates increased significantly over the time course of bleomycin-induced fibrosis, with a maximum at day seven. The expression of serotonin receptors 5-HT2A and 5-HT2B increased in the lung after bleomycin treatment, as assessed by PCR, specific binding and immunohistochemistry. Blockage of 5-HT2A receptors by ketanserin and 5-HT2B receptors by SB215505 reduced bleomycin-induced lung fibrosis, as demonstrated by reduced lung collagen content and reduced procollagen 1 and procollagen 3 mRNA expression. Serotonin antagonists promoted an antifibrotic environment by decreasing the lung mRNA levels of transforming growth factor-beta1, connective growth factor and plasminogen activator inhibitor-1 mRNA, but had minimal effects on lung inflammation as assessed by bronchoalveolar lavage cytology analysis. Interestingly, the 5-HT2B receptor was strongly expressed by fibroblasts in the fibroblastic foci in human idiopathic pulmonary fibrosis samples. In conclusion, the present study showed involvement of serotonin in the pathophysiology of bleomycin-induced lung fibrosis in mice and identified it as a potential therapeutic target in lung fibrotic disorders.