International consensus guideline for reporting transmission electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria).

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic condition. European and North American diagnostic guidelines recommend transmission electron microscopy (TEM) as one of a combination of tests to confirm a diagnosis. However, there is no definition of what constitutes a defect or consensus on reporting terminology. The aim of this project was to provide an internationally agreed ultrastructural classification for PCD diagnosis by TEM.A consensus guideline was developed by PCD electron microscopy experts representing 18 centres in 14 countries. An initial meeting and discussion were followed by a Delphi consensus process. The agreed guideline was then tested, modified and retested through exchange of samples and electron micrographs between the 18 diagnostic centres.The final guideline a) provides agreed terminology and a definition of Class 1 defects which are diagnostic for PCD; b) identifies Class 2 defects which can indicate a diagnosis of PCD in combination with other supporting evidence; c) describes features which should be included in a ciliary ultrastructure report to assist multidisciplinary diagnosis of PCD; and d) defines adequacy of a diagnostic sample.This tested and externally validated statement provides a clear guideline for the diagnosis of PCD by TEM which can be used to standardise diagnosis internationally.

Cell Spillage after Contained Electromechanical Morcellation Using a Specially Designed In-Bag System for Laparoscopic Myomectomy: Prospective Cohort Pilot Study.

STUDY OBJECTIVE: Few reports have investigated the use of endoscopic retrieval bags in the context of laparoscopic myomectomy with electromechanical morcellation. We performed a leak test of a specially designed endoscopic bag system in women undergoing laparoscopic myomectomy with contained electromechanical morcellation. DESIGN CLASSIFICATION: Prospective study. SETTING: University hospital. PATIENTS: Thirty-one women undergoing laparoscopic myomectomy with contained electromechanical morcellation. INTERVENTIONS: Electromechanical morcellation was introduced for large specimen extraction during laparoscopic procedures. Complications such as retained/disseminated parasitic tissue were documented. MEASUREMENTS AND MAIN RESULTS: Systematic peritoneal washings were performed at 3 specific times: at baseline, T1, once the peritoneal cavity was accessed laparoscopically; T2, when the myometrial incision was closed after myomectomy; and T3, after contained electromechanical morcellation. After retrieval of the endoscopic bag from the abdominal cavity, visual inspection and water test on the bag with NaCl infiltration were performed to detect leaks attributed to intraoperative perforations. A pathologist performed cytologic analyses on the 3 washings. The mean endoscopic bag procedure duration was 9 minutes. The use of a specially designed endoscopic bag system was found to be easy in 45% of cases, and no complications were reported. Cytologic washings were positive for smooth muscle cell detection in 8 cases (25.8%) at T2 and 3 cases (9.7%) at T3. All positive cases at T3 already had detectable smooth muscle cells at T2. After retrieval from the abdominal cavity, perforations on the optic access of the endoscopic bag were observed in 3 cases. CONCLUSION: The results from this pilot study are encouraging. The use of a specially designed endoscopic bag system could be an adjuvant to reduce the risk of disseminating cells during myomectomy.

[Transbronchial cryobiopsies : a minimally invasive tool for the diagnosis of interstitial lung disease]. / Cryobiopsies transbronchiques : diagnostic minimalement invasif de la fibrose pulmonaire.

The diagnosis of interstitial lung disease (ILD) is challenging and relies on a multidisciplinary discussion involving clinical, radiological and sometimes histological features. Bronchoscopic lung cryobiopsies have emerged as a new minimally invasive method of lung sampling and an alternative to surgical lung biopsies. A good diagnostic performance and excellent safety profile make it an interesting and worthful procedure which could decrease the number of patients without proper diagnosis and treatment. There is a need for further studies to standardize the technique in expert centers and to establish its role in the diagnostic work-up of ILD.

Le diagnostic des pneumopathies interstitielles (PI) est complexe et repose sur l'analyse d'éléments cliniques, radiologiques et parfois histologiques dans le cadre d'une discussion multidisciplinaire. Pour l'obtention de biopsies pulmonaires, les cryobiopsies transbronchiques constituent une nouvelle méthode minimalement invasive, alternative aux biopsies chirurgicales. Leur très bonne performance diagnostique et leur profil de sécurité favorable expliquent l'intérêt grandissant pour cette technique qui pourrait permettre de diminuer le nombre de patients n'ayant pas de diagnostic définitif établi et de traitement adapté. Des études restent encore nécessaires, au sein de centres experts, afin de standardiser les modalités pratiques de cette technique et de déterminer sa place dans l'algorithme de prise en charge des PI.

Tumor Necrosis Factor and Its Receptors Are Crucial to Control Mycobacterium bovis Bacillus Calmette-Guerin Pleural Infection in a Murine Model.

Tumor necrosis factor (TNF) is crucial to control Mycobacterium tuberculosis infection, which remains a leading cause of morbidity and mortality worldwide. TNF blockade compromises host immunity and may cause reactivation of latent infection, resulting in overt pulmonary, pleural, and extrapulmonary tuberculosis. Herein, we investigate the roles of TNF and TNF receptors in the control of Mycobacterium bovis bacillus Calmette-Guerin (BCG) pleural infection in a murine model. As controls, wild-type mice and those with a defective CCR5, a receptor that is crucial for control of viral infection but not for tuberculosis, were used. BCG-induced pleural infection was uncontrolled and progressive in absence of TNF or TNF receptor 1 (TNFR1)/TNFR2 (TNFR1R2) with increased inflammatory cell recruitment and bacterial load in the pleural cavity, and heightened levels of pleural and serum proinflammatory cytokines and chemokines, compared to wild-type control mice. The visceral pleura was thickened with chronic inflammation, which was prominent in TNF(-/-) and TNFR1R2(-/-) mice. The parietal pleural of TNF(-/-) and TNFR1R2(-/-) mice exhibited abundant inflammatory nodules containing mycobacteria, and these mice developed nonresolving inflammation and succumbed from disseminated BCG infection. By contrast, CCR5(-/-) mice survived and controlled pleural BCG infection as wild-type control mice. In conclusion, BCG-induced pleurisy was uncontrolled in the absence of TNF or TNF receptors with exacerbated inflammatory response, impaired bacterial clearance, and defective mesothelium repair, suggesting a critical role of TNF to control mycobacterial pleurisy.

Evaluation of Infection Resistance of Biodegradable versus Conventional Annuloplasty Rings in an in vivo Rat Subcutaneous Model.

BACKGROUND: Biodegradable atrioventricular annuloplasty rings are theoretically more infection resistant due to their intra-annular implantation technique and nonporous structures (monofilament of poly-1,4-dioxanone). The aim of this study was to investigate the infection resistance of a biodegradable annuloplasty ring (Kalangos-Bioring®) in a rat subcutaneous implantation model and to compare it with a commonly used conventional annuloplasty ring (Edwards Physio II®). METHODS: This study included 32 Wistar albino rats which were divided into 2 groups according to the implantation of sterile or infected annuloplasty rings as control and study groups. Each animal had 2 implantation pockets (made on the right and left side of the dorsal median line) where 1 cm of the biodegradable annuloplasty ring was implanted into one pocket and 1 cm of the conventional annuloplasty ring was implanted into the other pocket. The infection model was created by topical inoculation of 1 mL Staphylococcus aureus strain (2 × 107 colony-forming units/mL) into the implantation pockets before skin closure. Each group was equally divided into 4 subgroups according to different follow-up schedules. The animals were inspected for local as well as systemic infection signs, and the rings were explanted at weeks 2, 4, 9, and 14 following implantation. Implantation pockets were evaluated macroscopically as well as by histopathological examinations. Microbiological analysis of the explanted implants with surrounding tissue was done by using quantitative sonication method. RESULTS: Conventional ring-implanted pockets showed a more prominent inflammation reaction than the biodegradable ring-implanted pockets, and this characteristic was found to be accentuated with bacterial contamination. The sterile rings did not reveal any positive cultures in either group. The number of positive cultures found in conventional rings contaminated with S. aureus was greater than in the biodegradable ring group (11/16 vs. 2/16 positive cultures, respectively; p = 0.0032). The amounts of growing bacteria in the culture environment were also statistically significantly higher in the conventional ring group (7,175 ± 5,936 vs. 181 ± 130 colony-forming units/mL, respectively; p < 0.0005). CONCLUSIONS: This is the first experimental study confirming the theoretical advantage of the infection resistance of the biodegradable annuloplasty ring (Kalangos-Bioring®) when implanted in an active infectious environment. Large animal models mimicking clinical scenarios and clinical comparative studies are needed to verify our results.

Bacillus calmette-guerin infection in NADPH oxidase deficiency: defective mycobacterial sequestration and granuloma formation.

Patients with chronic granulomatous disease (CGD) lack generation of reactive oxygen species (ROS) through the phagocyte NADPH oxidase NOX2. CGD is an immune deficiency that leads to frequent infections with certain pathogens; this is well documented for S. aureus and A. fumigatus, but less clear for mycobacteria. We therefore performed an extensive literature search which yielded 297 cases of CGD patients with mycobacterial infections; M. bovis BCG was most commonly described (74%). The relationship between NOX2 deficiency and BCG infection however has never been studied in a mouse model. We therefore investigated BCG infection in three different mouse models of CGD: Ncf1 mutants in two different genetic backgrounds and Cybb knock-out mice. In addition, we investigated a macrophage-specific rescue (transgenic expression of Ncf1 under the control of the CD68 promoter). Wild-type mice did not develop severe disease upon BCG injection. In contrast, all three types of CGD mice were highly susceptible to BCG, as witnessed by a severe weight loss, development of hemorrhagic pneumonia, and a high mortality (∼ 50%). Rescue of NOX2 activity in macrophages restored BCG resistance, similar as seen in wild-type mice. Granulomas from mycobacteria-infected wild-type mice generated ROS, while granulomas from CGD mice did not. Bacterial load in CGD mice was only moderately increased, suggesting that it was not crucial for the observed phenotype. CGD mice responded with massively enhanced cytokine release (TNF-α, IFN-γ, IL-17 and IL-12) early after BCG infection, which might account for severity of the disease. Finally, in wild-type mice, macrophages formed clusters and restricted mycobacteria to granulomas, while macrophages and mycobacteria were diffusely distributed in lung tissue from CGD mice. Our results demonstrate that lack of the NADPH oxidase leads to a markedly increased severity of BCG infection through mechanisms including increased cytokine production and impaired granuloma formation.

Macrophage-specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1/MMP-9 pathways.

Reactive oxygen species (ROS) participate in the pathogenesis of emphysema. Among ROS-producing enzymes, NOX NADPH oxidases are thought to be responsible for tissue injury associated with several lung pathologies. To determine whether NOX2 and/or NOX1 participate in the development of emphysema, their expression patterns were first studied by immunohistochemistry in the lungs of emphysematous patients. Subsequently, we investigated their contribution to elastase-induced emphysema using NOX2- and NOX1-deficient mice. In human lung, NOX2 was mainly detected in macrophages of control and emphysematous lungs, while NOX1 was expressed in alveolar epithelium and bronchial cells. We observed an elevated number of NOX2-positive cells in human emphysematous lungs, as well as increased NOX2 and NOX1 mRNA expression in mouse lungs following elastase exposure. Elastase-induced alveolar airspace enlargement and elastin degradation were prevented in NOX2-deficient mice, but not in NOX1-deficient mice. This protection was independent of inflammation and correlated with reduced ROS production. Concomitantly, an elevation of sirtuin 1 (SIRT1) level and a decrease of matrix metalloproteinase-9 (MMP-9) expression and activity were observed in alveolar macrophages and neutrophils. We addressed the specific role of macrophage-restricted functional NOX2 in elastase-induced lung emphysema using Ncf1 mutant mice and Ncf1 macrophage rescue mice (Ncf1 mutant mice with transgenic expression of Ncf1 only in CD68-positive mononuclear phagocytes; the MN mouse). Compared to WT mice, the lack of functional NOX2 led to decreased elastase-induced ROS production and protected against emphysema. In contrast, ROS production was restored specifically in macrophages from Ncf1 rescue mice and contributes to emphysema. Taken together, our results demonstrate that NOX2 is involved in the pathogenesis of human emphysema and macrophage-specific NOX2 participates in elastase-induced emphysema through the involvement of SIRT1/MMP-9 pathways in mice.

Human papillomavirus genotype distribution among Cameroonian women with invasive cervical cancer: a retrospective study.

OBJECTIVES: We determined the human papillomavirus (HPV) types present in invasive cervical cancer (ICC) of women in Cameroon in order to estimate the potential efficacies of HPV prophylactic vaccines. METHODS: This is a retrospective study using 181 formalin-fixed paraffin-embedded cervical tissue samples of ICC collected from the Institute of Pathology, Gyneco-Obstetric and Pediatric Hospital, Yaoundé, Cameroon. HPV was detected by PCR using modified GP5+/GP6+ (MGP) primers. Genotyping was performed by reverse-blot hybridisation, which allowed the detection of 9 of the 14 high-risk HPV types. RESULTS: Of the 181 samples, 91.7% were squamous cell carcinomas and 6.6% were adenocarcinomas. Counting all the single and multiple infections, the three most common high-risk types in descending order were HPV16 (88%), HPV45 (32%) and HPV18 (14.8%). 54.9% of cases were infected with a single HPV type and 45.1% had two or more HPV infections. CONCLUSIONS: The frequencies of HPV16, HPV45 and multiple infections are all higher than previously reported. These observations have significant implications on the consideration of vaccination strategies because each vaccine has different duration and efficacies in cross-protection of different HPV types. The method used proved to be sensitive and cost-efficient for retrospective studies where fresh materials are not available.

BARD1 mediates TGF-ß signaling in pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-ß signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1ß, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis. METHODS: We investigated BARD1 expression as a function of TGF-ß in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients. RESULTS: FL BARD1 and BARD1ß were upregulated in response to TGF-ß in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1ß in fibrotic tissues. CONCLUSION: Our data suggest that FL BARD1 and BARD1ß might be mediators of pleiotropic effects of TGF-ß. In particular BARD1ß might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment.

Prevention of hyperoxia-induced bronchial hyperreactivity by sildenafil and vasoactive intestinal peptide: impact of preserved lung function and structure.

OBJECTIVE: Hyperoxia exposure leads to the development of lung injury and bronchial hyperreactivity (BHR) via involvement of nitric oxide (NO) pathway. We aimed at characterizing whether the stimulation of the NO pathway by sildenafil or vasoactive intestinal peptide (VIP) is able to prevent the hyperoxia-induced development of BHR. The respective roles of the preserved lung volume and alveolar architecture, the anti-inflammatory and anti-apoptotic potentials of these treatments in the diminished lung responsiveness were also characterized. MATERIALS AND METHODS: Immature (28-day-old) rats were exposed for 72 hours to room air (Group C), hyperoxia (>95%, Group HC), or hyperoxia with the concomitant administration of vasoactive intestinal peptide (VIP, Group HV) or sildenafil (Group HS). Following exposure, the end-expiratory lung volume (EELV) was assessed plethysmographically. Airway and respiratory tissue mechanics were measured under baseline conditions and following incremental doses of methacholine to assess BHR. Inflammation was assessed by analyzing the bronchoalveolar lavage fluid (BALF), while biochemical and histological analyses were used to characterize the apoptotic and structural changes in the lungs. RESULTS: The BHR, the increased EELV, the aberrant alveolarization, and the infiltration of inflammatory cells into the BALF that developed in Group HC were all suppressed significantly by VIP or sildenafil treatment. The number of apoptotic cells increased significantly in Group HC, with no evidence of statistically significant effects on this adverse change in Groups HS and HV. CONCLUSIONS: These findings suggest that stimulating the NO pathway by sildenafil and VIP exert their beneficial effect against hyperoxia-induced BHR via preserving normal EELV, inhibiting airway inflammation and preserving the physiological lung structure, whereas the antiapoptotic potential of these treatments were not apparent in this process.

Randomized comparison of vaginal self-sampling by standard vs. dry swabs for human papillomavirus testing.

BACKGROUND: To evaluate if human papillomavirus (HPV) self-sampling (Self-HPV) using a dry vaginal swab is a valid alternative for HPV testing. METHODS: Women attending colposcopy clinic were recruited to collect two consecutive Self-HPV samples: a Self-HPV using a dry swab (S-DRY) and a Self-HPV using a standard wet transport medium (S-WET). These samples were analyzed for HPV using real time PCR (Roche Cobas). Participants were randomized to determine the order of the tests. Questionnaires assessing preferences and acceptability for both tests were conducted. Subsequently, women were invited for colposcopic examination; a physician collected a cervical sample (physician-sampling) with a broom-type device and placed it into a liquid-based cytology medium. Specimens were then processed for the production of cytology slides and a Hybrid Capture HPV DNA test (Qiagen) was performed from the residual liquid. Biopsies were performed if indicated. Unweighted kappa statistics (к) and McNemar tests were used to measure the agreement among the sampling methods. RESULTS: A total of 120 women were randomized. Overall HPV prevalence was 68.7% (95% Confidence Interval (CI) 59.3-77.2) by S-WET, 54.4% (95% CI 44.8-63.9) by S-DRY and 53.8% (95% CI 43.8-63.7) by HC. Among paired samples (S-WET and S-DRY), the overall agreement was good (85.7%; 95% CI 77.8-91.6) and the κ was substantial (0.70; 95% CI 0.57-0.70). The proportion of positive type-specific HPV agreement was also good (77.3%; 95% CI 68.2-84.9). No differences in sensitivity for cervical intraepithelial neoplasia grade one (CIN1) or worse between the two Self-HPV tests were observed. Women reported the two Self-HPV tests as highly acceptable. CONCLUSION: Self-HPV using dry swab transfer does not appear to compromise specimen integrity. Further study in a large screening population is needed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01316120.

NOX enzymes: potential target for the treatment of acute lung injury.

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), is characterized by acute inflammation, disruption of the alveolar-capillary barrier, and in the organizing stage by alveolar pneumocytes hyperplasia and extensive lung fibrosis. The cellular and molecular mechanisms leading to the development of ALI/ARDS are not completely understood, but there is evidence that reactive oxygen species (ROS) generated by inflammatory cells as well as epithelial and endothelial cells are responsible for inflammatory response, lung damage, and abnormal repair. Among all ROS-producing enzymes, the members of NADPH oxidases (NOXs), which are widely expressed in different lung cell types, have been shown to participate in cellular processes involved in the maintenance of lung integrity. It is not surprising that change in NOXs' expression and function is involved in the development of ALI/ARDS. In this context, the use of NOX inhibitors could be a possible therapeutic perspective in the management of this syndrome. In this article, we summarize the current knowledge concerning some cellular aspects of NOXs localization and function in the lungs, consider their contribution in the development of ALI/ARDS and discuss the place of NOX inhibitors as potential therapeutical target.

Coronavirus disease 2019-associated coronary endotheliitis and thrombotic microangiopathy causing cardiogenic shock: a case report.

Background: Coronavirus disease 2019 (COVID-19) primarily affects the respiratory tract but serious cardiovascular complications have been reported. Up to one-third of patients admitted to the intensive care unit may develop an acute myocardial injury, characterized by cardiac troponin elevation. However, the pathology underlying COVID-19-associated myocardial injury has rarely been reported. Case summary: Three days after being diagnosed for a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a 52-year-old woman without a notable past medical history developed cardiogenic shock with severely reduced left ventricular ejection fraction (LVEF) at 25%. Coronary angiography was normal. Endomyocardial biopsy demonstrated coronary endotheliitis with multiple microvascular thromboses but no lymphocytic infiltrate and a negative polymerase chain reaction for SARS-CoV-2. The patient was implanted with a short-term LV assist device (Impella CP®, Abiomed, Aachen, Germany) and treated with therapeutic anticoagulation. She suffered from concomitant respiratory failure that required 14 days of orotracheal intubation, 10 days of dexamethasone, and broad-spectrum antibiotics. Clinical outcome was favourable with weaning of the Impella device after 6 days and full recovery of LVEF (65%) at 30 days. Cardiac magnetic resonance performed at Day 30 showed no evidence of myocarditis or scars and confirmed the normalization of LVEF. Discussion: This case highlights how COVID-19-associated coronary endotheliitis and thrombotic microangiopathy, in the absence of myocarditis, may induce transient severe LV dysfunction and cardiogenic shock.

Di-Tyrosine Crosslinking and NOX4 Expression as Oxidative Pathological Markers in the Lungs of Patients with Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a noninflammatory progressive lung disease. Oxidative damage is a hallmark of IPF, but the sources and consequences of oxidant generation in the lungs are unclear. In this study, we addressed the link between the H2O2-generating enzyme NADPH oxidase 4 (NOX4) and di-tyrosine (DT), an oxidative post-translational modification in IPF lungs. We performed immunohistochemical staining for DT and NOX4 in pulmonary tissue from patients with IPF and controls using validated antibodies. In the healthy lung, DT showed little or no staining and NOX4 was mostly present in normal vascular endothelium. On the other hand, both markers were detected in several cell types in the IPF patients, including vascular smooth muscle cells and epithelium (bronchial cells and epithelial cells type II). The link between NOX4 and DT was addressed in human fibroblasts deficient for NOX4 activity (mutation in the CYBA gene). Induction of NOX4 by Transforming growth factor beta 1 (TGFß1) in fibroblasts led to moderate DT staining after the addition of a heme-containing peroxidase in control cells but not in the fibroblasts deficient for NOX4 activity. Our data indicate that DT is a histological marker of IPF and that NOX4 can generate a sufficient amount of H2O2 for DT formation in vitro.

Mechanisms for lung function impairment and airway hyperresponsiveness following chronic hypoxia in rats.

Although chronic normobaric hypoxia (CH) alters lung function, its potential to induce bronchial hyperreactivity (BHR) is still controversial. Thus the effects of CH on airway and tissue mechanics separately and changes in lung responsiveness to methacholine (MCh) were investigated. To clarify the mechanisms, mechanical changes were related to end-expiratory lung volume (EELV), in vivo results were compared with those in vitro, and lung histology was assessed. EELV was measured plethysmographically in two groups of rats exposed to 21 days of CH (11% O(2)) or to normoxia. Total respiratory impedance was measured under baseline conditions and following intravenous MCh challenges (2-18 microg x kg(-1) x min(-1)). The lungs were then excised and perfused, and the pulmonary input impedance was measured, while MCh provocations were repeated under a pulmonary capillary pressure of 5, 10, and 15 mmHg. Airway resistance, tissue damping, and elastance were extracted from the respiratory impedance and pulmonary input impedance spectra. The increases in EELV following CH were associated with decreases in airway resistance, whereas tissue damping and elastance remained unaffected. CH led to the development of severe BHR to MCh (206 +/- 30 vs. 95 +/- 24%, P < 0.001), which was not detectable when the same lungs were studied in vitro at any pulmonary capillary pressure levels maintained. Histology revealed pulmonary arterial vascular remodeling with overexpression of alpha-smooth muscle actin antibody in the bronchial wall. These findings suggest that, despite the counterbalancing effect of the increased EELV, BHR develops following CH, only in the presence of intact autonomous nervous system. Thus neural control plays a major role in the changes in the basal lung mechanics and responsiveness following CH.

Precapillary pulmonary hypertension leads to reversible bronchial hyperreactivity in rats.

Congenital heart disease with left-to-right shunt may lead to precapillary pulmonary hypertension (PREPHT) with potential lung function impairment. The authors investigated the effects of PREPHT on lung responsiveness in a rat model of PREPHT by creating and repairing an abdominal aortocaval shunt (ACS). Rats were studied 4 weeks after the induction of ACS, and 4 weeks after its surgical repair. Control rats underwent sham surgery. To assess bronchial hyperreactivity, airway resistance (Raw) was measured at baseline and after increasing doses of methacholine. Raw was estimated by model fitting of the mechanical impedance of the respiratory system generated by forced oscillation technique. Lung morphological changes were assessed by histology. The prolonged presence of the ACS led to only minor changes in the basal respiratory mechanics, whereas it induced marked bronchial hyperreactivity, the methacholine-induced elevations in Raw being 49% +/- 5% before and 232% +/- 32% (P <.001) after ACS. These alterations were not associated with any changes in lung histology and were completely reversible on closure of the shunt. These results suggest that the induction of chronic increases in pulmonary blood flow and pressure causes reversible bronchial hyperreactivity. This may be consequent to the altered mechanical interdependence between the pulmonary vasculature and the respiratory tract.

[Idiopathic interstitial pneumonia: classification and diagnostic work-up]. / Les pneumopathies interstitielles diffuses idiopathiques: classification et démarche diagnostique.

Idiopathic interstitial pneumonias represent a group of complex lung diseases among which the most frequent types are idiopathic pulmonary fibrosis (IPF), idiopathic non-specific interstitial pneumonia (idiopathic NSIP), and cryptogenic organizing pneumonia (COP). Clinicians may rely on a precise classification of these diseases from an America-European consensus that has been published in 2002. However it appears that diagnosis should always be confirmed by a multidisciplinary team discussion with experience in the field. There are generally tremendous prognostic and therapeutic implications for the patient.

A quality control study on cytotechnologist-cytopathologist concordance and its relationship to the number of dots on the slide.

OBJECTIVE: To study cytotechnologist (CT)-cytopathologist (CP) concordance for evaluating individual CTs' performance and for quality assurance and educational feedback. STUDY DESIGN: The interpretations of individual CTs were compared with the final interpretations (according to the 2001 Bethesda System) of the CP. Concordance percentages and kappa values were calculated for each CT and correlated with the numbers of dots on each slide, years of experience and percentage of work hours devoted to cytology. RESULTS: A total of 10,453 Pap tests were screened by 9 CTs during one year, out of which 993 (9.5%) were referred to one CP for a final interpretation. Mean concordance between the aggregate CT interpretations and those of the CP was 65.5%. Five CTs had good concordance, 3 had moderately good concordance, and one had surprisingly poor concordance that contrasted with good subjective impressions. No correlation was found between concordance and the average number of dots per slide, screening experience in cervicovaginal cytology or percentage of work hours devoted to cytology. CONCLUSION: Monitoring CT-CP concordance rates can unveil performance issues not detected by subjective impressions. An excessive number of dots per slide may not reflect poor diagnostic precision so much as a lack of confidence in interpretation.

DDR1 role in fibrosis and its pharmacological targeting.

Discoidin domain receptor1 (DDR1) is a collagen activated receptor tyrosine kinase and an attractive anti-fibrotic target. Its expression is mainly limited to epithelial cells located in several organs including skin, kidney, liver and lung. DDR1's biology is elusive, with unknown downstream activation pathways; however, it may act as a mediator of the stromal-epithelial interaction, potentially controlling the activation state of the resident quiescent fibroblasts. Increased expression of DDR1 has been documented in several types of cancer and fibrotic conditions including skin hypertrophic scars, idiopathic pulmonary fibrosis, cirrhotic liver and renal fibrosis. The present review article focuses on: a) detailing the evidence for a role of DDR1 as an anti-fibrotic target in different organs, b) clarifying DDR1 tissue distribution in healthy and diseased tissues as well as c) exploring DDR1 protective mode of action based on literature evidence and co-authors experience; d) detailing pharmacological efforts attempted to drug this subtle anti-fibrotic target to date.