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Biomedical subjects

V Cottin

Publications and source records attributed to V Cottin.

At least 19 recordsLinked to original sources
PubMed2003

Interstitial lung disease in amyopathic dermatomyositis, dermatomyositis and polymyositis.

This study investigated interstitial pneumonia associated with amyopathic dermatomyositis, dermatomyositis and polymyositis, paying particular attention to muscular and/or cutaneous manifestations and their chronology relative to lung involvement. Patients included four males and 13 females, aged 51.7+/-10.8 yrs, who had surgical lung biopsy. Diagnoses included dermatomyositis (10 patients), polymyositis (four patients) and amyopathic dermatomyositis (three patients). Solitary respiratory manifestations preceded the onset of any skin or muscle disease in four cases (24%). Reticular and ground glass opacities were the most frequent computed tomography (CT) findings. Pathological review showed nonspecific interstitial pneumonia (eleven, 65%; cellular, two; cellular and fibrotic, five; fibrotic, four), usual interstitial pneumonia (two), organising pneumonia (two), lymphocytic interstitial pneumonia (one), and unclassifiable interstitial pneumonia (one). Nonspecific interstitial pneumonia was the most common histological pattern of interstitial pneumonia in patients with amyopathic dermatomyositis (three of three) and in patients with respiratory symptoms as the initial clinical manifestation of the connective tissue disease (three of four). Survival at 5 yrs was 50%. This study shows the clinician should remain alert to potential muscular or cutaneous manifestations whenever a pathological diagnosis of nonspecific interstitial pneumonia is made.

Adult↗
PubMed2003

[Churg-Strauss syndrome].

Churg-Strauss syndrome is a vasculitis associated with asthma and eosinophilia. Respiratory involvement is marked by generally severe and often steroid-dependent late-onset asthma associated with allergic rhinitis and sometimes nasal polyposis and recurrent sinusitis. Asthma generally precedes the systemic vasculitis by a few years. General signs, eosinophilic gastroenteritis, peripheral multiplex neuropathy, cutaneous vasculitis, nephropathy, or arthromyalgia, predominate. Cardiac involvement is often silent but of severe prognosis. The chest X-ray usually shows irregularly delimited and sometimes labile infiltrates. Perinuclear antineutrophil cytoplasmic autoantibodies (ANCA) are found in two-thirds of the patients and strongly suggest the diagnosis. Clinically, the diagnosis is established by the presence of asthma, peripheral eosinophilia > 1.5 G/L, and systemic vasculitis involving at least two extra-pulmonary organs. Histological confirmation is usually necessary (nerve and muscle biopsy), showing small-vessel eosinophilic vasculitis, tissue infiltration with eosinophils, and eosinophilic granulomas. Treatment includes corticosteroids, which should be associated with immunosuppressive agents (cyclophosphamide) in severe cases.

Churg-Strauss Syndrome↗
PubMed2001

Phosphorylation of the tumor necrosis factor receptor CD120a (p55) recruits Bcl-2 and protects against apoptosis.

Ligation of the tumor necrosis factor alpha receptor CD120a initiates responses as diverse as apoptosis and the expression of NF-kappaB-dependent pro-survival genes. How these opposing responses are controlled remains poorly understood. Here we demonstrate that phosphorylation by p42(mapk/erk2) inhibits the apoptotic activity of CD120a while preserving its ability to activate NF-kappaB. Phosphorylated CD120a is re-localized from the Golgi complex to tubular structures of the endoplasmic reticulum wherein it recruits Bcl-2. Antisense-mediated down-regulation of Bcl-2 antagonized the localization of CD120a to tubular structures and reversed the protection from apoptosis conferred by receptor phosphorylation. We propose that phosphorylation of CD120a represents a novel, Bcl-2-dependent mechanism by which the apoptotic activity of the receptor may be regulated. Thus, oncogenic activation of p42(mapk/erk2) may serve to inhibit the apoptotic activity of this death receptor while preserving NF-kappaB-dependent responses and may thus indirectly contribute to a failure to eliminate cells bearing oncogenes of the Ras-Raf-MEK-p42(mapk/erk2) pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2000

[Idiopathic diffuse interstitial lung disease].

The interstitial pneumonias are characterized by inflammatory and fibrosing lesions of the lung interstitium. Idiopathic interstitial pneumonias are now classified into four main clinicopathologic entities. Idiopathic pulmonary fibrosis has a chronic course with a poor response to therapy, and corresponds to the characteristic histopathologic lesions of usual interstitial pneumonia. Acute interstitial pneumonia, fulminant, is seen in young patients. Desquamative (alveolar macrophage) interstitial pneumonia, related to tobacco smoking, has a good prognosis. Recently individualized from usual interstitial pneumonia, nonspecific interstitial pneumonia has a better prognosis than idiopathic pulmonary fibrosis. This classification has both diagnostic and prognostic implications.

Acute Disease↗
PubMed2000

Phosphorylation of the membrane proximal region of tumor necrosis factor receptor CD120a (p55) at ERK consensus sites.

The interaction of tumor necrosis factor-alpha with its receptor CD120a (p55) initiates downstream signaling cascades that include the activation of the mitogen-activated protein kinase (MAPK), p42(mapk/erk2). The membrane proximal region of CD120a (p55) is Ser-, Thr-, and Pro-rich and contains four mitogen-activated protein kinase consensus phosphorylation sites. In recent work, we showed that CD120a (p55) itself is a target of phosphorylation by p42(mapk/erk2), and after phosphorylation, the receptor is redistributed from the cell surface and Golgi complex to intracellular tubular structures associated with elements of the endoplasmic reticulum. The goal of this study was to define the specific amino acid residues that are phosphorylated. Deletional mutagenesis of the cytoplasmic domain of CD120a (p55) indicated that two sites located between residues 207-254 and 250-300 were phosphorylated predominantly on Thr and Ser residues, respectively. Site-directed mutagenesis of Ser and Thr residues contained within the extracellular signal-regulated kinase (ERK) consensus sequences indicated that the preferred residues were Thr-236 and Ser-270. Primary phosphorylation at these sites appeared to enable subsequent phosphorylation at Ser-240 and Ser-244, although the level of phosphorylation of these latter two sites was less than the preferred sites. Through the use of specific ligation of CD120a (p55) alone and mice deficient in CD120a (p55), CD120b (p75), or both receptors, CD120a (p55) was shown to be necessary and sufficient for the induction of kinase activity. These findings thus suggest that the phosphorylation of Thr-236 and Ser-270 within the membrane proximal region of CD120a (p55) are the preferred sites of phosphorylation by p42(mapk/erk2) and may set in motion phosphorylation at other sites.

Animals↗
PubMed1999

Phosphorylation of tumor necrosis factor receptor CD120a (p55) by p42(mapk/erk2) induces changes in its subcellular localization.

The interaction of tumor necrosis factor-alpha (TNFalpha) with its receptor sets in motion downstream signaling events including the activation of members of the mitogen-activated protein kinase (MAPK) family. In this study, we show that p42(mapk/erk2) phosphorylates sequences present within the cytoplasmic domain of CD120a (p55). By using a GST-CD120a-(207-425) fusion protein as substrate, phosphorylation was induced following stimulation of mouse macrophages with TNFalpha, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and zymosan particles and was blocked by immunodepletion of p42(mapk/erk2) and by specific inhibition of p42(mapk/erk2) activation with PD098059. Transfection of COS-7 cells with CD120a (p55), wild-type p42(mapk/erk2), and constitutively active MEK-1 followed by metabolic labeling with [(32)P]orthophosphate indicated that p42(mapk/erk2) phosphorylated the cytoplasmic domain of CD120a (p55) in intact cells. As a consequence of phosphorylation, CD120a (p55) expression at the plasma membrane and Golgi apparatus was lost and the receptor accumulated in intracellular tubular structures associated with the endoplasmic reticulum. Mutation of the four Ser and Thr ERK consensus phosphorylation sites to Ala residues inhibited the ability of the receptor to redistribute to intracellular tubules in a p42(mapk/erk2)-dependent fashion; whereas mutation of the phosphorylation sites to Asp and Glu residues mimicked the effect of receptor phosphorylation. These findings thus indicate that the phosphorylation of CD120a (p55) alters the subcellular localization of the receptor and may thereby result in changes in its signaling properties.

Animals↗
PubMed1999

Small-cell lung cancer: patients included in clinical trials are not representative of the patient population as a whole.

PURPOSE: To determine the clinical characteristics of the subpopulation of patients not included in clinical trials, their outcome, and the reasons for their ineligibility and non-participation. PATIENTS AND METHODS: We studied 57 patients (out of 178 consecutive patients with SCLC), who were not included in any of the three successive clinical trials completed at our center during the study period. We also compared 37 patients excluded from the largest clinical trial to their 73 included counterparts. RESULTS: Reasons for ineligibility (n = 53) included low Karnofsky index (n = 17), advanced age (n = 12), non-feasible long-term follow-up (n = 12), previous history of cancer (n = 8), contraindication for anthracyclines (n = 5), and other medical reasons (n = 11). Only four eligible patients were not included in the trials. As compared to patients included in the studies, non-included patients had a significantly lower Karnofsky index, were older, presented more frequently with metastatic disease, and had a lower response rate to treatment and a shorter survival. However, exclusion from the trial was not an independent prognostic factor by multivariate analysis. CONCLUSIONS: Selection biases were unlikely in the three trials, based on the high ratio of included/eligible patients. However, the subgroup of patients included in the trials was not representative of the patient population as a whole because of restrictive eligibility criteria. Results from published clinical trials to the overall population should be extrapolated only with caution. We suggest that the proportion and major characteristics of ineligible and non-participating patients be mentioned in any publication of a clinical trial.

Adult↗
PubMed1998

Urinary eosinophil-derived neurotoxin/protein X: a simple method for assessing eosinophil degranulation in vivo.

BACKGROUND: Eosinophil-derived neurotoxin/protein X (EDN/EPX), one of the cationic granule proteins released by polymorphonuclear eosinophils, can be detected in human urine. OBJECTIVE: We sought to evaluate whether the urinary release of EDN/EPX was dependent on the blood eosinophil cell count, the bronchoalveolar eosinophil cell count, or both and on the clinical diagnosis. We also attempted to determine the precise kinetics of decrease of EDN excretion and eosinophil counts after the onset of corticosteroid treatment. METHODS: Daily urinary release of EDN/EPX was measured by radioimmunoassay in 28 patients with high hypereosinophilia (group 1), 32 patients with moderate hypereosinophilia (group 2), 26 patients without hypereosinophilia at the time of the study but with a known pulmonary disease involving eosinophils (group 3), and 13 control patients (group 4). RESULTS: The urinary excretion of EDN/EPX was significantly higher in patients from groups 1 or 2 than in patients from groups 3 or 4. Particularly high levels of EDN/EPX excretion were observed in patients from groups 1 or 2 with chronic eosinophilic pneumonia (chronic eosinophilic pneumonia: 4.7 +/- 8.1 mg/day, control subjects: 0.39 +/- 0.33 mg/day, p < 0.001). Urinary excretion of EDN/EPX was significantly correlated with blood (r = 0.66, p < 0.001) and differential bronchoalveolar (r = 0.62, p = 0.04) eosinophil cell counts in patients from group 1 but not from the other groups. Corticosteroid treatment was followed by a significant decrease in EDN/EPX excretion. The kinetics of decrease in EDN/EPX were delayed as compared with the dramatic drop in peripheral eosinophil counts. Distinct kinetics between urinary EDN/EPX and eosinophil counts differentiated the recurrence of chronic eosinophilic pneumonia from an asthma attack in one patient. CONCLUSION: Measurement of urinary EDN/EPX excretion may be a useful indicator of eosinophil degranulation in vivo.

Adolescent↗
PubMed1998

Nonspecific interstitial pneumonia. Individualization of a clinicopathologic entity in a series of 12 patients.

Nonspecific interstitial pneumonia/fibrosis (NSIP) has recently been individualized within the group of idiopathic interstitial pneumonias mainly based on a pathologic pattern of temporally uniform lesions distinct from usual, desquamative, and acute interstitial pneumonia. We studied 12 consecutive patients with NSIP at lung biopsy done as a diagnostic procedure for idiopathic interstitial lung disease. The patients were six males and six females, aged 52.5 +/- 11.8 yr. In 8 of 12 cases the pathologic lesions consisted of both cellular interstitial inflammation and fibrosis, whereas only cellular inflammation was present in three cases, and fibrosis in one. Dyspnea, cough, inspiratory crackles, and squeaks were the most common symptoms and signs. Six cases were cryptogenic. An associated disorder or a presumed cause was present in the other six patients, including underlying connective tissue disease (n = 3), organic dust exposure (n = 2), and prior acute lung injury (n = 1). Lung function tests found a restrictive ventilatory defect (11/12), impairment of TLCO (11/11), and hypoxemia at rest (7/12). Chest X-ray showed infiltrative opacities in all cases. Computed tomography of the chest in 11 cases mainly showed ground glass opacities (9/11), patchy areas of alveolar consolidation (6/ 11), and thickening of interlobular septas (5/11). All patients were treated with corticosteroids, and seven with immunosuppressive agents. All patients were alive at last follow-up, 50 +/- 40 mo after diagnosis. Ten patients (83%) were clinically improved or stabilized. Thus, despite its heterogeneity, NSIP deserves to be individualized as an original clinicopathologic entity and should be clearly distinguished from usual interstitial pneumonia, especially because of a better prognosis.

Acute Disease↗
PubMed1998

Respiratory bronchiolitis in smokers with spontaneous pneumothorax.

Respiratory bronchiolitis (RB) is defined by the accumulation of pigmented macrophages in the lumen and wall of respiratory and membranous bronchioles of smokers. The aim of this study was to determine whether spontaneous pneumothorax was associated with a high prevalence of RB. Seventy-nine consecutive patients who underwent a surgical procedure (thoracotomy or thoracoscopy) for recurrence or persistence of primary spontaneous pneumothorax despite thoracic drainage were studied retrospectively. RB was found in 70 of 79 (88.6%) smokers operated for spontaneous pneumothorax. Associated interstitial pathological abnormalities were present in 53 of 79 cases (67.1%). In nine patients, the pathological lesions were severe and resembled desquamative interstitial pneumonia. Emphysematous lesions were present in about one-third of the patients. Although the possible pathophysiological consequences of respiratory bronchiolitis remain speculative, this study demonstrates the high prevalence of this pathological abnormality in patients with pneumothorax requiring surgical treatment.

Adolescent↗
PubMed1997

Alveolar macrophages from sheep naturally infected by visna-maedi virus contribute to IL-8 production in the lung.

Sheep naturally infected by visna-maedi virus often develop a chronic interstitial lung disease characterized by an alveolitis comprising lymphocytes, neutrophils and macrophages. The alpha chemokine interleukin-8 (IL-8) was detected in cell free bronchoalveolar lavage fluid from naturally infected animals, confirmed by RT-PCR, presenting typical lesions of maedi and elevated total alveolar cell counts. No detectable IL-8 was found in the fluid obtained from uninfected animals. IL-8 concentration in alveolar fluid is correlated with alveolar neutrophil counts. Bronchoalveolar lavage cells from infected animals were found to contain a large amount of IL-8 mRNA and may contribute to IL-8 production. In situ hybridization showed that macrophages were the predominant cell type expressing IL-8 mRNA. Sustained production of IL-8 by alveolar macrophages during visna-maedi infection could suffice for neutrophil attraction to the alveoli, and may contribute to the development of lesions.

Animals↗
PubMed1997

[Respiratory function surveillance during prolonged treatment with low-dose methotrexate].

Long-term low-dose methotrexate (MTX) has a proven beneficial effect in patients with rheumatoid arthritis; the main drawback being the risk of interstitial pneumonia. Although estimations have varied, in our recent prospective analysis we observed 4 cases among 124 receiving MTX for rheumatological disorders, i.e. a risk rate of 3.2% Age, sex, disease duration, administration route and daily or cumulative dose do not appear to affect risk, but recent work suggest that renal failure, concomitent use of nonsteroid anti-inflammatory drugs, smoking, past pulmonary history or radiographic anomalies as well as recent withdrawal of corticosteroids are risk factors. Pulmonary function tests can be used to detect acute disorders and regular testing has been proposed to help predicted pulmonary complications in patients receiving long-term MTX. Unfortunately, minimal variations observed to date, for example in forced vital capacity or expiratory volume, do not appear to occur prior to clinical manifestations and may be due to normal aging processes or the pathological effect of the rheumatoid disease itself. In addition, due to the proven efficacy of MTX, randomized trials against a control group not given MTX would be ethically unacceptable. We are thus still unable to predict development of secondary pulmonary complications to long-term low-dose MTX. We therefore recommend testing pulmonary function at treatment onset to establish a reference for subsequent tests performed in case of clinical manifestations during MTX therapy. Patients should be counselled to consult in case of pulmonary symptoms in order to allow diagnosis as early as possible. The most recent data also would suggest that MTX may induce infraclinical alterations of pulmonary function although their significance remains to be clarified.

Antirheumatic Agents↗