[Mechanisms of deregulated response to hypoxia in sporadic amyotrophic lateral sclerosis: a clinical study]. / Mécanismes de dérégulation de la réponse à l'hypoxie dans la sclérose latérale amyotrophique.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motorneurons, leading to death in 3 to 5 years. Respiratory insufficiency and hypoxemia are closely linked during the clinical course of ALS. Chronic respiratory insufficiency and hypoxemia generally occur late in the disease course but rapid episodes of intermittent hypoxemia followed by reoxygenation can occur early and insidiously. Two pathways are involved in the response to hypoxemia: (i) hypoxia inducible factor-1 (HIF-1) and VEGF/HIF-2 and an erythropoietin (EPO) mediated pathway, in response to prolonged hypoxemia; and (ii) nuclear factor kappa-B (NFkappa-B) during acute hypoxemia followed by reoxygenation episodes, inducing inflammatory mediators: interleukin-6 (IL-6), TNF-alpha, cyclo oxygenase-2 (COX-2) and prostaglandin E-2 (PGE-2). Our aim was to specify the role of the different functional pathways of response to hypoxemia in sporadic ALS patients, compared with neurological controls and according to the level of hypoxemia. We report the results of several studies of hypoxemic and/or inflammatory mediators in the cerebrospinal fluid (CSF) from ALS patients, according to their respiratory status, showing a selective defect of HIF-1 mediated angiogenic factors (VEGF and angiogenin [ANG]) during chronic hypoxia in sporadic ALS patients, compared to hypoxemic neurological controls; contrasting with an early activation of the NFkappa-B pathway since the isolated desaturation stage (IL-6, TNF-alpha, PGE-2, angiopoietin-2) in the same cohort of sporadic ALS patients. All these results are consistent with a selective impairment of the HIF-1 pathway during chronic hypoxemia in ALS patients. Inflammatory mediators were strongly elevated, since the early stage of the disease until chronic hypoxemia, suggesting a compensatory mechanism.

Desloratadine relieves nasal congestion and improves quality-of-life in persistent allergic rhinitis.

BACKGROUND: Symptoms of allergic rhinitis (AR), particularly nasal congestion, can impair quality-of-life (QoL). However, only a modest correlation exists between these symptoms and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, suggesting that both be evaluated for a complete assessment of health. METHODS: Subjects with a > or =2-year history of moderate-to-severe AR to dust mite or cat dander were randomized to desloratadine 5 mg/day (n = 293) or placebo/day (n = 291) for 28 days. Primary endpoint was change from baseline in a.m./p.m. nasal congestion score. Secondary outcomes included change from baseline in total nasal symptom score, individual symptom scores and RQLQ scores (completed on days 1, 7, and 28). RESULTS: The Allergic Rhinitis and its Impact on Asthma criteria for persistent allergic rhinitis (PER) were fulfilled by 99% of subjects in the placebo arm. Between-treatment difference in a.m./p.m. nasal congestion score, observed from day 8 onward, significantly favored desloratadine (P = 0.0003). Desloratadine significantly improved a.m./p.m. nasal congestion and RQLQ scores after 1 week and at treatment end (P < 0.05). Improvements in 5 of 7 RQLQ domain scores exceeded the minimal important difference. On days 7 and 28, desloratadine was also significantly superior to placebo in mean change from baseline in a.m./p.m. total nasal symptom score and rhinorrhea score (both P < or = 0.01). Symptomatic benefit was primarily driven by improvement in nasal congestion and rhinorrhea. CONCLUSIONS: Desloratadine 5 mg/day significantly improved symptoms associated with PER, including nasal congestion, and provided significant improvement in QoL after 1 week of treatment.

Validity, reliability, and responsiveness of a new short Visual Simplified Respiratory Questionnaire (VSRQ) for health-related quality of life assessment in chronic obstructive pulmonary disease.

The Visual Simplified Respiratory Questionnaire (VSRQ) was designed to assess health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD). It contains eight items: dyspnea, anxiety, depressed mood, sleep, energy, daily activities, social activities and sexual life. Psychometric properties were assessed during a clinical trial that evaluated the impact of tiotropium on HRQoL of COPD patients. These included the determination of structure, internal consistency reliability, concurrent validity with the St George's Respiratory Questionnaire (SGRQ), test - retest reliability, clinical validity and responsiveness to change over two weeks. Minimal important difference (MID) was calculated; cumulative response curves (CRC) were based on the dyspnea item. Psychometric analyses showed that VSRQ structure was unidimensional. The questionnaire demonstrated good internal consistency reliability (Cronbach's alpha = 0.84), good concurrent validity with SGRQ (Spearman = -0.70) and clinical validity, good test-retest reproducibility (ICC = 0.77), and satisfactory responsiveness (standardized response mean = 0.57; Guyatt's statistic = 0.63). MID was 3.4; CRC median value of the 'minimally improved' patients was 3.5. In conclusion, VSRQ brevity and satisfactory psychometric properties make it a good candidate for large studies to assess HRQoL in COPD patients. Further validation is needed to extend its use in clinical practice.

Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD.

Clinical manifestations of chronic obstructive pulmonary disease (COPD), including airflow limitation, dyspnea, and activity limitation, ultimately lead to impaired health-related quality of life (HRQoL). This 9-month, randomized, double-blind, multicenter study compared the effect of once-daily tiotropium 18 microg and placebo on HRQoL, spirometric parameters, and exacerbations in 554 patients with moderate-to-severe COPD. HRQoL was assessed using the St. George's Respiratory Questionnaire (SGRQ) and the new 8-item Visual Simplified Respiratory Questionnaire (VSRQ), which is currently being validated. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end (Month 9). Mean +/- SD baseline SGRQ total score was 47.4 +/- 18.1. Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score vs placebo at study end (59.1% vs 48.2%, respectively; p = 0.029). Tiotropium significantly improved spirometric parameters (forced expiratory volume in 1 second [FEV1]: 0.11 +/- 0.02 L vs 0.01 +/- 0.02 L; between-group difference: 0.10 +/- 0.03 L, p = 0.0001) and reduced exacerbations vs placebo. Maintenance treatment with tiotropium provided significant and clinically relevant improvements in HRQoL, as measured by the SGRQ.

Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations.

This review is the synthesis of a working group on mild asthma. Mild asthma includes intermittent and persistent mild asthma according to the Global Initiative for Asthma (GINA) classification, and affects between 50% and 75% of asthmatic patients. Mild asthma is more frequent, more symptomatic, and less well controlled in children than in adults. Cohort studies from childhood to adulthood show that asthma severity usually remains stable over time. Nevertheless, mild asthma can lead to severe exacerbations, with a frequency ranging from 0.12 to 0.77 per patient-year. Severe exacerbations in mild asthma represent 30-40% of asthma exacerbations requiring emergency consultation. In mild asthma, inflammation and structural remodelling are constant, of varying intensity, but nonspecific. Therapy with inhaled corticosteroids (ICS) decreases bronchial inflammation, but has only a slight effect on structural remodelling, and, when stopped, inflammation immediately recurs. Permanent low-dose ICS therapy is the reference treatment for persistent mild asthma. Effectiveness is to be reassessed at 3 months, and if it is insufficient the patient is no longer considered mildly asthmatic, and treatment has to be stepped up. As mild asthma is the most frequent form of the disease, diagnosis and management require physicians' particular attention.

Keratinocyte growth factor improves alterations of lung permeability and bronchial epithelium in allergic rats.

Chronic allergic asthma is associated with marked inflammatory reaction, microvascular leakage and epithelium injury. As previously shown in a rat model of chronic asthma, these alterations increase lung permeability and distal airway fluid clearance. Keratinocyte growth factor (KGF) has been shown to induce epithelial cell proliferation and to protect from acute lung injuries. Therefore, the current authors evaluated the potential role of KGF treatment on lung permeability and airway inflammation in rats with chronic asthma. KGF (1 mg x kg(-1)) was administered intravenously before the last ovalbumin (OVA) challenge in sensitised rats. Permeability was assessed by the leak of radiolabelled albumin from the alveolar and systemic compartments. Histopathological analysis was also performed. Treatment with KGF decreased the leak of both markers and decreased the level of extravascular lung water in sensitised rats challenged with OVA. KGF treatment also reduced the inflammatory cell number in bronchoalveolar lavage fluid but not in bronchial mucosa. KGF markedly limited the allergen-induced alterations in epithelium integrity and the expression of the intercellular junction proteins beta-catenin and zonula occludens protein-1. In conclusion, keratinocyte growth factor administration markedly limits lung permeability and airway inflammation, an effect associated with a decrease in epithelium alterations during chronic allergic asthma. These data open new prospects in the therapeutic strategy of asthma.

IL-18 does not increase allergic airway disease in mice when produced by BCG.

Whilst BCG inhibits allergic airway responses in murine models, IL-18 has adversary effects depending on its environment. We therefore constructed a BCG strain producing murine IL-18 (BCG-IL-18) and evaluated its efficiency to prevent an asthma-like reaction in mice. BALB/cByJ mice were sensitized (day (D) 1 and D10) by intraperitoneal injection of ovalbumin (OVA)-alum and primary (D20-22) and secondary (D62, 63) challenged with OVA aerosols. BCG or BCG-IL-18 were intraperitonealy administered 1 hour before each immunization (D1 and D10). BCG-IL-18 and BCG were shown to similarly inhibit the development of AHR, mucus production, eosinophil influx, and local Th2 cytokine production in BAL, both after the primary and secondary challenge. These data show that IL-18 did not increase allergic airway responses in the context of the mycobacterial infection, and suggest that BCG-IL-18 and BCG are able to prevent the development of local Th2 responses and therefore inhibit allergen-induced airway responses even after restimulation.

[Hypersensitivity pneumonitis in a chicory worker]. / Pneumopathie d'hypersensibilité chez une endivière.

INTRODUCTION: We report a case of occupational hypersensitivity pneumonitis in a patient handling chicory leaves. CASE REPORT: The diagnosis was based symptoms of broncho-alveolitis with pyrexia, positive precipitins to moulds present on chicory, especially Fusarium, and the disappearance of the clinical and radiological manifestations following cessation of exposure to chicory. CONCLUSION: "Chicory worker's lung" is an occupational disease which should be considered in cases of respiratory symptoms suggestive of hypersensitivity pneumonitis and chronic exposure to chicory leaves.

High erythropoietin and low vascular endothelial growth factor levels in cerebrospinal fluid from hypoxemic ALS patients suggest an abnormal response to hypoxia.

Animal studies have highlighted the potentially neuroprotective role of vascular endothelial growth factor (VEGF). Low levels of this growth factor have been found in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). VEGF (and other proteins, such as erythropoietin (EPO)) are produced in response to hypoxia via a common pathway involving a specific transcription factor (hypoxia-inducible factor, HIF) and a hypoxia responsive element (HRE) in the respective genes' promoter regions. In this study, we report finding the expected, high levels of VEGF and EPO in CSF from hypoxemic neurological controls, whereas EPO (but not VEGF) levels are high in the CSF from hypoxemic ALS patients. Hence, the VEGF levels in CSF from patients with ALS were significantly lower than those seen in hypoxemic controls. There was a trend towards higher CSF levels of EPO in hypoxemic ALS patients than in hypoxemic controls. Our results suggest that VEGF may not be produced in sufficient amounts in chronically hypoxic ALS patients and that this dysfunction may participate in the pathogenesis of the disease. The high EPO levels in hypoxemic ALS patients nevertheless suggest an intact common oxygen-sensor pathway.

[Characteristics of mild asthma: descriptive epidemiology and nature of bronchial inflammation. Position of the Mild Asthma Working Group]. / Caractéristiques de l'asthme léger: épidémiologie descriptive et nature de l'inflammation bronchique.

INTRODUCTION: Update on the state of knowledge in the mild asthma (intermittent and persistent mild asthma, according to the GINA classification) literature, and position of a French Mild Asthma Working Group. STATE OF THE ART: The French Mild Asthma Working Group (11 lung specialists, 4 paediatricians, 1 pharmacologist, and 1 general practitioner) selected, analysed, and summarised the literature on the epidemiology, physiopathology, clinical signs, and management of mild asthma. The present article shows the position of the working group on mild asthma descriptive epidemiology (causal factors excluded) and the nature of the bronchial inflammation. Clinical signs and medicinal treatments will be presented in a second article. PERSPECTIVES: Between 50% and 75% of asthma patients, depending on the study, present mild asthma. Childhood-to-adulthood cohort monitoring found severity to be unchanged over developmental time. Its generally benign evolution may in some (<10%) cases be complicated by severe episodes. Inflammation and airway-wall remodelling were always found, although of variable intensity, and non-specific (except for absence of infiltration by polymorphonuclear neutrophils). Corticosteroid therapy by inhalation reduces bronchial inflammation, but with little impact on airway-wall remodelling. CONCLUSION: The present findings should help clinicians in identifying and understanding mild asthma.

[Pulmonary disease in dental laboratory technicians]. / Manifestations pulmonaires des prothésistes dentaires.

INTRODUCTION: The manufacture of dental prostheses exposes the technician to inhalation of various potentially dangerous dusts (silica, hard metals, dental alloys and acrylic resins). BACKGROUND AND VIEWPOINT: Inhalation of dusts produced by the technician in the work place may lead to several respiratory disorders (pneumoconiosis, hypersensitivity pneumonitis, asthma, lung cancer). The continuous development of new materials leads to further manifestations of these disorders and justifies their notification, even in the absence of an accepted occupational disease. This step is taken inconsistently as many dental technicians are not salaried or insured. CONCLUSION: The seriousness of some of these disorders and the absence of effective treatment makes it important to develop effective methods of prevention for the protection of individuals and groups, and for early detection.

Paradoxical response of VEGF expression to hypoxia in CSF of patients with ALS.

Vascular endothelial growth factor (VEGF) is implicated in motor neurone degeneration. In normal individuals, hypoxia is known to induce an overexpression of VEGF, as measured in CSF. We show that patients with ALS do not manifest this VEGF overexpression in the presence of hypoxia. Although VEGF gene expression is mainly stimulated by hypoxia, we have measured lower VEGF levels in cerebrospinal fluid (CSF) from hypoxaemic patients with amyotrophic lateral sclerosis (ALS) than in CSF from normoxaemic patients with ALS. In contrast, hypoxaemic neurological controls displayed higher levels than normoxaemic neurological controls. There was a negative correlation between VEGF levels and the severity of hypoxaemia in patients with ALS, suggesting deregulation of VEGF in ALS.

[Characteristics of mild asthma: clinical signs and medication use. Position statement of the Mild Asthma Working Group (174)]. / Caractéristiques de l'asthme léger: signes cliniques et traitements médicamenteux. Le point de vue du Groupe de Travail sur l'Asthme Léger.

OBJECTIVE: To update on the state of knowledge in mild asthma (intermittent and persistent mild asthma, according to the GINA classification) review the literature, and the position statement of the French Mild Asthma Working Group. METHODS: The French Mild Asthma Working Group (11 lung specialists, 4 paediatricians, 1 pharmacologist, and 1 general practitioner) selected, analysed, and summarised the literature on the descriptive epidemiology, physiopathology, clinical signs, and management of mild asthma. The position of the working group on the descriptive epidemiology (causal factors excluded) and the nature of the bronchial inflammation has been presented in a previous article. The present article focuses on the clinical features of mild asthma and the use of medication for it. RESULTS: Mild asthma was more frequent, more symptomatic, and less well controlled in children than in adults. Its generally benign evolution may in some (<10%) cases be complicated by severe episodes. Patients with mild persistent asthma require controller medication every day: permanent low-dose inhaled corticosteroid monotherapy is the reference foundation treatment for persistent mild asthma. CONCLUSIONS: The present findings should help clinicians and guide them in their approach to managing this condition.

Elevated IL-6 and TNF-alpha levels in patients with ALS: inflammation or hypoxia?

Abnormal levels of interleukin (IL)-6 were described in patients with ALS, related to an inflammatory process. The authors compared IL-6 and tumor necrosis factor alpha (TNF-alpha) levels in CSF and sera from 10 hypoxemics and 10 normoxemics patients with ALS to those of 10 hypoxemics and 10 normoxemics neurologic controls. The same pattern exists in patients with ALS and controls: the highest levels are found in hypoxic conditions and undetectable levels are found in normoxemic conditions. Elevated IL-6 levels in ALS could correspond to a normal response to hypoxemia.

[Anti IgE antibodies for the treatment of difficult asthma]. / Traitement par anticorps anti-IgE de l'asthme allergique difficile a contrôler.

INTRODUCTION: Immunoglobulin E (IgE) is a key factor of allergic reaction and is known to be involved in the immunopathology of asthma. In this review, we discuss the results of trials of a monoclonal antibody (omalizumab) against IgE in patients with allergic asthma. STATE OF THE ART: Omalizumab is a humanised murine IgG1 kappa monoclonal antibody which is administered subcutaneously every 2 to 4weeks at a dose calculated according to the patient's body weight and total plasma IgE concentrations. It binds free circulating IgE thus preventing it from binding to high affinity receptors. Omalizumab therapy significantly reduces asthma exacerbations, improves quality of life and has a steroid-sparing effect. It has a good safety profile. This treatment appears to be more effective in the patients with the most severe disease and the worst lung function. CONCLUSION AND PERSPECTIVES: Omalizumab therapy is an important novel treatment for difficult-to-control allergic asthma. Because of its systemic mechanism of action, it may be of particular use in patients displaying multiple allergic pathologies. It remains unknown whether the beneficial effects of omalizumab could be extended to patients with severe non allergic (so-called "intrinsic") asthma, a variant of the disease which is often difficult to control.

[Desensitisation to infliximab in patients with Crohn's disease]. / Accoutumance médicamenteuse a l'infliximab dans la maladie de Crohn.

BACKGROUND: Infliximab is a chimeric monoclonal antibody directed against tumour necrosis factor-alpha that has been shown to improve chronic refractory and fistulating Crohn's disease. Infliximab infusions have been associated both with immediate and delayed reactions. MATERIAL AND METHODS: Desensitisation was performed in four patients who had experienced immediate reactions to infliximab infusions and in one who had developed a delayed reaction. No therapeutic alternatives were available for these patients. Before desensitisation, skin tests were performed. RESULTS: Skin-tests were negative for all patients. Desensitisation was performed with serial dilutions of infliximab with monitoring of vital signs before each increment. After parenteral desensitisation, all five patients were able to tolerate infliximab infusion without complications or any requirement for antihistamines or steroids. However, two patients who had initially presented with an immediate reaction to infliximab experienced arthralgia and myalgia similar to a "serum sickness-type" of reaction 6 to 10 days after desensitisation. CONCLUSION: Even if there is no evidence of an allergic mechanism in infusion reactions to infliximab, successful desensitization can be achieved for patients experiencing acute reactions. The mechanism of desensitisation remains presently unknown. It is not yet possible to say if desensitization will be effective in preventing delayed reactions.

[Economic burden of COPD: the SCOPE study]. / Impact economique de la BPCO en France: etude SCOPE.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a major health problem. Few data about COPD economic burden are available. METHODS: SCOPE was an observational economical retrospective and prospective study conducted in France in 2001, by 114 general practitioners (GPs) and 57 lung specialists. The aim was to describe the burden of COPD patients and to estimate the annual cost according to severity stages. Health resource utilization was collected by questionnaires over a 12-month period for 285 patients. RESULTS: It was a cost-of-illness analysis. COPD patients followed by a lung specialist were more severe than patients followed by a GP and had a higher level of medical resource consumption. The COPD disease and its complications explained 66% of the total cost. The main cost drivers were inpatient care (35%, or 1509,9 euros/year/patient) and prescription medications (31%, or 1340,6 euros/year/patient). The direct total cost varied according to COPD severity on account of inpatient care and respiratory assistance. DISCUSSION: This study confirmed the economic burden of COPD in France. Actions allowed to slow down the disease's evolution and to anticipate the exacerbation could reduce the cost.