Elevated serum CC chemokine ligand (CCL)18 reflects lung fibrosis activity in systemic sclerosis (SSc) and could be an early marker of lung function worsening. Therefore, we sought to evaluate ...whether serum CCL18 levels at baseline could predict worsening of lung disease in SSc. In this prospective study, 83 SSc patients were analysed longitudinally over a 4-yr observation period for the risk of occurrence of combined deleterious events, defined as a 10% decrease from baseline of total lung capacity or forced vital capacity % predicted, or death, according to serum CCL18 at inclusion. Receiver operating characteristic (ROC) curve analysis was performed for prediction of events during the first year after inclusion. The best cut-off level of serum CCL18 for prediction of a combined event within the follow-up period was 187 ng · mL(-1), with 53% sensitivity and 96% specificity (area under the ROC curve 0.86; p < 0.001). After a mean ± SD follow-up of 33.7 ± 10.8 months, a higher rate of disease progression occurred in the group with serum CCL18 levels >187 ng · mL(-1). The adjusted hazard ratio was 5.36 (95% CI 2.44-11.75; p < 0.001). In summary, serum CCL18 is an accurate predictive biomarker for the identification of patients with a higher risk of subsequent scleroderma lung disease worsening.
•Individual cardiac output was predicted from PFT and CPET data of 31 subjects using a theoretical O2 capture model.•Predictions were validated to the value of cardiac output deduced from Fick ...principle.•Simple graphical approach to prediction using pre-calculated results is introduced.•Systematic studies showed that Hb concentration and P50 are important for personalized prediction.
It has been proposed that oxygen capture by the human lungs depends on four determinants: ventilation, cardiac output, oxygen partial pressure in the inspired air and the venous blood. Indeed, the theoretical-numerical model proposed recently by Kang et al. was able to interpret the known empirical relation between the average of the determinants and the average oxygen capture called VO2. This method is tested here at the individual level in a group of 31 subjects submitted to standard pulmonary function testing and cardiopulmonary exercise testing. For this, an inverse method is used in which individual cardiac output is predicted from the clinical test data. Comparison to the cardiac output deduced from Fick principle confirms that the dynamic model is a “microscopic” justification of the “macroscopic” Fick principle. It shows that in addition to the four determinants, two secondary determinants, namely hemoglobin concentration and Bohr effect, expressed here through P50, play significant roles.
The lung just like all other organs is affected by age. The lung matures by the age of 20 and age-related changes start around middle age, at 40-50 years. Exhaled nitric oxide (FENO) has been shown ...to be age, height and gender dependent. We hypothesize that the nitric oxide (NO) parameters alveolar NO (CANO), airway flux (JawNO), airway diffusing capacity (DawNO) and airway wall content (CawNO) will also demonstrate this dependence. Data from healthy subjects were gathered by the current authors from their earlier publications in which healthy individuals were included as control subjects. Healthy subjects (n = 433) ranged in age from 7 to 78 years. Age-stratified reference values of the NO parameters were significantly different. Gender differences were only observed in the 20-49 age group. The results from the multiple regression models in subjects older than 20 years revealed that age, height and gender interaction together explained 6% of variation in FENO at 50 ml s−1 (FENO50), 4% in JawNO, 16% in CawNO, 8% in DawNO and 12% in CANO. In conclusion, in this study we have generated reference values for NO parameters from an extended NO analysis of healthy subjects. This is important in order to be able to use these parameters in clinical practice.
Endothelial dysfunction is one of the main consequences of the toxic effects of cigarette smoke on the vascular system. Increasing evidence suggests that the small G-protein RhoA and its downstream ...effectors, the Rho-kinases (ROCKs), are involved in systemic endothelial dysfunction induced by cigarette smoke. This study aimed to evaluate the role of the RhoA/ROCKs pathway in pulmonary artery endothelial function in current smokers with normal lung function. Lung tissues were obtained from nonsmokers and smokers who underwent lobectomy for lung carcinoma. Arterial relaxation in response to acetylcholine (ACh) was assessed in isolated pulmonary arterial rings. Protein expressions and activities of endothelial nitric oxide synthase (eNOS), ROCKs and the myosin phosphatase subunit 1 (MYPT-1) were sought. Relaxation in response to ACh was significantly lower in smokers as compared with nonsmokers (n = 8 in each group), consistent with reduced eNOS activity in the former compared with the latter. eNOS protein expression remained, however, the same in both groups. Expression of ROCKs, guanosine triphosphate-RhoA and phosphorylated MYPT-1 were significantly increased in smokers compared with controls. Pulmonary endothelial dysfunction is present in smokers whose lung function has not yet been impaired. Reduced activity of eNOS accounts at least in part for this endothelial dysfunction. Increased expression and activity of ROCKs accounts for another part through direct or indirect inhibition of the Rho-A/ROCKs pathway on nitric oxide synthesis and sustained pulmonary vasoconstriction through inhibition of myosin phosphatase.
▶ Microvascular injuries, inflammatory cells, and fibrotic foci were well described. ▶ Endothelial activation induces inflammatory and autoimmunity activation. ▶ Cytokines and autoantibodies ...stimulate fibroblast proliferation and transformation. ▶ Oxidative stress via ROS formation plays a crucial role in fibroblast activation. ▶ Understanding of many signaling pathways paves the way to individualized treatment.
Fibrosis is characterized by disproportionate accumulation of collagens and other extracellular matrix substances, resulting in organ dysfunction and failure. In systemic sclerosis, cellular and molecular mechanisms involved in the pathophysiology of fibrosis are highly complex and yet barely understood. Anatomopathological findings showed the coexistence of patchy inflammatory cell infiltration, microvascular injuries, and fibrotic foci. One of the most commonly accepted hypotheses considers endothelial activation as the triggering phenomenon inducing inflammatory and autoimmunity activation. The resulting cytokines and autoantibodies production accelerates the proliferating rate of normal fibroblasts and their transformation into myofibroblasts, leading to diffuse fibrosis. This review aims to focus on cellular and molecular mechanisms implicated in the fibrogenesis of systemic sclerosis.
La fibrose est caractérisée par une accumulation excessive de collagène et d’autres substances de la matrice extracellulaire qui entraînent un dysfonctionnement des organes atteints. Dans la sclérodermie systémique, les mécanismes cellulaires et moléculaires impliqués dans la physiopathologie de la fibrose sont très complexes et ne sont que partiellement connus. Les examens anatomopathologiques ont montré la coexistence de foyers inflammatoires disséminés et de lésions microvasculaires, intercalés des foyers fibrosants contenant des myofibroblastes. L’une des hypothèses contemporaines considère l’activation des cellules endothéliales comme le phénomène initiateur, capables d’induire l’inflammation et l’auto-immunité dont les cytokines et les auto-anticorps résultant contribuent à stimuler les fibroblastes normaux en les transformant en myofibroblastes, responsables de la fibrose diffuse. Cette revue se propose de faire le point sur les mécanismes cellulaires et moléculaires de la fibrogénèse dans la sclérodermie systémique.
Inhaled nitric oxide (NO) is frequently administered to full term and preterm newborns in various clinical settings in order to alleviate pulmonary hypertension whilst improving oxygenation. However, ...the physiological effect of NO on early postnatal lung development has not yet been clearly described. We therefore investigated whether NO administered by inhalation affects lung development at early postnatal life.
Pregnant rats were placed in a chamber containing 5ppm (iNO-5ppm group) and 20ppm NO (iNO-20ppm group), started from the last day of their pregnancy in order to keep rat pups under ambient NO from birth to 7days postnatal. Control animals were kept at room air and all rat pups were sacrificed at postnatal day 7 and day 14.
Lung-to-body weight and wet-to-dry lung weight ratios did not significantly differ among 3 groups at postnatal day 7 and day 14. Vascular volume densities (Vv) in both NO groups (5 and 20ppm) were higher than controls (P<0.05; P<0.001). Pulmonary vessel number was significantly increased in iNO-20ppm group. Radial alveolar counts (RAC) and mean linear intercepts (MLI) markedly increased (consistent with increased alveolarization) in iNO-20ppm group. This was associated with upregulation of VEGF/VEGFR-2, MT1-MMP/MMP2 and HO-1 protein expression in iNO-20ppm group.
We concluded that inhaled NO at 20ppm enhanced lung development possibly through increased expression of HO-1, VEGF/VEGFR-2, and MMP2 at early stage of postnatal rat life.
Traditional approaches to medial temporo-occipital intra-axial brain tumors carry the risk of visual or language deficits related to brain retraction or transgression of deep fiber tracts. To reduce ...these risks, the microscopic supracerebellar transtentorial approach with the patient in the sitting position has been previously described for lesions in relative proximity to the tentorium.
We describe this approach performed with endoscopic tumor resection to allow better visualization and a more ergonomic operating position.
Four consecutive patients harboring a medial temporo-occipital lesion are reported. All were operated on while in the sitting position using frameless navigation and a supracerebellar transtentorial approach. Tumor resection was performed by 2 surgeons with endoscopic visualization.
Pathologies included intraparenchymal metastatic melanoma, cavernous hemangioma, and ganglioglioma, as well as an intraventricular metastatic tumor. The distance from the tentorium to the lesion ranged from 1 to 4 mm. Gross total resection was achieved in 3 of the 4 patients. The patient with a metastatic melanoma had an intentional near-total resection given the tumor encasing a branch of the posterior cerebral artery. The patient with the intraventricular tumor sustained a small but symptomatic infarct of the lateral geniculate region, resulting in a visual field deficit.
This small series suggests that the endoscopic supracerebellar transtentorial approach with the patient in the sitting position can be a safe and effective approach for removing medial temporo-occipital lesions. It allows excellent tumor visualization, eliminates the need for brain retraction, minimizes parenchymal transgression, and improves surgical ergonomics. Significant experience in endoscopy and excellent neuroanesthesia support are recommended before undertaking this approach.
Pulmonary hypertension (PH) is a complex disorder resulting from many etiologies that cause disturbances of normal pulmonary haemodynamics. Recent breakthroughs have led to a better understanding of ...the pathophysiology of the disease. In PH, haemodynamic disturbances are closely linked to structural changes and excessive remodeling of pulmonary vessels, leading to progressive narrowing of the pulmonary vascular lumen. Imbalances between pulmonary vasoconstrictors and vasodilators on the one hand, and factors favoring cell proliferation and apoptosis on the other hand, probably account for most cases of PH. This review aims to update readers with the current knowledge on the molecular physiopathology of PH and how this can progress the therapeutic of this disorder.
The measure of fractional exhaled nitric oxide (FENO) in the airways is a useful tool to guide the diagnosis and titration of inhaled corticosteroids in patients with asthma. However, its role in ...diagnosis of allergic rhinitis (AR), especially in subjects with asthma, is not well established.
To study the cutoff of nasal FENO in the diagnosis of subjects with AR and AR-asthma compared to age-matched subjects without AR or asthma and its correlations with the clinical and functional characteristics.
The study was cross sectional and descriptive. Subjects were grouped into control subjects, AR, and AR-asthma, based on the inclusion criteria. Exhaled NO (nasal FENO, bronchial FENO, and alveolar concentration of NO) was measured by multiple flow electro-luminescence device.
Six hundred twenty-eight subjects were included: 217 control subjects (children: n=98, 10±4 years; adults: n=119, 50±16 years), 168 subjects with AR (children: n=54, 10±3 years; adults: n=114, 49±15 years), and 243 subjects with AR-asthma (children: n=115, 10±3 years; adults: n=128, 51±14 years). Nasal peak inspiratory flow and peak expiratory flow were lower in subjects with AR and AR-asthma than in control subjects (
<0.01 and
<0.01; and
<0.05 and
<0.01, respectively). Nasal FENO levels were significantly higher in subjects with AR and AR-asthma than in control subjects (1614±629 and 1686±614 ppb vs 582±161 ppb;
<0.001 and
<0.001, respectively). In subjects with AR non-asthma, the cutoffs of nasal FENO for those diagnosed with AR were 775 ppb in children, 799 ppb in adults, and 799 in the general population (sensitivity: 92.68%, 92.63%, and 92.65%, respectively; specificity: 91.67%, 95.00%, and 96.87%, respectively). In subjects with AR-asthma, the cutoffs of nasal FENO were higher, especially in asthma children (1458 ppb; sensitivity: 72.97% and specificity: 95.83%).
Nasal FENO measurement is a useful technique for the diagnosis of AR in subjects with and without asthma.
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