Functional connectivity and information flow of the respiratory neural network in chronic obstructive pulmonary disease

Breathing involves a complex interplay between the brainstem automatic network and cortical voluntary command. How these brain regions communicate at rest or during inspiratory loading is unknown. This issue is crucial for several reasons: (i) increased respiratory loading is a major feature of several respiratory diseases, (ii) failure of the voluntary motor and cortical sensory processing drives is among the mechanisms that precede acute respiratory failure, (iii) several cerebral structures involved in responding to inspiratory loading participate in the perception of dyspnea, a distressing symptom in many disease. We studied functional connectivity and Granger causality of the respiratory network in controls and patients with chronic obstructive pulmonary disease (COPD), at rest and during inspiratory loading. Compared with those of controls, the motor cortex area of patients exhibited decreased connectivity with their contralateral counterparts and no connectivity with the brainstem. In the patients, the information flow was reversed at rest with the source of the network shifted from the medulla towards the motor cortex. During inspiratory loading, the system was overwhelmed and the motor cortex became the sink of the network. This major finding may help to understand why some patients with COPD are prone to acute respiratory failure. Network connectivity and causality were related to lung function and illness severity. We validated our connectivity and causality results with a mathematical model of neural network. Our findings suggest a new therapeutic strategy involving the modulation of brain activity to increase motor cortex functional connectivity and improve respiratory muscles performance in patients. Hum Brain Mapp 37:2736–2754, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Prevalence of autoantibodies in the course of Gaucher disease type 1: A multicenter study comparing Gaucher disease patients to healthy subjects

Objectives

Type 1 Gaucher disease may be related to the presence of autoantibodies. Their clinical significance is questioned.Primary endpoint was to compare the prevalence of autoantibodies in type 1 Gaucher disease patients with healthy subjects, seeking correlations with autoimmune characteristics. Secondary endpoints were to determine whether patients with autoantibodies reported autoimmunity-related symptoms and if genotype, splenectomy or treatment influenced autoantibodies presence.

Bronchial measurement with three-dimensional quantitative thin-section CT in patients with cystic fibrosis

PURPOSE: To prospectively compare bronchial measurements obtained with three-dimensional quantitative thin-section computed tomography (CT) with those obtained with thin-section CT scores in the assessment of the severity of pulmonary cystic fibrosis (CF). MATERIALS AND METHODS: Ethics committee approval was obtained. Sixteen patients with CF (mean age, 26.6 years; range, 18-42 years) and five healthy volunteers (mean age, 27.4 years; range, 21-44 years) gave written informed consent, underwent multi-detector row CT and a pulmonary function test (PFT), and were divided into three groups: group A, healthy volunteers; group B, patients with mild CF (forced expiratory volume in 1 second [FEV(1)] > 80%); and group C, patients with severe CF (FEV(1) < 80%). Two observers obtained thin-section CT scores with eight scoring systems. Bronchial cross-sectional wall area (WA), lumen area (LA), airway area, and wall thickness (WT) were measured with customized software and were normalized on the basis of subject body surface. Morphologic characteristics, PFT results, thin-section CT scores, and quantitative measurements were compared among the three groups with analysis of variance. Correlations among bronchial measurements, PFT results, and CT scores were calculated with the Spearman correlation coefficient. RESULTS: Thin-section CT scores were different between group C and either group A or group B (P < .05). WA and WT were significantly different among all groups (P < .05). Interscore correlations and correlations between bronchial parameters and scores were high (r > 0.89, P < .0001). Scores, WA, and WT were significantly correlated with PFT obstructive indexes (P < .047). CONCLUSION: WA and WT assessed with dedicated software on multi-detector row CT images allow evaluation of the severity of pulmonary CF.     

Does chemotherapy influence the quantification of SUV when contrast-enhanced CT is used in PET/CT in lymphoma?

Purpose In patients with lymphoma, we investigated the impact of contrast-enhanced CT on PET attenuation correction in lesions and normal tissues, particularly when PET/CT was performed after chemotherapy. Methods Fifty patients (51±18 years) with Hodgkin’s disease (n=17) or non-Hodgkin lymphomas (n=33) were studied before and after chemotherapy. PET/CT scans were performed 60 min after injection of FDG. Iopamiron 300 (iopamidol, 1.5 cc/kg) was injected immediately afterwards, followed 50 s later by a second craniocaudal CT (CT+). PET images were successively reconstructed using the unenhanced CT (PET−) and the CT+ (PET+) for attenuation correction, using iterative reconstruction (4 iterations, 8 subsets, 5 mm post-filtering). HU_mean, SUV_max and SUV_mean were measured before and after chemotherapy in ten non-tumoural ROIs [aorta, femur, kidney, lung, iliopsoas muscle, occipital cortex, T12 vertebra, liver, spleen and inferior vena cava (IVC)] and in tumoural lymphadenopathies or malignant tissues (n=397 and 51 VOIs respectively before and after chemotherapy) using a 3D-thresholding method (identical threshold for PET− and PET+). ROIs were defined on the PET− and automatically applied on the unenhanced CT (CT−), the CT+ and the PET+. Results In the non-tumoural tissues, HU_mean increased significantly in the CT+ compared with the CT− in the vessels and the highly vascularised organs, and slight increases were observed in the occipital cortex (+11%), the iliopsoas muscle (+6%) and the femur (+3%). SUV_max increased significantly in the PET+ compared with the PET− in the aorta (+14%), the liver (+10%), the spleen (+10%) and the IVC (+12%). SUV_mean increased significantly in the PET+ compared with the PET− in the aorta (+15%), the kidney (+13%), the liver (+11%), the spleen (10%) and the IVC (+12%). In the lesions, HU_mean was not significantly different before and after chemotherapy, whatever the normal region considered. SUV_max increased significantly after treatment in the T12 vertebra (+12%). SUV_mean increased significantly after treatment in the T12 vertebra (+13%) and in the liver (+12%). HU_mean increased significantly in the CT+ compared with the CT− in the lesions (+55%) before chemotherapy. SUV_max and SUV_mean increased significantly in the PET+ compared with the PET− in the lesions (+4%) only before chemotherapy. No significant difference was seen in measurements (HU_mean, SUV_max and SUV_mean) after chemotherapy. Conclusion Our study demonstrates that use of enhanced CT for attenuation correction has a negligible effect on quantification at staging and after chemotherapy. A “single-shot” enhanced PET/CT may thus be performed in the evaluation of patients with lymphoma at staging, during treatment and at follow-up.     

Validation of prognostic scores for survival in cancer patients beyond first-line therapy

Background

DNA methylation in the SHOX2 locus was previously used to reliably detect lung cancer in a group of critical controls, including 'cytologically negative' samples with no visible tumor cell content, at a high specificity based on the analysis of bronchial lavage samples. This study aimed to investigate, if the methylation correlates with SHOX2 gene expression and/or copy number alterations. An amplification of the SHOX2 gene locus together with the observed tumor-specific hypermethylation might explain the good performance of this marker in bronchial lavage samples.

Methods

SHOX2 expression, gene copy number and DNA methylation were determined in lung tumor tissues and matched morphologically normal adjacent tissues (NAT) from 55 lung cancer patients. Quantitative HeavyMethyl (HM) real-time PCR was used to detect SHOX2 DNA methylation levels. SHOX2 expression was assayed with quantitative real-time PCR, and copy numbers alterations were measured with conventional real-time PCR and array CGH.

Results

A hypermethylation of the SHOX2 locus in tumor tissue as compared to the matched NAT from the same patient was detected in 96% of tumors from a group of 55 lung cancer patients. This correlated highly significantly with the frequent occurrence of copy number amplification (p < 0.0001), while the expression of the SHOX2 gene showed no difference.

Conclusions

Frequent gene amplification correlated with hypermethylation of the SHOX2 gene locus. This concerted effect qualifies SHOX2 DNA methylation as a biomarker for lung cancer diagnosis, especially when sensitive detection is needed, i.e. in bronchial lavage or blood samples.