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.

Efficacy of intra-tendinous injection of platelet-rich plasma in treating tendinosis: comprehensive assessment of a rat model.

OBJECTIVES: To assess the potential of intra-tendinous injection of platelet rich plasma (PRP) to treat tendinosis (T+) in a rat model of patellar and Achilles T+, and evaluate its local toxicity. METHODS: Thirty rats (120 patellar and Achilles tendons) were used. We induced T+ into 80 tendons (patellar = 40, Achilles = 40) by injecting collagenase at day 0 under ultrasound (US) guidance. Clinical examination and US at day 3, followed by US-guided intra-tendinous injection of either PRP (PRPT+, n = 40) or physiological serum (ST+, n = 40, control). Follow-up was at days 6, 13, 18 and 25 using clinical, US and histological evaluation. To study PRP toxicity, we injected PRP into 40 normal tendons (PRPT-) and compared with 40 untreated normal tendons (T-). RESULTS: All PRPT+ showed better joint mobilisation compared with ST+ at day 6 (P = 0.005), day 13 (P = 0.02), day 18 (P = 0.003) and day 25 (P = 0.01). Similar results were found regarding US and histology, with smaller collagen fibre diameters (day 6, P = 0.003, day 25, P ≤ 0.004), less disorganisation and fewer neovessels (day 6, P = 0.003, day 25, P = 0.0003) in PRPT+ compared with ST+. Comparison between PRPT- and T- showed no PRP toxicity (P = 0.18). CONCLUSIONS: Our study suggests that mono-injection of PRP in T+ improves tendon healing, with no local toxicity. KEY POINTS: • We assessed the potential of platelet rich plasma (PRP) to treat tendinosis. • We treated patellar and Achilles tendinosis in a rat model. • We evaluated clinical, imaging and histological data. • Intra-tendinous PRP injection could be useful in the treatment of tendinosis.

Tumoral hypoxia in osteosarcoma in rats: preliminary study of blood oxygenation level-dependent functional MRI and 18F-misonidazole PET/CT with diffusion-weighted MRI correlation.

OBJECTIVE: The prognostic implication of oxygen concentration as a factor in recurrence of solid tumors has been proved. Hypoxic osteosarcoma, imaged with (18)F-misonidazole PET/CT, is the most frequent primary malignant bone tumor. The aim of our study was to determine the role of blood oxygenation level-dependent (BOLD) functional MRI in an osteosarcoma rodent model by comparison of oxygenation levels in BOLD functional MRI and (18)F-misonidazole PET/CT and correlating the findings with those of diffusion-weighted MRI (DWI). MATERIALS AND METHODS: After validation of a hypoxic rodent model, 3-T MRI of osteosarcoma grafted in eight rats, including anatomic, DWI, and BOLD sequences in ambient air and after 2 and 3 minutes of impregnation of 8 L/min of oxygen, was performed on days 10, 17, and 24 after tumor grafting. (18)F-misonidazole PET/CT was performed on day 26, and the rats were sacrificed on day 27 for specific screening of markers of hypoxia. We measured BOLD signal intensity in tumors and normal tissue and compared these results with those on apparent diffusion coefficient maps and (18)F-misonidazole uptake according to maximum standardized uptake value ratio between tumor and healthy spongy bone. RESULTS: Hypoxia was confirmed by histologic study in all cases. We found a significant difference (day 17, p = 0.0038; day 24, p = 0.0051) in the decrease in signal intensity of hypoxic tumor in the presence of oxygen compared with ambient air without relation to duration of oxygen impregnation (p = 0.06). We found a significant correlation (p = 0.003) between BOLD signal intensity and maximum standardized uptake value at (18)F-misonidazole PET/CT. We found no correlation between the decrease in BOLD signal intensity and apparent diffusion coefficient (p = 0.07). CONCLUSION: BOLD functional MRI may be a promising tool for noninvasive functional imaging of bone tumors, but additional developments are necessary to permit its use in clinical practice.

Diffusion lesion reversal after thrombolysis: a MR correlate of early neurological improvement.

BACKGROUND AND PURPOSE: In acute stroke, diffusion-weighted imaging (DWI) lesions are commonly considered markers of irreversible ischemia yet can occasionally reverse. However, the extent and clinical correlates of DWI reversal in thrombolyzed patients remain unclear. We assessed the extent of reversible acute DWI lesions (RADs) and their relationships with clinical outcome in patients thrombolyzed≤4.5 hours from onset. METHODS: Data were retrospectively analyzed. RAD was defined as an acute DWI lesion not part of a 24-hour DWI lesion as determined voxelwise. Associations with an early neurological improvement (early neurological improvement=ΔNational Institutes of Health Stroke Scale≥8 or National Institutes of Health Stroke Scale≤2 at 24 hours) or an excellent outcome (modified Rankin Scale≤1) were assessed in multivariate analyses. RESULTS: One hundred seventy-six patients were included. The median (interquartile range) time to treatment from onset was 150 minutes (120-194). Eighty-nine patients (50%) exhibited visually-detectable RAD irrespective of its extent. Over the whole population, the median percentage and volume of RAD were 11% (4-36) and 2.4 mL (0.5-8). Subtracting RAD from initial DWI altered perfusion-weighted imaging-DWI classification in 5 of 100 patients (shift from "no mismatch" to "mismatch" profile in all). Percent RAD was significantly greater in patients treated≤3 hours (P=0.049), without proximal occlusion (P=0.003), and in 24-hour recanalizers (P<0.001). Early neurological improvement was independently associated with percent RAD. This association increased with percent RAD split in quartiles in a "dose-dependent" manner (P for trend=0.01). Excellent outcome was independently associated with percent RAD (P for trend<0.001). CONCLUSIONS: DWI reversal was often sizeable in patients treated≤4.5 hours. It was strongly associated with, albeit not necessarily causal for, early neurological improvement.

Pulmonary radiofrequency ablation in patients with a single lung: feasibility, efficacy, and tolerance.

PURPOSE: To evaluate the feasibility, efficacy, and tolerance of pulmonary radiofrequency (RF) ablation for the treatment of lung tumors in patients with a single lung. MATERIALS AND METHODS: This was a retrospective study from four institutions, with waiver of institutional review board approval and of informed consent. From July 2003 to March 2009, 15 single-lung patients (nine men and six women; mean age, 64 years; age range, 42-82 years) with one to three lung tumors underwent 16 sessions of RF ablation. One patient underwent two sessions due to occurrence of new tumors. Eleven patients had primary lung cancer and four patients had metastases. The previous pneumonectomy was performed for the treatment of primary or secondary lung tumors. Twenty-one tumors measuring 4-37 mm (mean, 15.5 mm ± 8 [standard deviation]) were treated. All procedures were performed by using general anesthesia with intubation. Electrodes were expandable in 13 procedures and straight in three. The efficacy was evaluated with computed tomography (CT) or positron emission tomography (PET)/CT, performed 3, 6, 12, and 18 months and 2 years after treatment. The median follow-up was 17.6 months, with seven patients being followed at 1 year and three being followed at 2 years. Treatment tolerance was evaluated from results of clinical examination, follow-up CT, and CT performed immediately after completion of RF ablation. RESULTS: No procedural deaths occurred. Procedural complications observed at CT during RF ablation were mild parenchymal hemorrhages (n = 5; 31%). All pneumothoraces (n = 6; 37%) resolved after chest tube placement. Postprocedural complications included one case of pulmonary infection and two cases of limited hemoptysis. Complete tumor ablation was obtained in all RF sessions but one (15 of 16; 95%). Overall survival rate was 71.4% (95% confidence interval [CI]: 36%, 92%) at 2 years; cancer-specific survival was 100% at 2 years. The tumor-free survival was 58.7% (95% CI: 32%, 81%) at 1 year and 19.6% (95% CI: 4%, 58%) at 2 years. CONCLUSION: RF ablation appears to be a reasonable and safe option in patients with a single lung.

Cerebral microbleeds are frequent in infective endocarditis: a case-control study.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) have been described using MRI in patients with cardiovascular risk factors or prior stroke and could be an indicator of small vessel disease. CMBs have been reported in isolated cases of infective endocarditis (IE), but their frequency and the association of CMBs with IE have not yet been studied. METHODS: A case-control imaging study in a referral institutional tertiary care center was conducted. Systematic brain MRIs, including T2*-weighted sequences, were performed in 60 patients with IE within 7 days of hospital admission and in 120 age- and gender-matched control subjects without IE. Two neuroradiologists, who were blinded to patient characteristics, independently assessed the presence, location, and size of CMBs using a standardized form. RESULTS: The interobserver agreement level on the presence of CMBs was high with a kappa coefficient range (95% CI) of 0.70 (0.42 to 0.98) for subcortical regions to 0.91 (0.82 to 0.99) for cortical areas. CMBs were more prevalent in patients with IE (57% [n=34]) than in control subjects (15% [n=18]; matched OR, 10.06; 95% CI, 3.88 to 26.07). Moreover, the OR of IE increased gradually with CMBs number with an OR of 6.12 (95% CI, 2.09 to 17.94) for one to 3 CMBs and of 20.12 (95% CI, 5.20 to 77.80) for >3 CMBs. CONCLUSIONS: CMBs are highly frequent in patients with IE. The strong association found between IE and CMBs supports the need for further evaluation of CMBs as additional diagnostic criteria of IE.

Neural mechanisms underlying breathing complexity.

Breathing is maintained and controlled by a network of automatic neurons in the brainstem that generate respiratory rhythm and receive regulatory inputs. Breathing complexity therefore arises from respiratory central pattern generators modulated by peripheral and supra-spinal inputs. Very little is known on the brainstem neural substrates underlying breathing complexity in humans. We used both experimental and theoretical approaches to decipher these mechanisms in healthy humans and patients with chronic obstructive pulmonary disease (COPD). COPD is the most frequent chronic lung disease in the general population mainly due to tobacco smoke. In patients, airflow obstruction associated with hyperinflation and respiratory muscles weakness are key factors contributing to load-capacity imbalance and hence increased respiratory drive. Unexpectedly, we found that the patients breathed with a higher level of complexity during inspiration and expiration than controls. Using functional magnetic resonance imaging (fMRI), we scanned the brain of the participants to analyze the activity of two small regions involved in respiratory rhythmogenesis, the rostral ventro-lateral (VL) medulla (pre-Bötzinger complex) and the caudal VL pons (parafacial group). fMRI revealed in controls higher activity of the VL medulla suggesting active inspiration, while in patients higher activity of the VL pons suggesting active expiration. COPD patients reactivate the parafacial to sustain ventilation. These findings may be involved in the onset of respiratory failure when the neural network becomes overwhelmed by respiratory overload We show that central neural activity correlates with airflow complexity in healthy subjects and COPD patients, at rest and during inspiratory loading. We finally used a theoretical approach of respiratory rhythmogenesis that reproduces the kernel activity of neurons involved in the automatic breathing. The model reveals how a chaotic activity in neurons can contribute to chaos in airflow and reproduces key experimental fMRI findings.

Acceleration of tendon healing using US guided intratendinous injection of bevacizumab: first pre-clinical study on a murine model.

PURPOSE: Tendinopathy shows early disorganized collagen fibers with neo-angiogenesis on histology. Peri-tendinous injection of corticosteroid is the commonly accepted strategy despite the abscence of inflammation in tendinosis. The aim of our study was to assess the potential of intratendinous injection of an anti-angiogenic drug (bevacizumab, AA) to treat tendinopathy in a murine model of patellar and Achilles tendinopathy, and to evaluate its local toxicity. MATERIALS AND METHOD: Forty rats (160 patellar and Achilles tendons) were used for this study. We induced tendinosis (T+) in 80 tendons by injecting under ultrasonography (US) guidance Collagenase 1(®) (day 0 = D0, patellar = 40 and Achilles = 40). Clinical examination and tendon US were performed at D3, immediately followed by either AA (AAT+, n = 40) or physiological serum (PST+, n = 40, control) US-guided intratendinous injection. Follow-up at D6 and D13 using clinical, US and histology, and comparison between the 2 groups were performed. To study AA toxicity we compared the 80 remaining normal tendons (T-) after injecting AA in 40 (AAT-). RESULTS: All AAT+ showed a better joint mobilization compared to PST+ at D6 (p = 0.004) with thinner US tendon diameters (p<0.004), and less disorganized collagen fibers and neovessels on histology (p<0.05). There was no difference at D13 regarding clinical status, US tendon diameter and histology (p>0.05). Comparison between AAT- and T- showed no AA toxicity on tendon (p = 0.18). CONCLUSION: Our study suggests that high dose mono-injection of AA in tendinosis, early after the beginning of the disease, accelerates tendon's healing, with no local toxicity.