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.

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.

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.