Our results show an increase in agonist-induced calcium mobilization associated with an increase in MLC phosphorylation and an increase in ASM cell shortening in favor of agonist-induced hyperresponsiveness in HASM cells derived from obese subjects. Our studies suggest that obesity induces a retained phenotype of hyperresponsiveness in cultured human airway smooth muscle cells.
BackgroundObesity is a major worldwide public health issue. The main respiratory complication stemming from obesity is obesity hypoventilation syndrome (OHS). Most of the OHS patients diagnosed during an exacerbation are treated with non invasive ventilation (NIV). Up to date, no prospective study has demonstrated in real life conditions the feasibility of a systematic protocoled switch of NIV to continuous positive airway pressure (CPAP), once stability is achieved.MethodsIn this prospective study, we included stable patients with OHS, with moderate to severe concomitant obstructive sleep apnea (OSA) and without obstructive pulmonary disease, who had been undergoing NIV for more than 2 months. The following measurements were performed, first with NIV and then after the switch to CPAP: diurnal arterial blood gas measurements; nocturnal oximetry and capnometry; mean compliance and AHI; measures of quality of life and quality of sleep.Results22/30 patients accepted to participate in the study and 15/22 patients completed the study. There were no significant differences for pooled data in diurnal alveolar blood gases, nocturnal capnometry (p = 0.534), nocturnal oximetry (p = 0.218), mean compliance (p = 0.766), mean AHI (p = 0.334), quality of life or quality of sleep. Eighty percent of the patients treated in this study favored CPAP over NIV.ConclusionThis pilot study showed in real life conditions the possibility of a systematic switch of NIV to CPAP, in most stable patients with OHS, with similar efficacy on diurnal and nocturnal alveolar gas exchange, quality of life and quality of sleep.Trial registration ISRCTN13981084. Registered: 27 February 2017 (retrospectively registered)
The nongenomic mechanisms by which glucocorticoids modulate β2 agonist-induced-bronchodilation remain elusive. Our studies aimed to elucidate mechanisms mediating the beneficial effects of glucocorticoids on agonist-induced bronchodilation. Utilizing human precision-cut lung slices (hPCLS), we measured bronchodilation to formoterol, prostaglandin E2 (PGE2), cholera toxin (CTX), or forskolin in the presence and absence of budesonide. Using cultured human airway smooth muscle (HASM), intracellular cAMP was measured in live cells following exposure to formoterol, PGE2, or forskolin in the presence or absence of budesonide. We showed that simultaneous budesonide administration amplified formoterol-induced bronchodilation and attenuated agonist-induced phosphorylation of myosin light chain, a necessary signaling event mediating force generation. In parallel studies, cAMP levels were augmented by simultaneous exposure of HASM cells to formoterol and budesonide. Budesonide, fluticasone, and prednisone alone rapidly increased cAMP levels, but steroids alone had little effect on bronchodilation in hPCLS. Bronchodilation induced by PGE2, CTX, or forskolin was also augmented by simultaneous exposure to budesonide in hPCLS. Furthermore, HASM cells expressed membrane-bound glucocorticoid receptors that failed to translocate with glucocorticoid stimulation and that potentially mediated the rapid effects of steroids on β2 agonist-induced bronchodilation. Knockdown of glucocorticoid receptor-α had little effect on budesonide-induced and steroid-dependent augmentation of formoterol-induced cAMP generation in HASM. Collectively, these studies suggest that glucocorticoids amplify cAMP-dependent bronchodilation by directly increasing cAMP levels. These studies identify a molecular mechanism by which the combination of glucocorticoids and β2 agonists may augment bronchodilation in diseases such as asthma or chronic obstructive pulmonary disease.
BackgroundDisseminated tuberculosis (TB) or miliary TB is defined as lymphohematogenous dissemination of Mycobacterium tuberculosis bacilli, which may then affect virtually any organ system. The multiple organ involvement in disseminated TB can mimic metastatic cancer and can make the diagnosis challenging. False negatives are common therefore repeating microbiologic and histologic samples is essential.Case reportWe report the case of a young immunocompetent patient presenting with multiple atypical extra-pulmonary TB involvement. The patient presented with pulmonary, pleural, bilateral testicular and multiple bone involvement including calcanerium abscesses. These lesions were initially described as metastasis by the radiologist. Therefore lymphoma and metastatic testicular cancer as well as TB were high on the differential in this young foreign-born male. Pleural, broncho-alveolar lavage, bone marrow and cerebrospinal fluid acid-fast bacilli smear and microbiologic culture were all negative. However the histologic examination of the trans-bronchial biopsy and pleural biopsy showed necrotizing granuloma and helped to narrow down the diagnosis. The patient improved with RIPE therapy.ConclusionThis case illustrates the diagnostic difficulty of disseminated TB with atypical organ involvement. Culture is the gold standard for diagnosing TB but is a long process and with 23% of culture negative TB in the United-States, the diagnosis sometimes relies on thoroughly ruling-out differential diagnosis and histologic examination.
Authorship Contributions: DJD, SS, JR, and DEL conceived the study, had full access to the data in the study, and take responsibility for the integrity of the data and accuracy of the analyses. DJD and DEL wrote the manuscript. DJD, IP, and DEL designed the table and figure. DJD, SS, SKB, and DEL acquired the data. All authors provided feedback on the protocol and critically revised and approved the final version of the manuscript.
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