Satomi Shiota

Alterations in upper airway cross-sectional area in response to lower body positive pressure in healthy subjects

Background: Fluid accumulation in the neck during recumbency might narrow the upper airway (UA) and thereby contribute to its collapse in patients with obstructive sleep apnoea (OSA). It is hypothesised that acute fluid shifts from the legs to the upper body in healthy subjects would increase neck circumference and reduce the cross-sectional area of the UA (UA-XSA). Methods: In 27 healthy non-obese subjects of mean (SE) age 39 (3) years and body mass index 23.2 (0.6) kg/m2 studied while supine, leg fluid volume was measured using bioelectrical impedance, neck circumference using a mercury strain gauge and mean UA-XSA between the velum and the glottis using acoustic pharyngometry at end expiration. Measurements were made at baseline after which subjects were randomly assigned to a 5 min time control period or to a 5 min application of lower body positive pressure (LBPP) at 40 mm Hg by anti-shock trousers, separated by a 15 min washout period. Subjects then crossed over to the opposite arm of the study. Results: Compared with control, application of LBPP significantly reduced leg fluid volume (p<0.001) and increased neck circumference (p<0.001), both at 1 min and 5 min, and reduced UA-XSA after both 1 min (−0.15 cm2; 95% CI −0.23 to −0.09, p<0.001) and 5 min (−0.20 cm2; 95% CI −0.33 to −0.09, p<0.001). Conclusion: In healthy subjects, displacement of fluid from the legs by LBPP causes distension of the neck and narrowing of the UA lumen. Fluid displacement from the lower to the upper body while recumbent may contribute to pharyngeal narrowing and obstruction to airflow in patients with OSA. This may have particular pathological significance in oedematous states such as heart and renal failure.

Lower body positive pressure increases upper airway collapsibility in healthy subjects

We previously showed that rostral fluid displacement by lower body positive pressure (LBPP) narrows the upper airway (UA) and increases UA resistance, but effects on UA collapsibility remained unknown. To test if LBPP increases UA collapsibility, 13 healthy men were randomized into a control or LBPP arm then crossed over into the other arm with a 30-min washout in between. LBPP was applied by inflating anti-shock trousers wrapped around both legs to 40 mmHg. UA collapsibility was assessed by determining UA critical closing pressure (P crit) during application of different negative airway pressures. P crit and leg fluid volume were measured at baseline and after 5 min during both periods. LBPP caused a significant increase in P crit associated with a reduction in leg fluid volume. We conclude that rostral fluid displacement by LBPP increases UA collapsibility in healthy men, suggesting that fluid shift into the neck could increase UA collapsibility during sleep and thereby predispose patients with fluid overload states to obstructive sleep apnea.

Difference in upper airway collapsibility during wakefulness between men and women in response to lower-body positive pressure.

Fluid shift from the legs to the neck induced by LBPP (lower-body positive pressure) increases UA (upper airway) collapsibility in healthy men. Rostral fluid displacement during recumbency may therefore contribute to the pathogenesis of OSA (obstructive sleep apnoea). There is a higher prevalence of OSA in men than in women. We therefore hypothesized that UA collapsibility increases more in men in response to rostral fluid displacement than in women. UA collapsibility was assessed in healthy, non-obese men and women while awake by determining UA Pcrit (critical closing pressure) during application of different suction pressures to the UA. Subjects were randomized to 5 min control or LBPP arms after which they crossed-over into the other arm following a 30 min washout. LBPP was applied by inflating anti-shock trousers wrapped around both legs to 40 mmHg. Pcrit, leg fluid volume and neck circumference were measured at baseline and after 5 min of both control and LBPP periods. LBPP caused a decrease in leg fluid volume and an increase in neck circumference that did not differ between men and women. However, compared with the control period, LBPP induced a much greater increase in Pcrit in men than in women (7.2+/-1.8 compared with 2.0+/-1.5 cm H2O, P=0.035). We conclude that rostral fluid displacement by LBPP increases UA collapsibility more in healthy, non-obese men than in women. This may be one mechanism contributing to the higher prevalence of OSA in men than in women.

Predictive equations and the reliability of the impulse oscillatory system in Japanese adult subjects

Background:  The impulse oscillation system (IOS) measures respiratory impedance (Zrs) in terms of resistance (Rrs) and reactance (Xrs) at multiples of 5 Hz. These measurements can be used clinically to help diagnose and monitor respiratory disorders, independent of effort.

Chronic intermittent hypoxia/reoxygenation facilitate amyloid-β generation in mice.

Previous studies have shown a high prevalence of obstructive sleep apnea (OSA) among patients with Alzheimers disease (AD). However, it is poorly assessed whether chronic intermittent hypoxia (CIH), which is a characteristic of OSA, affects the pathophysiology of AD. We aimed to investigate the direct effect of intermittent hypoxia (IH) in pathophysiology of AD in vivo and in vitro. In vivo, 15 male triple transgenic AD mice were exposed to either CIH or normoxia (5% O2 and 21% O2 every 10 min, 8 h/day for 4 weeks). Amyloid-β (Aβ) profile, cognitive brain function, and brain pathology were evaluated. In vitro, human neuroblastoma SH-SY5Y cells stably expressing wild-type amyloid-β protein precursor were exposed to either IH (8 cycles of 1% O2 for 10 min followed by 21% O2 for 20 min) or normoxia. The Aβ profile in the conditioned medium was analyzed. CIH significantly increased levels of Aβ42 but not Aβ40 in the brains of mice without the increase in hypoxia-inducible factor 1, alpha subunit (HIF-1α) expression. Furthermore, CIH significantly increased intracellular Aβ in the brain cortex. There were no significant changes in cognitive function. IH significantly increased levels of Aβ42 in the medium of SH-SY5Y cells without the increase in the HIF-1α expression. CIH directly and selectively increased levels of Aβ42 in the AD model. Our results suggest that OSA would aggravate AD. Early detection and intervention of OSA in AD may help to alleviate the progression of the disease.

Protein-losing Enteropathy Caused by Intestinal or Colonic Lymphangiectasia Complicated by Sporadic Lymphangioleiomyomatosis: A Report of Two Cases

This report describes two patients with sporadic lymphangioleiomyomatosis complicated by protein-losing enteropathy (PLE). Imaging studies indicated retroperitoneal lymphangioleiomyomas and abnormalities of the adjacent digestive tract. Endoscopic mucosal biopsy revealed colonic lymphangiectasia in one patient; whereas the site in the other patient was intestinal. Treatment with sirolimus led to the complete resolution of PLE within several months; additionally, marked shrinkage was observed in the lymphangioleiomyomas of both cases. These findings suggest that colonic or intestinal lymphatic congestion due to neighboring lymphangioleiomyomas was the mechanism for the development of PLE. At the time of writing this report, the beneficial effect of sirolimus has lasted for more than 3 years.

Successful treatment with weekly high-dose erlotinib against meningeal metastases from epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma.

1016/j.resinv.2016.04.001 he Japanese Respiratory Society. Published by Else B, blood–brain barrier; CNS, central nervous s FR, epidermal growth factor receptor; MRI, ma e inhibitor hor. Tel.: þ81 3 5802 1063; fax: þ81 3 5802 1617. s: rkanema@juntendo.ac.jp (R. Kanemaru), ymorio .ac.jp (H. Takekawa), jo@juntendo.ac.jp (H. Jo), ffu .ac.jp (R. Koyama), sshiota@juntendo.ac.jp (S. Shio .ac.jp (K. Takahashi). limitations as a therapeutic strategy due to the blood–brain barrier (BBB). While therapeutic concentrations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the CNS cannot be easily established across the BBB at standard dosing regimens, erlotinib, an EGFR TKI, has been reported to achieve some penetration across the BBB, demonstrating a higher concentration than gefitinib, another EGFR TKI, in the cerebrospinal fluid [2]. In several series of patients

Practical surrogate marker of pulmonary dysanapsis by simple spirometry: an observational case-control study in primary care.

BackgroundWe see patients who present with spirometry airflow limitation despite their forced expiratory volume in one second (FEV1) as well as forced vital capacity (FVC) to be supernormal (FEV1/FVC < 70%, both the %FEV1 and the %FVC ≧100%) in asymptomatic healthy non-smokers. Based on previous studies, we hypothesized these spirometry conditions (results measured with spirometry) could be suitably used as a practical surrogate marker of pulmonary dysanapsis: the condition of disproportionate but physiologically normal growth between airways and lung parenchyma.MethodsWe compared the conventional surrogate marker of dysanapsis, maximum mid-expiratory flow to FVC (MMF/FVC), in SUBJECTS (FEV1/FVC < 70%, both the %FEV1 and the %FVC ≧100% in healthy non-smokers) (n = 25), in EMPHYSEMA (CT confirmed pulmonary emphysema, same spirometry results with SUBJECTS) (n = 55), and in CONTROLS (age- and height- matched, normal spirometry results) (n = 25). Next we added imaging analysis to evaluate the relationship between the cross sectional airway luminal area (X-Ai) and the lung volume results among the three groups.ResultsThe MMF/FVC was significantly lower in SUBJECTS and in EMPHYSEMA compared to CONTROLS. However, percent predicted peak expiratory flow (%PEFR) was significantly lower only in SUBJECTS and not in EMPHYSEMA compared to CONTROLS. The ratio of the X-Ai of the trachea and right apical bronchus to lung volume was significantly lower in SUBJECTS compared to CONTROLS.ConclusionThe simple spirometry conditions in SUBJECTS are highly suggestive of practical surrogate marker of pulmonary dysanapsis. Awareness of this concept would help to attenuate the risk of overdiagnosis of obstructive pulmonary disease.

Pulmonary Intravascular Large B-cell Lymphoma (IVLBCL) Disguised as an Asthma Exacerbation in a Patient with Asthma

A 62-year-old man with asthma presented with a 1-month history of wheezing and exertional dyspnea. Although the wheezing symptoms disappeared after systemic corticosteroid therapy, the exertional dyspnea and hypoxemia did not improve. A diagnosis of intravascular large B-cell lymphoma (IVLBCL) with pulmonary involvement was suspected because of the increased serum lactic dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) level, increased alveolar-arterial oxygen difference (AaDO2), decreased pulmonary diffusing capacity for carbon monoxide (DLCO) and scintigraphic, computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT findings. The patient was diagnosed as having IVLBCL with pulmonary involvement based on a pathological analysis of a random skin biopsy and a transbronchial lung biopsy. IVLBCL should be considered in patients with symptoms of asthma that are refractory to corticosteroid treatment.

Effects of transdermal tulobuterol on dyspnea and respiratory function during exercise in patients with chronic obstructive pulmonary disease

BACKGROUND Poor exercise tolerability is a major barrier to improving the quality of life of patients with chronic obstructive pulmonary disease (COPD). Although COPD is often treated with long-acting β2 adrenergic agonists, few studies have examined their effects on exercise tolerability. METHODS In this study, Japanese COPD patients were treated with 2 mg transdermal tulobuterol, a long-acting β2 agonist, once daily for 4 weeks. Spirometry and exercise tests were conducted at baseline and at the end of treatment. The patients conducted constant load (30 W for 5 min) and incremental load (starting at 10 W and increasing by 10 W every 1 min for 5 min to a maximum load of 50 W) exercise tests on a cycle ergometer. RESULTS Thirteen patients with stable COPD participated in this study (mean age ± standard deviation (SD), 69.5±9.7 years; smoking history 55.9±27.8 pack-years). Resting spirometric parameters were unchanged at the end of treatment. The maximum Borg scale for dyspnea and the Borg scale slope (BSS) decreased significantly from baseline to the end of treatment. The threshold load of dyspnea (TLD) increased slightly, although not significantly, in the constant load test but not in the incremental load test. There were no changes in respiratory parameters during exercise after treatment. CONCLUSIONS In conclusion, we found that treatment with transdermal tulobuterol for 4 weeks improved self-assessed dyspnea in Japanese COPD patients during constant and incremental exercise tests. This improvement in dyspnea may encourage patients to perform daily life activities or regular physical activity.