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Graphical abstract Sleep/wake cycle-dependent differences in molecular parameters controlling mitochondrial ability to regulate cellular levels of calcium and associated ROS production., Introduction Incidents of myocardial infarction and sudden cardiac arrest vary with time of the day, but the mechanism for this effect is not clear. We hypothesized that diurnal changes in the ability of cardiac mitochondria to control calcium homeostasis dictate vulnerability to cardiovascular events. Objectives Here we investigate mitochondrial calcium dynamics, respiratory function, and reactive oxygen species (ROS) production in mouse heart during different phases of wake versus sleep periods. Methods We assessed time-of-the-day dependence of calcium retention capacity of isolated heart mitochondria from young male C57BL6 mice. Rhythmicity of mitochondrial-dependent oxygen consumption, ROS production and transmembrane potential in homogenates were explored using the Oroboros O2k Station equipped with a fluorescence detection module. Changes in expression of essential clock and calcium dynamics genes/proteins were also determined at sleep versus wake time points. Results Our results demonstrate that cardiac mitochondria exhibit higher calcium retention capacity and higher rates of calcium uptake during sleep period. This was associated with higher expression of clock gene Bmal1, lower expression of per2, greater expression of MICU1 gene (mitochondrial calcium uptake 1), and lower expression of the mitochondrial transition pore regulator gene cyclophilin D. Protein levels of mitochondrial calcium uniporter (MCU), MICU2, and sodium/calcium exchanger (NCLX) were also higher at sleep onset relative to wake period. While complex I and II-dependent oxygen utilization and transmembrane potential of cardiac mitochondria were lower during sleep, ROS production was increased presumably due to mitochondrial calcium sequestration. Conclusions Taken together, our results indicate that retaining mitochondrial calcium in the heart during sleep dissipates membrane potential, slows respiratory activities, and increases ROS levels, which may contribute to increased vulnerability to cardiac stress during sleep-wake transition. This pronounced daily oscillations in mitochondrial functions pertaining to stress vulnerability may at least in part explain diurnal prevalence of cardiac pathologies.

Objective Hemodialysis access-related hand dysfunction is a common clinical feature of patients with chronic kidney disease (CKD) after arteriovenous fistula (AVF) placement. The heterogeneity in symptoms and the lack of a predictive association with changes in hemodynamic alterations precipitated by the AVF suggest that other factors are involved in the mechanisms responsible for causing hand and limb dysfunction postoperatively. To the best of our knowledge, no suitable animal models have provided a platform for performing preclinical experiments designed to elucidate the biologic drivers of access-related hand dysfunction. Therefore, our objective was to develop a novel murine AVF model that could be used to study dialysis access-related limb dysfunction. Methods Male 8-week-old C57BL/6J mice (n = 15/group) were exposed to either an adenine-supplemented diet to induce CKD or casein-based chow (control). Four weeks after the diet intervention, the mice were randomly assigned to receive an iliac AVF (n = 10/group) or sham surgery (n = 5/group) on the left hindlimb. The mice were sacrificed 2 weeks after surgery, and AVF specimens and hindlimb skeletal muscles were collected for further analysis. Results Before AVF or sham surgery, the glomerular filtration rates were significantly reduced and the blood urea nitrogen levels were significantly elevated in the CKD groups compared with the controls (P < .05). AVF surgery was associated with an ∼80% patency rate among the survivors (four control and three CKD mice died postoperatively). Patency was verified by changes in hemodynamics using Doppler ultrasound imaging and altered histologic morphology. Compared with sham surgery, AVF surgery reduced ipsilateral hindlimb perfusion to the tibialis anterior muscle (20%-40%) and paw (40%-50%), which remained stable until euthanasia. Analysis of gastrocnemius muscle mitochondrial respiratory function uncovered a significant decrease (40%-50%) in mitochondrial function in the AVF mice. No changes were found in the muscle mass, myofiber cross-sectional area, or centrally nucleated fiber proportion in the extensor digitorum longus and soleus muscles between the sham and AVF mice. Conclusions The results from the present study have demonstrated that iliac AVF formation is a practical animal model that facilitates examination of hemodialysis access-related limb dysfunction. AVF surgery produced the expected hemodynamic changes, and evaluation of the limb muscle revealed a substantial mitochondrial impairment that was present without changes in muscle size., Clinical Relevance Autogenous arteriovenous fistula creation remains the preferred vascular access option for patients requiring chronic hemodialysis therapy. However, access-related hand dysfunction (ARHD) remains highly prevalent in this population. Clinical management of the disability is difficult because of symptom heterogeneity and limited treatment options. Additionally, the current preclinical models do not adequately replicate the pathologic condition to allow for investigation of underlying mechanisms and to test new therapies. Therefore, medical progress has been marginal. In the present study, we have outlined a novel murine model to study ARHD and described the associated mitochondrial impairments, providing a unique tool for preclinical therapeutic development., Visual abstract

Highlights • An esophageal diverticulum is a rare condition. • Laparoscopic diverticulectomy with myotomy and fundoplication for an esophageal diverticulum is the common approach. • Mediastinoscopic esophagectomy for the patient who need esophagectomy could be an effective and noninvasive candidate procedure., Introduction An esophageal diverticulum is a rare condition, and surgery is indicated if symptomatic. We successfully performed mediastinoscopic esophagectomy for a giant esophageal diverticulum with stenosis. Presentation of case A 63-year-old man visited our hospital because of dysphagia. He had been pointed out an esophageal diverticulum at a local hospital 13 years before visiting our hospital. Upper gastrointestinal endoscopy revealed an esophageal diverticulum at the lower thoracic esophagus and the structural stenosis in the anal side of the diverticulum. Computed tomography showed a 54 mm esophageal diverticulum at the lower thoracic esophagus. Esophagectomy was required because of the structural stenosis. His medical history included chronic obstructive pulmonary disorder. So, we chose the mediastinal approach to avoid a respiratory complication. We performed mediastinoscopic esophagectomy and esophagogastrostomy via the retrosternal route. The postoperative course was good. At 9 months postoperation, there were no symptoms. Discussion Recently, laparoscopic diverticulectomy with myotomy and fundoplication has been considered the best approach in most cases. In the case with the structural stenosis, esophagectomy may be required. Conclusion Mediastinoscopic esophagectomy for the patient with poor respiratory function and who need esophagectomy could be an effective and noninvasive candidate procedure.

Tea polyphenols (TP) are the main active components of tea. In our study, the effect of TP on the menopause and aging related memory decline and the mechanisms focused on the brain glucose metabolism were clarified. In vivo, ovariectomy (OVX) combined with D-galactose (D-gal) injection were used to establish the memory decline model. TP administration improved the spatial memory by increasing the expressions of GLUT1, 3 and Tau protein O-GlcNAc glycosylation, decreasing Tau hyper-phosphorylation and the Aβ1-42 level, and improving the morphology of mitochondria in hippocampus. Furthermore, in vitro, PC12 cells were treated with Aβ1-42 and EGCG treatment regulated the mitochondrial respiratory function and glycolytic functions, improved the activities of the key enzymes in glycolysis and tricarboxylic acid cycle, increased the SOD activity and decreased the MDA levels in cells. Our study suggests that TP improve the memory in aging ovariectomized rats by regulating brain glucose metabolism.

Environmental inhalation exposures are inherently mixed (gases and particles), yet regulations are still based on single toxicant exposures. While the impacts of individual components of environmental pollution have received substantial attention, the impact of inhalation co-exposures is poorly understood. Here, we mechanistically investigated pulmonary inflammation and lung function decline after inhalation co-exposure and individual exposures to ozone (O3) and ultrafine carbon black (CB). Environmentally/occupationally relevant lung deposition levels in mice were achieved after inhalation of stable aerosols with similar aerodynamic and mass median distributions. X-ray photoemission spectroscopy detected increased surface oxygen contents on particles in co-exposure aerosols. Compared with individual exposures, co-exposure aerosols produced greater acellular and cellular oxidants detected by electron paramagnetic resonance (EPR) spectroscopy, and in vivo immune-spin trapping (IST), as well as synergistically increased lavage neutrophils, lavage proteins and inflammation related gene/protein expression. Co-exposure induced a significantly greater respiratory function decline compared to individual exposure. A synthetic catalase-superoxide dismutase mimetic (EUK-134) significantly blunted lung inflammation and respiratory function decline confirming the role of oxidant imbalance. We identified a significant induction of epithelial alarmin (thymic stromal lymphopoietin-TSLP)-dependent interleukin-13 pathway after co-exposure, associated with increased mucin and interferon gene expression. We provided evidence of interactive outcomes after air pollution constituent co-exposure and identified a key mechanistic pathway that can potentially explain epidemiological observation of lung function decline after an acute peak of air pollution. Developing and studying the co-exposure scenario in a standardized and controlled fashion will enable a better mechanistic understanding of how environmental exposures result in adverse outcomes., Graphical abstract Image 1, Highlights • Interaction with O3 mediates free radical production on the surface of carbon black (CB) particles. • Oxidants mediate co-exposure (CB + O3)-induced lung function decline. • EUK-134 (a synthetic superoxide-catalase mimetic) abrogates CB + O3-induced lung inflammation. • CB + O3 co-exposure induces greater lung inflammation than individual exposures. • Epithelial alarmin (TSLP) contributes significantly to the CB + O3 toxicity.

Coronavirus disease 2019 (COVID-19) is an emerging viral disease with a mortality that depends on the individual's condition. Underlying comorbidities are major risk factors for COVID-19-related morbidity and mortality. However, information regarding the clinical course of COVID-19 in patients with rare respiratory system diseases is lacking. Here, we present a case of severe COVID-19 in a patient with advanced sporadic lymphangioleiomyomatosis (LAM) who was awaiting lung transplantation. She experienced a marked worsening of her respiratory status despite the limited size of the infiltrations seen on chest computed tomography. She responded to treatment with dexamethasone and remdesivir, and did not require mechanical ventilation. She recovered her pre-COVID-19 respiratory function. This case illustrates that patients with severe lung parenchymal destruction due to advanced LAM are at risk of worsening hypoxemia, but may not have a bad outcome if managed appropriately. Prevention and early diagnosis of COVID-19 are crucial in patients with advanced LAM. Future studies are needed to improve understanding of the clinical features and optimal treatment of COVID-19 in patients with LAM.

Copper (Cu), one of the heavy metals, is far beyond the carrying capacity of the environment with Cu mining, industrial wastewater discharging and the use of Cu-containing pesticides. Intaking excess Cu can cause toxic effects on liver, kidney, heart, but few studies report Cu toxicity on brain tissue. It is noteworthy that most toxicity tests are based on rodent models, but large mammals chosen as animal models has no reported. To explore the relationship of the Cu toxicity and mitochondria-mediated apoptosis on hypothalamus in pigs, the content of Cu, histomorphology, mitochondrial related indicators, apoptosis, and AMPK-mTOR signaling pathway were detected. Results showed that Cu could accumulate in hypothalamus and lead to mitochondrial dysfunction, evidenced by the decrease of ATP production, activities of respiratory chain complex I-IV, and mitochondrial respiratory function in Cu-treated groups. Additionally, the genes and proteins expression of Bax, Caspase-3, Cytc in treatment group were higher than control group. Furthermore, the protein level of p-AMPK was enhanced significantly and p-mTOR was declined, which manifested that AMPK-mTOR signaling pathway was activated in Cu-treated groups. In conclusion, this study illuminated that the accumulation of Cu could cause mitochondrial dysfunction, induce mitochondria-mediated apoptosis and activate AMPK-mTOR pathway in hypothalamus.

The safe use of a mechanical ventilator should be followed by the fascination of intensivists with different respiratory function parameters. Naturally, this leads to the fact that these parameters should be monitored carefully and accurately. This work describes the monitoring of pressure and flow sensors in ventilation. Although end-tidal CO2 surveillance has become regular in the ICU, it is typically achieved by hold control modules incorporated into the monitoring a machine pumps the necessary amount of air through the lungs when the lungs need encouragement to take in air. Nowadays pressure sensors used in ventilators are of strain gauge type. Variable inductance type is used often in the machine. Ventilators are the pressure bag using a feedback loop from the patient's own breath, they regulate the air volume, pressure, and rate and flow in part. Oxygen ventilation systems use pressurized tanks of pure medical oxygen combined with filtered oxygen because patients with lung damage cannot obtain enough oxygen in the blood from ambient air. Moisturized ambient air to provide the patient with an oxygen-rich mixture of air. Up to 100% oxygen may be needed, depending on the severity of the trauma. The proposed work of this paper is the usage of PID controller, PID based Tyreus Luyben method to improve the pressure, flow of the ventilator. Gaussian Process Regression is used to train the samples and to minimize the error performance of the controller.

We present pathology of the peripheral nerves of a patient with Adult-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation p.D651N. The patient was a 72-year-old woman. She had hoarseness and underwent continuous positive airway pressure therapy at night due to sleep apnea. The patient died abruptly. Remarkable demyelination with tomacula formation was found in the phrenic nerve, vagal nerve, recurrent laryngeal nerve, and oculomotor nerves. The cause of death could have been insufficient reactivity to the aspiration or sudden onset of bilateral vocal cord palsy. We must pay attention to respiratory function and cranial nerve palsies in hereditary demyelinating neuropathies., Highlights • Patients with hereditary demyelinating neuropathy could die suddenly. • Demyelination of the phrenic and recurrent laryngeal nerves might be relevant. • Pathology of these nerves has been rarely reported.

Background Effective strategies are dramatically needed to prevent and improve the recovery from myocardial ischemia and reperfusion (I/R) injury. Direct interactions between the mitochondria and endoplasmic reticulum (ER) during heart diseases have been recently investigated. This study was designed to explore the cardioprotective effects of gypenoside XVII (GP-17) against I/R injury. The roles of ER stress, mitochondrial injury, and their crosstalk within I/R injury and in GP-17–induced cardioprotection are also explored. Methods Cardiac contractility function was recorded in Langendorff-perfused rat hearts. The effects of GP-17 on mitochondrial function including mitochondrial permeability transition pore opening, reactive oxygen species production, and respiratory function were determined using fluorescence detection kits on mitochondria isolated from the rat hearts. H9c2 cardiomyocytes were used to explore the effects of GP-17 on hypoxia/reoxygenation. Results We found that GP-17 inhibits myocardial apoptosis, reduces cardiac dysfunction, and improves contractile recovery in rat hearts. Our results also demonstrate that apoptosis induced by I/R is predominantly mediated by ER stress and associated with mitochondrial injury. Moreover, the cardioprotective effects of GP-17 are controlled by the PI3K/AKT and P38 signaling pathways. Conclusion GP-17 inhibits I/R-induced mitochondrial injury by delaying the onset of ER stress through the PI3K/AKT and P38 signaling pathways.

We tested a biomaterial-based approach to preserve the critical phrenic motor circuitry that controls diaphragm function by locally delivering minocycline hydrochloride (MH) following cervical spinal cord injury (SCI). MH is a clinically-available antibiotic and anti-inflammatory drug that targets a broad range of secondary injury mechanisms via its anti-inflammatory, anti-oxidant and anti-apoptotic properties. However, MH is only neuroprotective at high concentrations that cannot be achieved by systemic administration, which limits its clinical efficacy. We have developed a hydrogel-based MH delivery system that can be injected into the intrathecal space for local delivery of high concentrations of MH, without damaging spinal cord tissue. Implantation of MH hydrogel after unilateral level-C4/5 contusion SCI robustly preserved diaphragm function, as assessed by in vivo recordings of compound muscle action potential (CMAP) and electromyography (EMG) amplitudes. MH hydrogel also decreased lesion size and degeneration of cervical motor neuron somata, demonstrating its central neuroprotective effects within the injured cervical spinal cord. Furthermore, MH hydrogel significantly preserved diaphragm innervation by the axons of phrenic motor neurons (PhMNs), as assessed by both detailed neuromuscular junction (NMJ) morphological analysis and retrograde PhMN labeling from the diaphragm using cholera toxin B (CTB). In conclusion, our findings demonstrate that local MH hydrogel delivery to the injured cervical spinal cord is effective in preserving respiratory function after SCI by protecting the important neural circuitry that controls diaphragm activation.

Introduction Lymphatic anomalies (LAs) refer to a group of diseases involving systemic dysplasia of lymphatic vessels. These lesions are classified as cystic lymphatic malformation (macrocystic, microcystic or mixed), generalized lymphatic anomaly, and Gorham–Stout disease. LAs occur mainly in childhood, and present with various symptoms including chronic airway problems, recurrent infection, and organ disorders. Individuals with LAs often experience progressively worsening symptoms with a deteriorating quality of life. Although limited treatment options are available, their efficacy has not been validated in prospective clinical trials, and are usually based on case reports. Thus, there are no validated standards of care for these patients because of the lack of prospective clinical trials. Methods This open-label, single-arm, multicenter, prospective study will assess the efficacy and safety of a mammalian target of the rapamycin inhibitor sirolimus in the treatment of intractable LAs. Participants will receive oral sirolimus once a day for 52 weeks. The dose is adjusted so that the nadir concentration remains within 5–15 ng/ml. The primary endpoint is the response rate of radiological volumetric change of the target lesion confirmed by central review at 52 weeks after treatment. The secondary endpoints are the response rates at 12 and 24 weeks, respiratory function, pleural effusion, ascites, blood coagulation parameters, bleeding, pain, quality of life, activities of daily living, adverse events, side effects, laboratory examinations, vital signs, and pharmacokinetic data. Results This is among the first multicenter studies to evaluate sirolimus treatment for intractable LAs, and few studies to date have focused on the standard assessment of the efficacy for LAs treatment. Our protocol uses novel, uncomplicated methods for radiological assessment, with reference to the results of our previous retrospective survey and historical control data from the literature. Conclusions We propose a multicenter study to investigate the efficacy and safety of sirolimus for intractable LAs (SILA study; trial registration UMIN000028905). Our results will provide pivotal data to support the approval of sirolimus for the treatment of intractable LAs., Highlights • This is among the first multicenter studies to evaluate sirolimus for intractable LAs. • The study design is useful for evaluating sirolimus treatment in LAs. • Our study protocol uses novel, uncomplicated methods of radiological assessment.

Sorafenib is a standard targeted drug used to treat hepatocellular carcinoma (HCC). Notably, cytokine has been found to further enhance the therapeutic effectiveness of the targeted drug. Thereby, the aim of this study is to verify whether cytokine IL-2 could increase the anti-cancer effects of sorafenib on liver cancer in vitro. Huh7 cells were used in the present study and the cell apoptosis and migration were determined in response to sorafenib treatment. Then, siRNA and pathway blocker were used to determine the molecular mechanisms by which IL-2 enhance the therapeutic effectiveness of Huh7 liver cancer cell in vitro. The data in our study illustrated that sorafenib treatment induced apoptosis in Huh7 liver cancer cell in vitro, an effect that was accompanied with a drop in cell proliferation and migration. Biological investigation demonstrated that IL-2 supplementation further augmented the pro-apoptotic effects of sorafenib in vitro. At the molecular levels, the combination of IL-2 and sorafenib impaired mitochondrial respiratory function, reduced mitochondrial potential, promoted mitochondrial ROS overloading and activated mitochondrial apoptotic pathway. Meanwhile, we found that IL-2 supplementation induced mitochondrial stress via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. Blockade of the JNK signalling pathway and/or knockdown of TAZ could abrogate the inhibitor effects of IL-2/sorafenib on liver cancer survival, growth and mobility. Collectively, these data indicated that IL-2 supplementation could further augment the anti-cancer effectiveness of sorafenib via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. This finding identifies mitochondrial stress and the JNK-Hippo pathway as the potential targets to treat liver cancer.

Background: Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control. Methods: We conducted a single-center prospective cohort study involving 168 asthmatic children aged 4–17 years who visited the periodical asthma checkup program. Serum neopterin and biopterin levels were measured as pteridines at each visit along with measurement of FeNO, respiratory function tests, nasal eosinophil test, blood eosinophil count, and IgE level. We calculated coefficients for relation between pteridines and asthma control, which was assessed by questionnaires (JPAC: Japanese Pediatric Asthma Control Program). Results: A total of 168 participants aged 10.3 ± 3.39 years (mean ± SD) with asthma were recruited. The participants in this study contained 58 patients (34.5%) of complete-controlled based on JPAC, 132 patients (76.0%) of well-controlled group based on GINA. FeNO and serum neopterin level did not correlate with following period's JPAC scores. In contrast, serum biopterin level significantly correlated with following period's JPAC total score (Coefficients 0.398; 95% CI 0.164 to 0.632; p value 0.001) and frequency of wheezing during exercise (Coefficients 0.272; 95% CI 0.217 to 0.328; p value

Summary Background Being recently released from prison or discharged from hospital, or being dispensed opioids, benzodiazepines, or antipsychotics have been associated with an increased risk of fatal drug overdose. This study aimed to examine the association between these periods and non-fatal drug overdose using a within-person design. Methods In this self-controlled case series, we used data from the provincial health insurance client roster to identify a 20% random sample of residents (aged ≥10 years) in British Columbia, Canada between Jan 1, 2015, and Dec 31, 2017 (n=921 346). Individuals aged younger than 10 years as of Jan 1, 2015, or who did not have their sex recorded in the client roster were excluded. We used linked provincial health and correctional records to identify a cohort of individuals who had a non-fatal overdose resulting in medical care during this time period, and key exposures, including periods of incarceration, admission to hospital, emergency department care, and supply of medications for opioid use disorder (MOUD), opioids for pain (unrelated to MOUD), benzodiazepines, and antipsychotics. Using a self-controlled case series, we examined the association between the time periods during and after each of these exposures and the incidence of non-fatal overdose with case-only, conditional Poisson regression analysis. Sensitivity analyses included recurrent overdoses and pre-exposure risk periods. Findings We identified 4149 individuals who had a non-fatal overdose in 2015–17. Compared with unexposed periods (ie, all follow-up time that was not part of a designated risk period for each exposure), the incidence of non-fatal overdose was higher on the day of admission to prison (adjusted incidence rate ratio [aIRR] 2·76 [95% CI 1·51–5·04]), at 1–2 weeks (2·92 [2·37–3·61]), and 3–4 weeks (1·34 [1·01–1·78]) after release from prison, 1–2 weeks after discharge from hospital (1·35 [1·11–1·63]), when being dispensed opioids for pain (after ≥4 weeks) or benzodiazepines (entire use period), and from 3 weeks after discontinuing antipsychotics. The incidence of non-fatal overdose was reduced during use of MOUD (aIRRs ranging from 0·33 [0·26–0·42] to 0·41 [0·25–0·67]) and when in prison (0·12 [0·08–0·19]). Interpretation Expanding access to and increasing support for stable and long-term medication for the management of opioid use disorder, improving continuity of care when transitioning between service systems, and ensuring safe prescribing and medication monitoring processes for medications that reduce respiratory function (eg, benzodiazepines) could decrease the incidence of non-fatal overdose. Funding Murdoch Children's Research Institute and National Health and Medical Research Council.

Purpose Adjuvant durvalumab has become a standard treatment after chemoradiation therapy for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Accordingly, predicting radiation pneumonitis (RP) requiring steroidal treatment (steroid-RP) is of utmost importance because steroidal administration is reported to weaken the effectiveness of immunotherapy. However, grade 2 RP was used as an index of RP in previous studies, but it is an ambiguous definition because it includes not only steroid-RP but also a mild cough requiring only a cough medicine. Therefore, in this study, steroid-RP was used for evaluating RP, and the purpose of this study was to investigate predictive factors of steroid-RP, including original simple interstitial lung abnormality scores (ILASs). Methods and Materials A total of 145 patients with LA-NSCLC who received definitive radiation therapy (DRT) in our institution from January 2014 to May 2017 were identified. Original ILASs, performance status, age, respiratory function, Brinkman index, concurrent administration of chemotherapy, and dose–volume histogram metrics of the lung were analyzed to evaluate their association with steroid-RP. Additionally, 3 diagnostic radiologists evaluated the patients’ pre-DRT chest computed tomography images and determined the simple ILASs. ILASs were rated as follows: 0: none; 1: abnormality without honeycombing (ground-glass attenuation, fine reticular opacity, and microcysts); and 2: honeycombing. Results The median follow-up period was 729 days. Thirty-one patients (21.4%) experienced steroid-RP. In the univariate analysis, lung V5/V10/VS5, Brinkman index, and ILASs were significant predictive factors of steroid-RP. Additionally, multivariate analysis including Brinkman index ≥840, lung V5 ≥37%, and an ILAS ≥1 revealed that only an ILAS (P = .001) was an independent predictive factor of steroid-RP. Conclusions The original simple ILAS was an easy-to-use tool and a significant predictive factor of steroid-RP in DRT in patients with LA-NSCLC.

For persons infected with SARS-CoV-2, the virus affects the vital organ function, but especially the respiratory function. The experts have proposed several treatments for COVID patients with a good rate of success. For every age, there are indications of the maximum heart rate and the optimal heart rate range (between 60% and 90% of the maximum heart rate), which leads to an improvement for one’s physical condition. Because the Coronavirus particularly affects the respiratory function, after the convalescence period it is recommended to practice some respiratory exercises and low to moderate intensity physical activity.

Physiotherapeutic management for patients with COVID-19 emphasizes the importance of improving respiratory function by reducing respiratory effort and optimizing oxygenation. The need for an approach specific to patients who exhibit symptoms associated with infection with COVID-19 is shown in the main fact that patients who develop medium and severe forms of this disease have oftentimes one or more diagnosis in the cardiorespiratory, oncology, renal, metabolic, etc. fields. Such treatment must be individualized, taking into account the conditions associated with the health state of the patient. The treatment is drafted by overlapping the efforts of a multidisciplinary team: physician, assistants, and physiotherapist, all of them having the same achieved goal: ensuring, at discharge from the hospital, a patient with improved signs and symptoms, able to continue their daily activities on their own. Early rehabilitation therapy for patients with COVID-19 with critical stages and average stages aims to decrease breathing difficulties, provide relief of symptoms, relieve anxiety and depression, and decrease the incidence of complications. The intervention process of early rehabilitation is applied after a general clinical assessment. The functional respiratory assessment (the evaluation of the activity of the thoracic cage, the amplitude of diaphragm activity, the pattern and breathing frequency), the heart status, the capacity to mobilize, and the ability to realize ADL must be highlighted. The rehabilitation therapy of the patients with COVID-19 includes mainly the posture management and respiratory physiotherapy. Change of posture can change the ratio of ventilation/perfusion and may lead to an improvement in the exchange of gases, but may lead to an unexpected worsening. It is recommended to use the pillows and auxiliary devices which permit a comfortable, stable position, without the need of any effort of the patient. The postural drainage can reduce the influence of sputum on the respiratory tract, which is particularly important to improve the ratio V/Q (ventilation/perfusion). The patients need to be educated to get themselves in a position that will allow gravity to assist in draining the excretions of the pulmonary lobes or the lung segments. Standing is the best position of the body for breathing in the state of rest. Physical exercises can completely expand the lungs and help in removing secretions in the lung alveoli and respiratory ways. Also the vital capacity increases and improves the respiratory function. The breathing exercises are based on deep and slow breathing (in inspiration the patient must move the diaphragm actively) and on thoracic expansion combined with the mobilization of the scapular girdle (the inspiration must be deep and slow, during the inspiration the thoracic cage is moving forward and with the raising of the upper limbs; in the expiration the thoracic cage is moving rear, and the upper limbs return to the initial position). The active cycle of the respiratory techniques is composed of three phases (control of breathing, the thoracic expansion, and the expiration). The modality of a breathing cycle must be developed regarding the patient’s health status. Even if it is estimated that at the current time approximately 80% of patients who contact the virus do not develop symptoms and will recover without having any special treatment, the given repercussions due to prolonged hospitalization or quarantine at home will represent the beginning regarding the establishment of a respiratory recovery program, which will have as objectives the improvement of the quality of life, combating a sedentary lifestyle, and bringing some benefits in the psychosocial sphere of the individual, etc. The early mobilizations and the return to an active life must be encouraged for patients with COVID-19. The prevention of the complications due to prolonged immobilization, the transfers (changing position from sitting in standing and vice versa), obtaining the static and dynamic balance, and the realization of ADL are very important.

Objective To retrieve evolving respiratory measures in the first minutes after birth in normal neonates born at term using a respiratory function monitor. Study design We evaluated newborn babies delivered at term via cesarean after uncomplicated pregnancies. Immediately after birth, a respiratory function monitor with an adapted flowmeter and a face mask were applied at 2, 5, and 10 minutes after birth for 90 seconds in each period. We analyzed expired and inspired tidal volume, respiratory rate (RR), percentage of leakage, and number of analyzed breaths in each individual infant's recording using a respiratory research software. Results A total of 243 infants completed the study. The final data set included 59 058 (48.35%) valid observations for each of the variables representing the analysis of 32 801 breaths. With these data, we constructed a reference range with 10th, 25th, 50th, 75th, and 90th percentiles for expired tidal volume and RR. Tidal volumes plateaued earlier in female than in male infants. No correlation with delayed cord clamping, gestational age, maternal morbidity, or indication for cesarean delivery were established. Conclusions We have constructed a reference range with percentiles for inspired and expired tidal volumes and RR in newborn babies born at term for the first 10 minutes after birth. Reference ranges can be employed for research and can be useful in the clinical setting to guide positive pressure ventilation in the delivery room.

espanolRESUMEN El envejecimiento poblacional requiere de esfuerzos para ayudar a los adultos mayores a mantener una mayor calidad de vida e independencia. El canto en grupo (CG) ha mostrado beneficios en los dominios social, fisico y cognitivo, siendo una estrategia eficiente para alcanzar estos objetivos. Sin embargo, son escasos los ensayos controlados aleatorios (ECA) que evaluan intervenciones sistematicas de CG y la interaccion de sus efectos en dichos dominios. Asi, el presente ECA evaluo si una intervencion de CG de 34 sesiones mejora las funciones cognitivas en adultos mayores (funciones ejecutivas y memoria verbal) y si tiene efectos en los marcadores de inflamacion sistemica. Ademas, se quiso determinar si los cambios en los dominios social y fisiologico mediaban los efectos de la intervencion en la cognicion. Se asignaron 149 participantes a un grupo en lista de espera, que mantuvo sus niveles de actividad habituales, o a un grupo de intervencion. Se realizaron evaluaciones ciegas de los resultados al inicio, despues de la intervencion y durante el seguimiento. Los resultados confirmaron los efectos positivos del CG en la cognicion, especialmente sobre la memoria verbal. Tambien aportaron evidencias acerca del efecto protector del CG en la inflamacion sistemica. Los analisis de mediacion revelaron una compleja interaccion de, por un lado, la adherencia a la intervencion del CG y los cambios en la funcion respiratoria y el bienestar social y, por otro, la magnitud de la mejora cognitiva. Estos resultados situan a la socializacion y la funcion respiratoria como piezas clave en intervenciones multidimensionales de CG, maximizando los beneficios de estas sobre la cognicion en adultos mayores. EnglishABSTRACT Population aging prompts efforts to help older adults maintain a high quality of life and independence. Group singing (GS) has shown benefits on social, physical, and cognitive domains, being a cost-effective strategy to reach these goals. Nevertheless, randomized controlled trials (RCT) evaluating systematic GS interventions and the interplay between their effects on those domains are scarce. Thus, the present RCT assessed whether a 34-session GS intervention boosts older adults' cognitive functions (executive functions and verbal memory) and whether it has an impact on systemic inflammation markers. Additionally, it intended to determine whether changes in social or physiological domains mediated the intervention effects on cognition. One hundred and forty-nine participants were allocated to a waiting-list group, which kept their usual activity levels, or an intervention group. Blinded outcome assessments were conducted at baseline, post-intervention, and follow-up. Results confirmed positive effects of GS on cognition, especially marked for verbal memory. Evidence of GS's protective effect on systemic inflammation is also provided. Mediation analyses revealed a complex interaction of GS intervention engagement and respiratory function and social wellbeing changes with the magnitude of cognitive improvement. These results highlight socialization and respiratory functions as critical pieces of multidimensional GS interventions, maximizing their benefits on older adults' cognition.

Chronic alcoholism disrupts mitochondrial function and often results in alcoholic cardiomyopathy (ACM). Fas-activated serine/threonine kinase (FASTK) is newly recognized as a key post-transcriptional regulator of mitochondrial gene expression. However, the modulatory role of FASTK in cardiovascular pathophysiology remains totally unknown. In experimental ACM models, cardiac FASTK expression markedly declined. Ethanol directly suppressed FASTK expression at post-transcriptional level through NADPH oxidase-derived reactive oxygen species (ROS). Ethanol destabilized FASTK mRNA 3′-untranslated region (3′-UTR) and accelerated its decay, which was blocked by the clearance of ROS. Regnase-1 (Reg1), a ribonuclease regulating mRNA stability, was induced by ROS in ethanol-stimulated cardiomyocytes. Reg1 directly bound to FASTK mRNA 3′-UTR and promoted its degradation, whereas silencing of Reg1 reversed ethanol-induced FASTK downregulation. Compared to wild type control, alcohol-related myocardial morphological (hypertrophy, fibrosis and cardiomyocyte apoptosis) and functional (reduced ejection fraction and compromised cardiomyocyte contraction) anomalies were worsened in FASTK deficient mice. Mechanistically, FASTK ablation repressed NADH dehydrogenase subunit 6 (MTND6, a mitochondrial gene encoding a subunit of complex I) mRNA production and reduced complex I-supported respiration. Importantly, cardiomyocyte-specific upregulation of FASTK through intra-cardiac AAV9-cTNT injection mitigated myocardial mitochondrial dysfunction and restrained ACM progression. In vitro study showed that overexpression of FASTK ameliorated ethanol-induced MTND6 mRNA downregulation, complex I inactivation, and cardiomyocyte death, whereas these beneficial effects were counteracted by rotenone, a complex I inhibitor. Collectively, ROS-accelerated FASTK mRNA degradation via Reg1 underlies chronic ethanol ingestion-associated mitochondrial dysfunction and cardiomyopathy. Restoration of FASTK expression through genetic approaches might be a promising therapeutic strategy for ACM., Graphical abstract Image 1, Highlights • Ethanol accelerates cardiac FASTK mRNA degradation via NOX/ROS/Regnase-1 pathway. • Genetic FASTK deletion exacerbates alcoholic cardiomyopathy (ACM) via repressing mitochondiral function. • Cardiac overexpression of FASTK protects against ACM.

Objective: Individuals with exercise-induced bronchoconstriction (EIB) use ß2-agonists to reduce respiratory symptoms during acute exercise. The resulting bronchodilation could increase the dose of inhaled pollutants and impair respiratory function when exercise is performed in air pollution. We aimed to assess respiratory responses in individuals with EIB when completing a cycling bout while being exposed to diesel exhaust (DE) or filtered air (FA) with and without the inhalation of salbutamol (SAL), a short-acting ß2-agonist. Methods: In a double-blind, repeated-measures design, 19 participants with EIB (22-33 years of age) completed four visits: FA-placebo (FA-PLA), FA-SAL, DE-PLA, DE-SAL. After the inhalation of either 400 µg of SAL or PLA, participants sat in the exposure chamber for 60 min, breathing either FA or DE (PM2.5 = 300 μg/m3). Participants then cycled for 30 min at 50 % of peak work rate while breathing FA or DE. Respiratory responses were assessed via spirometry, work of breathing (WOB), fractional use of ventilatory capacity (V̇E/V̇E,CAP), area under the maximal expiratory flow-volume curve (MEFVAUC), and dyspnea during and following cycling. Results: Bronchodilation in response to SAL and acute cycling was observed, independent of FA/DE exposure. Specifically, FEV1 was increased by 7.7 % (confidence interval (CI): 7.2–8.2 %; p

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with intractable epilepsy. However, the pathogenesis of SUDEP seems to be poorly understood. Our previous findings showed that the incidence of seizure-induced respiratory arrest (S-IRA) was markedly reduced by atomoxetine in a murine SUDEP model. Because the central norepinephrine α-1 receptor (NEα-1R) plays a vital role in regulating respiratory function, we hypothesized that the suppression of S-IRA by atomoxetine was mediated by NE/NEα-1R interactions that can be reversed by NEα-1R antagonism. We examined whether atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) in DBA/1 mice can be reversed by intraperitoneal (IP) and intracerebroventricular (ICV) administration of prazosin, a selective antagonist of NEα-1R. The content and activity of tyrosine hydroxylase (TH), a rate-limiting enzyme for NE synthesis, in the lower brainstem was measured by ELISA. Electroencephalograms (EEG) were obtained from using the PTZ-evoked SUDEP model. In our models, atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or PTZ was significantly reversed by low doses of IP and ICV prazosin. Neither repetitive acoustic stimulation nor S-IRA reduced TH levels in lower brainstem. However, the enzyme activity of TH levels in lower brainstem was significantly increased by mechanical ventilation with DBA/1 mice, which makes the dying DBA/1 mice suffering from S-IRA and SUDEP recover. EEG data showed that although the protective effect of atomoxetine was reversed by prazosin, neither drug suppressed EEG activity. These data suggest that deficient synthesis of NE and norepinephrinergic neurotransmission contributed to S-IRA and that the NEα-1R is a potential therapeutic target for the prevention of SUDEP.

Allergic airway inflammation is one of the major pathological events involved in the development of asthma. The B cell-activating factor (BAFF)-mediated abnormal activation of B cells plays a key role in developing allergic airway inflammation. Here, we investigated the effects of Gu-Ben-Fang-Xiao decoction (GBFXD), a TCM decoction used in the prevention and treatment of allergic asthma, on allergic airway inflammation and BAFF-mediated B cell activation. A mouse model of OVA-Severe respiratory syncytial virus (RSV) induced asthma in the remission stage was administrated with GBFXD by gavage for four weeks, after which, the pulmonary function was evaluated. Pathological changes of the lung were observed by hematoxylin and eosin (HE) staining, and serum levels of IgE, BAFF, and inflammatory factors were detected by ELISA. The expression of BAFF, APRIL, and their related receptors in the lung and spleen was detected by Western blotting and RT-qPCR. Flow cytometry detected B cell subsets in the spleen, PBC, and monocyte subsets in bronchoalveolar lavage fluid (BALF). The results showed that GBFXD improved the lung function, alleviated the inflammatory changes of the lung tissue in OVA-RSV sensitized mice, and reduced levels of IL-6, TNF-α, IL1-β, INOS, IL13 as well as IL-15, IgE, BAFF in the serum of OVA-RAV mice. Additionally, GBFXD significantly reduced the proportion of CD19+CD27+ B cell subpopulation and IgE + B cell subpopulation in the PBC and spleen cells of mice. Furthermore, the expression of BAFF, APRIL, BAFFR, TACI, and AID decreased in the lung and spleen of GBFXD-treated mice, as well as the proportion of CD11b + BAFF + cell subsets in BALF. In conclusion, GBFXD has an inhibitory effect on the secretion of BAFF by pulmonary macrophages and the expression of BAFF-related receptors, thereby reducing B cell activation and the release of IgE. This proposed mechanism contributes to the improvement of allergic airway inflammation and respiratory function in an asthmatic mouse model.

Mounier-Kuhn syndrome or tracheobronchomegaly is a rare disease characterized by marked dilation of the trachea and proximal bronchi with recurrent lower tract respiratory infections. Computed tomography and bronchoscopy are the key tools to accomplish the diagnosis. This is a condition with a clinical polymorphism, symptoms vary from minor with preserved respiratory function, to very severe with life threatening exacerbations leading to respiratory failure and premature death. The treatment is mainly symptomatic, stenting or surgery are reserved to extreme cases.Herein, we report two cases of the same condition with different clinical signs and diverse outcome.

UCH-L1 is a deubiquitinating enzyme (DUB), highly abundant in neurons, with a sub-cellular localization dependent on its farnesylation state. Despite UCH-L1′s association with familial Parkinson's Disease (PD), the effects on mitochondrial bioenergetics and quality control remain unexplored. Here we investigated the role of UCHL-1 in mitochondrial dynamics and bioenergetics. We demonstrate that knock-down (KD) of UCH-L1 in different cell lines reduces the levels of the mitochondrial fusion protein Mitofusin-2, but not Mitofusin-1, resulting in mitochondrial enlargement and disruption of the tubular network. This was associated with lower tethering between mitochondria and the endoplasmic reticulum, consequently altering mitochondrial calcium uptake. Respiratory function was also altered, as UCH-L1 KD cells displayed higher proton leak and maximum respiratory capacity. Conversely, overexpression of UCH-L1 increased Mfn2 levels, an effect dramatically enhanced by the mutation of the farnesylation site (C220S), which drives UCH-L1 binding to membranes. These data indicate that the soluble cytosolic form of UCH-L1 regulates Mitofusin-2 levels and mitochondrial function. These effects are biologically conserved, since knock-down of the corresponding UCH-L1 ortholog in D. melanogaster reduces levels of the mitofusin ortholog Marf and also increases mitochondrial respiratory capacity. We thus show that Mfn-2 levels are directly affected by UCH-L1, demonstrating that the mitochondrial roles of DUBs go beyond controlling mitophagy rates., Graphical abstract Image 1

Visualizing mitochondria in living Dictyostelium discoideum cells using fluorescent dyes is often problematic due to variability in staining, metabolism of the dyes, and unknown potential effects of the dyes on mitochondrial function. We show that fluorescent labelling of mitochondria, using an N-terminal mitochondrial localization sequence derived from the D. discoideum protein GcvH1 (glycine cleavage system H1) attached to a red fluorescent protein enables clear mitochondrial imaging. We also show that this labelling has no effect upon mitochondria load or respiratory function., Highlights • Live-cell visualization of mitochondria dynamics is currently difficult in Dictyostelium discoideum. • We provide an easy and rapid procedure for visualizing mitochondria. • This technology employs a plasmid, REMIT-mRFPmars, expressing a mitochondrial targeting sequence linked to mRFPmars. • Expression of REMIT-mRFPmars does not alter mitochondrial load or function, providing a suitable tag for live-cell studies.

Audiogenic seizure-prone mice can be protected from seizure-associated death by exposure to an oxygen atmosphere or treatment with selective serotonergic reuptake inhibitors (SSRIs). We have shown previously in a rat model that epileptic seizure activity can spread through brainstem areas to cause sufficient laryngospasm for obstructive apnea and that the period of seizure-associated obstructive apnea can last long enough for respiratory arrest to occur. We hypothesized that both the oxygen-rich atmosphere and SSRIs function by prolonging the time to respiratory arrest, thus ensuring that seizure activity stops before the point of respiratory arrest to allow recovery of respiratory function. To test this hypothesis, we evaluated each preventative treatment in a rat model of controlled airway occlusion where the times to respiratory arrest can be measured. Adult male Sprague Dawley rats (median age = 66 days) were studied in the absence of any seizure activity. By directly studying responses to controlled airway occlusion, rather than airway occlusion secondary to seizure activity, we could isolate the effects of manipulations that might prolong respiratory arrest from the effects of those manipulations on seizure intensity. All group sizes were ≥ 8 animals per group. We found that both oxygen exposure and fluoxetine significantly increased the time to respiratory arrest by up to 65% (p .0001 for 5 min oxygen exposure; p = .031 for 25 mg/kg fluoxetine tested 60 min after injection) and, given that neither treatment has been shown to significantly alter seizure duration, these increases can account for the protection of either manipulation against death in sudden death models. Importantly, we found that 30 s of exposure to oxygen produced nearly the same protection as 5 min exposure suggesting that oxygen exposure could start after a seizure starts (p = .0012 for 30 s oxygen exposure). Experiments with 50% oxygen/50% air mixtures indicate that the oxygen concentration needs to be above about 60% to ensure that times to respiratory arrest will always be longer than a period of seizure-induced airway occlusion. Selective serotonin reuptake inhibitors, while instructive with regard to mechanism, require impractical dosing and may carry additional risk in the form of greater challenges for resuscitation. We conclude that oxygen exposure or SSRI treatment prevent seizure associated death by sufficiently prolonging the time to respiratory arrest so that respiratory function can recover after the seizure abates and eliminates the stimulus for seizure-induced apnea.

Obesity hypoventilation syndrome (OHS) has a wide range of manifestations that arise from the dysfunction of the systems affected by it. Many of these manifestations are discussed in other chapters of this book. This chapter will focus on the definition of OHS and its clinical presentation, predictors of OHS, grading its severity, abnormalities in respiratory function and sleep, and other less common manifestations.

Decline in respiratory function in patients with DMD starts during early teenage years and leads to early morbidity and mortality. Published evidence of efficacy for idebenone on respiratory function outcomes is currently limited to 12 months of follow-up time. Here we report data collected as retrospective cohort study (SYROS) from 18 DMD patients not using glucocorticoids who were treated with idebenone (900 mg/day) under Expanded Access Programs (EAPs). The objective was to assess the long-term respiratory function evolution for periods On-Idebenone compared to periods Off-Idebenone in the same patients. The mean idebenone exposure in the EAPs was 4.2 (range 2.4-6.1) years. The primary endpoint was the annual change in forced vital capacity percent of predicted (FVC%p) compared between Off-Idebenone and On-Idebenone periods. The annual rate of decline in FVC%p was reduced by approximately 50% from -7.4% (95% CI: -9.1, -5.8) for the Off-Idebenone periods to -3.8% (95% CI: -4.8, -2.8) for the On-Idebenone periods (N = 11). Similarly, annual change in peak expiratory flow percent of predicted (PEF%p) was -5.9% (95% CI: -8.0, -3.9) for the Off-Idebenone periods (N = 9) and reduced to -1.9% (95% CI: -3.2, -0.7) for the On-Idebenone periods during the EAPs. The reduced rates of decline in FVC%p and PEF%p were maintained for several years with possible beneficial effects on the rate of bronchopulmonary adverse events, time to 10% decline in FVC%p and risk of hospitalization due to respiratory cause. These long-term data provide Class IV evidence to further support the disease modifying treatment effect of idebenone previously observed in randomized, controlled trials. ispartof: NEUROMUSCULAR DISORDERS vol:30 issue:1 pages:5-16 ispartof: location:England status: published

Bronchopulmonary dysplasia (BPD) is an important complication of preterm birth. Survivors of BPD are at greater risk of adverse pulmonary and neurodevelopmental outcomes compared with preterm survivors without BPD. They are more frequently hospitalized in the early years following discharge from the neonatal unit, most commonly for respiratory indications. Children with BPD are more likely to experience asthma and wheeze than children without BPD. The respiratory function of children and adolescents with BPD shows evidence of greater airflow limitation than those without BPD. Adults with BPD may be at risk of earlier onset respiratory illnesses such as chronic obstructive airways disease. Compared with their preterm counterparts without BPD, BPD survivors are at greater risk of neurosensory and cognitive impairment. The consequences of prematurity are not confined to the nursery, preschool, or even adolescent years, but rather must be considered lifelong risk factors for respiratory and neurologic impairment. The vulnerable group of survivors who had BPD should be afforded additional surveillance and early intervention in the event of later-onset respiratory and neurologic illnesses.

Bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD) of prematurity result from the culmination of multiple exposures. Respiratory viral illnesses (RVIs) and either a dysregulated or an insufficient host response combine to have a significant detrimental effect on the injured lung of the premature infant. RVIs are now understood to contribute to the severity of BPD in exposed infants and account for a majority of outpatient healthcare visits after discharge from neonatal intensive care unit. Premature infants with early RVI are at high risk for postviral wheezing and diminished respiratory function, even without a preceding diagnosis of BPD. The pathogenesis of RVI-induced respiratory morbidity is thought to result from a combination of viral cytopathic effects and immune-mediated collateral damage. This chapter will review the epidemiology and pathogenesis of RVIs in premature infants, with a particular focus on the unique adaptive immune-system-mediated activities at play during early human development.