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In the field of respiratory clinical practice, the importance of measuring carbon dioxide (CO2) concentrations cannot be overemphasized. Within the body, assessment of the arterial partial pressure of CO2 (PaCO2) has been the gold standard for many decades. Non-invasive assessments are usually predicated on the measurement of CO2 concentrations in the air, usually using an infrared analyzer, and these data are clearly important regarding climate changes as well as regulations of air quality in buildings to ascertain adequate ventilation. Measurements of CO2 production with oxygen consumption yield important indices such as the respiratory quotient and estimates of energy expenditure, which may be used for further investigation in the various fields of metabolism, obesity, sleep disorders, and lifestyle-related issues. Measures of PaCO2 are nowadays performed using the Severinghaus electrode in arterial blood or in arterialized capillary blood, while the same electrode system has been modified to enable relatively accurate non-invasive monitoring of the transcutaneous partial pressure of CO2 (PtcCO2). PtcCO2 monitoring during sleep can be helpful for evaluating sleep apnea syndrome, particularly in children. End-tidal PCO2 is inferior to PtcCO2 as far as accuracy, but it provides breath-by-breath estimates of respiratory gas exchange, while PtcCO2 reflects temporal trends in alveolar ventilation. The frequency of monitoring end-tidal PCO2 has markedly increased in light of its multiple applications (e.g., verify endotracheal intubation, anesthesia or mechanical ventilation, exercise testing, respiratory patterning during sleep, etc.).

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Obstructive sleep apnea (OSA) patients are at risk for increased blood pressure and carotid intima-media thickness (IMT), with pulmonary hypertension and right-sided heart failure potentially developing as well. Chronic intermittent hypoxia (IH) has been used as an OSA model in animals, but its effects on vascular beds have not been evaluated using objective unbiased tools. Previously published and current experimental data in mice exposed to IH were evaluated for IMT in aorta and pulmonary artery (PA) after IH with or without normoxic recovery using software for meta-analysis, Review Manager 5. Because IMT data reports on PA were extremely scarce, atherosclerotic area percentage from lumen data was also evaluated. IH significantly increased IMT parameters in both aorta and PA as illustrated by Forest plots (P < 0.01), which also confirmed that IMT values after normoxic recovery were within the normal range in both vascular beds. One-sided scarce lower areas in Funnel Plots were seen for both aorta and PA indicating the likelihood of significant publication bias. Forest and Funnel plots, which provide unbiased assessments of published and current data, suggest that IH exposures may induce IMT thickening that may be reversed by normoxic recovery in both aorta and PA. In light of the potential likelihood of publication bias, future studies are needed to confirm or refute the findings. In conclusion, OSA may induce IMT thickening (e.g., aorta and/or PA), but the treatment (e.g., nasal continuous positive airway pressure) will likely lead to improvements in such findings.

Some patients with severe asthma also have fungal sensitization and are considered to have severe asthma with fungal sensitization. However, there is limited information on the clinical features of SAFS.To investigate the clinical characteristics of severe asthma with fungal sensitization.The present study enrolled 124 patients with severe asthma. We evaluated clinical aspects, such as various serum cytokines, fractional exhaled nitric oxide, pulmonary function, and serum immunoglobulin E (IgE). Fungal sensitization was assessed by determining serum levels of IgE specific to fungal allergens (Aspergillus, Alternaria, Candida, Cladosporium, Penicillium, and Trichophyton species and Schizophyllum commune). The protocol was registered at a clinical trial registry (www.umin.ac.jp/ctr/index-j.htm; UMIN 000002980).Thirty-six patients (29%) showed sensitization to at least 1 fungal allergen. The most common species were Candida (16%), Aspergillus (11%), and Trichophyton (11%). The rate of early-onset asthma (16 years of age) was higher in patients with fungal sensitization than in those without fungal sensitization (45% vs 25%; P = .02). Interleukin-33 levels were higher in patients with fungal sensitization than in those without fungal sensitization. Of patients with atopic asthma, Asthma Control Test scores were worse in patients with multiple fungal sensitizations than in patients with a single fungal sensitization or those without fungal sensitization.Severe asthma with fungal sensitization is characterized by early onset of disease and high serum levels of interleukin-33. Multiple fungal sensitizations are associated with poor asthma control.UMIN Clinical Trials Registry (UMIN-CTR; www.umin.ac.jp/ctr/index-j.htm): UMIN 000002980.

Although the incidence of postbulbar duodenal ulcers is low, many complications occur, such as hemorrhage, stenosis and perforation, and there are many points to be paid attention to with regard to its pathology. A high acid level has been pointed out as a cause, but this is not conclusive, and its association with Helicobacter pylori (Hp) infection is also unclear. We investigated chronic cases excluding acute cases such as acute duodenal mucosal lesion we encountered between 2001 and 2015. Five cases corresponded, accounting for 1.4% of all chronic duodenal ulcer cases, and there were more male patients (four patients were male), as previously reported. All cases were solitary punched-out ulcer on the medial side near the superior duodenal flexure, and many complications were observed such as melena in all patients, narrowing in 2, and penetration in 1. No specific pathology, such as Crohn’s disease, vasculitis, or Zollinger-Ellison syndrome, was noted, no patient was previously medicated with NSAIDs or low dose aspirin, and 3 patients were infected with Hp. All cases were healed by proton pump inhibitor administration or gastric acid secretion-suppressing treatment with selective proximal vagotomy. Recurrence after Hp eradication occurred in all of the 3 Hp-infected patients, suggesting that involvement of Hp in the cause of disease is unlikely.

Background and objective Body weight of patients with obstructive sleep apnea after initiation of nasal continuous positive airway pressure appears to increase. We hypothesized that intermittent hypoxia (IH) will decrease energy expenditure (EE), and that normoxic recovery will lead to body weight gains. Methods C57BL/6 J male mice were exposed to either 12 h/day of mild IH (alternating FIO2-10-11% and 21%; 640 s cycle), or severe IH (FIO2-6-7%-21%; 180 s cycle) or sham IH daily for 4 or 8 weeks. After exposures, EE was evaluated while mice were kept under normoxia for 5 weeks and organ histology was evaluated. Results EE was not decreased by IH. However, visceral white adipocyte size after normoxic recovery was significantly increased in severe IH in an intensity-dependent manner. Conclusion Our hypothesis that IH would decrease EE was not corroborated. However, IH and normoxic recovery seem to promote severity-dependent enlargement of visceral adipocytes, likely reflecting altered energy preservation mechanisms induced by IH.

A 42-year-old Japanese man developed Churg–Strauss syndrome 7 years after being diagnosed with chronic eosinophilic pneumonia. Prominent eosinophilia, subcutaneous nodules, and neuropathy in the left leg were seen. A pathological diagnosis of necrotizing vasculitis was determined by a biopsy of a subcutaneous nodule. The leg pain was severe and there was prominent atrophy of the thigh and calf, but the muscle weakness was mild. Serum anti-myeloperoxidase anti-neutrophil cytoplasmic antibody was positive. Because the initial treatment with an intravenous methylprednisolone pulse at 1 g/day for 3 days was not sufficient, a onetime treatment with intravenous cyclophosphamide at 15 mg/kg and intravenous immunoglobulin therapy (IVIG) at 400 mg/kg/day for 5 days were administered. Peripheral eosinophilia improved and the leg pain significantly improved. IVIG was repeated 1 month later and symptoms gradually improved further. The early diagnosis of Churg–Strauss syndrome and the early initiation of IVIG with cyclophosphamide were thought to be important.

Objectives: Recent reports on venous blood gas analysis have shown that venous bicarbonate concentration is useful in the evaluation of the body acid-base status. Most of these reports have been based on the Bland-Altman analysis comparing arterial and venous blood gas values. We intended to elucidate any factors that decrease the agreement between venous and arterial bicarbonate concentrations, which might impair the usefulness of venous blood gas analysis. Methods: Healthy volunteers and patients with various diseases (n = 141) were evaluated by simultaneous arterial and venous blood sampling and Bland-Altman analysis. The venous-arterial bicarbonate concentration difference was compared between healthy volunteers and untreated respiratory alkalosis patients. Intentional hyperventilation (30 or 60 breaths/min, for 3 min) was also performed on 6 healthy volunteers and the venous-arterial bicarbonate concentration difference was evaluated. Results: The relative average bias in bicarbonate concentration was 2.00 mEq/l with venous bicarbonate higher than arterial bicarbonate with 95% limits of agreement of ±4.15 mEq/l. Hyperventilation challenges increased the venous-arterial bicarbonate concentration difference in an intensity-dependent manner. The venous-arterial bicarbonate concentration difference was higher in untreated respiratory alkalosis patients than in healthy volunteers (P Conclusion: Although venous bicarbonate may be useful to evaluate the body acid-base status, hyperventilation increases the venous-arterial bicarbonate concentration difference. Physicians should keep this phenomenon in mind.

Objective: The Japanese drug use system allowed the “once-daily use” of inhaled corticosteroid (ICS) fluticasone furoate (FF) combined with a long acting beta-2 agonist (LABA) vilanterol (VI) against asthma for the first time in 2013. Until then, patients with asthma had to use ICS at least twice-daily. We investigated the real-world efficacy and problems of this drug (FF/VI). Methods: This was an open-label, uncontrolled, within-group time-series (before-after) design. Prior treatments of asthma (twice-daily use of ICS with or without LABA) were switched to once-daily use of FF/VI (200 μg/25 μg). Subjects were evaluated by lung function tests prior to, and 2–3 months after, the initiation of FF/VI. Questions on the asthma control test (ACT) and preference of drugs were asked to patients. Results: One hundred and twenty-eight Japanese asthma outpatients were enrolled from 2014–2018 and 107 subjects completed the study. Peak flow, instantaneous flow at 75% of the forced vital capacity (V75), V50, maximum mid-expiratory flow rate, forced expiratory volume in 1 s, and ACT score in FF/VI-using subjects were significantly increased (all p

A man taking antithrombotic agents was admitted because of melena. Upper gastrointestinal endoscopy revealed a large, pedunculated polyp bleeding from erosions on its top. The polyp was endoscopically resected, and histopathologically diagnosed as Brunner ’ s gland hyperplasia. It is commonly encountered as a small, raised lesion, but may enlarge or bleed. We report this case, with a review of the Japanese literature and discussion of the mechanism of bleeding. doi: http://dx.doi.org/10.4021/gr532e

A 60-year-old male presented with cough and fever (case 1), and a 77-year-old female patient with hemoptysis (case 2) were admitted to IUHW Shioya Hospital. Interferon gamma release assay (IGRA: QFT-3G and T-SPOT. TB) were both performed on each patient; the QFT-3G was positive and T-SPOT.TB was negative in both cases despite different final diagnosis. While case 1 was determined to have active tuberculosis, in case 2 active tuberculosis was eliminated as the diagnosis. The contradictory results in these patients should serve as a reminder to clinicians that they should not rely on the results of IGRA testing for the diagnosis of active tuberculosis. Keywords: Interferon Gamma Release Assay; Negative; Tuberculosis; T-SPOT; QFT

A middle-aged man with no symptom or history visited our hospital due to duodenal abnormality and fecal occult blood detected by health screening. Upper gastrointestinal endoscopy showed marked enlargement of the papilla of Vater surrounded by nodules, and biopsy disclosed non-caseating granuloma. Colonoscopy yielded findings suggestive of intestinal tuberculosis such as annular ulcers. Examination of the biopsy samples failed to make a diagnosis of tuberculosis, and no pulmonary lesion was found, but whole-blood interferon gamma release assay was positive. The duodenal lesion was also suspected to be tubercular, so antitubercular drugs were administered. As this resulted in the resolution of both lesions, a definite diagnosis of tubercular papillitis of Vater was made. Duodenal tuberculosis is rare, and a localized lesion of the major duodenal papilla is extremely rare. However, this case suggests that tuberculosis must be considered in the differential diagnosis of lesions of the papilla of Vater.

Introduction Since the invention of the pulse oximeter, physicians often or even routinely perform venous blood gas analysis (VBGA). However, it has not been generally agreed that the application of VBGA is practically meaningful in routine clinical situations such as in an ED. Methods We measured venous-arterial P co 2 difference ((v-a)P co 2) and arterial-venous pH difference ((a-v)pH), and analyzed the physiological factors that affect these differences in healthy volunteers and hyperventilation patients. Results In healthy volunteers, both (v-a)P co 2 and (a-v)pH increased during finger exercise or hyperventilation in an intensity-dependent manner. Doppler echography indicated that increases in (v-a)P co 2 and (a-v)pH during hyperventilation are induced by reduction of peripheral blood flow. Approximately 40% of patients with untreated respiratory alkalosis were found to be incorrectly diagnosed if based only on VBGA. Conclusions It must be noted that VBGA may lead to overestimation of acidosis and to underestimation of respiratory alkalosis when extremities muscles are active or patients are hyperventilating. Physicians should keep these limitations in mind when conducting VBGA.

Hepatopulmonary syndrome (HPS) (hypoxaemia due to intrapulmonary vasodilation and a right-to-left shunt associated with liver disease) resolves after liver transplantation. The authors describe a case of spontaneous resolution of HPS prior to liver transplantation. This patient was diagnosed with HPS associated with extra-hepatic biliary atresia when she was 10 years old. She exhibited digital clubbing, facial vascular dilation, cyanosis, and suffered from dyspnoea during exercise. The patient's PaO(2) at rest was 53.8 mm Hg in room air and a Technetium-99m macro-aggregated albumin lung perfusion scan demonstrated a right-to-left shunt. Although her symptoms and laboratory data supported a diagnosis of HPS, she nevertheless showed spontaneous resolution within 2 years. When she was 14 years old, pulmonary hypertension was evident upon examination of her echocardiogram. HPS may be improved or masked by an accidental overlap with pulmonary hypertension in the terminal stage of liver disease.

胸部X線所見分類で孤立結節性陰影1例, 多発粟粒状結節性陰影1例, 肺炎様陰影3例の細気管支肺胞上皮癌5例を胸部単純X線写真, X線CTと細気管支鏡所見を対比し検討した. 内視鏡所見は肺炎様陰影を呈した症例では細気管支は漿液性の分泌物が多く肺胞の方から湧き出てくる像がみられ, また, 細気管支に粘膜下主体型の腫瘍および閉塞像が認められた. 散在するポリープ様変化も認められ本症の進展形式を示唆した. 孤立結節性陰影の症例では結節隆起型の腫瘍がみられた. 多発粟粒状結節性陰影の症例では細気管支は全般的に狭窄を起こし粘膜面が蒼白に認められた. 初めて本症を内視鏡で観察することが出来た.

A 65-year-old man developed severe septic shock during thrombolytic treatment with urokinase for pulmonary thromboembolism associated with deep venous thrombosis of the right lower limb. Blood cultures were positive forKlebsiella pneumoniae and treatment was successful only when the antibiotics were infused via the same route as the urokinase.

A 52-year-old man with chronic granulomatous interstitial pneumonitis suffered from invasive group A streptococcal infection. His chest x-ray showed bilateral interstitial shadows in the lower lung fields since childhood. He was admitted to Keio University Hospital because of fever, productive cough, and necrosis of the distal extremity. The chest radiographic appearance worsened and he developed low blood pressure, liver dysfunction, thrombocytopenia, and lymphocytopenia. Blood culture yielded T-11 strainStreptococcus pyogenes, which generated type B and C pyrogenic exotoxins. This may be the first report to confirm T-11Streptococcus pyogenes as the causative organism for invasive group A streptococcal infection in Japan. The patient's condition improved after treatment with panipenem and subsequent combination therapy with high-dose penicillin G and gentamicin. An immunodeficiency state associated with the chronic granulomatous lung disease was strongly suspected.

We developed a new type of bronchoscope (BF-2.7T) and cytology brush (BC-0.7T) that permit collection of pulmonary cells during direct observation of the small airways. This kind of cell collection has been previously impossible. With our cytology brush, 3.58 +/- 2.76 x 10(4) cells were collected from small airways. The rate of living cells was 33.13 +/- 3.61 percent from the small airways. Analysis of endoscopic findings and investigation of pulmonary cells are very important for elucidating the pathophysiologic state of the small airways. The use of the BF-2.7T allowed collection of cancer cells under direct endoscopic vision in all five patients with peripheral lung cancer. They also contribute to our understanding of the relationship between exogenous factors and cells that compose the lung, and will provide means for treatment and prevention of diseases.

In order to assess the physiological abnormalities and the pathogenesis of adult respiratory distress syndrome (ARDS), especially that associated with pulmonary fat embolism, acute lung injury caused by monounsaturated nonsterified fat oleic acid (cis-9-octadecenoic acid) has been widely used in animal experiments. This lung injury results in an extensive, multifocal, and heterogeneously distributed lung damage with alveolar flooding, interstitial edema and microatelectasis. The ability to reduce the perfusion entering into damaged and edematous areas is essentially important in preserving blood oxygenation in ARDS.

In order to assess the physiological abnormalities and the pathogenesis of adult respiratory distress syndrome (ARDS), especially that associated with pulmonary fat embolism, acute lung injury caused by monounsaturated nonsterified fat oleic acid (cis-9-octadecenoic acid) has been widely used in animal experiments. This lung injury results in an extensive, multifocal, and heterogeneously distributed lung damage with alveolar flooding, interstitial edema and microatelectasis. These morphological changes have generally been considered to develop significant shunt flow causing severe hypoxemia and loss of lung compliance. Based on the microscopic examinations, however, Schoene et al. (1984) have failed to demonstrate a quantitative relationship between the morphological alterations and the amount of shunt in dogs with lung damage induced by oleic acid administration. Further, Brigham et al. (1983) have shown that gas exchange abnormality in patients with ARDS does not correlate with extent of pulmonary edema estimated from extravascular lung water but significantly with vascular permeability-surface area. They have inferred from their experimental findings that the ability of the lung circulation to reduce perfusion of damaged and edematous areas is essentially important in preserving blood oxygenation in ARDS.

Background: Asthma is a heterogeneous disease composed of various phenotypes. Periostin, a molecule inducible with interleukin (IL)-4 or IL-13 in bronchial epithelial cells, is a biomarker of “TH2-high” asthma. The objective of this study is to examine whether the serum periostin concentrations are correlated with the severity, specific phenotype(s), or comorbidity of asthma. Methods: Serum concentrations of periostin were measured in 190 Japanese asthmatic patients and 11 healthy controls. The protocol was registered under UMIN 000002980 in the clinical trial registry. Results: The serum concentrations of periostin were significantly higher (P ¼ 0.014) in asthmatics [70.0 (54.0e93.5) ng/ml] than in healthy subjects [57.0 (39.0e63.0) ng/ml], though we found no correlation between serum periostin concentrations and treatment steps required to control asthma. To characterize “high-periostin” phenotype(s), the patients with asthma were divided among tertiles based on the serum concentrations of periostin. The high-periostin group was older at onset of asthma (P ¼ 0.04), had a higher prevalence of aspirin intolerance (P ¼ 0.04) or concomitant nasal disorders (P ¼ 0.03e0.001), higher peripheral eosinophil counts (P < 0.001), and lower pulmonary function (P ¼ 0.02e0.07). The serum concentrations of periostin were particularly high in asthmatic patients complicated by chronic rhinosinusitis with nasal polyps and olfactory dysfunction. In contrast, neither atopic status, control status of asthma, nor quality of life were related with the “high-periostin” phenotype. Conclusion: Elevated periostin concentrations in serum were correlated with a specific phenotype of eosinophilic asthma, late-onset and often complicated by obstructive pulmonary dysfunction and nasal disorders.

Wistar Imamichi rat and human respiratory cilia were examined with anti-dynein antibody (AD2), which is specific for sea urchin sperm flagellar dynein. AD2-labelled fresh-frozen normal rat and human cilia stained clearly by immunofluorescence and the peroxidase-antiperoxidase (PAP) technique. On immunoelectron microscopy, AD2 labelled the outer dynein arms of normal human cilia. Paraffin-embedded normal human cilia also stained by immunofluorescence, although not always clearly. Neither the cilia of WIC-Hyd male rats, an animal model of Kartagener's syndrome, nor human cilia from patients with primary ciliary dyskinesia (PCD) reacted positively by the immunofluorescence or PAP technique. Western blots of normal rat cilia yielded a single band of about 450 kDa. In conclusion, AD2 recognizes the outer arm dynein heavy chains of healthy cilia and may be useful in diagnosing and classifying PCD light microscopically especially when only paraffin-embedded specimens are available. This approach may be of potential use for better defining and classifying PCD.