In vitro study on effect of bardoxolone methyl on cisplatin-induced cellular senescence in human proximal tubular cells.

Bardoxolone methyl [methyl-2-cyano-3, 12-dioxooleana-1, 9(11)dien-28-oate (CDDO-Me)], an activator of the nuclear factor erythroid-derived 2-related factor2 pathway, is a potential therapeutic candidate for the treatment of kidney diseases. However, its effect against cellular senescence remains unclear. This study aimed to investigate whether CDDO-Me protects cells against cisplatin-induced cellular senescence using an in vitro model. The human renal proximal tubular epithelial cell line HK-2 was treated with cisplatin for 6 h, followed by treatment with or without CDDO-Me (0.1 or 0.2 µmol/L). Senescence markers were analyzed using western blotting and real-time PCR. Apoptosis was evaluated through TUNEL staining. Cisplatin induced changes in the levels of markers specific for proliferation, cell cycle, and senescence in a time- and dose-dependent manner. Furthermore, IL-6 and IL-8 levels in the culture medium increased markedly. These data suggested that cellular senescence-like alterations occurred in HK-2 cells exposed to cisplatin. CDDO-Me treatment reversed the cisplatin-mediated alterations in the levels of cellular senescence markers. The antioxidant enzymes, HO1, NQO1, GPX1, and CAT were upregulated by CDDO-Me treatment. Furthermore, CDDO-Me treatment induced apoptosis in cisplatin-exposed HK-2 cells. Pretreatment with Ac-DEVD-CHO, the caspase inhibitor, suppressed the reversal effect of CDDO-Me against cisplatin-induced cellular senescence-like alterations. This study showed that CDDO-Me attenuated cisplatin-induced premature senescence of HK-2 cells. This beneficial effect may be related to Nrf2 activation. Our findings also showed that CDDO-Me induced apoptosis in cisplatin-treated HK-2 cells, potentially protecting the kidneys from cellular senescence. CDDO-Me appears to be a candidate treatment for acute kidney injury.

Clinical feasibility of remote intermittently scanned continuous glucose monitoring in coronavirus disease 2019 patients with and without diabetes during dexamethasone therapy.

The clinical utility of intermittently scanned continuous glucose monitoring (isCGM) in patients with coronavirus disease 2019 (COVID-19) is unclear. Hence, we investigated the accuracy of isCGM in COVID-19 patients during dexamethasone therapy. We evaluated the accuracy of the FreeStyle Libre via smartphone isCGM device compared to point-of-care (POC) fingerstick glucose level monitoring in 16 patients with COVID-19 (10 with and 6 without diabetes, 13 men; HbA1c 6.9 ± 1.0%). Overall, isCGM correlated well with POC measurements (46.2% and 53.8% within areas A and B of the Parkes error grid, respectively). The overall mean absolute relative difference (MARD) for isCGM compared to POC measurements was 19.4%. The MARDs were 19.8% and 19.7% for POC blood glucose measurements ranging from 70 to 180 mg/dL and >180 mg/dL, respectively. When divided according to the presence and absence of diabetes, both groups of paired glucose measurements showed a good correlation (56.3% and 43.7%, and 27.1% and 72.9% within the A and B areas in patients with and without diabetes, respectively), but the MARD was not significant but higher in patients without diabetes (16.5% and 24.2% in patients with and without diabetes). In conclusion, although isCGM may not be as accurate as traditional blood glucose monitoring, it has good reliability in COVID-19 patients with and without diabetes during dexamethasone therapy.

Recovery of respiratory muscle strength, physical function, and dyspnoea after lobectomy in lung cancer patients undergoing pulmonary rehabilitation: A retrospective study.

OBJECTIVE: To characterise changes in respiratory muscle strength, physical function, and dyspnoea in patients who underwent pre- and post-operative exercise intervention following lobectomy for non-small-cell lung cancer (NSCLC). METHODS: This retrospective study included NSCLC patients who underwent lobectomy via video-assisted thoracoscopic surgery (VATS) or posterolateral thoracotomy (PLT) and pre- and post-operative exercise intervention consisting of breathing, flexibility, resistance, aerobic exercises, coughing/huffing techniques, and early mobilisation. Maximum mouth inspiratory (Pimax) and expiratory pressures (Pemax), 6-min walk distance (6MWD), quadriceps force (QF), and modified Medical Research Council (mMRC) dyspnoea scale were evaluated preoperatively, at hospital discharge, and post-lobectomy 1 and 3 months. RESULTS: Data from 41 patients were analysed. At hospital discharge, the Pimax, Pemax, 6MWD, and mMRC dyspnoea scores were lower than pre-operatively; QF remained unchanged; Pimax and 6MWD recovered to pre-operative values at post-lobectomy 1 month; and Pemax and mMRC dyspnoea scores recovered at 3 months. During sub-analysis, Pimax and mMRC dyspnoea scores in the VATS (n = 24) and PLT groups (n = 17) recovered to pre-operative values at post-lobectomy 1 and 3 months. CONCLUSION: After lobectomy, respiratory muscle strength, physical function, and dyspnoea in patients who underwent exercise intervention returned to pre-operative values at post-lobectomy 3 months.

Real-world assessment of afatinib for patients with EGFR-positive non-small cell lung cancer.

Introduction Afatinib is used to treat patients with advanced non-small cell lung cancer (NSCLC) harboring common EGFR mutations; however, the clinicopathological factors that predict this drug's effectiveness in real-world settings remain unclear. We therefore evaluated the effectiveness of afatinib in such patients and assessed potential prognostic factors. Methods We retrospectively investigated patients with NSCLC who received first-line afatinib between July 2014 and August 2018. Variables (including sex, age, performance status, neutrophil-to-lymphocyte ratio, EGFR genotype, smoking status, clinical stage prior to treatment [stage IV vs.. postoperative recurrence], presence or absence of brain metastases, body surface area, any afatinib dose reductions, and afatinib starting dose [40 vs.. 20 or 30 mg]) were subjected to a Cox proportional hazards regression model to estimate progression-free survival (PFS). Results Forty-eight patients with a median age of 67 years were included; the objective response rate was 62.5% (30 patients). The median PFS was 14.1 months; the PFS periods were 11.8 and 15.9 months for patients receiving 40 mg versus 20-30 mg of afatinib (P = 0.41), respectively, and were 14.5 and 13.8 months for patients who required afatinib dose reduction and those who did not, respectively (P = 0.80). The PFS tended to be longer in patients without brain metastases (albeit not significantly). Ultimately, no significant predictive values for PFS were identified. Conclusions Afatinib is effective for patients with NSCLC harboring common EGFR mutations irrespective of their clinicopathological backgrounds. A direct comparison of afatinib and osimertinib in treatment-naïve patients is warranted to determine the optimal standard of care.

Impact of neutrophil-to-lymphocyte ratio in patients with EGFR-mutant NSCLC treated with tyrosine kinase inhibitors.

Background Exon 19 deletion and L858R point mutation in exon 21 of the epidermal growth factor receptor (EGFR) are the most commonly encountered mutations in patients with non-small cell lung cancer (NSCLC) and predict better clinical outcomes following treatment with EGFR-tyrosine kinase inhibitors (TKIs). The inflammatory indicator neutrophil-to-lymphocyte ratio (NLR) in peripheral blood serves as a predictive factor for NSCLC patients treated with chemotherapy. Here, we aimed to evaluate the correlation between NLR and clinical efficacy of EGFR-TKIs in NSCLC patients harboring EGFR mutations. Methods We retrospectively collected information of 205 patients with advanced NSCLC harboring exon 19 deletion or L858R point mutation and receiving gefitinib or erlotinib. The clinical outcomes in the NSCLC patients were evaluated based on NLR level before EGFR-TKI therapy. Results The optimal cut-off value for NLR was 3.55. The response rates in the low-NLR and high-NLR groups were 69.2% and 51.5%, respectively. The median progression-free survival (PFS) in the low-NLR and high-NLR groups were 15.7 months and 6.7 months, respectively. The median overall survival (OS) in the low-NLR and high-NLR groups were 37.6 months and 19.2 months, respectively. The multivariate analysis identified performance status (PS), NLR, stage, and smoking status as independent predictors of PFS. Moreover, the PS and NLR were identified as independent predictors of OS. Conclusions NLR was a significant predictor of clinical efficacy and OS in NSCLC patients harboring EGFR mutations treated with gefitinib or erlotinib.

Oxidative stress increases megalin expression in the renal proximal tubules during the normoalbuminuric stage of diabetes mellitus.

Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.

Phase I study of Nedaplatin, a platinum based antineoplastic drug, combined with nab-paclitaxel in patients with advanced squamous non-small cell lung cancer.

Background This study was designed to determine the recommended dose of a combination of nedaplatin (NED) and nab-paclitaxel (nab-PTX) in chemotherapy-naive patients with advanced squamous non-small-cell lung cancer (NSCLC). Methods Patients received escalating doses of NED on day 1 and nab-PTX on days 1, 8, and 15 every 4 weeks by an intravenous infusion for up to six cycles. Results A dose of 100 mg/m2 NED and 100 mg/m2 nab-PTX was determined to be the recommended dose for patients with advanced squamous NSCLC. The study had an overall response rate of 66.7% (95% confidence interval [CI]: 38.4-88.2) and disease control rate of 93.3% (95% CI: 68.1-99.8). The median progression-free survival time and survival time was 7.0 months (95% CI: 5.9-8.1) and 13.1 months (95% CI: 6.2-20.1), respectively. The most common adverse events were neutropenia (grade 3/4, 33%) and leukopenia (grade 3/4, 27%). Although peripheral neuropathy was observed in 5 patients (grade 1/2), non-hematological toxic effects were relatively mild. Febrile neutropenia, pneumonitis, and treatment-related death were not observed. Conclusions The combination of NED and nab-PTX was a tolerable and effective regimen and its recommended dose was 100 mg/m2 and 100 mg/m2, respectively, in chemotherapy-naive patients with advanced squamous NSCLC (UMIN000010963).

Smoking History as a Predictor of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non-Small Cell Lung Cancer Harboring EGFR Mutations.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKIs) therapy has been recognized as the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, resistance to EGFR-TKIs has been observed in certain subpopulations of these patients. We aimed to evaluate the impact of smoking history on the efficacy of EGFR-TKIs. METHODS: The records of patients (n = 248) with NSCLC harboring activating EGFR mutations who were treated with gefitinib or erlotinib at our institution between March 2010 and June 2016 were retrospectively reviewed, and the treatment outcomes were evaluated. RESULTS: The overall response rate and median progression-free survival (PFS) were 59.7% and 10.7 months, respectively. The overall response rate was significantly higher in the ex- and nonsmokers than in the current smokers (64.6 vs. 51.1%, p = 0.038). PFS also differed significantly between the current smokers and the ex- and nonsmokers (12.4 vs. 7.4 months, p = 0.016). Multivariate analysis identified smoking history as an independent predictor of PFS and overall survival. CONCLUSION: The clinical data obtained in this study provide a valuable rationale for considering smoking history as a predictor of the efficacy of EGFR-TKI in NSCLC patients harboring activating EGFR mutations.

Efficacy of Platinum-Based Chemotherapy for Relapsed Small-Cell Lung Cancer after Amrubicin Monotherapy in Elderly Patients and Patients with Poor Performance Status.

BACKGROUND: Previous studies have shown amrubicin to be an effective first- or second-line treatment option for small-cell lung cancer (SCLC). However, there have been few studies reporting the efficacy of platinum-based chemotherapy after amrubicin therapy. We aimed to evaluate the efficacy of platinum-based chemotherapy as second-line treatment for elderly patients and those with SCLC with poor performance status (PS) previously treated with amrubicin monotherapy. METHODS: The records of SCLC patients who received platinum-based chemotherapy as a second-line chemotherapy after first-line treatment with amrubicin monotherapy were retrospectively reviewed and the treatment outcomes were evaluated. RESULTS: A total of 48 patients were enrolled in this study. Forty-one patients (85%) received carboplatin plus etoposide. The overall response rate was 39.6%. The median progression-free survival and overall survival were 3.7 and 7.6 months, respectively. The efficacy of the platinum-based regimen did not differ with the type of relapse after amrubicin monotherapy. The most common adverse events were hematological toxicities, including grade 3 or 4 neutropenia (38%), leukopenia (33%), and thrombocytopenia (10%). CONCLUSIONS: Platinum-based chemotherapy is potentially a valid treatment option for elderly patients or those with extensive-stage SCLC with poor PS as second-line chemotherapy, who progressed after first-line treatment with amrubicin monotherapy.

Genioglossus muscle activity during sniff and reverse sniff in healthy men.

NEW FINDINGS: What is the central question of this study? Maximal sniff nasal inspiratory and reverse sniff nasal expiratory pressures are measured as inspiratory and expiratory muscle strength, respectively. Is the genioglossus muscle activated during short maximal inspiratory and expiratory efforts through the nose? What is the main finding and its importance? Genioglossus muscle activity occurred with inspiratory muscle activity during a maximal sniff and with expiratory muscle activity during a maximal reverse sniff. These results indicate that genioglossus muscle activity is closely related to the generation of maximal sniff nasal inspiratory and reverse sniff nasal expiratory pressures. ABSTRACT: Maximal sniff nasal inspiratory pressure (SNIPmax ) is widely used to assess inspiratory muscle strength. The sniff nasal inspiratory pressure (SNIP) is lower in patients with neuromuscular disease with bulbar involvement compared with those without, possibly owing to impaired upper airway muscle function. However, the degree to which the genioglossus (GG) muscle, one of the upper airway muscles, is activated during inspiratory and expiratory efforts through the nose remains unclear. Therefore, we examined GG activity during short and sharp inspiratory and expiratory efforts through the nose, i.e. sniff and reverse sniff manoeuvres. In eight normal young subjects, we inserted fine wire electrodes into the GG muscle, parasternal intercostal and scalene (inspiratory) muscles and transversus abdominis (expiratory) muscle. We assessed EMG activity of each muscle and measured SNIP and reverse sniff nasal expiratory pressure (RSNEP) during sniffs and reverse sniffs from low to high intensities in the sitting position. The highest SNIP and RSNEP were analysed as SNIPmax and maximal RSNEP (RSNEPmax ), respectively. In each subject, GG EMG activity increased linearly with increasing SNIP and RSNEP. The SNIPmax and RSNEPmax were -85.1 ± 15.9 and 83.2 ± 24.2 cmH2 O, respectively. Genioglossus EMG activity varied with EMG activity of the parasternal intercostal and scalene muscles during generation of SNIPmax and with EMG activity of the transversus abdominis muscle during RSNEPmax . Genioglossus EMG activity during generation of SNIPmax was higher than during RSNEPmax (62.9 ± 31.1% EMG of SNIPmax , P = 0.012). These results suggested that GG activity was closely related to the generation of both SNIPmax and RSNEPmax .

Impact of PD-L1 Expression in Patients with Surgically Resected Non-Small-Cell Lung Cancer.

BACKGROUND: Immunotherapy can become a crucial therapeutic option to improve the prognosis of patients with non-small-cell lung cancer (NSCLC). Here, we evaluated the impact of programmed cell death ligand-1 (PD-L1) expression in surgically resected NSCLCs. METHODS: We estimated PD-L1 expression in 229 consecutive NSCLC specimens using rabbit polyclonal antibodies to human PD-L1 in a SP263 immunohistochemical assay and evaluated PD-L1 expression for potential associations with clinicopathological parameters and survival time. RESULTS: PD-L1 expression was significantly higher in tumors from men or current smokers. Squamous cell carcinoma histology was independently associated with high PD-L1 expression according to multivariate analysis (p = 0.015). The 5-year survival rate of patients was 70%, and the difference in the 5-year survival rate according to PD-L1 expression was not statistically significant (high expression group [67%] vs. low expression group [68%]); however, the squamous cell carcinoma group exhibited significantly lower 5-year survival rates as compared to the non-squamous cell carcinoma group (53 and 71%, respectively; p = 0.026). CONCLUSION: Here, we revealed high PD-L1 expression and poor prognosis observed in patients with surgically resected squamous NSCLC as compared with non-squamous NSCLC. Our results support the identification of patient subsets that most likely respond to anti-PD-1 therapy as the first step in precision medicine.

Smoking History as a Predictor of Pemetrexed Monotherapy in Patients with Non-Squamous Non-Small Cell Lung Cancer.

BACKGROUND: Pemetrexed monotherapy has come to be recognized as the standard of care for second-line therapy of non-squamous non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) expression is recognized as a potential predictor of the response to pemetrexed-based chemotherapy in patients with advanced NSCLC. The purpose of this study was to identify useful predictors of the response to pemetrexed other than TS expression. METHODS: The records of non-squamous NSCLC patients without driver mutations who received pemetrexed monotherapy as a second or later line of chemotherapy at Kitasato University Hospital between March 2009 and October 2015 were retrospectively reviewed, and the treatment outcomes were evaluated. RESULTS: In the 116 patients with non-squamous NSCLC, the overall response rate and progression-free survival (PFS) were 10.3% and 2.1 months, respectively. The disease control rate and PFS differed significantly among current smokers and never-smokers/former light smokers (44.9 vs. 65.8%, and 1.8 vs. 4.0 months, respectively). Furthermore, multivariate analysis identified Eastern Cooperative Oncology Group Performance Status and smoking status as independent predictors of the PFS. CONCLUSION: The clinical data obtained in this study may provide a valuable basis for the use of smoking status as a predictor of pemetrexed monotherapy in wild-type NSCLC patients.

Effects of intermittent pneumatic compression of the thigh on blood flow velocity in the femoral and popliteal veins: developing a new physical prophylaxis for deep vein thrombosis in patients with plaster-cast immobilization of the leg.

Patients with plaster-cast immobilization of the lower limb have an estimated venous thromboembolism rate of 2.5 % without prophylaxis, which includes many fatal cases. However, there is no practical physical prophylaxis for deep-vein thrombosis (DVT) in these patients. The aim of this study was to examine the effects of intermittent pneumatic compression on the thigh alone (IPC to the thigh) on peak blood velocity (PBV) in the legs and to consider the possibility that IPC of the thigh could be used as physical prophylaxis for DVT in patients with plaster-cast immobilization of the lower leg. Nine healthy male volunteers and eighteen elderly males were recruited. We immobilized each subject's right lower leg and ankle with a plaster splint, and applied the ActiveCare+S.F.T.(®) (Medical Compression Systems, Inc.) device to each subject's right thigh. The PBV in the superficial femoral vein (PBVFV) and the popliteal vein (PBVPV) were measured using duplex Doppler ultrasonography. IPC to the thigh resulted in a 2.3-fold increase in PBVFV and a 3.0-fold increase in PBVPV compared with resting at supine in the elderly group. Although IPC to the thigh also increased PBVFV and PBVPV significantly in the sitting position, the change ratios of PBV in the supine and sitting positions were equal (2.6-fold increase in PBVFV and 2.9-fold increase in PBVPV). IPC to the thigh in supine and sitting positions significantly increased PBVFV and PBVPV, and could be a useful prophylaxis for DVT in patients with plaster-cast immobilization of the lower leg.

Impact of Smoking History on the Efficacy of Gefitinib in Patients with Non-Small Cell Lung Cancer Harboring Activating Epidermal Growth Factor Receptor Mutations.

BACKGROUND: Gefitinib treatment has come to be recognized as the standard therapy for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, resistance to gefitinib has been observed in certain subpopulations of these patients. The purpose of this study was to evaluate the impact of smoking status on the efficacy of gefitinib in patients with NSCLC harboring EGFR mutations. METHODS: The records of NSCLC patients harboring EGFR mutations who were treated with gefitinib at Kitasato University Hospital were retrospectively reviewed, and the treatment outcomes were evaluated. RESULTS: In 153 patients with NSCLC harboring EGFR mutations, the overall response rate and progression-free survival (PFS) were 66.7% and 9.0 months, respectively. PFS differed significantly among the current smokers and never-smokers/former light smokers (10.7 vs. 5.4 months, p=0.0002), and the response rate was significantly higher in the never-smokers/former light smokers than in the current smokers (72.3 vs. 55.8%, p=0.04). Multivariate analysis identified smoking status as an independent predictor of PFS. CONCLUSION: The clinical data obtained in this study provide a valuable rationale for considering smoking status as a predictor of the efficacy of gefitinib in patients with NSCLC harboring activating EGFR mutations.

Aminophylline increases respiratory muscle activity during hypercapnia in humans.

BACKGROUND: Theophylline is an old drug traditionally used as a bronchodilator, although it was recently shown to possess anti-inflammatory properties, enhance the actions of corticosteroid actions, and stimulate the respiratory neuronal network. Theophylline has been recognized as an important drug for not only asthma but also corticosteroid-insensitive chronic obstructive pulmonary disease (COPD). To clarify the role of theophylline in hypercapnic ventilatory responses in humans, we analyzed the effects of aminophylline administered at the usual clinical therapeutic doses on ventilation and augmentation of respiratory muscle contractility in room air and under 3 conditions of hypercapnia. STUDY DESIGN: We performed electromyography (EMG) of the parasternal intercostal muscle (PARA) and transversus abdominis muscle (TA) in 7 healthy subjects and recorded both ventilatory parameters and EMG data in room air and under 3 conditions of hypercapnia before (control) and during aminophylline administration. RESULTS: Before aminophylline administration (control), hypercapnic stimulation elicited ventilatory augmentation in a hypercapnia intensity-dependent manner. Ventilatory parameters (tidal volume, frequency of respiration, and minute ventilation) showed significant increases from lower PaCO2 levels during aminophylline administration when compared with the corresponding values before aminophylline administration. EMG activity of both PARA and TA increased significantly at each level of hypercapnia, and those augmentations were shown from lower PaCO2 levels during aminophylline administration. CONCLUSION: Aminophylline administered at the usual clinical therapeutic dose increases ventilation and EMG activity of both inspiratory and expiratory muscles during hypercapnia in healthy humans.

[A Case Strongly Suspected of Being Pulmonary Toxocariasis Showing Multiple Pulmonary Nodules with a Disappearing and Reappearing Halo Sign].

We report herein on a case strongly suspected of being pulmonary toxocariasis. A 22-year-old Indonesian man referred to our hospital presented with abnormal chest shadows upon medical examination. He had no symptoms. He did not have any pets nor did he eat raw beef or chicken. Hematological examination revealed eosinophilia and elevation of IgE. Chest computed tomography revealed 3 pulmonary nodules with the halo sign. We suspected a parasite infection and performed antiparasite antibody testing. Ascaris suum was slightly positive on the screening test. As specific antibody against the larval excretory-secretory products of Toxocara canis, measured at the National Institute of Infectious Diseases, was positive (level 3 up to 8). Subsequently, the abnormal chest shadows disappeared. However, two months later, 2 pulmonary nodules with the halo sign reappeared in other places. Diagnostic therapy with albendazole was performed for 8 weeks. Mild hepatic impairment emerged during therapy, but it was within the allowed range. Thereafter, the results improved for the imaging findings, eosinophilia, serum IgE level, and specific antibody. The antibody level became negative two months after the treatment had ended. We should consider toxocariasis in the differential diagnosis of migratory nodular shadows with the halo sign on chest computed tomography, and immunoserological testing is useful for the diagnosis.

[Two Cases of Rapidly Progressive Community-acquired Pneumonia Due to Pseudomonas aeruginosa].

Pseudomonas aeruginosa is a significant causative bacterium in hospital-acquired pneumonia and nursing and healthcare-associated pneumonia, but it seems to be rare in community-acquired pneumonia (CAP). We report two cases of severe CAP due to P. aeruginosa. Case 1: A 52-year-old man was referred to our hospital for chest and back pain. He was being treated for diabetes mellitus and had a long history of smoking. Chest images showed consolidation in the right upper lobe. Soon after hospitalization, he developed sepsis shock and died seven hours later. Case 2: A 73-year-old man with a history of heavy smoking was referred to our hospital for right chest pain. Chest images showed right upper lobe pneumonia. Although wide-spectrum antimicrobial agents were administrated, he died ten hours after admission. In both cases, there was a rapid progression to death, despite administration of a broad spectrum of antibiotics and treatment for sepsis. In cases of CAP involving the right upper lobe, the possibility of bacteremia and rapid progress should be considered.

Angiotensin-converting enzyme inhibition curbs tyrosine nitration of mitochondrial proteins in the renal cortex during the early stage of diabetes mellitus in rats.

Experiments were performed to evaluate the hypothesis that ACE (angiotensin-converting enzyme) inhibition (enalapril) suppresses 3-NT (3-nitrotyrosine) production in the renal cortex during the early stage of Type 1 DM (diabetes mellitus) in the rat. Enalapril was administered chronically for 2 weeks to subsets of STZ (streptozotocin)-induced DM and vehicle-treated sham rats. O(2)(-) (superoxide anion) and NO(x) (nitrate+nitrite) levels were measured in the media bathing renal cortical slices after 90 min incubation in vitro. SOD (superoxide dismutase) activity and 3-NT content were measured in the renal cortex homogenate. Renal cortical nitrated protein was identified by proteomic analysis. Renal cortical production of O(2)(-) and 3-NT was increased in DM rats; however, enalapril suppressed these changes. DM rats also exhibited elevated renal cortical NO(x) production and SOD activity, and these changes were magnified by enalapril treatment. 2-DE (two-dimensional gel electrophoresis)-based Western blotting revealed more than 20 spots with positive 3-NT immunoreactivity in the renal cortex of DM rats. Enalapril treatment blunted the DM-induced increase in tyrosine nitration of three proteins ACO2, GDH1 and MMSDH (aconitase 2, glutamate dehydrogenase 1 and methylmalonate-semialdehyde dehydrogenase), each of which resides in mitochondria. These data are consistent with enalapril preventing DM-induced tyrosine nitration of mitochondrial proteins by a mechanism involving suppression of oxidant production and enhancement of antioxidant capacity, including SOD activation.

Sniff and reverse-sniff nasal respiratory pressures after exacerbation of chronic obstructive pulmonary disease: A single-center prospective study.

BACKGROUND: and objective: This study examined the validity of sniff nasal inspiratory (SNIP) and reverse-sniff nasal expiratory pressures (RSNEP) for estimating respiratory muscle strength and for predicting poor life expectancy following exacerbation in patients with chronic obstructive pulmonary disease (COPD). METHODS: This prospective study included patients who were admitted for COPD exacerbation and underwent rehabilitation. At hospital discharge, SNIP, RSNEP, and maximum mouth inspiratory (MIP) and expiratory pressures (MEP) were measured, and the body mass index, degree of airflow obstruction, dyspnea, and exercise capacity (BODE) index was calculated by evaluating body mass index, forced expiratory volume in 1 s (FEV1), the Modified Medical Research Council Dyspnea Scale, and 6-min walk distance. RESULTS: Data from 43 patients (mean age 76.8 years, FEV1 42.8 % predicted) were analyzed. SNIP and RSNEP were moderately correlated with MIP and MEP, respectively. Bland-Altman plot means of SNIP (48.3 ± 17.5) and RSNEP (44.7 ± 23.8 cmH2O) were lower than those of MIP (54.8 ± 19.9) and MEP (76.4 ± 31.2 cmH2O), respectively, and the SNIP-MIP and RSNEP-MEP 95 % limits of agreement were wide. Logistic regression showed that SNIP and RSNEP were significantly associated with BODE score ≥7 (poor life expectancy), and predictive accuracy was 81.4 % when combining SNIP ≤49 and RSNEP ≤42 cmH2O. CONCLUSION: After exacerbation in patients with COPD, SNIP and RSNEP are useful indicators that complement MIP and MEP. Furthermore, a combined SNIP and RSNEP test may be beneficial in predicting poor life expectancy.

Efficacy and safety of single-dose ivermectin in mild-to-moderate COVID-19: the double-blind, randomized, placebo-controlled CORVETTE-01 trial.

Background: To investigate whether ivermectin inhibits SARS-CoV-2 proliferation in patients with mild-to-moderate COVID-19 using time to a negative COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test. Methods: CORVETTE-01 was a double-blind, randomized, placebo-controlled study (August 2020-October 2021) conducted in Japan. Overall, 248 patients diagnosed with COVID-19 using RT-PCR were assessed for eligibility. A single oral dose of ivermectin (200 µg/kg) or placebo was administered under fasting. The primary outcome was time to a negative COVID-19 RT-PCR test result for SARS-CoV-2 nucleic acid, assessed using stratified log-rank test and Cox regression models. Results: Overall, 112 and 109 patients were randomized to ivermectin and placebo, respectively; 106 patients from each group were included in the full analysis set (male [%], mean age: 68.9%, 47.9 years [ivermectin]; 62.3%, 47.5 years [placebo]). No significant difference was observed in the occurrence of negative RT-PCR tests between the groups (hazard ratio, 0.96; 95% confidence interval [CI] 0.70-1.32; p = 0.785). Median (95% CI) time to a negative RT-PCR test was 14.0 (13.0-16.0) and 14.0 (12.0-16.0) days for ivermectin and placebo, respectively; 82.1% and 84% of patients achieved negative RT-PCR tests, respectively. Conclusion: In patients with COVID-19, single-dose ivermectin was ineffective in decreasing the time to a negative RT-PCR test. Clinical Trial Registration: ClinicalTrials.gov, NCT04703205.