Search

Background: The efficacy of macrolides in the management of asthma has been studied but remains controversial. We conducted a systematic review and meta-analysis of macrolides in the management of adult patients with asthma., Methods: Randomized controlled trials of macrolides used in adult patients with asthma were searched for in MEDLINE, EMBASE, PsycINFO, Cochrane Library, CINAHL, and Igaku Chuo Zasshi databases to evaluate the efficacy and safety of macrolides., Results: Seventeen reports with macrolide treatment durations ranging from 6 to 48 weeks were included. Macrolides did not reduce exacerbations requiring hospitalization, severe exacerbations, or rescue use of short-acting beta-2 agonist inhalers; improve lung function; decrease peripheral blood or sputum neutrophil counts; or decrease fractional exhaled nitric oxide compared to placebo. Macrolides statistically improved asthma control and quality of life but by less than the minimal clinically important difference. Peripheral blood eosinophil counts as well as serum and sputum eosinophilic cationic protein concentrations were significantly decreased with macrolides compared to placebo. The improvement of asthma symptoms and airway hyperresponsiveness varied by study. The safety profile of macrolides was comparable to that of placebo., Conclusions: Although macrolides have some useful clinical aspects, there is not sufficient evidence to recommend their use in the management of adult patients with asthma., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

The pathophysiology of laryngopharyngeal reflux (LPR) and its impact on the vocal fold is not well understood, but may involve acid damage to vocal fold barrier functions. Two different components encompass vocal fold barrier function: the mucus barrier and tight junctions. Mucus retained on epithelial microprojections protects the inside of the vocal fold by neutralizing acidic damage. Tight junctions control permeability between cells. Here we developed an in vitro experimental system to evaluate acidic injury and repair of vocal fold barrier functions. We first established an in vitro model of rat vocal fold epithelium that could survive at least one week after barrier function maturation. The model enabled repeated evaluation of the course of vocal fold repair processes. Then, an injury experiment was conducted in which vocal fold cells were exposed to a 5-min treatment with acidic pepsin that injured tight junctions and cell surface microprojections. Both of them healed within one day of injury. Comparing vocal fold cells treated with acid alone with cells treated with acidic pepsin showed that acidic pepsin had a stronger effect on intercellular permeability than acid alone, whereas pepsin had little effect on microprojections. This result suggests that the proteolytic action of pepsin has a larger effect on protein-based tight junctions than on phospholipids in microprojections. This experimental system could contribute to a better understanding of vocal fold repair processes after chemical or physical injuries, as well as voice problems due to LPR pathogenesis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masanobu Mizuta, Ichiro Tateya reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Preoperative embolization for meningiomas is controversial regarding its effectiveness in reducing intraoperative blood loss and operative time. In contrast, some reports have documented improved surgical outcomes in large meningiomas. In this study, we retrospectively compared the outcomes of craniotomy for meningiomas with/without preoperative embolization with diluted N-butyl-2-cyanoacrylate (NBCA) primarily in a single institution., Methods: Data (World Health Organization grade, Simpson grade, maximum tumor diameter, intraoperative bleeding, operative time, history of hypertension, and time from embolization to craniotomy) of patients with initial intracranial meningiomas were compared with or without preoperative embolization from January 2015 to April 2022., Results: The embolization group consisted of 56 patients and the nonembolization group included 76 patients. Diluted NBCA (13% concentration for all patients) was used in 51 of 56 patients (91.1%) who underwent transarterial embolization. Permanent neurological complications occurred in 2 (3.6%) patients. Intraoperative bleeding was significantly lower in the embolization group for a maximum tumor diameter ≥40 mm (155 vs. 305 ml, respectively, p < 0.01). In the nonembolization group, for a maximum tumor diameter ≥30 mm, patients with hypertension had more intraoperative bleeding than non-hypertensive ones., Conclusions: Despite its limitations, the present results showed that, under certain conditions, preoperative embolization for intracranial meningiomas caused less intraoperative bleeding. The safety of treatment was comparable with that reported in the Japan Registry of NeuroEndovascular Therapy 3 (JR-NET3) with a complication rate of 3.7% for preoperative embolization of meningiomas, despite the treatment focused on the liquid embolization material., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To investigate roles of sarcopenia indexes in prediction of development of insulin resistance in nondiabetic older adults., Design: A 2-year follow-up cohort., Setting and Participants: The Tanno-Sobetsu study, a prospective observational cohort, included 194 community-dwelling nondiabetic older adults during 2017-2019., Methods: Lower limb, upper limb, appendicular, and trunk muscle masses by a bioelectrical impedance analysis, grip strength, knee extension torque, and walking speed were measured in study participants aged ≥65 years (79 men and 115 women) at baseline. Muscle mass and strength were divided by the weight, and then multiplied by 100 to calculate the weight ratio (%). Insulin resistance was assessed by homeostasis model (HOMA-IR) at baseline, and the study participants whose HOMA-IR was less than 1.73 at baseline were followed for a maximum of 2 years. The study endpoint was development of insulin resistance defined as HOMA-IR ≥1.73. The adjusted hazard ratio (HR) of each sarcopenia component for development of insulin resistance was calculated., Results: Lower limb muscle mass (HR 0.88, 95% CI 0.79-0.98) and appendicular muscle mass (HR 0.89, 95% CI 0.81-0.99), but not other sarcopenia components, were associated with the development of insulin resistance, independently of sex and age, HOMA-IR, and waist circumference at baseline., Conclusions and Implications: The loss of lower limb muscle mass is a significant risk factor for development of insulin resistance independently of obesity in nondiabetic older adults. The lower limb muscle mass may be a novel target of interventions for the prevention of diabetes in older adults., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Bile acid intermediates, 3α,7α,12α-trihydroxycholestanoic acid (THCA) and 3α,7α-dihydroxycholestanoic acid (DHCA), are metabolized in peroxisomes. Some peroxisomal disorders (PDs), such as Zellweger spectrum disorder (ZSD), show an accumulation of bile acid intermediates. In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities. In patients with ZSD, levels of bile acid intermediates can be lowered by a primary bile acid supplementation treatment; therefore, measuring their levels could help evaluate treatment effectiveness. Here, we established a method for the quantitative determination of bile acid intermediates (THCA/DHCA) for differentiating PDs and assessing bile acid treatment., Methods: Serum samples, obtained from patients with several forms of ZSD as well as peroxisomal β-oxidation enzyme deficiencies, were deproteinized and analyzed using liquid chromatography-mass spectrometry., Results: Levels of the bile acid intermediates increased significantly in patients with Zellweger syndrome (ZS) and slightly in patients with neonatal adrenoleukodystrophy and infantile Refsum disease (IRD), reflecting the severity of these diseases. One patient with ZS treated with primary bile acids for 6 months showed slightly decreased serum DHCA levels but significantly increased serum THCA levels. One patient with IRD who underwent living-donor liver transplantation showed a rapid decrease in serum THCA and DHCA levels, which remained undetected for 6 years. In all controls, THCA and DHCA levels were below the detection limit., Conclusion: The analytical method developed in this study is useful for diagnosing various PD and validating bile acid treatment. Additionally, it can help predict the prognosis of patients with PD and support treatment strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Macrophages aid in wound healing by changing their phenotype and can be a key driver of fibrosis. However, the contribution of macrophage phenotype to fibrosis following vocal fold injury remains unclear. Peroxisome proliferator-activated receptor-γ (PPARγ) is expressed mainly by macrophages during early wound healing and regulates the macrophage phenotype. This study aimed to evaluate the effects of pioglitazone (PIO), a PPARγ agonist, on the macrophage phenotype and fibrosis following vocal fold injury in rats. PIO was injected into the rat vocal folds on days 1, 3, 5, and 7 after injury, and the vocal fold lamina propria was evaluated on days 4 and 56 after injury. Moreover, THP-1-derived macrophages were treated with PIO, and the expression of proinflammatory cytokines under lipopolysaccharide/interferon-γ stimulation was analyzed. PIO reduced the expression of Ccl2 both in vivo and in vitro. Furthermore, PIO decreased the density of inducible nitric oxide synthase + CD68 + macrophages and inhibited the expression of fibrosis-related factors on day 4 after injury. On day 56 after injury, PIO inhibited fibrosis, tissue contracture, and hyaluronic acid loss in a PPARγ-dependent manner. These results indicate that PPARγ activation could inhibit accumulation of inflammatory macrophages and improve tissue repair. Taken together, these findings imply that inflammatory macrophages play a key role in vocal fold fibrosis., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Post-radiation fibrosis of the vocal folds is thought to cause vocal impairment. However, the mechanism by which this occurs has been poorly documented, probably because of the lack of an appropriate experimental animal model. The purpose of this study was to establish a simple and reproducible mouse model of laryngeal radiation to investigate the development of vocal fold fibrosis over time. C57BL/6 mice individually placed in a lead shield were irradiated with a single dose of 20 Gy. At 1, 2, and 6 months after irradiation, larynges were harvested and subjected to histological examination and gene expression analysis. Irradiated vocal folds showed time-dependent tissue contraction and increased collagen deposition, with no significant difference in the changes in hyaluronic acid levels. Transcriptional analysis revealed upregulated expressions of TGF-β1 and iNOS at 6 months, but downregulated expressions of Acta2, Col1a1, Col3a1, and MMP8. Moreover, elevated TGF-β1 and reduced downstream gene expression levels indicated the existence of an inhibitory factor over the TGF-β/Smad pathway. Discrepancies in histological and transcriptional studies of collagen might suggest that radiation-induced vocal fold fibrosis could be caused by the elongated turnover of collagen. Overall, we established a mouse model of radiation-induced vocal fold fibrosis using a simple protocol. Further investigations are warranted to elucidate the pathogenesis of irradiation-induced fibrosis in vocal folds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The membrane protein SIRPα is a cold stress-responsive signaling molecule in neurons. Cold stress directly induces tyrosine phosphorylation of SIRPα in its cytoplasmic region, and phosphorylated SIRPα is involved in regulating experience-dependent behavioral changes in mice. Here, we examined the mechanism of cold stress-induced SIRPα phosphorylation in vitro and in vivo. The levels of activated Src family protein tyrosine kinases (SFKs), which phosphorylate SIRPα, were not increased by lowering the temperature in cultured neurons. Although the SFK inhibitor dasatinib markedly reduced SIRPα phosphorylation, low temperature induced an increase in SIRPα phosphorylation even in the presence of dasatinib, suggesting that SFK activation is not required for low temperature-induced SIRPα phosphorylation. However, in the presence of pervanadate, a potent inhibitor of protein tyrosine phosphatases (PTPases), SIRPα phosphorylation was significantly reduced by lowering the temperature, suggesting that either the inactivation of PTPase(s) that dephosphorylate SIRPα or increased protection of phosphorylated SIRPα from the PTPase activity is important for low temperature-induced SIRPα phosphorylation. Inactivation of PTPase Shp2 by the allosteric Shp2 inhibitor SHP099, but not by the competitive inhibitor NSC-87877, reduced SIRPα phosphorylation in cultured neurons. Shp2 knockout also reduced SIRPα phosphorylation in the mouse brain. Our data suggest that Shp2, but not SFKs, positively regulates cold stress-induced SIRPα phosphorylation in a PTPase activity-independent manner., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Transient receptor potential vanilloid 1 (TRPV1) modulates pain. Studies have indicated that TRPV1 is upregulated in the spinal dorsal horn in the neuropathic pain model, but its mechanism is unknown. Here, we examined the mechanism by which TRPV1 modulates neuropathic pain by employing partial sciatic nerve ligation (pSNL) in adult male C57BL/6 J (wild-type: WT) and TRPV1 knockout (Trpv1-/-) mice. We analyzed mechanical/heat sensitivities (von Frey test/hot plate test) and glial/neuronal activities (Iba-1/GFAP/FosB by immunofluorescence) in laminae I and II in the L5 ipsilateral dorsal horn of the spinal cord. Mechanical/heat sensitivities, expression levels of microglial Iba-1 and astrocytic GFAP, and the number of FosB-positive neurons were significantly increased on days 7 and 14 in the pSNL group compared with the sham-operated and non-operated groups of both WT and Trpv1-/- mice. While mechanical sensitivity was comparable between WT and Trpv1-/- mice, the threshold against heat sensitivity was markedly prolonged in Trpv1-/- than WT mice on day 14 after pSNL. Conversely, the increment of FosB positive neurons was significantly attenuated in Trpv1-/- than WT mice on days 7 and 14 after pSNL. These results suggest that TRPV1 may modulate thermal perception via increased astrocytes in the dorsal horn of the spinal cord., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Purpose: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency., Methods: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24., Results: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease., Conclusion: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

The laryngotracheal cartilage is a cardinal framework for the maintenance of the airway for breathing, which occasionally requires reconstruction. Because hyaline cartilage has a poor intrinsic regenerative ability, various regenerative approaches have been attempted to regenerate laryngotracheal cartilage. The use of autologous mesenchymal stem cells (MSCs) for cartilage regeneration has been widely investigated. However, long-term culture may limit proliferative capacity. Human-induced pluripotent stem cell-derived MSCs (iMSCs) can circumvent this problem due to their unlimited proliferative capacity. This study aimed to investigate the efficacy of iMSCs in the regeneration of thyroid cartilage in immunodeficient rats. Herein, we induced iMSCs through neural crest cell intermediates. For the relevance to prospective future clinical application, induction was conducted under xeno-free/serum-free conditions. Then, clumps fabricated from an iMSC/extracellular matrix complex (C-iMSC) were transplanted into thyroid cartilage defects in immunodeficient rats. Histological examinations revealed cartilage-like regenerated tissue and human nuclear antigen (HNA)-positive surviving transplanted cells in the regenerated lesion. HNA-positive cells co-expressed SOX9, and type II collagen was identified around HNA-positive cells. These results indicated that the transplanted C-iMSCs promoted thyroid cartilage regeneration and some of the iMSCs differentiated into chondrogenic lineage cells. Induced MSCs may be a promising candidate cell therapy for human laryngotracheal reconstruction., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Childhood cerebral adrenoleukodystrophy (CCALD) is the most common phenotype of adrenoleukodystrophy (ALD) and is characterized by the progression of intellectual, psychic, visual, and gait disturbances. Progression of this intractable disease can only be prevented by hematopoietic stem cell transplantation during the early stages of the disease. The aim of this study was to clinically evaluate children with CCALD who have visual symptoms to enable early diagnosis., Methods: We enrolled 41 Japanese children with CCALD who had visual symptoms. We retrospectively analyzed age of onset, past medical history, initial symptoms, visual symptoms and findings on brain magnetic resonance imaging., Results: The median age of disease onset was 7 years (range 5-10 years). The most common visual symptom was strabismus (n = 22). There was only one patient with the triad of symptoms of Balint's syndrome. Seventeen patients had incomplete Balint's syndrome and showed one or two of the triad of symptoms. Almost all patients with complete or incomplete Balint's syndrome showed bilateral parieto-occipital white matter lesions., Conclusions: CCALD could develop into Balint's syndrome, especially the incomplete form. Therefore, CCALD should be considered when boys show new symptoms, including lack of eye contact or bumping into objects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The inner ear comprises four epithelial domains: the cochlea, vestibule, semicircular canals, and endolymphatic duct/sac. These structures are segregated at embryonic day 13.5 (E13.5). However, these four anatomical structures remain undefined at E10.5. Here, we aimed to identify lineage-specific genes in the early developing inner ear using published data obtained from single-cell RNA-sequencing (scRNA-seq) of embryonic mice. We downloaded 5000 single-cell transcriptome data, named 'auditory epithelial trajectory', from the Mouse Organogenesis Cell Atlas. The dataset was supposed to include otic epithelial cells at E9.5-13.5. We projected the 5000 ​cells onto a two-dimensional space encoding the transcriptional state and visualised the pattern of otic epithelial cell differentiation. We identified 15 clusters, which were annotated as one of the four components of the inner ear epithelium using known genes that characterise the four different tissues. Additionally, we classified 15 clusters into sub-regions of the four inner ear components. By comparing transcriptomes between these 15 clusters, we identified several candidates of lineage-specific genes. Characterising these new candidate genes will help future studies about inner ear development., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: We reported that the pancreas of the interferon-regulatory factor (IRF) 2 knock-out (KO) mouse represents an early phase of acute pancreatitis, including defective regulatory exocytosis, intracellular activation of trypsin, and disturbance of autophagy. The significantly upregulated and downregulated genes in the IRF2 KO pancreas have been reported. The catalogue of gene transcripts included two types of calcium-binding proteins (S100 calcium binding protein G [S100g] and Annexin A10 [Anxa10]), which were highly upregulated in the IRF2 KO pancreas. As the intracellular calcium signal plays a pivotal role in regulatory exocytosis and its disturbance is related to pancreatitis, we then evaluated the role of S100g and Anxa10 in acute pancreatitis., Method: We induced cerulein-pancreatitis in wild-type mice and examined the changes in the expression of these genes by qPCR and immunohistochemistry. We constructed S100g-overexpressing or Anxa10-overexpressing AR42J cells (AR42J-S100g, AR42J-Anxa10). We examined the changes in amylase secretion, intracellular calcium ([Ca 2+ ]i), and cell viability in these cells, when incubated with cholecystokinin (CCK)., Results: The expression of S100g and Anxa10 was increased in cerulean-induced pancreatitis. The acini were patchily stained for S100g and the cytosol of acini was evenly but weakly stained for Anxa10. Stimulation with 100pM CCK-8, decreased amylase secretion and inhibited the [Ca 2+ ]i increase in AR42J-S100g cells. These effects were weak in AR42J-Anxa10 cells. Cell viability was not changed by incubation with cerulein., Conclusion: In cerulean pancreatitis, the expression of S100g and Anxa10 was induced in the acini. S100g may work as a Ca 2+ buffer in acute pancreatitis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Although circulating leukocytes are non-adherent cells, they also undergo adhesion in response to external stimuli. To elucidate this switch mechanism, we investigated PMA-induced cell adhesion in myelomonocytic KG-1 cells. PMA induced microvillius collapse, decrease of cell surface rigidity and exclusion of sialomucin from adhesion sites. All these adhesion-contributing events are linked to dephosphorylation of Ezrin/Radixin/Moesin (ERM) proteins. Indeed, PMA-treatment induced quick decrease of phosphorylated ERM proteins, while expression of Moesin-T558D, a phospho-mimetic mutant, inhibited PMA-induced cell adhesion. PMA-induced cell adhesion and ERM-dephophorylation were inhibited by PKC inhibitors or by a phosphatase inhibitor, indicating the involvement of PKC and protein phophatase in these processes. In peripheral T lymphocytes, ERM-dephosphorylation by adhesion-inducing stimuli was inhibited by a PKC inhibitor. Combined, these findings strongly suggest that external stimuli induce ERM-dephosphorylation via the activation of PKC in leukocytes and that ERM-dephosphorylation leads to leukocytes' adhesion., Competing Interests: Declaration of competing interest Authors declare that there is no conflict of interest in this study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In clinical practice, we frequently experience patients with sarcoidosis who show relatively high but normal values of angiotensin-converting enzyme (ACE). The objective of this study was to reconsider the cut-off value of ACE., Methods: We studied 79 Japanese patients who were diagnosed as having sarcoidosis at our hospital. We excluded patients who had taken steroids or ACE inhibitors and patients with renal impairment. We respectively evaluated ACE values and performed receiver operating characteristic (ROC) analysis from a comparison with data for 299 normal Japanese subjects who showed ACE values in the current Japanese standard normal range (7.0-25.0IU/L)., Results: Patients with sarcoidosis had higher ACE values than those in normal subjects (ACE: 20.3IU/L [IQR, 16.0-24.4] vs. 15.4IU/L [IQR, 12.8-18.5]; p<0.001). However, 62 patients (78.5%) had normal ACE levels (cut-off value <25.0IU/L), and the sensitivity of ACE level for detecting sarcoidosis was only 21.5%. From ROC analysis, a cut-off value of 17.7IU/L (AUC: 0.727, 95% CI: 0.660-0.794, p<0.001) was the best cut-off value for detecting sarcoidosis and sensitivity increased to 67.0%., Conclusions: The possibility of sarcoidosis cannot be ruled out by using the current Japanese standard value even in patients who have normal ACE levels. Careful interpretation of this biomarker is needed., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: To study clinical significance of augmentation of intraoperative motor evoked potentials (MEPs) during direct open surgery for middle cerebral artery (MCA) aneurysms., Methods: Between 2009 and 2017, 134 MCA aneurysm surgeries were performed with intraoperative MEP monitoring. The frequency and cause of augmentation with >50% increase of MEP amplitude from baseline were studied. Factors associated with MEP augmentation were investigated., Results: MEP augmentation was demonstrated in 9 patients. All 9 events were observed just after application of the temporary clip to the parent artery. The ratio of the maximum amplitude to baseline was 2.6 ± 1.1 at an mean of 2.4 ± 1.1 minutes after parent artery occlusion. Ten patients who did not show MEP augmentation after parent artery occlusion were compared with the patients showing MEP augmentation. The distance of the temporary clip point from the midline was smaller in patients with MEP augmentation compared with patients without MEP augmentation (P = 0.033)., Conclusions: MEP augmentation was thought to be an early ischemic sign preceding a significant decrease in MEPs during MCA aneurysm surgery. Transient augmentation of MEPs was more frequently observed in cases with a temporary clip applied to the more proximal part of the MCA., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To assess the sensitivities of the Wells score (WS) and the revised Geneva score (RGS) and their prognostic values in the diagnosis of pulmonary embolism (PE) in the Japanese population., Methods: We conducted a retrospective chart review of patients with PE aged 16 years or older who were assessed between December 2008 and August 2014. Patients were divided into the PE unlikely and PE likely groups according to the WS and PE unlikely and PE likely groups according to the RGS. We also described the characteristics and three-month mortality of the patients. Univariate predictors with p < 0.05 were included in the multiple regression model. Fisher׳s exact test and Student׳s t-test were used for categorical and continuous variables, respectively., Results: PE was confirmed in 53 patients, and seven (13%) patients died within 3 months. The mean age was 66.0 ± 14.4 years. There were 32 female patients (60.4%). The RGS had a higher sensitivity than the WS (20.8% vs. 15.1%, P <0.01), although both scores had low yields. Mortality rate was significantly higher in patients with syncope than in those without (33.3% vs. 7.3%, respectively; P = 0.039). After age and sex adjustments, the presence of syncope showed a statistically significant association with mortality. The mortality rate did not significantly differ between the two groups categorized according to the WS (17.4% vs. 0%; P = 0.58) and RGS (21.7% vs. 14.3%; P = 1.00)., Conclusion: WS and RGS had low sensitivity in the diagnosis of PE and had limited prognostic values in a Japanese community hospital setting. Promoting awareness about the risk of mortality in patients with PE, especially those with syncope, is necessary., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: The frequency of the occurrence of adverse events associated with carotid artery stenting (CAS) is usually low, but serious adverse events such as cerebral hyperperfusion syndrome (CHS) may occur. Real-time monitoring is ideal for the early detection of adverse events during the surgical procedure. This study aimed to evaluate continuous blood glucose (BG) monitoring for the detection of adverse events during CAS., Methods: Forty patients undergoing scheduled CAS were prospectively enrolled. An artificial pancreas was used for continuous BG monitoring (once per minute), using venous blood extracted at a rate of 2 mL/hr during CAS. The primary endpoint was a correlation between BG change and adverse events., Results: CAS was discontinued in 1 patient, and BG was not measured in 5 patients (12.5%) because of the inability to extract blood. Among 34 evaluable patients, no patient developed CHS, but 3 patients (9%) experienced carotid occlusion intolerance. During CAS, BG was significantly higher in patients with carotid occlusion intolerance (median: 5 mg/dL) than in patients without carotid occlusion intolerance (median: 0 mg/dL) (P = 0.0221). A cutoff BG value ≥4 mg/dL during CAS showed 50% sensitivity and 100% specificity for the detection of carotid occlusion intolerance. There was no significant correlation between BG change and other adverse events., Conclusions: BG elevation may help detect carotid occlusion intolerance although it is still unknown whether BG monitoring can detect CHS. Further studies should validate that a cutoff BG elevation value of ≥4 mg/dL during CAS indicates carotid occlusion intolerance., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Preoperative evaluation of the risk of surgery-related blood loss in malignant soft tissue tumor resection is difficult because of wide variations in histological subtype, malignancy, location, and size. Ultrasonography is useful for the evaluation of blood flow around a soft tissue tumor and has the potential to preoperatively estimate intraoperative blood loss in tumor resection. To date, there has been no report regarding blood loss evaluation using ultrasonography in this field., Patients and Methods: The usefulness of information obtained by ultrasonography, including tumor size, vessel density in the tumor, and blood flow volume in the vessels, was analyzed for the prediction of intraoperative blood loss in malignant soft tissue tumor resection., Results: Vessel density in the tumor and blood flow in the vessels were identified as independent risk factors for blood loss. Using these factors, a new index for the prediction of blood loss was established. Receiver operating characteristic analyses revealed a high area under the curve value (0.80), confirming the accuracy of the index for the prediction of blood loss., Conclusion: Ultrasonography is a useful modality for predicting intraoperative blood loss in malignant soft tissue tumor surgery., (Copyright © 2018. Published by Elsevier B.V.)

Background: Deep vein thrombosis (DVT) develops after major orthopedic surgery despite the current use of prophylaxis. DVT frequently develops in the soleal vein (SV) and might develop easily at the site of SV dilatation because of blood flow stasis. However, whether preoperative SV dilatation detected by ultrasonography predicts DVT after major orthopedic surgery remains unknown., Objective: We examined whether SV dilatation detected by preoperative ultrasonography predicts DVT after major orthopedic surgery., Methods: Ultrasonography was performed preoperatively and postoperatively in 243 patients with orthopedic diseases (mean age of 67±13 years, 77% women) who underwent total hip arthroplasty (THA, n=180) or total knee arthroplasty (TKA, n=63). Presence of DVT was diagnosed by ultrasonography and SV diameter ≥10mm was defined as SV dilatation. Patients with preoperative DVT were excluded., Results: Sixty-nine patients (28%) developed postoperative DVT. SV dilatation was found in 24 patients (10%), and 16 (67%) of those patients had postoperative DVT. Multivariate logistic regression analysis showed that female gender [odds ratio (OR): 4.09, p=0.004], TKA (OR: 2.52, p=0.011), and SV dilatation (OR: 6.67, p<0.001), but not presence of comorbidities, medications, or plasma d-dimer value, independently predict postoperative DVT. Subgroup analyses according to the operation site showed that female gender (OR: 3.27, p=0.043) and SV dilatation (OR: 3.72, p=0.022) were independent predictors of postoperative DVT in the THA group. SV dilatation (OR: 12.0, p=0.027) was an independent predictor of postoperative DVT also in the TKA group., Conclusions: In addition to gender and TKA, SV dilatation detected by ultrasonography is an independent predictor of DVT after major orthopedic surgery. Determination of SV diameter by ultrasonography before major orthopedic surgery is useful for assessing the risk of postoperative DVT., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Asparagine synthetase (ASNS) deficiency was recently discovered as a metabolic disorder of non-essential amino acids, and presents as severe progressive microcephaly, intellectual disorder, dyskinetic quadriplegia, and intractable seizures., Methods: Two Japanese children with progressive microcephaly born to unrelated patients were analyzed by whole exome sequencing and novel ASNS mutations were identified. The effects of the ASNS mutations were analyzed by structural evaluation and in silico predictions., Results: We describe the first known Japanese patients with ASNS deficiency. Their clinical manifestations were very similar to reported cases of ASNS deficiency. Progressive microcephaly was noted during the prenatal period in patient 1 but only after birth in patient 2. Both patients had novel ASNS mutations: patient 1 had p.L145S transmitted from his mother and p.L247W which was absent from his mother, while patient 2 carried p.V489D and p.W541Cfs*5, which were transmitted from his mother and father, respectively. Three of the four mutations were predicted to affect protein folding, and in silico analyses suggested that they would be pathogenic., Conclusion: We report the first two Japanese patients with ASNS deficiency. Disease severity appears to vary among patients, as is the case for other non-essential amino acid metabolic disorders., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Mogamulizumab, a defucosylated humanized monoclonal antibody targeting C-C chemokine receptor 4, recently became available for the treatment of adult T-cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab in ATL treatment in patients on Hokkaido Island, Japan., Materials and Methods: A total of 125 patients with ATL treated from January 2010 to December 2014 in 20 hospitals affiliated with the Hokkaido Hematology Study Group were enrolled in the present retrospective study., Results: Of the 125 ATL patients, 62 (46.6%) presented with the acute type, 51 (38.3%) with the lymphoma type, and 12 (9.0%) with the chronic type; the latter group included 7 unfavorable chronic cases. The median age at diagnosis was 68 years (range, 35-86 years). The median survival for those with acute, lymphoma, and unfavorable chronic types was 302, 279, and 921 days, respectively. Advanced age, high lactate dehydrogenase level, poor performance status (3-4), and the existence of B symptoms were unfavorable prognostic factors for overall survival (OS). Survival rate calculated from the day of diagnosis was significantly higher in patients treated with mogamulizumab. The OS of individuals receiving hematopoietic stem cell transplantation (HSCT) was superior to that of the non-HSCT group. The median interval between the last mogamulizumab dose and allogeneic HSCT was 38 days (range, 21-53 days). Of the 22 HSCT recipients who were not treated with mogamulizumab, overall acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD occurred in 12 (54.5%) and 3 (13.6%) patients, respectively. However, overall aGVHD and grade III-IV aGVHD developed in 8 (88.9%) and 3 (33.3%) of the 9 HSCT recipients treated with mogamulizumab, respectively., Conclusion: Mogamulizumab improves OS in patients with ATL, although its use in HSCT patients might trigger severe GVHD. Determining the optimal pre-HSCT mogamulizumab treatment regimen is thus a priority., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Blood blister aneurysms (BBAs) of the internal carotid artery (ICA) are challenging vascular lesions for neurosurgeons because they are fragile and difficult to clip. They are commonly found at the dorsal wall of the ICA. Trapping is an alternative for these lesions, accompanied by vascular reconstruction. However, they are sometimes close to the posterior communicating artery and anterior choroidal artery., Case Description: A 30-year-old man presented with subarachnoid hemorrhage caused by rupture of a BBA in the right distal ICA. After construction of a high-flow bypass, the BBA was accessed via the standard pterional approach to end only in proximal clipping. Two weeks later, the remnant of the BBA showed a tendency to grow. Therefore, the anterior temporal approach was successfully used to obliterate the BBA using an oblique clip technique under direct inspection of patency of the perforators., Conclusions: The anterior temporal approach to a BBA in the distal ICA is amenable to application of the oblique clip technique, which can provide direct inspection of the perforators emanating from the posteromedial wall of the ICA as well as obliteration of the pathologic wall. Furthermore, less retraction of the frontal lobe is also reasonable for avoidance of premature rupture of a fragile BBA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a fast and reliable method for the identification of bacteria. A MALDI Sepsityper kit is generally used to prepare samples obtained directly from culture bottles. However, the relatively high cost of this kit is a major obstacle to introducing this method into routine clinical use. In this study, the accuracies of three different preparation methods for rapid direct identification of bacteria from positive blood culture bottles by MALDI-TOF MS analysis were compared., Methods: In total, 195 positive bottles were included in this study., Results: Overall, 78.5%, 68.7%, and 76.4% of bacteria were correctly identified to the genus level (score ≥1.7) directly from positive blood cultures using the Sepsityper, centrifugation, and saponin methods, respectively. The identification rates using the Sepsityper and saponin methods were significantly higher than that using the centrifugation method (Sepsityper vs. centrifugation, p<0.001; saponin vs. centrifugation, p=0.003)., Conclusions: These results suggest that the saponin method is superior to the centrifugation method and comparable to the Sepsityper method in the accuracy of rapid bacterial identification directly from blood culture bottles, and could be a less expensive alternative to the Sepsityper method., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Pulmonary hypertension (PH) is a strong predictor of mortality in patients with interstitial lung disease (ILD). However, patients with ILD often have poor outcomes even in the absence of PH. Pulmonary vascular resistance (PVR) assessed by right heart catheterization is a predictor of mortality in patients with ILD. However, the clinical utility of PVR assessed by Doppler echocardiography (PVRecho) as a predictor of the outcome in patients with ILD remains unclear. The aim of this study was to examine whether PVRecho independently predicts mortality in patients with ILD., Methods: Echocardiographic examinations were performed in 133 consecutively enrolled patients with ILD (age, 67±9 years; 53% men). Tricuspid annular plane systolic excursion (TAPSE) was measured, and PVRecho was calculated by the following formula: PVRecho=[TRV×10/time-velocity integral of right ventricular outflow (RVOT-VTI)]+0.16. Data for parameters of pulmonary functional tests and for serum biomarkers, which were measured within 3 months before or after the echocardiographic examinations, were collected., Results: During a mean follow-up period of 18±7 months, 13 patients died due to respiratory failure (n=10), heart failure (n=1), or unknown causes (n=2). In univariate analysis, body mass index, idiopathic pulmonary fibrosis, use of an antifibrotic drug (AD), RVOT-VTI, PVRecho, percentage of predicted vital capacity (%VC), percentage of predicted forced expiratory volume in 1second, and percentage of predicted diffusion capacity of the lungs for carbon monoxide (%DLco), but not TAPSE or serum biomarkers, were significantly associated with mortality. Cox proportional hazard multivariate analysis indicated that %VC [hazard ratio (HR): 0.92, p=0.001], use of AD (HR: 4.05, p=0.043), and PVRecho (HR: 3.79, p=0.029) independently predict mortality in patients with ILD. Replacement of %VC with %DLco in the multivariate analysis did not change the results: %DLco (HR: 0.90, p=0.001), use of AD (HR: 7.53, p=0.029), and PVRecho (HR: 3.65, p=0.020)., Conclusions: In addition to parameters of pulmonary function tests and use of AD, increased PVRecho is an independent predictor of mortality in patients with ILD who were evaluated for screening of PH by echocardiography., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Degenerative mitral stenosis (DMS) is found in the elderly population. However, there are a few reports regarding the prevalence rate of DMS and, its clinical characteristics. The aim of this study was to determine the relationship between age, gender, and the prevalence rate of DMS., Methods: Patients with DMS and rheumatic mitral stenosis (RMS) were searched retrospectively in consecutive patients who underwent echocardiography from January 2011 to December 2013 in a community hospital. DMS was defined as presence of both turbulent antegrade flow with a mean transmitral pressure gradient (PG) of ≥2mmHg and mitral annular calcification without restriction of leaflets tip motion., Results: We identified 19 patients (17 female and 2 male) with DMS (0.22%) and 19 patients with RMS in 8683 patients. The prevalence rate of DMS significantly increased with aging, especially in patients >90 years old. There was no significant difference in the prevalence rates of RMS among the age groups. Patients with DMS were older (86±8 years vs. 73±10 years, p<0.01) and had higher rates of hypertension and aortic stenosis, larger left ventricular mass index, and mean PG of aortic valve, smaller aortic valve area, less degree of left atrial dilatation, and lower rate of atrial fibrillation, compared with those values in patients with RMS., Conclusions: DMS is rare (0.22%) and almost exclusively found in females in routine echocardiography. The prevalence of DMS increases with aging to 2.5% in patients >90 years of age, and DMS is often associated with aortic valve stenosis., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The clinical course of idiopathic pulmonary fibrosis (IPF) shows great inter-individual differences. It is important to standardize the severity classification to accurately evaluate each patient׳s prognosis. In Japan, an original severity classification (the Japanese disease severity classification, JSC) is used. In the United States, the new multidimensional index and staging system (the GAP model) has been proposed. The objective of this study was to evaluate the model performance for the prediction of mortality risk of the JSC and GAP models using a large cohort of Japanese patients with IPF., Methods: This is a retrospective cohort study including 326 patients with IPF in the Hokkaido prefecture from 2003 to 2007. We obtained the survival curves of each stage of the GAP and JSC models to perform a comparison. In the GAP model, the prognostic value for mortality risk of Japanese patients was also evaluated., Results: In the JSC, patient prognoses were roughly divided into two groups, mild cases (Stages I and II) and severe cases (Stages III and IV). In the GAP model, there was no significant difference in survival between Stages II and III, and the mortality rates in the patients classified into the GAP Stages I and II were underestimated., Conclusions: It is difficult to predict accurate prognosis of IPF using the JSC and the GAP models. A re-examination of the variables from the two models is required, as well as an evaluation of the prognostic value to revise the severity classification for Japanese patients with IPF., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Peripheral administration of cholecystokinin (CCK)-8 or secretin activates oxytocin (OXT)-secreting neurons in the hypothalamus. Although OXT is involved in the regulation of feeding behavior, detailed mechanism remains unclear. In the present study, we examined the central OXTergic pathways after intraperitoneally (i.p.) administration of CCK-8 and secretin using male OXT-monomeric red fluorescent protein 1 (mRFP1) transgenic rats and male Wistar rats. I.p. administration of CCK-8 (50μg/kg) and secretin (100μg/kg) decreased food intake in these rats. While i.p. administration of CCK-8 decreased water intake, i.p. administration of secretin increased water intake. Immunohistochemical study revealed that Fos-Like-Immunoreactive cells were observed abundantly in the brainstem and in the OXT neurons in the dorsal division of the parvocellular paraventricular nucleus (dpPVN). We could observe marked increase of mRFP1 fluorescence, as an indicator for OXT, in the dpPVN and mRFP1-positive granules in axon terminals of the dpPVN OXT neurons in the nucleus tractus solitarius (NTS) after i.p. administration of CCK-8 and secretin. These results provide us the evidence that, at least in part, i.p. administration of CCK-8 or secretin might be involved in the regulation of feeding/drinking via a OXTergic pathway from the dpPVN to the NTS., (Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.)

Pelvic actinomycosis-like disease due to Propionibacterium propionicum has been very rare and only a few cases have been reported in the literature. We herein report a probable first case of a psoas abscess caused by P. propionicum. Since P. propionicum is indistinguishable from Actinomyces israelii by morphological features or routine biochemical tests, 16S rRNA gene sequencing was useful to discriminate these two species in this case., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: We previously demonstrated that a family predisposed to lung cancer harbored a V843I substitution in the epidermal growth factor receptor (EGFR) protein. We report here the further characterization of this mutant EGFR protein in the context of tumorigenicity and resistance to tyrosine kinase inhibitors (TKIs) of EGFR activity., Methods: Phosphorylation of EGFR and downstream signaling proteins of lung adenocarcinoma cell lines with EGFR mutations was assayed by flow cytometry. Susceptibility to TKIs of these cell lines, with or without suppression of mutant EGFR expression by small inhibitory RNA (siRNA), was investigated using a cellular viability assay. Furthermore, protein modeling was used to predict TKI binding to EGFR protein carrying the V843I mutation., Results: Phosphorylation of EGFR and downstream signaling proteins was elevated upon transfection with an EGFR gene with the V843I. Although the cell line with V843I + L858R demonstrated resistance to EGFR-TKIs, the cells became susceptible to TKIs upon incubation with siRNA specific for the V843I allele. The structural analysis suggested that TKI binding to EGFR would be sterically hindered by Arg841 in the double-mutant (V843I + L858R) EGFR., Conclusions: The V843I mutation contributes to tumorigenesis by promoting phosphorylation of EGFR and its downstream signaling proteins. This mutation also appears to provide resistance to EGFR-TKIs through structural modification of EGFR. These features are comparable with those in EGFR T790M mutation, suggesting that cases with germ-line V843I or T790M mutations could be categorized as a class of familial lung cancer syndrome with resistance to EGFR-TKIs.

Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5-positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosal healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5-RXFP4 signaling might play a role in an autocrine/paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors., (Copyright © 2013 Elsevier Inc. All rights reserved.)

KL-6, an epitope of MUC1 mucin expressed on type II pneumocytes and bronchiolar epithelia in humans, is a sensitive serum marker for interstitial pneumonia. However, an in vivo model for KL-6 has not been established because no KL-6 epitope is expressed in animals other than humans and apes. To investigate whether KL-6 is detectable in human MUC1-expressing (hMUC1-exp) mice and whether KL-6 level reflects the degree of lung injury, we examined serum and bronchoalveolar lavage fluid (BALF) levels of KL-6 and surfactant protein-D (SP-D) in either lipopolysaccharide (LPS)- or bleomycin (BLM)-induced lung injury models. KL-6 was expressed on type II pneumocytes and bronchiolar epithelial cells in naïve hMUC1-exp mice. Serum KL-6 levels in these mice were comparable to those in humans, and KL-6 levels in BALF were significantly higher than those in sera. In the LPS model, KL-6 levels in sera and BALF were slightly increased, although SP-D levels were markedly increased. During the inflammatory phase in the BLM model, KL-6 levels in sera were greatly increased, but those in BALF were decreased. Serum KL-6 levels were positively correlated with BALF albumin levels, a representative marker for increased the alveolar-capillary permeability. SP-D levels in sera and BALF were significantly increased compared to the corresponding levels in the LPS model. The increase in serum KL-6 levels appeared to be associated with the disruption of alveolar-capillary barrier after BLM-induced lung injury. This hMUC1-exp mouse can be used for assessment of KL-6 in vivo during lung injury., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Ciclesonide (CIC) is a highly safe, inhaled corticosteroid (ICS) that is converted into a pharmacologically active metabolite (des-isobutyryl-ciclesonide); this metabolite, in turn, exerts a local anti-inflammatory effect on lung tissue. The present study was undertaken to analyze the pharmacokinetics of des-isobutyryl-ciclesonide in the serum of Japanese children with bronchial asthma treated by repeated doses of CIC and to compare the data thus obtained with those obtained for Caucasian children with bronchial asthma., Methods: Eight Japanese children with bronchial asthma were treated for 7 days with CIC-hydrofluoroalkalane (CIC-HFA) 200 μg/day administered by a metered-dose inhaler. The study was designed to assess the pharmacokinetics after 7-day repeated administration by which the steady state can be achieved, based on the results of an earlier study involving healthy Japanese adult males who received 7-day repeated administration of CIC-HFA. Blood was sampled at multiple time points on Day 7 of treatment for measurement of the serum des-isobutyryl-ciclesonide level., Results: The pharmacokinetic parameters (AUC from time zero to last observed concentration [AUC(t)], AUC over the dosage interval τ at steady state [AUC(ss)], maximum concentration [C(max)], and terminal elimination half-life [T(1/2)]) and the temporal changes in the serum levels of des-isobutyryl-ciclesonide after repeated administration of CIC-HFA (200 μg/day) in Japanese children with bronchial asthma differed only slightly from those in Caucasian children with bronchial asthma. No serious adverse events were noted during the study period. Additionally, no abnormalities were detected in the serum cortisol level, other laboratory parameters, or vital signs., Conclusions: Our results suggest that there is little difference in the pharmacokinetics of des-isobutyryl-ciclesonide up on repeated administration of CIC-HFA between Japanese and Caucasian children with bronchial asthma. And our study suggests that CIC-HFA (200 μg/day, once daily) can be administered safely for 7 days, without raising any safety concerns.

Forced swim (FS) stress induces diverse biochemical responses in the brain of rodents. Here, we examined the effect of hypothermia induced by FS in cold water on the phosphorylation of FS-sensitive signaling molecules in the mouse brain. As we have shown previously, FS in cold water induced a significant increase in the level of tyrosine phosphorylation of SIRPα, a neuronal membrane protein, in mouse hippocampus, while such effect of FS was markedly reduced in mice subjected to FS in warm water. FS in cold water also induced phosphorylation of mitogen-activated protein kinase kinase (MEK) as well as of cAMP response element-binding protein (CREB), or dephosphorylation of α isoform of Ca(2+)/calmodulin-dependent protein kinase II (αCaMKII) in the hippocampus. These effects of FS on the phosphorylation of these molecules were also lost in mice subjected to FS in warm water. Genetic ablation of SIRPα did not change the phosphorylation states of these molecules in the brain. Forced cooling of anesthetized mice, which induced a marked increase in the phosphorylation of SIRPα, induced dephosphorylation of αCaMKII in the brain, while the same treatment did not affect the phosphorylation level of MEK and CREB. Hibernation also induced an increase and a decrease of the phosphorylation of SIRPα and αCaMKII, respectively, in the brain of chipmunk. These results suggest that hypothermia is a major element that determines the levels of phosphorylation of αCaMKII and SIRPα during the FS in cold water, while it is not for the phosphorylation levels of MEK and CREB., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Chronic hepatitis C virus (HCV) infection causes intra- and extra-hepatic complications. The elimination of HCV has been reported to be beneficial for asthmatic patients with HCV infection. Therefore, we hypothesized that chronic HCV infection might be associated with the severity of asthma., Methods: Asthmatic patients were prospectively enrolled from 13 outpatient settings. Hepatitis B surface (HBs) antigen and HCV-RNA were measured at the time of enrollment and evaluated along with the clinical characteristics of the patients including the age, sex, duration of asthma, atopic status, smoking history, and treatment step according to the Global Initiative for Asthma guideline., Results: Of 1327 asthmatic patients, 1258 patients (94.8%) were treated with inhaled corticosteroids, 18 patients were positive for HBs antigen (1.4%), and 32 patients (2.4%) were positive for HCV-RNA. When compared with HCV-RNA-negative patients, HCV-RNA-positive patients required significantly more drugs for the treatment of asthma. No such relationship was observed in patients with positive HBs antigen. A multivariate logistic regression analysis showed that the male sex, a long duration of asthma, status as a current smoker, and HCV-RNA positivity were independently associated with more severe asthma., Conclusions: These results suggest that chronic HCV infection is an independent factor that predisposes asthmatic patients to more severe asthma. The evaluation of chronic HCV infection may be helpful for the management of severe asthmatic patients without obvious factors associated with severe asthma.

The molecular basis for regulation of dendritic cell (DC) development and homeostasis remains unclear. Signal regulatory protein α (SIRPα), an immunoglobulin superfamily protein that is predominantly expressed in DCs, mediates cell-cell signaling by interacting with CD47, another immunoglobulin superfamily protein. We now show that the number of CD11c(high) DCs (conventional DCs, or cDCs), in particular, that of CD8-CD4+ (CD4+) cDCs, is selectively reduced in secondary lymphoid tissues of mice expressing a mutant form of SIRPα that lacks the cytoplasmic region. We also found that SIRPα is required intrinsically within cDCs or DC precursors for the homeostasis of splenic CD4+ cDCs. Differentiation of bone marrow cells from SIRPα mutant mice into DCs induced by either macrophage-granulocyte colony-stimulating factor or Flt3 ligand in vitro was not impaired. Although the accumulation of the immediate precursors of cDCs in the spleen was also not impaired, the half-life of newly generated splenic CD4+ cDCs was markedly reduced in SIRPα mutant mice. Both hematopoietic and nonhematopoietic CD47 was found to be required for the homeostasis of CD4+ cDCs and CD8-CD4- (double negative) cDCs in the spleen. SIRPα as well as its ligand, CD47, are thus important for the homeostasis of CD4+ cDCs or double negative cDCs in lymphoid tissues.

Introduction: Understanding the mechanisms of drug resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is essential to develop novel chemotherapies for non-small cell lung cancer (NSCLC). Therefore, we analyzed the expression and function of ATP-binding cassette (ABC) transporters in EGFR TKI-resistant NSCLC., Methods: In three newly established AG1478-resistant NSCLC cell lines, we evaluated the expression profile of ABC transporters and genotyping of ABCG2 by real-time polymerase chain reaction and elucidated their function by Hoechst dye efflux analyses. The growth-inhibitory effect of the topoisomerase I inhibitor Hoechst 33342, which is extruded by ABCG2, was also investigated in these cells using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay., Results: In AG1478-resistant cells, significantly less ABCG2 was expressed, and the ratios of the cells with a strong ability to extrude Hoechst dye were remarkably smaller than in the parent cells. Because of the ABCG2 downregulation and loss of function due to C421A/C421A homozygosity, PC-14AG50R was thus considered to be more sensitive to Hoechst 33342 than the parental cells. All AG1478-resistant cells were more sensitive to the combination of Hoechst 33342 and AG1478 than to single agent., Conclusions: Resistance to EGFR TKI in NSCLC is associated with the downregulation of ABCG2 expression. A topoisomerase I inhibitor alone or in combination with EGFR TKI might offer a promising strategy for treating NSCLC that is resistant to EGFR TKI.

Signal regulatory protein α (SIRPα) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on dendritic cells and macrophages. Wild-type (WT) C57BL/6 mice are known to be resistant to Leishmania major infection. We here found that C57BL/6 mice that express a mutant version of SIRPα lacking most of the cytoplasmic region manifested increased susceptibility to L. major infection, characterized by the marked infiltration of inflammatory cells in the infected lesions. The numbers of the parasites in footpads, draining lymph nodes and spleens were also markedly increased in the infected SIRPα mutant mice, compared with those for the infected WT mice. In addition, soluble leishmanial antigen-induced production of IFN-γ by splenocytes of the infected SIRPα mutant mice was markedly reduced. By contrast, the ability of macrophages of SIRPα mutant mice to produce nitric oxide in response to IFN-γ was almost equivalent to that of macrophages from WT mice. These results suggest that SIRPα is indispensable for protective immunity against L. major by the induction of Th1 response., (Copyright © 2010 Elsevier Inc. All rights reserved.)