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The reaction of potassium 2-t-Bu-germabenzenide, in which the anionic carbon atom of phenyl anion is replaced with a germanium atom, with benzil resulted in the 1:2 reaction to give a unique penta-coordinated germanate having a 1,3,2-dioxagermole skeleton. This clearly reflects the characteristics of the germabenzenide as a divalent germanium species.

We demonstrate an electric field control of an anomalous Hall effect emerging in CaIrO3/CaMnO3 heterostructures. We fabricate both electron-type and hole-type carrier samples by tuning epitaxial strain and, then, control the carrier density in a CaIrO3 layer via electric double layer gating technique. As the Fermi energy of CaIrO3 is tuned close to the Dirac line node, anomalous Hall conductivity is enlarged in both carrier-type samples. This result reveals that the anomalous Hall effect comes from the intrinsic origin, reflecting the Dirac-like dispersion in CaIrO3. We propose that band splitting induced by the interface ferromagnetism yields several band crossing points near the Dirac line node. These points act as a source of the Berry curvature and contribute to the anomalous Hall effect. [ABSTRACT FROM AUTHOR]

A case of Silver-Russell Syndrome with a typical cleft hand is presented. The association of cleft hand with this syndrome has never been reported before. [ABSTRACT FROM PUBLISHER]

Animal models for retinal degeneration are essential for elucidating its pathogenesis and developing new therapeutic strategies in humans. N-methyl-N-nitrosourea (MNU) has been extensively used to construct a photoreceptor-specific degeneration model, which has served to unveil the molecular process of photoreceptor degeneration as well as the mechanisms regulating the protective responses of remaining cells. Methyl methanesulphonate (MMS), also known to cause photoreceptor degeneration, is considered a good alternative to MNU due to its higher usability; however, detailed pathophysiological processes after MMS treatment remain uncharacterized. Here, we analyzed the time course of photoreceptor degeneration, Müller glial proliferation, and expression of secretory factors after MNU and MMS treatments in rats. While the timing of rod degeneration was similar between the treatments, we unexpectedly found that cones survived slightly longer after MMS treatment. Müller glia reentered the cell cycle at a similar timing after the two treatments; however, the G1/S transition occurred earlier after MMS treatment. Moreover, growth factors such as FGF2 and LIF were more highly upregulated in the MMS model. These data suggest that comparative analyses of the two injury models may be beneficial for understanding the complex regulatory mechanisms underlying the proliferative response of Müller glia., (© 2024. The Author(s).)

An 86-year-old male patient with sustained virological response of chronic hepatitis type C was diagnosed with hepatocellular carcinoma (HCC) in hepatic segment 3. He was treated with transcatheter arterial chemoembolization (TACE) and radiation therapy because the tumor was located at the edge of the liver and umbilical portion of the portal vein. The value of alpha-fetoprotein (AFP) which is a serological tumor marker decreased, and the tumor size did not increase;however, another tumor was recognized at S3 of the liver 15 months post-TACE. The patient underwent a second TACE, and computed tomography revealed HCC recurrence at S3, S8/4, and S1 of the liver 6 months later. The patient refused to undergo another treatment, but the AFP and Des-γ-carboxy prothrombin values and the tumor size decreased 3 months postrecurrence. Two months after multiple recurrences of HCC, he received the third dose of messenger RNA-based vaccine for severe acute respiratory syndrome coronavirus 2. Tumor regression may occur after an immune-inflammatory response induced by messenger RNA-based vaccine.

Retinal Müller glia have a capacity to regenerate neurons in lower vertebrates like zebrafish, but such ability is extremely limited in mammals. In zebrafish, Müller glia proliferate after injury, which promotes their neurogenic reprogramming while inhibiting reactive gliosis. In mammals, however, how the cell cycle affects the fate of Müller glia after injury remains unclear. Here, we focused on the expression of proneural transcription factors, Ngn2 and Ascl1, and a gliosis marker glial fibrillary acidic protein (GFAP) in rat Müller glia after N-methyl-N-nitrosourea (MNU)-induced photoreceptor injury and analyzed the role of Müller glia proliferation in the regulation of their expression using retinal explant cultures. Thymidine-induced G1/S arrest of Müller glia proliferation significantly hampered the expression of Ascl1, Ngn2, and GFAP, and release from the arrest induced their upregulation. The migration of Müller glia nuclei into the outer nuclear layer was also shown to be cell cycle-dependent. These data suggest that, unlike the situation in zebrafish, cell cycle progression of Müller glia in mammals promotes both neurogenic reprogramming and reactive gliosis, which may be one of the mechanisms underlying the limited regenerative capacity of the mammalian retina., (© 2023. The Author(s).)

The delivery of single atoms is highly desirable for the straightforward synthesis of complex molecules, however this approach is limited by a lack of suitable atomic transfer reagents. Here, we report a germanium atom transfer reaction employing a germanium analogue of the phenyl anion. The reaction yields a germanium-substituted benzene, along with a germanium atom which can be transferred to other chemical species. The transfer of atomic germanium is demonstrated by the formation of well-defined germanium doped molecules. Furthermore, computational studies reveal that the reaction mechanism proceeds via the first example of an aromatic-to-aromatic nuclear germanium replacement reaction on the germabenzene ring. This unusual reaction pathway was further probed by the reaction of our aromatic germanium anion with a molecular silicon species, which selectively yielded the corresponding silicon-substituted benzene derivative., (© 2023. The Author(s).)

Background: Endoscopic gastroduodenal stent (GDS) placement is widely used as a safe and effective method to rapidly improve gastrointestinal symptoms of malignant gastric outlet obstruction (MGOO). While previous studies reported the utility of chemotherapy after GDS placement for prognosis improvement, they did not fully address the issue of immortal time bias., Objectives: To examine the association between prognosis and clinical course following endoscopic GDS placement, using a time-dependent analysis., Design: Multicenter retrospective cohort study., Methods: This study included 216 MGOO patients who underwent GDS placement between April 2010 and August 2020. Data of patient baseline characteristics, including age, gender, cancer type, performance status (PS), GDS type and length, GDS placement location, gastric outlet obstruction scoring system (GOOSS) score, and history of chemotherapy before GDS were collected. The clinical course following GDS placement was evaluated by GOOSS score, stent dysfunction, cholangitis, and chemotherapy. A Cox proportional hazards model was used to identify prognostic factors after GDS placement. Stent dysfunction, post-stent cholangitis, and post-stent chemotherapy were analyzed as time-dependent covariates., Results: Mean GOOSS scores before and after GDS were 0.7 and 2.4, respectively, with significant improvement after GDS placement ( p  < 0.001). The median survival time after GDS placement was 79 [95% confidence interval (CI): 68-103] days. In multivariate Cox proportional hazards model with time-dependent covariates, PS 0-1 [hazard ratio (HR): 0.55, 95% CI: 0.40-0.75; p  < 0.001], ascites (HR: 1.45, 95% CI: 1.04-2.01; p  = 0.028), metastasis (HR: 1.84, 95% CI: 1.31-2.58; p  < 0.001), post-stent cholangitis (HR: 2.38, 95% CI: 1.37-4.15; p  = 0.002), and post-stent chemotherapy (HR: 0.01, 95% CI: 0.002-0.10; p  < 0.001) significantly affected prognosis after GDS placement., Conclusion: Post-stent cholangitis and tolerability to receive chemotherapy after GDS placement influenced prognosis in MGOO patients., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Background: Pembrolizumab is the recommended first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, its efficacy and safety for patients ≥75 years have not been prospectively investigated; this was the aim of this study., Methods: This multicenter and open-label single-arm phase II study was conducted at 12 institutions. Chemotherapy-naïve patients with advanced NSCLC and a PD-L1 TPS of ≥50% without EGFR mutations or translocation of the ALK received pembrolizumab every 3 weeks. The primary endpoint was progression-free survival (PFS) with a threshold of 4.3 months. The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and quality of life., Results: Twenty-six patients were enrolled between October 2017 and March 2020. The median PFS was 9.6 (95% confidence interval [CI] 2.1-20.6) months. The lower limit of the 95% CI did not exceed the target. The median OS was 21.6 months. The ORR and DCR were 41.7% and 70.8%, respectively. The proportion of patients with grade ≥3 treatment-related adverse events was 15.4%. The quality of life score did not change significantly during treatment., Conclusion: While this study showed that pembrolizumab was a tolerable treatment for elderly patients, the safety requires further confirmation in a larger study. Although the primary endpoint, the median PFS (9.6 months), was slightly shorter than that (10.3 months) of the previous phase III study (KEYNOTE-024 study), the median PFS did not achieve the expected value., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Recent reports have indicated that gut microbiota modulates the responses to stress through the microbiota-gut-brain axis in mice, suggesting a connection between gut microbiota and brain function. We hypothesized that the gut microbiota early in life would have an effect on aggressiveness, and examined how gut microbiota affect aggressive behaviors in mice. BALB/c mice were housed in germ-free (GF) and ex-germ-free (Ex-GF) isolators. An aggression test was performed between castrated and a non-castrated mice at 8 weeks of age; the mice were allowed to confront each other for 10 min in strictly contamination-free environments. To evaluate aggressive behavior related to gut microbiota, we orally administered diluted Ex-GF mouse feces to the offspring of GF mice at 0, 6, and 10 weeks. GF mice showed more aggression than Ex-GF mice. Furthermore, GF mice who were administered feces of the Ex-GF group at 0-week-old were less aggressive than the GF mice. These findings suggested that the gut microbiota in the early stages of development was likely to have an effect on aggressiveness. Maintenance of healthy gut microbiota early in life can affect the mitigation of aggressive behavioral characteristics throughout the lifetime., Competing Interests: Declaration of Competing Interest Natsuru Watanabe received research support from Shionogi & Co. Katsunaka Mikami received research support from Taisho Pharmaceutical, Otsuka Pharmaceutical, Shionogi & Co., Japanese Society for Probiotic Science; honoraria from Shionogi & Co., Shire Japan, Eli Lilly and Co., Meiji Holdings Co., Takeda Pharmaceutical, MIYARISAN PHARMACEUTICAL CO; and a consulting fee from Otsuka Pharmaceutical and Shionogi & Co. Tomokazu Hata received research support from Foundation of Kinoshita Memorial Enterprise. Keitaro Kimoto received research support from Otsuka Pharmaceutical, Shionogi & Co, and Taisho Pharmaceutical. Ryo Nishino received a consulting fee from Shionogi & Co. Fumiaki Akama has received research support from Otsuka Pharmaceutical and Shionogi & Co.; and honoraria from Dainippon Sumitomo Pharma, Pfizer, Shionogi & Co. and Eisai Co. KenjiYamamoto reports receiving grants and personal fees from Eisai Co., Ltd., Japan; grants and personal fees from Otsuka Pharmaceutical Co., Ltd., Japan; personal fees from Meiji Seika Pharma Co., Ltd.; personal fees from Sumitomo Dainippon Pharma Co., Ltd.; personal fees from Pfizer Japan Inc.; personal fees from Mitsubishi Tanabe Pharma Corporation; personal fees from Shionogi & Co.; personal fees from Eli Lilly and Company; personal fees from EPS Holdings, Inc.; grants from Grant-in-Aid for Scientific Research (16K10260) outside the submitted work. Nobuyuki Sudo has no conflict of interest. Yasuhiro Koga received research support from Meiji Holdings Co. Hideo Matsumoto received research support from, Dainippon Sumitomo, Otsuka Pharmaceutical, Shionogi & Co., KOIKE-YA Inc. Mental Clinic Yokohama Minatomirai, Kishi Byoin, Soushu Hospital, Kouzu Hospital, Tanzawa Hospital, Aikou Hospital, and Keyaki-no-mori Hospital; and honoraria from Eli Lilly and Co., Novartis Pharma, Yoshitomiyakuhin Corporation, GlaxoSmithKline, Dainippon Sumitomo, Pfizer, Meiji Seika Pharma, Otsuka Pharmaceutical, Janssen Pharmaceutical, Eisai Co., Shionogi & Co., Astellas Pharma, MSD and Mitsubishi Tanabe Pharma Corporation., (Copyright © 2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

We recently demonstrated that benzo[a]pyrene (BaP), the aryl hydrocarbon receptor (AhR) ligand, directly contributes to aggravation of cutaneous allergy in a mouse model of allergic dermatitis. The present study aimed to determine whether BaP-induced AhR activation results in development of airway inflammation. Initially, the potential for a direct relationship between BaP-induced AhR activation and airway inflammation was investigated in vivo, using a mouse model of type 2 helper T cell (Th2) hapten toluene-2,4-diisocyanate (TDI)-induced airway inflammation. Mice were orally administered BaP at 48, 24, and 4 h before the final allergen challenge. Oral administration of BaP showed a significant increase in lung inflammation and eosinophil infiltration. While expression of Th2 cytokines such as interleukin 4 (IL-4) and IL-13 was not affected by exposure to BaP, AhR activation significantly increased IL-33 expression. To confirm the in vivo results, in vitro experiments were performed using the human eosinophilic leukemia cell line (EOL-1), human bronchial epithelial cell line (BEAS-2B), and human lung adenocarcinoma epithelial cell line (A549). Results indicated that pre-treatment with BaP increased expression of IL-8 in house dust mite-activated EOL-1, BEAS-2B, and A549 cells. In addition, IL-33 levels in BEAS-2B cells were significantly increased after BaP exposure. Our findings indicated that BaP-induced AhR activation is involved in the pro-inflammatory response in respiratory allergy, and that this effect may be mediated by increased IL-33 expression and eosinophil infiltration., (© 2020 John Wiley & Sons, Ltd.)

Ferroelectricity in ultrathin films is destabilized by depolarization field, which leads to the reduction of spontaneous polarization or domain formation. Here, thickness dependence of remnant polarization in PbTiO 3 films is electrically revealed down to 2.6 nm by controlling the polarization direction with employing an electric double layer gating technique to suppress leakage current in ultrathin films. The remnant polarization for a 17 nm-thick film is similar to bulk value ~ 60 μC cm -2 and reduces to ~ 20 μC cm -2 for a 2.6 nm-thick film, whereas robust ferroelectricity is clearly observed in such ultrathin films. In-situ X-ray diffraction measurements under an external electric field reveal that the reduced tetragonality in ultrathin films is mostly recovered by cancelling out the depolarization field. Electric double layer gating technique is an excellent way for exploring physical properties in ultrathin ferroelectric films.

Axial chirality in N,N-dimethylaminopyridines as well as N,N-dipropylaminopyridines bearing an internal carboxy group were evaluated based on their racemization barriers and circular dichroism spectra. The half-life of racemization of N,N-dipropylaminopyridine derivative 2 was estimated to be 19.7 days at 20°C. Its enantiomers isolated as optically active forms showed positive-negative and negative-positive Cotton effects for (+)-2 and (-)-2, respectively, from 310 to 210 nm. Furthermore, (-)-2 was applied as a chiral nucleophilic catalyst and exhibited asymmetric induction in acylative kinetic resolution of 1-(1-naphthyl)ethane-1-ol., (© 2020 Wiley Periodicals, Inc.)

We evaluated the real effects of pollutants through a multi-generation study. We tested whether short-term exposure (48 h) of successive (first and second) generations of Chironomus yoshimatsui neonates (<24-h-old) to two acetylcholinesterase inhibitor insecticides, pyraclofos, and pirimicarb, would change insecticide sensitivity and life-cycle parameters over four generations. Additionally, we tested whether acetylcholinesterase (AChE) activity levels would be associated with this sensitivity change. Sensitivities (48 h EC 50 value, using immobility as the endpoint) in chironomids (<24-h-old) and insect life-cycle parameters (the number of larvae per egg mass and adult size) were investigated. Parental chironomids produced larvae that were less sensitive than those in the control group following the two 48 h pirimicarb exposure events, whereas exposure to pyraclofos did not affect sensitivity. The AChE activity in larvae with low sensitivity to pirimicarb was significantly higher than that in the control. Thus, increased AChE activity might be associated with low sensitivity. The life-cycle parameters in chironomids recovered from the effects of pyraclofos and pirimicarb suggested they could adapt to the insecticides by changing biomass allocation. Our study suggested potential chemical risks of insecticide stress and how aquatic organisms adapt to it.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that binds to various environmental chemicals and contributes to numerous toxicological effects. However, the direct effects of AhR on the development of allergic diseases are not fully understood. The main aim of this study was to elucidate the action of AhR in the development of cutaneous allergies. Initially, the potential for a direct relationship between AhR and the immune cells was investigated in vitro, using murine bone marrow-derived dendritic cells, human epidermal keratinocytes, and the mixed leukocyte reaction assay. Benzo[a]pyrene (BaP) and 6-formylindolo[3,2-b]carbazole were used as selective ligands for the AhR. Pretreatment with BaP and/or 6-formylindolo[3,2-b]carbazole significantly induced cytokine release by activated keratinocytes and T-cell proliferation, whereas interleukin-12 production in bone marrow-derived dendritic cells was reduced by AhR activation. To confirm the in vitro results, in vivo experiments were also performed in T-helper (Th)2-type hapten toluene-2,4-diisocyanate- and Th1-type hapten dinitrochlorobenzene-induced mouse models of allergic dermatitis. Mice were orally administered BaP at 48, 24 and 4 hours before the final allergen challenge. In the Th2 model, ear-swelling response and scratching behavior were promoted by BaP exposure, which supported the observed significant increases in local cytokine secretion. The infiltration of helper T cells, B cells and dendritic cells into the auricular lymph node was significantly enhanced by BaP administration, although Th1-type immune responses were not influenced by AhR activation. Our findings demonstrate that AhR activation directly activates keratinocytes and T cells, which leads to the exacerbation of Th2-type cutaneous allergy., (© 2019 John Wiley & Sons, Ltd.)

Folic acid (FA) deficiency is associated with several health problems, including megaloblastic anemia and fetal neural tube defects. Therefore, supplementation with FA is strongly recommended by governments worldwide. Recent published reports indicate that FA functions in immune system maintenance. The main objective of this study is to examine possible anti-inflammatory and antipruritic effects of FA using a mouse model of allergic dermatitis. The mouse model was developed by repetitive sensitization to the Th2-type hapten toluene-2,4-diisocyanate (TDI). During the development of allergic dermatitis, FA was orally administered to the mice at doses of 8, 160, 1000 or 10,000 μg/day for 5 weeks. The ear swelling response and scratching behavior were monitored after the TDI challenge. Serum, ear tissue and auricular lymph node samples were isolated for further analysis 24 h after the TDI challenge. The ear swelling response was reduced in a dose-dependent manner by FA administration, and a significant change was observed at a concentration of 10,000-μg/day group. Comparable results were obtained through histological evaluation and cytokine level measurement in the ear tissue samples. Oral administration of FA exhibited the inhibitory effect on T-cell infiltration and T-cell-related cytokine production in auricular lymph nodes. Scratching behavior was not altered by FA administration. The in vivo evidence was corroborated by in vitro results, which showed that FA treatment significantly interfered with T-cell proliferation in a dose-dependent manner. Our findings imply that subacute oral administration of FA elicits an anti-inflammatory response, mainly through inhibition of T-cell proliferation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The aim of this study is to identify the combined effect of multiple chemicals to the development of allergy. In this study, the effect of prenatal exposure to an organochlorine agent methoxychlor (MXC) and/or an organophosphate agent parathion (PARA) on trimellitic anhydride-induced allergic airway inflammation was examined in mice. Eosinophil infiltration in the bronchoalveolar lavage fluid (BALF) was significantly enhanced by MXC + PARA exposure compared to that of the control, MXC, and PARA groups. In the hilar lymph node, only slight increases in B-cell infiltration, as well as IL-6 and IL-9 secretions were observed in MXC + PARA group, and no effect was observed in the individual treatment groups. Our findings imply that prenatal exposure to some combinations of multiple chemicals may exacerbate the allergic inflammatory responses including eosinophils and cytokine production.

Although organisms belonging to different species and subspecies sometimes produce fertile offspring, a hallmark of the speciation process is reproductive isolation, characterized by hybrid sterility (HS) due to failure in gametogenesis. In mammals, HS is usually exhibited by males, the heterogametic sex. The phenotypic manifestations of HS are complex. The most frequently observed are abnormalities in both autosomal and sex chromosome interactions that are linked to meiotic prophase arrest or postmeiotic spermiogenesis aberrations and lead to defective or absent gametes. The aim of this study was to determine the HS phenotypes in intersubspecific F1 mice produced by matings between Mus musculus molossinus-derived strains and diverse Mus musculus domesticus-inbred laboratory mouse strains. Most of these crosses produced fertile F1 offspring. However, when female BALB/cJ (domesticus) mice were mated to male JF1/MsJ (molossinus) mice, the (BALBdomxJF1mol)F1 males were sterile, whereas the (JF1molxBALBdom)F1 males produced by the reciprocal crossings were fertile; thus the sterility phenotype was asymmetric. The sterile (BALBdomxJF1mol) F1 males exhibited a high rate of meiotic metaphase arrest with misaligned chromosomes, probably related to a high frequency of XY dissociation. Intriguingly, in the sterile (BALBdomxJF1mol)F1 males we observed aberrant allele-specific expression of several meiotic genes, that play critical roles in important meiotic events including chromosome pairing. Together, these observations of an asymmetrical HS phenotype in intersubspecific F1 males, probably owing to meiotic defects in the meiotic behavior of the XY chromosomes pair and possibly also transcriptional misregulation of meiotic genes, provide new models and directions for understanding speciation mechanisms in mammals., (© The American Genetic Association 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent studies have shown that the estrogen receptor α (ERα), but not ERβ, is involved in the proinflammatory and propruritic responses in cutaneous allergy. In addition, results from our recent study showed that while oral administration of the rather ERβ-selective agonist bisphenol A exacerbated the respiratory allergic inflammation, the potential inflammatory reaction in the skin was decreased after administration of bisphenol A. This study aimed to elucidate whether ERα and ERβ are involved in the progression of an allergic airway inflammation. We performed an in vivo experiment using an animal model of allergic airway inflammation using male BALB/c mice to confirm an increase in the proinflammatory response induced by propylpyrazoletriol (PPT), an ERα agonist, and diarylpropionitrile (DPN), an ERβ agonist. Oral administration of PPT or DPN showed a significant increase in the inflammation of the lung and infiltration of eosinophils. While the expression of Th2 cytokines such as interleukin 4 (IL-4) and IL-13 was not affected by exposure to PPT or DPN, administration of these agonists significantly increased the expression of IL-33. The mechanism underlying the development of such allergic inflammatory responses was determined by an in vitro study using the human bronchial epithelial cell line (BEAS-2B) and the human eosinophilic leukemia cell line (EoL-1). Activated cells were exposed to PPT or DPN for 24 h, and the cytokine levels were measured. The IL-33 levels in BEAS-2B cells increased significantly after exposure to PPT or DPN. In addition, pretreatment with PPT or DPN increased the expression of IL-8 in activated EoL-1 cells. Our findings indicate that ERα and ERβ are involved in the proinflammatory response in respiratory allergy, and their effects may be mediated by an increase in the expression of IL-33 and infiltration of eosinophils., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Bisphenol A (BPA) is used in various areas of daily life as a major component of plastic products. However, it is also known as a strong endocrine disruptor that affects the human immune system. Studies have indicated that BPA possibly exacerbates allergic diseases such as atopic dermatitis and asthma. The main aim of this study was to elucidate whether BPA is directly involved in the exacerbation of allergic inflammation. Initially, in vivo experiments with mouse models of allergic inflammation induced by Th2 type hapten toluene-2, 4-diisocyanate (TDI) was performed. Mice were subjected to oral administration of BPA 48, 24, and 4 h before challenge with TDI. Dermal challenge of TDI onto the ear auricle was performed for the allergic dermatitis model, and intratracheal challenge of TDI was performed for the allergic airway inflammation model. In the allergic dermatitis model, ear-swelling response was significantly downregulated by high doses of BPA. The opposite reaction was observed in the allergic airway inflammation model, including significant exacerbation of red coloration in the lung, local cytokine levels, and total IgE levels in serum by BPA administration. To confirm the in vivo results, in vitro experiments with human epidermal keratinocytes (HEKs) and bronchial epithelial (BEAS-2B) cells were carried out. Significant enhancement of cytokine release from BEAS-2B cells but not HEKs in the BPA-treated group supported the in vivo observations. Our results imply that exposure to BPA directly exacerbates allergic airway inflammation but not allergic dermatitis.

It has been reported that endogenous or exogenous estrogens can affect the immune system, resulting in immune disorders; however, their direct involvement in such conditions remains to be demonstrated. The purpose of this study was to investigate whether estrogen receptors (ER) are directly implicated in pro-pruritic and pro-inflammatory reactions in cutaneous allergy. Initially, enhancement of the pro-inflammatory response by several ER agonists [methoxychlor (MXC), β-estradiol (E2), propylpyrazoletriol (PPT; an ERα agonist), and diarylpropionitrile (DPN; an ERβ agonist)] was examined in vivo using a male BALB/c mouse model of allergic dermatitis induced by toluene-2,4-diisocyanate administration. The ear swelling response, itch response, and local cytokine secretion were measured. Subsequently, the mechanism underlying the development of such allergic reactions was analyzed in vitro using human epidermal keratinocytes, murine bone marrow-derived dendritic cells (mBMDCs), and the mixed leucocyte reaction assay. Activated cells were exposed to each ER agonist for 24 h, and cytokine secretion and cell proliferation were measured. Our in vivo experiments indicated significant upregulation of pro-inflammatory and pro-pruritic responses in the E2-, MXC-, and PPT-treated groups compared to the control group; however, no change was observed in the DPN-treated group. Levels of cytokines expressed by keratinocytes, such as TSLP and IL-33, were particularly increased by exposure to E2, MXC, or PPT. These in vivo results were confirmed in vitro in keratinocytes, but not mBMDCs or T cells. Our findings imply that ERα is involved in pro-inflammatory and pro-pruritic responses in cutaneous allergy through activation of keratinocytes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Tardigrades are microscopic animals that enter an ametabolic state called anhydrobiosis when facing desiccation and can return to their original state when water is supplied. The genomic sequencing of microscopic animals such as tardigrades risks bacterial contamination that sometimes leads to erroneous interpretations, for example, regarding the extent of horizontal gene transfer in these animals. Here, we provide an ultralow input method to sequence the genome of the tardigrade, Hypsibius dujardini, from a single specimen. By employing rigorous washing and contaminant exclusion along with an efficient extraction of the 50 ~ 200 pg genomic DNA from a single individual, we constructed a library sequenced with a DNA sequencing instrument. These libraries were highly reproducible and unbiased, and an informatics analysis of the sequenced reads with other H. dujardini genomes showed a minimal amount of contamination. This method can be applied to unculturable tardigrades that could not be sequenced using previous methods.

Purpose: This study aimed to investigate relationships between times in therapeutic range (TTR) or warfarin sensitivity indexes (WSI) and VKORC1-1639G>A and CYP2C9 polymorphisms in patients with left ventricular assist devices (LVAD)., Methods: Severe heart failure patients who received LVAD from January 1, 2013 to October 31, 2017 were recruited. Relationships between TTR or WSI and VKORC1-1639G>A and CYP2C9 gene polymorphisms were investigated immediately after LVAD implantation (period 1) and immediately prior to hospital discharge (period 2)., Results: Among 54 patients, 31 (72.1%) had VKORC1-1639AA and CYP2C9*1/*1 (AA group) polymorphisms and 12 (27.9%) had VKORC1-1639GA and CYP2C9*1/*1 (GA group) polymorphisms. During period 1, mean prothrombin time-international normalized ratio (PT-INR) values were significantly higher in the AA group than in the GA group (2.21 vs. 2.05, p < 0.0001). Mean WSI values were 1.68-fold greater in the AA group than in the GA group (1.14 vs. 0.68, p < 0.0001). In addition, times below the therapeutic range (TBTR) in the GA group were significantly greater than in the AA group during period 1 (39.8 vs. 28.3%, p = 0.032), and insufficient PT-INR was more frequent in the GA group than in the AA group. However, mean PT-INR values during period 2 did not differ and no significant differences in TTR, TATR, and TBTR values were identified. In subsequent multivariable logistic regression analyses, the VKORC1-1639GA allele was significantly associated with insufficient anticoagulation., Conclusion: Patients with the VKORC1-1639GA and CYP2C9*1/*1 alleles may receive insufficient anticoagulation therapy during the early stages after implantation of LVAD, and VKORC1-1639G>A and CYP2C9 genotyping may contribute to more appropriate anticoagulant therapy after implantation of LVAD.

Thoracic epidural anesthesia (TEA) and paravertebral block (PVB) have been performed for perioperative regional anesthesia in the trunk. However, TEA and PVB are associated with a risk of serious complications, such as pneumothorax, hypotension, or nerve damage. Retrolaminar paravertebral block (RLB) was introduced as a new alternative to PVB. This new approach might lower the risk of serious complications, but its use has not been well established yet. Therefore, we conducted a double-masked, placebo-controlled, randomized clinical trial to evaluate the efficacy of a double-level RLB for postoperative analgesia after breast cancer surgery. A total of 122 women who underwent breast cancer surgery with axillary lymph node dissection under general anesthesia were allocated into RLB group (60 patients) and Control group (62 patients). RLB was performed upon surgery completion with 15 ml ropivacaine (0.5%) for each lamina of the T2 and T4 vertebrae. In Control group, the same volume of normal saline was injected at each level. The time to first postoperative analgesic administration was significantly longer in RLB group than that in Control group (161.5 min vs. 64.0 min). The pain score in RLB group was significantly lower immediately after surgery. However, the number of patients requiring analgesics during the 12-hour post-surgical period was similar between RLB group (20 patients) and Control group (22 patients). In conclusion, the double-level RLB could delay the time to initial administration of analgesics, but this technique may be insufficient to reduce the analgesic requirement within the 12-hour postoperative period following breast cancer surgery.