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Background Although population studies have implicated emotional burden in asthma severity, the underlying genetic risk factors are not completely understood. We aimed to evaluate the genetic influence of a functional single-nucleotide polymorphism (SNP) in the stress-related μ-opioid receptor gene (OPRM1; A118G SNP, rs1799971) on asthma severity. Methods We initially assessed disease severity in asthmatic outpatients carrying A118G. Using an ovalbumin-induced experimental asthma rodent model harboring the functionally equivalent SNP, we investigated the mechanism by which this SNP influences the allergic immune response. Results Among 292 outpatients, 168 underwent airway hyperresponsiveness (AHR) to methacholine testing. Compared with patients carrying the AA and AG genotypes, those carrying the GG genotype exhibited enhanced AHR. The stress levels were presumed to be moderate among patients and were comparable among genotypes. Compared with Oprm1 AA mice, GG mice demonstrated aggravated asthma-related features and increased pulmonary interleukin-4+CD4+ effector and effector memory T cells under everyday life stress conditions. Intraperitoneal naloxone methiodide injection reduced effector CD4+ T cell elevation associated with increased eosinophil numbers in bronchoalveolar lavage fluid of GG mice to the levels in AA mice, suggesting that elevated Th2 cell generation in the bronchial lymph node (BLN) of GG mice induces enhanced eosinophilic inflammation. Conclusions Without forced stress exposure, patients with asthma carrying the OPRM1 GG genotype exhibit enhanced AHR, attributable to enhanced Th2 cell differentiation in the regional lymph node. Further research is necessary to elucidate the role of the OPRM1 A118G genotype in the Th2 cell differentiation pathway in the BLN.

Introduction: The enhanced type 2 helper (Th2) immune response is responsible for the pathogenesis of allergic asthma. To suppress the enhanced Th2 immune response, activation of the Th1 immune response has been an alternative strategy for anti-asthma therapy. In this context, effective Th1-inducing adjuvants that inhibit the development of allergic asthma but do not flare the side effects of the primary agent are required in clinical treatment and preventive medicine. Objective: In this study, we aimed to determine the regulation of the Th2 type immune response in asthma by a novel immunostimulatory oligodeoxynucleotide (ODN) derived from Cryptococcus neoformans, termed ODN112, which contains a cytosine-guanine (CG) sequence but not canonical CpG motifs. Methods: Using an ovalbumin-induced asthma mouse model, we assessed the effect of ODN112 on prototypical asthma-related features in the lung and on the Th1/Th2 profile in the lymph nodes and lung of mice treated with ODN112 during sensitization. Results and Conclusion: ODN112 treatment attenuated asthma features in mice. In the bronchial lymph nodes of the lungs and in the spleen, ODN112 increased interferon-γ production and attenuated Th2 recall responses. In dendritic cells (DCs) after allergen sensitization, ODN112 enhanced cluster of differentiation (CD) 40 and CD80 expression but did not alter CD86 expression. Interleukin-12p40 production from DCs was also increased in a Th2-polarizing condition. Our results suggest that ODN112 is a potential Th1-inducing adjuvant during Th2 cell differentiation in the sensitization phase.

Although SARS-CoV-2 can infect human placental tissue, vertical transmission is rare. Therefore, the placenta may function as a barrier to inhibit viral transmission to the foetus, though the mechanisms remain unclear. In this study, we confirmed the presence of the SARS-CoV-2 genome in human placental tissue by in situ hybridization with antisense probes targeting the spike protein; tissue staining was much lower when using sense probes for the spike protein. To the best of our knowledge, this is the first evidence directly indicating inefficient viral replication in the SARS-CoV-2-infected placenta. Additional studies are required to reveal the detailed mechanisms.

高度経済成長期以前の日本では、多くの山村で、自給を目的とした作物栽培が行われていた。また、焼畑に付随した茶などの換金作物栽培も行われ、人びとは暮らしを維持していた。昭和30年代に焼畑は衰退するが、現在までの山村の耕作地や作物の変化は、具体的に明らかになっていない。本研究では、静岡市井川地域の山村を対象に、個人の事例を通して耕作地の茶畑への転換と、耕作地の変化に伴う作物への影響について論じた。それらは次のようにまとめられる。1 耕作地は、焼畑や常畑、採草地の複合的利用から、高度経済成長期には、茶畑への転換と拡大がおこった。昭和60年頃からは、高齢化により茶畑は縮小化した。2 耕作地の変化に伴い、ヒエやオオムギなどの穀類の自給や、焼畑休閑後に自生した在来茶の利用は、昭和30年代から40年代にかけて終焉を迎えた。3 自給的作物栽培は、昭和30年代から続く常畑と茶畑の一部で現在も持続している。Before rapid economic growth occurred in Japan, crops were cultivated in many mountain villages for subsistence purposes. Cash crops such as tea were also cultivated in conjunction with slash-and-burn farming to sustain people’s livelihoods. Although slash-and-burn farming declined in the 1950s, the specific changes that took place in cultivated land and crops in mountain villages up to the present day have not been clarified. This study discusses the conversion of cultivated land to tea plantations and the impact of changes in cultivated land on crops through an examination of individual cases in mountain villages in the Ikawa area of Shizuoka City. A summary of the study is as follows: 1. Cultivated lands were converted to tea plantations from a combination of burnt fields, common fields, and grassland and expanded during the period of rapid economic growth. Starting at about 1985, tea plantations shrank in size due to the aging of the population.2. With the change in cultivated land, subsistence cultivation of grains, such as Japanese millet and barley, and the use of native tea that grew naturally after the slash-and-burn fallow period came to an end from the mid-1950s to the mid-1966s.3. Subsistence crop cultivation continues to this day in some continuous cultivation fields and tea plantations that have been in existence since the mid-1950s.

Urine bags are commonly used to collect urine samples from neonates. However, the sample can be contaminated by stool, or detachment of the bag due to body movement can lead to failure of the collection. A qualitative urine collection kit containing ten filter papers of 3.2 mm diameter was developed and clinically verified among 138 neonates. During a single diaper change (approximately 3 h), the rate of urine collection was calculated. Urine collection was considered to be successful if any filter paper in the urine collection sheet turned from blue to white. Of the 127 neonates who passed urine, 122 had a change in the filter paper. The urine collection rate was 96%, with changes in all 10 filter papers observed in 98 neonates (80%). Urine collection rate was not influenced by sex (p = 1.00), age at collection (p = 0.72), preterm birth (p = 1.00), low birth weight (p = 0.92), or fecal contamination (p = 1.00). The incidence of dermatitis was not higher than in the group in which urine bags were used (urine collection kit: 2/68 [3%]; urine bag: 5/68 [7%]; p = 0.44). Novel urine collection kits using filter paper can collect samples from neonates safely and with a high probability of success.

Women with congenital amino acid disorders, including maple syrup urine disease (MSUD), are at risk of metabolic crisis at delivery. There are still only a few case reports of maternal MSUD globally, and we are the first to report the successful perinatal management of a woman with classical MSUD in Japan. A healthy baby was delivered by scheduled cesarean section despite the presence of several uterine fibroids. With precise diet therapy and accurate preparation, she completed the postpartum period without metabolic decompensation. Although her clinical outcome was favorable, she experienced hypoproteinemia at delivery because the available branched-chain amino acid-free medical food did not contain sufficient protein to meet the recommended nutrient intake. Therefore, this case also indicates a potential issue regarding a shortage of variations in specific amino acid-free medical food in Japan, which should be addressed to achieve a better nutrient status of adults with MSUD and other amino acid disorders.

Background: X-ray pelvimetry is used for evaluation of pelvic inlet generally to diagnose cephalopelvic disproportion (CPD) or contracted inlet. Cesarean section delivery (C/S) is often performed for labor dystocia without CPD or contracted inlet. Here, we examined whether X-ray pelvimetry is useful to decide on mode of delivery in women with dystocia.Method: A total of 1118 pregnant women received X-ray pelvimetry before or during labor. Overall, 205 women with cesarean deliveries for indications except for dystocia were excluded. The remaining 913 women undergoing induction/augmentation were retrospectively investigated. Obstetrical and maternal variables were analyzed by univariate, multivariate or ROC analysis.Results: Among 913 women, 37 (4%), including three with contracted inlet and seven with CPD, gave birth by C/S, whereas 876 gave birth by vaginal delivery. Low maternal height, older age, small obstetrical conjugate, large weight and infant head size were significantly associated with risk of C/S for dystocia. Multivariate analysis revealed that the obstetrical conjugate was an independent variable for risk of C/S. The area under the ROC curve (AUC) and the optimal cut-off values, respectively, were as follows: obstetrical conjugate: 0.68 and 11.7 cm (odds ratio=4.27), transverse diameter: 0.59 and 11.4 cm (odds ratio=1.82), maternal height: 0.70 and 155.5 cm (odds ratio=4.33), and maternal weight before pregnancy: 0.55 and 49.7 kg (odds ratio=1.98).Conclusion: The obstetrical conjugate was an independent variable associated with risk of C/S for dystocia. Additionally, maternal height was comparable to the conjugate in term of diagnostic ability. Our data suggested that routine X-ray pelvimetry was not beneficial to identify women at risk of C/S for dystocia.

Cryptococcus deneoformans is an opportunistic fungal pathogen that frequently causes fatal meningoencephalitis in patients with impaired cell-mediated immune responses such as AIDS. Caspase-associated recruitment domain 9 (CARD9) plays a critical role in the host defense against cryptococcal infection, suggesting the involvement of one or more C-type lectin receptors (CLRs). In the present study, we analyzed the role of macrophage-inducible C-type lectin (Mincle), one of the CLRs, in the host defense against C. deneoformans infection. Mincle expression in the lungs of wild-type (WT) mice was increased in the early stage of cryptococcal infection in a CARD9-dependent manner. In Mincle gene-disrupted (Mincle KO) mice, the clearance of this fungus, pathological findings, Th1/Th2 response, and antimicrobial peptide production in the infected lungs were nearly comparable to those in WT mice. However, the production of interleukin-22 (IL-22), tumor necrosis factor alpha (TNF-α), and IL-6 and the expression of AhR were significantly decreased in the lungs of Mincle KO mice compared to those of WT mice. In in vitro experiments, TNF-α production by bone marrow-derived dendritic cells was significantly decreased in Mincle KO mice. In addition, the disrupted lysates of C. deneoformans, but not those of whole yeast cells, activated Mincle-triggered signaling in an assay with a nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cells expressing this receptor. These results suggest that Mincle may be involved in the production of Th22-related cytokines at the early stage of cryptococcal infection, although its role may be limited in the host defense against infection with C. deneoformans.

Introduction: Eosinophilic chronic rhinosinusitis (ECRS) is a refractory chronic disease defined by recurrent nasal polyps with severe eosinophilic infiltration. This is mainly due to enhanced type 2-dominant immune responses, but the underlying mechanism is still not fully understood. Objective and Methods: In the present study, we aimed to determine the characteristics of dendritic cells (DCs) and cytokine profiles of T cells in the peripheral blood of individuals with ECRS and age- and sex-matched healthy controls (HC). Results and Conclusion: The ratios of myeloid (m)DC1s to DCs and PD-L1+ mDC1s to mDC1s were higher in ECRS patients than in HC. The proportions of plasmacytoid (p)DCs in DCs, and human leukocyte antigen-DR+ pDCs and ILT3+ pDCs in pDCs were lower in ECRS patients than in HC. In a characterization of T cells, IL-4+CD4+, IFN-γ+CD4+, IL-4+IFN-γ+CD4+, IL-4+Foxp3+CD4+, IFN-γ+Foxp3+CD4+, IFN-γ+IL-4−Foxp3−CD4+, IL-4+CD8+, IL-4+IFN-γ+CD8+, and IL-4+Foxp3+CD8+ T-cell populations were significantly higher in ECRS patients than in HC. These results suggest that the enhanced immune regulation of mDC1, diminished capacity of pDCs, and increased proportion of the T-cell phenotypes in peripheral blood might be factors in ECRS pathogenesis.

Background Gender disparities in adult patients with asthma regarding its prevalence and severity are mainly due to enhanced type 2 T-helper (Th2) cytokine production in female patients compared to that in male patients. However, the pathways mediating this effect remain unclear. Objective We aimed to determine the roles of two major subsets of dendritic cells (DCs) in females, specifically those displaying CD11b or CD103, during enhanced Th2 priming after allergen exposure, using an ovalbumin-induced asthma mouse model. Methods Sex-based differences in the number of DCs at inflamed sites, costimulatory molecule expression on DCs, and the ability of DCs to differentiate naive CD4+ T cells into Th2 population were evaluated after allergen exposure in asthmatic mice. In addition, we assessed the role of 17β-oestradiol in CD103+ DC function during Th2 priming in vitro. Results The number of CD11bhigh DCs and CD103+ DCs in the lung and bronchial lymph node (BLN) was increased to a greater extent in female mice than in male mice at 16 to 20 hours after ovalbumin (OVA) inhalation. In BLNs, CD86 and I-A/I-E expression levels and antigen uptake ability in CD103+ DCs, but not in CD11bhigh DCs, were greater in female mice than in male mice. Furthermore, CD4+ T cells cultured with CD103+ DCs from female mice produced higher levels of interleukin (IL)-4, IL-5, and IL-13, compared with CD4+ T cells cultured with CD103+ DCs from male mice. The 17β-oestradiol-oriented enhancement of CD86 expression on CD103+ DCs after allergen exposure induced the enhanced IL-5 production from CD4+ T cells. Conclusions and clinical relevance These findings suggest that with regard to asthma, enhanced Th2 cytokine production in females might be attributed to 17β-oestradiol-mediated Th2-oriented CD103+ DCs in the BLN.

Background: The previous study on prognosis of preterm premature rupture of fetal membranes (pPROM) near the limit of viability showed various survival rate raging from 26 to 57 %%. This may be partly due to the fact that treatment of prematurely born babies vary from one country to another, or sometimes within a single country. In Japan, resuscitation efforts are made to newborns of early gestational age, normally from 22 weeks of gestation. Objective: To assess the natural history and short- and long-term prognosis in pregnancies complicated by preterm premature rupture of membranes (pPROM) near the limit of viability in a hospital in Japan. Method: We conducted a single-center retrospective cohort study. Cases with diagnosis of pPROM at a gestational age of 20–23 6/7 weeks and delivered in our hospital between April 2007 and December 2017 were examined. Result: 66 cases were included and of those, 54 (81.1 %) newborns survived to discharge. Of the neonates who survived to discharge, 42 (77.8 % of survivors) experienced severe morbidity at the time of discharge. Multivariate logistic regression analysis showed that later gestational age at pPROM and longer latency period were significantly associated with survival with no severe morbidities (per one day increase, adjusted odds ratio (OR) 1.37, 95 % CI 1.03–1.83, p = 0.033 and per one day increase, adjusted OR 1.11, 95 % CI 1.02–1.21, p = 0.015). Of 23 cases followed at 36 months, 8 (34.8 %) showed developmental delay. Conclusion: The survival rate was significantly higher than the previous studies, yet many of the survivors experienced short-term severe morbidity. Of those who experienced short-term severe morbidity, however, more than half showed normal range development at 36 months. Keywords: Preterm premature rupture of membrane, Near the limit of viability

Interferon (IFN)-&gamma, is mainly secreted by CD4+ T helper 1 (Th1), natural killer (NK) and NKT cells after skin injury. Although IFN-&gamma, is well known regarding its inhibitory effects on collagen synthesis by fibroblasts in vitro, information is limited regarding its role in wound healing in vivo. In the present study, we analyzed how the defect of IFN-&gamma, affects wound healing. Full-thickness wounds were created on the backs of wild type (WT) C57BL/6 and IFN-&gamma, deficient (KO) mice. We analyzed the percent wound closure, wound breaking strength, accumulation of leukocytes, and expression levels of COL1A1, COL3A1, and matrix metalloproteinases (MMPs). IFN-&gamma, KO mice exhibited significant attenuation in wound closure on Day 10 and wound breaking strength on Day 14 after wound creation, characteristics that are associated with prolonged neutrophil accumulation. Expression levels of COL1A1 and COL3A1 mRNA were lower in IFN-&gamma, KO than in WT mice, whereas expression levels of MMP-2 (gelatinase) mRNA were significantly greater in IFN-&gamma, KO than in WT mice. Moreover, under neutropenic conditions created with anti-Gr-1 monoclonal antibodies, wound closure in IFN-&gamma, KO mice was recovered through low MMP-2 expression levels. These results suggest that IFN-&gamma, may be involved in the proliferation and maturation stages of wound healing through the regulation of neutrophilic inflammatory responses.

We investigated the effect of zonisamide, a new antiepileptic drug, on voltage-dependent Ca2+ currents in cultured neurons of rat cerebral cortex. Whole-cell voltage-clamp recordings demonstrated at least two distinct voltage-dependent Ca2+ currents: (1) a low-threshold, rapidly inactivating component, T-type Ca2+ current, which is sensitive to 100 microM Ni2+, and (2) a high-threshold, slowly inactivating (long-lasting) component, L-type Ca2+ current. Zonisamide, a new anticonvulsant effective against maximal electroshock (MES) seizures in mice reduced T-type Ca2+ current in a dose-dependent manner. The mean percentage of reduction was 59.5 +/- 7.2% at 500 microM, but zonisamide had no effect on L-type Ca2+ current. A methylated analog of zonisamide, which is ineffective against MES seizures in mice, was tested at a concentration of 500 microM, and reduced neither T-type nor L-type Ca2+ current. These findings suggest that the effects of zonisamide against MES seizures might occur through the reduction of T-type Ca2+ current. Because drugs that are effective against MES seizures are thought to prevent seizure discharge spread, T-type Ca2+ channels could underlie a cellular mechanism of spreading activity in epileptic seizures.

右言語優位患者11名を含む側頭葉てんかん患者 (TLE) 77名について, アミタールテストによる言語記憶検査を行った。対象は, 左言語優位・左焦点群 (LL群) 23名, 左言語優位・右焦点群 (LR群) 43名, 右言語優位・左焦点群 (RL群) 5名, 右言語優位・右焦点群 (RR群) 6名であった。アミタール非注入時の記憶率は, 全体で83.1%(80.2～93.3%) であった。アミタール注入時の成績は, 右側注入時には, 右言語優位群 (RR, RL群) が著行明に低下し, 焦点側を含めた結果ではLR群のみが良好な成績を示した。左側注入時には, 左言語優位群の成績が著明に低下し, 焦点側を含めた結果では, RL群のみが良好な成績を示した。以上の結果から, 1) 言語優位側が左右のいずれであっても, 言語記憶は言語優位半球に依存していること, 2) TLEには焦点側半球に記憶低下につながる潜在的障害が存在すること, 3) 海馬を含む記憶系の保持には, 言語優位半球と海馬の機能維持がともに必要であることを結論した。

We investigated the effect of bromide on γ-aminobutyric acid (GABA)-activated currents in cultured cerebral neurons of the rat, employing whole-cell voltage- and current-clamp techniques. Application of 100 μM GABA elicited currents whose reversal potential was 0 mV with equal concentrations of chloride in both pipette and bath solutions and more negative than −60 mV with 159 mM chloride extracellularly and 4 mM chloride inside. Bicuculline blocked the currents. These findings showed that the currents were composed of chloride flux through GABA A receptor-coupled channels. Reversal potential revealed a permeability ratio of bromide with respect to chloride ( P Br / P Cl ) of 1.51. When 100 μM GABA was applied with the extracellular solution containing 140 mM bromide and 19 mM chloride, the currents were enhanced 2.00- and 1.91-fold at the holding potentials of t-20 mV and 0 mV, respectively. Extracellular solutions containing various concentrations of bromide substituted for the same amount of chloride were applied with 100μM GABA. The therapeutic concentration of 1C mM and 20 mM bromide enhanced the currents 1.28- and 1.36-fold of the control currents at the holding potential of-t 20 mV, respectively. Under current-clamp recording, a larger hyperpolarization was obtained by the application of GABA with a 140 mM bromide-containing solution. These findings suggest that bromide potentiated GABA-activated currents at the therapeutic concentrations ranging from 10 mM to 20 mM, causing the larger GABA-induced hyperpolarization. It is postulated that the antiepileptic effect of bromide might occur through the potentiation of inhibitory postsynaptic potentials elicited by GABA.