Diacron-Reactive Oxygen Metabolites Levels Are Initially Elevated in Patients with Bullous Pemphigoid.

ROS are involved in the pathogenesis of bullous pemphigoid (BP), but this involvement has not been fully elucidated. In this study, to further elucidate the pathogenic role of ROS in BP, we examined the results of the diacron-reactive oxygen metabolite test and the biological antioxidant potential test for 16 patients with BP who visited our hospital before being treated with systemic corticosteroids. In the patients with BP, the average diacron-reactive oxygen metabolite levels, expressed in Carratelli units, were significantly reduced at 1 month of treatment (from 335.6 ± 40.3 Carratelli units to 224.7 ± 61.6 Carratelli units, P < .001). Bullous Pemphigoid Disease Area Index (erosions/blisters) scores correlated with diacron-reactive oxygen metabolite levels (r = 0.51), suggesting that those levels reflect the disease severity. We also performed staining of 3,5-dibromotyrosine in skin tissues. The 3,5-dibromotyrosine is expected to be a marker of tissue damage related to inflammation and allergies. The 3,5-dibromotyrosine was stained in infiltrated cells around the dermis, throughout the blister fluid, and at the basement membrane within the blister. It is considered that tissue destruction caused by the myeloperoxidase released from neutrophils and by eosinophil peroxidase released from eosinophils is involved in blister formation. The results suggest that ROS play a role in BP.

Modification of the association between nausea and vomiting of pregnancy and anxiety by personality trait during early pregnancy: A longitudinal study of Japanese pregnant women.

AIM: This study aimed to elucidate whether personality traits modify the relationship between nausea and vomiting of pregnancy (NVP) and anxiety, stratified by three pregnancy periods: 5-8 weeks, 9-12 weeks, and 13-20 weeks. METHODS: This longitudinal study was conducted from August 2018 to February 2019 at a perinatal outpatient unit in a general hospital. We included 153 pregnant women aged ≥20 years and under 20 weeks of gestation at their first prenatal visit. They completed the Index of Nausea, Vomiting, and Retching, and the State-Trait Anxiety Inventory (STAI) to measure anxiety in terms of both trait (STAI-T) and state anxiety (STAI-S), and retook them at follow-up checkups for a maximum of three times. RESULTS: Using longitudinal data until 20 weeks' gestation, changes in NVP and trait anxiety were significantly associated with changes in state anxiety independently, with trait anxiety being more strongly involved than the change in NVP. This tendency was pronounced in the high-trait anxiety group with STAI-T scores of ≥45. Cross-sectional analyses by gestational week showed similar results in the low-trait anxiety group (STAI-T < 45). In the high-trait anxiety group, only trait anxiety was significantly associated with state anxiety up to 12 weeks gestation. However, only NVP was significantly associated with state anxiety after 13 weeks. CONCLUSIONS: Pregnant women who tend to be anxious temperamentally may have other factors that cause anxiety besides nausea immediately after the discovery of pregnancy. Understanding personality traits may help reduce anxiety in pregnant women.

Association between pregnant women fasting duration and neonatal hypoglycemia: A prospective cohort study.

OBJECTIVE: To evaluate the association between maternal fasting time before delivery and the occurrence of hypoglycemia in neonates immediately after birth. METHODS: This prospective single-center cohort study included pregnant women who delivered at the study institution between October 2021 and January 2023 and their neonates. The primary outcome was the incidence of neonatal hypoglycemia after birth, defined as a blood glucose level less than 47 mg/dL. Fasting time was categorized into quartiles, and the association between maternal fasting time and neonatal hypoglycemia was investigated. The crude or adjusted odds ratios of maternal fasting time for neonatal hypoglycemia were calculated using logistic regression analysis. RESULTS: The study included 663 pregnant women and 696 neonates. Compared with the reference group with a short fasting time of 4.3 h or less, the adjusted odds ratios for neonatal hypoglycemia were 1.47 (95% confidence interval [CI] 0.70-3.20) for middle fasting time (4.3-9.8 h), 4.05 (95% CI 2.02-8.56) for long fasting time (9.8-14.6 h), and 4.99 (95% CI 2.59-10.25) for very long fasting time (>14.6 h). In the subgroup analysis, the association between maternal fasting time and neonatal hypoglycemia showed different trends according to the mode of delivery. CONCLUSION: Maternal fasting time over 9-10 h before delivery was associated with the occurrence of neonatal hypoglycemia. Obstetrical management, considering not only maternal safety but also neonatal hypoglycemia prevention, is required.

Pentagamavunone-1 inhibits aggressive breast cancer cell proliferation through mitotic catastrophe and ROS-mediated activities: in vitro and in vivo studies.

Pentagamavunone-1 (PGV-1), an analog of curcumin, has been studied for its cytotoxic effects in 4T1, MCF7, MCF7/HER2, and T47D breast cancer cells. Its antiproliferative effect is partly mediated through G2/M arrest; however, its molecular mechanism during cell cycle progression remains unknown. In this study, we aimed to determine whether PGV-1 has any anticancer effects on highly aggressive breast cancer cells, with a focus on cell cycle regulatory activity, reactive oxygen species (ROS) generation, and their mediated effects on cancer cells. MDA-MB-231 (triple-negative) and HCC1954 (overexpressed HER2) immortalized human breast cancer cells were used in the study. PGV-1 exhibited cytotoxic activity with an irreversible antiproliferative impact on treated cells and had good selectivity when tested in fibroblast cells. Oral PGV-1 administration suppressed tumor growth in a cell-derived xenograft mouse model. PGV-1 induced the phosphorylation of Aurora A kinase and PLK1 in MDA-MB-231 cells, while PLK1 and cyclin B1 phosphorylation were enhanced in the PGV-1-treated HCC1954 cells during prometaphase arrest. Intracellular ROS production was substantially higher upon PGV-1 treatment following mitotic arrest, and this activity caused impairment of mitochondrial respiration, induced senescence, and subsequently triggered early-to-late apoptosis. Collectively, these results suggest that the molecular mechanism of PGV-1 involves the regulation of mitotic kinases to cause cell cycle arrest and the enhancement of ROS production to impair mitochondrial activity and induce cellular senescence. The therapeutic activities demonstrated by PGV-1 in this study show its potential as an appealing candidate for chemotherapy in breast cancer treatment.

Cultured fibroblasts of the Okinawa rail present delayed innate immune response compared to that of chicken.

The Okinawa rail is endemic to Okinawa Island and is categorized as an endangered animal. In this study, we focused on innate immunity because it is the first line of host defense. In particular, signals recognizing foreign RNA (e.g., viruses) are important for host defense because they activate the host immune system. The retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) families (RIG-I, MDA5, and LGP2) are sensors that activate innate immunity. Therefore, we analyzed these functions in the Okinawa rail using genomic and cellular analyses of fibroblasts. Fibroblasts can be obtained from dead individuals, allowing these cells to be obtained from dead individuals, which is particularly useful for endangered species. The MDA5 gene of Okinawa rail was sequenced using the Sanger method following PCR amplification and extraction of the amplified sequence from agarose gel. Additionally, mRNA expression analysis of cultured fibroblasts exposed to poly I:C was done. The MDA5 gene was found to be a mutated nonfunctional gene in the Okinawa rail. The mRNA expression rates of inflammatory cytokine genes type I IFN, and Mx1 were slower in Okinawa rail than in chicken cultured fibroblasts. Similar to the mRNA expression results, cell number and live cell ratio also slowly decreased in the Okinawa rail compared with chicken cultured fibroblasts, indicating that the innate immune reaction differs between chicken and the Okinawa rail. To the best of our knowledge, this is the first experimental evaluation of the loss of function of the Okinawa rail innate immune genes. In conclusion, our results provide a basis for conservation strategies for the endangered Okinawa rail.

Efficacy of the unified protocol for transdiagnostic cognitive-behavioral treatment for depressive and anxiety disorders: a randomized controlled trial.

BACKGROUND: The efficacy of the unified protocol of the transdiagnostic treatment for emotional disorders (UP) has been poorly studied in patients with depressive disorders. This study aimed to examine the efficacy of UP for improving depressive symptoms in patients with depressive and/or anxiety-related disorders. METHODS: This assessor-blinded, randomized, 20-week, parallel-group, superiority study compared the efficacy of the UP with treatment-as-usual (UP-TAU) v. wait-list with treatment-as-usual (WL-TAU). Patients diagnosed with depressive and/or anxiety disorders and with depressive symptoms participated. The primary outcome was depressive symptoms assessed by GRID-Hamilton depression rating scale (GRID-HAMD) at 21 weeks. The secondary outcomes included assessor-rated anxiety symptoms, severity and improvement of clinical global impression, responder and remission status, and loss of principal diagnosis. RESULTS: In total, 104 patients participated and were subjected to intention-to-treat analysis [mean age = 37.4, s.d. = 11.5, 63 female (61%), 54 (51.9%) with a principal diagnosis of depressive disorders]. The mean GRID-HAMD scores in the UP-TAU and WL-TAU groups were 16.15 (s.d. = 4.90) and 17.06 (s.d. = 6.46) at baseline and 12.14 (s.d. = 5.47) and 17.34 (s.d. = 5.78) at 21 weeks, with a significant adjusted mean change difference of -3.99 (95% CI -6.10 to -1.87). Patients in the UP-TAU group showed significant superiority in anxiety and clinical global impressions. The improvement in the UP-TAU group was maintained in all outcomes at 43 weeks. No serious adverse events were observed in the UP-TAU group. CONCLUSIONS: The UP is an effective approach for patients with depressive and/or anxiety disorders.

Organoids containing neural-like cells derived from chicken iPSCs respond to poly:IC through the RLR family.

There is still much room for development in pluripotent stem cell research on avian species compared to human stem cell studies. Neural cells are useful for the evaluation of risk assessment of infectious diseases since several avian species die of encephalitis derived from infectious diseases. In this study, we attempted to develop induced pluripotent stem cells (iPSCs) technology for avian species by forming organoids containing neural-like cells. In our previous study, we established two types iPSCs from chicken somatic cells, the first is iPSCs with PB-R6F reprogramming vector and the second is iPSCs with PB-TAD-7F reprogramming vector. In this study, we first compared the nature of these two cell types using RNA-seq analysis. The total gene expression of iPSCs with PB-TAD-7F was closer to that of chicken ESCs than that of iPSCs with PB-R6F; therefore, we used iPSCs with PB-TAD-7F to form organoids containing neural-like cells. We successfully established organoids containing neural-like cells from iPSCs using PB-TAD-7F. Furthermore, our organoids responded to poly:IC through the RIG-I-like receptor (RLR) family. In this study, we developed iPSCs technology for avian species via organoid formation. In the future, organoids containing neural-like cells from avian iPSCs can develop as a new evaluation tool for infectious disease risk in avian species, including endangered avian species.

Severity of SARS-CoV-2 infection in pregnant women and their neonates during the Omicron period compared to the pre-Omicron period: A retrospective cohort study.

AIM: To compare the clinical outcomes among women diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy, and their neonates, during the period when the Omicron variant predominated in Japan with those of the pre-Omicron variant period. METHODS: We conducted a retrospective single-center cohort study between August 1, 2020, and June 30, 2022. The cohort was divided into pre-Omicron group (August 1, 2020 to November 30, 2021) and Omicron group (December 1, 2021 to June 30, 2022). The primary outcome was maternal intensive care unit (ICU) admission during the perinatal period. The secondary outcomes were maternal oxygen administration before and after delivery, preterm birth (PTB), and low birth weight (LBW). RESULTS: During the study period, 81 pregnant women were admitted to the hospital with SARS-CoV-2 infection (pre-Omicron period, n = 28; Omicron period, n = 53). SARS-CoV-2 infection during the Omicron period was associated with lower risk of maternal ICU admission (adjusted-odds ratio [aOR]: 0.10, 95% confidence interval [CI]: 0.01-1.23, p = 0.072), oxygen administration via a nasal cannula or mask (aOR: 0.18, 95% CI: 0.03-0.96, p = 0.045), PTB (aOR: 0.15, 95% CI: 0.04-0.51, p = 0.002), and LBW (aOR: 0.13, 95% CI: 0.03-0.55, p = 0.005). CONCLUSION: Among pregnant women, SARS-CoV-2 infection during the Omicron period was associated with reduced risk of maternal ICU admission, requiring supplemental oxygen, PTB, and LBW. This can be attributable to lower virulence of the Omicron variant and higher vaccination coverage during the Omicron period.

Mature and immature ovarian teratomas share methylation profiles of imprinted genes: a MS-MLPA analysis.

Immature teratomas are a subset of ovarian teratomas, and the pathogenic relationship between mature and immature ovarian teratomas is unclear. Mature ovarian teratomas are parthenogenetic tumors that arise from a single oocyte/ovum, whereas the origin of immature ovarian teratomas has not been extensively investigated. Since parthenogenetic tumors contain only maternal genomes, genome imprinting in these tumors usually follows a maternal pattern. DNA methylation is among the most important mechanisms of genome imprinting. Therefore, we analyzed the methylation profile of imprinted genes by performing methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) of 25 imprinting control regions (ICRs) in 10 imprinted genes/gene clusters from formalin-fixed, paraffin-embedded samples obtained from 4 immature ovarian teratomas, 8 mature ovarian teratomas, and 4 ovarian yolk sac tumors (YSTs). Both the immature and mature components showed similar methylation levels in each ICR in immature teratomas. Overall, immature ovarian teratomas showed maternal methylation patterns of imprinted genes in concordance with their parthenogenetic origin. However, they also showed aberrant methylation levels in a few imprinted genes, suggesting that genome imprinting in immature teratomas may partially differ from that in mature teratomas. Microscopic foci of YST were seen in one immature teratoma; the YST component also showed a maternal methylation pattern, unlike the pure YSTs that showed irregular patterns. Thus, teratoma-associated YST and pure YST may have different pathogenic mechanisms.

Preclinical evaluation of pentagamavunone-1 as monotherapy and combination therapy for pancreatic cancer in multiple xenograft models.

We previously reported that pentagamavunone-1 (PGV-1) effectively inhibited cell proliferation in many types of human tumors, including pancreatic cancer, by inducing M phase (prometaphase) arrest, senescence, and apoptosis with few side effects. However, a detailed evaluation of the effects of PGV-1 on pancreatic cancer cells in an in vivo setting has not yet been conducted. The present study investigated the potential efficacy of PGV-1 as both monotherapy and combination therapy for pancreatic cancer using multiple xenograft mouse assays. A cell-line derived xenograft model (CDX-M) with pancreatic cancer cell line and a patient-derived xenograft mouse model (PDX-M) using resected pancreatic cancer samples without neoadjuvant chemotherapy were established in both heterotopic and orthotopic manners. PGV-1 effectively suppressed tumor formation at the heterotopic and orthotopic sites in CDX-M than in untreated mice. Combination therapy with PGV-1 and gemcitabine more effectively suppressed tumor formation than monotherapy with PGV-1 or gemcitabine when administered after tumor formation. Monotherapy with PGV-1 or gemcitabine less effectively suppressed tumor formation in PDX-M than in CDX-M, whereas combination therapy with PGV-1 and gemcitabine more effectively suppressed tumor formation. PGV-1 as monotherapy and combination therapy with gemcitabine effectively inhibited tumor formation and has potential as an anticancer candidate for pancreatic cancer.

Development and multicenter validation of an LC-MS-based bioanalytical method for antisense therapeutics.

Background: Many bioanalytical methods for antisense oligonucleotides (ASOs) using LC-MS have been reported. However, no data have been available on the reproducibility and robustness of a single bioanalytical method for ASOs. As such, in the current study, we evaluated the reproducibility and robustness of LC-MS-based bioanalytical methods for ASOs in multiple laboratories. Methods/Results: Seven independent laboratories were included in this study. Mipomersen was measured by ion-pairing LC-MS (IP-LC-MS) as a model ASO using different LC-MS. The validation results of calibration curve, accuracy, precision and selectivity met the criteria of conventional bioanalytical method validation guidelines using LC/GC-MS for drugs in all laboratories. Meanwhile, carryover (>20%) was detected in three laboratories. Conclusion: We first demonstrated the multicenter-validated IP-LC-MS bioanalytical method for ASOs. Our data showed that the method was sensitive, robust and reproducible. However, the occurrence of carryover should be carefully monitored in its future application.

Efficacy and Acceptability of Remote Cognitive Behavioral Therapy for Patients With Major Depressive Disorder in Japanese Clinical Settings: A Case Series.

Remote cognitive and behavioral therapy (CBT) via videoconference has been garnering attention as a means of improving access to CBT for depression, in particular during the coronavirus disease 2019 pandemic. However, there is a lack of evidence supporting its implementation in Japanese clinical settings. This case series aimed to establish preliminary evidence of whether remote CBT can be an effective therapy for major depression in Japanese clinical settings. Five patients who met the diagnostic criteria for major depressive disorder were enrolled and underwent remote CBT via videoconference and face-to-face assessment interviews. The results showed that remote CBT via videoconference improved depressive symptoms, enabling a relatively high level of patient satisfaction and working alliance. Moreover, detailed feedback from our patients showed that continuous monitoring was preferable for increasing treatment engagement. Further research is warranted to test the efficacy and acceptability of remote CBT via videoconference for treating major depression.

Corrigendum to "Growth standard charts for Japanese children with mean and standard deviation (SD) values based on the year 2000 national survey".

[This corrects the article DOI: 10.1297/cpe.25.71.].

Association between Obesity and Intake of Different Food Groups among Japanese with Type 2 Diabetes Mellitus-Japan Diabetes Clinical Data Management Study (JDDM68).

BACKGROUND: We investigated the association between various food groups and obesity in Japanese patients with type 2 diabetes. METHODS: 2070 patients with type 2 diabetes who attended 26 diabetes clinics throughout Japan were analyzed and were divided into obese and non-obese groups. Intakes of food groups determined by a food frequency questionnaire were compared. Odds ratios for obesity for quartiles of individual food groups were calculated using a logistic regression model. RESULTS: Non-obese patients consumed a larger variety of food groups than obese patients, with the diets of non-obese individuals closer to the traditional Japanese diet characterized by fish, seaweed, and soybeans/soy products. Among 21 food groups, low vegetable intake and high sweets intake were the most strongly associated with obesity in both men and women. Low intake of both fruits and vegetables and the combination of high intake of sweets and low intake of fruits were associated with obesity. CONCLUSIONS: Food groups and their combinations that were strongly associated with obesity in Japanese patients with type 2 diabetes were identified. Our findings also suggested an inverse association between the traditional Japanese diet and obesity.

Assessment of placental abruption with diffusion-weighted imaging.

AIM: To investigate whether placental abruption without fetal distress could be assessed by apparent diffusion coefficient (ADC) values in magnetic resonance imaging (MRI). METHODS: We conducted a retrospective case-control study at a single center. ADC values at the lesions of placental abruption in the abruption group (n = 8) were compared to those in the control group (n = 32). In the abruption group, ADC values at the sites of abruption were also compared to those at the nonabruption sites within the same placenta. RESULTS: The ADC values in the placental area above the abruption site in the abruption group showed lower values than those in the control group when the slice containing the umbilical cord insertion site was set as the reference, and those values were compared in each corresponding slice. Compared with average ADC values, those above the abruption site in the abruption group were also significantly lower than those in the control group (p < 0.001). Furthermore, ADC values at the area above abruption were lower than those at the nonabruption area of all planes in the abruption group. CONCLUSIONS: ADC values at the lesions above the placental abruption site were reduced compared to those in the normal placenta and those in the nonabruption area. Thus, it would be helpful to understand the pathophysiology of placental abruption in expectant management, although further investigations would be needed.

Prevalence of common aneuploidy in twin pregnancies.

The incidence of chromosomal abnormalities in twin pregnancies is not well-studied. In this retrospective study, we investigated the frequency of chromosomal abnormalities in twin pregnancies and compared the incidence of chromosomal abnormalities in dichorionic diamniotic (DD) and monochorionic diamniotic (MD) twins. We used data from 57 clinical facilities across Japan. Twin pregnancies of more than 12 weeks of gestation managed between January 2016 and December 2018 were included in the study. A total of 2899 and 1908 cases of DD and MD twins, respectively, were reported, and the incidence of chromosomal abnormalities in one or both fetuses was 0.9% (25/2899) and 0.2% (4/1908) in each group (p = 0.004). In this study, the most common chromosomal abnormality was trisomy 21 (51.7% [15/29]), followed by trisomy 18 (13.8% [4/29]) and trisomy 13 (6.9% [2/29]). The incidence of trisomy 21 in MD twins was lower than that in DD twins (0.05% vs. 0.5%, p = 0.007). Trisomy 21 was less common in MD twins, even when compared with the expected incidence in singletons (0.05% vs. 0.3%, RR 0.15 [95% CI 0.04-0.68]). The risk of chromosomal abnormality decreases in twin pregnancies, especially in MD twins.

Higher Iron Intake Is Independently Associated with Obesity in Younger Japanese Type-2 Diabetes Mellitus Patients.

We aimed to analyze the association between dietary iron intake and obesity assessed by BMI after adjustment for nutrient intake (macronutrients and fiber) and food groups. The study design was cross-sectional. Patients with type-2 diabetes (n = 1567; 63.1% males; mean age 62.3 ± 11.6 years) were included in the study. To assess diet, consumption of typical food groups was determined by a food frequency questionnaire. Obesity was defined as BMI ≥ 25 kg/m2. We performed a binary regression analysis between quartiles of iron intake and obesity by quartiles of age group. A direct linear association was found for the highest quartile of iron intake and obesity in the younger age group of 30 to 54 years (OR = 3.641, 95% CI = 1.020-12.990; p trend = 0.011). Multivariate analysis using food groups as opposed to nutrients revealed a positive trend for obesity in the younger age group after adjusting for lifestyle factors, energy intake and bean and vegetable intake (p trend = 0.023). In all participants, an inverse association was observed before adjustment by vegetable intake (OR = 0.453, 95% CI = 0.300-0.684; p trend = 0.001). Higher iron intake was associated with obesity independent of macronutrient and fiber intake but only in the youngest quartile of age group examined.

Preschool-children's height, trend, and causes: Japanese national surveys 1990-2010.

We observed trends in the height of children aged 3 to 6 in Japan using data from the National Growth Survey on Preschool Children in the years 1990, 2000, and 2010. Average standard deviation (SD) scores of height decreased from 0.39 (SD 1.02) in 1990 (n = 3,684) to 0.37 (SD 1.05) in 2000 (n = 2,981) and 0.33 (SD 1.07) in 2010 (n = 2,027). Mothers of children in later waves were taller, older, and more likely to be primiparous; children in later waves had shorter gestational age, lower birth weight, and were less likely to have been fed less with formula or solid foods before 6 mo. The only factor that consistently contributed to a reduction in children's height for both 1990-2000 and 2000-2010 was a reduction in birthweight SD score (indirect effect on height -1.5 [95% CI: -1.9, -1.1] mm for 1990-2000 and -1.2 [95% CI: -1.8, -0.8] mm for 2000-2010). Factors that contributed, although not significantly or consistently between the two periods, were changes in pre-pregnancy BMI, smoking during pregnancy, multiple pregnancies, gestational age, BMI at birth, and use of formula and solid foods before 6 mo. Secular increases in maternal age, height, and primiparity contributed to increasing children's height.