Current status of screening and management of gestational diabetes in early pregnancy: a questionnaire survey in Japan.

Our aim is to investigate the obstetric practices in Japan regarding the screening and management of gestational diabetes mellitus (GDM) diagnosed before 20 weeks of gestation (early-GDM). A web-based questionnaire survey was administered to 991 teaching hospitals between November 2021 and February 2022, and 602 responses were received (a response rate of 61%). Screening tests for all pregnant women in the first trimester were conducted in 553 (92%) hospitals, and nearly all of these hospitals (535/553 [97%]) adhered to an individual protocol, predominantly relying on random plasma glucose measurements (488/535 [91%]). A quarter (139 [26%]) implemented a risk profile assessment for GDM screening, taking into account factors such as previous gestational diabetes, prior macrosomia, and family history of diabetes. A small number (23 [4%]) targeted only women at high risk of GDM using the risk profile assessment. The majority of hospitals (501 [94%]) employed a 75 g oral glucose tolerance test as a diagnostic measure, and glycemic control for early-GDM was established in most hospitals (429 [80%]). Of the 535 hospitals that maintained an individual management protocol, 356 [67%] facilitated dietary management, self-monitoring of blood glucose, and insulin administration if needed to meet glycemic targets. Our survey revealed a widespread adoption of universal screening and subsequent treatment for early-GDM in Japan.

Associations of fasting plasma glucose and glycosylated hemoglobin levels at less than 24 weeks of gestation with hypertensive disorders of pregnancy: the BOSHI study.

This study aimed to evaluate the associations of fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels at <24 weeks of gestation with hypertensive disorders of pregnancy (HDP) and compare the strengths of the associations of HDP with FPG and HbA1c levels. Totally, 1,178 participants were included in this prospective cohort study. HDP, FPG, HbA1c, and potential confounding factors were included in multiple logistic regression models. The number of HDP cases was 136 (11.5%). When FPG and HbA1c were included in the model separately, quartile 4 (Q4) of FPG (87-125 mg/dL) and HbA1c (5.2-6.3% [33-45 mmol/mol]) levels had higher odds of HDP than quartile 1. The odds ratios (ORs) were 1.334 (95% confidence interval [CI]: 1.002-1.775) for Q4 of FPG and 1.405 (95% CI: 1.051-1.878) for Q4 of HbA1c. When the participants were divided into two categories based on the cut-off value with the maximum Youden Index of FPG or HbA1c, the ORs for high FPG (≥84 mg/dL) or high HbA1c (≥5.2% [33 mmol/mol]) were 1.223 (95% CI: 1.000-1.496) and 1.392 (95% CI: 1.122-1.728), respectively. When both FPG and HbA1c were included in the model simultaneously, the statistical significance of Q4 of FPG disappeared, whereas that of HbA1c remained. In two-category models, the same results were obtained. High FPG and HbA1c levels at <24 weeks of gestation were risk factors for HDP in pregnant Japanese women. In addition, high HbA1c levels were more strongly associated with HDP than high FPG levels.

Feasibility and efficacy of pemafibrate for prevention of maternal high-fat intake-induced glucose metabolic dysfunction in offspring.

Given the significance of the intrauterine lipid environment in glucose metabolic homeostasis in offspring, the present study was undertaken to investigate the feasibility and efficacy of pemafibrate, a triglyceride-lowering peroxisome proliferator-activated agent, for maternal high-fat diet (HFD) intake-induced glucose metabolic dysfunction in offspring. A mouse model of HFD-induced gestational obesity was employed, and pemafibrate was orally administered from day 10 of gestation until delivery. The influences of maternal pemafibrate treatment on biological processes and toxicity were evaluated in both newborns and 12-week-old offspring. The findings of a dose-dependent decrease of ß cell islet mass and of impairment of glucose tolerance and insulin sensitivity in offspring suggest that maternal pemafibrate intervention can prevent maternal HFD-intake-induced diabetes in offspring. Of particular interest in the prevention of future glucose metabolic dysfunction in offspring, low-dose maternal pemafibrate treatment (0.02 mg/kg/day) had sufficient efficacy and appeared to be safe in offspring. Therefore, pemafibrate may be a potential agent for the prevention of maternal high-fat exposure-induced diabetes in offspring. Abbreviations: CD, control diet; DEG, differentially expressed genes; GTT, glucose tolerance test; HFD, high-fat diet; ITT, insulin tolerance test; MC, 0.5w/v% methyl cellulose 400 solution; PPAR, triglyceride-lowering peroxisome proliferator-activated receptor; RNA-seq, RNA sequencing; TC, total cholesterol; TG, triglycerides.

Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks.

The preferential response to PARP inhibitors (PARPis) in BRCA-deficient and Schlafen 11 (SLFN11)-expressing ovarian cancers has been documented, yet the underlying molecular mechanisms remain unclear. As the accumulation of single-strand DNA (ssDNA) gaps behind replication forks is key for the lethality effect of PARPis, we investigated the combined effects of SLFN11 expression and BRCA deficiency on PARPi sensitivity and ssDNA gap formation in human cancer cells. PARPis increased chromatin-bound RPA2 and ssDNA gaps in SLFN11-expressing cells and even more in cells with BRCA1 or BRCA2 deficiency. SLFN11 was co-localized with chromatin-bound RPA2 under PARPis treatment, with enhanced recruitment in BRCA2-deficient cells. Notably, the chromatin-bound SLFN11 under PARPis did not block replication, contrary to its function under replication stress. SLFN11 recruitment was attenuated by the inactivation of MRE11. Hence, under PARPi treatment, MRE11 expression and BRCA deficiency lead to ssDNA gaps behind replication forks, where SLFN11 binds and increases their accumulation. As ovarian cancer patients who responded (progression-free survival >2 years) to olaparib maintenance therapy had a significantly higher SLFN11-positivity than short-responders (<6 months), our findings provide a mechanistic understanding of the favorable responses to PARPis in SLFN11-expressing and BRCA-deficient tumors. It highlight the clinical implications of SLFN11.

Neurodegenerative diseases associated with the disruption of proteostasis and their therapeutic strategies using chemical chaperones.

Aberrant proteostasis is thought to be involved in the pathogenesis of neurodegenerative diseases. Some proteostasis abnormalities are ameliorated by chaperones. Chaperones are divided into three groups: molecular, pharmacological, and chemical. Chemical chaperones intended to alleviate stress in organelles, such as the endoplasmic reticulum (ER), are now being administered clinically. Of the chemical chaperones, 4-phenylbutyrate (4-PBA) has been used as a research reagent, and its mechanism of action includes chaperone effects and the inhibition of histone deacetylase. Moreover, it also binds to the B-site of SEC24 and regulates COPII-mediated transport from the ER. Although its therapeutic effect may not be strong, elucidating the mechanism of action of 4-PBA may contribute to the identification of novel therapeutic targets for neurodegenerative diseases.

Use of the Japanese gestational diabetes mellitus diagnostic strategy during the COVID-19 pandemic in Japan: A questionnaire survey.

AIM: Some concerns exist that diagnosis of gestational diabetes mellitus (GDM) may be missed when the simplified diagnostic criteria of the Japanese Society of Diabetes and Pregnancy (JSDP) for GDM (published during the COVID-19 pandemic) are used. Moreover, limited data is available regarding how widespread these diagnostic criteria are used when managing GDM during the COVID-19 pandemic. Therefore, this study aimed to determine how GDM diagnosis has changed during the COVID-19 pandemic in Japan. METHODS: The changes in GDM diagnosis during the COVID-19 pandemic were investigated using an online questionnaire to 2159 obstetric facilities in Japan. The questionnaire collected data on facility type, awareness of Japanese GDM diagnostic strategies, modifications to diagnostic methods for early and late GDM, and opinions on GDM management, with the pandemic divided into seven periods. RESULTS: We received responses from 593 facilities (27%). Approximately 90% of the facilities did not change their diagnostic process for early GDM or late GDM (occurring after 24 weeks gestation). However, during the COVID-19 pandemic, 19 facilities discontinued the use of 75-g oral glucose tolerance tests before 24 weeks of gestation, and 17 facilities discontinued it after 24 weeks of gestation, instead using the aforementioned Japanese GDM diagnostic strategy. CONCLUSIONS: Although a limited number of facilities modified their diagnostic method in response to the COVID-19 pandemic, this study demonstrated that those that adjusted their diagnostic method primarily used the Japanese COVID-19 GDM strategy by the JSDP.

Effects of Levothyroxine Treatment on Fertility and Pregnancy Outcomes in Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Subclinical hypothyroidism, defined by elevated thyrotropin (TSH) and normal free thyroxine levels, is associated with adverse pregnancy outcomes, including preterm birth, pre-eclampsia, and small for gestational age. Despite the uncertainty regarding the effectiveness of levothyroxine (LT4) treatment on pregnancy outcomes in subclinical hypothyroidism, LT4 is widely administered with a pre-treatment threshold TSH level of 2.5 mU/L. The aim of this study is to investigate the efficacy of periconceptional LT4 treatment for subclinical hypothyroidism, including TSH levels >2.5 mU/L, and identify the characteristics of subclinical hypothyroidism that can benefit from LT4 treatment. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials from inception to February 2023. We analyzed the pooled effects of LT4 on subclinical hypothyroidism before and during pregnancy. The main outcomes before pregnancy were live birth, pregnancy, and miscarriage. The main outcomes during pregnancy were live birth, miscarriage, and preterm birth. We conducted subgroup analyses to compare the effects of LT4 on subclinical hypothyroidism with TSH levels of 2.5-4.0 and >4.0 mU/L. Results: Of the 888 studies identified, 27 full-text articles were screened for eligibility. Five studies on pre-conception treatment with 768 participants and eight studies on treatment during early pregnancy with 2622 participants were analyzed. One of the two studies on pre-conception treatment in subclinical hypothyroidism with TSH >4.0 mU/L had high risk of bias and the other was composed of 64 participants. Pre-conception LT4 treatment had no significant effect in improving rates of live births and pregnancies, or reducing miscarriages (risk ratio [RR], 95% confidence interval): 1.41 (0.84-2.36), 1.73 (0.88-3.39), and 0.46 (0.11-2.00), respectively. LT4 treatment during pregnancy was not significantly associated with higher rates of live births (RR 1.03, 0.98-1.09) nor decreased miscarriage rates (RR 1.01, 0.66-1.53). The effect of LT4 treatment on preterm birth during pregnancy was significantly different depending on the TSH values (p = 0.04); a positive effect was shown in the subclinical hypothyroidism subgroup with TSH >4.0 mU/L (RR 0.47, 0.20-1.10), while no significant effect was observed in the subgroup with TSH 2.5-4.0 mU/L (RR 1.35, 0.79-2.31). Conclusions: Pre-conceptional LT4 treatment for subclinical hypothyroidism does not improve fertility or decrease the incidence of miscarriages. However, further well-designed studies are needed for pre-conceptional treatment, especially in TSH >4.0 mU/L. LT4 treatment during pregnancy had a positive effect on preterm birth; nevertheless, this was only applicable to subclinical hypothyroidism with TSH >4.0 mU/L.

Maternal birth weight as an indicator of early and late gestational diabetes mellitus: The Japan Environment and Children's Study.

AIMS: This study aimed to investigate the association of maternal birth weight (MBW) with early and late gestational diabetes mellitus (GDM). METHODS: A total of 69318 pregnant Japanese women were included in this birth cohort study. The associations between maternal birth weight and early gestational diabetes mellitus (diagnosed at <24 gestational weeks) and late GDM (diagnosed at ≥24 gestational weeks) were investigated using a multinomial logistic regression model, with an maternal birth weight of 3000-3499 g as the reference category. RESULTS: Lower maternal birth weight was associated with higher odds of developing early and late gestational diabetes mellitus (P < 0.0001 and P < 0.0001, respectively). The adjusted odds ratios (aORs) for early gestational diabetes mellitus in participants with a MBW of <2500 g and 2500-2999 g were 1.345 (95% confidence interval [CI]: 0.912-1.984) and 1.338 (95% CI: 1.098-1.629), respectively. The aORs for late gestational diabetes mellitus in participants with a MBW of <2500 g and 2500-2999 g were, 1.657 (95% CI: 1.298-2.115) and 1.218 (95% CI: 1.058-1.402), respectively. CONCLUSIONS: Regardless of the gestational age when gestational diabetes mellitus was diagnosed, a lower maternal birth weight was associated with an increased risk of gestational diabetes mellitus. Furthermore, the association of a MBW <2500 g with late gestational diabetes mellitus tended to be stronger than that with early gestational diabetes mellitus.

Interaction effect between low birthweight and resistin gene rs1862513 variant on insulin resistance and type 2 diabetes mellitus in adulthood: Toon Genome Study.

AIMS/INTRODUCTION: Gene-environment interactions are considered to critically influence type 2 diabetes mellitus development; however, the underlying mechanisms and specific interactions remain unclear. Given the increasing prevalence of low birthweight (LBW) influenced by the intrauterine environment, we sought to investigate genetic factors related to type 2 diabetes development in individuals with LBW. MATERIALS AND METHODS: The interaction between 20 reported type 2 diabetes susceptibility genes and the development of type 2 diabetes in LBW (<2,500 g) individuals in a population-based Japanese cohort (n = 1,021) was examined by logistic regression and stratified analyses. RESULTS: Logistic regression analyses showed that only the G/G genotype at the rs1862513 locus of the resistin gene (RETN), an established initiator of insulin resistance, was closely related to the prevalence of type 2 diabetes in individuals with LBW. Age, sex and current body mass index-adjusted stratified analyses showed a significant interaction effect of LBW and the RETN G/G genotype on fasting insulin, homeostatic model assessment 2-insulin resistance, Matsuda index and the prevalence of type 2 diabetes (all P-values for interaction <0.05). The adjusted odds ratio for type 2 diabetes in the LBW + G/G genotype group was 7.33 (95% confidence interval 2.43-22.11; P = 0.002) compared with the non-LBW + non-G/G genotype group. Similar results were obtained after excluding the influence of malnutrition due to World War II. CONCLUSIONS: Simultaneous assessment of LBW and the RETN G/G genotype can more accurately predict the risk of future type 2 diabetes than assessing each of these factors alone, and provide management strategies, including early lifestyle intervention in LBW population.

Triceps surae muscle hypertrophy is greater after standing versus seated calf-raise training.

Background: The triceps surae muscle plays important roles in fundamental human movements. However, this muscle is relatively unresponsive to resistance training (difficult to hypertrophy) but prone to atrophy with inactivity compared with other muscles. Thus, identifying an effective training modality for the triceps surae is warranted. This study compared triceps surae muscle hypertrophy after standing/knee-extended versus seated/knee-flexed plantarflexion (calf-raise) training, where the gastrocnemius is lengthened and shortened, respectively. Methods: Fourteen untrained adults conducted calf-raise training with one leg in a standing/knee-extended position and the other leg in a seated/knee 90°-flexed position at 70% of one-repetition maximum. Each leg performed 10 repetitions/set, 5 sets/session, 2 sessions/week for 12 weeks. Before and after the intervention, magnetic resonance imaging scans were obtained to assess muscle volume of each and the whole triceps surae. Results: Muscle volume significantly increased in all three muscles and the whole triceps surae for both legs (p ≤ 0.031), except for the gastrocnemius muscles of the seated condition leg (p = 0.147-0.508). The changes in muscle volume were significantly greater for the standing than seated condition leg in the lateral gastrocnemius (12.4% vs. 1.7%), medial gastrocnemius (9.2% vs. 0.6%), and whole triceps surae (5.6% vs. 2.1%) (p ≤ 0.011), but similar between legs in the soleus (2.1% vs. 2.9%, p = 0.410). Conclusion: Standing calf-raise was by far more effective, therefore recommended, than seated calf-raise for inducing muscle hypertrophy of the gastrocnemius and consequently the whole triceps surae. This result and similar between-condition hypertrophy in the soleus collectively suggest that training at long muscle lengths promotes muscle hypertrophy.

A classification of the plantar intrinsic foot muscles based on the physiological cross-sectional area and muscle fiber length in healthy young adult males.

BACKGROUND: Plantar intrinsic foot muscles (PIFMs) are composed of 10 muscles and play an essential role in achieving functional diversity in the foot. Previous studies have identified that the morphological profiles of PIFMs vary between individuals. The morphological profiles of a muscle theoretically reflect its output potentials: the physiological cross-sectional area (PCSA) of a muscle is proportional to its maximum force generation, and the muscle fiber length (FL) is its shortening velocity. This implies that the PCSA and FL may be useful variables for characterizing the functional diversity of the individual PIFM. The purpose of this study was to examine how individual PIFMs can be classified based on their PCSA and FL. METHODS: In 26 healthy young adult males, the muscle volume and muscle length of seven PIFMs (abductor hallucis, ABDH; abductor digiti minimi, ABDM; adductor hallucis oblique head, ADDH-OH; ADDH transverse head, ADDH-TH; flexor digitorum brevis, FDB; flexor hallucis brevis, FHB; quadratus plantae, QP) were measured using magnetic resonance imaging. The PCSA and FL of each of the seven PIFMs were then estimated by combining the data measured from the participants and those of muscle architectural parameters documented from cadavers in previous studies. A total of 182 data samples (26 participants × 7 muscles) were classified into clusters using k-means cluster analysis. The optimal number of clusters was evaluated using the elbow method. RESULTS: The data samples of PIFMs were assigned to four clusters with different morphological profiles: ADDH-OH and FHB, characterised by large PCSA and short FL (high force generation and slow shortening velocity potentials); ABDM and FDB, moderate PCSA and moderate FL (moderate force generation and moderate shortening velocity potentials); QP, moderate PCSA and long FL (moderate force generation and rapid shortening velocity potentials); ADDH-TH, small PCSA and moderate FL (low force generation and moderate shortening velocity potentials). ABDH components were assigned equivalently to the first and second clusters. CONCLUSIONS: The approach adopted in this study may provide a novel perspective for interpreting the PIFMs' function based on their maximal force generation and shortening velocity potentials.

Single-cell transcriptomic architecture and cellular communication circuits of parametrial adipose tissue in pregnant mice.

AIMS: The activity and interactions of cellular subpopulations in the adipose tissue microenvironment are critical for the coordination of local and systemic adaptation during pregnancy. With a particular interest in parametrial adipose tissue (PmAT), single-cell RNA-sequencing (scRNA-seq) was utilized to unveil the gestative cellular composition and functional shift. MATERIALS AND METHODS: To identify cell-type-enriched transcriptome profiles, a total of 18,074 cells in adipose tissue were studied. The cell populations were cataloged, and signaling crosstalk between adipocytes and other composition factions via soluble and membrane-bound factors were evaluated. KEY FINDINGS: A marked decline of pregnancy adipocytes and relative elevation of non-adipocyte fractions were observed. A subpopulation of adipocytes, Adipo_5, with unique properties in the response to estrogen and the embryonic processes involved in pregnancy, was defined. Interactome analysis revealed the potential contribution of PmAT to the establishment of maternal-fetal immune tolerance. During gestation, adipocytes shut down outgoing signaling, resulting in deterioration of the resistin-related incoming signaling network in B cells, which would therefore benefit tissue-specific maternal-fetal tolerance. Furthermore, a subpopulation of adipocytes, Aipo_2, was also considered to take part in a paradigm shift in the process of pregnancy-induced chemical stiffness-triggered vesicular remodeling via the THBS signaling pathway network. SIGNIFICANCE: These data-derived findings will encourage investigation into the role of pregnant PmTA in pregnancy-related immunological, hypertensive and metabolic disorders, with the ultimate goal of establishing preventive strategies to mitigate these pregnancy-related health challenges. This translational aspect of our work holds significant promise for improving maternal and fetal well-being.

Development of two mouse strains conditionally expressing bright luciferases with distinct emission spectra as new tools for in vivo imaging.

In vivo bioluminescence imaging (BLI) has been an invaluable noninvasive method to visualize molecular and cellular behaviors in laboratory animals. Bioluminescent reporter mice harboring luciferases for general use have been limited to a classical luciferase, Luc2, from Photinus pyralis, and have been extremely powerful for various in vivo studies. However, applicability of reporter mice for in vivo BLI could be further accelerated by increasing light intensity through the use of other luciferases and/or by improving the biodistribution of their substrates in the animal body. Here we created two Cre-dependent reporter mice incorporating luciferases oFluc derived from Pyrocoeli matsumurai and Akaluc, both of which had been reported previously to be brighter than Luc2 when using appropriate substrates; we then tested their bioluminescence in neural tissues and other organs in living mice. When expressed throughout the body, both luciferases emitted an intense yellow (oFluc) or far-red (Akaluc) light easily visible to the naked eye. oFluc and Akaluc were similarly bright in the pancreas for in vivo BLI; however, Akaluc was superior to oFluc for brain imaging, because its substrate, AkaLumine-HCl, was distributed to the brain more efficiently than the oFluc substrate, D-luciferin. We also demonstrated that the lights produced by oFluc and Akaluc were sufficiently spectrally distinct from each other for dual-color imaging in a single living mouse. Taken together, these novel bioluminescent reporter mice are an ideal source of cells with bright bioluminescence and may facilitate in vivo BLI of various tissues/organs for preclinical and biomedical research in combination with a wide variety of Cre-driver mice.

The Influence of Nicotine on Trophoblast-Derived Exosomes in a Mouse Model of Pathogenic Preeclampsia.

Preeclampsia (PE) is a serious complication of pregnancy with a pathogenesis that is not fully understood, though it involves the impaired invasion of extravillous trophoblasts (EVTs) into the decidual layer during implantation. Because the risk of PE is actually decreased by cigarette smoking, we considered the possibility that nicotine, a critical component of tobacco smoke, might protect against PE by modifying the content of exosomes from EVTs. We investigated the effects of nicotine on our PE model mouse and evaluated blood pressure. Next, exosomes were extracted from nicotine-treated extravillous trophoblasts (HTR-8/SVneo), and the peptide samples were evaluated by DIA (Data Independent Acquisition) proteomic analysis following nano LC-MS/MS. Hub proteins were identified using bioinformatic analysis. We found that nicotine significantly reduced blood pressure in a PE mouse model. Furthermore, we identified many proteins whose abundance in exosomes was modified by nicotine treatment of EVTs, and we used bioinformatic annotation and network analysis to select five key hub proteins with potential roles in the pathogenesis or prevention of PE. EVT-derived exosomes might influence the pathogenesis of PE because the cargo delivered by exosomes can signal to and modify the receiving cells and their environment.

The Factors Influencing Pregnant Women's Selection of Media Sources to Obtain Information on COVID-19 in Japan in 2021.

Pregnant women presumably gather information about the coronavirus disease 2019 (COVID-19) from various sources. However, it is difficult for pregnant women who are not medical professionals to source the appropriate information because of the infodemic related to the COVID-19 pandemic. Therefore, the objective of our study was to investigate how pregnant women gathered information about COVID-19 and COVID-19 vaccination. To address this issue, we conducted an online questionnaire survey between 5 October and 22 November 2021, which was approved by the Ethics Committee of Nihon University School of Medicine. We received 4962 responses after excluding 1179 insufficient answers. Our study found that age, occupation, and infection-risk anxiety influenced the selection of media for obtaining information. Pregnant women who were older, medical professionals, public servants, or educators tended to rely on specialized medical websites, whereas housewives tended to use mass media, social media, and sources with uncertain scientific evidence. Additionally, the number of weeks of gestation and the method of conception (natural or assisted reproductive conception) affected the selection of media. The accessibility of COVID-19 information for pregnant women was determined by their social background and pregnancy status. We need to continue making efforts to ensure that appropriate information is readily available to pregnant women and their families.

Measures for pregnant women with coronavirus disease 2019 at the National University Hospital: 34th National University Perinatal Medical Center Conference.

As 2 years have passed since the outbreak of coronavirus disease 2019 (COVID-19), we had an examination of the measures taken at the perinatal medical and child centers during this period at 42 National University Hospital. The first questionnaire survey was conducted during March 17-25, 2022 and the second questionnaire survey was conducted during April 4-30, 2022. For the treatment of pregnant women with COVID-19, a public health center-coordinated triage system had been created and implemented in each region and prefecture. The issues related to the hospital management of pregnant women with COVID-19 include the hindrances to the normal functioning of the center, the limited number of hospital beds and medical care systems as the beds were dedicated to patients with COVID-19, and the problems associated with the mode of delivery. There were no set rules regarding the management of mothers and babies at delivery and thereafter. Initially, cesarean delivery was allowed in almost all cases to reduce the risk of exposure to medical staff. Furthermore, many institutions did not permit expressed breast milk feeding and direct breastfeeding during the quarantine period. The COVID-19 pandemic has been created a shortage of healthcare delivery systems. It is expected that the emergence of new infectious diseases and pandemics will cause the same pressure on systems providing healthcare in the future.

LIM1 contributes to the malignant potential of endometrial cancer.

Introduction: The incidence of endometrial cancer (EC) has been increasing worldwide. However, because there are limited chemotherapeutic options for the treatment of EC, the prognosis of advanced-stage EC is poor. Methods: Gene expression profile datasets for EC cases registered in The Cancer Genome Atlas (TCGA) was reanalyzed. Highly expressed genes in advanced-stage EC (110 cases) compared with early-stage EC (255 cases) were extracted and Gene Ontology (GO) enrichment analysis was performed. Among the enriched genes, Kaplan-Meier (KM) plotter analysis was performed. Candidate genes expression was analyzed in HEC50B cells and Ishikawa cells by RT-qPCR. In HEC50B cells, LIM homeobox1 (LIM1) was knocked down (KD) and cell proliferation, migration, and invasion ability of the cells were evaluated. Xenografts were generated using LIM1-KD cells and tumor growth was evaluated. Ingenuity Pathway Analysis (IPA) of RNA-seq data using LIM-KD cells was performed. Expression of phospho-CREB and CREB-related proteins were evaluated in LIM1-KD cells by western blotting and in xenograft tissue by immunofluorescent staining. Two different CREB inhibitors were treated in HEC50B and cell proliferation was evaluated by MTT assay. Results: Reanalysis of TCGA followed by GO enrichment analysis revealed that homeobox genes were highly expressed in advanced-stage EC. Among the identified genes, KM plotter analysis showed that high LIM1 expression was associated with a significantly poorer prognosis in EC. Additionally, LIM1 expression was significantly higher in high-grade EC cell lines, HEC50B cells than Ishikawa cells. Knockdown of LIM1 showed reduced cell proliferation, migration and invasion in HEC50B cells. Xenograft experiments revealed that tumor growth was significantly suppressed in LIM1-KD cells. IPA of RNA-seq data using LIM-KD cells predicted that the mRNA expression of CREB signaling-related genes was suppressed. Indeed, phosphorylation of CREB was decreased in LIM1-KD cells and LIM1-KD cells derived tumors. HEC50B cells treated by CREB inhibitors showed suppression of cell proliferation. Conclusion and discussion: Collectively, these results suggested that high LIM1 expression contributed to tumor growth via CREB signaling in EC. Inhibition of LIM1 or its downstream molecules would be new therapeutic strategies for EC.

Risk of fetal undergrowth in the management of gestational diabetes mellitus in Japan.

AIMS/INTRODUCTION: In Japan, the increasing frequency of underweight among women of reproductive age and the accompanying increase in the rate of low birth weight (LBW) are social issues. The study aimed to establish a prospective registry system for gestational diabetes mellitus (GDM) in Japan and to clarify the actual status of GDM according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. MATERIALS AND METHODS: Pregnant women with gestational diabetes mellitus and those in the normal glucose tolerance (NGT) group were enrolled in the Diabetes and Pregnancy Outcome for Mother and Baby study from October 2015. Pregnant women with positive glucose screening in early and mid-to-late pregnancy underwent a 75 g oral glucose tolerance test by gestational week 32. Gestational diabetes mellitus was diagnosed according to IADPSG criteria. Women with a positive glucose screening test at mid-to-late pregnancy but NGT were enrolled as references (NGT group). Treatment for gestational diabetes mellitus and maternal and neonatal pregnancy data were prospectively collected on outcomes. RESULTS: In total 1,795 singleton pregnancies (878 women with GDM and 824 NGT women) were analyzed. The risk of LBW and small-for-gestational age in the GDM group was significantly higher than in the NGT group. A similar relationship was found for LBW risk in the non-overweight/obese group but not in the overweight/obese group. CONCLUSIONS: We established a prospective GDM registry system in Japan. In the management of GDM in Japan, suppression of maternal weight gain may be associated with reduced fetal growth, especially in non-overweight/obese women with GDM; however, further investigation is required.

Network-driven intracellular cAMP coordinates circadian rhythm in the suprachiasmatic nucleus.

The mammalian central circadian clock, located in the suprachiasmatic nucleus (SCN), coordinates the timing of physiology and behavior to local time cues. In the SCN, second messengers, such as cAMP and Ca2+, are suggested to be involved in the input and/or output of the molecular circadian clock. However, the functional roles of second messengers and their dynamics in the SCN remain largely unclear. In the present study, we visualized the spatiotemporal patterns of circadian rhythms of second messengers and neurotransmitter release in the SCN. Here, we show that neuronal activity regulates the rhythmic release of vasoactive intestinal peptides from the SCN, which drives the circadian rhythms of intracellular cAMP in the SCN. Furthermore, optical manipulation of intracellular cAMP levels in the SCN shifts molecular and behavioral circadian rhythms. Together, our study demonstrates that intracellular cAMP is a key molecule in the organization of the SCN circadian neuronal network.

Triceps brachii hypertrophy is substantially greater after elbow extension training performed in the overhead versus neutral arm position.

The biarticular triceps brachii long head (TBLong) is lengthened more in the overhead than neutral arm position. We compared triceps brachii hypertrophy after elbow extension training performed in the overhead vs. neutral arm position. Using a cable machine, 21 adults conducted elbow extensions (90-0°) with one arm in the overhead (Overhead-Arm) and the other arm in the neutral (Neutral-Arm) position at 70% one-repetition maximum (1RM), 10 reps/set, 5 sets/session, 2 sessions/week for 12 weeks. Training load was gradually increased (+5% 1RM/session) when the preceding session was completed without repetition failure. 1RM of the assigned condition and MRI-measured muscle volume of the TBLong, monoarticular lateral and medial heads (TBLat+Med), and whole triceps brachii (Whole-TB) were assessed pre- and post-training. Training load and 1RM increased in both arms similarly (+62-71% at post, P = 0.285), while their absolute values/weights were always lower in Overhead-Arm (-34-39%, P < 0.001). Changes in muscle volume in Overhead-Arm compared to Neutral-Arm were 1.5-fold greater for the TBLong (+28.5% vs. +19.6%, Cohen's d = 0.61, P < 0.001), 1.4-fold greater for the TBLat+Med (+14.6% vs. +10.5%, d = 0.39, P = 0.002), and 1.4-fold greater for the Whole-TB (+19.9% vs. +13.9%, d = 0.54, P < 0.001). In conclusion, triceps brachii hypertrophy was substantially greater after elbow extension training performed in the overhead versus neutral arm position, even with lower absolute loads used during the training.HighlightsGrowing evidence suggests that resistance training at long muscle lengths promotes muscle hypertrophy, but its practical applications are yet to be explored.Triceps brachii muscle hypertrophy was substantially greater after cable elbow extension training performed in the overhead than neutral arm position, particularly in the biarticular triceps brachii long head, even with lower absolute loads lifted (i.e. lower mechanical stress to muscles/joints).Cable elbow extension training should be performed in the overhead rather than neutral arm position if one aims to maximise muscle hypertrophy of the triceps brachii or to prevent atrophy of this muscle.