Application Site of Transdermal Scopolamine Influences Efficacy and Drug Concentration in Salivary Glands in Rats.

Transdermal scopolamine applied to the postauricular area is used to treat drooling. We investigated the duration of action of scopolamine ointment and the effect of the application site on drug efficacy and concentration in the salivary glands of rats. Scopolamine ointment was applied to the skin over the salivary glands (SSG) and back (SB). Saliva volume was measured after intraperitoneal administration of pilocarpine. Blood and salivary glands were collected after scopolamine ointment application, and scopolamine concentrations in the plasma and salivary glands were measured. Saliva volume after application in the SSG group was significantly lower at all time points than in the non-treated group, and the change in saliva volume in the SSG group was greater than that in the SB group at all time points. This suggests that applying scopolamine ointment to the SSG strongly suppresses salivary secretion. Scopolamine concentration in the salivary glands of the SSG group was significantly higher at 9 h. The change in the efficacy of scopolamine ointment depending on the application site was due to the difference in transfer to the salivary glands. Transdermal administration of scopolamine to the skin over the salivary glands may have high efficiency in treating drooling.

Establishment of the early prediction models of low-birth-weight reveals influential genetic and environmental factors: a prospective cohort study.

BACKGROUND: Low birth weight (LBW) is a leading cause of neonatal morbidity and mortality, and increases various disease risks across life stages. Prediction models of LBW have been developed before, but have limitations including small sample sizes, absence of genetic factors and no stratification of neonate into preterm and term birth groups. In this study, we challenged the development of early prediction models of LBW based on environmental and genetic factors in preterm and term birth groups, and clarified influential variables for LBW prediction. METHODS: We selected 22,711 neonates, their 21,581 mothers and 8,593 fathers from the Tohoku Medical Megabank Project Birth and Three-Generation cohort study. To establish early prediction models of LBW for preterm birth and term birth groups, we trained AI-based models using genetic and environmental factors of lifestyles. We then clarified influential environmental and genetic factors for predicting LBW in the term and preterm groups. RESULTS: We identified 2,327 (10.22%) LBW neonates consisting of 1,077 preterm births and 1,248 term births. Our early prediction models archived the area under curve 0.96 and 0.95 for term LBW and preterm LBW models, respectively. We revealed that environmental factors regarding eating habits and genetic features related to fetal growth were influential for predicting LBW in the term LBW model. On the other hand, we identified that genomic features related to toll-like receptor regulations and infection reactions are influential genetic factors for prediction in the preterm LBW model. CONCLUSIONS: We developed precise early prediction models of LBW based on lifestyle factors in the term birth group and genetic factors in the preterm birth group. Because of its accuracy and generalisability, our prediction model could contribute to risk assessment of LBW in the early stage of pregnancy and control LBW risk in the term birth group. Our prediction model could also contribute to precise prediction of LBW based on genetic factors in the preterm birth group. We then identified parental genetic and maternal environmental factors during pregnancy influencing LBW prediction, which are major targets for understanding the LBW to address serious burdens on newborns' health throughout life.

Maternal Baseline Characteristics and Perinatal Outcomes: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

BACKGROUND: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. METHODS: Expectant mothers living in Miyagi Prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. RESULTS: A total of 23,406 pregnancies involving 23,730 fetuses resulted in 23,143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes, and hypertensive disorders of pregnancy. CONCLUSIONS: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.

Influence of climatic conditions in the mesothermal climate area on pregnancies following elective fresh single blastocyst transfer.

PURPOSE: To investigate the effect of climatic parameters in the mesothermal climate area on clinical pregnancy and live birth following fresh single blastocyst transfer. METHODS: This study investigated clinical pregnancies and live births that resulted from 555 ovarian stimulation cycles followed by fresh single blastocyst transfer. The samples were stratified according to climatic conditions (low T, temperature < 12.9 °C; middle T, 12.9 °C ≤ temperature < 22.6 °C; high T, temperature ≥ 22.6 °C; low H, relative humidity < 62.1%; middle H, 62.1% ≤ relative humidity < 66.5%; high H, relative humidity ≥ 66.5%; short S, sunlight duration < 5.2 h; middle S, 5.2 h ≤ sunlight duration < 6.7 h; long S, sunlight duration ≥ 6.7 h). Clinical pregnancy and live birth rates among three groups from each climatic parameter were compared. Multivariable analyses were performed to investigate the effects of climatic conditions on blastocyst development, endometrial thickness, clinical pregnancy, and live birth. RESULTS: A statistically significant difference was found in pregnancy rates among low T (48.8%), middle T (37.3%), and high T (36.6%) groups. Multivariable analyses revealed that temperature was associated with clinical pregnancy and live birth rates with adjustment for patient age, BMI, type of ovarian stimulation, endometrial thickness, and expansion grade of the transferred blastocyst. The association between climatic parameters and blastocyst development and endometrial thickness was not confirmed. CONCLUSIONS: This study suggests that lower temperatures in the mesothermal climate area could favorably affect the rates of clinical pregnancy and live birth achieved by fresh single blastocyst transfer.

Analysis of clinical outcomes and meiotic segregation modes following preimplantation genetic testing for structural rearrangements using aCGH/NGS in couples with balanced chromosome rearrangement.

Purpose: To retrospectively evaluate the effectiveness of PGT-SR by array comparative genomic hybridization (aCGH) or next-generation sequencing (NGS) in preventing recurrent miscarriages. Methods: Thirty one couples with balanced translocation who underwent 68 PGT-SR cycles between 2012 and 2020 were evaluated. A total of 242 blastocysts were biopsied for aCGH or NGS. The genetically transferable blastocysts were transferred in the subsequent frozen-thawed single embryo transfer cycle. Results: The genetically transferable blastocyst rate was 21.2% (51/241). Thirty five genetically transferable blastocysts were transferred into the uterine cavity. The clinical pregnancy rate was 57.1% (20/35), and the ongoing pregnancy rate was 100.0% (20/20). The incidence of interchromosomal effect (ICE) was influenced by ovarian stimulation protocol, female age, and carrier's gender, but dependent on the types of balanced translocation carriers. Furthermore, there was no significant difference in meiotic segregation modes in ovarian stimulation protocols and carrier's gender. Interestingly, the incidence of adjacent-1 segregation in ≧40 years group increased significantly compared with <35 years group. Conclusions: For the first time in Japan, we show the effectiveness of PGT-SR using aCGH or NGS, which enables comprehensive analysis of chromosomes, in the prevention of recurrent miscarriages. Furthermore, our results may support better genetic counseling of balanced translocation carriers for PGT-SR cycles.

Effect of X-ray exposure during hysterosalpingography on capabilities of female germ cells.

PURPOSE: To elucidate the effect of X-ray exposure during hysterosalpingography (HSG) on subsequent laboratory outcomes in in vitro fertilization (IVF). METHODS: A total of 1458 oocytes, consisting of 990 oocytes retrieved from 70 women (89 cycles) who underwent HSG prior to IVF and 468 oocytes from 45 women (57 cycles) who underwent IVF without HSG, were evaluated for their retrieval number, maturity, fertilization, and development post fertilization. X-ray exposure during HSG was recorded as reference air kerma (RAK) (mGy). Subjects were stratified according to the amount of RAK (Nil: IVF without HSG, L-RAK: RAK < 16.23, mH-RAK: RAK ≥ 16.23). The number of oocytes retrieved, oocyte maturation, fertilization, and embryo development was compared among 3 groups. Further, multivariate analyses were performed to investigate the effect of X-ray exposure on laboratory outcomes in IVF. RESULTS: There was a statistically significant difference in the fertilization rate among 3 groups (Nil: 71.6%, L-RAK: 80.5%, mH-RAK: 78.3%). The good-quality blastocyst rate in mH-RAK (46.2%) was significantly higher than L-RAK (35.3%) and Nil (32.4%). Multivariate analyses revealed that X-ray exposure was associated with higher fertilization, higher blastocyst development, and higher good-quality blastocyst development rates with adjustment for patient age, BMI, ovarian stimulation types, and fertilization methods. Association between X-ray exposure and the number of oocytes retrieved, and oocyte maturation was not confirmed. CONCLUSIONS: The present study suggests that X-ray exposure of the female reproductive organs during HSG could enhance the potential of oocytes rather than adversely.

A novel embryo quality scoring system to compare groups of embryos at different developmental stages.

PURPOSE: To construct a new embryonic quality scoring system to compare groups of embryos at different developmental stages. METHODS: Based on a hypothesis that the implantation potential of any embryo in an ovum pickup (OPU) cycle remains the same at any stage of development, be it day 2, 3, or 5, a new embryo quality scoring (EQS) system was designed. It was based on the analysis of the clinical results of 1610 single embryo transfers. We validated this scoring system in the comparison of embryonic quality between groups by evaluating the mean scores calculated at day 2, day 3, and day 5 for 957 embryos (150 cycles) from 3 different groups. We then compared EQSs of patients with pregnancy favorable factors (group A) such as young age and high AMH levels, with the patients with contra features (group B). RESULTS: We confirmed that each mean EQS assessed at different stages of embryonic development within the same group was similar. The mean EQSs on day 3 and day 5 in group A were significantly higher than the mean EQSs on days 2, 3, and 5 in group B. CONCLUSION: The novel EQS system proposed by us enables embryonic quality comparison between groups of embryos at different developmental stages.

The risk of secondary sex ratio imbalance and increased monozygotic twinning after blastocyst transfer: data from the Japan Environment and Children's Study.

BACKGROUND: Some studies have suggested that blastocyst transfer is associated with i) imbalance in the secondary sex ratio (SSR) (which favors male offspring), ii) increased incidence of monozygotic twins (MZT). In contrast, others have not found these changes. In this study, we evaluated the association between blastocyst transfer and SSR and MZT, considering potential parental confounders. METHODS: The Japan Environment and Children's Study is a large, nationwide longitudinal birth cohort study funded by the Ministry of the Environment of Japan. We used this large dataset, including 103,099 pregnancies, to further investigate the association between blastocyst transfer, SSR and MZT, using spontaneously conceived pregnancies, non-assisted reproductive technology (non-ART) treatment (intrauterine insemination and ovulation induction with timed intercourse) and cleavage stage embryo transfer for comparison. We evaluated the association with each group, the SSR, and the frequency of MZT, calculating the adjusted odds ratio (AOR) using multivariable logistic regression analyses, adjusting for potential parental confounders such as basic health and socioeconomic status. RESULTS: For each group (spontaneous conception vs. non-ART treatment vs. cleavage stage embryo transfer vs. blastocyst transfer), the percentages of males were 51.3% vs 50.7% vs 48.9% vs 53.4% and the monozygotic twinning rates per pregnancy were 0.27% vs 0.11% vs 0.27% vs 0.99% respectively. Multivariate logistic regression analyses indicated that blastocyst transfer was significantly associated with a higher SSR and higher incidence of MZT than the other three groups (SSR: AOR 1.095, 95% CI1.001-1.198; MZT: AOR 4.229, 95% CI 2.614-6.684). CONCLUSIONS: There are significant relationships between blastocyst transfer and SSR imbalance and a higher occurrence of MZT.

The timing of cumulus cell removal for intracytoplasmic sperm injection influences the capability of embryonic development.

PURPOSE: To determine whether the presence of intact cumulus cells during the preincubation period for ICSI should be considered as a critical factor in fertilization and embryonic development. METHODS: The cohort of this prospective randomized study was limited to infertile women younger than 39 years of age who underwent controlled ovarian stimulation for ICSI between October 2013 and May 2015 and whose embryos were to be incubated until day 5. Women with estradiol levels of <2000 pmol/L on the day of HCG injection were excluded. Cumulus cells were removed immediately after OPU in Group A and at 120 minutes after OPU in Group B. ICSI was performed with all mature oocytes, and fertilized oocytes were cultured to the blastocyst stage. Maturation, fertilization, blastocyst, good quality blastocyst, pregnancy, live birth, and miscarriage rates were compared. RESULTS: There were no significant differences in maturation, fertilization, blastocyst, pregnancy, live birth, or miscarriage rates between Groups A and B. However, the percentage of good quality blastocysts was significantly higher in Group B than Group A (52.0% vs 33.1%). CONCLUSIONS: Intact cumulus cells should be maintained during the preincubation period, as they are important to embryonic development after fertilization.

Strategic Methods for Recruiting Grandparents: The Tohoku Medical Megabank Birth and Three-Generation Cohort Study.

Involvement of family members, especially grandparents, in genome epidemiological research is important to investigate both genetic and environmental factors of common diseases. The aim of the present study was to establish strategies to obtain enough number of family recruitment, especially focusing on grandparents, for the Tohoku Medical Megabank Birth and Three-Generation Cohort Study. Our main strategies are summarized below. 1) We standardized informed consent process with reference materials to help people understand the consent form, 2) we created an invitation letter to contact family members, and 3) we recruited family members in several settings. To obtain informed consent, we were careful of explaining clearly the complex reasons as well as drawing people's attention. By the end of March 2017, the number of invitation letters distributed to family members through the pregnant women was 23,806, including 18,702 grandparents. Among the grandparents who received invitation letters, 2,935 (15.7%) responded to us. Furthermore, some grandparents were asked to provide informed consent with other family members by staff at maternal clinics or Community Support Centers, and others directly booked Community Support Centers without responding to the invitation letter. Grandparents joined the study anytime during mother's maternal check-ups or delivery. Overall, 8,054 grandparents participated in our birth cohort study. The setting in which most grandparents were recruited was our own facilities. Importantly, both paternal and maternal grandparents more frequently participated in the study if the father also participated. In conclusion, we are able to recruit not only pregnant women but also fathers and grandparents.

Determinants of polyunsaturated fatty acid concentrations in erythrocytes of pregnant Japanese women from a birth cohort study: study protocol and baseline findings of an adjunct study of the Japan environment & Children's study.

BACKGROUND: N-3 polyunsaturated fatty acids (n-3 PUFA) may have multiple beneficial effects on the outcome of pregnancy, maternal health and child development. The present study introduced the protocol of a birth cohort study to examine the beneficial effects of n-3 PUFA status in pregnant Japanese women as an adjunct study of the Japan Environment and Children's Study (JECS). METHODS: The JECS participants in the coastal areas of Miyagi Prefecture were further invited to participate in this adjunct study, and 1,878 pregnant women were enrolled prior to delivery. Their n-3 PUFA status was evaluated with fatty acid profiles in erythrocytes of maternal blood collected from 1,623 mothers at 24-30 weeks of gestation and cord blood from 1,505 deliveries. RESULTS: The baseline results, including comprehensive data on the fatty acid status and determinants affecting the PUFA status, were analyzed. In stepwise multivariate analyses, the cord blood docosahexaenoic acid (DHA) level was found to be significantly influenced by the DHA level in maternal blood, the child's sex, and the gestational period. The maternal DHA level was influenced by fish intake, maternal age, and the prepregnancy body mass index. While cord blood eicosapentaenoic acid (EPA) was influenced by maternal EPA, fish intake, and season at birth, additional factors such as maternal education, household income, and smoking habits affected the maternal EPA content. CONCLUSION: Further studies are warranted to clarify the nutritional impacts of n-3 PUFA in pregnant Japanese women of the cohort study.

Fermented Food Consumption and Psychological Distress in Pregnant Women: A Nationwide Birth Cohort Study of the Japan Environment and Children's Study.

Health benefits of fermented foods are attracting attention worldwide, and they have been traditionally eaten in Japan. Moreover, a recent study showed the association between the higher intake of yogurt and lower prevalence of depressive symptoms during pregnancy. Psychological problems, such as anxiety and depression, during pregnancy are serious health concerns and may increase the risk of adverse outcomes in children. In this study, we explored the association between fermented food consumption and psychological distress in 10,129 pregnant Japanese women, using the fixed data of the Japan Environment and Children's Study (JECS), an ongoing nation-wide birth cohort study. Food consumption was assessed with a semi-quantitative food frequency questionnaire (FFQ), and the Kessler 6-item psychological distress scale (K6) was administered to eligible women during their second or third trimester to eliminate overlap with the period of hyperemesis gravidarum. The mean median gestation in the subjects was 24.8 weeks. In total, 9,030 subjects completed the K6 questionnaire and FFQ. Importantly, the prevalence of the K6 score of ≥ 13 was 3.1% (280 subjects). This value was lower compared to precedent studies, which may reflect that cooperative and health conscious subject participated in the survey. The multivariate logistic regression analysis indicates that the intake of yogurt, lactic acid beverages, cheese, Japanese pickles, miso soup, or fermented soybeans was not significantly associated with a K6 score of ≥ 13. In conclusion, the present cohort study shows no association between fermented food consumption and psychological distress symptoms during the second or third trimester of pregnancy.

Comparison of the effects of eldecalcitol with either raloxifene or bisphosphonate on serum tartrate resistant acid phosphatase-5b, a bone resorption marker, in postmenopausal osteoporosis.

OBJECTIVE: This study analyzes whether concomitant raloxifene (RLX) or bisphosphonates (BP) plus eldecalcitol (ELD) has excessive suppressive effects on a bone resorption marker during the first 6 months of treatment in postmenopausal women in real-world setting. METHODS: 285 postmenopausal osteoporotic patients who had been treated with RLX or BP plus ELD were evaluated the bone resorption marker, serum tartrate resistant acid phosphatase-5b (TRACP-5b), during the first 6 months of treatment. RESULTS: In drug-naïve group (not received osteoporosis medications before the administration, n=70), the concomitant RLX or BP with ELD significantly decreased levels of TRACP-5b without severe suppression. In vitamin D switch group [RLX or BP plus alfacalcidol (ALF) and then switched to RLX or BP plus ELD, n=215], the replacing ALF with ELD further and significantly decreased TRACP-5b and tertile analyses based on baseline values were significantly decreased far more in the highest, compared with the lowest tertile in the ELD+RLX and ELD+BP groups. CONCLUSION: ELD combined with RLX or BP administered for 6 months to postmenopausal women with osteoporosis who were drug-naïve or who had switched medications significantly reduced and maintained TRACP-5b values within the reference range.

Werner syndrome with refractory cystoid macular edema and immunohistochemical analysis of WRN proteins in human retinas.

BACKGROUND: To present our findings in a case of Werner syndrome with refractory cystoid macular edema (CME) and to determine the expression and the distribution of WRN proteins in human retinas. CASE PRESENTATION: A 35-year-old man with Werner syndrome who developed CME after YAG laser treatment was studied. Optical coherence tomographic (OCT) scans were used to examine the CME in the right eye. The patient received topical eye drops (0.1% bromfenac sodium hydrate twice daily and 1% dorzolamide hydrochloride thrice daily), sub-Tenon triamcinolone injection thrice, intravitreal bevacizumab injection twice, and pars plana vitrectomy of the right eye. Genetic analyses were performed to diagnose the disease. To examine the expression and distribution of WRN proteins in the retinas, immunohistochemistry for WRN proteins was performed in human retinas. The CME in the right eye was not improved by any of the treatments. During the follow-up period, CME developed in the left eye. Genetic analyses detected compound heterozygosity, Mut4 and Mut11, in the WRN gene and the individual was diagnosed with Werner syndrome. Immunohistochemical analysis of WRN proteins expression in human retinas showed that WRN proteins were expressed in the parts of the Müller cells in the inner nuclear layer and outer nuclear layer. CONCLUSION: Patients with Werner syndrome can develop severe CME after laser treatment. A pathological link may exist between mutations in the WRN gene and the development of CME in patients with Werner syndrome.

Development of phenotyping algorithms for hypertensive disorders of pregnancy (HDP) and their application in more than 22,000 pregnant women.

Recently, many phenotyping algorithms for high-throughput cohort identification have been developed. Prospective genome cohort studies are critical resources for precision medicine, but there are many hurdles in the precise cohort identification. Consequently, it is important to develop phenotyping algorithms for cohort data collection. Hypertensive disorders of pregnancy (HDP) is a leading cause of maternal morbidity and mortality. In this study, we developed, applied, and validated rule-based phenotyping algorithms of HDP. Two phenotyping algorithms, algorithms 1 and 2, were developed according to American and Japanese guidelines, and applied into 22,452 pregnant women in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank project. To precise cohort identification, we analyzed both structured data (e.g., laboratory and physiological tests) and unstructured clinical notes. The identified subtypes of HDP were validated against reference standards. Algorithms 1 and 2 identified 7.93% and 8.08% of the subjects as having HDP, respectively, along with their HDP subtypes. Our algorithms were high performing with high positive predictive values (0.96 and 0.90 for algorithms 1 and 2, respectively). Overcoming the hurdle of precise cohort identification from large-scale cohort data collection, we achieved both developed and implemented phenotyping algorithms, and precisely identified HDP patients and their subtypes from large-scale cohort data collection.

Investigation of the effect and availability of ketamine on electroencephalography in cats with temporal lobe epilepsy.

In recent years, electroencephalography (EEG) in veterinary medicine has become important not only in the diagnosis of epilepsy, but also in determining the epileptogenic focus. In cats, sedation and immobilization, usually with medetomidine or dexmedetomidine, are necessary to place the electrodes and to obtain stable scalp EEG recordings. In this study, we hypothesized that, for cats with temporal lobe epilepsy (TLE), ketamine, a sedative/anesthetic and N-methyl-D-aspartate (NMDA) antagonist that activates the limbic system and is also used to treat refractory status epilepticus in dogs, would induce sufficient sedation and immobilization for EEG, as well as induce interictal epileptiform discharges (IEDs) that are more pronounced than those induced with medetomidine. We obtained EEG recordings from TLE cats and healthy cats administered either ketamine or medetomidine alone (study 1) or ketamine after medetomidine sedation (study 2). In study 1, the frequency of IEDs showed no statistically significant difference between ketamine and medetomidine in both TLE and healthy cats. Seizures were observed in 75% (9/12) cats of the TLE group with ketamine alone. When ketamine was administered after sedation with medetomidine (study 2), 3/18 cats in the TLE group developed generalized tonic-clonic seizure and 1/18 cats showed subclinical seizure activity. However, no seizures were observed in all healthy cats in both study 1 and study 2. Slow wave activity at 2-4 Hz was observed in many individuals after ketamine administration regardless studies and groups, and quantitative analysis in study 2 showed a trend toward increased delta band activities in both groups. While there was no significant difference in the count of IEDs between medetomidine and ketamine, ketamine caused seizures in cats with TLE similar to their habitual seizure type and with a higher seizure frequency. Our results suggest that ketamine may activate epileptiform discharges during EEG recordings. However, caution should be used for cats with TLE.

Effect of Nicotinamide Mononucleotide Concentration in Human Milk on Neurodevelopmental Outcome: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

(1) Background: Breast milk is the only source of nutrition for breastfed infants, but few studies have examined the relationship between breast milk micronutrients and infant neurodevelopmental outcome in exclusively breastfed infants. The aim of this study was to characterize the association between nicotinamide adenine dinucleotide (NAD)-related compounds in the breast milk of Japanese subjects and infant neurodevelopmental outcome. (2) Methods: A total of 150 mother-child pairs were randomly selected from the three-generation cohort of the Tohoku Medical Megabank in Japan. Infants were exclusively breastfed for up to 6 months. Breast milk was collected at 1 month postpartum, and the quantity of NAD-related substances in the breast milk was quantified. The mothers also completed developmental questionnaires at 6, 12, and 24 months. The relationship between the concentration of NAD-related substances in breast milk and developmental indicators was evaluated via ordinal logistic regression analysis. (3) Results: Nicotinamide mononucleotide (NMN) was quantified as the major NAD precursor in breast milk. The median amount of NMN in the breast milk was 9.2 µM. The NMN concentration in breast milk was the only NAD-related substance in breast milk that showed a significant positive correlation with neurodevelopmental outcome in infants at 24 months. (4) Conclusions: The results suggest that NMN in human milk may be an important nutrient for early childhood development.

Secondhand smoke exposure is associated with the risk of hypertensive disorders of pregnancy: the Japan Environment and Children's Study.

Hypertensive disorders of pregnancy (HDP) are associated with poor maternal and neonatal prognoses. Although several studies have indicated an effect of secondhand smoke (SHS) exposure on HDP, such evidence is lacking in Japan. Therefore, we analyzed data from the Japan Environment and Children's Study, a large-scale epidemiological investigation, to elucidate a possible link between SHS exposure and HDP risk. Data were obtained from the all-birth fixed datasets and included information on 104,062 fetuses and their parents. SHS exposure was assessed in terms of the frequency (rarely, 1-3, or 4-7 days/week) and the daily duration of exposure (<1, 1-2, or ≥2 h(s)/day). Modified Poisson regression model analyses were performed with adjustment for known risk factors for HDP. Additionally, the population attributable fractions (PAFs) of SHS exposure and maternal smoking to HDP prevalence were estimated. The relative risks of developing HDP among individuals with SHS exposures of 4-7 days/week and ≥2 h/day were 1.18 and 1.27 (95% confidence interval: 1.02-1.36 and 0.96-1.67), respectively, compared to the reference groups (rare exposure and <1 h/day). The PAFs for the risk of HDP due to SHS exposure and perinatal smoking were 3.8% and 1.8%, respectively. Japanese women with greater exposure to SHS have a higher risk of HDP after adjustment for possible confounding factors; thus, relevant measures are required to reduce SHS exposure to alleviate HDP risk. The association between second-hand smoking exposure and hypertensive disorders of pregnancy risk was analyzed using the JECS data. The relative risks in 4-7 days/week and ≥2 h/day of SHS exposures were 1.18 and 1.27, respectively. The PAFs due to SHS exposure and maternal smoking were 3.80% and 1.81%, respectively.

Involvement of cholesterol membrane transporter Niemann-Pick C1-like 1 in the intestinal absorption of lutein.

PURPOSE: Lutein is a carotenoid mainly found in green leafy vegetables and is located in the macula lutea in the human eye. Since humans cannot synthesize lutein de novo, it must be digested as food. The physiological importance of an orally administered compound depends on its interaction with target tissues. It is therefore important to clarify the absorption mechanism in the intestine. Cholesterol membrane transporters Niemann-Pick C1 Like 1 (NPC1L1) and scavenger receptor class B type 1 (SR-B1) are involved in the intestinal absorption of highly lipophilic compounds including cholesterol. Ezetimibe, a selective inhibitor of intestinal NPC1L1, is the widespread lipid-lowering agent. It is important to investigate the possibility of food-drug interactions in order to prevent undesirable and harmful clinical consequences. The aim of this work was to determine whether NPC1L1, SR-B1 and other transporters are involved in absorption of lutein. METHODS: Caco-2 cells were used for accumulation and permeability study of lutein. Lutein concentration was determined by an HPLC system. The cDNA of transporters was isolated from total RNA of Caco-2 cells, and the expression of these transporters was confirmed by RT-PCR (reverse transcription-polymerase chain reaction). RESULTS: Ezetimibe inhibited up to 40% of lutein accumulation by Caco-2 cell monolayers. Block lipid transport 1 (BLT-1), a selective chemical inhibitor of SR-B1, also inhibited lutein accumulation by Caco-2 cells. On the other hand, ATP-depletion reagents (sodium fluoride and sodium azide or carbonyl cyanide m-chlorophenylhydrazone) did not influence the accumulation or permeation of lutein significantly. CONCLUSIONS: The results show that lutein absorption is, at least in part, mediated by influx transporters NPC1L1 and SR-B1 rather than mediated by efflux transporters such as ABC (ATP-binding cassette) transporters.

Questionnaire survey on the usage of antiseizure drugs for dogs and cats in Japanese veterinary hospitals (2020).

Epilepsy is the most common neurological disorder in veterinary medicine. Recently, evidence-based recommendations or systematic reviews for using antiseizure drugs (ASDs) in dogs and cats have been published, but there are many differences in economic, geographical, and historical backgrounds and/or the availability of each ASD between countries. In the present study, we conducted a questionnaire survey on the usage of ASDs in 511 veterinary hospitals in Japan in 2020. As a result, zonisamide (ZNS) was the most commonly prescribed drug for idiopathic (83%) and structural epilepsy (76%) in dogs. In cats, phenobarbital was the most frequently prescribed drug for idiopathic (48%) and structural epilepsy (51%), but ZNS was also commonly prescribed (41% and 36%, respectively). Additionally, ZNS was the most frequently used ASD in combination therapy for canine idiopathic epilepsy. We also surveyed the frequency of measuring ASD blood levels; however, a relatively high percentage of hospitals (22%) did not perform such measurements. Although the evidence level for ZNS is still poor for both species, it is generally used as the first-line ASD in Japan. A large-scale and higher evidential study for ZNS and the education of practitioners for adequate antiseizure medication are required.