Urate Transporter ABCG2 Function and Asymptomatic Hyperuricemia: A Retrospective Cohort Study of CKD Progression.

RATIONALE & OBJECTIVE: Treatment of asymptomatic hyperuricemia is not commonly implemented. However, it is unclear whether urate deposition that begins during asymptomatic hyperuricemia can induce nephropathy. Dysfunction of ATP-binding cassette subfamily G member 2 (ABCG2), a urate efflux transporter, leads to elevated serum uric acid concentration (SUA). We investigated the association between asymptomatic hyperuricemia and decreased estimated glomerular filtration rate (eGFR), and the impact of ABCG2 on this relationship. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 1,885 Japanese adults undergoing routine health care follow-up between 2007 and 2017 who had eGFR ≥60 mL/min/1.73 m2, of which 311 had asymptomatic hyperuricemia (SUA >7.0 mg/dL). Study participants were classified into 3 categories of estimated ABCG2 function (full, 75%, and ≤50% function). PREDICTORS: Baseline SUA and estimated ABCG2 function. OUTCOME: Change in eGFR over time. ANALYTICAL APPROACH: Linear mixed-effect models were used to analyze the relationship between asymptomatic hyperuricemia, ABCG2 function, and eGFR decline. RESULTS: Asymptomatic hyperuricemia was negligibly associated with eGFR decline overall. However, among those with eGFR 60-89 mL/min/1.73 m2 and ≤50% ABCG2 function, eGFR decline was associated with asymptomatic hyperuricemia (P = 0.03). ABCG2 was not associated with eGFR reductions when the SUA was <6.0 mg/dL. Among participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, ≤50% ABCG2 function was associated with approximately 1.2-fold faster eGFR decline compared with fully functional ABCG2 (P = 0.02). Among the participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, the adjusted eGFR slopes (given as mean ± standard error of the mean, in mL/min/1.73 m2 per year) were -0.946 ± 0.049, -1.040 ± 0.046, and -1.148 ± 0.069 for full, 75%, and ≤50% ABCG2 function, respectively. LIMITATIONS: Lack of measurement of urinary urate and uremic toxins that are known to be transported by ABCG2, and no independent validation cohort. CONCLUSIONS: Asymptomatic hyperuricemia was not associated with eGFR decline, except when in the presence of ≤50% ABCG2 function. PLAIN-LANGUAGE SUMMARY: The urate transporter ABCG2 is a protein that regulates serum urate concentrations; when dysfunctional, it can lead to elevated serum concentrations of this compound (ie, hyperuricemia). Although persistent hyperuricemia induces gout and kidney injury, the effects on organs during the asymptomatic phase have yet to be established. Therefore, to clarify the relationship between ABCG2, asymptomatic hyperuricemia, and kidney function, we conducted a retrospective cohort study of 1,885 healthy participants, including 311 participants with asymptomatic hyperuricemia. We found that the coexistence of asymptomatic hyperuricemia and severe ABCG2 dysfunction was associated with the age-dependent decline in kidney function. We concluded that asymptomatic hyperuricemia represents a risk factor for chronic kidney disease, at least in individuals with highly dysfunctional ABCG2. This new finding highlights the potential importance of ABCG2 in the pathogenesis of hyperuricemia-induced kidney injury.

The Possible Effects of Zinc Supplementation on Postpartum Depression and Anemia.

Background and Objectives: The effects of postpartum zinc supplementation are still unclear. Our purpose in this study is to investigate the association between Zn supplementation and postpartum depression, defined by an Edinburgh Postnatal Depression Scale (EPDS) score ≥ 9, and the effect on the hematological status of postpartum women. Materials and Methods: We first investigated whether zinc supplementation affected the perioperative levels of zinc, hemoglobin, and hematocrit in 197 cases who underwent cesarean section and had postpartum anemia. Next, logistic regression analyses were performed on 148 eligible cases to determine the association between zinc supplementation and postpartum depression. Results: Postpartum zinc supplementation significantly improved the status of maternal blood zinc levels and reduced the risk of developing postpartum depression (adjusted odds ratio: 0.249; 95% confidence interval: 0.062-0.988; p = 0.048). Iron supplementation is a standard and effective strategy for treating anemia; however, the combination of oral iron plus zinc supplementation resulted in slightly significant negative effects on postpartum hemoglobin and hematocrit compared to oral iron supplementation only. Conclusions: Postpartum zinc supplementation causes a significant positive effect on postpartum depression (EPDS score ≥ 9). Zinc supplementation had a negative but transient influence on the hematological status in women with postpartum anemia treated with oral iron supplementation; however, the differences were not clinically significant. Thus, we did not regard it as an adverse effect to be considered, and postpartum zinc supplementation may be viewed as beneficial in postpartum women.

Current Issues within the Perinatal Mental Health Care System in Aichi Prefecture, Japan: A Cross-Sectional Questionnaire Survey.

Mental illnesses commonly occur in the reproductive age. This study aimed to identify the issues that exist within the perinatal mental health care system. A cross-sectional survey was conducted in Aichi Prefecture in central Japan. Questionnaires on the situation between 2016 and 2018 were mailed to the head physicians of 128 maternity care units, 21 neonatal intensive care units (NICUs), and 40 assisted reproductive technology (ART) units. A total of 82 (52.6 per 100,000 births) women were admitted to mental health care units during the perinatal period, and 158 (1.0 per 1000 births) neonates born to mothers with mental illness were admitted to NICUs. Approximately 40% of patients were hospitalized in psychiatric hospitals without maternity care units. Eighty-four (71.1%) and 76 (64.4%) maternity care units did not have psychiatrists or social workers, respectively. Moreover, 20-35% of the head physicians in private clinics, general hospitals, and ART units endorsed the discontinuation of psychotropic drug use during pregnancy. However, the corresponding figures were only 5% among those in maternal-fetal centers. Resources for perinatal mental illness might be limited. Perspectives on psychotropic drug use differed based on the type of facilities where the doctors were working.

Association between polymorphism at IGF-1 rs35767 gene locus and long-term decline in renal function: a Japanese retrospective longitudinal cohort study.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) acts on glucose and protein metabolism and human growth and also influences blood pressure and renal function. This study investigated whether the single-nucleotide polymorphism of IGF-1, rs35767, plays a role in metabolic syndrome indicators, including blood pressure, glucose metabolism, uric acid levels, and renal function. METHODS: In this retrospective longitudinal cohort study, blood samples from 1506 Japanese individuals were collected and used for genotyping for variant rs35767: T > C in the IGF-1 upstream promoter. Data were analyzed to identify associations between IGF-1 genotypes and patient biochemical parameters, including the components of metabolic syndrome and the long-term change in renal function. RESULTS: The cohort rs35767 genotypes included 650 CC carriers (43.2%), 687 TC carriers (45.6%), and 169 TT carriers (11.2%). Multiple regression analysis revealed no association between IGF-1 genotype and blood pressure, glycated hemoglobin level, and serum uric acid level. However, in females, blood pressure was negatively correlated with the TT genotype. Longitudinal observation revealed that the decline in eGFR over 10 years was greater in TT (- 18.51 ± 1.04 mL/min/1.73m2) than in CC carriers (- 16.38 ± 0.52 mL/min/1.73m2; P < 0.05). CONCLUSION: The present study suggests that renal function declines faster in individuals with the TT genotype at the IGF-1 rs35767 locus than in those with the CC genotype, suggesting that the TT genotype is associated with the long-term chronological decline in renal function.

A pitfall in diagnosing fetal abdominal lymphangioma: A report of two cases.

Typical ultrasound findings of fetal abdominal lymphangioma include thick-walled, multiseptated anechoic masses. Although a majority of cases can be suspected promptly by ultrasound examination, the two cases presented herein did not meet the standard criteria and were misleading. Both cases involved unilocular cysts without clear septations, but in retrospect were atypical findings of fetal abdominal lymphangioma. A few reports of misleading cases have been described previously; however, the precise characteristics have not been reported in detail. Therefore, in this case report, we focused predominantly upon the difficulties encountered in the prenatal diagnosis of abdominal lymphangioma based on ultrasound morphology alone.

Feasibility of using a handheld tissue hardness meter to quantify uterine contractions and its clinical application for obstetric bleeding management.

Postpartum haemorrhage (PPH) is a potentially life-threatening condition. Women undergoing caesarean section (CS) are at particular risk, and improvements in the management of PPH during CS are required. We investigated the use of a tissue hardness metre to quantify uterine contractions during CS with a view to its application for obstetric bleeding management. Fifty pregnant women at term who underwent elective CS were recruited. Using a tissue hardness metre, we measured uterine hardness twice during CS: after placental removal and before peritoneum closure. Each measurement was conducted at two standardised points: fundus and corpus uteri. Concurrently, obstetricians subjectively graded uterine contractions as weak, medium, or strong. The hardness metre accurately quantified the degree of uterine contraction assessed by the obstetricians, and could be an effective clinical tool for early recognition of intra-operative massive bleeding. IMPACT STATEMENT What is already known on this subject? Maintaining adequate uterine contraction leads to prevention of excessive blood loss, which decreases the incidence and severity of PPH. However, the assessment of uterine contraction is currently judged by obstetricians, who manually and subjectively evaluate uterine contraction according to uterine hardness. Therefore, uterine atony remains a clinical diagnosis without a universal definition. What do the results of this study add? The present study investigated the use of a tissue hardness metre to quantify uterine contractions during CS with a view to its application for obstetric bleeding management. The hardness metre was able to quantify the degree of uterine contraction perceived by obstetricians. Quantifying uterine hardness during CS correlates with the amount of intra-operative bleeding and is useful for early recognition of massive haemorrhage. What are the implications of these findings for clinical practice and/or further research? To improve the management of atonic PPH and avoid serious complications, the tissue hardness metre should be considered as a potential clinical tool during CS.

Possible Association between Cathepsin V and the Development of Placenta Accreta Spectrum Disorders.

BACKGROUND/AIMS: The study aimed to evaluate molecular changes related to trophoblast adhesion in placenta accreta spectrum (PAS) disorders. METHODS: A retrospective analysis of 10 PAS cases in which both the trophoblast adherent site and the non-adherent site were identified was performed in April 2010 and March 2013. Microarray analysis and reverse transcription polymerase chain reaction (RT-PCR) analyses were performed to extract upregulated genes in the adherent site. Gene expression changes were examined by immunohistochemistry. RESULTS: Microarray analysis showed that 157 transcripts were > 3-fold upregulated, including the following: a disintegrin and metalloproteinase-28 (ADAM28), 3.10-fold; cathepsin V (CTSV), 3.73-fold; cathepsin S (CTSS), 3.46-fold; and matrix metalloproteinase-19 (MMP19), 3.41-fold. RT-PCR showed relatively high mRNA expressions. On immunohistochemistry, extravillous trophoblast (EVT) at the non-adherent site showed weak or no CTSV expression, whereas EVT that invaded myometrium at the adherent site showed strong expression (histological score, median [min-max], 115.6 [37.6-153.6] vs. 184.8 [56.4-222.8], p < 0.05). MMP19 showed moderate staining, with no difference between the adherent and non-adherent sites. ADAM28 and CTSS showed weak or no staining. DISCUSSION: This limited study suggests that CTSV may be involved in the pathogenesis of PAS.

Maternal protein S activity is associated with massive hemorrhage during caesarean section: retrospective case-control study.

OBJECTIVE: The objective of this study is to identify any correlation between the maternal protein S (PS) activity, which decreases spontaneously during normal pregnancy, and the pregnancy outcome, especially the amount of bleeding during caesarean section (CS). MATERIALS AND METHODS: We analyzed 129 pregnant women who received elective CS at our hospital which is a tertiary perinatal center. The relationship between the amount of intraoperative hemorrhage and PS activity was estimated by simple linear regression. Univariate and multivariate analyses were also performed to determine whether or not the maternal PS activity was associated with massive hemorrhage (>1000 g). RESULTS: The maternal PS activity correlated with the amount of intraoperative hemorrhage (p = .048, r = 0.175) and could be an independent predictor of massive hemorrhage (odds ratio 1.06; 95% confidence interval 1.01-1.12; p = .013). CONCLUSIONS: Maternal PS activity was associated with the amount of hemorrhage during CS and the occurrence of massive hemorrhage. PS activity reduction naturally occurring during pregnancy could contribute to alleviation of massive hemorrhage.

Somatic symptom disorder manifested as acute abdominal pain during pregnancy preceding perinatal depression: a case report.

Somatic symptom disorder (SSD) occurring as abdominal pain during pregnancy can be very difficult to distinguish from physical diseases; prompt diagnosis and appropriate treatment are required. SSD can develop into perinatal depression, which may need intensive psychiatric intervention. Here, we present the first case report of SSD preceding perinatal depression. This case shows the clinical importance of SSD in obstetrics both as a cause of abdominal pain and as a precursor of depression.

The role of E2F8 in the human placenta.

Recent studies have reported that E2F transcription factor (E2F) 8, an atypical E2F transcription factor, serves a critical role in promoting the growth and development of the murine placenta. However, the function of E2F8 in the human placenta remains unknown. Invasion of extravillous trophoblasts (EVTs) into the maternal decidua is known to be important for the development of the human placenta. To investigate the role of E2F8 in human placental development, E2F8 localisation was examined in the human placenta and E2F8 mRNA expression was detected in primary cultured EVTs. The human EVT cell line, HTR­8/SVneo, was divided into two groups and treated separately, one with retrovirus expressing short hairpin (sh)­RNA against E2F8 (shE2F8 cells) and the other with non­target control shRNA (shControl cells). The cell functions, including cell cycle, proliferation, invasion and adhesion, were compared between the shE2F8 and shControl cells. A histological examination revealed that E2F8 was localised in the decidua cells, EVTs, and cytotrophoblasts in the placenta. E2F8 mRNA was confirmed to be expressed in cultured primary EVTs. No significant difference was observed in the cell cycle, proliferation or adhesion between the shE2F8 and shControl cells. The invasive ability was ~2­fold higher in the shE2F8 cells when compared with the shControl cells (P<0.01). Production of matrix metalloproteinase­1 was significantly increased in the shE2F8 cells when compared with the shControl cells (P<0.05). Taken together, E2F8 is present in the EVTs of the human placenta, but, unlike murine placenta, it may suppress the invasiveness of EVTs. E2F8 was also present in cytotrophoblasts in cell columns, which have no invasive ability and differentiate into EVTs. In conclusion, E2F8 also exists in the human placenta, and its function may be different from that in the murine placenta, although further investigation is required.

The rate of neonatal respiratory distress syndrome/transient tachypnea in the newborn and the amniotic lamellar body count in twin pregnancies compared with singleton pregnancies.

BACKGROUND: Whether or not the period of fetal lung maturity differs between twin and singleton pregnancies has not been clarified. We examined whether or not fetal lung maturity and fetal lung absorption are achieved earlier in twin fetuses than in singleton fetuses. METHODS: We registered 454 singleton pregnancies and 398 twin pregnancies with no congenital abnormalities affecting the respiratory function or neonatal deaths. All patients were delivered by Caesarean section without labor between 24 and 38 gestational weeks. The amniotic fluid samples were analyzed immediately without centrifugation. A multiple logistic regression analysis was performed to explore the relationship between twin pregnancy and neonatal respiratory distress syndrome and transient tachypnea of the newborn (RDS/TTN). RESULTS: The rate of RDS/TTN in infants was significantly higher and the lamellar body counts (LBCs) significantly lower in singleton pregnancies than that in twin pregnancies (P < .001). According to a multivariate logistic regression analysis, twin pregnancy (odds ratio, 0.34; 95% confidence interval, 0.22-0.55) was a significant preventive factor for neonatal RDS/TTN. CONCLUSIONS: We showed that twin fetuses experience more rapid lung maturation and lung fluid absorption than singleton fetuses, as confirmed by the higher LBC values in twin fetuses.

The impact of fertility treatment on the neonatal respiratory outcomes and amniotic lamellar body counts in twin pregnancies.

BACKGROUND: To elucidate the impact of fertility treatment on neonatal respiratory outcomes and amniotic lamellar body counts (LBCs) in twin pregnancies. METHODS: One hundred ninety twin pairs, including 99 dichorionic twin (DCT) and 91 monochorionic twin (MCT) pairs were registered at our institutions. All amniotic fluid samples were obtained from each sac at cesarean section. Samples were analyzed immediately after arrival at the laboratory without centrifugation. We divided the patients into 3 groups: the no therapy group (natural conception), the induced ovulation group (with or without intrauterine insemination), and the assisted reproductive technology (ART) group (in vitro fertilization or intracytoplasmic sperm injection). RESULTS: No statistically significant associations between the fertility treatment and the rates of neonatal RDS/TTN were observed in the whole study population (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.45-2.00), DCT (OR, 0.86; 95%CI, 0.30-2.47), and MCT (OR, 1.45; 95%CI, 0.41-5.11). In addition, there was no association between the fertility treatment and neonatal RDS/TTN in the propensity score analysis of the whole study population (OR, 1.25; 95%CI, 0.57-2.74). CONCLUSIONS: None of the individual types of fertility treatment had a direct impact on respiratory disorders such as RDS and TTN in twin infants.

Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model.

The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H2) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H2 attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Short-term memory, sociability and social novelty, and sensorimotor gating were evaluated using the Y-maze, three-chamber, and prepulse inhibition (PPI) tests, respectively, at postnatal 3 or 4 weeks. The number of neurons and oligodendrocytes was also analyzed at postnatal 5 weeks by immunohistochemical analysis. Offspring of the LPS-exposed dams showed deficits in short-term memory and social interaction, following neuronal and oligodendrocytic loss in the amygdala and cortex. Maternal H2 administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H2 on LPS-induced astrocytic activation, both in vivo and in vitro. The number of activated astrocytes with hypertrophic morphology was increased in LPS-exposed offspring, but decreased in the offspring of H2-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H2 administration. Overall, these findings indicate that maternal H2 administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life.

Effect of molecular hydrogen on uterine inflammation during preterm labour.

Intrauterine inflammation causes preterm birth and is associated with complications in preterm neonates. Thus, strategies aimed at suppressing inflammation are expected to be effective for reducing the risk of preterm birth and associated complications. Our previous studies demonstrated that molecular hydrogen (H2), an anti-inflammatory agent, prevented inflammation-induced impairment in foetal brain and lung tissues in lipopolysaccharide (LPS)-induced rodent models. However, it remains unclear whether H2 is capable of inhibiting preterm labour. The aim of the current study was therefore to investigate the effect of H2 on inflammation-induced preterm labour. Pregnant ICR (CD-1) mice were divided into three groups: Control, LPS and H2 water (HW) + LPS. In the control and LPS groups, vehicle and LPS, respectively, were intraperitoneally injected on embryonic day 15.5. In the HW + LPS group, HW was administered 24 h prior to LPS injection. The time from LPS administration to parturition was compared between the LPS and HW + LPS groups. Maternal uterus was collected 6 h after LPS injection and the transcript levels of pro-inflammatory cytokines, contractile-associated proteins (CAPs), matrix metalloproteinase-3 (Mmp3) and endothelin-1 (Et1) were assessed by reverse transcription-quantitative polymerase chain reaction. The protein levels of cyclooxygenase-2 (Cox2) were also evaluated by immunohistochemistry. The time from LPS administration to parturition in the HW + LPS group was significantly increased compared with that in the LPS group (33.5±3.4 vs. 18.3±8.8 h, respectively, P=0.020). H2 administration also resulted in significantly higher progesterone levels compared with LPS treatment alone (P=0.002). The transcript levels of pro-inflammatory cytokines, CAPs, Mmp3 and Et1 in the uteri of the LPS group were significantly higher than those in the control group (all P<0.05). In turn, all these levels with the exception of interleukin-8 and Mmp3 were significantly lower in the HW + LPS group compared with those in the LPS group (all P<0.05). The protein levels of Cox2 in the LPS group were also significantly increased compared with those in the control (P<0.001) and HW + LPS (P=0.003) groups. These results suggest that inflammation-induced changes in the uterus may be ameliorated through maternal H2 administration. Preventive H2 administration may therefore represent an effective strategy for the suppression of inflammation during preterm labour.

The expression of Toll-like receptor 5 in preterm histologic chorioamnionitis.

Spontaneous preterm birth is often caused by chorioamnionitis. Toll-like receptors (TLRs) have a role in the response of the innate immune system. The role of TLR5 in chorioamnionitis remains unclear: however, TLR5 was reported to have a significantly stronger effect on the induction of interleukin (IL)-6 when compared with other TLRs in amniotic epithelial cells. The aim of this study was to investigate TLR5 expression in placentas with preterm histologic chorioamnionitis (HCA). The expression levels of TLR5 were evaluated in the amnions, chorions, deciduae and villi with and without HCA using immunohistochemistry. The co-localization of IL-6 or IL-8 with TLR5 was examined by immunofluorescence. The production of IL-6 was examined in primary tissue cultured fetal membranes treated with and without the TLR5 agonist. The protein expression of TLR5 was significantly increased in amnions with HCA (p<0.05) and showed a trend toward an increase in chorions with HCA, whereas no significant difference was detected in the villi and decidua. TLR5 co-localized with IL-6 and IL-8 in amnions and chorions. IL-6 showed a significant increase (p<0.05) with the TLR5 agonist. These results suggest that TLR5 plays a role in the pathogenesis of preterm HCA and IL-6 production.

Simulation training is useful for shortening the decision-to-delivery interval in cases of emergent cesarean section.

OBJECTIVE: We examined the effect of simulation training for medical staff on the decision-to-delivery interval (DDI) in cases of emergent cesarean delivery and the effect of a shortened DDI on maternal and neonatal outcomes. MATERIAL AND METHODS: Our hospital is a tertiary perinatal center. As the simulation training was performed in March 2014, the study population was divided into two groups: pretraining group (November 2011-March 2014, 29 months: n = 15) and post-training group (April 2014-August 2016, 29 months: n = 35). RESULTS: The DDI was significantly shorter in the post-training group than in the pretraining group (p = .009). In particular, the decision-to-entering the operating room interval was significantly shorter in the post-training group than in the pretraining group (p = .003). The umbilical artery pH was significantly better in post-training group than in the pretraining group (p = .019). Furthermore, the umbilical artery pH was significantly improved by simulation training only in "irreversible" cases (p = .012). CONCLUSIONS: The DDI was significantly shortened by introducing simulation training. We also demonstrated a beneficial effect of the simulation training on the umbilical artery pH, especially in "irreversible" cases, without increasing the rate of maternal adverse outcome.