Relationship between Birth Order and Postnatal Growth until 4 Years of Age: The Japan Environment and Children's Study.

Later-borns tend to be shorter than first-borns in childhood and adulthood. However, large-scale prospective studies examining growth during infancy according to birth order are limited. We aimed to investigate the relationship between birth order and growth during the first 4 years of life in a Japanese prospective birth cohort study. A total of 26,249 full-term singleton births were targeted. General linear and multivariable logistic regression models were performed and adjusted for birth weight, parents' heights, maternal age at delivery, gestational weight gain, maternal smoking and alcohol drinking status during pregnancy, household income, breastfeeding status, and Study Areas. The multivariate adjusted mean length Z-scores in "first-borns having no sibling", "first-borns having siblings", "second-borns", and "third-borns or more" were -0.026, -0.013, 0.136, and 0.120 at birth and -0.324, -0.330, -0.466, and -0.569 at 10 months, respectively. Results similar to those at 10 months were observed at 1.5, 3, and 4 years. The adjusted odds ratios (95% confidence intervals) of short stature at 4 years in "first-borns having siblings", "second-borns", and "third-borns or more" were 1.08 (0.84-1.39), 1.36 (1.13-1.62), and 1.50 (1.20-1.88), respectively, versus "first-borns having no sibling". Birth order was significantly associated with postnatal growth and may be a factor predisposing to short stature in early childhood.

Adverse pregnancy outcomes of cancer survivors and infectious disease in their infants: The Japan Environment and Children's Study.

Birth cohort studies examining pregnancy and infant outcomes among adolescent and young adult (AYA) cancer survivors have been limited. The present study examined whether AYA cancer affects pregnancy outcomes of survivors and infectious diseases in their infants up to 1 year of age. Pregnant women were recruited for the Japan Environment and Children's Study, a nationwide, large-scale, prospective cohort study. The present study included 103,060 pregnant women and collected questionnaire-based data during the first and second/third trimester, and at 1 month, 6 months and 1 year after delivery. Adverse pregnancy outcomes and infectious diseases in infants up to 1 year of age were compared between AYA cancer survivors and pregnant women without a history of cancer using binominal logistic regression analyses and a multiple imputation method. Of 99,816 participants (3,244 were missing), 1,102 (1.1%) had a cancer history, including 812 participants (0.8%) with a history of cervical cancer. Among cervical cancer survivors, the adjusted (a)ORs were as follows: 3.25 (95% CI, 2.31-4.57; q=0.00) for a preterm birth <34 weeks' gestation; 2.82 (95% CI, 2.31-3.44; q=0.00) for a preterm birth <37 weeks' gestation; and 1.67 (95% CI, 1.36-2.06; q=0.00) for premature rupture of the membrane. Among the other cancer survivors, the aOR for caesarean section was 1.43 (95% CI, 1.10-1.87; q=0.0). Furthermore, lower respiratory tract inflammation in 1-year-old infants born by vaginal delivery increased significantly in cases with a history of cervical cancer (aOR, 1.77; 95% CI, 1.33-2.36; q=0.00). The present study identified the risk of lower respiratory tract inflammation in 1-year-old infants born by vaginal delivery in cervical cancer survivors for the first time. In addition, the frequency of caesarean section increased in all cancer survivors. No risk of congenital anomalies or other infections were found in the total group of cancer survivors.

Relationship Between Fasting Blood Glucose Levels in Middle Age and Cognitive Function in Later Life: The Aichi Workers' Cohort Study.

BACKGROUND: There is limited evidence regarding the relationship between Diabetes mellitus (DM) in middle age and mild cognitive impairment after a follow-up. Therefore, we investigated the relationship between fasting blood glucose (FBG) levels in middle age and cognitive function assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA-J) in later life, following over 15 years of follow-up in the Aichi Workers' Cohort Study in Japan. METHODS: Participants were 253 former local government employees aged 60-79 years in 2018 who participated in a baseline survey conducted in 2002. Using baseline FBG levels and self-reported history, participants were classified into the normal, impaired fasting glucose (IFG) and, and DM groups. Total MoCA-J score ranges from 0 to 30, and cognitive impairment was defined as MoCA-J score ≤25 in this study. A general linear model was used to estimate the mean MoCA-J scores in the FBG groups, adjusted for age, sex, educational year, smoking status, alcohol consumption, physical activity, body mass index, systolic blood pressure, total cholesterol, and estimated glomerular filtration rate. RESULTS: The mean MoCA-J score in the total population was 25.0, and the prevalence of MoCA-J score ≤25 was 49.0%. Multivariable-adjusted total MoCA-J scores were 25.2, 24.8, and 23.4 in the normal, IFG, and DM groups, respectively. The odds ratio of MoCA-J score ≤25 in the DM group was 3.29. CONCLUSION: FBG level in middle age was negatively associated with total MoCA-J scores assessed later in life, independent of confounding variables.

High Maternal Total Cholesterol Is Associated With No-Catch-up Growth in Full-Term SGA Infants: The Japan Environment and Children's Study.

Objectives: Infants born small for gestational age (SGA) with no catch-up growth (No-CU) are at high risk of intellectual and developmental disabilities. However, factors leading to No-CU among SGA infants are unclear. This study aimed to examine the association between maternal total cholesterol (TC) in mid-pregnancy and No-CU at 3 years among full-term SGA infants. Study Design: The Japan Environment and Children's Study (JECS) is a nationwide prospective birth cohort study. We extracted a total of 2,222 mothers and full-term SGA infants (length and/or weight <-2 standard deviation [SD]) without congenital abnormalities from the original JECS cohort comprising a total of 104,062 fetal records. According to the distribution of maternal TC in the entire cohort, participants were classified into nine groups per each fifth percentile with the 20th-79th percentiles (204-260 mg/dl) as the reference group. No-CU was defined by a Z-score of height at 3 years <-2 SD according to the growth standard charts for Japanese children. Multivariable-adjusted logistic regression models were carried out using multiple imputations. Additionally, a multiple-adjusted restricted cubic spline model was performed in the complete dataset. Results: A total of 362 (16.3%) children were No-CU at 3 years. After adjusting for the Z-score of birth weight, age of mother, smoking status, weight gain during pregnancy, breastfeeding and meal frequency at 2 years, and parents' heights, the odds ratio (95% confidence intervals) of No-CU was 2.95 (1.28-6.80) for children whose maternal TC levels were in the highest category (≥294 mg/dl), compared to the reference group. A multiple-adjusted restricted cubic spline model showed a non-linear trend of the significant association between high maternal TC and No-CU (p for linear trend = 0.05, p for quadratic trend <0.05). Conclusion: High maternal TC at mid-pregnancy was associated with No-CU among SGA infants. Such infants should be carefully followed up to introduce appropriate growth hormonal treatment. The findings may support previous animal experimental studies which indicated that maternal high-fat diet exposure induces impairment of growth and skeletal muscle development in the offspring. Future studies are required to elucidate the detailed mechanism.

Association of Maternal Total Cholesterol With SGA or LGA Birth at Term: the Japan Environment and Children's Study.

CONTEXT: Maternal cholesterol is important for fetal development. Whether maternal serum total cholesterol (maternal TC) levels in midpregnancy are associated with small (SGA) or large (LGA) for gestational age independent of prepregnancy body mass index (BMI) and weight gain during pregnancy is inconclusive. OBJECTIVE: This work aimed to prospectively investigate the association between maternal TC in midpregnancy and SGA or LGA. METHODS: The Japan Environment and Children's Study is a nationwide prospective birth cohort study in Japan. Participants in this study included 37 449 nondiabetic, nonhypertensive mothers with singleton birth at term without congenital abnormalities. Birth weight for gestational age less than the 10th percentile and greater than or equal to the 90th percentile were respectively defined as SGA and LGA by the Japanese neonatal anthropometric charts. RESULTS: The mean gestational age at blood sampling was 22.7 ±â€…4.0 weeks. After adjustment for maternal age, sex of child, parity, weight gain during pregnancy, prepregnancy BMI, smoking, alcohol drinking, blood glucose levels, household income, and study areas, 1-SD decrement of maternal TC was linearly associated with SGA (odds ratio [OR]: 1.20; 95% CI, 1.15-1.25). In contrast, 1-SD increment of maternal TC was linearly associated with LGA (OR: 1.13; 95% CI, 1.09-1.16). Associations did not differ according to prepregnancy BMI and gestational weight gain (P for interaction > .20). CONCLUSION: Maternal TC levels in midpregnancy were associated with SGA or LGA in a Japanese cohort. It may help to predict SGA and LGA. Favorable maternal lipid profiles for fetal development must be explored.

Scavenging of reactive oxygen species by astaxanthin inhibits epithelial-mesenchymal transition in high glucose-stimulated mesothelial cells.

BACKGROUND: High glucose concentrations influence the functional and structural development of the peritoneal membrane. We previously reported that the oral administration of astaxanthin (AST) suppressed peritoneal fibrosis (PF) as well as inhibited oxidative stress, inflammation, and epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) in a chlorhexidine-induced PF rat model. This suggests that oxidative stress induction of EMT is a key event during peritoneal damage. The present study evaluated the therapeutic effect of AST in suppressing EMT, in response to glucose-induced oxidative stress. METHODS: Temperature-sensitive mesothelial cells (TSMCs) were cultured in the presence or absence of AST and then treated with 140 mM glucose for 3 or 12 hours. Expression levels of TNF-α, TGF-ß, and VEGF were determined at the mRNA and protein levels, and nuclear factor kappa B (NF-κB) activity was evaluated. We measured NO2-/NO3- concentrations in cellular supernatants and determined 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in mitochondrial and nuclear DNA. The expressions of E-cadherin and alpha-smooth muscle actin (α-SMA) were evaluated by double immunofluorescence and protein levels. RESULTS: High glucose concentrations induced overproduction of reactive oxidative species (ROS), increasing 8-OHdG mitochondrial DNA and cytokine levels. The NF-κB pathway was activated in response to high glucose concentrations, whereas de novo α-SMA expression was observed with decreased E-cadherin expression. AST treatment attenuated ROS production, inflammatory cytokine production, NF-κB activation, and EMT. CONCLUSION: The findings of the present study indicate that AST may have an anti-EMT effect due to anti-oxidative and anti-inflammatory activities by scavenging glucose-induced ROS from mitochondria in PMCs. AST may be an efficacious treatment for PF.

Long-term outcome of encapsulating peritoneal sclerosis (EPS) patients in a single center.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is the most serious complication of peritoneal dialysis (PD) with a high mortality rate. The objective of the present study was to determine the clinical characteristics, the incidence rate, and the long-term outcome of EPS patients compared with control patients. METHODS: Two hundred and seventy patients with end-stage kidney disease were started on PD from 1987 to 2013 in the Juntendo University Hospital. EPS was diagnosed by clinical findings, radiological findings, and macroscopic inspection at the time of laparoscopy or surgical operation. Patient medical records were analyzed retrospectively, including clinical characteristics, laboratory findings, treatment modality, and outcomes. Using a Kaplan-Meier analysis, we compared the survival rate between EPS patients and control PD patients, matched for age, gender, diabetes, and duration of PD. RESULTS: Among 270 PD patients, 13 patients (4.8 %) developed EPS. The mean duration of PD was 120.5 ± 42.8 months. There were no significant difference in demographic findings between EPS and control PD patients. Among the EPS patients, seven patients died, of which four deaths were directly attributed to EPS. All four patients that had had surgical enterolysis were doing well and had no recurrences. No significant difference in the survival rate between EPS and control PD patients was observed in the Kaplan-Meier analysis. CONCLUSIONS: There was no significant difference in the survival rate between EPS patients and control PD patients. It appears that an early diagnosis by laparoscopy and accurate treatment, including surgical enterolysis, might improve mortality.

Comparison between the fixation of peritoneal dialysis catheters to the peritoneal wall and the conventional placement technique: clinical experience and follow-up of a new implant technique for peritoneal dialysis catheters.

Peritoneal dialysis (PD) catheters often become severely dislocated, which may lead to malfunction. With the aim of preventing this complication, we have developed a simple method of fixing the catheter downwards in the peritoneal cavity (fixation technique), a technique that does not require a laparoscope. Sixteen patients were implanted using the conventional placement technique and 25 patients were implanted using the fixation technique. The location of the catheter tip was classified from grade 1 (downward, normal) to 5 (dislocated). The frequency of dislocation (defined as the extended time and/or decrease in volume when draining the PD solution) was measured for both the fixation technique and conventional placement technique. There was a significant difference in grade between the fixation technique (2.72 ± 1.01) and conventional technique (3.92 ± 1.31). The time until first dislocation was significantly different between the fixation technique (59.3 ± 48.1 days) and conventional technique (8.8 ± 14.6 days). The time until any dislocation was significantly different between the fixation technique (69.2 ± 41.9 days) and conventional technique (12.9 ± 13.7 days). Complications were not significantly different between the fixation technique and conventional technique. The fixation technique appears to be simple, safe, and useful for preventing severe dislocation and for lengthening the time until dislocation in PD patients.

Paracrine effects of transplanted mesothelial cells isolated from temperature-sensitive SV40 large T-antigen gene transgenic rats during peritoneal repair.

BACKGROUND: The prevention and restoration of peritoneal damage is a critical mission in peritoneal dialysis (PD). Transplantation of mesothelial cells has been suggested to suppress peritoneal injury during PD. Few studies have examined the efficacy and safety of cell transplantation. We evaluated the paracrine effects of mesothelial transplantation during peritoneal repair using immortalized temperature-sensitive mesothelial cells (TSMCs) in chlorhexidine gluconate (CG)-induced peritoneal fibrosis rats. METHODS: Continuous-infusion pumps containing 8% CG were placed into the abdominal cavity for 21 days. After the removal of the pumps, the TSMCs were injected into the peritoneal cavity at Day 22 (Tx-1 group) or 29 (Tx-2 group). Morphological findings and mRNA expressions of regeneration-related factors were examined at Days 22, 29 and 35. RESULTS: Peritoneal thickness was aggravated in the Tx-1 group. Levels of transforming growth factor (TGF)-ß, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 mRNA in the Tx-1 group at Day 35 were comparable with those at Day 22. The levels of Snail, B-Raf and ERK-1, markers of epithelial to mesenchymal transition and of the RAS/MAPK pathway in the Tx-1 group, were significantly higher than those in the Tx-2 group. TGF-ß and VEGF were produced from the transplanted mesothelial cells and the surrounding cells in the Tx-1 group. CONCLUSION: It appears that the paracrine effect of transplanted mesothelial cells during peritoneal repair is associated with its surrounding condition. It is important to determine the most appropriate time for developing peritoneal repair through mesothelial transplantation.

An in-silico genomic survey to annotate genes coding for early development-relevant signaling molecules in the pearl oyster, Pinctada fucata.

The pearl oyster Pinctada fucata has great potential as a model system for lophotrochozoan developmental biology research. Pinctada fucata is an important commercial resource, and a significant body of primary research on this species has emphasized its basic aquaculture biology such as larval biology and growth, aquaculture, pearl formation and quality improvement, shell formation, and biomineralization. Recently, a draft genome sequence of this species was published, and many experimental resources are currently being developed, such as bioinformatics tools, embryo and larva manipulation methods, gene knockdown technique, etc. In this paper, we report the results from our genomic survey pertaining to gene families that encode developmental signaling ligands (Fgf, Hedgehog, PDGF/VEGF, TGFß, and Wnt families). We found most of the representative genes of major signaling pathways involved in axial patterning, as well as copies of the signaling molecule paralogs. Phylogenetic character mapping was used to infer a possible evolutionary scenario of the signaling molecules in the protostomes, and to reconstruct possible copy numbers of signaling molecule-coding genes for the ancestral protostome. Our reconstruction suggests that P. fucata retains the ancestral protostome gene complement, providing further justifications for the use of this taxon as a model organism for developmental genomics research.

Differentiation of bone marrow-derived cells into regenerated mesothelial cells in peritoneal remodeling using a peritoneal fibrosis mouse model.

Marked thickening of the peritoneum and vasculopathy in the submesothelial compact zone have been reported in long-term peritoneal dialysis patients. Bone marrow (BM)-derived cell lines are considered to be useful tools for therapy of various diseases. To clarify the role of BM-derived cells in the peritoneal fibrosis (PF) model, we analyzed several lineages of cells in the peritoneum. BM cells from green fluorescent protein (GFP) transgenic mice were transplanted into naïve C57Bl/6 mice. Chlorhexidine gluconate (CG) was injected intraperitoneally to induce PF. Immunohistochemical analysis was performed with parietal peritoneum using anti-Sca-1 or -c-Kit and -GFP antibodies. Isolated BM cells were also transplanted into the CG-stimulated peritoneum. BM-derived cells from GFP transgenic mice appeared in the submesothelium from days 14 to 42. Both GFP- and stem cell marker-positive cells were observed in the submesothelium and on the surface. Isolated c-Kit-positive cells, transplanted into the peritoneal cavity, differentiated into mesothelial cells. In this study, we investigated whether or not BM-derived cells play a role in the repair of PF and immature cells have the potential of inducing repair of the peritoneum. The findings of this study suggest a new concept for therapy of PF.

Establishment of a peritoneal mesothelial cell line from a transgenic rat harbouring the temperature-sensitive simian virus 40 large T-antigen gene.

BACKGROUND: Establishing a peritoneal mesothelial cell (MC) line in which the native characteristics of primary MCs are constantly maintained in vivo is of great significance for investigating their morphological and functional changes in peritoneal dialysis. We established transgenic (Tg) rats that expressed the temperature-sensitive tsA58 mutant of the simian virus 40 large T-antigen (tsSV40T), which served as a source of immortalized rat cell lines. The cells were immortalized at a permissive temperature of 33 degrees C, although they were differentiated at a non-permissive temperature of 38 degrees C. In this study, we established a novel MC line from tsSV40T Tg rats and evaluated its characteristics. METHODS: MCs were isolated from 8-week-old tsSV40T Tg rats and cloned. MCs from 8-week-old Wistar rats were used as controls. These cells were immunohistochemically and phenotypically evaluated by immunofluorescence, phase contrast and electron microscopy. The production of plasminogen activator inhibitor 1 (PAI-1) from MCs stimulated by tumour necrosis factor-alpha (TNF-alpha) was measured. RESULTS: The tsSV40T MCs showed a cobblestone-like appearance at 33 and 38 degrees C, which was similar to normal primary cultured MCs. Microvilli-like structures were observed on the cell surface by a scanning electron microscope at 33 and 38 degrees C. Wilms tumour-1 and pancytokeratin, as MC markers, were expressed at 33 and 38 degrees C. Following TNF-alpha stimulation, PAI-1 production of tsSV40T MCs was similar to that of normal primary cultured MCs. CONCLUSION: We established a novel, conditionally immortalized MC line that continuously retained the characteristics of primary cultured peritoneal MCs. This cell line might be a useful tool for various types of in vitro biological research on peritoneal dialysis.

Peritoneal fibrosis intervention.

Peritoneal fibrosis (PF) is invariably observed in patients undergoing long-term peritoneal dialysis (PD). The condition is thought to occur in response to a variety of insults, including bioincompatible dialysates (acidic solution, high glucose, glucose degradation products, or a combination), peritonitis, uremia, and chronic inflammation. Recently, the pathophysiologic mechanisms that contribute to the fibrosing process have been intensively studied. Transforming growth factor-beta has been shown to be a key mediator of PF. Loss of the mesothelial cell layer has been identified in several studies and shown to correlate with submesothelial thickening and vasculopathy. An association has also been identified between increased submesothelial thickness in the peritoneal membrane and increased solute transport, suggesting a relationship between PF and loss of ultrafiltration capacity. Thus, to maintain long-term PD and improve quality of life for patients, it is important to develop interventions for prevention and treatment of PF. Several strategies for peritoneal fibrosis intervention have been reported, including developing biocompatible dialysate, targeting mediators responsible for inflammation and fibrosis, and reconstituting the peritoneum using mesothelial or bone marrow-derived cells. Recent experimental trials in animal models and clinical studies are presented in this review.

Inhibitory effects of matrix metalloproteinase inhibitor ONO-4817 on morphological alterations in chlorhexidine gluconate-induced peritoneal sclerosis rats.

BACKGROUND: The activity of gelatinase, matrix metalloproteinase-2, in effluent was increased in peritoneal dialysis patients with encapsulated peritoneal sclerosis (EPS) and in chlorhexidine gluconate-induced peritoneal sclerosing (PS) animal models. The objective of the present study was to investigate the effect of matrix metalloproteinase inhibitor (ONO-4817), an anticancer agent with anti-angiogenesis and anti-infiltration effects, on the development of peritoneal fibrosis in chlorhexidine gluconate-induced PS rats. METHODS: Forty-five Sprague-Dawley (S-D) rats were intraperitoneally injected with saline as control (n = 15) or with chlorhexidine gluconate (CH) (1.5 ml/100 g) in the CH group (n = 15). ONO-4817 (5 mg/rat) was administered intravenously to CH rats (the ONO-4817 group, n = 15) from initiation to the end of the study. After 22 days of ONO-4817 administration, the rats were sacrificed and the parietal peritoneum was harvested. The gene expressions of transforming growth factor-beta (TGF-beta), alpha-smooth muscle actin (alpha-SMA) and type I collagen in the peritoneum were analysed by the reverse transcription-polymerase chain reaction (RT-PCR). Peritoneal tissues were also evaluated immunohistologically. RESULTS: ONO-4817 significantly inhibited thickening of the submesothelial layer and accumulation of type I collagen in the peritoneum. ONO-4817 also prevented increases of the number of macrophages and blood vessels. The expressions of TGF-beta, alpha-SMA and type I collagen in the peritoneum were markedly suppressed in ONO-4817-treated rats. CONCLUSION: It appears that the administration of the MMP inhibitor ONO-4817 might be a new approach to the amelioration of PS.