Association between maternal blood or cord blood metal concentrations and catch-up growth in children born small for gestational age: an analysis by the Japan environment and children's study.

BACKGROUND: Catch-up growth issues among children born small for gestational age (SGA) present a substantial public health challenge. Prenatal exposure to heavy metals can cause adverse effects on birth weight. However, comprehensive studies on the accurate assessment of individual blood concentrations of heavy metals and their effect on the failure to achieve catch-up growth remain unavailable. This study aimed to evaluate the effects of uterine exposure to toxic metals cadmium, lead, and mercury and essential trace metals manganese and selenium at low concentrations on the postnatal growth of children born SGA. METHODS: Data on newborn birth size and other factors were obtained from the medical record transcripts and self-administered questionnaires of participants in the Japan Environment and Children's Study. The blood concentrations of lead, cadmium, mercury, selenium, and manganese in pregnant women in their second or third trimester were determined by inductively coupled plasma mass spectrometry. These heavy metal concentrations were also assessed in pregnant women's cord blood. Furthermore, the relationship between each heavy metal and height measure/catch-up growth in SGA children aged 4 years was analyzed using linear and logistic regression methods. These models were adjusted for confounders. RESULTS: We studied 4683 mother-child pairings from 103,060 pregnancies included in the Japan Environment and Children's Study. Of these, 278 pairs were also analyzed using cord blood. At 3 and 4 years old, 10.7% and 9.0% of children who were born below the 10th percentile of body weight had height standard deviation scores (SDSs) below 2, respectively. Cord blood cadmium concentrations were associated with the inability to catch up in growth by 3 or 4 years old and the height SDS at 3 years old. In maternal blood, only manganese was positively associated with the height SDS of SGA children aged 2 years; however, it was not significantly associated with catch-up growth in these children. CONCLUSION: Cadmium exposure is associated with failed catch-up development in SGA children. These new findings could help identify children highly at risk of failing to catch up in growth, and could motivate the elimination of heavy metal (especially cadmium) pollution to improve SGA children's growth.

Individual and mixed metal maternal blood concentrations in relation to birth size: An analysis of the Japan Environment and Children's Study (JECS).

BACKGROUND: Growth restriction in the prenatal period is a significant public health concern. Metals can negatively affect birth size, and pregnant women may be exposed to metal mixtures. Comprehensive studies analyzing the effects of combined metal exposure with accurate individual blood metal concentrations are limited. The current study investigated the associations between maternal metal exposure and birth size in a large, nationwide Japanese cohort using individual and mixed model approaches. METHODS: Lead, cadmium, mercury, selenium, and manganese blood concentrations were measured in pregnant women in the Japan Environment and Children's Study (JECS). Measurements of infant birth size-including body weight, body length, and head and chest circumference-were collected. Linear and logistic regressions were used for birth size measurements and the odds of an infant being small in size for gestational age, respectively. Associations between combined metal mixtures and measurements at birth were evaluated using quantile g-computation and Bayesian kernel machine regression (BKMR). RESULTS: Of the 103,060 JECS pregnancies, 93,739 mother-infant pairs were analyzed. The linear regression models showed that lead, selenium, cadmium, and manganese-but not mercury-were associated with body weight. Cadmium was associated with length and chest circumference and mercury was associated with head circumference. Quantile g-computation revealed that manganese increased infant birth weight, length, head circumference, and chest circumference. Lead was the strongest negative factor for infant birth weight, length, head circumference, and chest circumference. The BKMR analysis revealed that the metals had an additive, rather than a synergistic effect. CONCLUSION: Metal exposure is associated with infant birth size, with lead and manganese playing a more significant role in Japan. The effects of prenatal combined metal exposure at low levels warrant public health attention.

Lecithin Inclusion by α-Cyclodextrin Activates SREBP2 Signaling in the Gut and Ameliorates Postprandial Hyperglycemia.

BACKGROUND: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. METHODS: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. RESULTS: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). CONCLUSIONS: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.

The relationship of maternal PCB, toxic, and essential trace element exposure levels with birth weight and head circumference in Chiba, Japan.

Maternal exposure to high levels of persistent organic pollutants (POPs) and trace elements is an important concern for fetal growth. In our previous study, we showed the polychlorinated biphenyl (PCB) levels in maternal serum from the Chiba Study of Mother and Child Health (C-MACH) cohort and their relationships between PCB levels in cord serum with birth weight of newborn. Various reports on the relationship between chemical exposure and birth status have been published; however, studies that analyze the effects of both PCB and metal exposure together in one cohort are still limited. In this study, we aimed to determine the relationship of maternal serum levels of PCBs and toxic and essential trace elements [mercury (Hg), manganese (Mn), selenium (Se), and cadmium (Cd)], with birth weight and head circumference, in the C-MACH cohort. The median concentration of total PCBs in maternal serum around 32 gestational weeks (n = 62) was 360 pg g-1 wet wt (41 ng g-1 lipid wt). The levels of Hg, Mn, Se, and Cd in maternal serum were 0.89, 0.84, 100, and 0.024 ng g-1, respectively. In this study, the Bayesian linear model determined the relationships of the birth weight and head circumference with combinations of PCB levels, toxic and essential trace elements, and questionnaire data. We found that PCB concentrations in maternal serum were weakly and negatively related to birth weight, whereas trace elements were not associated with birth weight. Serum PCB and Mn levels were negatively associated with head circumference, whereas other trace elements were not associated with head circumference. These results showed that maternal exposure to PCBs may be related to birth weight and head circumference, while maternal exposure to Mn is related to head circumference, even when adjusted based on the exposure levels of other contaminants, and maternal and fetal characteristics. Therefore, our findings indicate that maternal exposure to PCBs and Mn might be negatively related with birth weight and head circumference.

Association Between Serum Folate Levels and Caffeinated Beverage Consumption in Pregnant Women in Chiba: The Japan Environment and Children's Study.

BACKGROUND: Several studies have reported the adverse effects of caffeine intake during pregnancy on fetal health. However, the effects of caffeine intake from green and oolong teas has not been investigated, despite the considerable consumption of these teas in Japan and the potential inhibitory effects of catechins-chemicals present at relatively high levels in green and oolong teas-on folic acid absorption. The potential associations of serum folate levels with caffeinated beverage consumption and catechin levels remain largely unstudied. The present study aimed to determine these associations in pregnant Japanese women. METHODS: Pregnant women (n = 2,701) not receiving folate supplementation were enrolled at the Chiba Unit Center, a regional site of the Japan Environment and Children's Study (JECS). Serum folate levels were measured using an Access folate assay kit, and nutrient and caffeine intakes were assessed using a self-administered food frequency questionnaire that was previously evaluated in Japanese populations. RESULTS: The low and normal serum folate groups reported caffeine intakes of 42.3 mg/1,000 kcal and 34.4 mg/1,000 kcal, respectively, and tannin intakes of 40.8 mg/1,000 kcal and 36.3 mg/1,000 kcal, respectively. Multiple regression analyses revealed negative associations of serum folate levels with caffeine and tannin intakes and a positive association between serum folate levels and dietary folate intake. CONCLUSIONS: Considering the negative associations of caffeine and tannin levels with serum folate levels, pregnant women should consume caffeinated beverages, such as coffee and green/oolong teas, with caution.

[Two Cases Pancreatic Carcinoma Detected Incidentally during Treatment of Acute Abdomen from Other Causes].

We report 2 cases of pancreatic cancer discovered incidentally in the wake of acute abdomen from other causes. Case 1 is a 67-year-old man who was referred to our hospital in October 2010 for the treatment of an incarcerated right inguinal hernia. The hernia was manually reduced, and mesh plug hernioplasty was scheduled for the next day. A 2.9 cm diameter tumor was detected in the tail of the pancreas on plain CT at the first visit and confirmed on enhanced CT soon after the hernia repair. A follow-up abdominal CT scan approximately 1 month later showed modest enlargement of the tumor to 3.5 cm diameter. The patient underwent distal pancreatectomy with lymph node dissection in December 2010. The histopathological diagnosis was tubular adenocarcinoma(tub1>tub2). Comprehensive findings were pT2, pN0, cM0, fStage II . He was treated with adjuvant chemotherapy consisting of gemcitabine 1,000mg/m2 for 6 months after surgery, and at 5 years and 7 months after surgery, he was alive and recurrence-free. Case 2 is a 74-year-old man who presented to our hospital with lower abdominal pain and diarrhea in early January 2016. Colonoscopy and barium enema revealed severe stenosis of the rectum(Rs). Rectal biopsy confirmed adenocarcinoma of the rectum. In addition, an enhanced CT scan showed irregular dilatation of the pancreatic duct in the pancreatic tail. The patient underwent low anterior resection and distal pancreatectomy, which was performed following an intraoperative pancreatic ultrasound examination that supported a diagnosis of pancreatic cancer. Pathological and comprehensive findings of rectal cancer were tubular adenocarcinoma(tub2)and pT3, pN0, cM0, fStage II , and those of the pancreatic cancer were tubular adenocarcinoma(tub2)and pT1, pN0, cM0, fStage I . The patient was discharged from the hospital 46 days after surgery. However, he died 18 days later due to sudden out-of-hospital cardiopulmonary arrest.

[CR of All Target Lesions in a Patient with Metastatic Esophageal Cancer and Generalized Weakness Treated with Systemic Chemotherapy after Nutritional Support].

We report here a case of CR of all target lesions in a patient with esophageal cancer with multiple metastases treated with systemic chemotherapy after nutritionalsupport. A 75-year-old man was referred to our hospital with a diagnosis of multiple- metastatic esophagealcancer in June 2014. He showed generalized weakness with poor dietary intake, and he was initially admitted for nutritional support by parenteral nutrition. Biopsy specimens revealed mixed squamous- and adenocarcinoma: MtLtUtAeG, 13 cm, type 2, cT3, IM1-St, cN3, cM1(liver, lungs, and stomach), cStage IV b esophagealcarcinoma. We had initiated 5-FU/CDDP/docetaxel(DCF)chemotherapy in July 2014. The target lesions exhibited PR after 2 courses of chemotherapy, and the primary esophageal lesion was markedly reduced, but was still present. The patient's renalfunction deteriorated after 8 courses of DCF, and the chemotherapy protocolwas changed to single-agent docetaxelonce every 3 weeks. The patient underwent 20 courses of the chemotherapy, and over a period of approximately 1 year from March 2015, CR of all target lesions was noted, with IR/SD of the primary tumor. The patient has survived and remained in good condition for 23 months following the initial diagnosis.

[Treatment strategy of papillary thyroid carcinoma for the unmarried woman].

We report an unmarried woman with papillary thyroid cancer. The patient was a 20-year-old woman who had neck tumor. The ultrasonography (US), CT, and aspiration biopsy cytology (ABC) were performed. The diagnosis of the tumor was papillary carcinoma of thyroid. The total thyroidectomy plus lymph nodes dissection (D2a) were performed. Two years after the first operation, we recognized lymph nodes swelling at her right neck. The US guided ABC was performed. The diagnosis was the metastasis of lymph node from thyroid cancer. We performed lymph nodes dissection again. Three years after the first operation, we detected the swelleing of lymph nodes again at her right neck. We performed lymph nodes dissection again. We recommended a therapeutic use of iodine radioisotopes. However, she rejected the therapy because she strongly wanted to be pregnant. Generally speaking, it is difficult to determine the therapeutic use of iodine radioisotopes for unmarried women. After seven years from the first operation, she delivered a baby girl. We plan to use of iodine radioisotopes for adjuvant therapy when she delivers her 2nd baby. This case suggested that a treatment strategy for unmarried thyroid cancer patients should be made thoughtfully with care.

[A case of breast cancer postoperative metastases to the liver obtained cCR].

A case is a 55-year-old woman. We noticed the right breast lump in May 2006. It was papillotubular carcinoma, ER(-), PgR -), HER2 (3+) by needle biopsy. The patient was introduced to our department in November 2006 for a close inspection and treatment. The palpation showed a mass without a firm flexibility, which was a border indistinctness of about 2 cm in size in the right AB area. We did not find a distant metastasis either. We operated for Bt+Ax (level II) in December. It was T2N0M0, stage IIA papillotubular carcinoma, ER(-), PgR(-), HER2 (3+) with histopathology. We recommended an adjuvant therapy but the patient refused. Since then we followed her up. After two years from the operation, multiple metastases were observed to the liver, FEC therapy was started. CT revealed that metastasized tumors were disappeared after six courses of treatment. Echography obtained cCR. Generally speaking, chemotherapy was effective for breast cancer as we compared it to endemic cancer of other organs. Meanwhile, it has been reported that many kinds of newly developed medicines for the treatment are available and effective. On the other hand, a selection of therapeutic drugs could be a problem for metastasized organs.

Menstruation recovery after chemotherapy and luteinizing hormone-releasing hormone agonist plus tamoxifen therapy for premenopausal patients with breast cancer.

PURPOSE: Little is known about the period required for menstruation recovery after long-term luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen therapy following chemotherapy. In this study we investigated the period required for menstruation recovery after the therapy. METHODS: The subjects comprised 105 premenopausal breast cancer patients who had undergone surgery. All patients were administered an LH-RH agonist for 24 months and tamoxifen for 5 years following the postoperative adjuvant chemotherapy, and the status of menstruation recovery was examined. RESULTS: Menstruation resumed in 16 cases (15.2%) after the last LH-RH agonist treatment session. The mean period from the last LH-RH agonist treatment to the recovery of menstruation was 6.9 months. The rate of menstruation recovery was 35.5% in patients aged 40 years or younger and 8.0% in those aged 41 years or older, and it was significantly higher in those aged 40 years or younger. The period until menstruation recovery tended to be longer in older patients at the end of treatment. CONCLUSION: This study showed that menstruation resumed after treatment at higher rates in younger patients. However, because it is highly likely that ovarian function will be destroyed by the treatment even in young patients, it is considered necessary to explain the risk to patients and obtain informed consent before introducing this treatment modality.

[Indoleamine 2,3-dioxygenase activity during chemotherapy or hormone therapy in patients with breast cancer].

We evaluated the significance of indoleamine 2,3-dioxygenase (IDO) in breast cancer patients during chemotherapy or hormone therapy. IDO activity can be measured by tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured by high performance liquid chromatography (HPLC). The correlations about Trp/Kyn ratio between chemotherapy group and hormone therapy group in pre-chemotherapies or post-chemotherapies were studied. The Trp/Kyn ratio of chemotherapy group in post-FEC chemotherapy phase and in post-wPTX chemotherapy phase was higher than in pre-chemotherapy phase. And the Trp/Kyn ratio of chemotherapy group is significantly higher than hormone therapy in post-FEC chemotherapy phase and in post-wPTX chemotherapy phase. There were no significant changes for the Trp/Kyn ratio of hormone therapy group in each phase. These results suggest that the hormone therapy may be less invasive for breast cancer patients than the chemotherapy.

Fetal exposure to phytoestrogens--the difference in phytoestrogen status between mother and fetus.

The goal of this study was to investigate fetal exposure to phytoestrogens, estrogenic compounds derived from plants, by measuring serum concentrations of phytoestrogens in maternal and cord blood. This study included 51 mothers scheduled for cesarean section (C-section), to obtain the serum of mother and fetus at almost the same time. Serum concentrations of phytoestrogens, including genistein (Gen), daidzein (Dai), coumestrol (Cou), equol (Equ; a metabolite of Dai), and sulfate-conjugated Gen, were measured in maternal and cord blood samples by LC-MS/MS and HPLC. It was found that phytoestrogens were transferred from mother to fetus. The detection rates of Gen, Dai, Equ, and Cou in cord serum were 100%, 80%, 35%, and 0%, respectively. Levels of Gen and Dai were higher in cord than in maternal serum (mean=19.4 ng/ml vs.7.2 ng/ml and 4.3 ng/ml vs.1.8 ng/ml for Gen and Dai, respectively). However, a reverse pattern was seen for Equ (cord mean=0.9 ng/ml, maternal mean=2.0 ng/ml). The correlations were significant between the concentration levels of Gen and Dai, Gen and Equ, and Gen and Dai plus Equ in cord serum. However, in maternal serum, the correlations were weak. Also, in 8 of 10 cord serum samples, sulfate-conjugated Gen was detected (mean=5.2 ng/ml, standard deviation=4.7), but it was detected from only one maternal serum (8.7 ng/ml). This study demonstrates placental transfer of phytoestrogens from mother to fetus. It is suggested that the metabolic and/or excretion rates of phytoestrogens are different between mother and fetus and once phytoestrogens are transferred to the fetus, they tend to stay in the fetal side longer than in the maternal side. While the implications for the health and development of the newborn are not known, these data suggest that the effects of fetal exposure to phytoestrogens should be studied further.