Parenting attitude towards children with autism spectrum disorders: the Japan environment and children's study.

OBJECTIVE: The primary objective of this study was to investigate the parenting attitudes towards children with autism spectrum disorders in early childhood in Japan. DESIGN: This study was a cohort study. The participants were enrolled from January 2011 to March 2014. We obtained the prevalence of autism spectrum disorders at 3 years of age, parenting attitudes and other factors from questionnaires. We divided the participants into two groups, an autism spectrum disorders group and a non-autism spectrum disorders group, and compared the parenting attitudes. SETTING: This study used data from a Japanese birth cohort study: the Japan Environment and Children's Study, conducted across 15 regional centres in Japan. PARTICIPANTS: The full dataset of the Japan Environment and Children's Study comprised 104 059 records. We excluded 17 889 records because the answer for the autism spectrum disorders in the questionnaire was blank. As a result, we analysed the remaining 82 411 mother-child pairs. MAIN OUTCOME MEASURES: The primary outcome variable was parenting attitudes at 3.5 years of age, which was assessed using a questionnaire. We asked respondents 16 questions related to parenting attitudes, and they answered based on their behaviours. The independent variable was the prevalence of autism spectrum disorders at 3 years of age. RESULTS: Of the 82 411 participants, the children with autism spectrum disorders at 3 years of age were 372 (0.45%). In most questions about parenting attitudes, the autism spectrum disorders group had unfavourable responses. The difference was particularly noticeable when the parents taught their children social discipline. Unfavourable parenting attitudes were 16.6% in the autism spectrum disorders group and 0.8% in the non-autism spectrum disorders group in the question item with the largest difference between the two groups, a significant difference. CONCLUSIONS: Parents of children with autism spectrum disorders tended to have unfavourable attitudes, suggesting the importance of parental training.

Environments affect blood pressure in toddlers: The Japan Environment and Children's Study.

BACKGROUND: The primary objective of this study was to examine risk factors for toddler's hypertension. METHODS: Subjects of this study were children and parents participating in a national birth cohort study in Japan, the Japan Environment and Children's Study. We measured the children's blood pressure (BP) at 2 and 4 years old. We obtained children's and parents' backgrounds from the questionnaire. We investigated the factors that affect BP elevation. RESULTS: Within 4988 participants, the mean systolic BP at 2 years old was 91.2 mmHg for boys and 90.0 mmHg for girls. The mean systolic BP at 4 years old was 93.8 mmHg for boys and 93.1 mmHg for girls. Parental smoking was associated with elevated values of BP at 2 and 4 years old. Obesity, gestational hypertension, and parental lower education were associated with elevated values of BP at 4 years old. Hypertensive group had a significantly higher obesity rate. The mother's lower education and parental smoking were involved in hypertensive groups. CONCLUSION: Parental smoking had a significant effect on BP even in early toddlers. We emphasize the importance of avoiding second-hand smoking from early infancy to prevent future lifestyle-related illnesses including hypertension. IMPACT: The mean systolic BP at 2 years old was 91.2 mmHg for boys and 90.0 mmHg for girls. The mean systolic BP at 4 years old was 93.8 mmHg for boys and 93.1 mmHg for girls. Obesity, parental smoking, and lower education were associated with hypertension at 4 years old. Parental smoking was associated with hypertension at 2 and 4 years old. We emphasize the importance of avoiding second-hand smoking from early infancy.

Timing of Maternal Smoking Cessation and Newborn Weight, Height, and Head Circumference.

OBJECTIVE: To examine the relationship between timing of smoking cessation during pregnancy and anthropometric indices of newborns. METHODS: Mothers and neonates enrolled in the JECS (Japan Environment and Children's Study), a nationwide birth cohort study, were examined. Patients with full-term neonates were included in the analysis, and 73,025 mother-neonate pairs with complete data were identified. The mothers were classified into six groups according to smoking status during pregnancy (nonsmokers [Q1, n=44,198]; ex-smokers who quit before pregnancy [Q2, n=16,461]; ex-smokers who quit in the first trimester [Q3, n=8,948]; ex-smokers who quit in the second trimester [Q4, n=498]; ex-smokers who quit in the third trimester [Q5, n=651]; and smokers who smoked throughout pregnancy [Q6, n=2,269)]). Data on smoking were based on questionnaires administered in the first, second, or third trimester and 1 month after delivery. The primary outcomes were birth weight, height, and head circumference. RESULTS: Compared with nonsmokers (Q1), no adverse outcomes were observed for ex-smokers who quit before pregnancy (Q2). The mean adjusted weights of male and female neonates were 135 g and 125 g lower, respectively, in Q6 participants than in Q1 participants. Comparing Q1 and Q6 participants, height was 0.6 cm and 0.7 cm smaller for male and female neonates, respectively. Head circumference in neonates of Q6 participants was 0.3 cm and 0.3 cm smaller for male and female neonates, respectively, than that in Q1 participants. Across all three measures, smoking cessation in the first and second trimester reduced the differential in outcomes between nonsmokers and individuals who smoked throughout pregnancy. CONCLUSION: Smoking during pregnancy is associated with reduced newborn birth weight, height, and head circumference. Earlier smoking cessation during pregnancy reduces the adverse effects of smoking on fetal growth.

Salt loading with unilateral nephrectomy accelerates decline in glomerular filtration rate in the hypertensive, obese, type 2 diabetic SDT fatty rat model of diabetic kidney disease.

For the evaluation of novel therapeutic agents for diabetic kidney disease (DKD), it is desirable to examine their efficacy in animal models by using the glomerular filtration rate (GFR) as an index. For this purpose, animal models that demonstrate a short-term GFR decline because of disease progression are required. Therefore, we aimed to develop such an animal model of DKD by using obese type 2 diabetic spontaneously diabetic Torii (SDT) fatty rats treated with salt loading by drinking water containing sodium chloride with or without unilateral nephrectomy. As a result, we have found that 0.3% salt loading with unilateral nephrectomy or 0.8% salt loading alone caused a rapid GFR decline, hypertension and rapid development of tubulointerstitial fibrosis. Moreover, the addition of losartan to a mixed diet suppressed the GFR decline in SDT fatty rats treated with 0.3% salt loading with unilateral nephrectomy. These results suggest that the model of SDT fatty rats treated with 0.3% salt loading and unilateral nephrectomy could be used as a hypertensive DKD model for evaluating therapeutic agents based on suppression of GFR decline.

Enteropeptidase inhibitor SCO-792 effectively prevents kidney function decline and fibrosis in a rat model of chronic kidney disease.

BACKGROUND: Inhibiting enteropeptidase, a gut serine protease regulating protein digestion, suppresses food intake and ameliorates obesity and diabetes in mice. However, the effects of enteropeptidase inhibition on kidney parameters are largely unknown. Here, we evaluated the chronic effects of an enteropeptidase inhibitor, SCO-792, on kidney function, albuminuria and kidney pathology in spontaneously hypercholesterolaemic (SHC) rats, a rat chronic kidney disease (CKD) model. METHODS: SCO-792, an orally available enteropeptidase inhibitor, was administered [0.03% and 0.06% (w/w) in the diet] to 20-week-old SHC rats showing albuminuria and progressive decline in glomerular filtration rate (GFR) for five weeks. The effects of SCO-792 and the contribution of amino acids to these effects were evaluated. RESULTS: SCO-792 increased the faecal protein content, indicating that SCO-792 inhibited enteropeptidase in SHC rats. Chronic treatment with SCO-792 prevented GFR decline and suppressed albuminuria. Moreover, SCO-792 improved glomerulosclerosis and kidney fibrosis. Pair feeding with SCO-792 (0.06%) was less effective in preventing GFR decline, albuminuria and renal histological damage than SCO-792 treatment, indicating the enteropeptidase-inhibition-dependent therapeutic effects of SCO-792. SCO-792 did not affect the renal plasma flow, suggesting that its effect on GFR was mediated by an improvement in filtration fraction. Moreover, SCO-792 increased hydrogen sulphide production capacity, which has a role in tissue protection. Finally, methionine and cysteine supplementation to the diet abrogated SCO-792-induced therapeutic effects on albuminuria. CONCLUSIONS: SCO-792-mediated inhibition of enteropeptidase potently prevented GFR decline, albuminuria and kidney fibrosis; hence, it may have therapeutic potential against CKD.

Author Correction: CD8+ T cell activation by murine erythroblasts infected with malaria parasites.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses.

Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at G2/M. We explored the relative importance of the PT DNA damage response (DDR) in kidney fibrosis by genetically inactivating ataxia telangiectasia and Rad3-related (ATR), which is a sensor and upstream initiator of the DDR. In human chronic kidney disease, ATR expression inversely correlates with DNA damage. ATR was upregulated in approximately 70% of Lotus tetragonolobus lectin-positive (LTL+) PT cells in cisplatin-exposed human kidney organoids. Inhibition of ATR resulted in greater PT cell injury in organoids and cultured PT cells. PT-specific Atr-knockout (ATRRPTC-/-) mice exhibited greater kidney function impairment, DNA damage, and fibrosis than did WT mice in response to kidney injury induced by either cisplatin, bilateral ischemia-reperfusion, or unilateral ureteral obstruction. ATRRPTC-/- mice had more cells in the G2/M phase after injury than did WT mice after similar treatments. In conclusion, PT ATR activation is a key component of the DDR, which confers a protective effect mitigating the maladaptive repair and consequent fibrosis that follow kidney injury.

Genetic variation of blast (Pyricularia oryzae Cavara) resistance in rice (Oryza sativa L.) accessions widely used in Kenya.

A total of 47 rice accessions collected from Kenya were investigated the genetic variations and classified into two cluster groups, A and B, by polymorphism data of 65 simple sequence repeat (SSR) markers. Clusters A and B corresponded to Japonica and Indica Groups, respectively. The number of Japonica Group accessions was limited in comparison with those of the Indica Group. Based on their patterns of reaction to standard differential blast isolates (SDBIs), these accessions and 57 control cultivars including differential varieties and several accessions harboring partial resistance genes were classified again into three cluster groups: Ia (high resistance), Ib (intermediate resistance) and II (susceptible). The rice accessions from Kenya were classified only into groups Ia and Ib. The accessions from Kenya were finally classified into three categories, A-Ia, B-Ia and B-Ib, based on the two classifications of polymorphism of SSR markers and resistance. The Indica Group accessions had wider genetic variation for blast resistance than did the Japonica Group accessions. The three leading cultivars (Basmati 217, Basmati 370 and ITA 310) categorized into Cluster group Ia were susceptible to some SDBIs from Kenya. The genetic variation for blast resistance in Kenya was demonstrated as the first report using SDBIs.

IL-23 protection against Plasmodium berghei infection in mice is partially dependent on IL-17 from macrophages.

Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites.

CD8(+) T cell activation by murine erythroblasts infected with malaria parasites.

Recent studies show that some human malaria parasite species Plasmodium falciparum and P. vivax parasitize erythroblasts; however, the biological and clinical significance of this is unclear. To investigate further, we generated a rodent malaria parasite (P. yoelii 17XNL) expressing GFP-ovalbumin (OVA). Its infectivity to erythroblasts was confirmed, and parasitized erythroblasts were capable of initiating malaria infections. Experiments showed that MHC class I molecules were highly expressed on parasitized erythroblasts. As CD8(+) T cells recognize MHC class I and peptide complexes on target cells, and are involved in protection or pathology against malaria, we examined whether erythroblasts are targeted by CD8(+) T cells. Purified non-parasitized erythroblasts pulsed with OVA peptides were recognized by OVA-specific CD8(+) T cells. Crucially, parasitized erythroblasts isolated from GFP-OVA-, but not GFP- infected-mice, activated OT-I CD8(+) T cells, indicating that CD8(+) T cells recognize parasitized erythroblasts in an antigen-specific manner.

Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role.

Microglia perform both neuroprotective and neurotoxic functions in the brain, with this depending on their state of activation and their release of mediators. Upon P2X(7) receptor stimulation, for example, microglia release small amounts of TNF, which protect neurons, whereas LPS causes massive TNF release leading to neuroinflammation. Here we report that, in rat primary cultured microglia, nicotine enhances P2X(7) receptor-mediated TNF release, whilst suppressing LPS-induced TNF release but without affecting TNF mRNA expression via activation of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs). In microglia, nicotine elicited a transient increase in intracellular Ca(2+) levels, which was abolished by specific blockers of alpha7 nAChRs. However, this response was independent of extracellular Ca(2+) and blocked by U73122, an inhibitor of phospholipase C (PLC), and xestospongin C, a blocker of the IP(3) receptor. Repeated experiments showed that currents were not detected in nicotine-stimulated microglia. Moreover, nicotine modulation of LPS-induced TNF release was also blocked by xestospongin C. Upon LPS stimulation, inhibition of TNF release by nicotine was associated with the suppression of JNK and p38 MAP kinase activation, which regulate the post-transcriptional steps of TNF synthesis. In contrast, nicotine did not alter any MAP kinase activation, but enhanced Ca(2+) response in P2X(7) receptor-activated microglia. In conclusion, microglial alpha7 nAChRs might drive a signaling process involving the activation of PLC and Ca(2+) release from intracellular Ca(2+) stores, rather than function as conventional ion channels. This novel alpha7 nAChR signal may be involved in the nicotine modification of microglia activation towards a neuroprotective role by suppressing the inflammatory state and strengthening the protective function.

Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia.

After a brain insult, ATP is released from injured cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor necrosis factor (TNF). The release of TNF appears to be dependent on the P2X7 receptor. The inhibitors 1,4-diamino-2,3-dicyano-1,4-bis[2-amino-phenylthio]butadiene (U0126), anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)IH-imidazole (SB203580), which target MEK (mitogen-activated protein kinase kinase), JNK (c-Jun N-terminal kinase), and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA is strongly inhibited by U0126 and SP600125. SB203580 did not affect the increased levels of TNF mRNA but did prevent TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38 [but not extracellular signal-regulated kinase (ERK)] could be inhibited by brilliant blue G, a P2X7 receptor blocker, and by genistein and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, which are general and src-family-specific tyrosine kinase inhibitors, respectively. Most important, we found that treatment of the microglia in neuron-microglia cocultures with the P2X7 agonist 2'-3'-O-(benzoyl-benzoyl) ATP led to significant reductions in glutamate-induced neuronal cell death, and that either TNF-alpha converting enzyme inhibitor or anti-TNF readily suppressed the protective effect implied by this result. Together, these findings indicate that both ERK and JNK are involved in the regulation of TNF mRNA expression, that p38 is involved in the nucleocytoplasmic transport of TNF mRNA, and that a PTK (protein tyrosine kinase), possibly a member of the src family, acts downstream of the P2X7 receptor to activate JNK and p38. Finally, our data suggest that P2X7 receptor-activated microglia protect neurons against glutamate toxicity primarily because they are able to release TNF.