Search

• The effect of N 2 O on glycinergic transmission was studied in rat spinal neurons. • N 2 O enhanced glycine-induced whole-cell currents only at low glycine concentrations. • N 2 O inhibited both spontaneous and evoked glycinergic responses. • The inhibition was induced on the presynaptic side. • Suppressed Ca2+ influx may explain partial inhibition of evoked transmission. We investigated the effects of nitrous oxide (N 2 O) on glycinergic inhibitory whole-cell and synaptic responses using a "synapse bouton preparation," dissociated mechanically from rat spinal sacral dorsal commissural nucleus (SDCN) neurons. This technique can evaluate pure single- or multi-synaptic responses from native functional nerve endings and enable us to accurately quantify how N 2 O influences pre- and postsynaptic transmission. We found that 70 % N 2 O enhanced exogenous glycine-induced whole-cell currents (I Gly) at glycine concentrations lower than 3 × 10–5 M, but did not affect I Gly at glycine concentrations higher than 10–4 M. N 2 O did not affect the amplitude and 1/e decay-time of both spontaneous and miniature glycinergic inhibitory postsynaptic currents recorded in the absence and presence of tetrodotoxin (sIPSCs and mIPSCs, respectively). The decrease in frequency induced by N 2 O was observed in sIPSCs but not in mIPSCs, which was recorded in the presence of both tetrodotoxin and Cd2+, which block voltage-gated Na+ and Ca2+ channels, respectively. N 2 O also decreased the amplitude and increased the failure rate and paired-pulse ratio of action potential-evoked glycinergic inhibitory postsynaptic currents. N 2 O slightly decreased the Ba2+ currents mediated by voltage-gated Ca2+ channels in SDCN neurons. We found that N 2 O suppresses glycinergic responses at synaptic levels with presynaptic effect having much more predominant role. The difference between glycinergic whole-cell and synaptic responses suggests that extrasynaptic responses seriously modulate whole-cell currents. Our results strongly suggest that these responses may thus in part explain analgesic effects of N 2 O via marked glutamatergic inhibition by glycinergic responses in the spinal cord. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are well-known inhibitors of cyclooxygenases (COXs) and are widely used for the treatment of inflammatory pain; however several NSAIDs display COX-independent analgesic action including the inhibition of voltage-gated Na + channels expressed in primary afferent neurons. In the present study, we examined whether NSAIDs modulate tetrodotoxin-resistant (TTX-R) Na + channels and if this modulation depends on the extracellular pH. The TTX-R Na + currents were recorded from small-sized trigeminal ganglion neurons by using a whole-cell patch clamp technique. Among eight NSAIDs tested in this study, several drugs, including aspirin and ibuprofen, did not affect TTX-R Na + channels either at pH 7.4 or at pH 6.0. However, we found that indomethacin, and, to a lesser extent, ibuprofen and naproxen potently inhibited the peak amplitude of TTX-R Na + currents at pH 6.0. The indomethacin-induced inhibition of TTX-R Na + channels was more potent at depolarized membrane potentials. Indomethacin significantly shifted both the voltage-activation and voltage-inactivation relationships to depolarizing potentials at pH 6.0. Indomethacin accelerated the development of inactivation and retarded the recovery from inactivation of TTX-R Na + channels at pH 6.0. Given that indomethacin and several other NSAIDs could further suppress local nociceptive signals by inhibiting TTX-R Na + channels at an acidic pH in addition to the classical COX inhibition, these drugs could be particularly useful for the treatment of inflammatory pain. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory pain. It is well established that NSAIDs exert their analgesic effects by inhibiting cyclooxygenase to prevent the production of prostaglandins; however, several NSAIDs including diclofenac also modulate other ion channels expressed in nociceptive neurons. In this study, we investigated the pH-dependent effects of diclofenac on tetrodotoxin-resistant (TTX-R) Na + channels in rat trigeminal sensory neurons by using the whole-cell patch clamp technique. Diclofenac decreased the peak amplitude of TTX-R Na + currents (I Na ) in a concentration dependent manner. While diclofenac had little effect on the voltage-activation relationship, it significantly shifted the steady-state fast inactivation relationship toward hyperpolarized potentials. Diclofenac increased the extent of use-dependent inhibition of TTX-R Na + currents. Diclofenac also significantly accelerated the development of inactivation and retarded the recovery from inactivation of TTX-R Na + channels. The effects of diclofenac on TTX-R Na + channels were stronger at pH 6.0 than at pH 7.4 for most of the parameters tested. Considering that the extracellular pH falls in inflamed tissues, and that TTX-R Na + channels expressed on nociceptive neurons are implicated in the prostaglandin-mediated development and maintenance of inflammatory hyperalgesia, our findings could provide an additional analgesic effect of diclofenac under acidic pH conditions. [ABSTRACT FROM AUTHOR]

Under pathological conditions including inflammation, ischemia and incision, extracellular pH falls down as low as 5.4. Although some mediators play pivotal roles in the development and maintenance of inflammatory hyperalgesia by affecting the functional properties of tetrodotoxin-resistant (TTX-R) Na + channels, the roles of tissue acidosis in nociceptive transmission mediated by TTX-R Na + channels are largely unknown. In the present study, we have investigated the effect of acidic pH on TTX-R Na + currents (I Na ) in small-sized sensory neurons isolated from rat trigeminal ganglia using a whole-cell patch clamp technique. Acidic pH decreased the peak amplitude of TTX-R I Na in a pH-dependent manner, but weak acid (≥pH 6.0) had a minor inhibitory effect on the TTX-R I Na . Acidic pH also significantly shifted both the activation and steady-state fast inactivation relationships toward depolarized potentials. In addition, acidic pH had little effect on the use-dependent inhibition, and significantly retarded the development of inactivation and accelerated the recovery from inactivation of TTX-R Na + channels. The results suggest that weak acid (≥pH 6.0) makes TTX-R Na + channels to be suitable for the repetitive activation at depolarized membrane potentials. Given that both tissue acidosis and inflammatory mediators in inflamed or injured tissues act synergistically to promote nociceptive transmission by affecting the functional properties of TTX-R Na + channels, these channels would be, at least in part, a good target to treat inflammatory pain. [ABSTRACT FROM AUTHOR]

Abstract: Histaminergic neurons within the tuberomammillary nucleus (TMN) play an important role in sleep-wakefulness regulation. Here, we report the muscarinic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in mechanically dissociated rat histaminergic neurons using a conventional whole-cell patch clamp technique. Muscarine, a nonselective muscarinic acetylcholine (mACh) receptor agonist, reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that muscarine acts presynaptically to decrease the probability of spontaneous GABA release. The muscarine action on GABAergic mIPSC frequency was completely blocked by atropine, a nonselective mACh receptor antagonist, and tropicamide, an M4 receptor antagonist. The muscarine-induced decrease in mIPSC frequency was completely occluded in the presence of Cd2+, a general voltage-dependent Ca2+ channel blocker, or in a Ca2+-free external solution. However, pharmacological agents affecting adenylyl cyclase or G-protein coupled inwardly rectifying K+ channel activity did not prevent the inhibitory action of muscarine on GABAergic mIPSCs. These results suggest that muscarine acts on M4 receptors on GABAergic nerve terminals projecting to histaminergic neurons to inhibit spontaneous GABA release via the inhibition of Ca2+ influx from the extracellular space. Muscarine also inhibited action potential-dependent GABA release by activating presynaptic M4 receptors in more physiological conditions. The M4 receptor-mediated modulation of GABAergic transmission onto TMN neurons may contribute to the regulation of sleep-wakefulness. [Copyright &y& Elsevier]

Abstract: The marine red alga Porphyra yezoensis contains an actin gene family consisting of at least four isoforms (PyACT1, 2, 3 and 4). The amino acid identity between isoforms exceeds 83%, and each contains a putative nuclear export signal (NES). We scanned the sequences for amino acids in regions homologous to the intermonomeric interface of actin filaments. Few residues expected to engage in cross-linking were conserved between the four isoforms. The results of the sequence analyses suggest that PyACT2 probably functions in the nucleus as a monomer (G-actin) or in other unconventional forms. In addition, the distribution and position of the introns were different from those in florideophycean actin genes. The expression level of PyACT3 in matured gametophytes was significantly higher than in those in a vegetative state, although the mRNA was detected at similar levels in both apical and basal parts of thalli. The expression levels of PyACT2 and 4, on the other hand, did not change significantly between the matured and vegetative gametophytes. The PyACT3 may serve as a molecular marker for monitoring thallus maturation in this species. [Copyright &y& Elsevier]

Abstract: α-Lipoic acid (ALA) is an essential cofactor in mitochondrial multi-enzyme complexes related to energy production. However, it is unstable under light or heat, and its decomposition is accompanied by an unpleasant odor. Therefore, its stabilization by complex formation with the cationic polymer chitosan (CS) was investigated. The ALA dissolved in demineralized water was efficiently adsorbed on the precipitated insoluble CS particles, and an ALA–CS complex was obtained. The amount of ALA adsorbed on CS was affected by the CS species and the quantity ratio of ALA to CS. The ALA from the ALA–CS complex was released immediately by changing the pH. When ALA was incubated at 65°C, it melted and polymerized. In addition, some decomposition of ALA was also observed in the physical mixture of ALA with CS. However, the ALA–CS complex did not decompose at all under the same conditions. Thus, the stabilization of ALA was achieved by complex formation with CS. CS is useful as a material for the stabilization of ALA, leading to its clinical use. [Copyright &y& Elsevier]

Sacrococcygeal teratoma (SCT) is the most common fetal and neonatal tumor. While SCT is often associated with urological problems, the association between SCT and a urogenital sinus (UGS) anomaly is rare. A concurrent UGS anomaly may be an acquired condition due to resection of SCT because it is rarely found at birth. In our case in whom fetal imaging study showed an abdominal cystic lesion, SCT with a UGS anomaly was suspected at birth and confirmed by endoscopy before resection of SCT during the neonatal period. These findings revealed that UGS anomaly may develop congenitally. [ABSTRACT FROM AUTHOR]

Summary Introduction Renal abnormality is not a rare finding in infants with primary VUR. The pathophysiology of the renal abnormality is considered to be congenital or acquired. Congenital hypo/dysplastic kidney is a common finding in infants with primary VUR, especially in boys. However, the long-term impact of unilateral hypo/dysplastic kidney has not been elucidated. The aim of the current study is to clarify the long-term impact of unilateral hypo/dysplastic kidney with primary vesicoureteral reflux diagnosed in infancy. Material and methods The medical records of patients with primary VUR detected in infancy with unilateral hypo/dysplastic kidney on initial nuclear renal scan (<40% relative renal function) and no scar on the contralateral kidney were reviewed retrospectively. Among them, 29 patients who were followed for more than 5 years were included in this study. Their clinical outcomes including chronic kidney disease (CKD) stage using estimated glomerular filtration rate (GFR) and the incidences of hypertension and proteinuria were analyzed. Results Mean age at final visit was 12.4 years (range 5.9–22.2). Estimated GFR was evaluated in 26 patients at a mean age of 12.0 years (5.9–22.2). CKD stage was 1 in all. According to the guidelines of the Japanese Society of Hypertension, while none exceeded the standard level of systolic blood pressure (BP), two patients slightly exceeded the standard level of diastolic BP. In addition, no significant proteinuria was detected in all patients, although microalbuminemia was detected in 7.7% of patients. Discussion The prognosis of reflux nephropathy depends on the remnant renal tissue mass, that is, the number of normal nephrons. The normal congenital solitary kidney is reported to be hyperplastic with normal-sized glomeruli rather than hypertrophic ones with larger nephrons, and to have better long-term outcome regarding renal function. Accordingly, we speculated that patients with unilateral hypo/dysplastic kidney would have a similar number of nephrons to those without hypo/dysplastic kidney who have no or minimal scar as far as the contralateral kidney is well preserved. Long-term outcome of the current retrospective study was consistent with our speculation in terms of estimated GFR, proteinuria, or hypertension. Conclusions The present study demonstrated that significant clinical findings related to unilateral hypo/dysplastic kidney detected in infancy were rarely observed in the long term. Accordingly, unilateral hypo/dysplastic kidney seems to be a benign condition. To confirm this finding, further follow-up of these patients is necessary. Table Clinical outcome in infants with primary VUR and unilateral hypo/dysplastic kidney. Estimated GFR at final evaluation ( n = 26) 92.6–139.6 mL/min/1.73 m 2 , (CKD stage was 1 in all) Hypertension at final evaluation ( n = 29) Systolic hypertension None Diastolic hypertension 2 Proteinuria at final evaluation Proteinuria on dipstick ( n = 29) None Microalbuminuria (>30 mg/gCr) ( n = 26) 2 (7.7%) (33.6 mg/gCr, 39.0 mg/gCr) [ABSTRACT FROM AUTHOR]

Objective: To clarify the prevalence and chronological changes of testicular microlithiasis in isolated congenital undescended testes, retrospective chart review was performed.Materials and Methods: Among children with palpable isolated undescended testes who underwent orchiopexy at less than 3 years of age between January 2009 and May 2016, those who had preoperative testicular ultrasonography were enrolled. Testicular microlithiasis was classified as limited or classic.Results: Sixty-five patients (54 unilateral undescended testes and 11 bilateral undescended testes) were enrolled. Preoperative evaluation demonstrated limited testicular microlithiasis in only 2 undescended testes in 2 patients (1 with unilateral undescended testes and 1 with bilateral undescended testes). Of these patients, 1 with unilateral undescended testes had limited testicular microlithiasis and the other with bilateral undescended testes had classic testicular microlithiasis after surgery. Among 53 unilateral undescended testes without microlithiasis preoperatively, limited and classic testicular microlithiasis was found in 1 and 6 testes, respectively, during follow-up. Testicular microlithiasis was identified in 2 on the contralateral descended testis of unilateral undescended testes postoperatively. Among 10 patients with bilateral undescended testes without microlithiasis preoperatively, limited testicular microlithiasis was detected in 4 during follow-up. Testicular microlithiasis was not diminished or resolved during follow-up. The overall prevalence of testicular microlithiasis in undescended testes (21.1%) was significantly higher than that in the contralateral descended testis in patients with unilateral undescended testes (3.7%) (P < .01).Conclusion: Most testicular microlithiasis was identified postoperatively and never improved. The prevalence of testicular microlithiasis in isolated congenital undescended testes increased with time even if operated on early in life. [ABSTRACT FROM AUTHOR]

Per- and Polyfluoroalkyl substances (PFAS) have endocrine-disrupting effects. The ratio of the lengths of the second and fourth digits (2D:4D) is a noninvasive retrospective index of prenatal exposure to sex hormones, and estrogen receptor 1 (ESR1) polymorphisms may contribute to 2D:4D determination. We investigated whether ESR1 polymorphisms modify the effects of prenatal PFAS exposure on 2D:4D. Participants (n = 1024) with complete data in a prospective birth cohort study (the Hokkaido Study) were included, and maternal plasma in the third trimester was used to examine PFAS concentrations. 2D:4D was determined from photocopies of palms of children using Vernier calipers. ESR1 polymorphisms (rs2234693, rs9340799, and rs2077647) were genotyped by TaqMan polymerase chain reaction. PFAS and 2D:4D association with ESR1 polymorphisms was assessed by multiple linear regression adjusted for potential confounding factors. A 10-fold increase in maternal perfluorooctanoic acid (PFOA) concentration was associated with a 1.54% [95% confidence interval (CI): 0.40, 2.68] increase in mean 2D:4D in children with an AA genotype at rs9340799 and a 2.24% (95% CI: 0.57, 3.92) increase in children with an AA genotype at rs2077647. A 10-fold increase in perfluorododecanoic acid (PFDoDA) was associated with a significant increase in 2D:4D in children with the AA genotype [rs9340799, 1.18% (95% CI: 0.02, 2.34); and rs2077647, 1.67% (95% CI: 0.05, 3.28)]. These associations were apparent among males. A significant gene-environment interaction between PFOA or PFDoDA and ESR1 polymorphism was detected. These findings suggest that ESR1 polymorphisms modify the effects of prenatal exposure to PFAS on sex differentiation. • Per- and Polyfluoroalkyl substances (PFAS) affect 2D:4D in children. • Gene-environmental interaction detected between PFAS and ESR1 polymorphisms on 2D:4D. • These associations were apparent only among males. • ESR1 polymorphisms modify the effects of prenatal PFAS on 2D:4D among males. [ABSTRACT FROM AUTHOR]

• Curcumin and polyglycerol fatty acid ester have abbreviated as CUR and PGFE. • A novel amorphous CUR formulation with PGFE has stably enhanced water solubility. • The amorphous CUR has greatly improved absorbability. • The amorphous CUR has significantly reduced blood triglyceride concentrations. • As the mechanism, PGFE has suppressed CUR-CUR interaction and diffusion rate of CUR. Curcumin (CUR), a polyphenol, is an attractive component of functional foods, owing to various physiological activities. However, CUR is highly hydrophobic, insoluble in water, and difficult to absorb in the body. Here, we report an amorphous CUR formulation containing the dispersant polyglycerol fatty acid ester (PGFE), demonstrating high and stable water solubility. Improved water solubility enhanced the absorbability of CUR in our amorphous formulation along with enhanced triglyceride inhibition, compared to that in a commercial formulation. Nuclear Overhauser effect spectroscopy (NOESY) analysis revealed that PGFE reduced CUR-CUR interaction, resulting in higher dispersion and improved solubility of CUR. Taylor dispersion analysis showed a lower diffusion coefficient of CUR in the highly water-soluble formulation (with PGFE) than that in the low water-soluble formulation (without PGFE), which prevents recontact and recrystallization of CUR, which is trapped by PGFE. Overall, the amorphous CUR with high solubility could be used as a promising functional food. [ABSTRACT FROM AUTHOR]

Highlights • rs9340799 polymorphisms in the estrogen receptor affect the 2D:4D ratio. • The effect is more pronounced in the right hand of school-aged boys. • The effect is probably due to alterations in estrogen receptor activity. Abstract The ratio of the lengths of the 2nd and 4th digits (2D:4D) is considered an index of prenatal exposure to androgen. Indeed, androgen receptors have been linked to digit length, but estrogen receptors are rarely investigated in this context. Thus, we investigated the association between estrogen receptor 1 (ESR1) genetic polymorphisms and 2D:4D in school-aged children. The 2D:4D ratios were determined using Vernier calipers from photocopies of palms provided by 1800 children aged 7 years who were enrolled in an ongoing prospective cohort study in Hokkaido, Japan. The children were genotyped using cord blood collected at birth for single nucleotide polymorphisms in ESR1 , specifically PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The association between ESR1 polymorphisms and 2D:4D was assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the GG genotype at rs9340799 had a significantly lower 2D:4D in the right hand than boys with the AA/AG genotype (−0.96% lower, 95% confidence interval: −1.68 to −0.24). However, this association was detected only in boys born to non-smoking mothers. No significant differences were found between rs9340799 polymorphisms and 2D:4D among girls. There was also no link between 2D:4D and polymorphisms at rs2234693 and rs2077647. These data suggest that rs9340799 polymorphisms in ESR1 may contribute to digit length and 2D:4D. [ABSTRACT FROM AUTHOR]

This study assessed the estrogen-like potencies of bisphenol A (BPA) and its analogs (BPs) using in vivo and in silico approaches in zebrafish. Zebrafish embryos were exposed to 16 BPs, most of which concentration-dependently induced cytochrome P450 19A1b (CYP19A1b) expression. BPs-induced CYP19A1b expression was suppressed by fulvestrant, a nonselective high affinity antagonist for estrogen receptor (Esr) subtypes. For BPs that concentration-dependently induced CYP19A1b expression, we estimated their 50 % effective concentration (EC 50) and relative potencies (REPs) with respect to the potency of BPA for inducing CYP19A1b expression. BP C2, Bis-MP, and BPAF showed lower EC 50 than BPA, BPE, and BPF, while BPZ and BPB showed moderate EC 50. The REP order of the BPs was BP C2 (26) > Bis-MP (24) > BPAF (21) > BPZ (5.8) > BPB (2.7) > BPE (1.5) > BPF (0.63) > 2,4′-BPF (0.22), indicating that some BPs showed greater estrogenic potencies than BPA in our system. We also constructed in silico homology models of ligand binding domains for zebrafish Esr subtypes, including Esr1, Esr2a, and Esr2b. Molecular docking simulations of ligands with the Esr subtypes revealed the interaction energies of some BPs were lower than that of BPA. The interaction energies showed significant positive correlations with their EC 50 values for inducing CYP19A1b expression in vivo. This study showed that some BPA analogs have greater estrogenic potencies than BPA and that in silico simulations of interactions between ligands and Esr subtypes may help predict in vivo estrogenic potencies of untested chemicals. [Display omitted] • Zebrafish CYP19A1b is a good marker to assess estrogenic potencies of bisphenols. • Some BPA alternatives showed greater CYP19A1b induction potencies than BPA. • Homology models of zebrafish Esr subtypes were constructed. • In silico BPs-Esr docking simulation may help predict in vivo estrogenic potencies. [ABSTRACT FROM AUTHOR]

Limited numbers of pediatric intratesticular cystic lesions have been reported. Although the majority of pediatric intratesticular cystic masses are benign, natural history of testicular cystic lesion in children has been rarely reported so far. We report a case of intratesticular cystic lesion in a prepubertal child who underwent testis sparing surgery after shrinkage during conservative follow-up. As an initial strategy for intratesticular cystic lesions in prepubertal children, observational approach with serial ultrasonographic evaluations may be a management of choice. [ABSTRACT FROM AUTHOR]

Abstract: Recently, many cases of children presenting reversible splenial lesions during febrile illness (RESLEF) have been reported; however, their overall clinico-radiological features are unclear. To describe the clinico-radiological features, we retrospectively reviewed the etiology (pathogen), clinical course, laboratory data, magnetic resonance imaging and electroencephalography (EEG) findings, therapy, and prognosis of 23 episodes in 22 children (1 child recurred) who presented neurological symptoms, with RESLEF. The etiologies (pathogens) varied. Seizure occurred in 7 episodes, disturbance of consciousness (DC) in 13, and delirious behavior in 18. Serum sodium levels <136mEq/L were observed in 18 episodes. Lesions outside the splenium were found in 4 cases. Slow waves were observed on EEG in 10 episodes. Methylprednisolone pulse therapy was given in 7 cases. No case resulted in neurological sequelae. Among 23 episodes, clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) was diagnosed in 6 episodes, whereas non-MERS was observed in 17 episodes. No difference was observed in almost all the clinico-radiological features’ data between the 2 groups. The largest differences were observed in the rate of purposeless movement, DC, extension of the abnormal lesions outside the splenium, and marked slowing of background activity on EEG. RESLEF exhibit a spectrum of clinico-radiological features. These results suggest that non-MERS and MERS both are a part of a larger pathological condition, which we have termed as RESLEF spectrum syndrome. Given the view that such a syndrome exists, the clinical characteristics and position of non-MERS and MERS become clear. [Copyright &y& Elsevier]

Abstract: Glycine and GABA are the primary inhibitory neurotransmitters in the spinal cord and brain stem, with glycine exerting its physiological roles by activating strychnine-sensitive ionotropic receptors. Glycine receptors are also expressed in the brain, including the cortex and hippocampus, but their physiological roles and pharmacological properties are largely unknown. Here, we report the pharmacological properties of functional glycine receptors in acutely isolated rat CA3 neurons using conventional whole-cell patch clamp techniques. Both glycine and taurine, which are endogenous agonists of glycine receptors, elicited Cl− currents in a concentration-dependent manner. The glycine-induced current (I Gly) was inhibited by strychnine, picrotoxin or cyclothiazide in a concentration-dependent manner. At lower concentrations (0.01–1 µM), ICS-205,930 potentiated I Gly, but at higher concentrations (>10 µM) it inhibited I Gly. These pharmacological properties strongly suggest that CA3 neurons express functional strychnine-sensitive glycine receptors containing α2 subunits. Furthermore, at lower concentrations (1–30 µM), Zn2+ potentiated I Gly, but at higher concentrations (>100 µM) it inhibited I Gly. Considering that Zn2+ is synaptically co-released with glutamate from mossy fiber terminals that make excitatory synapses onto CA3 neurons, these results suggest that endogenous Zn2+ modulation of these glycine receptors may have an important role in the excitability of CA3 neurons. [Copyright &y& Elsevier]

Abstract: Several clinical reports have indicated that autistic patients often show disturbance of the circadian rhythm, which may be related to dysfunction of the serotonergic system in the brain. Using rats exposed prenatally to valproic acid (VPA) as an animal model of autism, we examined locomotor activity and feeding under a reversed 12-h light/dark cycle, and found disturbance of the circadian rhythm characterized by frequent arousal during the light/sleep phase. In addition, measurement of brain serotonin (5-HT) level using in vivo microdialysis showed that the brain 5-HT level in VPA-exposed rats was significantly higher than that in control rats. These results suggest that a higher brain 5-HT level might be responsible for the irregular sleep/awake rhythm in autism. [Copyright &y& Elsevier]

• We examined ESR1 SNPs, finger length of 2D:4D, and prenatal phthalate/BPA exposure. • rs2077647 AG/GG with high MEHP/ΣDEHP exposure resulted in feminized 2D:4D in boys. • No significant differences were found among girls. • ESR1 polymorphisms modified the effects of prenatal DEHP on mean 2D:4D among boys. Phthalates and bisphenol A (BPA) are estrogenic endocrine disruptors. Polymorphisms in the gene encoding estrogen receptor 1 (ESR1) may contribute to the ratio of the lengths of the second and fourth digits (2D:4D), which is considered an index of prenatal exposure to sex hormones. Thus, we investigated whether ESR1 polymorphisms modify the effects of prenatal exposure to phthalates and BPA on 2D:4D in a birth cohort. Maternal serum in the first trimester was used to determine prenatal exposure to these compounds. Six hundred twenty-three children (7 years of age) provided mean 2D:4D from photocopies and were genotyped for single nucleotide polymorphisms in ESR1 , particularly PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The associations among compound exposure, mean 2D:4D, and ESR1 polymorphisms were assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the AG/GG genotype at rs2077647 in the group exposed to high levels of mono(2-ethylhexyl) phthalate (MEHP) or Σ Di(2-ethylhexyl) phthalate (DEHP) showed feminized 2D:4D compared with boys with the AA genotype at rs2077647 who had low exposure to MEHP or ΣDEHP (MEHP: increase in mean 2D:4D of 1.51%, 95% confidence interval [CI]: 0.40–2.63; ΣDEHP: increase in mean 2D:4D of 1.37%, 95% CI: 0.25–2.49). No significant differences were found among girls. There were no associations between mean 2D:4D and metabolites other than MEHP or BPA. These data suggest that ESR1 polymorphisms modify the effects of prenatal exposure to DEHP on mean 2D:4D among boys. [ABSTRACT FROM AUTHOR]