On the Commemorative Ceremony and Symposium for the 20th Anniversary of Food Safety Commission, Cabinet Office, Government of Japan.

Food Safety Commission, Cabinet Office, Government of Japan (FSCJ) was established in 2003 and marked its 20th anniversary in 2023. FSCJ held a commemorative ceremony and symposium to celebrate its 20th anniversary at Mita conference hall (Mita, Minato-ku, Tokyo) on September 1st, 2023, which attracted a total of 164 on-site attendees including six media companies, as well as 460 online viewers. FSCJ Chairperson Dr. YAMAMOTO gave a summary of each session; Session 1 outlined the various future challenges against which risk assessment organizations must prepare. In Session 2, panelists shared information on the development of new evaluation methodologies and international collaborations in order to meet various global demands and issues. In Session 3, the FSCJ introduced its future initiatives and called for international collaboration in sharing information and expertise to address data gaps and emerging issues, to which all panelists expressed their support. The importance of personnel development to tackle these challenges was also raised. In concluding the seminar, Dr. YAMAMOTO expressed that the common understanding gained from this occasion was the most fruitful achievement, owing to the international colleagues who shared their thought-provoking presentations and insights.

On the Commemorative Ceremony and Symposium for the 20th Anniversary of Food Safety Commission, Cabinet Office, Government of Japan.

Food Safety Commission, Cabinet Office, Government of Japan (FSCJ) was established in 2003 and marked its 20th anniversary in 2023. FSCJ held a commemorative ceremony and symposium to celebrate its 20th anniversary at Mita conference hall (Mita, Minato-ku, Tokyo) on September 1st, 2023, which attracted a total of 164 on-site attendees including six media companies, as well as 460 online viewers. FSCJ Chairperson Dr. YAMAMOTO gave a summary of each session; Session 1 outlined the various future challenges against which risk assessment organizations must prepare. In Session 2, panelists shared information on the development of new evaluation methodologies and international collaborations in order to meet various global demands and issues. In Session 3, the FSCJ introduced its future initiatives and called for international collaboration in sharing information and expertise to address data gaps and emerging issues, to which all panelists expressed their support. The importance of personnel development to tackle these challenges was also raised. In concluding the seminar, Dr. YAMAMOTO expressed that the common understanding gained from this occasion was the most fruitful achievement, owing to the international colleagues who shared their thought-provoking presentations and insights.

Blockade of vasoactive intestinal peptide receptor 2 (VIPR2) signaling suppresses cyclin D1-dependent cell-cycle progression in MCF-7 cells.

Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a G protein-coupled receptor that binds to Gαs, Gαi, and Gαq proteins to regulate various downstream signaling molecules, such as protein kinase A (PKA), phosphatidylinositol 3-kinase (PI3K), and phospholipase C. In this study, we examined the role of VIPR2 in cell cycle progression. KS-133, a newly developed VIPR2-selective antagonist peptide, attenuated VIP-induced cell proliferation in MCF-7 cells. The percentage of cells in the S-M phase was decreased in MCF-7 cells treated with KS-133. KS-133 in the presence of VIP decreased the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and glycogen synthase kinase-3ß (GSK3ß), resulting in a decrease in cyclin D1 levels. In MCF-7 cells stably-expressing VIPR2, KS-133 decreased PI3K activity and cAMP levels. Treatment with the ERK-specific kinase (MEK) inhibitor U0126 and the class I PI3K inhibitor ZSTK474 decreased the percentage of cells in the S phase. KS-133 reduced the percentage of cells in the S phase more than treatment with U0126 or ZSTK474 alone and did not affect the effect of the mixture of these inhibitors. Our findings suggest that VIPR2 signaling regulates cyclin D1 levels through the cAMP/PKA/ERK and PI3K/AKT/GSK3ß pathways, and mediates the G1/S transition to control cell proliferation.

The efficacy and safety of intravenous immunoglobulin infusion in 12 h for the initial treatment of Kawasaki disease.

BACKGROUND: Approximately 10-20 % of individuals develop a recrudescent or persistent fever after intravenous immunoglobulin (IVIG) infusion for the initial treatment of Kawasaki disease. The aim of this study was to evaluate the efficacy and safety of the initial IVIG treatment of Kawasaki disease based on duration of infusion. METHODS: This retrospective, single-center study included 53 patients with Kawasaki disease who were initially treated with 2 g/kg of IVIG by means of a single infusion from June 2018 to August 2019. We classified patients into two groups based on the duration of the infusion: the 12-h group and the 24-h group. We compared the treatment response of the primary IVIG and its adverse events using the Mann-Whitney U test and Fisher's exact or Chi-square tests. RESULTS: There were no significant differences in the response to initial IVIG treatment between the two groups. The duration from treatment onset to defervescence was shorter in the 12-h group than the 24-h group (7 h vs. 12 h, respectively, p = 0.07); however, this was not significant. There were no significant between-group differences regarding adverse events. CONCLUSION: We concluded that the initial 12-h IVIG treatment was comparable to the 24-h treatment in terms of efficacy and safety. This will enable physicians to feel confident about pursuing a shorter course of treatment with similar results as conventional treatment and decide on administering additional therapy to their patients.

Quantitative prediction of transporter-mediated drug-drug interactions using the mechanistic static pharmacokinetic (MSPK) model.

Guidance/guidelines on drug-drug interactions (DDIs) have been issued in Japan, the United States, and Europe. These guidance/guidelines provide decision trees for conducting metabolizing enzyme-mediated clinical DDI studies; however, the decision trees for transporter-mediated DDIs lack quantitative prediction methods. In this study, the accuracy of a net-effect mechanistic static pharmacokinetics (MSPK) model containing the fraction transported (ft) of transporters was examined to predict transporter-mediated DDIs. This study collected information on 25 oral drugs with new active reagents that were used in clinical DDI studies as perpetrators (42 cases) from drugs approved in Japan between April 2016 and June 2020. The AUCRs (AUC ratios with and without perpetrators) of victim drugs were predicted using the net-effect MSPK model. As a result, 83 and 95% of the predicted AUCRs were within 1.5- and 2-fold error in the observed AUCRs, respectively. In cases where the victims were statins in which pharmacokinetics several transporters are involved, 70 and 91% of the predicted AUCRs were within 1.5- and 2-fold errors, respectively. Therefore, the net-effect MSPK model was applicable for predicting the AUCRs of victims, which are substrates for multiple transporters.

Integrated Use of In Vitro and In Vivo Information for Comprehensive Prediction of Drug Interactions Due to Inhibition of Multiple CYP Isoenzymes.

BACKGROUND: Mechanistic static pharmacokinetic (MSPK) models are simple, have fewer data requirements, and have broader applicability; however, they cannot use in vitro information and cannot distinguish the contributions of multiple cytochrome P450 (CYP) isoenzymes and the hepatic and intestinal first-pass effects appropriately. We aimed to establish a new MSPK analysis framework for the comprehensive prediction of drug interactions (DIs) to overcome these disadvantages. METHODS: Drug interactions that occurred by inhibiting CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in the liver and CYP3A in the intestine were simultaneously analyzed for 59 substrates and 35 inhibitors. As in vivo information, the observed changes in the area under the concentration-time curve (AUC) and elimination half-life (t1/2), hepatic availability, and urinary excretion ratio were used. As in vitro information, the fraction metabolized (fm) and the inhibition constant (Ki) were used. The contribution ratio (CR) and inhibition ratio (IR) for multiple clearance pathways and hypothetical volume (VHyp) were inferred using the Markov Chain Monte Carlo (MCMC) method. RESULT: Using in vivo information from 239 combinations and in vitro 172 fm and 344 Ki values, changes in AUC, and t1/2 were estimated for all 2065 combinations, wherein the AUC was estimated to be more than doubled for 602 combinations. Intake-dependent selective intestinal CYP3A inhibition by grapefruit juice has been suggested. By separating the intestinal contributions, DIs after intravenous dosing were also appropriately inferred. CONCLUSION: This framework would be a powerful tool for the reasonable management of various DIs based on all available in vitro and in vivo information.

[Development of the vasoactive intestinal peptide receptor 2 (VIPR2) antagonist peptide for the treatment of schizophrenia].

Schizophrenia affects approximately 24 million people worldwide. Existing medications for the treatment of schizophrenia work primarily by improving positive symptoms such as agitation, hallucinations, delusions, and aggression. They possess common mechanism of action (MOA), blocking to neurotransmitter receptors such as dopamine, serotonin, and adrenaline receptors. Although multiple agents are available for the treatment of schizophrenia, the majority do not address negative symptoms or cognitive dysfunction. In other cases, patients have drug-related adverse effects. The vasoactive intestinal peptide receptor 2 (VIPR2, also known as VPAC2 receptor) might be an attractive drug target for the treatment of schizophrenia because both clinical and preclinical studies have demonstrated a strong link between high expression/overactivation of VIPR2 and schizophrenia. Despite these backgrounds, the proof-of-concept of VIPR2 inhibitors has not been examined clinically. A reason might be that VIPR2 belongs to class-B GPCRs, and the discovery of small-molecule drugs against class-B GPCRs is generally difficult. We have developed a bicyclic peptide KS-133, which shows VIPR2 antagonist activity and suppresses cognitive decline in a mouse model relevant to schizophrenia. KS-133 has a different MOA from current therapeutic drugs and exhibits high selectivity for VIPR2 and potent inhibitory activity against a single-target molecule. Therefore, it may contribute to both the development of a novel drug candidate for the treatment of psychiatric disorders such as schizophrenia and acceleration of basic studies on VIPR2.

Sagittal alignment cut-off values for predicting future fall-related fractures in community-dwelling osteoporotic women.

PURPOSE: Determining the optimal cut-off value of sagittal alignment for detecting osteoporotic patients at high risk for fall-related fractures is essential for understanding fracture risk and informing clinicians and physical therapists. We determined the optimal cut-off value of sagittal alignment for detecting osteoporotic patients at high risk for fall-related fractures in this study. METHODS: In the retrospective cohort study, we enrolled a total of 255 women aged ≥ 65 years who visited an outpatient osteoporosis clinic. We measured participants' bone mineral density and sagittal alignment, including sagittal vertical axis (SVA), pelvic tilt, thoracic kyphosis, pelvic incidence, lumbar lordosis, global tilt, and gap score at the initial visit. The cut-off value for sagittal alignment that was significantly associated with fall-related fractures was calculated after using multivariate Cox proportional hazards regression analysis. RESULTS: Ultimately, 192 patients were included in the analysis. After a mean follow-up of 3.0 years, 12.0% (n = 23) had fractures due to falls. Multivariate Cox regression analysis confirmed that SVA (hazard ratio [HR] = 1.022, 95% confidence interval [CI] = 1.005-1.039) was the only independent predictor of fall-related fracture occurrence. The predictive ability of SVA for the occurrence of fall-related fractures was moderate (area under the curve [AUC] = 0.728, 95% CI = 0.623-0.834), with a cut-off value of 100 mm for SVA. SVA classified by cut-off value was also associated with an increased risk of developing fall-related fractures (HR = 17.002, 95% CI = 4.102-70.475). CONCLUSION: We found that assessing the cut-off value of sagittal alignment would be useful information in understanding fracture risk in postmenopausal older women.

Significance of Basal Membrane Permeability of Epithelial Cells in Predicting Intestinal Drug Absorption.

Drug absorption from the gastrointestinal tract is often restricted by efflux transport by P-glycoprotein (P-gp) and metabolism by CYP3A4. Both localize in the epithelial cells, and thus, their activities are directly affected by the intracellular drug concentration, which should be regulated by the ratio of permeability between apical (A) and basal (B) membranes. In this study, using Caco-2 cells with forced expression of CYP3A4, we assessed the transcellular permeation of A-to-B and B-to-A directions and the efflux from the preloaded cells to both sides of 12 representative P-gp or CYP3A4 substrate drugs and obtained the parameters for permeabilities, transport, metabolism, and unbound fraction in the enterocytes (fent) using simultaneous and dynamic model analysis. The membrane permeability ratios for B to A (RBA) and fent varied by 8.8-fold and by more than 3000-fold, respectively, among the drugs. The RBA values for digoxin, repaglinide, fexofenadine, and atorvastatin were greater than 1.0 (3.44, 2.39, 2.27, and 1.90, respectively) in the presence of a P-gp inhibitor, thus suggesting the potential involvement of transporters in the B membrane. The Michaelis constant for quinidine for P-gp transport was 0.077 µM for the intracellular unbound concentration. These parameters were used to predict overall intestinal availability (FAFG) by applying an intestinal pharmacokinetic model, advanced translocation model (ATOM), in which permeability of A and B membranes accounted separately. The model predicted changes in the absorption location for P-gp substrates according to its inhibition, and FAFG values of 10 of 12 drugs, including quinidine at varying doses, were explained appropriately. SIGNIFICANCE STATEMENT: Pharmacokinetics has improved predictability by identifying the molecular entities of metabolism and transport and by using mathematical models to appropriately describe drug concentrations at the locations where they act. However, analyses of intestinal absorption so far have not been able to accurately consider the concentrations in the epithelial cells where P-glycoprotein and CYP3A4 exert effects. In this study, the limitation was removed by measuring the apical and basal membrane permeability separately and then analyzing these values using new appropriate models.

Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer cell proliferation by enhancing the ERK pathway.

Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a class B G protein-coupled receptor with the neuropeptide VIP as a ligand. Increased VIPR2 mRNA expression and/or VIPR2 gene copy number has been documented in several cancers including breast carcinoma. However, the pathophysiological role of increased VIPR2 in the proliferation of breast cancer cells remains largely unknown. In this study, we found that VIPR2 overexpression in MCF-7 and MDA-MB-231 cells, human breast cancer cell lines, promoted cell proliferation. Increased VIPR2 also exacerbated intraperitoneal proliferation of breast cancer MDA-MB-231 cells in a tumor nude mouse model in vivo. Treatment with KS-133, a VIPR2-selective antagonist peptide, significantly inhibited VIP-induced cell proliferation in VIPR2-overexpressing MCF-7 and MDA-MB-231 cells. Overexpressed VIPR2 caused increases in the levels of cAMP and phosphorylated extracellular signal-regulated kinase (ERK), which involves a VIPR2 signaling pathway through Gs protein. Additionally, phosphorylation of vasodilator-stimulated phosphoprotein (Ser157) and cAMP response element binding protein (Ser133) in VIPR2-overexpressing MCF-7 cells was greater than that in control cells, suggesting the increased PKA activity. Moreover, an inhibitor of mitogen-activated protein kinase kinase, U0126, attenuated tumor proliferation in exogenous VIPR2-expressing MCF-7 and MDA-MB-231 cells at the same level as observed in EGFP-expressing cells treated with U0126. Together, these findings suggest that VIPR2 controls breast tumor growth by regulating the cAMP/PKA/ERK signaling pathway, and the excessive expression of VIPR2 may lead to an exacerbation of breast carcinoma.

[A new method for assessing depressive-like behaviors in female mice].

Depression is a common mental disorder and mainly characterized by persistent sadness and a lack of interest or pleasure in previously rewarding or enjoyable activities. Despair is also a common symptom of depression, and the forced swim and tail suspension tests are widely used to measure this behavior in rodents, but the results from these tests can include the effects on stress resistance in addition to depressive-like states. Reduced motivation is an important marker of psychiatric disorders, including depression, and thus we have previously developed the female encounter test, a novel and simple procedure for assessing reward-seeking behavior in adult male mice. Importantly, female mice should be considered in the development of animal models of depression and assessment of mouse behaviors since the lifetime prevalence of a major depressive disorder in women is almost twice that in men, and around one in seven women can develop postpartum depression. In this review, we summarized our recent research on the male encounter test for assessing motivation in adult female mice and introduced new topics on animal models and therapeutic drugs for postpartum depression.

Does locomotive syndrome severity predict future fragility fractures in community-dwelling women with osteoporosis?

OBJECTIVES: We investigated whether the locomotive syndrome (LS) severity affects future fragility fractures in osteoporosis patients. METHODS: In this retrospective cohort study, 315 women with osteoporosis (mean follow-up period, 2.8 years) were reviewed, of whom 244 were included in the analysis. At baseline, we obtained medical information, bone mineral density of the lumbar spine and femoral neck, and sagittal vertical axis. Additionally, LS risk was assessed using the two-step test, stand-up test, and 25-question geriatric locomotive function scale scores. The LS risk test results were used to classify LS severity, which was rated on a 4-point scale from stage 0 (robust) to 3 (worsening). Cox proportional hazards regression analysis was used to determine the association of the severity with future fragility fracture. RESULTS: Fragility fractures occurred in 37 of 315 participants (11.8%). This study showed that sagittal vertical axis (hazard ratio = 1.014; 95% confidence interval, 1.005-1.023; p value = 0.003) and LS severity (hazard ratio =1.748; 95% confidence interval, 1.133-2.699; p = 0.012) were independent risk factors for incidence of fragility fracture. CONCLUSIONS: This study revealed the LS severity to predicted fragility fractures. We suggested that the progression of LS associated with osteoporosis increases the fracture risk.

Roles of the monoaminergic system in the antidepressant effects of ketamine and its metabolites.

While the molecular target of (R,S)-ketamine (ketamine) is thought to be the NMDA receptor, subanesthetic doses of ketamine have been known to modulate monoaminergic neurotransmission in the central nervous system. Although the involvement of the serotonergic system in the antidepressant effects of ketamine has been reported in most studies of this topic, some recent studies have reported that the dopaminergic system plays a key role in the effects of ketamine. Additionally, several lines of evidence suggest that the antidepressant-like effects of (R)-ketamine might be independent of the monoaminergic system. Ketamine metabolites also differ considerably in their ability to regulate monoamine neurotransmitters relative to (S)-ketamine and (R)-ketamine, while (2R,6R)-hydroxynorketamine might share common serotonergic signaling mechanisms with ketamine. In the current review, we summarize the effects of ketamine and its metabolites on monoamine neurotransmission in the brain and discuss the potential roles of the monoaminergic system in the mechanism of action of ketamine.

AlphaFold version 2.0 elucidates the binding mechanism between VIPR2 and KS-133, and reveals an S-S bond (Cys25-Cys192) formation of functional significance for VIPR2.

The vasoactive intestinal peptide receptor 2 (VIPR2) has attracted attention as a drug target for the treatment of mental disorders, cancer, and immune diseases. In 2021, we identified the peptide KS-133 as a VIPR2-selective antagonist. In this study, we aimed to elucidate the binding mechanism between VIPR2 and KS-133. To this end, VIPR2/KS-133 and VIPR2/vasoactive intestinal peptide (VIP) complex models were constructed through AlphaFold version 2.0 and molecular dynamic simulations. Our models revealed that: (i) both KS-133 and VIP have helical structures, (ii) the interaction residues on VIPR2 for both peptides are similar, and (iii) the orientation of their helices upon their binding to VIPR2 are different by ∼45°. Interestingly, in the process of constructing the aforementioned models, an S-S bond formation between Cys25 and Cys192 of the human VIPR2 was identified. Although these two Cys residues are highly conserved among species (i.e., corresponding to Cys24 and Cys191 in the mouse), no previous reports regarding this S-S bond formation exist. In order to clarify the potential role of this S-S bond in the VIPR2 has functional consequences, a cell line expressing the mouse VIPR2(Cys24Ala, Cys191Ala) was generated. During the VIP stimulation of this cell line, the phosphorylation of AKT (a downstream signal marker of VIPR2) was found to be significantly attenuated, thereby suggesting that the S-S bond has a functional significance for VIPR2. Our study not only elucidates the VIPR2-binding mechanism of KS-133 for the first time, but also provides new insights into the structural biology of VIPR2.

Vasoactive intestinal peptide-VIPR2 signaling regulates tumor cell migration.

Phosphoinositide metabolism is critically involved in human cancer cell migration and metastatic growth. The formation of lamellipodia at the leading edge of migrating cells is regulated by metabolism of the inositol phospholipid PI(4,5)P2 into PI(3,4,5)P3. The synthesized PI(3,4,5)P3 promotes the translocation of WASP family verprolin homologous protein 2 (WAVE2) to the plasma membrane and regulates guanine nucleotide exchange factor Rac-mediated actin filament remodeling. Here, we investigated if VIPR2, a receptor for vasoactive intestinal peptide (VIP), has a potential role in regulating cell migration via this pathway. We found that silencing of VIPR2 in MDA-MB-231 and MCF-7 human breast cancer cells inhibited VIP-induced cell migration. In contrast, stable expression of exogenous VIPR2 promoted VIP-induced tumor cell migration, an effect that was inhibited by the addition of a PI3-kinase (PI3K)γ inhibitor or a VIPR2-selective antagonist. VIPR2 stably-expressing cells exhibited increased PI3K activity. Membrane localization of PI(3,4,5)P3 was significantly attenuated by VIPR2-silencing. VIPR2-silencing in MDA-MB-231 cells suppressed lamellipodium extension; in VIPR2-overexpressing cells, VIPR2 accumulated in the cell membrane on lamellipodia and co-localized with WAVE2. Conversely, VIPR2-silencing reduced WAVE2 level on the cell membrane and inhibited the interaction between WAVE2, actin-related protein 3, and actin. These findings suggest that VIP-VIPR2 signaling controls cancer migration by regulating WAVE2-mediated actin nucleation and elongation for lamellipodium formation through the synthesis of PI(3,4,5)P3.

Imipramine prevents Porphyromonas gingivalis lipopolysaccharide-induced microglial neurotoxicity.

Porphyromonas gingivalis (P. gingivalis) is a Gram-negative anaerobe involved in the pathogenesis of chronic periodontitis, including local inflammation of the oral cavity. However, periodontal disease has recently been identified as a significant factor in the pathogenesis of neural diseases, including Alzheimer's disease. A virulence factor, P. gingivalis-lipopolysaccharide (LPS-PG), is involved in pro-inflammatory responses, not only in peripheral tissues but also in the brain. In this study, we examined whether P. gingivalis-induced brain inflammation could be ameliorated by pharmacotherapy, using in vivo and in vitro studies. In an animal experiment, peripheral administration of LPS-PG induced inflammation in the hippocampus via microglial activation, which was inhibited by pre-treatment with the antidepressant imipramine. Similarly, LPS-PG-induced inflammation in MG-6 cells, a mouse microglial cell line, was inhibited by pre-treatment with imipramine, which caused imipramine-induced inhibition of NF-κB signaling. Culture media obtained from LPS-PG-treated MG-6 cells induced neuronal cell death in Neuro-2A cells, a mouse neuroblastoma cell line, which was prevented by pre-treatment of MG-6 cells with imipramine. These results indicate that imipramine inhibits LPS-PG-induced inflammatory responses in microglia and ameliorates periodontal disease-related neural damage.

Phospholipase C-related catalytically inactive protein enhances cisplatin-induced apoptotic cell death.

Cisplatin is one of the most widely used chemotherapeutic agents and induces caspase-9-mediated apoptosis. Here, we examined whether phospholipase C-related catalytically inactive protein (PRIP) enhances cisplatin-induced apoptosis of breast cancer cells. PRIP depletion increased expression of X-linked inhibitor of apoptosis protein (XIAP) by inhibiting protein degradation, which is downstream of the phosphatidylinositol 3-kinase/AKT pathway and inhibits apoptotic signaling by blocking caspase-9 activation. Conversely, the viability of MCF-7 cells transfected with Prip1 was significantly lower than that of control cells in the presence of cisplatin. The number of apoptotic nuclei and expression levels of cleaved caspase-9 and downstream cleaved caspase-7 and poly-ADP ribose polymerase were greater in PRIP1-expressing MCF-7 cells treated with cisplatin than in control cells. XIAP was decreased by expression of pleckstrin homology domain of PRIP1 (PRIP1-PH domain) that blocked phosphatidylinositol 4,5 bisphosphate metabolism. In an orthotopic transplantation model, combined administration of PRIP1-PH domain-containing liposomes and cisplatin reduced the size of MCF-7 tumors compared with cisplatin alone. Our findings demonstrate that PRIP promotes XIAP degradation by inhibiting PI(3,4,5)P3/AKT signaling and enhances cisplatin-induced apoptotic cell death. Therefore, we propose that PRIP1-PH liposomes are a novel agent to avoid cisplatin resistance.

Successful Preoperative Partial Splenic Artery and Aneurysm Embolization for Thrombocytopenia Associated with Failed Fontan Circulation.

Long-term complications after the Fontan procedure are important concerns for patients with pediatric and adult congenital heart disease. Although thrombocytopenia due to portal hypertension and hypersplenism is a well-known complication of the Fontan circulation, few studies have reported on its management. Herein we describe a young adult Fontan patient with thrombocytopenia and a splenic artery aneurysm caused by conduit stenosis. The patient required conduit replacement due to high venous pressure. We performed partial splenic artery embolization (PSE) and embolization of the aneurysm preoperatively to reduce the risk of bleeding, resulting in successful subsequent cardiac surgery. Preoperative evaluation of the splenic artery aneurysm was informative, and PSE was a safe and effective treatment option for thrombocytopenia to avoid bleeding during open-heart surgery in this patient.

Prenatal exposure to valproic acid causes allodynia associated with spinal microglial activation.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and social interaction and the presence of restricted, repetitive behaviors. Additionally, difficulties in sensory processing commonly occur in ASD. Sensory abnormalities include heightened or reduced sensitivity to pain, but the mechanism underlying sensory phenotypes in ASD remain unknown. Emerging evidence suggests that microglia play an important role in forming and refining neuronal circuitry, and thus contribute to neuronal plasticity and nociceptive signaling. In the present study, we investigated the age-dependent tactile sensitivity in an animal model of ASD induced by prenatal exposure to valproic acid (VPA) and subsequently assessed the involvement of microglia in the spinal cord in pain processing. Pregnant ICR (CD1) mice were intraperitoneally injected with either saline or VPA (500 mg/kg) on embryonic day 12.5. Male offspring of VPA-treated mothers showed mechanical allodynia at both 4 and 8 weeks of age. In the spinal cord dorsal horn in prenatally VPA-treated mice, the numbers and staining intensities of ionized calcium-binding adapter molecule 1-positive cells were increased and the cell bodies became enlarged, indicating microglial activation. Treatment with PLX3397, a colony-stimulating factor 1 receptor inhibitor, for 10 days resulted in a decreased number of spinal microglia and attenuated mechanical allodynia in adult mice prenatally exposed to VPA. Additionally, intrathecal injection of Mac-1-saporin, a saporin-conjugated anti-CD11b antibody to deplete microglia, abolished mechanical allodynia. These findings suggest that prenatal VPA treatment causes allodynia and that spinal microglia contribute to the increased nociceptive responses.

[Important Points at Interpretation ofNongenotoxic-Carcinogenicity Induced by Pesticidesin Rodent Bioassays].

Assessment of carcinogenicity is important for human health at dietary risk assessment of pesticide residues. This article indicated important points on interpretation of carcinogenicity in toxicological evaluation of pesticide residues based on principles of risk analysis in foods by CODEX to be a guide for risk assessors. This guidance was referred from the guidance on carcinogenicity evaluation by international and/or national organizations, and the interpretations of Food Safety Commissions of Japan (FSCJ) published in their risk assessment reports. We focused on carcinogenicity obtained from routine carcinogenicity bioassays in rodents. The guidance includes the purpose and usefulness of the bioassay studies, consideration points to be carcinogenicity and influencing factors to carcinogenicity in the test to judge carcinogenic hazard at hazard identification. Considering on human relevance as carcinogenic hazard also was proposed using practical case examples. Next, a carcinogenic hazard is evaluated on dose-response relationship to judge points of departure on carcinogenicity. At the end of this article, we challenged our recommendation on future assessment of carcinogenicity to progress from hazard to risk.