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Studies the detection and origin of 3-chloro-4-dichloromethyl-5-hydroxy-2(5H)furanone (MX) in river water. Sampling of river water; Extraction and fractionation of organic compounds; Determination of mutagenic activity by the Ames test; Chlorination of chemicals for isolation of MX.

Sjögren's syndrome (SS), an autoimmune disease primarily affecting the exocrine glands, particularly the lacrimal and salivary glands, typically manifests as sicca symptoms (dry mouth and dry eyes). However, these symptoms are uncommon in pediatric patients. We present a case of a 13-year-old boy diagnosed with SS following the detection of bilateral parotid gland microcalcifications during a computed tomography scan for headache evaluation. The patient presented with a chief complaint of persistent headaches and malaise. However, he did not have sicca symptoms. A plain head computed tomography scan revealed multiple microcalcifications within the bilateral parotid glands. The fat-suppressed T2-weighted magnetic resonance imaging scan showed bilateral parotid gland enlargement and scattered areas of high intensity within the parotid glands. The patient was diagnosed with SS based on a serological examination and salivary and lacrimal gland disorders. Treatment with hydroxychloroquine improved headache and fatigue substantially. The patient can now participate in sports and daily life activities without difficulty. These findings stress the importance of considering SS in the differential diagnosis of children with chronic headaches and malaise. The presence of calcification within the parotid gland should raise suspicion for SS, and imaging studies can be a valuable tool for diagnosis, providing crucial information for informed decision-making., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sugiyama et al.)

n-3 Long-chain polyunsaturated fatty acids (n-3 LC-PUFAs), including eicosapentaenoic acid (EPA), are essential multifunctional nutrients in animals. Microorganisms such as microalgae are known to be n-3 LC-PUFA producers in aquatic environments. Various aquatic invertebrates, including Harpacticoida copepods, and a few terrestrial invertebrates, such as the nematode Caenorhabditis elegans, possess n-3 LC-PUFA biosynthetic enzymes. However, the capacity for n-3 LC-PUFA biosynthesis and the underlying molecular mechanisms in terrestrial insects are largely unclear. In this study, we investigated the fatty acid biosynthetic pathway in the silkworm Bombyx mori and found that EPA was present in silkworms throughout their development. Stable isotope tracing revealed that dietary α-linolenic acid (ALA) was metabolized to EPA in silkworm larvae. These results indicated that silkworms synthesize EPA from ALA. Given that EPA is enriched in the central nervous system, we propose that EPA confers optimal neuronal functions, similar to docosahexaenoic acid, in the mammalian nervous system., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Uridine diphosphate- N -acetylglucosamine (UDP-GlcNAc) is one of the major nucleotide sugars in living organisms and serves as the key donor substrate for the post-translational modification of protein O -GlcNAcylation. It undergoes interconversion to its epimer uridine diphosphate- N -acetylgalactosamine (UDP-GalNAc), which acts as a sugar donor initiating mucin-type O -linked glycosylation. The intracellular levels of the two differ between the cell lines and largely fluctuate in response to metabolic perturbations, and recent studies have focused on the details of their biosynthesis or turnover. However, due to their similar chemical properties, sufficient resolution for the two epimers required non-volatile mobile phases that cannot be applied directly to a mass spectrometer. In this study, to implement simple liquid chromatography-mass spectrometry for UDP-GlcNAc and UDP-GalNAc, we optimized a condition of hydrophilic interaction liquid chromatography-mass spectrometry. We found that the use of ammonium hydroxide and an amide column with an optimized water-acetonitrile ratio, flow rate, and column temperature, provided complete separation of the two. The method allowed the analysis of intracellular levels, a stable isotope-labeled target, and patterns of product ion spectra in a single run with fewer sample preparation steps. The new method can be widely used for mass spectrometric analysis of UDP-GlcNAc and UDP-GalNAc.

Endocytosis is an essential biological process for nutrient absorption and intercellular communication; it can also be used to accelerate the cellular internalization of drug delivery carriers. Clarifying the cellular uptake mechanisms of unidentified endogenous and exogenous molecules and designing new effective drug delivery systems require an accurate, specific endocytosis analysis methodology. Therefore, we developed a method to specifically evaluate cellular internalization via three main endocytic pathways: clathrin- and caveolae-mediated endocytosis, and macropinocytosis. We first revealed that most known endocytosis inhibitors had no specific inhibitory effect or were cytotoxic. Second, we successfully established an alternative method using small interfering RNA to knock down dynamin-2 and caveolin-1, which are necessary for clathrin- and caveolae-mediated endocytosis, in HeLa cells. Third, we established another method to specifically analyze macropinocytosis using rottlerin on A431 cells. Finally, we validated the proposed methods by testing the cellular internalization of a biological molecule (insulin) and carriers (nanoparticles and cell-penetrating peptides). Through this study, we established versatile methods to precisely and specifically evaluate endocytosis of newly developed biopharmaceuticals or drug delivery systems., (© 2023 Federation of American Societies for Experimental Biology.)

Aging-induced neuroinflammation, also known as neuroinflammaging, plays a pivotal role in emotional disturbances, including depression and anxiety, in older individuals, thereby leading to cognitive dysfunction. Although numerous studies have focused on therapeutic strategies for cognitive impairment in older individuals, little research has been performed on treating its preceding emotional disturbances. Here, we examined whether Kampo formulas (kososan [KS], nobiletin-rich kososan [NKS], and hachimijiogan [HJG]) can ameliorate aging-induced emotional disturbances and neuroinflammation in mice. The depression-like behaviors observed in SAMP8 mice, relative to normally aging SAMR1 mice, were significantly prevented by treatment with Kampo formulas for 13 weeks. Western blot analysis revealed that hippocampal neuroinflammation was significantly abrogated by Kampo formulas. KS and NKS also significantly attenuated the hippocampal neuroinflammatory priming induced by lipopolysaccharide (LPS, 0.33 mg/kg, i.p. ) challenge in SAMP8 mice. Hippocampal IL-1β, IL-6, and MCP-1 levels were significantly decreased in NKS-treated SAMP8 mice. KS and NKS showed significantly reduced tau accumulation in the brains of SAMP8 mice. RNA-sequencing revealed that each Kampo formula led to unique dynamics of hippocampal gene expression and appeared to abrogate hippocampal inflammatory responses. HJG significantly blocked the LPS-induced increase in serum IL-6 and MCP-1. These results suggest that Kampo formulas would be useful for treating aging-induced depression, in part by regulating neuroinflammatory pathways. This finding may pave the way for the development of therapeutic strategies for aging-related emotional disturbances, which may contribute to the prevention of cognitive dysfunction in older individuals.

Background: The education system can serve as a community-based resource to support the provision of long-term follow-up care after large-scale disasters. While school-based interventions conducted after a disaster have been confirmed to reduce symptoms of depression and posttraumatic stress disorder (PTSD), adolescents often exhibit low treatment motivation. Traditional methods used to encourage treatment motivation include fun activities, such as applied improv (AIM). This study evaluated the intervention effects and improved motivation of an intervention program combining AIM with the behavioral activation approach (BAA)., Methods: Participants were 253 tenth graders, who were in fifth grade at the time the Great East Japan Earthquake of 2011, and 239 students were included in the analyses. Participants were divided into two groups: the BAA and AIM + BAA groups. Students in each group participated in one class-wide intervention session, which lasted 60 min. Depression, PTSD symptoms, behavioral activation, avoidance, and resilience were evaluated using psychological scales. A participant's evaluations of the intervention were confirmed using the impression sheet consisting of six items that measure comprehension, difficulty, efficacy, generalization, confirmation of a specific situation, and motivation., Results: A two-way analysis of variance (ANOVA) conducted using data from the psychological scale did not reveal a significant effect from the intervention program. However, the Mann-Whitney U -test, which used data from the impression sheet, showed a significant effect on comprehension ( p = 0.001), generalization ( p = 0.023), and motivation ( p = 0.025)., Conclusion: This study did not confirm the effectiveness of the BAA in reducing symptoms of depression and PTSD in adolescents. Regarding treatment motivation, the AIM + BAA group reported higher motivation than the BAA group. Thus, one session of AIM may contribute to improved treatment motivation in adolescents. AIM creates a safe environment and encourages engagement and participation in interventions. Treatment motivation is an important issue in adolescent therapy, and AIM may help solve this problem., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sugiyama, Koseki, Niikawa, Ito, Takahashi and Ishikawa.)

Aging causes psychological dysfunction and neurodegeneration, and can lead to cognitive impairments. Although numerous studies have reported that neurodegeneration and subsequent cognitive impairments are involved in neuroinflammation, relationship between psychological disturbance and neuroinflammation with aging (neuroinflammaging) remains unclear. Here, to clarify the relationship, we examined whether neuroinflammaging affects emotional behaviors in senescence-accelerated mouse prone 8 (SAMP8) mice. Microglial inflammatory responses to a subsequent lipopolysaccharide (LPS) challenge were significantly enhanced in male SAMP8 mice relative to normal aging senescence-accelerated mouse resistant 1 (SAMR1) mice at 17 weeks, but not 8 weeks of age. LPS injection also significantly increased brain and systemic inflammation in SAMP8 mice at 17 weeks. In a battery of behavioral tests, SAMP8 mice at 17 weeks, but not 8 weeks, exhibited anxiety- and depression-like behaviors and circadian rhythm disruption. Taken together, SAMP8 mice at 17 weeks possess a brain microenvironment in which it is easier to trigger neuroinflammatory priming; this may lead to an emergence of anxiety- and depression-like behaviors and circadian rhythm disruption. These findings provide new insights into the temporal relationship between neuroinflammaging and emotion., (Copyright © 2020. Published by Elsevier Inc.)

In liver microsomes, selexipag (NS-304; ACT-293987) mainly undergoes hydrolytic removal of the sulfonamide moiety by carboxylesterase 1 (CES1) to yield the pharmacologically active metabolite MRE-269 (ACT-333679). However, it is not known how much CES in the liver and intestine contributes to the hydrolysis of selexipag or how selexipag is metabolized in the intestine, including by hydrolysis. To obtain a better understanding of selexipag metabolism in humans, we determined the percentage contribution of CES1 and carboxylesterase 2 (CES2) to the hydrolysis of selexipag and 7 of its analogs with different sulfonamide moieties and evaluated its nonhydrolytic metabolism in human liver microsomes and human intestinal microsomes (HIMS). For selexipag, the percentage contributions of CES1 and CES2 in human liver microsomes were 77.0% and 9.99%, respectively, while the percentage contribution of CES2 in HIMS was 100%. In HIMS, the rate of hydrolysis of selexipag was the lowest among the compounds tested, and no difference between the presence and absence of nicotinamide adenine dinucleotide phosphate was noted. We infer from these results that selexipag is likely to be hydrolyzed by CES2 as well as CES1, and only selexipag itself and the MRE-269 produced by hydrolysis in the intestine would be absorbed after oral administration., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Visualization research often seeks designs that first establish an overview of the data, in accordance to the information seeking mantra: "Overview first, zoom and filter, then details on demand". However, in computational fluid dynamics (CFD), as well as in other domains, there are many situations where such a spatial overview is not relevant or practical for users, for example when the experts already have a good mental overview of the data, or when an analysis of a large overall structure may not be related to the specific, information-driven tasks of users. Using scientific workflow theory and, as a vehicle, the problem of viscous finger evolution, we advocate an alternative model that allows domain experts to explore features of interest first, then explore the context around those features, and finally move to a potentially unfamiliar summarization overview. In a model instantiation, we show how a computational back-end can identify and track over time low-level, small features, then be used to filter the context of those features while controlling the complexity of the visualization, and finally to summarize and compare simulations. We demonstrate the effectiveness of this approach with an online web-based exploration of a total volume of data approaching half a billion seven-dimensional data points, and report supportive feedback provided by domain experts with respect to both the instantiation and the theoretical model.

The relationship between Helicobacter pylori infection and gastric cancer associated with stomach lesions has been reported. Improvement of the adverse effects induced by H. pylori is required for human health. It has been reported that wasabi (Wasabiajaponica Matsum) leaves have various effects on bacteria and mammals. In this study, the effect was examined of wasabi leaf extract and allyl isothiocyanate (AIT), which is a main functional component of wasabi, on stomach lesions in Mongolian gerbils infected with H. pylori. After the gerbils infected with H. pylori were orally administrated with wasabi leaf extract and AIT for two weeks, colony forming units (CFU) of H. pylori, the degree of gastric mucosal erosion, and petechial hemorrhage in the stomachs of the gerbils were evaluated. Wasabi leaf extract and AIT exhibited a decreasing tendency of CFU in the stomachs. The degree of gastric mucosal erosion and petechial hemorrhage were significantly decreased by the intake of wasabi leaf extract and AIT. Wasabi leaf extract and AIT did not affect body weight, dietary intake, water intake, and the pH of the stomach. From these results, wasabi leaves and AIT may provide a natural remedy for stomach lesions induced by H. pylori.

In vitro estimating strategies for potential neurotoxicity are required to screen multiple substances. In a previous study, we showed that exposure to low-concentrations of some chemicals, such as organotin, decreased the expression of GluR2 protein, which is a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors, and led to neuronal vulnerability. This result suggested that GluR2 decreases as an index of neuronal cell sensitivity and vulnerability to various toxic insults. Accordingly, we developed a versatile method that is a large scale determination of GluR2 protein expression in the presence of environmental chemicals by means of AlphaLISA technology. Various analytical conditions were optimized, and then GluR2 protein amount was measured by the method using AlphaLISA. The GluR2 amounts were strongly correlated with that of measured by western blotting, which is currently used to determine GluR2 expression. An ideal standard curve could be written with the authentic GluR2 protein from 0 ng to 100 ng. Subsequently, twenty environmental chemicals were screened and nitenpyram was identified as a chemical which lead to decrease in GluR2 protein expression. This assay may provide a tool for detecting neurotoxic chemicals according to decreases in GluR2 protein expression.

The absolute optical power at 611 nm emitting from Eu doped Gd2O3 nano phosphors upon X-ray excitation from a microfocus X-ray source operated at 100 kV was measured with thin film photovoltaic cells (TFPCs), whose optical response was calibrated using an He-Ne laser at 632 nm. The same TFPCs were also used to determine the absorbed X-ray power by the nano phosphors. These measurements provided a convenient and inexpensive way to determine the absolute quantum efficiency of nano phosphors, normally a difficult task. The measured absolute X-ray-to-optical fluorescence efficiency of the nano phosphors annealed at 1100 °C was 3.2%. This is the first time such efficiency for Eu/Gd2O3 nano phosphors is determined, and the measured efficiency is a fraction of the theoretically predicted maximum efficiency of 10% reported in the literature.

Lignin modification has been a breeding target for the improvements of forage digestibility and energy yields in forage and bioenergy crops, but decreased lignin levels are often accompanied by reduced lodging resistance. The rice mutant gold hull and internode2 (gh2) has been identified to be lignin deficient. GH2 has been mapped to the short arm of chromosome 2 and encodes cinnamyl-alcohol dehydrogenase (CAD). We developed a long-culm variety, 'Leaf Star', with superior lodging resistance and a gh phenotype similar to one of its parents, 'Chugoku 117'. The gh loci in Leaf Star and Chugoku 117 were localized to the same region of chromosome 2 as the gh2 mutant. Leaf Star had culms with low lignin concentrations due to a natural mutation in OsCAD2 that was not present in Chugoku 117. However, this variety had high culm strength due to its strong, thick culms. Additionally, this variety had a thick layer of cortical fiber tissue with well-developed secondary cell walls. Our results suggest that rice can be improved for forage and bioenergy production by combining superior lodging resistance, which can be obtained by introducing thick and stiff culm traits, with low lignin concentrations, which can be obtained using the gh2 variety.

Objective: To clarify the effects of uterine myometrial suture techniques at prior caesarean section on the incidence of pathologically diagnosed placenta accreta in placenta praevia with prior caesarean section (PPPC)., Design: Case-control study., Setting: Eleven tertiary referral hospitals in central Japan., Population: A total of 98 cases of placenta praevia, a history of one or more prior caesarean sections, and a history of uterine transverse incision and usage of only absorbable thread for myometrial sutures at the prior caesarean section. Exclusions were a history of myomectomy or Strassmann's operation., Methods: Cases were grouped into a pathologically diagnosed placenta accreta group (38 cases) and a no accreta group (60 cases). Clinical characteristics including uterine suture methods at prior caesarean section were compared (single-layer versus double-layer closure; continuous versus interrupted sutures in the inner myometrial layer)., Main Outcome Measure: The incidence of placenta accreta., Results: No difference was found comparing single-layer with double-layer closure in the incidence of placenta accreta (37.1 versus 39.7%, P = 0.805); however, a significant difference was found comparing continuous with interrupted sutures (58.1 versus 29.9%, P = 0.008). Multivariable logistic regression analysis with stepwise selection for the eight factors meeting the criterion of P < 0.10 in univariate analysis was used, and four independent factors were selected, as follows: gravidity ≥ 3 (adjusted odds ratio, aOR, 3.4, 95% confidence interval, 95% CI, 0.99-11.6, P = 0.050); total praevia (versus non-total, aOR 18.4, 95% CI 3.2-107.0, P = 0.001); anterior/centre placenta (versus posterior, aOR 16.4, 95% CI 3.7-72.2, P < 0.001); and continuous sutures (versus interrupted, aOR 6.0, 95% CI 1.4-25.2, P = 0.015)., Conclusions: In this limited study, a history of continuous sutures on the inner side of the uterine wall showed potential to influence the development of placenta accreta in PPPC patients., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Aim: To report our experience with pregnancy outcomes after emergent laparoscopic surgery for acute adnexal disorders at less than 10 weeks of gestation when surgical intervention could be more invasive to intrauterine pregnancy., Methods: Gasless multiport laparoscopic surgery or transumbilical laparoendoscopic single-site surgery was performed with securing of the surgical view by the abdominal wall-lift method. Intraoperative autologous blood salvage and donation was performed in cases associated with significant hemoperitoneum., Results: Six cases of ovarian bleeding with ruptured corpus luteal cyst, three cases of adnexal torsion with corpus luteal cyst, and one case each of ruptured heterotopic ampullary pregnancy and heterotopic tubal stump isthmic pregnancy after salpingectomy were managed. For ruptured corpus luteal cyst, hemostasis was achieved by removal of hematoma followed by suturing. For adnexal torsion, detorsion with cyst aspiration was performed in two cases and detorsion alone was performed in one case. For ruptured heterotopic ampullary pregnancy, unilateral salpingectomy was performed. For ruptured heterotopic tubal stump isthmic pregnancy after salpingectomy, removal of the expelled villous tissue followed by hemostatic coagulation was performed. In five cases associated with massive hemoperitoneum, intraoperative autologous blood salvage and donation were performed to avoid homologous blood transfusion. After surgery, seven live births were achieved, while two cases of biochemical pregnancy loss and a case of complete miscarriage were noted., Conclusion: Although miscarriage could be a significant concern in the perioperative period, gasless laparoscopic surgery appeared to be feasible for management of acute adnexal disorders at less than 10 weeks of gestation., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

The present study was performed to investigate the histamine-induced airway effect of levocetirizine, an active enantiomer of cetirizine, by intranasal application using ddY mice. Nasal rubbing and sneezing after histamine application into the nasal cavity were used as an index of histamine-induced airway effect in mice. Intranasal application of levocetirizine inhibited both nasal rubbing and sneezing concentration-dependently, and the ED50 values were 0.62 (0.51-0.77) and 0.70 (0.51-1.02) %/site for nasal rubbing and sneezing, respectively. ED50 values of cetirizine were 1.24 (1.02-1.59) and 1.35 (1.02-2.08) %/site for nasal rubbing and sneezing, respectively. Levocetirizine also inhibited nasal rubbing and sneezing when administered orally. These results clearly indicate that levocetirizine was about two times more potent than cetirizine by intranasal application, similar to the findings of the former's affinity for human histamine H1 receptors. In addition, the present findings raise the expectation of the development of levocetirizine nasal drops.

Uterine adenomyoma is a nodular aggregated form of adenomyosis composed of heterotopic endometrial or endometrium-like structures in the myometrium, with adjacent myometrial hyperplasia. Although adenomyoma is not extremely rare, reports of adenomyoma showing exophytic subserosal growth are limited. A 32-year-old nulligravida woman had sudden onset of lower abdominal pain. In addition to a left endometriotic cyst, a heterogeneous mass lesion showing mural and exophytic subserosal growth was noted in the posterior wall of the uterus. In a two-port laparoscopic-assisted procedure, the subserosal nodule was excised using ultrasonic coagulating shears, followed by excision of the mural lesion using a round loop electrode and a high-frequency electrosurgical unit. The histopathologic diagnosis was adenomyoma., (Copyright © 2013 AAGL. Published by Elsevier Inc. All rights reserved.)

Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and β-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.

The atypical antipsychotic medication olanzapine is a useful agent in acute and maintenance treatment of schizophrenia and related disorders. It has beneficial effects on both positive and negative symptoms, an early onset of antipsychotic action and a favourable side effect profile. On the other hand, olanzapine has many reports of causing weight gain, glucose metabolism disturbances and lipidosis. We carried out blood tests (leptin, adiponectin, remnant-like lipoprotein cholesterol (RLP-C), total cholesterol, HbA1C, 75-OGTT and etc.) on patients with schizophrenia who had taken olanzapine. As a result, leptin, neutral lipid and RLP-C were significantly correlated by BMI. (The average blood test data and BMI revealed a normal range). Most analysis results of the lipoprotein fraction by a polyacrylamide-gel-electrophoresis method were normal patterns. Furthermore, the serum insulin concentrations from 75 g glucose tolerance (75 g-OGTT) 30 minutes later, in one third of patients receiving olanzapine, registered more than 100 microU/ml. The mechanism of the insulin secretion rise by olannzapine is unknown. Olanzapine may impair glucose tolerance due in part to increased insulin resistance. These findings do not necessarily imply that olanzapine is directly associated with a risk of impairment of weight gain, glucose metabolism disturbances and lipidosis. These results suggest that it is useful to promote diet cure and exercise therapy with patients with high BMI levels.

The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the murine brain. Earlier studies indicate that TMT-induced neuronal degeneration is enhanced by adrenalectomy and prevented by exogenous glucocorticoid. The aim of this study was to investigate the regulation of TMT neuroxicity by corticosterone receptors including type I (mineralocorticoid receptor, MR) and type II (glucocorticoid receptor, GR) in adult mice. The systemic injection of TMT at the dose of 2.0 or 2.8 mg/kg produced a marked elevation in the level of plasma corticosterone that was both dose and time dependent. The MR agonist aldosterone had the ability to exacerbate TMT cytotoxicity in the dentate granule cell layer, whereas its antagonist spironolactone protected neurons from TMT cytotoxicity there. In contrast, the GR antagonist mifepristone exacerbated the TMT cytotoxicity. Taken together, our data suggest TMT cytotoxicity is oppositely regulated by GR and MR signals, being exacerbated by MR activation in adult mice., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Proglucagon, which is encoded by the glucagon gene (Gcg), is the precursor of several peptide hormones, including glucagon and glucagon-like peptide 1 (GLP-1). Whereas glucagon stimulates hepatic glycogenolysis and gluconeogenesis, GLP-1 stimulates insulin secretion to lower blood glucose and also supports ß-cell proliferation and protection from apoptotic stimuli. Pregnancy is a strong inducer of change in islet function, however the roles of proglucagon-derived peptides in pregnancy are only partially understood. In the present study, we analyzed fertility and pregnancy-associated changes in homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcg(gfp/gfp)), which lack all the peptides derived from proglucagon. Female Gcg(gfp/gfp) mice could deliver and raise Gcg(gfp/gfp) pups to weaning and Gcg(gfp/gfp) pups from Gcg(gfp/gfp) dams were viable and fertile. Pregnancy induced ß-cell proliferation in Gcg(gfp/gfp) mice as well as in control mice. However, serum insulin levels in pregnant Gcg(gfp/gfp) females were lower than those in control pregnant females under ad libitum feeding, and blood glucose levels in pregnant Gcg(gfp/gfp) females were higher after gestational day 12. Gcg(gfp/gfp) females showed a decreased pregnancy rate and smaller litter size. The rate of successful breeding was significantly lower in Gcg(gfp/gfp) females and was not improved by experience of breeding. Taken together, proglucagon-derived peptides are not required for pregnancy-associated ß-cell proliferation, however, are required for regulation of blood glucose levels and normal reproductive capacity. Gcg(gfp/gfp) mice may serve as a novel model to analyze the effect of mild hyperglycemia during late gestational periods.

The organotin trimethyltin (TMT) is well known to cause neuronal damage in the central nervous system. To elucidate the mechanisms underlying the toxicity of TMT toward neurons, we prepared primary cultures of neurons from the neocortex of mouse embryos. A continuous exposure to TMT produced a decrease in cell viability as well as an increase in the number of cells with nuclear condensation/shrinkage at the exposure time window up to 24 hr. In addition to the events at the early time window, lactate dehydrogenase released was significantly elevated at the later exposure time from 36 to 48 hr. With a 3-hr exposure to TMT, a significant increase was observed in the activity of caspase 8, but not in that of caspase 9. TMT exposure produced no elevation in the level of cytochrome c released from mitochondria until 12 hr of exposure, with a significant facilitation of cytochrome c release at the exposure times of 16 and 24 hr. After the activation of caspase 8 by TMT exposure, caspase 3 activation and nuclear translocation of caspase-activated DNase were caused by exposure for 6 hr or longer. However, nuclear DNase II was elevated at the later time window of exposure. A caspase inhibitor completely prevented TMT from damaging the cells in any time window. Taken together, our data are the first demonstration that TMT toxicity is initially caused by activation of the caspase 8/caspase 3 pathway for nuclear translocation of DNases in cortical neurons in primary culture., (Copyright © 2011 Wiley-Liss, Inc.)

Salivary duct carcinoma (SDC) is a highly aggressive malignancy of the salivary glands. However, one type of SDC, which shows minimal invasion and better prognosis, is known as low-grade SDC (LG-SDC). This report presents an additional case of LG-SDC of the parotid gland. The patient was a 38-year-old Japanese woman who noticed painless swelling of the left parotid region. Grossly, the cut surface of the tumor was cystic. Microscopically, the tumor showed a multicystic pattern, which was lined by eosinophilic to clear atypical cells with cribriform or Roman bridge patterns. An immunohistochemical examination revealed the tumor was positive for cytokeratin (CK) 7 and epithelial membrane antigen, partially positive for androgen receptor and gross cystic disease fluid protein-15, and diffusely positive for Her-2/Neu, progesterone, and estrogen receptors. The cancer cells showed focal immunopositivity for S-100 protein. Immunostaining for p63, CK14, and calponin showed an in situ pattern in most areas of this tumor, whereas the tumor showed minimal invasion. The cancer cells were diffusely positive for MUC1 and MUC6 and focally positive for MUC2 and MUC4. Finally, the tumor was diagnosed to be LG-SDC. The differential diagnosis and the mucin pattern were evaluated.

An iliopsoas hematoma can occur either spontaneously or secondary to trauma or bleeding tendency due to hemophilia and anticoagulant therapy. Although liver cirrhosis is commonly associated with coagulopathy, iliopsoas hematoma is very rare. We herein, present a case of bilateral iliopsoas hematoma in a patient with alcoholic cirrhosis, and review the literature on muscle hematoma associated with cirrhosis. A 56-year-old man with alcoholic cirrhosis was admitted in a state of shock with anemia. The cause of anemia could not be detected, and the patient was treated conservatively. The site of bleeding was not detected with either gastroduodenal endoscopy or upper abdominal computed tomography, the latter of which did not include the iliopsoas muscle. He died on the 10th day of admission and bilateral iliopsoas hematomas were found on autopsy. An iron stain was positive in the iliopsoas muscle. Eight cases of muscle hematoma associated with cirrhosis, including the present case, were found in a review of the literature. Four of these cases involved the rectus abdominis muscle, 3 involved the iliopsoas muscle and 1 involved combined muscles. Alcoholic cirrhosis accounted for 75% of the cases. One case (12.5%) was associated with virus-related cirrhosis, and another with combined virus- and alcohol-related cirrhosis. The mortality rate was 75% despite early diagnosis and low risk scores for cirrhosis. Muscle hematoma in patients with cirrhosis is closely related to alcoholism, and the mortality rate of the condition is extremely high. In conclusion, muscle hematoma should be recognized as an important complication of cirrhosis.

Neural progenitor cells play an essential role in both the developing embryonic nervous system and in the adult brain, where the capacity for self-renewal would be important for normal brain functions. In the present study, we used embryonic cortical neural progenitor cells to investigate the effects of trimethyltin chloride (TMT) on the survival of neural progenitor cells. In cultures of cortical neural progenitor cells, the formation of round neurospheres was observed in the presence of epidermal growth factor and basic fibroblast growth factor within 9 days in vitro. The neurospheres were then harvested for subsequent replating and culturing for assessment of cell viability in either the presence or absence of TMT at the concentration of 5microM. Lasting exposure to TMT produced not only nuclear condensation in the cells in a time-dependent manner over a period of 6-24h, but also the release of lactate dehydrogenase into the culture medium. Immunoblot and immunocytochemical analyses revealed that TMT had the ability to activate both caspase-3 and calpain, as well as to cause nuclear translocation of deoxyribonuclease II, which is located within cytoplasm in intact cells. Additionally, treatment with a calpain inhibitor [trans-epoxysuccinyl-l-leucylamido-(4-guanidino) butane] and a caspase inhibitor [Z-Val-Ala-Asp(OMe)-CH2F] produced a significant reduction in damaged cells induced by TMT. Taken together, our data indicate that neural progenitor cells are highly susceptible to TMT in undergoing cell death via the activation of 2 parallel pathways, ones involving calpain and the other, caspase-3.

The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the murine brain. Earlier studies indicate that TMT-induced neuronal degeneration is enhanced by adrenalectomy. However, no evaluation has been attempted to determine the mechanism underlying the enhancement of TMT neurotoxicity by adrenalectomy and its implications in neuronal degeneration. To assess the implications and determine the mechanism of adrenalectomy-elicited enhancement of TMT neurotoxicity, we examined neuronal degeneration and associated signaling pathways in adrenalectomized mice. Adrenalectomy dramatically enhanced the TMT-induced neuronal damage in certain brain regions including the dentate gyrus, olfactory bulb, and anterior olfactory nucleus, in addition to exacerbating the behavioral abnormalities. TMT-induced activation of caspase-3 and calpain was also enhanced by adrenalectomy. The above events elicited by TMT were almost entirely prevented by treatment with dexamethasone. In addition to the above events, adrenalectomy clearly enhanced the activation of c-Jun-N-terminal kinases and the formation of 4-hydroxynonenal in the dentate gyrus following TMT treatment. The dentate granule cell damage induced by TMT was exacerbated by mifepristone, a glucocorticoid-receptor antagonist. Taken together, our data suggest that endogenous and exogenous glucocorticoids prevent neurodegeneration induced by TMT in the central nervous system by attenuating intensive oxidative stress and associated signaling pathways.