Search

We report the first case of bile duct mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) that had a mucinous carcinoma component. An 88-year-old man with biliary obstruction was diagnosed as having distal bile duct cancer using imaging examinations and endoscopic biopsy. The patient received the best supportive care without surgical resection for 13 months until death. An autopsy revealed a bulky mass involving the distal bile duct and multiple metastases in intra-abdominal lymph nodes, the liver, and the lungs. The primary cancer was microscopically diagnosed as a MiNEN, which consisted of mucinous adenocarcinoma and large cell-type neuroendocrine carcinoma (NEC) components. Metastatic lesions in the liver and lungs were composed of only NEC with rich extracellular mucin without adenocarcinoma cells. Using electron microscopy and immunohistochemistry, it was proved that all NEC cells in both primary and metastatic lesions had amphicrine features. On the basis of pathological findings, we thought that the MiNEN was initially derived from a mucinous adenocarcinoma that dedifferentiated to amphicrine NEC cells with mucin production., (© 2023. Japanese Society of Gastroenterology.)

Crystalline metals can have large theoretical elastic strain limits. However, a macroscopic block of conventional crystalline metals practically suffers a very limited elastic deformation of <0.5% with a linear stress-strain relationship obeying Hooke's law. Here, we report on the experimental observation of a large tensile elastic deformation with an elastic strain of >4.3% in a Cu-based single crystalline alloy at its bulk scale at room temperature. The large macroscopic elastic strain that originates from the reversible lattice strain of a single phase is demonstrated by in situ microstructure and neutron diffraction observations. Furthermore, the elastic reversible deformation, which is nonhysteretic and quasilinear, is associated with a pronounced elastic softening phenomenon. The increase in the stress gives rise to a reduced Young's modulus, unlike the traditional Hooke's law behaviour. The experimental discovery of a non-Hookean large elastic deformation offers the potential for the development of bulk crystalline metals as high-performance mechanical springs or for new applications via "elastic strain engineering.", (© 2022. The Author(s).)

The demand for biomaterials has been increasing along with the increase in the population of elderly people worldwide. The mechanical properties and high wear resistance of metallic biomaterials make them well-suited for use as substitutes or as support for damaged hard tissues. However, unless these biomaterials also have a low Young's modulus similar to that of human bones, bone atrophy inevitably occurs. Because a low Young's modulus is typically associated with poor wear resistance, it is difficult to realize a low Young's modulus and high wear resistance simultaneously. Also, the superelastic property of shape-memory alloys makes them suitable for biomedical applications, like vascular stents and guide wires. However, due to the low recoverable strain of conventional biocompatible shape-memory alloys, the demand for a new alloy system is high. The novel body-centered-cubic cobalt-chromium-based alloys in this work provide a solution to both of these problems. The Young's modulus of <001>-oriented single-crystal cobalt-chromium-based alloys is 10-30 GPa, which is similar to that of human bone, and they also demonstrate high wear and corrosion resistance. They also exhibit superelasticity with a huge recoverable strain up to 17.0%. For these reasons, the novel cobalt-chromium-based alloys can be promising candidates for biomedical applications., (© 2022 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

A previous study reported that scabronine G methyl ester (SG-ME) potentially enhances the in vitro secretion of neurotrophic factors such as nerve growth factor via the protein kinase C (PKC)-ζ pathway. However, it remains unknown whether SG-ME can improve cognitive dysfunctions in olfactory bulbectomized (OBX) mice. To address this question, we evaluated SG-ME-treated and untreated OBX mice in a passive avoidance test. We also investigated potential effects of SG-ME on several parameters: cell proliferation and cAMP response element-binding protein (CREB) phosphorylation in the hippocampal dentate gyrus by immunohistochemistry, brain-derived neurotrophic factor (BDNF) levels in the hippocampus by Western blotting, p -CREB levels in the hippocampus by MapAnalyzer, and long-term potentiation (LTP) by electrophysiology. On the 14th day after surgery OBX mice showed altered passive avoidance and decreases in both cell proliferation and long-term potentiation in the hippocampus, while these changes were reversed by SG-ME (20 μg/mouse) 24 h after the treatment. The improvement in memory deficits was prevented when SG-ME was co-administeredwith either zeta inhibitory peptide (PKC-ζ inhibitor), anti-BDNF antibody, ANA-12 (TrkB antagonist), U0126 (MEK inhibitor), H-89 (PKA inhibitor), LY294002 (PI3K inhibitor) or KN-93 (CaMKII inhibitor). We found that SG-ME enhanced brain-derived neurotrophic factor and p -CREB levels in the hippocampus while p -CREB was localized in neurons, but not in astrocytes nor microglial cells. These findings revealed the potential of SG-ME in improving memory impairments by enhancing cell proliferation and LTP via activation of the BDNF/CREB signaling pathway in neurons., (Copyright © 2020 Nakagawasai, Lin, Odaira, Takahashi, Nemoto, Moriguchi, Yabuki, Kobayakawa, Fukunaga, Nakada and Tan-No.)

We have previously reported that the carborane compound BE360, a novel selective estrogen receptor modulator, has a therapeutic potential against dementia. This study aimed to explore the effects and underlying mechanisms of BE360 on depression-like behaviors in ovariectomized (OVX) mice subjected to subchronic stress, which are postmenopausal depression models. BE360 was subcutaneously administrated using a mini-osmotic pump, for 2 weeks. Depression-like behaviors were evaluated using the forced swimming test. Neurogenesis in the hippocampal dentate gyrus (DG) was measured by analyzing cells expressing doublecortin (DCX) following 5-bromo-2'-deoxyuridine (BrdU) uptake. The levels of phosphorylated cyclic-AMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and Bcl-2 were measured using immunohistochemistry or immunoblotting. Depression-like behaviors in OVX + Stress-exposed mice improved after chronic treatment with BE360. BE360 treatment in OVX + Stress-exposed mice increased p-CREB, BDNF, and Bcl-2 expressions in the hippocampus. Immunohistochemistry showed that the number of BrdU/DCX double-positive cells in the DG of the hippocampus, which decreased significantly in OVX + Stress-exposed mice, increased after subchronic treatment with BE360. The present study demonstrates that BE360 exerts antidepressant effects via hippocampal neurogenesis, potentially activated through CREB/BDNF, Bcl-2 signaling pathways. These results indicate that BE360 may have therapeutic potential against postmenopausal depression., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Shape memory alloys recover their original shape after deformation, making them useful for a variety of specialized applications. Superelastic behavior begins at the critical stress, which tends to increase with increasing temperature for metal shape memory alloys. Temperature dependence is a common feature that often restricts the use of metal shape memory alloys in applications. We discovered an iron-based superelastic alloy system in which the critical stress can be optimized. Our Fe-Mn-Al-Cr-Ni alloys have a controllable temperature dependence that goes from positive to negative, depending on the chromium content. This phenomenon includes a temperature-invariant stress dependence. This behavior is highly desirable for a range of outer space-based and other applications that involve large temperature fluctuations., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric pathology, including anxiety and depression. The dextran sulfate sodium (DSS)-treated mouse is a well-characterized animal model of colitis that exhibits IBD-like and depressive-like changes. A recent study found that phosphorylated (p-) adenosine monophosphate-activated protein kinase (AMPK) was associated with anti-inflammatory and antidepressant effects. Our previous research in an animal model of major depression suggests that liver hydrolysate (LH) has an antidepressant effect and combats physical fatigue by enhancement via the hippocampal or peripheral p-AMPK pathway. In this study, we examined whether or not LH has antidepressant and anti-inflammatory effects in mice with DSS-induced changes. We evaluated colon inflammation in DSS-treated mice and used the tail suspension and forced swimming tests to confirm whether or not LH prevents IBD-like symptoms and depressive-like behavior. Hippocampal expression of AMPK, brain-derived neurotrophic factor (BDNF), doublecortin, and neuronal nuclear antigen proteins was assessed by Western blotting. Hippocampal neurogenesis and morphometric changes in the microglia and astrocytes were examined by immunohistochemistry. DSS-treated mice showed IBD-like pathology and depressive-like behavior, a reduction in the hippocampal neuronal nuclear antigen level and neurogenesis, and increased hippocampal activation of microglia and astrocytes. These changes were reversed by LH. DSS-treated mice showed enhanced hippocampal expression of p-AMPK and BDNF after administration of LH. LH prevented depressive-like behavior by enhancing hippocampal neurogenesis through the AMPK/BDNF pathway and anti-neuroinflammation in the hippocampus. LH may be a therapeutic option for patients with IBD and depression., Competing Interests: Declaration of Competing Interest Kotaro Yamada is an employee of Zeria Pharmaceutical Co., Ltd. (Tokyo, Japan)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Recently, we has reported that AMPK activator has antidepressant effect. Previous our study suggested that liver hydrolysate (LH) activated adenosine monophosphate-activated protein kinase (AMPK) in periphery. However, the effect of LH on depression is unclear. Therefore, we examines whether LH has antidepressant effect on olfactory bulbectomized (OBX) mice. OBX mice showed depressive-like behavior in tail-suspension test and reduction of hippocampal neurogenesis, while these changes were reversed by LH. LH enhanced hippocampal phosphate-AMPK, brain-derived neurotrophic factor (BDNF) and phosphate-cyclic adenosine monophosphate response element-binding protein (CREB) in OBX mice. These data indicate that LH may produce antidepressant effects via hippocampal AMPK/BDNF/CREB signaling., Competing Interests: Declaration of competing interest Kotaro Yamada is an employee of Zeria Pharmaceutical Co., Ltd. (Tokyo, Japan)., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Objectives　This study aimed to examine current relationships with neighbors among city dwellers and determine the factors associated with providing and accepting support in daily life.Methods　The "Survey to Enrich the Lives of Miyamae Ward Residents" was conducted with 1,000 people aged ≥30 years residing in Miyamae Ward, Kawasaki City. The survey items included baseline characteristics (e.g., sex, age, and residential status), relationships with neighbors, inclination to share personal information, and inclination to provide/accept support for the instrumental activities of daily living (IADL). To identify the factors associated with providing and accepting support for IADL, logistic regression analyses were performed with the following independent variables: baseline characteristics, neighborly relationships, inclination to share personal information, and inclination to provide support for the IADL.Results　We analyzed 407 respondents with complete responses. Among the different levels of neighborly relationships, 11.8% of the respondents were "cooperative with neighbors in daily life," 33.3% would "only stand and talk," 46.0% would "only exchange greetings," and 9.0% had "no relationships with neighbors." Among those willing to provide support, the highest proportions of responses were for "Calling on/watching over others" (60.1%) and "Helping to throw out garbage" (51.7%). In contrast, less than 30% of respondents were willing to seek support from neighbors and volunteers for these two activities. The factors significantly associated with a willingness to provide support were women and relationships with neighbors at the "stand and talk" level or higher. A disinclination to share personal information was inhibitory to providing support. The factors significantly associated with a willingness to accept support were women and the inclination to provide support according to IADL. Home ownership was inhibitory to accepting support.Conclusion　Fixed residential status and longer residence durations did not necessarily contribute to closer relationships with neighbors in urban areas. Although the respondents generally only exchanged greetings with neighbors, closer relationships are needed to facilitate a willingness to provide support to others. While many respondents were willing to provide simple assistance in daily life, rather fewer would seek help for the same activities. However, the acceptance of support was associated with the inclination to provide support, indicating a correlation between these two attitudes. In order to further encourage mutual support in daily life in urban areas, it is necessary to not only improve the level of relationships with neighbors, but also to implement initiatives that increase opportunities for people to gain experience providing support.

Objectives: In recent years, transboundary air pollution from mainland East Asia has led to growing concerns about air pollution in Japan. Air pollution is reportedly associated with the exacerbation of respiratory diseases. In this study, we assessed the effects of air pollution on respiratory symptoms and the health status of participants with and without chronic respiratory diseases., Methods: Participants (n=2753) with and without chronic respiratory diseases who visited healthcare facilities in Japan during February from 2010 to 2015 filled out a self-report questionnaire regarding their symptoms and perceived health status. Participants were followed up during April-May and June-July., Results: Oxidant concentrations were associated with respiratory symptoms, overall health, and quality of life (QoL). Suspended particulate matter (SPM) and particulate matter &lt;2.5 μm levels were associated with physical fitness; SPM was also associated with QoL. Recent experience of an Asian sand dust event had a significant effect on allergic symptoms, change in health, and QoL., Conclusions: Respiratory symptoms were more strongly affected by oxidants than by other pollutants. Significant associations of air pollutants were found with a comprehensive range of items related to perceived health status, including overall health and QoL. Although the effects of air pollutants on respiratory symptoms and health status were more apparent among patients with respiratory diseases, the adverse effects of air pollutants were significant even among participants without such conditions.

Background: Patients with inflammatory bowel disease (IBD), including those with ulcerative colitis and Crohn's disease, have higher rates of psychiatric disorders, such as depression and anxiety; however, the mechanism of psychiatric disorder development remains unclear. Mice with IBD induced by dextran sulfate sodium (DSS) in drinking water exhibit depressive-like behavior. The presence of Lactobacillus in the gut microbiota is associated with major depressive disorder. Therefore, we examined whether Enterococcus faecalis 2001 (EF-2001), a biogenic lactic acid bacterium, prevents DSS-induced depressive-like behavior and changes in peripheral symptoms., Methods: We evaluated colon inflammation and used the tail suspension test to examine whether EF-2001 prevents IBD-like symptoms and depressive-like behavior in DSS-treated mice. The protein expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), X-linked inhibitor of apoptosis protein (XIAP), and cleaved caspase-3 in the rectum and hippocampus was assessed by western blotting. Hippocampal neurogenesis, altered nuclear factor-kappa B (NFκB) p65 morphometry, and the localization of activated NFκB p65 and XIAP were examined by immunohistochemistry., Results: Treatment with 1.5% DSS for 7 days induced IBD-like pathology and depressive-like behavior, increased TNF-α and IL-6 expression in the rectum and hippocampus, activated caspase-3 in the hippocampus, and decreased hippocampal neurogenesis. Interestingly, these changes were reversed by 20-day administration of EF-2001. Further, EF-2001 administration enhanced NFκB p65 expression in the microglial cells and XIAP expression in the hippocampus of DSS-treated mice., Conclusion: EF-2001 prevented IBD-like pathology and depressive-like behavior via decreased rectal and hippocampal inflammatory cytokines and facilitated the NFκB p65/XIAP pathway in the hippocampus. Our findings suggest a close relationship between IBD and depression.

Adenosine monophosphate-activated protein kinase (AMPK) is critical for whole-body energy metabolism regulation. Recent studies have suggested that physical exercise ameliorates depressive-like behaviors via AMPK activation; however, the underlying mechanism is unclear. Here, we examined the effects and underlying mechanisms of AMPK activation on depressive-like behavior in olfactory bulbectomized (OBX) mice. We treated OBX mice with the AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleotide (AICAR) on the 7th or 14th day after bilateral bulbectomy and evaluated depressive-like behavior using the tail-suspension test (TST) and forced swimming test (FST) on the 21st day. The expression of phosphorylated AMPK, protein kinase C ζ (PKCζ), nuclear factor-kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), and cAMP response element-binding protein (CREB) in the hippocampus was assessed by western blotting. Hippocampal neurogenesis and localization of AMPK and phosphorylated NF-κB were examined by immunohistochemistry. Chronic AICAR treatment suppressed the prolonged immobility of OBX mice in the TST and FST, and increased the levels of phosphorylated AMPK, PKCζ, NF-κB, CREB, and BDNF. Hippocampal neurogenesis in OBX mice was promoted by chronic AICAR treatment. Co-administration of AICAR with the PKCζ inhibitor or the neurotrophic tyrosine kinase receptor type 2 (TrkB) antagonist, ANA-12, inhibited these effects. Phosphorylated AMPK was detected in mature and immature hippocampal neurons and microglia, while phosphorylated NF-κB was detected only in neurons in AICAR-treated OBX mice. These data indicate that AMPK activation produces anti-depressant effects, which are mediated by elevated hippocampal neurogenesis potentially via PKCζ/NF-κB/BDNF/TrkB/CREB signaling in neurons., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Methylazoxymethanol (MAM)-treated pregnant rat at gestation day (GD) 17 has been shown to be a valuable developmental animal model for schizophrenia. Yet, this model remains to be established in mice. In the present study, we examined behavioral, cytoarchitectural, and neurochemical changes in the offspring of MAM-treated mice and validated the model's face, construct and predictive validities. We found that in contrast to a single injection of MAM to dams at GD 15, 16 or 17, its daily administration from GD 15 to 17 led to deficits in prepulse inhibition (PPI) of startle in the post-pubertal offspring. In addition, we observed behavioral deficits in working memory and social interactions, as well as an increase in locomotor activity induced by the NMDA antagonist MK-801 in GD15-17 MAM offspring. These animals also showed a reduction in the volume of the prefrontal cortex (PFC) and hippocampus, neuroanatomical changes such as discontinuities and heterotopias in the hippocampus, and an increase of DA level and DOPAC/DA ratio in the medial PFC. Atypical antipsychotic drugs clozapine, risperidone, and aripiprazole, but not the typical drug haloperidol, reversed the deficit in PPI and social withdrawal in the offspring of MAM-treated dams. In contrast, MK-801-induced hyperactivity in MAM mice was reversed by both and typical or atypical antipsychotic drugs. Taken together, the treatment of pregnant mice with MAM during GD 15-17 offers a new approach to study neurobiological mechanisms involved in the pathogenesis of schizophrenia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Our previous study suggested that the non-competitive N-methyl-d-aspartate receptor antagonist memantine (MEM) inhibits dopamine (DA) reuptake and turnover by inhibiting brain monoamine oxidase. Clinical studies have reported that MEM may improve depressive symptoms; however, specific mechanisms underlying this effect are unclear. We performed emotional behavior, tail suspension, and forced swimming tests to examine whether MEM has antidepressant effects in olfactory bulbectomized (OBX) mice, an animal model of depression. Subsequently, we investigated the effects of MEM on the distribution of tyrosine hydroxylase (TH), altered microglia morphometry, and astrocyte and cell proliferation in the hippocampus with immunohistochemistry. We also investigated MEM effects on the levels of norepinephrine (NE), DA, and their metabolites with high performance liquid chromatography, and of neurotrophic, proinflammatory, and apoptotic molecules in the hippocampus with western blotting. Forty-two days after surgery, OBX mice showed depressive-like behaviors, as well as decreased levels of monoamines, reduced cell proliferation, and lower levels of TH, phospho(p)-TH (ser31 and ser40), p-protein kinase A (PKA), p-DARPP-32, p-ERK1/2, p-CREB, brain-derived neurotrophic factor (BDNF), doublecortin, NeuN, and Bcl-2 levels. In contrast, the number of activated microglia and astrocytes and the levels of Iba1, GFAP, p-IκB-α, p-NF-κB p65, TNF-α, IL-6, Bax, and cleaved caspase-3 were increased in the hippocampus. These changes (except for those in NE and Bax) were reversed with chronic administration of MEM. These results suggest that MEM-induced antidepressant effects are associated with enhanced hippocampal cell proliferation and neuroprotection via the PKA-ERK-CREB-BDNF/Bcl-2-caspase-3 pathway and increased DA levels., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Olfactory bulbectomized (OBX) mice exhibit depressive-like behaviors and memory deficits. We have reported that aripiprazole (ARI) ameliorates the behavioral hyper-responsivity to dopamine agonists and memory deficits in OBX mice; however, it is unclear whether ARI affects OBX-induced depressive-like behavior. To address this question, we evaluated the effect of ARI on depressive-like behavior in OBX mice using the forced swim test (FST). In addition, we investigated the effect of ARI on c-Fos expression in the prefrontal cortex (PFC), striatum, and hippocampus of OBX mice using western blotting. OBX mice exhibited a longer immobility duration in the FST 14 days after surgery. Depressive-like behavior in OBX mice was reversed 30 min after administration of ARI (0.01 or 0.03 mg/kg). In addition, c-Fos expression was increased in the PFC, but not the striatum or hippocampus, 30 min after acute administration of ARI. These effects were inhibited by administration of the selective 5-HT1A, D1, and D2 receptor antagonists, WAY100635, SCH23390, and L-741,626, respectively. These findings suggest that ARI produces an antidepressant effect in OBX mice that may be mediated by 5-HT 1A , D 1 , and D 2 receptors in the PFC., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Dopamine (DA) modulates cognitive functions in the prefrontal cortex (PFC) and hippocampus. Olfactory bulbectomy (OBX) in mice induces cognitive dysfunctions. Recently, we reported that aripiprazole (ARI) normalizes the behavioral hyper-responsivity to DA agonists in OBX mice. However, it remains unclear whether ARI affects OBX-induced cognitive dysfunctions. To address this question we evaluated ARI-treated and untreated OBX mice in a passive avoidance test. Then, we investigated the effects of ARI on cell proliferation in the hippocampal dentate gyrus by immunohistochemistry, and on c-fos levels in the PFC and hippocampus, as well as nerve growth factor (NGF) levels in the hippocampus by western blotting. On the 14th day after surgery OBX mice showed an alteration in passive avoidance and decreases in both cell proliferation and levels of p-ERK, p-CREB and NGF in the hippocampus. The cognitive dysfunctions in OBX mice improved 30min to 24h after the administration of ARI (0.01mg/kg). C-fos levels in the PFC but not in the hippocampus was increased 30min after the administration (early response). This early response was inhibited by the selective D 1 receptor antagonist SCH23390. Cell proliferation and NGF levels in the hippocampus increased 24h after ARI administration (late response), and these effects were also inhibited by SCH23390. The MEK1/2 inhibitor U0126 prevented ARI from improving the behavioral impairment as well as enhancing NGF levels in OBX mice. These findings revealed the potential of ARI to improve cognitive dysfunctions via D 1 receptors with the PFC and hippocampus being affected sequentially., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

We have reported that the carborane compound BE360 is a novel selective estrogen receptor modulator and new therapy option for osteoporosis. The aim of this study was to explore the effects and underlying mechanisms of BE360 on depressive-like behavior and memory impairment in the olfactory bulbectomized (OBX) mice, an experimental animal model of depression and dementia. BE360 was administered subcutaneously to mice using a mini-osmotic pump for 2 weeks. Depressive-like behavior was measured as the reduced intake of a sweet solution in the sucrose preference test. Short-term memory was assessed using the Y-maze test. Cell proliferation was assessed by the analysis of cells expressing 5-bromo-2'-deoxyuridine (BrdU) uptake. The expression of phosphorylated cyclic-AMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were measured by immunoblot. The depressive-like behavior and memory impairment in OBX mice were improved by the chronic treatment with BE360. Immunohistochemical analysis showed that the number of BrdU-positive cells in the dentate gyrus of the hippocampus significantly decreased in OBX mice whereas they increased after the chronic treatment with BE360. Immunoblotting studies revealed that pCREB and BDNF were significantly increased in the hippocampus of OBX mice treated with BE360. The present study has shown that BE360 has antidepressant and antidementia effects characterized by hippocampal cell proliferation potentially activated via CREB/BDNF signaling pathways. These results indicate that BE360 may have valuable therapeutic potential against depression and neurodegenerative diseases., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Large amounts of radioactive substances were released into the environment from the Fukushima Dai-ichi Nuclear Power Plants in eastern Japan as a consequence of the great earthquake (M 9.0) and tsunami of 11 March 2011. Radioactive substances discharged into the atmosphere first reached the Chiba Metropolitan Area on 15 March. We collected daily samples of air, fallout deposition, and tap water starting directly after the incident and measured their radioactivity. During the first two months maximum daily concentrations of airborne radionuclides observed at the Japan Chemical Analysis Center in the Chiba Metropolitan Area were as follows: 4.7 × 10(1) Bq m(-3) of (131)I, 7.5 Bq m(-3) of (137)Cs, and 6.1 Bq m(-3) of (134)Cs. The ratio of gaseous iodine to total iodine ranged from 5.2 × 10(-1) to 7.1 × 10(-1). Observed deposition rate maxima were as follows: 1.7 × 10(4) Bq m(-2) d(-1) of (131)I, 2.9 × 10(3) Bq m(-2) d(-1) of (137)Cs, and 2.9 × 10(3) Bq m(-2) d(-1) of (134)Cs. The deposition velocities (ratio of deposition rate to concentration) of cesium radionuclides and (131)I were detectably different. Radioactivity in tap water caused by the accident was detected several days after detection of radioactivity in fallout in the area. Radiation doses were estimated from external radiation and internal radiation by inhalation and ingestion of tap water for people living outdoor in the Chiba Metropolitan Area following the Fukushima accident., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Rv3671c, a putative serine protease, is crucial for persistence of Mycobacterium tuberculosis in the hostile environment of the phagosome. We show that Rv3671c is required for M. tuberculosis resistance to oxidative stress in addition to its role in protection from acidification. Structural and biochemical analyses demonstrate that the periplasmic domain of Rv3671c is a functional serine protease of the chymotrypsin family and, remarkably, that its activity increases on oxidation. High-resolution crystal structures of this protease in an active strained state and in an inactive relaxed state reveal that a solvent-exposed disulfide bond controls the protease activity by constraining two distant regions of Rv3671c and stabilizing it in the catalytically active conformation. In vitro biochemical studies confirm that activation of the protease in an oxidative environment is dependent on this reversible disulfide bond. These results suggest that the disulfide bond modulates activity of Rv3671c depending on the oxidative environment in vivo., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Mycobacterium tuberculosis can persist in macrophage phagosomes that acidify to a pH of approximately 4.5 after activation of the macrophage with gamma interferon. How the bacterium resists the low pH of the acidified phagosome is incompletely understood. A screen of 10,100 M. tuberculosis transposon mutants for mutants hypersensitive to pH 4.5 led to the discovery of 21 genes whose disruption attenuated survival of M. tuberculosis at a low pH (41). Here, we show that acid-sensitive M. tuberculosis mutants with transposon insertions in Rv2136c, Rv2224c, ponA2, and lysX were hypersensitive to antibiotics, sodium dodecyl sulfate, heat shock, and reactive oxygen and nitrogen intermediates, indicating that acid resistance can be associated with protection against other forms of stress. The Rv2136c mutant was impaired in intrabacterial pH homeostasis and unable to maintain a neutral intrabacterial pH in activated macrophages. The Rv2136c, Rv2224c, and ponA2 mutants were attenuated in mice, with the Rv2136c mutant displaying the most severe level of attenuation. Pathways utilized by M. tuberculosis for acid resistance and intrabacterial pH maintenance are potential targets for chemotherapy.

To investigate the role of oxygen-derived free radicals in the pathogenesis of tourniquet shock, the authors present an experimental animal model. Two groups of rats were fastened with rubber tubes on both thighs (1.5 kg/cm2) for 6 h under pentobarbital anaesthesia. One group was administered liposomal superoxide dismutase (L-SOD 30,000 U/kg body weight), and the other liposome as a control 3 h prior to tourniquet removal. No rats in the control group (n = 20) survived more than 24 h after reperfusion, whereas 55% of animals treated with L-SOD (n = 20) survived for 24 h or more, and two recovered completely (P less than 0.005). Blood samples were obtained from the abdominal aorta after laparotomy of anaesthetized rats of both groups at different time intervals. Changes in the hematocrit value and blood urea nitrogen during the early periods after reperfusion were attenuated by prior administration of L-SOD, and the total plasma SOD activity of the control animals decreased promptly and continuously throughout the experimental period. This experimental model was very useful to study the pathogenesis of tourniquet shock with respect to reproducibility, induction of the shock stages and mortality. It is thought that oxygen-free radicals are involved in the induction of tourniquet shock, and L-SOD was, to a certain extent, effective against reperfusion injury in the early stages of shock.

Seven kinds of DNA probes which recognize hypervariable loci were applied for paternity test. The putative father was decreased and unavailable for the test. The two legitimate children and their mother (the deceased's wife) and the four illegitimate children and their mother (the deceased's kept mistress) were available for analysis. Paternity index of four illegitimate child was investigated. Allelic frequencies and their confidence intervals among unrelated Japanese individuals were previously reported from our laboratory, and co-dominant segregation of the polymorphism was confirmed in family studies. Cumulative paternity indices of four illegitimate children from 16 kinds of standard blood group markers were 165, 42, 0.09, and 36, respectively. On the other hand, cumulative paternity indices from 7 kinds of DNA probes are 2,363, 4,685, 57,678, and 54,994, respectively, which are 14, 113, 640, 864, and 1,509 times higher than that from standard blood group markers. The DNA analyses gave nearly conclusive evidence that the putative father was the biological father of the children. Especially, the paternity relation of the third illegitimate child could not be established without the DNA analyses. Accordingly, DNA polymorphism is considered to be informative enough for paternity test.

Three kinds of variable number of tandem repeat DNA probes (VNTR: pYNZ22, pYNH24, and pYNZ2) showing hypervariable polymorphisms were studied. Allelic frequencies and their confidence intervals among Japanese individuals were obtained. Co-dominant segregation of the polymorphism was confirmed in family studies. Two a priori probabilities were calculated for each VNTR locus: exclusion probabilities for an alleged father/mother/child trio and for an alleged parent/child duo, and probabilities of matching of genotyped two unrelated individuals or two siblings. Availability as well as highly discriminating polymorphic pattern of VNTR loci makes it potentially very useful for forensic and human genetic purposes.

Four kinds of DNA probes that recognize hypervariable regions (HVR) were studied for parentage testing and individual identification. Allele frequencies and their confidence intervals among unrelated Japanese individuals were obtained. Codominant segregation of the polymorphism was confirmed in family studies. Two a priori probabilities were calculated for each HVR locus: the exclusion probabilities for an alleged father/mother/child trio and for an alleged parent/child duo, and the probabilities of matching of genotypes of two unrelated individuals or two siblings. The ease of availability of the probes and their highly discriminating polymorphic patterns mean they could be very useful for forensic purposes.

Wister albino pregnant rats were fed on pellets containing 3.5% L-phenylalanine (Phe) from 10 days before the expected date of birth. The diet was then switched to 7% Phe pellets at the third week after birth. Baby rats were reared with breast milk, and weaned at the end of the 4th week after birth; thereafter, they were reared with a normal diet for one week at the 5th week, and then were given 7% Phe diet from the 6th week. These rats, which were reared with a diet of high Phe, showed a similar metabolic pattern to that of human phenylketonuria (PKU) in the following aspects: definite suppression of the liver Phe hydroxylase activity, excretion of a large amount of phenylpyruvic acid (PPA) and phenyllactic acid (PLA) into urine, and an elvated level of blood Phe content. But, they had an excessive amount of blood tyrosine (Tyr), and concurrently excreted massive homogentisic acid (HGA) in urine just as in human tyrosinemia alkaptonuria. The absence of urinary o-hydroxyphenylacetic acid (o-HPAA) was also a distinct difference from human PKU. In some rats, mild inhibition of the liver Phe hydroxylase activity was observed. In other rats, there was no excretion of PPA into urine as in human hyperphenylalaninemia. Further, the regulatory mechanism of Phe catabolism of experimental PKU was discussed by analysing the enzyme activity of the liver Phe hydroxylase, phenylalanine-pyruvate (Phe-Pyr) transaminase and tyrosine alpha-ketoglutarate (Tyr-alpha-Kg) transaminase at different developmental stages of the rats.