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1.  Dysfunction of ventrolateral prefrontal cortex underlying social anxiety disorder: A multi-channel NIRS study 
NeuroImage : Clinical  2015;8:455-461.
Social anxiety disorder (SAD) is characterized by strong fear and anxiety during social interactions. Although ventrolateral prefrontal cortex (VLPFC) activity in response to emotional stimuli is related to pathological anxiety, little is known about the relationship between VLPFC activity and social anxiety. This study aimed to investigate whether VLPFC activity was involved in SAD and whether VLPFC activity was related to the level of social anxiety. Twenty-four drug-naïve patients with SAD and 35 healthy controls underwent near-infrared spectroscopy (NIRS) scanning while performing a verbal fluency task (VFT). Results indicated that, compared to the healthy controls, the SAD patients exhibited smaller changes of oxygenated hemoglobin (oxy-Hb) concentrations in the VLPFC during the VFT. Furthermore, the right VLPFC activation was negatively correlated with social avoidance. In contrast to the latter, the healthy controls exhibited a positive correlation between changes of oxy-Hb concentrations in the bilateral VLPFC and social fear. Our findings provide evidence for VLPFC dysfunction in SAD, and indicate that the VLPFC dysfunction may contribute to the difference between normal and abnormal social anxiety.
•We investigated ventrolateral prefrontal cortex (VLPFC) activity induced by the performance of the verbal fluency task.•Smaller changes of oxygenated hemoglobin (oxy-Hb) concentrations in bilateral VLPFC in SAD patients•Negative correlation between changes of oxy-Hb concentrations in right VLPFC and social avoidance in SAD patients•Positive correlation between changes of oxy-Hb concentrations in bilateral VLPFC and social fear in healthy subjects
PMCID: PMC4474365  PMID: 26106570
Social anxiety disorder; Ventrolateral prefrontal cortex; Emotion; Near-infrared spectroscopy (NIRS)
2.  GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease 
Molecular genetics and metabolism  2013;111(3):393-398.
Pelizaeus-Merzbacher-like disease is a rare hypomyelinating leukodystrophy caused by autosomal recessive mutations in GJC2, encoding a gap junction protein essential for production of a mature myelin sheath. A previously identified GJC2 mutation (c.-167G>A) in the promoter region is hypothesized to disrupt a putative SOX10 binding site; however, the lack of additional mutations in this region and contradictory functional data have limited the interpretation of this variant.
We describe two independent Pelizaeus-Merzbacher-like disease families with a novel promoter region mutation and updated in vitro functional assays.
A novel GJC2 mutation (c.-170G>A) in the promoter region was identified in Pelizaeus-Merzbacher-like disease patients. In vitro functional assays using human GJC2 promoter constructs demonstrated that this mutation and the previously described c.-167G>A mutation similarly diminished the transcriptional activity driven by SOX10 and the binding affinity for SOX10.
These findings support the role of GJC2 promoter mutations in Pelizaeus-Merzbacher-like disease. GJC2 promoter region mutation screening should be included in the evaluation of patients with unexplained hypomyelinating leukodystrophies.
PMCID: PMC4183365  PMID: 24374284
Leukodystrophy; Glia; Myelin; GJC2; Pelizaeus-Merzbacher
4.  Circulating AIM as an Indicator of Liver Damage and Hepatocellular Carcinoma in Humans 
PLoS ONE  2014;9(10):e109123.
Hepatocellular carcinoma (HCC), the fifth most common cancer type and the third highest cause of cancer death worldwide, develops in different types of liver injuries, and is mostly associated with cirrhosis. However, non-alcoholic fatty liver disease often causes HCC with less fibrosis, and the number of patients with this disease is rapidly increasing. The high mortality rate and the pathological complexity of liver diseases and HCC require blood biomarkers that accurately reflect the state of liver damage and presence of HCC.
Methods and Findings
Here we demonstrate that a circulating protein, apoptosis inhibitor of macrophage (AIM) may meet this requirement. A large-scale analysis of healthy individuals across a wide age range revealed a mean blood AIM of 4.99±1.8 µg/ml in men and 6.06±2.1 µg/ml in women. AIM levels were significantly augmented in the younger generation (20s–40s), particularly in women. Interestingly, AIM levels were markedly higher in patients with advanced liver damage, regardless of disease type, and correlated significantly with multiple parameters representing liver function. In mice, AIM levels increased in response to carbon tetrachloride, confirming that the high AIM observed in humans is the result of liver damage. In addition, carbon tetrachloride caused comparable states of liver damage in AIM-deficient and wild-type mice, indicating no influence of AIM levels on liver injury progression. Intriguingly, certain combinations of AIM indexes normalized to liver marker score significantly distinguished HCC patients from non-HCC patients and thus could be applicable for HCC diagnosis.
AIM potently reveals both liver damage and HCC. Thus, our results may provide the basis for novel diagnostic strategies for this widespread and fatal disease.
PMCID: PMC4193837  PMID: 25302503
5.  Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos 
Current biology : CB  2013;23(13):1181-1194.
In preimplantation mouse embryos, the first cell fate specification to the trophectoderm or inner cell mass occurs by the early blastocyst stage. The cell fate is controlled by cell position-dependent Hippo signaling, although the mechanisms underlying position-dependent Hippo signaling are unknown.
We showed that a combination of cell polarity and cell–cell adhesion establishes position-dependent Hippo signaling, where the outer and inner cells are polar and nonpolar, respectively. The junction-associated proteins angiomotin (Amot) and Amotl2 are essential for Hippo pathway activation and appropriate cell fate specification. In the nonpolar inner cells, Amot localizes to adherens junctions (AJs) and cell–cell adhesion activates the Hippo pathway. In the outer cells, the cell polarity sequesters Amot from basolateral AJs to apical domains, thereby suppressing Hippo signaling. The N-terminal domain of Amot is required for actin binding, Nf2/Merlin-mediated association with the E-cadherin complex, and interaction with Lats protein kinase. In AJs, Ser176 in the N-terminal domain of Amot is phosphorylated by Lats, which inhibits the actin-binding activity, thereby stabilizing the Amot–Lats interaction to activate the Hippo pathway.
We propose that the phosphorylation of S176 in Amot is a critical step for activation of the Hippo pathway in AJs and that cell polarity disconnects the Hippo pathway from cell–cell adhesion by sequestering Amot from AJ. This mechanism converts positional information into differential Hippo signaling, thereby leading to differential cell fates.
PMCID: PMC3742369  PMID: 23791731
6.  Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes 
Stem Cell Reports  2014;2(5):648-661.
Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation.
Graphical Abstract
•Modeling Pelizaeus-Merzbacher disease (PMD) using iPSC-derived oligodendrocytes•Increased ER stress involved in the apoptosis of PMD iPSC-derived oligodendrocytes•Abnormal myelin structures and ER morphologies in PMD iPSC-derived oligodendrocytes•Models for the pathophysiology of dysmyelinating disorders
Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Okano, Okada, and colleagues established iPSCs from two PMD patients carrying PLP1 missense mutation, differentiated them into oligodendrocytes in vitro, and demonstrated the involvement of ER stress in the pathogenic dysmyelination. This model is useful for the pathophysiological analysis of dysmyelinating neurological disorders.
PMCID: PMC4050482  PMID: 24936452
7.  Endoscopic transgastric drainage of a gastric wall abscess after endoscopic submucosal dissection 
A 63-year-old woman was referred to our hospital for further examination because of an incidental finding of early gastric cancer. Endoscopic submucosal dissection (ESD) was successfully performed for complete resection of the tumor. On the first post-ESD day, the patient suddenly complained of abdominal pain after an episode of vomiting. Abdominal computed tomography (CT) showed delayed perforation after ESD. The patient was conservatively treated with an intravenous proton pump inhibitor and antibiotics. On the fifth post-ESD day, CT revealed a gastric wall abscess in the gastric body. Gastroscopy revealed a gastric fistula at the edge of the post-ESD ulcer, and pus was found flowing into the stomach. An intradrainage stent and an extradrainage nasocystic catheter were successfully inserted into the abscess for endoscopic transgastric drainage. After the procedure, the clinical symptoms and laboratory test results improved quickly. Two months later, a follow-up CT scan showed no collection of pus. Consequently, the intradrainage stent was removed. Although the gastric wall abscess recurred 2 wk after stent removal, it recovered soon after endoscopic transgastric drainage. Finally, after stent removal and oral antibiotic treatment for 1 mo, no recurrence of the gastric wall abscess was found.
PMCID: PMC3921538  PMID: 24574787
Gastric wall abscess; Transgastric drainage; Delayed perforation; Endoscopic submucosal dissection; Early gastric cancer
8.  Frequent alteration of the protein synthesis of enzymes for glucose metabolism in hepatocellular carcinomas 
Journal of Gastroenterology  2013;49(9):1324-1332.
Cancer cells show enhanced glycolysis and inhibition of oxidative phosphorylation, even in the presence of sufficient oxygen (aerobic glycolysis). Glycolysis is much less efficient for energy production than oxidative phosphorylation, and the reason why cancer cells selectively use glycolysis remains unclear.
Biospecimens were collected from 45 hepatocellular carcinoma patients. Protein samples were prepared through subcellular localization or whole-cell lysis. Protein synthesis was measured by SDS-PAGE and immunoblotting. mRNA transcription was measured using quantitative RT-PCR. Statistical correlation among immunoblotting data and clinicolaboratory factors were analyzed using SPSS.
Enzymes for oxidative phosphorylation (SDHA and SDHB) were frequently decreased (56 and 48 % of patients, respectively) in hepatocellular carcinomas. The lowered amount of the SDH protein complex was rarely accompanied by stabilization of HIF1α and subsequent activation of the hypoxia response. On the other hand, protein synthesis of G6PD and TKT, enzymes critical for pentose phosphate pathway (PPP), was increased (in 45 and 55 % of patients, respectively), while that of ALDOA, an enzyme for mainstream glycolysis, was eliminated (in 55 % of patients). Alteration of protein synthesis was correlated with gene expression for G6PD and TKT, but not for TKTL1, ALDOA, SDHA or SDHB. Augmented transcription and synthesis of PPP enzymes were accompanied by nuclear accumulation of NRF2.
Hepatocellular carcinomas divert glucose metabolism to the anabolic shunt by activating transcription factor NRF2.
Electronic supplementary material
The online version of this article (doi:10.1007/s00535-013-0895-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4156784  PMID: 24203292
Aerobic glycolysis; Succinate dehydrogenase; HIF-1α; Pentose phosphate pathway; NRF2
9.  Effects of exposure to nanoparticle-rich diesel exhaust on 8-OHdG synthesis in the mouse asthmatic lung 
It has been demonstrated that exposure to diesel exhaust (DE) is associated with the induction and exacerbation of respiratory disorders; however, the impacts of DE containing mainly nanoparticles have been less studied. We have previously demonstrated that inhalation exposure to nanoparticle-rich DE (NR-DE) exacerbated allergic pulmonary inflammation, in the context of enhanced local expression of proinflammatory molecules. However, the underlying mechanisms have not been fully elucidated. 8-Hydroxydeoxyguanosine (8-OHdG) is a marker of oxidative damage, particularly in DNA. This study examined the effects of NR-DE on 8-OHdG synthesis in the lung in the presence or absence of an allergen. Institute for Cancer Research (ICR) mice were exposed by inhalation to four different gas compositions (control air, low-concentration DE, high-concentration DE and high-concentration DE without particulate matter) for 8 weeks, in the presence or absence of repetitive intratracheal administration of ovalbumin (OVA). Thereafter, we assessed the levels of 8-OHdG synthesis and expression in the lungs by means of enzyme immunoassay (EIA) and immunohistochemistry. The EIA revealed that the level of 8-OHdG was significantly higher in the high-concentration NR-DE-exposed and allergen-sensitized/stimulated group compared with that in the control air-exposed and allergen-treated group. The immunohistochemistry results demonstrated that the level of immunoreactive 8-OHdG was higher in the NR-DE-exposed and allergen-treated lungs compared with that in the corresponding control air-exposed lungs. The results suggested that NR-DE exposure enhanced 8-OHdG formation in asthmatic lungs. This, at least in part, is involved in the NR-DE-mediated exacerbation of the allergic pathophysiology that was identified in our previous study.
PMCID: PMC3786854  PMID: 24137251
nanoparticle-rich diesel exhaust; allergic pulmonary inflammation; oxidative stress; 8-OHdG
10.  Laparoscopic splenectomy for histiocytic sarcoma of the spleen 
Primary histiocytic sarcoma of the spleen is a rare but potentially lethal condition. It can remain asymptomatic or only mildly symptomatic for a long time. An 81-year-old woman presented with an extremely enlarged spleen. She suffered from progressive anemia and required a red blood cell transfusion once a month. Although computed tomography, ultrasonography, and magnetic resonance imaging were performed for diagnosis, a confirmed diagnosis was not obtained. Her enlarged spleen compressed her stomach, and she suffered from gastritis and a sense of gastric fullness just after meals. She underwent laparoscopic splenectomy for therapeutic and diagnostic purposes. Her post-operative course was uneventful. After surgery, her red blood cell and platelet counts increased markedly. The tumor was diagnosed as splenic histiocytic sarcoma. Post-surgical chemotherapy was not performed, and the patient died of liver failure due to liver metastasis 5 mo after surgery. Laparoscopic splenectomy is minimally invasive and useful for the relief of symptoms related to hematological disorders. However, in cases of an enlarged spleen, optimal views and working space are limited. In such cases, splenic artery ligation can markedly reduce the size of the spleen, thus facilitating the procedure. The case reported herein suggests that laparoscopic splenectomy may be useful for the treatment of splenic malignancy.
PMCID: PMC3664293  PMID: 23717746
Histiocytic sarcoma; Laparoscopic splenectomy; Malignancy; Splenomegaly; Chemotherapy
11.  Impediment to Symbiosis Establishment between Giant Clams and Symbiodinium Algae Due to Sterilization of Seawater 
PLoS ONE  2013;8(4):e61156.
To survive the juvenile stage, giant clam juveniles need to establish a symbiotic relationship with the microalgae Symbiodinium occurring in the environment. The percentage of giant clam juveniles succeeding in symbiosis establishment (“symbiosis rate”) is often low, which is problematic for seed producers. We investigated how and why symbiosis rates vary, depending on whether giant clam seeds are continuously reared in UV treated or non treated seawater. Results repeatedly demonstrated that symbiosis rates were lower for UV treated seawater than for non treated seawater. Symbiosis rates were also lower for autoclaved seawater and 0.2-µm filtered seawater than for non treated seawater. The decreased symbiosis rates in various sterilized seawater suggest the possibility that some factors helping symbiosis establishment in natural seawater are weakened owing to sterilization. The possible factors include vitality of giant clam seeds, since additional experiments revealed that survival rates of seeds reared alone without Symbiodinium were lower in sterilized seawater than in non treated seawater. In conclusion, UV treatment of seawater was found to lead to decreased symbiosis rates, which is due possibly to some adverse effects common to the various sterilization techniques and relates to the vitality of the giant clam seeds.
PMCID: PMC3628887  PMID: 23613802
12.  Nuclear localization of Prickle2 is required to establish cell polarity during early mouse embryogenesis 
Developmental Biology  2012;364(2):138-148.
The establishment of trophectoderm (TE) manifests as the formation of epithelium, and is dependent on many structural and regulatory components that are commonly found and function in many epithelial tissues. However, the mechanism of TE formation is currently not well understood. Prickle1 (Pk1), a core component of the planar cell polarity (PCP) pathway, is essential for epiblast polarization before gastrulation, yet the roles of Pk family members in early mouse embryogenesis are obscure. Here we found that Pk2−/− embryos died at E3.0–3.5 without forming the blastocyst cavity and not maintained epithelial integrity of TE. These phenotypes were due to loss of the apical-basal (AB) polarity that underlies the asymmetric redistribution of microtubule networks and proper accumulation of AB polarity components on each membrane during compaction. In addition, we found GTP-bound active form of nuclear RhoA was decreased in Pk2−/− embryos during compaction. We further show that the first cell fate decision was disrupted in Pk2−/− embryos. Interestingly, Pk2 localized to the nucleus from the 2-cell to around the 16-cell stage despite its cytoplasmic function previously reported. Inhibiting farnesylation blocked Pk2’s nuclear localization and disrupted AB cell polarity, suggesting that Pk2 farnesylation is essential for its nuclear localization and function. The cell polarity phenotype was efficiently rescued by nuclear but not cytoplasmic Pk2, demonstrating the nuclear localization of Pk2 is critical for its function.
PMCID: PMC3299875  PMID: 22333836
13.  Elucidating information processing in primate basal ganglia circuitry: a novel technique for pathway-selective ablation mediated by immunotoxin 
Employing a neuron-specific retrograde gene-transfer vector (NeuRet vector), we have recently developed a novel technique that achieves pathway-selective ablation in the primate brain. This technique is mediated by immunotoxin (IT) and eliminates a neuronal population that constitutes a particular pathway, leaving other pathways intact. By means of this technique, we have made an attempt to remove the hyperdirect pathway selectively from basal ganglia circuitry. The hyperdirect pathway links the motor cortex to the subthalamic nucleus (STN) directly and plays a crucial role in motor control. After electrical stimulation in the motor cortex, triphasic responses consisting of an early excitation, an inhibition, and a late excitation are usually elicited in the internal pallidal segment (GPi). Several pieces of pharmacophysiological evidence imply that the early excitation may be derived from the hyperdirect pathway. In our experiments, the NeuRet vector expressing human interleukin-2 receptor α-subunit was injected into the STN of macaque monkeys. Then, IT injections were performed into the supplementary motor area (SMA). When single neuron activity in the GPi was recorded in response to the SMA stimulation, it was found that the early excitation was significantly reduced with neither the inhibition nor the late excitation affected. The spontaneous firing rate and pattern of GPi neurons remained to be altered. This clearly indicates that IT-mediated tract targeting successfully eliminated the hyperdirect pathway with spontaneous activity of STN neurons unaffected. The electrophysiological findings were histologically confirmed by retrograde and anterograde neuronal labeling. The overall data define that the motor cortically driven early excitation in GPi neurons is conveyed through the hyperdirect pathway. The IT-mediated pathway-selective ablation technique will provide a powerful tool for elucidating information processing in various neural networks.
PMCID: PMC3760290  PMID: 24027499
basal ganglia; hyperdirect pathway; information processing; immunotoxin; lentivirus; vectors; gene transfer; primates
14.  Multisynaptic Inputs from the Medial Temporal Lobe to V4 in Macaques 
PLoS ONE  2012;7(12):e52115.
Retrograde transsynaptic transport of rabies virus was employed to undertake the top-down projections from the medial temporal lobe (MTL) to visual area V4 of the occipitotemporal visual pathway in Japanese monkeys (Macaca fuscata). On day 3 after rabies injections into V4, neuronal labeling was observed prominently in the temporal lobe areas that have direct connections with V4, including area TF of the parahippocampal cortex. Furthermore, conspicuous neuron labeling appeared disynaptically in area TH of the parahippocampal cortex, and areas 35 and 36 of the perirhinal cortex. The labeled neurons were located predominantly in deep layers. On day 4 after the rabies injections, labeled neurons were found in the hippocampal formation, along with massive labeling in the parahippocampal and perirhinal cortices. In the hippocampal formation, the densest neuron labeling was seen in layer 5 of the entorhinal cortex, and a small but certain number of neurons were labeled in other regions, such as the subicular complex and CA1 and CA3 of the hippocampus proper. The present results indicate that V4 receives major input from the hippocampus proper via the entorhinal cortex, as well as “short-cut” pathways that bypass the entorhinal cortex. These multisynaptic pathways may define an anatomical basis for hippocampal-cortical interactions involving lower visual areas. The multisynaptic input from the MTL to V4 is likely to provide mnemonic information about object recognition that is accomplished through the occipitotemporal pathway.
PMCID: PMC3525540  PMID: 23272220
15.  Help-seeking behavior among Japanese school students who self-harm: results from a self-report survey of 18,104 adolescents 
The aim of this study was to determine the prevalence of and factors associated with poor help-seeking among adolescents who self-harm and to explore the resources used for help.
A cross-sectional survey using an anonymous questionnaire was conducted in 47 junior and 30 senior high schools in Japan. Adolescent self-harm was defined as an adolescent who had harmed himself or herself in the previous year, as in previous studies reported in Western countries. Poor help-seeking was defined as not consulting anyone despite reporting current psychological or somatic complaints. Information about sociodemographic and psychological factors possibly associated with help-seeking, such as suicidal thoughts, depression, anxiety, and psychotic-like experiences, was also collected. Regression analyses were performed to examine associated factors.
A total of 18,104 students (8620 aged 12–15 years, 9484 aged 15–18 years), accounting for 93% of all students in the relevant student classes, participated in the study. Two hundred and seventy-six (3.3%) junior and 396 (4.3%) senior high school students reported having self-harmed. Of these, 40.6% of adolescents in junior and 37.6% in senior high schools were classified as poor help-seeking. Poor help-seeking with regard to self-harm was significantly more common in those who reported not having consulted anyone about psychological problems (odds ratio 9.2, 95% confidence interval 4.6–18.4 in juniors; odds ratio 9.9, confidence interval 5.5–17.9 in seniors) and in those with current suicidal ideation (odds ratio 2.0, confidence interval 1.0–3.7 in juniors; odds ratio 1.9, confidence interval 1.1–3.4 in seniors). Family members were approached significantly less often as a resource for help by students who self-harmed than by those who did not, and school nurses were more often consulted by those who did self-harm.
Around 40% of adolescents who self-harmed in the previous year did not seek help. School-based mental health should screen students at risk of self-harm, and educate school nurses about preventative care.
PMCID: PMC3509995  PMID: 23209369
self-harm; adolescence; help-seeking; prevention; Japan
16.  Irregular Bedtime and Nocturnal Cellular Phone Usage as Risk Factors for Being Involved in Bullying: A Cross-Sectional Survey of Japanese Adolescents 
PLoS ONE  2012;7(9):e45736.
A number of studies have tried to identify risk factors for being involved in bullying in order to help developing preventive measures; however, to our knowledge, no study has investigated the effect of nocturnal lifestyle behavior such as sleep pattern or cellular phone usage. In the present study, we aimed to investigate the relationship between school bullying and sleep pattern or nocturnal cellular phone usage in adolescents. The effect of school size on school bullying was also examined.
Data from the cross-sectional survey of psychopathologies conducted for 19,436 Japanese students from 45 public junior high schools (7th–9th grade) and 28 senior high schools (10th–12th grade) were analyzed.
Bullying status was significantly associated with irregular bedtime (OR = 1.23 and 1.41 for pure bullies and bully-victims, respectively) and e-mail exchange or calling after lights-out (OR = 1.53 and 1.31 for pure bullies and bully-victims, respectively) after controlling domestic violence and substance usage. In addition, school size was significantly associated with the increased risk of bullying in junior high school students (OR = 1.13 for bully-victims).
The present results suggested that sleep pattern and nocturnal cellular phone usage might be risk factors for being involved in school bullying in adolescents. Although further accumulation of data is needed, progressive trend towards nocturnal lifestyle and increasing usage of cellular phone might impair the well-being of adolescents. School-based interventions for lifestyle including sleep pattern and cellular phone usage may be encouraged to reduce school bullying.
PMCID: PMC3446940  PMID: 23029211
17.  Immunotoxin-Mediated Tract Targeting in the Primate Brain: Selective Elimination of the Cortico-Subthalamic “Hyperdirect” Pathway 
PLoS ONE  2012;7(6):e39149.
Using a neuron-specific retrograde gene-transfer vector (NeuRet vector), we established immunotoxin (IT)-mediated tract targeting in the primate brain that allows ablation of a neuronal population constituting a particular pathway. Here, we attempted selective removal of the cortico-subthalamic “hyperdirect” pathway. In conjunction with the direct and indirect pathways, the hyperdirect pathway plays a crucial role in motor information processing in the basal ganglia. This pathway links the motor-related areas of the frontal lobe directly to the subthalamic nucleus (STN) without relay at the striatum. After electrical stimulation in the motor-related areas such as the supplementary motor area (SMA), triphasic responses consisting of an early excitation, an inhibition, and a late excitation are usually detected in the internal segment of the globus pallidus (GPi). Several lines of pharmacophysiological evidence suggest that the early excitation may be derived from the hyperdirect pathway. In the present study, the NeuRet vector expressing human interleukin-2 receptor α-subunit was injected into the STN of macaque monkeys. Then, IT injections were made into the SMA. In these monkeys, single-neuron activity in the GPi was recorded in response to the SMA stimulation. We found that the early excitation was largely reduced, with neither the inhibition nor the late excitation affected. The spontaneous firing rate and pattern of GPi neurons remained unchanged. This indicates that IT-mediated tract targeting successfully eliminated the hyperdirect pathway selectively from the basal ganglia circuitry without affecting spontaneous activity of STN neurons. The electrophysiological finding was confirmed with anatomical data obtained from retrograde and anterograde neural tracings. The present results define that the cortically-driven early excitation in GPi neurons is mediated by the hyperdirect pathway. The IT-mediated tract targeting technique will provide us with novel strategies for elucidating various neural network functions.
PMCID: PMC3382612  PMID: 22761729
18.  Promoting effects of nanoparticles/materials on sensitive lung inflammatory diseases 
Although the adverse health effects of nanoparticles/materials have been proposed and are being clarified, their facilitating effects on preexisting pathological conditions have not been fully established. We provide insights into the environmental immunotoxicity of nanoparticles as an aggravating factor in hypersusceptible subjects, especially those with respiratory disorders, using our in vivo models. We first examined the effects of nanoparticles/materials on lung inflammation induced by bacterial endotoxin (lipopolysaccharide) as a test model against innate immunity, and demonstrated that nanoparticles instilled through both an intratracheal tube and an inhalation system can exacerbate lung inflammation. Secondly, we examined the effects of nanoparticles/materials on allergic pathophysiology, and showed that repetitive pulmonary exposure to nanoparticles has aggravating effects on allergic airway inflammation, including adjuvant effects on Th2-milieu. Taken together, nanoparticle exposure may synergistically facilitate pathological inflammatory conditions in the lung via both innate and adaptive immunological abnormalities.
PMCID: PMC3078294  PMID: 21431802
Nanoparticles; Nanomaterials; Lung inflammation; Sensitivity; Asthma
19.  The development of agoraphobia is associated with the symptoms and location of a patient's first panic attack 
The place where a patient experiences his/her first panic attack (FPA) may be related to their agoraphobia later in life. However, no investigations have been done into the clinical features according to the place where the FPA was experienced. In particular, there is an absence of detailed research examining patients who experienced their FPA at home. In this study, patients were classified by the location of their FPA and the differences in their clinical features were explored (e.g., symptoms of FPA, frequency of agoraphobia, and severity of FPA).
The subjects comprised 830 panic disorder patients who were classified into 5 groups based on the place of their FPA (home, school/office, driving a car, in a public transportation vehicle, outside of home), The clinical features of these patients were investigated. Additionally, for panic disorder patients with agoraphobia at their initial clinic visit, the clinical features of patients who experienced their FPA at home were compared to those who experienced their attack elsewhere.
In comparison of the FPAs of the 5 groups, significant differences were seen among the 7 descriptors (sex ratio, drinking status, smoking status, severity of the panic attack, depression score, ratio of agoraphobia, and degree of avoidance behavior) and 4 symptoms (sweating, chest pain, feeling dizzy, and fear of dying). The driving and public transportation group patients showed a higher incidence of co-morbid agoraphobia than did the other groups. Additionally, for panic disorder patients with co-morbid agoraphobia, the at-home group had a higher frequency of fear of dying compared to the patients in the outside-of-home group and felt more severe distress elicited by their FPA.
The results of this study suggest that the clinical features of panic disorder patients vary according to the place of their FPA. The at-home group patients experienced "fear of dying" more frequently and felt more distress during their FPA than did the subjects in the other groups. These results indicate that patients experiencing their FPA at home should be treated with a focus on the fear and distress elicited by the attack.
PMCID: PMC3349583  PMID: 22494552
Place of first panic attack; Panic attack symptoms; Subtype of panic disorder; Agoraphobia
20.  Constitutively expressed Protocadherin-α regulates the coalescence and elimination of homotypic olfactory axons through its cytoplasmic region 
Olfactory sensory neuron (OSN) axons coalesce into specific glomeruli in the olfactory bulb (OB) according to their odorant receptor (OR) expression. Several guidance molecules enhance the coalescence of homotypic OSN projections, in an OR-specific- and neural-activity-dependent manner. However, the mechanism by which homotypic OSN axons are organized into glomeruli is unsolved. We previously reported that the clustered protocadherin-α (Pcdh-α) family of diverse cadherin-related molecules plays roles in the coalescence and elimination of homotypic OSN axons throughout development. Here we showed that the elimination of small ectopic homotypic glomeruli required the constitutive expression of a Pcdh-α isoform and Pcdh-α's cytoplasmic region, but not OR specificity or neural activity. These results suggest that Pcdh-α proteins provide a cytoplasmic signal to regulate repulsive activity for homotypic OSN axons independently of OR expression and neural activity. The counterbalancing effect of Pcdh-α proteins for the axonal coalescence mechanisms mediated by other olfactory guidance molecules indicate a possible mechanism for the organization of homotypic OSN axons into glomeruli during development.
PMCID: PMC3472330  PMID: 23087612
olfactory; axon; protocadherin; Pcdh; convergence; elimination; neural circuit; neuron
21.  Genome-Wide Association Study Identifies HLA-DP as a Susceptibility Gene for Pediatric Asthma in Asian Populations 
PLoS Genetics  2011;7(7):e1002170.
Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1×10−8) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (Pcombined = 2.3×10−10, odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10−10, OR = 1.52, and DPB1*0901: P = 2.0×10−7, OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.
Author Summary
Asthma is the most common chronic disorder in children, and asthma exacerbation is an important cause of childhood morbidity and hospitalization. Here, taking advantage of recent technological advances in human genetics, we performed a genome-wide association study and follow-up validation studies to identify genetic variants for asthma. By examining 6,428 Asians, we found rs987870 and HLA-DPA1*0201/DPB1*0901 were associated with pediatric asthma. The association signal was stretched in the region of HLA-DPB2, collagen, type XI, alpha 2 (COL11A2), and Retinoid X receptor beta (RXRB), but strong linkage disequilibrium in this region made it difficult to specifically identify causative variants. Interestingly, the SNP (or the HLA-DP allele) associated with pediatric asthma (Th-2 type immune diseases) in the present study confers protection against Th-1 type immune diseases, such as type 1 diabetes and rheumatoid arthritis. Therefore, the association results obtained in the present study could partially explain the inverse relationship between asthma and Th-1 type immune diseases and may lead to better understanding of Th-1/Th-2 immune diseases.
PMCID: PMC3140987  PMID: 21814517
22.  Particulate Matter–Induced Health Effects: Who Is Susceptible? 
PMCID: PMC3222982  PMID: 21719374
23.  Identification of dihalogenated proteins in rat intestinal mucosa injured by indomethacin 
Previous studies have shown that activated neutrophils and their myeloperoxidase (MPO)-derived products play a crucial role in the pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-related small intestinal injury. The aim of the present study is to identify dihalogenated proteins in the small intestine on indomethacin administration. Intestinal damage was induced by subcutaneous administration of indomethacin (10 mg/kg) in male Wistar rats, and the severity of the injury was evaluated by measuring the area of visible ulcerative lesions. Tissue-associated MPO activity was measured in the intestinal mucosa as an index of neutrophil infiltration. The dihalogenated proteins were separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) using novel monoclonal antibodies against dibromotyrosine (DiBrY), and they were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) peptide mass fingerprinting and a Mascot database search. Single administration of indomethacin elicited increased ulcerative area and MPO activity in the small intestine. 2D-PAGE showed an increased level of DiBrY-modified proteins in the indomethacin-induced injured intestinal mucosa and 6 modified proteins were found. Enolase-1 and albumin were found to be DiBrY modified. These proteins may be responsible for the development of neutrophil-associated intestinal injury induced by indomethacin.
PMCID: PMC3045693  PMID: 21373273
indomethacin; dibromotyrosine; albumin; enolase
25.  Efficient hemostatic method for endoscopic submucosal dissection of colorectal tumors 
AIM: To evaluate a new hemostatic method using hemostatic forceps to prevent perforation and perioperative hemorrhage during colonic endoscopic submucosal dissection (ESD).
METHODS: We studied 250 cases, in which ESD for colorectal tumors was performed at the Kyoto Prefectural University of Medicine or Nara City Hospital between 2005 and 2010. We developed a new hemostatic method using hemostatic forceps in December 2008 for the efficient treatment of submucosal thick vessels. ESD was performed on 126 cases after adoption of the new method (the adopted group) and the new method was performed on 102 of these cases. ESD was performed on 124 cases before the adoption of the new method (the unadopted group). The details of the new method are as follows: firstly, a vessel was coagulated using the hemostatic forceps in the soft coagulation mode according to the standard procedure, and the coagulated vessel was removed using the forceps in the “endocut” mode without perioperative hemorrhage. Secondly, the partial surrounding submucosa was dissected using the forceps in the endocut mode. In the current study, we evaluated the efficacy of this method.
RESULTS: Coagulated vessels were successfully removed using the hemostatic forceps in all 102 cases without severe perioperative hemorrhage. Moderate perioperative hemorrhage occurred in five cases (4.9%); however, it was stopped by immediately reuse of the hemostatic forceps. The partial surrounding submucosa was dissected using the forceps in all 102 cases. In the adopted group, the median operation time was 105 min. The proportion of endoscopic en bloc resection was 92.8% (P < 0.01) compared to 80.6% in the unadopted group. The postoperative hemorrhage and perforation rates were 2.3% and 2.3%. The rate of perforation was significantly lower than that in the unadopted group (9.6%, P < 0.01). We evaluated the ease of use of this method by allowing our three trainees to performed ESD on 46 cases, which were accomplished without any severe hemorrhage.
CONCLUSION: The new method effectively treated submucosal thick vessels and shows promise for the prevention of perforation and perioperative hemorrhage in colonic ESD.
PMCID: PMC2932923  PMID: 20806436
Endoscopic submucosal dissection; Colorectal tumor; Hemostatic forceps; Perforation; Perioperative hemorrhage

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