Reproductive isolation between sympatric Anguilla japonica and Anguilla marmorata.

Species-specific restriction fragment length polymorphism in the intron of the androgen receptor gene (ar5) was found in glass to silver-stage individuals of Anguilla japonica (n = 51) and A. marmorata (n = 21). The sequence analysis of 16S rDNA from 328 anguillid leptocephali collected in the North Equatorial Current of the western North Pacific Ocean revealed the specimens to be A. japonica (n = 194), A. marmorata (n = 128), A. bicolor pacifica (n = 5) and A. luzonensis (n = 1). All leptocephali of A. japonica and A. marmorata were monomorphic and did not share an allele at the ar5 locus, indicating that the two species are reproductively isolated.

Utility and validity of DISC1 mouse models in biological psychiatry.

We have seen an era of explosive progress in translating neurobiology into etiological understanding of mental disorders for the past 10-15 years. The discovery of Disrupted-in-schizophrenia 1 (DISC1) gene was one of the major driving forces that have contributed to the progress. The finding that DISC1 plays crucial roles in neurodevelopment and synapse regulation clearly underscored the utility and validity of DISC1-related biology in advancing our understanding of pathophysiological processes underlying psychiatric conditions. Despite recent genetic studies that failed to identify DISC1 as a risk gene for sporadic cases of schizophrenia, DISC1 mutant mice, coupled with various environmental stressors, have proven successful in satisfying face validity as models of a wide range of human psychiatric conditions. Investigating mental disorders using these models is expected to further contribute to the circuit-level understanding of the pathological mechanisms, as well as to the development of novel therapeutic strategies in the future.

DISC1 regulates trafficking and processing of APP and Aß generation.

We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia. RNAi knockdown of DISC1 in mature primary cortical neurons led to a significant increase in the levels of intracellular α-C-terminal fragment of APP (APP-CTFα) and the corresponding N-terminal-secreted ectodomain product sAPPα. DISC1 knockdown also elicited a significant decrease in the levels of amyloid beta (Aß)42 and Aß40. These aberrant proteolytic events were successfully rescued by co-expression of wild-type DISC1, but not by mutant DISC1 lacking the amino acids required for the interaction with APP, suggesting that APP-DISC1 protein interactions are crucial for the regulation of the C-terminal proteolysis. In a genetically engineered model in which a major full-length DISC1 isoform is depleted, consistent changes in APP processing were seen: an increase in APP-CTFα and decrease in Aß42 and Aß40 levels. Finally, we found that knockdown of DISC1 increased the expression of APP at the cell surface and decreased its internalization. The presented DISC1 mechanism of APP proteolytic processing and Aß peptide generation, which is central to Alzheimer's disease pathology, suggests a novel interface between neurological and psychiatric conditions.

Satisfaction with bispectral index monitoring of propofol-mediated sedation during endoscopic submucosal dissection: a prospective, randomized study.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is one of the most complex and lengthy endoscopic procedures, so deep sedation during ESD is indispensable. Our study aims were to determine whether bispectral index (BIS) monitoring is useful in titrating and reducing the dose of the sedative propofol during ESD, and to measure the satisfaction of patients and endoscopists involved in this complex and lengthy endoscopic therapy. PATIENTS AND METHODS: We performed a prospective, randomized clinical trial from July 2006 to February 2008. A total of 156 patients, with gastric neoplasm to be treated using ESD, were randomized to two groups. The BIS group (n = 78) was monitored for propofol sedation using BIS, and the no-BIS group (n = 78) was monitored by standard methods only. The two groups were compared by evaluating the doses of propofol administered to patients and the satisfaction scores (scale of 0 - 10) of patients and endoscopists. RESULTS: Although there were no significant differences between the two groups in the mean dose of propofol used (BIS group vs. no-BIS group, 5.32 mg/kg/hour vs. 4.85 mg/kg/hour; P = 0.10), the satisfaction scores of the patients (9.15 vs. 7.94; P < 0.01) and endoscopists (8.53 vs. 6.42; P < 0.001) were significantly higher with BIS monitoring. CONCLUSIONS: Monitoring with BIS during the ESD procedure did not lead to a reduction in the dose of propofol required, but did lead to higher satisfaction scores from the patients and endoscopists. A complicated and prolonged endoscopic treatment such as ESD can be carried out with optimal safety, control, and comfort by using BIS to monitor propofol sedation.

Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly.

Disrupted-in-schizophrenia-1 (DISC1) is one of major susceptibility factors for a wide range of mental illnesses, including schizophrenia, bipolar disorder, major depression and autism spectrum conditions. DISC1 is located in several subcellular domains, such as the centrosome and the nucleus, and interacts with various proteins, including NudE-like (NUDEL/NDEL1) and activating transcription factor 4 (ATF4)/CREB2. Nevertheless, a role for DISC1 in vivo remains to be elucidated. Therefore, we have generated a Drosophila model for examining normal functions of DISC1 in living organisms. DISC1 transgenic flies with preferential accumulation of exogenous human DISC1 in the nucleus display disturbance in sleep homeostasis, which has been reportedly associated with CREB signaling/CRE-mediated gene transcription. Thus, in mammalian cells, we characterized nuclear DISC1, and identified a subset of nuclear DISC1 that colocalizes with the promyelocytic leukemia (PML) bodies, a nuclear compartment for gene transcription. Furthermore, we identified three functional cis-elements that regulate the nuclear localization of DISC1. We also report that DISC1 interacts with ATF4/CREB2 and a corepressor N-CoR, modulating CRE-mediated gene transcription.

Intra-arterial chemoradiotherapy for locally advanced oral cavity cancer: analysis of therapeutic results in 134 cases.

The objective of this study was to investigate the therapeutic results of arterial injection therapy via the superficial temporal artery for 134 cases of stages III and IV (M0) oral cavity cancer retrospectively, and to clarify the prognostic factors. We administered intra-arterial chemoradiotherapy by continuous infusion of carboplatin in 65 cases from January 1993 to July 2002. Systemic chemotherapy was performed on 26 cases at the same time. We administered intra-arterial chemoradiotherapy by cisplatin with sodium thiosulphate in 69 cases from October 2002 to December 2006. Systemic chemotherapy was performed on 48 cases at the same time. The 3-year local control rate was 68.6% (T2-3: 77.9%; T4: 51.3%), and the 3-year survival rate was 53.9% (stage III: 62.9%; stage IV: 45.3%). Regarding the results of multivariate analysis of survival rates, age (<65), selective intra-arterial infusion, and the use of cisplatin as an agent for intra-arterial infusion were significant factors. The therapeutic results of intra-arterial chemoradiotherapy via the superficial temporal artery were not inferior to the results of surgery. In particular, the results of arterial injection therapy by cisplatin with sodium thiosulphate were excellent, so we believe that it will be a new therapy for advanced oral cavity cancer.

The actions of azelnidipine, a dihydropyridine-derivative Ca antagonist, on voltage-dependent Ba2+ currents in guinea-pig vascular smooth muscle.

BACKGROUND AND PURPOSE: Although azelnidipine is used clinically to treat hypertension its effects on its target cells, Ca2+ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltage-dependent L-type Ca2+ channels were investigated in guinea-pig portal vein. EXPERIMENTAL APPROACH: The inhibitory potency of azelnidipine on spontaneous contractions in guinea-pig portal vein was compared with those of other dihydropyridine (DHP)-derived Ca antagonists (amlodipine and nifedipine) by recording tension. Also its effects on voltage-dependent nifedipine-sensitive inward Ba2+ currents (IBa) in smooth muscle cells dispersed from guinea-pig portal vein were investigated by use of a conventional whole-cell patch-clamp technique. KEY RESULTS: Spontaneous contractions in guinea-pig portal vein were reduced by all of the Ca antagonists (azelnidipine, Ki = 153 nM; amlodipine, Ki = 16 nM; nifedipine, Ki = 7 nM). In the whole-cell experiments, azelnidipine inhibited the peak amplitude of IBa in a concentration- and voltage-dependent manner (-60 mV, Ki = 282 nM; -90 mV, Ki = 2 microM) and shifted the steady-state inactivation curve of IBa to the left at -90 mV by 16 mV. The inhibitory effects of azelnidipine on IBa persisted after 7 min washout at -60 mV. In contrast, IBa gradually recovered after being inhibited by amlodipine, but did not return to control levels. Both azelnidipine and amlodipine caused a resting block of IBa at -90 mV. Only nifedipine appeared to interact competitively with S(-)-Bay K 8644. CONCLUSIONS AND IMPLICATIONS: These results suggest that azelnidipine induces long-lasting vascular relaxation by inhibiting voltage-dependent L-type Ca2+ channels in vascular smooth muscle.

Actions of ZD0947, a novel ATP-sensitive K+ channel opener, on membrane currents in human detrusor myocytes.

BACKGROUND AND PURPOSE: ATP-sensitive K+ channels (K(ATP) channels) play important roles in regulating the resting membrane potential of detrusor smooth muscle. Actions of ZD0947, a novel KATP channel opener, on both carbachol (CCh)-induced detrusor contractions and membrane currents in human urinary bladder myocytes were investigated. EXPERIMENTAL APPROACH: Tension measurements and patch-clamp techniques were utilized to study the effects of ZD0947 in segments of human urinary bladder. Immunohistochemistry was also performed to detect the expression of the sulphonylurea receptor 1 (SUR1) and the SUR2B antigens in human detrusor muscle. KEY RESULTS: ZD0947 (> or = 0.1 microM) caused a concentration-dependent relaxation of the CCh-induced contraction of human detrusor, which was reversed by glibenclamide. The rank order of the potency to relax the CCh-induced contraction was pinacidil > ZD0947 > diazoxide. In conventional whole-cell configuration, ZD0947 (> or = 1 microM) caused a concentration-dependent inward K+ current which was suppressed by glibenclamide at -60 mV. When 1 mM ATP was included in the pipette solution, application of pinacidil or ZD0947 caused no inward K+ current at -60 mV. Gliclazide (< or =1 microM), a selective SUR1 blocker, inhibited the ZD0947-induced currents (Ki = 4.0 microM) and the diazoxide-induced currents (high-affinity site, Ki1 = 42.4 nM; low-affinity site, Ki2 = 84.5 microM) at -60 mV. Immunohistochemical studies indicated the presence of SUR1 and SUR2B proteins, which are constituents of KATP channels, in the bundles of human detrusor smooth muscle. CONCLUSIONS AND IMPLICATIONS: These results suggest that ZD0947 caused a glibenclamide-sensitive detrusor relaxation through activation of glibenclamide-sensitive KATP channels in human urinary bladder.

Mechanisms of neuronal cell death in Huntington's disease.

Huntington's disease (HD) is a genetically dominant neurodegenerative condition caused by an unique mutation in the disease gene huntingtin. Although the Huntington protein (Htt) is ubiquitously expressed, expansion of the polyglutamine tract in Htt leads to the progressive loss of specific neuronal subpopulations in HD brains. In this article, we will summarize the current understanding on mechanisms of how mutant Htt can elicit cytotoxicity, as well as how the selective sets of neuronal cell death occur in HD brains.

Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation.

In the developing cerebellar cortex, granule neuron precursors (GNPs) proliferate and commence differentiation in a superficial zone, the external granule layer (EGL). The molecular basis of the transition from proliferating precursors to immature differentiating neurons remains unknown. Notch signaling is an evolutionarily conserved pathway regulating the differentiation of precursor cells of many lineages. Notch2 is specifically expressed in proliferating GNPs in the EGL. Treatment of GNPs with soluble Notch ligand Jagged1, or overexpression of activated Notch2 or its downstream target HES1, maintains precursor proliferation. The addition of GNP mitogens Jagged1 or Sonic Hedgehog (Shh) upregulates the expression of HES1, suggesting a role for HES1 in maintaining precursor proliferation.

Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons.

In the developing cerebellum, granule neuron axon outgrowth is a key step toward establishing proper connections with Purkinje neurons, the principal output neuron of the cerebellum. During a search for genes that function in this process, we identified a receptor tyrosine kinase discoidin domain receptor 1 (DDR1) expressed in granule cells throughout their development. Overexpression of a dominant-negative form of DDR1 in immature granule cells results in severe reduction of neurite outgrowth in vitro, in dissociated primary culture, and in vivo, in organotypic slices of neonatal cerebellum. Granule cells that fail to extend axons are positive for differentiation markers such as TAG-1 and the neuron-specific class III beta-tubulin, suggesting that development is affected after granule cells commit to terminal differentiation. DDR1 activation appears to be mediated by its ligand, collagen, which is localized to the pial layer of the developing cerebellum, thereby leading to granule cell parallel fiber extension. Our results therefore indicate that collagen-DDR1 signaling is essential for granule neuron axon formation and further suggest a unique role of pia in cerebellar cortex histogenesis.

[Treatment of renal cell carcinoma extending into the right atrium with extra-corporeal circulation using high-grade hypothermia: a case report].

A 68-year-old woman underwent surgical treatment for renal cell carcinoma associated with tumor thrombus extending into the right atrium. Although the tumor thrombus reached the level of the right atrium, there were no other apparent metastases. Combination therapy with interferon alfa plus tegafur/uracil (UFT) was attempted with the expectation of reducing the tumor thrombus, but there was no change. Successful management was achieved with right radical nephrectomy, right auriculotomy, and partial cavectomy using cardiopulmonary bypass under high-grade hypothermia. After removal of the tumor and thrombus, blood loss was 13,900 ml during the patient's recovery. She had mild heart failure for about two weeks after the operation, but recovered. She was discharged on the 40th day after the operation. Proper preparation for blood transfusion is the key point of this operation.

Computerized tomographic ureteroscopy for diagnosing ureteral tumors.

PURPOSE: Helical computerized tomography (CT) image acquisition has led to the availability of improved data sets for CT endoscopic imaging that represent virtual endoscopy using CT. We assessed the usefulness of CT ureteroscopic imaging for diagnosing ureteral tumors. MATERIALS AND METHODS: A total of 16 patients with ureteral stenosis underwent surface rendering CT ureteroscopy after the intravenous administration of contrast material and furosemide. To distinguish ureteral tumors from ureteral strictures 2 observers blinded to other patient history and evaluation data independently and prospectively evaluated CT ureteroscopy with reformatted CT ureterograms in these 16 patients. CT ureteroscopic images were then correlated with surgical and pathological findings, which served as the gold standard. RESULTS: Surgical and pathological findings in the 16 patients revealed 16 ureteral tumors, including carcinoma in 10 (carcinoma in situ in 1, fibroepithelial polyps in 2 and hyperplastic polypoids in 4), inflammatory intrinsic stricture in 2 and extrinsic stricture in 4 caused by retroperitoneal fibrosis in 2 and lymph node metastasis in 2. CT ureteroscopy correctly detected all lesions except 1 carcinoma in situ, 1 polypoid carcinoma and 1 hyperplastic polypoid. The sensitivity and specificity of CT ureteroscopy for detecting ureteral tumors and carcinoma were 81% and 100%, and 80% and 75%, respectively, when tumors without stalks were considered carcinoma. CONCLUSIONS: CT ureteroscopy is useful for visualizing the complex morphology of ureteral tumors and distinguishing tumor from ureteral stricture.

Persistently high Epstein-Barr virus (EBV) loads in peripheral blood lymphocytes from patients with chronic active EBV infection.

Chronic active Epstein-Barr virus infection (CAEBV) is a severe illness with unusual EBV activation that persists for years, and its pathogenesis is largely unknown. After the creation of an accurate and reproducible polymerase chain reaction system to quantify EBV DNA, virus loads in peripheral blood lymphocytes (PBL) were determined in 54 children: 15 with CAEBV, 16 with infectious mononucleosis (IM), and 23 healthy children. Children with CAEBV and those with IM had high virus loads. Lower loads were detected in 47% of seropositive healthy donors. There were two distinct differences between children with CAEBV and those with IM: The former had greater viral replication (10(3)-10(7) copies/2.5x10(5) PBL) than those with IM, and viral replication declined in children with IM whereas active replication persisted for years in subjects with CAEBV. Persisting high virus loads are a possible diagnostic criterion for CAEBV. EBV loads may enable classification and prognosis of EBV infections.

A mouse serine/threonine kinase homologous to C. elegans UNC51 functions in parallel fiber formation of cerebellar granule neurons.

The formation of the cerebellar circuitry depends on the outgrowth of connections between the two principal classes of neurons, granule neurons and Purkinje neurons. To identify genes that function in axon outgrowth, we have isolated a mouse homolog of C. elegans UNC51, which is required for axon formation, and tested its function in cerebellar granule neurons. Murine Unc51.1 encodes a novel serine/threonine kinase and is expressed in granule cells in the cerebellar cortex. Retroviral infection of immature granule cells with a dominant negative Unc51.1 results in inhibition of neurite outgrowth in vitro and in vivo. Moreover, infected neurons fail to express TAG-1 or neuron-specific beta-tubulin, suggesting that development is arrested prior to this initial step of differentiation. Thus, Unc51.1 signals the program of gene expression leading to the formation of granule cell axons.

Focal pachypolymicrogyria in three siblings.

The malformation of focal pachypolymicrogyria might be the manifestation of an X-linked recessive disorder according to the results of this study. Three siblings revealed focal pachypolymicrogyria on magnetic resonance imaging (MRI) and had a strong family history of epilepsy and mental retardation. All three siblings had the same mother; the father of Patient 1 was not related to the mother, but the father of Patients 2 and 3 was related to her. The MRI of the father of Patients 2 and 3 demonstrated focal pachypolymicrogyria. The mother's MRI was normal. In this family, epilepsy or mental retardation was found mainly in the males (Patient 3 was an exception), and they were all born to female members of this family, not male. Patient 3 was probably a homozygote with an X-linked recessive inheritance, and therefore, she demonstrated the most severe clinical findings.