The KCNH3 inhibitor ASP2905 shows potential in the treatment of attention deficit/hyperactivity disorder.

N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine [ASP2905] is a potent and selective inhibitor of the potassium voltage-gated channel subfamily H member 3 (KCNH3) that was originally identified in our laboratory. KCNH3 is concentrated in the forebrain, and its overexpression in mice leads to cognitive deficits. In contrast, Kcnh3 knockout mice exhibit enhanced performance in cognitive tasks such as attention.

ASP6537, a novel highly selective cyclooxygenase-1 inhibitor, exerts potent antithrombotic effect without "aspirin dilemma".

Introduction: Aspirin inhibits both the cyclooxygenase (COX)-1-dependent production of thromboxane A2 (TXA2) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I2 (PGI2) in vessel walls, resulting in "aspirin dilemma." Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect.

Methods: We evaluated the inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test.

Brain-derived neurotrophic factor alters cell migration of particular progenitors in the developing mouse cerebral cortex.

Effects of brain-derived neurotrophic factor (BDNF) on cell migration from the ventricular zone to the cortical plate (CP) in developing mouse cerebral cortex were examined. BDNF (700 ng) was injected into the brain ventricle of 13- or 14-day-old embryos (E13 or E14) after the intraperitoneal administration of 5-bromodeoxyuridine (BrdU) to pregnant mice. BDNF injection at E13 increased the number of BrdU-positive cells migrated into the CP until E15, and caused them to become localized in much deeper layers (V-VI) than expected (IV-V, as in the vehicle-treated mice) by postnatal day 1.

Administration of FGF-2 to embryonic mouse brain induces hydrocephalic brain morphology and aberrant differentiation of neurons in the postnatal cerebral cortex.

Fibroblast growth factor-2 (FGF-2) was injected into mouse cerebral ventricles at embryonic day (E) 14 in utero and its effects on developing brain morphology and expression of various cell- or differentiation-associated protein markers in the cerebral cortex were examined. High doses of FGF-2 (200 or 300 ng) caused encephalic alternations such as deformation of the calvarium, enlargement of the ventricular spaces, and thinning of the cerebral cortex. There was no gross abnormality in the alignment of the cerebral neuronal layers, however, both cell number and cell density of the upper layers (II/III) and the lower layers (IV-VI) of the cerebral cortex were increased.

Effectiveness of interferon treatment for patients with chronic hepatitis C virus infection and normal aminotransferase levels.

To determine the effects of interferon treatment, we studied 77 Japanese patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase (ALT). Of 77 patients, 37 were given natural interferon-alpha for 24 weeks, and 40 not given interferon acted as controls. Serum samples were tested for HCV RNA and genotypes by polymerase chain reaction (PCR).

Aberrant expression of neurotrophic factors in the ventricular progenitor cells of infant congenitally hydrocephalic rats.

Objects: This study was conducted to investigate the roles of neurotrophic factors in the development of hydrocephalus in HTX rats.

Methods: Expressions of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and fibroblast growth factor (FGF)-1 were examined immunohistochemically in the cerebral cortex and ventricular zone of 6-day-old rats with congenital hydrocephalus (HTX rats). In the ventricular zone of hydrocephalic rats, potent BDNF-like immunoreactivity (-LI) and weak but significant signals for NT-3- and FGF-1-LIs were observed.

Induction of a physiologically active brain-derived neurotrophic factor in the infant rat brain by peripheral administration of 4-methylcatechol.

Effects of 4-methylcatechol (4MC), a known potent stimulator of nerve growth factor (NGF) synthesis, on expression of brain-derived neurotrophic factor (BDNF) mRNA and BDNF-like immunoreactivity (BDNF-LI) was investigated in infant rat brains. A single intraperitoneal administration of 4MC caused transient increases in the levels of BDNF mRNA and BDNF-LI in neurons of the cerebral cortex from 1 to 3 h and 3 to 12 h, respectively, after the injection. Repetitive injections of 4MC to newborn rats (12-h intervals for 10 days) caused a marked and dose-dependent elevation of the level of BDNF mRNA in the whole brain besides elevating the number of cells containing calbindin D-28 and enhancing its immunoreactive intensity in the pyriform cortex and hippocampus.

4-methylcatechol increases brain-derived neurotrophic factor content and mRNA expression in cultured brain cells and in rat brain in vivo.

Practical use of brain-derived neurotrophic factor (BDNF) as therapy is limited by two serious problems, i.e., its inability to cross the blood-brain barrier and its instability in the bloodstream.

Brain-derived neurotrophic factor prevents neuronal cell death induced by corticosterone.

Corticosterone (CORT), one of the glucocorticoids, causes neuronal damage in the hippocampus, but the mechanism(s) of action underlying its effects remains unknown. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that belongs to the neurotrophin family, affects the survival and/or differentiation of various types of neurons in vitro, and is able to antagonize neuronal death induced by various brain insults or neurotoxins in vivo. In this study, the effects of CORT on BDNF protein contents and mRNA expression were investigated in relation to neuronal survival/death of cultured rat hippocampal neurons, because the colocalization of BDNF with its receptor, TrkB, suggests that BDNF may exert its putative protective and trophic effects through an autocrine mechanism in the hippocampus.

Endogenous neurotrophin-3 is retrogradely transported in the rat sciatic nerve.

To address the active transport of neurotrophins, nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 in the peripheral nerves, we examined the levels of proteins and messenger RNAs in the sciatic nerve of adult rats following transection, using enzyme immunoassays and reverse transcription polymerase chain reaction method, respectively. Neurotrophin-3 protein increased one day after transection only in the distal segment next to the transection site and returned to the original level two days later. This was considered to reflect accumulation of neurotrophin-3 transported from the periphery toward the neuronal cell bodies, because the neurotrophin-3 messenger RNA level was not changed in any sciatic segments during this experimental period.

Differences between interferon-alpha and -beta treatment for patients with chronic hepatitis C virus infection.

To compare virological, biochemical, and immune responses to human lymphoblastoid interferon (IFN-alpha) and human fibroblast interferon (IFN-beta) in patients with chronic hepatitis C virus (HCV) infection, 120 patients were randomly assigned to three groups (group A, 60 patients receiving IFN-alpha, 6 million units (MU) once a day, daily for one month and thrice weekly for five months; group B, 40 patients receiving 6 MU IFN-beta once a day daily for two months; and group C, 20 patients receiving 3 MU IFN-beta twice a day (6 MU/day) daily for two months). Serum soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) levels were measured by enzyme-linked immunosorbent assay. Patients with sustained clearance of serum HCV RNA detected by polymerase chain reaction (PCR) at six months after IFN treatment were defined as having complete response to IFN treatment.

Large dose natural interferon alpha therapy for patients with chronic hepatitis C.

To evaluate the efficacy of large dose interferon treatment for patients with chronic hepatitis C virus (HCV) infection, we studied 99 Japanese patients treated with either 6 million units (MU) or 9 MU natural interferon alpha. Serum samples were tested for HCV RNA by polymerase chain reaction (PCR). HCV RNA genotypes were determined by PCR with type-specific preimers, and the HCV RNA level was measured by competitive PCR.

Elevation of serum soluble interleukin-2 receptor levels in patients with hepatitis C virus infection.

To determine serum soluble interleukin-2 receptor (sIL-2 R) levels in hepatitis C virus (HCV) infection, serum sIL-2 R was measured in 260 subjects with chronic HCV infection, including 100 patients who had previously been treated with natural interferon (IFN) alpha, and in 51 HCV RNA-negative controls. Serum sIL-2 R levels in asymptomatic HCV carriers, patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) were significantly higher than those of healthy controls and subjects who were positive for anti-HCV and negative for HCV RNA (P < 0.01, respectively).

Long term survey of hepatitis C virus infection in hemodialysis units in Fukuoka, Japan.

To examine prevalence of hepatitis C virus (HCV) infection and liver dysfunction in hemodialysis units, we surveyed markers for HCV infection and serum alanine aminotransferase (ALT) in hemodialysis patients. 204 hemodialysis patients (111 men and 93 women; mean age, 53 +/- 12 years) in four hemodialysis units in Fukuoka, Japan were investigated. All serum samples were tested for antibody to HCV (anti-HCV) by second-generation enzyme-linked immunosorbant assay (ELISA).

Serum levels of soluble interleukin-2 receptors and effects of interferon-alpha for patients with chronic hepatitis C virus.

To characterize the role of serum soluble interleukin-2 receptor (sIL-2R) in hepatitis C virus (HCV) infection, the level of sIL-2R was measured by ELISA in 117 subjects with chronic HCV infection and in 23 healthy controls. HCV RNA was detected by polymerase chain reaction in all subjects with HCV infection. Forty-seven patients with chronic hepatitis and 10 with liver cirrhosis were treated for six months with natural interferon-alpha.

A preliminary study of retreatment of chronic hepatitis C with interferon.

Nine patients with chronic hepatitis C virus (HCV) infection and no complete response to the first treatment with natural interferon (IFN)-alpha, were prescribed a second treatment with IFN. Five patients (Group A) with unsustained levels serum alanine aminotransferase (ALT) after the first treatment were administrated the same species of IFN but in a higher dose. The remaining four patients (Group B), with no normalization of ALT throughout the observation period of the first treatment, were administrated IFN-beta.

A statistical analysis of predictive factors of response to human lymphoblastoid interferon in patients with chronic hepatitis C.

Objective: To determine markers predictive of effective interferon treatment for patients with chronic hepatitis C virus (HCV) infection, we studied 80 Japanese patients treated for 6 months with natural interferon-alpha.

Methods: Serum samples were tested for HCV RNA by two-stage polymerase chain reaction (PCR). HCV RNA were grouped into four genotypes by amplification of core-gene sequences by PCR with type-specific primers, and the level of HCV RNA was measured by competitive PCR.

Inverse correlation between the titre of antibody to hepatitis C virus and the degree of hepatitis C viraemia.

We titrated 277 hepatitis C virus (HCV) antibody-positive serum samples from 235 volunteer blood donors as well as from 42 outpatients of a hospital for elderly people and studied the relation of the titre of HCV antibody to the presence of HCV RNA, of antibody to C100 protein (anti-c100) and of antibody to GOR epitope (anti-GOR). Liver dysfunction was measured also. Of 177 HCV RNA-positive serum samples, 87 were tested for the degree of HCV viraemia by means of a competitive assay.

Prevalence and role of hepatitis C viraemia in haemodialysis patients in Japan.

A second generation assay for antibody to hepatitis C virus (anti-HCV) was used in order to establish the exact prevalence of HCV infection in haemodialysis patients. HCV RNA was sought by the polymerase chain reaction in order to determine whether haemodialysis patients with anti-HCV had been infected with HCV in the past or were presently infected. Of 357 patients, 198 (55.

Improved detection of antibodies to hepatitis C virus by the second-generation assay in patients with chronic non-A, non-B liver disease.

Serum samples from 337 Japanese patients with chronic non-A, non-B liver disease were tested for antibodies to hepatitis C virus (HCV) by means of first-generation (c100-3; anti-c100) and second-generation (pHCV-34, pHCV-31, c100-3; anti-HCV II) enzyme linked immunosorbent assays (ELISA) and for antibody to the GOR epitope (anti-GOR) also by ELISA. Anti-HCV II was detected in 314 (93.2%), anti-c100 in 247 (81.

Amino acid sequence of the major component of Nostoc muscorum ferredoxin.

The amino acid sequence of the major component of ferredoxin isolated from a blue-green alga, Nostoc muscorum, grown under N2 as the sole nitrogen source has been studied. The use of a combination of sequence analyzer, carboxypeptidases, and manual Edman degradations on tryptic and chymotryptic peptides of carboxymethylferredoxin has established the amino acid seuqence, which consists of 98 amino acid residues. Only four cysteine residues were present, located at positions 41, 46, 49, and 79.