Cyclosporin A Treatment in Intrinsic Canine Atopic Dermatitis (Atopic-like Dermatitis): Open Trial Study.

In this study, dogs were separated into two groups and treated with immunosuppressant (Cyclosporin A: CsA). The first group was the canine atopic dermatitis (CAD) group, which is similar to extrinsic atopic dermatitis (AD) in humans (treated with a CsA dose of 2.5-5.5 mg/kg, n=8), and the second group was the canine atopic-like dermatitis (ALD) group, which is similar to intrinsic AD in humans (treated with a CsA dose of 2.5-6.5 mg/kg, n=14). The canine atopic dermatitis extent and severity index (CADESI)-4 was evaluated before treatment (PRE) and after treatment (POST) to assess the effectiveness of CsA for the two groups. In the CAD group, CADESI-4 showed no change (PRE:79±29, POST:77±28) and out of the eight dogs, no dogs showed complete remission, three dogs showed partial remission, and five dogs showed no effect. Whereas in the ALD group, CADESI-4 showed a significant reduction (PRE: 61±42, POST: 32±25, p<0.01) and out of the 14 dogs, 11 dogs showed complete remission, two dogs showed partial remission, and one dog showed no effect. The results indicate that the immunosuppressant showed effectiveness for the dogs diagnosed with ALD. One dog had to be treated for a year and eight months, which was the longest period in the study, this dog presented with hyperplasia of the lymphoidgland and mammary tumor.

Fluoxetine (SSRI) treatment of canine atopic dermatitis: a randomized, double-blind, placebo-controlled, crossover trial.

This study investigated effects of a fluoxetine (selective serotonin reuptake inhibitors; SSRI, 1 mg/kg) on pruritus in canine atopic dermatitis (CAD). After 4-weeks of base-line observation, 8 dogs with CAD entered a 2-months randomized, double-blind, placebo-controlled, crossover trial comparing fluoxetine with placebo. Clinical efficacy was evaluated using a Canine Atopic Dermatitis Extent and Severity Index (CADESI-03) and Pruritus Visual Analog Scale (PVAS). Six dogs completed the study [two out of eight dogs (both of them were Shiba Inu) dropped out from the study due to a depression]. CADESI-03 and PVAS between fluoxetine and placebo showed no significant difference statistically (P > 0.05 and P > 0.05 respectively). Fluoxetine showed no efficacy on pruritus in CAD. Further researches are needed for the treatment on pruritus of CAD.

Protonation behavior and solution properties of amine oxide surfactants containing a pyridyl group.

Hydrogen bonding between surfactant molecules plays an important role in self-assembly formation. For long alkyl chain amine oxide surfactants, the specific protonation degree dependence of some solution properties has been considered to be due to hydrogen bonding between protonated and deprotonated species. In addition to this type of hydrogen bonding, we introduced a pyridyl group into an alkylamine oxide molecule as a new hydrogen-bonding site. The pyridyl group has three different structural isomers based on the position of the substituent. An amine oxide group in pyridylamine oxides was preferentially protonated. In addition, protonation of the pyridyl group revealed a pronounced substituent position effect on the critical micelle concentration, micellar size, and solubilization of oil-soluble dye into micelles. The intermolecular or intramolecular hydrogen bond formation could be controlled by altering the substituent position.

SNP-based analysis of the HLA locus in Japanese multiple sclerosis patients.

Although several major histocompatibility complex (MHC)-wide single-nucleotide polymorphism (SNP) studies have been performed in populations of European descent, none have been performed in Asian populations. The objective of this study was to identify human leukocyte antigen (HLA) loci associated with multiple sclerosis (MS) in a Japanese population genotyped for 3534 MHC region SNPs. Using a logistic regression model, two SNPs (MHC Class III SNP rs422951 in the NOTCH4 gene and MHC Class II SNP rs3997849, susceptible alleles A and G, respectively) were independently associated with MS susceptibility (204 patients; 280 controls), two (MHC Class II SNP rs660895 and MHC Class I SNP rs2269704 in the NRM gene, susceptible alleles G and G, respectively) with aquaporin-4- (AQP4-) MS susceptibility (149 patients; 280 controls) and a single SNP (MHC Class II SNP rs1694112, susceptible allele G) was significant when contrasting AQP4+ against AQP4- patients. Haplotype analysis revealed a large susceptible association, likely DRB1*04 or a locus included in the DRB1*04 haplotype, with AQP4- MS, which excluded DRB1*15:01. This study is the largest study of the HLA's contribution to MS in Japanese individuals.

Beneficial effect of interferon-beta treatment in patients with multiple sclerosis is associated with transient increase in serum IL-6 level in response to interferon-beta injection.

In order to predict the clinical benefit of interferon-beta (IFN-beta) to patients with multiple sclerosis (MS), the following markers were investigated; (1) chronological change of cytokines (IFN-gamma, TNF-alpha, IL-6, IL-10, and TGF-beta) after administration of IFN-beta, (2) untoward effects of IFN-beta such as headache and arthralgia, (3) backgrounds of the patients such as age and relapse rate, (4) efficacy of IFN-beta therapy assessed by the change of relapse rate and progression of disability. Chronological blood sampling was performed 0, 10, and 24 h after injection of IFN-beta. The increase of serum IL-6 level in response to IFN-beta administration was associated with headache, arthralgia, relapse rate before treatment, and disability score at the initiation of the therapy. Significant association of change of serum TNF-alpha with age and headache was also observed. The important finding in this study was that patients with a transient increase in IL-6 in response to IFN-beta showed a slow disease progression. This result suggests that this transient increase in the serum IL-6 predicts favorable response to IFN-beta treatment.

The clinical significance of colonoscopy in hemorrhagic colitis due to enterohemorrhagic Escherichia coli O157:H7 infection.

BACKGROUND AND STUDY AIMS: Although hemorrhagic colitis due to enterohemorrhagic Escherichia coli O157:H7 (O157) infection has recently attracted increasing attention as an important enteric infection, the colonoscopic findings associated with this disease have not been sufficiently characterized. The aim of this study is to characterize the colonoscopic features of hemorrhagic colitis due to O157 infection. PATIENTS AND METHODS: The colonoscopic findings in ten patients with hemorrhagic colitis due to O157 infection were retrospectively reviewed. To assess the severity of inflammation in each part of the large intestine, colonoscopic findings were categorized into four grades: grade 1, intact mucosa; grade 2, sporadic erythema and erosion; grade 3, mostly diffuse inflammation; and grade 4, diffuse, severe inflammation. RESULTS: Eight out of ten patients had grade 4 findings in the cecum and ascending colon, grade 3 in the transverse colon and descending colon, and grade 2 in the sigmoid colon. Two of these eight patients also had grade 4 inflammation in the proximal transverse colon. Five of these eight patients revealed longitudinal ulcer-like lesions in the transverse colon and/or descending colon. The remaining two patients had grade 3 findings in the cecum to the descending colon and grade 2 findings in the sigmoid colon. All patients exhibited grade 1 finding in the terminal ileum and the rectum. Based on these colonoscopic findings, the ten patients were divided into the typical group (eight patients) and the mild-type group (two patients). CONCLUSIONS: The characteristic colonoscopic findings in most patients with hemorrhagic colitis due to O157 infection were as follows: 1) severe inflammation, including primarily marked edema and facile hemorrhage, and 2) inflammation predominating at the right-side colon; and 3) frequent appearance of longitudinal ulcer-like lesions.

Density dependent modulation of cell cycle protein expression in astrocytes.

The proliferation of type-1 astrocytes is strongly inhibited by homotypic cell-contact. To examine the mechanisms mediating this inhibition of proliferation, the expression of cell cycle related proteins was compared between exponential growth-phase and contact-inhibited astrocytes. Expression of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 was upregulated 10-fold in confluent compared with growth-phase cultures. Density-induced expression of p27Kip1 was reversible. When confluent cultures of astrocytes expressing high levels of p27Kip1 were replated at low density, the expression of p27Kip1 decreased rapidly. In contrast to p27Kip1, the expression levels of the cell cycle protein, cyclin A was decreased ten-fold in confluent cultures compared with those in growth phase. In addition, the ratio of hyperphosphorylated to hypophosphorylated retinoblastoma protein (pRb) decreased concomitantly with the increase of p27Kip1 and the decrease of cyclin A levels. These results suggest that increased expression of p27Kip1 and decreased expression of cyclin A underlie the reduction in proliferation of contact inhibited astrocytes. High levels of mitogenic stimulation could transiently override contact-dependent inhibition of astrocyte proliferation. Addition of exogenous epidermal growth factor (EGF) resulted in elevated proliferation at high density and formation of multiple cell layers. Addition of EGF did not substantially alter levels of p27Kip1 or cyclin A, but did elevate the levels of cyclin D1. Such changes in cell cycle protein expression may contribute to elevated cell proliferation seen in reactive gliosis after injury to the adult CNS.

Selective cell-cycle arrest and induction of apoptosis in proliferating neural cells by ganglioside GM3.

Control of cell proliferation and cell survival is critical during development of the vertebrate central nervous system (CNS). Much of the cell death seen during early stages of CNS development occurs through apoptosis; however, the factors that induce this early apoptosis are not clearly understood. Gangliosides, sialylated glycosphingolipids, are expressed in the CNS and have been proposed to regulate cell growth and differentiation. Here we show that the simple ganglioside GM3 selectively inhibits the proliferation of and induces apoptosis of actively dividing astrocyte precursors and other neural progenitors. The inhibition of astrocyte precursor proliferation by GM3 appears to be mediated in part by the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1). During neonatal development there is extensive cell proliferation and little apoptosis in the ventricular and subventricular zones of the CNS. This proliferation was dramatically inhibited and the degree of apoptosis dramatically increased following intraventricular administration of GM3. These data suggest that GM3, a simple ganglioside, may regulate cell proliferation and death in the CNS and as such may have potential for brain tumor therapy.

GM3 as a novel growth regulator for human gliomas.

The simple ganglioside GM3 inhibits proliferation and induces apoptosis in proliferating immature rodent CNS cells. To determine whether GM3 influenced the expansion of human neural tumors the effects of GM3 treatment on primary human brain tumors were assayed. Here we demonstrate that GM3 treatment dramatically reduces cell numbers in primary cultures of high-grade human glioblastoma multiforme (GBM) tumors and the rat 9L cell gliosarcoma cell line. By contrast, GM3 treatment had little effect on cell number in cultures of normal human brain. A single injection of GM3 3 days after intracranial implantation of 9L tumor cells in a murine xenograft model system resulted in a significant increase in the symptom-free survival period of host animals. The effects of GM3 were not restricted to GBMs and 9L cells. Cultures of high-grade ependymomas, mixed gliomas, astrocytomas, oligodendrogliomas, and gangliogliomas were all susceptible to GM3 treatment. These results suggest that GM3 may have considerable value as a selectively toxic chemotherapeutic agent for human high-grade gliomas.

Leptomeningeal signet-ring cell carcinomatosis presenting with ophthalmoplegia, areflexia and ataxia.

We report a very rare case of occult leptomeningeal carcinomatosis (LC) in whom repeated cytological examination did not show malignant cells in cerebrospinal fluid (CSF) and the primary focus was not discovered by extensive survey. The patient presented with ophthalmoplegia, ataxia and areflexia mimicking Miller Fisher syndrome (MFS) at the initial stage, and later, the clinical profile and laboratory findings including CSF examination simulated tuberculous meningitis. Postmortem autopsy disclosed metastatic signet-ring cell carcinoma infiltrating into cranial nerves and leptomeninges. We would like to emphasize that LC sometimes shows symptoms and signs similar to MFS or tuberculous meningitis.

Improvement of anti-Hu-associated paraneoplastic sensory neuropathy after chemoradiotherapy in a small cell lung cancer patient.

A 66-year-old man developed progressive painful dysesthesia in his hands and feet over 3 months. His vibration sense was impaired and sensory nerve action potentials of the limbs were not evoked. Biopsy of the peroneal nerve revealed sensory neuropathy. Positive anti-Hu antibody facilitated delineation of a right hilar mass and a metastatic lymph node in thoracic CT scan. He was diagnosed as small cell lung cancer associated with paraneoplastic sensory neuropathy. A complete response was achieved through chemotherapy (carboplatin and etoposide) and subsequent radiation therapy. Notably, his neurological conditions, although not changed during the hospitalization, gradually improved afterwards.

Control of oligodendrocyte precursor proliferation mediated by density-dependent cell cycle protein expression.

The proliferation of oligodendrocyte precursors is closely regulated in the developing vertebrate CNS. In previous studies we have demonstrated a cell-type-specific density-dependent feedback mechanism that contributes to the control of oligodendrocyte progenitor cell clonal expansion in vitro. Here we demonstrate a density-dependent reduction in the proliferation of oligodendrocyte precursors. This inhibition of proliferation is correlated with increases in expression levels of the cell cycle inhibitor p27(Kip1), reductions in the expression of cyclin A and changes in the relative phosphorylation levels of Rb. These changes are reversible on replating at low density suggesting that additional signals are required for terminal oligodendrocyte differentiation.

Isaacs' syndrome successfully treated by immunoadsorption plasmapheresis.

We report a 70-year-old woman with Isaacs' syndrome (acquired neuromyotonia) who showed a marked improvement after immunoadsorption plasmapheresis (IAP). She developed hyperhidrosis in her teens, and slowly progressive symptoms of neuromyotonia for over 50 years. An in vitro investigation of her serum with patch-clamp technique suggested the presence of antibodies against potassium channels. She was treated with IAP, which brought disappearance of her symptoms. Though the symptoms started to recur in 3 weeks, moderate improvement has been maintained by immunosuppressive drug treatment.

HTLV-I-associated myelopathy manifested after renal transplantation.

We report a patient with HTLV-I-associated myelopathy (HAM), who developed symptoms of myelopathy 4 years after cadaveric renal transplantation. Since he was seronegative before the transplantation, it is suggested that HTLV-I infection was transmitted via renal graft transplantation. He has been treated with immunosuppressive agents such as cyclosporin A (CsA), mycophenolate mofetil (MMF), and prednisolone (PSL) to prevent graft rejection. This case suggested that these immunosuppressive agents are poorly effective in suppressing either the onset or progression of HAM/TSP.

Novel chiral bisoxazoline ligands with a biphenyl backbone: preparation, complexation, and application in asymmetric catalytic reactions

Novel C(2)-symmetric chiral bisoxazoline ligands 1 were easily prepared from enantiomerically pure 2-amino alcohols and achiral 2, 2'-biphenyldicarboxylic acid via the corresponding amide and mesylate as intermediates. Since these ligands bear only two ortho-substituents on the biphenyl backbone, the biphenyl axis is not fixed, and the two diastereomers of these ligands exist in equilibrium in solution. Interestingly, when the ligands 1 were coordinated with a metal ion, only one of the two possible diastereomer complexes, an (S,aS,S)-complex, can be formed depending on the combination of the ligand and the metal ion. Thus, copper(I) afforded only the (S,aS,S)-complexes with all ligands 1, while zinc(II), palladium(II), and silver(I) afforded the (S,aS, S)-complexes as the sole product only with 1b, which has a bulky tert-butyl group on the oxazoline ring, and a mixture of the two diastereomer complexes with 1a,c,d. The copper(I)-catalyzed asymmetric cyclopropanation of styrene with diazoacetate proceeded successfully with these ligands and good to excellent enantioselectivities were afforded.

[A case of Gerstmann-Sträussler-Scheinker syndrome (P102L) accompanied by optic atrophy].

We report a patient with Gerstmann-Sträussler-Scheinker syndrome (GSS102) who developed optic atrophy. He had been complaining of slowly progressive postural unsteadiness and pain in both legs for 3 years. Visual acuity subacutely worsened in the last half year. His father and two aunts, who already died, had been diagnosed to have dementia. It is uncertain whether they had optic atrophy or not. He was alert but apathetic. Neurological examination revealed cerebellar ataxia, painful dysesthesia and loss of deep tendon reflexes in the lower limbs. Fundoscopic examination revealed bilateral optic atrophy without retinal degeneration, which has never been reported in GSS. A brain MRI showed mild atrophy of cerebellar hemispheres without signal abnormalities of optic nerves. DNA analysis of prion gene revealed point mutation at codon 102 (P102L), which was relatively common mutation in GSS. Other mutations were not found. Only two patients of Creutzfeldt-Jakob disease with optic atrophy have been reported. This case seems to be important to investigate why optic tracts are generally spared in prion disease.

The significance of hepatitis G virus in serum of patients with sporadic fulminant and subfulminant hepatitis of unknown etiology.

Excluding acute hepatic failure caused by drugs, the etiology of fulminant hepatitis (FH) remains unknown in many patients. There are conflicting data about a possible pathogenic role for the hepatitis G virus (HGV) in patients with cryptogenic fulminant hepatitis (non-A-E FH). We investigated the presence of circulating HGV in 36 patients with well-documented non-A-E fulminant and 5 patients with subfulminant hepatitis from 3 geographic locations in the United States. Serum HGV RNA was determined by reverse transcriptase-polymerase chain reaction using primers from the NS5 region of the HGV genome. HGV RNA was also measured before and after liver transplantation in 5 patients and at different time points in 7 patients. Serum samples were recoded and reanalyzed for HGV RNA using different primer sets to assess the validity of the HGV RNA assay. HGV was present in serum of 14 of the 36 patients (38.8%) with non-A-E fulminant hepatitis. Twenty percent of patients from the Northeast, 11% of the patients from the Southeast, and 50% from the Mid-Atlantic regions of the United States had circulating HGV RNA. The use of therapeutic blood products was significantly associated with the presence of serum HGV RNA (P <.02). Retesting for HGV RNA with different primers was positive in all but 1 case. HGV RNA is not causally related to non-A-E fulminant hepatitis. The finding of HGV RNA in serum from these patients is likely related to the administration of blood product transfusion after the onset of fulminant hepatitis.

Crosstalk between the interleukin-6 (IL-6)-JAK-STAT and the glucocorticoid-nuclear receptor pathway: synergistic activation of IL-6 response element by IL-6 and glucocorticoid.

Cytokines and steroid hormones use different sets of signal transduction pathways, which seem to be unrelated. Interleukin-6 (IL-6) uses JAK tyrosine kinase and STAT (signal transducer and activator of transcription) transcription factor. Glucocorticoid binds glucocorticoid receptor (GR), which is a member of the steroid receptor superfamily. We have studied the crosstalk between the IL-6-JAK-STAT and glucocorticoid-nuclear receptor pathways. IL-6 and glucocorticoid synergistically activated the IL-6 response element on the rat alpha2-macroglobulin promoter (APRE)-driven luciferase gene. The exogenous expression of GR enhanced the synergism. The exogenous expression of dominant negative STAT3 completely abolished the IL-6 plus glucocorticoid-induced activation of the APRE-luciferase gene. Tyrosine phosphorylation of STAT3 stimulated by IL-6 alone was not different from that by IL-6 plus glucocorticoid. The protein level of STAT3 was also not increased by glucocorticoid stimulation. The time course of STAT3 tyrosine phosphorylation by IL-6 plus glucocorticoid was not different from that by IL-6 alone. The synergism was studied on the two other IL-6 response elements, the junB promoter (JRE-IL-6) and the interferon regulatory factor-1 (IRF-1) promoter (IRF-GAS) which could be activated by STAT3. The synergistic activation by glucocorticoid on the IL-6-activated JRE-IL-6 and the IRF-GAS-driven luciferase gene was not detected. Glucocorticoid did not change the mobility of IL-6-induced APRE-binding proteins in a gel shift assay. These results suggest that the synergism was through the GR and STAT3, and the coactivation pathway which was specific for APRE was the target of glucocorticoid.

Two patients with acute hepatitis B with suspected sexual transmission of hepatitis G virus.

Two patients with acute hepatitis B with suggested sexual transmission of hepatitis G virus (HGV) are reported. A total of 18 patients with community acquired acute hepatitis B were analyzed in this study. Two of the 18 patients (patients 1 and 2) were positive for serum HGV RNA at the initial consultation. Both patients had had sexual contact with prostitutes several weeks before the onset of acute hepatitis, and hepatitis B virus (HBV) was suggested to be infected through the sexual contacts. These patients showed no other history of exposure to possible transmission routes for blood-borne hepatitis viruses. Patient 1 was diagnosed as with acute HGV infection because the antibody to HGV envelope-2 protein seroconverted to positive during the course of acute hepatitis. HGV RNA was negative in a serum sample collected from patient 2 before the onset of acute hepatitis, also suggesting acute HGV infection. These results indicate that in patients 1 and 2 HGV was infected along with HBV through sexual contact. The clinical manifestations of acute hepatitis in the two patients with HGV co-infection did not differ from those in the 16 patients with HBV infection alone.