Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide.

It is known that, besides its direct cytotoxic effect as an alkylating chemotherapeutic agent, cyclophosphamide also has immuno-modulatory effects, such as depletion of CD4+CD25+ regulatory T cells. However, its optimal concentration has not yet been fully elucidated. Therefore, we first compared the effects of different doses of cyclophosphamide on T cell subsets including CD4+CD25+ T cells in mice.

Acetazolamide acts directly on the human skeletal muscle chloride channel.

Acetazolamide, a carbonic anhydrase inhibitor, is used empirically in neuromuscular diseases with episodic ataxia, weakness, and myotonia, although not all of the mechanisms responsible for its therapeutic effects are understood. To elucidate whether acetazolamide acts directly on the human skeletal muscle voltage-gated chloride channel (ClC-1), which is associated with myotonia, we evaluated the effects of acetazolamide on ClC-1 expressed in cultured mammalian cells, using whole-cell recording. Acetazolamide significantly shifted the voltage dependency of the open probability (P(o)) toward negative potentials in a dose-dependent manner, resulting in an increase of chloride conductance at voltages near the resting membrane potential.

Evidence for the role of small ubiquitin-like modifier 4 as a general autoimmunity locus in the Japanese population.

Context: Recently, an association of a single nucleotide polymorphism, 163A>G encoding M55V, in the gene SUMO4, which has been shown to be a negative feedback regulator for nuclear factor kappaB, has been reported in type 1 diabetes.

Objective: To establish whether SUMO4 locus contributes to the genetic susceptibility to other autoimmune disorders, a case-control analysis was carried out using genomic DNA from type 1 diabetes, autoimmune thyroid disease (AITD), rheumatoid arthritis (RA), and primary Sjögren's syndrome.

Subjects: A total of 1480 samples, including 929 cases (411 patients with type 1 diabetes, 292 AITD, 172 RA, and 54 primary Sjögren's syndrome) and 551 healthy control subjects of Japanese origin participated in the study.

Serum levels of interleukin-6 and its soluble receptors in patients with hepatitis C virus infection.

Interleukin-6 (IL-6) is an important cytokine in liver regeneration, and elevated levels of IL-6 have been demonstrated in patients with chronic liver diseases (CLD). Many biological effects of IL-6 depend on naturally occurring soluble IL-6 receptors. In the present study we measured the concentrations of IL-6 and its soluble receptors in the sera of patients with CLD related to hepatitis C virus (HCV) infection.

Characterization of peripheral natural killer cells in primary Sjögren's syndrome: impaired NK cell activity and low NK cell number.

The aim of this study was to compare the number of peripheral blood natural killer (NK) cells, NK cell activity, expression of NK cell activating receptors, and serum cytokine levels in patients with primary Sjögren's syndrome (SS) vs normal controls. The authors found that NK cell number, NK cell killing activity, and the expression of activating receptors CD2 and NKG2D were significantly decreased, and the expression of NKp46, as well as the percentage of apoptotic NK cells, were significantly increased in primary SS patients compared with healthy controls. NK cell killing activity on a per-cell basis was similar in primary SS patients and healthy controls.

Guidelines for the proper use of etanercept in Japan.

Application of biological agents targeting inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) dramatically caused a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-TNF-alpha monoclonal antibody, has initially been introduced to Japan in 2003 and shown to be dramatically effective in alleviating arthritis refractory to conventional treatment. However, serious adverse events such as bacterial pneumonia, tuberculosis, and Pneumocystis jiroveci pneumonia were reported to be in relatively high incidence; i.

14-3-3 protein, total tau and phosphorylated tau in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease and neurodegenerative disease in Japan.

1. Sporadic Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and fatal disease. Patients with CJD usually become akinetic mutism within approximately 6 months.

Twenty-four-week follow-up examination of a leukocytapheresis therapy in rheumatoid arthritis.

Several clinical trials have demonstrated that leukocytapheresis (LCAP) is a safe and effective therapy for patients with refractory rheumatoid arthritis (RA). However, most of those reports were limited to short-term clinical observation. We have treated 11 RA patients with LCAP and observed them for 24 weeks after the final administration.

Infliximab is effective for Takayasu arteritis refractory to glucocorticoid and methotrexate.

We have experienced a Takayasu arteritis (TA) patient, successfully treated with infliximab, who did not respond well to conventional therapy with glucocosteroid and methotrexate. Takayasu arteritis had developed in a 24-year-old woman (March 2003) who had been treated with glucocorticoid including methylprednisolone pulse therapy and methotrexate; however, she relapsed during the tapering of the dosage of oral prednisolone. Nineteen months after the first administration of glucocorticoid, 3 mg/kg of infliximab was introduced to the patient.

Significant inhibition of TRAIL-mediated fibroblast-like synovial cell apoptosis by IFN-gamma through JAK/STAT pathway by translational regulation.

The pathway of interferon-gamma (IFN-gamma)-induced suppression in tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) was investigated. rTRAIL triggered FLS apoptosis in a type II cell death manner, whereas IFN-gamma pretreatment significantly inhibited TRAIL-mediated apoptosis. As disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp ase (IETD ase) activity, and the appearance of hypodiploid DNA + cells were markedly suppressed in IFN-gamma-treated FLS in response to TRAIL, IFN-gamma-induced suppression was supposed to achieve at upstream of caspase-8.

Hepatitis B-related polyarteritis nodosa presenting necrotizing vasculitis in the hepatobiliary system successfully treated with lamivudine, plasmapheresis and glucocorticoid.

A 64-year-old man was admitted for alithiasic cholecystitis. Necrotizing vasculitis was detected in a gallbladder obtained at the cholecystectomy. Slight elevation of transaminases, HBe antigens and hepatitis B-DNA (HBV-DNA) were detected in the patient.

Radiation dose-response relationships for thyroid nodules and autoimmune thyroid diseases in Hiroshima and Nagasaki atomic bomb survivors 55-58 years after radiation exposure.

Context: Effects of irradiation on thyroid diseases such as thyroid nodules and autoimmune thyroid diseases have not been evaluated among people exposed to radiation more than 50 years in the past.

Objective: To evaluate the prevalence of thyroid diseases and their radiation-dose responses in atomic bomb survivors.

Design, Setting, And Participants: Survey study comprising 4091 cohort members (mean age, 70 [SD, 9] years; 1352 men and 2739 women) who participated in the thyroid study at the Radiation Effects Research Foundation.

Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations.

The protein tyrosine phosphatase, nonreceptor 22 gene (PTPN22) maps to human chromosome 1p13.3-p13.1 and encodes an important negative regulator of T-cell activation, lymphoid-specific phosphatase (Lyp).

Increasing hepatitis C virus-associated hepatocellular carcinoma mortality and aging: Long term trends in Japan.

Background: The incidence of hepatocellular carcinoma (HCC) in Japan has been increasing. The aim of the study was to determine the epidemiological trends in HCC mortality in Japan.

Methods: We reviewed the medical records of all patients whose death was caused by liver disease between 1981 and 2000 at two hospitals.

Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis.

Background: Although the pathogenesis of non-alcoholic steatohepatitis (NASH) remains poorly understood, proinflammatory cytokines seem to play an important role in the process of NASH. We have undertaken this study in order to elucidate the role of proinflammatory cytokines and their soluble receptors in NASH patients.

Methods: Serum cytokines and soluble cytokine receptors levels were determined using an enzyme-linked immunosorbent assay kit in 23 patients with NASH, 21 patients with simple steatosis, and 18 healthy volunteers.

Immunosuppressant FK506 inhibits matrix metalloproteinase-9 induction in TNF-alpha-stimulated human hepatic stellate cells.

Activated hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic inflammation and fibrosis through the production of matrix metalloproteinases (MMPs). Cytokines and growth factors are thought to activate HSCs. TNF-alpha has pleiotropic functions in hepatitis, but its role in liver fibrosis remains elusive.

Pathomorphological study on small nodular lesions in hepatitis C virus-related cirrhosis.

We examined pathomorphologically small nodular lesions in hepatitis C virus-related cirrhosis (type C cirrhosis). Small nodular lesions seen in the non-cancerous areas of 128 consecutively resected hepatocellular carcinomas (HCCs) associated with type C cirrhosis were selected for the study. From these, 18 large regenerative nodules (LRNs), 14 low-grade dysplastic nodules (LDNs), 10 high-grade DNs (HDNs), and 12 well-differentiated HCCs were detected.

Adenovirus encoding the thyrotropin receptor A-subunit improves the efficacy of dendritic cell-induced Graves' hyperthyroidism in mice.

Stimulating the immune system by in vivo expression of the thyrotropin receptor (TSHR) is an efficient means to induce Graves' disease experimentally. For example, BALB/c mice injected with dendritic cells (DCs) infected with adenovirus encoding the full-length TSHR (AdTSHR) develop hyperthyroidism, albeit at a low incidence (36%). Recent observations suggest that the shed TSHR A-subunit, rather than the full-length receptor, is the autoantigen responsible for initiating/enhancing immune responses leading to thyroid stimulating antibodies (TSAb) and hyperthyroidism.

Do glucose and lipid metabolism affect cancer development in Nagasaki atomic bomb survivors?

The relationship between lipid or glucose metabolism and cancer has not yet been elucidated. We conducted 75-g oral glucose tolerance tests (75-g OGTTs) and lipid measurements between 1983 and 1985 in 516 Nagasaki atomic bomb survivors. Excluding those who already had cancer at the baseline examinations and those who developed cancers or died of any cause within 5 yr after the baseline examinations, we determined incident cancer cases until 2000 in the remaining 451 subjects (214 males and 237 females) and evaluated, by means of the Cox proportional hazard model, whether glucose or lipid metabolism predicts cancer development.

Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model.

Diabetic nephropathy is one of the major microvascular complications in diabetes and is the leading cause of end-stage renal disease worldwide. Among various factors, angiogenesis-associated factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2 are involved in the development of diabetic nephropathy. We previously reported the therapeutic efficacy of antiangiogenic tumstatin peptide in the early diabetic nephropathy model.

[Diagnosis and prediction of joint destruction found in patients with rheumatoid arthritis using by biochemical markers].

Rheumatoid arthritis(RA) is characterized by localized destruction of synovium, cartilage, and bone. Loss of bone in RA is not only localized in joints but is also generalized. In RA, bone loss seems to be related to elevated bone resorption, while data of bone formation are conflicting.

Clinical benefits of hepatocellular carcinoma surveillance: a single-center, hospital-based study.

Although there is no definitive evidence that hepatocellular carcinoma (HCC) screening in high-risk groups improves survival, many physicians screen high-risk populations with various tools such as alpha-fetoprotein (AFP) and ultrasonography (USG). The aim of this study was to clarify clinical differences between HCC patients diagnosed by surveillance and those with incidentally detected HCC. Two hundred and seventy-one Japanese patients with HCC diagnosed between January 1991 and December 2001 were recruited.

Laminin-induced autoimmune myositis in rats.

The present study aimed to examine if immunization with laminin causes myositis in rats and whether the pathologic findings mirror human polymyositis and dermatomyositis. Rats were immunized with an emulsion of laminin and complete Freund's adjuvant. As a result, muscle fiber necrosis with infiltrating macrophages was frequently observed and mononuclear cells were observed in the endomysium.