An Inverse Correlation of Human Peripheral Blood Regulatory T Cell Frequency with the Disease Activity of Ulcerative Colitis

Evidence suggests that CD4⁺CD25⁺ regulatory T cells play a crucial role in the suppression of intestinal inflammation. However, their role in the suppression of inflammatory bowel disease has not yet been addressed. We examined the proportion of regulatory T cells in inflammatory bowel disease. First, we isolated CD4⁺CD45RO⁺CD25⁺ T cells from the peripheral blood of healthy persons and showed that these cells suppressed T cell proliferation profoundly and expressed FoxP3 abundantly, revealing that they are regulatory cells. Then the proportion of CD45RO⁺CD25⁺ in peripheral blood CD4⁺ T cells was analyzed in patients and healthy controls by flow cytometry. CD4⁺CD45RO⁺CD25⁺ T cell frequency was significantly lower in active ulcerative colitis than in the control and inactive ulcerative colitis. CD4⁺CD45RO⁺CD25⁺ T cell frequency was inversely correlated with the clinical and endoscopic severity of ulcerative colitis. These results suggest that a deficiency of regulatory T cells is associated with the progression of ulcerative colitis. This work was supported in part by Health and Labour Science Research Grants from the Japanese Ministry of Health, Labour and Welfare and Research on Measures for Intractable Disease.     

Open-label, dose-titration and continuation study to assess efficacy, safety, and pharmacokinetics of anagrelide in treatment-naïve Japanese patients with essential thrombocythemia

Although anagrelide is widely used for the treatment of essential thrombocythemia (ET) in the USA and Europe, it is not licensed in Japan. Existing literature has reported differences in polymorphism and activity of CYP1A2 in Japanese and non-Japanese ethnic groups, which may alter anagrelide metabolism. We intended to identify the optimum dosage of anagrelide in treatment-naïve Japanese patients with ET and assess its long-term safety and efficacy. Twelve patients with ET and a platelet count of ≥80 × 10⁴/μL were enrolled. Anagrelide was administered at an initial dose of 0.5 mg/day (weeks 1–4), then increased to 1.0 mg/day (weeks 5–8). During the following maintenance (weeks 9–52) and continuation periods (weeks 53–104), the dose was adjusted according to patient safety data and to maintain target platelet counts (<60 × 10⁴/μL). Increasing the dose led to a decrease in mean platelet count, and target platelet counts were maintained in 11 patients. Adverse events were mild or moderate, and none led to discontinuation. This cohort of Japanese patients exhibited higher pharmacokinetic exposures of anagrelide and its active metabolite than those previously documented in non-Japanese patients. These differences were modest, suggesting specific dosing regimens for Japanese patients are not required.     

Rines/RNF180, a novel RING finger gene-encoded product, is a membrane-bound ubiquitin ligase

We identified and characterized a novel RING finger gene, Rines / RNF180 , which is well conserved among vertebrates. Putative Rines gene product (Rines) contains a RING finger domain, a basic coiled-coil domain, a novel conserved domain (DSPRC) and a C-terminal hydrophobic region that is predicted to be a transmembrane domain. N-terminally epitope tagged-Rines (Nt-Rines) was detected in the endoplasmic reticulum membrane/nuclear envelope in cultured mammalian cells. Nt-Rines was not extracted by high salt or alkaline buffers and was degraded in intact endoplasmic reticulum treated with proteinase K, indicating that Nt-Rines is an integral membrane protein with most of its N-terminal regions in the cytoplasm. Rines was expressed in brain, kidney, testis and uterus of adult mice, and in developing lens and brain, particularly in the ventricular layer of the cerebral cortex at embryonic stages. In cultured cells, Nt-Rines can bind another protein and promoted its degradation. The degradation was inhibited by proteasomal inhibitors. In addition, Nt-Rines itself was heavily ubiquitinated and degraded by proteasome. The involvement of Rines in the ubiquitin–proteasome pathway was further supported by its binding to the UbcH6 ubiquitin-conjugating enzyme and by its trans-ubiquitination enhancing activities. These results suggest that Rines is a membrane-bound E3 ubiquitin ligase.     

Ionic polymerization under an electric field. XI. Field effect and catalyst strength

The influence of an electric field on homopolymerizations and copolymerizations of styrene catalyzed by stannic chloride/trichloroacetic acid (SnCl₄/TCA) or titanium tetrachloride-trichloroacetic acid (TiCl₄/TCA) in binary mixtures of toluene and 1.2-dichloroethane was investigated. The field enhancement in the homopolymerization increased with increasing dielectric constant of solvent, and, passing through a maximum value, decreased with further increase in the dielectric constant. The value of the dielectric constant, at which the field effect showed a maximum value, increased with catalyst in the order: TiCl₄/TCA < SnCl₄/TCA < boron trifluoride etherate (BF₃OEt₂). This order was the same as that for the field effect on the rate of homopolymerization in pure 1.2-dichloroethane. The reactivity of styrene in the copolymerization of styrene and indene in pure 1.2-dichloroethane increased in the order: BF₃OEt₂ < SnCl₄/TCA < TiCl₄/TCA. The electric field increased the reactivity of styrene in the copolymerization in the order: TiCl₄/TCA < SnCl₄/TCA < BF₃OEt₂. It was concluded from the observed sequence, on the basis of the mechanism proposed previously, that the catalyst strength for the Styrene polymerization increases in the order: BF₃OEt₂ < SnCl₄/TCA < TiCl₄/TCA. This sequence was in agreement with that reported earlier.