Clinical efficacy of abatacept in Japanese rheumatoid arthritis patients

Objectives

The purpose of this study was to examine the treatment retention and efficacy of abatacept, the first member of a new class of biologic agents, in Japanese rheumatoid arthritis (RA) patients during clinical practice.

Methods

A retrospective multicenter study was conducted with patients who underwent abatacept therapy for 24 weeks (n = 143).

Results

Patients at baseline had a mean age of 63.5 years, a mean disease duration of 11.3 years, and a mean disease activity score in 28 joints (DAS28) of 4.5. Overall retention of abatacept treatment was 83.2 % at 24 weeks, when 46.2 % of patients achieved DAS28-defined low disease activity (LDA; DAS28 <3.2) and 26.6 % achieved DAS28-defined remission (DAS28 <2.6). LDA was achieved in a significantly higher proportion of patients without prior biologics therapy compared to those with prior biologics (60.9 vs. 34.2 %, p = 0.001). There was no significant difference between patients with or without concomitant methotrexate (MTX) therapy (45.2 vs. 47.5 %).

Conclusions

Abatacept therapy appears to be highly effective and well tolerated during clinical treatment of RA. Abatacept was particularly effective in patients with no history of biologics use, and did not appear to be dependent on concomitant MTX therapy.     

Imidazole antifungals, but not triazole antifungals, increase membrane Zn2+ permeability in rat thymocytes Possible contribution to their cytotoxicity

The use of zinc as a nutritional supplement has become common in many countries. Since zinc has diverse actions, it may be difficult to predict its synergistic and/or antagonistic action in simultaneous presence of drug(s). The combination of imidazole antifungals, but not triazole antifungals, with 3-30 microM ZnCl2 significantly increased the lethality of rat thymocytes. Since intracellular Zn2+ exerts various actions on the process of cell death, there is a possibility that imidazole antifungals, but not triazole antifungals, increases concentration of intracellular Zn2+ ([Zn2+]i). To test the possibility, we examined the effects of imidazole and triazole antifungals on [Zn2+]i of rat thymocytes in absence and presence of extracellular Zn2+ by the use of FluoZin-3, a fluorescent Zn2+ indicator. Imidazole antifungals (clotrimazole, econazole, and oxiconazole) increased the [Zn2+]i in the presence of extracellular Zn2+ while it was not the case for triazole antifungals (itraconazole and fluoconazole). Thus, it is suggested that imidazole antifungals increase the membrane permeability of Zn2+. The potency order in the augmentation of FluoZin-3 fluorescence by imidazole antifungals in the presence of extracellular Zn2+ was the same as that in their cytotoxic action. Therefore, the cytotoxic action of imidazole antifungals may be related to their action on membrane Zn2+ permeability.     

Bone morphogenetic protein rescues the lack of secondary cartilage in Runx2-deficient mice

Secondary cartilages including mandibular condylar cartilage have unique characteristics. They originate from alkaline phosphatase (ALP)-positive progenitor cells of the periosteum, and exhibit characteristic modes of differentiation. They also have a unique extracellular matrix, and coexpress type I, II and X collagens. We have previously shown that there is a total absence of secondary cartilages in Runx2-deficient (Runx2-/-) mice. To clarify whether Runx2 is essential for chondrocytic differentiation of secondary cartilages, we performed an organ culture system using mandibular explants derived from Runx2-/- mice at embryonic day 18.0. Since mRNA for bone morphogenetic protein 2 (BMP2) was strongly expressed in osteoblasts of condylar anlagen in wild-type mice, and was down-regulated in those of Runx2-/- mice, we chose to investigate BMP2 effects on secondary cartilage formation. Condensed mesenchymal cells of mandibular condylar anlagen in precultured explants were ALP-positive and expressed type I collagen and Sox9. After culture with recombinant human (rh) BMP2, chondrocytic cells showing ALP activity and expressing Sox5, Sox9, and type I and II collagens, appeared from mesenchymal condensation. This expression profile was comparable with the reported pattern of chondrocytes in mouse secondary cartilages. However, chondrocyte hypertrophy was not observed in the explants. These findings indicate that BMP2 partially rescued chondrocyte differentiation but not chondrocyte hypertrophy in secondary cartilage formation in Runx2-/- mice. Runx2 is required for chondrocyte hypertrophy in secondary cartilage formation, and it is likely that BMP2, which is abundantly secreted by osteoblasts in condylar anlagen, contributes to the early process of secondary cartilage formation.     

Potassium-adsorption filter for RBC transfusion: a phase III clinical trial

BACKGROUND: Within the past 2 years, three cases of cardiac arrest just after rapid transfusion of RBCs preserved for over 7 days after 15-Gy irradiation were found. This severe complication caused transient hyperkalemia. To prevent potassium (K(+)) overload by RBC transfusion at the bedside, a K(+)-adsorption filter made of sodium polystyrene sulfonate was developed. STUDY DESIGN AND METHODS: After in vitro and animal safety and efficacy tests, a Phase III clinical trial was conducted with 65 patients given transfusions via the newly developed filter (filter group) and 37 patients in whom the filter was not used (control group) and transfusions were given at twice the usual flow rate (20 mL/min). RESULTS: More than 85-percent (94.4+/-3.8%) removal of K(+) in RBCs in mannitol-adenine-phosphate (MAP) that had been preserved for more than 14 days or that were used 3 days after 15-Gy irradiation (calculated K(+): 3.8+/-1.3 mEq/bag) was achieved in 82 of 83 bags of MAP RBCs in the filter group, with 79.6 percent removed in the other, even in rapid transfusions. RBC recovery 1 day after transfusion, determined by increments in RBCs, Hb, and Hct, were 24 and 0.4 x 10(4) per microL, 0.7 and 0.3 g per dL, and 1.6 and 0 percent, respectively, in the filter and control groups. No adverse transfusion reactions, such as hypotension, anaphylactoid reactions, or asthma-like attacks, were observed, except for one case of urticaria in the filter group. Mild fever (within 1 degrees C) after transfusion was observed in both groups. Serologic markers of hemolysis rose slightly in both groups, but there was no significant difference between the two groups. CONCLUSION: The newly developed K(+)-adsorption filter is useful, especially in a rapid transfusion setting.     

Optic chiasm in the species of order Clupeiformes,family Clupeidae: Optic chiasm of Spratelloides gracilis shows an opposite laterality to that of Etrumeus teres

In most teleost fishes, the optic nerves decussate completely as they project to the mesencephalic region. Examination of the decussation pattern of 25 species from 11 different orders in Pisces revealed that each species shows a specific chiasmic type. In 11 species out of the 25, laterality of the chiasmic pattern was not determined; in half of the individuals examined, the left optic nerve ran dorsally to the right optic nerve, while in the other half, the right optic nerve was dorsal. In eight other species the optic nerves from both eyes branched into several bundles at the chiasmic point, and intercalated to form a complicated decussation pattern. In the present study we report our findings that Spratelloides gracilis, of the order Clupeiformes, family Clupeidae, shows a particular laterality of decussation: the left optic nerve ran dorsally to the right (n=200/202). In contrast, Etrumeus teres, of the same order and family, had a strong preference of the opposite (complementary) chiasmic pattern to that of S. gracilis (n=59/59), revealing that these two species display opposite left–right optic chiasm patterning. As far as we investigated, other species of Clupeiformes have not shown left–right preference in the decussation pattern. We conclude that the opposite laterality of the optic chiasms of these two closely related species, S. gracilis and E. teres, enables investigation of species-specific laterality in fishes of symmetric shapes.     

ErbB receptor tyrosine kinase/NF-κB signaling controls mammosphere formation in human breast cancer

Breast cancer is one of the most common cancers in humans. However, our understanding of the cellular and molecular mechanisms underlying tumorigenesis in breast tissues is limited. Here, we identified a molecular mechanism that controls the ability of breast cancer cells to form multicellular spheroids (mammospheres). We found that heregulin (HRG), a ligand for ErbB3, induced mammosphere formation of a breast cancer stem cell (BCSC)-enriched population as well as in breast cancer cell lines. HRG-induced mammosphere formation was reduced by treatment with inhibitors for phosphatidyl inositol 3-kinase (PI3K) or NF-κB and by expression of IκBα-Super Repressor (IκBαSR), a dominant-negative inhibitor for NF-κB. Moreover, the overexpression of IκBαSR in breast cancer cells inhibited tumorigenesis in NOD/SCID mice. Furthermore, we found that the expression of IL8, a regulator of self-renewal in BCSC-enriched populations, was induced by HRG through the activation of the PI3K/NF-κB pathway. These findings illustrate that HRG/ErbB3 signaling appears to maintain mammosphere formation through a PI3K/NF-κB pathway in human breast cancer.     

Prevalence of restless legs syndrome in Japanese patients with chronic liver disease

Aim: Sleep disturbance is a major complication in patients with chronic liver disease, but causes are unclear. The aim of this study was to clarify the prevalence of restless legs syndrome (RLS) in Japanese chronic liver disease patients and investigate the influence on sleep and quality of life. Methods: The study included 149 consecutive outpatients with chronic liver disease at Nagasaki University Hospital between September 2008 and March 2010. The presence of RLS was evaluated by a written survey using the questionnaire for the epidemiological surveillance of the international RLS research group in 2003. In addition, 89 cases, including all RLS patients, were evaluated for sleep quality and health-related quality of life. Sleep quality was evaluated by using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI), and health-related quality of life was evaluated by the Japanese SF-36 Health Survey. Result: Twenty-five of the 149 patients (16.8%) fulfilled the diagnostic criteria for RLS. The median global PSQI score of the RLS group was significantly higher than the non-RLS group (9 vs 5, P < 0.01). The number of poor sleepers (global PSQI score, >5) in the RLS group was significantly higher than in the non-RLS group (P < 0.05). In SF-36, the mental component summary score of the RLS group was 43.8 ± 10.8, which was significantly lower than the non-RSL group (49.8 ± 10.5; P < 0.05). Conclusion: This is the first report that clarifies the prevalence of RLS in Japanese chronic liver disease patients. RLS worsens quality of sleep and life in chronic liver disease patients.     

Formation of vesicles-in-a-vesicle with asymmetric lipid components using a pulsed-jet flow method

Lipid distribution in intracellular vesicles is different from that in the plasma membrane of eukaryotic cells. The lipid components in the intracellular vesicles are composed of phosphatidylserine and phosphatidylethanolamine in the outer leaflet and phosphatidylcholine and sphingomyelin in the inner leaflet. The lipid asymmetricities both in the intracellular vesicle membrane and the plasma membrane contribute to synaptic transmission functions. In this study, we developed a cell-sized asymmetric lipid vesicle system containing small-sized asymmetric lipid vesicles (of diameter 200–1000 nm) (asymmetric vesicles-in-a-vesicle), emulating lipid components in the plasma membrane and intracellular vesicle membrane of eukaryotic cells, using microfluidic technology. We successfully constructed an artificial exocytosis system using the asymmetric vesicles-in-a-vesicle system. This asymmetric vesicles-in-a-vesicle system will be helpful in understanding the mechanisms of vesicle transport, such as neurotransmission and exocytosis.

We develop a cell-sized asymmetric lipid vesicle system containing small-sized asymmetric lipid vesicles using microfluidic technology.