Mouse model of dermal fibrosis induced by one-time injection of bleomycin-poly(L-lactic acid) microspheres

Objective. Animal models are useful tools to study various aspectsof human diseases. Bleomycin (BLM)-induced scleroderma mousehas been widely investigated as an animal model of scleroderma.Repeated injections of BLM, either daily or every other day,for 3–4 weeks are required to induce scleroderma in mice.Poly(L-lactic acid) (PLA) is a biodegradable, biocompatibleand bioabsorbable device that has been widely investigated forcontrolled drug release. In this study, we fabricated BLM-containingPLA microspheres and subcutaneously injected them into C3H micefor only one time. Methods. Treated skins were harvested at days 7 and 21. Then,histological examination and collagen content measurement assaywere performed. The mRNA expression of 1(I) collagen (COL1A1),monocyte chemoattractant protein-1 (MCP-1), TGF-β₁ andconnective tissue growth factor (CTGF) were quantified by real-timePCR. Results. Dermal fibrosis was histologically observed at day7 after injection and remained present at day 21. Tissue responsesagainst BLM-PLA microspheres alone were mild. Soluble collagencontent and expression level of 1(I) collagen mRNA were significantlyelevated at day 21. Expression levels of MCP-1 mRNA and TGF-β₁mRNA at day 7 and CTGF mRNA at day 21 were also elevated. Conclusion. The present study demonstrated for the first timethat one-time injection of BLM-PLA microspheres can induce dermalfibrosis in C3H mice. BLM-PLA microspheres thus offer a labour-saving,simple and powerful tool to establish an animal model of BLM-induceddermal fibrosis. KEY WORDS: Bleomycin, Scleroderma, Mouse model, Dermal fibrosis, Drug delivery system, Poly(L-lactic acid) Submitted 11 October 2007; revised version accepted 24 January 2008.     

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell–derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2^V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33–expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34⁺ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2^V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs.     

Usefulness of pet ownership as a modulator of cardiac autonomic imbalance in patients with diabetes mellitus, hypertension, and/or hyperlipidemia

Among patients with coronary artery disease, pet owners exhibit a greater 1-year survival rate than nonowners. Lifestyle-related diseases are well-known risk factors for coronary artery disease and induce imbalances in autonomic nervous activity. The purpose of the present study was to determine whether pet ownership modulates cardiac autonomic nervous activity imbalance in patients with lifestyle-related diseases such as diabetes mellitus, hypertension, and hyperlipidemia. A total of 191 patients (mean age 69 ± 8 years) were interviewed about their pet ownership status and were classified into pet owner and nonowner groups. After recording a 24-hour Holter electrocardiogram for heart rate variability analysis, frequency-domain and nonlinear-domain analyses were performed to determine the high-frequency (HF) and low-frequency (LF) components, LF/HF ratio, and entropy. The heart rate variability parameters were assessed for 24 hours, during the day (8.00 A.M. to 5.00 P.M.), and during the night (0:00 A.M. to 6.00 A.M.), and compared between the 2 groups. To evaluate the potential predictive factors for cardiac autonomic imbalance, univariate and multivariate analyses of HF and LF/HF were conducted for potential confounding variables. The pet owner group exhibited significantly greater HF(24h), HF(day), HF(night), entropy(24h), entropy(day), and entropy(night) and significantly lower LF/HF(24h) and LF/HF(night) compared to the nonowner group. On multivariate analysis, pet ownership was independently and positively associated with HF(24h,) HF(day), and HF(night) and inversely associated with LF/HF(24h) and LF/HF(night). In conclusion, these results suggest that pet ownership is an independent modulator of cardiac autonomic imbalance in patients with lifestyle-related diseases.     

Successful Treatment of γ-Heavy-Chain Disease with Rituximab and Fludarabine

An 84-year-old Japanese man was admitted because of pancytopenia. The bone marrow was hypoplastic with a predominance of abnormal small lymphocytes and grape cells, which were positive for CD19 and CD20, and partially for the surface ?-light chain. Systemic CT scanning showed neither lymph node swelling nor hepatosplenomegaly. Serum immunoelectrophoresis and rocket immunoselection assays showed the presence of monoclonal IgG protein without a corresponding light chain and faint IgM? monoclonal protein. Histologic analysis of the clot preparation of the bone marrow aspirate facilitated a diagnosis of lymphoplasmacytic lymphoma (LPL). PCR analysis of the marrow cells demonstrated a clonal rearrangement of the immunoglobulin heavy-chain gene. From these results, we made a final diagnosis of γ-heavy-chain disease (γ-HCD) with underlying LPL localized in the bone marrow. We performed only a single course of immunochemotherapy (rituximab and fludarabine) in view of severely impaired hematopoiesis, which resulted in marked reduction of lymphoma cells and improvement of hematopoiesis. This report suggests the efficacy of rituximab plus fludarabine therapy for LPL-associated γ-HCD.     

Range of Motion of the Temporomandibular Joint in Rheumatoid Arthritis: Relationship to the Severity of Disease

The purpose of this study was to determine the frequency and nature of temporomandibular joint (TMJ) involvement in rheumatoid arthritis (RA) patients with symptoms in this joint, and to investigate the relationship of symptoms to the C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and Steinbrocker stage. Clinical examination of the range of motion of the TMJ was performed in 218 RA patients. In addition, correlations between the maximal mouth opening and the severity of RA were studied. Restriction in opening the mouth (defined as ≤ 30 mm movement in the central incisor region from the fully occluded to maximally open positions) was observed in 12.8% of the RA patients (28/218). The CRP, ESR and Steinbrocker stage were all correlated with maximal opening (p < 0.05). There was a positive correlation between the severity of RA and the range of motion of the jaw.