IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions

Atopic dermatitis (AD) is a pruritic inflammatory skin disease. Because IL-18 directly stimulates T cells and mast cells to release AD-associated molecules, Th2 cytokines, and histamine, we investigated the capacity of IL-18 to induce AD-like inflammatory skin disease by analyzing KIL-18Tg and KCASP1Tg, which skin-specifically overexpress IL-18 and caspase-1, respectively. They spontaneously developed relapsing dermatitis with mastocytosis and Th2 cytokine accumulation accompanied by systemic elevation of IgE and histamine. Stat6-deficient KCASP1Tg displayed undetectable levels of IgE but manifested the same degree of cutaneous changes, whereas IL-18-deficient KCASP1Tg evaded the dermatitis, suggesting that IL-18 causes the skin changes in the absence of IgE/stat6. KIL-18Tg and IL-1-deficient KCASP1Tg took longer to display the lesion than KCASP1Tg. Thus, AD-like inflammation is initiated by overrelease of IL-18 and accelerated by IL-1. Our present study might provide insight into understanding the pathogenesis of and establishing therapeutics for chronic inflammatory skin diseases including AD.     

Demonstration of cooperative contribution of MET- and EGFR-mediated STAT3 phosphorylation to liver regeneration by exogenous suppressor of cytokine signalings

BACKGROUND/AIMS: As conditional knockout mice for stat3 are impaired in liver regeneration after partial hepatectomy while those for gp130 have defects in early STAT3 phosphorylation but have normal DNA synthesis, late STAT3 phosphorylation induced independently of gp130 seems to be essential for liver regeneration. Since HGF and EGF can activate STAT3 via gp130-independent MET and EGFR, respectively, we assumed that these factors account for STAT3-dependent liver regeneration. Here, we investigated this hypothesis by introducing suppressor of cytokine signaling (SOCS)-1 and SOCS3, potent negative regulators of STAT3 signaling, selectively in hepatocytes. METHODS: We generated recombinant adenoviruses expressing socs1 and socs3. RESULTS: Hepatocytes infected with socs1-virus lacked STAT3 phosphorylation in response to IL-6 and HGF, while cells infected with socs3-virus lacked the response to all of IL-6, HGF and EGF, indicating that those SOCS proteins differently regulate EGFR signaling. Mice infected with socs3-virus exhibited severe and persistent impairment while those with socs1-virus showed only delayed regeneration, indicating requirement of both MET and EGFR signalings. CONCLUSIONS: These results clearly demonstrated that MET- and EGFR-mediated STAT3 signalings cooperatively contribute to liver regeneration and could provide new insights into tissue homeostasis.     

Fluvastatin improves arterial stiffness in patients with coronary artery disease and hyperlipidemia: a 5-year follow-up study.

BACKGROUND: The present study was designed to test the hypothesis that fluvastatin might improve arterial stiffness, as assessed with pulse wave velocity (PWV), in patients with coronary artery disease (CAD) and hyperlipidemia over the long term. METHODS AND RESULTS: Ninety-three patients were randomly assigned to either fluvastatin (group A, n=50) or bezafibrate (group B, n=43) and followed for 5 years. There was no difference in the clinical findings between the 2 groups. In group A, there was a progressive reduction in the brachial-ankle PWV along with a decrease in serum low-density lipoprotein-cholesterol (LDL-C) and C-reactive protein (CRP) by 12 months after fluvastatin, and the improvement was maintained until 5 years after treatment. In group B, despite identical lowering of the serum lipid, PWV was progressively increased. In group A, the percentage change in PWV correlated significantly with that of the serum CRP (r=0.49, p<0.001), but not with that of the serum LDL-C after treatment. CONCLUSIONS: The beneficial vascular effects of fluvastatin persisted for a long period in patients with CAD and hyperlipidemia. Its anti-inflammatory action might contribute to the favorable effects on arterial stiffness.     

Rectal Cancer With Disseminated Carcinomatosis of the Bone Marrow: Report of a Case

We report a rare case of disseminated carcinomatosis of the bone marrow from rectal cancer with disseminated intravascular coagulation (DIC). A 65-year-old man was admitted with melena and low back pain at rest. X-ray examination showed rectal cancer with multiple bone metastases. Laboratory examination showed severe anemia and DIC. Histologic examination showed disseminated carcinomatosis of the bone marrow. The DIC was considered to be caused by disseminated carcinomatosis of the bone marrow from rectal cancer, and we immediately started treatment with anti-DIC therapy and anticancer chemotherapy with the modified FOLFOX6 regimen (mFOLFOX6). After some response to therapy, the patient''s general condition deteriorated, and he died 128 days after admission. This is the first English report showing disseminated carcinomatosis of the bone marrow from colorectal cancer treated with mFOLFOX6.Key words: Bone marrow neoplasms, Rectal neoplasms, Disseminated intravascular coagulationBone metastases diffusely invading the bone marrow with disseminated intravascular coagulation (DIC) and microangiopathic hemolytic anemia (MHA) tend to accompany solid tumors; this condition is called disseminated carcinomatosis of the bone marrow,¹ and it is associated with an extremely poor prognosis. Among solid tumors, DIC is most commonly associated with breast cancer, prostate cancer, and lung cancer^2,3; carcinomatosis arising from colorectal cancer is rare.Herein we report on a patient with disseminated carcinomatosis of the bone marrow with rectal cancer who developed acute DIC and was treated with a modified FOLFOX6 regimen (mFOLFOX6). We also review 11 similar previously reported cases.^4–10     

Suppression of ventricular fibrillation by electrical modification of the Purkinje system in hypertrophic cardiomyopathy

A 56-year-old man in hypertrophic cardiomyopathy had an electrical storm caused by ventricular fibrillation (VF). Mapping during the initiation of the VF triggered by a premature ventricular contraction (PVC1), with right bundle branch block (RBBB)-like morphology and superior axis, demonstrated a prominent Purkinje–muscle junction (PMJ) delay at the distal portion of the left posterior fascicle. Delivery of radiofrequency (RF) energy to this area abolished the VF triggered by the PVC1. However, VF emerged by triggering another PVC (PVC2) with RBBB-like morphology and inferior axis. Similarly, the initiation of VF was associated with the PMJ delay at the peripheral left anterior fascicle, where RF delivery completely suppressed the VF. The PMJ delay and subsequent Purkinje–muscle reentry-like activity could be essential for the initiation of the Purkinje-related VF.     

Weekend versus weekday hospital admission and outcomes during hospitalization for patients due to worsening heart failure: a report from Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)

The day of the week of admission may influence the length of stay and in-hospital death. However, the association between the admission day of the week and in-hospital outcomes has been inconsistent in heart failure (HF) patients among studies reported from Western countries. We thus analyzed this association in HF patients encountered in routine clinical practice in Japan. We studied the characteristics and in-hospital treatment in 1620 patients hospitalized with worsening HF by using the database of the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Patients were divided into two groups according to weekday (n = 1355; 83.6 %) or weekend admission (n = 265; 16.4 %). The mean age was 70.7 years and 59.4 % were male. Etiology was ischemic in 34.0 %, and mean left ventricular ejection fraction was 42.5 %. Patients admitted on the weekend were significantly older and had more comorbidities, and more severe symptoms and signs of HF on admission. Length of stay was comparable between weekend and weekday admission (35.2 ± 47.0 days vs 33.6 ± 32.0 days, P = 0.591). Crude in-hospital mortality did not differ between patients admitted on the weekend and weekdays (7.5 % vs 5.2 %, P = 0.136). Even after adjustment for covariates in multivariable modeling with patients admitted on weekday as the reference, in-hospital death was comparable between patients admitted on the weekend and weekdays (adjusted odds ratio 1.125, 95 % confidence interval 0.631–2.004, P = 0.691). Among patients hospitalized for worsening HF, admission day of the week did not affect in-hospital death and length of stay.