The differences in the involvements of loci of promoter region and Ile50Val in interleukin-4 receptor α chain gene between atopic dermatitis and Japanese cedar pollinosis

BackgroundAtopic dermatitis (AD) and Japanese cedar pollinosis (JCP) are common chronically allergic diseases associated with the activation of T-helper 2 cells. Recent studies have shown that polymorphisms in the genes for IL-4 receptor α chain (IL4RA) may contribute to susceptibility of AD and JCP, although the differences in the involvements of loci of IL4RA gene between AD and JCP are unclear. In this study, we investigated the role of polymorphisms in IL-4RA gene in conferring susceptibility to the development of AD and/or JCP using a family analysis and an association analysis in a Japanese population.MethodsFive polymorphisms in the IL-4RA gene, C-3223 T, T-1914C, T-890C, Ile50Val and Glu375Ala, have been genotyped using PCR-based methods in 75 trios families, including 15 AD families, 30 JCP families, and 30 families with combination of AD and JCP in the family analysis. Forty-five AD, 60 JCP and 125 control children constituted the association study.ResultsThe transmission disequilibrium test showed that the allele of Ile50 was significantly transmitted to children with JCP alone (p < 0.05). Haplotype analysis showed that the -3223 T/Ile50 haplotype was preferentially transmitted to both AD (p < 0.01) and JCP children (p < 0.01), while that the C-3223/Ile50 haplotype was preferentially transmitted to only JCP children (p < 0.01). The association study showed that -3223 T and haplotype of -3223 T/Ile50 were associated with aD children, but not with JCP. Ile50 was associated with both AD and JCP.ConclusionsOur data suggest that -3223 T and the -3223 T/Ile50 haplotype were risk factors for AD. Ile50 allele seems to be involved in both JCP and AD. Interactions of the IL-4RA loci may play a role both conferring susceptibility and modulating severity of AD.     

Plasminogen deficiency attenuates postnatal erythropoiesis in male C57BL/6 mice through decreased activity of the LH-testosterone axis

Novel roles for the serine protease plasmin have been implicated recently in physiological and pathological processes. However, whether plasmin is involved in erythropoiesis is not known. In the present study, we studied the consequences of plasminogen deficiency on erythropoiesis in plasminogen-deficient (Plg knockout [KO]) mice. Erythroid differentiation was attenuated in male Plg KO mice and resulted in erythroblastic accumulation within the spleen and bone marrow, with increased apoptosis in the former, erythrocytosis, and splenomegaly, whereas similar erythropoietic defect was less prominent in female Plg KO mice. In addition, erythrocyte lifespan was shorter in both male and female Plg KO mice. Erythropoietin levels were compensatory increased in both male and female Plg KO mice, and resulted in a higher frequency of burst-forming units-erythroid within the spleen and bone marrow. Surprisingly, we found that male Plg KO mice, but not their female counterparts, exhibited normochromic normocytic anemia. The observed sex-linked erythropoietic defect was attributed to decreased serum testosterone levels in Plg KO mice as a consequence of impaired secretion of the pituitary luteinizing hormone (LH) under steady-state condition. Surgical castration causing testosterone deficiency and stimulating LH release attenuated erythroid differentiation and induced anemia in wild-type animals, but did not further decrease the hematocrit levels in Plg KO mice. In addition, complementation of LH using human choriogonadotropin, which increases testosterone production, improved the erythropoietic defect and anemia in Plg KO mice. The present results identify a novel role for plasmin in the hormonal regulation of postnatal erythropoiesis by the LH-testosterone axis.     

Expression of MMP-1, MMP-9 and TIMP-2 in prostate carcinoma and their influence on prognosis and survival

Purpose

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) participate in tumorigenesis, and their association with disease outcome is highly controversial. The present study investigates the influence of MMP-1, MMP-9 and TIMP-2 on different clinicopathologic variables and disease-free survival (DFS) of patients with prostate carcinoma.

Methods

Hundred and forty-five cases are included in the study, and levels of MMP/TIMP expressions are assessed in three tissue compartments (i.e., tumor, stroma and normal glands) with immunohistochemistry.

Results

Matrix metalloproteinase-1 expression in tumor cells was associated with lower Gleason scores, pretreatment prostate-specific antigen levels and lower incidence of vascular, perineural and extracapsular invasions. Moreover, MMP-9 positivity and TIMP-2 expression in normal glands were correlated with lower Gleason patterns and early stage at presentation. Expression of MMP in tumor cells and the presence of TIMP-2 in normal glands were associated with better DFS.

Conclusion

Variability of MMP/TIMP expressions from case to case makes it difficult to evaluate their impact on clinical outcome. However, these proteins might be new and promising targets for prostate cancer therapy in the future.     

Lamivudine Therapy in Acute Leukemia Patients who are Hepatitis B Surface Antigen Carriers

Background: Reactivation of hepatitis B in patients receiving chemotherapy for acute leukemia may give rise to a variety of clinical patterns including hepatitis, asymtomatic hepatic dysfunction, massive hepatic necrosis and fatal hepatic failure. Lamivudine is a nucleoside analogue which can directly suppress Hepatitis B virus (HBV) replication. We reviewed our combined experience to evaluate the role of lamivudine as prophylaxis in acute leukemia patients who were HBsAg carriers treated with chemotherapy between July 2000 and October 2002 at the Numune Education and Research Hospitals (Ankara, Turkey) retrospectively.

Methods: We investigated 75 acute leukemia patients who received chemotherapy. Thirteen (17.3%) of 75 acute leukemia patients were HbsAg positive and of 7 (53.3%) were HBV DNA positive. Two patients (patients 5 and 6) had a chemotherapy regimen that included corticosteroids and were HBsAg and HBV DNA negative but anti HBc total positive. HBsAg positive patients with or without HBV DNA positivity were treated with a dose of 100 mg/day lamivudine commencing when chemotherapy was initiated. Lamivudine started at the beginning of chemotherapy and was maintained for 6 months following the cessation of chemotherapy. During lamivudine treatment, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Gama glutamile transpeptidase (GGT), Alkaline phosphatase (ALP) were followed.

Results: Of the 8 patients who presented with hepatic dysfunction during the first chemotherapy cycle, 4 improved during the second course. After completing chemotherapy, the levels of hepatic enzymes were in the normal range in all but one patient. With lamivudune prophylaxis, HBV DNA positivity did not develop in any of the HBV DNA negative patients. The two patients who received corticosteroids with their first chemotherapy cycle became positive for HBsAg and HBV DNA and were given Lamivudine when the seroconversion was established. Median follow up from the diagnosis of leukemia was 14.5 months. Survival rate at the end of follow up was 5 (38%) for the 13 patients.

Conclusions: As this infection is endemic in our country and the exposure to blood products is high in these patients, HBV infection is more common. Prophylaxis with daily administration of lamivudine to HBsAg carriers who are candidates for chemotherapy seems to be effective and may prevent chemotherapy induced HBV reactivation and hepatic failure.     

Serum neopterin as well as ferritin,soluble interleukin-2 receptor,KL-6 and anti-MDA5 antibody titer provide markers of the response to therapy in patients with interstitial lung disease complicating anti-MDA5 antibody-positive dermatomyositis

Abstract

Objective: This study identified biomarkers that can be used to assess disease activity and response to therapy in patients with interstitial lung disease complicating anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive clinically amyopathic dermatomyositis (CADM).

Methods: In 15 patients with interstitial lung disease complicating anti-MDA5 Ab-positive CADM, anti-MDA5 Ab, neopterin, interleukin (IL)-18, ferritin, and soluble interleukin 2 receptor (sIL-2R) levels were measured in cryopreserved serum specimens before and at multiple times after remission induction therapy, and their correlations were assessed.

Results: Anti-MDA5 Ab, neopterin, IL-18, ferritin, and sIL-2R levels did not differ significantly between patients who survived and those who succumbed to the disease. In many cases, serum anti-MDA5 Ab titers were over the upper limit (over 150 index value) before treatment in the usual measuring method, and gradually decreased to the normal range at stable phase. Meanwhile, serum neopterin levels (21.6 [15.3–48.3] nmol/L) were significantly elevated in newly diagnosed patients and fell to 6.8 (5–11.4) nmol/L at 6 months after treatment introduction.

Conclusions: Elevated serum neopterin as well as ferritin, sIL-2R, KL-6, and anti-MDA5 Ab titer might help identify patients with interstitial lung disease complicated with DM and might be useful in monitoring response to therapy.     

Radiofrequency ablation therapy for hepatocellular carcinoma in elderly patients

Background and Aim: With the aging of society, the number of elderly patients with hepatocellular carcinoma (HCC) has been increasing in Japan. The Government of Japan defines elderly as being over 65 and has divided the elderly into two stages: the first elderly stage (< 75 years old) and the second elderly stage (≥ 75). We investigated the efficacy and safety of radiofrequency ablation therapy (RFA) in patients in the second elderly stage in comparison with other HCC patients, retrospectively. Methods: Two hundred six patients with HCC, who were within the Milan criteria, with low‐grade performance status (0 or 1) and a Child‐Pugh classification of A or B were enrolled. All were treated with RFA from January 2000 to December 2008 as an initial therapy and were divided into elderly HCC group (e‐HCC group; ≥ 75, n = 63) and non e‐HCC group (< 75, n = 143), and their clinical data and survival rates were compared. Results: Age and the level of protein induced by vitamin K absence or antagonist (PIVKA‐II) were higher in the e‐HCC group as compared with the non e‐HCC group (78.3 ± 3.2 vs 64.2 ± 7.5 years, 676.3 ± 2643.7 vs 142.4 ± 442.2 mAU/mL: P < 0.01, respectively). There were no significant differences for Child‐Pugh class, tumor node metastasis stage, and Japan Integrated Stage score and in survival rates after 3, and 5 years between the groups (e‐HCC group: 82.5% and 49.7%, respectively; non e‐HCC group: 78.3% and 57.5%, respectively). There were no severe complications in the e‐HCC group. Conclusions: Elderly HCC patients, who have good performance status, should be treated in the same manner and with the same strategy as young HCC patients.     

Functional analysis of an established mouse vascular endothelial cell line

BACKGROUND: In vitrostudies using cell lines are useful for the understanding of cellular mechanisms. The purpose of our study is to develop a new immortalized aortic vascular endothelial cell (EC) line that retains endothelial characteristics and can facilitate the study of ECs. METHODS: A mouse aortic vascular EC line (MAEC) was established from p53-deficient mouse aorta and cultured for over 100 passages. The expression of endothelial markers was assessed, and the function of this cell line was analyzed by tube formation and binding assays. RESULTS: MAEC retained many endothelial properties such as cobblestone appearance, contact-inhibited growth, active uptake of acetylated low-density lipoprotein, existence of Weibel-Palade bodies and several EC markers. MAECs exhibited tube formation activity both in vitro and in vivo. Furthermore, crucially, tumor necrosis factor alpha, an inflammatory cytokine, promoted lymphocyte adhesion to MAECs, suggesting that MAECs may facilitate the study of atherosclerosis and local inflammatory reactions in vitro. CONCLUSION: We describe the morphological and cell biological characteristics of MAEC, providing strong evidence that it retained endothelial properties. This novel cell line can be a useful tool for studying the biology of ECs.     

Adiponectin replenishment ameliorates obesity-related hypertension

Patients with obesity are susceptible to hypertension. We have reported that the plasma adiponectin levels are decreased in obesity and that adiponectin has many defensive properties against obesity-related diseases, such as type 2 diabetes and coronary artery disease. The aim of this study was to determine the relationship between adiponectin and hypertension in mice. We measured blood pressure and heart rate directly by a catheter in the carotid artery and indirectly by automatic sphygmomanometer at the tail artery. Obese KKAy mice had significantly lower plasma adiponectin levels and higher systolic blood pressure than control C57BL/6J mice at 21 weeks of age. Adenovirus-delivered adiponectin significantly decreased blood pressure in KKAy mice. The direct role of adiponectin on blood pressure regulation under insulin resistance-free state was investigated in adiponectin-knockout (KO) mice. Adiponectin KO mice developed hypertension when maintained on a high-salt diet (8% NaCl) without insulin resistance. The hypertension of salt-fed adiponectin KO mice was associated with reduced mRNA levels of endothelial NO synthase (eNOS) and prostaglandin I(2) synthase in aorta and low metabolite levels of endothelial NO synthase and prostaglandin I(2) synthase in plasma. Adiponectin therapy lowered the elevated blood pressure and corrected the above mRNA levels to those of the wild type. Our results suggest that hypoadiponectinemia contributes to the development of obesity-related hypertension, at least in part, directly, in addition to its effect via insulin resistance, and that adiponectin therapy can be potentially useful for hypertension in patients with the metabolic syndrome.