Time for a new language for asthma control : Results from REALISE Asia

Acknowledgments: This study was supported and funded by Mundipharma Pte Ltd. Online survey and statistical analysis were performed by Pei-Li Teh, Rachel Howard, Tsin-Li Chua, and Jie Sun of Research Partnership Pte Ltd. Medical writing support was provided by Sen-Kwan Tay of Research2Trials Clinical Solutions Pte Ltd.Peer reviewedPublisher PD

Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor κB-dependent pathway in patients with rheumatoid arthritis

Inflammatory mediators have been recognized as being important in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-17 is an important regulator of immune and inflammatory responses, including the induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence for the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. Although some cytokines (IL-15 and IL-23) have been reported to regulate IL-17 production, the intracellular signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the regulation of IL-17 production in RA. Peripheral blood mononuclear cells (PBMC) from patients with RA (n = 24) were separated, then stimulated with various agents including anti-CD3, anti-CD28, phytohemagglutinin (PHA) and several inflammatory cytokines and chemokines. IL-17 levels were determined by sandwich enzyme-linked immunosorbent assay and reverse transcription–polymerase chain reaction. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody with or without anti-CD28 and PHA (P < 0.05). Among tested cytokines and chemokines, IL-15, monocyte chemoattractant protein-1 and IL-6 upregulated IL-17 production (P < 0.05), whereas tumor necrosis factor-α, IL-1β, IL-18 or transforming growth factor-β did not. IL-17 was also detected in the PBMC of patients with osteoarthritis, but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K/Akt pathway; activation of this pathway resulted in a pronounced augmentation of nuclear factor κB (NF-κB) DNA-binding activity. IL-17 production by activated RA PBMC is completely or partly blocked in the presence of the NF-κB inhibitor pyrrolidine dithiocarbamate and the PI3K/Akt inhibitor wortmannin and LY294002, respectively. However, inhibition of activator protein-1 and extracellular signal-regulated kinase 1/2 did not affect IL-17 production. These results suggest that signal transduction pathways dependent on PI3K/Akt and NF-κB are involved in the overproduction of the key inflammatory cytokine IL-17 in RA

Intraabdominal Cryptococcal Lymphadenitis in a Patient with Systemic Lupus Erythematosus

Cryptococcal infection is a rare, yet well recognized complication of systemic lupus erythematosus (SLE). We present a case of mesenteric and retroperitoneal cryptococcal lymphadenitis resulting in the obstruction of the stomach and proximal duodenum in a patient suffering from SLE, while recently she did not receive any immunosuppressive treatment. A 42-yr-old woman was admitted due to high fever and diffuse abdominal pain for three weeks. Abdominal computed tomography (CT) scan showed multiple conglomerated lymphadenopathies in the retroperitoneum and the mesentery resulting in luminal narrowing of the third portion of the duodenum. Cryptococcal lymphadenitis was proven by needle biopsy and she was treated with intravenous liposomal amphotericin B, followed by oral fluconazole. After fourteen-month antifungal therapies, the clinical symptoms and follow-up images improved. This case emphasize that the intrinsic immunological defects of SLE may be directly responsible for the predisposition to fungal infections

Alk2/ACVR1 and Alk3/BMPR1A Provide Essential Function for Bone Morphogenetic Protein–Induced Retinal AngiogenesisHighlights

OBJECTIVE: Increasing evidence suggests that bone morphogenetic protein (BMP) signaling regulates angiogenesis. Here, we aimed to define the function of BMP receptors in regulating early postnatal angiogenesis by analysis of inducible, endothelial-specific deletion of the BMP receptor components Bmpr2 (BMP type 2 receptor), Alk1 (activin receptor-like kinase 1), Alk2, and Alk3 in mouse retinal vessels. APPROACH AND RESULTS: Expression analysis of several BMP ligands showed that proangiogenic BMP ligands are highly expressed in postnatal retinas. Consistently, BMP receptors are also strongly expressed in retina with a distinct pattern. To assess the function of BMP signaling in retinal angiogenesis, we first generated mice carrying an endothelial-specific inducible deletion of Bmpr2. Postnatal deletion of Bmpr2 in endothelial cells substantially decreased the number of angiogenic sprouts at the vascular front and branch points behind the front, leading to attenuated radial expansion. To identify critical BMPR1s (BMP type 1 receptors) associated with BMPR2 in retinal angiogenesis, we generated endothelial-specific inducible deletion of 3 BMPR1s abundantly expressed in endothelial cells and analyzed the respective phenotypes. Among these, endothelial-specific deletion of either Alk2/acvr1 or Alk3/Bmpr1a caused a delay in radial expansion, reminiscent of vascular defects associated with postnatal endothelial-specific deletion of BMPR2, suggesting that ALK2/ACVR1 and ALK3/BMPR1A are likely to be the critical BMPR1s necessary for proangiogenic BMP signaling in retinal vessels. CONCLUSIONS: Our data identify BMP signaling mediated by coordination of ALK2/ACVR1, ALK3/BMPR1A, and BMPR2 as an essential proangiogenic cue for retinal vessels

Clinical Outcomes of Patients treated for Cervical Pregnancy with or without Methotrexate

The objective of this study is to describe the clinical outcomes of patients treated for cervical pregnancy with or without methotrexate (MTX) and to evaluate the effects of MTX in the treatment of cervical pregnancy. Between January 1993 and February 2000, 31 patients were diagnosed with cervical pregnancy. Twenty-two patients were treated with MTX chemotherapy and nine patients were treated with surgical procedures without MTX treatment. In the non-MTX treatment group, three patients underwent total abdominal hysterectomy, five required adjuvant procedures to control the bleeding during dilatation and curettage (D&C) and only one patient was treated with a simple D&C. In the MTX treatment group, fourteen (63.6%) patients were treated with only MTX and eight (36.4%) cases underwent concomitant procedures (simple curettage, curettage and Foley catheter tamponade, cervical cerclage, ligation of the descending branches of uterine arteries, or ligation of hypogastric arteries). The uterus was preserved in all cases and three women delivered healthy babies in their subsequent pregnancy. In conclusion, early diagnosis, appropriate MTX regimen in combination of necessary adjuvant conservative procedures could contribute to successful treatment with preservation of the uterus and future reproductive ability

Detection of Sentinel Lymph Nodes in patients with Early Stage Cervical Cancer

The purpose of this study was to determine the feasibility of identifying the sentinel lymph nodes (SNs) as well as to evaluate factors that might influence the SN detection rate in patients with cervical cancer of the uterus. Eighty nine patients underwent intracervical injection of 1% isosulfan blue dye at the time of planned radical hysterectomy and lymphadenectomy between January 2003 and December 2003. With the visual detection of lymph nodes that stained blue, SNs were identified and removed separately. Then all patients underwent complete pelvic lymph node dissection and/or para-aortic lymph node dissection. SNs were identified in 51 of 89 (57.3%) patients. The most common site for SN detection was the external iliac area. Metastatic nodes were detected in 21 of 89 (23.5%) patients. One false negative SN was obtained. Successful SN detection was more likely in patients younger than 50 yr (p=0.02) and with a history of preoperative conization (p=0.05). However, stage, histological type, surgical procedure and neoadjuvant chemotherapy showed no significant difference for SN detection rate. Therefore, the identification of SNs with isosulfan blue dye is feasible and safe. The SN detection rate was high in patients younger than 50 yr or with a history of preoperative conization

Melanotic neuroectodermal tumor of infancy

A case of melanotic neuroectodermal tumor of infancy was presented. This tumor occurred in the right maxillary alveolar ridge of 3-month-old female infant, showing bluish enlargement of alveolar mucosa with the displacement of central deciduous incisor. We described the gross, microscopic, and ultrastructural findings of this tumor. This case appears to be the first case of MNTI, reported in a Korean.