Angiogenesis, which is a critical step in the initiation and progression of rheumatoid arthritis (RA), involves pro-angiogenic factors, including interleukin (IL)-8 and vascular endothelial growth factor (VEGF). We investigated the role of Toll-like receptor 3 (TLR3) in the regulation of pro-angiogenic factors in RA fibroblast-like synoviocytes (FLS).
FLS were isolated from RA synovial tissues and stimulated with the TLR3 ligand, poly (I:C). The levels of VEGF and IL-8 in the culture supernatants were measured using enzyme-linked immunosorbent assays, and the mRNA levels were assessed by semiquantitative reverse transcription-polymerase chain reaction. The expression patterns of VEGF and IL-8 in the RA synovium and osteoarthritis (OA) synovium were compared using immunohistochemistry.
The expression levels of TLR3, VEGF, and IL-8 were significantly higher in the RA synovium than in the OA synovium. VEGF and IL-8 production were increased in the culture supernatants of RA FLS stimulated with poly (I:C), and the genes for these proteins were up-regulated at the transcriptional level after poly (I:C) treatment. Treatment with inhibitors of nuclear factor-kappaB (NF-κB), i.e., pyrrolidine dithiocarbamate and parthenolide, abrogated the stimulatory effect of poly (I:C) on the production of VEGF and IL-8 in RA FLS.
Our results suggest that the activation of TLR3 in RA FLS promotes the production of proangiogenic factors, in a process that is mediated by the NF-κB signaling pathway. Therefore, targeting the TLR3 pathway may be a promising approach to preventing pathologic angiogenesis in RA.
Toll-like receptor 3; Arthritis, rheumatoid; Vascular endothelial growth factor; Interleukin-8; Synovial fibroblast
A 63-year-old female diagnosed with relapsed multiple myeloma visited our hospital complaining of a persistent cough. Since July 2006, she had been taking 100 mg thalidomide daily and gradually developed shortness of breath and a persistent dry cough. A chest X-ray and computed tomography showed ground glass opacities in both lungs. An open lung biopsy of the right middle lobe under general anesthesia revealed chronic peribronchial inflammation, mild interstitial fibrosis, and intra-alveolar macrophage infiltration, with some hemosiderin features, compatible with non-specific interstitial pneumonia (NSIP). After discontinuing the thalidomide, the patient's symptoms did not deteriorate, although the radiographs did not improve. The patient is alive and well with regular outpatient follow-up without progression of the NSIP.
Lung diseases, interstitial; Thalidomide; Multiple myeloma
This study was undertaken to identify the intracellular signaling pathway involved in induction of macrophage migration inhibitory factor (MIF) in human rheumatoid arthritis (RA) synovial fibroblasts.
Human RA synovial fibroblasts were treated with concanavalin A (ConA), various cytokines, and inhibitors of signal transduction molecules. The production of MIF by synovial fibroblasts was measured in culture supernatants by ELISA. The expression of MIF mRNA was determined using reverse transcriptase polymerase chain reaction (RT-PCR) and real-time PCR. Phosphorylation of p38 mitogen-activated protein (MAP) kinase in synovial fibroblasts was confirmed using Western blotting. The expression of MIF and p38 MAP kinase in RA synovium was determined using dual immunohistochemistry.
The production of MIF by RA synovial fibroblasts increased in a dose-dependent manner after ConA stimulation. MIF was also induced by interferon-γ, CD40 ligand, interleukin-15, interleukin-1β, tumor necrosis factor-α, and transforming growth factor-β. The production of MIF by RA synovial fibroblasts was significantly reduced after inhibition of p38 MAP kinase. The expression of MIF and p38 MAP kinase was upregulated in the RA synovium compared with the osteoarthritis synovium.
These results suggest that MIF production was induced through a p38 MAP-kinase-dependent pathway in RA synovial fibroblasts.
Macrophage, migration-inhibitory factors; Arthritis rheumatoid; Synovial fibroblast; p38 mitogen-activated protein kinases
The bone marrow functions not only as the primary B-lymphocyte-producing organ but also as a secondary lymphoid organ for CD4 and CD8 cell responses and a site of preferential homing and persistence for memory T cells. Bone marrow T (BM-T) cells are distinguished from peripheral blood T cells by surface phenotype, cytokine secretion profile, and immune functions. In this study, we evaluated the alloreactive potential of donor lymphocyte infusion (DLI) using BM-T cells in mixed chimerism compared to that using spleen T (SP-T) cells.
Cells were prepared using established procedures. BM-T cells were obtained as a by-product of T-cell depletion in BM grafting and then cryopreserved for subsequent DLI. We performed DLI using BM-T cells in allogeneic mixed chimera mice on post-BMT day 21.
When the same dose of T cells, 5-10×105 (Thy1.2+), fractionated from BM and spleen were administered into mixed chimeras, the BM-T group showed complete chimeric conversion, with self-limited graft-versus-host disease (GVHD) and no pathological changes. However, the SP-T group showed persistent mixed chimerism, with pathological signs of GVHD in the liver and intestine.
Our results suggest that DLI using BM-T cells, even in small numbers, is more potent at inducing chimeric conversion in mixed chimerism than DLI using SP-T cells. Further study is needed to determine whether cryopreserved BM-T cells are an effective cell source for DLI to consolidate donor-dominant chimerism in clinical practice without concerns about GVHD.
Chimerism, mixed; Infusion, donor lymphocyte; T-cells, bone marrow
Hypertrophic cardiomyopathy (HCM) with hypertrophy of the basal septum is the most common etiology of left ventricular outflow tract (LVOT) obstruction.
In this article, we report the case of a patient with a structurally normal heart who developed hemodynamic deterioration due to severe LVOT obstruction following treatment with catecholamines. Hypovolemia accompanied with a hyperdynamic condition, resulting from catecholamine treatment, may cause dynamic LVOT obstruction due to the systolic anterior motion of the mitral valve leaflet. The solution for this is early recognition and correction of aggravating factors such as, withdrawal of catecholamine therapy and volume replacement.
Left ventricular outflow obstruction; Catecholamines
Mycobacterium avium complex (MAC) infection is a common opportunistic infection in patients with AIDS (acquired immune deficiency syndrome). Pulmonary involvement of MAC may range from asymptomatic colonization of the respiratory tract to invasive parenchymal or cavitary disease. However, endobronchial lesions with MAC infection are rare in immunocompetent and immunosuppressed hosts. Here, we report MAC infection presenting as an endobronchial mass in a patient with AIDS.
Mycobacterium avium complex; Endobronchial mass; AIDS
Metastases to the adrenal glands are frequently found at autopsy. In practice, adrenal metastases have generally been accepted as evidence of blood-borne systemic disease. So, clinically curable adrenal metastases is a rare malady. The role for surgical resection in adrenal metastases has not been clearly defined. A 45-year-old man initially underwent total gastrectomy with D2 lymph node dissection for treating his advanced gastric cancer. A solitary adrenal metastases was resected 1 year later. The patient has survived for 3 years and no further evidence of disease was found on his last follow-up examination. We report here on this case to show that for selected cases, surgical resection of adrenal metastases is feasible and this procedure may extend survival for metastatic gastric cancer patients.
Gastric cancer; Metastases; Adrenalectomy
Post-transplant lymphoproliferative disorders (PTLD) have been recognized as a complication of immunosuppression and occur with a reported incidence of 1 to 8% of recipients receiving solid organ transplantation. PTLD are classified into two major categories, polymorphic and monomorphic PTLD. The majority of the monomorphic PTLD cases are non-Hodgkin's lymphoma of B-cell origin. Hodgkin's disease is not part of the typical spectrum of PTLD; however, it has been rarely reported. We describe a case of Hodgkin's disease following renal transplantation. A 41-year-old man developed right cervical lymphadenopathy following renal transplantation 116 months previously for chronic renal failure of unknown origin. He had been taking cyclosporine, mycophenolate mofetil and prednisone. A lymph node biopsy revealed mixed cellularity Hodgkin's disease. Immunohistochemical staining was positive for CD30 and EBV-latent membrane protein-1. No other site of disease was identified. The immunosuppressive agents were reduced (mycophenolate mofetil was discontinued, cyclosporine dose reduced from 200 mg to 150 mg and prednisone continued at 5 mg). After 2 cycles of ABVD followed by radiation therapy (3600 cGy), he achieved complete remission.
Post-transplant lymphoproliferative disorder; Hodgkin's disease; Renal transplantation
Polychondritis is an inflammatory disorder that affects various catilagenous structures, and the clinical features include auricular, nasal and respiratory tract chondritis. It also involves the eyes, audiovestibular apparatus, joints and vascular structures. Polychondritis can be associated with several rheumatologic diseases such as systemic lupus erythematosus, rheumatoid arthritis and systemic vasculitis. However, polychondritis is a rare complication of Behçet's disease (BD) and only ten cases with combined BD and polychondritis have been reported on around the world. In this report, we describe a 40-year-old Korean man with BD who suffered from polychondritis that manifested as bilateral auricular chondritis, conjunctivitis and arthritis.
Polychondritis; Behçet's disease
The aim of this study was to determine the prognostic significance of the expression of p53 and retinoblastoma (Rb) gene products in cases of curatively resected gastric adenocarcinoma, by immunohistochemical analysis.
Between January 1996 and December 2001, 736 curatively resected gastric cancer patients underwent immunohistochemical staining for p53 or Rb proteins (pRb), and we retrospectively analyzed the correlation of our results with the clinical outcomes of these cases.
High levels of expression of p53 (>25% p53-positive cells) and Rb (>50% Rb-positive cells) proteins were detected in 40.1% and 43.7% of cases, respectively. Tubular type was found to frequently exhibit higher levels of p53 expression (high expression in 44.2%) than signet ring cell type (high expression in 26.0%) (p=0.042). The incidence of vascular invasion was lower in the high pRb expressors (43.2%) than in the pRb low expressors (56.8%), but this was not a statistically significant discrepancy (p=0.063). Preoperative CEA levels were found to be low in high pRb expressors: initial CEA level in the high pRb expressors was 2.31±3.30 ng/mL, and was 5.18±24.80 ng/mL in the low pRb expressors (p=0.033). Tumor depth and node metastasis were both independent of the levels of expression of p53 and Rb proteins. The seven-year overall survival rate and relapse-free survival rates of patients were 87.2% and 75.7%, respectively. Multivariate Cox regression analysis indicated that tumor stage, tumor size, patient age and pRb expression were the significant prognostic factors with regard to overall survival, and tumor stage and age were both significant factors with regard to relapse-free survival.
Immunohistochemical staining of retinoblastoma gene products was an independent prognostic factor for the prediction of overall survival in curatively resected gastric cancer patients.
Gastric cancer; Prognosis; p53; Rb gene; Immunohistochemistry