Secondary synovial chondromatosis of the subacromial subdeltoid bursa with coexisting glenohumeral osteoarthritis: Case report.

RATIONALE: Synovial chondromatosis of the shoulder joint is uncommon; this condition usually affects the knee joint and the hip joint. Lesions of multiple chondral nodules form in the synovium and are usually found within the joint capsule. Treatment of synovial chondromatosis consists of loose body removal and synovectomy. In synovial chondromatosis of the shoulder, arthroscopic loose body removal and synovectomy have been reported with good outcomes. Arthroplasty can be a treatment option when osteoarthritis co-occurs at the affected joint. Since incidence of glenohumeral joint osteoarthritis is low compared to osteoarthritis of the knee or hip joints, reports of shoulder synovial chondromatosis treated with arthroplasty are scarce. PATIENT CONCERNS: A 79-year-old woman presented with right shoulder pain with loss of motion for several years without a history of trauma. DIAGNOSES: Degenerative changes in the humeral head and glenoid were noted and multiple loose bodies were found in the subdeltoid bursa, and the subacromial bursa. The pathology of loose bodies showed degenerated cartilage tissue and some bony components. Characteristic concentric rings of calcification were observed, indicative of secondary synovial chondromatosis. The diagnosis was secondary synovial chondromatosis of the subacromial subdeltoid bursa with coexisting glenohumeral osteoarthritis. INTERVENTIONS: The patient was treated with loose body removal, extensive synovectomy, bursectomy and reverse total shoulder arthroplasty. OUTCOMES: Visual analog scale for shoulder pain, range of motion of shoulder joint had improved demonstrating a good short-term outcome and there was no radiographic evidence of disease recurrence. LESSONS: In synovial chondromatosis of the shoulder, loose bodies may form in the bursa. In combination with degenerative osteoarthritis of the glenohumeral joint, arthroplasty is a viable option.

Gastric Calcifying Fibrous Tumor Manifesting as a Subepithelial Tumor.

A gastric subepithelial tumor is a common finding during upper gastric endoscopy. The differential diagnosis of such lesions is broad, and sometimes a rare disease can be diagnosed. A calcifying fibrous tumor (CFT) is a rare, benign mesenchymal tumor that usually affects children and young adults. To our knowledge, a CFT of the tubular gastrointestinal tract is very rare with fewer than 30 cases of gastric CFTs reported in the literature.

Phytocomponent 4-hydroxy-3-methoxycinnamaldehyde ablates T-cell activation by targeting protein kinase C-θ and its downstream pathways.

Autoreactive T-cell responses have a crucial role in the pathology and clinical course of autoimmune diseases. Therefore, controlling the activation of these cells is an important strategy for developing therapies and therapeutics. Here, we identified that 4-hydroxy-3-methoxycinnamaldehyde (4H3MC) has a therapeutic potential for T-cell activation by modulating protein kinase C-θ (PKCθ) and its downstream pathways. Pre- and post-treatment with 4H3MC prevented IL-2 release from human transformed and untransformed T cells at the micromolar concentrations without any cytotoxic effects, in fact more efficiently than its structural analogue 4-hydroxycinnamic acid-a previously reported T-cell inhibitor. In silico analysis showed that 4H3MC is a potential inhibitor of PKC isotypes, including PKCθ-a crucial PKC isotype in T cells. Consistently, 4H3MC significantly blocked PKC activity in vitro and also inhibited the phosphorylation of PKCθ in T cells. 4H3MC had no effect on TCR-mediated membrane-proximal-signalling events such as phosphorylation of Zap70. Instead, it attenuated the phosphorylation of mitogen-activated protein kinases (ERK and p38) and promoter activities of NF-κB, AP-1 and NFAT. Taken together, our results provide the evidences that 4H3MC may have curative potential as a novel immune modulator in a broad range of immunopathological disorders by modulating PKCθ activity.

A patient with eosinophilic gastroenteritis presenting with acute pancreatitis and ascites.

Eosinophilic gastroenteritis (EGE) is a rare disease characterized by focal or diffuse eosinophilic infiltration of the gastrointestinal tract, especially the stomach and duodenum. EGE has vague, nonspecific symptoms, including nausea, vomiting, abdominal pain, diarrhea, weight loss, ascites, and malabsorption. Here, we report a patient with EGE presenting with concurrent acute pancreatitis and ascites. A 68-year-old woman was admitted with abdominal pain, nausea, vomiting, and watery diarrhea. Laboratory findings revealed elevated serum titers of amylase, lipase, and peripheral blood eosinophil count. An abdominopelvic computed tomography scan showed a normal pancreas, moderate amount of ascites, and duodenal thickening. A esophagogastroduodenoscopy showed patchy erythematous mucosal lesions in the 2nd portion of the duodenum. Biopsies from the duodenum indicated eosinophilic infiltration in the lamina propria. The patient was successfully treated with prednisolone and montelukast. Despite its unusual occurrence, EGE may be considered in the differential diagnosis of unexplained acute pancreatitis, especially in a patient with duodenal edema on imaging or peripheral eosinophilia.

Aplotaxene blocks T cell activation by modulation of protein kinase C-θ-dependent pathway.

Aplotaxene, (8Z, 11Z, 14Z)-heptadeca-1, 8, 11, 14-tetraene, is one of the major components of essential oil obtained from Inula helenium root, which is used in Oriental medicine. However, the effects of aplotaxene on immunity have not been investigated. Here, we show that aplotaxene inhibits T cell activation in terms of IL-2 and CD69 expression. Aplotaxene, at a concentration that optimally inhibits IL-2 production, has little effect on apoptotic or necrotic cell death, suggesting that apoptosis is not a mechanism for aplotaxene-mediated inhibition of T cell activation. Aplotaxene affects neither superantigeninduced conjugate formation between Jurkat T cells and Raji B cells nor clustering of CD3 and LFA-1 at the immunological synapse. Aplotaxene significantly inhibits PKC-θ phosphorylation and translocation to the immunological synapse, and blocks PMA-induced T-cell receptor internalization. Furthermore, aplotaxene leads to inhibition of mitogen-activated protein kinases (JNK, ERK and p38) phosphorylation and NF-κB, NF-AT, and AP-1 promoter activities in Jurkat T cells. Taken together, our findings provide evidence for the immunosuppressive effect of aplotaxene on activated T cells through the modulation of the PKC-θ and MAPK pathways, suggesting that aplotaxene may be a novel immunotherapeutic agent for immunological diseases related to the overactivation of T cells.

Dynamic motile T cells highly respond to the T cell stimulation via PI3K-Akt and NF-κB pathways.

T lymphocytes (T cells) circulate from the blood into secondary lymphoid organs for immune surveillance. In this study, we hypothesized that circulating T cells are heterogeneous and can be grouped according to their differential migratory capacity in response to chemoattractants, rather than expressions of certain receptors or cytokines. We further hypothesized that, at least in part, this intrinsic difference in motility may be related to the T cell function. We established motile (m-T) and non-motile T (nm-T) cell lines based on their response to the chemokine SDF-1α. m-T cells showed more irregular and polarized morphologies than nm-T cells did. Interestingly, m-T cells produced higher levels of IL-2, a marker for T cell activation, than nm-T cells did after stimulation; however, no differences were observed in terms of surface expression of T cell receptors (TCR), adhesion molecules LFA-1 and ICAM-1, and chemokine receptor CXCR4. Both cell lines also showed similar membrane events (i.e., T cell-APC conjugation, LFA-1 accumulation at the immunological synapse, and TCR internalization). In contrast, PKC-θ, a downstream of PI3K-Akt pathway was constitutively activated in m-T cells and the activation was more prominent during T cell stimulation. Consequently, NF-κB activity was selectively upregulated in m-T cells. This study is the first, to our knowledge, to demonstrate that T cells can be subcategorized on the basis of their intrinsic migratory capacity in relation to T cell activation.

Identifying Polymorphisms in IL-31 and Their Association with Susceptibility to Asthma.

BACKGROUND: Interleukin 31 (IL-31) is a T helper type 2 effector cytokine that plays an important role in the pathogenesis of atopic and allergic diseases. IL-31 may be involved in promoting allergic inflammation and in inducing airway epithelial responses such as allergic asthma. METHODS: Single-base extension analysis was used to detect the genotypes of IL-31 single nucleotide polymorphisms (SNPs), and we compared the genotype and allele frequencies of the IL-31 SNPs between patients with asthma and healthy controls. RESULTS: There were no significant differences in the genotype and allele frequencies of the IL-31 SNPs between patients with asthma and healthy controls. Furthermore we compared the genotype and allele frequencies of IL-31 SNPs between patients with atopic asthma, those with non-atopic asthma and healthy controls. This showed that the SNPs were not associated with the susceptibility to atopic asthma. There were no significant differences in the haplotype frequencies of IL-31 SNPs between patients with asthma and healthy controls. In patients with asthma, the IL-31 SNPs were significantly correlated with total serum levels of IgE (p=0.035). CONCLUSIONS: Our results indicate that, the IL-31 SNPs may be associated with IgE production in patients with asthma.

Phytocomponent p-Hydroxycinnamic acid inhibits T-cell activation by modulation of protein kinase C-θ-dependent pathway.

The phytocomponent p-hydoxycinnamic acid (HCA) has been shown to have many beneficial effects in terms of antioxidant activity, inhibition of melanogenesis, bone resorption, and platelet activity, and stimulation of mineralization. However, effects of HCA in immune functions have not been investigated. Here, we show that HCA has a profound effect on IL-2 production in Jurkat T cells as well as in human peripheral blood leukocytes. HCA, at a concentration that optimally inhibits IL-2 production, had little effect on apoptotic or necrotic cell death of Jurkat T cells, suggesting that apoptosis is not a mechanism for HCA-induced T-cell suppression. On the contrary, HCA dramatically inhibited PKC-θ accumulation and further phosphorylation at the immunological synapse which formed at the contact site between T cells and superantigen SEE-loaded antigen presenting cells. In addition, HCA significantly inhibited ERK and p38 kinase phosphorylation in both anti-CD3/28- and PMA/A23187-stimulated T cells. Consequently, HCA inhibited both AP-1 and NF-κB promoter activities in Jurkat T cells. Collectively, our results provide evidence for the immunosuppressive effect of HCA on activated T cells, through modulation of PKC-θ pathway.

Eupatilin exhibits a novel anti-tumor activity through the induction of cell cycle arrest and differentiation of gastric carcinoma AGS cells.

In many cases, the process of cancer cell differentiation is associated with the programmed cell death. In the present study, interestingly, we found that eupatilin, one of the pharmacologically active ingredients of Artemisia asiatica that has been reported to induce apoptosis in human gastric cancer AGS cells, also triggers differentiation of these cells. Treatment of AGS cells with eupatilin induced cell cycle arrest at the G(1) phase with the concomitant induction of p21(cip1), a cell cycle inhibitor. This led us to test whether eupatilin may trigger AGS cells to differentiate into the matured phenotypes of epithelial cells and this phenomenon may be coupled to the apoptosis. Eupatilin induced changes of AGS cells to a more flattened morphology with increased cell size, granularity, and mitochondrial mass. It also markedly induced trefoil factor 1 (TFF1), a gene responsible for the gastrointestinal cell differentiation. Eupatilin dramatically induced redistribution of tight junction proteins such as occludin and ZO-1, and F-actin at the junctional region between cells. It also induced phosphorylation of extracellular signal-regulated kinase 2 and p38 kinase. Blockade of ERK signaling by PD098059 or the dominant-negative ERK2 significantly reduced eupatilin-induced TFF1 and p21 expression as well as ZO-1 redistribution, indicating that ERK cascades may mediate eupatilin-induced AGS cell differentiation. Collectively, our results suggest that eupatilin acts as a novel anti-tumor agent by inducing differentiation of gastrointestinal cancer cells rather than its direct role in inducing apoptotic cell death.

Ammonium glycyrrhizinate protects gastric epithelial cells from hydrogen peroxide-induced cell death.

Glycyrrhiza uralensis has a potential for preventing or ameliorating gastric mucosal ulceration. To understand the molecular mechanism about the medicinal effect of G. uralensis, we isolated four single compounds from G. uralensis and one related compound and screened for the cellular protective effect against H(2)O(2)-induced damage in gastric epithelial AGS cells. Interestingly, we found that ammonium glycyrrhizinate (AG) prepared from glycyrrhizin dramatically protects AGS cells from H(2)O(2)-induced damage as measured by the integrity of actin cytoskeleton. AG also inhibited FeSO(4)-induced reactive oxygen radicals in a dose-dependent manner, suggesting the role for AG as a free radical scavenger. To better understand the protective role of AG at the transcriptional level, we performed genome-wide expression profiling using high-density oligonucleotide microarrays, followed by validation using RT-PCR. Among the 33,096 genes that were screened in the microarray, 936 genes were found to be differentially expressed in a statistically significant manner in the presence or absence of H(2)O(2) and AG. Among the 936 genes, 51 genes were differentially expressed at least 3-fold in response to the H(2)O(2) treatment. AG blocked the expression of genes related to apoptotic cell death (GDF15, ATF3, TNFRSF10A, NALP1) or oxidative stress path-ways (HMOX1) which was elevated in response to H(2)O(2) treatment, suggesting a potential protective role for AG in oxidative stress-induced cell death. Collectively, current results demonstrate that AG is a novel antioxidant that could be effective for the treatment of gastric diseases related to the oxidative stress-induced mucosal damage.