130 research outputs found
Interleukin-6 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension
Interleukin-6 (IL-6) is a pleiotropic cytokine with a wide range of biologic activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Recent accumulating evidence indicates a pathologic role for IL-6 in promoting proliferation of both smooth muscle and endothelial cells in the pulmonary arterioles, resulting in development of pulmonary arterial hypertension (PAH). Here, we describe a patient with mixed connective tissue disease and severe, refractory PAH. Her functional activity and hemodynamic parameters dramatically responded to tocilizumab, a humanized monoclonal antibody to human IL-6 receptor, which was aimed at treating multicentric Castleman's disease. It appears that IL-6 blockade may hold promise as an adjunct drug in treatment of PAH in idiopathic form as well as in association with connective tissue disease
Novel Point Mutations in the Steroid Sulfatase Gene in Patients with X-Linked Ichthyosis: Transfection Analysis Using the Mutated Genes
X-linked ichthyosis is caused by steroid sulfatase deficiency which results from abnormalities in its coding gene. The majority of X-linked ichthyosis patients (â90%) have complete or partial deletions of the steroid sulfatase gene. In this study, we examined the mutations of the steroid sulfatase gene in two unrelated X-linked ichthyosis patients without complete deletion of the gene. Polymerase chain reactionâsingle-strand conformation polymorphism and direct sequencing analyses showed that each patient has a different single base pair substitution within exon 8 encoding the C-terminal half of the steroid sulfatase polypeptide. Both mutations resulted in the transversion of functional amino acids: a GâC substitution at nucleotide 1344, causing a predicted change of a glycine to an arginine, and a CâT substitution at nucleotide 1371, causing a change from a glutamine to a stop codon. In vitro steroid sulfatase cDNA expression using site-directed mutagenesis revealed that these mutations are in fact pathogenic and reflect the levels of steroid sulfatase enzyme activities in each of the X-linked ichthyosis patients
Amyloidosis-induced Lower Gastrointestinal Bleeding in a Patient with Multiple Myeloma
We reported a case of gastrointestinal amyloidosis associated with multiple myeloma (MM), presenting with an unusual abdominal condition causing right upper abdominal pain and hematochezia. An abdominal examination revealed a huge tender mass below the right costal margin. A barium enema examination demonstrated a filling defect in the transverse colon and abdominal computed tomography disclosed an inhomogeneous mass. There was no evidence of thrombocytopenia or a coagulation factor deficiency. A surgical specimen showed deposit of amyloid substance in the colon. As this case illustrates, the absence of systemic symptoms of amyloidosis and nonspecific radiological findings in gastrointestinal amyloidosis may make the diagnosis difficult. Therefore, we recommend that a diagnosis of amyloidosis-induced bleeding of the colon should be considered in patients with multiple myeloma with obscure hemorrhaging
Eczéma allergique de contact : Comment ré-induire une tolérance ?
LâeczĂ©ma allergique de contact est une dermatose inflammatoire frĂ©quente, due Ă lâactivation de lymphocytes T (LT) CD8+ cytotoxiques spĂ©cifiques dâhaptĂšnes en contact avec la peau. Les LT CD4+ sont, quant Ă eux, douĂ©s dâune fonction rĂ©gulatrice et tolĂ©rogĂšne, puisquâils limitent lâinflammation cutanĂ©e chez les patients (rĂ©gulation) et prĂ©viennent le dĂ©veloppement des LT effecteurs chez les individus sains (tolĂ©rance) : lâeczĂ©ma correspond donc Ă une rupture de la tolĂ©rance immunitaire aux haptĂšnes prĂ©sents dans lâenvironnement quotidien. Plusieurs sous-populations de LT CD4+ rĂ©gulateurs (LT reg), parmi lesquelles celle des LT CD4+CD25+ naturels, sont impliquĂ©es dans la tolĂ©rance et la rĂ©gulation de lâeczĂ©ma, via la production des cytokines immunosuppressives IL-10 (interleukine-10) et TGFÎČ (transforming growth factor ÎČ). Les travaux en cours ont pour objectif de rĂ©-induire une tolĂ©rance immunitaire dans lâeczĂ©ma, soit en amĂ©liorant les mĂ©thodes existantes dâinduction de tolĂ©rance aux haptĂšnes (tolĂ©rance orale, tolĂ©rance Ă faibles doses, immunothĂ©rapie spĂ©cifique, tolĂ©rance induite par les rayons ultraviolets), soit en dĂ©veloppant de nouvelles molĂ©cules capables dâactiver les LT reg. Plus gĂ©nĂ©ralement, les donnĂ©es issues de ces travaux devraient pouvoir ĂȘtre appliquĂ©es au traitement des maladies auto-immunes ou allergiques, caractĂ©risĂ©es par un dĂ©ficit fonctionnel ou quantitatif en Ltreg Ă lâorigine dâune rupture de la tolĂ©rance aux auto-antigĂšnes ou aux allergĂšnes de lâenvironnement.Allergic contact dermatitis (ACD) is a skin inflammatory disease mediated by activation of CD8+ cytotoxic T cells specific for haptens in contact with the skin. CD4+ T cells behave as both regulatory and tolerogenic cells since they down-regulate the skin inflammation in patients with ACD (regulation) and prevent the developement of eczema (tolerance) in normal individuals. Thus, ACD corresponds to a breakdown of immune tolerance to haptens in contact with the skin. Several regulatory CD4+ T cell subsets (Treg), especially CD4+CD25+ natural Treg cells, are involved in immunological tolerance and regulation to haptens through the production of the immunosuppressive cytokines IL-10 and TGF-ÎČ. Ongoing strategies to re-induce immune tolerance to haptens in patients with eczema include improvement of existing methods of tolerance induction (oral tolerance, low dose tolerance, allergen-specific immunotherapy, UV-induced tolerance) as well as development of new drugs able to activate IL-10 producing Treg cells in vivo. Ongoing and future progress in this area will open up new avenues for treatment of eczema and more generally autoimmune and allergic diseases resulting from a breakdown of tolerance to autoantigens and allergens, respectively
A questionnaire-based comparative study of postoperative quality of life between laryngotracheal separation and tracheoesophageal diversion
Purpose: Whether tracheoesophageal diversion (TED) is preferable to laryngotracheal separation (LTS) is unclear. This study examined the need for tracheoesophageal anastomosis by reviewing complications after TED and LTS and administering a questionnaire on postoperative quality of life.Patients and methods: Medical records of TED/LTS cases performed at a single institution from 2003 to 2015 were retrospectively reviewed and a questionnaire was administered to parents of patients at an outpatient visit.Results: A total of 40 TED and 18 LTS cases were included. Complications occurred in six TED cases and one LTS case, with no significant differences between groups (P=0.42). A total of 22 parents of patients (TED 16 cases; LTS six cases) completed the questionnaire. Voice production was reported in three TED cases and two LTS cases. Patients indicated that suctions were âdecreasedâ in 13 and âunchangedâ in two TED cases, but âdecreasedâ in one and âunchangedâ in five LTS cases (P=0.0055). Readmissions were âincreasedâ in one and âdecreasedâ in 14 TED cases, but âdecreasedâ in three and âunchangedâ in three LTS cases (P=0.015).Conclusion: Postoperative complication rate was equivalent between groups, and the numbers of suctions and readmissions were decreased in the TED group. Therefore, tracheoesophageal anastomosis should be performed more commonly.Keywords: complication, laryngotracheal separation, quality of life questionnaire, tracheoesophageal diversio
Host Prostaglandin E2-EP3 Signaling Regulates Tumor-Associated Angiogenesis and Tumor Growth
Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3â/â) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3â/â, in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3â/â, compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3â/â. These results demonstrate significance of host stromal PGE2-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors
Increased Expression of Macrophage-Inducible C-type Lectin in Adipose Tissue of Obese Mice and Humans
Pharmacokinetics of sepantronium bromide (YM155), a small-molecule suppressor of survivin, in Japanese patients with advanced solid tumors: dose proportionality and influence of renal impairment
Anti-tumor effects of interferon-beta cell therapy in murine model of melanoma
Purpose: Recombinant interferon beta (IFN-ÎČ) has been used for a treatment of cancers. However, the efficacy of recombinant IFN-ÎČ is limited because of its short half-life and side effects. To overcome these problems, we focused on the efficacy of cell-based therapy (cell therapy) using IFN-ÎČ-producing cells in the treatment of melanoma.Methods: IFN-ÎČ-producing therapeutic cells were constructed by gene transduction using retrovirus vector. Anti-tumor effects of the cell therapy were investigated by a murine melanoma model.Results: IFN-ÎČ cell therapy significantly suppressed the proliferation of B16 melanoma in vitro and the growth of B16-derived tumor in vivo, accompanied with the activation of natural killer (NK) cells. IFN-ÎČ cell therapy did not show any systemic side-effects concerning hepatic dysfunction and bone marrow suppression.Conclusion: IFN-ÎČ cell therapy could be a candidate as a novel cancer treatment.
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