Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome.

Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.

In vitro toxicity assessment of crosslinking agents used in hyaluronic acid dermal filler.

Hyaluronic acid (HA) dermal fillers are produced by crosslinking HA with agents, such as 1,4-butanediol diglycidyl ether (BDDE) and poly (ethylene glycol) diglycidyl ether (PEGDE) to acquire desired properties. Thus, the safety evaluation of these crosslinkers is needed at the cellular level. In the present study, cell viability, cytotoxicity, membrane integrity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and inflammatory responses were evaluated in the human keratinocyte cell line, HaCaT and human dermal fibroblast cell line, HDF in response to treatment with the crosslinkers. In both the cell lines, BDDE significantly decreased cell viability at 100-1000 ppm, while PEGDE showed a decrease at 500-1000 ppm. In HaCaT cells, BDDE markedly increased cytotoxicity (lactate dehydrogenase release) at 100-1000 ppm, but PEGDE showed an increase at 500-1000 ppm. Cells treated with BDDE (100 ppm) caused alteration in the integrity of cell membrane and shape. In both the cell lines, BDDE-treated cells showed significantly higher ROS levels and MMP loss than PEGDE-treated cells. Also, BDDE-treated cells exhibited higher COX-2 expression at 100 ppm. Expression of inflammatory cytokines (TNF-α, and IL-1 ß) was higher in BDDE-treated cells. Taken together, PEGDE-treated cells showed markedly lower cytotoxicity, ROS production, and inflammatory responses than BDDE-treated cells. Our data suggest that PEGDE is safer than BDDE as a crosslinker in HA dermal fillers.

Identification of Shared Genes and Pathways in Periodontitis and Type 2 Diabetes by Bioinformatics Analysis.

Introduction: It is well known that the presence of diabetes significantly affects the progression of periodontitis and that periodontitis has negative effects on diabetes and diabetes-related complications. Although this two-way relationship between type 2 diabetes and periodontitis could be understood through experimental and clinical studies, information on common genetic factors would be more useful for the understanding of both diseases and the development of treatment strategies. Materials and Methods: Gene expression data for periodontitis and type 2 diabetes were obtained from the Gene Expression Omnibus database. After preprocessing of data to reduce heterogeneity, differentially expressed genes (DEGs) between disease and normal tissue were identified using a linear regression model package. Gene ontology and Kyoto encyclopedia of genes and genome pathway enrichment analyses were conducted using R package 'vsn'. A protein-protein interaction network was constructed using the search tool for the retrieval of the interacting genes database. We used molecular complex detection for optimal module selection. CytoHubba was used to identify the highest linkage hub gene in the network. Results: We identified 152 commonly DEGs, including 125 upregulated and 27 downregulated genes. Through common DEGs, we constructed a protein-protein interaction and identified highly connected hub genes. The hub genes were up-regulated in both diseases and were most significantly enriched in the Fc gamma R-mediated phagocytosis pathway. Discussion: We have identified three up-regulated genes involved in Fc gamma receptor-mediated phagocytosis, and these genes could be potential therapeutic targets in patients with periodontitis and type 2 diabetes.

The incidence and clinical features of PEGylated filgrastim-induced acute aortitis in patients with breast cancer.

Although PEGylated filgrastim-induced aortitis is very rare and unknown clinically, some cases were reported and increasing, especially in breast cancer patients. The present study investigated the prevalence, clinical features and treatment of aortitis induced by PEGylated filgrastim in patients with breast cancer. A total of 2068 consecutive patients who underwent neoadjuvant/adjuvant chemotherapy with PEGylated filgrastim for breast cancer were enrolled. From the medical record, clinical, laboratory, medication, and imaging evaluation findings were collected. PEGylated filgrastim-induced aortitis was established in 0.3% of the study population. Common clinical presentations included extremely high fever and chest/back pain with high levels of inflammatory markers without any signs of infection. Contrast-enhanced computed tomography scans revealed typical enhancing wall thickening and periaortic soft tissue infiltration at various levels of aorta. All patients improved rapidly after treatment with modest doses of prednisolone (0.5 mg/kg/day) without any complications. Clinicians should be aware of aortitis as a possible complication of granulocyte-colony stimulating factor therapy, especially PEGylated filgrastim, given the frequent misdiagnoses in neutropenic patients undergoing chemotherapy.

Induction of mitochondrial dysfunction by poly(ADP-ribose) polymer: implication for neuronal cell death.

Poly(ADP-ribose) polymerase-1 (PARP-1) mediates neuronal cell death in a variety of pathological conditions involving severe DNA damage. Poly(ADP-ribose) (PAR) polymer is a product synthesized by PARP-1. Previous studies suggest that PAR polymer heralds mitochondrial apoptosis-inducing factor (AIF) release and thereby, signals neuronal cell death. However, the details of the effects of PAR polymer on mitochondria remain to be elucidated. Here we report the effects of PAR polymer on mitochondria in cells in situ and isolated brain mitochondria in vitro. We found that PAR polymer causes depolarization of mitochondrial membrane potential and opening of the mitochondrial permeability transition pore early after injury. Furthermore, PAR polymer specifically induces AIF release, but not cytochrome c from isolated brain mitochondria. These data suggest PAR polymer as an endogenous mitochondrial toxin and will further our understanding of the PARP-1-dependent neuronal cell death paradigm.

[Esophageal sinus formation due to cyanoacrylate injection for esophageal variceal ligation-induced ulcer bleeding in a cirrhotic patient].

Intravariceal injection of N-butyl-2-cyanoacrylate is widely used for the hemostasis of bleeding gastric varices, but not routinely for esophageal variceal hemorrhage because of various complications such as pyrexia, bacteremia, deep ulceration, and pulmonary embolization. We report a rare case of esophageal sinus formation after cyanoacrylate obliteration therapy for uncontrolled bleeding from post-endoscopic variceal ligation (EVL) ulcer. A 50-year-old man with alcoholic liver cirrhosis presented with hematemesis. Emergent esophagogastroscopy revealed bleeding from large esophageal varices with ruptured erosion, and bleeding was initially controlled by EVL, but rebleeding from the post-EVL ulcer occurred at 17th day later. Although we tried again EVL and the injections of 5% ethanolamine oleate at paraesophageal varices, bleeding was not controlled. Therefore, we administered 1 mL cyanoacrylate diluted with lipiodol and bleeding was controlled. Three months after the endoscopic therapy, follow-up endoscopy showed medium to large-sized esophageal varices and sinus at lower esophagus. Barium esophagography revealed an outpouching in esophageal wall and endoscopic ultrasonography demonstrated an ostium with sinus. It is noteworthy that esophageal sinus can be developed as a rare late complication of endoscopic cyanoacrylate obliteration therapy.

Heme oxygenase-1 signals are involved in preferential inhibition of pro-inflammatory cytokine release by surfactin in cells activated with Porphyromonas gingivalis lipopolysaccharide.

Porphyromonas gingivalis is considered the major pathogen of periodontal disease, which leads to chronic inflammation in oral tissues. P. gingivalis-produced lipopolysaccharide (LPS) is a key factor in the development of periodontitis. It is established that surfactin produced by Bacillus subtilis confers anti-inflammatory properties. However, the underlying mechanisms responsible for surfactin-induced anti-inflammatory actions in the context of periodontitis are poorly understood. In this study, we investigated whether surfactin affected P. gingivalis LPS-induced pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-12, and determined that it significantly inhibited their production. Surfactin-mediated inhibition was mainly due to blocked activation of P. gingivalis LPS-triggered nuclear factor-κB. We also examined whether the regulatory effect of surfactin on P. gingivalis LPS-stimulated human THP-1 macrophages was mediated by the induction of heme oxygenase-1 (HO-1) signals, and determined that surfactin also induced HO-1 mRNA and protein expression via activation of Nrf-2. Additionally, we found that small interfering RNA-mediated knock-down of Nrf-2 significantly inhibited surfactin-induced HO-1 expression. Furthermore, inhibition of phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) significantly decreased surfactin-induced HO-1 expression, which is consistent with the suggestion that surfactin-induced HO-1 expression occurs via PI3K/Akt, ERK, and Nrf-2. Treatment with a selective inhibitor of HO-1 reversed the surfactin-mediated inhibition of pro-inflammatory cytokines, suggesting that surfactin induces anti-inflammatory effects by activating Nrf-2-mediated HO-1 induction via PI3K/Akt and ERK signaling. Collectively, these observations support the potential of surfactin as a candidate in strategies to prevent caries, periodontitis, or other inflammatory diseases.