Inhibitory effect of fucoidan on TNF-α-induced inflammation in human retinal pigment epithelium cells

Sargassum horneri (S. horneri) is a brown seaweed that contains a fucose-rich sulfated polysaccharide called fucoidan and is known to possess beneficial bioactivities, such as anti-inflammatory, antiviral, antioxidative, and antitumoral effects. This study aimed to determine the anti-inflammatory effects of AB_SH (hydrothermal extracts from S. horneri) and its bioactive compound (fucoidan) against tumor necrosis factor alpha (TNF-α)-induced inflammation in human retinal pigment epithelial (RPE) cells. AB_SH did not exhibit any cytotoxicity, and it decreased the mRNA expression of interleukin (IL)-6 and IL-8 and the production of the cytokines IL-6 and TNF-α. It also suppressed the expression levels of phosphorylated nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), including c-Jun amino-terminal kinases (JNK), p38 protein kinases (p38), and extracellular signal-regulated kinase (ERK) proteins, suggesting that AB_SH inhibits activation of the NF-kB/MAPK signaling pathway. Since fucoidan was identified in the composition analysis of AB_SH, it was additionally shown to be required for its anti-inflammatory effects in TNF-α-stimulated human RPE cells. In line with the AB_SH results, fucoidan reduced the mRNA levels of IL-6, IL-1ß, and IL-8 and production of the cytokines IL-6, TNF-α, and IL-8 through the downregulation of the NF-kB/MAPK signaling pathway in a dose-dependent manner. Collectively, the ability of AB_SH from S. horneri hydrothermal extracts to reduce inflammation indicates that it may be a good functional ingredient for managing ocular disorders

Endoplasmic Reticulum (ER) Stress Enhances Tip60 (A Histone Acetyltransferase) Binding to the Concanavalin A

Herein, we report that the concanavalin A binding of Tip60 (a target of the human immunodeficiency virus type 1-encoded transactivator Tat interacting protein 60 KD; a histone acetyltransferase; HAT) is enhanced as the result of endoplasmic reticulum (ER) stress. The cell expression of Tip60 combined with site-directed mutagenesis analysis was used to identify the glutamine 324 residue as the lecithin binding (Concanavalin A; Con A) site. The Tip60 N324A mutant strain, which seems to be the Con A binding-deficient, was attenuated the protein-protein interactions with FE65 and its protein stability, but its ability of G0-G1 cell cycle arrest was not interrupted. Interestingly, both HAT activity and the nuclear localization of Tip60 N324A mutant were enhanced than those of Tip60 WT. Thus, our results indicate that the Con A binding deficient of Tip60 seems to be one of the most pivotal posttranslational modifications (such as N-glycosylation) for its functional regulation signal, which is generated in response to ER stress

Current Status and Survival Impact of Infectious Disease Consultation for Multidrug-Resistant Bacteremia in Ventilated Patients: A Single-Center Experience in Korea

Background We evaluated the current status and survival impact of infectious disease consultation (IDC) in ventilated patients with multidrug-resistant (MDR) bacteremia. Methods One hundred sixty-one consecutive patients from a single tertiary care hospital were enrolled over a 5-year period. Patients with at least one of the following six MDR bacteremias were included: methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase-producing gram-negative bacteria (Escherichia coli and Klebsiella pneumonia), carbapenem-resistant gram-negative rods (Acinetobacter baumannii and Pseudomonas aeruginosa), and vancomycin-resistant Enterococcus faecium. Results Median patient age was 66 years (range, 18 to 95), and 57.8% of subjects were male. The 28-day mortality after the day of blood culture was 52.2%. An IDC was requested for 96 patients based on a positive blood culture (59.6%). Patients without IDC had significantly higher rate of hemato-oncologic diseases as a comorbidity (36.9% vs. 11.5%, P < 0.001). Patients without an IDC had higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (median, 20; range, 8 to 38 vs. median, 16; range, 5 to 34, P < 0.001) and Sequential Organ Failure Assessment (SOFA) score (median, 9; range, 2 to 17 vs. median, 7; range, 2 to 20; P = 0.020) on the day of blood culture and a higher 28-day mortality rate (72.3% vs. 38.5%, P < 0.001). In patients with SOFA ≥9 (cut-off level based on Youden’s index) on the day of blood culture and gram-negative bacteremia, IDC was also significantly associated with lower 28-day mortality (hazard ratio [HR], 0.298; 95% confidence interval [CI], 0.167 to 0.532 and HR, 0.180; 95% CI, 0.097 to 0.333; all P < 0.001) based on multivariate Cox regression analysis. Conclusions An IDC for MDR bacteremia was requested less often for ventilated patients with greater disease severity and higher 28-day mortality after blood was drawn. In patients with SOFA ≥9 on the day of blood culture and gram-negative bacteremia, IDC was associated with improved 28-day survival after blood draw for culture

Life-Threatening Acute Hyponatremia with Generalized Seizure Induced by Low-Dose Cyclophosphamide in a Patient with Breast Cancer

Cyclophosphamide is commonly used in the treatment of malignant diseases. Symptomatic severe hyponatremia induced by low-dose cyclophosphamide is very uncommon worldwide. Recently we experienced a case of a 56-year-old woman with breast cancer who developed severe hyponatremia with generalized seizure after the first cycle of adjuvant chemotherapy with doxorubicin and cyclophosphamide. Her laboratory test showed a serum sodium of 116 mmol/L. Her hyponatremia was initially treated with hypertonic saline solution and furosemide. She completely recovered without neurological deficits after slow correction of the serum sodium concentration over two days. Clinicians must always keep in mind that life-threatening acute hyponatremia can be induced by intravenous cyclophosphamide during chemotherapy, even if the dosage is low

Combined aberrant expression of E-cadherin and S100A4, but not β-catenin is associated with disease-free survival and overall survival in colorectal cancer patients

BACKGROUND/AIMS: Epithelial-to-mesenchymal transition (EMT) in cancers is related to metastasis, recurrence, and poor prognosis. We evaluated whether EMT-related proteins can act as prognostic biomarkers in colorectal cancer (CRC) patients. METHODS: We evaluated the expression of E-cadherin, β-catenin, and S100A4 by immunohistochemistry (IHC) in 333 CRC tissues from the tumor center and invasive margin. Tumor budding, cell grade, tumor stage, type of tumor growth, peritumoral lymphocyte infiltration (TLI), and perineural- or lymphovascular invasion were evaluated as pathological parameters. mRNA levels of E-cadherin, N-cadherin, β-catenin, and S100A4 from 68 specimens from the same set were analyzed by real time quantitative RT-PCR. RESULTS: Loss of E-cadherin, nuclear β-catenin, and gain of S100A4 were higher in the invasive margin than in the tumor center. Loss of E-cadherin was associated with cell grade, macroscopic type, perineural invasion, and tumor budding, β-catenin with microsatellite instability and tumor site, and S100A4 with growth type, macroscopic type, AJCC stage, lymphovascular invasion, and perineural invasion. The aberrant expression of E-cadherin and S100A4 not β-catenin in the invasive margin was a significant and independent risk factor for disease-free and overall-survival by multivariate analysis, along with AJCC stage and perineural invasion. mRNA levels of β-catenin and S100A4 were correlated with the IHC findings at the tumor invasive margin. E-cadherin and N-cadherin showed a weak inverse correlation. CONCLUSIONS: The combination of loss of E-cadherin and gain of S100A4 in the tumor invasive margin can be used to stratify patients with the same AJCC stage into different survival groups. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/939828962924467

Prevalence of Frailty and Aging-Related Health Conditions in Older Koreans in Rural Communities: a Cross-Sectional Analysis of the Aging Study of Pyeongchang Rural Area

Frailty has been previously studied in Western countries and the urban Korean population; however, the burden of frailty and geriatric conditions in the aging populations of rural Korean communities had not yet been determined. Thus, we established a population-based prospective study of adults aged ≥ 65 years residing in rural communities of Korea between October 2014 and December 2014. All participants underwent comprehensive geriatric assessment that encompassed the assessment of cognitive and physical function, depression, nutrition, and body composition using bioimpedance analysis. We determined the prevalence of frailty based on the Cardiovascular Health Study (CHS) and Korean version of FRAIL (K-FRAIL) criteria, as well as geriatric conditions. We recruited 382 adults (98% of eligible adults; mean age: 74 years; 56% women). Generally, sociodemographic characteristics were similar to those of the general rural Korean population. Common geriatric conditions included instrumental activity of daily living disability (39%), malnutrition risk (38%), cognitive dysfunction (33%), multimorbidity (32%), and sarcopenia (28%), while dismobility (8%), incontinence (8%), and polypharmacy (3%) were less common conditions. While more individuals were classified as frail according to the K-FRAIL criteria (27%) than the CHS criteria (17%), the CHS criteria were more strongly associated with prevalent geriatric conditions. Older Koreans living in rural communities have a significant burden of frailty and geriatric conditions that increase the risk of functional decline, poor quality of life, and mortality. The current study provides a basis to guide public health professionals and policy-makers in prioritizing certain areas of care and designing effective public health interventions to promote healthy aging of this vulnerable population

Generation of Skeletal Muscle Organoids from Human Pluripotent Stem Cells to Model Myogenesis and Muscle Regeneration

In vitro organoids derived from human pluripotent stem cells (hPSCs) have been developed as essential tools to study the underlying mechanisms of human development and diseases owing to their structural and physiological similarity to corresponding organs. Despite recent advances, there are a few methodologies for three-dimensional (3D) skeletal muscle differentiation, which focus on the terminal differentiation into myofibers and investigate the potential of modeling neuromuscular disorders and muscular dystrophies. However, these methodologies cannot recapitulate the developmental processes and lack regenerative capacity. In this study, we developed a new method to differentiate hPSCs into a 3D human skeletal muscle organoid (hSkMO). This organoid model could recapitulate the myogenesis process and possesses regenerative capacities of sustainable satellite cells (SCs), which are adult muscle stem/progenitor cells capable of self-renewal and myogenic differentiation. Our 3D model demonstrated myogenesis through the sequential occurrence of multiple myogenic cell types from SCs to myocytes. Notably, we detected quiescent, non-dividing SCs throughout the hSkMO differentiation in long-term culture. They were activated and differentiated to reconstitute muscle tissue upon damage. Thus, hSkMOs can recapitulate human skeletal muscle development and regeneration and may provide a new model for studying human skeletal muscles and related diseases

Evaluation of 28 Human Embryonic Stem Cell Lines for Use as Unrelated Donors in Stem Cell Therapy: Implications of HLA and ABO Genotypes

For human embryonic stem cells (hESCs) to be used clinically, it is imperative that immune responses evoked by hESCs and their derivates after transplantation should be prevented. Human leukocyte antigens (HLA) and ABO blood group antigens are important histocompatibility factors in graft rejection. HLA matching between recipient and unrelated donors, in particular, is important in improving outcomes in hematopoietic cell transplantation (HCT). We have established and successfully maintained 29 hESC lines and analyzed the HLA and ABO genotypes of these lines. HLA-A, -B, -C and -DR (DRB1) genotyping was performed by polymerase chain reaction (PCR) sequence-based typing and ABO genotyping was carried out by PCR restriction fragment length polymorphism methods. To determine what proportion of the Korean population would be covered by these cell lines in organ transplantation, 27 cell lines with HLA-A, -B, and -DR data were evaluated for HCT (cord blood) donors and 28 cell lines with HLA-DR and ABO data were evaluated for solid organ (kidney) transplantation donors, and then compared the data with those from 6,740 donated cord bloods. When <= 2 HLA mismatches are allowed for HCT, as currently accepted for cord blood transplantation, it was estimated that about 16% and 25% of the possible recipients can find one or more donor cell lines with mismatches at A, B, DRB1 allele level and at A, B antigen/DRB1 allele level, respectively. When HLA-DR antigen level matching and ABO compatibility was considered for solid organ (kidney) transplantation, it was estimated that about 29% and 96% of the possible recipients can find one or more ABO-compatible donor cell lines with 0 and 1 DR mismatches, respectively. 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A case report of chronic granulomatous disease presenting with aspergillus pneumonia in a 2-month old girl

Chronic granulomatous disease (CGD) is an uncommon inherited disorder caused by mutations in any of the genes encoding subunits of the superoxide-generating phagocyte NADPH oxidase system, which is essential for killing catalase producing bacteria and fungi, such as Aspergillus species, Staphylococcus aureus, Serratia marcescens, Nocardia species and Burkholderia cepacia. In case of a history of recurrent or persistent infections, immune deficiency should be investigated. Particularly, in the case of uncommon infections such as aspergillosis in early life, CGD should be considered. We describe here a case of CGD that presented with invasive pulmonary aspergillosis in a 2-month-old girl. We confirmed pulmonary aspergillosis noninvasively through a positive result from the culture of bronchial alveolar lavage fluid, positive serological test for Aspergillus antigen and radiology results. She was successfully treated with Amphotericin B and recombinant IFN-γ initially. Six weeks later after discharge, she was readmitted for pneumonia. Since there were infiltrates on the right lower lung, which were considered as residual lesions, voriconazole therapy was initiated. She showed a favorable response to the treatment and follow-up CT showed regression of the pulmonary infiltrates