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Skin rash is a well-known predictive marker of the response to cetuximab (Cmab) in metastatic colorectal cancer (mCRC). However, the mechanism of skin rash development is not well understood. Following exposure to EGFR-targeted therapies, changes in IL-8 levels have been reported. The aim of this study was to evaluate the association between skin rash and inflammatory cytokine levels, including IL-8. Between 2014 and 2017, we prospectively enrolled 38 mCRC patients who underwent chemotherapy with either Cmab or bevacizumab (Bmab) at two hospitals. We performed multiplex cytokine ELISA with 20 inflammatory cytokines including E-selectin, GM-CSF, IFN-alpha, IFN-γ, IL-1 alpha, IL-1 beta, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IP-10, MCP-1, MIP-1 alpha, MIP-1 beta, P-selectin, sICAM-1, and TNF-alpha at baseline before cycle 1, 24 h after cycle 1, before cycle 2 (= 14 d), and before cycle 3 (= 28 d). Cytokine levels were compared using ANOVA after log-transformation. IL-8 genotypes in 30 patients treated with Cmab were determined using the polymerase chain reaction restriction fragment length polymorphism technique. Depending on the RAS mutational status, 30 and eight patients were treated with Cmab and Bmab-based chemotherapy, respectively. Skin rash developed in 23 (76.6%) of the 30 patients treated with Cmab plus FOLFIRI, after cycle 1. Only the mean log-transformed serum IL-8 level in patients with skin toxicity was statistically lower (2.83 ± 0.15) than in patients who did not experience skin toxicity (3.65 ± 0.27) and received Bmab (3.10 ± 0.26) (ANOVA test, p value = 0.0341). In addition, IL-8 polymorphism did not affect IL-8 levels, skin toxicity, or tumor response in Cmab treated patients. This study suggests that the inflammatory cytokine levels might be affected by Cmab exposure and are associated with the development of skin rash in mCRC patients. Further studies are warranted to evaluate this interaction in Cmab treated patients.

Background The available data are not sufficient to understand the clinical impact of statin intensity in elderly patients who undergo percutaneous coronary intervention (PCI) due to acute myocardial infarction (AMI). Methods Using the COREA-AMI registry, we sought to compare the clinical impact of high- versus low-to-moderate-intensity statin in younger (Results In younger patients, high-intensity statin showed the better clinical outcomes than low-to-moderate-intensity statin (TVF: 79 [5.4%] vs. 329 [6.8%], adjusted hazard ratio [aHR] 0.76; 95% confidence interval [CI] 0.59–0.99; P = 0.038). However, in elderly patients, the incidence rates of the adverse clinical outcomes were similar between two statin-intensity groups (TVF: 38 [11.4%] vs. 131 [10.6%], aHR 1.1; 95% CI 0.76–1.59; P = 0.63). Conclusions In this AMI cohort underwent PCI, high-intensity statin showed the better 1-year clinical outcomes than low-to-moderate-intensity statin in younger patients. Meanwhile, the incidence rates of adverse clinical events between high- and low-to-moderate-intensity statin were not statistically different in elderly patients. Further randomized study with large elderly population is warranted.

Purpose Endothelin-1 (ET-1) is a potent vasoconstrictor which seems to be involved in the pathogenesis of diabetic retinopathy (DR). However, studies on intraocular ET-1 in DR have been limited. Thus, we investigated aqueous ET-1 levels in patients with DR. Methods A total 85 subjects were included in this prospective study. Those were classified into three groups: advanced DR group included those with severe nonproliferative DR or proliferative DR, whereas early DR group included those with mild nonproliferative DR or moderative nonproliferative DR. Those who underwent cataract surgery and had no concomitant ocular disease were included in the control group. Aqueous humor levels of ET-1 were obtained before intravitreal bevacizumab injection (IVB) and after 1 month for the DR patients, and at the time of cataract surgery for the control group. Results Advanced DR group included 40 eyes (47.1%), whereas early DR group did 19 eyes (22.4%), and control group (26 eyes, 30.5%). Mean aqueous ET-1 level was 10.1±4.1 pg/mL (6.0–21.0 pg/mL) in advanced DR group, 1.9±0.7 pg/mL (0.6–2.8 pg/mL) in early DR group, and 2.1±1.0 pg/mL (0.7–3.9 pg/mL) in control group (P < 0.001). Advanced DR group was further subdivided into severe nonproliferative DR (15 eyes, 12.8%) and proliferative DR (25 eyes, 34.3%). Mean aqueous ET-1 level was 10.1±4.3 pg/mL (6.0–20.1 pg/mL) in patients with severe nonproliferative DR, and 10.0±4.0 pg/mL (6.0–21.0 pg/mL) in those with proliferative DR (P = 0.928) at baseline. Mean ET-1 level at 1 month after intravitreal injection was 2.5±1.0 pg/mL (0.3–4.8 pg/mL) in patients with severe proliferative DR and 2.9±1.7 pg/mL (1.0–7.0 pg/mL) in those with proliferative DR (P = 0.443). Mean aqueous ET-1 level was significantly reduced in both groups (P < 0.001, respectively). Conclusion The mean aqueous ET-1 level was significantly higher in the eyes with advanced DR than those with early DR and the control group. The mean aqueous ET-1 level was significantly reduced after intravitreal injections in the advanced DR group. Based on our results, future studies on the exact role of ET-1 in the pathogenesis of DR and future implication for intervention would be helpful for managing DR.

ObjectiveWe explored the clinical significances of the relationships among sphenoid sinus aeration, intersphenoid sinus septum (ISS), and internal carotid artery (ICA).MethodsWe retrospectively reviewed the preoperative paranasal sinus computed tomography scans and the medical charts of 490 patients who were treated by the endoscopic endonasal transsphenoidal approach. We analyzed sphenoid sinus pneumatization, number of ISS, and positional relationships between the ICA and ISS (including ICA prominence and the thickness of surrounding bone).ResultsISS were often present in the ICAs of patients with presellar pneumatization (36.2%; p = 0.042). Sphenoid sinus pneumatization status significantly differed according to number of ISS (p < 0.001), ICA prominence (p < 0.001), ISS insertion into the ICA (p = 0.042), and distance from ISS to ICA (p = 0.004). When sphenoid sinus aeration was poor, the ICA was not prominent, and the ISS were attached to or lay close to the paraclival ICA.ConclusionsPatients with presellar pneumatization exhibited less prominent ICAs, and more ISS attached to or near the paraclival ICA, than did other patients. Therefore, particular caution is required when using the endoscopic endonasal transsphenoidal approach to treat patients with poor sphenoid sinus aeration.

Although pentoxifylline (PTX) was identified as a competitive non-selective phosphodiesterase inhibitor, its pharmacological effect has not been clearly elucidated. The present study explored the effect of low dose 10 μg/mL PTX (therapeutic dose) compared to high dose 300 μg/mL PTX (experimental dose) in RAW 264.7 cells through immunoprecipitation-based high performance liquid chromatography (IP-HPLC), immunohistochemistry, and western blot. 10 μg/mL PTX increased the expression of proliferation (Ki-67, PCNA, cyclin D2, cdc25A), epigenetic modification (KDM4D, PCAF, HMGB1), protein translation (DOHH, DHPS, eIF5A1), RAS signaling (KRAS, pAKT1/2/3, PI3K), NFkB signaling (NFkB, GADD45, p38), protection (HSP70, SOD1, GSTO1/2), survival (pAKT1/2/3, SP1, sirtuin 6), neuromuscular differentiation (NSEγ, myosin-1a, desmin), osteoblastic differentiation (BMP2, RUNX2, osterix), acute inflammation (TNFα, IL-1, CXCR4), innate immunity (β-defensin 1, lactoferrin, TLR-3, -4), cell-mediated immunity (CD4, CD8, CD80), while decreased the expression of ER stress (eIF2α, eIF2AK3, ATF6α), fibrosis (FGF2, CTGF, collagen 3A1), and chronic inflammation (CD68, MMP-2, -3, COX2) versus the untreated controls. The activation of proliferation by 10 μg/mL PTX was also supported by the increase of cMyc-MAX heterodimer and β-catenin-TCF1 complex in double IP-HPLC. 10 μg/mL PTX enhanced FAS-mediated apoptosis but diminished p53-mediated apoptosis, and downregulated many angiogenesis proteins (angiogenin, VEGF-A, and FLT4), but upregulated HIF1α, VEGFR2, and CMG2 reactively. Whereas, 300 μg/mL PTX consistently decreased proliferation, epigenetic modification, RAS and NFkB signaling, neuromuscular and osteoblastic differentiation, but increased apoptosis, ER stress, and fibrosis compared to 10 μg/mL PTX. These data suggest PTX has different biological effect on RWA 264.7 cells depending on the concentration of 10 μg/mL and 300 μg/mL PTX. The low dose 10 μg/mL PTX enhanced RAS/NFkB signaling, proliferation, differentiation, and inflammation, particularly, it stimulated neuromuscular and osteoblastic differentiation, innate immunity, and cell-mediated immunity, but attenuated ER stress, fibrosis, angiogenesis, and chronic inflammation, while the high dose 300 μg/mL PTX was found to alleviate the 10 μg/mL PTX-induced biological effects, resulted in the suppression of RAS/NFkB signaling, proliferation, neuromuscular and osteoblastic differentiation, and inflammation.

PURPOSE:The survival benefit of second-line chemotherapy in patients with metastatic gastric cancer (MGC) has recently been established. We conducted a nationwide population-based outcomes study of patients with MGC receiving second-line chemotherapy to better understand real-world treatment patterns and outcomes. MATERIALS AND METHODS:Data were collected from the Health Insurance Review and Assessment Service database. We identified 509 newly diagnosed patients with MGC in 2010 who received second-line chemotherapy. These patients were divided into three groups for analyses: Group A comprised all patients who received second-line chemotherapy (N = 509); Group B comprised those who received fluoropyrimidine (Fp) plus platinum as first-line treatment, followed by irinotecan-based or taxane-based regimens as second-line chemotherapy (N = 284); and Group C comprised those who received Fp plus cisplatin as first-line treatment, followed by 5-fluorouracil (5-FU)/oxaliplatin, irinotecan-based, or taxane-based regimens as second-line chemotherapy (N = 184). RESULTS:Among patients who received first-line chemotherapy, 47.2% (509/1,078) continued to receive second-line chemotherapy. The most commonly used second-line chemotherapy regimens were 5-FU/irinotecan, 5-FU/oxaliplatin, and docetaxel. The median overall survival (OS) of all 509 patients was 5.2 months. The time from the start date of first-line chemotherapy to the start date of second-line chemotherapy > 6.1 months was an independent prognostic factor for improved OS. The type of chemotherapy regimen was not a significant factor affecting OS. CONCLUSION:The findings provide a better understanding of second-line treatment patterns and outcomes in patients with MGC and will help guide treatment decisions in real-world clinical practice.

PURPOSE:There is limited data on third-line chemotherapy in patients with metastatic gastric cancer (MGC). This study was conducted to assess third-line treatment patterns, outcomes, and clinical parameters related to survival outcomes in patients with MGC. METHODS:Using the Korean Health Insurance Review and Assessment Service (HIRA) database, a nationwide population-based outcomes study was conducted. From the HIRA database, patients newly diagnosed in 2010 with MGC were identified (N = 1,871), and of these, 229 patients who had received third-line chemotherapy were finally selected for this study. RESULTS:Prior to third-line chemotherapy, more than 90% of patients received fluoropyrimidine and platinum, and 43.7% and 40.6% received taxane and irinotecan, respectively. Various third-line chemotherapy regimens containing taxane (docetaxel or paclitaxel), irinotecan, or oxaliplatin were prescribed. The median overall survival (OS) of all patients receiving third-line chemotherapy was 4.4 months. The median time from the start date of first-line chemotherapy to the start date of third-line chemotherapy (TF1T3) was 9.5 months, and a longer TF1T3 was the only factor that was significantly associated with an increased OS. The median OS of patients who had received fluoropyrimidine, platinum, and taxane followed by third-line irinotecan-based therapy was similar to that of patients who had received fluoropyrimidine, platinum, and irinotecan followed by third-line taxane-based therapy (p = 0.894). CONCLUSION:In patients with MGC receiving third-line chemotherapy, TF1T3 was the only significant factor associated with OS. The sequence of using taxane and irinotecan as subsequent therapy after first-line failure was not shown to impact survival outcome.

Tumor burden is important to predict clinical behaviors of cancer such as lymph node metastasis (LNM). Tumor size has been used as a parameter of tumor burden such as indication of endoscopic resection in early gastric cancer (EGC) to predict LNM. Thus, we aimed to investigate whether tumor area can be more helpful to predict clinical behaviors than longest diameter of tumor in EGC.3,059 patients who underwent gastrectomy for EGC were reviewed retrospectively. Tumor area was calculated by multiplying long and short diameter of the tumor in surgical specimen. Longest diameter means maximal longitudinal diameter of tumor in specimen. Clinicopathologic features were compared between longest diameter and area using area under receiver operating characteristic (AUROC) curves.Longest diameter and area of tumor showed a strong correlation (correlation coefficient 0.859, p

Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and energy metabolism via the hypoxia-inducible factor-1α (HIF-1α) and peroxisome-proliferator-activating receptor-γ coactivator-1α (PGC-1α)/estrogen-related receptor α (ERRα) pathways, respectively, in astrocytes. However, evidence of cross-talk between both pathways in HO metabolite-mediated mitochondrial biogenesis has not been well elucidated. Here, we found that HIF-1α was upregulated in astrocytes after ischemic brain injury following exposure to the carbon monoxide (CO)-releasing compound CORM-2. Experiments with pharmacological inhibitors and target-specific siRNAs revealed that HIF-1α levels were highly correlated with increased PGC-1α and ERRα levels, which were linked to the HO metabolites CO- and bilirubin-induced activation of apical L-type Ca2+ channel and sequential Ca2+-dependent signal transduction. Moreover, HIF-1α was stabilized in a proline hydroxylase-dependent manner by transient induction of intracellular hypoxia via the PGC-1α/ERRα-induced increases in mitochondrial biogenesis and oxygen consumption. HIF-1α knockdown blocked HO-1 system-mediated transcriptional expression of ERRα, but not of PGC-1α, suggesting a possible involvement of HIF-1α in ERRα-mediated mitochondrial biogenesis. These data suggest that the HO-1-derived metabolites, CO and bilirubin, elevate astrocytic mitochondrial function via a HIF-1α/ERRα circuit coupled with L-type Ca2+ channel activation and PGC-1α-mediated oxygen consumption. This circuit may play an important role in repairing neurovascular function after focal ischemic brain injury by stimulating mitochondrial biogenesis.

PURPOSE:Targeting of vascular endothelial growth factor receptors (VEGFRs) has potential anti-angiogenic effects because VEGFR-2 is the major signaling regulator of VEGF/VEGFR pathways. We aimed to elucidate the drug mechanism and anti-tumor efficacy of TTAC-0001, a novel, fully human anti-VEGFR-2/KDR monoclonal antibody, in mouse orthotopic breast cancer model using multi-modal bioimaging. MATERIALS AND METHODS:We used orthotopic xenograft tumor model in which human breast cancer cells (MDA-MB-231) were injected into the right mammary fat pad of Balb/c nude mice. We investigated its biodistribution using serial fluorescence imaging after injecting fluorescent-labelled-drug and mode of action using Matrigel plug angiogenesis assays. The anti-tumor efficacy of drug was assessed using ultrasonography and bioluminescence imaging. Histopathologic analyses, including hematoxylin and eosin staining and immunohistochemistry with anti-CD31 and anti-Ki-67 antibodies, were performed. Each experiment had four groups: control, bevacizumab 10 mg/kg (BVZ-10 group), TTAC-0001 2 mg/kg (TTAC-2 group), and TTAC-0001 10 mg/kg (TTAC-10 group). RESULTS:The TTAC-10 group showed good tumor targeting that lasted for at least 6 days and had a good anti-angiogenic effect with decreased hemoglobin content and fewer CD31-positive cells in the Matrigel plug. Compared with BVZ-10 and TTAC-2 groups, the TTAC-10 group showed the strongest anti-tumor efficacy, inhibiting tumor growth as detected by ultrasonography and bioluminescence imaging. The TTAC-10 group also showed the lowest viable tumor and micro-vessel areas and the lowest Ki-67 index in histopathologic analyses. CONCLUSION:We firstly demonstrated that TTAC-0001 effectively inhibited tumor growth and neovascularization in mouse orthotopic breast cancer model. It may provide a future treatment option for breast cancer.

Corals and their associated fauna are extremely diverse in tropical waters and form major reefs. In the high-latitude temperate zone, corals living near their distribution limit are considered marginal communities because they are particularly extremely sensitive to environmental and climatic changes. In this study, we examined the diversity and host usage of coral-associated barnacles on Jeju Island, Korea, the northern coral distribution limit in the East China Sea. In this study, only three coral-associated barnacles-from two genera in two subfamilies-were collected. The Pyrgomatinid barnacles Cantellius arcuatus and Cantellius cf. euspinulosum were found only on the corals Montipora millepora and Alveopora japonica, respectively. The Megatrematinid barnacle Pyrgomina oulastreae, relatively a generalist, was found on Psammocora spp. (both profundacella and albopicta) and Oulastrea crispata corals. The host usage of these three barnacles does not overlap. DNA barcode sequences of the C. arcuatus specimens collected in the present study matched those collected in Kochi in Japan, Taiwan, Malaysia and Papua New Guinea, suggesting that this species has a wide geographical distribution. C. arcuatus covers a wider host range in Taiwan waters, inhabiting Montipora spp. and Porites spp., which suggests that the host specificity of coral-associated barnacles varies with host availability. C. cf. euspinulosum probably has a very narrow distribution and host usage. The sequences of C. cf. euspinulosum on Jeju Island do not match those of any known sequences of Cantellius barnacles in the Indo-Pacific region. P. oulastreae probably prefers cold water because it has been reported in temperate regions. Coral-associated barnacles in marginal communities have considerably lower diversity than their subtropical and tropical counterparts. When host availability is limited, marginal coral-associated barnacles exhibit higher host specificity than those in subtropical and tropical reef systems.

PURPOSE:To evaluate the potential role of 18F-fluorodeoxyglucose-positron emission tomography/computerized tomography (FDG-PET/CT) for predicting treatment response after radiotherapy (RT) in patients with spinal metastases. MATERIALS AND METHODS:A retrospective analysis was performed of 42 patients with spinal metastases who received RT from January 2010 to December 2014. All patients underwent FDG-PET/CT before and after treatment. Changes in metabolic responses, expressed as the maximum, mean, peak standardized uptake values (SUVmax, SUVmean, SUVpeak), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were analyzed to determine their association with clinical outcomes. RESULTS:The median age at the time of spinal metastasis diagnosis was 58 years. Median progression-free survival (PFS) and overall survival after RT were 15 months and 22.4 months, respectively. RT produced a significant decrease in SUVmean (2.27 to 1.41), SUVmax (6.87 to 2.99), SUVpeak (5.75 to 2.33) and TLG (52.84 to 24.17) when compared with the baseline values (p70% reduction in maximum SUV after treatment was independently associated with good PFS (p = 0.036). CONCLUSIONS:RT is an effective treatment for patients with spinal metastases, and there were significant changes in PET parameters compared with baseline. The metabolic response measured by SUV and TLG changes in FDG-PET/CT correlated with the clinical outcomes, especially with shorter PFS in patients who had higher residual maximum SUV after treatment.

Accumulating evidence suggests that the glutamatergic system plays a major role in the pathophysiology of obsessive compulsive disorder (OCD) and empathic processing. Particularly, genetic influence of glutamate transporter gene (SLC1A1) on OCD has been frequently replicated in previous studies, but several studies did not replicate the result. Therefore, we aimed to replicate the associations between the SLC1A1 and OCD in a Korean population. In addition, we investigated the influence of SLC1A1 on trait empathy, impairments in which are characteristic of OCD. Six single-nucleotide polymorphisms (SNP) of SLC1A1 were genotyped in 615 patients with OCD and 508 healthy controls. The interpersonal reactivity index (IRI)-which consists of four subscales (perspective taking, PT; fantasy seeking, FS; empathic concern, EC; personal distress, PD)-was assessed from 277 patients with OCD and 395 controls. There were no significant associations between OCD and SNPs or haplotypes of SLC1A1. Patients with OCD exhibited significantly lower PT and higher PD scores than controls. The C-T-G haplotype at rs301430-rs301434-rs3087879 of SLC1A1 was significantly associated with higher PD scores after adjusted for age, sex, and OCD status. Our results suggest that six common SNPs of SLC1A1 may not contribute to the development of OCD, but may contribute to certain aspect of trait empathy such as personal distress. However, insufficient sample size and limited number of SLC1A1 SNPs may have reduced the likelihood of detecting significant associations. Therefore, further studies with larger sample size and more tag SNPs of the SLC1A1 gene were warranted.

The increasing water crisis makes fresh water a valuable resource, which must be used wisely. However, with growing population and inefficient waste treatment systems, the amount of wastewater dispelled in rivers is increasing abominably. Utilizing this freely available waste-water along with biodiesel industry waste- crude glycerol for bio-hydrogen production is being reported here. The bacterial cultures of Bacillus thuringiensis strain EGU45 and Bacillus amyloliquefaciens strain CD16 produced2.4-3.0 L H2/day/L feed during a 60 days continuous culture system at hydraulic retention time of 2 days. An average H2 yield of 100-120 L/L CG was reported by the two strains. Recycling of the effluent by up to 25% resulted in up to 94% H2 production compared to control.

INTRODUCTION:White matter lesions (WMLs), detected as hyperintensities on T2-weighted MRI, represent small vessel disease in the brain and are considered a potential risk factor for memory and cognitive impairment in older adults. The purpose of this study was to evaluate the association between WMLs and cerebral amyloid-β (Aβ) burden in patients with cognitive impairment. METHODS:A total of 83 patients with cognitive impairment, who underwent brain MRI and F-18 florbetaben PET, were included prospectively: 19 patients were cognitively unimpaired, 30 exhibited mild cognitive impairment (MCI), and 34 exhibited dementia. The Fazekas scale was used to quantify WMLs on T2-weighted brain MR images. Cerebral Aβ burden was quantitatively estimated using volume-of-interest analysis. Differences in cerebral Aβ burden were evaluated between low-WML (Fazekas scale ≤1) and high-WML (Fazekas scale ≥2) groups. The relationship between the Fazekas rating and cerebral Aβ burden was evaluated using linear regression analysis after adjusting for age and sex. RESULTS:In the overall cohort, the high-WML group exhibited significantly higher Aβ burden compared with the low-WML group (P = 0.011) and cerebral Aβ burden was positively correlated with Fazekas rating (β = 0.299, P = 0.006). In patients with MCI, the high-WML group exhibited significantly higher Aβ burden compared with the low-WML group (P = 0.019) and cerebral Aβ burden was positively correlated with Fazekas rating (β = 0.517, P = 0.003). CONCLUSION:The presence of WMLs was associated with cerebral Aβ burden in patients with MCI. Our findings suggest that small vessel disease in the brain is related to Alzheimer's disease pathology.

[This corrects the article DOI: 10.1371/journal.pone.0188321.].

Allergic rhinitis (AR) and rhinosinusitis (RS) negatively impact psychological well-being and health-related quality of life (HRQoL). However, few population-based studies have investigated the effects of these conditions on mental health and HRQoL.To explore independent associations of AR and/or RS with mental health and HRQoL using data from the 2013-2015 Korea National Health and Nutrition Examination Survey (KNHANES).The KNHANES is a nationwide cross-sectional survey of the non-institutionalized population of Korea. A total of 15,441 adults completed the clinical examination and the health questionnaire. We divided all participants into four groups: AR-/RS-, AR-/RS+, AR+/RS-, and AR+/RS+. Logistic regression analyses were performed after adjustment for sociodemographic characteristics, general health behaviors, and other comorbidities.The AR+/RS+ group contained the highest proportion of subjects with perceived stress and depressed mood. Subjects with AR+/RS+ also had more frequent problems in terms of pain/discomfort and anxiety/depression. After adjusting for all confounders, the odds ratios (ORs) were 2.96 (p = 0.009) for depressed mood and 3.17 (p = 0.013) for suicidal ideation in the AR+/RS+ group compared with in the AR-/RS- group. The AR+/RS- group reported more perceived stress (OR, 1.56, p = 0.003) and depression (OR, 1.72, p = 0.024) compared with the AR-/RS- group. In terms of the ORs for HRQoL, the AR+/RS+ group reported more problems in terms of self-care (OR, 3.73, p = 0.038) and more pain/discomfort (OR 2.19, p = 0.006) compared with the AR-/RS- group.In the Korean population, AR and RS exerted a synergistic negative impact on mental health and HRQoL, especially suicidal ideation. Most patients seek help from clinicians for impaired HRQoL. Therefore, clinicians should consider the underlying mental health and HRQoL of patients with AR and/or RS, as these may be impaired by their conditions.

Epidemiological studies have indicated that smoking is a pivotal risk factor for the progression of several chronic diseases. Nicotine, the addictive component of cigarettes, has powerful pathophysiological properties in the body. Although the effects of cigarette smoking on corneal re-epithelialization have been studied, the effects of nicotine on corneal wound healing-related neovascularization and fibrosis have not been fully demonstrated. The aim of this study was to evaluate the effects of chronic administration of nicotine on corneal wound healing following acute insult induced by an alkali burn. BALB/C female mice randomly received either vehicle (2% saccharin) or nicotine (100 or 200 μg/ml in 2% saccharin) in drinking water ad libitum. After 1 week, animals were re-randomized and the experimental group was subjected to a corneal alkali burn, and then nicotine was administered until day 14 after the alkali burn. A corneal alkali burn model was generated by placing a piece of 2 mm-diameter filter paper soaked in 1N NaOH on the right eye. Histopathological analysis and the expression level of the pro-angiogenic genes vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) revealed that chronic nicotine administration enhanced alkali burn-induced corneal neovascularization. Furthermore, the mRNA expression of the pro-fibrogenic factors α-smooth muscle actin (αSMA), transforming growth factor-β (TGF-β), and collagen α1 (Col1) was enhanced in the high-concentration nicotine-treated group compared with the vehicle group after corneal injury. Immunohistochemical analysis also showed that the αSMA-positive area was increased in chronic nicotine-treated mice after corneal alkali burn. An in vitro assay found that expression of the α3, α7, and β1 nicotinic acetylcholine receptor (nAChR) subunits was significantly increased by chemical injury in human corneal fibroblast cells. Moreover, alkali-induced fibrogenic gene expression and proliferation of fibroblast cells were further increased by treatment with nicotine and cotinine. The proliferation of such cells induced by treatment of nicotine and cotinine was reduced by inhibition of the PI3K and PKC pathways using specific inhibitors. In conclusion, chronic administration of nicotine accelerated the angiogenic and fibrogenic healing processes in alkali-burned corneal tissue.

We evaluated the effect of serum-free and xeno-cultivation (SFXFM) on the characterization, proliferation, and differentiation properties of human nasal stem cells (airway tissue; hTMSCs). hTMSCs were isolated from 10 patients, after which patient samples were separated into two groups, an SFXFM group and a control group. The control group was treated with bovine serum-containing medium. FACS analysis revealed that SFXFM-cultured hTMSCs maintained a characteristic mesenchymal stem cell phenotype. hTMSC proliferation was not influenced by SFXFM. In addition, upregulation of IL-8 and GM-CSF and downregulation of RANTES expression were shown in response to SFXFM. Moreover, two-lineage differentiation properties (osteocyte and adipocyte) of hTMSCs were enhanced under SFXFM. Finally, the genetic stability of SFXFM-cultured hTMSCs was demonstrated by normal karyotype results. SFXFM enables good expansion, multipotentiality, and normal genotype maintenance of MSCs. Moreover, this approach serves as a substitute to conventional media for the cultivation of capable MSCs for upcoming medical applications.

Thirty-six VLBW infants who underwent F-18 fluorodeoxyglucose (F-18 FDG) brain PET and MRI were prospectively enrolled, while infants with evidence of parenchymal brain injury on MRI were excluded. The regional glucose metabolic ratio and asymmetry index were calculated. The asymmetry index more than 10% (right > left asymmetry) or less than -10% (left > right asymmetry) were defined as abnormal. Regional cerebral glucose metabolism were compared between right and left cerebral hemispheres, and between the following subgroups: multiple gestations, premature rupture of membrane, bronchopulmonary dysplasia, and low-grade intraventricular hemorrhage.In the individual analysis, 21 (58.3%) of 36 VLBW infants exhibited asymmetric cerebral glucose metabolism. Fifteen infants (41.7%) exhibited right > left asymmetry, while six (16.7%) exhibited left > right asymmetry. In the regional analysis, right > left asymmetry was more extensive than left > right asymmetry. The metabolic ratio in the right frontal, temporal, and occipital cortices and right thalamus were significantly higher than those in the corresponding left regions. In the subgroup analyses, the cerebral glucose metabolism in infants with multiple gestations, premature rupture of membrane, bronchopulmonary dysplasia, or low-grade intraventricular hemorrhage were significantly lower than those in infants without these.VLBW infants without structural abnormalities have asymmetry of cerebral glucose metabolism. Decreased cerebral glucose metabolism are noted in infants with neurodevelopmental risk factors. F-18 FDG PET could show microstructural abnormalities not detected by MRI in VLBW infants.

Enterovirus 71 (EV71) is a major causative agent of hand-foot-and-mouth disease (HFMD) frequently occurring in children. HFMD induced by EV71 can cause serious health problems and has been reported worldwide, particularly in the Asia-Pacific region. In this study, we assessed the immunogenicity of a formalin-inactivated HFMD vaccine using an EV71 strain (FI-EV71 C4a) isolated from a Korean patient. The vaccine candidate was evaluated in mice to determine the vaccination doses and vaccine schedules. BALB/c mice were intramuscularly administered 5, 10, or 20 μg FI-EV71 vaccine, followed by a booster 2 weeks later. EV71-specific antibodies and neutralizing antibodies were induced and maintained until the end of the experimental period in all vaccinated groups. To determine the effectiveness of adjuvant for the EV71 vaccine, three adjuvants, i.e., aluminium hydroxide gel, monophosphoryl lipid A, and polyinosinic-polycytidylic acid, were administered separately with the FI-EV71 vaccine to mice via the intramuscular route. Mice administered the FI-EV71 vaccine formulated with all three adjuvants induced a significantly increased antibody response compared with that of the single adjuvant groups. The vaccinated group with triple adjuvants exhibited more rapid induction of EV71-specific and neutralizing antibodies than the other groups. These results suggested that the role of adjuvant in inactivated vaccine was important for eliciting effective immune responses against EV71. In conclusion, our results showed that FI-EV71 was a potential candidate vaccine for prevention of EV71 infection.

Left-right asymmetric organ development is critical to establish a proper body plan of vertebrates. In zebrafish, the Kupffer's vesicle (KV) is a fluid-filled sac which controls asymmetric organ development, and a properly inflated KV lumen by means of fluid influx is a prerequisite for the asymmetric signal transmission. However, little is known about the components that support the paracellular tightness between the KV luminal epithelial cells to sustain hydrostatic pressure during KV lumen expansion. Here, we identified that the claudin5a (cldn5a) is highly expressed at the apical surface of KV epithelial cells and tightly seals the KV lumen. Downregulation of cldn5a in zebrafish showed a failure in organ laterality that resulted from malformed KV. In addition, accelerated fluid influx into KV by combined treatment of forskolin and 3-isobutyl-1-methylxanthine failed to expand the partially-formed KV lumen in cldn5a morphants. However, malformed KV lumen and defective heart laterality in cldn5a morphants were significantly rescued by exogenous cldn5a mRNA, suggesting that the tightness between the luminal epithelial cells is important for KV lumen formation. Taken together, these findings suggest that cldn5a is required for KV lumen inflation and left-right asymmetric organ development.

[This corrects the article DOI: 10.1371/journal.pone.0175845.].

Unregulated activation of nuclear factor-κB (NF-κB) plays a critical role in the pathogenesis of Crohn's disease. In this study, we investigated the clinical characteristics and disease outcome of Crohn's disease patients with varying levels of the NF-κB activation.Crohn's disease patients who underwent surgical bowel resection were divided into two groups, based on the activation status of NF-κB. NF-κB activation was assessed by the immunoreactivity of nuclear NF-κB during immunohistochemical staining of bowel resection specimens. We compared the demographic, clinical and histologic characteristics between groups. Furthermore, the occurrence of reoperation, readmission, and medication change due to disease flare-up were investigated according to NF-κB activation status.Among 83 Crohn's disease patients, 47 (56%) showed high NF-κB activity and 36 (44%) showed low NF-κB activity. Patients with high NF-κB activity had higher frequency of ileocolonic involvement (P = 0.028) and lower frequency of perianal involvement (P = 0.042) relative to those with low NF-κB activity. Total histologic scores were significantly higher in patients with high NF-κB activity than those with low NF-κB activity (P = 0.044). There was no significant difference in the frequency of reoperation, readmission, and medication change in relation to NF-κB activation status.Crohn's disease patients with high NF-κB activation showed specific clinical manifestations of higher frequency of ileocolonic involvement and lower frequency of perianal involvement relative to those with low NF-κB activation. High NF-κB activity was associated with higher histologic scores. However, the NF-κB activity did not affect the outcome and disease course after surgery.

Whether plasma ghrelin/obestatin levels are associated with Helicobacter pylori (H. pylori) infection, subtypes of functional dyspepsia (FD), and gastric mucosal histology has not yet been established in elderly patients.The aim of this study was to determine whether plasma ghrelin and obestatin levels are related to gastric mucosal histology, H. pylori infection, and FD subtypes in elderly patients with FD.Ninety-two patients diagnosed with FD and older than 60 years (median age 69.4; range 60-88) were included. Clinical symptoms investigated included postprandial fullness, epigastric pain, epigastric soreness, nausea, and vomiting. According to the Rome III criteria, patients diagnosed with FD were divided into two subtypes: epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). Plasma ghrelin and obestatin levels were measured using enzyme immunoassay, and histological examination of gastric mucosa was performed. H. pylori infection was determined by histopathological examination of gastric mucosal biopsy and/or Campylobacter-like organism test.In our study, plasma ghrelin levels and plasma ghrelin/obestatin (G/O) ratio were significantly lower in subjects with intestinal metaplasia compared with those without intestinal metaplasia (ghrelin, p = 0.010; G/O ratio, p = 0.012). On the other hand, there were no significant differences in plasma ghrelin and obestatin levels between H. pylori-positive and H. pylori-negative groups. (ghrelin, p = 0.130; obestatin, p = 0.888). Similarly, no significant differences were detected between the EPS and PDS groups (ghrelin, p = 0.238; obestatin, p = 0.710).Patients with intestinal metaplasia, a known precursor of gastric cancer, had significantly less plasma ghrelin levels and G/O ratio than those without intestinal metaplasia.

BACKGROUND:To investigate changes in the neural retina according to the presence of retinal nerve fiber layer (RNFL) defects in type 2 diabetes, and to determine the association between inner retina thickness and the severity of diabetic complications. METHODS:We studied non-glaucomatous patients with type 2 diabetes and control subjects Circumpapillary RNFL and macula ganglion cell-inner plexiform layer (GCIPL) thicknesses were measured by spectral-domain optical coherence tomography. In patients with type 2 diabetes, a cardiovascular autonomic function test (AFT) was performed, which included the heart rate parameter of beat-beat variation-with deep breathing, in response to the Valsalva maneuver, and on postural change from lying to standing. The results of each test were scored as 0 for normal and 1 for abnormal. A total AFT score of 1 was defined as early cardiovascular autonomic neuropathy (CAN), and an AFT score≥ 2 as definite CAN. RESULTS:We compared control eyes (n = 70), diabetic eyes with RNFL defects (n = 47), and eyes without RNFL defects (n = 30). The average RNFL and GCIPL thicknesses were significantly different among groups (all, P

Patients with advanced hepatocellular carcinoma (HCC) with jaundice have an extremely poor prognosis. Although biliary drainage can resolve obstructive jaundice, signs of obstruction may not be evident. This study evaluated the role of endoscopic biliary drainage in patients with advanced HCC and obstructive jaundice.From 2010 to 2015, 74 patients underwent endoscopic biliary drainage for obstructive jaundice due to advanced HCC. Jaundice resolution was defined as complete response and total bilirubin concentration below 3 mg/dl.The technical success rate in the 74 patients was 92.1% (70/76). Of the 70 patients who underwent successful biliary drainage, 48 (68.6%) and 22 (31.4%) were Child-Pugh classes B and C, respectively, and 10 (14.3%) and 60 (85.7%) were BCLC stages B and C, respectively. Intrahepatic bile duct (IHD) dilatation was observed in 35 patients (50%). After drainage, the complete response rate was 35.7% (25/70). The mean time to resolution was 17.4 ±8.5 days. However, jaundice was re-aggravated in 74.3% (15/25) after a mean 103.5 ±96.4 days. Multivariate analysis showed that the absence of ascites, presence of IHD dilatation, normal range of prothrombin time, and lower MELD score were significantly associated with complete response. The overall survival rate was 15.7% (11/70) and the median survival time is 28 days (95% confidence interval 2.6-563 days). Complete response and HCC treatment after drainage were significantly associated with survival.Effective endoscopic biliary drainage is an important palliative treatment in patients with advanced HCC and obstructive jaundice, especially those with IHD dilatation and preserved liver function, as determined by ascites, prothrombin time, and MELD score.

OBJECTIVE:Non-alcoholic fatty liver disease (NAFLD) has become a common and important chronic liver disease worldwide. Previous studies have indicated that NAFLD has an adverse effect on the quality of life, but information is lacking about the impact of NAFLD on female sexual dysfunction. The aim of this study was to determine the association between NAFLD and female sexual dysfunction in premenopausal women. METHODS:This retrospective study consisted of premenopausal women who were sexually active and visited the outpatient clinic for a routine health check-up between January 2010 and December 2011. Based on the examination of the liver ultrasound scan, the study population was divided into 2 groups: cases with NAFLD and normal controls (cases without NAFLD). The female sexual function was compared between the two groups of cases. For the assessment of sexual function, a female sexual function index (FSFI) questionnaire was used. RESULTS:Four hundred seventy women were included, and the prevalence of NAFLD and female sexual dysfunction were 67/470 (14.3%) and 238/470 (50.6%), respectively. Cases with NAFLD had a lower total FSFI score and higher rate of female sexual dysfunction than the normal control [median score of total FSFI (interquartile range): 24.7 (21.9-27.8) in NAFLD vs. 26.7 (23.7-29.8) in normal control, p

Accumulation of metal contaminants in soil as a result of various industrial and anthropogenic activities has reduced soil fertility significantly. Phytoextraction of metal contaminants can improve soil fertility and provide inexpensive feedstock for biorefineries. We investigated the hyperaccumulation capacity of sunflower (Helianthus annuus) biomass by cultivating these plants in various concentrations of metal contaminants. Sunflowers were grown in soils contaminated with various levels of heavy metals (10-2,000 mg/kg dry soil). The degree of metal uptake by different parts of the biomass and the residual concentration in the soil were estimated through inductively coupled plasma mass spectrometry. An almost 2.5-fold hyperaccumulation of Zn2+ was observed in the leaf and flower biomass compared with the concentration in the soil. For the subsequent saccharification of biomass with hyperaccumulated contaminants, a fungal lignocellulosic consortium was used. The fungal consortium cocktail retained more than 95% filter paper activity with 100 mM Ni2+ ions even after 36 h. The highest saccharification yield (SY, 87.4%) was observed with Ni2+ as the contaminant (10 mg/kg dry wt), whereas Pb2+ (251.9 mg/kg dry wt) was the strongest inhibitor of biomass hydrolysis, resulting in only a 30% SY. Importantly, the enzyme cocktail produced by the fungal consortium resulted in almost the same SY (%) as that obtained from a combination of commercial cellulase and β-glucosidase. Significant sugar conversion (61.7%) from H. annuus biomass hydrolysate occurred, resulting in the production of 11.4 g/L of bioethanol. This is the first study to assess the suitability of phytoremediated sunflower biomass for bioethanol production.

The diagnostic performance of supersonic shear imaging (SSI) in comparison with those of transient elastography (TE) and acoustic radiation force impulse imaging (ARFI) for staging fibrosis in nonalcoholic fatty liver disease (NAFLD) patients has not been fully assessed, especially in Asian populations with relatively lean NAFLD compared to white populations. Thus, we focused on comparing the diagnostic performances of TE, ARFI, and SSI for staging fibrosis in a head-to-head manner, and identifying the clinical, anthropometric, biochemical, and histological features which might affect liver stiffness measurement (LSM) in our prospective biopsy-proven NAFLD cohort. In this study, ninety-four patients with biopsy-proven NAFLD were included prospectively. Liver stiffness was measured using TE, SSI, and ARFI within 1 month of liver biopsy. The diagnostic performance for staging fibrosis was assessed using receiver operating characteristic (ROC) analysis. Anthropometric data were evaluated as covariates influencing LSM by regression analyses. Liver stiffness correlated with fibrosis stage (p < 0.05); the area under the ROC curve of TE (kPa), SSI (kPa), and ARFI (m/s) were as follows: 0.757, 0.759, and 0.657 for significant fibrosis and 0.870, 0.809, and 0.873 for advanced fibrosis. Anthropometric traits were significant confounders affecting SSI, while serum liver injury markers significantly confounded TE and ARFI. In conclusion, the LSM methods had similar diagnostic performance for staging fibrosis in patients with NAFLD. Pre-LSM anthropometric evaluation may help predict the reliability of SSI.

Cancer cells explore a broad mutational landscape, bringing the possibility that tumor-specific somatic mutations could fall in the same codons as germline SNVs and leverage their presence to produce substitutions with a larger impact on protein function. While multiple, temporally consecutive mutations to the same codon have in the past been detected in the germline, this phenomenon has not yet been explored in the context of germline-somatic variant co-occurrences during cancer development. We examined germline context at somatic mutation sites for 1395 patients across four cancer cohorts (breast, skin, colon, and head and neck) and found 392 codon-level co-occurrences between germline and somatic variants, including over a dozen in well-known cancer genes. We found that for the majority of these co-occurrence events, traditional somatic calling led to an inaccurate representation of the protein site and a significantly lower predicted impact on protein fitness. We conclude that these events often lead to imprecise annotation of somatic variants but do not appear to be a frequent source of driver events during cancer development.

Emerging evidence has suggested that hydrogen sulfide (H2S) may alleviate the cellular damage associated with cerebral ischemia/reperfusion (I/R) injury. In this study, we assessed using 1H-magnetic resonance imaging/magnetic resonance spectroscopy (1H-MRI/MRS) and histologic analysis whether H2S administration prior to reperfusion has neuroprotective effects. We also evaluated for differences in the effects of H2S treatment at 2 time points. 1H-MRI/MRS data were obtained at baseline, and at 3, 9, and 24 h after ischemia from 4 groups: sham, control (I/R injury), sodium hydrosulfide (NaHS)-30 and NaHS-1 (NaHS delivery at 30 and 1 min before reperfusion, respectively). The total infarct volume and the midline shift at 24 h post-ischemia were lowest in the NaHS-1, followed by the NaHS-30 and control groups. Peri-infarct volume was significantly lower in the NaHS-1 compared to NaHS-30 and control animals. The relative apparent diffusion coefficient (ADC) in the peri-infarct region showed that the NaHS-1 group had significantly lower values compared to the NaHS-30 and control animals and that NaHS-1 rats showed significantly higher relative T2 values in the peri-infarct region compared to the controls. The relative ADC value, relative T2 value, levels of N-acetyl-L-aspartate (NAA), and the NAA, glutamate, and taurine combination score (NGT) in the ischemic core region at 24 h post-ischemia did not differ significantly between the 2 NaHS groups and the control except that the NAA and NGT values were higher in the peri-infarct region of the NaHS-1 animals at 9 h post-ischemia. In the ischemic core and peri-infarct regions, the apoptosis rate was lowest in the NaHS-1 group, followed by the NaHS-30 and control groups. Our results suggest that H2S treatment has neuroprotective effects on the peri-infarct region during the evolution of I/R injury. Furthermore, our findings indicate that the administration of H2S immediately prior to reperfusion produces the highest neuroprotective effects.

The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for oral mucositis (OM) induced by intensive chemotherapy with hematopoietic stem cell transplantation. In this phase 2 study, patients were randomized to either rhEGF (50 microg/mL) or placebo in a 1:1 ratio. The primary endpoint was incidence of National Cancer Institute (NCI) grade ≥2 OM. A total of 138 patients were enrolled in this study. In the intention-to-treat analysis, rhEGF did not reduce the incidence of NCI grade ≥2 OM (p = 0.717) nor reduce its duration (p = 0.725). Secondary endpoints including the day of onset and duration of NCI grade ≥2 OM, the incidence of NCI grade ≥3 OM and its duration, and patient-reported quality of life were also similar between the two groups. In the per-protocol analysis, however, the duration of opioid analgesic use was shorter in the rhEGF group (p = 0.036), and recipients in the rhEGF group required a lower cumulative dose of opioid analgesics than those in the placebo group (p = 0.046), among patients with NCI grade ≥2 OM. Adverse events were mild and transient. This study found no evidence to suggest that rhEGF oral spray reduces the incidence of OM. However, further studies are needed to investigate the effect of rhEGF on OM-induced pain reduction after intensive chemotherapy.

Type I interferons (IFNs) play an important role in antiviral immunity as well as immunopathogenesis of diverse chronic viral infections. However, the precise mechanisms regulating the multifaceted effects of type I IFNs on the immune system and pathological inflammation still remain unclear. In order to assess the immunological dynamics associated with rapid viral clearance in chronic hepatitis C patients during the acute phase of type I IFN therapy, we analyzed multiple parameters of virological and immunological responses in a cohort of 59 Korean hepatitis C patients who received pegylated IFN-α and ribavirin (IFN/RBV). Most of the Korean patients had favorable alleles in the IFN-λ loci for responsiveness to IFN/RBV (i.e., C/C in rs12979860, T/T in rs8099917, and TT/TT in rs368234815). Rapid virological response (RVR) was determined mainly by the hepatitis C virus genotype. Among the cytokines analyzed, higher plasma levels of IL-17A and FGF were observed in non-RVR patients infected with viral genotype 1 and IP-10 was consistently elevated in RVR group infected with genotype 2 during the early phase of antiviral therapy. In addition, these three cytokines were correlated each other, suggesting a functional linkage of the cytokines in antiviral responses during IFN/RBV therapy. A low baseline frequencies of regulatory T cells and γδ T cells, but high level of group 2 innate lymphoid cells, in peripheral bloods were also significantly associated with the RVR group, implicating a potential role of the cellular immunity during the early phase of IFN/RBV therapy. Therefore, the immunological programs established by chronic hepatitis C and rapid disruption of the delicate balance by exogenous type I IFN might be associated with the subsequent virological outcomes in chronic hepatitis C patients.

BACKGROUND & AIMS:The impact of marijuana on nonalcoholic fatty liver disease (NAFLD) is largely unknown. We studied the association between marijuana and NAFLD utilizing cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) from 2005-2014 and NHANES III (1988-1994). METHODS:Suspected NAFLD was diagnosed if serum alanine aminotransferase (ALT) was > 30 IU/L for men and > 19 IU/L for women in the absence of other liver diseases (NHANES 2005-2014). In NHANES III cohort, NAFLD was defined based on ultrasonography. RESULTS:Of the 14,080 (NHANES 2005-2014) and 8,286 (NHANES III) participants, prevalence of suspected NAFLD and ultrasonographically-diagnosed NAFLD were inversely associated with marijuana use (p < 0.001). Compared to marijuana-naïve participants, marijuana users were less likely to have suspected NAFLD (odds ratio [OR]: 0.90, 95% confidence interval [CI]: 0.82-0.99 for past user; OR: 0.68, 95% CI: 0.58-0.80 for current user) and ultrasonographically-diagnosed NAFLD (OR: 0.75, 95% CI: 0.57-0.98 for current user) in the age, gender, ethnicity-adjusted model. On multivariate analysis, the ORs for suspected NAFLD comparing current light or heavy users to non-users were 0.76 (95% CI 0.58-0.98) and 0.70 (95% CI 0.56-0.89), respectively (P for trend = 0.001) with similar trends in ultrasonographically-diagnosed NAFLD (OR: 0.77, 95% CI: 0.59-1.00 for current user; OR: 0.71, 95% CI: 0.51-0.97 for current light user). In insulin resistance-adjusted model, marijuana use remained an independent predictor of lower risk of suspected NAFLD. CONCLUSIONS:In this nationally representative sample, active marijuana use provided a protective effect against NAFLD independent of known metabolic risk factors. The pathophysiology is unclear and warrants further investigation.

BACKGROUND:It is unclear whether sleep duration and quality are associated with chronic kidney disease (CKD) and glomerular hyperfiltration. The aim of this study was to examine the association of sleep duration and quality with CKD and glomerular hyperfiltration in young and middle-aged adults. METHODS:We conducted a cross-sectional study of men and women who underwent a health checkup examination, including assessment of sleep duration and quality (n = 241,607). Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2, and glomerular hyperfiltration was defined as eGFR above the age-/sex-specific 95th percentile. RESULTS:In a multinomial logistic regression analysis adjusting for relevant confounders, the adjusted prevalence ratios for CKD (95% confidence interval) comparing sleep durations of ≤ 5, 6, 8, and 9 hours with 7 hours were 1.22 (0.95-1.55), 0.93 (0.75-1.14), 0.97 (0.75-1.26), and 1.56 (1.06-2.30) in men and 0.98 (0.68-1.43), 1.03 (0.72-1.46), 1.39 (0.97-2.00), and 1.31 (0.78-2.22) in women, respectively. The corresponding prevalence ratios (95% confidence interval) for glomerular hyperfiltration were 1.00 (0.93-1.08), 0.97 (0.91-1.03), 1.03 (0.94-1.13), and 1.39 (1.13-1.72) in men and 1.04 (0.95-1.14), 0.96 (0.90-1.04), 1.11 (1.02-1.20), and 1.28 (1.14-1.45) in women, respectively. Poor subjective sleep quality was associated with glomerular hyperfiltration in men and women. CONCLUSION:In this large study of young and middle-aged adults, we found that long sleep duration was associated with CKD and glomerular hyperfiltration. Additionally, poor subjective sleep quality was associated with increased prevalence of glomerular hyperfiltration, suggesting the importance of adequate quantity and quality of sleep for kidney function.

The purpose of this study was to evaluate gray matter (GM) and white matter (WM) volume alterations in whole-brain structures in patients with schizophrenia and healthy controls using voxel-based morphometry (VBM), and further to assess the correlation between GM and WM volume variations and symptom severity in schizophrenia. A total of 22 patients with schizophrenia and 22 age-matched healthy controls participated. Magnetic resonance image data were processed using SPM8 software with diffeomorphic anatomical registration via an exponentiated Lie algebra (DARTEL) algorithm. Patients with schizophrenia exhibited significantly decreased GM volumes of the insula, superior temporal gyrus (STG), gyrus rectus, and anterior cingulate cortex (ACC) compared with healthy controls. The GM volumes of the STG and gyrus rectus were negatively correlated with the positive scales on the Positive and Negative Syndrome Scale (PANSS) and those of the STG and ACC were negatively correlated with the negative scales. The durations of illness in schizophrenia were negatively correlated with the GM volumes of the insula, STG, and ACC. Patients with schizophrenia exhibited significantly decreased WM volumes of the superior frontal gyrus, inferior temporal gyrus, and STG. The WM volumes of the STG were negatively correlated with the duration of illness. Our findings suggest that GM and WM volume abnormalities in the STG are associated with the psychopathology of schizophrenia.

BACKGROUND:We performed this retrospective study to identify predictors of right paraesophageal lymph node metastasis, and reviewed previous studies related to this topic. METHODS:Between June 2005 and March 2015, 1107 patients were diagnosed with papillary thyroid carcinoma and underwent surgery at Pusan National University Hospital. RESULTS:Right paraesophageal lymph node metastasis was observed in 171 (15.4%) patients. Multivariate analyses showed that the risk of right paraesophageal metastasis was significantly associated with tumor size, location, a higher number of metastatic central lymph nodes, and lateral lymph node metastasis. In a meta-analysis of the eligible studies, tumor size, number of metastatic central lymph nodes, and lateral lymph node metastasis showed significant relationships with the risk of right paraesophageal metastasis. CONCLUSIONS:In patients with risk factors such as those identified in our study, the possibility of right paraesophageal metastasis should be kept in mind, and careful inspection and dissection are required.

In upper gastrointestinal bleeding (UGIB) patients, early risk stratification allows appropriate therapy that may be helpful for reducing morbidity and mortality.to evaluate the efficacy of red-cell distribution width (RDW) for prediction of high-risk in UGIB patients.We conducted a clinical retrospective observational study based on data for UGIB patients from 2012 to 2013. The primary outcome was the high-risk UGIB, defined as those who required urgent intervention and/or 30-days mortality. RDW was categorized into four quartiles: Q1 (≤12.8%), Q2 (12.9-14.4%), Q3 (14.5-16.5%), and Q4 (≥16.6%), and multivariable analysis was performed after adjustment of multiple other risk factor. We also evaluated the efficacy of addition of RDW scores to the Pre-endoscopic Rockall Score (PRS) and the Glasgow Blatchford Score (GBS) scoring system.Of 360 UGIB patients, 229 (63.6%) were high risk. In multivariable analysis, Q3 and Q4 were strongly associated with high risk; odds ratio (95% Confidence Interval) was 3.144 (1.250-7.905) and 4.182 (1.483-11.790) respectively (all p < 0.05). For lower GBS score group (≤ 6), the incidence of high risk was higher in Q4 (30%) and Q3 (20%) than in Q2 (12.5%) and Q1 (11.4%). For lower PRS group (≤ 2), the incidence of high-risk was higher in Q4 (73.7%) and Q3 (57.1%) than in Q1 (35.4%). Receiver operating characteristic analysis showed higher discrimination power in PRS + RDW (Area Under Curve [AUC] = 0.749) than PRS (AUC = 0.715) alone (p = 0.036). Otherwise GBS + RDW (AUC = 0.873) did not show a significant higher discrimination power than the GBS (AUC = 0.864) alone (p = 0.098).For UGIB patients, a high RDW (≥ 14.5%) was strongly associated with high risk UGIB. In practice, the combination of RDW with the PRS scoring indexes may increase the accuracy of risk stratification.

The photothermal effect of a marine-oriented xanthophyll carotenoid, astaxanthin (AXT), was characterized based on its potential absorption of visible laser light and conversion of optical light energy into heat for thermal treatment. As an antioxidant and anticancer agent, AXT extracted from marine material can be utilized for photothermal therapy due to its strong light absorption. The current study investigated the feasibility of the marine-based material AXT to increase the therapeutic efficacy of chemo-photothermal therapy (PTT) by assessing photothermal sessions in both cells and tumor tissues. A quasi-cw Q-switched 80 W 532 nm laser system was utilized to induce thermal necrosis in in vitro and in vivo models. An in vitro cytotoxicity study of AXT was implemented using squamous cell carcinoma (VX2) and macrophage (246.7) cell lines. In vivo PTT experiments were performed on 17 rabbits bearing VX2 tumors on their eyes that were treated with or without intratumoral injection of AXT at a dose of 100 μl (300 μg/ml) followed by laser irradiation at a low irradiance of 0.11 W/cm2. Fluorescence microscopy images revealed cellular death via apoptosis and necrosis owing to the dual chemo-photothermal effects induced by AXT. In vivo experimental results demonstrated that the AXT-assisted irradiation entailed a temperature increase by 30.4°C after tumor treatment for 4 min. The relative variations in tumor volume confirmed that the tumors treated with both AXT and laser irradiation completely disappeared 14 days after treatment, but the tumors treated under other conditions gradually grew. Due to selective light absorption, AXT-assisted laser treatment could be an effective thermal therapy for various drug-resistant cancers.

The aim of this study was to investigate histomorphological and immunophenotypic features in pill-induced esophagitis. We comparatively evaluated the histomorphological, immunophenotypic features of pill-induced esophagitis vs. reflux esophagitis, as well as clinical information and endoscopic findings. Fifty-two tissue pieces from 22 cases of pill-induced esophagitis, 46 pieces from 20 reflux esophagitis, and 16 pieces from 14 control samples were subjected to immunohistochemistry for inflammatory infiltrates (CD3 for T lymphocyte, CD20 for B lymphocyte, CD56 for NK cell, CD68 for macrophage, CD117 for mast cell) and eosinophil chemotaxis-associated proteins (Erk, leptin, leptin receptor, pSTAT3, phospho-mTOR). As a result, Histomorphology showed that a diffuse pattern of dilated intercellular spaces was more frequently observed in pill-induced esophagitis, while reactive atypia and subepithelial papillary elongation were more often found in reflux esophagitis (P < 0.05, respectively). Interestingly, intraepithelial eosinophilic microabscess, intraepithelial pustule and diffuse pattern of dilated intercellular spaces were observed in 14% (3 cases), 9% (2 cases) and 32% (7 cases) of pill-induced esophagitis, respectively, but in no cases of reflux esophagitis. Regarding intraepithelial inflammatory infiltrates in pill-induced esophagitis, T lymphocytes were the most common cells, followed by eosinophil; 11 and 7 in one x400 power field, respectively. Intraepithelial pSTAT3-positive pattern was more frequently observed in pill-induced esophagitis than in reflux esophagitis, at 45% (10 cases) versus 10% (2 cases), respectively (P < 0.05). Considering the distal esophageal lesion only, intraepithelial pustule, diffuse dilated intercellular spaces and stromal macrophages were more frequently found in distal pill-induced esophagitis, whereas reactive atypia and intraepithelial mast cells in reflux esophagitis (P < 0.05, respectively). In conclusion, diffuse dilated intercellular spaces, intraepithelial eosinophil microabscess, pustule, T lymphocytes, eosinophils, and pSTAT3 positivity can be added to histopathological features of pill-induced esophagitis, other than non-specific ulcer. Besides, distal pill-induced esophagitis may be histopathologically differentiated from reflux esophagitis.

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

Pancreatic stellate cells (PSCs) play a major role to fibrotic islet destruction observed in diabetic patients and animal model of diabetes. Exendin-4 (Ex-4) is a potent insulinotropic agent and has been approved for the treatment of type 2 diabetes. However, there have been no reports demonstrating the effects of Ex-4 on pancreatic islet fibrosis. In this study, Ex-4 treatment clearly attenuated fibrotic islet destruction and improved glucose tolerance and islet survival. GLP-1 receptor expression was upregulated during activation and proliferation of PSCs by hyperglycemia. The activation of PKA pathway by Ex-4 plays a role in ROS production and angiotensin II (Ang II) production. Exposure to high glucose stimulated ERK activation and Ang II-TGF- β1 production in PSCs. Interestingly, Ex-4 significantly reduced Ang II and TGF-β1 production by inhibition of ROS production but not ERK phosphorylation. Ex-4 may be useful not only as an anti-diabetic agent but also as an anti-fibrotic agent in type 2 diabetes due to its ability to inhibit PSC activation and proliferation and improve islet fibrosis in OLETF rats.

To analyze the clinical features and prognostic factors associated with the survival of patients with a very rare occurrence of brain metastasis (BM) from differentiated thyroid cancer (DTC).A total of 37 patients with DTC who were diagnosed with BM between 1995 and 2014 were included. We reviewed the clinical characteristics, treatment modalities, and image findings of BM. Factors associated with survival were evaluated, and the patients were divided into three prognostic groups (Groups A, B, and C) for comparative analysis.The median age at BM was 63 years, and the median time from initial thyroid cancer diagnosis to BM was 3.8 years. The median survival and the 1-year actuarial survival rate after BM were 8.8 months and 47%, respectively. According to univariate and multivariate analyses, four good prognostic factors (GPFs) were identified including age ≤ 60 years, PS ≤ ECOG 2, ≤ 3 BM sites, and without extracranial metastasis prior to BM. Three prognostic groups were designed based on age and number of remaining GPFs: patients ≤ 60 years of age with at least 2 GPFs (Group A) had the most favorable prognosis with a median survival of 32.8 months; patients ≤ 60 years of age with fewer than 2 GPFs and those > 60 years of age with at least 2 GPFs (Group B) had an intermediate prognosis with a median survival of 9.4 months; and patients > 60 years of age with fewer than 2 GPFs (Group C) had the least favorable prognosis with a median survival of 1.5 months.The survival of patients with BM form DTC differed among the prognostic groups based on the total number of good prognostic factors.

To identify prognostic factors and define the optimal management of patients with supratentorial primitive neuroectodermal tumors (sPNETs), we investigated treatment outcomes and explored the prognostic value of specific molecular markers.A total of 47 consecutive patients with pathologically confirmed sPNETs between May 1985 and June 2012 were included. Immunohistochemical analysis of LIN28, OLIG2, and Rad51 expression was performed and correlated with clinical outcome.With a median follow-up of 70 months, 5-year overall survival (OS) and progression-free survival (PFS) was 55.5% and 40%, respectively, for all patients. Age, surgical extent, and radiotherapy were significant prognostic factors for OS and PFS. Patients who received initially planned multimodal treatment without interruption (i.e., radiotherapy and surgery (≥subtotal resection), with or without chemotherapy) showed significantly higher 5-year OS (71.2%) and PFS (63.1%). In 29 patients with available tumor specimens, tumors with high expression of either LIN28 or OLIG2 or elevated level of Rad51 were significantly associated with poorer prognosis.We found that multimodal treatment improved outcomes for sPNET patients, especially when radiotherapy and ≥subtotal resection were part of the treatment regimen. Furthermore, we confirmed the prognostic significance of LIN28 and OLIG2 and revealed the potential role of Rad51 in sPNETs.

[This corrects the article DOI: 10.1371/journal.pone.0100870.].

The biosynthesis of carboxylic acids including fatty acids from biomass is central in envisaged biorefinery concepts. The productivities are often, however, low due to product toxicity that hamper whole-cell biocatalyst performance. Here, we have investigated factors that influence the tolerance of Escherichia coli to medium chain carboxylic acid (i.e., n-heptanoic acid)-induced stress. The metabolic and genomic responses of E. coli BL21(DE3) and MG1655 grown in the presence of n-heptanoic acid indicated that the GadA/B-based glutamic acid-dependent acid resistance (GDAR) system might be critical for cellular tolerance. The GDAR system, which is responsible for scavenging intracellular protons by catalyzing decarboxylation of glutamic acid, was inactive in E. coli BL21(DE3). Activation of the GDAR system in this strain by overexpressing the rcsB and dsrA genes, of which the gene products are involved in the activation of GadE and RpoS, respectively, resulted in acid tolerance not only to HCl but also to n-heptanoic acid. Furthermore, activation of the GDAR system allowed the recombinant E. coli BL21(DE3) expressing the alcohol dehydrogenase of Micrococcus luteus and the Baeyer-Villiger monooxygenase of Pseudomonas putida to reach 60% greater product concentration in the biotransformation of ricinoleic acid (i.e., 12-hydroxyoctadec-9-enoic acid (1)) into n-heptanoic acid (5) and 11-hydroxyundec-9-enoic acid (4). This study may contribute to engineering E. coli-based biocatalysts for the production of carboxylic acids from renewable biomass.