Utility of the Global Leadership Initiative on Malnutrition criteria for the nutritional assessment of patients with end-stage renal disease receiving chronic hemodialysis.

BACKGROUND: Malnutrition is associated with adverse outcomes in patients on chronic haemodialysis. Thus, identifying accurate methods for diagnosing malnutrition is essential. The present retrospective study investigated the utility of the new Global Leadership Initiative on Malnutrition (GLIM) criteria in patients undergoing chronic haemodialysis. METHODS: Phase angle and fat-free mass index (FFMI) were derived using bioelectrical impedance analysis. Malnutrition was determined when the subjects had at least one phenotypic criterion (weight loss, low body mass index [BMI] or FFMI). RESULTS: This study included 103 patients undergoing chronic haemodialysis and 46 (44.7%) patients were diagnosed as malnourished. Malnutrition determined using the GLIM criteria was associated with increased risks of all-cause death (hazard ratio = 3.0, p = 0.044) and infection requiring hospitalisation (hazard ratio = 2.4, p = 0.015), independent of age, sex and comorbidities. However, malnutrition was not related to major adverse cardiovascular events (p = 0.908). We further evaluated the longitudinal changes in phenotypic parameters. Subjects with median levels of high-sensitivity C-reactive protein exceeding 5 mg L-1 exhibited decreased body weight and BMI (p = 0.015 and 0.016, respectively). In addition, body weight, BMI and FFMI were reduced in subjects with a median protein catabolic rate of < 1.0 mg kg-1 day-1 , even after adjustment for age, sex and comorbidities (p = 0.026, 0.053 and 0.039, respectively). CONCLUSIONS: Malnutrition assessed using the GLIM criteria could be a useful predictor of mortality and infection in patients on chronic haemodialysis. To improve nutritional status, approaches for decreasing inflammation and increasing protein intake are needed.

Impact of Downtime on Clinical Outcomes in Critically Ill Patients with Acute Kidney Injury Receiving Continuous Renal Replacement Therapy.

Continuous renal replacement therapy (CRRT) downtime is considered a quality indicator; however, it remains uncertain whether downtime affects outcomes. This study retrospectively investigated the impact of downtime on clinical outcomes. Patients were classified as downtime <20% or ≥20% of potential operative time over 4 days from CRRT initiation. Patients with ≥20% downtime were matched to those with <20% downtime using 1:2 propensity score matching. There were 88 patients with <20% downtime and 44 patients with ≥20% downtime. The cumulative effluent volume was lower in patients with ≥20% downtime (p < 0.001). The difference in levels of urea and creatinine widened over time (p = 0.004 and <0.001). At days 2 and 3, daily fluid balance differed (p = 0.046 and 0.031), and the levels of total carbon dioxide were lower in those with ≥20% downtime (p = 0.038 and 0.020). Based on our results, ≥20% downtime was not associated with increased 28 day mortality; however, a subgroup analysis showed the interaction between downtime and daily fluid balance (p = 0.004). In conclusion, increased downtime could impair fluid and uremic control and acidosis management. Moreover, the adverse effect of downtime on fluid control may increase mortality rate. Further studies are needed to verify the value of downtime in critically ill patients requiring CRRT.

Association between toothbrushing and non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. Periodontitis, as chronic inflammatory destructive disease, is associated metabolic syndromes bidirectionally. Toothbrushing is an essential and important way to manage periodontitis through mechanical removal of biofilm at periodontal tissue. We aimed to assess the association between toothbrushing frequency and the prevalent NAFLD in nationally representative Korean adults. Among adults aged 19 years and older who participated in the Korea National Health and Nutrition Examination Survey in 2010, a total of 6,352 subjects were analyzed. NAFLD was defined as fatty liver index ≥60. Multiple logistic regression analysis was used to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). An inverse association between toothbrushing frequency and NAFLD was found. The adjusted ORs (95% CIs) of NALFD was 0.56 (0.35-0.91) in the group who performed toothbrushing ≥ 3 per day compared to the group that performed toothbrushing ≤ 1 per day. For those with toothbrushing frequency ≤1 per day, the adjusted OR (95% CIs) of NAFLD was 2.26 (1.22-4.19) in smokers and 4.52 (1.97-10.38) in subjects with diabetes mellitus (DM), compared to those without the disease and with toothbrushing frequency ≥2 per day, respectively. Our results indicate that higher frequency of toothbrushing is inversely associated with NAFLD. As a modifiable oral habit, regular toothbrushing may be recommended to lower risk of NAFLD, especially in high risk groups such as smokers and diabetic patients.

GSK-3ß inhibition by curcumin mitigates amyloidogenesis via TFEB activation and anti-oxidative activity in human neuroblastoma cells.

The translocation of transcription factor EB (TFEB) to the nucleus plays a pivotal role in the regulation of basic cellular processes, such as lysosome biogenesis and autophagy. Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, which is important in maintaining cellular homeostasis during environmental stress. Furthermore, oxidative stress is a critical cause for the progression of neurodegenerative diseases. Curcumin has anti-oxidative and anti-inflammatory activities, and is expected to have potential therapeutic effects in various diseases. In this study, we demonstrated that curcumin regulated TFEB export signalling via inhibition of glycogen synthase kinase-3ß (GSK-3ß); GSK-3ß was inactivated by curcumin, leading to reduced phosphorylation of TFEB. We further showed that H2O2-induced oxidative stress was reduced by curcumin via the Nrf2/HO-1 pathway in human neuroblastoma cells. In addition, we showed that curcumin induced the degradation of amyloidogenic proteins, including amyloid-ß precursor protein and α-synuclein, through the TFEB-autophagy/lysosomal pathway. In conclusion, curcumin regulates autophagy by controlling TFEB through the inhibition of GSK-3ß, and increases antioxidant gene expression in human neuroblastoma cells. These results contribute to the development of novel cellular therapies for neurodegenerative diseases.

CO ameliorates cellular senescence and aging by modulating the miR-34a/Sirt1 pathway.

Oxidative stress is recognised as a key factor that can lead to cellular senescence and aging. Carbon monoxide (CO) is produced by haemoxygenase-1 (HO-1), which exerts cytoprotective effects in aging-related diseases, whereas the effect of CO on cellular senescence and aging has not been elucidated. In the current study, we clearly demonstrated that CO delays the process of cellular senescence and aging through regulation of miR-34a and Sirt1 expression. CO reduced H2O2-induced premature senescence in human diploid fibroblast WI-38 cells measured with SA-ß-Gal-staining. Furthermore, CO significantly decreased the expression of senescence-associated secretory phenotype (SASP), including TNF-α IL-6, and PAI-1 and increased the transcriptional levels of antioxidant genes, such as HO-1 and NQO1. Moreover, CO apparently enhanced the expression of Sirt1 through down-regulation of miR-34a. Next, to determine whether Sirt1 mediates the inhibitory effect of CO on cellular senescence, we pre-treated WI-38 cells with the Sirt1 inhibitor Ex527 and a miR-34a mimic followed by the administration of H2O2 and evaluated the expression of SASP and antioxidant genes as well as ROS production. According to our results, Sirt1 is crucial for the antiaging and antioxidant effects of CO. Finally, CO prolonged the lifespan of Caenorhabditis elegans and delayed high-fat diet-induced liver aging. Taken together, these findings demonstrate that CO reduces cellular senescence and liver aging through the regulation of miR-34a and Sirt1.

Association between Fatty Liver Index and Periodontitis: the Korea National Health and Nutrition Examination Survey.

It has been suggested that periodontitis is associated with metabolic abnormalities including non-alcoholic fatty liver disease (NAFLD). The fatty liver index (FLI) is a non-invasive surrogate marker and predictor of NAFLD. We aimed to determine whether FLI itself would be associated with periodontitis through a secondary analysis of previously reported nationally representative probability sample data of the Korean population. FLI was calculated from a previously developed algorithm which combines measures of body mass index (BMI), waist circumference, triglyceride, and gamma-glutamyl transferase (GGT). Periodontitis was diagnosed based on the Community Periodontal Index (CPI) developed by the World Health Organization. Of 4,272 participants, 26.1% were diagnosed with periodontitis. Higher FLI was associated with a higher prevalence of periodontitis (Odds ratio (OR) highest vs. lowest quartile of FLI,1.63; 95% confidence interval (CI), 1.23-2.16; P = 0.001 for trend) adjusting for confounding factors. In the highest FLI quartile, prevalence of periodontitis was higher in individuals with diabetes (OR highest vs. lowest quartile of FLI, 2.89; 95% CI, 1.01-8.27 for diabetic subgroup; OR highest vs. lowest quartile of FLI, 1.45; 95% CI, 1.07-1.96 for non-diabetic subgroup). In summary, FLI was associated with prevalent periodontitis.

CO ameliorates endothelial senescence induced by 5-fluorouracil through SIRT1 activation.

Endothelial senescence is the main risk factor that contributes to vascular dysfunction and the progression of vascular disease. Carbon monoxide (CO) plays an important role in preventing vascular dysfunction and in maintaining vascular physiology or homeostasis. The application of exogenous CO has been shown to confer protection in several models of cardiovascular injury or disease, including hypertension, atherosclerosis, balloon-catheter injury, and graft rejection. However, the mechanism by which CO prevents endothelial senescence has been largely unexplored. The aim of this study was to evaluate the effects of CO on endothelial senescence and to investigate the possible mechanisms underlying this process. We measured the levels of senescence-associated-ß-galactosidase activity, senescence-associated secretory phenotype, reactive oxygen species (ROS) production, and stress granule in human umbilical vein endothelial cells and the WI-38 human diploid fibroblast cell line. We found that 5-fluorouracil (5FU)-induced ROS generation was inhibited by CO-releasing molecules (CORM)-A1 treatment, and endothelial senescence induced by 5FU was attenuated by CORM-A1 treatment. The SIRT1 inhibitor EX527 reversed the inhibitory effect of CO on the 5FU-induced endothelial senescence. Furthermore, SIRT1 deficiency abolished the stress granule formation by CO. Our results suggest that CO alleviates the endothelial senescence induced by 5FU through SIRT1 activation and may hence have therapeutic potential for the treatment of vascular diseases.

Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression.

Acetaminophen (APAP) is widely used as an antifebrile and analgesic drug at recommended doses, whereas an overdose of APAP can cause severe liver damage. The molecular mechanisms underlying APAP-induced liver damage remain incompletely understood. Carbon monoxide (CO), an end-product of heme oxygenase (HO)-1 activity, can confer anti-inflammatory and antiapoptotic properties in cellular models of toxicity via regulation of mitochondrial function. The objective of this study was to evaluate the effects of CO on APAP-induced hepatotoxicity and CO's relationship to regulation of endoplasmic reticulum (ER) stress and mitochondrial signaling using CO-releasing molecules or low concentrations of CO applied as pretreatment or posttreatment. Using genetic deletion or knockdown approaches in alpha mouse liver cells or primary hepatocytes, respectively, we investigated the role of HO-1 and the mitophagy regulator protein Parkin on APAP-induced expression of the ER stress-associated apoptosis regulator cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)/enhancer-binding protein homologous protein (CHOP). We found that CO induced Parkin expression in hepatocytes via the protein kinase RNA-like ER kinase/eukaryotic translation initiation factor 2-α/activating transcription factor-4 signaling pathway. Additionally, CO gas inhalation significantly alleviated APAP-induced liver damage in vivo and correspondingly reduced serum alanine aminotransferase and aspartate aminotransferase levels as well as proinflammatory cytokines and reduced the expression of CHOP in liver tissues while dramatically increasing hepatic HO-1 and Parkin expression. We found that the protective effects of CO on APAP-induced liver damage were mediated by down-regulation of CHOP at a transcriptional and post-translational level via induction of HO-1 and Parkin, respectively, and associated with decreases in reactive oxygen species production and JNK phosphorylation. We conclude that CO may represent a promising therapeutic agent for APAP-induced liver injury.-Chen, Y., Park, H.-J., Park, J., Song, H.-C., Ryter, S. W., Surh, Y.-J., Kim, U.-H., Joe, Y., Chung, H. T. Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression.

Refractory healing after surgical therapy of osteonecrosis of the jaw: associated risk factors in aged patients.

Purpose: Osteonecrosis of the jaw (ONJ), both medication-related and non medication-related, mainly occurs in aged patients. It needs surgical intervention. Refractory healing after an operation of ONJ can significantly lower the quality of life of elderly patients. The purpose of this study was to determine risk factors associated with refractory healing in aged patients. Patients and methods: We performed a retrospective study of ONJ in aged patients who underwent surgical treatments in a single institute during a 12-year period. Multiple logistic regression analysis was used to determine independent risk factors associated with refractory healing. Results: A total of 122 patients were included. Of them, 25 patients were identified as the refractory group and 97 patients as the control group. Diabetes mellitus (DM) (AOR=5.03, 95% CI: 1.74-14.52) and glucocorticoid administration (AOR=7.97, 95% CI: 2.52-25.23) were found to be significant risk factors for refractory healing of ONJ. Conclusion: DM and medication of glucocorticoid might be risk factors for refractory healing of ONJ.

Carbon monoxide induces the assembly of stress granule through the integrated stress response.

Stress granules (SGs) are membraneless and phase-dense organelles that form transiently in response to a variety of harmful stimuli, including oxidative, heat, osmotic, ultraviolet light and chemotoxic stresses, and thus providing protective effects, allowing survivals. Carbon monoxide (CO), a gaseous second messenger, is synthesized by heme-oxygenases, and exerts anti-inflammatory, anti-proliferative and anti-apoptotic effects in a variety of cellular- and tissue-injury models. Several reports indicate that low levels of mitochondrial reactive oxygen species (mtROS) generated by CO can selectively activate PERK-eIF2α integrated stress response (ISR) to preserve the cellular homeostasis. Hence, CO can confer protection against cellular stresses. However, the mechanisms underlying the cyto-protective effects of CO against various harmful stimuli remain to be elucidated. Here, we sought to examine whether CO induces the SG assembly, and uncover its molecular mechanisms. We treated WI-38 cells and primary mouse embryonic fibroblasts (MEFs) with CO-releasing molecule 2 (CORM2) or CO gas, and found the SG assemblies were gradually increased in time and dose dependent manners. Next, we used Mito-TEMPO, an mtROS scavenger, to explore if mtROS might be involved in the CO-induced SG assembly. Furthermore, we confirmed the involvement of ISR consisted of PERK-eIF2α signaling pathway induced by CO for the SGs assembly. Finally, the inhibition of SG assembly by ISR inhibitor further verified CO-induced ISR might be responsible for SG. Taken together, in this study, we first demonstrated that CO is a novel SG inducer by activating ISR. Moreover, mtROS might be an initiator for the CO-induced ISR responsible for SG assembly.

Clinical and pathologic features related to the impacted third molars in patients of different ages: A retrospective study in the Korean population.

BACKGROUND/PURPOSE: The surgical extraction of impacted third molars (ITMs) is a common surgical procedure in dentistry. If prophylactic removal of ITMs is beneficial, however, is a still disputed issue. The aim of this study was to analysis the pathologic changes in impacted third molars (ITMs) and adjacent teeth according to patient age groups in the Korean population to determine if the prophylactic removal of ITMs is to be supported or not. MATERIALS AND METHODS: A retrospective study of patients who underwent surgical extraction of impacted third molars was performed. The patients were divided into 5 groups according to their age. Each group was analyzed with respect to patients' chief complaints, specific pathologic conditions in ITMs, and the damage to adjacent teeth due to untreated ITMs. RESULTS: In this study, 2883 impacted third molars in 1109 patients were analyzed. The most common patients' chief complaint was pain, and the frequency of pain was significantly higher in older age groups. The frequency and severity of pathologic changes in ITMs and adjacent second molars due to ITMs were increased with advancing age. CONCLUSION: Based on the results of this study, we conclude that the prophylactic removal of ITMs that have a higher probability of pathologic changes can be considered to be a reasonable treatment modality in younger patients to reduce morbidity resulting from surgical extraction compared with patients who attained advanced age.

Improved protocols for histamine sensitization testing of acellular pertussis vaccines.

The histamine sensitization test is a widely used method for measuring the residual toxicity of pertussis toxin in acellular pertussis vaccines. Although it has been used as a routine assay for decades, the current protocols are difficult to standardize because the test results vary considerably and are based on several factors, including mouse strain, age and sex. In this study, we observed that mice of strains CD1, ddY and C57/BL6 were sufficiently sensitive to pertussis toxin among six mice strains tested and that aged male mice were more sensitive to pertussis toxin than younger or female mice. Using this animal model, we showed pertussis toxin dose-dependent responses in the two histamine sensitization test protocols based on either lethal end-point determination or mouse rectal temperature measurement. Sensitivity to pertussis toxin was further enhanced by the addition of lipopolysaccharide in both methods. With these improvements, pertussis toxin activity can be estimated more accurately and reproducibly using a reduced number of animals.

Three-dimensional interpretation of intercanine width change in children: a 9-year longitudinal study.

INTRODUCTION: The immutability of intercanine width has long been the subject of discussion. The aims of this study were to describe the longitudinal intercanine width changes of children from 6 to 14 years of age and to interpret them with a 3-dimensional method. METHODS: Complete dental stone casts were annually prepared for 66 subjects (50 girls, 16 boys) from 6 to 14 years of age. By using 3-dimensional laser scanning and reconstruction software, virtual casts were constructed. Intercanine width was measured as well as the related 3-dimensional measurements, such as the area of the intercanine triangle, the intercanine angle, the radius of the inscribed circle, and the angles formed by the virtual axes of the canines and the occlusal plane. The measurement changes over time were analyzed by using mixed-effects analysis for longitudinal data. RESULTS: There were slight decreases in intercanine widths for both sexes and both arches. However, the amounts of change were relatively small when compared with the initial values and individual random variability. The values of area, the angles formed by the virtual axes of the canines and the occlusal plane, and the radius showed decreasing trends, whereas the intercanine angle exhibited increasing trends during the observation period. Although the intercanine width changed over time, it was not clinically significant, showing relative stability. CONCLUSIONS: The intercanine width of an untreated subject after stabilization in the mouth is considered to be quite stable, even though individual variation is great.

Synthesis and characterization of a native, oligomeric form of recombinant severe acute respiratory syndrome coronavirus spike glycoprotein.

We have expressed and characterized the severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein in cDNA-transfected mammalian cells. The full-length spike protein (S) was newly synthesized as an endoglycosidase H (endo H)-sensitive glycoprotein (gp170) that is further modified into an endo H-resistant glycoprotein (gp180) in the Golgi apparatus. No substantial proteolytic cleavage of S was observed, suggesting that S is not processed into head (S1) and stalk (S2) domains as observed for certain other coronaviruses. While the expressed full-length S glycoprotein was exclusively cell associated, a truncation of S by excluding the C-terminal transmembrane and cytoplasmic tail domains resulted in the expression of an endoplasmic reticulum-localized glycoprotein (gp160) as well as a Golgi-specific form (gp170) which was ultimately secreted into the cell culture medium. Chemical cross-linking, thermal denaturation, and size fractionation analyses suggested that the full-length S glycoprotein of SARS-CoV forms a higher order structure of approximately 500 kDa, which is consistent with it being an S homotrimer. The latter was also observed in purified virions. The intracellular form of the C-terminally truncated S protein (but not the secreted form) also forms trimers, but with much less efficiency than full-length S. Deglycosylation of the full-length homotrimer with peptide N-glycosidase-F under native conditions abolished recognition of the protein by virus-neutralizing antisera raised against purified virions, suggesting the importance of the carbohydrate in the correct folding of the S protein. These data should aid in the design of recombinant vaccine antigens to prevent the spread of this emerging pathogen.