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Suicide is a leading cause of death worldwide, presenting a serious public health problem. We aimed to investigate the biological basis of suicide completion using proteomics on postmortem brain tissue. Thirty-six postmortem brain samples (23 suicide completers and 13 controls) were collected. We evaluated the proteomic profile in the prefrontal cortex (Broadmann area 9, 10) using tandem mass tag-based quantification with liquid chromatography–tandem mass spectrometry. Bioinformatics tools were used to elucidate the biological mechanisms related to suicide. Subgroup analysis was conducted to identify common differentially expressed proteins among clinically different groups. Of 9801 proteins identified, 295 were differentially expressed between groups. Suicide completion samples were mostly enriched in the endocannabinoid and apoptotic pathways (CAPNS1, CSNK2B, PTP4A2). Among the differentially expressed proteins, GSTT1 was identified as a potential biomarker among suicide completers with psychiatric disorders. Our findings suggest that the previously under-recognized endocannabinoid system and apoptotic processes are highly involved in suicide.

Limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH), a common immunometabolic disease that can progress to hepatic cirrhosis and cancer. Glabridin and its derivatives are potential therapeutics for some metabolic diseases. However, the therapeutic effects of glabridin and its derivatives on NASH and their biological functions are unclear. This study demonstrated the role of synthetic glabridin derivatives (SGDs) in alleviating hepatic steatosis and inflammation in a biopsy-confirmed rodent NASH model. SGDs exerted therapeutic effects by activating autophagy and the antioxidant defense system, which mitigate NASH pathogenesis. The cellular target of HSG4112, an SGD, was paraoxonase 2. These findings will enable the development of novel therapeutics for NASH in the future.

Telomere length has emerged as a cumulative marker for lifestyle, psychosocial stress, and cytotoxic environments. We aimed to examine the possible association between leukocyte telomere length (LTL) and completed suicide.This study included 71 suicide completers and 117 healthy controls for whom LTL was determined by the ratio of the telomere repeat copy number to the single-copy gene copy number (T/S ratio). We compared the LTL between the suicide completers and the healthy controls and estimated the odds ratio (OR) for suicide for each age group, applying a generalized estimating equation (GEE).LTL was significantly shortened in the suicide completers as compared with the controls, overall subjects, or within-age categories (≤29 and 30-49 years). Furthermore, a longer LTL was associated with significantly decreased odds of completed suicide for those aged ≤29 years and 30-49 years (OR = 0.11, 95% confidence interval [CI] 0.03-0.37, p .001 for the ≤29-year age group; OR = 0.54, 95% CI 0.34-0.84, p = .006 for the 30- to 49-year age group).This study provides evidence regarding the relationship between shortened LTL and completed suicide, especially in those aged50 years. Future research should further assess potential confounders and examine underlying mechanisms.

Objectives To identify optimum sample conditions for human brains, we compared the clearing efficiency, antibody staining efficiency, and artifacts between fresh and cadaver samples. Methods Fresh and cadaver samples were cleared using X-CLARITY™. Clearing efficiency and artifact levels were calculated using ImageJ, and antibody staining efficiency was evaluated after confocal microscopy imaging. Three staining methods were compared: 4-day staining (4DS), 11-day staining (11DS), and 4-day staining with a commercial kit (4DS-C). The optimum staining method was then selected by evaluating staining time, depth, method complexity, contamination, and cost. Results Fresh samples outperformed cadaver samples in terms of the time and quality of clearing, artifacts, and 4′,6-diamidino-2-phenylindole (DAPI) staining efficiency, but had a glial fibrillary acidic protein (GFAP) staining efficiency that was similar to that of cadaver samples. The penetration depth and DAPI staining improved in fresh samples as the incubation period lengthened. 4DS-C was the best method, with the deepest penetration. Human brain images containing blood vessels, cell nuclei, and astrocytes were visualized three-dimensionally. The chemical dye staining depth reached 800 µm and immunostaining depth exceeded 200 µm in 4 days. Conclusions We present optimized sample preparation and staining protocols for the visualization of three-dimensional macrostructure in the human brain.

Obtaining a histological fingerprint from the in-vivo brain has been a long-standing target of magnetic resonance imaging (MRI). In particular, non-invasive imaging of iron and myelin, which are involved in normal brain functions and are histopathological hallmarks in neurodegenerative diseases, has practical utilities in neuroscience and medicine. Here, we propose a biophysical model that describes the individual contribution of paramagnetic (e.g., iron) and diamagnetic (e.g., myelin) susceptibility sources to the frequency shift and transverse relaxation of MRI signals. Using this model, we develop a method, χ-separation, that generates the voxel-wise distributions of the two sources. The method is validated using computer simulation and phantom experiments, and applied to ex-vivo and in-vivo brains. The results delineate the well-known histological features of iron and myelin in the specimen, healthy volunteers, and multiple sclerosis patients. This new technology may serve as a practical tool for exploring the microstructural information of the brain.

Immunoglobulin A nephropathy (IgAN) involves repeated events of gross haematuria with concurrent upper airway infections. The mucosal immune system, especially the tonsil, is considered the initial site of inflammation, although the role of the tonsillar microbiota has not been established in IgAN. In this study, we compared the tonsillar microbiota of patients with IgAN (n = 21) and other glomerular diseases (n = 36) as well as, healthy controls (n = 23) from three medical centres in Korea. The microbiota was analysed from tonsil swabs using the Illumina MiSeq system based on 16S rRNA gene. Tonsillar bacterial diversity was higher in IgAN than in other glomerular diseases, although it did not differ from that of healthy controls. Principal coordinates analysis revealed differences between the tonsillar microbiota of IgAN and both healthy and disease controls. The proportions of Rahnella, Ruminococcus_g2, and Clostridium_g21 were significantly higher in patients with IgAN than in healthy controls (corrected p

Although the benefits of sauna bathing have been demonstrated in epidemiological studies, sauna deaths have been reported. The aim of this study was to determine the demographic and forensic characteristics associated with different blood alcohol concentrations (BACs) in sauna deaths in Korea. In this retrospective analysis, data were collected from a nationwide pool in Korea between January 2008 and December 2015 to determine the role of alcohol intoxication in sauna deaths based on the subjects’ BAC and to evaluate the demographic and forensic characteristics associated with different BACs. One hundred and three deaths were classified into 2 groups: the non-intoxication (NI) group (BAC

This study aimed to determine the role of acute alcohol use among suicide decedents based on their blood alcohol concentrations (BAC), and identify sociodemographic and clinical characteristics associated with the differences in BAC.Data were collected from nationwide autopsies conducted between May 2015 and November 2015 in South Korea. A total of 683 suicide decedents were classified into three groups according to the BAC at the time of autopsy: no alcohol (NA) group (BAC0.01%), no intoxication (NI) group (0.01≤BAC0.08%), and intoxication (I) group (BAC≥0.08%). Sociodemographic data and clinical factors related to suicide among the three groups were analyzed using a multinomial logistic regression analysis.Among the suicide decedents (N=683), the NA group was 55.6% (N=380), NI group was 15.7% (N=107), and I group was 28.7% (N=196). History of suicide attempts (odds ratio [OR]: 1.798, 95% confidence interval [CI]: 1.073-3.012) and absence of medical illness (OR: 1.633, CI: 1.038-2.571) were higher in the I group compared to the NA group. Psychiatric and medical illness triggers of suicide were significantly lower in the I group than the NA group (OR: 0.325, CI: 0.118-0.892). Being male (OR: 2.494, CI: 1.363-4.565) and financial problems as triggers of suicide (OR: 3.234, CI: 1.636-6.393) were higher in the NI group than in the NA group. Being male and having financial problems were associated with no intoxication (0.01≤BAC0.08%), whereas the history of suicide attempts and absence of medical and/or psychiatric illness were associated with acute alcohol intoxication (BAC≥0.08%) in the suicide decedents.Suicide decedents had different characteristics based on different BACs identified in the autopsy. The differences in acute alcohol intoxication and no intoxication in suicide decedents may have implications for the targeted prevention of suicides related to alcohol.

Background:Despite increased neuronal death, senile plaques, and neurofibrillary tangles observed in patients suffering from Alzheimer’s disease (AD), the detailed mechanism of cell death in AD is still poorly understood.Method:We hypothesized that p38 kinase activates and then phosphorylates Bax, leading to its translocation to mitochondria in AD brains compared to controls. The aim of this study was to investigate the role of p38 kinase in phosphorylation and sub-cellular localization of pro-apoptotic Bax in the frontal cortex of the brains from AD and control subjects. Increased oxidative stress in AD individuals compared to control was evaluated by measuring the levels of carbonylated proteins and oxidized peroxiredoxin, an antioxidant enzyme. The relative amounts of p38 kinase and phospho-Bax in mitochondria in AD brains and controls were determined by immunoblot analysis using the respective antibody against each protein following immunoprecipitation.Results:Our results showed that the levels of oxidized peroxiredoxin-SO3and carbonylated proteins are significantly elevated in AD brains compared to controls, demonstrating the increased oxidative stress.Conclusion:The amount of phospho-p38 kinase is increased in AD brains and the activated p38 kinase appears to phosphorylate Thr residue(s) of Bax, which leads to its mitochondrial translocation, contributing to apoptosis and ultimately, neurodegeneration.

Purpose The purpose of this study was to evaluate the efficacy of unicompartmental knee arthroplasty (UKA) in young active Asian patients by analyzing clinical outcomes, complications and survival rates. Materials and Methods Eighty-two knees were evaluated with a minimum follow-up of 5 years after Oxford phase 3 UKA in patients less than 60 years of age at the time of surgery. Their mean age was 54.7 years (range, 44 to 59 years). The mean follow-up period was 8.9 years (range, 5.3 to 12 years). Kaplan–Meier survivorship analysis was used to estimate implant survival. Results Including 3 bearing dislocations, 1 medial tibial collapse and 1 lateral osteoarthritis, the total complication rate was 6.1% (5/82). Of the 3 cases of bearing dislocation, 2 cases were resolved by replacing with a thicker bearing and 1 case was converted to total knee arthroplasty (TKA) due to repeated dislocation. The two knees with a medial tibial collapse and a lateral osteoarthritis were converted to TKA. The 10-year cumulative survival rate using Kaplan-Meier survival method was 94.7% (95% confidence interval: 88.7%–100%). Conclusions Oxford medial UKA was reliable and effective in young active Asian patients providing good clinical results and survival rate in the mid-term follow-up.

Background The autopsy is the medical examination of a deceased person that mainly provides information on the cause and manner of death. Two types are conducted in Korea: clinical and legal, depending on its purpose. Despite this procedure's importance, autopsy rates have been decreasing worldwide. The aim of this study was to determine the nationwide autopsy rate in Korea and compare it with that in other countries. Methods We collected data of autopsies performed between 2001 and 2015 by searching previously published literature on autopsy statistics and by requesting data from the relevant institutions. We calculated the autopsy rate by using mortality data from Statistics Korea; furthermore, we investigated the type of autopsy performed by institution as well as by geographical region. Results The total autopsy rate in Korea increased from 2.16% in 2001 to 2.60% in 2015. In terms of autopsy types, however, clinical autopsy rates decreased from 0.17% in 2001 to 0.03% in 2015, while legal autopsy rates increased from 1.99% to 2.57% during the same period. Moreover, the clinical autopsy rate tended to decrease throughout the period, while the legal autopsy rate fluctuated between 2001 and 2010 but steadily increased thereafter. Conclusion The autopsy rate in Korea is lower compared to that of the advanced countries. These findings implicate the need for nationwide policy to promote both clinical and legal autopsy, which remain crucial parts of medical science and public health., Graphical Abstract

Fructose intake is known to induce obesity, insulin resistance, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the effects of fructose drinking on gut leakiness, endotoxemia, and NAFLD and study the underlying mechanisms in rats, mice, and T84 colon cells. Levels of ileum junctional proteins, oxidative stress markers, and apoptosis-related proteins in rodents, T84 colonic cells, and human ileums were determined by immunoblotting, immunoprecipitation, and immunofluorescence analyses. Fructose drinking caused microbiome change, leaky gut, and hepatic inflammation/fibrosis with increased levels of nitroxidative stress marker proteins cytochrome P450-2E1 (CYP2E1), inducible nitric oxide synthase, and nitrated proteins in small intestine and liver of rodents. Fructose drinking significantly elevated plasma bacterial endotoxin levels, likely resulting from decreased levels of intestinal tight junction (TJ) proteins (zonula occludens 1, occludin, claudin-1, and claudin-4), adherent junction (AJ) proteins (β-catenin and E-cadherin), and desmosome plakoglobin, along with α-tubulin, in wild-type rodents, but not in fructose-exposed Cyp2e1-null mice. Consistently, decreased intestinal TJ/AJ proteins and increased hepatic inflammation with fibrosis were observed in autopsied obese people compared to lean individuals. Furthermore, histological and biochemical analyses showed markedly elevated hepatic fibrosis marker proteins in fructose-exposed rats compared to controls. Immunoprecipitation followed by immunoblot analyses revealed that intestinal TJ proteins were nitrated and ubiquitinated, leading to their decreased levels in fructose-exposed rats. Conclusion: These results showed that fructose intake causes protein nitration of intestinal TJ and AJ proteins, resulting in increased gut leakiness, endotoxemia, and steatohepatitis with liver fibrosis, at least partly, through a CYP2E1-dependent manner.

Previous research on senior center attendance has focused mainly on the differences between senior center users and nonusers. However, this study explored the predictors distinguishing 3 categories of senior center users: users, nonusers, and former users. The data for this study were drawn from the 2004 National Survey on Living Status and Social Needs of the Korean Older Population, conducted jointly by the Korea Ministry of Health and Welfare and the Korea Institute for Health and Social Affairs. A total of 3,009 elderly persons aged 65 years and older living in the community were analyzed. Results showed there are significant predictors distinguishing both nonusers from users and nonusers from former users. However, no significant differences were found between former users and users. Overall, this study moderately supports the findings of previous studies and revealed contradictory results for gender, education, and location of residence variables. Older Koreans who are male, educated, social...

Background There has been a campaign by the National Education on Sleeping Habits and Living Environment, to reduce the incidence of sudden infant death syndrome (SIDS). However, more than 100 infants die suddenly and unexplainably before the age of 1 year in Korea. Long QT syndrome (LQTS), an inheritable cardiac disease, has been reported to likely be associated with up to 14% of SIDS cases. However, genetic studies of the association between SIDS and LQTS have not yet been conducted in Korea. Methods We conducted genetic analysis using genomic DNA extracted from paraffin-embedded tissue blocks from 200 SIDS cases autopsied between 2005 and 2013. We analyzed the following genetic mutations associated with LQTS, KCNQ1, SCN5A, KCNE1, KCNE2, KCNJ2, and CAV3. Results Of the 200 SIDS cases, 58% involved male infants (116 male and 84 female infants, respectively), the mean age was 140 days (median, 107 days; range, 24–270 days), and they were all of Asian-Korean ethnicity. SIDS IA category criteria comprised 45 cases (22.5%) while the rest were SIDS IB. Fifteen infants (7.5%) had R1193Q in SCN5A, of doubtful pathogenicity, and no pathogenic LQTS variants were observed. Conclusion This genetic investigation of LQTS in SIDS showed a low diagnostic yield. These findings suggest that LQTS molecular autopsy could be cautiously conducted in selected cases with family involvement to improve the available genetic counseling information. Meanwhile, a national SIDS registry should be established to document and evaluate the genetic risk of SIDS in Korea., Graphical Abstract

Background: Aquaporin-11 (AQP11) is a novel member of the aquaporin family. Disruption of the murine Aqp11 gene causes severe proximal tubular injury and renal failure. The rs2276415 (G>A) single-nucleotide polymorphism in the human AQP11 gene results in glycine to serine substitution in a functionally important domain. In this study, the role of the genetic predispositions of AQP11 rs2276415 (G>A) on renal allograft outcomes was evaluated. Methods: A total of 198 pairs of donors and recipients were enrolled in this study. Long-term graft survival was traced and clinical parameters that could have influenced graft outcome were collected through the electronic medical record system. Results: The genotype distribution and allele frequency of rs2276415 polymorphism were not different between donors and recipients. Despite similar allele frequencies between donors and recipients, the minor allele rs2276415 (GA+AA) of AQP11 from the donors, but not from the recipients, had a harmful effect on the graft survival compared with the wild-type donor (GG; P=0.029). This association was significant after adjusting for several risk factors including age, sex, human leukocyte antigen mismatch, donor type, hypertension, and diabetes mellitus (P=0.032). Conclusion: A donor-derived, not recipient-derived, genetic AQP11 polymorphism has different effects on graft outcome. Thus, the genetic influence from donors should be carefully considered for proper management of allografts after kidney transplantation.

Background The diagnostic criteria for bathtub drownings are not standardized, and the risk factors associated with bath-related deaths are unclear. Methods We analyzed a Korean nationwide database of bath-related deaths that occurred between January 2008 and December 2015. Eighty-four cases were enrolled after reviewing 31,123 autopsy records. Results The subjects' ages ranged from 18 to 91 years, with a mean age ± standard deviation of 61.3 ± 16.0 years. Bath-related deaths in the winter were approximately 4.6-fold greater than those in the summer. Of the 84 subjects, the primary cause of death in 57 (67.9%) was drowning in the bath; 24 (28.6%) drowned of other causes such as natural diseases, and 3 (3.6%) died of acute alcohol intoxication. We analyzed water-inhalation signs to establish criteria for bathtub drowning diagnosis. There were significantly higher incidences of hyperinflated lungs, water in the sphenoid sinus and stomach/duodenal contents, and Paltauf's spots (subpleural hemorrhage) in bathtub-drowned subjects compared to non-drowned individuals (P < 0.01). Multiple signs of water inhalation were significantly associated with bathtub drowning (P < 0.01). The two leading contributory causes of bath-related death were cardiovascular diseases and alcohol intoxication (binge drinking before bathing). Conclusion The diagnosis of bath-related deaths could present considerable medico-legal problems; therefore, a comprehensive autopsy with a thorough scene investigation can clarify the cause of death in these situations. Preventive strategies for reducing such deaths should target alcohol drinking before bathing and long soaking times in bathtubs, especially among elderly individuals with preexisting cardiovascular diseases., Graphical Abstract

Background & Aims Binge alcohol exposure causes gut leakiness, contributing to increased endotoxemia and inflammatory liver injury, although the molecular mechanisms are still elusive. This study was aimed at investigating the roles of apoptosis of enterocytes and nitration followed by degradation of intestinal tight junction (TJ) and adherens junction (AJ) proteins in binge alcohol-induced gut leakiness. Methods The levels of intestinal (ileum) junctional complex proteins, oxidative stress markers and apoptosis-related proteins in rodents, T84 colonic cells and autopsied human ileums were determined by immunoblot, immunoprecipitation, immunofluorescence, and mass-spectral analyses. Results Binge alcohol exposure caused apoptosis of gut enterocytes with elevated serum endotoxin and liver injury. The levels of intestinal CYP2E1, iNOS, nitrated proteins and apoptosis-related marker proteins were significantly elevated in binge alcohol-exposed rodents. Differential, quantitative mass-spectral analyses of the TJ-enriched fractions of intestinal epithelial layers revealed that several TJ, AJ and desmosome proteins were decreased in binge alcohol-exposed rats compared to controls. Consistently, the levels of TJ proteins (claudin-1, claudin-4, occludin and zonula occludens-1), AJ proteins (β-catenin and E-cadherin) and desmosome plakoglobin were very low in binge alcohol-exposed rats, wild-type mice, and autopsied human ileums but not in Cyp2e1-null mice. Additionally, pretreatment with specific inhibitors of CYP2E1 and iNOS prevented disorganization and/or degradation of TJ proteins in alcohol-exposed T84 colonic cells. Furthermore, immunoprecipitation followed by immunoblot confirmed that intestinal TJ and AJ proteins were nitrated and degraded via ubiquitin-dependent proteolysis, resulting in their decreased levels. Conclusions These results demonstrated for the first time the critical roles of CYP2E1, apoptosis of enterocytes, and nitration followed by ubiquitin-dependent proteolytic degradation of the junctional complex proteins, in promoting binge alcohol-induced gut leakiness and endotoxemia, contributing to inflammatory liver disease. Lay summary Binge alcohol exposure causes gut leakiness, contributing to increased endotoxemia and inflammatory liver injury. Our results demonstrated for the first time the critical roles of apoptosis of enterocytes and nitration followed by ubiquitin-dependent proteolytic degradation of the junctional complex proteins in promoting this gut leakiness and endotoxemia. These results provide insight into the molecular mechanisms of alcohol-induced inflammatory liver disease.

Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed to investigate the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2e1-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6 g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria while liver histology obtained at 6 h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria and triglycerides. All these changes including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetyl-cysteine, both of which suppressed the oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-α, hepatic cytokines, CYP2E1 and lipid peroxidation with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of pro-apoptotic proteins and decreased levels of active (phosphorylated) p-AKT, p-AMPK and peroxisome proliferator-activated receptor-alpha (PPAR-α), all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2e1-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seem critical in the binge alcohol-mediated increased nitroxidative stress, gut leakage, endotoxemia, and altered fat metabolism, and inflammation, contributing to hepatic apoptosis and steatohepatitis.

The purpose of this study is to investigate the likelihood of unicompartmental knee arthroplasty (UKA) in patients with chondrosis in the patellofemoral joint. We evaluated the pain and functional changes in the patellofemoral joint of 62 patients who underwent medial UKA for medial compartmental osteoarthritis with symptoms in the patellofemoral joint. They were analyzed by the patellofemoral score of Lonner at postoperative 3months, 6months, 1year, and 2years prospectively. Preoperatively, the grade by total score was poor in all 62 cases, but it was improved to 36 excellent (58%), 16 good (26%), and 10 fair (16%), and there were no poor cases at 2years. The last follow-up showed satisfactory results in pain score, function score, and total score (p0.05). Regarding this result, we believe chondrosis in the patellofemoral joint is not a contraindication to UKA, even in patients with patellofemoral joint symptoms.

An enzyme β-galactosidase or β-galactohydrolase [EC3.2.1.23], commonly called lactase, mediates galacto-oligosaccharide (GOS) synthesis under conditions of high substrate concentrations. Also, lactase hydrolyzes β(1→4) lactose into glucose and galactose, the latter is successively transferred to free lactose to make various oligosaccharides via transgalactosylation. GOS is non-digestible to human digestive enzymes and has been used as a functional prebiotics. Among the 24 lactic acid bacteria (LAB) strains used, Lactobacillus paracasei YSM0308 was selected based on its exhibition of the highest β-galactoside hydrolysis activity, and the crude lactase was prepared for examination of reaction conditions to affect the GOS synthesis. Lactase activity was measured with a spectrophotometer using ONPG (o-nitropheyl β-D-galactopyranoside) method. Lactase activity was not detected in the culture supernatant and was mostly present in the cell pellet after centrifugation. Activity of the crude lactase preparation ranges from102 to 1,053 units/mL, with the highest activity determined for L. paracasei YSM0308. Optimal conditions for GOS synthesis are as follows: concentration of whey powder, pH, temperature, and time were 30%, pH 6.5-7.0, 30oC, and 4 h, respectively. The final GOS concentration was 19.41% (w/v) by the crude YSM0308 lactase, which was obtained from strain YSM0308 grown in the 10% (w/v) reconstituted whey-based medium.

Increased nitroxidative stress causes mitochondrial dysfunctions through oxidative modifications of mitochondrial DNA, lipids, and proteins. Persistent mitochondrial dysfunction sensitizes the target cells/organs to other pathological risk factors and thus ultimately contributes to the development of more severe disease states in alcoholic and nonalcoholic fatty liver disease. The incidences of nonalcoholic fatty liver disease continuously increase due to high prevalence of metabolic syndrome including hyperlipidemia, hypercholesterolemia, obesity, insulin resistance, and diabetes. Many mitochondrial proteins including the enzymes involved in fat oxidation and energy supply could be oxidatively modified (includingS-nitrosylation/nitration) under increased nitroxidative stress and thus inactivated, leading to increased fat accumulation and ATP depletion. To demonstrate the underlying mechanism(s) of mitochondrial dysfunction, we employed a redox proteomics approach using biotin-N-maleimide (biotin-NM) as a sensitive biotin-switch probe to identify oxidized Cys residues of mitochondrial proteins in the experimental models of alcoholic and acute liver disease. The aims of this paper are to briefly describe the mechanisms, functional consequences, and detection methods of mitochondrial dysfunction. We also describe advantages and limitations of the Cys-targeted redox proteomics method with alternative approaches. Finally, we discuss various applications of this method in studying oxidatively modified mitochondrial proteins in extrahepatic tissues or different subcellular organelles and translational research.

Background The influence of acute alcohol consumption on the factors related to suicide remains understudied. Thus, the present study investigated the relationship between blood alcohol content (BAC) and the lethality of suicide methods. Methods Autopsy data on 315 South Korean suicide completers with a positive BAC were collected from a nationwide pool between May 2015 and November 2015, and the methods were dichotomised as suicide methods of low lethality (SMLL; drug/chemical overdose and sharp objects, n = 67) and suicide methods of high lethality (SMHL; everything else, n = 243). BAC at the time of autopsy and various suicide-related factors of these two groups were compared with logistic regression analyses. Results Compared to suicide completers with a BAC in the lowest range of 0.011–0.049%, suicide completers with a BAC in the range of 0.150–0.199% were more likely to use SMHL (odds ratio [OR]: 3.644, 95% confidence interval [CI]: 1.221–10.874). Additionally, the adoption of SMHL was significantly associated with the absence of a psychiatric illness (OR: 0.433, 95% CI: 0.222–0.843) and a younger age; the OR for high BAC among subjects in their 40s was 0.266 (95% CI: 0.083–0.856); in their 50s, 0.183 (95% CI: 0.055–0.615); and in their 60s, 0.057 (95% CI: 0.015–0.216). Conclusions The relationship between BAC and suicide method lethality was represented by a bell-shaped pattern in which suicide methods of high lethality were more likely to be used by suicide completers with mid-range BAC levels. The increased impulsivity and impairments in particular executive functions, including planning and organization, associated with acute alcohol use may influence the selection of a particular suicide method based on its lethality.

Aldehyde dehydrogenases (ALDHs) represent large family members of NAD(P)+-dependent dehydrogenases responsible for the irreversible metabolism of many endogenous and exogenous aldehydes to the corresponding acids. Among 19 ALDH isozymes, mitochondrial ALDH2 is a low Km enzyme responsible for the metabolism of acetaldehyde and lipid peroxides such as malondialdehyde and 4-hydroxynonenal, both of which are highly reactive and toxic. Consequently, inhibition of ALDH2 would lead to elevated levels of acetaldehyde and other reactive lipid peroxides following ethanol intake and/or exposure to toxic chemicals. In addition, many East Asian people with a dominant negative mutation in ALDH2 gene possess a decreased ALDH2 activity with increased risks for various types of cancer, myocardial infarct, alcoholic liver disease, and other pathological conditions. The aim of this review is to briefly describe the multiple post-translational modifications of mitochondrial ALDH2, as an example, after exposure to toxic chemicals or under different disease states and their pathophysiological roles in promoting alcohol/drug-mediated tissue damage. We also briefly mention exciting preclinical translational research opportunities to identify small molecule activators of ALDH2 and its isozymes as potentially therapeutic/preventive agents against various disease states where the expression or activity of ALDH enzymes is altered or inactivated.

Interleukin-22 (IL-22), which acts as either a proinflammatory or anti-inflammatory cytokine in various disease models, is markedly up-regulated in chronic liver diseases, including hepatitis B and C. In this report, we demonstrate a strong correlation between IL-22 expression in the liver with active, inflammatory human liver disease. To clarify the role of IL-22 up-regulation in the pathogenesis of liver diseases, liver-specific IL-22 transgenic (IL-22TG) mice, under the control of albumin promoter, were developed. Despite elevated IL-22 serum levels ranging from 4,000 to 7,000 pg/mL, IL-22TG mice developed normally without obvious adverse phenotypes or evidence of chronic inflammation (except for slightly thicker epidermis and minor inflammation of the skin) compared with wild-type mice. Interestingly, IL-22TG mice were completely resistant to concanavalin A-induced T cell hepatitis with minimal effect on liver inflammation and had accelerated liver regeneration after partial hepatectomy. Although they did not spontaneously develop liver tumors, IL-22TG mice were more susceptible to diethylnitrosamine-induced liver cancer. Microarray analyses revealed that a variety of antioxidant, mitogenic, acute phase genes were up-regulated in the livers of IL-22TG mice compared with those from wild-type mice.These findings indicate that localized production of IL-22 in the liver promotes hepatocyte survival and proliferation but primes the liver to be more susceptible to tumor development without significantly affecting liver inflammation.

Peroxisome proliferator-activated receptor-α (PPARα) has been implicated in a potent anti-inflammatory activity. However, no information is available on whether PPARα can affect signal transducers and activator of transcription proteins (STATs) in acute liver damage. Thus, this study was aimed to investigate the in vivo role of PPARα in elevating STATs as well as oxidative/nitrosative stress in a model of lipopolysaccharide (LPS)-induced acute hepatic inflammatory injury. Using age-matched Ppara-null and wild-type (WT) mice, we demonstrate that the deletion of PPARα aggravates LPS-mediated liver injury through activating STAT1 and NF-κB-p65 accompanied by increased levels of pro-inflammatory cytokines. Furthermore, the activities of key anti-oxidant enzymes and mitochondrial complexes were significantly decreased while lipid peroxidation and protein nitration were elevated in LPS-exposed Ppara-null mice compared to WT. These results indicate that PPARα is important in preventing LPS-induced acute liver damage by regulating STAT1 inflammatory signaling pathways and oxidative/nitrosative stress.

Emerging evidence suggests that the lack of PPARα enhances hepatic steatosis and inflammation in Ppara-null mice when fed a high-fat diet (HFD). Thus, the aim of this study was to determine whether Ppara-null mice are more susceptible to nonalcoholic steatohepatitis (NASH) than their wild-type (WT) counterparts following short-term feeding with a HFD. Age-matched male WT and Ppara-null mice were randomly assigned to consume ad libitum a standard Lieber-DeCarli liquid diet (STD) (35% energy from fat) or a HFD (71% energy from fat) for 3 wk. Liver histology, plasma transaminase levels, and indicators of oxidative/nitrosative stress and inflammatory cytokines were evaluated in all groups. Levels of lobular inflammation and the NASH activity score were greater in HFD-exposed Ppara-null mice than in the other 3 groups. Biochemical analysis revealed elevated levels of ethanol-inducible cytochrome P450 2E1 and TNFα accompanied by increased levels of malondialdehyde as well as oxidized and nitrated proteins in Ppara-null mice. Elevated oxidative stress and inflammation were associated with activation of c-Jun-N-terminal kinase and p38 kinase, resulting in increased hepatocyte apoptosis in Ppara-null mice fed a HFD. These results, with increased steatosis, oxidative stress, and inflammation observed in Ppara-null mice fed a HFD, demonstrate that inhibition of PPARα functions may increase susceptibility to high fat-induced NASH.

Yoo S H, Lee K, Chae J Y & Moon K C (2011) Histopathology 58, 191–197 CD151 expression can predict cancer progression in clear cell renal cell carcinoma Aims: CD151 is known to be implicated in cancer progression and metastasis. The aim was to evaluate the expression of CD151 in clear cell renal cell carcinoma (CCRCC) and to assess its prognostic significance. Methods and results: The expression of CD151 was evaluated in 489 cases of CCRCC by immunohistochemistry. Immunoreactivity was classified into four categories (minimal, 0–10% positive cells; focal, 10–50% positive cells; diffuse moderate, >50% positive cells with moderate staining intensity; diffuse strong, >50% positive cells with strong staining). To determine the statistical significance of CD151 expression in CCRCC, all cases were divided into two groups based on their CD151 expression level: a CD151-low group (n = 257; minimal and focal) and a CD151-high group (n = 232; diffuse). Expression of CD151 was correlated positively with pT, pN, pM categories, pathological tumour–node–metastasis (pTNM) stage, nuclear grade, tumour size and patient’s age. The CD151-high group had significantly shorter cancer-specific survival (P

Background: The authors report the results of preserving the infrapatellar branch of the saphenous nerve during unicompartmental knee arthroplasty to prevent lateral skin numbness. Methods: All 100 cases had medial compartmental osteoarthritis and a minimally invasive technique had been used. The mean follow-up duration was two years and eight months (range, 24 to 42 months). Results: The classification according to the location of this nerve was observed as either Mochida Type I with 76 cases (76%), Type II with 16 cases (16%), and unclassified type with 8 cases (8%). In Type I, the nerve was saved in 62 cases (82%), but could not be preserved in Type II because of the surgical procedure. These results showed that the mean distance from the joint line to the nerve of Type I was 9.13 mm (range, 4 to 15 mm) and the nerve passed inferiorly. Conclusions: This study showed the location of this nerve can be predicted ahead of the procedure, which will help preserve it during the surgery.

This article presents a new methodology to generate optimal trajectories in controlling an automated excavator. By parameterizing all the actuator displacements with B-splines of the same order and with the same number of control points, the coupled actuator limits, associated with the maximum pump flowrate, are described as the finite-dimensional set of linear constraints to the motion optimization problem. Several weighting functions are introduced on the generalized actuator torque so that the solution to each optimization problems contains the physical meaning. Numerical results showing that the generated motions of the excavator are fairly smooth and effectively save energy, which can prevent mechanical wearing and possibly save fuel consumption, are presented. A typical operator's manoeuvre from experiments is referred to bring out the standing features of the optimized motion.

In recent years, there has been an increasing interest in peri-articular injections (PAI) to control post-operative pain after total knee arthroplasty (TKA). Previous studies have evaluated the effect of PAI using multimodal analgaesic protocols, but the concomitant use of patient-controlled analgesia (PCA) may has masked the genuine effects of PAI. We investigated the efficacy of PAI compared with PCA and determined whether conventional PCA can be effectively replaced with PAI after TKA.Eighty patients undergoing unilateral TKA were randomised into two groups. The PCA group consisted of patients who used PCA after surgery, while the PAI group included patients who did not use PCA post-operatively but were given PAI during surgery. We measured changes in visual analogue scale (VAS) scores, straight leg raising (SLR), range of motion (ROM) and consumption of antiemetics or analgaesics.Pain levels in the PAI group were significantly lower than in the PCA group during two weeks post-operatively (p 0.05).; functional recovery in the SLR test showed no difference between groups (p 0.05).; mean ROM showed no difference; (p 0.05) and there was no difference in the number of patients who needed additional analgaesics. However, antiemetic use was significantly lower for the PAI group (p 0.05).PAI offered improved pain control and minimal side effects compared with PCA. Thus, PAI can replace conventional PCA for controlling post-operative pain after TKA.

Background: Caveolin-1, as a major component of caveolae, is involved in the regulation of cell cycle by impacting various signaling pathways. Previous studies of caveolin-1 in cancer showed two contrary results. In most in vitro studies, caveolin-1 played a role as a tumor suppressor. On the other hand, the elevated expression of caveolin-1 was often reported to be associated with poor clinical outcome in human studies. These results indicate differential biological functions of caveolin-1 depending on the development and progression stage of cancer in vivo. Methods: To clarify the correlation between the clinicopathologic profiles of pulmonary squamous cell carcinomas and the expression of caveolin-1, 107 cases of formalin-fixed and paraffin-embedded tissues of pulmonary squamous cell carcinomas were immunohistochemically evaluated for the expression of caveolin-1 by the tissue-array method. Results: Caveolin-1 was expressed in 34 cases (31.7%) among 107 cases of pulmonary squamous cell carcinoma. The expression of caveolin-1 was statistically correlated with pathologic stage (stage I and II vs. III; P

Background: We assessed computed tomographic (CT) features of postoperative complications and recurrent tumors in gastric cancer patients who underwent radical surgery. Methods: We performed a retrospective study of 397 patients who had undergone radical surgery for the treatment of gastric carcinoma and underwent postoperative CT in our institution over a 2-year period. Patients were assigned to one of two groups: group A consisted of 47 patients who underwent CT for complications in the early postoperative period, and group B consisted of 355 patients who underwent CT for evidence of tumor recurrence during the follow-up period. We classified recurrent tumors into four categories: local recurrence, lymph node metastasis, peritoneal seeding, and remote metastasis. Results: In group A, localized fluid collections or abscesses in the surgical bed were found in 38 patients (81%) and usually involved the left subphrenic area (74%) or the superior recess of the lesser sac (47%). In group B, recurrent tumors were found in 196 patients (55%). Among these, lymph node metastasis was the most common pattern (52%), followed by peritoneal seeding (44%), local recurrence (40%), and remote metastasis (37%). Conclusion: CT after radical surgery for the treatment of gastric carcinoma frequently shows postoperative complications or tumor recurrence. Familiarity with the common postoperative complications and patterns of the tumor recurrence is a prerequisite to accurate interpretation of CT findings in these patients.

Binge drinking, a common pattern of alcohol ingestion, is known to potentiate liver injury caused by chronic alcohol abuse. This study was aimed at investigating the effects of acute binge alcohol on hypoxia-inducible factor-1α (HIF-1α)-mediated liver injury and the roles of alcohol-metabolizing enzymes in alcohol-induced hypoxia and hepatotoxicity. Mice and human specimens assigned to binge or nonbinge groups were analyzed for blood alcohol concentration (BAC), alcohol-metabolizing enzymes, HIF-1α-related protein nitration, and apoptosis. Binge alcohol promoted acute liver injury in mice with elevated levels of ethanol-inducible cytochrome P450 2E1 (CYP2E1) and hypoxia, both of which were colocalized in the centrilobular areas. We observed positive correlations among elevated BAC, CYP2E1, and HIF-1α in mice and humans exposed to binge alcohol. The CYP2E1 protein levels (r = 0.629, p = 0.001) and activity (r = 0.641, p = 0.001) showed a significantly positive correlation with BAC in human livers. HIF-1α levels were also positively correlated with BAC (r = 0.745, p < 0.001) or CYP2E1 activity (r = 0.792, p < 0.001) in humans. Binge alcohol promoted protein nitration and apoptosis with significant correlations observed between inducible nitric oxide synthase and BAC, CYP2E1, or HIF-1α in human specimens. Binge-alcohol-induced HIF-1α activation and subsequent protein nitration or apoptosis seen in wild type were significantly alleviated in the corresponding Cyp2e1-null mice, whereas pretreatment with an HIF-1α inhibitor, PX-478, prevented HIF-1α elevation with a trend of decreased levels of 3-nitrotyrosine and apoptosis, supporting the roles of CYP2E1 and HIF-1α in binge-alcohol-mediated protein nitration and hepatotoxicity. Thus binge alcohol promotes acute liver injury in mice and humans at least partly through a CYP2E1-HIF-1α-dependent apoptosis pathway.

We present a novel heterogeneous Fenton-like catalyst of LiFePO4 (LFP). LFP has been widely used as an electrode material of a lithium ion battery, but we observed that commercial LFP (LFP-C) could act as a good Fenton-like catalyst to decompose rhodamine 6G. The catalytic activity of LFP-C microparticles was much higher than a popular catalyst, magnetite nanoparticles. Furthermore, we found that the catalytic activity of LFP-C could be further increased by increasing the specific surface area. The reaction rate constant of the hydrothermally synthesized LFP microcrystals (LFP-H) is at least 18 times higher than that of magnetite nanoparticles even though the particle size of LFP is far larger than magnetite nanoparticles. The LFP catalysts also exhibited a good recycling behavior and high stability under an oxidizing environment. The effects of the experimental parameters such as the concentration of the catalysts, pH, and the concentration of hydrogen peroxide on the catalytic activity of LFP were also analyzed.