Exacerbation of non-steroidal anti-inflammatory drug-induced enteropathy in C-C chemokine receptor type 7-deficient mice.

BACKGROUND AND AIM: Non-steroidal anti-inflammatory drugs (NSAIDs) induce intestinal enteropathy and the pathophysiology is related to immune-mediated mechanisms. We aimed to investigate the role of C-C chemokine receptor type 7 (CCR7) which regulates immune cell migration in NSAID-induced enteropathy. METHODS: Injury of the small intestine was evaluated 24 h after the subcutaneous injection of indomethacin in CCR7-deficient (Ccr7-/- ) and wild-type (WT) mice. The cellular profile and cytokine production in intestinal cells were analyzed. Indomethacin-induced enteropathy was evaluated in mice adoptively transferred with CD103+ dendritic cells (DCs) from Ccr7-/- or WT mice. RESULTS: Indomethacin induced more severe intestinal injury in Ccr7-/- mice than in WT mice. The major inflammatory cytokines were not increased and the proportion of regulatory T cells following indomethacin injection was not decreased in Ccr7-/- mice compared with WT mice. The expression of interleukin (IL)-22 binding protein (IL-22BP), which inhibits IL-22 activity, was significantly higher in CD103+ DCs from Ccr7-/- mice than those from WT mice. Mice adoptively transferred with CD103+ DCs isolated from Ccr7-/- mice exhibited more severe intestinal injury following indomethacin injection compared with those adoptively transferred with CD103+ DCs of WT mice. Ccr7-/- mice injected with indomethacin showed a significant reduction in regenerating islet-derived 1 (Reg1) mRNA expression, which is regulated by IL-22, in intestinal epithelial cells. CONCLUSIONS: C-C chemokine receptor type 7 deficiency exacerbated NSAID-induced enteropathy in association with an altered phenotype of CD103+ DCs that produces IL-22BP. CCR7 contributes to protect the small intestine from NSAID-induced mucosal injury.

Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Use of a convolutional neural network for classifying microvessels of superficial esophageal squamous cell carcinomas.

BACKGROUND AND AIM: The morphological diagnosis of microvessels on the surface of superficial esophageal squamous cell carcinomas using magnifying endoscopy with narrow-band imaging is widely used in clinical practice. Nevertheless, inconsistency, even among experts, remains a problem. We constructed a convolutional neural network-based computer-aided diagnosis system to classify the microvessels of superficial esophageal squamous cell carcinomas and evaluated its diagnostic performance. METHODS: In this retrospective study, a cropped magnifying endoscopy with narrow-band images from superficial esophageal squamous cell carcinoma lesions was used as the dataset. All images were assessed by three experts, and classified into three classes, Type B1, B2, and B3, based on the Japan Esophagus Society classification. The dataset was divided into training and validation datasets. A convolutional neural network model (ResNeXt-101) was trained and tuned with the training dataset. To evaluate diagnostic accuracy, the validation dataset was assessed by the computer-aided diagnosis system and eight endoscopists. RESULTS: In total, 1777 and 747 cropped images (total, 393 lesions) were included in the training and validation datasets, respectively. The diagnosis system took 20.3 s to evaluate the 747 images in the validation dataset. The microvessel classification accuracy of the computer-aided diagnosis system was 84.2%, which was higher than the average of the eight endoscopists (77.8%, P < 0.001). The area under the receiver operating characteristic curves for diagnosing Type B1, B2, and B3 vessels were 0.969, 0.948, and 0.973, respectively. CONCLUSIONS: The computer-aided diagnosis system showed remarkable performance in the classification of microvessels on superficial esophageal squamous cell carcinomas.

Oligosaccharide-dependent anti-inflammatory role of galectin-1 for macrophages in ulcerative colitis.

BACKGROUND AND AIM: Galectin-1 plays a protective role against colitis by binding with polylactosamine structures on macrophages in ß-1,4-galactosyltransferase I-deficient mice, but the precise function of galectin-1 remains unknown. In the present study, we investigated the anti-inflammatory role of galectin-1 on macrophages to ameliorate ulcerative colitis in both animal model and human tissue samples. METHODS: The expression of galectin-1 in colonic tissues of ulcerative colitis patients was evaluated by immunohistochemistry. Cytokine production of mouse bone marrow-derived macrophages (BMDMs) cultured with galectin-1 was investigated. Galectin-1 binding capacity and polylactosamine expression in macrophages stimulated with lipopolysaccharides were evaluated by flow cytometry. BMDMs cultured with galectin-1 were transferred into Recombination activating gene (Rag) 2-/- mice, and the severity of the dextran sodium sulfate-induced colitis model was investigated. Furthermore, RNA sequencing was performed to characterize macrophages treated with galectin-1. RESULTS: In ulcerative colitis patients, tissue expression of galectin-1was decreased in inflamed mucosa compared with non-inflamed mucosa. Galectin-1 induced interleukin-10 production in BMDMs, and the interleukin-10 production was abrogated by lactose, which inhibits the interaction of oligosaccharide-galectin binding. Dextran sodium sulfate colitis was significantly ameliorated in Rag2-/- mice undergoing galectin-1-treated BMDM transfer compared with those undergoing vehicle-treated BMDM transfer. RNA sequencing revealed that treatment with galectin-1 increased the expression of CCAAT/enhancer binding protein ß and CD163, but decreased the expression of CD80 on BMDMs. CONCLUSION: Galectin-1, whose expression is decreased in the inflamed mucosa of ulcerative colitis patients, can ameliorate murine colitis by conferring oligosaccharide-dependent anti-inflammatory properties to macrophages.

Novel mass spectrometry-based comprehensive lipidomic analysis of plasma from patients with inflammatory bowel disease.

BACKGROUND AND AIM: Lipids play important roles in inflammation and may be involved in the pathophysiology of inflammatory bowel disease (IBD). Here, we evaluated the characteristics of the plasma lipid profile in patients with IBD. METHODS: Plasma samples were collected from 20 patients with Crohn's disease (CD), 20 patients with ulcerative colitis (UC), and 10 healthy volunteers (HVs) after overnight fasting. The subjects were men between 20 and 49 years of age with no history of hyperlipidemia. A total of 698 molecular species in 22 lipid classes were analyzed by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS: Lipid classes of lysophosphatidic acid, lysophosphatidylserine (LPS), phosphatidylserine (PS), and shingosine-1-phosphate (S1P) were significantly increased in UC patients compared with the HV. The LPS, PS, and S1P levels were significantly increased, while those of lysophosphatidylinositol and phosphatidylcholine were significantly decreased in CD patients compared with HV. Among PS species, the levels of PSacyl (PSa) 40:3, PSa 38:3, and PSa 42:4 were significantly higher in CD patients, both active and remissive stage, than in HV. The LPS 18:0 level was significantly higher in CD and UC patients compared with HV. PSa 40:3 and PSa 38:3 levels positively correlated with the Crohn's Disease Activity Index, erythrocyte sedimentation rate, and platelet count and negatively correlated with hemoglobin, hematocrit, and albumin levels in CD patients. CONCLUSION: The lipid profile in IBD patients exhibits significant alterations, and PS levels are associated with clinical disease activity in CD patients.

Hyperuricemia is a significant risk factor for the onset of chronic kidney disease.

BACKGROUND: Recent studies have shown that hyperuricemia is an independent risk factor for cardiovascular disease. However, few studies have examined whether hyperuricemia is a risk factor for chronic kidney disease (CKD), so to investigate the significance of hyperuricemia as a risk factor for CKD, we analyzed data collected in annual health check-ups. METHODS: The data of 11,048 subjects who underwent an annual health check-up were analyzed in cross-sectional and longitudinal studies. RESULTS: After adjustment for covariate factors, a multivariate logistic regression analysis showed that age, systolic blood pressure, diastolic blood pressure, LDL-cholesterol, triglyceride, HbA1c, and uric acid (hazard ratio: 1.66) were independently and significantly associated with CKD. We also analyzed the data of 1,652 subjects who underwent annual health check-ups for 5 consecutive years. Over that 5-year period, 93 subjects developed CKD. We compared the baseline data of the subjects who developed CKD with the data of those who did not, and we found significant between-group differences in gender, age, HDL-cholesterol, the estimated glomerular filtration rate, and uric acid. After adjustment for several covariate factors, a multivariate Cox regression analysis showed that only age and hyperuricemia (hazard ratio: 1.36) were independent risk factors for the development of CKD. CONCLUSIONS: We found that hyperuricemia is an independent risk factor for the development of CKD.

Relationship between serum uric acid and serum oxidative stress markers in the Japanese general population.

BACKGROUND: Increased production of reactive oxygen species is a condition that is associated with, and plays a role in the progression of, various disorders such as hypertension, atherosclerosis, and diabetes. PURPOSE: To assess in vivo oxidative stress levels and antioxidant potential and to analyze the relationship with serum uric acid (UA) levels. METHODS AND RESULTS: Oxidative stress levels (derivatives of reactive oxygen metabolites, d-ROMs) and antioxidant potential (biological antioxidant potential, BAP) were measured in individuals who underwent a general health screening test, and data were analyzed from 8,025 individuals (2,953 women and 5,072 men) who were free from UA-lowering medication. Higher serum UA levels were associated with increased levels of d-ROMs in both genders, and this trend was more prominent in women. In addition, higher UA levels were also associated with higher BAP in both genders, although the dose dependence was not apparent in men. These associations remained statistically significant after adjusting for age, blood pressure, renal function, albuminuria, C-reactive protein, and insulin resistance index. CONCLUSIONS: In individuals who underwent general health screening, serum UA levels were positively associated with both d-ROMs and BAP levels. Whether lowering of UA by lifestyle modification or by medication alters d-ROM/BAP levels awaits further investigations. .

Relationship between coffee consumption, oxidant status, and antioxidant potential in the Japanese general population.

BACKGROUND: Several previous studies have demonstrated an association between habitual coffee intake and reduced risk of diabetes, cardiovascular morbidity and total mortality. Although the cause and effect relationship could not be determined through epidemiological data, antioxidant properties of coffee ingredients are presumed. METHODS: In the current study, by analyzing the data from 9877 subjects (mean age 59.2±10.4 years) who underwent general health screening, we evaluated the extent of in vivo oxidative stress by measuring derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP). RESULTS: The mean levels of d-ROM and BAP were significantly lower in women than in men. By univariate analysis (ANOVA), coffee consumption showed a graded negative association with d-ROM value in men, but not in women. Coffee consumption was unrelated to BAP levels in men and women. Smoking was significantly associated with increased d-ROM and decreased BAP values in men. Multivariate-adjusted analysis showed that coffee intake of three or more cups per day was an independent negative correlate of d-ROM value in men. Sugar use was negatively associated with d-ROM and BAP values in women. CONCLUSIONS: Among an essentially healthy population, coffee intake was negatively associated with d-ROMs in men, but not in women. Whether the favorable effect of coffee, if present, is related to lower oxidative stress levels needs further investigation.

Relationship between estimated glomerular filtration rate, albuminuria, and oxidant status in the Japanese population.

BACKGROUND: In the general population, reported levels of oxidative stress and antioxidant potential seem to vary. The aim of this study was to investigate the levels of oxidant status markers in relation to estimated glomerular filtration rate (eGFR) and albuminuria in Japanese population. METHODS: Data were analyzed from 8335 individuals who underwent a general health screening test. For the estimation of albuminuria, urinary albumin-to-creatinine ratio (UAER) was calculated. Oxidant status was determined by assessing derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP). RESULTS: After adjusting for age, high blood pressure, depressor agent use, CRP, smoking status, multivariate logistic regression analysis showed that the lowest eGFR quartile was associated negatively with the top d-ROM quartile in men (odds ratio 0.78 [95% CI 0.62-0.98, P = 0.034]) and the highest UAER was associated with the top d-ROM in men (odds ratio 1.68) [95% CI 1.35-2.10, P < 0.001]. In addition, both the first eGFR quartile and the fourth UAER quartile showed significant positive association with low BAP levels in men, but not in women. CONCLUSIONS: Among men who underwent general health screening, lower eGFR and increased albuminuria was negatively and positively, respectively, associated with higher oxidative stress levels, whereas both conditions were positively associated with lower antioxidant potential levels.

Carbon dioxide insufflation reduces the relapse of ulcerative colitis after colonoscopy: A randomized controlled trial.

BACKGROUND AND AIM: Colonoscopy is necessary for diagnosing and surveilling patients with ulcerative colitis, though it may cause disease flares. Colonoscopy with carbon dioxide (CO2) insufflation decreases abdominal discomfort; however, its effect on exacerbation incidence in ulcerative colitis remains unclear. Therefore, this study aimed to evaluate the colonoscopy effects using CO2 insufflation in patients with ulcerative colitis. METHODS: Overall, 96 remissive patients with ulcerative colitis (partial Mayo score ≤ 2) who underwent total colonoscopy between March 2015 and December 2019 at Osaka University Hospital were enrolled and blindly randomized to the CO2 (n = 45) and air (n = 51) insufflation group (UMIN-CTR, number: UMIN000018801). The post-procedural abdominal discomfort and the clinical relapse (partial Mayo score ≥ 3) rate within 8 weeks were evaluated. RESULTS: Baseline backgrounds did not differ between the groups. The mean abdominal fullness and pain scores were significantly lower in the CO2 group than in the Air group immediately (p = 0.0003, p = 0.0003) and 30 min (p < 0.0001, p < 0.0001) after colonoscopy. While the overall clinical relapse rate remained unchanged between the groups, the clinical relapse rate at 8 weeks after colonoscopy was significantly lower in the CO2 group than in the Air group in patients not in complete remission (Mayo endoscopic subscore ≥ 1, p = 0.049; or partial Mayo score ≥ 1, p = 0.022). CONCLUSIONS: CO2 insufflation can reduce abdominal discomfort in remissive patients with ulcerative colitis and decrease clinical relapse at 8 weeks after colonoscopy for those not in complete remission.

Seasonal variations in gut microbiota and disease course in patients with inflammatory bowel disease.

BACKGROUND AND AIM: Environmental factors are associated with onset and course of inflammatory bowel disease (IBD). Our previous study by about 1,100 IBD patients revealed half of the patients experienced seasonal exacerbation of disease. We investigated the seasonality of fecal microbiota composition of IBD patients. METHODS: Fecal samples were consecutively collected in each season from IBD outpatients and healthy controls between November 2015 and April 2019. Participants who were treated with full elemental diet or antibiotics within 6 months or had ostomates were excluded. Bacterial profiles were analyzed by 16S rRNA sequencing, and the changes between the diseases and seasons were compared. RESULTS: A total of 188 fecal samples were analyzed from 47 participants comprising 19 Crohn's disease (CD) patients, 20 ulcerative colitis (UC) patients, and 8 healthy controls (HC). In CD patients, the phylum Actinobacteria and TM7 were both significantly more abundant in autumn than in spring and winter, but not in UC patients and HC. Moreover, the genera Actinomyces, a member of Actinobacteria, and c_TM7-3;o_;f_;g_ (TM7-3), that of TM7, were significantly more abundant in autumn than in spring, and the abundance of Actinomyces was significantly correlated with that of TM7-3 throughout the year in CD patients, but not in UC patients and HC. CD patients with high abundance of TM7-3 in the autumn required significantly fewer therapeutic intervention than those without seasonal fluctuation. CONCLUSIONS: Oral commensals Actinomyces and its symbiont TM7-3 were correlatively fluctuated in the feces of CD patients by season, which could affect the disease course.

Infantile-Onset Isolated Neurohypophyseal Langerhans Cell Histiocytosis with Central Diabetes Insipidus: A Case Report.

Central diabetes insipidus (CDI) is a rare disease in children and has a variety of etiologies. The major causes of CDI with pituitary stalk thickening (PST) are germinoma, Langerhans cell histiocytosis (LCH), and Lymphocytic infundibulo-neurohypophysitis, which are difficult to differentiate by imaging and require pathological diagnosis. We report a case of infantile-onset isolated neurohypophyseal LCH diagnosed by pathological findings. A 2-year-old girl presented with polydipsia and polyuria. CDI was diagnosed and treatment with oral desmopressin was initiated. Magnetic resonance imaging (MRI) of the head showed PST and absence of high-signal intensity of posterior pituitary on T1-weighted images. Follow-up MRI scans showed that the tumor mass was gradually increasing and extending posteriorly toward the area near the mamillary body. Simultaneously, anterior pituitary dysfunction was observed. She underwent a biopsy of the PST and LCH was diagnosed by immunohistochemical analysis. DNA analysis showed no BRAF V600E mutation. Monotherapy with 2-Chlorodeoxyadenosine reduced the tumor size but did not improve pituitary function. Isolated neurohypophyseal LCH should be considered in infantile-onset cases of CDI with PST. 2-CdA treatment resulted in rapid PST shrinkage. Further cases are needed to determine whether early diagnosis and treatment can prevent anterior pituitary dysfunction.

Lysophosphatidylserines derived from microbiota in Crohn's disease elicit pathological Th1 response.

Microbiota alteration and IFN-γ-producing CD4+ T cell overactivation are implicated in Crohn's disease (CD) pathogenesis. However, it remains unclear how dysbiosis enhances Th1 responses, leading to intestinal inflammation. Here, we identified key metabolites derived from dysbiotic microbiota that induce enhanced Th1 responses and exaggerate colitis in mouse models. Patients with CD showed elevated lysophosphatidylserine (LysoPS) concentration in their feces, accompanied by a higher relative abundance of microbiota possessing a gene encoding the phospholipid-hydrolyzing enzyme phospholipase A. LysoPS induced metabolic reprogramming, thereby eliciting aberrant effector responses in both human and mouse IFN-γ-producing CD4+ T cells. Administration of LysoPS into two mouse colitis models promoted large intestinal inflammation. LysoPS-induced aggravation of colitis was impaired in mice lacking P2ry10 and P2ry10b, and their CD4+ T cells were hyporesponsive to LysoPS. Thus, our findings elaborate on the mechanism by which metabolites elevated in patients with CD harboring dysbiotic microbiota promote Th1-mediated intestinal pathology.

Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25-0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26-0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly (P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns.

Association between changes in obesity parameters and incidence of chronic kidney disease in Japanese individuals.

Obesity increases the risk for chronic kidney disease (CKD). By analyzing data on individuals who underwent general health screening in two consecutive years, we investigated whether changes in body mass index (BMI) or waist circumference (WC) were associated with the appearance or disappearance of the CKD components; micro-/macroalbuminuria (> or =30 mg urinary albumin per gram creatinine) and a low estimated glomerular filtration rate (eGFR; <60 ml/min/1.73 m(2)). Logistic regression analysis showed that in men with micro-/macroalbuminuria at the first visit, a BMI reduction of > or =0.42 or a WC reduction of > or =3.0 cm over the 1-year period resulted in a significantly reduced incident of micro-/macroalbuminuria at the second visit. On the other hand, a BMI gain of > or =0.33 over 1 year in men without micro-/macroalbuminuria and a low eGFR at the fist visit significantly increased the incident of micro-/macroalbuminuria and a low eGFR, respectively, at the second visit. These findings indicate that lowering the obesity indexes in men with micro-/macroalbuminuria reduced the incidence of this condition at the 1-year follow-up and that, on the contrary, an increase in BMI in men without micro-/macroalbuminuria and a low eGFR at the first examination increased the risk of these conditions during the 1-year follow-up period.

Relationship between albuminuria, low eGFR, and carotid atherosclerosis in Japanese women.

In this cross-sectional study, we have investigated whether chronic kidney disease components were associated with carotid plaque and carotid intima-media thickening in women. Between April 2005 and May 2006, 830 women underwent general health screening including carotid ultrasonography and urinary albumin excretion, and were enrolled in the study. Of these individuals examined, 83 (10%) had albuminuria, 203 (24%) had low estimated GFR (eGFR), and 24 (3%) had both albuminuria and low eGFR. Univariate analysis showed that albuminuria, but not low eGFR, was associated with carotid plaque, and that both albuminuria and low eGFR were positively associated with carotid intima-media thickening. Age-adjusted logistic regression analysis showed that albuminuria was positively associated with carotid plaque with an odds ratio of 2.48 (95% CI 1.49-4.11, p < 0.001). On the other hand, association between albuminuria and carotid intima-media thickening was not statistically significant after age adjustment. Positive association between albuminuria and carotid plaque was present when either hypertension or high fasting glucose was absent. In conclusion, in Japanese women who underwent general health screening, albuminuria, but not low eGFR, was positively associated with carotid plaque.

Plasma amino acid profile associated with fatty liver disease and co-occurrence of metabolic risk factors.

Fatty liver disease (FLD) increases the risk of diabetes, cardiovascular disease, and steatohepatitis, which leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Thus, the early detection of FLD is necessary. We aimed to find a quantitative and feasible model for discriminating the FLD, based on plasma free amino acid (PFAA) profiles. We constructed models of the relationship between PFAA levels in 2,000 generally healthy Japanese subjects and the diagnosis of FLD by abdominal ultrasound scan by multiple logistic regression analysis with variable selection. The performance of these models for FLD discrimination was validated using an independent data set of 2,160 subjects. The generated PFAA-based model was able to identify FLD patients. The area under the receiver operating characteristic curve for the model was 0.83, which was higher than those of other existing liver function-associated markers ranging from 0.53 to 0.80. The value of the linear discriminant in the model yielded the adjusted odds ratio (with 95% confidence intervals) for a 1 standard deviation increase of 2.63 (2.14-3.25) in the multiple logistic regression analysis with known liver function-associated covariates. Interestingly, the linear discriminant values were significantly associated with the progression of FLD, and patients with nonalcoholic steatohepatitis also exhibited higher values.

Current dietary salt intake of Japanese individuals assessed during health check-up.

Excess salt intake is a risk factor for increased blood pressure (BP) and hypertension. To prevent hypertension, the reduction of salt intake is promoted in many countries. For people with hypertension or cardiovascular disease (CVD), a more severe restriction of salt intake is indispensable. Japanese individuals consume high quantities of salt, and it is thus important to determine the degree to which the salt intake of these individuals has been restricted. Here, we investigated the current level of salt consumption of Japanese individuals using data obtained during annual health check-ups. A total of 10 762 individuals were assessed who underwent annual health check-ups at our institution in 2011. The estimated daily salt intake (EDSI) was calculated using spot urine samples. The average EDSI was 7.83±2.02 g per day. BP increased in proportion to the EDSI, and multivariate logistic regression analysis showed that the EDSI was a significant and independent risk factor for hypertension. The average EDSI of the subjects with hypertension or a history of CVD was higher than that of the subjects without these diseases. The subjects who drank more heavily showed higher EDSIs. This study demonstrated that the average EDSI of the subjects needing to restrict their salt intake because of past or present illnesses was high. To achieve adherence to the recommended reduction of salt intake, more efforts are required.

Plasma Free Amino Acid Profiles Predict Four-Year Risk of Developing Diabetes, Metabolic Syndrome, Dyslipidemia, and Hypertension in Japanese Population.

Plasma free amino acid (PFAA) profile is highlighted in its association with visceral obesity and hyperinsulinemia, and future diabetes. Indeed PFAA profiling potentially can evaluate individuals' future risks of developing lifestyle-related diseases, in addition to diabetes. However, few studies have been performed especially in Asian populations, about the optimal combination of PFAAs for evaluating health risks. We quantified PFAA levels in 3,701 Japanese subjects, and determined visceral fat area (VFA) and two-hour post-challenge insulin (Ins120 min) values in 865 and 1,160 subjects, respectively. Then, models between PFAA levels and the VFA or Ins120 min values were constructed by multiple linear regression analysis with variable selection. Finally, a cohort study of 2,984 subjects to examine capabilities of the obtained models for predicting four-year risk of developing new-onset lifestyle-related diseases was conducted. The correlation coefficients of the obtained PFAA models against VFA or Ins120 min were higher than single PFAA level. Our models work well for future risk prediction. Even after adjusting for commonly accepted multiple risk factors, these models can predict future development of diabetes, metabolic syndrome, and dyslipidemia. PFAA profiles confer independent and differing contributions to increasing the lifestyle-related disease risks in addition to the currently known factors in a general Japanese population.

Serum gamma-glutamyltransferase level is associated with serum superoxide dismutase activity and metabolic syndrome in a Japanese population.

BACKGROUND: Serum gamma-glutamyltransferase level has attracted considerable attention as a predictor of various conditions, such as cardiovascular disease and cancer. Although the mechanism that links the serum gamma-glutamyltransferase level to these diseases is not fully understood, one explanation is that gamma-glutamyltransferase may be closely related to oxidative stress. We conducted a large cross-sectional study to evaluate the relationship between serum gamma-glutamyltransferase and oxidative stress. METHODS: We examined anti-oxidative stress activity and accumulation of oxidative stress in serum obtained from 2907 subjects who underwent a complete health check-up. We used serum total superoxide dismutase activity as an index of anti-oxidative stress activity. Superoxide dismutase is one of the most important intracellular and extracellular defense systems against superoxide, but the relationship between serum superoxide dismutase activity and the serum gamma-glutamyltransferase level is unclear. RESULTS: The serum gamma-glutamyltransferase level was negatively correlated with serum superoxide dismutase activity, a correlation that was observed even within the normal range. A subgroup analysis stratified by the amount of alcohol consumed also showed a similar correlation. In contrast, the serum gamma-glutamyltransferase level was positively correlated with serum lipid peroxide level, even in the normal range. Furthermore, an increased serum gamma-glutamyltransferase level was significantly associated with the progression of metabolic syndrome and carotid artery intima-media thickness. CONCLUSIONS: The serum gamma-glutamyltransferase level, even in the normal range, was significantly associated with anti-oxidative stress activity, the accumulation of oxidative stress, metabolic syndrome, and atherosclerosis. Measuring the serum gamma-glutamyltransferase level is simple and inexpensive, and this level can be used as a sensitive marker of oxidative stress and metabolic syndrome.