Clinicopathological Features of Remnant Gastric Cancer After Gastrectomy.

BACKGROUND: Remnant gastric cancer (RGC) encompasses all cancers arising from the remnant stomach. Various studies have reported on RGC and its prognosis, but no consensus on its surgical treatment and postoperative management has been reached. Moreover, the correlation between the clinicopathological characteristics and long-term outcomes of RGC remains unclear. This study investigated the clinicopathological factors associated with the long-term survival of RGC patients. METHODS: The medical records (March 1993-September 2020) of 104 RGC patients from Tokyo Medical University Hospital database were analyzed. Of these 104 patients, the medical records of 63 patients who underwent surgical curative resection were analyzed using R. Kaplan-Meier plots of cumulative incidence of RGC were made. Differences in survival rates were compared using the log-rank test. Prognostic factors were analyzed using multivariate Cox regression analysis (P < .05). RESULTS: Of the 104 RGC patients, 63 underwent total remnant stomach excision. The median time from the first surgery to the total excision was 10 years. The 5-year survival rate of the 63 RGC patients was .55 ((95% CI); .417-.671). The clinicopathological factors that were significantly associated with the long-term outcome of the RGC patients were tumor diameter (≥3.5 cm), presence or absence of combined resection of multiple organs, tumor invasion (deeper than T2), TNM stage, and postoperative morbidity. The multivariate Cox regression analysis showed that tumor invasion depth was the only independent prognostic factor for RGC patients [HR (95% CI): 5.49 (2.629-11.5), P ≤ .005]. CONCLUSIONS: Among prognostic factors, tumor invasion depth was the only independent factor affecting RGC's long-term outcome.

Use of Polyglycolic Acid Sheets for the Prevention of Pancreatic Fistula after Laparoscopic Gastrectomy: A Single-Center Retrospective Study.

BACKGROUND: Laparoscopic gastrectomy (LG) indications have been extended to advanced gastric cancer requiring expansive lymph node dissection. Despite the huge benefits of this minimally invasive surgery, major complications such as postoperative pancreatic fistula (POPF) remain a concern. With technical advances in surgical procedures, the treatment outcomes of gastric cancer surgery have improved. However, effective methods for preventing POPF have not yet been established. Herein, we examined the usefulness of polyglycolic acid (PGA) sheets for preventing POPF after LG. METHODS: We retrospectively assessed 142 patients who underwent curative LG at our institution between January 2017 and August 2022. The 142 patients were divided into 2 groups; PGA group (n = 61): the site of lymph node dissection at the superior margin of the pancreas and pancreatic head was covered with PGA sheets, and nPGA group (n = 81): the site was not covered. We retrospectively compared the short-term surgical outcomes including POPF incidence. RESULTS: There was no significant difference in the background factors between the 2 groups and in the incidence of Grade II or higher postoperative complications according to the Clavien-Dindo (CD) classification. However, the incidence of CD Grade II or higher POPF was significantly lower in the PGA group than in the nPGA group (.0% vs 2.3%, respectively, P = .007). CONCLUSIONS: There was no POPF in any of the 61 patients in the PGA group. This outcome suggests that POPF incidence may be reduced by covering the lymph node dissection site with PGA sheets after LG.

Structural effect of amine N-oxides on the facilitation of α-glucosidase-catalyzed hydrolysis reactions.

Activation and stabilization of enzymes is an important issue in their industrial application. We recently reported that synthetic betaines, derived from cellular metabolites, structure-dependently increased the activity and stability of various enzymes including hydrolases, oxidases, and synthetases simply by mixing them into the reaction buffer. In this report, we focus on amine N-oxides, which are similarly important metabolites in cells with a highly polarized N-oxide bond, and investigate their enzyme stabilization and activation behavior. It was revealed that synthetic amine N-oxides structure-dependently activate α-glucosidase-catalyzed hydrolysis reactions similarly to betaines. The subsequent comparison of the kinetic parameters, the optimal concentration range for activation, and the maximal activity, suggested that amine N-oxides facilitate hydrolysis reactions via the same mechanism as betaines, because no differences were confirmed. However, the enzyme stabilization effect of amine N-oxides was slightly superior to that of betaines and the temporal stability of the enzyme in aqueous solutions was higher in the low amine N-oxide concentration range. The rheological properties, CD spectra, and dynamic fluorescence quenching experiments suggested that the suppression of unfavorable conformational perturbation was related to the difference in the hydration environments provided by the surrounding water molecules. Thus, we clarified that amine N-oxides facilitate enzyme reactions as a result of their similarity to betaines and provide a superior stabilizing effect for enzymes. Amine N-oxides show potential for application in enzyme storage and long-term reactions.

Discovery of potent liver-selective stearoyl-CoA desaturase-1 (SCD1) inhibitors, thiazole-4-acetic acid derivatives, for the treatment of diabetes, hepatic steatosis, and obesity.

SCD1 is a rate-limiting enzyme in the conversion of saturated fatty acids to monounsaturated fatty acids. SCD1 inhibitors have potential effects on obesity, diabetes, acne, and cancer, but the adverse effects associated with SCD1 inhibition in the skin and eyelids are impediments to clinical development. To avoid mechanism-based adverse effects, we explored the compounds that selectively inhibit SCD1 in the liver in an ex vivo assay. Starting from a systemically active lead compound, we focused on the physicochemical properties tPSA and cLogP to minimize exposure in the off-target tissues. This effort led to the discovery of thiazole-4-acetic acid analog 48 as a potent and liver-selective SCD1 inhibitor. Compound 48 exhibited significant effects in rodent models of diabetes, hepatic steatosis, and obesity, with sufficient safety margins in a rat toxicology study with repeated dosing.

Postnatal BMI changes in children with different birthweights: A trial study for detecting early predictive factors for pediatric obesity.

The purpose of this study was to clarify the degree of early postnatal growth by birthweight and detect early predictive factors for pediatric obesity. Body mass index (BMI) and degree of obesity were examined in children in the fourth year of elementary school and second year of junior high school. Their BMI at birth and three years of age were also examined. Based on birthweight, participants were divided into three groups: low (< 2500 g), middle (2500-3500 g), and high (> 3500 g). Furthermore, according to the degree of obesity, they were divided into two groups: obese (20% ≤) and non-obese (20% >). The change of BMI from birth to three years of age (ΔBMI) showed a strong inverse relationship with birthweight and was significantly different among the three birthweight groups (low > middle > high). The ΔBMI and BMI at three years of age were higher in obese than in non-obese children and showed significant positive correlations with the degree of obesity. Early postnatal growth might be determined by birthweight and was higher in obese than in non-obese children. The ΔBMI from birth to three years of age and BMI at age of three years could be predictive factors for pediatric obesity.

Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion].

This clinical practice guideline of the diagnosis and treatment of adrenal insufficiency (AI) including adrenal crisis was produced on behalf of the Japan Endocrine Society. This evidence-based guideline was developed by a committee including all authors, and was reviewed by a subcommittee of the Japan Endocrine Society. The Japanese version has already been published, and the essential points have been summarized in this English language version. We recommend diagnostic tests, including measurement of basal cortisol and ACTH levels in combination with a rapid ACTH (250 µg corticotropin) test, the CRH test, and for particular situations the insulin tolerance test. Cut-off values in basal and peak cortisol levels after the rapid ACTH or CRH tests are proposed based on the assumption that a peak cortisol level ≥18 µg/dL in the insulin tolerance test indicates normal adrenal function. In adult AI patients, 15-25 mg hydrocortisone (HC) in 2-3 daily doses, depending on adrenal reserve and body weight, is a basic replacement regime for AI. In special situations such as sickness, operations, pregnancy and drug interactions, cautious HC dosing or the correct choice of glucocorticoids is necessary. From long-term treatment, optimal diurnal rhythm and concentration of serum cortisol are important for the prevention of cardiovascular disease and osteoporosis. In maintenance therapy during the growth period of patients with 21-hydroxylase deficiency, proper doses of HC should be used, and long-acting glucocorticoids should not be used. Education and carrying an emergency card are essential for the prevention and rapid treatment of adrenal crisis.

Urinary myo-inositol levels in Japanese schoolchildren with normal glucose tolerance.

BACKGROUND: Urinary myo-inositol (UMI) level is elevated in adult diabetic patients, and also increases after glucose loading. However, the relationship between UMI and plasma glucose levels in children is unknown. We aimed to assess whether UMI is a practical marker for glucose intolerance in children or not. METHODS: In Study 1 (328 schoolchildren), fasting and postprandial UMI were measured, with ΔUMI defined as the difference between fasting and postprandial UMI levels. In Study 2, oral glucose tolerance tests and UMI measurements were conducted in 18 children with suspected having diabetes. RESULTS: For Study 1, ΔUMI was observed [-0.65 (-3.9, 1.35) mg/g creatinine]. For Study 2, children with diabetes or impaired glucose tolerance had a significantly higher ΔUMI than children with normal glucose tolerance. CONCLUSIONS: These studies demonstrated the normal range of UMI in children and possibility of a novel biomarker for early detection of glucose intolerance in children.

Development of waist circumference percentiles for Japanese children and an examination of their screening utility for childhood metabolic syndrome: a population-based cross-sectional study.

BACKGROUND: In Japan, waist circumference (WC) percentiles to screen for childhood metabolic syndrome (MetS) are unavailable. The objectives of this study were to develop WC and WC-to-height ratio (WC/Ht) percentile curves by age and sex for Japanese children, and to test their utility in screening for MetS in children with obesity who are otherwise healthy. METHODS: The WC and WC/Ht percentiles were developed using the LMS method of summarizing growth standards, which monitors changing skewness (L), medians (M), and coefficients of variation (S) in childhood distributions. A representative dataset was used, which consisted of 3,634 boys and 3,536 girls aged 4.5-12.75 years in Shizuoka prefecture, Japan, between 2010 and 2012. Children who were obese (355 boys and 230 girls) aged 6-12 years from Osaka prefecture, Japan, were screened for childhood MetS using the new percentiles and the International Diabetes Federation's (IDF's) definition of MetS. RESULTS: The number of participants with certain metabolic abnormalities (high systolic and diastolic blood pressure, and a high level of triglycerides) was significantly higher in boys aged 10-12 years, with a WC ≥ 90th percentile, than among those with a WC < 90th percentile. None of the participants with a WC < 90th percentile exhibited two or more metabolic abnormalities, regardless of their age or sex. Among the participants aged 10-12 years, 11.4 % of boys and 4.4 % of girls with a WC ≥ 90th percentile were diagnosed with MetS. CONCLUSIONS: The new percentiles may have a certain level of potential to screen Japanese children for childhood MetS in accordance with the IDF definition.

[Desflurane Anesthesia in a Morbidly Obese Patient with Severe Obstructive Sleep Apnea].

A 33-year-old morbidly obese patient (body mass index = 59.5 kg x m(-2)) with severe obstructive sleep apnea was scheduled to undergo osteosynthesis of right radial, ulnar and femoral fractures under general anesthesia. Awake intubation under conscious sedation using fantanyl and midazolam was performed by the Pentax-AWS Airwayscope. By using desflurane under continuous infusion of remifentanil 0.2-0.5 µg x kg(-1) x min(-1), BIS values were maintained between 40 and 60 during the surgery. Although duration of surgery was long (430 minutes), the times from discontinuation of the anesthetic drug to eye opening and extubation were 82 seconds and 8.5 minutes, respectively. Respiratory depression was minimal during postoperative period. In this case desflurane was safely used in a morbidly obese patient with severe obstructive sleep apnea.

Enhanced Immunostimulating Activity of Lactobacilli-Mimicking Materials by Controlling Size.

The design and synthesis of materials capable of activating the immune system in a safe manner is of great interest in immunology and related fields. Lactobacilli activate the innate immune system of a host when acting as probiotics. Here, we constructed lactobacilli-mimicking materials in which polysaccharide-peptidoglycan complexes (PS-PGs) derived from lactobacilli were covalently conjugated to the surfaces of polymeric microparticles with a wide variety of sizes, ranging from 200 nm to 3 µm. The artificial lactobacilli successfully stimulated macrophages without cytotoxicity. Importantly, we found that the size of artificial lactobacilli strongly influenced their immunostimulating activities, and that artificial lactobacilli of 1 µm exhibited 10-fold higher activity than natural lactobacilli. One major advantage of the artificial lactobacilli is facile control of size, which cannot be changed in natural lactobacilli. These findings provide new insights into the design of materials for immunology as well as the molecular biology of lactobacillus.

Significance of anionic functional group in betaine-type metabolite analogs on the facilitation of enzyme reactions.

Using synthetic sulfobetaine library, the enzyme activation behavior has been investigated. Comparison of enzyme activation behavior revealed that sulfobetaines equally facilitate enzyme reactions, being consistent with that of carboxybetaines. The subsequent kinetic and solution property analyses clarified that both the kinetic parameter and hydration property changes are identical with those of carboxybetaines, indicating that the difference in the anionic functional group of the betaine structure scarcely affects the enzyme activation. On the other hand, comparison of carboxy- or sulfo-betaines with tetraalkylammonium salts, whose counteranion binds to the ammonium cation intermolecularly, revealed that the activation ability for enzymes of tetraalkylammonium salts is considerably smaller than that of carboxy- or sulfo-betaines. These findings give us a hint to design the useful betaine-type enzyme activators.

Cryoprotective ability of betaine-type metabolite analogs during freezing denaturation of enzymes.

OBJECTIVE: To evaluate an analog library of betaine-type cellular metabolites, which are naturally found in polar fish for survival in subzero temperatures, for preventing denaturation of enzymes during freezing. RESULTS: Comparison of the cryoprotective ability of reported cryoprotectants, such as dimethylsulfoxide, glycerol, ectoine, hydroxyectoine, and trehalose, with betaine-type analogs using α-glucosidase revealed that analogs introducing C3-C6 alkyl chains into an ammonium cation retained 20 % higher activity than the control cryoprotectants at the same concentration. In particular, the analog possessing triplicate n-butyl chains showed a profound effect. It allowed retention of enzyme activity to 95 % even after 100 freeze-thaw cycles, while addition of the control cryoprotectants decreased the activity to 10-20 %. The cryoprotective ability of betaine-type analogs can be applied not only to α-glucosidase but also other enzymes such as ß-glucosidase, alkaline phosphatase, lactose dehydrogenase, sulfatase, and horseradish peroxidase. CONCLUSION: Synthetic betaine-type metabolite analogs possess practicable cryoprotective ability for various enzymes, and are considerably superior to previously reported cryoprotectants.

[Very late thrombosis of a drug-eluting stent presenting during the operation].

We report a case of very late thrombosis of sirolimus-eluting stent 38 months after implantation of a drug-eluting stent. An 81-year-old woman was suffering from acute cholecystitis and cholelithiasis and laparoscopic cholecystectomy was scheduled. Seven days before the operation, the patient's aspirin was replaced with heparin injection, which was discontinued 4 hours before the operation. During the operation we noticed ST-segment elevation on the monitor. An urgent coronary angiography was performed immediately after the operation, and stent thrombosis was found. Removal of the thrombosis and plain old balloon angioplasty was performed. We should exercise extreme caution for patients undergoing operation after implantation of DES quite a long time ago. We should have concrete guidelines for the treatment of DES patients in the perioperative period.

The lipid fraction of human milk initiates adipocyte differentiation in 3T3-L1 cells.

BACKGROUND: The prevalence of childhood obesity has increased worldwide over the past decade. Despite evidence that human milk lowers the risk of childhood obesity, the mechanism is not fully understood. AIMS: We investigated the direct effect of human milk on differentiation of 3T3-L1 preadipocytes. STUDY DESIGN AND SUBJECTS: 3T3-L1 preadipocytes were treated with donated human milk only or the combination of the standard hormone mixture; insulin, dexamethasone (DEX), and 3-isobututyl-1-methylxanthine (IBMX). Furthermore, the induction of preadipocyte differentiation by extracted lipids from human milk was tested in comparison to the cells treated with lipid extracts from infant formula. Adipocyte differentiation, specific genes as well as formation of lipid droplets were examined. RESULTS: We clearly show that lipids present in human milk initiate 3T3-L1 preadipocyte differentiation. In contrast, this effect was not observed in response to lipids present in infant formula. The initiation of preadipocyte differentiation by human milk was enhanced by adding the adipogenic hormone, DEX or insulin. The expression of late adipocyte markers in Day 7 adipocytes that have been induced into differentiation with human milk lipid extracts was comparable to those in control cells initiated by a standard adipogenic hormone cocktail. CONCLUSIONS: These results demonstrate that human milk contains bioactive lipids that can initiate preadipocyte differentiation in the absence of the standard adipogenic compounds via a unique pathway.

Specific reduction of G6PT may contribute to downregulation of hepatic 11ß-HSD1 in diabetic mice.

Pre-receptor activation of glucocorticoids via 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1 (HSD11B1)) has been identified as an important mediator of the metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) mediates 11ß-HSD1 amplifying tissue glucocorticoid production by driving intracellular NADPH exposure to 11ß-HSD1 and requires glucose-6-phosphate transporter (G6PT (SLC37A4)) to maintain its activity. However, the potential effects of G6PT on tissue glucocorticoid production in type 2 diabetes and obesity have not yet been defined. Here, we evaluated the possible role of G6PT antisense oligonucleotides (G6PT ASO) in the pre-receptor metabolism of glucocorticoids as related to glucose homeostasis and insulin tolerance by examining the production of 11ß-HSD1 and H6PDH in both male db/+ and db/db mouse liver tissue. We observed that G6PT ASO treatment of db/db mice markedly reduced hepatic G6PT mRNA and protein levels and substantially diminished the activation of hepatic 11ß-HSD1 and H6PDH. Reduction of G6pt expression was correlated with the suppression of both hepatic gluconeogenic enzymes G6Pase and PEPCK and corresponded to the improvement of hyperglycemia and insulin resistance in db/db mice. Addition of G6PT ASO to mouse hepa1-6 cells led to a dose-dependent decrease in 11B-Hsd1 production. Knockdown of G6PT with RNA interference also impaired 11B-Hsd1 expression and showed comparable effects to H6pdh siRNA on silencing of H6pdh and 11B-Hsd1 expression in these intact cells. These findings suggest that G6PT plays an important role in the modulation of pre-receptor activation of glucocorticoids and provides new insights into the role of G6PT in the development of type 2 diabetes.

Expression of 11beta-hydroxysteroid dehydrogenase 2 contributes to glucocorticoid resistance in lymphoblastic leukemia cells.

Synthetic glucocorticoids (GCs) form a crucial first-line treatment for childhood acute lymphoblastic leukemia (ALL). However prolonged GC therapy frequently leads to GC-resistance with an unclear molecular mechanism. 11ß-hydroxysteroid dehydrogenase (11ß-HSD) 2 inactivates GCs within cells. Here, we show the association between GC sensitivity and 11ß-HSD2 expression in human T-cell leukemic cell lines. 11ß-HSD2 mRNA and protein levels were considerably higher in GC-resistant MOLT4F cells than in GC-sensitive CCRF-CEM cells. The 11ß-HSD inhibitor, carbenoxolone pre-treatment resulted in greater cell death with prednisolone assessed by methyl-thiazol-tetrazolium assay and caspase-3/7 assay, suggesting that 11ß-HSD2 is a cause of GC-resistance in ALL.

Abdominal obesity is associated with cardiovascular risk in Japanese children and adolescents.

BACKGROUND: Metabolic syndrome is listed as a risk for atherosclerosis. However, changes in that risk during childhood and adolescence have not been well-documented. It is also unclear whether individuals with abdominal obesity, but with as yet undiagnosed metabolic syndrome, have cardiovascular risks. METHODS AND RESULTS: Ninety-two patients were studied at the Hamamatsu University School of Medicine Department of Pediatrics. Physical measurements including abdominal circumference (AC), body mass index (BMI), body fat (BF), intima media thickness (IMT), arterial elasticity: beta index (Beta), carotid artery compliance (CAC), and Young's elastic modulus (YEM) using ultrasonography were taken. A positive correlation between systolic blood pressure, AC, BMI, and BF was observed (AC, r = 0.717, p < 0.001; BMI, r = 0.672, p < 0.001; BF, r = 0.518, p < 0.001). IMT showed a weak positive correlation with AC, BMI and BF (AC, r = 0.211, p = 0.044; BMI, r = 0.233, p = 0.025; BF, r = 0.232, p = 0.026). The relationship between AC, BMI, BF and arterial elasticity, especially in AC, positively correlated with beta index and YEM but negatively correlated with CAC. CONCLUSION: We suggest that AC is the most sensitive marker in the detection of arterial elasticity, even in school age children. Earlier pre-diagnostic intervention, especially in the prevention of abdominal obesity, may reduce the incidence of metabolic syndrome in children and adolescents.

Prevalence of congenital heart disease assessed by echocardiography in 2067 consecutive newborns.

AIM: There are discrepancies in the reported prevalence of congenital heart disease (CHD). This study prospectively evaluated the prevalence of CHD in consecutive newborns using echocardiographic screening. METHODS: A cohort screening study was conducted in an unselected series of all live-birth newborns. Two-dimensional and colour Doppler echocardiography was performed at 0-4 days of life in 2067 consecutive neonates who were born at the Hamamatsu University Hospital, Japan, between May 2005 and April 2010. RESULTS: There were 104 cases of CHD in the 2067 live births. Ventricular septal defect and patent ductus arteriosus were the most frequent cardiac abnormalities. The prevalence of newborns with CHD who had signs or symptoms of CHD and/or required invasive intervention was 21.3 per 1000 live births. However, 60 patients (29.0 per 1000 live births) with CHD were asymptomatic and did not need invasive intervention. The overall prevalence of CHD in this series was 50.3 per 1000 live births. CONCLUSION: This prospective study using echocardiography for all newborns shows a higher prevalence of CHD than almost all of the previous studies.

Age and sex differences in fat distribution in non-obese Japanese children.

OBJECTIVE: To assess fat distribution in non-obese Japanese children and adolescents. DESIGN: 130 non-obese Japanese children (73 boys and 57 girls) from Kikugawa, Hamamatsu were included. The visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by computed tomography (CT) and calculated (in cm(2)). Subjects were divided into three groups based on age: group A (6-10 years), group B (11-15 years), and group C (16-20 years). RESULTS: Girls had more subcutaneous fat than boys in groups B and C (P<0.01). Boys had an age-dependent increase in visceral fat, but girls did not. In group C (16-20 years), boys had more visceral fat than girls (P<0.01). CONCLUSIONS: In non-obese Japanese children, there are significant differences in visceral and subcutaneous fat amounts by age and sex. VFA seems to accumulate more in boys than in girls, and SFA is more prevalent in girls than boys.