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Several medications are commonly administered to older Japanese patients. Since some of them have not been included in previously developed scales to estimate the anticholinergic burden, we have developed a new muscarinic receptor binding-based anticholinergic burden scale. This study aimed to investigate the functional inhibitory effects of 60 medications, classified as anticholinergic burden scales 3 and 2 by the anticholinergic burden scale, on muscarinic receptor-mediated contractions in the bladder and ileum. The relaxation response induced by these drugs on isolated rat bladders and ileum smooth muscles constricted by carbachol was assessed using the organ bath method. All drugs inhibited smooth muscle contractile responses induced by the muscarinic receptor activation in a concentration-dependent manner in the rat bladder and ileum. Notably, variations were observed in the relaxation responses of the drugs, and the function EC 50 values were positively correlated with the binding IC 50 values in the bladder and ileum. The results of this study provide functional pharmacological evidence for the muscarinic receptor binding-based anticholinergic burden scale. Implementation of this scale may help reduce the risk of constipation and urinary retention, which are common side effects associated with anticholinergic drugs., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Background: Liver resection offers substantial advantages over open liver resection (OLR) for patients with hepatocellular carcinoma (HCC) in terms of reduced intraoperative blood loss and morbidity. However, there is limited evidence comparing the indications and perioperative outcomes with the open versus laparoscopic approach for resection. This study aimed to compare postoperative outcomes between patients undergoing laparoscopic liver resection (LLR) and OLR for HCC with clinically significant portal hypertension (CSPH)., Methods: A total of 316 HCC patients with CSPH (the presence of gastroesophageal varices or platelet count < 100,000/ml and spleen diameter > 12 cm) undergoing minor liver resection at eight centers were included in this study. To adjust for confounding factors between the LLR and OLR groups, an inverse probability weighting method analysis was performed., Results: Overall, 193 patients underwent LLR and 123 underwent OLR. After weighting, LLR was associated with a lower volume of intraoperative blood loss and the incidence of postoperative complications (including pulmonary complications, incisional surgical site infection, and paralytic ileus) compared to the OLR group. The 3-, 5-, and 7-year postoperative recurrence-free survival rates were 39%, 26%, and 22% in the LLR group and 49%, 18%, and 18% in the OLR group, respectively (p = 0.18). And, the 3-, 5-, and 7-year postoperative overall survival rates were 71%, 56%, and 44% in the LLR group and 76%, 51%, 44% in the OLR group, respectively (p = 0.87)., Conclusions: LLR for HCC patients with CSPH is clinically advantageous by lowering the volume of intraoperative blood loss and incidence of postoperative complications, thereby offering feasible long-term survival., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: The present study aimed to develop a pharmacological evidence-based anticholinergic burden scale (ABS) through a direct assessment of muscarinic receptor-binding activities of 260 medications commonly used in older adults., Methods: The muscarinic receptor-binding activities of 260 drugs were assessed by the displacement of specific [N-methyl- 3 H]scopolamine methyl chloride binding in the rat brain. The maximum blood concentrations (C max ) of drugs after their administration to subjects were cited from their interview forms., Results: In total, 96 of 260 drugs displayed concentration-dependent muscarinic receptor binding in rat brain. Based on muscarinic receptor-binding activity (IC 50 ) and C max after the administration at clinical doses in humans, we rated ABS 3 (strong) for 33 drugs and ABS 2 (moderate) for 37 drugs. There was an approximate similarity between muscarinic receptor-binding activities (IC 50 ) and C max of 33 drugs (ABS 3) after their administration at clinical doses in humans. Furthermore, 26 drugs were defined as ABS 1 (weak) by muscarinic receptor-binding activity. The remaining 164 drugs exhibited slight or no significant muscarinic receptor-binding activities at high concentration of 100 μM, and they were defined as ABS 0. There was a marked similarity for 28 drugs (ABS 3) between the present ABS data and their previous scoring data in the literature., Conclusions: To our knowledge, the present study developed the first comprehensive pharmacological evidence-based ABS of drugs based on muscarinic receptor-binding activity, which provides guidance as to which drugs may be discontinued to reduce anticholinergic burden. Geriatr Gerontol Int 2023; 23: 558-564., (© 2023 University of Shizuoka. Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Perivascular adipose tissue (PVAT) enhances vascular relaxation of mesenteric arteries in SHRSP.Z- Lepr fa /IzmDmcr rats (SPZF), a metabolic syndrome model. We investigated and compared the effects of PVAT on the renal artery in SPZF with those on SHR/NDmcr-cp rats (CP). Renal arteries with and without PVAT were isolated from 23-week-old SPZF and CP. The effects of PVAT on acetylcholine- and nitroprusside-induced relaxation were examined using bioassays with phenylephrine-contracted arterial rings. Acetylcholine-induced relaxations without PVAT in SPZF and CP were 0.7- and 0.5-times lower in females than in males, respectively. In the presence of PVAT, acetylcholine-induced relaxations increased 1.4- and 2-times in male and female CP, respectively, but did not differ in SPZF. Nitroprusside-induced relaxation with and without PVAT was 0.7-times lower in female than in male SPZF but did not differ in CP. Angiotensin-II type-1 receptor (AT1R)/AT1R-associated protein mRNA ratios were lower in CP than in the SPZF and negatively correlated with the difference in arterial relaxation with and without PVAT. The effects of renal artery PVAT differed between the SPZF and CP groups. Higher levels of enhanced AT1R activity in SPZF PVAT may drive these differences by impairing the vascular smooth muscle responses to nitric oxide.

Background: Surgical resection for patients with hepatic and extrahepatic colorectal metastases remains controversial. This study aimed to determine the efficacy of curative resection of distant extrahepatic metastatic lesions in patients with colorectal liver metastases (CRLM)., Methods: From 2007 to 2019, 377 patients with CRLM were treated; of these, 323 patients underwent hepatectomy, and 54 patients with extrahepatic metastases (EHM) had received only chemotherapy. Survival and recurrence were compared between patients with and without EHM. Variables potentially associated with survival were analyzed in univariate and multivariate analyses., Results: Among patients who underwent hepatectomy, the median, 3-, and 5-year overall survival rates for patients with EHM (n = 60) were 32 months, 47%, and 28%, respectively, while those for patients without EHM (n = 263) were 115 months, 79%, and 66%, respectively (p < 0.001). Furthermore, outcomes were similar in R2 patients with EHM and those with unresectable tumors. However, outcomes were significantly better in the R0/1 group than in the R2 and unresectable groups (p < 0.001). Among patients with EHM, multivariate analysis revealed that higher clinical risk score, incomplete resection of all EHM, extrahepatic disease detected intraoperatively, and previous treatment with neoadjuvant chemotherapy were independently associated with worse survival., Conclusions: In patients with CRLM with EHM (liver + one organ), gross curative resection is necessary when surgical treatment is contemplated, and resection of liver metastases should be performed in patients with CRLM with smaller and fewer tumors (e.g., H1)., (© 2021. The Society for Surgery of the Alimentary Tract.)

Regulation of arterial tone by perivascular adipose tissue (PVAT) differs between sexes. In male SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF), PVAT exerts a compensatory relaxation effect for the loss of endothelium-mediated vasorelaxation, which occurs during the early stages of metabolic syndrome. However, this effect deteriorates by 23 weeks of age. Here, therefore, we compared the effects of PVAT in female and male SHRSP.ZF. Acetylcholine-induced relaxation in superior mesenteric artery without PVAT did not differ between 23-week-old females and males. However, the presence of PVAT enhanced relaxation in 23-week-old females, but not in males. The mRNA levels of angiotensin II type 1 receptor (AT1R) in PVAT did not differ between sexes, but AT1R-associated protein (ATRAP) and apelin levels were higher in females than in males. We observed a positive relationship between differences in artery relaxation with and without PVAT and ATRAP or apelin mRNA levels. In 30-week-old females, PVAT-enhanced relaxation disappeared, and mRNA levels of AT1R increased, while apelin levels decreased compared to 23-week-old females. These results demonstrated that in SHRSP.ZF, PVAT compensation for endothelium dysfunction extended to older ages in females than in males. Apelin and AT1R/ATRAP expression in PVAT may be predictors of favorable effects., (© 2022 S. Karger AG, Basel.)

Objectives: To examine the effects of vibegron, a selective β 3 -adrenoceptor agonist, used to treat overactive bladder, on muscarinic receptors in the rat bladder, and to predict the occupancy levels of muscarinic receptors by vibegron in the bladders of humans orally administered a clinical dose., Methods: Muscarinic receptors in the rat bladder and other tissues were examined by a radioligand binding assay using [N-methyl- 3 H]scopolamine chloride. The occupancy levels of muscarinic receptors by vibegron in bladders of humans after its oral administration were predicted from the estimation of unbound concentrations in human plasma and urine in the literature., Results: Vibegron (0.1-100 μmol/L) inhibited specific [N-methyl- 3 H]scopolamine chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. The 50% inhibitory concentration value of vibegron in the bladder was approximately twofold higher than that in the heart, and approximately 315- and 3.5-fold lower than those in the submaxillary gland and brain, respectively. Therefore, the binding affinity of vibegron for muscarinic receptors was higher in the heart and bladder than in the submaxillary gland and brain. By using the rat bladder receptor binding affinity, occupancy levels of muscarinic receptors in the human bladder were predicted to be 51-91% until 24 h after its oral administration at 50 mg of vibegron., Conclusions: This is the first study to suggest that vibegron binds to muscarinic receptors in the rat bladder and other tissues, with a potentially higher affinity for the M 2 subtype than the M 1 and M 3 subtypes. These results might be clinically relevant for pharmacotherapy with vibegron for overactive bladder., (© 2021 The Japanese Urological Association.)

Arterial perivascular adipose tissue (PVAT) can elicit vasodilator signals complementary to those elicited by the endothelium in SHRSP.Z- Lepr fa /IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS). Here, we tested whether a glucose cotransporter 2 inhibitor (SGLT2-i; tofogliflozin) increased this PVAT effect to prevent the deterioration of cardiac function in aging SHRSP.ZF rats. Tofogliflozin treatments (1 or 10 mg/kg/day) or vehicle (control) were administered for 10 weeks by oral gavage to SHRSP.ZF rats, starting at 13 weeks of age. At 23 weeks of age, glucose levels in the serum and urine (24 h after the last administration) were determined using commercial kits. Vasodilator responsiveness of PVAT-surrounded or PVAT-free superior mesenteric arteries was determined using acetylcholine with organ-bath methods. Cardiac ventricular function and coronary flow were determined using Langendorff heart preparations. Serum and urine glucose levels in SGLT2-i treatment groups did not differ from those in the controls, but the ratios of glycated to non-glycated albumin were lower than those in the controls. Tofogliflozin treatments did not alter relaxations in the presence of PVAT or affect relaxations of PVAT-free arteries. Left ventricular systolic pressures, maximum rate of pressure decline, and coronary flow in ex vivo hearts did not differ among the treatment groups. PVAT effects and cardiac dysfunction were not altered by tofogliflozin treatment in SHRSP.ZF rats with MetS. These results do not provide strong evidence to support the use of SGLT2-i as a cardiovascular protective therapy in MetS, which occurs prior to the onset of type 2 diabetes.

Background: Intractable serous (not chylous) ascites (IA) that infrequently develops early following pancreaticoduodenectomy (PD) for pancreatic cancer is a life-threatening problem. The relationship between neoadjuvant chemoradiotherapy (NACRT) for pancreatic cancer and the incidence of IA following PD has not been evaluated. This study aims to identify the risk factors associated with IA that develops early after PD for pancreatic cancer., Methods: We retrospectively identified 94 patients who underwent PD for pancreatic cancer at the Department of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan, from April 2012 to March 2020. Data on 29 parameters were obtained from medical records. Univariate and multivariate analyses were conducted to identify independent risk factors. Levels of serum albumin were compared before and after NACRT to analyze its effect. Survival analysis was also conducted., Results: Of the 92 patients included in this study, 8 (8.70%) were categorized into the IA group. Multivariate analysis identified NACRT [odds ratio (OR) 27, 95% confidence interval (CI) 1.87-394, p = 0.016)] and hypoalbuminemia (≤ 1.6 g/dl) just after the operation (OR 50, 95% CI 1.68-1516, p = 0.024) as risk factors. The level of serum albumin was significantly decreased following NACRT. The IA group had poorer prognosis than the control group., Conclusions: IA is a serious problem that aggravates patient's prognosis. Postoperative lymphatic leak might be a trigger of IA. NACRT was a major risk factor, followed by hypoalbuminemia caused by various reasons. These factors may act synergistically and cause IA.

Benzodiazepines (BDZs) and non-BDZ sedative-hypnotics are effective for the management of chronic insomnia; however, they are associated with adverse effects such as headache, dizziness, and palpitations. Furthermore, long-term use of these medications is associated with decreased blood pressure (BP) or depressed baroreflex function. Therefore, here, we assessed whether BDZs and non-BDZs cause vasorelaxation directly. Vasorelaxation in response to 22 BDZs, 2 non-BDZs, and tandospirone was determined by myograph methods using isolated Wistar rat thoracic aortas. All the drugs relaxed phenylephrine-contracted rat aortas in a concentration-dependent manner. Zolpidem and tandospirone caused over 80% relaxation at a concentration of 10 μM; diazepam, estazolam, etizolam, and tofisopam caused 60-70% relaxation; whereas 18 other BDZs (alprazolam, bromazepam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, ethyl loflazepate, flunitrazepam, flurazepam, lorazepam, lormetazepam, midazolam, nimetazepam, nitrazepam, oxazepam, temazepam, and triazolam) and zaleplon caused less than 50% relaxation. The relaxation was partially but significantly inhibited to the same extent by a nitric oxide (NO) synthase antagonist and after endothelium removal. Binding assay of gamma-aminobutyric acid type A receptors was performed using [ 3 H]flunitrazepam. No correlation was observed between vasorelaxation at a concentration of 10 μM and the binding affinities for 23 drugs. The study demonstrated that zaleplon, zolpidem, tandospirone, and many BDZs cause vasorelaxation to different extents via endothelial NO-dependent and endothelium-independent pathways. In conclusion, the direct vasodilatory effects of these drugs may be involved in the mechanisms underlying their adverse effects. Additionally, the decreased BP observed in persons who take BDZs or non-BDZs may be partly due to direct vasodilation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Metabolic syndrome (MetS) increases the risk of kidney disease. In SHRSP.Z-Lepr fa /IzmDmcr (SHRSP.ZF) rats with MetS, protease-activated receptor 2 (PAR2)-mediated vasorelaxation is preserved in the aorta at 20 weeks of age (weeks) via enhancement of nitric oxide production but impaired at 30 weeks by oxidative stress. However, impairment of PAR2-mediated vasorelaxation of renal arteries and its possible implications for kidney disease are unclear. We used organ baths to assess PAR2-mediated vasorelaxation of isolated renal arteries, colorimetric methods to measure urinary protein levels as an index of renal function, and western blot to determine expression of PAR2 and nephrin proteins in the kidneys of SHRSP.ZF rats at 10, 20, and 30 weeks. We assessed renal arteries and kidney function for effects of orally administered GB88, a pathway-dependent PAR2 antagonist, from 10 to 18 weeks, and azilsartan, an angiotensin II type 1 receptor blocker, from 13 to 23 weeks. PAR2-mediated vasorelaxation was slightly lower at 20 weeks and attenuated significantly at 30 weeks compared with those at 10 weeks. Urinary protein levels were increased at 20 and 30 weeks. Decreased protein expression of PAR2 and nephrin in the kidney were observed at 30 weeks. Administration of GB88 increased blood pressure (BP) and proteinuria. Azilsartan reduced the high BP and the impaired PAR2-mediated vasorelaxation, but did not restore the increase in urinary protein levels and decreased PAR2 and nephrin protein expression in the kidney. PAR2 activation in the kidney may be associated with maintenance of BP and urinary protein excretion in MetS., (© 2020 John Wiley & Sons Australia, Ltd.)

Background: The effectiveness of adjuvant transcatheter arterial chemo- or/and chemoembolization therapy after curative hepatectomy of initial hepatocellular carcinoma (HCC) is controversial. This study aimed to evaluate whether hepatectomy combined with adjuvant transcatheter arterial infusion therapy (TAI) for initial HCC has better long-term survival outcomes than hepatectomy alone., Methods: From January 2012 to December 2014, a prospective randomized controlled trial of patients with initial HCC was conducted. Then, 114 initial HCC patients were recruited to undergo hepatectomy with adjuvant TAI (TAI group, n = 55) or hepatectomy alone (control group, n = 59) at our institution. The TAI therapy was performed twice, at 3 and 6 months after curative hepatectomy (UMIN 000011900)., Results: The patients treated with TAI had no serious side effects, and operative outcomes did not differ between the two groups. No significant differences were found in the pattern of intrahepatic recurrence or time until recurrence between the two groups. Moreover, no significant differences were found in the relapse-free survival or overall survival. Low cholinesterase level (< 200) had been identified as a risk factor affecting relapse-free survival. Furthermore, compared with surgery alone, adjuvant TAI with hepatectomy improved the overall survival for lower-cholinesterase patients., Conclusions: Adjuvant TAI is safe and feasible, but it cannot reduce the incidence of postoperative recurrence or prolong survival for patients who underwent curative hepatectomy for initial HCC.

Background: Delta-shaped anastomosis is a common method of intracorporeal gastroduodenostomy in totally laparoscopic distal gastrectomy. One common postoperative complication of this procedure is anastomotic stenosis, and endoscopic balloon dilatation is a major remedy for such complications. Other treatment strategies are necessary to manage unsuccessful endoscopic balloon dilatation., Case Presentation: We present a case where systemic steroid treatment was applied in sustained anastomotic stenosis after endoscopic balloon dilatation. We performed delta-shaped anastomosis in laparoscopic distal gastrectomy to treat early-stage gastric cancer in a patient. The patient experienced abdominal pain post-surgery; subsequent investigation revealed edematous anastomotic stenosis. The stenosis sustained even after endoscopic balloon dilatation and local steroid injection. Consequently, we applied systemic steroid treatment., Conclusion: Systemic steroid treatment improved the stenosis and no recurrence was observed. These results suggest that systemic steroid application could be useful to treat anastomotic stenosis.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract; most of them have gain-of-function mutations of the KIT gene. There have been rare cases of families with multiple GISTs, that had autosomal dominant germline KIT mutations. Here, we present a case of multiple GISTs caused by a novel germline KIT mutation. Intraoperatively, the main tumor was present in the body of the stomach, and multiple small nodules were detected mainly in the upper and middle part of the gastric wall; several nodules were also present in the small bowel wall. The main tumor and surrounding nodules were resected. DNA sequencing of the tumor tissue, adjacent normal mucosal tissue, and peripheral blood leukocytes revealed that the patient had germline Asp820Gly mutation in exon 17 of the KIT gene. This is the first case with germline Asp820Gly mutation in exon 17 of the KIT gene.

In vitro and in vivo binding sites of [ 3 H]-labeled 5-hydroxymethyltolterodine (5-HMT), a new radioligand for labeling muscarinic receptors in rat tissues were characterized. Specific [ 3 H]5-HMT binding in rat tissues was saturable and of high affinity in each tissue. The dissociation constant (K d ) was significantly lower in bladder and heart than in submaxillary gland. Significant levels of in vivo specific [ 3 H]5-HMT binding by intravenous injection of the radioligand were detected in tissues, except for cerebral cortex. Thus, [ 3 H]5-HMT was shown to specifically label muscarinic receptors in rat tissues, suggesting a useful radioligand for labeling muscarinic receptors with high affinity., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest to disclose. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors., (Copyright © 2019 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Total pancreatectomy is performed for chronic pancreatitis, tumors involving the entire pancreas or remnant pancreas after pancreatectomy. Gastric venous congestion and bleeding may be associated with total pancreatectomy. We report the case of a patient who underwent left gastric vein to splenic vein bypass to relieve gastric venous congestion during total pancreatectomy for remnant pancreatic cancer., Case Presentation: A 60-year-old woman underwent subtotal stomach-preserving pancreaticoduodenectomy for cancer of the pancreatic head. A follow-up computed tomography revealed a low-density tumor of the remnant pancreas. The pathological diagnosis was adenocarcinoma on endoscopic ultrasound-fine needle aspiration. Total resection of the remnant pancreas was performed for the tumor 3 years after the initial surgery. We ligated the splenic vein at the point of distal side of the left gastric vein confluent. Immediately, the vein congestion around the stomach was confirmed. We found the stenosis of the confluent between the left gastric vein and splenic vein. We subsequently anastomosed the left gastric vein and splenic vein, following which the gastric venous congestion was relieved., Conclusion: In cases wherein all the drainage veins from the stomach are removed, an anastomosis between the left gastric vein and splenic vein can be effectively used to prevent gastric venous congestion and bleeding after total pancreatectomy.

Introduction: Reduced port surgery (RPS) has been garnering interest as a novel minimally invasive surgery lately., Aim: The authors examined the relationship between the number of ports and surgical outcomes after laparoscopic hepatectomy (LH)., Materials and Methods: Between January 2012 and April 2019, 209 patients who underwent laparoscopic partial resection and lateral sectionectomy were retrospectively analyzed with respect to operative variables and surgical outcomes. Patients were divided into 5 groups by the number of ports used. Student's t test, the χ test, the likelihood-ratio test, Fisher exact test, or Mann-Whitney U test were used to analyze the data., Results: Operative duration was significantly longer in patients with a larger number of ports than in those with a smaller number of ports. Chronological pain scores according to the visual analog scale (VAS) on postoperative days 1, 2, 4, and 7 were not associated with the number of ports and wound length in the umbilical region. The frequency of using additional analgesic agents was not significantly different between the groups. VAS scores and the number of additional analgesic agents used were smaller in patients in whom non-steroidal anti-inflammatory drugs were regularly administered postoperatively than in those in whom the drug was not regularly administered postoperatively. LH had a 3.4% complication rate (Clavien-Dindo classification >IIIA); however, this was not significantly different between the groups., Conclusions: No significant difference in postoperative pain was observed between RPS and conventional methods, although operative durations were shorter with RPS. However, RPS for LH may be associated with excellent cosmetic results compared with conventional methods.

Diarrhea is often caused by changes in lifestyle, stress, or side effects of drugs. Acanthopanax senticosus root extract (ASRE) has long been used as a functional food remedy with anti-fatigue, neuroprotective, and immunomodulatory activities. However, it is unclear whether ASRE has beneficial effects on gastrointestinal (GI) motility. Therefore, we first investigated whether ASRE directly affects contractile functions of the isolated mouse ileum, and then assessed its effects on GI transit of a charcoal meal in normal mice and a carbachol (CCh)-induced diarrhea mouse model. ASRE caused contraction of the isolated mouse ileum and the maximum contraction was approximately half of that induced by acetylcholine (ACh) administration. In the presence of atropine, this ASRE-induced contraction disappeared, while relaxation responses were observed. However, ASRE reduced potassium chloride- and ACh-induced contractions, and the inhibitory effect was not counteracted by a β-blocker. Administration of a nitric oxide synthase inhibitor or potassium channel blockers did not affect the ASRE-induced relaxation. Oral administration of ASRE for 1 and 4 d reduced the increased GI transit in CCh-treated but did not affect the GI transit of normal mice. These results indicate that ASRE exhibited dual effects of contraction via muscarinic receptors and direct relaxation on mouse ileal function, and its relaxant effect could be useful in treating diarrhea symptoms, resulting in an increase in the parasympathetic nerve activities.

Background: Hepatectomy is currently recommended as the most reliable treatment for colorectal liver metastases. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial., Methods: Two-hundred ninety-five patients who underwent hepatectomy were retrospectively analyzed for the risk factors and the outcomes for early recurrence within 6 months. The remnant liver volumes (RLVs) and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after the operation., Results: Early recurrence developed in 88/295 patients (29.8%). Colorectal cancer lymph node metastasis, synchronous liver metastasis, and multiple liver metastases were independent risk factors for the occurrence of early recurrence (p < 0.001, 0.032, and 0.019, respectively). Patients with early recurrence had a poorer prognosis than did patients who developed later recurrence (p < 0.001). Patients who underwent surgery or other local treatment had better outcomes. The changes in RLV and laboratory data after postoperative month 2 were not significantly different between the 2 groups., Conclusion: Patients with early recurrence within 6 months had a poorer prognosis than did patients who developed later recurrence. However, patients who underwent repeat hepatectomy for recurrence had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival., (© 2019 S. Karger AG, Basel.)

Background: Laparoscopic hepatic resection has been developed as a minimally invasive surgery; however, laparoscopic repeat minor hepatic resection (LRH) carries a higher risk of damage to other organs because of postoperative changes to and losses of anatomical landmarks. The current standard approach at many facilities has been to perform open repeat minor hepatic resection (ORH). This paper describes the surgical outcomes, procedure safety, and utility of ORH versus LRH, as well as the laparoscopic techniques used in LRH., Methods: Between February 2010 and May 2018, the data of 142 patients who underwent LRH or ORH at a single institution were retrospectively reviewed. Surgical outcomes, procedure safety, and procedure utility data were analyzed., Results: Forty-five patients underwent LHR and 97 patients underwent ORH. The conversion rate from LHR to OHR was 13.3%. After propensity score matching (PSM), the estimated blood loss was significantly lower in the LRH group than in the ORH group (50 mL vs. 350 mL; P < 0.001). The LRH group had an 8.1% complication rate, while the ORH group had a complication rate of 24.3% (P = 0.044). The postoperative length of stay was significantly shorter in the LHR group than in the OHR group (9 days vs. 11 days) (P = 0.024)., Conclusion: LRH can be performed safely using various surgical devices. More favorable results are achieved with LRH than with ORH in terms of surgical outcomes including intraoperative bleeding, postoperative complications, and postoperative lengths of stay.

Purpose: Perivascular adipose tissues (PVAT) are involved in the regulation of vascular tone. In mesenteric arteries, the compensatory vasodilatory effects of PVAT appear when vascular relaxation is impaired and disappear at around 23 weeks of age in SHRSP.Z-Lepr fa /IzmDmcr (SHRSP.ZF) rats with metabolic syndrome (MetS). The renin-angiotensin system is involved in the development of endothelium and vascular dysfunction. Therefore, we investigated whether azilsartan, a potent angiotensin II type 1 (AT1) receptor antagonist, can protect against the deterioration of the PVAT compensatory vasodilator function that occurs with aging in MetS., Methods: Two age groups of SHRSP.ZF rats (13 and 20 weeks of age) were administered azilsartan or vehicle through oral gavage once daily for 10 weeks. The vasodilation response of the isolated superior-mesenteric arteries upon addition of endothelium-dependent and -independent agonists was determined in the presence or absence of PVAT using organ bath methods., Results: In vivo treatment with azilsartan improved the acetylcholine-induced vasodilation in mesenteric arteries with and without PVAT at both time-points. The mRNA levels of AT1 receptor and AT1 receptor-associated protein were unchanged in PVAT upon azilsartan treatment. Furthermore, in vitro treatment with azilsartan (0.1 and 0.3 μM for 30 min) did not affect the compensatory effect of PVAT on vasodilation in response to acetylcholine in SHRSP.ZF rat mesenteric arteries., Conclusions: Our results provide evidence supporting the use of azilsartan for the long-term protection against vascular dysfunctions in MetS. Azilsartan did not improve the dysfunction of PVAT-mediated modulation of vascular tone during MetS. The protective effect of azilsartan is mediated by restoring the endothelium- and vascular smooth muscle-mediated mechanisms.

Background: Postoperative chemotherapy for treating colorectal liver metastasis (CLM) has been introduced with the aim of improving therapeutic outcomes. However, there is no consensus on the utility of multidisciplinary treatments with postoperative chemotherapy. Therefore, we evaluated surgical outcomes in patients with CLMs who underwent hepatectomy, while focusing on the effects of post-hepatectomy chemotherapy on remnant liver regeneration., Methods: Two hundred ninety patients who underwent hepatectomy were retrospectively analyzed using propensity score matching. Postoperative outcomes were evaluated with a focus on the effects of post-hepatectomy chemotherapy on regeneration of the remnant liver in patients with CLM. The remnant liver volumes (RLVs) were measured postoperatively using multi-detector computed tomography on day 7 and months 1, 2, 5, and 12 after the operation., Results: RLV regeneration and postoperative blood laboratory data did not differ significantly between patients who received postoperative chemotherapy and those who did not receive postoperative chemotherapy immediately after surgery or at any time point from postoperative day 7 to postoperative month 12. The recurrence rates, including same and other segmental intrahepatic recurrences, as well as the resection frequency of the remnant liver were not significantly different between the two groups., Conclusion: Postoperative chemotherapy may be of small significance for patients with CLM in terms of the remnant liver volume regeneration and functional recovery.

Although Acanthopanax senticosus root extract (ASRE), a functional food used in Japan, improves peripheral blood circulation and exerts vasorelaxant effects in rats under healthy conditions, the underlying mechanisms currently remain unclear. Therefore, we investigated the mechanisms responsible for ASRE-induced relaxation in isolated thoracic aortas using organ bath techniques and examined whether ASRE affects systemic and peripheral circulation using a photoplethysmographic tail-cuff system and noncontact laser tissue blood flow meter in Wistar rats. Similar to acetylcholine (ACh), ASRE induced dose-dependent relaxation in aortas pre-contracted with phenylephrine; however, in contrast to ACh, ASRE-induced relaxation was partially inhibited by treatments with antagonists of nitric oxide (NO) synthase and soluble guanylyl cyclase as well as by endothelium removal. Contractile responses to phenylephrine or potassium chloride were observed in the presence of ASRE. The oral administration of ASRE (900 mg/kg/d for 1 wk) decreased systolic blood pressure in rats 3 h after the treatment and did not affect heart rate, tail blood flow, mass, or velocity; this decreasing effect was not observed on day 2. A 1-wk treatment with ASRE did not affect vasorelaxation in response to ASRE. These results demonstrate that ASRE induces vasorelaxation via endothelial NO production and an NO-independent pathway in rats. Based on these findings, positive impacts of ASRE on blood pressure and peripheral blood circulation cannot be expected under healthy conditions as the systemic effects of ASRE are temporary. Instead, caution is needed to prevent the occurrence of side effects (i.e., orthostatic dizziness) at the beginning of ASRE dosing., Competing Interests: The authors declare no conflicts of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Royal jelly (RJ) is widely used as a cosmetic or dietary supplement to relieve various health disorders, such as dry skin, fatigue, and menopause. RJ has been recommended to improve constipation on a commercial basis. However, the detailed mechanisms by which RJ influences intestinal motility and whether RJ improves constipation remain unclear. Therefore, we investigated the effects of RJ on the motility of mouse ileum both in vitro and in vivo . Using myograph methods, RJ dose-dependently induced contractions of isolated ileal segments, which were inhibited by treatment with atropine. Eserine sulfate, a cholinesterase inhibitor, enhanced the RJ-induced contractions, whereas RJ treated with acetylcholinesterase did not result in ileum contraction. RJ-induced contractions were not affected by N G -nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, although nicotine-induced contractions were significantly enhanced. In contrast, in a gastrointestinal (GI) transit model, single oral administration of 300 mg/kg RJ did not affect GI transit in both normal mice and the loperamide-induced constipation model mice. These results demonstrate that acetylcholine in RJ directly acted on the muscarinic receptors of the mouse intestinal smooth muscle, causing it to contract in vitro . In contrast, single oral administration of RJ did not improve constipation. This study is the first to evaluate the effects of RJ on the motility of mouse ileum in in vitro and in vivo experiments for the validation of application of RJ as a gentle laxative.

Background: Post-hepatectomy liver regeneration is of great interest to liver surgeons, and understanding the process of regeneration could contribute to increasing the safety of hepatectomies and improving prognoses., Methods: Five hundred thirty-eight patients who underwent hepatectomy were retrospectively analyzed. Postoperative outcomes were evaluated, with a focus on the effects of portal vein resection and resected liver volume on remnant liver regeneration in patients with liver tumors. Remnant liver volumes (RLVs) and laboratory data were measured postoperatively using multidetector computed tomography on day 7 and months 1, 2, 5, 12, and 24 after the operation., Results: Liver regeneration speed peaked at 1 week postoperatively and gradually decreased. Regeneration with large resections was longer than that with small resections, with the remnant liver regeneration rate being significantly lower in the former at all time points. Remnant liver regeneration plateaued around 5 months postoperatively, when regeneration is almost complete. Up to 1 month postoperatively, laboratory data were significantly worse when more portal veins was resected. After 2 months postoperatively, these data recovered to near normal levels., Conclusion: The speed and rate of remnant liver regeneration primarily showed a strong correlation with the number of resected portal veins and the amount of removed liver parenchyma. The larger the resection ratio, the longer it took the liver to regenerate. We confirmed that recovery of the liver's functional aspects accompanies recovery of the RLV.

Extracellular vesicles (EVs) are secretory membrane vesicles containing lipids, proteins, and nucleic acids; they function in intercellular transport by delivering their components to recipient cells. EVs are observed in various body fluids, i.e., blood, saliva, urine, amniotic fluid, and ascites. EVs secreted from cancer cells play important roles in the formation of their environment, including fibrosis, angiogenesis, evasion of immune surveillance, and even metastasis. However, EVs in gastric juice (GJ-EVs) have been largely unexplored. In this study, we sought to clarify the existence of GJ-EVs derived from gastric cancer patients. GJ-EVs were isolated by the ultracentrifuge method combined with our own preprocessing from gastric cancer (GC) patients. We verified GJ-EVs by morphological experiments, i.e., nanoparticle tracking system analysis and electron microscopy. In addition, protein and microRNA markers of EVs were examined by Western blotting analysis, Bioanalyzer, or quantitative reverse transcription polymerase chain reaction. GJ-EVs were found to promote the proliferation of normal fibroblast cells. Our findings suggest that isolates from the GJ of GC patients contain EVs and imply that GJ-EVs partially affect their microenvironments and that analysis using GJ-EVs from GC patients will help to clarify the pathophysiology of GC.

Introduction: The gravest problem facing medicine is caring for an aging society and the comorbidities that develop with age, including an increasing prevalence of cardiac disease. Unrecognized or untreated cardiac disease increases the risk of complications in patients undergoing laparoscopic liver resection (LLR). We herein describe the preoperative status, perioperative outcomes, and postoperative courses of patients with or without cardiac disease who undergo LLR., Material and Methods: The data of 339 patients who underwent LLR at a single institution between 2010 and 2018 were retrospectively reviewed. Their preoperative status, surgical outcomes, and postoperative courses were analyzed., Results: Of 339 patients who underwent LLR, one was excluded for pre-existing severe valvular disease. Of the remaining 338 patients, 16 had coexisting cardiac disease and 322 did not. The patients with coexisting cardiac disease had a mean left ventricular ejection fraction of 66% (22-74%). LLR was performed after cardiac function was controlled in the patients with cardiac disease; there were no instances of increased central venous pressure (CVP) or destabilized vital signs during surgery. Intraoperative CVP did not differ between the groups ( p = 0.521). There were no significant differences in the demographics except for age, operative characteristics, and surgical outcomes between the groups., Conclusions: Patients with non-severe or controlled severe cardiac disease do not exhibit different postoperative courses compared to patients without coexisting cardiac disease. Uncontrolled severe cardiac disease can lead to unstable vital signs during surgery, such as increased CVP. In such cases, treating the cardiac disease should be prioritized., Competing Interests: The authors declare no conflict of interest.

Purpose: Neoadjuvant chemotherapy (NAC) for resectable liver metastasis from colorectal cancer (CRLM) is used widely, but its efficacy lacks clear evidence. This study aimed to clarify its worth and develop appropriate treatment strategies for CRLM., Methods: We analyzed, retrospectively, the clinicopathological factors and outcomes of 137 patients treated for resectable CRLM between 2006 and 2015, with upfront surgery (NAC - group; n = 117) or initial NAC treatment (NAC + group; n = 20)., Results: The time to surgical failure (TSF) and overall survival (OS) after initial treatment were significantly worse in the NAC + group than in the NAC - group (P = 0.002 and P = 0.032, respectively). At hepatectomy, the NAC + group had a lower median prognostic nutrition index (PNI), higher rates of a positive Glasgow Prognostic Score (P = 0.002) and more perioperative blood transfusions (P = 0.027) than the NAC - group. Moreover, the serum albumin (P = 0.006), PNI (P ≤ 0.001) and lymphocyte-to-monocyte ratio (P ≤ 0.001) were significantly decreased and the GPS positive rate was increased from 15 to 35% in the NAC + group. The OS rates did not differ significantly according to the NAC response (5-year OS rates-CR/PR 67%, SD 60%, PD 38%)., Conclusions: Patients with resectable CRLM should undergo upfront hepatectomy because NAC did not improve OS after initial treatment in these patients.

We evaluated the effects of anticholinergic drugs principally used for the therapy of overactive bladder (OAB) on the activity of P-glycoprotein, an efflux transport protein, in Caco-2 cells. The time-dependent changes in the fluorescence of residual rhodamine 123, a P-glycoprotein activity marker, in the apical region of Caco-2 cells were measured in the presence of anticholinergic drugs using time-lapse confocal laser scanning microscopy. The effect of anticholinergic drugs on human P-glycoprotein ATPase activity was also measured. The fluorescence of residual rhodamine 123 in untreated Caco-2 cells decreased over time. The gradual decrease in the fluorescence was significantly inhibited by treatment with cyclosporine A, darifenacin, and trospium. In contrast, oxybutynin, N-desethyl-oxybutynin (DEOB), propiverine, and its active metabolites (M-1, M-2), imidafenacin, solifenacin, or tolterodine had little effect on the efflux of rhodamine 123. P-Glycoprotein ATPase activity was increased by darifenacin. Darifenacin and trospium reduced the rhodamine 123 transfer across the apical cell membrane. These data suggest that darifenacin and trospium interact with P-glycoprotein. Additionally, darifenacin influenced P-glycoprotein ATPase activity. These results suggest that darifenacin may be a substrate of P-glycoprotein. This study is the first paper to test simultaneously the effects of 10 anticholinergic drugs used currently for the therapy of OAB, on the P-glycoprotein.

α,β-Unsaturated carbonyl compounds readily form adducts with SH or NH 2 residues, which are nucleophilic agents, by Michael addition. Glutathione (GSH) is a tripeptide that contains an SH residue and functions as an antioxidant. We demonstrated previously that acrolein (ACR), crotonaldehyde (CA), and methyl vinyl ketone (MVK) are present in nicotine- and tar-removed cigarette smoke extract (CSE) and reacted with GSH in B16-BL6 mouse melanoma cells to form GSH-ACR, GSH-CA, and GSH-MVK adducts, suggesting a possible mechanism for CSE-induced cytotoxicity. In this study, we searched for novel α,β-unsaturated carbonyl compounds other than ACR, CA, and MVK. We selected candidate compounds in CSE based on accurate mass values generated using LC/MS analysis of products formed between CSE and GSH, and identified these using GC/MS analysis and library screening. As a result, we isolated trans-2-methyl-2-butenal, 2-methyl-2-cyclopenten-1-one, 3-methyl-2-cyclopenten-1-one, and furfural, which were poorly reactive with GSH and only very weakly inhibited growth of Colon-26 mouse carcinoma cells and BALB/3T3 clone A31 mouse normal cells. We also isolated 2-cyclopenten-1-one, trans-2-pentenal, 3-methyl-2-butenal and ethyl vinyl ketone, which were highly reactive with GSH and significantly inhibited the growth of both cell lines. Our data suggest that the reactivity of compounds in CSE with GSH may be positively correlated with the effect on inhibiting cell growth. Notably, trans-2-pentenal showed marked inhibition of carcinoma cells growth, whereas this compound exhibited little inhibitory effect on normal cells. trans-2-Pentenal may be a potent candidate or seed for antitumor agents.

Perivascular adipose tissue (PVAT) can regulate vascular tone. In mesenteric arteries of SHRSP.Z- Lepr fa /IzmDmcr rats (SHRSP.ZF) with metabolic syndrome, vascular dysfunction is compensated by PVAT-dependent mechanisms that disappear with increasing age. In this study, we investigated the mechanisms of the age-related changes and responsible factor(s) involved in the enhancing effects of mesenteric arterial PVAT in SHRSP.ZF. Acetylcholine- and sodium nitroprusside-induced relaxations of isolated arteries were greater with PVAT than without PVAT at 17 and 20 weeks of age (wks), and as expected, this enhancement by the presence of PVAT disappeared at 23 wks. PVAT mRNA levels of angiotensin II type 1 (AT1) receptor-associated protein was less and AT1 receptor was unchanged at 23 wks when compared to 20 wks. At 20 wks, the enhanced acetylcholine-induced relaxation by the presence of PVAT was inhibited by N -acetyl-l-cysteine (NAC). Acetylcholine-induced relaxation of arteries without PVAT was increased in the presence of exogenously added apelin. PVAT mRNA level of apelin was higher in SHRSP.ZF than in control Wistar-Kyoto rats, and the level was decreased with aging. These results suggest that AT1 receptor activation in PVAT, and changes in the regulation of apelin and a NAC-sensitive factor are related to the age-dependent deterioration of the vasodilation enhancing effects of mesenteric arterial PVAT in SHRSP.ZF.

Rationale: Liposarcoma (LPS) is a rare malignant soft-tissue tumor. Management of LPS is relatively difficult, because there are no characteristic symptoms, or biomarkers, nor any established effective treatment. Hence, the report of the accumulation of each LPS case is necessary. We experienced an extremely rare case of torsion caused by a primary small bowel mesentery LPS., Patient's Concern: A 70-year-old male consulted our hospital with the complaints of abdominal pain and sudden vomiting., Diagnosis: No lump could be palpated, and tumor markers tested were within normal limits. However, computed tomography revealed an intestinal obstruction caused by torsion of the small bowel due to an LPS tumor., Interventions: After decompression of the intestinal obstruction by use of an ileus tube, surgical treatment was performed with rapidity., Outcome: The torsion was found to be caused by the tumor that originated from the small bowel mesentery. The tumor was resected along with a portion of the small bowel. The growth of adipose tissues of various sizes and containing atypical cells was detected by histopathological examination. Also, immunohistochemical examination resulted in positive immuno-reactions for MDM2, CDK4, and p16INK4, which indicated the tumor to be a de-differentiated LPS. The patient was discharged on postoperative day 14 without any complications, and no recurrence of the tumor was observed at 5 years after the operation., Lessons: LPS should be considered in differential diagnosis of bowel torsion, and careful management is required because of the high possibility of recurrence. Patients should be followed carefully for at least 5 years, and further accumulation of data will be required in order to establish the appropriate management of LPS.

Aims: Royal jelly (RJ) has a variety of reported biological activities, including vasorelaxation and blood pressure-lowering effects. Although functional foods are positively used for health, the effects of RJ on the cardiovascular system in healthy individuals have not been well studied. Therefore, we investigated the mechanisms underlying the vasorelaxation effects of RJ in healthy control rats to evaluate whether the peripheral circulation was increased., Main Methods: We used fresh RJ to examine the vasorelaxation effects and related mechanisms in Wistar rats using organ bath techniques. Furthermore, we measured changes in tail blood circulation, systolic blood pressure (sBP), and heart rate (HR) after the oral administration of RJ to control rats and nitro-l-arginine methyl ester (l-NAME)-treated rats (0.5 mg/ml dissolved in distilled drinking water for 1 week). Concentrations of acetylcholine (ACh) in the RJ were measured using a commercial kit., Key Findings: RJ caused vasorelaxation of isolated rat aortas and superior mesenteric arteries, and this effect was inhibited by atropine (10 -5 M, 15 min) or L-NAME (10 -4 M, 20 min) and endothelium-denuded arterial ring preparations. Oral RJ increased tail blood flow and mass in control rats 1 h after treatment without affecting velocity, sBP, or HR. These effects were not observed in L-NAME-treated rats. RJ contained approximately 1000 μg/g of ACh., Significance: The present study demonstrated that RJ is composed of muscarinic receptor agonist(s), likely ACh, and induces vasorelaxation through nitric oxide (NO) production from the vascular endothelium of healthy rats, leading to increased tail blood circulation. Thus, fresh RJ may improve peripheral circulation in healthy individuals., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)