Prophylactic use of a self-assembling peptide hydrogel for preventing delayed bleeding after endoscopic sphincterotomy: A propensity score-matched analysis.

BACKGROUND AND AIM: Delayed endoscopic sphincterotomy-related bleeding (ES bleeding) is an unavoidable adverse event (AE) that can have serious ramifications. Intraoperative ES bleeding, which stops spontaneously in most cases, is a known risk factor for delayed bleeding. This study aimed to examine the preventive effect of a novel self-assembling peptide (SAP) for delayed ES bleeding in patients who attained spontaneous hemostasis after intraoperative ES bleeding. METHODS: A total of 1507 patients met the eligibility criteria for inclusion in this study. The rates of delayed ES bleeding and AE besides bleeding were compared between patients administered the SAP (SAP group) and those who were simply observed after spontaneous hemostasis of intraoperative ES bleeding (control group). Propensity score matching was performed to adjust for differences between the groups. RESULTS: The rate of delayed ES bleeding was significantly lower in the SAP group than that in the control group (0.9% vs 3.8%, P = 0.044). The rates of AEs other than bleeding were 2.4% and 3.8% in the SAP and control groups, respectively, and the difference lacked statistical significance (P = 0.481). Multivariate analysis revealed that the use of SAP was significantly associated with a lower frequency of delayed ES bleeding (odds ratio, 0.35; 95% confidence interval, 0.13-0.98; P = 0.047). CONCLUSIONS: Self-assembling peptide may be a simple, safe, and useful way to reduce the risk of delayed ES bleeding in patients who experienced intraoperative ES bleeding and obtained subsequent spontaneous hemostasis.

Endoscopic radiofrequency ablation for ingrowth occlusion after bilateral metal stent placement for malignant hilar biliary obstruction: a prospective pilot study.

BACKGROUND AND AIMS: Endoscopic biliary radiofrequency ablation (RFA) may be an option for the treatment of ingrowth occlusion after self-expandable metal stent (SEMS) deployment; however, its utility remains uncertain. This study aimed to examine the feasibility of RFA for the palliation of ingrowth after bilateral SEMS placement in patients with malignant hilar biliary obstruction. METHODS: This prospective, single-center, pilot study enrolled 30 patients who met the eligibility criteria between April 2020 and March 2022. Study outcomes were technical success, clinical success, recurrent biliary obstruction (RBO), and adverse events (AEs) besides RBO associated with RFA for ingrowth occlusion. Furthermore, factors predictive of clinical success were evaluated. RESULTS: Technical and clinical success rates were 93.3% (28/30) and 71.4% (20/28), respectively. The rates of early and late AEs were 6.7% (2/30) and 10.0% (2/20), respectively. The incidence rate of RBO after RFA was 45.0% (9/20), and the median time to RBO was 163 days. Multivariate analysis of the factors affecting clinical success revealed a positive association between the recanalization diameter on the ingrown part within the SEMS (odds ratio, 1.13; 95% confidence interval, 1.01-1.26; P = .038). The calculated optimal cutoff for the ratio of the recanalization diameter to the SEMS diameter for predicting clinical success was 51.1%. CONCLUSIONS: Endoscopic biliary RFA elicited promising results, with good long-term stent patency and without the requirement of any additional stent placement, for the palliation of ingrowth occlusion after bilateral SEMS placement. However, the clinical success rate was insufficient, necessitating improvements in the future. (Clinical trial registration number: UMIN000040154.).

Endoscopic Ultrasound-Guided Hepaticogastrostomy with Antegrade Stenting Without Dilation Device Application for Malignant Distal Biliary Obstruction in Pancreatic Cancer.

BACKGROUND: Endoscopic ultrasound-guided hepaticogastrostomy with antegrade stenting (EUS-HGAS) is a promising therapeutic option for malignant distal biliary obstruction (MDBO) in the event of transpapillary approach failure. Eliminating the fistula dilation step may further decrease the incidence of adverse events (AE) and simplify the procedure. AIMS: This study focused on MDBO associated with pancreatic cancer and aimed to examine the utility of EUS-HGAS without the use of any dilation devices. METHODS: This retrospective study investigated consecutive patients in whom the transpapillary approach had failed or was difficult, and who underwent EUS-HGAS without dilation device usage, using a tapered small-diameter catheter, ultrathin delivery system, and tapered dedicated plastic stent. The outcomes of this study included the technical success, clinical success, AE incidence, and recurrent biliary obstruction (RBO) associated with the procedure. RESULTS: During the study period, EUS-HGAS without dilation device usage was attempted for 57 patients with MDBO due to pancreatic cancer. The technical and clinical success rates were 91.2% (52/57) each. The median procedural time was 25 min. The rates of early and late AE besides RBO were 3.5% (2/57) and 1.9% (1/52), respectively. The incidence rate of RBO was 30.8% (16/52), and the median time to RBO was 245 days. The rate of successful endoscopic reintervention for RBO via the fistula was 100% (16/16). CONCLUSIONS: EUS-HGAS without the use of dilation devices showed good technical feasibility with a low AE rate. It may be a useful option for MDBO associated with pancreatic cancer when the transpapillary approach is difficult.

Endoscopic Ultrasound-Guided Naso-gallbladder Drainage Using a Dedicated Catheter for Acute Cholecystitis After Transpapillary Metal Stent Placement for Malignant Biliary Obstruction.

BACKGROUND: Acute cholecystitis is a significant adverse event after self-expandable metal stent (SEMS) placement for malignant biliary obstruction (MBO); however, no appropriate treatment strategy has been established for its management. AIMS: This study aimed to examine the feasibility and utility of endoscopic ultrasound-guided naso-gallbladder drainage (EUS-NGBD) for the management of acute cholecystitis occurring after SEMS placement. METHODS: This retrospective study investigated consecutive patients with acute cholecystitis after SEMS placement for unresectable MBO, in whom EUS-NGBD was attempted. The study outcomes included technical success, clinical success, procedure time, adverse event, and cholecystitis recurrence, associated with the procedure. RESULTS: During the study period, EUS-NGBD was performed for SEMS-related acute cholecystitis in 30 patients with MBO. The technical and clinical success rates were 96.7% (29/30) and 96.6% (28/29), respectively. The median procedure time was 15 min, and rate of procedure-related adverse event was 3.3% (1/30). The median duration from the procedure to tube removal was 9 days. No adverse events were observed after removal. The median hospitalization duration after the procedure was 14 days, and the median duration to the (re-)start of chemotherapy from cholecystitis onset was 13 days. The median overall survival after EUS-NGBD was 123 days, and the rate of cholecystitis recurrence until death was 4.2% (1/28). CONCLUSIONS: This study demonstrated that EUS-NGBD possesses good technical and clinical feasibility with an acceptable adverse event rates and short hospitalization and chemotherapy withdrawal period. Therefore, EUS-NGBD may be a good option for the treatment of SEMS-related cholecystitis in patients with MBO.

Scissor-type knife precut in balloon enteroscopy-assisted ERCP for patients with difficult biliary cannulation and surgically altered anatomy (with video).

BACKGROUND AND AIMS: Balloon enteroscopy-assisted ERCP (BE-ERCP) is useful for treating pancreatobiliary disease in patients with surgically altered anatomy (SAA); however, biliary cannulation, including the precut technique, is often challenging. This study aimed to examine the feasibility of scissor-type knife precutting (SKP) during BE-ERCP in patients with SAA. METHODS: This retrospective study investigated consecutive patients who underwent BE-ERCP and SKP for difficult biliary cannulation between 2016 and 2021. The study outcomes included the technical success and adverse event rates associated with SKP during BE-ERCP. RESULTS: During the study period, 125 patients with native duodenal papillae underwent BE-ERCP, and the papilla was reached in 116 patients. The success rate of biliary cannulation with the standard cannulation approach alone was 67.2% (78/116), which increased to 77.6% (90/116) with the inclusion of advanced cannulation techniques besides precutting and further improved to 87.9% (102/116) with the addition of needlife precutting. SKP was attempted in 12 patients in whom all other cannulation approaches were difficult or resulted in failure. The technical success rate of SKP was 66.7% (8/12); thus, SKP increased the final success rate of biliary cannulation to 94.8% (110/116). The rate of adverse events associated with SKP was 8.3% (1/12). CONCLUSIONS: This is the first study to report the use of the SKP technique for difficult biliary cannulation in patients with SAA, which may serve as a useful option for salvage cannulation during BE-ERCP.

Comparison of the removal ability of basket catheters for small bile duct stones impacted in the corner pocket of the lower bile duct.

BACKGROUND : Endoscopic stone extraction is often challenging in patients with a significant lower bile duct corner pocket, where small stones are likely to escape and become impacted. This study aimed to determine the utility of different types of baskets for retrieving corner pocket stones. METHODS : Seven types of retrieval baskets were evaluated on silicone models. The study outcomes included the characteristics of each basket and technical success rates associated with the retrieval of stones impacted in the corner pocket. RESULTS : The overall success rate was only 27.5 %, with significant differences between the baskets (P < 0.001). Only three baskets yielded successful removal. The success rates were 10 %, 25 %, and 70 % with the 8-wire Nitinol Basket, RASEN, and VorticCatch V, respectively, all of which are helical eight-wire baskets. RASEN and VorticCatch V share similar characteristics, including a strong spiral wire and smaller interwire spaces at their distal ends. The addition of rotation significantly increased the success rate to 80 % with the 8-wire Nitinol Basket (P < 0.001) and 90 % with RASEN (P < 0.001). CONCLUSIONS : Robust helical eight-wire baskets with smaller interwire spaces at the tip may be effective for extracting corner pocket stones, while the addition of rotational motion may improve the efficacy of retrieval.

Endobiliary Radiofrequency Ablation Using a Short-Type Balloon Enteroscope in Patients with Surgically Altered Anatomy.

BACKGROUND: Endoscopic radiofrequency ablation (RFA) is expected to prolong stent patency for malignant biliary obstruction (MBO). However, its feasibility when used in conjunction with a balloon enteroscope (BE) in patients with surgically altered anatomy (SAA) remains unknown. AIMS: This study aimed to investigate the feasibility of RFA combined with metal stent insertion under BE guidance for MBO in patients with SAA. METHODS: Thirty-seven patients who underwent treatment between October 2016 and January 2021 and met the eligibility criteria were investigated retrospectively. Study outcomes included technical and clinical success, recurrent biliary obstruction (RBO), and other adverse events besides RBO associated with RFA with metal stent placement using BE. RESULTS: Technical and clinical success rates were 100% (37/37) each. The rates of early and late adverse events were 8.1% (3/37) and 8.1% (3/37), respectively. RBO occurred in 32.4% (12/37) of the patients, and the median time to RBO was 296 days. The cause of RBO was ingrowth in eight patients, overgrowth in three patients, and indeterminate in one patient. All reinterventions for RBO were successful using the BE approach; all ingrowths, except one, were recanalized using additional RFA without additional stent placement. The frequency of reintervention-related adverse events was 9.1% (1/11). The median time to RBO after reintervention was 166 days. CONCLUSIONS: This study demonstrated the technical safety and feasibility as well as good long-term outcomes of endobiliary RFA combined with metal stent placement under BE guidance. This approach may be a useful option for treating MBO in patients with SAA.

Safety and Efficacy of Gemcitabine Plus Nab-Paclitaxel for Metastatic Pancreatic Cancer Patients Undergoing Biliary Stent Placement.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) is the first-line chemotherapeutic regimen for metastatic pancreatic cancer (MPC); however, there are concerns regarding its safety in patients undergoing biliary stent placement. This study aimed to examine the tolerability and efficacy of GnP in MPC patients who underwent biliary stent placement. METHODS: A total of 105 MPC patients who had received GnP treatment between 2015 and 2020 were included and investigated. The patients were divided into two groups: those undergoing biliary stent placement for symptomatic biliary obstruction (BO) (With-BO group) and those without biliary stent placement (Without-BO group). The best tumor response, overall survival (OS), and adverse events in each group were compared. RESULTS: The partial response, stable disease, and progressive disease rates were 22%, 61%, and 14.6% in the With-BO group, and 26.6%, 46.9%, and 21.9% in the Without-BO group, respectively, with no significant differences. The median OS was 12.2 months and 14.6 months in the With-BO and Without-BO groups, respectively (P = 0.483). Grade 3 or higher biliary tract-related events were significantly more common in the With-BO group (41.5%) than in the Without-BO group (1.6%) (P < 0.001), but all events were managed successfully by urgent intervention. The rates of any treatment-related toxicities, including febrile neutropenia, were not significantly different, and there were no chemotherapy-related deaths in either group. CONCLUSIONS: GnP can be as tolerable and effective in MPC patients with biliary stents as in those without biliary stents. However, careful management and appropriate reintervention to treat biliary tract-related adverse events are required.

Effect of Central Corticotropin-Releasing Factor on Hepatic Lipid Metabolism and Inflammation-Related Gene Expression in Rats.

Corticotropin-releasing factor (CRF) in the brain acts on physiological and pathophysiological modulation of the hepatobiliary system. Central CRF administration aggravates experimental acute liver injury by decreasing hepatic blood flow. Conversely, minimal evidence is available regarding the effect of centrally acting CRF on hepatic lipid metabolism and inflammation. We examined whether central CRF affects hepatic lipid metabolism and inflammation-related gene expression in rats. Male Long Evans rats were intracisternally injected with CRF (10 µg) or saline. Rats were sacrificed 2 h, 6 h, and 24 h after the CRF injection, the liver was isolated, and mRNA was extracted. Next, hepatic lipid metabolism and inflammation-related gene expression were examined. Hepatic SREBF1 (sterol regulatory element-binding transcription factor 1) mRNA levels were significantly increased 6 h and 24 h after intracisternal CRF administration when compared with those in the control group. Hepatic TNFα and IL1ß mRNA levels increased significantly 6 h after intracisternal CRF administration. Hepatic sympathectomy or guanethidine treatment, not hepatic branch vagotomy or atropine treatment, inhibited central CRF-induced increase in hepatic SREBF1, TNFα and IL1ß mRNA levels. These results indicated that central CRF affects hepatic de novo lipogenesis and inflammation-related gene expression through the sympathetic-noradrenergic nervous system in rats.

Effect of Adrenergic Agonists on High-Fat Diet-Induced Hepatic Steatosis in Mice.

The autonomic nervous system, consisting of sympathetic and parasympathetic branches, plays an important role in regulating metabolic homeostasis. The sympathetic nervous system (SNS) regulates hepatic lipid metabolism by regulating adrenergic receptor activation, resulting in the stimulation of hepatic very-low-density lipoprotein-triglyceride (TG) production in vivo. However, only a few studies on the relationship between SNS and hepatic steatosis have been reported. Here, we investigate the effect of adrenergic receptor agonists on hepatic steatosis in mice fed a high-fat diet (HFD). The α-adrenergic receptor agonist phenylephrine (10 mg/kg/d) or the ß-adrenergic receptor agonist isoproterenol (30 mg/kg/d) was coadministered with HFD to male mice. After five weeks, hepatic steatosis, TG levels, and hepatic fat metabolism-related biomarkers were examined. HFD treatment induced hepatic steatosis, and cotreatment with phenylephrine, but not isoproterenol, attenuated this effect. Phenylephrine administration upregulated the mRNA levels of hepatic peroxisome proliferator-activated receptor alpha and its target genes (such as carnitine palmitoyltransferase 1) and increased hepatic ß-hydroxybutyrate levels. Additionally, phenylephrine treatment increased the expression of the autophagosomal marker LC3-II but decreased that of p62, which is selectively degraded during autophagy. These results indicate that phenylephrine inhibits hepatic steatosis through stimulation of ß-oxidation and autophagy in the liver.

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called "diabetic hepatopathy or diabetic liver disease". NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

Comparison of Efficacy between Pemafibrate and Omega-3-Acid Ethyl Ester in the Liver: the PORTRAIT Study.

AIM: No pharmacotherapeutic treatment has been established for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). This trial compared the effects of pemafibrate and omega-3-acid ethyl ester on hepatic function in patients with hypertriglyceridemia complicated by MASLD. METHODS: Patients with hypertriglyceridemia complicated by MASLD were enrolled, randomly assigned to the pemafibrate or omega-3-acid ethyl ester group, and followed for 24 weeks. The primary endpoint was the change in alanine aminotransferase (ALT) from baseline to week 24. The secondary endpoints included other hepatic enzymes, lipid profiles, and hepatic fibrosis biomarkers. RESULTS: A total of 80 patients were enrolled and randomized. The adjusted mean change in ALT from baseline to week 24 was significantly lower in the pemafibrate group (-19.7±5.9 U/L) than in the omega-3-acid ethyl ester group (6.8±5.5 U/L) (intergroup difference, -26.5 U/L; 95% confidence interval, -42.3 to -10.7 U/L; p=0.001). Pemafibrate significantly improved the levels of other hepatic enzymes (aspartate aminotransferase and gamma-glutamyl transpeptidase), lipid profiles (triglycerides, total cholesterol, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol), and hepatic fibrosis biomarkers (Mac-2 binding protein glycan isomer and Fibrosis-4 index). No cases of discontinuation due to adverse drug reactions were identified in either group, and there were no safety concerns. CONCLUSIONS: Pemafibrate is recommended over omega-3-acid ethyl ester for lipid management and MASLD treatment in patients with hypertriglyceridemia complicated by MASLD. The study results may contribute to the development of future treatment strategies for patients with MASLD/MASH.

Double bare metal stent deployment combined with intraductal radiofrequency ablation for malignant distal biliary obstruction: a prospective pilot study.

Although uncovered self-expandable metal stents (SEMSs) possess certain advantages such as averting cystic duct obstruction and stent migration, they are susceptible to ingrowth occlusion. The combination of the double bare stent (DBS) and endobiliary radiofrequency ablation (RFA) may reduce ingrowth. Hence, this study aimed to examine the utility of this method for the treatment of unresectable malignant distal biliary obstruction (MDBO). This prospective, single-center, pilot study enrolled 51 patients who met the eligibility criteria between February 2020 and January 2022. The study outcomes included technical success, clinical success, recurrent biliary obstruction (RBO), and other adverse events (AE) besides RBO associated with DBS placement with RFA for MDBO. The technical success rate was 98.0% (50/51). Clinical success was achieved in all patients in whom technical success was achieved. The rates of early and late AEs were 5.9% (3/51) and 8.0% (4/50), respectively. The incidence rate of RBO was 38.0% (19/50). Sludge occlusion, ingrowth occlusion, and overgrowth occlusion occurred in 26.0% (13/50), 8.0% (4/50), and 2.0% (1/50) of patients, respectively (the main cause of RBO was undeterminable in 1 patient). The median time to RBO was 241 days. DBS with RFA showed good technical feasibility, good long-term outcomes, acceptable AE rates, and most importantly, a low ingrowth occlusion rate when employed for the treatment of MDBO.

Comparison of the mechanical properties of retrieval basket catheters for bile duct stones: An experimental study.

BACKGROUND: Although numerous retrieval baskets are currently available for the extraction of bile duct stones, their mechanical properties have not been evaluated. This study aimed to ascertain the characteristics of retrieval baskets for bile duct stones by examining their mechanical properties. METHODS: This experimental study tested the mechanical properties of seven retrieval baskets for bile duct stones. The radial force (RF) was measured using a dedicated measurement device and the axial force (AF) was measured using the conventional manual method. RESULTS: The mean RF differed significantly among the baskets (p < 0.001) and was the strongest for VorticCatch (1.62 N ± 0.02) and COAXIS (1.62 N ± 0.04), followed by RASEN (1.27 N ± 0.02), Memory Basket (0.95 N ± 0.01), 8-wire Nitinol Basket (0.93 N ± 0.01), StoneHunter (0.78 N ± 0.01) and Flower Basket (0.37 N ± 0.01), respectively. The mean AF differed significantly among the baskets (p < 0.001) and was the highest for VorticCatch (0.668 N ± 0.032), followed by COAXIS (0.629 N ± 0.041), StoneHunter (0.574 N ± 0.037), 8-wire Nitinol Basket (0.546 N ± 0.010), Memory Basket (0.542 N ± 0.024), RASEN (0.435 N ± 0.008) and Flower Basket (0.297 N ± 0.011), respectively. The baskets were categorized into four groups with comparable mechanical properties based on the RF and AF: group 1, low RF and low AF; group 2, moderate RF and moderate AF; group 3, high RF and moderate AF; and group 4, high RF and high AF. CONCLUSIONS: This study revealed distinct mechanical properties of various retrieval baskets used for extracting bile duct stones, which may enhance the understanding of their action. Our results could also aid the development of retrieval baskets in future.

Mac-2 binding protein glycosylation isomer, the FIB-4 index, and a combination of the two as predictors of non-alcoholic steatohepatitis.

Approximately 10% non-alcoholic fatty liver disease (NAFLD) cases progress to non-alcoholic steatohepatitis (NASH). Liver biopsy, the gold standard for diagnosing NASH and associated liver fibrosis, is invasive with a risk of life-threatening complications. Therefore, reliable non-invasive biomarkers for predicting NASH are required to prevent unnecessary liver biopsies. We evaluated the performance of two non-invasive fibrosis markers, Mac-2 binding protein glycosylation isomer (M2BPGi) and the FIB-4 index for predicting the fibrosis staging, NAFLD activity scoring (NAS) index, and NASH. We also analyzed the correlation between the two markers. The sensitivities, specificities, positive predictive values (PPV), and negative predictive values of the FIB-4 index, M2BPGi, and a combination of both markers for NASH diagnosis were evaluated. The M2BPGi and FIB-4 index showed a good performance in diagnosing NASH, the fibrosis stage, and the NAS index in NAFLD patients. While both markers were well-correlated with each other in most cases, no correlation was found in some patients. Compared with the FIB-4 index or the M2BPGi alone, a combination of the two showed a higher specificity, PPV, and accuracy for NASH diagnosis. The M2BPGi and the FIB-4 index are easily accessible and reliable liver fibrosis markers. Diseases other than liver disease may cause dissociation between the two markers, causing failure to predict NASH. However, the combination of both markers can compensate for their disadvantages. Because the PPV of the combination was relatively high, patients who test positive for both markers should undergo liver biopsy for NASH diagnosis.

Characteristics of bile acid composition in high fat diet-induced nonalcoholic fatty liver disease in obese diabetic rats.

Bile acid has attracted attention as a signal transmission molecule in energy metabolism. Although a high-fat diet (HFD) or obesity is known to increase hepatic fat content and alter bile acid composition, the changes in bile acid composition due to HFD or obesity remain to be elucidated. We sought to examine the bile acid composition in high fat diet-induced non-alcoholic fatty liver disease (NAFLD) in obese diabetic rats. Eight-week-old male spontaneously diabetic Torii fatty (SDTF) rats or control rats were fed an HFD. Twelve weeks post the commencement of HFD, serum and hepatic bile acid compositions and serum GLP-1 levels, which is stimulated by the secondary bile acid deoxycholic acid (DCA), were measured. The correlation between the bile acid composition and serum GLP-1 levels was also examined. While serum and hepatic levels of cholic acid (CA), a primary bile acid, tended to decrease in HFD-fed control rats, they were significantly decreased in HFD-fed SDTF rats. Hepatic CYP8B1, which plays a role in CA synthesis, the mRNA levels were significantly decreased in HFD-fed control and SDTF rats. In contrast, while serum and hepatic DCA levels were not changed in HFD-fed control rats, they were decreased in HFD-fed SDTF rats. Hepatic DCA/CA did not change in HFD-fed SDTF rats, but significantly increased in HFD-fed control rats. While serum GLP-1 levels were not changed in SDTF rats, they were significantly increased in HFD-fed control rats. Hepatic DCA/CA tended to correlate with serum GLP-1 levels, which tended to negatively correlate with the hepatic triglyceride content in SDTF rats. These results indicate that relatively increased DCA might contribute to an increase in serum GLP-1 levels, which inhibits hepatic steatosis in NAFLD.

Gemcitabine plus nab-paclitaxel with initial dose reduction for older patients with advanced pancreatic cancer.

OBJECTIVES: For older patients with pancreatic cancer (PC), the benefits of gemcitabine plus nab-paclitaxel (GnP) are still uncertain, and the toxicity may be excessive. We aimed to examine the efficacy and safety of modified GnP (m-GnP), which is a nab-paclitaxel reduced regimen, for older patients (≥75 years) with advanced PC. MATERIALS AND METHODS: In total, 34 patients met the eligibility criteria for study inclusion between 2015 and 2020. We evaluated the overall survival (OS), progression-free survival (PFS), best response, and adverse events associated with m-GnP treatment. RESULTS: The median OS and PFS were 15.4 months and 5.9 months, respectively. The best response was partial response in 29% (10/34), stable disease in 53% (18/34), and progressive disease in 15% of patients (5/34); one patient was not evaluated. Among the grade 3 or higher hematological adverse events, neutropenia was the most frequent, occurring in 38% of patients (13/34), whereas febrile neutropenia occurred in 3% (1/34). Grade 3 or higher non-hematological adverse events occurred in 12% of patients (4/34). Early discontinuation owing to intolerable adverse events occurred in one patient, and there were no chemotherapy-related deaths. CONCLUSIONS: The present study demonstrated that m-GnP exhibited good efficacy with acceptable toxicity. To avoid early discontinuation and maintain dose intensities, initial dose reduction may be a good option for older patients with PC when receiving GnP.

Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice.

Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Tabernaemontana divaricate, attenuates hepatic fibrosis in mice. We have previously shown that CnP inhibits non-alcoholic steatohepatitis (NASH) using a methionine-choline-deficient (MCD) diet-fed mouse model. However, little is known about the CnP mediated inhibition of hepatic steatosis in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse models. CnP (0.5 and 1 µg/g/body weight) was co-administered along with a high-fat diet to male BALB/c mice. After nine weeks of administering the high-fat diet, hepatic steatosis, triglyceride, and hepatic fat metabolism-related markers were examined. Administration of a high-fat diet for 9 weeks was found to induce hepatic steatosis. CnP dose-dependently attenuated the high-fat diet-induced hepatic steatosis. The diet also attenuated hepatic peroxisome proliferator-activated receptor alpha (PPARA) mRNA levels. PPARA is known to be involved in ß-oxidation. CnP upregulated the mRNA levels of hepatic PPARA and its target genes, such as carnitine palmitoyl transferase 1 (CPT1) and CPT2, in a dose-dependent manner in the liver. Furthermore, levels of hepatic ß-hydroxybutyrate, which is a type of ketone body, were increased by CnP in a dose-dependent manner. Finally, CnP increased the expression of the autophagosomal marker LC3-II and decreased the expression of p62, which are known to be selectively degraded during autophagy. These results indicate that CnP inhibits hepatic steatosis through the stimulation of ß-oxidation and autophagy in the liver. Therefore, CnP might prove to be a suitable therapeutic target for NAFLD.

Congenital malformations in Japanese macaques (Macaca fuscata) at Takasakiyama.

From the late 1960s to the early 1970s, many congenitally malformed infants were born into provisioned Japanese macaque troops. Although the exact cause of this problem was not determined, the occurrence of malformations decreased thereafter. We examined possible factors such as total population size, number of adult females, birth rate, and volume of provisioned food. Agrichemicals attached to provisioned food are suspected as the main cause, as other factors were found to have no influence. Many more malformations were seen in males compared with females, in feet compared with hands, and in the fourth compared with other digits. We confirmed that the frequency of congenital malformation was high during the 1960s through to the mid-1970s when increased levels of provisioned food were given and that the incidence of congenital malformations was also elevated among wild macaques during this time.