Morphological,Functional, and Tissue Characterization of Silent Myocardial Involvement in Patients With Primary Biliary Cholangitis

1. Download : Download high-res image (419KB)
2. Download : Download full-size image

     

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

Current standards and future perspectives in adjuvant treatment for biliary tract cancers

Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ~20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60–70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, which included a variety of additional tumours (e.g. pancreatic and ampullary tumours); most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies.Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community.This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored.     

原位肝移植术后缺血型胆道病变20例

目的探讨原位肝移植术后缺血型胆道病变（ITBL）的病因及预防、诊断和治疗的措施。方法回顾性分析1999年2月至2005年4月间291例次原位肝移植后发生ITBL患者的临床资料。结果291例次原位肝移植术后共发生ITBL 20例（6．9％）。术后发生ITBL的高危因素为：原发病为重型乙型肝炎、供受者ABO血型不符、供肝冷保存时间超过12h和术后肝动脉病变。其发生率分别为12．5％（9／71）、20．0％（2／10）、11．1％（9／81）和60％（3／5）。采用药物、经内镜逆行胰胆管造影（ERCP）介入、胆道外科手术及再次肝移植等方法治疗，有效率为80．0％（16／20）、治愈率为50．0％（10／20），与ITBL相关的病死率为10．0％（2／20），与ITBL相关的移植物功能丧失发生率为20．0％（4／20）。结论针对ITBL的高危因素进行相应处理是预防ITBL的有效措施。胆道造影和核磁共振胆胰管成像对诊断ITBL有很高的敏感性和特异性。根据不同的病因和病变程度采用适当的方法治疗ITBL，可获得良好的疗效。     

Preservation of Bile Ductules Mitigates Bile Duct Loss

The finer branches of the biliary tree (FBBT) contain a regenerative compartment. We hypothesized that preservation of the FBBT together with its microvasculature will lead to recovery of biliary damage and prolonged preservation of bile ductules during the development of chronic liver allograft rejection. The interlobular bile ducts, portal bile ductules and extraportal biliary cells with and without microvessels were studied in sequential biopsies in five patients who fulfilled the Banff criteria of early chronic rejection (CR) (imminence group). Biopsies of CR patients (n = 12) served as controls. Biopsies were double immunostained with CD34 (microvessels) and cytokeratin 7 (biliary structures). Proliferation and proangiogenic activity were assessed with Ki67 and VEGF-A immunostaining. Severe damage of bile ducts in the imminence group did not progress to significant bile duct loss. This was associated with a high proliferative activity in all biliary structures and preservation of the microvascular compartment. VEGF-A expression was increased in all but the reperfusion biopsies. In conclusion, both regenerative activity of the FBBT and an intact microvascular compartment are associated with less damage of the biliary tree and could therefore be prerequisites for biliary regeneration.     

Effects of galanin on insulin and glucagon secretion in the rat

Galanin-like immunoreactivity has been visualized in nerve fibers in the islets of Langerhans, suggesting an involvement of galanin in the neural regulation of islet function. In this study, we investigated the effects of galanin on basal and stimulated insulin and glucagon secretion by infusing the peptide at three different dose rates in rats. We also studied the direct effect of galanin on insulin secretion from freshly isolated rat islets. At 320 pmol/kg/min, but not at 20 or 80 pmol/kg/min, galanin lowered basal plasma insulin levels. In contrast, basal plasma glucagon levels were lowered by galanin already at 20 and 80 pmol/kg/min. Furthermore, galanin inhibited both glucose- and arginine-induced insulin release at all three dose levels, whereas arginine-induced glucagon release was not affected by galanin. Glucose-stimulated insulin secretion from isolated rat islets was dose-dependently suppressed by galanin (10^-6-10^-8M). Therefore, it is concluded that galanin in rats inhibits insulin secretion, both in vivo and in vitro, and that at lower dose levels, the peptide also inhibits basal glucagon release.     

Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5-hydroxy- and N4-acetyl-metabolites in man

Hydroxylation is the predominant pathway of metabolism for sulfatroxazole in the body, accounting for 70 per cent of the dose. Fifteen per cent of the dose is acetylated unimodally and 10 per cent is excreted unchanged. The half-lives of sulfatroxazole and its metabolites 5-hydroxysulfatroxazole and N4-acetylsulfatroxazole are approximately 22 h after administration of sulfatroxazole. N4-acetylsulfatroxazole, taken as parent drug, is eliminated by renal excretion (92 per cent of the dose). The initial elimination half-life of N4-acetylsulfatroxazole is 4.5 h, which later increases to 70 h as the result of the acetylation-deacetylation equilibrium. Probenecid inhibits the renal excretion of the metabolites 5-hydroxy- and N4-acetylsulfatroxazole. Inhibition of the N4-acetyl metabolite favours the deacetylation, which results in an increase of the T 1/2 of sulfatroxazole from 20 to 30 h. The protein binding value of sulfatroxazole is 84 per cent, that of N4-acetylsulfatroxazole is 37 per cent. Sulfatroxazole is excreted renally by passive processes, while the metabolites are excreted by both passive and active processes.     

Sonographic evaluation of gallbladder kinetics: in vitro and in vivo comparison of different methods to assess gallbladder emptying.

In an in vitro study, 10 gallbladders of adult pigs and 6 gallbladders of lambs, all removed immediately after slaughtering, were stimulated in a water bath by electric means to induce active contraction. Gallbladder emptying was followed by ultrasonography employing five measurement procedures: (1) gallbladder width, (2) longitudinal planimetry, (3) transverse planimetry, (4) ellipsoid method, and (5) sum of cylinders method. In an in vivo investigation, gallbladder emptying of 30 volunteers (12 healthy subjects, 18 diabetics) was evaluated in the same way after ingestion of a fatty meal. Gallbladder width was found to be unsuitable to estimate the decrease in gallbladder volume due to a nonlinear relation of the parameters. Longitudinal planimetry tended to be less valid than transverse planimetry in assessing gallbladder volume reduction. The most valid estimation of gallbladder volume decreases was obtained by the two three-dimensional procedures. However, in neither in vitro nor in vivo could a significant difference between the sum of cylinders method and the ellipsoid method in determining relative volume reduction be established. We conclude that a three-dimensional measurement procedure should be used for valid assessments of gallbladder motility. However, according to our data there is no advantage in using the time-consuming sum of cylinders method compared to the simple ellipsoid method.     

急性胆源性胰腺炎的微创治疗

目的探讨应用十二指肠镜及腹腔镜治疗急性胆源性胰腺炎(ABP)的有效性。方法回顾性分析5年间对94例ABP患者进行微创治疗的临床资料。ABP合并胆囊结石的59例行行单纯腹腔镜胆囊切除术(LC);胆总管结石14例内镜下乳头括约肌切开取石术(EST),同时置入鼻胆管引流(ENBD),其中3例联合LC;对胆囊结石合并胆总管结石21例行ERCP EST,联合LC治疗。结果全组术后再次发作胰腺炎1例,胆道出血1例,均为ERCP EST患者;另肺部感染2例,切口感染1例,5例均经非手术治疗痊愈。全组有效率100%。结论十二指肠镜及腹腔镜联合应用于治疗ABP效果好。微创技术是目前ABP理想的治疗方法。     

Biliary stent causing colovaginal fistula: case report.

OBJECTIVES: Perforation of the bowel during placement of a biliary stent is a known complication of this procedure. We report the endoluminal loss of a biliary stent during routine stent extraction that ultimately led to a chronic colovaginal fistula. This case emphasizes the need for evaluation of fecal passage of stents in patients with a known dislodged prosthesis. CASE REPORT: A 65-year-old white female underwent biliary stent placement for an episode of choledocholithiasis. The stent was lost in the duodenum during routine extraction. The patient was managed expectantly. She denied ever passing this stent via the rectum and began to develop symptoms of colovaginal fistula. Evaluation found a retained biliary stent in the sigmoid colon and a fistula into the vagina. The patient underwent elective low anterior resection and colovaginal fistula repair. DISCUSSION: Reports exist of migration of stents that lead to acute colonic perforation and the need for emergent surgery. For this reason, it has been suggested that dropped or migrated stents be purposefully retrieved. However, if the option of expectant observation is used, it is important to clearly document the fecal passage of these stents and be prepared to retrieve these objects if they have a prolonged bowel transit time.