Iain H. McKillop

Rodent models of alcoholic liver disease: Of mice and men

Alcoholic liver disease (ALD) is a major cause of acute and chronic liver disease worldwide. The progressive nature of ALD is well described; however, the complex interactions under which these pathologies evolve remain to be fully elucidated. Clinically there are no clear biomarkers or universally accepted, effective treatment strategies for ALD. Experimental models of ALD are an important component in identifying underlying mechanisms of alcohol-induced injury to develop better diagnostic markers, predictors of disease progression, and therapeutic targets to manage, halt, or reverse disease progression. Rodents remain the most accessible model for studying ALD pathology. Effective rodent models must mimic the natural history of ALD while allowing examination of complex interactions between multiple hepatic, and non-hepatic, cell types in the setting of altered metabolic or oxidative/nitrosative stress, inflammatory responses, and sensitivity to cytotoxic stress. Additionally, mode and duration of alcohol delivery influence hepatic response and present unique challenges in understanding disease pathology. This review provides an overview of rodent models of ALD, their strengths and weaknesses relative to human disease states, and provides insight of the potential to develop novel rodent models to simulate the course of human ALD.

Silibinin inhibits ethanol metabolism and ethanol-dependent cell proliferation in an in vitro model of hepatocellular carcinoma

Chronic ethanol consumption is a known risk factor for developing hepatocellular carcinoma (HCC). The use of plant-derived antioxidants is gaining increasing clinical prominence as a potential therapy to ameliorate the effects of ethanol on hepatic disease development and progression. This study demonstrates silibinin, a biologically active flavanoid derived from milk thistle, inhibits cytochrome p4502E1 induction, ethanol metabolism and reactive oxygen species generation in HCC cells in vitro. These silibinin-mediated effects also inhibit ethanol-dependent increases in HCC cell proliferation in culture.

Collagen–elastin ratio predicts burst pressure of arterial seals created using a bipolar vessel sealing device in a porcine model

BackgroundBipolar electrosurgical devices are used to generate rapid and efficient hemostasis in a wide range of surgical procedures. Of the factors that influence seal integrity, vessel (artery) diameter has been considered the most important variable. In this study we hypothesized that the relative ratio of the components that form the seal (collagen and elastin) determine the degree of vessel distensibility and play an equally important role in defining seal strength.MethodsPorcine carotid, renal, iliac, and femoral arteries were sealed using a bipolar electrosurgical device in vivo. Following removal, arterial diameter was measured and vessels’ seals tested for arterial burst pressure (ABPr). Samples were then analyzed histologically and biochemically for collagen and elastin content.ResultsArteries with the highest collagen–elastin ratio (C/E) (renal) consistently demonstrated significantly higher burst pressures than those arteries with lower C/E ratios (iliac and femoral) independent of artery diameter.ConclusionUsing arteries of distinct anatomical origin and physiological function, we demonstrate that total collagen content, and more specifically C/E ratio, in porcine arteries is a more accurate predictor of ABPr than vessel size alone.

The use of a novel MUC1 antibody to identify cancer stem cells and circulating MUC1 in mice and patients with pancreatic cancer.

MUC1 is over‐expressed and aberrantly glycosylated in >60% of human pancreatic cancer (PC). Development of novel approaches for detection and/or targeting of MUC1 are critically needed and should be able to detect MUC1 on PC cells (including cancer stem cells) and in serum.

Real-time three-dimensional guided ultrasound targeting system for microwave ablation of liver tumours: a human pilot study.

OBJECTIVESnThis study aimed to evaluate a novel three-dimensional ultrasound (US) guidance system for use in hepatic microwave ablation (MWA).nnnMETHODSnAn in vitro assessment was performed in which users with different degrees of experience were evaluated for accuracy in targeting phantom lesions embedded in agar using US alone, or US in conjunction with the InVision™ System (IVS). An eight-patient pilot trial of the IVS was then performed in the setting of open hepatic MWA, in which lesions would otherwise have been targeted with conventional US.nnnRESULTSnIn vitro studies demonstrated that the IVS significantly improved targeting accuracy at all levels of operator experience (novice, beginner and expert). In the human trial, a total of 31 tumours were targeted and all lesions were hit in one pass, as assessed by independent US image observations. There were no adverse operative events; however, there was minor line-of-sight interference with the infra-red tracking mechanism when some lesions high on the dome of the liver were targeted.nnnCONCLUSIONSnThe IVS significantly increased the accuracy of complex targeting procedures of phantom lesions and enhanced targeting in an eight-patient clinical pilot study. During the accrual phase of this pilot study, the development of improved non-optical tracking hardware obviated the requirement to maintain a direct line of sight. The trial was then halted prematurely in order to focus on the application of the IVS utilizing this non-optical modality.

Novel 3-D laparoscopic magnetic ultrasound image guidance for lesion targeting

OBJECTIVESnAccurate laparoscopic liver lesion targeting for biopsy or ablation depends on the ability to merge laparoscopic and ultrasound images with proprioceptive instrument positioning, a skill that can be acquired only through extensive experience. The aim of this study was to determine whether using magnetic positional tracking to provide three-dimensional, real-time guidance improves accuracy during laparoscopic needle placement.nnnMETHODSnMagnetic sensors were embedded into a needle and laparoscopic ultrasound transducer. These sensors interrupted the magnetic fields produced by an electromagnetic field generator, allowing for real-time, 3-D guidance on a stereoscopic monitor. Targets measuring 5 mm were embedded 3-5 cm deep in agar and placed inside a laparoscopic trainer box. Two novices (a college student and an intern) and two experts (hepatopancreatobiliary surgeons) targeted the lesions out of the ultrasound plane using either traditional or 3-D guidance.nnnRESULTSnEach subject targeted 22 lesions, 11 with traditional and 11 with the novel guidance (n= 88). Hit rates of 32% (14/44) and 100% (44/44) were observed with the traditional approach and the 3-D magnetic guidance approach, respectively. The novices were essentially unable to hit the targets using the traditional approach, but did not miss using the novel system. The hit rate of experts improved from 59% (13/22) to 100% (22/22) (P < 0.0001).nnnCONCLUSIONSnThe novel magnetic 3-D laparoscopic ultrasound guidance results in perfect targeting of 5-mm lesions, even by surgical novices.

Alcoholic and non-alcoholic steatohepatitis.

This paper is based upon the Charles Lieber Satellite Symposia organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallorys hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

Evaluation of absorbable and permanent mesh fixation devices: adhesion formation and mechanical strength

PurposeLaparoscopic ventral hernia repair is commonly performed with mesh prostheses; however, there is no standard for fixation devices used to secure mesh to the abdominal wall. This study is a functional comparison of novel, screw-type absorbable and permanent fixation devices with a traditional titanium fixation device.MethodsFifteen pigs each underwent the laparoscopic placement of two 11xa0×xa014-cm mesh prostheses and were randomized for mesh fixation with either titanium spiral tacks (TS), absorbable screw-type fasteners (SF), or permanent screw-type fasteners (PF) (nxa0=xa010 mesh prostheses for each fixation group). Adhesions were assessed laparoscopically at 4xa0weeks. The fixation devices were also embedded in porcine abdominal rectus muscle for ex vivo mechanical testing along with partial thickness polypropylene suture (PR) as a control group (nxa0=xa040 for each group). Maximum pull-off forces were measured. All statistical tests were two-tailed, and a P-valuexa0<xa00.05 was considered to be significant.ResultsThe mean tenacity adhesion scores were 1.40xa0±xa00.52 (PF), 1.7xa0±xa00.82 (SF), and 2.6xa0±xa01.07 (TS). Adhesions in the PF group were significantly less tenacious compared with the TS group (Pxa0=xa00.01). Quantitative adhesion scores were not significantly different among groups. The maximum pull-off forces, measured in Newtons, were 28.61xa0Nxa0±xa04.89xa0N (TS), 22.71xa0Nxa0±xa07.86xa0N (SF), 16.98xa0Nxa0±xa07.59xa0N (PF), and 20.83xa0Nxa0±xa06.25xa0N (PR). The pull-off force in the TS group was higher than all of the other groups (Pxa0<xa00.001). The SF group also had a higher pull-off force compared with the PF group (Pxa0<xa00.001).ConclusionsThe screw-type absorbable and permanent fixation devices provided adequate fixation and were associated with decreased adhesions in this porcine model.

Altered aquaporin expression and role in apoptosis during hepatic stellate cell activation

Background: Hepatic stellate cells (HSCs) are effector cells of hepatic fibrosis contributing to excessive collagen deposition and scar matrix formation. Sustained HSC activation leads to hepatic cirrhosis, a leading cause of liver‐related death. Reversal of hepatic fibrosis has been attributed to the induction of HSC apoptosis. Aquaporins (AQPs) are critical proteinacious channels that mediate cellular water loss during the initiation and progression of apoptosis.

Laparoscopic microwave ablation of human liver tumours using a novel three-dimensional magnetic guidance system

BACKGROUNDnAccurate antenna placement is essential for effective microwave ablation (MWA) of lesions. Laparoscopic targeting is made particularly challenging in liver tumours by the needles trajectory as it passes through the abdominal wall into the liver. Previous optical three-dimensional guidance systems employing infrared technology have been limited by interference with the line of sight during procedures.nnnOBJECTIVEnThe aim of this study was to evaluate a newly developed magnetic guidance system for laparoscopic MWA of liver tumours in a pilot study.nnnMETHODSnThirteen patients undergoing laparoscopic MWA of liver tumours gave consent to their participation in the study and were enrolled. Lesion targeting was performed using the InnerOptic AIM™ 3-D guidance system to track the real-time position and orientation of the antenna and ultrasound probe.nnnRESULTSnA total of 45 ablations were performed on 34 lesions. The median number of lesions per patient was two. The mean ± standard deviation lesion diameter was 18.0 ± 9.2u2009mm and the mean time to target acquisition was 3.5u2009min. The first-attempt success rate was 93%. There were no intraoperative or immediate postoperative complications. Over an average follow-up of 7.8 months, one patient was noted to have had an incomplete ablation, seven suffered regional recurrences, and five patients remained disease-free.nnnCONCLUSIONSnThe AIM™ guidance system is an effective adjunct for laparoscopic ablation. It facilitates a high degree of accuracy and a good first-attempt success rate, and avoids the line of site interference associated with infrared systems.