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While acute anal fissures can be treated with topical therapy to reduce sphincter hypertonia (e.g., isosorbide dinitrate, glyceryl trinitrate, diltiazem), chronic fissures may require more invasive instrumental therapy. Currently, the golden standard remains lateral internal sphincterotomy; however, this carries the long-term risk of faecal incontinence. Fissurectomy can be a valuable alternative, but is less efficient because of absence of correction of underlying hypertonia. In this study, we aim to evaluate the additional effect of injection of botulinum toxin during fissurectomy in the treatment of chronic anal fissures. A single-centre retrospective analysis of 293 isolated superficial fissurectomies with or without injection of botulinum toxin was performed, with pain relief as primary endpoint. The majority of patients undergoing fissurectomy were women (65%, mean age 45.0 years vs. 35% men, mean age 48.3 years), often because of ventral fissures (30% in women vs. 8% in men). Fissurectomy resulted in resolution of complaints in 81.1%, while additional injection of botulinum toxin resulted in resolution in 90.1% (p

Early detection of precursor lesions of anal cancer in HIV-seropositive patients Although anal cancer is rare in the overall population, its incidence is increasing in the last decades. Especially HIV-seropositive patients have an increased risk of developing anal squamous cell carcinoma (SCC), mainly because of the high prevalence of high-grade anal intraepithelial neoplasia (AIN) among these patients. High-grade AIN is a precursor lesion for anal SCC associated with human papillomavirus (HPV) infection. Despite the lack of direct evidence demonstrating that AIN identification reduces the risk of anal cancer, experts think that screening and treatment of high-risk patients will prevent the disease. This article aims to review the current literature about AIN and discusses the screening options, including digital rectal examination, anal cytology and high-resolution anoscopy.

Background To improve detection of mucosal lesions during colonoscopy a number of imaging modalities have been suggested, including high definition and virtual chromoendoscopy. Given the theoretical advantage of these new imaging techniques, we aimed to investigate their use for the detection of polyps in patients referred for colonoscopy in a large tertiary hospital. Methods Demographic, endoscopic, and histological data from 1855 consecutive patients undergoing colonoscopy were collected prospectively. Patients were randomly assigned to three endoscopy systems (Fujinon, Olympus, or Pentax) in combination with four modalities: conventional white-light colonoscopy (n = 505), high definition white-light colonoscopy (n = 582), virtual chromoendoscopy (n = 285) and high definition virtual chromoendoscopy (n = 483). Results The mean adenoma detection rate (ADR) was 34.9 %, and the adenoma per colonoscopy rate (APCR) was 2.1. No significant differences were noted between the three endoscopy systems. Moreover, no differences in ADR or APCR were observed between the four imaging modalities. High definition white-light colonoscopy resulted in a significantly higher detection of sessile serrated adenomas (8.2 % vs. 3.8 %; P Conclusions No significant differences in ADR or APCR between different endoscopy systems, high definition, and/or virtual chromoendoscopy could be observed in routine colonoscopies in the general population. High definition endoscopy was associated with a significantly higher detection rate of serrated adenomas and adenocarcinomas.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) is the first-line treatment for large sessile and flat colorectal polyps in Western centres, however recurrence after EMR continues to be a challenge. The aim of this study is to assess efficacy, safety and recurrence rate of EMR in a tertiary centre and to identify risk factors for recurrence at first surveillance endoscopy (SE1). PATIENTS AND METHODS: We performed a retrospective study of 165 sessile and flat colorectal lesions ≥15 mm, treated by EMR between 2017-2019. We used multivariate logistic regression to identify independent risk factors for recurrence at SE1. RESULTS: EMR was performed for 165 colorectal polyps in 142 patients with technical success in 158 cases (95,2%). SE1 data for 117 of 135 eligible cases (86,7%) showed recurrent adenoma in 19 cases (16,2%) after a median time of 6,2 months (IQR 5-9,9). This was primarily treated endoscopically (78,9%). Independent risk factors for recurrence at SE1 were lesion size ≥40 mm (OR 4,03; p=0,018) and presence of high-grade dysplasia (HGD) (OR 3,89; p=0,034). Early adverse event occurred in 4 patients (2,4%), with 3 bleeding complications and one perforation. Twelve patients (7,2%) presented with delayed bleeding of which 3 required transfusion, with radiological intervention in one case. All other complications were managed either conservatively (n=8) or endoscopically (n=5). CONCLUSIONS: EMR is a safe and effective treatment for large sessile and flat colorectal lesions with low recurrence rates. Lesion size ≥40 mm and presence of HGD were identified as risk factors for early recurrence, highlighting the importance of compliance to follow-up in these cases. ispartof: ACTA GASTRO-ENTEROLOGICA BELGICA vol:85 issue:1 pages:47-55 ispartof: location:Belgium status: accepted

BackgroundAlthough evidence suggests frequent gastrointestinal (GI) involvement during coronavirus disease 2019 (COVID-19), endoscopic findings are scarcely reported.AimsWe aimed at registering endoscopic abnormalities and potentially associated risk factors among patients with COVID-19.MethodsAll consecutive patients with COVID-19 undergoing endoscopy in 16 institutions from high-prevalence regions were enrolled. Mann-Whitney U, χ2 or Fisher’s exact test were used to compare patients with major abnormalities to those with negative procedures, and multivariate logistic regression to identify independent predictors.ResultsBetween February and May 2020, during the first pandemic outbreak with severely restricted endoscopy activity, 114 endoscopies on 106 patients with COVID-19 were performed in 16 institutions (men=70.8%, median age=68 (58–74); 33% admitted in intensive care unit; 44.4% reporting GI symptoms). 66.7% endoscopies were urgent, mainly for overt GI bleeding. 52 (45.6%) patients had major abnormalities, whereas 13 bled from previous conditions. The most prevalent upper GI abnormalities were ulcers (25.3%), erosive/ulcerative gastro-duodenopathy (16.1%) and petechial/haemorrhagic gastropathy (9.2%). Among lower GI endoscopies, 33.3% showed an ischaemic-like colitis.Receiver operating curve analysis identified D-dimers >1850 ng/mL as predicting major abnormalities. Only D-dimers >1850 ng/mL (OR=12.12 (1.69–86.87)) and presence of GI symptoms (OR=6.17 (1.13–33.67)) were independently associated with major abnormalities at multivariate analysis.ConclusionIn this highly selected cohort of hospitalised patients with COVID-19 requiring endoscopy, almost half showed acute mucosal injuries and more than one-third of lower GI endoscopies had features of ischaemic colitis. Among the hospitalisation-related and patient-related variables evaluated in this study, D-dimers above 1850 ng/mL was the most useful at predicting major mucosal abnormalities at endoscopy.Trial registration numberClinicalTrial.gov (ID: NCT04318366).

Introduction : Hemorrhoidal disease is a common problem that arises when hemorrhoidal structures become engorged and/or prolapse through the anal canal. Both conservative and invasive treatment options are diverse and guidance to their implementation is lacking. Methods : A Delphi consensus process was used to review current literature and draft relevant statements. These were reconciliated until sufficient agreement was reached. The grade of evidence was determined. These guidelines were based on the published literature up to June 2020. Results : Hemorrhoids are normal structures within the anorectal region. When they become engorged or slide down the anal canal, symptoms can arise. Every treatment for symptomatic hemorrhoids should be tailored to patient profile and expectations. For low-grade hemorrhoids, conservative treatment should consist of fiber supplements and can include a short course of venotropics. Instrumental treatment can be added case by case : infrared coagulation or rubber band ligation when prolapse is more prominent. For prolapsing hemorrhoids, surgery can be indicated for refractory cases. Conventional hemorrhoidectomy is the most efficacious intervention for all grades of hemorrhoids and is the only choice for non-reducible prolapsing hemorrhoids. Conclusions : The current guidelines for the management of hemorrhoidal disease include recommendations for the clinical evaluation of hemorrhoidal disorders, and their conservative, instrumental and surgical management.

ispartof: ENDOSCOPY vol:53 issue:9 pages:E332-E333 ispartof: location:Germany status: published

ispartof: GASTROINTESTINAL ENDOSCOPY vol:92 issue:5 pages:1141-1142 ispartof: location:United States status: published

Summary box #### What is already known about this subject? #### What are the new findings? #### How might it impact on clinical practice in the foreseeable future? In this prospective multicentre …

On March 11, 2020 the World Health Organization declared COVID-19 pandemic, leading to a subsequent impact on the entire world and health care system. Since the causing Severe Acute Respiratory Syndrome Coronavirus 2 houses in the aerodigestive tract, activities in the gastrointestinal outpatient clinic and endoscopy unit should be limited to emergencies only. Health care professionals are faced with the need to perform endoscopic or endoluminal emergency procedures in patients with a confirmed positive or unknown COVID-19 status. With this report, we aim to provide recommendations and practical relevant information for gastroenterologists based on the limited amount of available data and local experience, to guarantee a high-quality patient care and adequate infection prevention in the gastroenterology clinic. ispartof: DIGESTIVE ENDOSCOPY vol:32 issue:5 pages:723-731 ispartof: location:Australia status: published

BACKGROUND: The COVID-19 pandemic, declared by WHO on March 13, 2020, had a major global impact on the healthcare system and services. In the acute phase, the presence of the SARS-CoV-2 virus in the aerodigestive tract limited activities in the gastroenterology clinic and procedures to emergencies only. Motility and function testing was interrupted and as we enter the recovery phase, restarting these procedures requires a safety-focused approach with adequate infection prevention for patients and healthcare professionals. METHODS: We summarized knowledge on the presence of the SARS-CoV-2 virus in the aerodigestive tract and the risk of spread with motility and functional testing. We surveyed 39 European centers documenting how the pandemic affected activities and which measures they are considering for restarting these measurements. We propose recommendations based on current knowledge as applied in our center. RESULTS: Positioning of catheters for gastrointestinal motility tests carries a concern for aerosol-borne infection of healthcare workers. The risk is low with breath tests. The surveyed centers stopped almost all motility and function tests from the second half of March. The speed of restarting and the safety measures taken varied highly. CONCLUSIONS AND INFERENCES: Based on these findings, we provided recommendations and practical relevant information for motility and function test procedures in the COVID-19 pandemic era, to guarantee a high-quality patient care with adequate infection prevention. ispartof: NEUROGASTROENTEROLOGY AND MOTILITY vol:32 issue:7 ispartof: location:England status: published

Background Data concerning laparoscopic sacrocolpopexy (LSCP) in elder women are scarce. We compared intra-operative and early-postoperative complications associated with laparoscopic colpo-, cervico-, or hysteropexy in women under and above 70 years. Methods Retrospective assessment by an independent investigator of a prospective cohort of 571 consecutive women undergoing LSCP in a tertiary unit over an 18-year period. Data included were patient demographics, operative variables, intra-operative, and early (≤ 3 months) postoperative complications. Complications were graded according to the Clavien-Dindo classification and mesh complications categorized using the International Urogynaecological Association (IUGA)-classification. Findings Median age was 66 (IQR 15, range 27-91) and 204 (35.7%) patients were older than 70 years. There were no deaths. Strategic conversion rate was 2.3% (13/571), the majority because of extensive adhesions yet early in our experience. Reactive conversion rate was 0.7% (4/571). Among 554 patients who had a completed LSCP, there were 20 intra-operative complications (3.6%), mostly bladder (1.3%) and vaginal (1.1%) injuries. Eighty-four patients had a total of 95 early-postoperative Dindo ≥ II complications (15.1%). Most common complications were infectious and treated medically (Dindo II). Clinically major complications are rare (III = 3.1% and IV = 0.2%). Reoperation for suspected bleeding (IIIb = 0.7%) was the most common reintervention, typically without demonstrable cause. Most mesh complications were vaginal exposures. Septuagenarians were not more likely to have an intra-operative (4.0 vs 3.3% p = 0.686) or early-postoperative complication (13.6 vs 16.0% p = 0.455) than younger patients. Mesh complications were also equally uncommon. Conclusions LSCP is as well-tolerated by women above 70 years as by younger women.

Gastrointestinal endoscopic (GIE) procedures present a known source of risk for COVID-19 transmission from patients to healthcare workers (GIE-HCW). Despite a growing body of clinical data including overall HCW transmission risk, no reports currently exist describing the risk or predictors of GIE-HCW infection in the GIE setting. Our international multicenter study aimed to describe outcomes and modifying factors in a cohort of GIE-HCWs matched to specific COVID-19 patient endoscopic exposures.

Injection of botulinum toxin into the internal anal sphincter is a well-documented intervention to reduce anal hypertonia in the treatment of anal fissures. In patients receiving chemotherapy, painful anal conditions are frequent, secondary to change in bowel habits and reduced immunity. However, injection of botulinum toxin is often not offered due to fear of complications. In this retrospective longitudinal observational study, performed in a tertiary hospital setting, we analysed patient characteristics, outcome and complication rates of botulinum toxin injection in patients actively receiving chemotherapy. Twenty-six patients were treated with 20–50 IU botulinum toxin while actively receiving chemotherapy because of intractable pain and hypertonia. The fissure was located dorsally in 69% (n = 18) and ventrally in 19% (n = 5), while in 3 patients (12%), no fissure was documented. The majority of the patients (88%, n = 23) had complete (54%, n = 14) or partial (35%, n = 9) relief of pain. In three patients, additional anal pathology developed in the weeks following botulinum toxin injection: thrombosis of grade IV haemorrhoids, perianal haematoma and an intersphincteric abscess. Injection of botulinum toxin in the anal sphincters is a safe and effective analgesic option in patients with anal fissure while actively receiving chemotherapy.

Multipotent Adult Progenitor Cells (MAPCs) are one potential stem cell source to generate functional hepatocytes or β-cells. However, human MAPCs have less plasticity than pluripotent stem cells (PSCs), as their ability to generate endodermal cells is not robust. Here we studied the role of 14 transcription factors (TFs) in reprogramming MAPCs to induced endodermal progenitor cells (iENDO cells), defined as cells that can be long-term expanded and differentiated to both hepatocyte- and endocrine pancreatic-like cells. We demonstrated that 14 TF-iENDO cells can be expanded for at least 20 passages, differentiate spontaneously to hepatocyte-, endocrine pancreatic-, gut tube-like cells as well as endodermal tumor formation when grafted in immunodeficient mice. Furthermore, iENDO cells can be differentiated in vitro into hepatocyte- and endocrine pancreatic-like cells. However, the pluripotency TF OCT4, which is not silenced in iENDO cells, may contribute to the incomplete differentiation to mature cells in vitro and to endodermal tumor formation in vivo. Nevertheless, the studies presented here provide evidence that reprogramming of adult stem cells to an endodermal intermediate progenitor, which can be expanded and differentiate to multiple endodermal cell types, might be a valid alternative for the use of PSCs for creation of endodermal cell types. ispartof: PLOS ONE vol:13 issue:5 ispartof: location:United States status: published

OBJECTIVES The Z allele (Glu342Lys) in α1-antitrypsin (AAT) deficiency is a combined deficiency and dysfunctional allele. Carrying one Z allele induces a risk of a more aggressive evolution in patients with a chronic liver disease. As most of the carriers of Z allele do not have overt liver disease, it is likely that Z allele-containing livers have been used previously for liver transplantation. We analyzed the incidence, epidemiology, and clinical features of AAT accumulation in the hepatocytes after liver transplantation. METHODS Follow-up biopsies of liver transplant recipients were analyzed with periodic acid Schiff staining until 2006 (n=486); from 2006 on (n=303), all biopsies were stained with a specific monoclonal antibody against mutated AATZ protein. Genotyping of both recipient and donor was performed in the case of positive staining. RESULTS Of 789 liver transplantation patients, six patients (0.8%) showed mutated AATZ accumulation in the transplanted liver. Mutation analysis confirmed the presence of the Z allele in all donor organs including one transplanted organ with the SZ phenotype. There was a clear concordance between the isoelectrical focusing of the recipient AAT after transplantation and the genotype of the donor. CONCLUSION Presumed healthy donor organs containing the Z allele were used for transplantation in 0.8% of cases in our series. As the presence of a Z allele is an independent risk factor of aggravation of chronic liver disease, AATZ accumulation in biopsies after liver transplantation should be actively looked for.

Background and aim This technical review is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the utilization of advanced endoscopic imaging in gastrointestinal (GI) endoscopy. Methods This technical review is based on a systematic literature search to evaluate the evidence supporting the use of advanced endoscopic imaging throughout the GI tract. Technologies considered include narrowed-spectrum endoscopy (narrow band imaging [NBI]; flexible spectral imaging color enhancement [FICE]; i-Scan digital contrast [I-SCAN]), autofluorescence imaging (AFI), and confocal laser endomicroscopy (CLE). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adopted to define the strength of recommendation and the quality of evidence. Main recommendations 1. We suggest advanced endoscopic imaging technologies improve mucosal visualization and enhance fine structural and microvascular detail. Expert endoscopic diagnosis may be improved by advanced imaging, but as yet in community-based practice no technology has been shown consistently to be diagnostically superior to current practice with high definition white light. (Low quality evidence.) 2.We recommend the use of validated classification systems to support the use of optical diagnosis with advanced endoscopic imaging in the upper and lower GI tracts (strong recommendation, moderate quality evidence). 3.We suggest that training improves performance in the use of advanced endoscopic imaging techniques and that it is a prerequisite for use in clinical practice. A learning curve exists and training alone does not guarantee sustained high performances in clinical practice. (Weak recommendation, low quality evidence.) Conclusion Advanced endoscopic imaging can improve mucosal visualization and endoscopic diagnosis; however it requires training and the use of validated classification systems.

Multipotent adult progenitor cells (MAPCs) are isolated from bone marrow-derived mesenchymal stem cell cultures. Human MAPCs (commercially available as a clinical-grade product termed MultiStem®) possess the capacity to be expanded long term; however, the differentiation potential of human MAPC is restricted mainly to the mesodermal lineage. Both rodent and human MAPCs have been shown to be effective in improving outcome of preclinical models of ischemic cardiac, vascular and neurological diseases, where the mechanism of action is mainly via trophic, cytoprotective, and/or immunomodulatory effects, as actual cellular replacement is rare. Human MAPCs are currently being evaluated in a number of phase I/II clinical trials in patients with stroke, acute myocardial infarction (AMI), inflammatory bowel disease (IBD), and in patients undergoing BM transplantation for the prevention of acute graft-versus-host disease (GvHD).

Background & Aims Worldwide, about 180million people are chronically infected with the hepatitis C virus (HCV). Current in vitro culture systems for HCV depend chiefly on human hepatoma cell lines. Although primary human hepatocytes support HCV infection in vitro , and immunodeficient mice repopulated with human hepatocytes support HCV infection in vivo , these models are limited because of shortage of human livers to isolate hepatocytes. Therefore, there is significant interest in the establishment from of a HCV culture system in human stem cell-derived hepatocyte-like cells. Methods Human embryonic stem cell (hESC)-derived hepatocytes were infected with HCV in the presence or absence of direct acting antivirals. After inoculation, replication of HCV was analyzed extensively. Results We demonstrate that hESC-derived hepatocytes can be infected with the HCV JFH1 genotype 2a, resulting in the production of viral RNA in the stem cell progeny. Viral replication is inhibited by a non-nucleoside HCV polymerase-inhibitor (HCV-796), a cyclophilin binding molecule (Debio 025-Alisporivir) and the protease inhibitor VX-950 (Telaprevir). Stem cell-derived hepatocytes produced, for more than 10days, the HCV core protein as well as virions that were capable of re-infecting hepatoma cells. Conclusions Hepatocytes derived from hESC support the complete HCV replication cycle (including the production of infectious virus), and viral replication in these cells is efficiently inhibited by selective inhibitors of HCV replication.

UNLABELLED: The role of progenitor cells in liver repair and fibrosis has been extensively described, but their purification remains a challenge, hampering their characterization and use in regenerative medicine. To address this issue, we developed an easy and reproducible liver progenitor cell (LPC) isolation strategy based on aldehyde dehydrogenase (ALDH) activity, a common feature shared by many progenitor cells. We demonstrate that a subset of nonparenchymal mouse liver cells displays high levels of ALDH activity, allowing the isolation of these cells by fluorescence-activated cell sorting. Immunocytochemistry and qPCR analyses on freshly isolated ALDH(+) cells reveal an enrichment in cells expressing liver stem cell markers such as EpCAM, CK19, CD133, and Sox9. In culture, the ALDH(+) population can give rise to functional hepatocyte-like cells as illustrated by albumin and urea secretion and cytochrome P450 activity. ALDH1A1 expression can be detected in canals of Hering and bile duct epithelial cells and is increased on liver injury. Finally, we showed that the isolation and differentiation toward hepatocyte-like cells of LPCs with high ALDH activity is also successfully applicable to human liver samples. CONCLUSION: High ALDH activity is a feature of LPCs that can be taken advantage of to isolate these cells from untreated mouse as well as human liver tissues. This novel protocol is practically relevant, because it provides an easy and nontoxic method to isolate liver stem cells from normal tissue for potential therapeutic purposes.

Hepatosplenic γδ T-cell lymphoma is a rare lymphoproliferative disorder originating from natural killer–like Vδ1-lymphocytes. This subtype has been described after different types of solid organ transplants. In this article, we describe the first 2 cases after liver transplantation. Both patients had thrombocytopenia with (hepato)splenomegaly but without peripheral lymphadenopathies and sinusoidal infiltration of the liver and spleen by monomorphic γδ-lymphocytes on pathological examination. The clinical and pathological findings, immunophenotypical profile, prognosis, and treatment are highlighted. In order to make an early diagnosis, physicians who take care of liver transplant recipients should be aware of the characteristic features of this posttransplant lymphoproliferative disorder. Therefore, a diagnostic algorithm is proposed. Liver Transpl 15:686–692, 2009. © 2009 AASLD.

Objective: To report a case of a patient who developed an acute and transient, tender, and bilateral swelling of the thyroid that occurred during fine-needle aspiration (FNA) of a solitary nodule in the left thyroid lobe; to add accurate ultrasound measurements to support our clinical observation; and to analyze a possible underlying mechanism of this rare condition. Results and clinical follow-up: The calculated thyroid volume increased from 23 to 57mL before and at 4 minutes, respectively, after the needle aspiration, but the thyroid volume returned to prediagnostic level after 4 hours. Cytology, serum calcitonin, and histology were concordant, and the nodule was diagnosed as a medullary thyroid carcinoma. Immunohistochemistry was positive for calcitonin, chromogranin, and the very potent vasodilator calcitonin gene-related peptide (CGRP). Conclusion: This is a rare case of acute and transient thyroid swelling during a common procedure as FNA of a thyroid nodule. This is the first case with documented acute volume expansion quantified by ultrasound measurements supporting our clinical observation, which is in accordance with two historical case reports. The clinical and ultrasound data support the hypothesis of vasodilation as the underlying mechanism, possibly evoked by the release of the vasodilator CGRP. ispartof: Thyroid vol:18 issue:1 pages:81-84 ispartof: location:United States status: published

A 33-year old male patient was referred to the endoscopy unit because of heartburn and dysphagia lasting for 6 weeks. Symptoms improved only slightly after 4 weeks’ treatment with pantoprazole. No information was available regarding his medical history or medication intake. Endoscopy revealed a pale esophageal mucosa with multiple small white spots, predominantly in the distal esophagus (●" Fig.1). Cardia, stomach, and duodenum were normal. A biopsy specimen of the esophagus showed an increased number of eosinophils (peak count 150 per high power field [hpf]), concentrated within the surface epithelium, which is compatible with the presence of eosinophilic microabscesses (●" Fig.1). The symptoms suggestive of esophageal dysfunction, together with the pathological findings of eosinophil-predominant inflammation led to the diagnosis of eosinophilic esophagitis. Eosinophilic esophagitis is a clinicopathological diagnosis based on the presence of symptoms associated with esophageal dysfunction combined with biopsy findings of eosinophil-predominant inflammation. Common clinical presentations in adults are dysphagia, food impaction, refractory heartburn, central chest pain that is not responsive to antacids, and upper abdominal pain. It is a disease affecting all age groups, with a male predominance [1–3]. Typically, endoscopy reveals esophageal rings (so-called trachealization or feline esophagus) and longitudinal furrows as presented in●" Fig.2 (from a patient with long-standing episodes of recurrent food impaction and dysphagia, and a peak eosinophil count of 110/hpf at biopsy). Other endoscopic features include white plaques, strictures, narrowing of the esophagus, and pallor or decreased vasculature [4]. Eosinophil-predominant inflammation on biopsy is generally considered to be present when there is a minimum of 15 eosinophils per hpf on microscopy. It is important to exclude alternative causes of esophageal eosinophilia such as gastroesophageal reflux disease, celiac disease, Crohn’s disease, infection, hypereosinophilic syndrome, achalasia, drug hypersensitivity, vasculitis, pemphigoid vegetans, connective tissue disease, and graftversus-host disease [5].

A 28-year-old patient admitted with jaundice, vomiting and deteriorating coagulopathy was diagnosed with acute liver failure. After listing for urgent transplantation, he developed Boerhaave's syndrome and massive hemobilia, two life-threatening complications. Massive hemobilia secondary to a fistula between the right hepatic artery and the right bile duct occurred several days after transjugular biopsy and was controlled with fluid resuscitation, transfusion and arterial embolization. Two days later he was transplanted successfully, and is currently doing well after more than 72 months. Aggressive treatment of potentially reversible complications during acute liver failure whilst awaiting transplantation is mandatory to allow survival of these patients. ispartof: JBR-BTR vol:97 issue:6 pages:361-363 ispartof: location:Belgium status: published

We describe the case of a 26-year-old man with acute liver failure secondary to ingestion of khat (Catha edulis) leaves. In fact, this is the first case of acute liver failure due to khat reported outside the United Kingdom. The combination of specific epidemiologic data (young man of East African origin) and clinical features (central nervous system stimulation, withdrawal reactions, toxic autoimmune-like hepatitis) led to the diagnosis. Mechanisms of action and potential side effects of khat are elaborated on.

A 59-year-old man was admitted because of nausea and fatigue. He had been diagnosed with gastric adenocarcinoma 7 months earlier, and because of gastric outlet obstruction had undergone total gastrectomy with esophagojejunostomy and omentectomy (pT3N3bM0R1). Postoperatively, platinum-based chemotherapy was initiated, followed by radiochemotherapy (5-fluorouracil + 45 Gy) approximately 2 weeks before admission.

Embryonic stem cells (ESCs) are pluripotent stem cells, because they can be propagated indefinitely, and differentiate into cells of all three germ layers (endoderm, mesoderm, and ectoderm), shown by teratoma and embryoid body (EB) formation. Following blastocyst injection, mouse ESCs contribute to all somatic and germ-line lineages. ESCs are derived from the inner cell mass (ICM) of the blastocyst and are true pluripotent stem cells. Oct4 is expressed in the pre-gastrulation embryo, primordial germ cells, the ICM, and germ cells. While normal expression levels of Oct4 maintain mouse ESC self-renewal, a decrease in expression to 200% to primitive endoderm differentiation. In recent years more and more has become known about what regulates the expression of Oct4.

Differentiation of human stem cells to hepatocytes is crucial for industrial applications as well as to develop new therapeutic strategies for liver disease. The protocol described here, using sequentially growth factors known to play a role in liver embryonic development, efficiently differentiates human embryonic stem cells (hESC) as well as human-induced pluripotent stem cells (hiPSC) to hepatocytes by directing them through defined embryonic intermediates, namely, mesendoderm/definitive endoderm and hepatoblast and hepatocyte phenotype. After 28 days, the final differentiated progeny is a mixture of cells, comprising cells with characteristics of hepatoblasts and a smaller cell fraction with morphological and phenotypical features of mature hepatocytes. An extensive functional characterization of the stem cell progeny should be used to confirm that differentiated cells display functional characteristics of mature hepatocytes including albumin secretion, glycogen storage, and several detoxifying functions such as urea production, bilirubin conjugation, glutathione S-transferase activity, cytochrome activity and drug transporter activity.

Heterozygous deletion or mutation in hepatocyte nuclear factor 1 homeobox B/transcription factor 2 (HNF1B/TCF2) causes renal cyst and diabetes syndrome (OMIM #137920). Mice with homozygous liver-specific deletion of Hnf1β revealed that a complete lack of this factor leads to ductopenia and bile duct dysplasia, in addition to mild hepatocyte defects. However, little is known about the hepatic consequences of deficient HNF1B function in humans. Three patients with heterozygous HNF1B deficiency were found to have normal bile duct formation on radiology and routine liver pathology. Electron microscopy revealed a paucity or absence of normal primary cilia. Therefore, heterozygous HNF1B deficiency is associated with ciliary anomalies in cholangiocytes, and this may cause cholestasis.

The role of progenitor cells in liver repair and fibrosis has been extensively described but their purification remains challenging, hampering their characterization and use in regenerative medicine. To address this issue, we developed an easy and reproducible liver progenitor cell (LPC) isolation strategy based on aldehyde dehydrogenase (ALDH) activity, a common feature shared by many progenitor cells. We demonstrate that a subset of non-parenchymal mouse liver cells displays high levels of ALDH activity, enabling the isolation of these cells by fluorescence activated cell sorting. Immunocytochemistry and qPCR analyses on freshly isolated ALDH(+) cells reveal an enrichment in cells expressing liver stem-cell markers such as EpCAM, CK19, CD133 and Sox9. In culture, the ALDH(+) population can give rise to functional hepatocyte-like cells as illustrated by albumin and urea secretion and cytochrome P450 activity. ALDH1A1 expression can be detected in canals of Hering and bile duct epithelial cells and is increased upon liver injury. Finally, we could show that the isolation and differentiation towards hepatocyte-like cells of LPCs with high ALDH activity is also successfully applicable to human liver samples. (HEPATOLOGY 2011.) CONCLUSIONS: High ALDH activity is a feature of LPCs that can be taken advantage of to isolate these cells from untreated mouse as well as from human liver tissues. This novel protocol is practically relevant, as it provides an easy and non-toxic method to isolate liver stem cells from normal tissue for potential therapeutic purposes.

In this chapter we will discuss the data published regarding expression of two key ESC transcription factors, Oct4 and Nanog, in adult stem cells. In an introduction, we will discuss what is known regarding these two genes during embryonic development, as well as the evidence existing for the presence of pseudogenes as well as alternative spliced forms of these two genes. We will also address the tools available (or not) to discriminate between these different forms of Oct4 and Nanog, and how these might help in elucidating in the future; whether adult somatic stem cells express the Oct4 and Nanog genes that are known to play a role in the self-renewal and pluripotency characteristics of ESC, and whether such expression plays a role in the potency of adult tissue derived stem cells.

Differentiation of stem cells to hepatocytes has industrial applications, as well as the potential to develop new therapeutic strategies for liver disease. The protocol described here, sequentially using cytokines that are known to have a role in liver embryonic development, efficiently differentiates rat multipotent adult progenitor cells (rMAPCs) to hepatocyte-like cells by directing them through defined embryonic intermediates, namely, primitive streak/mesendoderm/definitive endoderm, hepatoblast and hepatocyte-like phenotype. After 20 days, the final differentiated multipotent adult progenitor cell progeny is a mixture of cells, comprising cells with the characteristics of hepatoblasts and a smaller cell fraction with the morphological and phenotypical features of mature hepatocytes, as well as other mesodermal cells and some persistent undifferentiated rMAPCs. A detailed functional characterization of the stem cell progeny is also described; this should be used to confirm that differentiated cells display the functional characteristics of mature hepatocytes, including albumin secretion, glycogen storage and several detoxifying functions such as urea production, bilirubin conjugation, glutathione S-transferase activity and cytochrome activity. ispartof: NATURE PROTOCOLS vol:5 issue:7 pages:1324-1336 ispartof: location:England status: published

Common variable immunodeficiency (CVID) is an immunodeficiency disease characterized by diminished ability to produce immunoglobulins. CVID has an estimated incidence of 1:10.000 to 1:200.000 (male:female 1:1) and usually presents in the second and third decade, although it also has a peak of incidence in childhood. The exact pathophysiology remains unclear. CVID can be associated with autoimmune, granulomatous and gastrointestinal diseases and patients have a predisposition to malignancies (especially non-Hodgkin lymphoma). Since different organ systems can be affected, all clinicians need to be aware of this entity, especially when confronted with patients with recurrent infections and/or multiple autoimmune diseases.