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Hepatitis C virus:Is it time to say goodbye yet? Perspectives and challenges for the next decade

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World Journal of Hepatology 2015年第5期7卷 725-737页

作者： heidi Barth Laboratoire de virologie Hopitaux Universitaires de Strasbourg67000 StrasbourgFrance

The majority of individuals exposed to hepatitis C virus(HCv) establish a persistent infection,which is a leading cause of chronic liver disease,cirrhosis and hepatocellular *** progress has been made during the past twenty-five years in understanding the HCv life cycle and immune responses against HCv *** evidence indicates that host genetic factors can significantly influence the outcome of HCv infection and the response to interferon alpha-based antiviral *** arrival of highly effective and convenient treatment regimens for patients chronically infected with HCv has improved prospects for the eradication of HCv *** trials are evaluating the best anti-viral drug combination,treatment doses and *** new treatments are better-tolerated and have shown success rates of more than 95%.However,the recent breakthrough in HCv treatment raises new questions and challenges,including the identification of HCvinfected patients and to link them to appropriate health care,the high pricing of HCv drugs,the emergence of drug resistance or naturally occurring polymorphism in HCv sequences which can compromise HCv treatment ***,we still do not have a vaccine against *** this concise review,we will highlight the progress made in understanding HCv infection and *** will focus on the most significant unsolved problems and the key future challenges in the management of HCv infection.

关键词： Pathogenesis Host genetics Direct-actingantivirals Drug resistance vaccine Hepatitis C virus

Stool therapy may become a preferred treatment of recurrent Clostridium difficile?

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World Journal of Gastroenterology 2013年第29期19卷 4635-4637页

作者： Dinesh vyas heidi E L'Esperance Arpita vyas Department of Surgery College of Human Medicine Michigan State University East Lansing MI 48912 United States Department of Pediatrics College of Human Medicine Michigan State University East Lansing MI 48912 United States

Fecal enemas were first reported to successfully treat life threatening enterocolitis in 1958, but fecal therapy to treat Clostridium difficile (C. difficile ) infection has remained esoteric and not well investigated until recently. In the past few years, systematic reviews of case series and case reports of fecal microbiota transplant for recurrent C. difficile infection have become available and validate use of fecal transplant for C. difficile enterocolitis. Methods of fecal transplant reported in the literature include: nasogastric tube, gastroscope, duodenal tube, colonoscopy, rectal tube, and fecal enemas administered at home; no method has been shown to be superior. A recent randomized study published in New England Journal of Medicine found fecal transplant to be superior to oral vancomycin alone in treatment of recurrent C. difficile enterocolitis. The significance of this trial cannot be underestimated as it lends credibility to the idea of intentionally using microbes to combat disease, providing an alternative to the older paradigm of disease eradication through use of antimicrobials.

关键词： Clostridium difficile Enterocolitis Pseudomembranous Fecal transplantation vancomycin

Total joint replacement in inhibitor-positive haemophilia:Long-term outcome analysis in fifteen patients

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World Journal of Orthopedics 2017年第10期8卷 777-784页

作者： heidi Danielson Riitta Lassila Pekka Ylinen Timo Yrj?nen Orton Ortho-paedic Hospital Invalid Foundation Helsinki University and Coagulation Disorders unit Department of Haematology and Comprehensive Cancer CentreHelsinki University Hospital

AIM To collect data from joint replacement in inhibitor patients, evaluate haemostatic and patient outcomes, and analyse the *** We report our 21-year, single-centre cumulative experience of 15 joint arthroplasties in six inhibitor *** Two low responder inhibitor patients were in the early days treated with FvIII, whereas bypassing agents were used in the rest of the high responder patients. The primary haemostatic outcome was good in 8/15, fair in 4/15 and poor in 3/15 operations. The overall patient outcome, including joint health and patient satisfaction, was good in 10/15, fair 4/15 and poor in 1/15. No deep infections were observed. Cost analysis was most beneficial in low responders and in two immune-tolerized, high responder patients. In all cases, factor replacement comprised the main treatment *** Our experience supports the initial use of bypassing agents as well as preoperative immune-tolerance induction when possible. Despite the challenges of haemostasis and severe joint disease, total joint arthroplasty can reach a good outcome, even in inhibitor patients. The risk for deep infection might be smaller than previously reported. Individual planning, intense multidisciplinary teamworkand execution of operations should be centralised in a professional unit.

关键词： Haemophilia Joint replacement Inhibitor Cost analysis Arthroplasty

Role of soluble factors and three-dimensional culture in in vitro differentiation of intestinal macrophages

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World Journal of Gastroenterology 2007年第7期13卷 1032-1041页

作者： Tanja Spoettl Martin Hausmann Katrin Menzel heidi Piberger Hans Herfarth Juergen Schoelmerich Frauke Bataille Gerhard Rogler Department of Internal Medicine I and Institute of Pathology University of Regensburg Regensburg 93042 Germany

AIM: To examine the factor(s) involved in differentiation of intestinal macrophages (IMACs) using a recently established in vitro model. METHODS: To test whether soluble or membrane bound factors induce IMAC-differentiation, freshly elutriated monocytes (MO) were incubated with conditioned media or cell membranes of intestinal epithelial cells (IEC) or cultured with IEC in transwell systems. To determine the importance of an active migration of MO, three- dimensional aggregates from a 1:1-mixture of MO and IEC were examined by immunohistochemistry and flow cytometry. Apoptosis was examined by caspase-3 Western blots. Extracellular matrix production in differentiation models was compared by immunohistochemistry. RESULTS: IMAC differentiation was observed in a complex three-dimensional co-culture model (multicellular spheroid, MCS) with IEC after migration of MO into the spheroids. By co-culture of MO with conditioned media or membrane preparations of IEC no IMAC differentiation was induced. Co-culture of MO with IEC in transwell- cultures, with the two cell populations separated by a membrane also did not result in intestinal-like differentiation of MO. In contrast to IEC-spheroids with immigrating MO in mixed MCS of IEC and MO only a small subpopulation of MO was able to survive the seven day culture period. CONCLUSION: Intestinal-like differentiation of MO in vitro is only induced in the complex three-dimensional MCS model after immigration of MO indicating a roleof cell-matrix and/or cell-cell interactions during the differentiation of IMACs.

关键词： Intestinal macrophages Intestinal epithelialcells Multicellular spheroids Inflammatory boweldisease Tolerance differentiation

Neutralizing antibodies in hepatitis C virus infection

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World Journal of Gastroenterology 2007年第36期13卷 4824-4830页

作者： Mirjam B Zeisel Samira Fafi-Kremer Isabel Fofana heidi Barth Franoise Stoll-Keller Michel Doffo■l Thomas F Baumert Inserm U748Strasbourg France Université Louis Pasteur Strasbourg France Liver Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutesof Health Bethesda MD United States Universitaires de Strasbourg Strasbourg France Service d'Hépatogastro-entérologie Hpitaux Universitaires de Strasbourg

Hepatitis C virus (HCv) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous viral clearance occurs in about 20%-30% of acutely infected individuals and results in resolution of infection without sequaelae. Both viral and host factors appear to play an important role for resolution of acute infection. A large body of evidence suggests that a strong, multispecific and long-lasting cellular immune response appears to be important for control of viral infection in acute hepatitis C. Due too the lack of convenient neutralization assays, the impact of neutralizing responses for control of viral infection had been less defined. In recent years, the development of robust tissue culture model systems for HCv entry and infection has finally allowed study of antibody-mediated neutralization and to gain further insights into viral targets of host neutralizing responses. In addition, detailed analysis of antibody-mediated neutralization in individual patients as well as cohorts with well defined viral isolates has enabled the study of neutralizing responses in the course of HCv infection and characterization of the impact of neutralizing antibodiesfor control of viral infection. This review will summarize recent progress in the understanding of the molecular mechanisms of antibody-mediated neutralization and its impact for HCv pathogenesis.

关键词： Hepatitis C virus virus-host cell interaction viral entry Neutralizing antibodies

The growth of Staphylococcus aureus and Escherichia coli in low-direct current electric fields

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International Journal of Oral Science 2014年第1期6卷 7-14页

作者： Dunya Zituni heidi Schtt-Gerowitt Marion Kopp Martin Krnke Klaus Addicks Christian Hoffmann Martin Hellmich Franz Faber Wilhelm Niedermeier Department of Prosthetic Dentistry School of Dental and Oral Medicine Cologne University Institute for Medical Microbiology Immunology and HygieneCologne University Institute for Anatomy I Cologne University Institute for Medical Statistics Informatics and Epidemiology Cologne University Department of Pre-Clinical Dentistry School of Dental and Oral Medicine Cologne University

Electrical potentials up to 800 mv can be observed between different metallic dental restorations. These potentials produce fields in the mouth that may interfere with microbial communities. The present study focuses on the impact of different electric field strengths （EFS） on the growth of Staphylococcus aureus （ATCC 25923） and Escherichia coil （ATCC 25922） in vitro. Cultures of S. aureus and E. coil in fluid and gel medium were exposed to different EFS. Effects were determined by calculation of viable counts and measurement of inhibition zones. In gel medium, anodic inhibition zones for S. aureuswere larger than those for E. coliat all field strength levels. In fluid medium, the maximum decrease in the viable count of S. aureus cells was at 10 v.m-1. Field-treated S. aureus cells presented ruptured cell walls and disintegrated cytoplasm. Conclusively, S. aureus is more sensitive to increasing electric field strength than E. coll.

关键词： direct current Escherichia coli electrogaNanism gold electrode Staphylococcus aureus

Association of rare SPINK1 gene mutation with another base substitution in chronic pancreatitis patients

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World Journal of Gastroenterology 2006年第33期12卷 5352-5356页

作者： viacheslav N Kalinin Jussuf T Kaifi heidi Schwarzenbach Anatoly S Sergeyev Bjoern C Link Dean Bogoevski Yogesh vashist Jakob R Izbicki Emre F Yekebas Department of General Visceral and Thoracic Surgery University Medical Center Hamburg-Eppendorf Hamburg Germany Institute for Tumor Biology University Medical Center Hamburg-Eppendorf Hamburg Germany Research Centre for Medical Genetics Moscow Russia

AIM: To verify and expand the known spectrum of serine protease inhibitor Kazal type 1 (SPINK1) gene mutations in chronic pancreatitis. METHODS: DNA extracted from 172 chronic pancreatitis patients was assayed for SPINK1 gene mutations by PCR and DNA sequencing. A control cohort of 90 unrelated healthy individuals was analysed by the same methods for presence of common populational polymorphisms, and frequency of five-loci haplotypes was calculated. Linkages of gene aberrations in single SPINK1 gene copies were analysed by long-distance PCR followed by allele-specifi c PCR and DNA sequencing. RESULTS: The most frequent SPINK1 gene mutation N34S was found at a frequency of 6%. Furthermore, we detected the heterozygous intervening sequence (IvS) 3 + 2 T > C mutated gene in 2 German patients and 1 Macedonian chronic pancreatitis patient. In all three SPINK1 gene copies an additional rare base substitution was found: 5’untranslated region (UTR)-215 G > A. Poly-morphism analysis revealed that all three affected genes carried the same fi ve-loci haplotype. DNA sequencing of another chronic pancreatitis-related gene PRSS1 (cationic trypsinogen) did not reveal any mutations in these 3 ***: We found in 3 (2%) of 172 chronic pancreatitis patients an IvS3 + 2 T > C SPINK1 gene mutation and a base substitution 5’UTR-215 G > A inthe same gene copy. Most probably the 5’UTR-215 G >A represents a rare polymorphism and not a mutationas previously concluded. Haplotype analysis suggests acommon origin of the IvS3 + 2 T > C mutation in thesepatients.

关键词： Chronic pancreatitis Serine protease inhibitor Kazal type 1 Gene mutations

Symptom management during and after treatment with concurrent chemoradiotherapy for oropharyngeal cancer:A review of the literature and areas for future research

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World Journal of Clinical Oncology 2016年第2期7卷 220-226页

作者： heidi Mason Mary Beth De Rubeis Nancy Burke Melissa Shannon Danielle Karsies Gregory Wolf Avi Eisbruch Francis Worden University of Michigan School of Nursing

Patients with locally advanced oropharyngeal cancer are at risk for poor outcomes due to the multi-modal nature of treatment and the potential for treatmentrelated *** treatment with concurrent chemotherapy and radiotherapy has drastically reduced the need for a debilitating and disfiguring surgery,treatment related toxicities are often difficult to *** toxicities include mucositis,skin desquamation,depression,cachexia,fatigue and nausea and *** to control these symptoms can adversely affect the patient's ability to complete their treatment *** there are many promising new treatments in the area of symptom management for this patient population,a review of the literature reflects the need for more research.

关键词： Head and neck cancer Chemoradiotherapy Depression Fatigue Cachexia Nausea Desquamation Mucositis vomiting

Gene expression changes in blood RNA after swimming in a chlorinated pool

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Journal of Environmental Sciences 2017年第8期29卷 250-261页

作者： Lucas A.Salas Laia Font-Ribera Mariona Bustamante Lauro Sumoy Joan O.Grimalt Sarah Bonnin Maria Aguilar heidi Mattlin Manuela Hummel Anna Ferrer Manolis Kogevinas Cristina M.villanueva ISGlobal Centre for Research in Environmental Epidemiology(CREAL)Barcelona Spain Department of Epiderniology The Geisel School of Medicine at Dartmouth Lebanon NH USA Universitat Pompeu Fabra (UPF) Barcelona Spain CIBER Epiclemiologia y Salud Publica (CIBERESP) Barcelona Spain IMIM (Hospital del Mar Medical Research Institute) Barcelona Spain Genomics and Disease Centre for Genomic Regulation (CRG) The Barcelona Institute of Science and Technology Barcelona Spain Genomics Core Facility Centre for Genomic Regulation (CRG) The Barcelona Institute of Science and Technology Barcelona Spain Institute of Predictive and Personalized Medicine of Cancer (IMPPC) Institut Germans Trias i Pujol (IGTP) Can Ruti Campus Badalona Spain Department of Environmental Chemistry Institute of Environmental Assessment and Water Research (CSIC) Barcelona Spain

Exposure to disinfection by-products（DBP） such as trihalomethanes（THM） in swimming pools has been linked to adverse health effects in humans, but their biological mechanisms are unclear. We evaluated short-term changes in blood gene expression of adult recreational swimmers after swimming in a chlorinated pool. volunteers swam 40 min in an indoor chlorinated pool. Blood samples were drawn and four THM（chloroform,bromodichloromethane, dibromochloromethane and bromoform） were measured in exhaled breath before and after swimming. Intensity of physical activity was measured as metabolic equivalents（METs）. Gene expression in whole blood m RNA was evaluated using Illumina Human HT-12v3 Expression-Bead Chip. Linear mixed models were used to evaluate the relationship between gene expression changes and THM exposure. Thirty-seven before-after pairs were analyzed. The median increase from baseline to after swimming were： 0.7 to 2.3 for MET, and 1.4 to 7.1 μg/m^3 for exhaled total THM（sum of the four THM）.Exhaled THM increased on average 0.94 μg/m^3 per 1 MET. While 1643 probes were differentially expressed post-exposure. Of them, 189 were also associated with exhaled levels of individual/total THM or MET after False Discovery Rate. The observed associations with the exhaled THM were low to moderate（Log-fold change range：-0.17 to 0.15）. In conclusion, we identified short-term gene expression changes associated with swimming in a pool that were minor in magnitude and their biological meaning was unspecific. The high collinearity between exhaled THM levels and intensity of physical activity precluded mutually adjusted models with both covariates. These exploratory results should be validated in future studies.

关键词： Trihalomethanes Disinfection by-products Gene expression Swimming pools Metabolic rate