Just For Fun; Whats Up With Pruney Fingers?

The reason I find this interesting is because about 8 years ago, I read an article about a four year old child who had severed nerves in three fingers.
;
Sometime later the mother was playing with her toddler in the family pool and noticed those three little fingers were starting to prune, she reported it to her physician. Good news ensued,  the "pruney fingers" meant the child's nerves were slowly improving...lovely story.

Over at Nature  today I read an article by Ed Yong , who writes that Mark Changizi, an evolutionary neurobiologist has a theory - "he suggests wrinkling of wet digits evolved for a reason."

Here is a bit of what  Mark Changizi and his colleagues had to say.

Changizi thinks that the wrinkles act like rain treads on tyres. They create channels that allow water to drain away as we press our fingertips on to wet surfaces. This allows the fingers to make greater contact with a wet surface, giving them a better grip.

Scientists have known since the mid-1930s that water wrinkles do not form if the nerves in a finger are severed, implying that they are controlled by the nervous system.

"I stumbled upon these nearly century-old papers and they immediately suggested to me that pruney fingers are functional," says Changizi. "I discussed the mystery with my student Romann Weber, who said, 'Could they be rain treads?' 'Brilliant!' was my reply."

Read more............

Submission of a phase III clinical trial application for Livatag® in the treatment of primary liver cancer to the French Drug Agency (Afssaps).

BioAlliance Pharma SA (Paris:BIO) (Euronext Paris - BIO), a company dedicated to specialty and orphan oncology products, today announces the submission of a phase III clinical trial application for Livatag® in the treatment of primary liver cancer to the French Drug Agency (Afssaps).

This application follows the phase II survival data announced by BioAlliance Pharma in March 2011 and showing a doubled median survival in Livatag® treated patients (32 months, to be compared with 15 months for patients treated with best of care TACE transarterial chemoembolisation with a cytotoxic drug). This 17 months difference in survival strongly reinforces the interest in the product and justifies a phase III clinical trial application.

These results have been accepted for oral communication at the International Liver Cancer Association (ILCA) 2011 congress.

Moreover, BioAlliance has validated a new administration regimen in animal models, which significantly reduces acute pulmonary adverse events. The phase II trial had been hold in July 2008 due to pulmonary toxicity, whereas patients' survival has been followed up, upon request from the independent study Drug Safety Monitoring Board.

" The survival data jointly with the validated administration scheme aiming to prevent acute pulmonary adverse events justify to re-open the dialog with the French Drug Agency, for a phase III clinical trial that could be initiated in 2012", comments Pierre Attali, COO, Strategy and Medical Affairs of BioAlliance Pharma.

"This application represents a major step within the final development stage of Livatag® before registration, as it has been granted an orphan drug status. The primary liver cancer still represents a high unmet medical need in terms of survival. The global potential turnover of such a product can be evaluated between 800 million and 1 billion Euros. We expect a launch on the market in a 3 to 5 years time, according to the clinical trial results, either through international partnerships, or through direct commercialization in Europe", comments Judith Greciet, COO, Operations & R&D.

About Livatag®

Primary liver cancer, or hepatocellular carcinoma, is the fifth cancer in incidence and the third leading cause of cancer deaths worldwide. This cancer is highly chemo-resistant, very often diagnosed at an advanced stage and still represents a high unmet medical need.

Livatag® is a treatment presented in nanoparticles able to deliver doxorubicin in chemoresistant cells. Livatag® was granted an orphan drug status in Europe and in the United States.

Livatag® is today the leader in the orphan oncology products portfolio, also including clonidine Lauriad™ in the prevention of radiotherapy-induced oral mucositis in patients with head and neck cancer (phase II) and AMEP® in metastatic melanoma (phase I).

Source:
BioAlliance Pharma
International Liver Cancer Association
http://www.medicalnewstoday.com/releases/229824.php

Telaprevir-Incivek; New Hep C drug reduces treatment time

Telaprevir may also improve effectiveness of treatment

CBC News Posted: Jun 29, 2011 12:26 PM ET
 
Adding a new hepatitis C drug to standard medications improves the effectiveness of treatment for the liver disease, an international trial involving a doctor and patients from British Columbia suggests.

Hepatitis C is usually transmitted by blood, often through piercings, tattoos or injection drug use. It can lead to scarring of the liver, which in some cases forces patients to seek a transplant.

About 30 per cent of people with the infection who need a transplant die while waiting for a new liver, said Dr. Eric Yoshida, head of gastroenterology at the University of British Columbia and Vancouver General Hospital.

Yoshida was a co-author of a Phase 3 trial published in the New England Journal of Medicine. The study randomly assigned either a placebo or the treatment without either the patients or researchers knowing who received the drug — the gold standard form of clinical research.

Until now, treatments were less than 50 per cent effective.

"Now you're approaching 80 per cent. For most of these patients, this means that the likelihood of clearing the virus and needing a liver transplant or developing liver cancer suddenly goes way down," said Yoshida, who also leads the B.C. hepatitis program.

Side-effect comparison
The new drug, called telaprevir, was approved by the U.S. Food and Drug Administration in May, and Yoshida expects Health Canada will soon follow.

The standard treatment for hepatitis C has been a combination of two drugs, pegylated-interferon and ribavirin, which are given for a year. If telaprevir is added to the cocktail, the treatment time is reduced to six months, the researchers found.

In the study, anemia, gastrointestinal side-effects, and skin rashes occurred at a higher rate among patients receiving telaprevir than among those receiving peginterferon–ribavirin alone.

The overall rate of discontinuation of the treatment regimen due to side-effects was 10 per cent in the telaprevir group compared with seven per cent in other group, the study's authors found.

Nearly a quarter of a million Canadians have the disease.

Several study authors said they had financial ties to pharmaceutical companies, including Tibotec and Vertex Pharmaceuticals, which funded the research.

Hepatitis C News; Treatment GT 2 and 3 and Another Tylenol Recall

Shortening of treatment duration in patients with chronic hepatitis C genotype 2 and 3 - impact of ribavirin dose - a randomized multicentre trial

Chronic hepatitis C (CHC) Patients, infected with genotype (GT) 2 or 3 are treated with Peg-IFN and ribavirin (RBV) (800 mg/day) for 24 weeks. Treatment duration can be shortened to 12-16 weeks if a higher dose of RBV (1.000/1.200 mg/day) was used without considerable loss of responsiveness or increased risk of relapse.

Previously we have shown that in patients with CHC, GT 2/3 RBV can be reduced to 400 mg/day if administered for 24 weeks without an increase in relapse rates. Therefore we investigated the efficacy of a reduced RBV dosage of 400 mg/day with shorter treatment duration (16 weeks).

Methods: Treatment naive patients with CHC, GT 2/3 were randomized to receive 180mug peginterferonalpha2a/week in combination with either 800 (group C) or 400 mg/d (group D) for 16 weeks.

The primary endpoint was SVR.

Results: 12 months after the first patient was randomized a inferior outcome of group D as compared to group C was noted, therefore the study was terminated. At study termination 89 patients were enrolled (group C: 31, D: 51).

The SVR rate was statistically different in the two study groups with 51.6% in group C and 28.4% in group D (p=0.038). Patients with low viral load had higher SVR rates (C: 67%, D: 33%) than those with high viral load (C: 33%, D: 21%).

Conclusion: Both treatment duration and the dose of RBV play a major role to optimize outcome of patients with GT3.

If one intends to shorten the treatment weight based RBV dose should be used, if lower RBV doses are used patients should be treated for at least 24 weeks as. A treatment regimen with a reduced RBV dosage and shortened treatment duration is associated with low SVR rates due to high relapse rates.Trial registration: NCT01258101
Author: Andreas MaieronSigrid Metz-GercekThomas-Matthias ScherzerHermann LaferlGabriele FischerMartin BischofMichael GschwantlerPeter Ferenci

Credits/Source: BMC Research Notes 2011, 4:220

NortonPrograms may curb hepatitis C in drug users

By Amy

NEW YORK | Wed Jun 29, 2011 12:01am IST

NEW YORK (Reuters Health) - Programs that give injection drug users clean needles or safer drug substitutes may help cut their odds of contracting the liver infection hepatitis C, a new study suggests.

The hepatitis C virus is passed through contact with infected blood. Health care workers are particularly vulnerable, as are people who get tattoos in unclean environments. But in the U.S., most of the roughly 18,000 new infections each year occur when people who inject opiates, like heroin, share tainted needles or syringes.

Studies have found that clean-needle programs do reduce needle-sharing, and they seem to curb drug users' risk of infection with HIV, the virus that causes AIDS. The same appears true of programs that get addicts into treatment with opiate "substitutes" like methadone, which is taken orally instead of injected.

But there has been little evidence that these programs help cut the spread of hepatitis C.

A problem with the hepatitis C virus is that it's much easier to transmit than HIV. Even a faint amount of blood on a shared needle, for example, might be enough to infect another person.

But the new findings, published in the journal Addiction, suggest that needle and opiate-substitution programs can make a difference in hepatitis C risk, according to senior researcher Matthew Hickman, a professor of public health at the University of Bristol in the UK.

Combining the results from six previous studies of UK programs, Hickman's team found that drug users with the highest "coverage" from clean-needle programs were about half as likely to contract hepatitis C as other users.

Among users who said they got enough clean needles to cover all of their injections, just under 4 percent tested positive for hepatitis C during the studies, which lasted up to a year. That compared with 7 percent of drug users who didn't get clean needles for all their injections.

Similarly, the rate of new hepatitis C infection was 3 percent among drug users who were currently taking an opiate substitute (usually oral methadone), versus 7 percent among those not on treatment.

Drug users participating in both types of programs fared best of all, with a new infection rate of 2 percent.

"The implication is that hepatitis C transmission can be reduced by opiate substitution therapy and needle and syringe programs, especially their combination," Hickman told Reuters Health in an email.

While the study looked only at UK programs, it's likely the results would be similar in other countries, he said.

The study has its limits. It combined the results of several observational studies, where researchers "observed" groups of injection drug users who chose to use or not use the needle and opiate substitution programs.

Leaving the choice to the individual makes it hard to show that the programs are what caused hepatitis C infection rates to go down. There may be other differences between people who used the programs and those who didn't that would explain the results.

The findings are also based on small numbers, Hickman's team points out. The researchers had usable information on 919 program participants across the six study sites, and there were 40 cases of new hepatitis C infection.

Still, Hickman said the study starts to fill a gap in the knowledge of how well injection drug use programs are working.

In the U.S., new cases of hepatitis C infection have fallen sharply since the 1980s, according to Centers for Disease Control and Prevention. In the early 1990s, doctors found a way to detect the virus in blood, which meant they could make sure it wasn't transmitted in blood transfusions.

But chronic hepatitis C infection, the agency says, remains a major public health problem.

Between 75 and 85 percent of people infected with hepatitis C develop chronic infection, which can eventually cause serious liver diseases like cirrhosis (scarring of the liver) and liver cancer. Hepatitis C presently accounts for about a third of the liver transplants done in the U.S. each year.

An estimated 3.2 million Americans have chronic hepatitis C, about half of whom are unaware of it. (The initial infection most often causes no symptoms.)

There are medications for treating chronic hepatitis C, although they are not effective for everyone and have side effects like fatigue, nausea, headache and sleep problems.

According to Hickman, one question for future studies is whether treating chronic hepatitis C in injection drug users helps reduce transmission.

SOURCE: bit.ly/lMvRUW  Addiction, online May 25, 2011.


Health personnel spread hepatitis

LAHORE,PAKISTAN:  29 June 2011 (IRIN) - A year after Muhammad Ahsan’s elder brother, Muhammad Rafiq, 40, died of hepatitis C, the family has learnt that the widow, Amna Bibi, 35, has also contracted the infection.

“We spent over Rs 150,000 [US$1,764] on my brother’s treatment. The doctors prescribed injections and medicines that were really expensive. How are we to find more money for my sister-in-law and what will become of their three young children if she dies?” asks Ahsan who earns Rs 20,000 (US$235) a month as an office telephone operator, and has two children of his own to support.

Hepatitis is a viral infection spread through the transfusion of blood and body fluids, sexual contact and the use of improperly sterilized instruments. According to the World Health Organization, all five types of the hepatitis virus (A, B, C, D and E) exist in Pakistan.

Hepatitis A and E can be spread through faecal (sewage) contamination of food or drinking water, while B, C and D can be spread through transfusion of blood and body fluids, sexual contact and use of contaminated instruments which are not sterilized properly. While hepatitis A and B have an effective vaccine, the other types have no known vaccine for prevention.

A 2008 study on the prevalence of the disease carried out by the Pakistan Medical Research Council (PMRC), found that 12 million out of a population of 165 million were infected by hepatitis B or C. Mortality rates due to liver failure caused by hepatitis C were also among the highest in the world, according to medical researchers who noted that “Pakistan carries one of the world's highest burdens of chronic hepatitis and mortality due to liver failure and hepatocellular carcinomas.”

The lack of access to medical care for people like Ahsan is a factor in this.

Unsafe techniques

But what is especially alarming is the finding that healthcare practitioners themselves are responsible, in many cases, for the spread of the virus due to unsafe techniques. These include the re-use of syringes and needles. According to the PMRC, nearly 15 percent of paramedics are themselves infected by the hepatitis virus, as are 7.3 percent of nurses, 6.8 percent of doctors and 5.2 percent of medical students based at major hospitals.

The improper disposal of hospital waste adds to the risks. “Sharp waste generated at hospitals and similar settings contribute to a minimum of 20 percent of all infections in the country,” PMRC deputy director Waqaruddin Ahmed said.

“The published literature on the modes of transmission of hepatitis B and hepatitis C in Pakistan implicate contaminated needle use in medical care and drug abuse and unsafe blood and blood product transfusion as the major causal factors,” the researchers noted.

Media reports have suggested one in every 10 Pakistanis suffers from hepatitis B or C, and that the failure to implement laws such as the Safe Blood Transfusion Act of 2002 which puts in place rules for the screening of donated blood, has exacerbated the situation.

“One of the problems is the widespread belief among patients that injections are more effective than oral medications. People who come to clinics, such as the one I practice at, frequently demand an injection even when pills are available. This contributes to the spread of diseases such as hepatitis, since needles are quite often re-used at some places,” Aziz Ahmed, a doctor in Lahore, told IRIN.

The theft and re-sale of hospital waste, quite often by hospital staff, makes matters worse.

“There are people in this hospital - lab assistants, nurses, cleaners and others who take away used items, such as IV [intravenous] bags, and re-sell them in the market,” a doctor at a government hospital in Lahore, who asked not to be named, told IRIN. “Who knows what illnesses are spreading because of this?”
[This report does not necessarily reflect the views of the United Nations]
.
Pharmaceuticals

June 29, 2011, 9:03 a.m. EDT

Research Report on Vertex Pharmaceuticals Inc. and PharmAthene, Inc. - Gaining in the Bio Pharmaceutical Sector

MACAU, Jun 29, 2011 (MARKETWIRE via COMTEX) -- Today, www.EquityMarketsInc.com announced its research report highlighting Vertex Pharmaceuticals Inc . /quotes/zigman/79675/quotes/nls/vrtx VRTX +4.13% and PharmAthene, Inc. /quotes/zigman/1507997/quotes/nls/pip PIP -6.21% . Full content and research is available at www.EquityMarketsInc.com/research.php .


This sector demonstrates renewed investor interest as new and lucrative therapies come to market. The FDA approved the first new drug in 50 years to treat auto-immune disorder lupus in March 2011, and we expect approval of new treatments for Hepatitis C virus around mid-year. The 2010 health care reform act authorized the FDA, will establish a regulatory pathway for approving "biosimilar" drugs, which in turn will increase production and shorten FDA approval times. Longer term, it is expected that a wider acceptance of biomarker research and genetic-targeted clinical studies to help limit expense. It is viewed that therapeutics for cancer and infectious diseases and autoimmune and inflammatory treatments are primary growth areas.

Equity Markets has reviewed Vertex Pharmaceuticals Inc. which is in the business of discovering, developing and commercializing small molecule drugs for the treatment of diseases. The Company is engaged in phase-I clinical trials and/or nonclinical activities with respect to a range of additional drug candidates, including compounds intended for the treatment of hepatitis C virus (HCV) infection, cystic fibrosis (CF) and influenza. In November 2010, the Company submitted a new drug application (NDA), requesting approval to market telaprevir in the United States for the treatment of patients with chronic HCV infection. The full research report on Vertex Pharmaceuticals Inc . /quotes/zigman/79675/quotes/nls/vrtx VRTX +4.13% is available here: www.EquityMarketsInc.com/researchfile4634.php  .

Equity Markets is covering PharmAthene, Inc. as a biodefense company engaged in the development and commercialization of medical countermeasures against biological and chemical weapons. It has five product candidates in various stages of development: SparVax, recombinant protective antigen (rPA) anthrax vaccine; Valortim, a human monoclonal antibody for the prevention and treatment of anthrax infection; Protexia, a recombinant enzyme (butyrylcholinesterase), which mimics a natural bioscavenger for the prevention or treatment of nerve agent poisoning by organophosphate compounds. The full research report on PharmAthene, Inc. /quotes/zigman/1507997/quotes/nls/pip PIP -6.21% is available here: www.EquityMarketsInc.com/researchfile4891.php  .

About Equity Markets Our mission at Equity Markets is to be the best source of content and research, while educating, enlightening and informing investors. Equity Markets combines street smart analysts and professional market researchers to provide investors with detailed company profiles and market coverage.
'
R&D Spending In India Is Projected To Mushroom

By Ed Silverman // June 29th, 2011 // 8:00 am

Last year, the pharmaceutical industry spent about $2 billion on assorted R&D activities in India, but that figure is expected to reach a whopping $25 billion by 2025. The reasons are varied, but can be traced to expanding activities by Indian companies, additional government investment and a growing pool of qualified researchers, according to a new report by the Boston Consulting Group.


The optimistic forecast reflects declining R&D productivity in regions where such work has traditionally been conducted, notably the US and Western Europe. Already, the picture is changing. In 2002, pharma spent $25.3 billion in the US, which accounted for 83 percent of the worldwide total. By 2009, that grew to $35.4 million, but represented 76 percent of the total. There were also percentage declines in Western Europe and Japan.

Stem Cells

The promise of stem cell-based gene therapy
Will depend on novel gene delivery tools

New Rochelle, NY, June 29, 2011—Sophisticated genetic tools and techniques for achieving targeted gene delivery and high gene expression levels in bone marrow will drive the successful application of gene therapy to treat a broad range of diseases. Examples of these cutting-edge methods are presented in a series of five provocative articles in the latest issue of Human Gene Therapy, a peer-reviewed journal published by Mary Ann Liebert, Inc. (http://www.liebertpub.com/ ). The articles are available free online at www.liebertpub.com/hum

Barese and Dunbar highlight the advances in gene marking techniques that are enabling selection and targeting of specific immune cell populations for cell and gene therapy. The success of marking studies will help optimize gene transfer for immunotherapeutics and improve patient survival, conclude the authors in the review article "Contributions of Gene Marking to Cell and Gene Therapies."

Giordano et al. explore the use of PCR and next-generation DNA sequencing methods to identify specific gene products that are associated with successful long-term transfer of therapeutic genes to bone marrow. They report their findings in the research article entitled "Clonal Inventory Screens Uncover Monoclonality Following Serial Transplantation of MGMTP140K-Transduced Stem Cells and Dose-Intense Chemotherapy."

As a model for therapeutic gene delivery to bone marrow and peripheral blood cells to treat lysosomal storage disorders, Walia et al. describe successful gene replacement in a primate model of Farber disease. The study, "Autologous Transplantation of Lentivector/Acid Ceramidase-Transduced Hematopoietic Cells in Nonhuman Primates," reports the ability to replace acid ceramidase (AC) gene activity and reduced ceramide levels in blood cells transduced with the AC gene.

Hunter et al. present a study that compares the use of a human gene promoter with a mouse promoter-enhancer for achieving high levels of gene expression in a dog model of leukocyte adhesion deficiency type 1. "Gene Therapy for Canine Leukocyte Adhesion Deficiency with Lentiviral Vectors Using the Murine Stem Cell Virus and Human Phosphoglycerate Kinase Promoters" describes the study results.

Evidence to support the effective use of chromatin insulators—a class of DNA regulatory elements—to improve the expression and safety of gene transfer vectors is the focus of the Methods Review by David Emery entitled "The Use of Chromatin Insulators to Improve the Expression and Safety of Integrating Gene Transfer Vectors."

"Bone marrow-directed gene therapy was the first model considered in the treatment of genetic diseases and remains one of the most successful models in terms of clinical efficacy," says James M. Wilson, MD, PhD, Editor-in-Chief, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

###

Human Gene Therapy, the Official Journal of the European Society of Gene and Cell Therapy, British Society for Gene Therapy, French Society of Cell and Gene Therapy, German Society of Gene Therapy, and five other gene therapy societies is an authoritative peer-reviewed journal published monthly in print and online that presents reports on the transfer and expression of genes in mammals, including humans. Related topics include improvements in vector development, delivery systems, and animal models, particularly in the areas of cancer, heart disease, viral disease, genetic disease, and neurological disease, as well as ethical, legal, and regulatory issues related to the gene transfer in humans. Complete tables of content and a free sample issue may be viewed online at www.liebertpub.com/hum

Mary Ann Liebert, Inc. is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Tissue Engineering, Stem Cells and Development, and Cellular Reprogramming. Its biotechnology trade magazine, Genetic Engineering & Biotechnology News (GEN), was the first in its field and is today the industry's most widely read publication worldwide. A complete list of the firm's 60 journals, books, and newsmagazines is available at www.liebertpub.com.

Mary Ann Liebert, Inc. 140 Huguenot St., New Rochelle, NY 10801-5215 http://www.liebertpub.com/
Phone: (914) 740-2100 (800) M-LIEBERT Fax: (914) 740-2101

FDA

J&J recalls more Tylenol Extra Strength pills


On Tuesday June 28, 2011, 8:01 pm EDT


FORT WASHINGTON, Pa. (AP) -- Johnson & Johnson on Tuesday announced another Tylenol recall due to a musty moldy odor linked to a trace chemical.

The company's McNeil Consumer Healthcare unit is recalling one product lot of Tylenol Extra Strength Caplets made in February 2009 and distributed in the U.S. The recall totals 60,912 bottles, each of which has 225 caplets.

McNeil said it has received a small number of reports about the pills' odor, which has been linked in past J&J recalls to the presence of trace amounts of "2,4,6-tribromoanisole." TBA is a byproduct of a chemical preservative sometimes used on shipping pallets.

Besides causing an unpleasant odor, TBA has been associated with temporary and non-serious gastrointestinal symptoms.

Since September 2009, New Brunswick, N.J.-based Johnson & Johnson has had about two dozen recalls of prescription and nonprescription medicines, replacement hips, contact lenses and diabetes test strips, including tens of millions of bottles of children's and adult Tylenol and Motrin.

The reasons have ranged from metal and other contaminants, to nauseating odors and packaging issues. Joint replacement systems so painful they required corrective surgery were also recalled, as were contact lenses that irritated eyes, along with potentially contaminated syringes full of the antipsychotic drug Invega.

The high-profile lapses have tugged at J&J's revenue, profit and stock price, as well as its once-stellar reputation. J&J has said that it has inspected more than 100 plants around the world and invested millions to improve the quality of its manufacturing and satisfy federal regulators, who have three of its factories under scrutiny.

The product lot number for the recalled Tylenol Extra Strength product can be found on the side of the bottle label -- it is ABA619 300450444271.

Customers should stop using the product from the lot immediately and contact McNeil at http://www.tylenol.com/  or by calling 1-888-222-6036 for instructions on receiving a refund or product coupon.


FDA-Approved Diabetes Simulator Commercially Available


Released: 6/29/2011 12:05 AM EDT

Source: University of Virginia

Newswise — June 29, 2011 — A computer-based diabetes simulation tool developed by University of Virginia researchers is now commercially available, thanks to a partnership with the Charlottesville-based medical research firm The Epsilon Group. The simulator is the only protocol that has been accepted by the U.S. Food and Drug Administration as an alternative to animal testing of Type 1 diabetes control strategies.

Boris P. Kovatchev and Marc D. Breton of the U.Va. Center for Diabetes Technology developed the simulator in collaboration with Claudio Cobelli and Chiara Dalla Man at the University of Padova, Italy. The U.Va. Patent Foundation granted Epsilon, a division of Medical Automation Systems Inc., an exclusive license to the technology in April.

"It takes a tremendous amount of time and resources to conduct animal testing for clinical trials, often only to find that a treatment doesn't work," said Miette H. Michie, interim executive director and CEO of the U.Va. Patent Foundation. "Through their innovative diabetes simulator, Drs. Kovatchev and Breton and their collaborators have provided an FDA-accepted substitute for animal trials, allowing effective treatments to reach the market – and start impacting patients – much sooner."

The simulator uses a software algorithm to model the human metabolic system. Based on patient data from 300 children, adolescents and adults with Type 1 diabetes, the algorithm uses 26 different parameters to mimic human metabolism at the individual level, through several distinct patient profiles. Within these individual profiles, variables such as diet, exercise behavior and insulin intake can be manipulated to test the accuracy or effectiveness of a new product under varying conditions – or to compare it to existing products.

According to the researchers, this technology is an improvement over other simulators, which provide only average or group-level results.

"This simulator allows 'in silico' pre-clinical experiments to be conducted at the level of an individual, revealing inter-personal differences due to treatment," said Kovatchev, director of the diabetes technology center at U.Va. and an internationally renowned diabetes technology scientist.

Kovatchev and Breton are researchers in the U.Va. School of Medicine's Department of Psychiatry and Neurobehavioral Sciences. Kovatchev holds a joint appointment in the School of Engineering and Applied Science's Department of Systems and Information Engineering and was named U.Va. Patent Foundation's 2011 Edlich-Henderson Inventor of the Year for the development of novel computational methods that have advanced the state of diabetes research.

Approximately 60 academic and industrial sites are already using a test version of the simulator for research purposes.

Kurt Wassenaar, Epsilon CEO, said that computational modeling can help improve and accelerate new products for diabetes care. "We are very enthusiastic about the opportunity to build and provide a robust commercial version of the model technology to the diabetes research and disease management community," he said.

The simulator project has been funded by the Juvenile Diabetes Research Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases. A patent on the simulator is pending.

Diabetics get blood vessels made from donor cells

Three dialysis patients have received the world's first blood vessels grown in a lab from donated skin cells. It's a key step toward creating a supply of ready-to-use arteries and veins that could be used to treat diabetics, soldiers with damaged limbs, people having heart bypass surgery and others.

The goal is to one day have a refrigerated inventory of these in various sizes and shapes that surgeons could order up as needed like bandages and other medical supplies.

The work so far is still early-stage. Three patients in Poland have received the new vessels, which are working well two to eight months later. But doctors are excited because this builds on earlier success in about a dozen patients given blood vessels grown in the lab from their own skin - a process too long and expensive to be practical.

"This version, built from a master donor, is available off the shelf and at a dramatically reduced cost," estimated at $6,000 to $10,000, said Todd McAllister, chief of Cytograft Tissue Engineering Inc., the San Francisco-area company leading the work.

The American Heart Association considers it so promising that the group featured it on Monday in the first of a new series of webcasts about cutting-edge science.

"This is tremendously exciting," because the failure of blood vessels used in dialysis is "a huge public health problem," said Duke University's Dr. Robert Harrington, a heart expert who had no role in the work.

If a larger study getting under way now in Europe and South America shows success, "this is big news," Harrington said.

Kidney failure, which is common in diabetics, requires dialysis to filter wastes from the blood through a connection between an artery and a vein called a shunt. It gets punctured several times a week to hook patients up to the dialysis machine, and complications include blood clots, clogging and infection.

Continue Reading....

---

Online:

Company and video: http://www.cytograft.com/

Marilynn Marchione can be followed at http://twitter.com/MMarchioneAP



© 2011 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed. Learn more about our Privacy Policy and Terms of Use.

The effects of milk thistle on hepatic fibrosis due to methotrexate in rat

The effects of milk thistle on hepatic fibrosis due to methotrexate in rat

Authors:
Ghaffari AR
Department of Internal Medicine, Sina hospital, Tabriz University of Medical Sciences, Liver and Gastrointestinal Research Center, Tabriz , IR Iran

Noshad H
Department of Internal Medicine, Sina Hospital, Tabriz University of Medical Sciences, Tabriz , IR Iran

Ostadi A
Department of Internal Medicine, Sina Hospital, Tabriz University of Medical Sciences, Tabriz , IR Iran

Ghojazadeh M
Department of Physiology, Tabriz University of Medical Sciences, Tabriz, IR Iran

Asadi P
Department of Internal Medicine, Sina Hospital, Tabriz University of Medical Sciences, Tabriz, IR Iran

Correspondence:
Hamid Noshad ,
Department: Department of Internal Medicine, Sina Hospital, Tabriz University of Medical Sciences
Address: Department of Internal Medicine, Sina Hospital, Tabriz University of Medical Sciences
City: Tabriz
Country: IR Iran
E-mail: hamidnoshad1@yahoo.com
Tel: +98-9143115927
Fax: +98-411-5415023

Abstract:

Background:
Extracts of milk thistle (MT), Silybum marianum, have been used as medical remedies since the time of ancient Greece. Methotrexate is a potentially hepatotxic drug.
Objectives: To clarify the hepatoprotective effects of MT on methotrexate.

Materials and Methods:
From January 2010 to April 2010, 30 male rats were recruited into three 10-rat subgroups in Tabriz University of Medical Sciences. Normal saline was injected intraperitoneally in the first group (A; the controls); intraperitoneal methotrexate plus oral MT extract were administered to the second group (B) and intraperitoneal methotrexate alone was given to the third group (C). Pre- and post-interventional measuring of serum parameters were carried out every 15 days. After six weeks, the rats were decapitated and histopathological evaluation of liver was done.

Results:
Serum liver enzymes (AST, ALT), alkaline phosphatase, total and direct bilirubin, creatinine and BUN were measured on days 0, 15, 30, 45. They were significantly higher in the group C, comparing with other two groups. Serum albumin was the least in group C animals as well. There were no significant differences between groups A and B. The mean±SD fibrosis score using semi-quantitative scoring system (SSS) was 1.25±0.46, 1.40±0.52 and 6.70±0.82, in groups A, B and C, respectively (p<0.001). Conclusions: MT extract can effectively prevent methotrexate-induced liver dysfunction and fibrosis in rats.

Keywords: Milk thistle; Silybum marianum; Methotrexate; Drug toxicity; Liver; Rats
--------------------------------

Implication for health policy/practice/research/medical education: Silymarine has effects on some pathophysiological processes of liver disorders. Doing animal studies help us to better understanding these mechanisms. Please cite this paper as: Ghaffari AR, Noshad H, Ostadi A, Ghojazadeh M, Asadi P. The effects of milk thistle on hepatic fibrosis due to methotrexate in rat. Hepat Mon. 2011;11(6):464-8. Article history: Received: 31 Jan 2011 Revised: 26 Feb 2011 Accepted: 04 Mar 2011 2011 Kowsar M.P.Co.
All rights reserved.

Introduction: 1.

Background Methotrexate (MTX) is a potent hepatotoxic agent. This drug is effective in various cancers and immunologic disorders. It is used frequently in rheumatoid arthritis and psoriasis. This drug when used without follow-up has many side effects like hepatotoxicity and bone marrow suppression. MTX is accumulated in liver and is hepatotoxic. It seems that folic acid can reduce MTX side effects but it is not completely clarified. Clinicians use the drug frequently, so they would like to reduce its side effects especially its hepatotoxic effects (1). It was shown that milk thistle (Silybum marianum) has beneficial effects on hepatotoxicity (2). The objective of this study was to clarify the effect of MT on MTX-induced hepatotoicity in an animal model. In animal models, it has been shown that MT prevents atherosclerotic plaque formation in aorta. It has been shown that the cisplatin and cyclosporine side effects reduced when MT was administered in mice (3, 4). Reports showed that silymarin promote DNA polymerase, stabilize all membranes, inhibits free radicals and increases glutathione concentration, so it could protect liver from hepatotoxic agents. Silibinin is able to stimulate the activity of the DNA-dependent RNA polymerase I and causes an increase in rRNA synthesis. It accelerates formation of intact rRNA polymerase with resultant formation of new hepatocytes (5). Silymarin inhibits lipoxygenase cycle, leukotrienes and free radicals formation in mice Kupffer cells, so inflammation may be reduced (6). Treatment with MT has been usual since 2000 years ago and it is mentioned as a hepatoprotective agent (7). MT is found in many areas all around the world and is cultured in North and South parts of Iran. This drug is absorbed via the gastrointestinal tract; the maximum blood level is reached after 2-4 hours. The half-life of the drug is six hours. About 80% of MT is secreted into the bile and its bioavailability depends on its formulation (8). Sylibin is the most effective agents in MT and is known as an antioxidant and hepatoprotective agent. Its concentration in bile is 60 times greater than the blood. Silymarin has various cardiovascular effects (9). Silymarin inhibits liver enzymes like gamaglutamil transpeptidase (GGT), alanine transaminase (ALT) and aspartate transaminase (AST) in rats (5). This drug blocks hepatic fibrosis due to biliary obstruction in mice. In one study a formulation of silymarin extract (Legalon) was used in 2637 patients with chronic liver disease for eight weeks when the liver enzymes remarkably decreased in 88% of patients.

Side effects were seen in lesser than 1% of patients (10). Silymarin is widely used in poisoning with Amanita fungus and reduces mortality significantly (60%-80%). The effects of silymarin on alcoholic liver damages are controversial, but in a controlled double blind clinical trial this drug could improve liver enzyme level and histopathologic liver features after four weeks in alcoholic hepatotoxicity (11). In one study, silymarin could reduce mortality in patients with alcoholic cirrhosis after four years. In another study, however, silymarin could not reduce hepatic mortality in cirrhotic patients (12). Silymarin effects on hepatic damages due to hepatitis are also controversial. In a double blind clinical trial, 20 patients with chronic active hepatitis received 240 mg of silybin complex (silipide) two times a day for seven days; the GGT level reduced significantly (13). In another study, 29 patients with viral hepatitis treated with silymarin and 28 patients received placebo; serum bilirubin, AST and ALT levels significantly reduced in the treatment group but in another study with 151 patients with viral hepatitis this drug could not improve their clinical condition (14). Silymarin has other therapeutic effects. It reduces LDL cholesterol level and atherosclerotic plaque formation in rabbit and mice (15). This agent has some mild side effects like allergic reactions in sensitive patients. In animal models, silymarin in higher doses has not any side effects. Long-term use of this drug was safe. Silymarin also is safe in pregnancy, lactation and children (12). 2.

Objectives
This study tries to determine the hepatoprotective effects of MT on MTX-induced hepatotoxicity.

Materials And Methods:
In an experimental study, 30 rats (weigh 250-300 g) were used. The rats were in animal house for one week and had access to water and food ad libitum. Temperature was kept at 37 °C. After one week, the rats were randomly divided into three equal groups: Group A rats received normal saline (600 mg/kg); group B received MTX (100 μg/kg) intraperitoneally and silymarin (600 mg/kg) orally; group C rats received MTX (100 μg/kg) intraperitoneally alone. We used 1 mL of MTX (1000 mg/10 mL) and diluted it in 99 mL of normal saline and then 1 mL of product was diluted in 9 mL of normal saline (100 µg/mL MTX). It was injected by insulin syringes. MT was administered orally by a special syringe for rats after four hours. This study was done in Education Development Center of Tabriz University of Medical Sciences, Tabriz, Iran. The study was conducted under supervision of a zoologist and pharmacist, professional in these kinds of animal studies. MT seeds were obtained from different areas of Aras river in East Azarbayjan, North-West of Iran.

In pharmacognosy laboratory of pharmacy faculty, dry seeds were milled and processed with hexane; the silymarin and its flavonolignan were extracted using succilating method. After solvent evaporation, the amount of the total flavonolignans of silymarin was measured by spectrophotometry. Extracted materials were fractionated, using SPE (sep-pak) cartridges and methanol-water mixture. Solvent of the obtained fractions was evaporated and the product was used in this study. Tabriz University of Medical Sciences Ethical Committee approved this study. All animals received humane care according to the criteria outlined in the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 86-23 revised 1985). For biochemical studies, blood samples were taken before the intervention and 15, 30 and 45 days post-intervention. Serum samples were examined for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkalin phosphatase (ALP), blood urea nitrogen (BUN), creatinine (Cr), bilirubin (Bil), and albumin (Alb). Every morning (8-9 am), MTX was injected; MT was given orally by special syringe four hours later. Six weeks after intervention, rats were killed, their livers were fixed in 10% formalin and studied for histopathologic changes. The samples were scored using a semi-quantitative scoring system (SSS) (16) as below: < 2: normal; 2-6: mild fibrosis; 6-10: moderate fibrosis; > 10: sever fibrosis;

The data were analyzed by SPSS® for Windows® ver 17. The continuous variables were first tested to see if they were distributed normally. Descriptive statistics, including the mean and standard deviation (SD) was calculated for all variables. One-way ANOVA or Kruskal-Wallis test was used to compare means of three or more groups. Pairwise comparisons of the study groups were performed using Tukey's HSD and Mann-Whitney U test as post hoc tests. A p < 0.05 was considered statistically significant.


Results:

Biochemical parameters were measured before the intervention, and 15, 30, and 45 days after the intervention. The creatinine level was significantly different among all the studied groups (p < 0.001) but groups A and B. Therefore, creatinine level was lower in patients treated with MT (Table 1). BUN was also significantly different among the studied groups (p < 0.001). BUN level was better in rats treated with MT (Table 1). ALT was also significantly different among all (p < 0.001) but groups A and B (p = 0.211). ALT level was lower in group B (Table 1). AST level was also significantly different among all studied groups (p < 0.001) (Table 1). Total bilirubin level was significantly different among all (p < 0.001) but groups A and B was not remarkable. Total bilirubin level was lower in rats treated with MT (Table 1). Direct bilirubin level was significantly different among all studied groups (p < 0.001) (Table 1).
Albumin level was significantly different among the studied groups (p < 0.001) (Table 1). Bilirubin was lower and albumin was higher in group B rats. ALP was also significant among the studied groups (p = 0.01). The difference between groups A and C was significant (p = 0.01) but it was not among other paired groups (Table 1). It must be emphasized that we did not measure prothrombin time. The mean ± SD SSS score was 1.25 ± 0.49 in group A, 1.40 ± 0.52 in group B and 6.70 ± 0.82 in group C rats. The score was significantly higher in group C (p < 0.001)-fibrosis was more severe in rats exposed to MTX without MT extract. The mean SSS score was significantly different among the studied groups. Difference between paired groups was only significant between groups A and C (p < 0.001) and also groups B and C (p < 0.001) (Figure 1).

Table 1. Mean±SD of measured biochemical parameters in the studied groups
Figure 1. Error bar chart of SSS scores at the end of the study.


Discussion:

In this study protective effects of MT on MTX-induced liver damage in rats was investigated. We found that the mean levels of ALT, AST, ALP and bilirubin in rats that received MTX plus MT were significantly lower than those animals received only MTX. Difference of studied parameters between MTX plus MT and control group (that received only normal saline) was not significant. Up to now, various studies revealed protective effects of MT in hepatic damages (17). In these studies, it was shown that extract of MT reduced treatment period of acute and chronic hepatitis (18). Protective effects of MT in fatty liver, cirrhosis, viral hepatitis, ischemic liver damage and cancer was shown previously (19). In our study, also SSS score in MTX plus MT group was significantly lower than that in MTX group which reflected protective effects of MT. Buzzelli and colleagues showed that administration of MT extract to 20 patients with chronic active hepatitis reduced serum liver enzymes, ALP and bilirubin levels after seven weeks (20). In our study, liver enzymes and bilirubin were reduced in rats received MT. Giese showed that MT extract has antihepatitic effects (21). Dhiman also emphasized protective effects of MT on hepatic disease (22). Mayer revealed protective and curative effects of MT on viral hepatitis (23). Rambaldi and colleagues showed these protective and curative effects in viral and alcoholic hepatitis (24). Jacobs et al. emphasized the protective effects of MT extracts in hepatic disease (25). Other investigators like Gassileth (2008), Ross (2008), Raina (2008), and Ramakrishnan (2008), also emphasized the efficacy of MT extract on liver disease and its safety (7, 26-28). Protective mechanisms of MT extract in liver disease are mentioned in different studies (29-31). Some of them are antioxidant, anti- lipid peroxidase, anti-fibrinolytic, anti-inflammatory and immunomodulatory effects, induction of cell formation, glutathione inhibition, reduction of leukotrienes, reduction of tumor promoters and P450 inhibition. We found that the mean BUN and creatinine level were lower in the group that received MT extract. So reno-protective effects are also proposed (32). In animal studies, this drug prevented atherosclerotic plaque formation in aorta (33). Previous studies revealed that silymarin prevents acetaminophen and tetrachloromethane hepatotoxic effects (22). Reports showed that MT may promote DNA polymerase, stabilize all membrane, inhibit free radicals and increase glutathione concentration, so it protects liver against hepatotoxic agents (34). Promotion of DNA polymerase leads to rRNA synthesis and hepatocellular regeneration. By increasing glutathione concentration, it stabilizes superoxide dismutase and glutathione peroxidase (18). Different animal studies showed that silymarin protects hepatocytes against viruses, chemical agents, fungal toxins and alcohol-premedication. This drug protects animals against fatal effects of Amanita toxins (12, 35). Silymarin premedication prevents hepatotoxic effects of halothane, thallium tetrachloride and acetaminophen in animal studies (7). Silymarin inhibits liver enzymes like gamma-glutamyl transpeptidase (GGT), ALT and AST in rats (36). In one study, Silymarin could reduce mortality in patients with alcoholic cirrhosis after four years. On the other hand, in another study, silymarin could not reduce hepatic mortality in cirrhotic patients (35). In our study it was shown that MT extract protects liver against MTX hepatotoxic effects. Liver enzymes (AST, ALT and ALP), bilirubin and albumin remain unchanged. Also MT extract prevents kidney injury due to MTX in rat. BUN and creatinine levels remain unchanged. MT extract significantly prevents liver damage due to MTX in rat, so similar human studies are required. Studies on the effect of MT extracts on drug-induced kidney injury are therefore warranted. Similar results would justify use of MT extract in patients receiving MTX as a prophylactic agent against hepatic side effects.

Financial support
None declared.

Conflict of interest
None declared.


Acknowledgments:
We thank Dr.somi for his assistance.

References:

1. West SG. Methotrexate hepatotoxicity. Rheum Dis Clin North Am. 1997;23(4):883-915. [PubMed]

2. Pepping J. Milk thistle: Silybum marianum. Am J Health Syst Pharm. 1999;56(12):1195-7. [PubMed]

3. Bokemeyer C, Fels LM, Dunn T, Voigt W, Gaedeke J, Schmoll HJ, et al. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer. 1996;74(12):2036-41. [PubMed]

4. Zima T, Kamenikova L, Janebova M, Buchar E, Crkovska J, Tesar V. The effect of silibinin on experimental cyclosporine nephrotoxicity. Ren Fail. 1998;20(3):471-9. [PubMed]

5. Valenzuela A, Aspillaga M, Vial S, Guerra R. Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Med. 1989;55(5):420-2. [PubMed]

6. Dehmlow C, Erhard J, de Groot H. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology. 1996;23(4):749-54. [PubMed]

7. Ross SM. Milk thistle (Silybum marianum): an ancient botanical medicine for modern times. Holist Nurs Pract. 2008;22(5):299-300. [PubMed]

8. Weyhenmeyer R, Mascher H, Birkmayer J. Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. Int J Clin Pharmacol Ther Toxicol. 1992;30(4):134-8. [PubMed]

9. Asghar Z, Masood Z. Evaluation of antioxidant properties of silymarin and its potential to inhibit peroxyl radicals in vitro. Pak J Pharm Sci. 2008;21(3):249-54. [PubMed]

10. Altorjay I, Dalmi L, Sari B, Imre S, Balla G. The effect of silibinin (Legalon) on the the free radical scavenger mechanisms of human erythrocytes in vitro. Acta Physiol Hung. 1992;80(1-4):375-80. [PubMed]

11. Pares A, Planas R, Torres M, Caballeria J, Viver JM, Acero D, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol. 1998;28(4):615-21. [PubMed]

12. Barve A, Khan R, Marsano L, Ravindra KV, McClain C. Treatment of alcoholic liver disease. Ann Hepatol. 2008;7(1):5-15. [PubMed]

13. Magliulo E, Gagliardi B, Fiori GP. [Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres (author's transl)]. Med Klin. 1978;73(28-29):1060-5. [PubMed]

14. Bode JC, Schmidt U, Durr HK. [Silymarin for the treatment of acute viral hepatitis? Report of a controlled trial (author's transl)]. Med Klin. 1977;72(12):513-8. [PubMed]

15. Skottova N, Krecman V. Dietary silymarin improves removal of low density lipoproteins by the perfused rat liver. Acta Univ Palacki Olomuc Fac Med. 1998;141:39-40. [PubMed]

16. Chevallier M, Guerret S, Chossegros P, Gerard F, Grimaud JA. A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: comparison with morphometric studies. Hepatology. 1994;20(2):349-55. [PubMed]

17. Pradeep K, Mohan CV, Gobianand K, Karthikeyan S. Silymarin modulates the oxidant-antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats. Eur J Pharmacol. 2007;560(2-3):110-6. [PubMed]

18. Saller R, Melzer J, Reichling J, Brignoli R, Meier R. An updated systematic review of the pharmacology of silymarin. Forsch Komplementmed. 2007;14(2):70-80. [PubMed]

19. Loguercio C, Federico A, Trappoliere M, Tuccillo C, de Sio I, Di Leva A, et al. The effect of a silybin-vitamin e-phospholipid complex on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci. 2007;52(9):2387-95. [PubMed]

20. Buzzelli G, Moscarella S, Giusti A, Duchini A, Marena C, Lampertico M. A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol. 1993;31(9):456-60. [PubMed]

21. Giese LA. Milk thistle and the treatment of hepatitis. Gastroenterol Nurs. 2001;24(2):95-7. [PubMed]

22. Dhiman RK, Chawla YK. Herbal medicines for liver diseases. Dig Dis Sci. 2005;50(10):1807-12. [PubMed]

23. Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepat. 2005;12(6):559-67. [PubMed]

24. Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev. 2005(2):CD003620. [PubMed]

25. Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA. Milk thistle for the treatment of liver disease: a systematic review and meta-analysis. Am J Med. 2002;113(6):506-15. [PubMed]

26. Cassileth B. Milk thistle. Oncology (Williston Park). 2008;22(11):1319. [PubMed]

27. Raina K, Rajamanickam S, Singh RP, Deep G, Chittezhath M, Agarwal R. Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model. Cancer Res. 2008;68(16):6822-30. [PubMed]

28. Ramakrishnan G, Jagan S, Kamaraj S, Anandakumar P, Devaki T. Silymarin attenuated mast cell recruitment thereby decreased the expressions of matrix metalloproteinases-2 and 9 in rat liver carcinogenesis. Invest New Drugs. 2009;27(3):233-40. [PubMed]

29. Schuppan D, Jia JD, Brinkhaus B, Hahn EG. Herbal products for liver diseases: a therapeutic challenge for the new millennium. Hepatology. 1999;30(4):1099-104. [PubMed]

30. Thakur SK. Silymarin-A hepatoprotective agent. Gastroenterol Today. 2002;6:78-82. [PubMed]

31. Gebhardt R. Oxidative stress, plant-derived antioxidants and liver fibrosis. Planta Med. 2002;68(4):289-96. [PubMed]

32. Gaedeke J, Fels LM, Bokemeyer C, Mengs U, Stolte H, Lentzen H. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant. 1996;11(1):55-62. [PubMed]

33. Krecman V, Skottova N, Walterova D, Ulrichova J, Simanek V. Silymarin inhibits the development of diet-induced hypercholesterolemia in rats. Planta Med. 1998;64(2):138-42. [PubMed]

34. Kren V, Walterova D. Silybin and silymarin--new effects and applications. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005;149(1):29-41. [PubMed]

35. Tsai JH, Liu JY, Wu TT, Ho PC, Huang CY, Shyu JC, et al. Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats. J Viral Hepat. 2008;15(7):508-14. [PubMed]

36. Detaille D, Sanchez C, Sanz N, Lopez-Novoa JM, Leverve X, El-Mir MY. Interrelation between the inhibition of glycolytic flux by silibinin and the lowering of mitochondrial ROS production in perifused rat hepatocytes. Life Sci. 2008;82(21-22):1070-6. [PubMed]

Role of living donor liver transplantation in the treatment of hepatitis C virus infection

Role of living donor liver transplantation in the treatment of hepatitis C virus infection

Authors:
Tsoulfas G
Department of Surgery, Aristoteleion University of Thessaloniki, Thessaloniki, Greece

Agorastou P
Department of Gastroenterology, Aristoteleion University of Thessaloniki, Thessaloniki, Greece

Correspondence:
Georgios Tsoulfas,
Department: Department of Surgery, Aristoteleion University of Thessaloniki
Address: Department of Surgery, Aristoteleion University of Thessaloniki, 66 Tsimiski Street, 54622
City: Thessaloniki
Country: Greece
E-mail: tsoulfasg@msn.com
Tel: +30-6971895190


Abstract:

Hepatitis C virus (HCV) infection is one of the most common indications for liver transplantation worldwide. Because of the existing organ shortage, adult-to-adult living donor liver transplantation (LDLT) has become an important method of expanding the donor pool to meet the ever-increasing need. However, despite advantages such as the quality of the hepatic graft and the timing of the transplant, the exact role of LDLT in the treatment of HCV is still unclear. In this review, we aim to address some of these issues in an effort to highlight both the advantages and disadvantages, as well as to identify the main challenges, of using LDLT for treating patients with HCV infection.
Keywords: Hepatitis C virus; Living donor; Liver transplantation; Liver cirrhosis; Treatment


--------------------------------------------------------------------------------

Implication for health policy/practice/research/medical education:
This paper addresses the role of an important resource of society (living donor liver transplantation) in the treatment of a very difficult disease (hepatitis C virus infection).
Please cite this paper as:
Tsoulfas G, Agorastou P. Role of living donor liver transplantation in the treatment of hepatitis C virus infection. Hepat Mon. 2011;11(6):427-33.
Article history:
Received: 02 Jan 2011
Revised: 17 Mar 2011
Accepted: 17 Apr 2011
2011 Kowsar M.P.Co. All rights reserved.


Manuscript:

1. Introduction
Cirrhosis due to chronic hepatitis C virus (HCV) infection is one of the leading indications for liver transplantation (LT) worldwide. Studies have shown that 75-85% of individuals infected with HCV develop chronic infection, which persists for at least 6 months after onset, with the rate of chronic infection varying by age, gender, race, and immune system status (1). Long-term infection has been associated with serious clinical sequelae, including the development of hepatic fibrosis, cirrhosis of the liver, portal hypertension, and hepatocellular carcinoma (HCC) (2-4). Although the natural history of HCV infection is believed to be variable, it is estimated that up to 20% of chronically infected individuals will develop liver cirrhosis over a 20- to 25-year period and that these individuals are at increased risk of developing HCC (2, 4). The magnitude of the impact of HCV becomes more evident if we consider that in the USA, there are nearly 10,000 deaths annually due to HCV-related diseases, that HCV is responsible for nearly half of all HCC cases, and that the risk of developing HCC after the onset of cirrhosis is 3-4% per year (5). As a result, HCV-cirrhosis, which accounts for 35-40% of all cases of cirrhosis, has become the most common indication for LT in the USA (6).
Unfortunately, the increased need for livers is exacerbated by an organ shortage. In an effort to expand the limited donor pool, there has been increased focus on living donor liver transplantation (LDLT). In general, individuals with decompensated cirrhosis who meet the standard indications for LT, do not have any contraindications, and have a Model for End-stage Liver Disease (MELD) score of 15 or higher are appropriate candidates for LDLT. Patients with a lower MELD score would not benefit from any form of LT, whereas those with a significantly higher MELD score are potentially too sick to justify the use of a living donor liver graft (7). The problem, however, remains that the number of LDLT surgeries being conducted is low. One explanation for this is that the strenuous process that all potential living donors have to go through leads to a high rate of attrition among donors. In a report from 1 center, there was a 50% rate of attrition, mainly because of medical co-morbidities, psychosocial factors, financial issues, and the availability of an organ from a deceased donor during the evaluation process (8). Given the fact that in most centers only about one-third of the patients on the list may have an available living donor and of these, no more than half may undergo the evaluation successfully, only about 15% of patients on the list have the option of a LDLT (9). A second explanation is the severity of the donor surgery. Although living donors have an overall perception that donation is a positive event they do not regret participating in, with very few durable side effects, it is still a surgery that may lead to complications in 20-40% of donors and carries a mortality risk of 0.3-0.5% for the donor (10, 11). Two highly publicized donor deaths led to a significant drop in the number of centers in the USA performing the procedure and the number of LDLT cases between 2001 and 2003 (12-14).
Overall, it is clear that the relationship between end-stage liver disease secondary to HCV and LDLT is one of necessity. LDLT is a tremendous tour de force, both technically and ethically, presenting several challenges to the medical community because it is a unique procedure in which healthy people undergo a high-risk operation that has no benefit to their health. HCV infection is a leading indication for LT, and in the face of organ shortage, every effort should be made to expand the donor pool to meet the needs of the patients with HCV infection. In addition, patients with HCC usually have a low MELD score, as their main problem and more imminent threat is not one of hepatic insufficiency, but rather one of advancing cancer. For these patients, the option of LDLT presents an opportunity for a timely cure. As a result, the need for living donation is unlikely to decrease any time soon, and thus, it is important to determine the parameters for its proper role in the treatment of HCV infection.

2. LDLT for HCV: Issues and challenges
2.1. Graft quality
Compared to a full-sized deceased donor organ, a living donor allograft has significantly less hepatic mass; this finding has led to the suggestion that the living donor allograft should be treated as an "extended donor criteria" organ (15). A reason for concern is the small-for-size syndrome, characterized by synthetic dysfunction, elevated aminotransferases, and prolonged cholestasis (16). Small-for-size syndrome may resolve with supportive care and time, with transaminases returning to normal within days, but cholestasis can take weeks to resolve. The problem is that an allograft with transaminitis and cholestasis is particularly vulnerable to the acidosis, hypoglycemia, renal insufficiency or failure, and infections that may occur in the immediate postoperative period, leading to potentially irreversible damage that may prove deadly without retransplantation. It should also be stressed that small-for-size syndrome is not solely the result of transplanting a smaller volume graft, but is also the direct result of graft hemodynamics, as excessive portal inflow, combined with compromised venous drainage of the partial graft, can lead to overperfusion and decreased function of the allograft (17-19).
These valid concerns are outweighed by the significantly lower cold ischemia time of the living donor allograft than the deceased donor organ, as well as the fact that the donor is a healthy, extensively screened individual (20). Assessment of potential donors includes both medical and psychosocial evaluations, performed by separate medical teams, to ensure that the donor is fully informed of the potential risks to themselves and the alternatives that the recipient may have in the event that the living donation does not proceed. The option to stop the process at any time is given in a way that would not affect the relationship of the donor with the recipient. The third portion of the evaluation involves the anatomical assessment in which the quality, quantity, and anatomy of the donor's liver is considered. This thorough procedure leads to results at least as good as those achieved with organs from deceased donors, as we will see later in the paper.

2.2. Timing of transplantation
Determining the appropriate timing for an LT, particularly for patients with HCV infection, requires a balancing act. In particular, the recipient has to be healthy enough to undergo the LT safely, but on the other hand sick enough so that the morbidity and mortality associated with the procedure do not outweigh the benefits (21). This is even more critical for patients with HCV infection, in whom being able to avoid premature transplant allows a delay in the recurrence of HCV in the new graft, which may prolong the recipient's life, as well as allow time for the development of improved antiviral therapy. The principal advantage of LDLT is that it allows the transplant team to choose the proper timing, thereby decreasing the risk of decompensation or death of a patient while on the waiting list, as well as providing flexibility, which can allow an attempt at pretransplant viral eradication (22, 23). If it is possible to proceed to the transplant with a recipient negative for serum HCV RNA on therapy, then the percentage of posttransplant HCV recurrence after LDLT is very low (10%) and could essentially constitute a cure for HCV infection through transplantation (24). Furthermore, it is easier for a patient with a lower MELD score to tolerate a full-dose regimen for HCV eradication, and once viral eradication is achieved, one can proceed to the LDLT and achieve the optimal result. This approach could potentially cure about 40% of the individuals with HCV who undergo LDLT (25).

2.3. Results of LDLT for HCV
Comparable data between LDLT and deceased donor liver transplantation (DDLT) for HCV have been reported using the UNOS database (26). In this large study comparing transplant recipients with chronic HCV who received an LDLT (No. = 279) to those who received a DDLT (No. = 3955), the one-year survival rate was 87% in both groups and 2-year survival rate was 83% and 81% in the LDLT and DDLT groups, respectively (p = 0.68). Several other studies have shown similar results, either using UNOS data or single, large center experience, and demonstrated no negative impact of LDLT on the results of liver transplantation for HCV infection (27-29). The Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL), a multicenter study of 275 liver transplants (181 LDLT and 94 DDLT) is one of the largest studies from which conclusions can be drawn (30). This study showed an overall statistically significant survival advantage for DDLT than for LDLT (82% vs. 74% at 3 years). However, a previous study showed poorer results when patients were separated into 3 groups: the cases of DDLT, the first 20 cases of LDLT performed at the center, and the remaining LDLT cases (31). In this study, although DDLT was more advantageous than LDLT (in the group of the first 20 LDLT cases), there was no difference in survival or rate of progression to fibrosis between the DDLT and the later LDLT cases. This raised the issue of center experience and the effect of the learning curve, as LDLT poses certain unique technical challenges such as vascular problems, biliary complications, and small-for-size syndrome (32, 33). Allowing for the importance of center experience may mean that LDLT for HCV infection may be at least as safe as DDLT. This still leaves the question of increased and more aggressive recurrence of HCV infection after LDLT than after DDLT.

2.4. HCV recurrence after LDLT
LDLT grafts have tremendous growth potential, as the graft regenerates 150,000 hepatocytes every second in the first week after transplantation and doubles in size within 4 weeks (34, 35). Although this is beneficial in restoring the necessary hepatocyte mass for the patient, it raises concerns regarding the effect that it may have on viral replication and the development of cholestatic hepatitis, a rapidly progressive and virulent form of HCV infection. Factors believed to work in favor of decreased HCV recurrence in LDLT than in DDLT include less acute cellular rejection with less immunosuppression; younger, healthier recipients; fewer African-American LDLT recipients; lower HCV posttransplantation viral load; and the opportunity for pretransplantation treatment to eradicate HCV or reduce the viral load (36-38). The factors that may be responsible for the more aggressive recurrence pattern sometimes seen with LDLT include increased HLA matching of the recipient with the donor, especially since a significant number are relatives, and the very active hepatocyte regeneration, leading to increased intrahepatocyte HCV proliferation (39, 40). Moreover, experimental data suggest that liver regeneration induces low-density lipoprotein receptor expression, which might facilitate HCV entrance into the hepatocytes (41, 42).
While 2 large studies have shown a similar incidence and severity of HCV recurrence between LDLT and DDLT recipients, a third study found that the incidence of cholestatic hepatitis is significantly greater in LDLT recipients (26, 43-45). In an effort to resolve this discrepancy, a careful comparison of protocol liver biopsies from 23 LDLT and 53 DDLT recipients did not reveal significant differences in the degree of hepatic inflammation between the 2 groups over 3 years, and similar amounts of fibrosis in the LDLT group (43).

2.5. Treatment for HCV recurrence after LDLT
The fact that HCV may recur earlier and, potentially, in a more aggressive form after LDLT means that strategies for HCV recurrence treatment are crucial. Treating DDLT-candidate patients with HCV infection is not usually feasible before the transplant to achieve viral resolution because the patients cannot tolerate full-dose treatment with ribavirin and interferon, given their state of hepatic dysfunction. The alternative, aggressive, preemptive treatment after LT has not shown great success (46, 47). LDLT has a distinct advantage over DDLT in the treatment of HCV recurrence because it is possible to treat recipients for HCV infection aggressively prior to the transplant, as they are more stable and can tolerate treatment. In addition, it is possible to arrange the timing of the transplant, so that it proceeds as soon as viral clearance is achieved. This has been shown to lead to a sustained virological response, and is thus the most definitive way to address the issue of recurrence (48).

2.6. Immunosuppression in LDLT for HCV infection
Another key issue in dealing with the conundrum of HCV recurrence after LT is the choice of immunosuppression. Standard posttransplant immunosuppression consists of a calcineurin inhibitor (cyclosporine or tacrolimus), a tapering dose of corticosteroids, and in the majority of cases, an antiproliferating agent for lymphocytes (mycophenolate mofetil or azathioprine). Antibodies to T cells (antithymocyte globulin) or to the interleukin-2 receptor (basiliximab) are less often used as induction agents, to either delay the initiation of the calcineurin inhibitor to protect renal function, or to proceed with a very rapid steroid taper. Although clear data in favor of a single baseline immunosuppression regimen are limited, there is an agreement that more intense immunosuppressive regimens can lead to worse outcomes. That is, patients receiving high bolus steroids and induction therapies in the form of antibodies to lymphocytes or interleukin-2 receptor are more likely to encounter HCV-induced graft failure and undergo a rapid progression to cirrhosis secondary to cholestatic hepatitis (49, 50). The problem is that these agents are also used to treat rejection, which has been associated with decreased survival in patients with HCV infection (51). The difficulties become even more apparent if we consider that differentiating between HCV recurrence and acute rejection on the basis of a biopsy examination may not be straightforward, as both have an element of portal inflammation and there is significant overlap.
The above-mentioned issues in finding the optimal immunosuppression regimen for patients with HCV infection after LT are even more evident in the case of LDLT in which rejection is more prevalent. This leads to a balancing act between finding the appropriate amount of immunosuppression to avoid rejection on one hand, and avoiding uncontrolled recurrence of HCV on the other hand (52). The main destabilizing factors are rapid changes in the level of immunosuppression, which leads to intense viral replication. Several strategies, such as rapidly tapering steroids or steroid-free immunosuppression with or without induction antibodies, have been employed to achieve this balance. However, stemming from experience, the most sound practice appears to be the attainment of adequate immunosuppression to avoid the incidence of rejection, and treating any episodes that may occur with gradual increases in the existing regimen, rather than using bolus steroids or antibodies (53).

2.7. Retransplantation and LDLT for HCV infection
The accelerated recurrence of HCV infection after LT raises the issue of whether to retransplant patients with graft failure. Results for retransplantation for HCV recurrence have been discouraging overall (54-56). Although many studies have demonstrated that HCV-positive retransplant recipients have worse survival rates than HCV-negative recipients, there is conflicting data regarding whether or not the cause of allograft failure in HCV-positive patients influences survival. Most studies have actually demonstrated that recurrent HCV as a cause of allograft failure is less common and that allograft loss in HCV-positive recipients is much more likely to be caused by a nonfunctioning allograft, hepatic artery thrombosis, and chronic rejection (57-59). Most data suggest that survival after retransplantation is poor in patients with HCV infection, even in those retransplanted for non-HCV-related indications (57, 60, 61).
To deal with this problem, arguments ranging from performing retransplantation for HCV-induced allograft failure early in its disease course to refusing retransplantation to patients infected with HCV because it is unnecessary and futile have been forwarded (56, 60, 62). This is exactly where the use of LDLT raises important ethical and practical issues and offers certain possibilities with regard to the treatment of HCV-positive recipients. In particular, LDLT would not deplete the donor organ pool and would lead to the use of scarce deceased donor organs by patients who are awaiting primary liver transplantation. Despite inferior outcomes, a better tactic may be to consider retransplantation for recurrent HCV in those patients whose primary transplant was an LDLT, as the initial allograft did not deplete the donor pool.

2.8. HCC and LDLT
Patients with HCV infection have a higher rate of HCC, and since a pretransplant diagnosis of HCC has been shown to be an independent predictor of reduced overall patient survival beyond 90 days, timely LT is of the outmost importance (30). The most effective approach to reduce the dropout rate on the LT waiting list is to expand the number of available livers. A primary strategy towards this goal is the use of LDLT. Decision analyses, taking into account the risk of dropout while on the waiting list (4% per month), the expected survival of the recipient using the Milan criteria (70% at 5 years), and the risk for the donor (0.3-0.5% mortality), suggest that this is a cost-effective approach if the wait time exceeds 7 months (63). Recently, MELD exception points for HCC were modified, as new data showed that former prioritization points for HCC were unfairly favoring access to DDLT for these patients. Compared to DDLT, LDLT offers the advantage of timely access to LT, while at the same time preserving the equity principle by not depleting the donor pool. Additionally, the development of live donation has stimulated discussion about the expansion of the tumor burden limits for HCC patients. Since transplantation can be performed in a timely manner and with recent staging, there have been proposals that LDLT may be an option for patients whose tumor stage does not allow listing for DDLT. Deceased donor livers would then be allocated to patients with the best potential outcome (within Milan criteria and survival of 70% at 5 years), and living donation livers would benefit patients with a lower survival. Although this has a sound theoretical basis, data are not yet available to support utilizing such expanded criteria (64). Furthermore, this policy of using LDLT for HCC patients outside the currently accepted criteria raises the question of what would happen if these patients require retransplantation. Overall, LDLT remains an important alternative for patients with HCV infection and HCC of small size, as it provides access to LT in a timely manner.

2.9. Economic aspects of LDLT for HCV infection
In current times of fiscal constraint in most countries worldwide, any evaluation of a treatment ultimately requires that society consider the financial burden associated with that treatment. Several studies have attempted to evaluate the extensive resources required for LDLT. A single center in New York found no increase in resources by examining the billing data (65). As financial cost has many different faces, a study using the A2ALL outcome data showed that although the cost increased with LDLT, the survival of patients awaiting transplantation also increased (66). An increase of 0.5 quality-adjusted life years resulted from being on a waiting list, with the possibility of receiving both deceased and live donation, than from being on a waiting list with only the possibility of deceased donation. The cost of a transplant from the latter list was on average $151,613, whereas that from a list with both options was $208,149. Although LDLT represents a higher immediate cost, we must consider that there are factors that will counterbalance this cost. These include the learning curve that leads to the performance of LDLTs with fewer complications and quicker return to full activity for the donors, as well as the fact that we are able to transplant patients before they become too sick, thus affording a quicker recovery for the recipient. Additional comprehensive outcomes studies are needed to obtain a more detailed picture of the financial aspects of LDLT.

3. Conclusion
The outcomes and patient survival after LDLT for treatment of HCV infection appear to be comparable to those of patients undergoing DDLT. The main advantage for the recipient is a decrease in the waiting time, which can prove to be life saving. From a global perspective, the advantage becomes even more evident in countries with no history of DDLT and in which LDLT has proven to be an excellent way to increase the donor pool. However, concerns remain about the problem of aggressive HCV recurrence, as well as the safety of the donor. That these concerns have led a great number of centers to decide against retransplantation for patients with HCV recurrence, makes LDLT all the more important. This is because LDLT does not deplete the deceased donor pool, and hence, these patients should not be excluded if retransplantation is necessary. In addition, the continuous increase in the number of patients with HCV infection worldwide means that this group of patients that present a challenge to the health system cannot and must not be ignored, irrespective of the difficulties in the management of their condition. It is imperative that these issues are addressed in a multicenter effort, such as the A2ALL study, and with careful long-term follow-up.

Financial support
None declared.

Conflict of interest
None declared.


References:

1. Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36(5 Suppl 1):S21-9. [PubMed]

2. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002;19(3):1-46. [PubMed]

3. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology. 1997;26(3 Suppl 1):15S-20S. [PubMed]

4. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39(4):1147-71. [PubMed]

5. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9(4):331-8. [PubMed]

6. Szabo E, Lotz G, Paska C, Kiss A, Schaff Z. Viral hepatitis: new data on hepatitis C infection. Pathol Oncol Res. 2003;9(4):215-21. [PubMed]

7. Freeman RB. The impact of the model for end-stage liver disease on recipient selection for adult living liver donation. Liver Transpl. 2003;9(10 Suppl 2):S54-9. [PubMed]

8. Trotter JF, Wachs M, Trouillot T, Steinberg T, Bak T, Everson GT, et al. Evaluation of 100 patients for living donor liver transplantation. Liver Transpl. 2000;6(3):290-5. [PubMed]

9. Rudow DL, Russo MW, Hafliger S, Emond JC, Brown RS, Jr. Clinical and ethnic differences in candidates listed for liver transplantation with and without potential living donors. Liver Transpl. 2003;9(3):254-9. [PubMed]

10. Castedal M, Andersson M, Polanska-Tamborek D, Friman S, Olausson M, Fehrman-Ekholm I. Long-term follow-up of living liver donors. Transplant Proc. 2010;42(10):4449-54. [PubMed]

11. Trotter JF, Wachs M, Everson GT, Kam I. Adult-to-adult transplantation of the right hepatic lobe from a living donor. N Engl J Med. 2002;346(14):1074-82. [PubMed]

12. Brown RS, Jr., Russo MW, Lai M, Shiffman ML, Richardson MC, Everhart JE, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med. 2003;348(9):818-25. [PubMed]

13. Miller C, Florman S, Kim-Schluger L, Lento P, De La Garza J, Wu J, et al. Fulminant and fatal gas gangrene of the stomach in a healthy live liver donor. Liver Transpl. 2004;10(10):1315-9. [PubMed]

14. Russo MW, Brown RS, Jr. Adult living donor liver transplantation. Am J Transplant. 2004;4(4):458-65. [PubMed]

15. Renz JF, Kin C, Kinkhabwala M, Jan D, Varadarajan R, Goldstein M, et al. Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation. Ann Surg. 2005;242(4):556-63; discussion 63-5. [PubMed]

16. Tucker ON, Heaton N. The 'small for size' liver syndrome. Curr Opin Crit Care. 2005;11(2):150-5. [PubMed]

17. Gonzalez HD, Liu ZW, Cashman S, Fusai GK. Small for size syndrome following living donor and split liver transplantation. World J Gastrointest Surg. 2010;2(12):389-94. [PubMed]

18. Kiuchi T, Kasahara M, Uryuhara K, Inomata Y, Uemoto S, Asonuma K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation. 1999;67(2):321-7. [PubMed]

19. Shimada M, Ijichi H, Yonemura Y, Harada N, Shiotani S, Ninomiya M, et al. The impact of splenectomy or splenic artery ligation on the outcome of a living donor adult liver transplantation using a left lobe graft. Hepatogastroenterology. 2004;51(57):625-9. [PubMed]

20. Gali B, Rosen CB, Plevak DJ. Living Donor Liver Transplantation: Selection, Perioperative Care, and Outcome. J Intensive Care Med. 2011;[Epub ahead of print]. [PubMed]

21. Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port FK, Wolfe RA. The survival benefit of liver transplantation. Am J Transplant. 2005;5(2):307-13. [PubMed]

22. Liu CL, Lam B, Lo CM, Fan ST. Impact of right-lobe live donor liver transplantation on patients waiting for liver transplantation. Liver Transpl. 2003;9(8):863-9. [PubMed]

23. Russo MW, LaPointe-Rudow D, Kinkhabwala M, Emond J, Brown RS, Jr. Impact of adult living donor liver transplantation on waiting time survival in candidates listed for liver transplantation. Am J Transplant. 2004;4(3):427-31. [PubMed]

24. Everson GT. Treatment of patients with hepatitis C virus on the waiting list. Liver Transpl. 2003;9(11):S90-4. [PubMed]

25. Everson GT. Should we treat patients with chronic hepatitis C on the waiting list? J Hepatol. 2005;42(4):456-62. [Link]

26. Bozorgzadeh A, Jain A, Ryan C, Ornt D, Zand M, Mantry P, et al. Impact of hepatitis C viral infection in primary cadaveric liver allograft versus primary living-donor allograft in 100 consecutive liver transplant recipients receiving tacrolimus. Transplantation. 2004;77(7):1066-70. [PubMed]

27. Rodriguez-Luna H, Vargas HE, Sharma P, Ortiz J, De Petris G, Balan V, et al. Hepatitis C virus recurrence in living donor liver transplant recipients. Dig Dis Sci. 2004;49(1):38-41. [PubMed]

28. Thuluvath PJ, Yoo HY. Graft and patient survival after adult live donor liver transplantation compared to a matched cohort who received a deceased donor transplantation. Liver Transpl. 2004;10(10):1263-8. [PubMed]

29. Van Vlierberghe H, Troisi R, Colle I, Ricciardi S, Praet M, de Hemptinne B. Hepatitis C infection-related liver disease: patterns of recurrence and outcome in cadaveric and living-donor liver transplantation in adults. Transplantation. 2004;77(2):210-4. [PubMed]

30. Terrault NA, Shiffman ML, Lok AS, Saab S, Tong L, Brown RS, Jr., et al. Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation. Liver Transpl. 2007;13(1):122-9. [PubMed]

31. Olthoff KM, Merion RM, Ghobrial RM, Abecassis MM, Fair JH, Fisher RA, et al. Outcomes of 385 adult-to-adult living donor liver transplant recipients: a report from the A2ALL Consortium. Ann Surg. 2005;242(3):314-23, discussion 23-5. [PubMed]

32. Broelsch CE, Frilling A, Testa G, Cicinnati V, Nadalin S, Paul A, et al. Early and late complications in the recipient of an adult living donor liver. Liver Transpl. 2003;9(10 Suppl 2):S50-3. [PubMed]

33. Schemmer P, Mehrabi A, Friess H, Sauer P, Schmidt J, Buchler MW, et al. Living related liver transplantation: the ultimate technique to expand the donor pool? Transplantation. 2005;80(1 Suppl):S138-41. [PubMed]

34. Baltz AC, Trotter JF. Living donor liver transplantation and hepatitis C. Clin Liver Dis. 2003;7(3):651-65, viii. [PubMed]

35. Marcos A, Fisher RA, Ham JM, Shiffman ML, Sanyal AJ, Luketic VA, et al. Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver transplantation. Transplantation. 2000;69(7):1375-9. [PubMed]

36. Kam I. Adult-adult right hepatic lobe living donor liver transplantation for status 2a patients: too little, too late. Liver Transpl. 2002;8(4):347-9. [PubMed]

37. Liu LU, Bodian CA, Gondolesi GE, Schwartz ME, Emre S, Roayaie S, et al. Marked Differences in acute cellular rejection rates between living-donor and deceased-donor liver transplant recipients. Transplantation. 2005;80(8):1072-80. [PubMed]

38. Takatsuki M, Uemoto S, Inomata Y, Egawa H, Kiuchi T, Fujita S, et al. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation. 2001;72(3):449-54. [PubMed]

39. Cotler SJ, Gaur LK, Gretch DR, Wile M, Strong DM, Bronner MP, et al. Donor-recipient sharing of HLA class II alleles predicts earlier recurrence and accelerated progression of hepatitis C following liver transplantation. Tissue Antigens. 1998;52(5):435-43. [PubMed]

40. Manez R, Mateo R, Tabasco J, Kusne S, Starzl TE, Duquesnoy RJ. The influence of HLA donor-recipient compatibility on the recurrence of HBV and HCV hepatitis after liver transplantation. Transplantation. 1995;59(4):640-2. [PubMed]

41. Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1999;96(22):12766-71. [PubMed]

42. Monazahian M, Böhme I, Bonk S, Koch A, Scholz C, Grethe S, et al. Low density lipoprotein receptor as a candidate receptor for hepatitis C virus. Journal of Medical Virology. 1999;57(3):223-9. [Link]

43. Gaglio PJ, Malireddy S, Levitt BS, Lapointe-Rudow D, Lefkowitch J, Kinkhabwala M, et al. Increased risk of cholestatic hepatitis C in recipients of grafts from living versus cadaveric liver donors. Liver Transpl. 2003;9(10):1028-35. [PubMed]

44. Garcia-Retortillo M, Forns X, Llovet JM, Navasa M, Feliu A, Massaguer A, et al. Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation. Hepatology. 2004;40(3):699-707. [PubMed]

45. Shiffman ML, Stravitz RT, Contos MJ, Mills AS, Sterling RK, Luketic VA, et al. Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation. Liver Transpl. 2004;10(10):1248-55. [PubMed]

46. Sheiner PA, Boros P, Klion FM, Thung SN, Schluger LK, Lau JY, et al. The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after liver transplantation. Hepatology. 1998;28(3):831-8. [PubMed]

47. Yedibela S, Schuppan D, Muller V, Schellerer V, Tannapfel A, Hohenberger W, et al. Successful treatment of hepatitis C reinfection with interferon-alpha2b and ribavirin after liver transplantation. Liver Int. 2005;25(4):717-22. [PubMed]

48. Abdelmalek MF, Firpi RJ, Soldevila-Pico C, Reed AI, Hemming AW, Liu C, et al. Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C. Liver Transpl. 2004;10(2):199-207. [PubMed]

49. Charlton M, Seaberg E, Wiesner R, Everhart J, Zetterman R, Lake J, et al. Predictors of patient and graft survival following liver transplantation for hepatitis C. Hepatology. 1998;28(3):823-30. [PubMed]

50. Nelson DR, Soldevila-Pico C, Reed A, Abdelmalek MF, Hemming AW, Van der Werf WJ, et al. Anti-interleukin-2 receptor therapy in combination with mycophenolate mofetil is associated with more severe hepatitis C recurrence after liver transplantation. Liver Transpl. 2001;7(12):1064-70. [PubMed]

51. Charlton M, Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Liver Transpl Surg. 1999;5(4 Suppl 1):S107-14. [PubMed]

52. Maluf DG, Stravitz RT, Cotterell AH, Posner MP, Nakatsuka M, Sterling RK, et al. Adult living donor versus deceased donor liver transplantation: a 6-year single center experience. Am J Transplant. 2005;5(1):149-56. [PubMed]

53. Eason JD, Nair S, Cohen AJ, Blazek JL, Loss GE, Jr. Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy. Transplantation. 2003;75(8):1396-9. [PubMed]

54. Berenguer M, Prieto M, Palau A, Rayon JM, Carrasco D, Juan FS, et al. Severe recurrent hepatitis C after liver retransplantation for hepatitis C virus-related graft cirrhosis. Liver Transpl. 2003;9(3):228-35. [PubMed]

55. Ghobrial RM, Farmer DG, Baquerizo A, Colquhoun S, Rosen HR, Yersiz H, et al. Orthotopic liver transplantation for hepatitis C: outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center experience. Ann Surg. 1999;229(6):824-31; discussion 31-3. [PubMed]

56. Rosen HR, Martin P. Hepatitis C infection in patients undergoing liver retransplantation. Transplantation. 1998;66(12):1612-6. [PubMed]

57. Facciuto M, Heidt D, Guarrera J, Bodian CA, Miller CM, Emre S, et al. Retransplantation for late liver graft failure: predictors of mortality. Liver Transpl. 2000;6(2):174-9. [PubMed]

58. Sheiner PA, Schluger LK, Emre S, Thung SN, Lau JY, Guy SR, et al. Retransplantation for recurrent hepatitis C. Liver Transpl Surg. 1997;3(2):130-6. [PubMed]

59. Testa G, Crippin JS, Netto GJ, Goldstein RM, Jennings LW, Brkic BS, et al. Liver transplantation for hepatitis C: recurrence and disease progression in 300 patients. Liver Transpl. 2000;6(5):553-61. [PubMed]

60. Carithers RL, Jr. Recurrent hepatitis C after liver transplantation. Liver Transpl Surg. 1997;3(5 Suppl 1):S16-7. [PubMed]

61. Dickson RC, Caldwell SH, Ishitani MB, Lau JY, Driscoll CJ, Stevenson WC, et al. Clinical and histologic patterns of early graft failure due to recurrnet hepatitis C in four patients after liver transplantation. Transplantation. 1996;61(5):701-5. [PubMed]

62. Ghobrial RM, Colquhoun S, Rosen H, Hollis P, Ponthieux S, Pakrasi A, et al. Retransplantation for recurrent hepatitis C following tacrolimus or cyclosporine immunosuppression. Transplant Proc. 1998;30(4):1470-1. [PubMed]

63. Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, Hadengue A. Living donor liver transplantation for early hepatocellular carcinoma: A life-expectancy and cost-effectiveness perspective. Hepatology. 2001;33(5):1073-9. [PubMed]

64. Pomfret EA, Washburn K, Wald C, Nalesnik MA, Douglas D, Russo M, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl. 2010;16(3):262-78. [PubMed]

65. Lai JC, Pichardo EM, Emond JC, Brown RS, Jr. Resource utilization of living donor versus deceased donor liver transplantation is similar at an experienced transplant center. Am J Transplant. 2009;9(3):586-91. [PubMed]

66. Northup PG, Abecassis MM, Englesbe MJ, Emond JC, Lee VD, Stukenborg GJ, et al. Addition of adult-to-adult living donation to liver transplant programs improves survival but at an increased cost. Liver Transpl. 2009;15(2):148-62. [PubMed]

http://hepatmon.com/view/?id=638