Magnetic Resonance Elastography: Accurately identify the presence and progression of hepatic fibrosis

What Is Magnetic Resonance Elastography (MRE) ?

Today on the blog we have a small update on Magnetic Resonance Elastography (MRE) this entry will include abstracts from 2011, and an article written this month by By Benjamin E. Tubb, M.D., Ph.D.

A few years back we read at Mayo about a new technology called Magnetic Resonance Elastography (MRE) - the latest form of elastography to detect tissue elasticity. MRE provides an early warning in detecting hardening of the liver, and can detect liver fibrosis before it turns into cirrhosis. The technique uses sound waves to see if a patient's liver is harder than it should be - or if it's developing fibrosis.

Hepatitis C and B can lead to long-term liver damage including fibrosis and cirrhosis. Because viral hepatitis causes chronic liver inflammation the formation of scar tissue or fibrosis may occur overtime.

How Does MRE Work?

The Texture Or Stiffness Of The Liver Is Measured By Color Coded Images

During a physical examination of the liver a physician may push or feel for the liver, referred to as palpation. If the liver is healthy it will feel soft. A liver that has fibrosis or scar tissue will feel a bit firmer, and a liver that has progressed to cirrhosis is extremely hard.

With this technology (MRE), the texture of the liver, or stiffness can be measured by images of the liver coded with different colors.

The stiffest areas of the liver show up as red on the elastogram. The softest most flexible parts of the liver show up as purple.



The top picture is Elastograms of a normal liver, the bottom picture is a liver with grade 3 fibrosis, validated by biopsy.

Comparing the two slides we notice the top *soft- healthy liver is coded in purple. The texture or *stiffness of the liver with fibrosis is coded in red .

Thus far early results have shown that MRE is highly accurate in detecting moderate to severe liver fibrosis in many different types of liver disease. This technique may offer a noninvasive alternative to liver biopsy.


November Article

From Intrinsic Imaging

Magnetic Resonance Elastography: A Novel Technique for Evaluation of Liver Disease

By Benjamin E. Tubb, M.D., Ph.D., Board Certified Radiologist, Intrinsic Imaging

Nov 21 2011

San Antonio (TX), Boston (MA)

Magnetic resonance elastography is an emerging MRI technology that provides sensitive and semi-quantitative assessment of tissue stiffness. The most promising clinical application for MR Elastography is the assessment of liver stiffness as a surrogate marker of liver disease and fibrosis. Liver fibrosis is the primary pathologic process in cirrhosis which affects millions of Americans and causes significant morbidity and mortality. The incidence of liver disease and cirrhosis is increasing, especially cirrhosis related to chronic viral hepatitis and nonalcoholic fatty liver disease (NAFLD). When incorporated into a comprehensive liver MRI exam, elastography provides a sensitive assessment for early diffuse liver disease and a semi-quantitative assessment for stage and progression of fibrosis.

Management of patients with liver disease such as chronic viral hepatitis or NAFLD involves careful monitoring for the development and progression of liver inflammation, fibrosis, and cirrhosis. This is usually achieved through a combination of physical exam, laboratory testing, and imaging. Imaging may include abdominal ultrasound, CT, or MRI exams. However, all of these tests may remain normal during the early stages of liver disease. The liver does not demonstrate gross morphological abnormalities such as nodular contour or segmental atrophy until advanced stages of fibrosis; complications of cirrhosis such as portal venous hypertension, splenomegaly, and ascites also indicate advanced disease. Therefore, in patients with potential early disease, liver biopsy is often used to assess for presence of active liver inflammation and fibrosis. Liver biopsy is an expensive and invasive procedure with associated risks. Also, liver biopsy suffers from sampling error, sometimes underestimating or overestimating the actual degree of liver disease.

MR Elastography has been developed by Dr. Richard Ehman and colleagues at the Mayo Clinic as a noninvasive mechanism of evaluating tissue stiffness. Dr. Ehman's group and others have demonstrated that patients with liver disease have progressively increased stiffness of their liver tissue which can be detected and quantified with MR Elastography, years before the development of gross anatomic abnormalities of liver size and shape that are detectable by other imaging modalities.

MR Elastography requires specialized equipment and software, which are included with some new MRI scanners and can be added to many installed scanners. The necessary equipment is relatively simple: a small disc-shaped transducer is placed over the patient's upper abdomen by the technologist at the start of the exam, and the transducer is connected through a flexible plastic tube to a speaker-like device, which creates low frequency sound waves at a fixed frequency of approximately 40-90 Hertz. These sound waves pass through the transducer and cause small vibrations within the patient's abdomen, without discomfort to the patient. These vibrations create pressure waves within the liver which are detectable through sensitive MR sequences. Specifically, MR Elastography employs phase contrast MR sequences which are sensitive to the direction and amplitude of tissue motion. In patients with chronic liver disease, as the liver tissue becomes stiffer, the wavelength of the pressure waves becomes longer. This can be visualized in color-coded images, and specialized image analysis software can measure the wavelengths and provide quantitative estimates of tissue stiffness, throughout the liver or within a specific region of interest. Tissue elasticity results are reported in kilopascals (kPa). The entire MR Elastography acquisition can be performed in 1 minute, with negligible increase in overall length of the MRI exam.

Studies have demonstrated that MR Elastography provides highly reliable measurements, with little test-retest variation. Normal subjects demonstrate consistent liver stiffness measurements with mean of 2.2 kPa and standard deviation of 0.3 kPa, corresponding to normal soft liver tissue. Patients with increasing degrees of liver fibrosis demonstrate a direct correlation between elastography measurements and stage of fibrosis defined in liver biopsy specimens. Importantly, patients with early liver disease and stage 0 or stage 1 fibrosis demonstrate elevated liver stiffness measurements of approximately 3.5-4.0 kPa. Using a cut-off value of 2.93 kPa, Yin et al. achieved remarkable sensitivity of 98% and a specificity of more than 99% for differentiating any stage of liver fibrosis from normal liver tissue (reference below). Using a cut-off value of 4.89 kPa, these researchers were able to differentiate early disease with stages 0-1 fibrosis from more advanced disease with stages 2-4 fibrosis, with 86% sensitivity and 85% specificity. These results represent a marked improvement over other available tests for early liver disease and will enable greatly improved detection of early liver fibrosis in patients at risk.

MR elastography will allow clinicians to more sensitively and accurately identify the presence and progression of hepatic fibrosis in patients with chronic liver disease, especially the large number of patients with viral hepatitis (5 million Americans) and nonalcoholic fatty liver disease (31 million Americans). MR elastography results will potentially help guide clinicians' decisions about when to perform invasive liver biopsy and how and when to adjust patient therapy. As improved therapies become available, including therapies targeted at slowing, preventing, or even reversing hepatic fibrosis, the highly repeatable and quantitative measurements obtained by MR Elastography will provide accurate assessment of treatment responses.

Some therapies are already in use for treatment of chronic viral hepatitis, such as *Blog Note-(new protease inhibitors) Interferon and Ribavirin, and clinicians may begin to use elastography results to assess the necessity and efficacy of these treatments. Within the larger number of patients with NAFLD, approximately 10-20% will develop active liver inflammation and fibrosis, termed nonalcoholic steatohepatitis (NASH), with significant risk of progression to cirrhosis. Currently there are no specific therapies for NASH, but there is tremendous research interest in this direction. Experimental treatments for NASH include trials of newer antidiabetic medications that increase insulin sensitivity and may reduce liver injury. NIH-sponsored studies of these medications in patients with NASH are underway, including trials of rosiglitazone, pioglitazone, and metformin. There are many other pharmaceutical agents in development for the prevention and treatment of liver fibrosis. MR elastography will play an important role in future trials of these agents, providing noninvasive and quantitative measurements of liver fibrosis, potentially complementing or partially replacing liver biopsy in assessment of patients’ stage and progression of liver disease.

About the Author

Dr. Tubb is a Board Certified Radiologist at Intrinsic Imaging. He obtained his radiology residency training at Johns Hopkins Hospital after completing the combined MD-PhD program at Baylor College of Medicine in Houston, TX. His PhD research was in Molecular and Cellular Biology, with multiple peer-reviewed publications and experience in experiment design and data analysis. During his radiology residency, Dr. Tubb received a one year RSNA Resident Research Award and designed a research project involving targeted MRI contrast agents and high resolution pancreatic imaging. He served as chief resident at Johns Hopkins and also served on the admissions committee. Following residency, Dr. Tubb completed a one year MRI fellowship at the University of Pennsylvania, with broad experience in body/oncologic, breast, spine, and musculoskeletal imaging. Dr. Tubb is actively involved with the design and implementation of the imaging components of clinical trials, as well as application of new imaging technology such as MRI elastography for evaluation of liver disease.

MR elastography (MRE) Abstracts 2011-2010

2011

September 2011

MR elastography for noninvasive assessment of hepatic fibrosis: Experience from a tertiary center in asia;
Kim BH, Lee JM, Lee YJ, Lee KB, Suh KS, Han JK, Choi BI; Journal of Magnetic Resonance Imaging (Sep 2011)

PURPOSE:

To determine the sensitivity and specificity of MR elastography (MRE) in the staging of hepatic fibrosis (HF) using histopathology as the reference standard in an Asian population.

MATERIALS AND METHODS:

MRE was performed on 55 patients with chronic liver diseases or biliary diseases and on 5 living related liver donors (48 men and 12 women; mean age, 55.7 years). MRE was performed with modified, phase-contrast, gradient-echo sequences, and the mean stiffness values were measured on the elastograms in kilopascals(kPa). Receiver operating characteristic curve analysis was performed to determine the cutoff value and accuracy of MRE for staging HF. Histopathologic staging of HF according to the METAVIR scoring system served as the reference.

RESULTS:

Liver stiffness increased systematically along with the fibrosis stage. With a shear stiffness cutoff value of 3.05 kPa, the predicted sensitivity and specificity for differentiating significant liver fibrosis (≥ F2) from mild fibrosis (F1) were 89.7% and 87.1%, respectively. In addition, MRE was able to discriminate between patients with severe fibrosis (F3) and those with liver cirrhosis (sensitivity, 100%; specificity, 92.2%), with a shear stiffness cutoff value of 5.32 kPa.

CONCLUSION:

MRE could be a promising, noninvasive technique with excellent diagnostic accuracy for detecting significant HF and liver cirrhosis. J. Magn. Reson. Imaging 2011. © 2011 Wiley-Liss, Inc.

Magnetic resonance elastography and biomarkers to assess fibrosis from recurrent hepatitis C in liver transplant recipients.

Lee VS, Miller FH, Omary RA, Wang Y, Ganger DR, Wang E, Rao S, Levitsky J.

Division of Hepatology, Northwestern University Feinberg School of Medicine, 676 N. Street Clair, Chicago, IL 60611, USA.

Abstract
BACKGROUND:

Imaging techniques evaluating liver stiffness (magnetic resonance elastography [MRE]) and biomarkers may be useful indicators of fibrosis stage in hepatitis C virus (HCV)+patients. Our aim was to compare the accuracy of MRE and biomarkers in staging fibrosis because of recurrent HCV in liver transplant (LT) recipients with hepatocellular carcinoma.

METHODS:

Liver magnetic resonance imaging and MRE, FIBROSpectII, aspartate aminotransferase-to-platelet ratio index (aspartate aminotransferase [AST]: platelet index), AST:alanine aminotransferase ratio, and magnetic resonance imaging/MRE-guided biopsies targeting the stiffest regions (right and left lobes) were performed in HCV+LT recipients. Sensitivity, specificity, positive predictive value (PPV)/negative predictive value (NPV), and likelihood ratios were calculated for the best cutoff by receiver operating characteristic analysis.

RESULTS:

Thirty-two recipients were included: 28 men, age 60 (±6.4) years, and time since LT 3.25 (±1.68) years. Both MRE (P=0.0001) and FIBROSpectII (P=0.009) were significantly different between no fibrosis and more than or equal to stage 1 groups, whereas aspartate aminotransferase-to-platelet ratio index and AST:alanine aminotransferase ratio were not different.

Areas under the receiver operating characteristic curve were 0.87 for MRE and 0.84 for FIBROSpectII. MRE cutoff of 3.81 kPa had 87.5% sensitivity, 79.2% specificity, 58.3% PPV, and 95.0% NPV; FIBROSpectII cutoff of 42 had 87.5% sensitivity, 70.0% specificity, 53.8% PPV, and 93.3% NPV for detection of more than or equal to stage 1 fibrosis. Two patients had high MRE values because of unexpected acute rejection and portal vein thrombosis.

CONCLUSIONS:

MRE and FIBROSpectII are highly sensitive in detecting fibrosis due to recurrent HCV. Both are limited by the low specificity/PPV and confounding because of other graft complications. Values below the MRE and FIBROSpectII cutoffs, however, strongly suggest the absence of fibrosis and may avert the need for protocol biopsy staging.

July 2011

Test-retest repeatability of MR elastography for noninvasive liver fibrosis assessment in hepatitis C;

Shire NJ, Yin M, Chen J, Railkar RA, Fox-Bosetti S, Johnson SM, Beals CR, Dardzinski BJ, Sanderson SO, Talwalkar JA, Ehman RL; Journal of Magnetic Resonance Imaging (Jul 2011)

PURPOSE:

To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by MR elastography (MRE) in healthy and hepatitis-C-infected subjects.

MATERIALS AND METHODS:

A biopsy-correlated repeatability study using four-slice MRE was conducted in five healthy and four HCV-infected subjects. Subjects were scanned twice on day 1 and after 7-14 days. Each slice was acquired during a 14-s breath-hold with a commercially available acquisition technique (MR-Touch, GE Healthcare).

Results were analyzed by two independent analysts.

RESULTS:

The intraclass correlation coefficient (ICC) was 0.85 (90% confidence interval [CI]: 0.71 to 0.98) for the between-scan average of maximum stiffness within each slice and 0.88 (90% CI: 0.78 to 0.99) for the average of mean stiffness within each slice for the primary analyst. For both analysts, the average of the mean liver stiffness within each slice was highly reproducible with ICC of 0.93 and 0.94. Within-subject coefficients of variation ranged from 6.07% to 10.78% for HCV+ and healthy subjects.

CONCLUSION:

MRE is a highly reproducible modality for assessing liver stiffness in HCV patients and healthy subjects and can discriminate between moderate fibrosis and healthy liver. MRE is a promising modality for noninvasive assessment of liver fibrosis

(Clinicaltrials.gov identifier: NCT00896233). J. Magn. Reson. Imaging 2011;. © 2011 Wiley-Liss, Inc.

Dynamic Postprandial Hepatic Stiffness Augmentation Assessed With MR Elastography in Patients With Chronic Liver Disease;

Yin M, Talwalkar JA, Glaser KJ, Venkatesh SK, Chen J, Manduca A, Ehman RL; American Journal of Roentgenology 197 (1), 64-70 (Jul 2011)

OBJECTIVE

MR elastography (MRE) is an MRI-based technique for quantitatively assessing tissue stiffness by studying shear wave propagation through tissue. The goal of this study was to test the hypothesis that hepatic MRE performed before and after a meal will result in a postprandial increase in hepatic stiffness among patients with hepatic fibrosis because of transiently increased portal pressure.

SUBJECTS AND METHODS

Twenty healthy volunteers and 25 patients with biopsyproven hepatic fibrosis were evaluated. Preprandial MRE measurements were performed after overnight fasting. A liquid test meal was administered, and 30 minutes later a postprandial MRE acquisition was performed. Identical imaging parameters and analysis regions of interest were used for pre- and postprandial acquisitions.

RESULTS

The results in the 20 subjects without liver disease showed a mean stiffness change of 0.16 ± 0.20 kPa (range, -0.12 to 0.78 kPa) or 8.08% ± 10.33% (range, -5.36% to 41.7%). The hepatic stiffness obtained in the 25 patients with hepatic fibrosis showed a statistically significant increase in postprandial liver stiffness, with mean augmentation of 0.89 ± 0.96 kPa (range, 0.17-4.15 kPa) or 21.24% ± 14.98% (range, 7.69%-63.3%).

CONCLUSION

MRE-assessed hepatic stiffness elevation in patients with chronic liver disease has two major components: a static component reflecting structural change or fibrosis and a dynamic component reflecting portal pressure that can increase after a meal. These findings will provide motivation for further studies to determine the potential value of assessing postprandial hepatic stiffness augmentation for predicting the progression of fibrotic disease and the development of portal hypertension. The technique may also provide new insights into the natural history and pathophysiology of chronic liver disease.

2010

Magnetic Resonance Elastography Holds Promise for Detecting, Staging Liver Fibrosis

By Cheryl Lathrop

BOSTON -- November 5, 2010 -- Magnetic resonance elastography (MRE) shows a combination of high sensitivity and specificity, and holds promise as a noninvasive imaging procedure for detecting and staging liver fibrosis, researchers said here at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

Yi Wang, MD, Northwestern University, Chicago, Illinois, and colleagues reported findings from their study at a poster session here on November 1.

Accurate determination of the extent of hepatic fibrosis is essential in patients with chronic liver disease, as it determines disease progression and selection of therapy. Liver biopsy has been the gold standard for the diagnosis of fibrosis, although it is invasive and associated with sampling errors, risks, and low patient acceptance.

In MRE, mechanical waves are transmitted through the abdomen, and the speed of the propagation of these waves through the liver is evaluated to assess the liver’s elasticity. The prototype system was developed at the Mayo Clinic, Rochester, Minnesota, and consists of an acoustic driver, a gradient-echo MRE pulse sequence, and software for data analysis.

Between October 2008 and November 2009, 127 consecutive patients with suspected cirrhosis or portal hypertension were prospectively evaluated, of which 42 didn’t have a documented histopathology, leaving a final cohort of 76 patients. Four transaxial slices were acquired, and quantitative images displaying shear stiffness were generated by processing the acquired images with a direct inversion algorithm.

The predictive value was determined by constructing a receiver operator characteristic curve of the sensitivity versus 1-sensitivity, and calculating area under the curve. Liver biopsy was obtained within 1 year of the MRE acquisition.

Liver stiffness values measured on MRE increased in parallel with the degree of fibrosis. Liver tissues without fibrosis (F0) had lower median shear stiffness than tissues with any degree of fibrosis (P less then .0001). A positive linear correlation between shear stiffness values and stage of fibrosis was seen (P less then .0001).

The MRE showed a great ability to identify fibrosis stage >=2 and demonstrated a combination of high sensitivity (91%) and specificity (97%).

The study had 2 limitations: The small number of F2-F3 patients may lead to bias; and the fibrosis stage may have changed in the period of time between the liver biopsy and the MRE.

However, MRE is an excellent option to characterise liver fibrosis, concluded Dr. Wang.

[Presentation title: Detection of Hepatic Fibrosis by Magnetic Resonance Elastography. Abstract 1317]

Quack medicines, insect immigrants, and what eats what among secrets revealed by DNA barcodes

Global 'barcode blitz' accelerates; 450 experts converge on Adelaide Nov. 28-Dec. 3

The newfound scientific power to quickly "fingerprint" species via DNA is being deployed to unmask quack herbal medicines, reveal types of ancient Arctic life frozen in permafrost, expose what eats what in nature, and halt agricultural and forestry pests at borders, among other applications across a wide array of public interests.

This is the cover of the report: "Barcoding Life Highlights 2011."

The explosion of creative new uses of DNA "barcoding" -- identifying species based on a snippet of DNA -- will occupy centre stage as 450 world experts convene at Australia's the University of Adelaide Nov. 28 to Dec. 3.

DNA barcode technology has already sparked US Congressional hearings by exposing widespread "fish fraud" -- mislabelling cheap fish as more desirable and expensive species like tuna or snapper. Other studies this year revealed unlisted ingredients in herbal tea bags.

Hot new applications include:

Substitute ingredients in herbal medicines

High demand is causing regular "adulteration or substitution of herbal drugs," barcoding experts have discovered.

Indeed, notes Malaysian researcher Muhammad Sharir Abdul Rahman, one fraudster in his country treated rubber tree wood with quinine to give it a bitter taste similar to Eurycoma longifolia -- a traditional medicine for malaria, diabetes and other ailments.

A library of DNA barcodes for Malaysia's 1,200 plant species with potential medicinal value is in development, eventually offering "a quick one step detection kit" to reduce fraud in the lucrative herbal medicine industry, says Mr. Sharir.

His concerns resonate in other countries around the true contents of certain brands of ginseng and other products.

DNA barcode libraries are under construction for the medicinal plants of several other nations as well, including South Africa, India and Nigeria.

Barcoding permafrost

From the woolly rhino to plants and mushrooms, scientists using DNA are deciphering what lived in the ancient Arctic environment, creating new insights into climate change in the process.

"DNA barcoding" analyses of cylinders of sediment cored from Arctic permafrost ranging in age from 10,000 to several hundred thousand years have shed light on past animal and fungal distributions and allowed researchers to infer which plant species likely co-existed.

DNA analyses of permafrost sediment 15,000 to 30,000 years old from northeastern Siberia revealed a grassland steppe plain during the glacial period supporting a diverse mammal community, including bison, moose and the DNA of the rare woolly rhino, the first ever found in permafrost sediments.

Caption:

Completing regional inventories. For most applications, a regional barcode library answers the question "what organism is this?" Researchers recently completed a library that characterizes 1,264 of the 1,338 species (94 percent) of butterflies and large moths of Germany. Local agricultural pests and invasive species can now be identified by DNA and distinguished from non-harmful relatives. In Japan, botanists established a library of rbcL barcodes for 689 of the 783 local ferns and horsetails (94 percent), creating a naming tool that works for all life stages, including gametophyte forms often indistinguishable by appearance.

Says University of Oslo-based researcher Eva Bellemain, who will present project BarFrost (Barcoding of Permafrost): "In the Arctic, fossils are scarce and time-consuming to find and analyze. However, DNA is one tough molecule. It had to be in order to serve its purpose the last billion years and more. Incredibly, it can linger in soil for tens of thousands of years and stay relatively intact."

What eats what

The technology can even distinguish species contained in the gut or dung of animals, revealing what eats what. University of Adelaide researcher Hugh Cross, for example, will detail his investigation into the diet of Australia's fast-growing, 1 million-strong population of wild camels, which severely impact the country's ecology.

Introduced in the 1800s as pack animals, Australia's wild camels eat an estimated 80% of available plant species in their range.

Says conference organizer David Schindel, Executive Secretary of the CBOL, based at the Smithsonian Institution, Washington, D.C.: "Biologists used to sit and wait and watch to learn how food webs work in Nature and what happens when they collapse. Now they can process stomach contents and dung samples to get the complete picture in a few hours."

Invasive pests

Until now, border inspection to keep agricultural pests, disease-carrying insects and invasive species from entering a country has been a hit-and-miss effort. Barcoding offers a tool to get same-day answers for accepting or rejecting imports, an issue of acute economic importance to Australia and New Zealand.

With European Union funding, a consortium of 20 universities, research institutes, and other organizations are partners in Project QBoL (Quarantine Barcode of Life, www.qbol.org), developing a library of DNA barcodes to help quickly identify common invasive organisms that authorities want to stop at national borders.

With the new DNA barcode tool, inspectors can more easily and surely identify and thus prevent the entry of invading pests including bacteria, fungi, fruit flies, other insects, nematodes, viruses, plants and other organisms. Trade of timber cut from endangered species may also be slowed with barcodes to identify wood and lumber products.

Hundreds of topics in Adelaide

"From tea to tuna, DNA identification is entering everyday life," remarked Jesse Ausubel, chair of the International Barcode of Life (iBOL) initiative, a 6-year program now in midstream of a group of the most active labs building the barcode library.

Adds Dr. Schindel: "Like Google and Wikipedia, DNA barcoding scarcely existed a decade ago, and now we are a vibrant community built on 21st century scientific tools."

"DNA barcoding is the express lane to solving many of Nature's mysteries relevant to a spectrum of national interests."

He notes that scores of additional topics will be explored in Adelaide, spanning health, cultural and environmental protection, such as:

• Identifying the prey of disease-carrying insects based on analysis of their meals of blood
• "Barcoding Nemo" and other species of the ornamental fish trade
• Identifying mushrooms and molds
• Assessment of the global status of pollinators such as bees, and
• Assessing water quality

The blood meals of biting insects

Resembling a common housefly, the African tsetse fly transmits Human African trypanosomiasis, AKA sleeping sickness, to people and animals. One of the world's most dangerous disease vectors, it spread the 2008 epidemic in which 48,000 Ugandans died. And the annual economic impact is estimated at US$4.5 billion, with around 3 million cattle killed every year.

Caption: In East Africa, researchers analyzed blood meals of tsetse flies (Glossina swynnertoni), the vector of trypanosomiasis, documenting geographic differences in animal hosts, helping inform local control strategies.

Scientists are using DNA barcodes to identify tsetse fly species and their prey based on analysis of the insect's blood meals, unravelling the relationship between hosts and vectors.

By developing the barcode library, tools and ability to readily distinguish species of tsetse flies, mosquitos, ticks and other vectors of diseases such as malaria, leishmaniasis, schistosomiasis, Japanese encephalitis, and Lyme disease, scientists can map risk areas more efficiently and alert authorities to the spread of health threats.

Barcoders have taken up an ambitious five-year goal a comprehensive library of 10,000 insect species that damage or destroy so many human lives: 3,000 mosquito, 1,000 sandfly, 2,000 blackfly, 2,000 flea and 1,000 tick species.

Nemo and friends

According to scientists, over 1 billion ornamental fish -- comprising more than 4,000 freshwater and 1,400 marine species -- are traded internationally each year, a US $5 billion industry growing annually at 8 percent.

Researchers at work on this issue include Gulab Khedkar of India, who says: "To facilitate ornamental fish trading, and in compliance of (India's) Biodiversity Act, a universal method must validate the ornamental fish with their species names. This can help assure a sustainable ornamental fish trade."

Fungi

Fungi are a taxonomic group of many major, distinct evolutionary lineages, ranging from mushrooms to molds. Although two species of fungi can be more distantly related than a fish is related to an insect, all fungi are classified in the same group.

Researchers at the conference are expected to announce the selection of the barcode region for fungi. The standard barcode regions used for animals and plants is not effective for fungi and an international working group has been conducting comparative analyses of candidate regions for two years. The decision is expected to open the floodgates to fungal barcoding research.

A project on indoor fungi that cause human health problems will also be unveiled in Adelaide, showing the enormous potential for fungal studies.

Australian scientist Wieland Meyer argues that, given steadily increasing invasive fungal infections, inadequate identification, limited therapies and the emergence of resistant strains, "there is an urgent need to improve fungal identification" to improve the successful treatment.

Fungi also provide humanity with food and antibiotics and the services of fermentation and decay. DNA-based taxonomy promises to revolutionize understanding of fungal diversity and connect the their life stages.

Barcoders aim to create a library of at least 10,000 fungal species by 2015, especially for indoor fungi, for basidiomycetes (the "higher fungi") and for pathogens of agriculture and forestry.

Insect pollinators

The ecosystem service of plant pollination by insects has a global value estimated at more than $400 billion a year.

Facilitated by the International Barcode of Life (iBOL), barcoders are surveying long-term population trends by assembling barcode libraries for all bees and other important pollinators -- flies and beetles. In combination with campaigns to barcode moths, butterflies and birds, they will provide the database needed to assess the state of pollinator communities worldwide.

Assessing water quality

Scientists in Southern California and elsewhere are pioneering barcodes to assess freshwater marine water quality and its impact on marine life in, sand, sediment, and rocks or in mud in rivers and offshore.

Traditionally after collecting a bulk water sample, taxonomists must identify by sight several thousand invertebrates, a process requiring months and thousands of dollars. DNA barcodes enable them to analyze bulk samples in a fraction of the time at a fraction of the cost.

Similar projects underway in Korea, Iraq, Belgium and the Baltic region will be presented in Adelaide.

DNA barcoding is emerging as the tool of choice for monitoring water quality, DNA barcode libraries of aquatic insects under construction. New technologies are being developed and tested that will allow faster and more complete analyses of entire biological communities in streamwater on 'DNA microchips' and through next-generation sequencing.

Says Dr. Schindel: "It used to take weeks or months to analyze the organisms in streams to determine water quality. Now it takes hours at a fraction the cost."

A global barcode blitz

Scientists in Adelaide will also advance progress towards an international library of barcodes for 500,000 plant, animal and fungi species within five years - "a barcode blitz" that could transform biology science. The Barcode of Life Database includes more than 167,000 reliably named and provisional species today. Butterflies and moths are the largest well-analyzed group so far, with over 60,000 named and provisional species -- much of the world's estimated total of 170,000.

Gold mines for barcoding are the world's museums and herbaria, where countless species specimens are concentrated and organized thanks to great investments of time and dollars.

A year ago, a team of five Biodiversity Institute of Ontario researchers conducted a barcode blitz in the Australian National Insect Collection. Focusing on moths and butterflies for 10 weeks, they processed over 28,000 specimens representing over 8,000 species and 65 per cent of the country's 10,000 known insect species. Meanwhile at the Smithsonian Institution's National Museum of Natural History, another team recently barcoded over 3,000 frozen bird tissues from over 1,400 species, adding more than 500 new species to the world avian DNA library, now covering about 40% of known birds.

New techniques for DNA extraction are bringing older and older specimens in natural history museums into the age range where DNA barcoding can be effective. These breakthroughs will open up new research questions about changes in species over the past centuries of human impact on natural populations.

The Munich Botanical Garden is the latest institution with an important collection of authoritative reference specimens opening its collection to a DNA barcode blitz.

###

The ability to identify and distinguish known and unknown species ever more quickly, cheaply, easily and accurately based on snippets of DNA code grew from a research paper in 2003 to a burgeoning global enterprise today, led by the Consortium for the Barcode of Life (CBOL) at the Smithsonian Institution.

The International Barcode of Life Conference in Adelaide is the 4th in a series that began at the Natural History Museum, London, in February, 2005.

In 2005, there were 33,000 records covering 12,700 species in the Barcode of Life Data Systems (BOLD) at the University of Guelph, Canada. Showing a more than 40-fold increase, almost 1.4 million records are now banked, representing roughly 167,000 known and provisional species (see www.barcodinglife.org/views/taxbrowser_root.php).

The Consortium for the Barcode of Life (CBOL) develops DNA barcoding as a global standard for species identification. With more than 200 member organizations from more than 50 countries, CBOL builds global participation, sets community standards, and organizes and supports working groups, workshops, networks, training opportunities, and international conferences held every two years. Free and open to all, CBOL promotes general awareness of barcoding through an information website (www.barcodeoflife.org) and information sharing through Connect (http://connect.barcodeoflife.net), the Barcode of Life social network.

The largest biodiversity genomics initiative ever launched, the International Barcode of Life (iBOL, http://ibol.org) aims to create by the end of the year 2015 a reference library of 5 million standardized DNA sequences capable of identifying 500 thousand species, more than a quarter of all known species on Earth. Headquartered in Canada, the iBOL program is the creation of more than 100 scientists from more than 20 countries. Launched in 2010 with support from Genome Canada and Ontario Genomics Institute, iBOL's participants commit resources—financial support, human effort, and specimens—toward the 5M/500K goal.

Agenda in Adelaide: www.dnabarcodes2011.org/conference/program/schedule/index.php

Major sponsors of the global barcoding movement include:

Chinese Academy of Sciences
CONABIO and CONACYT (Mexico)
Genome Canada
German Federal Ministry of Education and Research (BMBF)
International Development Research Centre (Canada)
Richard Lounsbery Foundation
Ministry of Science and Technology (Brazil)
Gordon and Betty Moore Foundation
Natural Sciences and Engineering Research Council (Canada)
Ontario Genomics Institute
Ontario Ministry of Research and Innovation
Alfred P. Sloan Foundation
Smithsonian Institution
University of Adelaide
University of Guelph

Hepatitis C - Dry Mouth and Treatment

Hey Doc, I thought the only side effect was dry mouth?

During HCV therapy dry mouth is a common irritating side effect, known clinically as xerostomia.

Xerostomia can lead to an increased risk for dental problems such as tooth decay, gum problems, mouth sores and other infections in the mouth.

Other drugs such as antidepressants also cause dry mouth, however, giving up that antidepressant during therapy just isn't going to happen. Unless you want channel your inner child, or Charlie Sheen, which isn't all that attractive. Well, either is interferon.

Interferon = Ugly
A point to ponder : Who remains attractive during therapy?

Not me! Interferon made this blogger so ugly that fear quickly engulfed my three teenagers. I celebrated, as each adolescent became increasingly kind to me - all at the same time, and it wasn't even Christmas! Who knew being under the "influence"of interferon would have its advantages?

Anyhoo, today on the blog are a few tips for dealing with that annoying side effect, and some insight into what happens to the salivary gland during therapy. I figured the gland just sort of died, but apparently it comes back to life after treatment.

So tell me, which drug is the culprit?

Well folks, from the December 2011 issue of Hepatitis Monthly we have a brief report entitled Ribavirin Impairs Salivary Gland Function in Hepatitis C Patients During Combination Treatment With Pegylated Interferon Alfa-2a, ya think?

To read the full text Click Here , or read the discussion provided below.

We Begin With Tips And Help

Dry Mouth

PREVENTIVE STRATEGIES

.

1. Maintain good oral hygiene, performing mouth care before and after meals and at bedtime. Gently floss the teeth once daily after brushing.

2. Inspect the mouth daily for patches while on therapy.

3. Maintain good denture care.

4. Maintain a high-protein nutritional diet; avoid a high-carbohydrate diet, especially sugary foods that provide “empty” calories.

5. Avoid alcohol and tobacco.
.

Symptomatic patients should be advised to:

.

1. Choose moist foods (yogurts, puddings, etc), adding sauces, gravies, and other lubricants to foods whenever possible. Dry foods such as breads, crackers, or dry meats are not well tolerated alone.

2. Use ice chips to keep mouth lubricated and provide comfort.

3. Use topical salivary stimulation methods, such as sugarless mints and gum, but avoid citric acid–containing solutions or foods, such as lemons. Products sweetened with Xylitol may have an antibacterial benefit.

4. Rinse mouth frequently with saline solution.

5. Use fluoride treatment regimen, as recommended by patient’s dentist.

6. Attend to any dental caries that may exist and receive dental check for new-onset caries with prolonged xerostomia.

7. Avoid carbonated beverages, which can be painful ..

Solutions

,

Available With Prescription

What Is Magic Mouthwash ?

Timothy Moynihan, M.D.

..

"Magic mouthwash" is the term given to a solution prepared by pharmacists and used to treat mouth sores (oral mucositis)

.

Oral mucositis can be extremely painful and can result in an inability to eat, speak or swallow. Magic mouthwash may be used to treat mouth sores that result from some forms of chemotherapy and radiation therapy.

.

There are many versions of magic mouthwash. Your doctor will likely write a prescription listing the ingredients and the amount of each.

Magic mouthwash usually contains at least three of these basic ingredients:
An antibiotic to kill bacteria around the sore
An antihistamine or local anesthetic to reduce pain and discomfort
An antifungal to reduce fungal growth
A corticosteroid to treat inflammation
An antacid to enhance coating of the other ingredients inside the mouth .

..

Most formulations of magic mouthwash are intended to be used every four to six hours, and to be held in your mouth for one to two minutes before being either spit out or swallowed. It's recommended that you don't eat or drink for 30 minutes after using magic mouthwash so that the medicine has time to produce an effect.

.

It's unclear how effective magic mouthwash is in treating oral mucositis. That's because of the lack of standardization in the formulations of mouthwash, and poorly designed studies done to gather data.

.

If you have mouth sores that cause you pain and discomfort, talk with your doctor. Side effects of magic mouthwash may include problems with taste, a burning or tingling sensation in the mouth, drowsiness, constipation, diarrhea, and nausea.
Click Here For More Information


Available Over The Counter

What Is Biotène?

Biotene Products:
Biotene Moisturizing Mouth Spray
Biotene Oral Balance Liquid
Biotene Oral Rinse
Biotene Dry Mouth Toothpaste
Biotene Dry Mouth Gum
Biotene Oral Balance Gel

,.

The strength of the Biotène products lies in their ingredients: they contain antibacterial enzymes found naturally in human saliva. Together, these ingredients re-create the natural oral protection found in the mouth, providing antibacterial and healing properties. Only Biotène's bio-enzyme products can help maintain a healthy balance of oral flora, reducing harmful bacteria while sustaining beneficial bacteria. Recommended for everyone susceptible to cavities, bad breath, mouth sores, and gum disease.

Biotène contains three primary enzymes - Glucose Oxidase, Lactoperoxidase, and Lysozyme, which are carefully balanced for a special function in boosting and replenishing saliva's own defenses. When used daily, Biotène reduces harmful bacteria, but leaves beneficial bacteria necessary for healthy teeth and oral tissues.

Ribavirin Impairs Salivary Gland Function in Hepatitis C Patients DuringCombination Treatment With Pegylated Interferon Alfa-2a


Alessio Aghemo 1, Maria Grazia Rumi 2*, Sara Monico 1, Matteo Banderali 3, Antonio Russo 4,Francesco Ottaviani 3, Mauro Vigano 2, Roberta D’Ambrosio 1, Massimo Colombo 11 Migliavacca Center for Liver Disease, Division of Gastroenterology 1, IRCCS Fondazione Ca’ Granda Hospital, University of Milan, Milan, Italy2 Department of Hepatology, St. Joseph’s Hospital, University of Milan, Milan, Italy 3 Department of Clinical Sciences, “L. Sacco “Hospital, University of Milan, Milan, Italy4 Departments of Epidemiology and Biostatistics, San Carlo Borromeo Hospital, Milan, Italy

Hepat Mon.2012;11(11) :in press. DOI: 10.5812/kowsar.1735143X.733

A B S T R A C T

Background: Xerostomia is a common adverse event of unknown etiology
observed during pegylated interferon (PegIFN)/Ribavirin (Rbv) treatment.

Objectives: To assess the frequency and mechanisms of xerostomia
during PegIFN/Rbv therapy.

Patients and Methods: Thirty-one naïve patients with chronic hepatitis C
consecutively received PegIFN-α2a (180 αg/week) plus Rbv (800–1200 mg/day).
The controls were 10 patients with chronic hepatitis B who received PegIFN-α2a (180 αg/week). During treatment and follow-up, all patients underwent basal and masticatory stimulated sialometry, otorhinolaryngoiatric (ORL) examination, and a questionnaire survey to subjectively assess symptoms of oral dryness.

Results: Twenty-seven patients on PegIFN/Rbv and 4 on PegIFN
(87% vs. 40%, P = 0.006) reported xerostomia.

Thirty patients on PegIFN/Rbv combination therapy and 2 patients on monotherapy had ORL signs of salivary gland hypofunction (97% vs. 20%, P less then 0.0001). Mean basal (A) and stimulated (B) salivary flow rates mL/min)progressively decreased during PegIFN/Rbv treatment (A, 0.49 at baseline vs. 0.17 at the end of treatment, P less then 0.0001; B, 1.24 at baseline vs. 0.53 at the end of treatment, P = 0.0004).

At week 24 following PegIFN/Rbv treatment, salivary flow rates were similar to baseline (A, 0.53 at the end of follow-up vs. 0.49 at baseline; B, 1.19 at the end of follow-up vs. 1.24 at baseline). Salivary function was unaffected in monotherapy patients.

Conclusions:Rbv causes salivary gland hypofunction in hepatitis C patients receiving PegIFN/Rbv therapy,which promptly reverts to normal upon cessation of treatment.

Discussion Only

Click Here For PDF

Approximately 12% of all patients with HCV infection receiving PegIFN/Rbv therapy ultimately develop xerostomia, which in turn increases the risk of symptoms like dental cavities, nausea, and constipation.

Our study demonstrates that dry mouth occurring during anti-HCV
therapy results from a reversible inhibition of salivary gland function.
At the same time, we show that symptoms of mouth dryness are enhanced in HCV patients receiving PegIFN/Rbv therapy compared to HBV patients receiving monotherapy with PegIFN, indicating a direct role of Rbv.

Indeed, patients receiving PegIFN monotherapy showed no salivary dysfunction, while only a few of them reported mild and transient symptoms of mouth dryness. This is consistent with reports of the effects of other drugs such as antidepressants,where, similar to our PegIFN monotherapy patients, xerostomia is not directly caused by salivary gland impairment, as the secretory function of salivary glands is preserved (17).

In our study, no HCV or HBV patient required treatment with antidepressant drugs, ruling out any influence of these drugs on observed salivary flow rates.
While we ignore the pathogenetic mechanisms of Rbv-induced hyposialia, we may speculate that the changes in salivary flow in patients receiving PegIFN/Rbv might result from an alteration of exocytosis and/or liquid transport of the exocrine glands (18).

However,we acknowledge that unfortunately our study cannot provide any
information on this matter, as it was not designed for this endpoint. Moreover, we believe that the exact pathogenic mechanisms behind this observation can be unraveled only through studies evaluating sialochemistry and eventually by salivary gland biopsies in patients undergoing Pe-gIFN/Rbv therapy. Whatever the underlying mechanisms of Rbv-induced hyposialia, the absence of a correlation between hyposialia and Rbv dosing discourages Rbv dose-adjustment for patients with this undesired effect. Moreover, the recognition that salivary gland function is only temporarily impaired during PegIFN/Rbv treatment encourages counseling and treatment of the symptoms of hyposialia with oral hydration or administration of saliva substitutes.

Treatment of xerostomia by ORL specialists may improve the patient’s quality of life by attenuating the impairment of the sense of taste, halitosis, and interference with functions such as speech, chewing, and swallowing (19), thereby not ompromising adherence to Rbv dosing.

This finding has important clinical implications, since maintaining high Rbv doses will be essential in the future to maximize the antiviral effect of protease inhibitors of HCV replication, as recently shown by Phase II and III trials (20-23). While we acknowledge that the present study was conducted on a relatively small number of patients, we think that the prospective enrollment and the presence of a control group receiving PegIFN monotherapy allows the data generated here to be confidently extrapolated to clinical practice (24).
Moreover, the risk of intrapatient variations due to age, smoking or other unrecognized environmental factors was attenuated by the saliva flow tests carried out at different time points, and the risk of interpatient variation was eliminated by the 100% compliance of the study participants (25).

The enrollment of a control group of HCV patients receiving Rbv monotherapy in our study would have further reinforced our findings, effectively eliminating the possibility that HCV itself might play a role in the development of xerostomia, whilst also allowing us to precisely determine which drug is the causal agent of salivary gland hypofunction.

However,in the study design process we considered incorporating such a control group unethical, due to the minimal to no antiviral effect associated with Rbv monotherapy, coupled with the potentially serious adverse events linked to its intake (18).

In conclusion, this study demonstrates that Rbv is responsible for xerostomia occurring during anti-HCV therapy, causing transient salivary gland hypofunction that does not appear to be dose-dependent and is promptly reverted upon cessation of treatment.

Association between Chronic Viral Hepatitis Infection and Breast Cancer Risk: a Nationwide Population-based Case-control Study

Association between Chronic Viral Hepatitis Infection and Breast Cancer Risk: a Nationwide Population-based Case-control Study

The complete article is available as a provisional PDF.

Fu-Hsiung Su email, Shih-Ni Chang email, Pei-Chun Chen email, Fung-Chang Sung email, Chien-Tien Su email and Chih-Ching Yeh email

BMC Cancer 2011, 11:495doi:10.1186/1471-2407-11-495
Published: 24 November 2011
Abstract (provisional)

Introduction

In Taiwan, there is a high incidence of breast cancer and a high prevalence of viral hepatitis. In this case-control study, we used a population-based insurance dataset to evaluate whether breast cancer in women is associated with chronic viral hepatitis infection.

Methods

From the claims data, we identified 1958 patients with newly diagnosed breast cancer during the period 2000-2008. A randomly selected, age-matched cohort of 7832 subjects without cancer was selected for comparison. Multivariable logistic regression models were constructed to calculate odds ratios of breast cancer associated with viral hepatitis after adjustment for age, residential area, occupation, urbanization, and income. The age-specific (less then 50 years and more then 50 [greater than or equal to]50 years) risk of breast cancer was also evaluated.

Results

There were no significant differences in the prevalence of hepatitis C virus (HCV) infection, hepatitis B virus (HBV), or the prevalence of combined HBC/HBV infection between breast cancer patients and control subjects (p = 0.48). Multivariable logistic regression analysis, however, revealed that age less then; 50 years was associated with a 2-fold greater risk of developing breast cancer (OR = 2.03, 95% CI = 1.23-3.34).

Conclusions

HCV infection, but not HBV infection, appears to be associated with early onset risk of breast cancer in areas endemic for HCV and HBV. This finding needs to be replicated in further studies.


Material and methods
Data sources

Data used in this study were retrieved from the National Health Insurance Research Database (NHIRD), which is maintained by the National Health Research Institute (NHRI), Taiwan. The single-payer National Health Insurance (NHI) program in Taiwan was initiated in March, 1995 to provide comprehensive and affordable health care to all of the island’s residents. By the end of 1996, this insurance program covered more than 96% of the population and has contracted with 97% of hospitals and clinics in the country [23].

The NHRI randomly selected data from the insured population to establish a representative sub-dataset comprised of 1 M insured enrollees during the period 1996–2000. There is no significant difference in the distribution of gender, age, or average payroll-related insurance payment between the individuals in the NHRID and the original medical claims for all enrollees under the NHI program. The data files are linkable through an encrypted but unique personal identification number and thus provide patient-level information on demographic characteristics, medical history, registry of medical facilities, detailsof inpatient orders, ambulatory care visits, dental services, and prescriptions. Diagnoses are coded according to the International Classification of Disease, Ninth revision (ICD-9-CM). As the dataset was released with de-identified secondary data for public research purposes, the study was exempt from full review by the Institutional Review Board.

Study sample
Patients with newly diagnosed breast cancer (ICD-9-CM code 174 and 175) during the period 2000–2008 were identified from the registry for Catastrophic Illness Patients Database. The insurance coverage for catastrophic illnesses is the extension of the Taiwan’s NHI to protect people with serious disease against catastrophic financial burden and subsequent impoverishment. Breast cancer was placed in the category of NHI-defined “Catastrophic Illnesses”, and the NHI covers the treatment costs incurred by this disease. In this study, our
purpose was to observe mainly the association between chronic viral hepatitis (HBV or HCV)and breast cancer. The etiologies of other types chronic hepatitis, such as autoimmune, chemical,alcoholic-related hepatitis, as well as non-alcoholic fatty liver disease were not included as our study subjects. For HBV infection recorded in the database, the presence of HBs Ag was the major serum marker. Patients with the history of HIV were excluded from the present study to minimize the inclusion of occult HBV infection (the persistence of hepatitis B virus (HBV) in hepatitis B surface antigen (HBs Ag) negative) among patients with the HBV/HIV coinfection [24]. Hence, we excluded patients with a history of HIV (ICD-9-CM 042, 043, 044, and V08),
chronic hepatitis (ICD-9-CM 070.9, 571.4, 571.8, 571.9, and 573.3) without mentioning hepatitis B (ICD-9-CM 070.2, 070.3, and V02.61) or hepatitis C (ICD-9-CM 070.41, 070.44, 070.51, 070.54, and V02.62) infection. After excluding two cases of HIV and 468 subjects with chronic hepatitis without mentioning hepatitis B or hepatitis C, 1958 subjects with breast cancer were enrolled in this study.

Control subjects were randomly extracted from the remaining subjects in the database with an identical exclusion criterion to cases.

The comparison group comprised randomly selected age and sex-matched individuals without a history of breast cancer. The control to patient ratio was 4:1. The age of each study subject was based on the difference in time between the index date and the date of birth. Originally, 434,659 female subjects were retrieved from the NHIRD. After excluding 9,738 subjects with cancers other than breast cancer, 260 cases with HIV, and 69,756 subjects with chronic hepatitis other than hepatitis B or hepatitis C, 354,905 subjects were eligible for the selection of control subjects. Finally, a total of 7,832 controls were enrolled in this study.

Statistical analysis
We compared the distributions of demographic characteristics, including age, occupation, urbanization level, and personal income between breast cancer patients and control subjects using Chi-square tests. Potential confounders included in this study were monthly income, level of urbanization (4 levels with Level 1 referring to the “most urbanized” and Level 4 referring to the “least urbanized” communities), and the geographical location of the community in which the patient resided (northern, central, eastern, and southern Taiwan). We selected NT $15,000 and
NT $30,000 as the income level cutoff points in Taiwan. Multivariable logistic regressionanalysis was conducted to assess the association of viral hepatitis with the risk of breast cancer,after adjusting for variables that were significantly related to breast cancer from the prior Chisquare analyses. The age-specific odds ratios of breast cancer associated with viral hepatitis were also examined by two individual logistic regression models (one for age less then;50 years and the other one for age more then 50 years).

To address the hypothesis of the presence of an association between HCV and early onset breast cancer, interaction between HCV status and age of developing breast cancer was tested by a logistic regression analysis. All analyses were performed by SAS statistical software (version 9.1 for Windows; SAS Institute, Inc., Cary, NC, USA), and the significance level was set at 0.05. Results Characteristics of the study subjects Table 1 compares the distributions of demographic characteristics between the patient group and the control group. Most subjects were in the 40–60-year age group (64.3% in the patient group and the control group). Breast cancer patients were more likely than control subjects to have white-collar occupations (55.4% vs. 51.3%, p = 0.001), live in areas with the highest urbanization level (34.4% vs. 31.7%, p = 0.03), and have higher incomes (15.7% vs. 12.6%, p =0.0004).

Table 1 Demographic characteristics between breast cancer patients and non-breast cancer
subjects in 2000–2008

Click On Tables To Enlarge








Overall risk and age-specific risk of breast cancer
The logistic regression analysis showed that viral hepatitis was not significantly associated with breast cancer, although the risk was greater for subjects with HCV (adjusted OR = 1.28, 95% CI = 0.95–1.78) than for those with HBV (adjusted OR = 1.05, 95% CI = 0.85–1.28) or both (adjusted OR = 1.08, 95% CI = 0.65–1.80) (Table 2).

However, the multivariable regression model revealed that HCV patients aged less than 50 years had a significant 2.03-fold higher risk of breast cancer (OR = 2.03, 95% CI = 1.23–3.34) (Table 3). The interaction between HCV status and age (less then;50 years and more then 50 years) of developing breast cancer was statistically significant (p = 0.019) (not shown in Table). Table 3 Odds ratios and 95% confidence interval of breast cancer associated with viral hepatitis by age




Discussion
In this large-scale, population-based study in an area where both viral hepatitis and breast cancer are prevalent, we found no significant association between breast cancer risk and HBV or HCV seropositivity; however, age-stratification analysis showed that HCV patients aged less than 50 years had a significant two-fold greater risk of breast cancer.

Although breast cancer is mainly a postmenopausal disease, breast cancer in younger females often shows more aggressive clinical features and worse prognosis [3]. Studies have shown that high-risk and low-risk tumors present different age distributions, suggesting that breast cancer comprises a mixture of two different disease processes [3,25]. The epidemiology of breast cancer in women living in Asia differs from that in women living in North America or Europe. The peak incidence age is between 40 years and 50 years among Asian women, whereas in the United
States and Europe, it peaks among women in the sixth decade of life [2,5,26,27]. This variation in peak incidence age may be due to multiple factors, including geographic variation, racial/ethnic background, genetic variation, lifestyle, environmental factors, socioeconomic status, utilization of screening mammography, stage of disease at diagnosis, and the availability of appropriate care [1,21]
In 1997, Richardson proposed that breast cancer risk is associated with late exposure to common viruses [10]. Since then, numerous studies have shown that EBV, HPV, and cytomegalovirus infections are associated with the development of breast cancer [12,14,15,28,29].
Few studies, however, have evaluated the relationship between HCV or HBV infection and breast tumor development. A higher prevalence of HCV has been observed in elderly patients with tumors of the colon/rectum, prostate, breast, bladder, or kidney [30-32] as well as in elderly patients with hepatocarcinoma [33] or non-Hodgkin lymphoma [16,19]. Malaguarnera et al. reported that HCV RNA was detectable in sera in 11% of breast cancer patients and in 6.6% of control subjects, although there was no significant difference between the two groups [30].
Bruno et al. recently reported that HCV infection most likely plays an important role in the development of hepatocellular carcinoma as well as breast cancer [32]. In contrast, the results of a recent case-control study conducted by Larrey and his colleagues suggest that chronic HCV infection is not a strong promoter of breast carcinoma in adult females of any age [31]. However, a relatively small number of breast cancer patients in the control group may have masked the true significance of the infection after age stratification. Similarly, we found that chronic HCV infection was not significantly associated with breast cancer; however, after stratification by age (sub-grouped into less then 50 years and more then50 years), chronic HCV infection was more prevalent among patients with early-onset breast cancer than among those with late-onset of the disease. This finding also suggests that breast cancer may comprise a mixture of two different disease processes, and that HCV may act as a promoter of carcinogenesis in young patients. Further studies are needed.

The mechanism responsible for the oncogenetic role of HCV is not well understood, but it involves immunity and autoimmunity disorders [30,34,35]. Mechanisms of direct and indirect carcinogenesis by which infections may contribute to cancer development have been suggested.
Immunosuppression or induction of reactive oxygen species via inflammatory reactions have been suggested as the two most prominent pathways for indirect infectious carcinogens. Unlike the immunosuppressive mechanism induced by HIV, the mechanism by which Hepatitis B and C viruses contribute to cancer still remains obscure [11].

In this study, neither infection with HBV alone nor HBV/HCV coinfection was correlated with breast cancer. HBV and HCV are both hepatotropic viruses. Their coinfection is associated with clinically and histologically more severe liver disease and higher risk of the development of hepatocellular carcinoma [22,36]. However, HCV infection has been reported to predispose patients to extrahepatic disorders involving renal, dermatologic, hematologic, and rheumatologic
systems as well as autoimmune abnormalities [37-39].

Extrahepatic manifestations may result from immunologic triggered mechanisms as well as virus invasion and replication that affect extrahepatic tissues and organs. Only HCV has the lymphotropic character that is assumed to be the cause of HCV-associated extrahepatic manifestation [40]. That may explain why we found that HCV, but not HBV, was associated with breast cancer. Further prospective cohort studies are required to verify this result.

This study has several important limitations. First, some hepatitis infected patients without obvious clinical symptoms might not receive medical services. As a result, some hepatitis infected subjects are included in the control group. However, if viral hepatitis infection is associated causally with breast cancer, this is classification may lead the estimated HRs toward the null and further strengthen our finding. Therefore, we are confident of the positive association between HCV and early-onset breast cancer. Second, using ICD codes to select patients with diagnoses of breast cancer, HBV infection, HCV infection, or other comorbid medical conditions may be less accurate than selecting patients in a clinical setting. However, the
BNHI randomly samples a fixed percentage of claims from every hospital and randomly
interviews patients and reviews charts each year to verify the validity of diagnoses and the quality of care. Patients with confirmed breast cancer in Taiwan are placed in the category of “Catastrophic Illness”, and the BNHI covers the treatment costs incurred by those patients.
Hence, the diagnosis is relatively accurate and the patients are representative of the population in Taiwan. Third, the majority of the residents in Taiwan are of Chinese ethnicity. The ability to generalize the results to other racial/ethnic groups is unclear given that the transmission route of viral hepatitis infection in Chinese might not be completely the same as that in other ethnic groups. Finally, important variables that might be related to both hepatitis and breast cancer were unavailable in the insurance claims database, including family cancer history, body mass index, environmental exposure, nutritional status, physical activity level, hormone receptor status of breast cancer, cigarette smoking, and alcohol consumption. Therefore, we cannot rule out some of the potential confounding effects associated with these factors.

Conclusions
In summary, this population-based study suggests that chronic HCV infection is associated with early-onset breast cancer and that chronic HBV infection is not associated with breast cancer.

Further studies are needed to apply our finding to other regions or races and to clarify the underlying pathophysiological mechanisms behind the association of chronic viral hepatitis with breast cancer.

Abbreviations
CI, Confidence interval; EBV, Epstein-Barr virus; HBV, Hepatitis B virus; HCV, Hepatitis C
virus; HPV, Human papillomaviruses; HIV, Human immunodeficiency virus; ICD-9-CM,
International classification of disease diagnoses, ninth revision; NHI, National
Health Insurance;
NHIRD, National Health Insurance Research Database; NT, New Taiwanese Dollar; OR, Odds ratio
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
FHS helped to design, analyze and interpret the data and drafted the manuscript. SNC, PCC, FCS, and CTS helped to perform statistical analysis and data interpretation. CCY conceived of the study, participated in study design, analysis, and interpretation, and critically revised the manuscript. All authors read and approved the final manuscript.
Acknowledgments
The data used in this study were retrieved from the National Health Insurance Research Database
provided by the Bureau of National Health Insurance, Department of Health, Taiwan and
managed by the National Health Research Institutes. The interpretations and conclusions mentioned in this study do not represent the opinions or suggestions from the Bureau of National Health Insurance, Department of Health, or the National Health Research Institutes in Taiwan.
This study was supported by the National Sciences Council, Executive Yuan (grant numbers DOH 97-HP-1101, 2008–2010), China Medical University Hospital (grant number 1MS1, DMR-94-080), Taiwan Department of Health Clinical Trial and Research Center and for Excellence (grant number DOH 100-TD-B-111-004), and Taiwan Department of Health Cancer Research Center for Excellence (DOH100-TD-C-111-005).

References

Happy Thanksgiving

Happy Thanksgiving

My Family

This Thanksgiving I am thankful for my lovely family and two healthy grandchildren which have unintentionally filled an empty space in my heart.

The HCV Community

I give thanks today for the possibility of now curing hepatitis C. We have gone from a 44% chance at a cure with standard therapy to a 69-75% cure rate with the two new drugs telaprevir and boceprevir.

I am sending out hope to all those brave people who have struggled with the consequences of HCV, and pray that your personal journey will be successful and safe.

May this holiday be filled with love, creating lasting memories for you and your family.

Hepatitis C -The Brain on Fire: Inflammation and Depression

The Brain on Fire: Inflammation and Depression

Inflammation and Its Effects on Mood

Published on November 23, 2011
by James M. Greenblatt, M.D.

Interferons, a form of cytokines which activate the immune system and act as antiviral agents, is a common treatment for hepatitis C infection. Research and clinical studies have shown that interferon therapy can actually lead to depression in patients who have hepatitis C. It's been reported that between 20% and 30% of patients who have hepatitis C and who receive interferon treatment are at risk for depression.

We have all had the flu or at least know what it feels like.

The miserable collection of symptoms includes lack of energy, difficulty concentrating, sleepiness, loss of appetite, and general malaise.

For most of us these symptoms disappear within a few days. For some, it takes much longer. Although we tend to blame the influenza virus for making us feel miserable, the symptoms are actually a result of our immune system trying to combat the virus.

The symptoms of the flu are brought on by proteins, pro-inflammatory cytokines, our bodies produce in order to fight the flu and other infections.

When the immune system is under attack from physical injury, infections, or toxins, the immune system generates an inflammatory response. Inflammation is a normal physiological process that is now understood to play a major role in many chronic medical illnesses, including cancer, heart disease, diabetes, asthma, and obesity. In each of these cases inflammation causes the release of cytokines. Cytokines, which come in many different classes, including anti- and pro-inflammatory, behave as messengers and signal cells of the immune system.

The effects of pro-inflammatory cytokines can cause a diverse array of physical and psychological symptoms. When this happens it is referred to as sickness behavior.

Recently, scientists have been able to demonstrate how the symptoms of sickness behavior mirror those of depression. Researchers and health professionals are now beginning to understand the connection between inflammation and depression.

One study found that patients with major depressive disorder had significantly higher levels of the pro-inflammatory cytokine TNF-alpha than their non-depressed counterparts. In addition, patients with depression had low levels of anti-inflammatory cytokines.
Researchers have also found that eight weeks of Zoloft treatment was able to decrease some pro-inflammatory cytokines seen in depressed patients. On Zoloft, the depressed patients also saw an increase in anti-inflammatory cytokines.

A study involving depressed patients classified as non-responders supplemented the patients' standard antidepressant treatment with the addition of aspirin, an anti-inflammatory. More than 50% of these patients responded to this combination treatment. At the end of the study more than 80% of the group responsive to the anti-inflammatory went into remission.
Cytokines, the messengers during inflammation, are also used to treat infections and autoimmune disorders. So-called autoimmune disorders are clear examples of how an unregulated immune system can cause destructive damage to many different organs and tissues. Some of the most common autoimmune diseases include rheumatoid arthritis, multiple sclerosis, thyroid disease, and celiac disease.

Interferons, a form of cytokines which activate the immune system and act as antiviral agents, is a common treatment for hepatitis C infection. Research and clinical studies have shown that interferon therapy can actually lead to depression in patients who have hepatitis C. It's been reported that between 20% and 30% of patients who have hepatitis C and who receive interferon treatment are at risk for depression.

In one study, nearly a third of patients with chronic hepatitis C who received interferon treatment displayed psychiatric symptoms after four weeks of treatment. Symptoms included mania, hypomania, and depression. Over the years I have had to admit patients for inpatient psychiatric treatment for depression and suicidal behavior following interferon therapy.

It appears that inflammation and the complicated collection of immune system chemical messengers called cytokines play an important role in brain function and may cause psychological symptoms.

When the brain is aggravated by any source-stress, infections, trauma, stroke, poisons, or nutritional deficiencies-inflammation spurs the release of pro- inflammatory cytokines, which may affect mood. Scientists have proposed many mechanisms as to how this may occur.

One mechanism as to how an unregulated immune system may contribute to depression is quite well understood. Cytokines activate an enzyme, indoleamine 2,3-dioxygenase (IDO), which degrades serotonin resulting in low levels of the neurotransmitter. IDO also degrades the precursor to serotonin, tryptophan. Decreased levels of the neurotransmitter serotonin are likely the contributing factor to the development of depressive symptoms. The inflammatory process' contribution to the constant destruction of serotonin decreases the chances of recovery.

For too many years we have tried to correlate depression with a deficiency of serotonin and related neurotransmitters in the brain. Using medications based on this theory has yielded dismal results, barely better than a placebo. If we understand the underlying physiological abnormalities contributing to mood disorders, then we are likely to benefit from more effective solutions.

Understanding the connection between depression and inflammation gives researchers and pharmaceutical companies incentive to look for alternative medications to treat depression. In the meantime there are, however, well-researched lifestyle and nutritional interventions that are known to decrease inflammation and improve mood: exercise, stress reduction, nutritional supplements (i.e. omega-3 fatty acids), and optimizing vitamin D levels. Chronic stress is one of the major preventable contributors to inflammation and immune dysregulation.

For each individual the inflammatory response is likely precipitated by a unique and complex interaction of causative agents. Infection, stress, nutritional deficiencies, and sedentary lifestyles are the most common factors. Individual, personalized understanding of inflammation and its contributions to the physiology of mood disorders is a critical, but often neglected component of integrative therapies for depression. By neglecting the underlying cause of depression, recovery is less likely.

In case you missed it:
Video- Psychiatric Complications of Hepatitis C Treatment - Part 1 and Part 2

Research finds HIV-killing compound

(Medical Xpress) -- A powerful topical preventative for HIV, the virus that causes AIDS, could soon be in the works thanks to a newly discovered molecular compound that research at Texas A&M University and the Scripps Research Institute shows dissolves the virus on contact.

The ability of the synthetic compound known as “PD 404,182” to break apart the AIDS-causing virus before it can infect cells was discovered by Zhilei Chen, assistant professor in the university’s Artie McFerrin Department of Chemical Engineering, and her team of researchers. Their findings appear in the November online edition of Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

“This is a virucidal small-molecule compound, meaning that it has the ability to kill a virus; in this case that virus is HIV,” Chen says. “Basically, it acts by breaking the virus open. We found that when HIV comes in contact with this compound, it breaks open and loses its genetic material. In a sense, the virus ‘dissolves,’ and its RNA becomes exposed. Since RNA is pretty unstable, once it is exposed it’s gone very quickly and the virus is rendered non-infectious.”



In other words, the compound works by quickly ripping open the virus before it can inject its genetic material into a human cell. What’s more – and perhaps even more important -– the compound, Chen explains, achieves this by acting on something within the virus other than its viral envelope protein, meaning that the virus can’t alter its proteins to bolster its resistance -– something that’s made HIV notoriously difficult to treat.

“We believe this compound is not working on the viral protein of the viruses but on something else common in all the viruses on which we tested it -- some cellular material common in these viruses,” Chen notes. “Because this compound is acting on a component that is not encoded by the virus, it will be difficult for the virus to evolve resistance against this compound.”

While not a cure for HIV, the compound demonstrates significant potential for use as a preventative, specifically in the form of a topical gel that could be applied in the vaginal canal, Chen explains.

“We conducted a number of tests to demonstrate that this compound remains active in vaginal fluid and is not rendered ineffective,” Chen says. “In the form of a vaginal gel, the compound would serve as a barrier, acting almost instantaneously to destroy the virus before it could infect a cell, thereby preventing HIV transmission from one person to another.”

Surprisingly, Chen and her team did not set out to discover an HIV preventative. Instead, they were conducting screenings of molecules for use in potential drug therapies targeting hepatitis C virus, which causes the dangerous and often fatal disease of the liver. Employing a screening system developed by Chen, the team screened thousands of molecular compounds, in search of those that could block aspects of the HCV life cycle.

During the course of the screenings, the team made an interesting discovery: Not only was PD 404,182 an HCV inhibitor, it also worked on lentiviruses (the group’s negative control in its experimental procedures). Intrigued by that finding, Chen then tested PD 404,182 on HIV, which itself is a lentivirus and found the compound to be even more effective on HIV than on HCV.

“We believe PD 404,182 acts through a unique and important mechanism,” Chen notes. “Most of the known virucidal compounds interact with the virus membrane, but our compound does not appear to interact with the virus membrane. Instead, it bypasses interaction with the membrane and still compromises the structural integrity of the virus.”

The ability of the compound to avoid interaction with the virus membrane is important because human cells have similar membranes, Chen notes. If the compound were to disrupt the structure of the virus membrane, it could also disrupt and ultimately kill human cells. PD 404,182 doesn’t interact with these membranes and is therefore a more attractive option for clinical treatment, Chen says.

As is the case with any potential pharmaceutical, several key steps are still needed before it winds up on drug store shelves. In addition to several rounds of animal studies to ensure the compound is safe for humans, further collaborations with chemists are needed to continue to improve the efficiency of the compound. Chen says. What’s more, Chen also plans to further explore the mechanism by which PD 404,182 breaks apart HIV.


Provided by Texas A&M University
Source