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Archive for the ‘Patient Experience: Personal Memories of Invasive Medical Intervantion’ Category

NIMHD welcomes nine new members to the National Advisory Council on Minority Health and Health Disparities

Reporter: Stephen J. Williams, Ph.D.

The National Institute on Minority Health and Health Disparities (NIMHD) has announced the appointment of nine new members to the National Advisory Council on Minority Health and Health Disparities (NACMHD), NIMHD’s principal advisory board. Members of the council are drawn from the scientific, medical, and lay communities, so they offer diverse perspectives on minority health and health disparities.

The NACMHD, which meets three times a year on the National Institutes of Health campus, Bethesda, Maryland, advises the secretary of Health and Human Services and the directors of NIH and NIMHD on matters related to NIMHD’s mission. The council also conducts the second level of review of grant applications and cooperative agreements for research and training and recommends approval for projects that show promise of making valuable contributions to human knowledge.

The next meeting of the NACMHD will be held on Thursday, Sept. 10, 8:30 a.m.-5:00 p.m. on the NIH campus. The meeting will be available on videocast at http://www.videocast.nih.gov.

NIMHD Director Eliseo J. Pérez-Stable, M.D., is pleased to welcome the following new members

Margarita Alegría, Ph.D., is the director of the Center for Multicultural Mental Health Research at Cambridge Health Alliance and a professor in the department of psychiatry at Harvard Medical School, Boston. She has devoted her career to researching disparities in mental health and substance abuse services, with the goal of improving access to and equity and quality of these services for disadvantaged and minority populations.

Maria Araneta, Ph.D., a perinatal epidemiologist, is a professor in the Department of Family and Preventive Medicine at the University of California, San Diego. Her research interests include maternal/pediatric HIV/AIDS, birth defects, and ethnic health disparities in type 2 diabetes, regional fat distribution, cardiovascular disease, and metabolic abnormalities.

Judith Bradford, Ph.D., is director of the Center for Population Research in LGBT Health and she co-chairs The Fenway Institute, Boston. Dr. Bradford has participated in health research since 1984, working with public health programs and community-based organizations to conduct studies on lesbian, gay, bisexual, and transgender people and racial minority communities and to translate the results into programs to reduce health disparities.

Linda Burhansstipanov, Dr.P.H., has worked in public health since 1971, primarily with Native American issues. She is a nationally recognized educator on cancer prevention, community-based participatory research, navigation programs, cultural competency, evaluation, and other topics. Dr. Burhansstipanov worked with the Anschutz Medical Center Cancer Research Center — now the University of Colorado Cancer Research Center — in Denver for five years before founding Native American Cancer Initiatives, Inc., and the Native American Cancer Research Corporation.

Sandro Galea, M.D., a physician and epidemiologist, is the dean and a professor at the Boston University School of Public Health. Prior to his appointment at Boston University, Dr. Galea served as the Anna Cheskis Gelman and Murray Charles Gelman Professor and chair of the Department of Epidemiology at the Columbia University Mailman School of Public Health, New York City. His research focuses on the causes of brain disorders, particularly common mood and anxiety disorders, and substance abuse.

Linda Greene, J.D., is Evjue Bascom Professor of Law at the University of Wisconsin–Madison Law School. Her teaching and academic scholarship include constitutional law, civil procedure, legislation, civil rights, and sports law. Most recently, she was the vice chancellor for equity, diversity, and inclusion at the University of California, San Diego.

Ross A. Hammond, Ph.D., a senior fellow in the Economic Studies Program at the Brookings Institution, Washington, D.C., is also director of the Center on Social Dynamics and Policy. His primary area of expertise is using mathematical and computational methods from complex systems science to model complex dynamics in economic, social, and public health systems. His current research topics include obesity etiology and prevention, tobacco control, and behavioral epidemiology.

Hilton Hudson, II, M.D., is chief of cardiothoracic surgery at Franciscan Healthcare, Munster, Indiana and a national ambassador for the American Heart Association. He also is the founder of Hilton Publishing, Inc., a national publisher dedicated to producing content on solutions related to health, wellness, and education for people in underserved communities. Dr. Hilton’s book, “The Heart of the Matter: The African American Guide to Heart Disease, Heart Treatment and Heart Wellness” has impacted at-risk patients nationwide.

Brian M. Rivers, Ph.D., M.P.H., currently serves on the research faculty at the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. He is also an assistant professor in the Department of Oncologic Sciences at the University of South Florida College of Medicine, Tampa. Dr. Rivers’ research efforts include examination of unmet educational and psychosocial needs and the development of communication tools, couple-centered interventions, and evidence-based methods to convey complex information to at-risk populations across the cancer continuum.

NIMHD is one of NIH’s 27 Institutes and Centers. It leads scientific research to improve minority health and eliminate health disparities by conducting and supporting research; planning, reviewing, coordinating, and evaluating all minority health and health disparities research at NIH; promoting and supporting the training of a diverse research workforce; translating and disseminating research information; and fostering collaborations and partnerships. For more information about NIMHD, visit http://www.nimhd.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Faces of Breast Cancer: Find Your Story, Join the Conversation

“Without the experience of cancer, I might not have taken the time to be an ice climber, risked being a sculptor or upended my life to move closer to my granddaughter,” writes Amy, of Baltimore, one of hundreds of women and men around the world who tell their stories on the Faces of Breast Cancer project — The New York Times’s newly redesigned and enhanced interactive feature for those whose lives have been touched by the disease.

Listen to Audio

Readers can now search a database of breast cancer stories to find people like themselves — men and women with similar diagnoses, challenges or family situations — and learn from their experiences. Readers can alsosubmit their own stories sharing photos, memories, setbacks and victories from their breast cancer journey. And now everyone can join the conversation on subjects like body image, family, career — the whole host of things that change after a cancer diagnosis.

Faces of Breast Cancer aims to bring together the community of people behind the statistics, people who have learned, lost and loved after a life-changing diagnosis. We invite you to browse the stories, find someone like yourself, join the conversation and submit your own story.

SOURCE

http://well.blogs.nytimes.com/2014/10/28/faces-of-breast-cancer-find-your-story-join-the-conversation/?emc=eta1

 

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What do you know about Plants and Neutraceuticals?

Author and Curator: Larry H. Bernstein, MD, FCAP

 

This is a series of articles that is within a multipart series on related and standalone topics of discussion that raise some issues and controversies, but perhaps open our eyes to our relationship to the environment and its effects on living organisms, our uniqueness among eukeriotes, and or interdependence with the living plant and animal world.  In our self-centerness, there is a cross-cultural, perhaps innate tendancy to disregard this interdependence and to disrupt our surroundings in the same manner that families within diverse and mixed-societies become corrupted.  The amazing use of herbal medicines precedes the development of a formal scientific method, and has existed in Asia and Africa for centuries, and probably prior to biblical record.   Of course, there is substantial knowledge in the last century that has led to a better understanding of previously unknown medicinal benefits from the emergence of organic, inorganic and medicinal chemistry, aligned with discoveries in microbiology, and of fungi and algae, and the only recent development of synthetic biology and application of chemical engineering to biology.  These topics do not stand alone.

The series will be segmented as follows:

  1. An introduction to plants and the microbiome.
  2. What do you know about plants and neutraceuticals?
  3. Antimicrobial and drug resistance.
  4. Proteomics
  5. Metabolomics
  6. What do you know about plants and neutraceuticals?

 

Other articles published in this Open Access Online Scientific Journal include the following:

The Omega-3 Lie

http://pharmaceuticalintelligence.com/2014/06/02/the-omega-lie/

The Discovery and Properties of Avemar – Fermented Wheat Germ Extract: Carcinogenesis Suppressor
http://pharmaceuticalintelligence.com/2014/06/09/the-discovery-and-properties-of-avemar-fermented-wheat-germ-extract-carcinogenesis-suppressor-2/

Garden Cress Extract Kills 97% of Breast Cancer Cells in Vitro
http://pharmaceuticalintelligence.com/2014/06/21/garden-cress-extract-kills-97-of-breast-cancer-cells-in-vitro/

Moringa Oleifera Kills 97% of Pancreatic Cancer Cells in Vitro
http://pharmaceuticalintelligence.com/2014/06/21/moringa-oleifera-kills-97-of-pancreatic-cancer-cells-in-vitro/

The Gonzalez protocol: Worse than useless for pancreatic cancer  SJ Williams, PhD
http://pharmaceuticalintelligence.com/2014/06/17/the-gonzalez-protocol-worse-than-useless-for-pancreatic-cancer/

Plant flavonoid found to reduce inflammatory response in the brain: luteolin
http://pharmaceuticalintelligence.com/2014/06/29/plant-flavonoid-found-to-reduce-inflammatory-response-in-the-brain-luteolin/

Omega-3 fatty acids protect eyes against retinopathy, study finds  A Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2014/06/28/omega-3-fatty-acids-protect-eyes-against-retinopathy-study-finds/

2,000-year-old herb regulates autoimmunity and inflammation / Chang Shan, from a type of hydrangea that grows in Tibet and Nepal
http://pharmaceuticalintelligence.com/2014/06/27/2000-year-old-herb-regulates-autoimmunity-and-inflammation-chang-shan-from-a-type-of-hydrangea-that-grows-in-tibet-and-nepal/

Turmeric-based drug effective on Alzheimer flies
http://pharmaceuticalintelligence.com/2014/06/27/turmeric-based-drug-effective-on-alzheimer-flies/

Plant flavonoid luteolin blocks cell signaling pathways in colon cancer cells
http://pharmaceuticalintelligence.com/2014/06/26/plant-flavonoid-luteolin-blocks-cell-signaling-pathways-in-colon-cancer-cells/

Study Finds Shu Gan Liang Xue Herbal Formula Has Breast Cancer Anti Tumor Effect
http://pharmaceuticalintelligence.com/2014/06/25/study-finds-shu-gan-liang-xue-herbal-formula-has-breast-cancer-anti-tumor-effect/

HMPC Q&A Documents on Herbal Medicinal Products published
http://pharmaceuticalintelligence.com/2014/06/25/hmpc-qa-documents-on-herbal-medicinal-products-published/

Health benefit of anthocyanins from apples and berries noted for men
http://pharmaceuticalintelligence.com/2014/07/06/health-benefit-of-anthocyanins-from-apples-and-berries-noted-for-men/

Carrots Cut Men’s Prostate Cancer Risk by 50%
http://pharmaceuticalintelligence.com/2014/07/03/carrots-cut-mens-prostate-cancer-risk-by-50/

A Recipe To Make Cannabis Oil For A Chemotherapy Alternative
http://pharmaceuticalintelligence.com/2014/07/02/a-recipe-to-make-cannabis-oil-for-a-chemotherapy-alternative/

Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease
http://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-in-renal-disease/

Scientists develop new cancer-killing compound from salad plant / 1,200 times more specific in killing certain kinds of cancer cells than currently available drugs
http://pharmaceuticalintelligence.com/2014/07/17/scientists-develop-new-cancer-killing-compound-from-salad-plant-1200-times-more-specific-in-killing-certain-kinds-of-cancer-cells-than-currently-available-drugs/

Protein heals wounds, boosts immunity and protects from cancer – Lactoferrin
http://pharmaceuticalintelligence.com/2014/07/17/protein-heals-wounds-boosts-immunity-and-protects-from-cancer-lactoferrin/

Malnutrition in India, high newborn death rate and stunting of children age under five years
http://pharmaceuticalintelligence.com/2014/07/15/malnutrition-in-india-high-newborn-death-rate-and-stunting-of-children-age-under-five-years/

Inula helenium ( elecampane ) 100% Effective against MRSA in vitro, 200 Strains
http://pharmaceuticalintelligence.com/2014/07/15/inula-helenium-elecampane-100-effective-against-mrsa-in-vitro-200-strains/

Thymoquinone, an extract of nigella sativa seed oil, blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death.
http://pharmaceuticalintelligence.com/2014/07/15/thymoquinone-an-extract-of-nigella-sativa-seed-oil-blocked-pancreatic-cancer-cell-growth-and-killed-the-cells-by-enhancing-the-process-of-programmed-cell-death/

Cinnamon is lethal weapon against E. coli O157:H7
http://pharmaceuticalintelligence.com/2014/07/15/cinnamon-is-lethal-weapon-against-e-coli-o157h7/

Garlic compound fights source of food-borne illness better than antibiotics (100 times more effective than two popular antibiotics)
http://pharmaceuticalintelligence.com/2014/07/15/garlic-compound-fights-source-of-food-borne-illness-better-than-antibiotics-100-times-more-effective-than-two-popular-antibiotics/

Study suggests consuming whey protein before meals could help improve blood glucose control in people with diabetes
http://pharmaceuticalintelligence.com/2014/07/12/study-suggests-consuming-whey-protein-before-meals-could-help-improve-blood-glucose-control-in-people-with-diabetes/

 

There are several other contents to consider.

Synthetic derivatives of THC may weaken HIV-1 infection to enhance antiviral therapies

Federation of American Societies for Experimental Biology     April 30, 2013

Summary:

A new research report shows that compounds that stimulate the cannabinoid type 2 receptor in white blood cells, specifically macrophages, appear to weaken HIV-1 infection.

A new use for compounds related in composition to the active ingredient in marijuana may be on the horizon: a new research report published in the Journal of Leukocyte Biology shows that compounds that stimulate the cannabinoid type 2 (CB2) receptor in white blood cells, specifically macrophages, appear to weaken HIV-1 infection. The CB2 receptor is the molecular link through which the pharmaceutical properties of cannabis are manifested. Diminishing HIV-1 infection in this manner might make current anti-viral therapies more effective and provide some protection against certain HIV-1 complications.

“The synthetic compounds we used in our study may show promise in helping the body fight HIV-1 infection,'” said Yuri Persidsky, M.D., Ph.D., a researcher involved in the work from the Department of Pathology and Laboratory Medicine at Temple University School of Medicine in Philadelphia, PA. “As compounds like these are improved further and made widely available, we will continue to explore their potential to fight other viral diseases that are notoriously difficult to treat.”

To make this discovery, scientists used a cell culture model to infect human macrophages with HIV-1 and added synthetic compounds similar to the active ingredient in marijuana to activate the CB2 receptor. At different times during the infection, samples from the culture were taken to see if the replication of the HIV virus was decreased. The researchers observed diminished HIV growth and a possible protective effect from some HIV-1 complications.

“HIV/AIDS has posed one of the most significant health challenges in modern medicine,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. “Recent high profile vaccine failures mean that all options need to be on the table to prevent or treat this devastating infection. Research on the role of cannabinoid type 2 receptors and viral infection may one day allow targeting these receptors to be part of combination therapies that use exploit multiple weaknesses of the virus simultaneously.”

Story Source:

The above story is based on materials provided by Federation of American Societies for Experimental BiologyNote: Materials may be edited for content and length.

Journal Reference:

S. H. Ramirez, N. L. Reichenbach, S. Fan, S. Rom, S. F. Merkel, X. Wang, W.-z. Ho, Y. Persidsky. Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonistsJournal of Leukocyte Biology, 2013; 93 (5): 801     http://dx.doi.org:/10.1189/jlb.1012523

Federation of American Societies for Experimental Biology. “Synthetic derivatives of THC may weaken HIV-1 infection to enhance antiviral therapies.” ScienceDaily. ScienceDaily, 30 April 2013. <www.sciencedaily.com/releases/2013/04/130430131530.htm>.

 

Marijuana-like chemicals inhibit human immunodeficiency virus (HIV) in late-state AIDS

Mount Sinai Medical Center          March 20, 2012

Summary:

Marijuana-like chemicals trigger receptors on human immune cells that can directly inhibit a type of human immunodeficiency virus (HIV) found in late-stage AIDS, research suggests.

Mount Sinai School of Medicine researchers have discovered that marijuana-like chemicals trigger receptors on human immune cells that can directly inhibit a type of human immunodeficiency virus (HIV) found in late-stage AIDS, according to new findings published online in the journal PLoS ONE.

Medical marijuana is prescribed to treat pain, debilitating weight loss and appetite suppression, side effects that are common in advanced AIDS. This is the first study to reveal how the marijuana receptors found on immune cells — called cannabinoid receptors CB1 and CB2 — can influence the spread of the virus. Understanding the effect of these receptors on the virus could help scientists develop new drugs to slow the progression of AIDS.

“We knew that cannabinoid drugs like marijuana can have a therapeutic effect in AIDS patients, but did not understand how they influence the spread of the virus itself,” said study author Cristina Costantino, PhD, Postdoctoral Fellow in the Department of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine. “We wanted to explore cannabinoid receptors as a target for pharmaceutical interventions that treat the symptoms of late-stage AIDS and prevent further progression of the disease without the undesirable side effects of medical marijuana.”

HIV infects active immune cells that carry the viral receptor CD4, which makes these cells unable to fight off the infection. In order to spread, the virus requires that “resting” immune cells be activated. In advanced AIDS, HIV mutates so it can infect these resting cells, gaining entry into the cell by using a signaling receptor called CXCR4. By treating the cells with a cannabinoid agonist that triggers CB2, Dr. Costantino and the Mount Sinai team found that CB2 blocked the signaling process, and suppressed infection in resting immune cells.

Triggering CB1 causes the drug high associated with marijuana, making it undesirable for physicians to prescribe. The researchers wanted to explore therapies that would target CB2 only. The Mount Sinai team infected healthy immune cells with HIV, then treated them with a chemical that triggers CB2 called an agonist. They found that the drug reduced the infection of the remaining cells.

“Developing a drug that triggers only CB2 as an adjunctive treatment to standard antiviral medication may help alleviate the symptoms of late-stage AIDS and prevent the virus from spreading,” said Dr. Costantino. Because HIV does not use CXCR4 to enhance immune cell infection in the early stages of infection, CB2 agonists appear to be an effective antiviral drug only in late-stage disease.

As a result of this discovery, the research team led by Benjamin Chen, MD, PhD, Associate Professor of Infectious Diseases, and Lakshmi Devi, PhD, Professor of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine, plans to develop a mouse model of late-stage AIDS in order to test the efficacy of a drug that triggers CB2 in vivo. In 2009 Dr. Chen was part of a team that captured on video for the first time the transfer of HIV from infected T-cells to uninfected T-cells.

Funding for this study was provided to Drs. Chen and Devi by the National Institutes of Health in Bethesda, Maryland. Dr. Costantino is supported by a National Institutes of Health Clinical and Translational Science Award grant awarded to Mount Sinai School of Medicine.

Story Source:

The above story is based on materials provided by Mount Sinai Medical Center. Note: Materials may be edited for content and length.

Journal Reference:

Cristina Maria Costantino, Achla Gupta, Alice W. Yewdall, Benjamin M. Dale, Lakshmi A. Devi, Benjamin K. Chen Cristina Maria Costantino. Cannabinoid Receptor 2-Mediated Attenuation of CXCR4-Tropic HIV Infection in Primary CD4 T CellsPLoS ONE, 20 Mar 2012   http://dx.doi.org:/10.1371/journal.pone.0033961

Mount Sinai Medical Center. “Marijuana-like chemicals inhibit human immunodeficiency virus (HIV) in late-state AIDS.” ScienceDaily. ScienceDaily, 20 March 2012. <www.sciencedaily.com/releases/2012/03/120320195252.htm>.

 

Identification of Endocannabinoid System-Modulating N‑Alkylamides from Heliopsis helianthoides var. scabra and Lepidium meyenii

Z Hajdu, S Nicolussi, M Rau, L Lorantfy, P Forgo, J Hohmann, D Csupor, J Gertsch

†Department of Pharmacognosy, University of Szeged, H-6720 Szeged, Hungary

‡Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland

J. Nat. Prod. Apr 2, 2014    http://dx.doi.org:/10.1021/np500292g

 

Arachidonoyl-mimicking

Arachidonoyl-mimicking

 

 

http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jnprdf/2014/jnprdf.2014.77.issue-7/np500292g/production/pdfimages_v02/master.img-000.jpg

 

ABSTRACT: The discovery of the interaction of plant-derived N-alkylamides (NAAs) and the mammalian endocannabinoid system (ECS) and the existence of a plant endogenous Nacylethanolamine signaling system have led to the re-evaluation of this group of compounds. Herein, the isolation of seven NAAs and the assessment of their effects on major protein targets in the ECS network are reported. Four NAAs, octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid isobutylamide (1), octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid 2′-methylbutylamide (2), hexadeca-2E,4E,9Z-triene-12,14-diynoic acid isobutylamide (3), and hexadeca-2E,4E,9,12-tetraenoic acid 2′-methylbutylamide (4), were identified from Heliopsis helianthoides var. scabra. Compounds 2−4 are new natural products, while 1 was isolated for the first time from this species. The previously described macamides, N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (5), N-benzyl-(9Z,12Z,15Z)-octadecatrienamide (6), and N-benzyl-(9Z,12Z)-octadecadienamide (7), were isolated from Lepidium meyenii (Maca). NMethylbutylamide 4 and N-benzylamide 7 showed submicromolar and selective binding affinities for the cannabinoid CB1 receptor (Ki values of 0.31 and 0.48 μM, respectively). Notably, compound 7 also exhibited weak fatty acid amide hydrolase (FAAH) inhibition (IC50 = 4 μM) and a potent inhibition of anandamide cellular uptake (IC50 = 0.67 μM) that was stronger than the inhibition obtained with the controls OMDM-2 and UCM707. The pronounced ECS polypharmacology of compound 7 highlights the potential involvement of the arachidonoyl-mimicking 9Z,12Z double-bond system in the linoleoyl group for the overall cannabimimetic action of NAAs. This study provides additional strong evidence of the endocannabinoid substrate mimicking of plant-derived NAAs and uncovers a direct and indirect cannabimimetic action of the Peruvian Maca root.

 

Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network
JC Nwachukwu, S Srinivasan, NE Bruno, AA Parent, TS Hughes, et al.
eLife Apr 2014;10.7554/eLife.02057  http://dx.doi.org/10.7554/eLife.02057

Resveratrol has beneficial effects on aging, inflammation and metabolism, which are thought to result from activation of the lysine deacetylase, sirtuin 1 (SIRT1), the cAMP pathway, or AMP-activated protein kinase. Here we report that resveratrol acts as a pathway-selective estrogen receptor-α (ERα) ligand to modulate the inflammatory response but not cell proliferation. A crystal structure of the ERα ligand-binding domain (LBD) as a complex with resveratrol revealed a unique perturbation of the coactivator-binding surface, consistent with an altered coregulator recruitment profile. Gene expression analyses revealed significant overlap of TNFα genes modulated by resveratrol and estradiol. Furthermore, the ability of resveratrol to suppress interleukin-6 transcription was shown to require ERα and several ERα coregulators, suggesting that ERα functions as a primary conduit for resveratrol activity.

 

Diets rich in antioxidant resveratrol fail to reduce deaths, heart disease or cancer

Johns Hopkins Medicine    May 12, 2014

Summary:   A study of Italians who consume a diet rich in resveratrol — the compound found in red wine, dark chocolate and berries — finds they live no longer than and are just as likely to develop cardiovascular disease or cancer as those who eat or drink smaller amounts of the antioxidant.

A study of Italians who consume a diet rich in resveratrol — the compound found in red wine, dark chocolate and berries — finds they live no longer than and are just as likely to develop cardiovascular disease or cancer as those who eat or drink smaller amounts of the antioxidant.

“The story of resveratrol turns out to be another case where you get a lot of hype about health benefits that doesn’t stand the test of time,” says Richard D. Semba, M.D., M.P.H., a professor of ophthalmology at the Johns Hopkins University School of Medicine and leader of the study described May 12 in JAMA Internal Medicine. “The thinking was that certain foods are good for you because they contain resveratrol. We didn’t find that at all.”

Despite the negative results, Semba says, studies have shown that consumption of red wine, dark chocolate and berries does reduce inflammation in some people and still appears to protect the heart. “It’s just that the benefits, if they are there, must come from other polyphenols or substances found in those foodstuffs,” he says. “These are complex foods, and all we really know from our study is that the benefits are probably not due to resveratrol.”

The new study did not include people taking resveratrol supplements, though few studies thus far have found benefits associated with them.

Semba is part of an international team of researchers that for 15 years has studied the effects of aging in a group of people who live in the Chianti region of Italy. For the current study, the researchers analyzed 24 hours of urine samples from 783 people over the age of 65 for metabolites of resveratrol. After accounting for such factors as age and gender, the people with the highest concentration of resveratrol metabolites were no less likely to have died of any cause than those with no resveratrol found in their urine. The concentration of resveratrol was not associated with inflammatory markers, cardiovascular disease or cancer rates.

Semba and his colleagues used advanced mass spectrometry to analyze the urine samples.

The study participants make up a random group of people living in Tuscany where supplement use is uncommon and consumption of red wine — a specialty of the region — is the norm. The study participants were not on any prescribed diet.

Resveratrol is also found in relatively large amounts in grapes, peanuts and certain Asiatic plant roots. Excitement over its health benefits followed studies documenting anti-inflammatory effects in lower organisms and increased lifespan in mice fed a high-calorie diet rich in the compound.

The so-called “French paradox,” in which a low incidence of coronary heart disease occurs in the presence of a high dietary intake of cholesterol and saturated fat in France, has been attributed to the regular consumption of resveratrol and other polyphenols found in red wine.

Story Source:

The above story is based on materials provided by Johns Hopkins MedicineNote: Materials may be edited for content and length.

Johns Hopkins Medicine. “Diets rich in antioxidant resveratrol fail to reduce deaths, heart disease or cancer.” ScienceDaily. ScienceDaily, 12 May 2014. <www.sciencedaily.com/releases/2014/05/140512214128.htm>.

Journal Reference:

Richard D. Semba, Luigi Ferrucci, Benedetta Bartali, Mireia Urpí-Sarda, Raul Zamora-Ros, Kai Sun, Antonio Cherubini, Stefania Bandinelli, Cristina Andres-Lacueva. Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling AdultsJAMA Internal Medicine, 2014;
http://dx.doi.org:/10.1001/jamainternmed.2014.1582

 

Curcumin  regulates gene expression of insulin like growth factor, B-cell CLL/lymphoma 2 and antioxidant enzymes in streptozotocin induced diabetic rats
Sabryl M El-Bahr
BMC Complementary and Alternative Medicine 2013, 13:368
http://7thspace.com/headlines/449258/curcumin_regulates_gene_expression_of_insulin_like_growth_factor_b_cell_clllymphoma_2_and_antioxidant_enzymes_in_streptozotocin_induced_diabetic_rats.html
The effects of curcumin on the activities and gene expression of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-S-transferase (G-ST), B-cell CLL/lymphoma 2 (Bcl-2) and insulin like growth factor-1 (IGF-1) in diabetic rats were studied.

The effects of curcumin on the activities and gene expression of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-S-transferase (G-ST), B-cell CLL/lymphoma 2 (Bcl-2) and insulin like growth factor-1 (IGF-1) in diabetic rats were studied.
Methods: Twenty four rats were assigned to three groups (8 rats for each). Rats of first group were non diabetic and rats of the second group were rendered diabetic by streptozotocin (STZ).
Both groups received vehicle, corn oil only (5 ml/kg body weight) and served as negative and positive controls, respectively. Rats of the third group were rendered diabetic and received oral curcumin dissolved in corn oil at a dose of 15 mg/5 ml/kg body weight for 6 weeks.
Results: Diabetic rats showed significant increase of blood glucose, thiobarbituric acid reactive substances (TBARS) and activities of all antioxidant enzymes with significant reduction of reduced glutathione (GSH) compare to the control non diabetic group.
Gene expression of Bcl2, SOD, CAT, GPX and GST was increased significantly in diabetic untreated rats compare to the control non diabetic group. The administration of curcumin to diabetic rats normalized significantly their blood sugar level and TBARS values and increased the activities of all antioxidant enzymes and reduced glutathione concentration.
In addition, curcumin treated rats showed significant increase in gene expression of IGF-1, Bcl2, SOD and GST compare to non diabetic and diabetic untreated rats.
Conclusion: Curcumin was antidiabetic therapy, induced hypoglycemia by up-regulation of IGF-1 gene and ameliorate the diabetes induced oxidative stress via increasing the availability of GSH, increasing the activities and gene expression of antioxidant enzymes and Bcl2. Further studies are required to investigate the actual mechanism of action of curcumin regarding the up regulation of gene expression of examined parameters.

Antioxidant biomaterial promotes healing

Purple corn anthocyanins inhibit diabetes-associated glomerular monocyte activation and macrophage infiltration 

Kang MK, Li J, Kim JL, Gong JH, Kwak SN, Park JH, Lee JY, Lim SS, Kang YH.
1Department of Food and Nutrition, Hallym University, Chuncheon, Korea; and 2Department of Biochemistry, School of Medicine, Hallym University, Chuncheon, Korea

Am J Physiol Renal Physiol 303: F1060–F1069, 2012. http://dx.doi.org:/10.1152/ajprenal.00106.2012
Diabetic nephropathy (DN) is one of the major diabetic complications and the leading cause of end-stage renal disease. In early DN, renal injury and macrophage accumulation take place in the pathological environment of glomerular vessels adjacent to renal mesangial cells expressing proinflammatory mediators. Purple corn utilized as a daily food is rich in anthocyanins exerting disease-preventive activities as a functional food. This study elucidated whether anthocyanin-rich purple corn extract (PCA) could suppress monocyte activation and macrophage infiltration. In the in vitro study, human endothelial cells and THP-1 monocytes were cultured in conditioned media of human mesangial cells exposed to 33 mM glucose (HG-HRMC). PCA decreased the HG-HRMC-conditioned, media-induced expression of endothelial vascular cell adhesion molecule-1, E-selectin, and monocyte integrins-_1 and -_2 through blocking the mesangial Tyk2 pathway. In the in vivo animal study, db/db mice were treated with 10 mg/kg PCA daily for 8 wk. PCA attenuated CXCR2 induction and the activation of Tyk2 and STAT1/3 in db/db mice. Periodic acid-Schiff staining showed that PCA alleviated mesangial expansion-elicited renal injury in diabetic kidneys. In glomeruli, PCA attenuated the induction of intracellular cell adhesion molecule-1 and CD11b. PCA diminished monocyte chemoattractant protein-1 expression and macrophage inflammatory protein 2 transcription in the diabetic kidney, inhibiting the induction of the macrophage markers CD68 and F4/80. These results demonstrate that PCA antagonized the infiltration and accumulation of macrophages in diabetic kidneys through disturbing the mesangial IL-8-Tyk-STAT signaling pathway. Therefore, PCA may be a potential renoprotective agent treating diabetes-associated glomerulosclerosis.

 

Proximate analysis, phytochemical screening, and total phenolic and flavonoid content of Philippine bamboo Schizostachyum lumampao

Jovale Vincent V. Tongco1*, Remil M. Aguda2 and Ramon A. Razal1

1 Department of Forest Products and Paper Science, College of Forestry and Natural Resources,; 2 Institute of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños, College, Laguna, Philippines

Journal of Chemical and Pharmaceutical Research, 2014, 6(1):709-713

____________________________________________________________________________________________

ABSTRACT

The chemical composition of the leaves of Schizostachyum lumampao, known as “buho” in the Philippines, was determined for its potential use as herbal tea with potential health benefits, such as antioxidant properties. Proximate analysis using standard AOAC methods showed that the air-dried leaves contain 10 % moisture, 30.5 % ash, 22.1 % crude protein, 1.6 % crude fat, 28.7 % crude fiber, and 7.2 % total sugar (by difference). Using a variety of reagents for qualitative phytochemical screening, saponins, diterpenes, triterpenes, phenols, tannins, and flavonoids were detected in both the ethanolic and aqueous leaf extracts, while phytosterols were only detected in the ethanolic extract. Using UV-Vis spectrophotometry, the total phenolic content (in GAE) were 76.7 and 13.5 gallic acid equivalents per 100 g air-dried sample for the ethanolic and aqueous extracts, respectively. The total flavonoid content were 70.2 and 17.86 mg quercetin equivalents per 100 g air-dried sample for the ethanolic and aqueous extracts, respectively. This preliminary study showed the total amount of phenolics and flavonoids present in buho, the phytochemicals present, and its proximate analysis.

 

Comparison of Nutritional Quality of the Vegan, Vegetarian, Semi-Vegetarian, Pesco-Vegetarian and Omnivorous Diet

Peter Clarys 1,2,Tom Deliens 1Inge Huybrechts 3,4Peter Deriemaeker 1,2Barbara Vanaelst 4Willem De Keyzer 4,5Marcel Hebbelinck 1 and Patrick Mullie 1,2,6

(This article belongs to the Special Issue Vegan diets and Human health)

Nutrients 20146(3), 1318-1332;    http://dx.doi.org:/10.3390/nu6031318

Abstract: The number of studies comparing nutritional quality of restrictive diets is limited. Data on vegan subjects are especially lacking. It was the aim of the present study to compare the quality and the contributing components of vegan, vegetarian, semi-vegetarian, pesco-vegetarian and omnivorous diets. Dietary intake was estimated using a cross-sectional online survey with a 52-items food frequency questionnaire (FFQ). Healthy Eating Index 2010 (HEI-2010) and the Mediterranean Diet Score (MDS) were calculated as indicators for diet quality. After analysis of the diet questionnaire and the FFQ, 1475 participants were classified as vegans (n = 104), vegetarians (n = 573), semi-vegetarians (n = 498), pesco-vegetarians (n = 145), and omnivores (n = 155). The most restricted diet, i.e., the vegan diet, had the lowest total energy intake, better fat intake profile, lowest protein and highest dietary fiber intake in contrast to the omnivorous diet. Calcium intake was lowest for the vegans and below national dietary recommendations. The vegan diet received the highest index values and the omnivorous the lowest for HEI-2010 and MDS. Typical aspects of a vegan diet (high fruit and vegetable intake, low sodium intake, and low intake of saturated fat) contributed substantially to the total score, independent of the indexing system used. The score for the more prudent diets (vegetarians, semi-vegetarians and pesco-vegetarians) differed as a function of the used indexing system but they were mostly better in terms of nutrient quality than the omnivores.

Comment (Larry H. Bernstein, MD): This article is problematic and makes me curious about the HEI-2010 and the MDS scoring systems.  Low intake of saturated fat gives weight to the vegan diet. The vegetarian diet would have higher content of high quality protein, and the omnivorous diet would be just as good if the fat were trimmed, and there was sufficient fruits and vegetables.  The problem is that quality of protein is not even weighted.  The ration of S/N is 1:20+ in plant sourced AAs, but it is 1:12.5 in animal sourced AAs.  This has consequences.

Influences of dietary methionine and cysteine on metabolic responses to immunological stress by Escherichia coli lipopolysaccharide injection, and mitogenic response in broiler chickens

BY K. TAKAHASHI, N. OHTA AND Y. AKIBA

Department of Animal Science, Faculty of Agriculture, Tohoku University, Sendai-shi, 981 Japan
British Journal of Nutrition (1997), 78, 815-821

The present experiments were conducted to investigate influences of dietary methionine and cysteine on metabolic responses to immunological stress induced by Escherichia coli lipopolysaccharide (LPS) injection, and concanavalin A (Con A)-induced mononuclear cell (MNC) proliferation in male broiler chickens. In Expt 1, chicks (12 d of age) were fed on a S amino acid (SAA)-deficient diet (5.6 g SAMg diet) or on three kinds of SAA-sufficient diet (9.3 g SAAkg diet; low-, medium- and high-cysteine diets) which contained 2.8, 4.65 and 6.5 g cysteinekg diet, respectively. Plasma (11-1 acid glycoprotein (AGP) concentration and interleukin (IL)-l-like activity in chicks fed on the SAA deficient diet were lower following a single injection of LPS than those in chicks fed on the SAAsufficient diets. At 16 h after LPS injection, plasma Fe and Zn concentrations and body weight were reduced, but AGP concentration and IL-1-like activity in plasma were significantly increased. These changes in body weight, plasma Zn and Fe concentrations following injection of LPS were not affected by dietary methi0nine:cysteine ratios. Plasma AGP concentration and IL-1-like activity in chicks fed on the high-cysteine diet were, however, greater than those in chicks fed on the other diets following a single injection of LPS. In Expt 2, chicks (7 d of age) were fed on the SAA-sufficient diets as in Expt 1 for 10 d. MNC proliferation in spleen induced by Con A in chicks fed on the high cysteine diet was greater than that in chicks fed on the low- or medium-cysteine diet. The results suggest that dietary cysteine has an impact on the immune and inflammatory responses.

The present experiment showed that plasma IL-1 like activity following LPS injection and T cell activity of the spleen estimated by Con A-induced MNC proliferation were greater in chicks fed on the high-cysteine diet than in chicks fed on the low- or medium cysteine diet, even though the diets contained 9.3 g SAA kg diet which is recommended by the National Research Council (1984) feeding standard. Tsiagbe et al. (19874 showed that cysteine was 70-84 % as efficient as methionine in enhancing IgG production and in delaying hypersensitivity to PHA-P stimulation. Thus dietary cysteine is not only important for T-cell function and antibody production, but also for macrophage response to LPS in broilers. However, our previous study (Takahashi et al. 1995) showed that a low-protein diet enhanced plasma IL-1-like activity compared with a high-protein diet in chicks, even though the supply of SAA from the diet in chicks fed on a low-protein diet was much less than that in chicks fed on a high-protein diet. These observations suggest that supply of SAA may not be the only factor affecting the immune responses. The combined results of the previous (Takahashi et al. 1995) and the present experiments, suggest that, as well as the supply of SAA, the methionine:cysteine ratio in the diet is an important factor affecting some immune responses, e.g. IL- 1-like activity, AGP concentration in plasma and mitogenic response of MNC in spleen. The present results also suggest that dietary cysteine intake has an impact on the immune and inflammatory responses, although replacement of cysteine with methionine in diets would not impair growth and reproduction within certain ratios in the diet (Graber & Baker, 1971; Ohta & Ishibashi, 1994 and the present study).

Methionine: Cysteine: Acute-phase response: Lipopolysaccharide

 

Antioxidant scaffolds for tissue engineering

When a foreign material like a medical device or surgical implant is put inside the human body, the body always responds. According to Northwestern’s Guillermo Ameer, most of the time, that response can be negative and affect the device’s function.

“You will always get an inflammatory response to some degree,” said Ameer, professor of biomedical engineering in McCormick School of Engineering and Applied Science and professor of surgery in the Feinberg School of Medicine. “A problem with commonly used plastic materials, in particular, is that in addition to that inflammatory response, oxidation occurs.”

We all need oxygen to survive, but a high concentration of oxygen in the body can cause oxidative reactions to fall out of balance, which modifies natural proteins, cells, and lipids and causes them to function abnormally. This oxidative stress is toxic and can contribute to chronic disease, chronic inflammation, and other complications that may cause the failure of implants.

For the first time ever, Ameer and his team have created a biodegradable biomaterial that is inherently antioxidant. The material can be used to create elastomers, liquids that turn into gels, or solids for building devices that are more compatible with cells and tissues. The research is described in the June 26 issue of Biomaterials.

“Plastics can self-oxidize, creating radicals as part of their degradation process,” Ameer said. “By implanting devices made from plastics, the oxidation process can injure nearby cells and create a cascade that leads to chronic inflammation. Our materials could significantly reduce the inflammatory response that we typically see.”

Ameer created the biomaterial, which is a polyester based on citric acid, by incorporating vitamin C as part of the building blocks. In preliminary experiments, his team coated vascular grafts with the antioxidant biomaterial, and the grafts were evaluated in animals by Ameer’s long-time collaborator Melina Kibbe, professor of surgery and the Edward G. Elcock Professor of Surgical Research at Feinberg and a vascular surgeon at Northwestern Memorial Hospital.

As part of the foreign body response, grafts tend to inflame nearby cells and slowly scar over time, which eventually leads to failure. When the antioxidant vascular graft was implanted, however, the scarring was significantly reduced. Ameer’s team, funded by a proof-of-concept grant from the Northwestern University Clinical and Translational Sciences Institute, also found that a water-soluble, thermo-reversible version of the material sped of the healing of diabetic ulcers. Because the material is biodegradable, it harmlessly is absorbed by the body over time.

“In the past, people have added antioxidant vitamins to a polymer and blended it in,” Ameer said. “That can affect the mechanical properties of the material and limit how much antioxidant you can add, so it doesn’t work well. What we’re doing is different. We’re building a material that is already inherently, intrinsically antioxidant.”

Ameer said the new biomaterial could be used to create scaffolds for tissue engineering, coat or build safer medical devices, promote healing in regenerative medicine, and protect cells, genes, and viruses during drug delivery. He added that the new biomaterial is easy to make and inexpensive.

“Citric acid is affordable and in pretty much everything we come in contact with on a daily basis—food and beverages, skin and hair products, drugs, etc.,” Ameer said. “It’s a common, inexpensive raw material to use, and our system can stabilize vitamin C, an antioxidant that we are all familiar with.”

The first author of the study was Robert van Lith, a PhD candidate in Ameer’s research laboratory.

Source: Northwestern Univ.

 

Pomegranate for Your Cardiovascular Health

Michael Aviram, D.Sc,* and Mira Rosenblat, M.Sc.

The Lipid Research Laboratory, The Rappaport Faculty of Medicine and Research Institute, Technion-Institute of Technology, and Rambam Medical Center, Haifa, Israel
Rambam Medical Center J 2013;4 (2):e0013.

ABSTRACT

Pomegranate is a source of some very potent antioxidants (tannins, anthocyanins) which are considered to be also potent anti-atherogenic agents. The combination of the above unique various types of pomegranate polyphenols provides a much wider spectrum of action against several types of free radicals. Indeed, pomegranate is superior in comparison to other antioxidants in protecting low-density lipoprotein (LDL, “the bad cholesterol”) and high-density lipoprotein (HDL, “the good cholesterol”) from oxidation, and as a result it attenuates atherosclerosis development and its consequent cardiovascular events. Pomegranate antioxidants are not free, but are attached to the pomegranate sugars, and hence were shown to be beneficial even in diabetic patients. Furthermore, pomegranate antioxidants are unique in their ability to increase the activity of the HDL-associated paraoxonase 1 (PON1), which breaks down harmful oxidized lipids in lipoproteins, in macrophages, and in atherosclerotic plaques. Finally, unique pomegranate antioxidants beneficially decrease blood pressure. All the above beneficial characteristics make the pomegranate a uniquely healthy fruit.

Abbreviations: AAPH, 2,2′-azobis amidinopropane hydrochloride; ACE, angiotensin-converting enzyme; BP, blood pressure; CAS, carotid artery stenosis; CHD, coronary heart disease; CIMT, carotid intima-media thickness; EDV, end-diastolic velocity; GAE, gallic acid equivalents; HDL, high-density lipoprotein; HMDM, human monocyte-derived macrophages; LDL, low-density lipoprotein; LPDS, lipoprotein-deficient serum; MI, myocardial infarction; Ox-LDL, oxidized LDL; PJ, pomegranate juice; POMxl, an extract of the pomegranate outer peel; PON, paraoxonase; PSV, peak systolic velocity; ROS, reactive oxygen species; TAS, total antioxidant status; TBARS, thiobarbituric acid reactive substances; TGs, triglycerides; VLDL, very-low-density lipoprotein.
Citation: Aviram M, Rosenblat M. Pomegranate for Your Cardiovascular Health. RMMJ 2013;4 (2):e0013.
http://dx.doi.org:/10.5041/RMMJ.10113

 

Cocoa Phenolic Extract Protects Pancreatic Beta Cells against Oxidative Stress

 


MÁ Martín, S Ramos, I Cordero-Herrero, L Bravo and L Goya
1 Department of Metabolism and Nutrition, Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN–CSIC), Madrid 28040, Spain
2 Centro de Investigación Biomédica en red de Diabetes y Enfermedades Metabólicas Asociadas (ISCIII), Madrid 28039, Spain

Nutrients 2013, 5, 2955-2968;  http://dx.doi.org:/10.3390/nu5082955

Abstract: Diabetes mellitus is associated with reductions in glutathione, supporting the critical role of oxidative stress in its pathogenesis. Antioxidant food components such as flavonoids have a protective role against oxidative stress-induced degenerative and age-related diseases. Flavonoids constitute an important part of the human diet; they can be found in most plant foods, including green tea, grapes or cocoa and possess multiple biological activities. This study investigates the chemo-protective effect of a cocoa phenolic extract (CPE) containing mainly flavonoids against oxidative stress induced by tert-butylhydroperoxide (t-BOOH) on Ins-1E pancreatic beta cells. Cell viability and oxidative status were evaluated. Ins-1E cells treatment with 5–20 μg/mL CPE for 20 h evoked no cell damage and did not alter ROS production. Addition of 50 μM t-BOOH for 2 h increased ROS and carbonyl groups content and decreased reduced glutathione level. Pre-treatment of cells with CPE significantly prevented the t-BOOH-induced ROS and carbonyl groups and returned antioxidant defences to adequate levels. Thus, Ins-1E cells treated with CPE showed a remarkable recovery of cell viability damaged by t-BOOH, indicating that integrity of surviving machineries in the CPE-treated cells was notably protected against the oxidative insult.
Keywords: antioxidant defences; cocoa flavanols; dietary polyphenols; Ins-1E cells; oxidative biomarkers; type 2 diabetes mellitus

 

Flavones as isosteres of 4(1H)-quinolones: discovery of ligand efficient and dual stage antimalarial lead compounds

T Rodrigues, AS Ressurreição, FP da Cruz, IS Albuquerque, J Gut, MP Carrasco, D Gonçalves, RC Guedes, et al.

1Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Facultyof Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal
2Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
3Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, California, 94143, U.S.A.
4 REQUIMTE, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Porto, R. do Campo Alegre, 4169-007 Porto, Portugal
Reference: EJMECH 6410  European Journal of Medicinal Chemistry

PII: S0223-5234(13)00580-1   http://dx.doi.org:/10.1016/j.ejmech.2013.09.008

ABSTRACT: Malaria is responsible for nearly one million deaths annually, and the increasing prevalence of multi-resistant strains of Plasmodium falciparum poses a great challenge to controlling the disease. A diverse set of flavones, isosteric to 4(1H)-quinolones, were prepared and profiled for their antiplasmodial activity against the blood stage of P. falciparum W2 strain, and the liver stage of the rodent parasite l.berghei. Ligand efficient leads were identified as dual stage antimalarials, suggesting that scaffold optimization may afford potent antiplasmodial compounds.

 cite as: T. Rodrigues, A.S. Ressurreição, F.P. da Cruz, I.S. Albuquerque, J. Gut, M.P.

Carrasco, D. Gonçalves, R.C. Guedes, D.J.V.A. dos Santos, M.M. Mota, P.J. Rosenthal, R. Moreira, M. Prudêncio, F. Lopes, Flavones as isosteres of 4(1H)-quinolones: discovery of ligand efficient and dual stage antimalarial lead compounds, European Journal of Medicinal Chemistry (2013),

http://dx.doi.org:/10.1016/j.ejmech.2013.09.008  

 

Silencing of the sulfur rich α-gliadin storage protein family in wheat grains (Triticumae stivum L.) causes nounintended side-effects on other metabolites
C Zörb, D Becker, M Hasler, KH Mühling, V Gödde, K Niehaus and CM Geilfus
1 Institute of Biology, University Leipzig, Leipzig, Germany
2 Biocentre Klein Flottbek, EBBT, University of Hamburg, Hamburg, Germany
3 Lehrfach Variations statistik, 4 Institute of Plant Nutrition and Soil Science, Christian Albrechts University Kiel, Kiel, Germany
5 Department of Proteome and Metabolome Research, Faculty of Biology, Bielefeld University, Bielefeld, Germany
Frontiers in Plant Science 17 Sept, 2013;  http://dx.doi.org:/10.3389/fpls.2013.00369

Wheat is an important source of proteins and metabolites for human and animal nutrition. To assess the nutritional quality of wheat products, various protein and diverse metabolites have to be evaluated. The grain storage protein family of the α-gliadins are suggested to be the primary initiator of the inflammatory response to gluten in Celiac disease patients .With the technique of RNAi, the α-gliadin storage protein fraction in wheat grains was recently knocked down. From a patient’s perspective, this is a desired approach, however, this study aims to evaluate whether such a down-regulation of these problematic α-gliadins also has unintended side-effects on other plant metabolites. Such uncontrolled and unknown arbitrary effects on any metabolite in plants designated for food production would surely represent an avoidable risk for the consumer. In general,
α-gliadins are rich in sulfur, making their synthesis and content dependent on the sulfur supply. For this reason, the influence of the application of increasing sulfur amounts on the metabolome of α-gliadin-deficient wheat was additionally investigated because it might be possible that e.g., considerable high/low amounts of S might increase or even induce such unintended effects that are not observable under moderate S nutrition. By silencing the α-gliadin genes, a recently developed wheat-line that lacks the set of 75 corresponding α-gliadin proteins has become available. The plants were subsequently tested for RNAi– induced effects on metabolites that were not directly attributable to the specific effects of the RNAi– approach on the α-gliadin proteins. For this,GC-MS-based metabolite profiles were recorded. A comparison of wild type with gliadin-deficient plants cultivated in pot experiments revealed no differences in all 109 analyzed metabolites, regardless of the S-nutritional status.No unintended effects attributable to the RNAi– based specific genetic deletion of a storage protein fraction were observed.
Keywords: sulfur, wheat, gliadin, metabolites, Celiac disease, GC-MS

 

Olive oil intake and risk of cardiovascular disease and mortality in the PREDIMED Study

Guasch-Ferré et al. BMC Medicine 2014, 12(78):1741-7015 http://www.biomedcentral.com/1741-7015/12/78

Abstract

Background: It is unknown whether individuals at high cardiovascular risk sustain a benefit in cardiovascular disease from increased olive oil consumption. The aim was to assess the association between total olive oil intake, its varieties (extra virgin and common olive oil) and the risk of cardiovascular disease and mortality in a Mediterranean population at high cardiovascular risk.

Methods: We included 7,216 men and women at high cardiovascular risk, aged 55 to 80 years, from the PREvención con DIeta MEDiterránea (PREDIMED) study, a multicenter, randomized, controlled, clinical trial. Participants were randomized to one of three interventions: Mediterranean Diets supplemented with nuts or extra-virgin olive oil, or a control low-fat diet. The present analysis was conducted as an observational prospective cohort study. The median follow-up was 4.8 years. Cardiovascular disease (stroke, myocardial infarction and cardiovascular death) and mortality were ascertained by medical records and National Death Index. Olive oil consumption was evaluated with validated food frequency questionnaires. Multivariate Cox proportional hazards and generalized estimating equations were used to assess the association between baseline and yearly repeated measurements of olive oil intake, cardiovascular disease and mortality.

Results: During follow-up, 277 cardiovascular events and 323 deaths occurred. Participants in the highest energy-adjusted tertile of baseline total olive oil and extra-virgin olive oil consumption had 35% (HR: 0.65; 95% CI: 0.47 to 0.89) and 39% (HR: 0.61; 95% CI: 0.44 to 0.85) cardiovascular disease risk reduction, respectively, compared to the reference. Higher baseline total olive oil consumption was associated with 48% (HR: 0.52; 95% CI: 0.29 to 0.93) reduced risk of cardiovascular mortality. For each 10 g/d increase in extra-virgin olive oil consumption, cardiovascular disease and mortality risk decreased by 10% and 7%, respectively. No significant associations were found for cancer and all-cause mortality. The associations between cardiovascular events and extra virgin olive oil intake were significant in the Mediterranean diet intervention groups and not in the control group.

Conclusions: Olive oil consumption, specifically the extra-virgin variety, is associated with reduced risks of cardiovascular disease and mortality in individuals at high cardiovascular risk.

Trial registration: This study was registered at controlled-trials.com (http://www.controlled-trials.com/ISRCTN35739639). International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.

Keywords: Olive oil, Cardiovascular, Mortality, Mediterranean Diet, PREDIMED

 

Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial

Tresserra-Rimbau et al. BMC Medicine 2014, 12(77): 1741-7015;  http://www.biomedcentral.com/1741-7015/12/77

Abstract

Background: Polyphenols may lower the risk of cardiovascular disease (CVD) and other chronic diseases due to their antioxidant and anti-inflammatory properties, as well as their beneficial effects on blood pressure, lipids and insulin resistance. However, no previous epidemiological studies have evaluated the relationship between the intake of total polyphenols intake and polyphenol subclasses with overall mortality. Our aim was to evaluate whether polyphenol intake is associated with all-cause mortality in subjects at high cardiovascular risk.

Methods: We used data from the PREDIMED study, a 7,447-participant, parallel-group, randomized, multicenter, controlled five-year feeding trial aimed at assessing the effects of the Mediterranean Diet in primary prevention of cardiovascular disease. Polyphenol intake was calculated by matching food consumption data from repeated food frequency questionnaires (FFQ) with the Phenol-Explorer database on the polyphenol content of each reported food. Hazard ratios (HR) and 95% confidence intervals (CI) between polyphenol intake and mortality were estimated using time-dependent Cox proportional hazard models.

Results: Over an average of 4.8 years of follow-up, we observed 327 deaths. After multivariate adjustment, we found a 37% relative reduction in all-cause mortality comparing the highest versus the lowest quintiles of total polyphenol intake (hazard ratio (HR) = 0.63; 95% CI 0.41 to 0.97; P for trend = 0.12). Among the polyphenol subclasses, stilbenes and lignans were significantly associated with reduced all-cause mortality (HR =0.48; 95% CI 0.25 to 0.91; P for trend = 0.04 and HR = 0.60; 95% CI 0.37 to 0.97; P for trend = 0.03, respectively), with no significant associations apparent in the rest (flavonoids or phenolic acids).

Conclusions: Among high-risk subjects, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes. These results may be useful to determine optimal polyphenol intake or specific food sources of polyphenols that may reduce the risk of all-cause mortality.

Clinical trial registration: ISRCTN35739639.

Keywords: Polyphenol intake, All-cause mortality, PREDIMED, Mediterranean diet, Stilbenes, Lignans

 

Effects of Walnuts on Endothelial Function in Overweight Adults with Visceral Obesity: A Randomized, Controlled, Crossover Trial

David L Katz MD, MPHa, Anna Davidhi BSa, Yingying Ma MD, RVTa, Yasemin Kavak BSa,et al.
a Yale University Prevention Research Center, Griffin Hospital, Derby, Connecticut
Journal of the American College of Nutrition,  2013; 31(6) :415-423

Objectives: Metabolic syndrome is a precursor of diabetes and cardiovascular disease (CVD). Walnut ingestion has been shown to reduce CVD risk indices in diabetes. This randomized controlled crossover trial was performed to investigate the effects of daily walnut consumption on endothelial function and other biomarkers of cardiac risk in a population of overweight individuals with visceral adiposity.

Methods: Forty-six overweight adults (average age, 57.4 years; 28 women, 18 men) with elevated waist circumference and 1 or more additional signs of metabolic syndrome were randomly assigned to two 8-week sequences of walnut-enriched ad libitum diet and ad libitum diet without walnuts, which were separated by a 4-week washout period. The primary outcome measure was the change in flow-mediated vasodilation (FMD) of the brachial artery. Secondary measures included serum lipid panel, fasting glucose and insulin, Homeostasis Model Assessment–Insulin Resistance values, blood pressure, and anthropometric measures.

Results: FMD improved significantly from baseline when subjects consumed a walnut-enriched diet as compared with the control diet (1.4% 6 2.4% versus 0.3% 6 1.5%; p¼0.019). Beneficial trends in systolic blood pressure reduction were seen, and maintenance of the baseline anthropometric values was also observed. Other measures were unaltered.

Conclusion: Daily ingestion of 56 g of walnuts improves endothelial function in overweight adults with visceral adiposity. The addition of walnuts to the diet does not lead to weight gain. Further study of the potential role of walnut intake in diabetes and CVD prevention is warranted.

To cite this article: David L Katz MD, MPH, Anna Davidhi BS, Yingying Ma MD, RVT, Yasemin Kavak BS, Lauren Bifulco MPH & Valentine Yanchou Njike MD, MPH (2012) Effects of Walnuts on Endothelial Function in Overweight Adults with Visceral Obesity: A Randomized, Controlled, Crossover Trial, Journal of the American College of Nutrition, 31:6, 415-423, http://dx.doi.org:/10.1080/07315724.2012.10720468

 

Additional references

Antioxidant properties of ten high yielding rice varieties of Bangladesh

AK Dutta, PS Gope, S Banik, S Makhnoon, MA Siddiquee, Y Kabir
Asian Pacific Journal of Tropical Biomedicine (2012)S99-S103

Role Of Dietary Fiber In Improving Human Physiology And In Controlling Diseases
Yadav Pn, Srivastava S and Narayan Rp
IJBPAS, January, 2014, 3(1): 98-112

The Importance of Prebiotics in Functional Foods and Clinical Practice

VM Caselato de Sousa, EF dos Santos, VC Sgarbieri
Food and Nutrition Sciences, 2011, 2, 133-144http://dx.doi.org:/10.4236/fns.2011.22019

Phloem-specific expression of a melon Aux/IAA in tomato plants alters auxin sensitivity and plant development
Guy Golan, Rotem Betzer and Shmuel Wolf*
The Robert H. Smith Facultyof Agriculture, Food and Environment,Otto Warburg Minerva Center for Agricultural Biotechnology,The Robert H. Smith Institute of Plant Sciences and Genetics in Agriculture,The Hebrew University of Jerusalem, Rehovot, Israel
Frontiers in Plant Science Aug 2013; http://dx.doi.org:/10.3389/fpls.2013.00329

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The Experience of a Patient with Thyroid Cancer

Interviewer and Curator: Larry H Bernstein, MD, FCAP

 

Thyroid cancer is usually a fairly innocuous disease, but it can present in different ways. There are are perhaps two main types – medullary, and follicular.  But an anaplastic type is also a third uncommon type.  It is speculative for me to suggest that the anaplastic type is a progression of either of the two main types.  A RAS genotype coexists with the aggressive anaplastic carcinoma.  Thyroid cancers are BRAF positive in genotype.  The histological feature that is used to identify this neoplasm is the presence of “sammoma bodies”.  It is more common in women, and less common in the elderly, and the incidence appears to have increased regionally in recent years.  A recent paper suggests a common specific feature with breast cancer, which is unconfirmed.

When we consider thyroid disease, we start with euthyroid status, hypothyroid and hyperthyroid, all of which are related to the synthetic activity of the gland, that has a right and left lobe joined by a isthmus.  In the midwestern US there is a deficiency of iodine, which leads to nodular thyroid goiter.  The Mayo brothers pioneered in thyroid surgery at their clinic in Rochester, MN.  This led to the insertion of iodine in table salt (Morton’s salt- “when it rains, it pours).  Hyperthyroid status is over production of the hormone by an overactive gland. It is usually primary disease, called Grave’s Disease, after the physician who described it. I am not aware of the occurrence secondary to hyperactivity of the pituitary gland, which would result in both an increased thyroid stimulating hormone (TSH), thyrotropin, and elevated thyroid hormone, except by a primary neoplasm of thyrotropin secreting cells.  The two hormones are under feedback control.  This feedback is a valuable diagnostic indicator because the TSH is suppressed with Grave’s disease.  The TSH assay is very accurate, and as the TSH falls, the TH increases, but the TH assay has never been as accurate as the TSH. The TH is transported in serum by three proteins: thyroxin-binding globulin (TBG), albumin, and trans-thy-retin (TTR), a quadruplex peptide with one subunit binding to retinol-binding protein (RPB), which transports retinol, vitamin A).  The importance of TTR is not a subject for discussion here, but it has extremely important ties to metabolic disease that includes hyperhomocysteinemia and Alzheimer’s disease, as this protein is produced by both the liver and the choroid plexus, but the CP production declines in the elderly.  The TTR metabolism is closely linked to total body sulfur, measured by K+ isotope measurement of lean body mass (fat free mass), and is a more accurate measure than use of urinary creatinine loss, which only measure the structural body mass, but not the visceral component.

There is another twist to the story in that thyroid hormone may be depressed over time secondary to an autoantibody to thyroid “peroxidase”, leading to destruction of the gland.  The thyroid antibody that occurs has been recently reported to be a “peroxidase” antibody in common with the mammary gland.  The disorder is denominated – Hashimoto’s thyroiditis. The presence of thyroid antibody may occur with Grave’s disease, with an occular protrusion with inflammation of the adductor muscles of eye movement.  This is termed “exophthalmus”.  However, thyroid eye disease is known to occur with hypo-, hyper-, and euthyroid status.

I here describe the long and difficult search to identify a confusing case.

 

Family history: Mother had thyroid cancer, surgically cured at Mayo Clinic. Sister had Hashimoto’s thyroiditis. Father had severe rheumatoid arthritis.

History of Illness.  The patient is a male over 65 years age who attended a discussion group for several years and participated in supervised fitness exercises and did daily walks for 2-3 years prior to the discovery of the problem when he recalls, his voice was weak in making presentations to the discussion group (age 86 and over).

At the end of summer, 2013, he experienced shortness of breath and dizziness on walking.  His physician had been concerned about the change of voice prior to this.  He had a history of sleep apnea, and he was actively trying to lose weight.  Cardiac and vascular examination of carotid and of peripheral circulation were unexpectedly excellent.  Pulmonary studies were good.

A visit to an ENT physician did not explain the voice impairment.  An unexpected low TSH result came back < 0.01, compared to a normal result 9 months earlier. This was the first indication of an active cyst or Grave’s disease. The patient was referred for ultrasound exam, and a thyroid panel was ordered.  The result of the ultrasound was an enlarged right lobe with two large degenerate cysts, and a central small calcified cyst.  The cyst was biopsied and it was malignant. It was BRAF pos and RAS negative.

He was referred to the nearest world-class academic center for further endocrine evaluation.  The endocrinologist palpated a thyroid enlargement, and a biopsy was performed of the lymph nodes under a full scan of the neck.  Surgery was scheduled and a surgeon skilled in endocrine surgery and cancer removed the thyroid, and noted that the right lobe compressed the recurrent laryngeal nerve.  This was consistent with en ENT examination of the larynx that showed paralysis of the right larynx.  The good news was that the prediction was that the nerve innovation was good, and would return.

There were a few involved lymph nodes in the removed specimen. The patient was put on synthroid. The next step was to schedule I131 radioiodine treatment by oral tablets.  This required a preparatory diet of no salt or iodine intake prior to treatment.  There was also a 5 day isolation for beta ray emission (which kills residual thyroid cells).  The neck was scanned with a gamma scanned prior to induction of treatment, which required a dose of synthetic TSH and a low dose of I131.   The patiemt is recovered for 14 days post treatment and has regained much energy.

There is a residual burden of the thyroid eye disease that requires special optical care because of loss of distance perception with diplopia.  This is stable, but any surgical repair would have to wait for a year.

 

Notes from PathologyOutlines.com, Nathan Pernick, Editor-in-Chief

Thyroid gland

Reviewer: Zubair W. Baloch, M.D., Shahidul Islam, M.D., Ph.D., Ricardo R. Lastra, M.D., Michelle R. Pramick, M.D., Phillip A. Williams, M.D., MSC (see Reviewers page)

Revised: 11 July 2014, last major update IN PROGRESS
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.

Endocrine abnormalities and thyroid gland
Hyperthyroidism

Reviewer: Shahidul Islam, M.D., Ph.D.

General
=======================================================

  • Accelerated thyroid hormone biosynthesis and secretion by thyroid gland
  • Early symptoms: anxiety, palpitations, rapid pulse, fatigue, muscle weakness, tremor, weight loss, diarrhea, heat intolerance, warm skin, excessive perspiration, menstrual changes, hand tremor
  • Ocular changes: wide staring gaze and lid lag due to sympathetic overstimulation of levator palpebrae superioris

Thyrotoxicosis: hypermetabolic clinical syndrome due to elevated serum T3 or T4

Types
=======================================================

  • Primary hyperthyroidism: intrinsic thyroid abnormality
    • Low TSH, high free T4, normal TRH stimulation test
  • Secondary hyperthyroidism: high TSH, abnormal TRH stimulation test
  • Subclinical hyperthyroidism: low TSH (< 0.1 µIU/ml), normal T3 and T4 (Eur J Endocrinol 2005;152:1), no clinical hyperthyroidism
  • T3 hyperthyroidism: 1-4%ofhyperthyroid patients
    • Low TSH, high free T3, normal free T4
    • Associated with early treatment of hyperthyroidism with antithyroid drugs
  • T4 hyperthyroidism:highT4, normal T3

Graves’ disease (85%)

Micro images
=======================================================

Diffuse hyperplasia of thyroid gland

Additional references
=======================================================

Hashimoto’s thyroiditis

General
=======================================================

  • Autoimmune disease with goiter, elevated circulating anti-thyroid peroxidase and anti-thyroglobulin antibodies
  • First described by Hakaru Hashimoto in 1912 (World J Surg 2008;32:688)

Epidemiology
=======================================================

Clinical features

Clinical features
=======================================================

  • Adults present with painless, gradual thyroid failure due to autoimmune destruction, may initially have transient hyperthyroidism
  • Children have variable hypothyroidism and reversion to euthyroidism so must monitor thyroid function (Clin Endocrinol (Oxf) 2009;71:451)
  • Associated with HLA-DR5 (goitrous form), HLA-DR3 (atrophic form)
  • May coexist with SLE, rheumatoid arthritis, Sjögren’s syndrome, pernicious anemia, type 2 diabetes, Graves’ disease, chronic active hepatitis, adrenal insufficiency, MALT lymphoma of gastrointestinal tract (80:1 relative risk), other B cell lymphomas
  • Associated with well differentiated thyroid cancer (J Am Coll Surg 2007;204:764)
  • May evolve into thyroid lymphoma (J Clin Pathol 2008;61:438)

 

Laboratory
=======================================================

  • Autoantibodies include:
    • Anti-TSH (specific for Hashimoto’s and Graves’ disease)
    • Anti-thyroglobulin (less sensitive but similar specificity as anti-thyroid peroxidase, Clin Chem Lab Med 2006;44:837)
    • Anti-thyroid peroxidase (previously called antimicrosomal antibody, sensitive but not specific as 20% of adult women without disease have these antibodies); anti-iodine transporter (rare)
    • Note: anti-TSH antibodies block the TSH receptor in Hashimoto’s disease but stimulate the TSH receptor in Graves’ disease

Papillary carcinoma

  • 75-80% of thyroid carcinomas
  • Occult tumors in 6% at autopsy (1 to 10 mm), 46% multicentric, 14% with nodal metastases (Am J Clin Pathol 1988;90:72)
  • Occult tumors in up to 24% with other thyroid disease, but with male predominance (Mod Pathol 1996;9:816)

Epidemiology
=======================================================

  • Usually women (70%) of reproductive age

Clinical features
=======================================================

Prognostic factors
=======================================================

  • 10 year survival is 98%, similar to general population (versus 92% for follicular carcinoma); 100% if under age 20, even with nodal metastases
  • Cervical nodal involvement does NOT affect prognosis
  • 5-20% have local recurrences, 10-15% have distant metastases (lung, bones, CNS)
  • Poorer prognosis:
    • Age 40+ or elderly, male (possibly), local invasion (associated with higher incidence of nodal metastases, Arch Pathol Lab Med 1998;122:166), distant metastases (other sites worse than lung, Surgery 2008;143:35), large tumor size, multicentricity, tall cell, columnar or diffuse sclerosing variants
    • Poorly differentiated, anaplastic or squamous foci

added July 14, 2014

Summary – Intraoperative laryngeal nerve monitoring
Objectives: The aim of this study was to stimulate the recurrent laryngeal nerve during thyroidectomy or parathyroidectomy and to record the muscle responses in an attempt to predict postoperative vocal fold mobility.
Patients and methods: Intraoperative recurrent laryngeal nerve monitoring during general anaesthesia was performed by using an electrode-bearing endotracheal tube (nerve integrity monitor EMG endotracheal tube [Medtronic Xomed, Jacksonville, Flo, USA]). Two hundred and fifteen recurrent laryngeal nerves from 141 patients undergoing total thyroidectomy (n = 74),
hemithyroidectomy (n = 63), or parathyroidectomy (n = 4) were prospectively monitored. In each case, the muscle potential was recorded after stimulation of the recurrent laryngeal nerve by a monopolar probe.
Results: The nerve stimulation threshold before and after dissection that induced a muscle response of at least 100 V ranged from 0.1 to 0.85 mA (mean 0.4 mA). The supramaximal stimulation intensity was defined as 1 mA. The amplitude of muscle response varied considerably from one patient to another, but the similarity of the muscle response at supramaximal intensity between pre- and postdissection and between postdissection at the proximal and distal exposed
portions of the nerve was correlated with normal postoperative vocal fold function. Inversely, alteration of the muscle response indicated a considerable risk of recurrent laryngeal nerve palsy, but was not predictive of whether or not this lesion would be permanent.  http://dx.doi.org:/10.1016/j.anorl.2011.09.003

Summary – Prognostic impact of tumour multifocality in thyroid papillary microcarcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 175—178

Objective: The objective of this study was to evaluate the prognostic impact of tumour multifocality in papillary thyroid microcarcinoma (PTMC).
Methods: All patients who underwent total thyroidectomy and central neck dissection for PTMC in our institution between 1990 and 2007 were included in this retrospective study. Statistical correlations between tumour multifocality and various clinical or pathological prognostic parameters were assessed by univariate and multivariate analyses.
Results: A total of 160 patients (133 women and 27 men; mean age: 47.8 ± 13.7 years) were included in this study. Tumour multifocality was demonstrated in 59 (37%) patients. Central neck metastatic lymph node involvement was identified in 46 (28%) patients. No statistical correlation was demonstrated between tumour multifocality and the following factors: age, gender, tumour size, extension beyond the thyroid, metastatic central neck lymph node involvement and risk of recurrence. A tumour diameter greater than 5 mm was associated with a higher risk of recurrence (P = 0.008).
Conclusion: Tumour multifocality does not appear to have a prognostic impact in PTMC.   http://dx.doi.org:/10.1016/j.anorl.2011.11.003

Positron emission tomography thyroid carcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 251—256

Objectives: Recurrence is observed in 15—20% of patients under surveillance following treatment of differentiated thyroid cancer (DTC). However, due to cell dedifferentiation, the recurrence may be iodine-negative, thereby compromising detection. For this reason, new methods of exploration are indispensable to enable localization of such recurrences. The purpose of this work is to review the contribution of positron emission tomography—computed tomography (PET-CT) in the exploration of iodine-negative recurrent DTC.
Method: A comprehensive review and discussion of the medical literature was carried out.
Results: Depending on the report, the sensitivity of PET-CT ranged from 70% to 85%, with up to 90% specificity. However, the large number of false negatives, which can reach 40%, is the
disadvantage of this examination. PET-CT results lead to change in the therapeutic strategy in approximately 50% of patients with isolated raised serum thyroglobulin levels, and surgical exploration of a precise anatomical area in the neck.
Conclusion: As post-treatment recurrence of a DTC can affect patient survival, a thorough diagnostic work-up is required in these cases. Where thyroglobulin levels are elevated with no uptake on 131-iodine scans, PET-CT can be a useful complementary exploration, especially for localizing the site of recurrence.
http://dx.doi.org:/10.1016/j.anorl.2012.01.003
French ENT Society (SFORL) practice guidelines for lymph-node management in adult differentiated thyroid carcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 197—206

Cervical and mediastinal lymph-node management differentiated thyroid carcinoma of the follicular epithelium (DTC) remains controversial. Depending on the situation, pre-operative staging and indications for and extent of lymph-node dissection are still matters of debate, even in case of palpable nodes found on primary surgery. Procedural indications for adenectomy, selective neck dissection, and anatomic regional extension of dissection are not clearly defined.

Questions raised:

• what is lymph-node involvement in DTC?
• what is the prognostic value of lymph-node invasion: for
recurrence, and for survival?

• what baseline assessment is required ahead of treatment
of papillary thyroid carcinoma to assess possible lymphnode
involvement?

• what are the principles of lymph-node surgery?
Central and lateral dissection, and dissection extended to the mediastinum;
• what is the iatrogenesis in cN0 and cN+ neck?
• what is the impact of central and lateral neck dissection on recurrence, survival, secondary treatment and surveillance in cN0 and cN+ ?
• in cN0 patients, when neck dissection is considered, what lymph-node regions should be indicated?
http://www.orlfrance.org/ download.php?id=159.

Molecular Diagnosis for Indeterminate Thyroid Nodules on Fine Needle Aspiration
Expert Rev Mol Diagn. 2013;13(6):613-62

Somatic mutation testing, mRNA gene expression platforms, protein immunocytochemistry and miRNA panels have improved the diagnostic accuracy of indeterminate thyroid nodules, and although no test is perfectly accurate, in the authors’ opinion, these methods will most certainly become an important part of the diagnostic tools for clinicians and cytopathologists in the future.

Several point mutations and gene rearrangements have been identified in thyroid cancer. The most common somatic mutation in differentiated thyroid cancer  has been studied as a potential tool to enhance the diagnostic accuracy of indeterminate FNA lesions – BRAF. This mutation occurs in papillary, poorly differentiated and anaplastic thyroid cancer and causes a V600E substitution in the BRAF protein, which results in neoplastic progression by aberrant activation of the MAPK pathway. The BRAF V600E mutation, along with RET/PTC rearrangements, are a hallmark of thyroid cancer and a vast majority of indeterminate thyroid nodules harboring either one of these two mutations are malignant on final pathology.

The RAS proto-oncogene encodes three different membrane associated GTP proteins: HRAS, KRAS and NRAS. Mutation of these domains causes increased signal transduction through both the MAPK and the PI3K/AKT pathways. These mutations are highly prevalent in FTC and in the follicular variant of papillary thyroid cancer (40–50%) and seldom detected in the classic variant papillary thyroid cancer (10%). RAS mutations have also been identified in benign FA; however, it is unclear whether RAS-positive FA have a higher chance of progression to cancer.

Recurrence detection in differentiated thyroid cancer patients..
Clinical endocrinology, Vol. 72, No. 4. (10 September 2009), pp. 558-563, doi:10.1111/j.1365-2265.2009.03693.x

There was a correlation between TgAb level and recurrence (p = 0.032).
). Recurrence was found in 37.5% of 24 TgAb+/Tg- patients who showed a gradually increasing tendency in serial measurements of TgAb. Sixteen cervical foci (21.1%) missed on neck USG and 17 lesions (22.4%) located outside the neck were additionally detected with PET/CT in TgAb+ patients.

Solving the mystery of iodine uptake
Science 20 June 2014: Vol. 344 no. 6190 p. 1355    http://dx.doi.org:/10.1126/science.344.6190.1355-a

The cell membrane protein NIS (sodium/iodine symporter) transports iodine into thyroid cells, but because iodine concentrations outside of the cell are so low, how it does so is a mystery. The key? Moving two sodium ions along with the iodine ion, Nicola et al found. NIS also does not bind sodium very tightly, but the high concentrations of sodium outside the cell allow one sodium ion to bind. This binding increases the affinity of NIS for a second sodium ion and also for iodine. With the three ions bound, NIS changes its conformation so that it opens to the inside of the cell, where the sodium concentration is low enough for NIS to release its sodium ions. When the sodium goes away, so does NIS’s affinity for iodine, leading NIS to release it.

 

 

 

 

 

 

 

 

 

 

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Heart Transplant (HT) Indication for Heart Failure (HF): Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers

Heart Transplant (HT) Indication for Heart Failure (HF) – Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers:

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 10/15/2013

http://archive.is/5kQgj

Practice Guideline | October 2013

2013 ACCF/AHA Guideline for the Management of Heart FailureA Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

Clyde W. Yancy, MD, MSc, FACC, FAHA; Mariell Jessup, MD, FACC, FAHA; Biykem Bozkurt, MD, PhD, FACC, FAHA; Javed Butler, MBBS, FACC, FAHA; Donald E. Casey, MD, MPH, MBA, FACP, FAHA; Mark H. Drazner, MD, MSc, FACC, FAHA; Gregg C. Fonarow, MD, FACC, FAHA; Stephen A. Geraci, MD, FACC, FAHA, FCCP; Tamara Horwich, MD, FACC; James L. Januzzi, MD, FACC; Maryl R. Johnson, MD, FACC, FAHA; Edward K. Kasper, MD, FACC, FAHA; Wayne C. Levy, MD, FACC; Frederick A. Masoudi, MD, MSPH, FACC, FAHA; Patrick E. McBride, MD, MPH, FACC; John J.V. McMurray, MD, FACC; Judith E. Mitchell, MD, FACC, FAHA; Pamela N. Peterson, MD, MSPH, FACC, FAHA; Barbara Riegel, DNSc, RN, FAHA; Flora Sam, MD, FACC, FAHA; Lynne W. Stevenson, MD, FACC; W.H. Wilson Tang, MD, FACC; Emily J. Tsai, MD, FACC; Bruce L. Wilkoff, MD, FACC, FHRS

 

This article has THREE Parts:

Part One: National Organizations Addressing the Heart Transplant (HT) Indication for Heart Failure (HF)

Part Two: Procedure Outcomes of Heart Transplant (HT) Indication for Heart Failure (HF)

  • Center for Heart Failure @Cleveland Clinic, and
  • Transplant Center @Mayo Clinic

Part Three: Research  on Heart Transplant (HT) and Alternative Solutions Indicated for Heart Failure (HF)

  • Center for Heart Failure @Cleveland Clinic, and
  • Transplant Center @Mayo Clinic

Part One

National Organizations Addressing the 

Heart Transplant (HT) Indication for Heart Failure (HF)

The Clinical Deliberation of the Heart Failure Diagnosis and the Heart Transplant Treatment Decision

have taken central stage as it is related to

  • patient safety
  • prolongation of life
  • quality of life post procedure
  • procedure outcomes, and
  • cost of care for the patient diagnosed with Heart  Failure

VIEW VIDEO –  Sudden Cardiac Death in Heart Failure

http://theheart.medscape.org/viewarticle/803124

We present below four National institutions with pubic mandate to promote all Healthcare aspects of Cardiovascular Diseases.

A.            2020 Vision of the Heart Failure Society of America (HFSA)

Special Communication: The Heart Failure Society of America in 2020: A Vision for the Future

Journal of Cardiac Failure Vol. 18 No. 2 2012 written by BARRY H. GREENBERG, MD,1,3 INDER S. ANAND, MD, PhD,2 JOHN C. BURNETT JR, MD,2,3 JOHN CHIN, MD,2,3 KATHLEEN A. DRACUP, RN, DNSc,3 ARTHUR M. FELDMAN, MD, PhD,3 THOMAS FORCE, MD,2,3 GARY S. FRANCIS, MD,3 STEVEN R. HOUSER, PhD,2 SHARON A. HUNT, MD,2 MARVIN A. KONSTAM, MD,3 JOANN LINDENFELD, MD,2,3 DOUGLAS L. MANN, MD,2,3 MANDEEP R. MEHRA, MD,2,3 SARA C. PAUL, RN, DNP, FNP,2,3 MARIANN R. PIANO, RN, PhD,2 HEATHER J. ROSS, MD,2 HANI N. SABBAH, PhD,2 RANDALL C. STARLING, MD, MPH,2 JAMES E. UDELSON, MD,2 CLYDE W. YANCY, MD, MSc,3 MICHAEL R. ZILE, MD,2 AND BARRY M. MASSIE, MD2,3

From the 1Chair, ad hoc Committee for Strategic Development, Heart Failure Society of America; 2Member of Executive Council, Heart Failure Society of America and 3Member, ad hoc Committee for Strategic Development, Heart Failure Society of America.

They write:

The preceding 2 decades had been marked by unprecedented insights into the underlying pathophysiology of cardiac dysfunction that were paralleled by therapeutic advances that, for the first time, were shown to clearly improve outcomes in heart failure patients. At the same time, heart failure prevalence was rapidly increasing throughout the world because of the aging of the population, improved survival of patients with myocardial infarction and other cardiac conditions, and inadequate treatment of common risk factors such as hypertension.

More recently the Heart Failure Society successfully promoted establishment of Advanced Heart Failure and Transplant Cardiology as an American Board of Internal Medicine recognized secondary subspecialty of cardiology developed a board review course to help physicians prepare for the certification examination for the new subspecialty and created a national heart failure review course.

The Society has Advocacy goals, membership goals – to increase by 10% per year for 3 years from all disciplines of Heart Failure.

Education Goals:

The Heart Failure Society of America will be recognized for its innovative approaches to educating and content dissemination on heart failure targeting

  • healthcare professionals and patients
  • Grow and enhance the annual meeting through innovative approaches
  • Continue board review course
  • Increase web-based programs for patients and health care providers
  • Enhance the website as a portal for information dissemination for health care professionals and patients
  • Grow and enhance the relevance and value of the Journal of Cardiac Failure

Journal of Cardiac Failure Vol. 18 No. 2 2012

B.            American Heart Association Research on the National Cost of Care of Heart Failure

Conceptual analysis of projection done by the AHA regarding the increase in the Cost of Care for the the American Patient in Heart Failure were developed in the following two articles:

Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States -A Policy Statement From the American Heart Association (Aviva Lev-Ari)

Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems (Justin Pearlman, Larry H Bernstein and Aviva Lev-Ari)

C. National Heart, Lung, And Blood Institute  (NHLBI)’s Ten year Strategic Research Plan

Heart Transplantation: NHLBI’s Ten year Strategic Research Plan to Achieving Evidence-based Outcomes (Larry H Bernstein and Aviva Lev-Ari)

National Heart, Lung, And Blood Institute Working Group identified the most urgent knowledge gaps in Heart Transplantation Research. These gaps require to address the following 4 specific research directions:

  • enhanced phenotypic characterization of the pre-transplant population
  • donor-recipient optimization strategies
  • individualized immunosuppression therapy, and
  • investigations of immune and non-immune factors affecting late cardiac allograft outcomes.

D. Donor-Recipient Optimization Strategies – 33,640 Cases in the United Network for Organ Sharing database – Organ Donor’s Age is BEST predictor for survival after Heart Transplant

IF the donor age is in the 0- to 19-year-old group the median survival of 11.4 years follows the Heart Transplant.

The effect of ischemic time on survival after heart transplantation varies by donor age: An analysis of the United Network for Organ Sharing database

The Journal of Thoracic and Cardiovascular Surgery ● February 2007

J Thorac Cardiovasc Surg 2007;133:554-9

Mark J. Russo, MD, MS,a,b Jonathan M. Chen, MD,a Robert A. Sorabella, BA,a Timothy P. Martens, MD,a

Mauricio Garrido, MD,a Ryan R. Davies, MD,a Isaac George, MD,a Faisal H. Cheema, MD,a Ralph S. Mosca, MD,a Seema Mital, MD,c Deborah D. Ascheim, MD,b,d Michael Argenziano, MD,a Allan S. Stewart, MD,a Mehmet C. Oz, MD,a and Yoshifumi Naka, MD, PhDa

Objectives:

(1) To examine the interaction of donor age with ischemic time and their effect on survival and

(2) to define ranges of ischemic time associated with differences in survival.

Methods: The United Network for Organ Sharing provided de-identified patientlevel data. The study population included 33,640 recipients undergoing heart transplantation between October 1, 1987, and December 31, 2004. Recipients were divided by donor age into terciles: 0 to 19 years (n  10,814; 32.1%), 20 to 33 years (11,410, 33.9%), and 34 years or more (11,416, 33.9%). Kaplan-Meier survival functions and Cox regression were used for time-to-event analysis. Receiver operating characteristic curves and stratum-specific likelihood ratios were generated to compare 5-year survival at various thresholds for ischemic time.

Results: In univariate Cox proportional hazards regression, the effect of ischemic time on survival varied by donor age tercile: 0 to 19 years (P .141), 20 to 33 years (P .001), and 34 years or more (P .001). These relationships persisted in multivariable regression. Threshold analysis generated a single stratum (0.37-12.00 hours) in the 0- to 19-year-old group with a median survival of 11.4 years. However, in the 20- to 33-year-old-group, 3 strata were generated: 0.00 to 3.49 hours (limited), 3.50 to 6.24 hours (prolonged), and 6.25 hours or more (extended), with median survivals of 10.6, 9.9, and 7.3 years, respectively. Likewise, 3 strata were generated in the group aged 34 years or more: 0.00 to 3.49 (limited), 3.50 to 5.49 (prolonged), and 5.50 or more (extended), with median survivals of 9.1, 8.5, and 6.3 years, respectively.

Conclusions: The effect of ischemic time on survival after heart transplantation is dependent on donor age, with greater tolerance for prolonged ischemic times among grafts from younger donors. Both donor age and anticipated ischemic time must be considered when assessing a potential donor.

J Thorac Cardiovasc Surg 2007;133:554-9

Part Two

Procedures Outcomes of Heart Transplant (HT) Indication for Heart Failure (HF)

  • Center for Heart Failure @Cleveland Clinic, and

  • Transplant Center @Mayo Clinic

 

Center for Heart Failure @Cleveland Clinic: Institution Profile

Heart failure (sometimes called congestive heart failure or ventricular dysfunction) means your heart muscle is not functioning as well as it should. Either the left ventricle (lower chamber of the heart) is not contracting with enough force (systolic heart failure), or the ventricles are stiff and do not relax and fill properly (diastolic heart failure). The treatment of heart failure requires a specialized multidisciplinary approach to manage the overall patient care plan.

The George M and Linda H Kaufman Center for Heart Failure is one of the premier facilities in the United States for the care of people with heart failure.

  • The Kaufman Center Heart Failure Intensive Care was the recipient of the Beacon Award of Excellence for continuing improvements in providing the highest quality of care for patients. With over 6,000 ICUs in the Unites States, the Center joins a distinguished group of just 300 to receive this honor that recognizes the highest level of standards in patient safety and quality in acute and critical care.
  • In 2011, Cleveland Clinic received the American Heart Association’s Get With The Guidelines Heart Failure GOLD Plus Certification for improving the quality of care for heart failure patients. Gold Plus distinction recognizes hospitals for their success in using Get With The Guidelines treatment interventions. This quality improvement program provides tools that follow proven, evidence-based guidelines and procedures in caring for heart failure patients to prevent future hospitalizations.

http://my.clevelandclinic.org/heart/departments-centers/heart-failure.aspx

The Kaufman Center for Heart Failure Team brings together clinicians that specialize in cardiomyopathies and ischemic heart failure. The team includes physicians and nurses from Cardiovascular Medicine, Cardiothoracic Surgery, Radiology, Infectious Disease, Immunology, Pathology, Pharmacy, Biothetics and Social Work with expertise in diagnostic testing, medical and lifestyle management, surgical procedures, and psychosocial support for patients with:

Please note Hypertrophic Cardiomyopathy is treated by our Hypertrophic Cardiomyopathy Center.

Patients at Cleveland Clinic Kaufman Center for Heart Failure have available to them the full array of diagnostic testing, treatments and specialized programs.

»Services Provided for Heart Failure Patients
»Specialized Programs for Heart Failure
http://my.clevelandclinic.org/heart/departments-centers/heart-failure.aspx

Outcomes of Heart Failure and Heart Transplant @Cleveland Clinic

1,570 Number of heart transplants performed at Cleveland Clinic since inception of the Cardiac Transplant Program in 1984.

The survival rates among patients who have heart transplants at Cleveland Clinic exceeds the expected rates. Of the 150 transplant centers in the United States, Cleveland Clinic is one of only three that had better-than-expected one-year survival rates in 2011.

Ventricular Assist Device Volume 2007 – 2011

2007 – N = 23

2008 – N = 48

2009 – N = 76

2010 – N = 51

2011 – N = 56

Mechanical circulatory support (MCS) devices are used in patients with heart failure to preserve heart function until transplantation (bridge-to-transplant) or as a final treatment option (destination therapy). Cleveland Clinic has more than 20 years of experience with MCS devices for both types of therapy.

LVAD In-Hospital Mortality 2007 – 2011

Cleveland Clinic continues to make improvements to reduce mortality rates among patients who are placed on mechanical circulatory support. The mortality rate among patients who have a left ventricular assist device (LVAD) has been drastically reduced over the past five years.5% in 2011

VAD Mortality 2011

The mortality rate among Cleveland Clinic patients placed on ventricular assist devices (VADs) was much lower than expected in 2011. Observed 10%, Expected 17.5%

Heart Failure – National Hospital Quality Measures

This composite metric, based on four heart failure hospital quality process measures developed by the Centers for Medicare and Medicaid Services (CMS), shows the percentage of patients who received all the recommended care for which they were eligible. Cleveland Clinic has set a target of UHC’s 90th percentile.

Cleveland Clinic, 2010 (N = 1,194) 93.9%

Cleveland Clinic, 2011 (N = 1,163) 96.9%

UHC Top Decile, 2011 99.2%

SOURCE

University HealthSystem Consortium (UHC) Comparative Database, January through November 2011 discharges.

The Centers for Medicare and Medicaid Services (CMS) calculates two heart failure outcome measures: all-cause mortality and all-cause readmission rates, each based on Medicare claims and enrollment information. Cleveland Clinic’s performance appears below.

Heart Failure All-Cause 30-Day Mortality (N = 762)  July 2008 – June 2011

Cleveland Clinic 9.2%

National Average 11.6%

Heart Failure All-Cause 30-Day Readmission (N = 1,029)  July 2008 – June 2011

Cleveland Clinic 27.3%

National Average 24.7%

SOURCE:

hospitalcompare.hhs.gov

Cleveland Clinic’s heart failure risk-adjusted 30-day mortality rate is below the national average; the difference is statistically significant. Our heart failure risk-adjusted readmission rate is higher than the national average; that difference is also statistically significant. To further reduce this rate, a multidisciplinary team was tasked with improving transitions from hospital to home or post-acute care facility. Specific initiatives have been implemented in each of these focus areas: communication, education and follow-up.

http://my.clevelandclinic.org/Documents/outcomes/2011/outcomes-hvi-2011.pdf

Lung and Heart-Lung Transplant

In 2011, 51% of lung transplant patients were from outside the state of Ohio.

Cleveland Clinic surgeons transplanted 111 lungs in 2011. Our Lung and Heart-Lung Transplant

Program is the leader in Ohio and among the best programs in the country.

July 2010 – June 2011

160 Performed in 2009

Liver-Lung

Heart-Lung

Double Lung

Single Lung

53.5% Idiopathic

Primary Disease of Lung Transplant Recipients (N = 101)

Source: Scientific Registry of Transplant Recipients. March 2011. Ohio, Lung Centers, Cleveland Clinic. Table 7

Cleveland Clinic surgeons transplanted 111 lungs in 2011. Our Lung and Heart-Lung Transplant Program is the leader in Ohio and among the best programs in the country.

July 2010 – June 2011

53.5% Idiopathic Pulmonary Fibrosis (N = 54)

26.7% Emphysema/Chronic Obstructive Pulmonary Disease (N = 27)

9.9% Cystic Fibrosis (N = 10)

6.9% Idiopathic Pulmonary Arterial Hypertension (N = 7)

3.0% Other (N = 3)

Peripheral Vascular Diseases

Lower Extremity Interventional

Procedure Volume

2011

Angioplasty 451

Atherectomy 74

Stenting 260

Thrombolysis 91

Lower Extremity Surgery Volume and Mortality (N = 303)

A total of 229 lower extremity bypass surgeries were performed in 2011. The 30-day

mortality rate was 0 percent. Cleveland Clinic’s vascular surgeons have expertise in this area

and strive to use autologous vein grafts.

2011 Volume

Bypass 229

Thrombectomy 74

2011 30-Day Mortality (%)

Bypass 0%

Noninvasive Vascular Lab Ultrasound Study Distribution (N = 36,775)

2011

The Noninvasive Vascular Laboratory provides service seven days a week to diagnose arterial and

venous disorders throughout the vascular tree and for follow-up after revascularization procedures,

such as bypass grafts and stents. In 2011, 36,775 vascular lab studies were performed.

47% Venous Duplex (N = 17,284)

36% Arterial Duplex (N = 13,239)

17% Physiologic Testing (N = 6,252)

http://my.clevelandclinic.org/Documents/outcomes/2011/outcomes-hvi-2011.pdf

Transplant Center @Mayo Clinic: Heart Transplant Procedures Outcomes

Mayo Clinic History

Dr. W.W. Mayo with a horse and carriage.

Dr. W.W. Mayo

Portrait of the two Mayo brothers.

Drs. William (left) and Charles Mayo

Mayo Clinic developed gradually from the medical practice of a pioneer doctor, Dr. William Worrall Mayo, who settled in Rochester, Minn., in 1863. His dedication to medicine became a family tradition when his sons, Drs. William James Mayo and Charles Horace Mayo, joined his practice in 1883 and 1888, respectively.

From the beginning, innovation was their standard and they shared a pioneering zeal for medicine. As the demand for their services increased, they asked other doctors and basic science researchers to join them in the world’s first private integrated group practice.

Although the Mayo doctors were initially viewed as unconventional for practicing medicine through this teamwork approach, the benefits of a private group practice were undeniable.

As the success of their method of practice became evident, so did its acceptance. Patients discovered the advantages to a “pooled resource” of knowledge and skills among doctors. In fact, the group practice concept that the Mayo family originated has influenced the structure and function of medical practice throughout the world.

Along with its recognition as a model for integrated group practice, “the Mayos’ Clinic” developed a reputation for excellence in individual patient care. Doctors and students came from around the world to learn new techniques from the Mayo doctors, and patients came from around the world for diagnosis and treatment. What attracted them was not only technologically advanced medicine, but also the caring attitude of the doctors.

Through the years, Mayo Clinic has nurtured and developed its founders’ style of working together as a team. Shared responsibility and consensus still provide the framework for decision making at Mayo.

That teamwork in medicine is carried out today by more than 55,000 doctors, nurses, scientists, students and allied health staff at Mayo Clinic locations in the Midwest, Arizona and Florida.

http://www.mayoclinic.org/history/

http://www.mayoclinic.org/tradition-heritage-artifacts/2-1.html

2013 – Transplant Center @ Mayo Clinic:

Alternative Solutions to Treatment of Heart Failure

Mayo Clinic, with transplant services in Arizona, Florida and Minnesota, performs more transplants than any other medical center in the world. Mayo Clinic has pre-eminent adult and pediatric transplant programs, offering cardiac, liver, kidney, pancreas and bone marrow transplant services. Since performing the first clinical transplant in 1963, Mayo’s efforts to continually improve and expand organ transplantation have placed Mayo at the leading edge of clinical and basic transplant research worldwide. Research activities in the Transplant Center at Mayo Clinic have contributed significantly to the current successful outcomes of organ transplantation.

Transplant research articles

  1. Innovation in transplant surgical techniques
  2. Intestinal transplantation
  3. Laparoscopic donor nephrectomy
  4. Living-donor transplantation
  5. Mayo Clinic launches hand transplant program
  6. Multidisciplinary team approach
  7. Multiorgan transplants
  8. Paired kidney donation
  9. Pediatric services in transplant
  10. Regenerative medicine
  11. Toward a bioartificial liver: Buying time, boosting hope

VIEW VIDEO on LVAD

VIEW VIDEO on  Mayo Clinic Heart Attack Study
People who survive a heart attack face the greatest risk of dying from sudden cardiac death (SCD) during the first month after leaving the hospital, according to a long-term community study by Mayo Clinic researchers of nearly 3,000 heart attack survivors.
Sudden cardiac death can happen when the hearts electrical system malfunctions; if treatment — cardiopulmonary resuscitation and defibrillation — does not happen fast, a person dies.
After that first month, the risk of sudden cardiac death drops significantly — but rises again if a person experiences signs of heart failure. The research results appear in the Nov. 5 edition of Journal of the American Medical Association.
Veronique Roger, M.D., a Mayo Clinic cardiologist provides an overview of the study and it’s findings.
For more information on heart attacks, click on the following link:http://www.mayoclinic.org/heart-attack/

VIEW VIDEO on Mayo Clinic Regenerative Medicine Consult Service – Stem Cell Transplantation post MI

In a proof-of-concept study, Mayo Clinic investigators have demonstrated that induced pluripotent stem (iPS) cells can be used to treat heart disease. iPS cells are stem cells converted from adult cells. In this study, the researchers reprogrammed ordinary fibroblasts, cells that contribute to scars such as those resulting from a heart attack, converting them into stem cells that fix heart damage caused by infarction. The findings appear in the current online issue of the journal Circulation.
Timothy Nelson, M.D., Ph.D., first author on the Mayo Clinic study, talks about the study and it’s findings.

Heart Transplant: Volumes and success measures Transplant Center@ Mayo Clinic

Mayo Clinic doctors’ experience and integrated team approach results in transplant outcomes that compare favorably with national averages. Teams work with transplant recipients before, during and after surgery to ensure the greatest likelihood of superior results.

Volumes and statistics are maintained separately for the three Mayo Clinic locations. Taken together or separately, transplant recipients at Mayo Clinic enjoy excellent results.

Volumes

Arizona

More than 100 heart transplants have been completed since the program began in 2005.

Florida

Surgeons at Mayo Clinic in Florida have performed more than 167 heart transplants and eight heart-lung transplants since the program began in 2001. Mayo surgeons have performed combined transplants, such as heart-kidney and heart-lung-liver transplants.

Minnesota

Mayo Clinic’s outcomes for heart transplantation compare favorably with national norms. Doctors at Mayo Clinic in Minnesota have transplanted more than 450 adult and pediatric patients, including both isolated heart transplants and combined transplants such as heart-liver, heart-kidney and others.

Success Measures

Heart Transplant Patient Survival — Adult

  1. Arizona

Mayo Clinic Hospital
(Phoenix, AZ)

  1. 1-month survival: 97.50%(n=40) • 2009-2011
  2. 1-year survival: 94.63%(n=40) • 2009-2011
  3. 3-year survival: 82.22%(n=45) • 2006-2008
  4. n = number of patients

National Average

  1. 1-month survival: 95.89%
  2. 1-year survival: 90.21%
  3. 3-year survival: 81.79%

Source: Scientific Registry of Transplant Recipients, July 2012

  1. Florida

Mayo Clinic Hospital**
(Jacksonville, FL)

  1. 1-month survival: 95.08%(n=61) • 2009-2011
  2. 1-year survival: 91.50%(n=61) • 2009-2011
  3. 3-year survival: 81.82%(n=44) • 2006-2008
  4. n = number of patients
  5. **Surgeries before April 11, 2008, were performed at St. Luke’s Hospital in Jacksonville, FL.

National Average

  1. 1-month survival: 95.89%
  2. 1-year survival: 90.21%
  3. 3-year survival: 81.79%

Source: Scientific Registry of Transplant Recipients, July 2012

  1. Minnesota

Saint Marys Hospital
(Mayo Clinic)

  1. 1-month survival: 95.83%(n=48) • 2009-2011
  2. 1-year survival: 95.83%(n=48) • 2009-2011
  3. 3-year survival: 82.61%(n=46) • 2006-2008
  4. n = number of patients

National Average

  1. 1-month survival: 95.89%
  2. 1-year survival: 90.21%
  3. 3-year survival: 81.79%

Source: Scientific Registry of Transplant Recipients, July 2012

Heart Transplant Patient Survival — Children

  1. Minnesota

Saint Marys Hospital
(Mayo Clinic)

  1. 1-month survival: 100.00%(n=5) • 2009-2011
  2. 1-year survival: 100.00%(n=5) • 2009-2011
  3. 3-year survival: 60.00%(n=5) • 2006-2008
  4. n = number of patients

National Average

  1. 1-month survival: 96.38%
  2. 1-year survival: 91.31%
  3. 3-year survival: 82.93%

Source: Scientific Registry of Transplant Recipients, July 2012

Heart Donor Organ (Graft) Survival — Adult

  1. Arizona

Mayo Clinic Hospital
(Phoenix, AZ)

  1. 1-month survival: 97.56%(n=41) • 2009-2011
  2. 1-year survival: 94.77%(n=41) • 2009-2011
  3. 3-year survival: 82.22%(n=45) • 2006-2008
  4. n = number of patients

National Average

  1. 1-month survival: 95.71%
  2. 1-year survival: 89.91%
  3. 3-year survival: 80.92%

Source: Scientific Registry of Transplant Recipients, July 2012

  1. Florida
  2. Mayo Clinic Hospital**
    (Jacksonville, FL)

    1. 1-month survival: 95.08%(n=61) • 2009-2011
    2. 1-year survival: 91.50%(n=61) • 2009-2011
    3. 3-year survival: 80.00%(n=45) • 2006-2008
    4. n = number of patients
    5. **Surgeries before April 11, 2008, were performed at St. Luke’s Hospital in Jacksonville, FL.

    National Average

    1. 1-month survival: 95.71%
    2. 1-year survival: 89.91%
    3. 3-year survival: 80.92%

Source: Scientific Registry of Transplant Recipients, July 2012

  1. Minnesota

Saint Marys Hospital
(Mayo Clinic)

  1. 1-month survival: 93.88%(n=49) • 2009-2011
  2. 1-year survival: 93.88%(n=49) • 2009-2011
  3. 3-year survival: 82.61%(n=46) • 2006-2008
  4. n = number of patients

National Average

  1. 1-month survival: 95.71%
  2. 1-year survival: 89.91%
  3. 3-year survival: 80.92%

Source: Scientific Registry of Transplant Recipients, July 2012

Heart-Lung Transplant Patient Survival — Adult

  1. Florida

Mayo Clinic Hospital**
(Jacksonville, FL)

  1. 1-month survival: 0.00%(n=0) • 2009-2011
  2. 1-year survival: 0.00%(n=0) • 2009-2011
  3. 3-year survival: 0.00%(n=1) • 2006-2008
  4. n = number of patients
  5. **Surgeries before April 11, 2008, were performed at St. Luke’s Hospital in Jacksonville, FL.

National Average

  1. 1-month survival: 89.04%
  2. 1-year survival: 80.12%
  3. 3-year survival: 56.36%

Source: Scientific Registry of Transplant Recipients, July 2012

  1. Minnesota

Saint Marys Hospital
(Mayo Clinic)

  1. 1-month survival: 100.00%(n=2) • 2009-2011
  2. 1-year survival: 100.00%(n=2) • 2009-2011
  3. 3-year survival: 100.00%(n=1) • 2006-2008
  4. n = number of patients

National Average

  1. 1-month survival: 89.04%
  2. 1-year survival: 80.12%
  3. 3-year survival: 56.36%

Source: Scientific Registry of Transplant Recipients, July 2012

Heart-Lung Donor Organ (Graft) Survival — Adult

  1. Florida

Mayo Clinic Hospital**
(Jacksonville, FL)

  1. 1-month survival: 0.00%(n=0) • 2009-2011
  2. 1-year survival: 0.00%(n=0) • 2009-2011
  3. 3-year survival: 0.00%(n=1) • 2006-2008
  4. n = number of patients
  5. **Surgeries before April 11, 2008, were performed at St. Luke’s Hospital in Jacksonville, FL.

National Average

  1. 1-month survival: 89.04%
  2. 1-year survival: 80.02%
  3. 3-year survival: 57.93%

Source: Scientific Registry of Transplant Recipients, July 2012

  1. Minnesota

Saint Marys Hospital
(Mayo Clinic)

  1. 1-month survival: 100.00%(n=2) • 2009-2011
  2. 1-year survival: 100.00%(n=2) • 2009-2011
  3. 3-year survival: 100.00%(n=1) • 2006-2008
  4. n = number of patients

National Average

  1. 1-month survival: 89.04%
  2. 1-year survival: 80.02%
  3. 3-year survival: 57.93%

Source: Scientific Registry of Transplant Recipients, July 2012

 

Part Three

Research  on Heart Transplant (HT) and Alternative Solutions Indicated for Heart Failure (HF)

  • Center for Heart Failure @Cleveland Clinic, and

  • Transplant Center @Mayo Clinic

The Editorial decision to focus on Research on Heart Transplant (HT) and Alternative Solutions Indicated for Heart Failure (HF) is covered in 

Chapter 5

Invasive Procedures by Surgery versus Catheterization

and had yielded one Sub-Chapter (5.8)  The Human Heart & Heart-Lung Transplant. This Sub-Chapter deals with

  • Heart Failure – Organ Transplant: The Human Heart & Heart-Lung Transplant,
  • Implantable Assist Devices and the Artificial Heart,

This Chapter 5 is in Volume Three in a forthcoming three volume Series of e-Books on Cardiovascular Diseases

Cardiovascular Diseases: Causes, Risks and Management

The Center for Heart Failure @Cleveland Clinic’s, and the Transplant Center @Mayo Clinic’s Institutions Profiles, Procedures Outcomes and Selection of their Research are  now in: 

Volume Three

Management of Cardiovascular Diseases

Justin D. Pearlman MD ME PhD MA FACC, Editor

Leaders in Pharmaceutical Business Intelligence, Los Angeles

Aviva Lev-Ari, PhD, RN

Editor-in-Chief BioMed E-Book Series

Leaders in Pharmaceutical Business Intelligence, Boston

avivalev-ari@alum.berkeley.edu

5.8  The Human Heart & Heart-Lung Transplant, Implantable Assist Devices and the Artificial Heart

Aviva Lev-Ari, PhD, RN

5.8.3 Mechanical Circulatory Assist Devices as a Bridge to Heart Transplantation or as “Destination Therapy“: Options for Patients in Advanced Heart Failure

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.4 Heart Transplantation: NHLBI’s Ten year Strategic Research Plan to Achieving Evidence-based Outcomes

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.5 Orthotropic Heart Transplant (OHT): Effects of Autonomic Innervation / Denervation on Atrial Fibrillation (AF) Genesis and Maintenance

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.6 After Cardiac Transplantation: Sirolimus acts asimmunosuppressant Attenuates Allograft Vasculopathy

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.7 Prognostic Marker Importance of Troponin I in Acute Decompensated Heart Failure (ADHF)

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.8.8 Alternative Models of Artificial Hearts PENDING 

Larry H. Bernstein, Justin D. Pearlman, and A. Lev-Ari

From other Sub-Chapters in Chapter 5:

5.6.1 The Cardio-Renal Syndrome (CRS) in Heart Failure (HF)

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

5.4.3 Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device:Abiomed’s Symphony | Comments

Aviva Lev-Ari, PhD, RN

 

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Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test

Reporter: Aviva Lev-Ari PhD, RN

Published: May 16, 2013

To the Editor:

Opinion Twitter Logo.

For Op-Ed, follow@nytopinion and to hear from the editorial page editor, Andrew Rosenthal, follow@andyrNYT.

In her thoughtful article about her choice to undergo a double mastectomy, Angelina Jolie said the cost of genetic testing for BRCA1 and BRCA2 mutations “remains an obstacle for many women” (“My Medical Choice,” Op-Ed, May 14).

Our BRACAnalysis test has been used by more than a million women to assess their risk of hereditary breast and ovarian cancer.

The test remains widely reimbursed by insurance companies, with more than 95 percent of at-risk women covered and with an average out-of-pocket cost of about $100. And, thanks to preventive care provisions in the Affordable Care Act, many patients can receive BRACAnalysis testing with no out-of-pocket costs.

For patients in need, Myriad offers a patient assistance program that offers testing at reduced costs or free of charge.

PETER MELDRUM

President and Chief Executive

Myriad Genetics

Salt Lake City, May 16, 2013

To the Editor:

Jolie’s Disclosure of Preventive Mastectomy Highlights Dilemma” (front page, May 15) discusses Angelina Jolie’s decision to undergo prophylactic surgery after testing positive for a BRCA1 mutation. It should be noted that not all hereditary breast and ovarian cancer is attributable to mutations in BRCA1 and BRCA2.

An alternative dilemma exists when a patient has a very strong family history of breast and ovarian cancer, especially diagnosed at young ages, and the BRCA test is negative.

The patient is left wondering what to do next. These patients should consider a new method of testing for multiple genetic mutations via next-generation sequencing, which can often be ordered as part of a research protocol in academic centers.

SUSAN KLUGMAN

Bronx, May 15, 2013

The writer, a clinical geneticist, is director of reproductive genetics at Montefiore Medical Center and an associate professor at Albert Einstein College of Medicine.

 

http://www.nytimes.com/2013/05/17/opinion/genetic-testing-for-women-at-risk-of-cancer.html?src=recg

 

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Reporter: Aviva Lev-Ari, PhD, RN

 

Diagnosed With Clear Cell Sarcoma (Soft Tissue Melanoma)

by VonTuck on Thu Oct 30, 2008 12:00 AM

Hello All

I’ve been reading the posts with great interest and sorrow over the last couple of weeks. I have been waiting to post until my final pathology came in and I had a solid diagnosis. Well, yesterday afternoon I received it.

I have been diagnosed with clear cell sarcoma (CCS) of the right ankle. In my reading I have seen it is also called soft tissue melanoma (which is still confusing me). It appears in my reading, to learn about the enemy within me, that this is about as rare of a cancer as there is, and there has been little to no research done, to include viable chemo treatment plans after surgical intervention.

I am a 46 year old retired military male. The symptoms (lump, swelling, mild pain, etc) struck me 2.5 years ago during my last couple of months in Afghanistan. Upon my return the lump and discomfort went away, allowing me to dismiss it as a problem.

About a year ago I began to experience severe swelling and, at times, excrutiating pain. I finally went to the doctor. At that time it was diagnosed as a synovial cyst and I was told not to worry about it unless the pain got worse or the lump got larger. Next episode it was diagnosed as gout, but a week later, when my uric acid levels were below normal, they realized there was a problem. (This is the “misdiagnosed” picture we all have heard so much about)

I was finally sent to an ortho joint specialist, and he knew after a 10 minute exam that I was in trouble. The following MRI confirmed a “cancerous mass” and the intial prognosis was synovial sarcoma (probably spindle cell). The CT scan came back clean for the lungs, abdomen, and vital organs. At that time, due to the encompassing size of the mass, I opted for below the knee amputation versus limb salvage and all the inherent risks that go along with it, as well as the prolonged reconstructive surget. I was then biopsied.

It took 2 weeks to the day for the final pathology report to come back. The reason was that they had an extremely difficult time identifying that it was CCS because, as my surgeon put it, “we don’t see this everyday”.

Now the amputation is a MUST. I have a PET scan on Monday, and we are all praying that it has not infiltrated my lymphatic system (which CCS is notorious for doing). My amputation is Nov. 12th.

I am looking forward to posting my experience on here. I hope it can be learned from, as well as if anyone else out there is in a similar situation, to share the information and good and bad experiences. I will do my best, health permitting, to post regularly.

I am not frightened of the amputation, but I am terrified of lymphatic compromise. I am trying to keep a positive attitude and can only hope for the best.

Thanks for reading, and I look forward to the interaction with all of you in this forum.

Love and prayers to you all

VonTuck

http://www.cancercompass.com/message-board/message/all,29831,0.htm

 

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Curator: Aviva Lev-Ari, PhD, RN

On 3/13/2013 Forbes Science Writer, Metthew Herper, presented a curated article about the protein Cas9. With a compelling title like 

This Protein Could Change Biotech Forever, we drew over 40 comments. 

A tiny molecular machine used by bacteria to kill attacking viruses could change the way that scientists edit the DNA of plants, animals and fungi, revolutionizing genetic engineering. The protein, called Cas9, is quite simply a way to more accurately cut a piece of DNA.

“This could significantly accelerate the rate of discovery in all areas of biology, including gene therapy in medicine, the generation of improved agricultural goods, and the engineering of energy-producing microbes,” says Luciano Marraffini of Rockefeller University.

The ability to make modular changes in the DNA of bacteria and primitive algae has resulted in drug and biofuel companies such as Amyris and LS9. But figuring out how to make changes in the genomes of more complicated organisms has been tough.

http://www.forbes.com/sites/matthewherper/2013/03/19/the-protein-that-could-change-biotech-forever/?goback=.gde_48920_member_227143277

In this article we bring all the pieces to one place, telling the evolution of a series of discoveries, which together may have the Protein, Cas9,  changing the Biotech Industry forever with its contributions to Diagnosing Diseases and Gene Therapy by Precision Genome Editing and Cost-effective microRNA Profiling. 

MicroRNA detection on the cheap

MIT alumni’s startup provides rapid, cost-effective microRNA profiling, which is beneficial for diagnosing diseases.
Rob Matheson, MIT News Office
March 28, 2013
Current methods of detecting microRNA (miRNA) — gene-regulating molecules implicated in the onset of various diseases — can be time-consuming and costly: The custom equipment used in such tests costs more than $100,000, and the limited throughput of these systems further hinders progress.
Two MIT alumni are helping to rectify these issues through their fast-growing, Cambridge-headquartered startup, Firefly BioWorks Inc., which provides technology that allows for rapid miRNA detection in a large number of samples using standard lab equipment. This technology has helped the company thrive — and also has the potential to increase the body of research on miRNA, which could help lead to better disease diagnosis and screening.The company’s core technology, called Optical Liquid Stamping (OLS) — which was invented at MIT by Firefly co-founder and Chief Technical Officer Daniel C. Pregibon PhD ’08 — works by imprinting (or stamping) microparticle structures onto photosensitive fluids. The resulting three-dimensional hydrogel particles, encoded with unique “barcodes,” can be used for the detection of miRNAs across large numbers of samples. These particles are custom-designed for readout in virtually any flow cytometer, a cost-effective device that’s accessible to most scientists.“Our manufacturing process allows us to make very sophisticated particles that can be read on the most basic instruments,” says co-founder and CEO Davide Marini PhD ’03.The company’s first commercial product, FirePlex miRSelect, an miRNA-detection kit that uses an assay based on OLS-manufactured particles and custom software, began selling about a year ago. Since then, the company has drawn a steady influx of customers (primarily academic and clinical scientists) while seeing rapid revenue growth.

To date, most of the company’s revenue has come from backers who see value in Firefly’s novel technology. In addition to a cumulative $2.5 million awarded through Small Business Innovation Research grants — primarily from the National Cancer Institute — the company has attracted $3 million from roughly 20 independent investors. Its most recent funding came from a $500,000 grant from the Massachusetts Life Sciences Center.

Pregibon developed the technology in the lab of MIT chemical engineering professorPatrick Doyle, a Firefly co-founder who serves on the company’s scientific advisory board. Firefly’s intellectual property is partially licensed through the Technology Licensing Office at MIT, along with several other Firefly patents. Firefly’s technology, from OLS to miRNA detection, has been described in papers published in several leading journals, including ScienceNature MaterialsNature Protocols and Analytical Chemistry.

Shifting complexity from equipment to particle

The success of the technology, Marini says, derives from an early business decision to focus attention on the development of the hydrogel particle instead of the equipment needed. Essentially, this allowed the co-founders to focus on developing a high-quality miRNA assay and hit the market quickly with particles that are universally readable on basic lab instrumentation.

“Imagine sticking a microscopic barcode on a microscopic product,” Marini says. “How do you scan it? At the beginning we thought we would have to build our own scanner. This would have been an expensive proposition. Instead, by using a few clever tricks, we redesigned the barcode to make it readable by existing instruments. You can write these ‘barcodes,’ and all you need is one scanner to read different codes. To quote an investor: ‘It shifts the complexity from the equipment to the particle.’”

Firefly’s particles appear to a standard flow cytometer as a series of closely spaced cells; these data are recorded and the company’s FireCode software then regroups them into particle information, including miRNA target identification and quantity.

But why, specifically, did the company choose a flow cytometer as its primary “scanner”? Pregibon answers: “To start, there are nearly 100,000 cytometers worldwide. In addition, we are now seeing a trend where flow cytometers are getting smaller and closer to the bench — closer to the actual researcher. We’re finding that people are tight for money because of the economy and are trying to conserve capital as much as possible. In order to use our products, they can either buy a very inexpensive bench-top flow cytometer or use one that already exists in their core facility.”

In turn, opting out of equipment development and manufacturing costs has helped the company stay financially sound, says Marini, who worked in London’s financial sector before coming to MIT. As an additional perk, the manufacturers of flow cytometers have begun “courting” Firefly, Marini says, because “our products help expand the capability of their systems, which are now exclusively used to analyze cells.”

The company’s FirePlex kit allows researchers to assay (or analyze) roughly 70 miRNA targets simultaneously across 96 samples of a wide variety — including serum, plasma and crude cell digests — in approximately three hours.

This is actually a “middle-ground” assaying technique, Pregibon says, and saves researchers time and money: Until now, scientists were forced to use separate techniques to look at a few miRNA targets over thousands of samples, or vice versa.

Marini adds that if a scientist suspects a number of miRNAs, perhaps 50 or so, could be involved in a pancreatic-cancer pathway, the only way to know for sure is to test those 50 targets over hundreds of samples. “There’s nowhere to do this today in a cost-effective, timely manner. Our tech now allows that,” he says.

‘Over the bridge of validation’

Because miRNAs are so important in the regulation of genes, and ultimately proteins, they have implications in a broad range of diseases, from cancer to Alzheimer’s disease. Several studies have suggested these relationships, but the field currently lacks the validation required to definitively demonstrate clinical utility.

With that in mind, Pregibon hopes that Firefly’s technology will help push miRNA-based diagnoses “over the bridge of validation,” giving scientists the means to validate miRNA signatures they discover in diagnosing diseases such as cancer. “That’s where we want to fit in,” he says. “With the help of a technology like ours, you’ll start to see more tests hitting the market and ultimately, more people benefitting from early cancer detection.”

Firefly’s aim is to strengthen preventive medicine in the United States. “In the long term, we see these products helping in the shift from reactive to preventative medicine,” Marini says. “We believe we will see a proliferation of tools for detection of diseases. We want to move away from the system we have now, which is curing before it’s too late.”

Pregibon says Firefly’s technology can be used across several molecule classes that are important in development and disease research: proteins, messenger RNA and DNA, among many others. “Essentially, the possibilities are endless,” Pregibon says.

Editing the genome with high precision

New method allows scientists to insert multiple genes in specific locations, delete defective genes.
Anne Trafton, MIT News Office
 
Researchers at MIT, the Broad Institute and Rockefeller University have developed a new technique for precisely altering the genomes of living cells by adding or deleting genes. The researchers say the technology could offer an easy-to-use, less-expensive way to engineer organisms that produce biofuels; to design animal models to study human disease; and  to develop new therapies, among other potential applications.To create their new genome-editing technique, the researchers modified a set of bacterial proteins that normally defend against viral invaders. Using this system, scientists can alter several genome sites simultaneously and can achieve much greater control over where new genes are inserted, says Feng Zhang, an assistant professor of brain and cognitive sciences at MIT and leader of the research team.“Anything that requires engineering of an organism to put in new genes or to modify what’s in the genome will be able to benefit from this,” says Zhang, who is a core member of the Broad Institute and MIT’s McGovern Institute for Brain Research.Zhang and his colleagues describe the new technique in the Jan. 3 online edition ofScience. Lead authors of the paper are graduate students Le Cong and Ann Ran.Early effortsThe first genetically altered mice were created in the 1980s by adding small pieces of DNA to mouse embryonic cells. This method is now widely used to create transgenic mice for the study of human disease, but, because it inserts DNA randomly in the genome, researchers can’t target the newly delivered genes to replace existing ones.

In recent years, scientists have sought more precise ways to edit the genome. One such method, known as homologous recombination, involves delivering a piece of DNA that includes the gene of interest flanked by sequences that match the genome region where the gene is to be inserted. However, this technique’s success rate is very low because the natural recombination process is rare in normal cells.

More recently, biologists discovered that they could improve the efficiency of this process by adding enzymes called nucleases, which can cut DNA. Zinc fingers are commonly used to deliver the nuclease to a specific location, but zinc finger arrays can’t target every possible sequence of DNA, limiting their usefulness. Furthermore, assembling the proteins is a labor-intensive and expensive process.

Complexes known as transcription activator-like effector nucleases (TALENs) can also cut the genome in specific locations, but these complexes can also be expensive and difficult to assemble.

Precise targeting

The new system is much more user-friendly, Zhang says. Making use of naturally occurring bacterial protein-RNA systems that recognize and snip viral DNA, the researchers can create DNA-editing complexes that include a nuclease called Cas9 bound to short RNA sequences. These sequences are designed to target specific locations in the genome; when they encounter a match, Cas9 cuts the DNA.

This approach can be used either to disrupt the function of a gene or to replace it with a new one. To replace the gene, the researchers must also add a DNA template for the new gene, which would be copied into the genome after the DNA is cut.

Each of the RNA segments can target a different sequence. “That’s the beauty of this — you can easily program a nuclease to target one or more positions in the genome,” Zhang says.

The method is also very precise — if there is a single base-pair difference between the RNA targeting sequence and the genome sequence, Cas9 is not activated. This is not the case for zinc fingers or TALEN. The new system also appears to be more efficient than TALEN, and much less expensive.

The new system “is a significant advancement in the field of genome editing and, in its first iteration, already appears comparable in efficiency to what zinc finger nucleases and TALENs have to offer,” says Aron Geurts, an associate professor of physiology at the Medical College of Wisconsin. “Deciphering the ever-increasing data emerging on genetic variation as it relates to human health and disease will require this type of scalable and precise genome editing in model systems.”

The research team has deposited the necessary genetic components with a nonprofit called Addgene, making the components widely available to other researchers who want to use the system. The researchers have also created a website with tips and tools for using this new technique.

Engineering new therapies

Among other possible applications, this system could be used to design new therapies for diseases such as Huntington’s disease, which appears to be caused by a single abnormal gene. Clinical trials that use zinc finger nucleases to disable genes are now under way, and the new technology could offer a more efficient alternative.

The system might also be useful for treating HIV by removing patients’ lymphocytes and mutating the CCR5 receptor, through which the virus enters cells. After being put back in the patient, such cells would resist infection.

This approach could also make it easier to study human disease by inducing specific mutations in human stem cells. “Using this genome editing system, you can very systematically put in individual mutations and differentiate the stem cells into neurons or cardiomyocytes and see how the mutations alter the biology of the cells,” Zhang says.

In the Science study, the researchers tested the system in cells grown in the lab, but they plan to apply the new technology to study brain function and diseases.

The research was funded by the National Institute of Mental Health; the W.M. Keck Foundation; the McKnight Foundation; the Bill & Melinda Gates Foundation; the Damon Runyon Cancer Research Foundation; the Searle Scholars Program; and philanthropic support from MIT alumni Mike Boylan and Bob Metcalfe, as well as the newscaster Jane Pauley.

SOURCE:
Published online 2012 September 4. doi:  10.1073/pnas.1208507109
PMCID: PMC3465414
PNAS Plus

Cas9–crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria

ABSTRACT

Clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide adaptive immunity against viruses and plasmids in bacteria and archaea. The silencing of invading nucleic acids is executed by ribonucleoprotein complexes preloaded with small, interfering CRISPR RNAs (crRNAs) that act as guides for targeting and degradation of foreign nucleic acid. Here, we demonstrate that the Cas9–crRNA complex of the Streptococcus thermophilus CRISPR3/Cas system introduces in vitro a double-strand break at a specific site in DNA containing a sequence complementary to crRNA. DNA cleavage is executed by Cas9, which uses two distinct active sites, RuvC and HNH, to generate site-specific nicks on opposite DNA strands. Results demonstrate that the Cas9–crRNA complex functions as an RNA-guided endonuclease with RNA-directed target sequence recognition and protein-mediated DNA cleavage. These findings pave the way for engineering of universal programmable RNA-guided DNA endonucleases.

Keywords: nuclease, site-directed mutagenesis, RNA interference, DNA interference

Comparison with Other RNAi Complexes

The mechanism proposed here for the cleavage of dsDNA by the Cas9–crRNA complex differs significantly from that for the type I-E (former “Ecoli”) system (7). In the E. coli type I-E system crRNA and Cas proteins assemble into a large ribonucleoprotein complex, Cascade, that facilitates target recognition by enhancing sequence-specific hybridization between the crRNA and complementary target sequences (7). Target recognition is dependent on the PAM and governed by the seed crRNA sequence located at the 5′ end of the spacer region (24). However, although the Cascade–crRNA complex alone is able to bind dsDNA containing a PAM and a protospacer, it requires an accessory Cas3 protein for DNA cleavage. Cas3 is an ssDNA nuclease and helicase that is able to cleave ssDNA, producing multiple cuts (10). It has been demonstrated recently that Cas3 degrades E. coli plasmid DNA in vitro in the presence of the Cascade–crRNA complex (25). Thus, current data clearly show that the mechanistic details of the interference step for the type I-E system differ from those of type II systems, both in the catalytic machinery involved and the nature of the molecular mechanisms.

In type IIIB CRISPR/Cas systems, present in many archaea and some bacteria, Cmr proteins and cRNA assemble into an effector complex that targets RNA (612). In Pyrococcus furiosus the RNA-silencing complex, comprising six proteins (Cmr1–Cmr6) and crRNA, binds to the target RNA and cleaves it at fixed distance from the 3′ end. The cleavage activity depends on Mg2+ ions; however, individual Cmr proteins responsible for target RNA cleavage have yet to be identified. The effector complex of Sulfolobus solfataricus, comprising seven proteins (Cmr1–Cmr7) and crRNA, cuts invading RNA in an endonucleolytic reaction at UA dinucleotides (13). Importantly, these two archaeal Cmr–crRNA complexes perform RNA cleavage in a PAM-independent manner.

Overall, we have shown that the Cas9–crRNA complex in type II CRISPR/Cas systems is a functional homolog of Cascade in type I systems and represents a minimal DNAi complex. The simple modular organization of the Cas9–crRNA complex, in which specificity for DNA targets is encoded by crRNAs and the cleavage enzymatic machinery is brought by a single, multidomain Cas protein, provides a versatile platform for engineering universal RNA-guided DNA endonucleases. Indeed, by altering the RNA sequence within the Cas9–crRNA complex, programmable endonucleases can be designed both for in vitro and in vivo applications. To provide proof of principle of such a strategy, we engineered de novo into a CRISPR locus a spacer targeted to a specific sequence on a plasmid and demonstrated that such a plasmid is cleaved by the Cas9–crRNA complex at a sequence specified by the designed crRNA. Experimental demonstration that RuvC and HNH active-site mutants of Cas9 are functional as strand-specific nicking enzymes opens the possibility of generating programmed DNA single-strand breaks de novo. Taken together, these findings pave the way for the development of unique molecular tools for RNA-directed DNA surgery.

SOURCE:

Cheap and easy technique to snip DNA could revolutionize gene therapy

By Robert Sanders, Media Relations | January 7, 2013

BERKELEY —A simple, precise and inexpensive method for cutting DNA to insert genes into human cells could transform genetic medicine, making routine what now are expensive, complicated and rare procedures for replacing defective genes in order to fix genetic disease or even cure AIDS.

Cas9 protein on DNA
The bacterial enzyme Cas9 is the engine of RNA-programmed genome engineering in human cells. Graphic by Jennifer Doudna/UC Berkeley.
IMAGE SOURCE:

Discovered last year by Jennifer Doudna and Martin Jinek of the Howard Hughes Medical Institute and University of California, Berkeley, and Emmanuelle Charpentier of the Laboratory for Molecular Infection Medicine-Sweden, the technique was labeled a “tour de force” in a 2012 review in the journal Nature Biotechnology.

That review was based solely on the team’s June 28, 2012, Science paper, in which the researchers described a new method of precisely targeting and cutting DNA in bacteria.

Two new papers published last week in the journal Science Express demonstrate that the technique also works in human cells. A paper by Doudna and her team reporting similarly successful results in human cells has been accepted for publication by the new open-access journal eLife.

“The ability to modify specific elements of an organism’s genes has been essential to advance our understanding of biology, including human health,” said Doudna, a professor of molecular and cell biology and of chemistry and a Howard Hughes Medical Institute Investigator at UC Berkeley. “However, the techniques for making these modifications in animals and humans have been a huge bottleneck in both research and the development of human therapeutics.

“This is going to remove a major bottleneck in the field, because it means that essentially anybody can use this kind of genome editing or reprogramming to introduce genetic changes into mammalian or, quite likely, other eukaryotic systems.”

“I think this is going to be a real hit,” said George Church, professor of genetics at Harvard Medical School and principal author of one of the Science Express papers. “There are going to be a lot of people practicing this method because it is easier and about 100 times more compact than other techniques.”

“Based on the feedback we’ve received, it’s possible that this technique will completely revolutionize genome engineering in animals and plants,” said Doudna, who also holds an appointment at Lawrence Berkeley National Laboratory. “It’s easy to program and could potentially be as powerful as the Polymerase Chain Reaction (PCR).”

The latter technique made it easy to generate millions of copies of small pieces of DNA and permanently altered biological research and medical genetics.

Cruise missiles

Two developments – zinc-finger nucleases and TALEN (Transcription Activator-Like Effector Nucleases) proteins – have gotten a lot of attention recently, including being together named one of the top 10 scientific breakthroughs of 2012 by Science magazine. The magazine labeled them “cruise missiles” because both techniques allow researchers to home in on a particular part of a genome and snip the double-stranded DNA there and there only.

Researchers can use these methods to make two precise cuts to remove a piece of DNA and, if an alternative piece of DNA is supplied, the cell will plug it into the cut instead. In this way, doctors can excise a defective or mutated gene and replace it with a normal copy. Sangamo Biosciences, a clinical stage biospharmaceutical company, has already shown that replacing one specific gene in a person infected with HIV can make him or her resistant to AIDS.

Both the zinc finger and TALEN techniques require synthesizing a large new gene encoding a specific protein for each new site in the DNA that is to be changed. By contrast, the new technique uses a single protein that requires only a short RNA molecule to program it for site-specific DNA recognition, Doudna said.

In the new Science Express paper, Church compared the new technique, which involves an enzyme called Cas9, with the TALEN method for inserting a gene into a mammalian cell and found it five times more efficient.

“It (the Cas9-RNA complex) is easier to make than TALEN proteins, and it’s smaller,” making it easier to slip into cells and even to program hundreds of snips simultaneously, he said. The complex also has lower toxicity in mammalian cells than other techniques, he added.

“It’s too early to declare total victory” over TALENs and zinc-fingers, Church said, “but it looks promising.”

Based on the immune systems of bacteria

Doudna discovered the Cas9 enzyme while working on the immune system of bacteria that have evolved enzymes that cut DNA to defend themselves against viruses. These bacteria cut up viral DNA and stick pieces of it into their own DNA, from which they make RNA that binds and inactivates the viruses.

UC Berkeley professor of earth and planetary science Jill Banfield brought this unusual viral immune system to Doudna’s attention a few years ago, and Doudna became intrigued. Her research focuses on how cells use RNA (ribonucleic acids), which are essentially the working copies that cells make of the DNA in their genes.

Doudna and her team worked out the details of how the enzyme-RNA complex cuts DNA: the Cas9 protein assembles with two short lengths of RNA, and together the complex binds a very specific area of DNA determined by the RNA sequence. The scientists then simplified the system to work with only one piece of RNA and showed in the earlier Science paper that they could target and snip specific areas of bacterial DNA.

“The beauty of this compared to any of the other systems that have come along over the past few decades for doing genome engineering is that it uses a single enzyme,” Doudna said. “The enzyme doesn’t have to change for every site that you want to target – you simply have to reprogram it with a different RNA transcript, which is easy to design and implement.”

The three new papers show this bacterial system works beautifully in human cells as well as in bacteria.

“Out of this somewhat obscure bacterial immune system comes a technology that has the potential to really transform the way that we work on and manipulate mammalian cells and other types of animal and plant cells,” Doudna said. “This is a poster child for the role of basic science in making fundamental discoveries that affect human health.”

Doudna’s coauthors include Jinek and Alexandra East, Aaron Cheng and Enbo Ma of UC Berkeley’s Department of Molecular and Cell Biology.

Doudna’s work was sponsored by the Howard Hughes Medical Institute.

RELATED INFORMATION

SOURCE:
http://newscenter.berkeley.edu/2013/01/07/cheap-and-easy-technique-to-snip-dna-could-revolutionize-gene-therapy/

Matthew Herper, Forbes Staff on 3/24/2013

 A Cancer Patient’s Quest Hits DNA Pay Dirt

 

Kathy Giusti

Kathy Giusti has faced her cancer with the verve of an entrepreneur. Now her fight with multiple myeloma has moved to a new front: DNA.

Giusti was a 37-year-old marketing executive at Searle (now part of Pfizer) when she was diagnosed in 1996 with myeloma, a deadly blood and bone marrow cancer. She had a 1-year-old daughter. Sixty percent of myeloma patients die within five years, but Giusti beat the odds, living for a decade and a half through multiple rounds of drug therapy and a bone marrow transplant from her twin sister.

She has also changed the way her disease is treated. Giusti founded an advocacy group, the Multiple Myeloma Research Foundation, that works with companies like NovartisCelgene, and Merck to develop new treatments. It played a key role in the development of Velcade and Revlimid, two of the biggest advances in treating the disease, which is diagnosed in 20,000 patients a year.

Now a new research effort, funded with $14 million of MMRF money, has revealed new hints at what causes the disease and potential avenues for treating it. “This is going to be the next wave of how health care gets changed over time,” Giusti says. The results are published in the current issue of Nature.

Working with patient samples collected by the MMRF and using DNA sequencers made by Illumina of San Diego, researchers at the Broad Institute of MIT and Harvard sequenced the genes of 38 myeloma tumors and the DNA of the patients in whom they were growing. Tumors are twisted versions of the people in which they are growing; their DNA is mutated and disfigured, turning them deadly. By comparing DNA from healthy cells with malignant ones, researchers can find genetic differences that might be what led the tumors to go bad in the first place.

This experiment would have been unthinkable just a few years ago, when sequencing a human being was so expensive that all the people whose DNA had been read out could fit in a small room. In 2005, the idea of producing 38 DNA sequences was laughable. Now it’s par for the course, and researchers expect thousands of genomes will be sequenced by the end of the year – and experiments like this are expected to become commonplace.

What’s so exciting is that sometimes the DNA changes scientists find are completely unexpected. “There were genes we found to be recurrently mutated and yet no one had any clue that they had anything to do with multiple myeloma or any other cancer,” says Todd Golub, the Broad researcher who led the study. He splits his time with the Dana-Farber Cancer Institute.

One gene, called FAM46C, was mutated in 13% of the cancers, but has never been studied in humans. “It appears no one had been working on it,” says Golub, but from studies in yeast and bacteria it appears that it has to do with how the recipes in genes are used to make proteins, the building blocks of just about everything in the body.

Another surprise gene, called BRAF, is generating excitement because it is the target of a skin cancer drug developed by Plexxikon, a small biotech firm that is partnered with Roch and is being purchased by Daiichi Sankyo. For the 4% of myeloma patients who have this mutation, this drug might be an option. The challenge will be testing it: it will be difficult to find enough of these patients to conduct a clinical trial. The MMRF says early discussions on such a study are moving forward. Giusti imagines that in the future, the MMRF may fund studies not of myeloma, but of a mix of different cancers caused by similar genetic mutations.

Several of the genes seem involved in the proteins that help guide epigenetics, a kind of molecular code written on DNA that may represent another kind of genetic code. The MMRF is already supporting some small drug companies that hope to create cancer drugs that target this second code.

Golub, the Broad scientist, says that right now it doesn’t make sense for most multiple myeloma patients to get their full DNA sequences outside of clinical trials, although he can imagine that for patients who have failed every available treatment it might make sense as a way to come up with another drug to try.

Giusti says, however, that the kinds of genetic tests that are done are changing the way that patients understand their disease. “Patients like me are starting to know, ‘I have this DNA translocation, maybe a proteasome inhibitor [a type of drug] is better for me.’ We become forerunners in the role patient can plan and the importance it has in drug development.”

Moving past old ways of thinking about inventing new medicines to a new path that is based on genetics and a flood of biological data is going to be difficult. But Giusti has never been afraid of hard — and she is sure there will be ways to drive the science forward.

SOURCE:

http://www.forbes.com/sites/matthewherper/2011/03/24/a-cancer-patients-quest-hits-dna-pay-dirt/

REFERENCES

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465414/

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Reporter: Aviva Lev-Ari, PhD, RN

Simulations Show Young Surgeons Face Special Concerns With Operating Room Distractions

Article Date: 03 Dec 2012 – 1:00 PST

A study has found that young, less-experienced surgeons made major surgical mistakes almost half the time during a “simulated” gall bladder removal when they were distracted by noises, questions, conversation or other commotion in the operating room.

In this analysis, eight out of 18, or 44 percent of surgical residents made serious errors, particularly when they were being tested in the afternoon. By comparison, only one surgeon made a mistake when there were no distractions.

Exercises such as this in what scientists call “human factors engineering” show not just that humans are fallible – we already know that – but work to identify why they make mistakes, what approaches or systems can contribute to the errors, and hopefully find ways to improve performance.

The analysis is especially important when the major mistake can be fatal.

This study, published in Archives of Surgery, was done by researchers from Oregon State University and the Oregon Health and Science University, in the first collaboration between their respective industrial engineering and general surgery faculty.

“This research clearly shows that at least with younger surgeons, distractions in the operating room can hurt you,” said Robin Feuerbacher, an assistant professor in Energy Systems Engineering at OSU-Cascades and lead author on the study. “The problem appears significant, but it may be that we can develop better ways to address the concern and help train surgeons how to deal with distractions.”

The findings do not necessarily apply to older surgeons, Feuerbacher said, and human factors research suggests that more experienced people can better perform tasks despite interruptions. But if surgery is similar to other fields of human performance, he said, older and more experienced surgeons are probably not immune to distractions and interruptions, especially under conditions of high workload or fatigue. Some of those issues will be analyzed in continued research, he said.

This study was done with second-, third- and research-year surgical residents, who are still working to perfect their surgical skills. Months were spent observing real operating room conditions so that the nature of interruptions would be realistic, although in this study the distractions were a little more frequent than usually found.

Based on these real-life scenarios, the researchers used a virtual reality simulator of a laparoscopic cholecystectomy – removing a gall bladder with minimally invasive instruments and techniques. It’s not easy, and takes significant skill and concentration.

While the young surgeons, ages 27 to 35, were trying to perform this delicate task, a cell phone would ring, followed later by a metal tray clanging to the floor. Questions would be posed about problems developing with a previous surgical patient – a necessary conversation – and someone off to the side would decide this was a great time to talk about politics, a not-so-necessary, but fairly realistic distraction.

When all this happened, the results weren’t good. Major errors, defined as things like damage to internal organs, ducts and arteries, some of which could lead to fatality, happened with regularity. 

Interrupting questions caused the most problems, followed by sidebar conversations. And for some reason, participants facing disruptions did much worse in the afternoons, even though conventional fatigue did not appear to be an issue.

“We’ve presented these findings at a surgical conference and many experienced surgeons didn’t seem too surprised by the results,” Feuerbacher said. “It appears working through interruptions is something you learn how to deal with, and in the beginning you might not deal with them very well.” 

SOURCE:

http://www.medicalnewstoday.com/releases/253456.php

 

Events that should never occur in surgery (“never events“) happen at least 4,000 times a year in the U.S. according to research from Johns Hopkins University.

 

The findings, published in Surgery, is the first of its kind to reveal the true extent of the prevalence of “never events” in hospitals through analysis of national malpractice claims. They observed that over 80,000 “never events” occurred between 1990 and 2010.

They estimate that at least 39 times a week a surgeon leaves foreign objects inside their patients, which includes stuff like towels or sponges. In addition surgeons performing the wrong surgery or operating on the wrong body part occurs around 20 times a week.

Marty Makary, M.D., M.P.H., an associate professor of surgery at the Johns Hopkins University School of Medicine, said:

“There are mistakes in health care that are not preventable. Infection rates will likely never get down to zero even if everyone does everything right, for example. But the events we’ve estimated are totally preventable. This study highlights that we are nowhere near where we should be and there’s a lot of work to be done.”

The researchers believe that this finding could help ensure that better systems are developed to prevent these “never events” which should never happen. 

The study examined data from the National Practitioner Data Bank which handles medical malpractice claims to calculate the total number of wrong-site-, wrong-patient and wrong-procedure surgeries.

Over 20 years. they found more than 9,744 paid malpractice claims which cost over $1.3 billion. Of whom 6.6% died, while 32.9% were permanently injured and 59.2% were temporarily injured. 

Around 4,044 never events occur annually in the U.S., according to estimates made by the research team who analyzed the rates of malpractice claims due to adverse surgical events. 

Many safety procedures have been implemented in medical centers to avoid never events, such as timeouts in the operating rooms to check if surgical plans match what the patient wants. In addition to this, an effective way of avoiding surgeries that are performed on the wrong body part is using ink to mark the site of the surgery. In order to prevent human error, Makary notes that electronic bar codes should be implemented to count sponges, towels and other surgical instruments before and after surgery. 

It is a requirement that all hospitals report the number of judgments or claims to the NPDB. Makary did note, however, that these figures could be low because sometimes items left behind after surgery are never discovered. 

Most of these events occurred among patients in their late 40s, surgeons of the same age group accounted for more than one third of the cases. More than half (62%) of the surgeons responsible for never events were found to be involved in more than one incident. 

Makary comments the importance of reporting never events to the public. He stresses that by doing so, patients will have more information about where to go for surgery as well as putting pressure on hospitals to maintain their quality of care. Hospitals should report any never events to the Join Commission, however this is often overlooked and more enforcement is necessary. 

Written by Joseph Nordqvist 
Copyright: Medical News Today 

SOURCE:

http://www.medicalnewstoday.com/articles/254426.php

 

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Reporter: Aviva Lev-Ari, PhD, RN

Personal Tale of JL’s Whole Genome Sequencing

Word Cloud by Daniel Menzin

Unexpected scary findings: the tale of John Lauerman’s whole genome sequencing

FEBRUARY 15, 2012
Joe Thakuria draws John Lauerman's blood
Joe Thakuria draws John Lauerman’s blood for whole genome sequencing. By Madeleine Price Ball, licensed under CC-BY-SA.

Madeleine Price Ball, PhD is a PGP research scientist in George Church’s lab at Harvard Medical School.

Several months ago John Lauerman, a reporter for Bloomberg News, approached the Personal Genome Project interested in having his whole genome sequenced. While we have hundreds of genomes in the sequencing pipeline, of the dozen or so genomes we have sequenced to-date, so far the results have been for the most part uneventful.

Lauerman’s case was different: we found something rare and “famous”, and something that nobody could have anticipated by looking through family history: a mutation that was acquired rather than inherited. This genetic variant (JAK2-V617F) is one of a number of mutations that can accumulate in blood stem cells, a precursor that could lead to several rare blood diseases.

Last night Lauerman published his experience, and we encourage all participants to read it. It confronts us with a scenario that seems likely to affect others who forge into this new and unknown territory: the very real possibility that whole genome sequencing may uncover something unexpected, ambiguous, and scary. This certainly isn’t an outcome we anticipate for most participants, but it is a rare possibility all should be aware of. Would you rather know that you carry such a variant, even if that knowledge might not help your health at all? Although some would decline, PGP participants are the sort of people who say: “Yes, I’ll take that risk, I’d rather know!” [see footnote]

His experience also illustrates potential for the Personal Genome Project to guide health care, for himself and for those who follow. The JAK2-V617F variant is so rarely seen in healthy individuals, we have very little understanding of what to expect. It has almost always been seen after a patient is diagnosed with a disease, not before. Will he develop one of these diseases? If so, which one? Perhaps many people carry the variant but never develop any symptoms of disease. In coming years Lauerman will likely continue to monitor his blood for signs of disease. It is possible that he will never develop the disease, and we hope this is the case. On the other hand, through monitoring he may detect disease sooner than he otherwise would have. By making his experiences public, his case can inform future individuals who confront the same finding.

As we move onward to sequencing hundreds and thousands of genomes, we can’t promise such interpretations will be made in a timely manner. We’re working with other groups to improve our ability to interpret genomes — and PGP participants are the perfect testbed for this development! — but it’s much harder than you might think. Genome data is made public in 30 days, but months or even years could pass before a serious and potentially scary variant is noticed. Participating in the PGP not only means that you risk learning ambiguous and scary news, but that it may be uncovered long after your data has been made public. We are always grateful to participants who choose to step into that unknown territory of genome sequencing, and who share their data so that others may learn.


Footnote: In the early stages of enrollment, individuals interested in joining the Personal Genome Project are asked to think about whether there are specific types of genetic information that they might not want to learn about themselves. Our examples include medical conditions with no effective cures or therapies, cancer, degenerative diseases, and stigmatized traits (e.g. mental illness). We do not offer the review or redacting of such information on a case-by-case basis. Only participants who wish to take the risk of learning such information are allowed to proceed with enrollment.

SOURCE:

http://blog.personalgenomes.org/2012/02/15/unexpected-scary-findings-the-tale-of-john-lauermans-whole-genome-sequencing-2/lauerman_blood_draw/

http://www.personalgenomes.org/

Harvard Mapping My DNA Turns Scary as Threatening Gene Emerges

By John Lauerman – Feb 15, 2012 12:01 AM ET

Four months after I walked into a lab at Harvard University and gave a vial of blood to have my genome sequenced, my search to understand my DNA led me to Mark Sanders, a former Indiana firefighter.

It took a little while to explain why I was calling and then he told me his story:

Sophie Liu, research scientist at Complete Genomics Inc., at a sequencing center at the company’s research facility in Mountain View, California. Photographer: David Paul Morris/Bloomberg

Feb. 15 (Bloomberg) — Bloomberg News reporter John Lauerman talks about the results of his genome sequencing. The genome contains the DNA instructions for making all the body’s cells and tissues. Lauerman discussed the report with a team from Harvard Medical School’s Personal Genome Project, who will use the results in their efforts to better understand variations in the human genome and their implications for health and disease. (Source: Bloomberg)

Joseph Thakuria, clinical director of the Personal Genome Project draws blood from Bloomberg reporter John Lauerman for the Project at Harvard Medical School in Boston on Sept. 13, 2011. Photographer: Madeleine Price Ball/Harvard Medical School via Bloomberg

Deep Breath

After recovering, Sanders retired from firefighting to garden and play the fiddle. He knows other myelofibrosis patients who haven’t fared as well.

“I had been so physically fit all my life,” he said. “There’s no reason or rhyme to why I have it or got it, and there’s not a lot of people around you can talk to who have it.”

I hung up the phone and took a deep breath. DNA in his blood cells carried the same rare genetic variant that my sequencing had revealed.

The variant is linked to a group of blood disorders, of which primary myelofibrosis is the most serious. Doctors don’t know whether this gene variant itself causes disease, yet it is seen so often in three blood disorders that its presence is used to confirm their diagnosis. I had to consider that my future might hold a fate similar to Sanders’s.

Genome-Sequencing Report

My path to Sanders began on Monday, Jan. 2, when I was sitting alone in my office in downtown Boston. Just after 4 p.m., I got an e-mail message from Madeleine Ball, a Harvard University researcher, telling me that the results of my genome sequencing were ready. The procedure is gaining use in cancer clinics and children’s hospitals, and will become increasingly common as the cost drops to $1,000, no more than that of many diagnostic procedures, such as MRI or colonoscopy, manufacturers and researchers say.

Before even a minute had gone by, the lengthy report was there for me to view.

“Here it is,” I thought, clicking on my inbox. “Mortality in an e-mail.”

Even as my DNA was chopped up, labeled, photographed and decoded by machines in California, the speed and power of sequencing was exploding. Life Technologies Corp. (LIFE) said Jan. 10 that its new Ion Proton machine will be able to sequence an entire genome in a day, for $1,000. Last month,Roche Holding AG (ROG) made a $5.7 billion hostile bid forIllumina Inc. (ILMN), which said it will also soon have machines that can provide 24-hour genome sequencing. Google Inc. (GOOG) and Amazon.com Inc. were investing in technologies to manage the tidal wave of information coming from these machines.

Personal Struggle

Now my own deciphered genome, the chemical instructions for making all the cells and tissues of my body, was complete. That evening marked the start of a medical and personal struggle to understand the report’s findings. The genome rules our bodies in ways that remain enigmatic. Many of the diseases and medical conditions I thought would emerge in the analysis, didn’t. At the same time, there were unpleasant surprises that cast a shadow on my future and now confront me and my family with tough medical decisions.

Before my sample was taken, I met with Denise Lautenbach, a genetic counselor who works in research programs at Harvard Medical School. We’d discussed the possible revelations that might come. My father, grandfather and some uncles have suffered from a shaking disorder called essential tremor. I worried about other conditions that run in my family, such as thyroid disease, diabetes and depression. While dementia isn’t a theme, I was curious about whether I have the APOE4 gene variant that raises the risk of Alzheimer’s disease.

Breast Cancer Risk

I also prepared by speaking with others who have had their genomes sequenced. Greg Lucier, chief executive officer of sequencer maker Life Technologies, discovered he has a gene that might raise the risk of breast cancer in himself and his daughter. Would I find out the same thing? What about far rarer conditions, such as amyotrophic lateral sclerosis and Huntington’s disease, both of which can be predicted by sequencing?

My mind raced as I scanned the results that late Monday afternoon, looking for familiar words and phrases that might be connected to other conditions that run in my family.

Good Report

It appeared to be a good report. I saw a genetic variant linked to slightly higher-than-normal risk of an age-related eye disease called macular degeneration. No surprise; about 10 percent of the U.S. develops this condition, and my mother has it. There was a variant linked to higher schizophrenia risk; again, not a huge boost in odds of a disease that affects about 1 percent of the population (and which I’m probably too old to develop). There were gene variants linked to liver and bowel disease, neither of which I suffer from.

Then my eyes were drawn back to the top of the report and a variant called JAK2-V617F. I realized then that the list was ranked in order of medical importance. Clicking on an entry brought me to a few pages of medical information, and those pages were linked to published scientific and medical studies. I began reading about JAK2 more closely.

This wasn’t good. The report classified the JAK2 variant’s clinical importance as “high,” and its impact as “well- established pathogenic,” meaning harmful. It’s seen frequently in people with rare “cancer-like” blood diseases. Indeed, as the report said, doctors test for the JAK2 variant to confirm cases of these diseases, called myeloproliferative disorders.

Unclear View

Did that mean that I already had a rare disease? My eyes widened. I read on.

Researchers currently see the variant as “one of an accumulation of changes that leads to the development of these cancer-like diseases,” the report said. “It is unclear how to view the presence of the variant in people who don’t have symptoms of the disease.”

After about 40 minutes of reading and thinking, I remained mystified. The report said “cancer-like.” I kept staring at the word “cancer,” while the companion “like” seemed to disappear. I’ve written about other people’s illnesses for years. What had started out as a cutting-edge science story was beginning to feel more like an unsettling visit to the doctor’s office with its confusion, struggles to understand, and shivers of dread.

Puzzling Medical News

“How worried should I be?” I kept thinking. Anticipation had been building inside me for months. Now my results were here and I barely knew what to make of the most important one.

I picked up the phone and called my wife, Judi, who’s a nurse. After 21 years of marriage, we’re accustomed to regular discussions of medical issues, in part because Judi has type 1 diabetes, which requires daily monitoring and insulin. Still, this was some of the most serious and puzzling medical news I’d ever received. I was careful to keep from sounding frightened.

“I got my results,” I said when she picked up the phone. I poured out the details, focusing on the JAK2 variant.

Judi’s voice was calm. I didn’t have any of the symptoms of diseases associated with the gene, she said. I’m usually energetic and active; that meant it wasn’t clear what the variant meant in my case.

“At least if there is a problem, we’ll find it earlier if you’re evaluated yearly,” she said.

“They told me that none of these results should be used to make medical decisions,” I said. “I’ll meet with the researchers later this week to talk about everything.”

New Chapter?

We agreed that, overall, the report was good news. I didn’t realize there was more news to come.

I left the office and got on my bike, which I had ridden to work that day. I pedaled carefully to make it home safely through the streets of Boston, which is never guaranteed, genes or no genes.

Three days after getting my results, I took a seat in the office of George Church, the Harvard scientist who started the Personal Genome Project that arranged my sequencing. Joe Thakuria, the clinical geneticist and project medical director who took my blood sample in this same office in September, was there to lead the discussion of my results. The team had been through meetings like this before, having analyzed and released the genomes of 10 people, including Church, in 2008. I was already feeling a stomach full of emotions: was this about to be a new chapter in my life? And if so, how long would that chapter be?

Thakuria asked if I had any questions before we began. I told them how thrilled I was that I hadn’t seen certain genes that I expected given my family’s medical history, such as the variant for essential tremor. I’d seen nothing in my report about Alzheimer’s risk, which I considered a good sign.

Not Bad News

The researchers stopped me. The technology used to sequence my DNA has difficulty penetrating certain portions of the genome. One such region contains the gene that makes a blood fat called apolipoprotein E. Consequently, my results might not show whether I have the version of a gene, called APOE4, which raises the risk of Alzheimer’s disease.

Never mind, I thought. I can live without that knowledge.

The absence of the gene for benign tremor, the condition my father and grandfather had, wasn’t necessarily such good news, the team explained. As-yet unknown genes might cause the same condition. No news wasn’t always good news; it just wasn’t bad news.

‘Very Rare’

With the three of us, along with Ball and Alexander Zaranek, another project researcher, crowded around the table in Church’s office, the team then turned to the JAK2 variant. The appearance of the gene in my blood had surprised even the Harvard scientists.

“This is probably the most serious variant that we’ve actually seen to date in the study,” Thakuria said. “It’s very rare.”

The JAK2 gene contains the DNA code for making a protein used to send signals through cells. About two out of 1,000 people have the V617F variant, which was discovered in 2005 and appears to encourage blood cells to grow and divide.

Many scientists believe it’s an acquired gene variant, meaning that I wasn’t born with it and my children and other blood relatives probably don’t have it. While JAK2 may have arisen in response to my own habits, at this point, it’s unclear what may have led to the mutation.

Blood Disorders

The JAK2 variant is found in about 90 percent of people with polycythemia vera, an oversupply of red blood cells. This disease is usually treated with drugs or phlebotomy, the draining of some blood from the system. It’s also frequently found in patients with essential thrombocytosis, an overproduction of platelets that usually requires no treatment and can be addressed with blood-thinners when patients have symptoms. It’s also used to diagnose primary myelofibrosis, the condition Sanders, the former firefighter, had. About 10 percent of these cases can develop into dangerous leukemias.

That’s three conditions linked to one gene. One of the three has a possibility of becoming cancerous, Thakuria said.

“I don’t want you to fret about this,” he said. It was the first of several times I would hear him say it.

At that point, Thakuria opened up a link to a 2010 study attached to the report. Scientists have been conducting studies of individual genes for years. The team had found a study of 10,507 people in Copenhagen who gave blood samples and then were followed for as long as 18 years. The Copenhagen researchers went back and analyzed the blood samples; 18 had the JAK2 variant.

‘Very Scary Figure’

What it showed was that 14 of the 18 people with the variant developed cancer in their lifetimes. All of the 18 died within the study period.

“That’s a very scary figure,” Thakuria said.

Information was starting to wash over me without really penetrating. I struggled to keep thinking of good questions for the team. Instead, I started asking myself questions: “What am I doing here? What are these people telling me?” I searched the faces arrayed around me, trying to see whether any of the researchers looked as panicked as I felt.

I tried to listen closely as Thakuria explained what the variant and the study might mean. There were a number of shortcomings in the Copenhagen study that made it difficult to interpret, he said. For example, he said, the authors had been liberal in their use of the word “cancer.” Some of the disorders developed by patients with the JAK2 variant were of the milder variety such as polycythemia vera, which isn’t typically classified as a cancer.

Issue of Deaths

Then there was the issue of deaths. It wasn’t clear whether people with the variant had died of the conditions they had been diagnosed with, or other causes, Thakuria said. Half of them had died in their 80s, and seven had died in their 70s. This is not far from average life expectancy, he pointed out.

“Half of them could have died of bicycle accidents,” he said, smiling.

There were other reasons not to fret, Thakuria said. Although the JAK2 variant often shows up in these conditions, no one knows precisely what role it plays. It may be a cause of the disorders, or an effect of changes elsewhere in the genome. The JAK2 variant was unlikely to be the only cause of these diseases; several things — things that remain unknown to us — would probably have to go wrong before any disease would arise. In this context, the gene wasn’t quite so scary, Thakuria said.

Black and White

I thought about a conversation I’d had with Ball just a few days earlier, while my genome were still being analyzed. I had called to see when the results were coming. She said they were “interesting,” but didn’t want to discuss them until a clinical geneticist had a chance to review them. Her voice sounded like she didn’t want to reveal everything she knew.

“I wish everything were black and white,” she said. “Unfortunately, things just don’t turn out that way very often.”

The researchers said I now needed to confirm that the sequencing was correct with another round of testing using a different technique. I would give another blood sample. If the variant was there, we’d talk more about what steps to take.

The meeting lasted almost two hours, and I left Church’s office with Thakuria. We walked to a restaurant about halfway between Harvard Medical School and Fenway Park to sit and have a drink. I continued to quiz him on the relationship between the JAK2 variant and the diseases we’d been talking about.

Ask Again

Sitting on a barstool next to Thakuria and listening to him discuss the JAK2 variant, I felt reassured. It occurred to me that this wasn’t how most people would receive the news of their results. As a reporter working on a story about genomics, I had access to experts that many people wouldn’t. What will happen as more people get results from broad genome sequencing?

I spoke about this during a meeting with Harold Varmus, director of the U.S. National Cancer Institute, and a co-winner of a Nobel Prize in 1989 for his work to find genes that promote the growth of cancer cells. I mentioned I had just received my results.

“How do you feel?” he asked.

“It’s been an interesting process,” I said. “It’s still playing out.”

Varmus nodded. Gathering genetic data from thousands of people can help researchers understand health by correlating gene variations with diseases, he said. He was concerned, however, that companies may not always ensure that people who have undergone sequencing will get a full understanding of their results.

‘How to Deal’

“Accumulating the information and studying it is good,” he said. “My concern is whether individuals are getting guidance on how to deal with the information.”

“People are being told they have a certain gene variant. In a mass population, that increases the risk of some diseases by, say, two-fold. That might be true in a mass population, but in any single individual’s genome, it’s not certain what that means.”

The Harvard researchers are struggling with these same issues, and are still working to streamline and improve their approach to giving results to study participants, Thakuria said.

“As we get more information from participants like you, we’ll gain a much better understanding of how to do it,” Thakuria said.

Animal Studies

I still felt like someone who kept shaking a toy Magic 8 Ball and getting the message: “Concentrate and ask again.” I decided to do a little research on my own. I found a 2010 study in the journal Blood showing that when the JAK2 variant was added to the genomes of mice, the animals later suffered from disorders similar to those seen in people with the gene.

This is just one of several animal studies suggesting that the JAK2 variant contributes directly to blood disorders, said John Crispino, a professor at Northwestern University Feinberg School of Medicine, who studies the gene. Skeptics point out that drugs that interfere with JAK2 don’t cure patients suffering from the gene-linked blood disorders.

“The field is mixed,” he said. “My bias is that the JAK2 variant contributes to the pathology of the disease.”

I wanted to find out what kind of people have the JAK2 mutation I have, and what’s happened to them. In addition to Sanders, the Indiana firefighter, I spoke with Bob Rosen, chairman of theMPN Research Foundation, a Chicago-based advocacy group for people with myeloproliferative disorders, and he had a surprise for me.

Red Blood Cells

About 14 years ago, Rosen went to a doctor because of pain in his fingers and toes. A complete blood count revealed high levels of red blood cells. He was diagnosed with polycythemia vera and was first treated with phlebotomy. He now takes a drug that controls his blood cell levels. With his treatment, he’s still able to work out, and had been playing basketball on the day I called him.

“I’ve been lucky,” he said. “The risk is that, over time, new symptoms will emerge or there will be a progression to something worse.”

A small percentage of patients with polycythemia vera can develop more serious conditions, such as primary myelofibrosis and certain leukemias, Rosen said. I hadn’t realized this, or hadn’t absorbed it, until now.

Another Surprise

Then, another surprise arrived. Looking at my report, I saw it had been updated electronically, as the genome project research team had told me would happen from time to time. Now, the second entry on my list of variants was labeled “APOE- C130R” — that’s another name for the APOE4 gene associated with increased risk of Alzheimer’s disease.

I kept reading, recalling that I had been told my ApoE result wasn’t accessible with the technology used to sequence my genome. As it turned out, the technology had worked after all. I was at increased risk for Alzheimer’s.

This was exactly the kind of news I had hoped I wouldn’t receive.

A few days later I got an e-mail from Ball, of the Harvard team.

“Sorry this was missed earlier,” she said in the e-mail. She recommended that I look at the studies she’d collected on APOE4, some of which casts doubt on the role of the variant as a strong factor in causing Alzheimer’s. According to one estimate, people who have one copy of the gene, as I do, have a 3 percent increased risk of developing the disease by age 80.

Better to Know

One of my parents must have had this gene variant in order for me to get it. Yet my mother is in her late 70s and my father is 80; neither of them has Alzheimer’s disease. The longer I thought about it, the less I worried.

I talked with my two children, Hanna and James, about their feelings regarding the JAK2 and Alzheimer’s gene variants. My daughter, a sophomore in college, said she thinks it’s an advantage to be aware of a health threat.

“If there’s a treatment for it, you could start earlier,” she said. “It’s better to know.”

My next stop was to see my doctor. While she didn’t want her name used in this story, she agreed to let me write about our conversations and paraphrase her comments.

I followed an aide into an exam room. Nothing about my body had changed since the genome test was done. I still had normal blood pressure and pulse, and my weight was steady.

My doctor had heard of the JAK2 variant. If the result was confirmed, I would need to have my blood count tested. If there was an oversupply of red blood cells or platelets, or signs of damaged bone marrow, we would start thinking about treatment, such as removing blood. She asked me how I was feeling.

‘Not Sick’

“I feel fine,” I said. “I’m not sick.”

I didn’t mention that every time I thought about the JAK2 variant, itching followed. I had read that itching was one of the symptoms of polycythemia vera. Even as I write these words, I’m scratching my forehead. I never feel itchy when not thinking about my genome. I also started noticing memory lapses.

This kind of behavior is often called “medical student syndrome,” because doctors in training who are learning to diagnose new diseases turn their skills on themselves. I assumed it was this syndrome I was suffering from, rather than a blood disorder.

It seemed like a good time to return to the Boston office of Aubrey Milunsky, the director of the Boston University Center for Human Genetics who had warned me in May that having my genome sequenced would just cause me needless worry.

“Why would you want to know that?” he had asked me then.

Milunsky was well-acquainted with the JAK2 variant on my report. Just as the team at Harvard had said, he mentioned that there was little known about the long-term impact of the variant in people. He noted that it’s also associated with some cases of dangerous clotting in abdominal blood vessels.

“You know it’s there, but you don’t know what it means,” he said. “You’re smack in the territory of inviting anxiety into your life. And this may have no meaning whatsoever in your entire life.”

Useful Vigilance

I disagreed. The results had actually taken some uncertainty out of my life, I told Milunsky. We all bear some health risks, and that’s why doctors recommend, for instance, that everyone get regular checkups and those 50 and older undergo tests for colon cancer. I have a rare mutation linked to rare conditions, most cases of which can be treated. Wouldn’t it make sense for me to undergo a blood test regularly to see whether my blood counts had changed?

Such vigilance might be beneficial, and it might not, Milunsky said. I might live the rest of my life with my health unaffected by the variant. Yet the exercise had shown that I had discovered things I’d rather not know, he said. Others who undergo the same procedure will surely find out that they have mutations that practically guarantee they will develop serious and perhaps even fatal diseases, he said.

Huntington’s Disease

Indeed, a 1999 study in the American Journal of Human Genetics found that about 1 percent of 4,527 people who were told they had the gene that causes Huntington’s disease, a progressive nervous system disorder, attempted or committed suicide, or were hospitalized for psychiatric reasons.

Medical researchers are still trying to determine when it makes sense to do more common tests for breast and prostate cancer. A certain percentage of people who get positive results on these screening exams will go on to have unneeded treatment that may cause harm. In October, a government panel recommended that blood tests used to screen for prostate cancer should only be performed on men with symptoms. The same panel said in 2009 that women should start getting mammograms at age 50, rather than 40.

On Jan. 25, at about 11 p.m., I got a phone call from Thakuria. We had arranged to speak late in the day to accommodate busy schedules.

‘Mutation Confirmed’

“The mutation confirmed,” he said. He didn’t say “JAK2,” but I knew that was what he was talking about.

The next step for me is to have my white and red blood-cell levels measured, along with those of platelets. Doctors will also study the appearance of these cells under a microscope and check to see how much oxygen my blood can carry. I expect these tests to be normal. If they aren’t, it’s possible that I’ll start getting blood drawn from my system or drug treatment for polycythemia vera. I may need to take a blood thinner, such as aspirin, to counteract the effects of excess platelets. Should I have evidence of more serious disease, stronger treatment may be needed.

“I’m not going to lie to you: I’d rather you didn’t have it,” Thakuria said. “This isn’t like one of those mutations that have specific recommendations. There are no guidelines here. This is part of being on the frontier.”

To contact the reporter on this story: John Lauerman in Boston at jlauerman@bloomberg.net

To contact the editor responsible for this story: Jonathan Kaufman at

jkaufman17@bloomberg.net

SOURCE:

http://www.bloomberg.com/news/2012-02-15/harvard-mapping-my-dna-turns-scary-as-threatening-gene-emerges.html

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