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Archive for the ‘Origins of Cardiovascular Disease’ Category

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 Biology. Note: 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 agonists. Journal 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 Cells. PLoS 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 Medicine. Note: 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 Adults. JAMA 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 1, Inge Huybrechts 3,4, Peter Deriemaeker 1,2, Barbara Vanaelst 4, Willem De Keyzer 4,5, Marcel Hebbelinck 1 and Patrick Mullie 1,2,6

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

Nutrients 2014, 6(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, 133-144;  http://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

Read Full Post »

Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL): Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 9/15/2025

Jamal Rana MD FACCJamal Rana MD FACC  

• 2ndVerified • 2ndChair (APIC) Medical Specialties & Interventional Services, People Operations, Professional Development TPMG | Clinician Researcher | Past President California ACC I Professor Department of Clinical Science KPSOMChair (APIC) Medical Specialties & Interventional Services, People Operations, Professional Development TPMG | Clinician Researcher | Past President California ACC I Professor Department of Clinical Science KPSOM4d

•  4 days ago • Visible to anyone on or off LinkedIn

“The Importance of Being Ernest” about #LDL Cholesterol

Our latest paper out in JACC Journals, led by Dr. Peng & Dr. Eugenia Gianos.
LINK: https://lnkd.in/gNqrjzSv

⚡ We asked if cumulative LDL-Cholesterol exposure in individuals with a Coronary artery Calcium hashtag#CAC of 0 associated with higher rates of long-term cardiovascular events?
⚡ We found that despite CAC of 0, long-term cumulative LDL-C exposure is associated with significantly higher CVD risk, highlighting hashtag#early individualized risk factor optimization and hashtag#CVDprevention across the hashtag#lifecourse.
⚡ Although patients with CAC = 0 have overall low CVD risk, their risk is not zero, and that risk increases with cumulative LDL-C exposure.
⚡ Cumulative LDL-C exposure during early adulthood starting in one’s teens to early 20s contributes to increased risk.
⚡ I have started to use the term hashtag#LDLYears more and more. From lifestyle to so many pharmaceutical therapy options, focusing primary prevention is still better than secondary prevention, as many patients do not survive their 1st heart attack!

Original Article

JACC Journals › JACC › Archives › Vol. 86 No. 9

25 August 2025

Impact of LDL-Cholesterol When the Coronary Artery Calcium Score Is 0: Long-Term Cardiovascular Events

Authors: Allison W. Peng, Alexander C. Razavi, John T. Wilkins, Norrina B. Allen, Laurence S. Sperling, Jamal S. Rana, Tia Bimal, Seamus P. Whelton, Michael J. Blaha, Roger S. Blumenthal, and Eugenia Gianos egianos@northwell.eduAuthors Info & Affiliations

Publication: JACC, Volume 86, Number 9

https://www.jacc.org/doi/abs/10.1016/j.jacc.2025.06.053

 

@@@@@@@@@

Lower LDL Still Best: Very Low Levels of LDL Linked with Reduced CV Events

July 28, 2014

 

 

AMSTERDAM, THE NETHERLANDS — The question of how low LDL-cholesterol levels should be in the present statin era, recently addressed with the new US clinical guidelines, is once again questioned with the new publication of a patient-level meta-analysis of eight clinical trials investigating statin therapy[1].

 

The new meta-analysis, published July 28, 2014 in the Journal of the American College of Cardiology, suggests that lowering LDL-cholesterol levels to very low levels results in a significant reduction in cardiovascular events. Individuals with LDL-cholesterol levels <50 mg/dL had a significantly lower risk of major cardiovascular events compared with individuals who had higher LDL-cholesterol levels, including those with LDL levels 50 to <75 mg/dL and 75 to <100 mg/dL.

 

The Results From the Meta-analysis

 

The investigators, including first author Dr Matthijs Boekholdt (Academic Medical Center), analyzed eight trials and 38 153 patients treated with statin therapy. The studies included some of the landmark statin trials, including AFCAPS-TexCAPS , 4S , LIPID , SPARCL , TNT , IDEAL , and JUPITER .

 

The investigators observed a large degree of interindividual variability in the reductions of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B (apoB) levels with statin therapy. Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.

 

Compared with individuals with LDL-cholesterol levels >175 mg/dL, which served as the reference group, individuals who achieved lower levels of LDL cholesterol had a significantly lower risk of major cardiovascular events. For those with LDL-cholesterol levels <50 mg/dL, 50 to <75 mg/dL, and 75 to <100 mg/dL, the relative reduction in risk was 56%, 49%, and 44%, respectively. Regarding the end point of major coronary events and cerebrovascular events, a similar trend was observed with lower LDL cholesterol levels.

 

 

Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL)

 

Outcome LDL <50 50 to <75 75 to <100 100 to <125 125 to <150 150 to <175 > 175
Major cardiovascular events 0.44 (0.35–0.55) 0.51 (0.42–0.62) 0.56 (0.46–0.67) 0.58 (0.48–0.69) 0.64 (0.53–0.79) 0.71 (0.56–0.89) 1.00 (ref)

 

 

References

 

  1. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoprotein and the risk for cardiovascular events. J Am Coll Cardiol 2014; DOI:10.1016.j.jacc.2014.02.615. Available at:http://content.onlinejacc.org/journal.aspx
  2. Ben-Yehuda O, DeMaria AN. LDL-cholesterol after the ACC/AHA 2013 guidelines. J Am Coll Cardiol 2014; DOI:10.1016.j.jacc.2014.05.020. Available at: http://content.onlinejacc.org/journal.aspx

SOURCE

http://www.medscape.com/viewarticle/828967?nlid=62503_2562&src=wnl_edit_medp_card&uac=93761AJ&spon=2

 

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Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI ­Marker of Disease Severity or Genetic Determination?

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The Cardiorenal Syndrome in Heart Failure: Cardiac? Renal? syndrome?

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

Voices from the Cleveland Clinic On Circulating apoA1: A Biomarker for a Proatherogenic Process in the Artery Wall

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Voice from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator

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Atherogenesis: Predictor of CVD ­ the Smaller and Denser LDL Particles

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Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke ­ Atherosclerosis.  

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Recombinant Human Lecithin-Cholesterol Acyltransferase (rhLCAT): New Biomarker for Atherosclerosis

Aviva Lev-Ari, PhD, RN

Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

Leptin Signaling in Mediating the Cardiac Hypertrophy associated with Obesity

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

Publications on Heart Failure by Prof. William Gregory Stevenson, M.D.

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CVD Prevention and Evaluation of Cardiovascular Imaging Modalities: Coronary Calcium Score by CT Scan Screening to justify or not the Use of Statin

Aviva Lev-Ari, PhD, RN

 

 

 

 

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Why did this occur? The matter of Individual Actions Undermining Trust, The Patent Dilemma and The Value of a Clinical Trials

Why did this occur? The matter of Individual Actions Undermining Trust, The Patent Dilemma and The Value of a Clinical Trials

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

 

he large amount of funding tied to continued research and support of postdoctoral fellows leads one to ask how following the money can lead to discredited work in th elite scientific community.

Moreover, the pressure to publish in prestigious journals with high impact factors is a road to academic promotion.  In the last twenty years, it is unusual to find submissions for review with less than 6-8 authors, with the statement that all contributed to the work.  These factors can’t be discounted outright, but it is easy for work to fall through the cracks when a key investigator has over 200 publications and holds tenure in a great research environment.  But that is where we find ourselves today.

There is another issue that comes up, which is also related to the issue of carrying out research, and then protecting the work for commercialization.  It is more complicated in the sense that it is necessary to determine whether there is prior art, and then there is the possibility that after the cost of filing patent and a 6 year delay in obtaining protection, there is as great a cost in bringing the patent to finasl production.

I.  Individual actions undermining trust.

II. The patent dilemma.

III. The value of a clinical trial.

IV. The value contributions of RAP physicians
(radiologists, anesthesiologists, and pathologists – the last for discussion)
Those who maintain and inform the integrity of medical and surgical decisions

 

I. Top heart lab comes under fire

Kelly Servick

Science 18 July 2014: Vol. 345 no. 6194 p. 254 DOI: 10.1126/science.345.6194.25

 

In the study of cardiac regeneration, Piero Anversa is among the heavy hitters. His research into the heart’s repair mechanisms helped kick-start the field of cardiac cell therapy (see main story). After more than 4 decades of research and 350 papers, he heads a lab at Harvard Medical School’s Brigham and Women’s Hospital (BWH) in Boston that has more than $6 million in active grant funding from the National Institutes of Health (NIH). He is also an outspoken voice in a field full of disagreement.

So when an ongoing BWH investigation of the lab came to light earlier this year, Anversa’s colleagues were transfixed. “Reactions in the field run the gamut from disbelief to vindication,” says Mark Sussman, a cardiovascular researcher at San Diego State University in California who has collaborated with Anversa. By Sussman’s account, Anversa’s reputation for “pushing the envelope” and “challenging existing dogma” has generated some criticism. Others, however, say that the disputes run deeper—to doubts about a cell therapy his lab has developed and about the group’s scientific integrity. Anversa told Science he was unable to comment during the investigation.

“People are talking about this all the time—at every scientific meeting I go to,” says Charles Murry, a cardiovascular pathologist at the University of Washington, Seattle. “It’s of grave concern to people in the field, but it’s been frustrating,” because no information is available about BWH’s investigation. BWH would not comment for this article, other than to say that it addresses concerns about its researchers confidentially.

In April, however, the journal Circulation agreed to Harvard’s request to retract a 2012 paper on which Anversa is a corresponding author, citing “compromised” data. The Lancet also issued an “Expression of Concern” about a 2011 paper reporting results from a clinical trial, known as SCIPIO, on which Anversa collaborated. According to a notice from the journal, two supplemental figures are at issue.

For some, Anversa’s status has earned him the benefit of the doubt. “Obviously, this is very disconcerting,” says Timothy Kamp, a cardiologist at the University of Wisconsin, Madison, but “I would be surprised if it was an implication of a whole career of research.”

Throughout that career, Anversa has argued that the heart is a prolific, lifelong factory for new muscle cells. Most now accept the view that the adult heart can regenerate muscle, but many have sparred with Anversa over his high estimates for the rate of this turnover, which he maintained in the retracted Circulation paper.

Anversa’s group also pioneered a method of separating cells with potential regenerative abilities from other cardiac tissue based on the presence of a protein called c-kit. After publishing evidence that these cardiac c-kit+cells spur new muscle growth in rodent hearts, the group collaborated in the SCIPIO trial to inject them into patients with heart failure. In The Lancet, the scientists reported that the therapy was safe and showed modest ability to strengthen the heart—evidence that many found intriguing and provocative. Roberto Bolli, the cardiologist whose group at the University of Louisville in Kentucky ran the SCIPIO trial, plans to test c-kit+ cells in further clinical trials as part of the NIH-funded Cardiovascular Cell Therapy Research Network.

But others have been unable to reproduce the dramatic effects Anversa saw in animals, and some have questioned whether these cells really have stem cell–like properties. In May, a group led by Jeffery Molkentin, a molecular biologist at Cincinnati Children’s Hospital Medical Center in Ohio, published a paper in Nature tracing the genetic lineage of c-kit+ cells that reside in the heart. He concluded that although they did make new muscle cells, the number is “astonishingly low” and likely not enough to contribute to the repair of damaged hearts. Still, Molkentin says that he “believe[s] in their therapeutic potential” and that he and Anversa have discussed collaborating.

Now, an anonymous blogger claims that problems in the Anversa lab go beyond controversial findings. In a letter published on the blog Retraction Watch on 30 May, a former research fellow in the Anversa lab described a lab culture focused on protecting the c-kit+ cell hypothesis: “[A]ll data that did not point to the ‘truth’ of the hypothesis were considered wrong,” the person wrote. But another former lab member offers a different perspective. “I had a great experience,” says Federica Limana, a cardiovascular disease researcher at IRCCS San Raffaele Pisana in Rome who spent 2 years of her Ph.D. work with the group in 1999 and 2000, as it was beginning to investigate c-kit+ cells. “In that period, there was no such pressure” to produce any particular result, she says.

Accusations about the lab’s integrity, combined with continued silence from BWH, are deeply troubling for scientists who have staked their research on theories that Anversa helped pioneer. Some have criticized BWH for requesting retractions in the midst of an investigation. “Scientific reputations and careers hang in the balance,” Sussman says, “so everyone should wait until all facts are clearly and fully disclosed.”

 

II.  Trolling Along: Recent Commotion About Patent Trolls

July 17, 2014

PriceWaterhouseCoopers recently released a study about 2014 Patent Litigation. PwC’s ultimate conclusion was that case volume increased vastly and damages continue a general decline, but what’s making headlines everywhere is that “patent trolls” now account for 67% of all new patent lawsuits (see, e.g., Washington Post and Fast Company).

Surprisingly, looking at PwC’s study, the word “troll” is not to be found. So, with regard to patent trolls, what does this study really mean for companies, patent owners and casual onlookers?

First of all, who are these trolls?

“Patent Troll” is a label applied to patent owners who do not make or manufacture a product, or offer a service. Patent trolls live (and die) by suing others for allegedly practicing an invention that is claimed by their patents.

The politically correct term is Non-practicing Entity (NPE). PwC solely uses the term NPE, which it defines as an entity that does not have the capability to design, manufacture, or distribute products with features protected by the patent.

So, what’s so bad about them?

The common impression of an NPEs is a business venture looking to collect and monetize assets (i.e., patents). In the most basic strategy, an NPE typically buys patents with broad claims that cover a wide variety of technologies and markets, and then sues a large group of alleged patent infringers in the hope to collect a licensing royalty or a settlement. NPEs typically don’t want to spend money on a trial unless they have to, and one tactic uses settlements with smaller businesses to build a “war chest” for potential suits with larger companies.

NPEs initiating a lawsuit can be viewed positively, such as a just defense of the lowly inventor who sold his patent to someone (with deeper pockets) who could fund the litigation to protect the inventor’s hard work against a mega-conglomerate who ripped off his idea.

Or NPE litigation can be seen negatively, such as an attorney’s demand letter on behalf of an anonymous shell corporation to shake down dozens of five-figure settlements from all the local small businesses that have ever used a fax machine.

NPEs can waste a company’s valuable time and resources with lawsuits, yet also bring value to their patent portfolios by energizing a patent sales and licensing market. There are unscrupulous NPEs, but it’s hardly the black and white situation that some media outlets are depicting.

What did PwC say about trolls?

Well, the PwC study looked at the success rates and awards of patent litigation decisions. One conclusion is that damages awards for NPEs averaged more than triple those for practicing entities over the last four years. We’ll come back to this statistic.

Another key observation is that NPEs have been successful 25% of the time overall, versus 35% for practicing entities. This makes sense because of the burden of proof the NPEs carry as a plaintiff at trial and the relative lack of success for NPEs at summary judgment. However, PwC’s report states that both types of entities win about two-thirds of their trials.

But what about this “67% of all patent trials are initiated by trolls” discussion?

The 67% number comes from the RPX Corporation’s litigation report (produced January 2014) that quantified the percentage of NPE cases filed in 2013 as 67%, compared to 64% in 2012, 47% in 2011, 30% in 2010 and 28% in 2009.

PwC refers to the RPX statistics to accentuate that this new study indicates that only 20% ofdecisions in 2013 involved NPE-filed cases, so the general conclusion would be that NPE cases tend to settle or be dismissed prior to a court’s decision. Admittedly, this is indicative of the prevalent “spray and pray” strategy where NPEs prefer to collect many settlement checks from several “targets” and avoid the courtroom.

In this study, who else is an NPE?

If someone were looking to dramatize the role of “trolls,” the name can be thrown around liberally (and hurtfully) to anyone who owns and asserts a patent without offering a product or a service. For instance, colleges and universities fall under the NPE umbrella as their research and development often ends with a series of published papers rather than a marketable product on an assembly line.

In fact, PwC distinguishes universities and non-profits from companies and individuals within their NPE analysis, with only about 5% of the NPE cases from 1995 to 2013 being attributed to universities and non-profits. Almost 50% of the NPE cases are attributed to an “individual,” who could be the listed inventor for the patent or a third-party assignee.

The word “troll” is obviously a derogatory term used to connote greed and hiding (under a bridge), but the term has adopted a newer, meme-like status as trolls are currently depicted as lacking any contribution to society and merely living off of others’ misfortunes and fears. [Three Billy Goats Gruff]. This is not always the truth with NPEs (e.g., universities).

No one wants to be called a troll—especially in front of a jury—so we’ve even recently seen courts bar defendants from referring to NPEs as such colorful terms as a “corporate shell,” “bounty hunter,” “privateer,” or someone “playing the lawsuit lottery.” [Judge Koh Bans Use Of Term ” Patent Troll” In Apple Jury Trial]

Regardless of the portrayal of an NPE, most people in the patent world distinguish the “trolls” by the strength of the patent, merits of the alleged infringement and their behavior upon notification. Often these are expressed as “frivolity” of the case and “gamesmanship” of the attorneys. Courts are able to punish plaintiffs who bring frivolous claims against a party and state bar associations are tasked with monitoring the ethics of attorneys. The USPTO is tasked with working to strengthen the quality of patents.

What’s the take-away from this study regarding NPEs?

The study focuses on patent litigation that produced a decision, therefore the most important and relevant conclusion is that, over the last four years, average damages awards for NPEs are more than triple the damages for practicing entities. Everything else in these articles, such as the initiation of litigation by NPEs, settlement percentages, and the general behavior of patent trolls is pure inference beyond the scope of the study.

This may sound sympathetic to trolls, but keep in mind that the study highlights that NPEs have more than triple the damages on average compared to practicing entities and it is meant to shock the reader a bit. One explanation for this is that NPEs are in the best position to choose the patents they want to assert and choose the targets they wish to sue—especially when the NPE is willing to ride that patent all the way to the end of a long, expensive trial. Sometimes settling is not an option. Chart 2b indicates that the disparity in the damages awarded to NPEs relative to practicing entities has always been big (since 2000), but perhaps going from two-fold from 2000 – 2009 to three times as much in the past 4 years indicates that NPEs are improving at finding patents and/or picking battles to take all the way to a court decision. More than anything, this seems to reflect the growth in the concept of patents as a business asset.

The PwC report is chock full of interesting patterns and trends of litigation results, so it’s a shame that the 67% number makes the headlines—far more interesting are the charts comparing success rates by 4-year periods (Chart 6b) or success rates for NPEs and practicing entities in front of a jury verusin front of a bench (Chart 6c), as well as other tables that reveal statistics for specific districts of the federal courts. Even the stats that look at the success rates of each type of NPE are telling because the reader sees that universities and non-profits have a higher success rate than non-practicing companies or individuals.

What do we do about the trolls?

The White House has recently called for Congress to do something about the trolls as horror stories of scams and shake-downs are shared. A bill was gaining momentum in the Senate, when Senator Leahy took it off the agenda in early July. That bill had miraculously passed 325-91 in the House and President Obama was willing to sign it if the Senate were to pass it. The bill was opposed by trial attorneys, universities, and bio-pharmaceutical businesses who felt as though the law would severely inhibit everyone’s access to the courts in order to hinder just the trolls. Regardless, most people think that the sitting Congressmen merely wanted a “win” prior to the mid-term elections and that patent reform is unlikely to reappear until next term.

In the meantime, the Supreme Court has recently reiterated rules concerning attorney fee-shifting on frivolous patent cases, as well as clarifying the validity of software patents. Time will tell if these changes have any effects on the damages awards that PwC’s study examined or even if they cause a chilling of the number of patent lawsuit filings.

Furthermore, new ways to challenge the validity of asserted patents have been initiated via the America Invents Act. For example, the Inter Partes Review (IPR) has yielded frightening preliminary statistics as to slowing, if not killing, patents that have been asserted in a suit. While these administrative trials are not cheap, many view these new tools at the Patent Trial and Appeals Board as anti-troll measures. It will be interesting to watch how the USPTO implements these procedures in the near future, especially while former Google counsel, Acting Director Michelle K. Lee, oversees the office.

In the private sector, Silicon Valley has recently seen a handful of tech companies come together as the License on Transfer Network, a group hoping to disarm the “Patent Assertion Entities.” Joining the LOT Network comes via an agreement that creates a license for use of a patent by anyone in the LOT network once that patent is sold. The thought is that the NPEs who consider purchasing patents from companies in the LOT Network will have fewer companies to sue since the license to the other active LOT participants will have triggered upon the transfer and, thus, the NPE will not be as inclined to “troll.” For instance, if a member-company such as Google were to sell a patent to a non-member company and an NPE bought that patent, the NPE would not be able to sue any members of the LOT Network with that patent.

Other notes

NPEs are only as evil as the people who run them—that being said, there are plenty of horror stories of small businesses receiving phantom demand letters that threaten a patent infringement suit without identifying themselves or the patent. This is an out-and-out scam and a plague on society that results in wasted time and resource, and inevitably higher prices on the consumer end.

It is a sin and a shame that patent rights can be misused in scams and shake-downs of businesses around us, but there is a reason that U.S. courts are so often used to defend patent rights. The PwC study, at minimum, reflects the high stakes of the patent market and perhaps the fragility. Nevertheless, merely monitoring the courts may not keep the trolls at bay.

I’d love to hear your thoughts.

*This is provided for informational purposes only, and does not constitute legal or financial advice. The information expressed is subject to change at any time and should be checked for completeness, accuracy and current applicability. For advice, consult a suitably licensed attorney or patent agent.

 

III. Large-scale analysis finds majority of clinical trials don’t provide meaningful evidence

Ineffective Treatments, Medical Ethics • Tags: Center for Drug Evaluation and Research, Clinical trial, CTTI, Duke University Hospital, FDA, Food and Drug Administration, National Institutes of Health, United States National Library of Medicine

04 May 2012

DURHAM, N.C.— The largest comprehensive analysis of ClinicalTrials.gov finds that clinical trials are falling short of producing high-quality evidence needed to guide medical decision-making. The analysis, published today in JAMA, found the majority of clinical trials is small, and there are significant differences among methodical approaches, including randomizing, blinding and the use of data monitoring committees.

“Our analysis raises questions about the best methods for generating evidence, as well as the capacity of the clinical trials enterprise to supply sufficient amounts of high quality evidence to ensure confidence in guideline recommendations,” said Robert Califf, M.D., first author of the paper, vice chancellor for clinical research at Duke University Medical Center, and director of the Duke Translational Medicine Institute.

The analysis was conducted by the Clinical Trials Transformation Initiative (CTTI), a public private partnership founded by the Food and Drug Administration (FDA) and Duke. It extends the usability of the data in ClinicalTrials.gov for research by placing the data through September 27, 2010 into a database structured to facilitate aggregate analysis. This publically accessible database facilitates the assessment of the clinical trials enterprise in a more comprehensive manner than ever before and enables the identification of trends by study type.

 

The National Library of Medicine (NLM), a part of the National Institutes of Health, developed and manages ClinicalTrials.gov. This site maintains a registry of past, current, and planned clinical research studies.

“Since 2007, the Food and Drug Administration Amendment Act has required registration of clinical trials, and the expanded scope and rigor of trial registration policies internationally is producing more complete data from around the world,” stated Deborah Zarin, MD, director, ClinicalTrials.gov, and assistant director for clinical research projects, NLM. “We have amassed over 120,000 registered clinical trials. This rich repository of data has a lot to say about the national and international research portfolio.”

This CTTI project was a collaborative effort by informaticians, statisticians and project managers from NLM, FDA and Duke. CTTI comprises more than 60 member organizations with the goal of identifying practices that will improve the quality and efficiency of clinical trials.

“Since the ClinicalTrials.gov registry contains studies sponsored by multiple entities, including government, industry, foundations and universities, CTTI leaders recognized that it might be a valuable source for benchmarking the state of the clinical trials enterprise,” stated Judith Kramer, MD, executive director of CTTI.

The project goal was to produce an easily accessible database incorporating advances in informatics to permit a detailed characterization of the body of clinical research and facilitate analysis of groups of studies by therapeutic areas, by type of sponsor, by number of participants and by many other parameters.

“Analysis of the entire portfolio will enable the many entities in the clinical trials enterprise to examine their practices in comparison with others,” says Califf. “For example, 96% of clinical trials have ≤1000 participants, and 62% have ≤ 100. While there are many excellent small clinical trials, these studies will not be able to inform patients, doctors and consumers about the choices they must make to prevent and treat disease.”

The analysis showed heterogeneity in median trial size, with cardiovascular trials tending to be twice as large as those in oncology and trials in mental health falling in the middle. It also showed major differences in the use of randomization, blinding, and data monitoring committees, critical issues often used to judge the quality of evidence for medical decisions in clinical practice guidelines and systematic overviews.

“These results reinforce the importance of exploration, analysis and inspection of our clinical trials enterprise,” said Rachel Behrman Sherman, MD, associate director for the Office of Medical Policy at the FDA’s Center for Drug Evaluation and Research. “Generation of this evidence will contribute to our understanding of the number of studies in different phases of research, the therapeutic areas, and ways we can improve data collection about clinical trials, eventually improving the quality of clinical trials.”

Related articles

 

IV.  Lawmakers urge CMS to extend MU hardship exemption for pathologists

 

Eighty-nine members of Congress have asked the Centers for Medicare & Medicaid Services to give pathologists a break and extend the hardship exemption they currently enjoy for all of Stage 3 of the Meaningful Use program.In the letter–dated July 10 and addressed to CMS Administrator Marilyn Tavenner–the lawmakers point out that CMS had recognized in its 2012 final rule implementing Stage 2 of the program that it was difficult for pathologists to meet the Meaningful Use requirements and granted a one year exception for 2015, the first year that penalties will be imposed. They now are asking that the exception be expanded to include the full five-year maximum allowed under the American Recovery and Reinvestment Act.

“Pathologists have limited direct contact with patients and do not operate in EHRs,” the letter states. “Instead, pathologists use sophisticated computerized laboratory information systems (LISs) to support the work of analyzing patient specimens and generating test results. These LISs exchange laboratory and pathology data with EHRs.”

Interestingly, the lawmakers’ exemption request is only on behalf of pathologists, even though CMS had granted the one-year hardship exception to pathologists, radiologists and anesthesiologists.

Rep. Tom Price (R-Ga.), one of the members spearheading the letter, had also introduced a bill (H.R. 1309) in March 2013 that would exclude pathologists from the incentives and penalties of the Meaningful Use program. The bill, which has 31 cosponsors, is currently sitting in committee. That bill also does not include relief for radiologists or anesthesiologists.

CMS has provided some flexibility about the hardship exceptions in the past, most recently by allowing providers to apply for one due to EHR vendor delays in upgrading to Stage 2 of the program.

However, CMS also noted in the 2012 rule granting the one-year exception that it was granting the exception in large part because of the then-current lack of health information exchange and that “physicians in these three specialties should not expect that this exception will continue indefinitely, nor should they expect that we will grant the exception for the full 5-year period permitted by statute.”

To learn more:
– read the letter (.pdf)

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Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: : Views by Larry H Bernstein, MD, FCAP

 

Author: Larry H Bernstein, MD, FCAP

This review has examined a compendium of well regarded documents drawn from 248 articles in Circulation Cardiovascular Genetics from March 2010 to March 2013. The large amount of evidence obtained from large population studies identifying Genome Wide Analysis Studies (GWAS) examines a host of cardiac and vascular diseases in which there is association between specific single nucleotide peptides (SNPs), and gene loci, that may play or have no significant role in developing heart disease. It certainly is evidence of the role that the American Heart Association has is in supporting the leading research today for tomorrow’s patients.   It is too early to sort them out, but it speaks to a large volume of discovery in this area.

It raises another issue that we have been confronted with mostly since the second half of the 20th century.  What is that issue?  The issue, it appears to me, is the vast improvements in analytical technology so that “imprecision” is far less likely to be a confounder in biological measurements and this lends access to far better accuracy?  But from that question arises another! Accuracy only refers to what is measured, but does it give us better ability to explain a complex and dynamic process?  In other words, what is what we are looking at representative of in manageable events?   I think that this is the most important idea that should come out of the recent criticism of the trajectory that molecular genetics been on in the last 5 years.

It was still in an era that “BIG’ science was not the normal.  One could spend an enormous effort at stepwise purification of a protein or enzyme, or other biomolecule starting with a slurry made from 100 lbs of “chicken heart”, for example.  These separations were based on negative charges on the molecules and positive charges on the column, and the molecules of no interest were eluted by gradient elution.  Much was learned about large scale preparation from small scale trials.  But this work was not undertaken without the intent to carry out a number of investigations to understand the “functionality” of a link in a metabolic pathway.  The studies that followed the purification required kinetic investigation with a coenzyme, or with a synthetically modified coenzyme, amino acid sequencing, NMR studies, etc.  You could not put together a “mechanism” without having the minimum amount of necessary information for a reliable account.  It is probably this requirement that led to today’s “BIG” science, that is founded upon multiple methods, now large data bases, and teams of investigators across institutions and continents.  The acquisition of knowledge has been astounding, but the integration of knowledge has not caught up.

However, let’s see if we can sort out the most meaningful signals from what I too am beginning to call the “noisy channel”.  As often happens, important areas of research are opened up that are followed by significant discovery and, in the long run, many other dead end publications that have no lasting significance.  In order to do justice to the work, I’ll pick through documents I find interesting, keeping in mind there is a hidden layer of complexity of which only sufficient information leads to a better understanding.  As much literature calls attention to, much of what ails us has nothing to do with classical Mendelian genetics, and has a postgenomic component.

The most fascinating aspect of this is the withering “dark matter” of the genome. While that component may be silent or expressed, the understanding comes at a higher observed order.  The dark became light! The expression became subtle, like weak bond interactions. The underlying organization is a component of the adaptive ability of an organism or individual in an environment with plants and animals in a changing climate, at particular altitudes, with given water supplies, with disease vectors, and with endogenous sources of essential nutrients.  This brings into focus the regulatory role of the genome as just as important a factor as transmission of the genetic code, especially in somatic cell populations.

The remainder of this discussion deals specifically with my observations on cardiovascular genomics. The following conclusion is appropriate, if incomplete, at this time on circulating miRNAs, particularly miR-133a:

  • elevated levels of circulating miR-133a in patients with cardiovascular diseases originate mainly from the injured myocardium.
  • Circulating miR-133a can be used as a marker for cardiomyocyte death, and
  • it may have functions in cardiovascular diseases.

Circulation: Cardiovascular Genetics. 2011;4:446-454.

Strikingly, in plasma from

  • acute myocardial infarction patients, cardiac myocyte–associated miR-208b and -499 were highly elevated, 1600-fold (P<0.005) and 100-fold (P<0.0005), respectively, as compared with control subjects. Receiver operating characteristic curve analysis revealed an area under the curve of 0.94 (P<10−10) for miR-208b and 0.92 (P<10−9) for miR-499. BothmicroRNAs correlated with plasma troponin T, indicating release of microRNAs from injured cardiomyocytes.
  • In patients with acute heart failure, only miR-499 was significantly elevated (2-fold), whereas
  • no significant changes in microRNAs studied could be observed in diastolic dysfunction.

Remarkably, plasma microRNA levels were not affected by a wide range of clinical confounders, including

  • age,
  • sex,
  • body mass index,
  • kidney function,
  • systolic blood pressure, and
  • white blood cell count.

This is miRNA with a different twist.  It appears that there are 3 types found in AMI(133a, 208b, 409).  But type 409 alone is increased with acute heart failure (no mention of chronic cardiomyopathy and no effect of estimated GFR, or of age).

If the problem was just of AMI, then we have to know what this brings to the table.  As it is the hs-troponins have yet to be shown to effectively not only increase the high sensitivity of the tests, but to decrease the confusion generated by the elevation.  The enormous improvement of a test that may be superior to the hs-ctn’s is for the patient with very indeterminiate shortness of breath, a nondefinitive ECG, and in a prodromal phase of AMI.  This happened in the past, and it may happen now, and it may account for many cases of silent MI that were found at autopsy.

Cited by
Plasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure Eur J Heart Fail. 2013;0:hft018v1-hft018,


Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases   Am. J. Physiol. Heart Circ. Physiol.. 2012;303:H1085-H1095,

Circulation Editors’ Picks: Most Read Articles in Cardiovascular Genetics Circulation. 2012;126:e163-e169,

MicroRNAs in Patients on Chronic Hemodialysis (MINOS Study) CJASN. 2012;7:619-623,

Novel techniques and targets in cardiovascular microRNA research Cardiovasc Res. 2012;93:545-554,

Microparticles: major transport vehicles for distinct microRNAs in circulationCardiovasc Res. 2012;93:633-644,

Profiling of circulating microRNAs: from single biomarkers to re-wired networksCardiovasc Res. 2012;93:555-562,

Small but smart–microRNAs in the centre of inflammatory processes during cardiovascular diseases, the metabolic syndrome, and ageing   Cardiovasc Res. 2012;93:605-613,

Circulation: Heart Failure Editors’ Picks: Most Important Papers in Pathophysiology and Genetics Circ Heart Fail. 2012;5:e32-e49

Use of Circulating MicroRNAs to Diagnose Acute Myocardial Infarction   Clin. Chem. 2012;58:559-567,

Circulating microRNAs to identify human heart failure   Eur J Heart Fail. 2012;14:118-119,

Next Steps in Cardiovascular Disease Genomic Research–Sequencing, Epigenetics, and Transcriptomics  Clin. Chem. 2012;58:113-126,

Most Read in Cardiovascular Genetics on Biomarkers, Inherited Cardiomyopathies and Arrhythmias, Metabolomics, and GenomicsCirc Cardiovasc Genet. 2011;4:e24-e30,

MicroRNA-126 modulates endothelial SDF-1 expression and mobilization of Sca-1+/Lin- progenitor cells in ischaemia  Cardiovasc Res. 2011;92:449-455,

The use of genomics for treatment is another matter, and has several factors, e.g., age, residual function after AMI, comorbidities

This is a lot of interesting work that opens as many questions as it answers. The observations are real, and they lead to questions relating to the heart and the circulation.  Maybe it will generate answers to very tough issues concerning hypertension, renal disease and the heart.  It is far too early to tell.  It appears that we are about to hear a cacophony of miR’s in a symphony on cardiac and circulatory diseases not be be pieced together soon. But we have many more tools at our disposal than we did when Karmen discovered and made a distinction between

  • Aspartate and Alanine aminotransferases in the late 1950s, followed in the 1960s by
  • Creatine phosphokinase, the
  • MB-isoenzyme of CK by Sobel, Shell and Kjeckshus,
  • isoenzyme-1 of lactate dehydrogenase, and later the
  • Troponins,

leading to the programs to “reduce the extent of infarct damage”.

Then came the

  • and B-type natriuretic peptides (BNP),

which are still not fully understood in their role in congestive heart failure and inrenal disease.

One item strikes the imagination as a fruitful area of further study.   Genetic Determinants of Potassium Sensitivity and Hypertension.    Integrated Computational and Experimental Analysis of the Neuroendocrine Transcriptome in Genetic Hypertension Identifies Novel Control Points for the Cardiometabolic Syndrome

Essential hypertension, a common complex disease, displays substantial genetic influence. Contemporary methods to dissect the genetic basis of complex diseases such as the genomewide association study are powerful, yet a large gap exists betweens the fraction of population trait variance explained by such associations and total disease heritability.

Revised 7/17/2014
 Gene expression profiles associated with acute myocardial infarction and risk of cardiovascular deathJ Kim, NGhasemzadeh, DJEapen, NC Chung, JD Storey,AAQuyyumi and GGibsonKim et al. Genome Medicine 2014, 6:40http://genomemedicine.com/content/6/5/40

Abstract

Background: Genetic risk scores have been developed for coronary artery disease and atherosclerosis, but are not predictive of adverse cardiovascular events. We asked whether peripheral blood expression profiles may be predictive of acute myocardial infarction (AMI) and/or cardiovascular death.

Methods: Peripheral blood samples from 338 subjects aged 62 ± 11 years with coronary artery disease (CAD) were analyzed in two phases (discovery N = 175, and replication N = 163), and followed for a mean 2.4 years for cardiovascular death. Gene expression was measured on Illumina HT-12 microarrays with two different normalization procedures to control technical and biological covariates. Whole genome genotyping was used to support comparative genome-wide association studies of gene expression. Analysis of variance was combined with receiver operating curve and survival analysis to define a transcriptional signature of cardiovascular death.

Results: In both phases, there was significant differential expression between healthy and AMI groups with overall down-regulation of genes involved in T-lymphocyte signaling and up-regulation of inflammatory genes. Expression quantitative trait loci analysis provided evidence for altered local genetic regulation of transcript abundance in AMI samples. On follow-up there were 31 cardiovascular deaths. A principal component (PC1) score capturing covariance of 238 genes that were differentially expressed between deceased and survivors in the discovery phase significantly predicted risk of cardiovascular death in the replication and combined samples (hazard ratio = 8.5, P< 0.0001) and improved the C-statistic (area under the curve 0.82 to 0.91, P= 0.03) after adjustment for traditional covariates.

Conclusions: A specific blood gene expression profile is associated with a significant risk of death in Caucasian subjects with CAD. This comprises a subset of transcripts that are also altered in expression during acute myocardial infarction.

MicroRNA References

Lecture Contents delivered at Koch Institute for Integrative Cancer Research, Summer Symposium 2014: RNA Biology, Cancer and Therapeutic Implications, June 13, 2014 @MIT    Curator of Lecture Contents: Aviva Lev-Ari, PhD, RN https://pharmaceuticalintelligence.com/wp-admin/post.php?post=23174&action=edit

3:15 – 3:45, 6/13/2014, Laurie Boyer “Long non-coding RNAs: molecular regulators of cell fate”
http://pharmaceuticalintelligence.com/2014/06/13/315-345-2014-laurie-boyer-long-non-coding-rnas-molecular-regulators-of-cell-fate/

Plasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure. Dickinson BA, Semus HM, Montgomery RL, Stack C, Latimer PA, et al.  Eur J Heart Fail. 2013 Jun; 15(6):650-9.  http://dx.doi.org:/10.1093/eurjhf/hft018

Circulating microRNAs – Biomarkers or mediators of cardiovascular disease?  S Fichtlscherer, AM Zeiher, S Dimmeler. Arteriosclerosis, Thrombosis, and Vascular Biology.2011; 31:2383-2390.
http://dx.doi.org:/10.1161/​ATVBAHA.111.226696

Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases. AJ Tijsen, YM Pinto, and EE Creemers. Am J Physiol Heart Circ Physiol 303: H1085–H1095, 2012.  http://dx.doi.org:/10.1152/ajpheart.00191.2012.

MicroRNAs in Patients on Chronic Hemodialysis (MINOS Study). Emilian C, Goretti E, Prospert F, Pouthier D, Duhoux P, et al. Clin J Am Soc Nephrol  (CJASN)2012;  7: 619-623. http://dx.doi.org:/10.2215/CJN.10471011

Plasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure.BA Dickinson, HM Semus, RL Montgomery, C Stack, PA Latimer, et al.
Eur J Heart Fail 2013 Jun 6;15(6):650-9. http://www.pubfacts.com/detail/23388090/Plasma-microRNAs-serve-as-biomarkers-of-therapeutic-efficacy-and-disease-progression-in-hypertension

Circulating MicroRNAs: Novel Biomarkers and Extracellular Communicators in Cardiovascular Disease?  Esther E. Creemers, Anke J. Tijsen, Yigal M. Pinto.  Circulation Research. 2012; 110: 483-495    http://dx.doi.org:/10.1161/​CIRCRESAHA.111.247452

Novel techniques and targets in cardiovascular microRNA research.  Dangwal S, Bang C, Thum T.Cardiovasc Res. 2012 Mar 15; 93(4):545-54.  http://dx.doi.org:/10.1093/cvr/cvr297

Microparticles: major transport vehicles for distinct microRNAs in circulation. Diehl P, Fricke A, Sander L, Stamm J, Bassler N, Htun N, et al.  Cardiovasc Res. 2012 Mar 15; 93(4):633-44. http://dx.doi.org:/10.1093/cvr/cvs007.

Profiling of circulating microRNAs: from single biomarkers to re-wired networks. A  Zampetaki,  P Willeit, I Drozdov, S Kiechl and M Mayr. Cardiovasc Res 2012; 93 (4): 555-562.  http://dx.doi.org:/10.1093/cvr/cvr266

Small but smart–microRNAs in the centre of inflammatory processes during cardiovascular diseases, the metabolic syndrome, and ageing. Schroen B, Heymans S.  Cardiovasc Res. 2012; 93(4):605-613.  http://dx.doi.org:/10.1093/cvr/cvr268

Therapeutic Inhibition of miR-208a Improves Cardiac Function and Survival During Heart Failure.  RL Montgomery, TG Hullinger, HM Semus, BA Dickinson, AG Seto, et al.
http://dx.doi.org:/10.1161/​CIRCULATIONAHA.111.030932

Circulating microRNAs to identify human heart failure.  Seto AG, van Rooij E.
Eur J Heart Fail. 2012;14(2):118-119.  http://dx.doi.org:/10.1093/eurjhf/hfr179.

Use of Circulating MicroRNAs to Diagnose Acute Myocardial Infarction.  Y Devaux, M Vausort, E Goretti, PV Nazarov, F Azuaje. Clin Chem. 2012; 58:559-567.  http://dx.doi.org:/10.1373/clinchem.2011.173823

Next Steps in Cardiovascular Disease Genomic Research–Sequencing, Epigenetics, and Transcriptomics  RB Schnabel, A Baccarelli, H Lin, PT Ellinor, and EJ Benjamin.
Clin Chem . 2012 Jan; 58(1): 113–126.  http://dx.doi.org:/10.1373/clinchem.2011.170423

MicroRNA-133 Modulates the {beta}1-Adrenergic Receptor Transduction Cascade.  A Castaldi, T Zaglia, V Di Mauro, P Carullo, G Viggiani, et al.  Circ. Res..2014; 115:273-283.
http://dx.doi.org:/10.1161/​CIRCRESAHA.115.303252

Development of microRNA therapeutics is coming of age.  E van Rooij, S Kauppinen.  EMBOMol Med.. 2014; 6:851-864.  http://dx.doi.org:/10.15252/emmm.201100899

Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation.   J Wang, Y Bai, N Li, W Ye, M Zhang,et al. PNAS 2014; 111: 9181-9186.
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1405411111/-/DCSupplemental.

MicroRNA-126 modulates endothelial SDF-1 expression and mobilization of Sca-1+/Lin- progenitor cells in ischaemia  Cardiovasc Res. 2011; 92:449-455,
http://dx.doi.org:/10.1093/cvr/cvr227

The use of genomics for treatment is another matter, and has several factors, e.g., age, residual function after AMI, comorbidities

 

 

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Malnutrition in India, High Newborn Death Rate and Stunting of Children Age Under Five Years

Curator: Larry H Bernstein, MD, FCAP

 

A lead report in the New York Times focuses on a major public health problem in India today, with the irony of high growth rate and malnutrition and stunting of children under age 5 years that occurs in the majority and wealthy Hindu population, but not to any comparable degree in the Muslim population or in Bangladesh.  This is prevalent along the Ganges River, which crosses India below the Himalaya Mountains.  The inference is that the problem is perhaps solely related to poor sanitation, which is to a large degree indisputable, and the disease is related to the gut microbiome (not so stated), that leaves an intestinal mucosa with flattened epithelia, and no observation is made of the submucosal thymic-derived T-cell lymphocyte population, the largest in the human body.

Moreover, I might point out that the turnover of the intestinal epithelium with its large surface area is very high under normal metabolic circumstances.  The result is that the children are malnourished, and they have visceral protein losses as well as somatic protein loss (stunted growth, probably affecting both skeletal muscle and the metaphyseal growth plates of long bones).  This is not quite stated this way.

The irony is that they have sufficient food supply, except that if there is a diarrhea or intestinal malabsorption at an early age, the children just might not eat, except for perhaps soft foods.  So it is not explicitly cleat that their is sufficient animal protein in the diet, which has a S:N ratio that is roughly twice that of an exclusively plant diet.  The distinction is made between marasmus and kwashiorkor in that in kwashiorkor the protein deficiency is in the visceral compartment.  Consequently, there is a reprioriotization of the liver to synthesize acute phase proteins with a decline in albumin, transthyretin, and retinol-binding protein.  This is not insignificant, even though there may also be an inflammatory state, as from repeated infections.

I certainly would be interested in seeing data from the ongoing study that measures the serum protein analytes, and also a measurement of serum red cell Hb, serum cysteine, homocysteine, and glutathione, and perhaps a muscle biopsy.

I go directly to the article at this point.

Poor Sanitation in India May Afflict Well-Fed Children With Malnutrition

By GARDINER HARRIS      JULY 13, 2014
http://www.nytimes.com/2014/07/15/world/asia/poor-sanitation-in-india-may-afflict-well-fed-children-with-malnutrition.html

SHEOHAR DISTRICT, India — He wore thick black eyeliner to ward off the evil eye, but Vivek, a tiny 1-year-old living in a village of mud huts and diminutive people, had nonetheless fallen victim to India’s great scourge of malnutrition.

His parents seemed to be doing all the right things. His mother still breast-fed him. His family had six goats, access to fresh buffalo milk and a hut filled with hundreds of pounds of wheat and potatoes. The economy of the state where he lives has for years grown faster than almost any other. His mother said she fed him as much as he would eat and took him four times to doctors, who diagnosed malnutrition. Just before Vivek was born in this green landscape of small plots and grazing water buffalo near the Nepali border, the family even got electricity.

So why was Vivek malnourished?

‘Bihar grew at 12% last 7 years’

Abhay Singh, TNN | Feb 15, 2014, 02.15AM IST

 

Bihar's average annual growth rate has been 12% in the last seven fiscal years

Bihar’s average annual growth rate has been 12% in the last seven fiscal years

 

 

The report has taken 1999-2006 as the cut-off period to highlight spectacular Bihar turnaround story achieved under CM Nitish Kumar.

PATNA: Bihar’s average annual growth rate has been 12% in the last seven fiscal years, one of the highest among all Indian states, on the back of high growth rate achieved in the agriculture and allied sectors. Besides, advancement has also been made in healthcare and education.

The state’s Economic Survey Report for 2013-14, which was tabled in the assembly on Friday, has concluded this. The summary of the report said, “During 1990-91 to 2005-06, the state’s income at constant prices grew at an annual rate of 5.7%.” It said after that the economy witnessed a turnaround and grew at an annual rate of 12%. “The rate of growth achieved by the economy during 2006-13 is not only much higher, but also one of the highest among all Indian states.”

The report has taken 1999-2006 as the cut-off period to highlight spectacular Bihar turnaround story achieved under CM Nitish Kumar.

 

Poor Sanitation Linked to Malnutrition in India

New research on malnutrition, which leads to childhood stunting, suggests that a root cause may be an abundance of human waste polluting soil and water, rather than a scarcity of food.

SANITATION - bathing in Ganges River contaminated by human waste

SANITATION – bathing in Ganges River contaminated by human waste

 

 

Like almost everyone else in their village, Vivek and his family have no toilet, and the district where they live has the highest concentration of people who defecate outdoors. As a result, children are exposed to a bacterial brew that often sickens them, leaving them unable to attain a healthy body weight no matter how much food they eat.

“These children’s bodies divert energy and nutrients away from growth and brain development to prioritize infection-fighting survival,” said Jean Humphrey, a professor of human nutrition at Johns Hopkins Bloomberg School of Public Health. “When this happens during the first two years of life, children become stunted. What’s particularly disturbing is that the lost height and intelligence are permanent.”

Two years ago, Unicef, the World Health Organization and the World Bank released a major report on child malnutrition that focused entirely on a lack of food. Sanitation was not mentioned. Now, Unicef officials and those from other major charitable organizations said in interviews that they believe that poor sanitation may cause more than half of the world’s stunting problems.

“Our realization about the connection between stunting and sanitation is just emerging,” said Sue Coates, chief of water, sanitation and hygiene at Unicef India. “At this point, it is still just an hypothesis, but it is an incredibly exciting and important one because of its potential impact.”

This research has quietly swept through many of the world’s nutrition and donor organizations in part because it resolves a great mystery: Why are Indian children so much more malnourished than their poorer counterparts in sub-Saharan Africa?

A child raised in India is far more likely to be malnourished than one from the Democratic Republic of Congo, Zimbabwe or Somalia, the planet’s poorest countries. Stunting affects 65 million Indian children under the age of 5, including a third of children from the country’s richest families.

This disconnect between wealth and malnutrition is so striking that economists have concluded that economic growth does almost nothing to reduce malnutrition.

Half of India’s population, or at least 620 million people, defecate outdoors. And while this share has declined slightly in the past decade, an analysis of census data shows that rapid population growth has meant that most Indians are being exposed to more human waste than ever before.

In Sheohar, for instance, a toilet-building program between 2001 and 2011 decreased the share of households without toilets to 80 percent from 87 percent, but population growth meant that exposure to human waste rose by half.

“The difference in average height between Indian and African children can be explained entirely by differing concentrations of open defecation,” said Dean Spears, an economist at the Delhi School of Economics. “There are far more people defecating outside in India more closely to one another’s children and homes than there are in Africa or anywhere else in the world.”

 

SANITATION-children defecate outside - 162 million malnourished and stunted

SANITATION-children defecate outside – 162 million malnourished and stunted

 

Not only does stunting contribute to the deaths of a million children under the age of 5 each year, but those who survive suffer cognitive deficits and are poorer and sicker than children not affected by stunting. They also may face increased risks for adult illnesses like diabetes, heart attacks and strokes.

“India’s stunting problem represents the largest loss of human potential in any country in history, and it affects 20 times more people in India alone than H.I.V./AIDS does around the world,” said Ramanan Laxminarayan, vice president for research and policy at the Public Health Foundation of India.

India is an increasingly risky place to raise children. The country’s sanitation and air quality are among the worst in the world. Parasitic diseases and infections like tuberculosis, often linked with poor sanitation, are most common in India. More than one in four newborn deaths occur in India.

Open defecation has long been an issue in India. Some ancient Hindu texts advised people to relieve themselves far from home, a practice that Gandhi sought to curb.

“The cause of many of our diseases is the condition of our lavatories and our bad habit of disposing of excreta anywhere and everywhere,” Gandhi wrote in 1925.

SANITATION-disposing of excreta anywhere and everywhere

SANITATION-disposing of excreta anywhere and everywhere

 

 

Other developing countries have made huge strides in improving sanitation. Just 1 percent of Chinese and 3 percent of Bangladeshis relieve themselves outside compared with half of Indians. Attitudes may be just as important as access to toilets. Constructing and maintaining tens of millions of toilets in India would cost untold billions, a price many voters see no need to pay — a recent survey found that many people prefer going to the bathroom outside.

Few rural households build the sort of inexpensive latrines that have all but eliminated outdoor waste in neighboring Bangladesh.

“We need a cultural revolution in this country to completely change people’s attitudes toward sanitation and hygiene,” said Jairam Ramesh, an economist and former sanitation minister.

India’s government has for decades tried to resolve the country’s stubborn malnutrition problems by distributing vast stores of subsidized food. But more and better food has largely failed to reverse early stunting, studies have repeatedly shown.

India now spends about $26 billion annually on food and jobs programs, and less than $400 million on improving sanitation — a ratio of more than 60 to 1.

Lack of food is still an important contributor to malnutrition for some children, and some researchers say the field’s sudden embrace of sanitation has been overdone. “In South Asia, a more important factor driving stunting is diet quality,” said Zulfiqar A. Bhutta, a director of the Center for Global Child Health at the Hospital for Sick Children in Toronto.

Studies are underway in Bangladesh, Kenya and Zimbabwe to assess the share of stunting attributable to poor sanitation. “Is it 50 percent? Ninety percent? That’s a question worth answering,” said Dr. Stephen Luby, a professor of medicine at Stanford University who is overseeing a trial in Bangladesh that is expected to report its results in 2016. “In the meantime, I think we can all agree that it’s not a good idea to raise children surrounded by poop.”

Better sanitation in the West during the 19th and early 20th centuries led to huge improvements in health long before the advent of vaccines and antibiotics, and researchers have long known that childhood environments play a crucial role in child death and adult height.

The present research on gut diseases in children has focused on a condition resulting from repeated bacterial infections that flatten intestinal linings, reducing by a third the ability to absorb nutrients. A recent study of starving children found that they lacked the crucial gut bacteria needed to digest food.

In a little-discussed but surprising finding, Muslim children in India are 17 percent more likely to survive infancy than Hindus, even though Muslims are generally poorer and less educated. This enormous difference in infant mortality is explained by the fact that Muslims are far more likely to use latrines and live next to others also using latrines, a recent analysis found.

So widespread housing discrimination that confines many Muslims to separate slums may protect their children from increased exposure to the higher levels of waste in Hindu communities and, as a result, save thousands of Indian Muslim babies from death each year.

SANITATION-one in 4 newborn deaths related to sanitation

SANITATION-one in 4 newborn deaths related to sanitation

 

 

Discussion:

The coexistence of poor sanitation, where has a very large cultural barrier, with serious protein-energy malnutrition, is a toxic mix.  There is the comparison with the Muslim population at the adjoining border of the Ganges River outflow in Bangladesh.  One might also look at the catholic Portuguese population in Goa, the Jewish population in Mumbai and Kochi, and the nearby Catholic population.  There is no malnutrition in those populations, or in the Siiks.  This is undoubtedly a cultural phenomenon of ancient origin.  (The migration of the jews and of the catholics to Kochi occurred around the Indian Ocean at the time of Christ.  The catholic population in Goa was from Portugal.

I don’t think we have enough of the story here.  The Ganges river flows centrally across India, and is not far from the Himalayas.  This has some significance in the sufficiency of animal protein availability, and most importantly, of what I might expect of the tissue S:N ratio, which is critical for availability of methionine, S-adenosyl methionine, and mitochondrial energy reactions.  These are also mediated by transsulfuration reactions and by cystathionine beta-synthase.  Detailed discussions are available elsewhere.   It has been pointed out by Vernon Young and Yve Ingenbleek that sulfur is insufficient in the soil where there is not a lava flow of volcanic ash, which could be the case here.  So it is at best not a good geographic situation, even before compounding the issue.

The relationship to heart attack and stroke is established for elevated homocysteine.

Homocysteine and Vascular Disease
STEVEN E . S. MINER , M.D. , DAVID E .C. COLE *, M.D. , PHD. AND DUNCAN J . STEWART, M.D.
Cardiology Rounds   A U G U S T 1 9 9 6 ;  I(5)

Homocysteine is a naturally occurring, sulfur-containing amino acid. Continuously formed and catabolized in vivo, its metabolism is dependent on a complex interaction of genetics and physiology (Fig. 1). Its relevance is based on the increasing recognition of the correlation between elevated levels of homocysteine and human disease.

Table 1
Selected Determinants of Plasma Homocysteine*
1. Genetic
• Cystathionine-beta-synthase:
heterozygote mutations 0.5-1.5% {451}
• Methionine synthase: rare
• MTHFR: heterozygote mutations
approximately 50% {403}
2. Physiologic
• age: Hcy increases with increasing age {336}
• sex: pre-and post-menopausal women
have lower levels than men {247}
• diet: related to methionine and vitamin cofactor
(folate, vitamins B6 and B12) intake {437}
• alcohol: relationship unclear {375}
3. Pathologic
• vitamin deficiency: increased homocysteine
concentrations {10}
• renal disease: increase correlated
with increasing serum creatinine {81}
• transplantation: increased levels {149, 435}
• post stroke: transiently decreased levels {341}
• severe psoriasis: elevated levels {438}
4. Medications
• oral contraceptives/hormone replacement:
decreased levels {269}
• corticosteriods: increased {159}
• cyclosporine: increased {393}
• smoking: increased {336}

Abstracts of Interest
Serum total homocysteine and coronary heart disease in middleaged
British men.
IJ PERRY, H REFSUM, RW MORRIS, SB EBRAHIM, PM UELAND, AG SHAPER.
D E PA RTMENT OF PRIMARY CARE & POPULATION SCIENCES, ROYAL FREE
H O S P I TAL SCHOOL OF MEDICINE, LONDON, AND DEPA RTMENT OF CLINICAL
B I O L O G Y, UNIVERSITY OF BERGEN, NORWAY.
Serum total homocysteine (tHcy) levels are inversely associated with dietary intake of folic acid and B vitamins. Raised tHcy levels have been linked with coronary heart disease (CHD). We have examined the association between tHcy concentration and the subsequent risk of CHD, using a nested case control study design, within a prospective study of cardiovascular disease in British men. tHcy concentration was measured in serum samples, stored at entry to the study, from 110 incident cases of myocardial infarction and 118 controls. Cases were randomly sampled from events which occured after the first five years of follow-up. Cases and controls were frequency matched by town and age group. Levels of homocysteine [geometric mean (95% CI)] were significantly higher in cases than controls: homocysteine 13.5 (12.6 – 14.3) μmol/L vs 11.9 (11.3 – 12.6) μmol/L; p=0.005. There was a graded increase in the relative risk (odds ratio; OR) of CHD in the 2nd, 3rd and 4th quartile of tHcy (OR 1.4, 1.9, 2.2; trend p=0.006) relative to the first quartile. Adjustment for age, town, social class, body mass index, smoking, physical activity, alcohol intake, hypertensive status, serum cholesterol, and serum creatinine did not attenuate this association, (OR 2.1, 2.3, 2.7; trend p=0.04). tHcy levels were higher at baseline in men with evidence of pre-existing CHD and (as expected) adjustment for this factor attenuated the linear association between tHcy and subsequent events, trend p=0.07. The findings suggest that homocysteine is an independent risk factor for CHD
with no threshold level.
Reprinted from Heart, Volume 75 /Number 5 (Supplement 1), May 1996.
Homocysteine and Coronary Atherosclerosis
ELLEN L. MAYER, MD, DONALD W. JACOBSEN, PHD, KILLIAN ROBINSON, MD,
FACC, CLEVELAND, OHIO
The conventional risk factors for premature coronary artery disease include smoking, hyperlipidemia, hypertension, diabetes and a positive family history. However, many patients have precocious atherosclerosis without having any of these standard risk factors. Identification of other markers that increase the risk of coronary disease may improve our understanding of the pathophysiologic mechanisms of this disorder and allow the development of new preventive or therapeutic measures. An elevated plasma homocysteine level has recently received greater attention as an important risk factor for vascular disease, including coronary atherosclerosis. This review discusses the biochemistry of homocysteine and the related metabolic importance of folate, vitamin B6 (pyridoxine) and B12 (cobalamin) as well as a number of essential enzymes. The major factors that influence homocysteine concentration are genetic, nutritional and pathologic.
There is a large body of experimental and clinical evidence for high plasma homocysteine to be a risk factor for vascular disease, including coronary atherosclerosis.
Excerpted from Journal of the American College of Cardiology 1996;27:517-27

An important meta-analysis by Boushey et al in 1995 further quantified the magnitude of risk. In their analysis of all major studies available at that time, they found a linear, independent risk  for increments in homocysteine. There were no levels above or below which an incremental rise in homocysteine did not affect cardiovascular risk. Specifically, every 5 μmol/L increment in homocysteine was found to be associated with odds ratios of 1.6 for m e n ; (95% Cl 1.4-1.7) and 1.8 for women; (95% CI 1.3-1.9) for coronary artery disease.

Cystathionine beta synthase (CBS) catalyzes the reaction taking homocysteine to cystathionine. This enzyme requires pyridoxine as a co-factor and is an integral part of the transsulfuration or
pyridoxine – dependent pathway. 33 distinct mutations have been identified with heterozygosity occurring at a prevalence of 0.5-1.5%. The majority of heterozygotes will have normal fasting homocysteine levels, but can be detected with a methionine load test.

Hyperhomocysteinemia is a Biomarker of Sulfur-Deficiency in Human Morbidities

Yves Ingenbleek
Laboratory of Nutrition, University Louis Pasteur Strasbourg, France
The Open Clinical Chemistry Journal, 2009, 2, 49-60

Abstract: Methionine (Met) is crucially involved in the synthesis of S-compounds endowed with molecular, structural and functional properties of survival value. Dietary Met may undergo transmethylation processes to release homocysteine (Hcy) which may either be regenerated to Met following remethylation (RM) pathways or catabolized along the transsulfuration
(TS) cascade. The activity of enzymes governing RM and TS pathways is depending on pyridoxine, folate and cobalamin bioavailability. Dietary restriction in any of these watersoluble B-vitamins may lead to hyperhomocysteinemia (HHcy) causing a panoply of cardiovascular disorders. Taken together, the vitamin triad only affords partial account of Hcy variance, prompting the search for additional causal factor(s). Body composition studies demonstrate that nitrogen (N) and sulfur (S) maintain tightly correlated concentrations in tissues of both healthy subjects and diseased patients. Any morbid condition characterized by insufficient N intake or assimilation, as seen in protein malnutrition or intestinal malabsorption, reduces body S accretion rates. Excessive urinary N-losses, as reported in acute or chronic inflammatory disorders, entail proportionate obligatory S-losses. As a result, lean body mass (LBM) undergoes downsizing and concomitant depletion of N and S body stores which depresses the activity of cystathionine-􀀁-synthase, thereby promoting upstream accumulation of Hcy and overstimulation of RM processes. HHcy thus appears as the dark side of efforts developed by S-deprived patients to safeguard Met homeostasis. Irrespective of vitamin-B status, Hcy values are negatively correlated with LBM shrinkage well identified by the serial measurement of plasma transthyretin (TTR). The S deprivation theory fulfills the gap and allows full causal coverage of the metabolic anomaly, hence providing together with vitamin-deficiencies an unifying overview of the main nutritional determinants implicated in HHcy epidemiology.

The Oxidative Stress of Hyperhomocysteinemia Results from Reduced Bioavailability of Sulfur-Containing Reductants

Yves Ingenbleek
Laboratory of Nutrition, Faculty of Pharmacy, University Louis Pasteur Strasbourg, France
The Open Clinical Chemistry Journal, 2011, 4, 34-44

Abstract: Vegetarian subjects consuming subnormal amounts of methionine (Met) are characterized by subclinical protein malnutrition causing reduction in size of their lean body mass (LBM) best identified by the serial measurement of plasma transthyretin (TTR). As a result, the transsulfuration pathway is depressed at cystathionine-beta-synthase (C-b-S) level triggering the upstream sequestration of homocysteine (Hcy) in biological fluids and promoting its conversion to Met. Maintenance of beneficial Met homeostasis is counterpoised by the drop of cysteine (Cys) and glutathione (GSH) values downstream to CbS causing in turn declining generation of hydrogen sulfide (H2S) from enzymatic sources. The biogenesis of H2S via non-enzymatic reduction is further inhibited in areas where earth’s crust is depleted in elemental sulfur (S8) and sulfate oxyanions. Combination of subclinical malnutrition and S8-deficiency thus maximizes the defective production of Cys, GSH and H2S reductants, explaining persistence of unabated oxidative burden. The clinical entity increases the risk of developing cardiovascular diseases (CVD) and stroke in underprivileged plant-eating populations regardless of Framingham criteria and vitamin-B status. Although unrecognized up to now, the nutritional disorder is one of the commonest worldwide, reaching top prevalence in populated regions of Southeastern Asia. Increased risk of hyperhomocysteinemia and oxidative stress may also affect individuals suffering from intestinal malabsorption or westernized communities
having adopted vegan dietary lifestyles.

 

 

 

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Life-work in Engineering of Improved Heart Valve

Curator and Reporter: Larry H Bernstein, MD, FCAP

 

An authority and author of the book on cardiovascular valve devices is challenged by patient’s mother to go beyond what is available.  The results are splendid after re-engineering the design to the problem.

 

Reverse Engineering A Human Heart Valve

By Jim Pomager

aortic valve - a remarkable piece of biomechanical engineering

aortic valve – a remarkable piece of biomechanical engineering

 

 

 

The aortic valve is a remarkable piece of biomechanical engineering. On any given day, the leaflets (or cusps) of a healthy aortic valve will open and close 100,000+ times, allowing the proper amount of blood to flow from the heart to the rest of the body. Over a lifetime, a healthy valve endures more than 3.4 billion heartbeats.

Unfortunately, the aortic valve doesn’t always remain healthy. (What organ does?) According to the American Heart Association, up to 1.5 million people in the United States suffer from aortic stenosis (AS), a calcification of the aortic valve that narrows its opening and restricts blood flow. In the early stages, the disease is often asymptomatic, but as it progresses, it can cause chest pain, weakness, and difficulty breathing. And in approximately 300,000 people worldwide, the condition develops into severe AS, which has a one-year survival rate of approximately 50 percent, if left untreated.

Fortunately, there are treatment options.  The most common and successful is aortic valve replacement (AVR), wherein a mechanical or tissue-based valve is substituted for the diseased valve. For decades, replacement valves were implanted via open heart surgery, which involves an extended hospital stay and months of recovery. But in recent years, a promising new approach has emerged: transcatheter aortic valve implementation (TAVI), also known as transcatheter aortic valve replacement (TAVR). In TAVI, a tissue-based artificial valve is delivered into the diseased heart valve via a blood vessel, rather than through a large incision in the chest.

TAVI has many benefits, the most obvious (and compelling) of which is its noninvasiveness, which means shorter recovery times and faster attainment of quality-of-life outcomes for the patient. Replacement of a transcatheter aortic valve (TAV) can also be a minimally invasive exercise — a second TAV can simply be implanted within the first.

On the other hand, the use of TAVI procedures in U.S. hospitals is not yet widespread (though it is growing rapidly). The longevity of current-generation TAVs also remains unknown because it is an emerging technology, compared to evidence of 15+ years for surgically implanted heart valves. Plus, TAVI is only approved in the U.S. for use in AS patients who are either ineligible for surgical valve replacement or at high risk. (TAVI has been available in Europe since 2007, and clinical trials are underway in the U.S. for its use in intermediate-risk patients.)

What’s really needed is an improved TAV — one that outperforms current transcatheter valves, is as durable as a surgical valve, and operates more like … well, a healthy human aortic valve. Such a valve would open the door to TAVI’s use in the hundreds of thousands of lower-risk (and generally younger) AS patients whose only current option is a surgically implanted valve, and who would rather not have their chest opened.

Now, a man who has dedicated his professional career to studying the aortic valve has invented a new artificial valve design that he says will revolutionize TAVI. And if everything goes according to plan, his TAV will reach European patients in 2015 and U.S. patients soon after. How did he and his startup company design such technology? By reverse engineering the aortic valve.

The Man Behind The Valve

Mano Thubrikar

Mano Thubrikar

 

 

 

Mano Thubrikar, quite literally wrote the book on heart valves and heart disease — two of them, in fact. His The Aortic Valve (1989) and Vascular Mechanics and Pathology (2007) are leading textbooks in cardiovascular studies, and the former is widely used as a guide in the design of bioprosthetic heart valves.

After earning an undergraduate degree in metallurgy, a master’s in materials science, and a Ph.D. in biomedical engineering, Dr. Thubrikar spent the first 30 years of his career exclusively in academic research. He studied the aortic valve and bioprostheses from almost every conceivable angle while working at the University of Virginia (UVA) and at the Carolinas Medical Center and the University of North Carolina (UNC) at Charlotte.

But in 2003, Dr. Thubrikar received a phone call that would change the trajectory of his career and set him on the path to develop a novel TAV technology. A woman contacted him to discuss her son, a 35-year-old athlete with a calcified aortic valve. The condition was the result of a bicuspid valve, a congenital condition where the aortic valve has two cusps, rather than the customary three. The man needed a valve replacement, and his only choice was to have a mechanical heart valve surgically implanted. However, the surgical valve meant he would have to stay on anticoagulants for the rest of his life, effectively ending his athletic pursuits. Dr. Thubrikar informed the mother that there just weren’t any treatments available that would allow her son to continue his active lifestyle.

“Didn’t you write the book on the aortic valve?” she asked. “Why didn’t you make a valve that my son could use?”

The conversation and question deeply affected the researcher. “I went home and was so disturbed,” he told me during a recent visit to his office. “I talked to my wife and said, “You know what? Years of research, writing papers, and giving presentations — that’s done. I now need to make a heart valve.”

Soon after, Dr. Thubrikar left Carolinas Medical Center to embark on his new mission. He joined artificial heart valve pioneer Edwards Lifesciences as a Distinguished Scientist, but left after it became clear that the company’s plans for him didn’t align with his own.

So in 2007 — coincidentally, the same year Edwards launched the first commercially available TAV device — Dr. Thubrikar returned to academia, joining the staff at the South Dakota School of Mines & Technology. There he spent the next three years working on a new artificial valve design — one based on decades of research on the physics behind the human aortic valve.

Looking To The Human Body For Design Output
According to Dr. Thubrikar’s research, the natural aortic valve follows four strong design principles for maximum longevity and optimal hemodynamic performance. Those criteria are:

1. A specific coaptation height — When the valve’s three leaflets come together to close the valve, there is some surface-to-surface contact between the leaflets, rather than an edge-to-edge seal. This safety margin helps prevent against blood leakage back into the left ventricle.

2. No folds in the leaflets — Natural aortic valve cusps flex without folding. Folds would crease the tissue and cause unwanted stress on the leaflets, negatively impacting durability.

3. Minimum overall height — Extra height would produce dead space, which can lead to a variety of issues.

4. Minimum leaflet flexion — The human aortic valve manages to open completely with the leaflets moving only 70 degrees, not the 90 degrees you might expect. Again, this improves the valve’s longevity.

“You almost need to be a solid geometry design engineer to understand the math and the equations behind these principles,” he explained. “With these criteria, however, you have design parameters for the aortic valve. The mathematical equations give you the output of how an artificial valve should be designed.”

Dimensions of the natural aortic valve

Dimensions of the natural aortic valve

Dimensions of the natural aortic valve

 

 

Based on these four principles, Dr. Thubrikar reverse engineered the aortic heart valve, developing a new artificial valve design that mimics the aortic valve’s precise geometry. In October 2010, he launched a startup company called Thubrikar Aortic Valve, Inc. to commercialize his new creation, which he calls Optimum TAV and touts as “nature’s valve by design.”

“When someone asks me, ‘How does your valve compare with Edwards’?’ or ‘How does your valve compare with Medtronic’s?’, I say ‘We don’t compare our valve to them,'” Dr. Thubrikar told me. “We compare our valve with the natural aortic valve.”

On the surface, Optimum TAV looks similar to other artificial heart valves on the market, with three leaflets of bovine pericardium tissue mounted on a metal stent-frame. (In fact, the design is often mistaken for another widely used surgical valve.) But according to Dr. Thubrikar, it has a unique combination of features that will help it overcome the major design limitations of current-generation TAVs (if we’re going to compare). Those design limitations include:

  • Suture holes in the leaflet body — While all TAVs (including Optimum TAV) are constructed by sewing animal tissue to a metal frame, piercing the flexion zone of the leaflets leads to potential wear. Optimum TAV does not have a single suture hole in the working portion of the leaflet body.
  • Blood flow through frame — Some TAV frames are as tall as 5 cm in height, extending up into the aorta once implanted. As a result, blood must pass through the frame to enter the coronary arteries. Proteins in the blood will accumulate on the frame, and can eventually break loose and cause thromboembolisms (blood clots).  Optimum TAV is only 2 cm in height. (Related, the low height of the Thubrikar valve also makes it less likely to require a pacemaker.)
  • Thick outer frame — The thicker the frame, the smaller the valve opening will be, allowing less blood to pass through. This opening is referred to as the valve’s EOA, or effective orifice area. The average EOA of a surgical valve is around 1.9 cm2, and some TAVs have EOAs as small as 1.5 cm2(technically, a mild form of stenosis). In bench tests, Optimum TAV’s EOA was 2.3 to 2.4 cm2. (A healthy aortic valve has an EOA of approximately 2.7 cm2.)
  • Clipped calcified leaflets — Some current TAVs are anchored to the patient’s original valve using a paper-clip like mechanism. In this design, there is the potential that the TAVs leaflets will come into contact with the old, calcified leaflets during the operation, causing wear. Optimum TAV’s design eliminates the possibility of contact between the leaflets and native valve.
  • Paravalvular leakage — In some cases, a space forms between the outside of a TAV and the surrounding heart tissue, and blood can leak through. Optimum TAV has a high skirt to prevent this type of gap from developing. In addition, Optimum TAV’s novel frame architecture allows it to conform to and seal off either a round or elliptical annulus (the ring-shaped base of the original valve). This is particularly helpful in minimizing or eliminating leakage in bicuspid patients, who often have an irregularly shaped annulus.
  • Balloon expansion — TAV frames made of stainless steel must be forced open by a balloon. The TAV’s tissue can get caught between the balloon and the frame and potentially tear. Optimum TAV’s frame is made of nitinol, which automatically expands once deployed from the catheter.

 

optimum TAV

optimum TAV

 

 

Optimum TAV

“Other technologies have built-in issues,” Dr. Thubrikar said. “To be able to avoid those problems in a comprehensive fashion is no small feat.”

Trial By Fire
During the two and a half years following the establishment of Thubrikar Aortic Valve, Optimum TAV seemed to be moving steadily toward market. The company raised enough funding to get started, primarily from friends, family, physicians, entrepreneurs, and technology industry executives. Patent applications were filed, suppliers were selected, valves were painstakingly produced (by hand, over one-and-a-half to two days each), and preclinical testing began.

Members of the Thubrikar Aortic Valve team

Members of the Thubrikar Aortic Valve team

 

 

Members of the Thubrikar Aortic Valve team (left to right): Deodatt Wadke, member of the board of directors and cofounder; Samir Wadke, executive director of business development and cofounder; Dr. Mano Thubrikar, president and founder; Samuel Evans, research engineer II; and Nikhil Heble, counsel, secretary, and cofounder

But the fledgling company was dealt a major setback in April 2013, when a fire destroyed the Horsham, Pa. office building to which the Thubrikar Aortic Valve laboratory had recently relocated (from South Dakota). All of its equipment was destroyed and needed to be replaced. The company had to relocate to nearby Norristown, Pa. Not an ideal scenario for a startup trying to make the most of extremely limited resources.

The company was undeterred by the fire, and the last year has been a successful one for Thubrikar. The company completed most of its preclinical testing (including implants in 12 animals and two diseased human cadaver hearts), reached design freeze on Optimum TAV, filed a provisional patent application for its proprietary delivery catheter, and achieved almost $2 million in total funding. Perhaps the biggest milestone came in August 2013, when Optimum TAV met the International Organization for Standardization’s (ISO’s) durability requirements by surpassing 200 million cycles in a third-party ISO certified laboratory.

The durability testing has continued, and Optimum TAV continues to function beyond 390 million cycles, which approximates 11 years in vivo. Surgical valves typically last anywhere from 12 to 18 years, and Thubrikar expects his valve to last at least that long.

“I would not be surprised if it surpasses the longevity of even the surgical valve,” he said.

The company also received its first institutional investment, from Delaware Crossing Investor Group (DCIG), in 2014. The primary DCIG investor, Marv Woodall, led the commercialization of the world’s first stents as president of Johnson & Johnson Interventional Systems (now Cordis) and was on the board of director of the first TAV company, Percutaneous Valve Technologies (PVT, now part of Edwards Lifesciences). Thubrikar has recruited him as its business advisor.

What Lies Ahead
Like many other developers of novel medical devices, Thubrikar Aortic Valve has decided to take its product to market through Europe initially, given European regulators’ comfort level with TAV and the FDA’s steep requirement for clinical trials. “We have spoken to the FDA and will continue to do so on a regular basis,” according to Dr. Thubrikar. “But they asked for a lot more preclinical testing than the European Notified Bodies to start a clinical trial.”

The company is now working to raise an additional $2 million to $10 million, and expects the granting of its patent for Optimum TAV in 2014. The finances will enable Thubrikar to not only conduct a first-in-human (FIH) feasibility study in up to 15 patients this year, but also to expand to a full European clinical trial of about 65 additional patients in 2015. If all goes well, a 2015 CE Mark for Optimum TAV isn’t out of the question.

However, trial success is vital, since today’s investors — and large companies in search of technology acquisitions — wait for significant clinical data to accumulate before backing a medical device. “We realize that until we actually implant the valve in a patient, other companies will think, ‘You don’t know what can go wrong,'” Dr. Thubrikar explained. “We had one big company say, ‘We will pay you four times as much once the product is in a patient.’ They want you to de-risk everything, to work out all the bugs yourself on your own dime.”

Yet Dr. Thubrikar thinks its only a matter of time until his life’s work finally arrives in the hands of interventional cardiologists, who he said have been “knocking at his door” since he first presented a paper on the technology in 2012. Since then, he has spoken at several of the largest interventional cardiology conferences, and word continues to spread about Optimum TAV. Like many other researchers-turned-entreprenuers, he steadfastly believes that his invention will eventually reach the market, where it can begin helping patients — like the one whose mother contacted him a decade ago.

“If hell freezes over, if we don’t get any money, I don’t care,” he said. “I don’t care how it happens. We are going to make a heart valve. That’s the only mission in my life.”

For more information on Thubrikar Aortic Valve and Optimum TAV, visit http://tavi.us/.

 

 

 

 

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Genomics, Proteomics and standards

Larry H. Bernstein, MD, FCAP, Curator

http://pharmaceuticalintelligence/7/6/2014/Genomics, Proteomics and standards

This article is a look at where the biomedical research sciences are in developing standards for development in the near term.

 

Let’s Not Wait for the FDA: Raising the Standards of Biomarker Development – A New Series

published by Theral Timpson on Tue, 07/01/2014 – 15:03

We talk a lot on this show about the potential of personalized medicine. Never before have we learned at such breakneck speed just how our bodies function. The pace of biological research staggers the mind and hints at a time when we will “crack the code” of the system that is homo sapiens, going from picking the low hanging fruit to a more rational approach. The high tech world has put at the fingertips of biologists just the tools to do it. There is plenty of compute, plenty of storage available to untangle, or decipher the human body. Yet still, we talk of potential.

Chat with anyone heavily involved in the life science industry–be it diagnostics or pharma– and you’ll quickly hear that we must have better biomarkers.

Next week we launch a series, Let’s Not Wait for the FDA: Raising the Standards of Biomarker Development, where we will pursue the “hotspots” that are haunting those in the field.

The National Biomarker Development Alliance (NBDA) is a non profit organization based at Arizona State University and led by the formidable Anna Barker, former deputy director of the NCI. The aim of the NBDA is to identify problem areas in biomarker development–from the biospecimen and sampling issues to experiment design to bioinformatics challenges–and raise the standards in each area. This series of interviews is based on their approach. We will purse each of these topics with a special guest.

The place to start is with samples. The majority of researchers who are working on biomarker assays don’t give much thought to the “story” of their samples. Yet the quality of their research will never exceed the quality of the samples with which they start–a very scary thought according toCarolyn Compton, a former pathologist, now professor of pathology at ASU and Johns Hopkins. Carolyn worked originally as a clinical pathologist and knows first hand the the issues around sample degradation. She left the clinic when she was recruited to the NCI with the mission of bringing more awareness to the issue of bio specimens. She joins us as our first guest in the series.

That Carolyn has straddled the world of the clinic and the world of research is key to her message. And it’s key to this series. As we see an increased push to “translate” research into clinical applications, we find that these two worlds do not work enough together.

Researchers spend a lot of time analyzing data and developing causal relationships from certain biological molecules to a disease. But how often do these researchers consider how the history of a sample might be altering their data?

“Garbage in, garbage out,” says Carolyn, who links low quality samples with the abysmal non-reproducable rate of most published research.

Two of our guests in the series have worked on the adaptive iSpy breast cancer trials. These are innovative clinical trials that have been designed to “adapt” to the specific biology of those in the trial. Using the latest advances in genetics, the iSPY trials aim to match experimental drugs with the molecular makeup of tumors most likely to respond to them. And the trials are testing multiple drugs at once.

Don Berry is known for bringing statistics to clinical trials. He designed the iSpy trials and joins us to explain how these new trials work and of the promise of the adaptive design.

Laura Esserman is the director of the breast cancer center at UCSC and has been heavily involved in the implementation of the iSpy trials. Esserman is concerned that “if we keep doing conventional clinical trials, people are going to give up on doing them.” An MBA as well as an MD, Esserman brings what she learned about innovation in the high-tech industry to treatment for breast cancer.

From there we turn to the topic of “systems biology” where we will chat with George Poste, a tour de force when it comes to considering all of the various aspects of biology. Anyone who has ever been present for one of George’s presentations has no doubt come away scratching your head wondering if we’ll ever really glimpse the whole system that is a human being. If there is one brain that has seen all the rooms and hallways of our complex system, it’s George Poste.

We’ll finish the series by interviewing David Haussler from UCSC of Genome Browser fame. Recently Haussler has worked extensively on an NCI project, The Cancer Genome Atlas, to bring together data sets and connect cancer researchers around the world. What is the promise and pitfalls David sees with the latest bioinformatics tools?

George Poste says that in the literature we have identified 150,000 biomarkers that have causal linkage to disease. Yet only 100 of these have been commercialized and are used in the clinic. Why is the number so low? We hope to come up with some answers in this series.

 

 

Why Hasn’t Clinical Genetics Taken Off? (part 2)

published by Sultan Meghji on Fri, 06/20/2014 – 14:49

 

In my previous post, I made the broad comment that education of the patient and front line doctors was the single largest barrier to entry for clinical genetics. Here I look at the steps in the scientific process and where the biggest opportunities lie:

The Sequencing (still)

PCR is a perfectly reasonable technology for sequencing in the research lab today, but the current configuration of technologies need to change. We need to move away from an expert level skill set and a complicated chemistry process in the lab to a disposable, consumer friendly set of technologies. I’m not convinced PCR is the right technology for that and would love to see nanopore be a serious contender, but lack of funding for a broad spectrum of both physics-only as well as physical-electrical startups have slowed the progress of these technologies. And waiting in the wings, other technologies are spinning up in research labs around the world. Price is no longer a serious problem in the space – reliable, repeatable, easy to use sequencing technologies are. The complexity of the current technology (both in terms of sample preparation and machine operation) is a big hurdle.

The Analysis (compute)

Over the last few years, quite a bit of commentary and effort has been put into making the case that the compute is a significant challenge (including more than a few comments by yours truly in that vein!). Today, it can be said with total confidence that compute is NOT a problem. Compute has been commoditized. Through excellent new software to advanced platforms and new hardware, it is a trivial exercise to do the analysis and costs tiny amounts of money ($<25 per sample on a cloud provider appears to be the going rate for a clinical exome in terms of platform & infrastructure cost). Integration with the sequencer and downstream medical middleware is the biggest opportunity.

The Analysis (value)

The bigger challenge on the analysis is the specific things being analyzed as mapped to the needs of the patient. We are still in a world where the vast majority of the sequencing work is being done in support of a specific patient with a specific disease. There isn’t even broad consensus yet in the scientific community about the basics of the pipeline (see my blog posthere for an attempt at capturing what I’m seeing in the market). A movement away from the recent trend in studying specific indications (esp. cancer) is called for. Broadening the sample population will allow us to pick simpler, clearer and easier pipelines which will then make them more adoptable. It would be a massive benefit to the world if the scientific, medical and regulatory communities would get together and start creating, in a crowdsourced manner, a small number of databases that are specifically useful to healthy people. Targeting things like nutrition, athletics, metabolism, and other normal aspects of daily life. A dataset that could, when any one person’s DNA is references, would find something useful. Including the regulators is key so that we can begin to move away from the old fashioned model of clearances that still permeate the industry.

The Regulators

Beyond the broader issues around education I referenced in my previous post, there is a massive upgrade in the regulation infrastructure that is needed. We still live in a world of fax machines, overnight shipping of paper documents and personal relationships all being more important than the quality of the science you as an innovator are bringing to bear.

Consider the recent massive growth in wearables, fitness trackers and other instrumentation local to the human body. Why must we treat clinical genetics simply as a diagnostic and not, as it should be, as a fundamental set of quantitative data about your body that you can leverage in a myriad of ways. Direct to consumer (DTC) genetics companies, most notably 23andme, have approached this problem poorly – instead of making it valuable to the average consumer, what they’ve done is attempted to straddle the line between medical and not. The Fitbit model has shown very clearly that lifestyle activities can be directly harnessed to build commercial value in scaling health related activities without becoming a regulatory issue. It’s time for genetics to do the same thing.

 

 

Development and Role of the Human Reference Sequence in Personal Genomics

Posted by @finchtalk on July 3, 2014

discovery in a digital world

 

 

 

A few weeks back, we published a review about the development and role of the human reference genome. A key point of the reference genome is that it is not a single sequence. Instead it is an assembly of consensus sequences that are designed to deal with variation in the human population and uncertainty in the data. The reference is a map and like a geographical maps evolves though increased understanding over time.

From the Wiley On Line site:

Abstract

Genome maps, like geographical maps, need to be interpreted carefully. Although maps are essential to exploration and navigation they cannot be completely accurate. Humans have been mapping the world for several millennia, but genomes have been mapped and explored for just a single century with the greatest advancements in making a sequence reference map of the human genome possible in the past 30 years. After the deoxyribonucleic acid (DNA) sequence of the human genome was completed in 2003, the reference sequence underwent several improvements and today provides the underlying comparative resource for a multitude genetic assays and biochemical measurements. However, the ability to simplify genetic analysis through a single comprehensive map remains an elusive goal.

Key Concepts:

  • Maps are incomplete and contain errors.
  • DNA sequence data are interpreted through biochemical experiments or comparisons to other DNA sequences.
  • A reference genome sequence is a map that provides the essential coordinate system for annotating the functional regions of the genome and comparing differences between individuals’ genomes.
  • The reference genome sequence is always product of understanding at a set point in time and continues to evolve.
  • DNA sequences evolve through duplication and mutation and, as a result, contain many repeated sequences of different sizes, which complicates data analysis.
  • DNA sequence variation happens on large and small scales with respect to the lengths of the DNA differences to include single base changes, insertions, deletions, duplications and rearrangements.
  • DNA sequences within the human population undergo continual change and vary highly between individuals.
  • The current reference genome sequence is a collection of sequences, an assembly, that include sequences assembled into chromosomes, sequences that are part of structurally complex regions that cannot be assembled, patches (fixes) that cannot be included in the primary sequence, and high variability sequences that are organised into alternate loci.
  • Genetic analysis is error prone and the data require validation because the methods for collecting DNA sequences create artifacts and the reference sequence used for comparative analyses is incomplete.

Keywords:DNA sequencing

 

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An FDA advisory committee unanimously recommended approval of the Lutonix drug-coated balloon PTA catheter for the treatment of patients with femoropopliteal occlusive disease.

 

Reporter: Aviva Lev-Ari, PhD, RN

 

SOURCE

http://www.crbard.com/prlanding.aspx?releaseID=1939652

Circulatory System Devices Advisory Panel Provides a Unanimous Favorable Recommendation to FDA for the Lutonix® Drug Coated Balloon

Lutonix® DCB one step closer to becoming the first FDA-approved drug coated balloon for the treatment of patients with femoropopliteal occlusive disease

 

MURRAY HILL, N.J.–(BUSINESS WIRE)–Jun. 12, 2014– C. R. Bard, Inc. (NYSE:BCR) today announced that the U.S. Food and Drug Administration’s (FDA) Circulatory System Devices Advisory Panel provided a unanimous favorable recommendation to FDA for use of the Lutonix® Drug Coated Balloon PTA Catheter (DCB) in the U.S. The Lutonix® DCB is currently under review by FDA for improving luminal diameter and reducing the incidence of restenosis for the treatment of obstructive de novo or non-stented restenotic lesions (≤ 15 cm in length) in native femoropopliteal arteries with reference vessel diameters of 4 mm to 6 mm. If approved, it is expected that the Lutonix® DCB will be the first and only FDA-approved DCB available in the U.S.

Data presented at today’s advisory committee meeting included one-year primary endpoint data from the LEVANT 2 pivotal study, which is a global, prospective, single-blind, randomized, 54-site study (42 sites in the U.S. and 12 in Europe) that enrolled all patients under one protocol. LEVANT 2 investigators have submitted a manuscript for publication with a top-tier medical journal.

At one year, LEVANT 2 demonstrated superior primary patency of the target lesion with the Lutonix®DCB for the efficacy endpoint (73.5% vs. 56.8%, p<0.001 by Kaplan-Meier time-to-event analysis) and non-inferiority for the safety endpoint; both endpoints were compared to standard percutaneous transluminal balloon angioplasty (PTA).

The secondary efficacy endpoint results at one year for patients randomized to treatment with the Lutonix® DCB demonstrated superiority in binary restenosis (26.5% vs. 43.2%, p<0.001 by Kaplan-Meier time-to-event analysis at 365 days) when compared to uncoated balloons, and measurable but not statistically significant improvement in freedom from target lesion revascularization (TLR) (89.7% vs. 84.8%, p=0.1673 by Kaplan-Meier time-to-event analysis).

Comparing results to other trials can be challenging and misleading, as each study may have varying patient profiles, protocol structures and other criteria that may affect the reported outcomes. LEVANT 2 raises the bar for scientific rigor in superficial femoral artery (SFA) trials and was designed to reduce bias in the results in order to accurately and scientifically assess and compare the long-term performance of key clinical measures. Two key aspects of the study design differentiate this trial from recent SFA studies. First, unlike some other SFA trials, the LEVANT 2 clinical trial did not count bail-out stenting as a primary patency or TLR failure. Second, to reduce the potential introduction of bias into the subjective clinical decision for revascularization, the protocol required the clinical assessment to be performed by a physician who was blinded to the treatment group and the doppler patency measurement.

This methodology of blinding the evaluating physicians in SFA trials is unique to LEVANT 2. Published data suggest that trials with less rigorous blinding methodologies have shown physicians to intervene more often in the control arm than in the treatment arm, even when presented with similar objective results such as binary restenosis. This can have a significant impact on subjective results, such as TLR. For example, the blinding methodology in LEVANT 2 showed very similar rates of intervention when binary restenosis occurred in either arm of the trial. If instead the evaluating physicians in LEVANT 2 had intervened at the rates in unblinded DCB trials when binary restenosis occurred (as estimated from public data), the company estimates the comparable freedom from TLR for LEVANT 2 could have been approximately 94% in the treatment arm compared to approximately 78% in the control arm at one year.

PTA balloons are a well-established and accepted treatment for peripheral arterial disease (PAD) according to the American College of Cardiology and American Heart Association guidelines. The Lutonix® DCB is a standard angioplasty balloon that is coated with a low dose of the anti-restenotic agent, paclitaxel, and is designed as adjunct therapy to standard mechanical dilatation of the vessel to restore blood flow. Successful treatment of PAD in the femoropopliteal arteries requires improved blood flow (patency) for longer periods of time. PTA is typically the first and preferred method to treat patients with PAD.

“The PAD patient population is growing and the variety of treatment needs for these challenging patients is increasing,” said Kenneth Rosenfield, M.D., Section Head for Vascular Medicine and Intervention, Massachusetts General Hospital and LEVANT 2 Co-Primary Investigator. “There is a need to improve upon the current well-established treatment modality and the Lutonix® DCB can be another tool to treat PAD in the difficult anatomy of the femoropopliteal artery without leaving an implant behind.”

The FDA will consider the positive recommendation of the advisory panel in its review of the PreMarket Approval (PMA) Application that was submitted by C. R. Bard in November 2013. Currently, the Lutonix® DCB is available commercially in Europe.

Timothy M. Ring, chairman and chief executive officer of C. R. Bard, commented, “We are hopeful that the unanimous positive recommendation for Lutonix® DCB is the next step in establishing a new standard of care for those patients in the U.S. confronted with femoropopliteal occlusive disease. Clinicians have been calling for a first-line alternative treatment to expand the therapy options for this painful, progressive and debilitating disease and we look forward to working closely with the FDA as it completes its review.”

About Peripheral Arterial Disease (PAD) and Treatment Options

PAD is a life-threatening condition that narrows arteries and reduces blood flow to limbs1 putting millions of people in danger of heart attack, stroke and potential lower-extremity amputation.2 The American Heart Association (AHA) estimates that PAD affects at least 8 million Americans with approximately 3 percent of people younger than 60 years and 20 percent of people older than 70 years affected by lower-extremity peripheral arterial disease.

There are both noninvasive and invasive SFA treatment options available, each of which has associated limitations. The most conservative approach is treatment with pharmacotherapy and/or exercise with risk factor modification; however, the effectiveness of these treatment options is often limited by patient intolerance to medication or lack of medication efficacy. Surgical bypass is at the other end of the spectrum. For most patients who fail conservative therapy alone, interventionalists and surgeons will typically offer percutaneous endovascular procedure as the initial treatment option, as a lower risk alternative to surgical bypass. PTA is the first-line, standard-of-care treatment for PAD, according to the American College of Cardiology and American Heart Association 2011 guideline; however, it is limited by its relative lack of long-term patency.

1 Why PAD Matters – American Heart Association Web site. Available at:http://www.heart.org/HEARTORG/Conditions/More/PeripheralArteryDisease/Why-PAD-Matters_UCM_301303_Article.jsp.

2 Peripheral Arterial Disease – NIH National Heart, Lung, and Blood Institute. Available at:https://www.nhlbi.nih.gov/health/health-topics/topics/pad/.

C. R. Bard, Inc. (www.crbard.com), headquartered in Murray Hill, NJ, is a leading multinational developer, manufacturer and marketer of innovative, life-enhancing medical technologies in the fields of vascular, urology, oncology and surgical specialty products.

The FDA advisory panel vote should not be construed as an indication of the likelihood of the product gaining regulatory approval or being successful commercially. This press release may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, which are based on management’s current expectations, the accuracy of which is necessarily subject to risks and uncertainties. These statements are not historical in nature and use words such as “anticipate”, “estimate”, “expect”, “project”, “intend”, “forecast”, “plan”, “believe”, and other words of similar meaning in connection with any discussion of future operating or financial performance. Many factors may cause actual results to differ materially from anticipated results including product developments, sales efforts, income tax matters, the outcomes of contingencies such as legal proceedings, and other economic, business, competitive and regulatory factors. The company undertakes no obligation to update its forward-looking statements. Please refer to the Cautionary Statement Regarding Forward-Looking Information in our March 31, 2014 Form 10-Q for more detailed information about these and other factors that may cause actual results to differ materially from those expressed or implied.

 

Source: C. R. Bard, Inc.

C. R. Bard, Inc.
Investor Relations:
Todd W. Garner, 908-277-8065
Vice President, Investor Relations
or
Media Relations:
Scott T. Lowry, 908-277-8365
Vice President and Treasurer

 

 

SOURCE

http://www.crbard.com/prlanding.aspx?releaseID=1939652

 

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PINNACLE Patients: Inappropriate Prasugrel (Effient, Lilly/Daiichi Sankyo) Use in “One in Five”: Prior Stroke or TIA can increase the risk of Bleeding

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 7/4/2021

Prasugrel outperforms ticagrelor among PCI patients

Prasugrel is associated with better outcomes than ticagrelor when treating acute coronary syndrome (ACS) patients who undergo percutaneous coronary intervention (PCI), according to new findings published in JAMA Cardiology.

The study’s authors evaluated data from the ISAR-REACT 5 trial, focusing on more than 3,000 patients presenting with ACS and treated with PCI from September 2013 to February 2018. The primary endpoint was a composite of all-cause mortality, myocardial infarction and stroke after one full year. Its safety endpoint was Bleeding Academic Researching Consortium (BARC) type three to five bleeding.

“This analysis is, to our knowledge, the first study to directly compare outcomes between ticagrelor-based and prasugrel-based strategies in patients with ACS who are treated with PCI,” wrote lead author J. J. Coughlan, MB, BCh, a specialist at the Technical University of Munich in Germany, and colleagues. “The PCI procedure for these patients reflected contemporary practice with new-generation drug-eluting stents.”

While 1,676 patients with a mean age of 64.4 years old received ticagrelor, 1,701 patients with a mean age of 64.7 years old received prasugrel. Overall, the study’s primary endpoint occurred in 9.8% of patients from the ticagrelor group and 7.1% of the prasugrel group. Myocardial infarctions were observed in 5.3% of the ticagrelor group and 3.8% of the prasugrel group. The study’s safety endpoint occurred in 5.3% of patients from the ticagrelor group and 4.9% of the prasugrel group.

“Overall, these data support the preference for a prasugrel-based strategy vs a ticagrelor-based strategy in patients presenting with ACS who are treated with PCI,” the authors concluded. “Because these observations are based on a post-randomization subgroup, these findings should be regarded as hypothesis generating, and dedicated randomized clinical trials may be warranted to confirm these findings.”

Click here for the full analysis.

Results of Prior study are:

Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization

Matthew T. Roe, M.D., M.H.S., Paul W. Armstrong, M.D., Keith A.A. Fox, M.B., Ch.B., Harvey D. White, M.B., Ch.B., D.Sc., Dorairaj Prabhakaran, M.D., D.M., Shaun G. Goodman, M.D., Jan H. Cornel, M.D., Ph.D., Deepak L. Bhatt, M.D., M.P.H., Peter Clemmensen, M.D., D.M.Sc., Felipe Martinez, M.D., Diego Ardissino, M.D., Jose C. Nicolau, M.D., Ph.D., William E. Boden, M.D., Paul A. Gurbel, M.D., Witold Ruzyllo, M.D., Anthony J. Dalby, M.D., Darren K. McGuire, M.D., M.H.Sc., Jose L. Leiva-Pons, M.D., Alexander Parkhomenko, M.D., Ph.D., Shmuel Gottlieb, M.D., Gracita O. Topacio, M.D., Christian Hamm, M.D., Gregory Pavlides, M.D., Assen R. Goudev, M.D., Ali Oto, M.D., Chuen-Den Tseng, M.D., Ph.D., Bela Merkely, M.D., Ph.D., D.Sc., Vladimir Gasparovic, M.D., Ph.D., Ramon Corbalan, M.D., Mircea Cinteză, M.D., Ph.D., R. Craig McLendon, R.N., Kenneth J. Winters, M.D., Eileen B. Brown, Ph.D., Yuliya Lokhnygina, Ph.D., Philip E. Aylward, B.M., B.Ch., Ph.D., Kurt Huber, M.D., Judith S. Hochman, M.D., and E. Magnus Ohman, M.B., Ch.B. for the TRILOGY ACS Investigators

N Engl J Med 2012; 367:1297-1309 October 4, 2012DOI: 10.1056/NEJMoa1205512

BACKGROUND

The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated.

METHODS

In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel.

RESULTS

At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group.

CONCLUSIONS

Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number,NCT00699998.)

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMoa1205512

Inappropriate Prasugrel Use in One in Five PINNACLE Patients

June 09, 2014

HOUSTON, TX — Nearly one in five patients treated withprasugrel (Effient, Lilly/Daiichi Sankyo) in the PINNACLEregistry is receiving the drug inappropriately or for a nonrecommended indication, according to a new analysis[1].

Among more than 27 500 patients treated with prasugrel at 123 US practices, almost 14% had a documented prior history of stroke or transient ischemic attack (TIA): two conditions singled out in a boxed warning in the drug packaging. According to that labeling, prior stroke or TIA can increase the risk of bleeding.

An additional 4.4% of patients in the analysis were taking prasugrel despite being 75 years of age or older with no diabetes or prior MI, the analysis suggests. Dr Ravi Hira(Baylor College of Medicine, Houston, TX) and colleagues published their findings last month in an online research letter in the Journal of the American College of Cardiology.

Current ACC/AHA guidelines for STEMI and unstable angina/NSTEMI give prasugrel a class I recommendation for use at the time of PCI but advise against its use (class III) in patients with a prior TIA or stroke. In TRILOGY ACS , prasugrel was no better than clopidogrel in reducing CV events in patients with ACS who were not treated invasively, and as such, the drug is not approved for medically managed patients.

In an interview with heartwire , Hira said he and his coinvestigators had their interest piqued after seeing a number of non-ACS patients or patients with a history of stroke/TIA referred to their practices. “That got us thinking, let’s see if we can assess the rate of inappropriate or off-label use” in a larger population, he said.

Practice patterns in inappropriate prasugrel use varied significantly between hospitals across the sample, Hira et al note, although there were no differences seen according to patient age or gender. Inappropriate or off-label prasugrel use was more common in patients with comorbidities, including diabetes, hypertension, dyslipidemia, atrial fibrillation, heart failure, peripheral artery disease (PAD), and CABG, they note.

That hints at the possibility that physicians are opting to use a more potent antiplatelet drug in patients whom they fear are at higher risk of ischemic events, Hira commented.

But clearly not all practitioners have the same concerns with inappropriate use, ranging from 0% to 90% within individual practices. Differences at the practice level mean that two “identical” patients treated at two randomly chosen practices would receive radically different care, with the risk of inappropriate prasugrel treatment being as much as 189% increased at one facility vs another.

A further problem identified by the investigators was use of triple therapy—aspirin, warfarin, and prasugrel. In PINNACLE, triple therapy was seen in 15.4% of the sample, despite the fact that the use of prasugrel on top of warfarin and aspirin has not been studied.

“It’s possible that triple therapy with prasugrel in this group, even when appropriate, may lead to increased rates of major bleeding and offset any anti-ischemic benefit of prasugrel,” the authors write.

PINNACLE is an outpatient registry, so one possibility is that patients are being placed on prasugrel during hospital admission, not by the cardiology practices enrolled in PINNACLE, suggesting “there may be a disconnect between inpatient and outpatient care,” Hira said. He and his colleagues also could not review the reasons underlying a physician’s decision to put a patient on prasugrel instead of clopidogrel or the other newer antiplatelet drug, ticagrelor (Brilinta, AstraZeneca). Moreover, stroke and TIA were self-reported in the study.

Hira points out that there are no warnings against the use of ticagrelor in patients with prior TIA or stroke (although it is contraindicated in patients with a history of intracranial hemorrhage). PINNACLE is now collecting information on ticagrelor use. He and his colleagues hope to analyze this newer data to also assess inappropriate use of ticagrelor as well as the drivers of any decision to use prasugrel over ticagrelor and vice versa.

Hira had no conflicts of interest. Disclosures for the coauthors are listed in the article.

SOURCE

http://www.medscape.com/viewarticle/826397?nlid=58944_2562&src=wnl_edit_medp_card&uac=93761AJ&spon=2

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