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Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Posted in Academic Publishing, Acute Myocardial Infarction, Advanced Drug Manufacturing Technology, Alzheimer's Disease, Atherogenic Processes & Pathology, Autologous Cell Therapy, Automated Cell Processing, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Bone Disease and Musculoskeletal Disease, Bone marrow derived cells, Ca2+ triggered activation, Ca2+ triggered activation, Cachexia, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, Cytoskeleton, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Electrophysiology, Endothelial cells, Epigenetics and Cardiovascular Risks, Etiology, Evolutionary cognition, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Expression, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medical and Population Genetics, Medical Device Therapies for Altzheimer’s Disease, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Na-K transport, Na-K-ATPase, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Oxidative phosphorylation, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Phosphorylation, PKC, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, S-nitrosylation, Signaling, Skeletal muscle regeneration, Statistical Methods for Research Evaluation, Stem Cells for Regenerative Medicine, Stents & Tools, Synaptic vesicle, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Translational Effectiveness, Translational Science, Ubiquitinylation, Water Transporters, tagged bioengineering, Cardiovascular Disorders, computational biology, Coronary artery disease, DNA Sequencing, functional proteomics, gene expression, gene silencing, genetic engineering, Heart Failure, Human Genome Project, Hypertension, MicroRNA, mtRNA, myocardial infarction, nitric oxide, Nitric oxide synthase, Personalized medicine, protein modifications, Proteomics, reverse engineering, RNA, signaling pathways, Stem cell, synbiology on April 28, 2014| Leave a Comment »

Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Article ID #135: Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1. Published on 4/28/2014

WordCloud Image Produced by Adam Tubman

 

Part 1 of Volume 4 in the e-series A: Cardiovascular Diseases and Translational Medicine, provides a foundation for grasping a rapidly developing surging scientific endeavor that is transcending laboratory hypothesis testing and providing guidelines to:

• Target genomes and multiple nucleotide sequences involved in either coding or in regulation that might have an impact on complex diseases, not necessarily genetic in nature.
• Target signaling pathways that are demonstrably maladjusted, activated or suppressed in many common and complex diseases, or in their progression.
• Enable a reduction in failure due to toxicities in the later stages of clinical drug trials as a result of this science-based understanding.
• Enable a reduction in complications from the improvement of machanical devices that have already had an impact on the practice of interventional procedures in cardiology, cardiac surgery, and radiological imaging, as well as improving laboratory diagnostics at the molecular level.
• Enable the discovery of new drugs in the continuing emergence of drug resistance.
• Enable the construction of critical pathways and better guidelines for patient management based on population outcomes data, that will be critically dependent on computational methods and large data-bases.

What has been presented can be essentially viewed in the following Table:

 

Summary Table for TM – Part 1

 

 

 

There are some developments that deserve additional development:

1. The importance of mitochondrial function in the activity state of the mitochondria in cellular work (combustion) is understood, and impairments of function are identified in diseases of muscle, cardiac contraction, nerve conduction, ion transport, water balance, and the cytoskeleton – beyond the disordered metabolism in cancer.  A more detailed explanation of the energetics that was elucidated based on the electron transport chain might also be in order.

2. The processes that are enabling a more full application of technology to a host of problems in the environment we live in and in disease modification is growing rapidly, and will change the face of medicine and its allied health sciences.

 

Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering

Kristala L. J. Prather: Part-1    <iBiology > iBioSeminars > Biophysics & Chemical Biology >

http://www.ibiology.org Lecturers generously donate their time to prepare these lectures. The project is funded by NSF and NIGMS, and is supported by the ASCB and HHMI.
Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”.

http://synthetic_biology/Introduction_to_Synthetic_Biology_and_Metabolic_Engineering/Kristala_ L.J._Prather/E2/iBiology.htm#/sthash.71kZ0ofr.dpuf

Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.  Learn more about how Kris became a scientist at

http://science360.gov/obj/video/753bb4fa-aafb-4315-848e-51066ed9799a/finding-way-kristala-l-jones-prather-phd 

Prather 1: Synthetic Biology and Metabolic Engineering  2/6/14IntroductionLecture Overview In the first part of her lecture, Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”. The key material in building these machines is synthetic DNA. Synthetic DNA can be added in different combinations to biological hosts, such as bacteria, turning them into chemical factories that can produce small molecules of choice. In Part 2, Prather describes how her lab used design principles to engineer E. coli that produce glucaric acid from glucose. Glucaric acid is not naturally produced in bacteria, so Prather and her colleagues “bioprospected” enzymes from other organisms and expressed them in E. coli to build the needed enzymatic pathway. Prather walks us through the many steps of optimizing the timing, localization and levels of enzyme expression to produce the greatest yield. Speaker Bio: Kristala Jones Prather received her S.B. degree from the Massachusetts Institute of Technology and her PhD at the University of California, Berkeley both in chemical engineering. Upon graduation, Prather joined the Merck Research Labs for 4 years before returning to academia. Prather is now an Associate Professor of Chemical Engineering at MIT and an investigator with the multi-university Synthetic Biology Engineering Reseach Center (SynBERC). Her lab designs and constructs novel synthetic pathways in microorganisms converting them into tiny factories for the production of small molecules. Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.

VIEW VIDEOS

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=0

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=12

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=74

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=129

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=168

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk

 

David Bartel: micro-RNAs

 

I. Introduction to microRNAs

https://www.youtube.com/watch?feature=player_embedded&v=dupzE66J8u4#t=0

– See more at: http://www.ibiology.org/ibioseminars/genetics-gene-regulation/david-bartel-part-1.html#sthash.nGGr1tIt.dpuf

II. Regulatory Effects of Mammalian microRNAs

https://www.youtube.com/watch?feature=player_embedded&v=TcZK_A_wcWQ#t=0

https://www.youtube.com/watch?feature=player_embedded&v=TcZK_A_wcWQ

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

in INTECH
Current Basic and Pathological Approaches to
the Function of Muscle Cells and Tissues – From Molecules to HumansLarissa Lipskaia, Isabelle Limon, Regis Bobe and Roger Hajjar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48240

1. Introduction
Calcium ions (Ca ) are present in low concentrations in the cytosol (~100 nM) and in high concentrations (in mM range) in both the extracellular medium and intracellular stores (mainly sarco/endo/plasmic reticulum, SR). This differential allows the calcium ion messenger that carries information
as diverse as contraction, metabolism, apoptosis, proliferation and/or hypertrophic growth. The mechanisms responsible for generating a Ca signal greatly differ from one cell type to another.

In the different types of vascular smooth muscle cells (VSMC), enormous variations do exist with regard to the mechanisms responsible for generating Ca signal. In each VSMC phenotype (synthetic/proliferating and contractile [1], tonic or phasic), the Ca signaling system is adapted to its particular function and is due to the specific patterns of expression and regulation of Ca.
For instance, in contractile VSMCs, the initiation of contractile events is driven by mem- brane depolarization; and the principal entry-point for extracellular Ca is the voltage-operated L-type calcium channel (LTCC). In contrast, in synthetic/proliferating VSMCs, the principal way-in for extracellular Ca is the store-operated calcium (SOC) channel.
Whatever the cell type, the calcium signal consists of  limited elevations of cytosolic free calcium ions in time and space. The calcium pump, sarco/endoplasmic reticulum Ca ATPase (SERCA), has a critical role in determining the frequency of SR Ca release by upload into the sarcoplasmic
sensitivity of  SR calcium channels, Ryanodin Receptor, RyR and Inositol tri-Phosphate Receptor, IP3R.
Synthetic VSMCs have a fibroblast appearance, proliferate readily, and synthesize increased levels of various extracellular matrix components, particularly fibronectin, collagen types I and III, and tropoelastin [1].
Contractile VSMCs have a muscle-like or spindle-shaped appearance and well-developed contractile apparatus resulting from the expression and intracellular accumulation of thick and thin muscle filaments [1].

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

 

Figure 1. Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs.

Left panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Contractile re-sponse is initiated by extracellular Ca influx due to activation of Receptor Operated Ca (through phosphoinositol-coupled receptor) or to activation of L-Type Calcium channels (through an increase in luminal pressure). Small increase of cytosolic due IP3 binding to IP3R (puff) or RyR activation by LTCC or ROC-dependent Ca influx leads to large SR Ca IP3R or RyR clusters (“Ca -induced Ca SR calcium pumps (both SERCA2a and SERCA2b are expressed in quiescent VSMCs), maintaining high concentration of cytosolic Ca and setting the sensitivity of RyR or IP3R for the next spike.
Contraction of VSMCs occurs during oscillatory Ca transient.
Middle panel: schematic representa tion of atherosclerotic vessel wall. Contractile VSMC are located in the media layer, synthetic VSMC are located in sub-endothelial intima.
Right panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Agonist binding to phosphoinositol-coupled receptor leads to the activation of IP3R resulting in large increase in cytosolic Ca calcium pumps (only SERCA2b, having low turnover and low affinity to Ca depletion leads to translocation of SR Ca sensor STIM1 towards PM, resulting in extracellular Ca influx though opening of Store Operated Channel (CRAC). Resulted steady state Ca transient is critical for activation of proliferation-related transcription factors ‘NFAT).
Abbreviations: PLC – phospholipase C; PM – plasma membrane; PP2B – Ca /calmodulin-activated protein phosphatase 2B (calcineurin); ROC- receptor activated channel; IP3 – inositol-1,4,5-trisphosphate, IP3R – inositol-1,4,5- trisphosphate receptor; RyR – ryanodine receptor; NFAT – nuclear factor of activated T-lymphocytes; VSMC – vascular smooth muscle cells; SERCA – sarco(endo)plasmic reticulum Ca sarcoplasmic reticulum.

 

Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson

I’ll start with the productivity plot, as this one isn’t new. For a discussion of the substantial performance increase in sequencing compared to Moore’s Law, as well as the difficulty of finding this data, please see this post. If nothing else, keep two features of the plot in mind: 1) the consistency of the pace of Moore’s Law and 2) the inconsistency and pace of sequencing productivity. Illumina appears to be the primary driver, and beneficiary, of improvements in productivity at the moment, especially if you are looking at share prices. It looks like the recently announced NextSeq and Hiseq instruments will provide substantially higher productivities (hand waving, I would say the next datum will come in another order of magnitude higher), but I think I need a bit more data before officially putting another point on the plot.

 

cost-of-oligo-and-gene-synthesis

Illumina’s instruments are now responsible for such a high percentage of sequencing output that the company is effectively setting prices for the entire industry. Illumina is being pushed by competition to increase performance, but this does not necessarily translate into lower prices. It doesn’t behoove Illumina to drop prices at this point, and we won’t see any substantial decrease until a serious competitor shows up and starts threatening Illumina’s market share. The absence of real competition is the primary reason sequencing prices have flattened out over the last couple of data points.

Note that the oligo prices above are for column-based synthesis, and that oligos synthesized on arrays are much less expensive. However, array synthesis comes with the usual caveat that the quality is generally lower, unless you are getting your DNA from Agilent, which probably means you are getting your dsDNA from Gen9.

Note also that the distinction between the price of oligos and the price of double-stranded sDNA is becoming less useful. Whether you are ordering from Life/Thermo or from your local academic facility, the cost of producing oligos is now, in most cases, independent of their length. That’s because the cost of capital (including rent, insurance, labor, etc) is now more significant than the cost of goods. Consequently, the price reflects the cost of capital rather than the cost of goods. Moreover, the cost of the columns, reagents, and shipping tubes is certainly more than the cost of the atoms in the sDNA you are ostensibly paying for. Once you get into longer oligos (substantially larger than 50-mers) this relationship breaks down and the sDNA is more expensive. But, at this point in time, most people aren’t going to use longer oligos to assemble genes unless they have a tricky job that doesn’t work using short oligos.

Looking forward, I suspect oligos aren’t going to get much cheaper unless someone sorts out how to either 1) replace the requisite human labor and thereby reduce the cost of capital, or 2) finally replace the phosphoramidite chemistry that the industry relies upon.

IDT’s gBlocks come at prices that are constant across quite substantial ranges in length. Moreover, part of the decrease in price for these products is embedded in the fact that you are buying smaller chunks of DNA that you then must assemble and integrate into your organism of choice.

Someone who has purchased and assembled an absolutely enormous amount of sDNA over the last decade, suggested that if prices fell by another order of magnitude, he could switch completely to outsourced assembly. This is a potentially interesting “tipping point”. However, what this person really needs is sDNA integrated in a particular way into a particular genome operating in a particular host. The integration and testing of the new genome in the host organism is where most of the cost is. Given the wide variety of emerging applications, and the growing array of hosts/chassis, it isn’t clear that any given technology or firm will be able to provide arbitrary synthetic sequences incorporated into arbitrary hosts.

 TrackBack URL: http://www.synthesis.cc/cgi-bin/mt/mt-t.cgi/397

 

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

28 Nov 2013 | PR Web

Dr. Jon Rowley and Dr. Uplaksh Kumar, Co-Founders of RoosterBio, Inc., a newly formed biotech startup located in Frederick, are paving the way for even more innovation in the rapidly growing fields of Synthetic Biology and Regenerative Medicine. Synthetic Biology combines engineering principles with basic science to build biological products, including regenerative medicines and cellular therapies. Regenerative medicine is a broad definition for innovative medical therapies that will enable the body to repair, replace, restore and regenerate damaged or diseased cells, tissues and organs. Regenerative therapies that are in clinical trials today may enable repair of damaged heart muscle following heart attack, replacement of skin for burn victims, restoration of movement after spinal cord injury, regeneration of pancreatic tissue for insulin production in diabetics and provide new treatments for Parkinson’s and Alzheimer’s diseases, to name just a few applications.

While the potential of the field is promising, the pace of development has been slow. One main reason for this is that the living cells required for these therapies are cost-prohibitive and not supplied at volumes that support many research and product development efforts. RoosterBio will manufacture large quantities of standardized primary cells at high quality and low cost, which will quicken the pace of scientific discovery and translation to the clinic. “Our goal is to accelerate the development of products that incorporate living cells by providing abundant, affordable and high quality materials to researchers that are developing and commercializing these regenerative technologies” says Dr. Rowley

 

Life at the Speed of Light

http://kcpw.org/?powerpress_pinw=92027-podcast

NHMU Lecture featuring – J. Craig Venter, Ph.D.
Founder, Chairman, and CEO – J. Craig Venter Institute; Co-Founder and CEO, Synthetic Genomics Inc.

J. Craig Venter, Ph.D., is Founder, Chairman, and CEO of the J. Craig Venter Institute (JVCI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic and environmental research. He is also Co-Founder and CEO of Synthetic Genomics Inc. (SGI), a privately-held company dedicated to commercializing genomic-driven solutions to address global needs.

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed.  This research culminated with the February 2001 publication of the human genome in the journal, Science. Dr. Venter and his team at JVCI continue to blaze new trails in genomics.  They have sequenced and a created a bacterial cell constructed with synthetic DNA,  putting humankind at the threshold of a new phase of biological research.  Whereas, we could  previously read the genetic code (sequencing genomes), we can now write the genetic code for designing new species.

The science of synthetic genomics will have a profound impact on society, including new methods for chemical and energy production, human health and medical advances, clean water, and new food and nutritional products. One of the most prolific scientists of the 21st century for his numerous pioneering advances in genomics,  he  guides us through this emerging field, detailing its origins, current challenges, and the potential positive advances.

His work on synthetic biology truly embodies the theme of “pushing the boundaries of life.”  Essentially, Venter is seeking to “write the software of life” to create microbes designed by humans rather than only through evolution. The potential benefits and risks of this new technology are enormous. It also requires us to examine, both scientifically and philosophically, the question of “What is life?”

J Craig Venter wants to digitize DNA and transmit the signal to teleport organisms

http://pharmaceuticalintelligence.com/2013/11/01/j-craig-venter-wants-to-digitize-dna-and-transmit-the-signal-to-teleport-organisms/

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

http://pharmaceuticalintelligence.com/2013/02/11/2013-genomics-the-era-beyond-the-sequencing-human-genome-francis-collins-craig-venter-eric-lander-et-al/

Human Longevity Inc (HLI) – $70M in Financing of Venter’s New Integrative Omics and Clinical Bioinformatics

http://pharmaceuticalintelligence.com/2014/03/05/human-longevity-inc-hli-70m-in-financing-of-venters-new-integrative-omics-and-clinical-bioinformatics/

 

 

Where Will the Century of Biology Lead Us?

By Randall Mayes

A technology trend analyst offers an overview of synthetic biology, its potential applications, obstacles to its development, and prospects for public approval.

• In addition to boosting the economy, synthetic biology projects currently in development could have profound implications for the future of manufacturing, sustainability, and medicine.
• Before society can fully reap the benefits of synthetic biology, however, the field requires development and faces a series of hurdles in the process. Do researchers have the scientific know-how and technical capabilities to develop the field?

Biology + Engineering = Synthetic Biology

Bioengineers aim to build synthetic biological systems using compatible standardized parts that behave predictably. Bioengineers synthesize DNA parts—oligonucleotides composed of 50–100 base pairs—which make specialized components that ultimately make a biological system. As biology becomes a true engineering discipline, bioengineers will create genomes using mass-produced modular units similar to the microelectronics and computer industries.

Currently, bioengineering projects cost millions of dollars and take years to develop products. For synthetic biology to become a Schumpeterian revolution, smaller companies will need to be able to afford to use bioengineering concepts for industrial applications. This will require standardized and automated processes.

A major challenge to developing synthetic biology is the complexity of biological systems. When bioengineers assemble synthetic parts, they must prevent cross talk between signals in other biological pathways. Until researchers better understand these undesired interactions that nature has already worked out, applications such as gene therapy will have unwanted side effects. Scientists do not fully understand the effects of environmental and developmental interaction on gene expression. Currently, bioengineers must repeatedly use trial and error to create predictable systems.

Similar to physics, synthetic biology requires the ability to model systems and quantify relationships between variables in biological systems at the molecular level.

The second major challenge to ensuring the success of synthetic biology is the development of enabling technologies. With genomes having billions of nucleotides, this requires fast, powerful, and cost-efficient computers. Moore’s law, named for Intel co-founder Gordon Moore, posits that computing power progresses at a predictable rate and that the number of components in integrated circuits doubles each year until its limits are reached. Since Moore’s prediction, computer power has increased at an exponential rate while pricing has declined.

DNA sequencers and synthesizers are necessary to identify genes and make synthetic DNA sequences. Bioengineer Robert Carlson calculated that the capabilities of DNA sequencers and synthesizers have followed a pattern similar to computing. This pattern, referred to as the Carlson Curve, projects that scientists are approaching the ability to sequence a human genome for $1,000, perhaps in 2020. Carlson calculated that the costs of reading and writing new genes and genomes are falling by a factor of two every 18–24 months. (see recent Carlson comment on requirement to read and write for a variety of limiting  conditions).

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

http://pharmaceuticalintelligence.com/2013/11/28/startup-to-strengthen-synthetic-biology-and-regenerative-medicine-industries-with-cutting-edge-cell-products/

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

http://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Synthesizing Synthetic Biology: PLOS Collections

http://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

Capturing ten-color ultrasharp images of synthetic DNA structures resembling numerals 0 to 9

http://pharmaceuticalintelligence.com/2014/02/05/capturing-ten-color-ultrasharp-images-of-synthetic-dna-structures-resembling-numerals-0-to-9/

Silencing Cancers with Synthetic siRNAs

http://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

Genomics Now—and Beyond the Bubble

Futurists have touted the twenty-first century as the century of biology based primarily on the promise of genomics. Medical researchers aim to use variations within genes as biomarkers for diseases, personalized treatments, and drug responses. Currently, we are experiencing a genomics bubble, but with advances in understanding biological complexity and the development of enabling technologies, synthetic biology is reviving optimism in many fields, particularly medicine.

BY MICHAEL BROOKS    17 APR, 2014     http://www.newstatesman.com/

Michael Brooks holds a PhD in quantum physics. He writes a weekly science column for the New Statesman, and his most recent book is The Secret Anarchy of Science.

The basic idea is that we take an organism – a bacterium, say – and re-engineer its genome so that it does something different. You might, for instance, make it ingest carbon dioxide from the atmosphere, process it and excrete crude oil.

That project is still under construction, but others, such as using synthesised DNA for data storage, have already been achieved. As evolution has proved, DNA is an extraordinarily stable medium that can preserve information for millions of years. In 2012, the Harvard geneticist George Church proved its potential by taking a book he had written, encoding it in a synthesised strand of DNA, and then making DNA sequencing machines read it back to him.

When we first started achieving such things it was costly and time-consuming and demanded extraordinary resources, such as those available to the millionaire biologist Craig Venter. Venter’s team spent most of the past two decades and tens of millions of dollars creating the first artificial organism, nicknamed “Synthia”. Using computer programs and robots that process the necessary chemicals, the team rebuilt the genome of the bacterium Mycoplasma mycoides from scratch. They also inserted a few watermarks and puzzles into the DNA sequence, partly as an identifying measure for safety’s sake, but mostly as a publicity stunt.

What they didn’t do was redesign the genome to do anything interesting. When the synthetic genome was inserted into an eviscerated bacterial cell, the new organism behaved exactly the same as its natural counterpart. Nevertheless, that Synthia, as Venter put it at the press conference to announce the research in 2010, was “the first self-replicating species we’ve had on the planet whose parent is a computer” made it a standout achievement.

Today, however, we have entered another era in synthetic biology and Venter faces stiff competition. The Steve Jobs to Venter’s Bill Gates is Jef Boeke, who researches yeast genetics at New York University.

Boeke wanted to redesign the yeast genome so that he could strip out various parts to see what they did. Because it took a private company a year to complete just a small part of the task, at a cost of $50,000, he realised he should go open-source. By teaching an undergraduate course on how to build a genome and teaming up with institutions all over the world, he has assembled a skilled workforce that, tinkering together, has made a synthetic chromosome for baker’s yeast.

 

Stepping into DIYbio and Synthetic Biology at ScienceHack

Posted April 22, 2014 by Heather McGaw and Kyrie Vala-Webb

We got a crash course on genetics and protein pathways, and then set out to design and build our own pathways using both the “Genomikon: Violacein Factory” kit and Synbiota platform. With Synbiota’s software, we dragged and dropped the enzymes to create the sequence that we were then going to build out. After a process of sketching ideas, mocking up pathways, and writing hypotheses, we were ready to start building!

The night stretched long, and at midnight we were forced to vacate the school. Not quite finished, we loaded our delicate bacteria, incubator, and boxes of gloves onto the bus and headed back to complete our bacterial transformation in one of our hotel rooms. Jammed in between the beds and the mini-fridge, we heat-shocked our bacteria in the hotel ice bucket. It was a surreal moment.

While waiting for our bacteria, we held an “unconference” where we explored bioethics, security and risk related to synthetic biology, 3D printing on Mars, patterns in juggling (with live demonstration!), and even did a Google Hangout with Rob Carlson. Every few hours, we would excitedly check in on our bacteria, looking for bacterial colonies and the purple hue characteristic of violacein.

Most impressive was the wildly successful and seamless integration of a diverse set of people: in a matter of hours, we were transformed from individual experts and practitioners in assorted fields into cohesive and passionate teams of DIY biologists and science hackers. The ability of everyone to connect and learn was a powerful experience, and over the course of just one weekend we were able to challenge each other and grow.

Returning to work on Monday, we were hungry for more. We wanted to find a way to bring the excitement and energy from the weekend into the studio and into the projects we’re working on. It struck us that there are strong parallels between design and DIYbio, and we knew there was an opportunity to bring some of the scientific approaches and curiosity into our studio.

 

 

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Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Posted in Cell Biology, Signaling & Cell Circuits, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Human Immune System in Health and in Disease, Human Sensation and Cellular Transduction: Physiology and Therapeutics, Innovation in Immunology Diagnostics, Interviews with Scientific Leaders, Ionic Transporters Na+, K, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Na-K transport, Na-K-ATPase, Nephrology, Nephrology & Regenerative medicine, Neurohumoral Transmission, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Pre-Clinical Animal Model Development, Signaling, Systemic Inflammatory Response Related Disorders, Water Transporters on March 3, 2014| Leave a Comment »

Richard Lifton, MD, PhD of Yale University & Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Curator: Aviva Lev-Ari, PhD, RN

Article ID #118: Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension. Published on 3/3/2014

WordCloud Image Produced by Adam Tubman

 

Yale’s Lifton receives $3 million science prize at gala Silicon Valley ceremony

Friday, December 13, 2013

Bill Hathaway / 203-432-1322

Read this article on YaleNews

Richard Lifton, Sterling Professor of Genetics and chair of the Department of Genetics, has received a $3 million Breakthrough Prize in Life Sciences, created by top Silicon Valley entrepreneurs.

Lifton was one of eight scientists honored Dec. 12 with $21 million in prizes at gala ceremonies hosted by actor Kevin Spacey in Mountain View, California. Celebrities — including Conan O’Brien, Glenn Close, Rob Lowe, and Michael C. Hall — handed out awards to six winners of the life sciences prizes and two co-winners of the Breakthrough Prize in Fundamental Physics.

“Scientists should be celebrated as heroes, and we are honored to be part of today’s celebration,” said Google co-founder Sergey Brin and his wife, biologist and entrepreneur Anne Wojcicki, two of the event’s sponsors.

Lifton, who is also an investigator for the Howard Hughes Medical Institute, was recognized for his pioneering work to identify the genetic and biochemical underpinnings of hypertension, a disease that affects more than 1 billion people worldwide and that contributes to 17 million deaths annually from heart attack and stroke. Lifton and his colleagues identified patients around the world with exceptionally high or low blood pressure due to single gene mutations. They identified the mutated genes and established their role in salt reabsorption by the kidney and regulation of blood pressure. The work gave scientific rationale to limit dietary salt intake and suggested rational combinations of antihypertensive medications and development of new therapies.

Other sponsors of the event are Chinese internet entrepreneur Jack Ma and Cathy Zhang; Russian entrepreneur and venture capitalist Yuri Milner and his wife, Julia Milner; and Facebook founder Mark Zuckerberg and Priscilla Chan.

At the end of the ceremonies, which will be televised on the Science Channel at 9 p.m. on Jan. 27, Milner and Zuckerberg announced the creation of a $3 million Breakthrough Prize in Mathematics that will be awarded next year.

Additional information on the prizes can be found atwww.breakthroughprizeinlifesciences.org or www.fundamentalphysicsprize.org.

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SOURCE

http://www.bizjournals.com/sanfrancisco/prnewswire/press_releases/California/2013/12/13/NY33121

THE DISCOVERY

Laliotis MD, Zhang J, Volkman HM, Kahle KT, Hoffmann, KE, Toka HR, Nelson-Williams C, Ellison, DH, Flavell, R, Booth, CJ, Lu Y, Geller, DS, Lifton, RP. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nature Genetics, in press

Earlier Research Results on this discovey

Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):680-4. Epub 2003 Jan 6.

Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.

Wilson FH¹, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, Hebert SC, Gamba G, Lifton RP.

Author information

Abstract

Mutations in the serine-threonine kinases WNK1 and WNK4 [with no lysine (K) at a key catalytic residue] cause pseudohypoaldosteronism type II (PHAII), a Mendelian disease featuring hypertension, hyperkalemia, hyperchloremia, and metabolic acidosis. Both kinases are expressed in the distal nephron, although the regulators and targets of WNK signaling cascades are unknown. The Cl(-) dependence of PHAII phenotypes, their sensitivity to thiazide diuretics, and the observation that they constitute a “mirror image” of the phenotypes resulting from loss of function mutations in the thiazide-sensitive Na-Cl cotransporter (NCCT) suggest that PHAII may result from increased NCCT activity due to altered WNK signaling. To address this possibility, we measured NCCT-mediated Na(+) influx and membrane expression in the presence of wild-type and mutant WNK4 by heterologous expression in Xenopus oocytes. Wild-type WNK4 inhibits NCCT-mediated Na-influx by reducing membrane expression of the cotransporter ((22)Na-influx reduced 50%, P < 1 x 10(-9), surface expression reduced 75%, P < 1 x 10(-14) in the presence of WNK4). This inhibition depends on WNK4 kinase activity, because missense mutations that abrogate kinase function prevent this effect. PHAII-causing missense mutations, which are remote from the kinase domain, also prevent inhibition of NCCT activity, providing insight into the pathophysiology of the disorder. The specificity of this effect is indicated by the finding that WNK4 and the carboxyl terminus of NCCT coimmunoprecipitate when expressed in HEK 293T cells. Together, these findings demonstrate that WNK4 negatively regulates surface expression of NCCT and implicate loss of this regulation in the molecular pathogenesis of an inherited form of hypertension.

Free PMC Article

Images from this publication.See all images (4)Free text

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed/12515852

LISTEN TO AUDIO TAPE by Prof. Richard Lifton

http://streaming.yale.edu/opa/podcasts/audio/schools/health_and_medicine/lifton_092007.mp3

January 27, 2014

Richard Lifton

Yale’s Richard Lifton is one of eight world-changing researchers whose work is celebrated during a program airing tonight (Jan. 27) on the Science Channel at 9 p.m. EST.

Lifton, Sterling Professor of Genetics and chair of the Department of Genetics, received a $3 million Breakthrough Prize in Life Sciences, created by top Silicon Valley entrepreneurs.

The Science Channel program features the Dec. 12 ceremony where Lifton and others received their prize. The festivities were hosted by actor Kevin Spacey and featured such celebrities as Conan O’Brien, Glenn Close, Rob Lowe, and Michael C. Hall, as well as tech leaders Mark Zuckerberg, Larry Page, Sergey Brin, Anne Wojcicki, Jimmy Wales, and Yuri Milner.

SOURCE

http://news.yale.edu/2014/01/27/tonight-lifton-honored-star-studded-ceremony

Yale consortium awarded $6 million to study therapies for vascular disease

Tuesday, January 21, 2014

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Contact

Helen Dodson / 203-436-3984

Stacey Buba / 203-432-1333

Read this article on YaleNews

An international research team spearheaded by William C. Sessa, the Alfred Gilman Professor of Pharmacology and professor of medicine (cardiology), has been awarded a $6 million Transatlantic Networks of Excellence grant from the Fondation Leducq in France.

Sessa will be the U.S. coordinator for the consortium as it explores the mechanisms of secreted microRNAs and microRNA-based therapies for vascular disease. Sessa will be joined by a European coordinator, Dr. Thomas Thum, director of the Institute for Molecular and Translational Therapeutic Strategies at Hanover Medical School in Germany, and five investigators including recent Yale recruit, Carlos Fenandez-Hernando, associate professor of comparative medicine. The grant will be distributed over five years.

Sessa is director of the vascular biology and therapeutics program and vice chairman of pharmacology at Yale School of Medicine.

Sessa has long worked at the intersection of pharmacology and cardiovascular disease. He is on the scientific advisory board of the William Harvey Research Institute and NIHR Biomedical Research Unit in London, and also served on the joint strategy committee for the Yale-UCL collaborative in cardiovascular research.

“I am grateful to Fondation Leducq for funding this new international collaboration to find new and effective ways to treat a disease that kills millions of people each year,” Sessa said. “We have assembled a fantastic team of world class scientists to tackle the basic questions of how microRNAs are packaged and transferred between cells, and their therapeutic potential in vascular diseases.”

Fondation Leducq is a French non-profit health research foundation. Its mission is to improve human health through international efforts to combat cardiovascular disease. To this end, Fondation Leducq created the Transatlantic Networks of Excellence in Cardiovascular Research Program, which is designed to promote collaborative research involving centers in North America and Europe in the areas of cardiovascular and neurovascular disease.

Yale has had two previous Leducq grants — to Dr. Richard Lifton, chair of genetics, and Dr. Michael Simons, director of the Yale Cardiovascular Research Center.

SOURCE

http://bbs.yale.edu/about/article.aspx?id=6569

International Activity

• YALE-UCL Collaborative
  London, United Kingdom (2011)
  Dr. Lifton is on the Joint Strategy Committee for the Yale-UCL Collaborative, an alliance which will provide opportunities for high-level scientific research, clinical and educational collaboration across the institutions involved: Yale University, Yale School of Medicine, Yale-New Haven Hospital and UCL (University College London) and UCL Partners
• Transatlantic Network on Hypertension-Renal Salt Handling in the Control of Blood Pressure
  France (2007)
  Drs Hebert and Lifton will join leading researchers in Switzerland, France and Mexico in a transatlantic collaboration aimed at pinpointing the kidney’s role in high blood pressure.

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Education & Training

M.D.

Stanford University (1982)

Ph.D.

Stanford University (1986)

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Honors & Recognition

• National Academy of Sciences
• The Basic Science Prize
  American Heart Association
• Homer Smith Award
  American Society of Nephrology
• MSD International Award
  International Society of Hypertension

Research Interests

Molecular genetics of common human diseases

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Research Summary

The common human diseases that account for the vast majority of morbidity and mortality in human populations are known to have underlying inherited components. Advances in human genetics have made the identification of genetic variants contributing to these traits feasible. Such identification promises to revolutionize the diagnostic and therapeutic approaches to these disorders. We have focused on cardiovascular and renal disease. To date, we have identified mutations underlying more than 20 human diseases; these include a host of diseases that define molecular determinants of hypertension, stroke and heart attack. We have gone on from these starting points to use biochemistry and animal models to define the physiologic mechanisms linking genotype and phenotype. These findings have provided new insight into normal and disease biology, are identifying new pathways underlying disease pathogenesis, and are identifying new targets for development of novel therapeutics.

Extensive Research Description

Cardiovascular disease is the leading cause of death world-wide. Epidemiologic studies have identified hypertension, high cholesterol, diabetes and smoking as major risk factors. By investigation of rare families recruited from around the world that segregate single genes with large effect, we have identified genes that contribute to these traits, putting a molecular face on their pathogenesis. For example, we have identified mutations in 8 genes that cause high blood pressure (hypertension) and another 8 that cause low blood pressure. These mutations all converge on a final common pathway, the regulation of net salt reabsorption in the kidney. These findings have established the key role of variation in renal salt handling in blood pressure variation, and have led to changes in the approach to treatment of this disease in the general population. They have also identified new therapeutic targets that are predicted to have greater efficacy with reduced side effects. Finally, they have identified new signaling pathways involved in the regulation of blood pressure homeostasis. We have taken similar approaches to another common disease, osteoporosis, with the identification of gain of function mutations in LRP5, a component of the Wnt signaling pathway, in development of high bone density. This finding has led to intensive efforts to identify small molecules that impact this pathway to protect against and/or reverse osteoporosis in the general population. Ongoing studies use both emerging and novel approaches to identification of genes that contribute to disease burden in the population, and to understanding the pathways that link genes to disease. Mutations that affect blood pressure in humans. A diagram of a nephron, the filtering unit of the kidney, is shown. The molecular pathways mediating NaCl reabsorption in individual renal cells along the nephron are shown, along with the pathway of the renin-angiotensin system, a major regulator of renal salt reabsorption. Inherited diseases affecting these pathways are indicated, with hypertensive disorders in red and hypotensive disorders in blue. From Lifton, Gharavi, and Geller. Cell, 104:545-556, 2001.

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Selected Publications

• Mani, A., et al. (2007). LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278-82.
• Ring, A.M., et al. (2007). An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis. Proc. Natl. Acad. Sci. (USA) 104:4025-9.
• Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann, KE, Toka HR, Nelson-Williams C, Ellison, DH, Flavell, R, Booth, CJ, Lu Y, Geller, DS, Lifton, RP. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nature Genetics, in press.
• Wilson FH, Hariri A, Farhi A, Zhao H, Peterson K, Toka HR, Nelson- Williams C, Raja KM, Kashgarian M, Shulman GI, Scheinman SJ, Lifton RP. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science, 306:1190-94, 2004.
• Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptor-related protein 5. New Engl J Med. 346:1513-1521, 2002.
• Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP. Human Hypertension Caused by Mutations in WNK Kinases. Science, 293:1107-1112, 2001.
• Lifton RP, Gharavi A, Geller DS. Molecular mechanisms of human hypertension. Cell, 104:545-556, 2001.
• Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai TF, Sigler P, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science, 289:119-123, 2000.
• Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ reabsorption. Science, 285:103-106, 1999.

SOURCE
http://bbs.yale.edu/people/richard_lifton-3.profile

PubMed Results: 10

Select item 225138461.

Protein phosphatase 1 modulates the inhibitory effect of With-no-Lysine kinase 4 on ROMK channels.

Lin DH, Yue P, Rinehart J, Sun P, Wang Z, Lifton R, Wang WH.

Am J Physiol Renal Physiol. 2012 Jul 1;303(1):F110-9. doi: 10.1152/ajprenal.00676.2011. Epub 2012 Apr 18.

PMID:

22513846

[PubMed – indexed for MEDLINE]

Free PMC Article

Related citations

Select item 165287062.

Haplotype analysis in the presence of informatively missing genotype data.

Liu N, Beerman I, Lifton R, Zhao H.

Genet Epidemiol. 2006 May;30(4):290-300.

PMID:

16528706

[PubMed – indexed for MEDLINE]

Related citations

Select item 165282533.

Familial aggregation of primary glomerulonephritis in an Italian population isolate: Valtrompia study.

Izzi C, Sanna-Cherchi S, Prati E, Belleri R, Remedio A, Tardanico R, Foramitti M, Guerini S, Viola BF, Movilli E, Beerman I, Lifton R, Leone L, Gharavi A, Scolari F.

Kidney Int. 2006 Mar;69(6):1033-40.

PMID:

16528253

[PubMed – indexed for MEDLINE]

Related citations

Select item 127823554.

Mice lacking the B1 subunit of H+ -ATPase have normal hearing.

Dou H, Finberg K, Cardell EL, Lifton R, Choo D.

Hear Res. 2003 Jun;180(1-2):76-84.

PMID:

12782355

[PubMed – indexed for MEDLINE]

Related citations

Select item 113430495.

Glucocorticoid-remediable aldosteronism is associated with severe hypertension in early childhood.

Dluhy RG, Anderson B, Harlin B, Ingelfinger J, Lifton R.

J Pediatr. 2001 May;138(5):715-20.

PMID:

11343049

[PubMed – indexed for MEDLINE]

Related citations

Select item 102327426.

Elevated ambulatory blood pressure in 20 subjects with Williams syndrome.

Broder K, Reinhardt E, Ahern J, Lifton R, Tamborlane W, Pober B.

Am J Med Genet. 1999 Apr 23;83(5):356-60.

PMID:

10232742

[PubMed – indexed for MEDLINE]

Related citations

Select item 97986657.

Coincident acute myelogenous leukemia and ischemic heart disease: use of the cardioprotectant dexrazoxane during induction chemotherapy.

Woodlock TJ, Lifton R, DiSalle M.

Am J Hematol. 1998 Nov;59(3):246-8.

PMID:

9798665

[PubMed – indexed for MEDLINE]

Related citations

Select item 95012578.

In vivo phosphorylation of the epithelial sodium channel.

Shimkets RA, Lifton R, Canessa CM.

Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3301-5.

PMID:

9501257

[PubMed – indexed for MEDLINE]

Free PMC Article

Related citations

Select item 91562619.

Autotransplantation for relapsed or refractory non-Hodgkin’s lymphoma (NHL): long-term follow-up and analysis of prognostic factors.

Rapoport AP, Lifton R, Constine LS, Duerst RE, Abboud CN, Liesveld JL, Packman CH, Eberly S, Raubertas RF, Martin BA, Flesher WR, Kouides PA, DiPersio JF, Rowe JM.

Bone Marrow Transplant. 1997 May;19(9):883-90.

PMID:

9156261

[PubMed – indexed for MEDLINE]

Free Article

Related citations

Select item 881130410.

Clinical use of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in neutropenia associated with malignancy.

Lifton R, Bennett JM.

Hematol Oncol Clin North Am. 1996 Aug;10(4):825-39. Review.

PMID:

8811304

[PubMed – indexed for MEDLINE]

Related citations

SOURCE

http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&itool=pubmed_AbstractPlus&term=%22Lifton+R%22%5BAuthor%5D

 

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

Posted in Atherogenic Processes & Pathology, Cardiovascular Pharmacogenomics, Chemical Biology and its relations to Metabolic Disease, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Interviews with Scientific Leaders, Medical and Population Genetics, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Nutrition and Phytochemistry, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Systemic Inflammatory Response Related Disorders on January 21, 2014| Leave a Comment »

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

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #107: Voices from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator. Published on 1/21/2014

WordCloud Image Produced by Adam Tubman

This article covers the following related topics:

I. Voices from Cleveland Clinic: Love ‘Em or Leave ‘Em: Experts on Both Sides Debate the New Lipid Guidelines

http://www.medscape.com/viewarticle/819288?nlid=45683_2562&src=wnl_edit_medp_card&uac=93761AJ&spon=2

II.  JAMA Weighs In on CVD Guidance, Statins in Primary Prevention

http://www.medscape.com/viewarticle/814960

III.  How Good Is the New ACC/AHA Risk Calculator?

http://www.medscape.com/viewarticle/814579

IV.  New Cholesterol Guidelines Abandon LDL Targets

http://www.medscape.com/viewarticle/814152

V. New CV Risk-Assessment Guidance Counts Stroke With CHD Risk

http://www.medscape.com/viewarticle/814206

VI.  NIH Says ATP 4, JNC 8 Guidance Out ‘in a Matter of Months’ (With a Twist)

http://www.medscape.com/viewarticle/806563

VII.  New European Hypertension Guidelines Released: Goal Is Less Than 140 mm Hg for All

http://www.medscape.com/viewarticle/806367

VIII.  New guidelines on primary stroke prevention from AHA/ASA

http://www.medscape.com/viewarticle/790766

IX.  New ACC/AHA/NHLBI Guidance on Lifestyle for CVD Prevention

http://www.medscape.com/viewarticle/814139

X. New Obesity Guidelines: Authoritative ‘Roadmap’ to Treatment

http://www.medscape.com/viewarticle/814202

XI.  USPSTF Updates Adult Obesity-Overweight Screening Guidelines

http://www.medscape.com/viewarticle/766342

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

Love ‘Em or Leave ‘Em: Experts on Both Sides Debate the New Lipid Guidelines

Michael O’Riordan

January 20, 2014

DALLAS, TX and WASHINGTON, DC — It has been two months since the new clinical guidelines for the treatment of cholesterol were published^[1], and feedback is starting to slowly emerge as clinicians begin incorporating the recommendations into clinical practice.

The American College of Cardiology (ACC) and American Heart Association (AHA) guidelines, which were developed in conjunction with the National Heart, Lung, and Blood Institute (NHLBI), were a radical departure from previous iterations, most notably in their abandonment of LDL-cholesterol targets. In the past, clinicians were advised to treat patients with cardiovascular disease to less than 100 mg/dL or the optional goal of less than 70 mg/dL.

As reported by heartwire  at the time, the expert panel stated there was simply no evidence from randomized, controlled clinical trials to support treatment to a specific target. As a result, the new guidelines make no recommendations for specific LDL-cholesterol or non-HDL targets for the primary and secondary prevention of atherosclerotic cardiovascular disease.

Dr Stanley Hazen

For one clinician, Dr Stanley Hazen (Cleveland Clinic, OH), the strict adherence to only clinical-trial data is a limitation and not a strength of the new guidelines.

“First, it ignores a wealth of information on the pathophysiology of the disease process. Second, it presumes that the reason trials are designed is to answer guideline questions,” he told heartwire . “They aren’t. Trials are designed by pharmaceutical companies trying to get claims issued on their drugs. More important, the absence of randomized clinical-trial data does not justify inaction if LDL cholesterol remains elevated.”

Accelerating Vascular Age

In his commentary published January 8, 2014 in the Cleveland Clinic Journal of Medicine, Hazen, along with first author Dr Chad Raymond (Cleveland Clinic, OH), lay out their concerns with the clinical guidelines and highlight some of the shortcoming with the new recommendations^[2].

For Hazen, there are multiple reasons that physicians should continue to treat to specific LDL-cholesterol targets, the first and foremost being that patients are different and no single treatment fits such a large and heterogeneous patient population at risk for cardiovascular disease and stroke. The guidelines simply call for a moderate- or high-dose statin in high-risk patients depending on the clinical scenario and no subsequent assessment of LDL cholesterol.

“In the very highest-risk patients, the ones with extraordinarily high levels of cholesterol, those who get maximally tolerated statins, if there is still a substantial LDL-cholesterol burden, they are going to have substantial residual risk,” he said. “The preponderance of data in aggregate shows that there is higher residual risk proportionate to the LDL level that’s remaining. The new guidelines completely ignore the pathophysiology of the disease process—a disease that takes decades to develop.”

The clinical guidelines are unique among documents past in that the emphasis is strictly on statin therapy rather than LDL-cholesterol-lowering medications more generally. In individuals with atherosclerotic cardiovascular disease, high-intensity statin therapy—such as rosuvastatin (Crestor, AstraZeneca) 20 to 40 mg or atorvastatin 40 to 80 mg—should be used to achieve at least a 50% reduction in LDL cholesterol unless otherwise contraindicated or when statin-associated adverse events are present. In that case, doctors should use a moderate-intensity statin. Similarly, for those with LDL-cholesterol levels >190 mg/dL, a high-intensity statin should be used with the goal of achieving at least a 50% reduction in LDL-cholesterol levels.

For Hazen, the new clinical guidelines “turn back the clock on cardiovascular disease prevention” and have the potential to both overtreat older low-risk patients and undertreat those who are young yet are at higher lifetime risk.

For example, he cites a 25-year-old man who presents because his 45-year-old father just died from a heart attack. He has a fasting total cholesterol level of 310 mg/dL, HDL cholesterol of 50 mg/dL, triglyceride level of 400 mg/dL, and LDL cholesterol of 180 mg/dL. Even with the strong family history of premature coronary disease, because of his young age, the current guidelines do not suggest treatment because they do not apply to those less than 40 years old. However, even if his age were 40, his calculated 10-year risk would be <7.5% based on a new and controversial risk calculator published alongside the guidelines.

“I can’t imagine there is a lipidology expert or cardiologist out there who would think that this patient does not deserve aggressive preventive efforts and intervention,” said Hazen. “It is lifetime risk and lifetime exposure to higher LDL cholesterol that contributes to the disease process. Ignoring that scientific fact in a document whose focus is on treating cholesterol to prevent cardiovascular disease is simply illogical.”

A Massive Paradigm Shift

Speaking with heartwire , Dr James de Lemos (University of Texas Southwestern Medical Center, Dallas) suspects there remains some hesitancy on the part of practicing primary-care physicians to adopt the guidelines, mainly because they are a “massive paradigm shift that dramatically changes the approach to disease.” He said while there are always early adopters, there have been some questions as to which major journals and cardiology organizations would line up behind them (and nearly all have, with the exception of the American Association of Clinical Endocrinologists ).

For cardiologists, on the other hand, the shift to focus on four specific types of patients is not so dramatic, because these are patients they routinely see in clinical practice. For de Lemos, it is reasonable to focus on at-risk patients and treat according to that level of risk. He still incorporates measuring LDL-cholesterol levels, however, noting that the measurement can provide some reassurance or concern depending on the threshold achieved with treatment, dietary changes, and exercise.

Dr Mariel Jessup

To heartwire , Dr Mariel Jessup (University of Pennsylvania, Philadelphia), the president of the AHA, said that immediately following their publication many of her colleagues began implementing the guidelines and using the new calculator for risk assessment. In doing so, they identified patients on statins who did not require the lipid-lowering drugs as well as patients who weren’t on them but should be.

“In the first week, we were all coming to terms with what contributes to risk,” said Jessup. She added that she hasn’t heard a great deal of criticism about the guidelines and believes most physicians are getting on board with the new changes.

She noted that a member of the Penn faculty recently delivered medical grand rounds on the new lipid guidelines and while it was mostly positive, one criticism that arose was the emphasis on randomized, controlled clinical-trial data. Jessup said that even though the new guidelines focus on clinical-trial data, this does not negate findings from observational or epidemiological studies.

Dr Roger Blumenthal

Dr Roger Blumenthal (Johns Hopkins Ciccarone Preventive Cardiology Center, Baltimore, MD), on the other hand, predicts a return to LDL treatment goals in the not-so-distant future.

“I think the guidelines will revert back to the way they were once we get a positive study showing that adding another agent to a statin reduces risk,” Blumenthal said. He predicts positive results with anacetrapib (Merck, Whitehouse Station, NJ), the novel cholesteryl ester transfer protein (CETP) inhibitor, or one of the investigational proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, when given on top of statins. “When that happens, the new randomized controlled trial data would support going lower than what would be achieved with giving just 40 mg or 80 mg of atorvastatin.”

In very selected patients, Blumenthal still aggressively targets to low LDL levels, even if this requires adding a second agent. For example, in patients treated with a statin, LDL cholesterol might be reduced to 80 mg or so, but triglyceride levels remain high or HDL cholesterol is low. He notes that the ACCORD study with fenofibrate was borderline nonsignificant in patients with low HDL cholesterol and high triglyceride levels. Beyond fibrates, he notes there have been angiographic studies published in support of the “lower-is-better” hypothesis.

Jessup said that most physicians understand why the LDL targets were eliminated, but many institutions used the thresholds as a performance measure. Penn Health, for example, used the number of patients treated to the old LDL-cholesterol targets as an internal marker of performance for physicians in internal medicine and general practice. “As you struggle to come up with an easily defined target that you can use to talk about quality in a large practice, and not just among cardiologists, that’s one less target you can use,” said Jessup.

Concerns Among Clinicians as Well

Dr Rita Redberg

Dr Rita Redberg (University of California, San Francisco) also has significantconcerns about the new guidelines, albeit for entirely different reasons. An outspoken critic when the guidelines were presented, her views have not changed, telling heartwire that she is already looking forward to the next version of the cholesterol guidelines. When they were first published and presented, Redberg, along with Dr John Abramson (Harvard Medical School, Boston, MA), argued that statins were beneficial for individuals with heart disease but do not reduce the risk of death in individuals with a 10-year risk of cardiovascular disease of less than 20%.

“I have not been implementing these guidelines because I don’t think they’re in the best interests of my patients, and I really do look forward to the revisions,” she said. “I’m all for looking at risk, and I’m all for targeting prevention strategies on the basis of risk, so I think this is a strong point of the new guidelines. However, that is really undermined by the risk calculator, in which anybody over age 65 basically needs to be on a statin. I don’t think the data support this.”

The new cholesterol guidelines weathered a rough roll-out their first week when Drs Paul Ridker and Nancy Cook (Brigham and Women’s Hospital, Boston, MA) calculated the 10-year risk of cardiovascular events in three large-scale primary prevention cohorts—the Women’s Health Study(WHS), the Physicians’ Health Study (PHS), and the Women’s Health Initiative Observational Study (WHI-OS)—and found the new algorithm overestimated the risk by 75% to 150%.

Dr James de Lemos

To de Lemos, the controversial aspect of the new guidelines remains in the primary-prevention population. For those without cardiovascular disease but who have LDL-cholesterol levels ranging from 70 mg/dL to 189 mg/dL and a 10-year risk of cardiovascular disease >7.5%, physicians can initiate treatment with a statin. Given the controversy surrounding the risk calculator, there have been suggestions that people who don’t need statins will receive treatment.

“It doesn’t mean the concept is flawed,” de Lemos told heartwire , “but it just might not be ready to implement widely.” As a result, he suspects that physicians might be keeping the risk calculator at arm’s length until it is studied and debated further. As for his own use, de Lemos said he doesn’t calculate 10-year risk in every patient, even though he is fairly aggressive with initiating statin therapy, and that his decisions are more intuitive and empirical, something which he doesn’t see changing.

Jessup said the risk calculator, as well as the clinical guidelines, will be updated as new information emerges. While she was not able to speak to specifics, Jessup is aware of researchers testing the predictive strength of the risk calculator in different cohorts to see how well it performs. In general, she said the calculator performs reasonably well.

Some Docs Finding the Calculator Helpful

Dr Sekar Kathiresan

Dr Sekar Kathiresan (Brigham and Women’s Hospital, Boston, MA), who runs a primary-prevention clinic, does use the new clinical guidelines and the new risk calculator to inform his decisions about whether or not to start patients with a moderate- or high-dose statin. He said Ridker and Cook raise a valid scientific point in terms of how well it is calibrated, but this should be put in perspective, given that physicians for the past 20 years or so have used the Framingham Risk Score, a score derived from a few thousand white individuals from one town in the US. The new risk equation increases the population sampled, includes different ethnicities, and is derived from more than one geographic area.

“Is the pooled-cohort equation perfect?” he asked. “No, it won’t be perfect, because it’s an attempt to estimate risk on a sample of 25 000 people.”

Blumenthal made similar comments, telling heartwire that the risk calculator is a better way to estimate risk in women and African Americans, for example. Given that the risk calculator might overestimate risk, he expands his definition of intermediate risk to include patients with a 5% to 15% 10-year risk of cardiovascular disease. In doing so, even if the risk calculator overestimates by a factor of two, they have some wiggle room in discussing care with the patient.

In addition, Blumenthal said the guidelines emphasize a discussion with the patient about care in those with a 10-year risk exceeding 7.5%, just as would be done with an intermediate-risk patient. The discussion can lead to further refinement of risk by taking family history into account or by performing a computed tomography (CT) scan to assess coronary artery calcium (CAC).

To Kathiresan, moving away from LDL-cholesterol targets will require some time before they become readily accepted, mainly because physicians have gotten used to the targets. For the most part, though, he views the changes to the guidelines as more of a “tweak.”

“I don’t find them as radical as some people do,” Kathiresan told heartwire . “I actually think the major thing that was accomplished was taking the focus away from using medications to change lab tests and to now focus on medication proven to reduce the risk of disease. This is a huge plus for the new guidelines.”

In cardiology, the evidence base is very rich, with many trials and millions of dollars spent to evaluate whether specific medicines work to reduce disease risk in specific clinical situations, he added. This is the evidence that should be used to inform clinical practice. For this reason, he entirely agrees with the new focus on statins and not simply lipid-lowering agents.

“There is an incredible amount of inappropriate use of both niacin and fibrates in the US, all based on the fact that they change lab tests,” said Kathiresan. “The clinical-trial evidence for those two medicines is disappointingly poor.”

Hazen is a coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. He is a paid consultant to the Cleveland Heart Lab, Esperion, Liposciences, Merck, Pfizer, and Procter & Gamble. He has received research funds from Abbott, Astra Zeneca, Cleveland Heart Lab, Esperion, Liposciences, Procter & Gamble, and Takeda. In addition, he is entitled to royalty payments for inventions/discoveries related to cardiovascular diagnostics and therapeutics from Abbott Laboratories, Cleveland Heart Lab, Esperion, Frantz Biomarkers, and Liposciences . 

de Lemos acknowledges grant support from Roche Diagnostics and Abbott Diagnostics and has consulted for Diadexus. 

Kathiresan reports serving as a consultant to Merck, Pfizer, Celera, and Alnylam.

Jessup, Blumenthal, and Redberg report no conflicts of interest.

REFERENCES

1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association. J Am Coll Cardiol 2013. Article. Circulation 2013. Article.
2. Raymond C, Cho L, Rocco M, Hazen SL. New cholesterol guidelines: Worth the wait? Cleve Clin J Med 2014; DOI: 10.3949/ccjm.81a.13161. Article

SOURCE

http://www.medscape.com/viewarticle/819288#1

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Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)

Posted in Atherogenic Processes & Pathology, Best evidence, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cardiovascular Research, Curation, Curation methodology, Diabetes Mellitus, Discovery process, Evidence-based decision-making, Evolutionary cognition, Experimental validation, Explanatory, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Indigent Nutrition, Innovation in Immunology Diagnostics, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medicare and Medicaid, Metabolomics, Nephrology, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Systemic Inflammatory Response Related Disorders, Theoretic convergence, Translational Effectiveness, Translational Research, Translational Science, Uninsured and Underinsured, tagged AMI, Arterial stiffness, comorbidities - type 2 DM, COPD, coronary vascular disease, Diabetes management, Diabetes mellitus type 2, hs-CPR, Nutrition and Metabolism Disorders, Nutritional Supplements, prediabetes, proinflammatory, statins, waist circumference on January 15, 2014| Leave a Comment »

Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)

Curator:  Larry H. Bernstein, MD, FCAP

Article ID #106: Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD). Published 1/15/2014

WordCloud Image Produced by Adam Tubman

This is a multipart article that develops the pathological effects of type-2 diabetes in the progression of a systemic inflammatory disease with a development of neuropathy, and fully developing into cardiovascular disease.  It also identifies a systemic relationship to the development of chronic obstructive pulmonary disease (COPD).

The more we learn about diabetes, we learn about its generalized systemic effects.

This article has the following SIX Parts:

Part 1. Role of Autonomic Cardiovascular Neuropathy in Pathogenesis of ischemic heart disease in patients with diabetes mellitus

Part 2. A Longitudinal Cohort Study of the Cardiovascular Experience of Individuals at High Risk for Diabetes

Part 3.  Clinical significance of cardiovascular dysmetabolic syndrome

Part 4.   Waist circumference a good indicator of future risk for type 2 diabetes and cardiovascular disease

Part 5.   How to use C-reactive protein in acute coronary care

Part 6.  Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony

INTRODUCTION

Type 2 diabetes mellitus is a common chronic disease which develops insidiously over time, and is associated with obesity, nutritional imbalance (high fructose beverages, high starch and processed foods, carbohydrate excess intake, and an imbalance of proinflammatory to anti-inflammatory polyunsaturated  fatty acids), which makes it an acquired and manageable disease.  The long term effects of T2DM is played out on cardiovascular disease and stroke-risk, obstructive sleep apnea, progressive renal insufficiency, development of neuropathy, congestive heart failure and chronic obstructive pulmonary disease, all of which are occuring related to an systemic inflammatory condition that proceeds for some time prior to the identification of overt diabetes.
A detailed story of a significant part of these associations continues in the SIX Part series.

Part 1. Role of Autonomic Cardiovascular Neuropathy in Pathogenesis of ischemic heart disease in patients with diabetes mellitus

This article is an abstract only of a related publication of the pathogenesis of autonomic neuropathy in diabetics leading to ischemic heart disease.

Subjects: Medicine (General), Medicine, Medicine (General),
Health Sciences Authors: Popović-Pejičić Snježana, Todorović-Đilas Ljiljana, Pantelinac Pavle
Publisher: Društvo lekara Vojvodine Srpskog lekarskog društva
Publication: Medicinski Pregled 2006; 59(3-4): Pp 118-123 (2006) ISSN(s): 0025-8105  Added to DOAJ: 2010-11-11
http://dx.doi.org/10.2298/MPNS0604118P  http://www.doiserbia.nb.rs/img/doi/0025-8105/2006/0025-81050604118P.pdf

Keywords: diabetes mellitus, autonomic nervous system diseases, heart diseases, myocardial ischemia, comorbidity

Introduction.

Diabetes is strongly associated with macrovascular complications, among which

• ischemic heart disease is the major cause of mortality.

Autonomic neuropathy increases the risk of complications, which calls for an early diagnosis. The aim of this study was to determine

• both presence and extent of cardiac autonomic neuropathy,

in regard to the type of diabetes mellitus, as well as

• its correlation with coronary disease and
• major cardiovascular risk factors.

Material and methods. We have examined 90 subjects, classified into three groups, with 30 patients each: those with type 1 diabetes, type 2 diabetes and control group of healthy subjects. All patients underwent

• cardiovascular tests (Valsalva maneuver, deep breathing test, response to standing, blood pressure response to standing sustained, handgrip test),
• electrocardiogram,
• treadmill exercise test and
• filled out a questionnaire referring to major cardiovascular risk factors: smoking, obesity, hypertension, and dyslipidemia.

Results. Our results showed that cardiovascular autonomic neuropathy was

• more frequent in type 2 diabetes,
• manifesting as autonomic neuropathy.

In patients with autonomic neuropathy, regardless of the type of diabetes,

• the treadmill test was positive, i.e. strongly correlating with coronary disease.

In regard to coronary disease risk factors,

• the most frequent correlation was found for obesity and hypertension.

Discussion

Cardiovascular autonomic neuropathy is considered to be the principal cause of arteriosclerosis and coronary disease. Our results showed that the occurrence of cardiovascular autonomic neuropathy increases the risk of coronary disease due to dysfunction of autonomic nervous system.

Conclusions

Cardiovascular autonomic neuropathy is a common complication of diabetes that significantly correlates with coronary disease. Early diagnosis of cardiovascular autonomic neuropathy points to increased cardiovascular risk, providing a basis for preventive and therapeutic measures.

Part 2. A Longitudinal Cohort Study of the Cardiovascular Experience of Individuals at High Risk for Diabetes

This second part is a description of a longitudinal cohort study of individuals at high-risk for diabetes.  Unlike the SSA study, the study is not focused on protein-energy malnutrition.

Protocol for ADDITION-PRO: a longitudinal cohort study of the cardiovascular experience of individuals at high risk for diabetes recruited from Danish primary care

Subjects: Public aspects of medicine, Medicine, Public Health, Health Sciences
Authors: Johansen NB, Hansen Anne-Louise S, Jensen TM, Philipsen A, Rasmussen SS, Jørgensen ME, Simmons RK, Lauritzen T, Sandbæk A, Witte DR
Publisher: BioMed Central    Date of publication: 2012 Dec Published in: BMC Public Health 2012; 12(1): 1078    ISSN(s): 1471-2458   Added to DOAJ: 2013-03-12 http://dx.doi.org/10.1186/1471-2458-12-1078       http://www.biomedcentral.com/1471-2458/12/1078

Keywords: Diabetes, Cardiovascular disease, Primary care, Complications, Microvascular, Impaired fasting glucose, Impaired glucose intolerance, Aortic stiffness, Physical activity, Body composition

Background

Screening programmes for type 2 diabetes inevitably find more individuals at high risk for diabetes than people with undiagnosed prevalent disease. While well established guidelines for the treatment of diabetes exist, less is known about treatment or prevention strategies for individuals found at high risk following screening. In order to make better use of the opportunities for primary prevention of diabetes and its complications among this high risk group, it is important to

• quantify diabetes progression rates and to examine
• the development of early markers of cardiovascular disease and
• microvascular diabetic complications.

We also require a better understanding of the

• mechanisms that underlie and drive early changes in cardiometabolic physiology.

The ADDITION-PRO study was designed to address these issues among individuals at different levels of diabetes risk recruited from Danish primary care.

Methods/Design

ADDITION-PRO is a population-based, longitudinal cohort study of individuals at high risk for diabetes. 16,136 eligible individuals were identified at high risk following participation in a stepwise screening programme in Danish general practice between 2001 and 2006.

• All individuals with impaired glucose regulation at screening,
• those who developed diabetes following screening, and
• a random sub-sample of those at lower levels of diabetes risk

were invited to attend a follow-up health assessment in 2009–2011 (n = 4,188), of whom 2,082 (50%) attended. The health assessment included

• detailed measurement of anthropometry,
• body composition,
• biochemistry,
• physical activity and
• cardiovascular risk factors including aortic stiffness and central blood pressure.

All ADDITION-PRO participants are being followed for incident cardiovascular disease and death.

Discussion

The ADDITION-PRO study is designed to increase

• understanding of cardiovascular risk and
• its underlying mechanisms among individuals at high risk of diabetes.

Key features of this study include

• (i) a carefully characterised cohort at different levels of diabetes risk;
• (ii) detailed measurement of cardiovascular and metabolic risk factors;
• (iii) objective measurement of physical activity behaviour; and
• (iv) long-term follow-up of hard clinical outcomes including mortality and cardiovascular disease.

Results will inform policy recommendations concerning cardiovascular risk reduction and treatment among individuals at high risk for diabetes. The detailed phenotyping of this cohort will also allow a number of research questions concerning early changes in cardiometabolic physiology to be addressed.

Part 3.  Clinical significance of cardiovascular dysmetabolic syndrome

This study also addresses the issue of diabetes insulin resistance leading to cardiovascular dysmetabolic syndrome.

Subjects: Diseases of the circulatory (Cardiovascular) system,
Specialties of internal medicine, Internal medicine, Medicine, Cardiovascular, Medicine (General), Health Sciences
Authors: Deedwania Prakash C Publisher: BioMed Central            Date of publication: 2002 Jan
Published in: Trials 2002; 3: 1(2)   ISSN(s): 1468-6708  Added to DOAJ: 2004-06-03
http://dx.doi.org/10.1186/1468-6708-3-2   http://cvm.controlled-trials.com/content/3/1/2

Keywords: cardiovascular dysmetabolic syndrome, coronary heart disease, diabetes mellitus, hyperinsulinemia, insulin resistance

Although diabetes mellitus is predominantly a metabolic disorder,

• recent data suggest that it is as much a vascular disorder.
• Cardiovascular complications are the leading cause
  • of death and disability in patients with diabetes mellitus.

A number of recent reports have emphasized that

• many patients already have atherosclerosis in progression
• at the time they are diagnosed with clinical evidence of diabetes mellitus.

The increased risk of atherosclerosis and cardiovascular complications in diabetic patients is related to

• the frequently associated dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, and endothelial dysfunction.

The evolving knowledge regarding the variety of

• metabolic,
• hormonal, and
• hemodynamic abnormalities in patients with diabetes mellitus

has led to efforts designed for early identification of individuals at risk of subsequent disease. It has been suggested that

• insulin resistance, the key abnormality in type II diabetes,
• often precedes clinical features of diabetes by 5–6 years.

Careful attention to the criteria described for the cardiovascular dysmetabolic syndrome

• should help identify those at risk at an early stage.

The application of nonpharmacologic as well as newer emerging pharmacologic therapies can have beneficial effects

• in individuals with cardiovascular dysmetabolic syndrome and/or diabetes mellitus
• by improving insulin sensitivity and related abnormalities.

Early identification and implementation of appropriate therapeutic strategies would be necessary

• to contain the emerging new epidemic of cardiovascular disease related to diabetes.

Part 4.   Waist circumference a good indicator of future risk for type 2 diabetes and cardiovascular disease

Subjects: Public aspects of medicine, Medicine, Public Health, Health Sciences
Authors: Siren Reijo, Eriksson Johan G, Vanhanen Hannu
Publisher: BioMed Central      Date of publication: 2012 Aug
Published in: BMC Public Health 2012; 12: 1(631)    ISSN(s): 1471-2458   Added to DOAJ: 2013-03-12
http://dx.doi.org/10.1186/1471-2458-12-631    http://www.biomedcentral.com/1471-2458/12/631

Keywords: Waist circumference, Type 2 diabetes, Cardiovascular disease, Middle-aged men

Background

Abdominal obesity is a more important risk factor than overall obesity in

• predicting the development of type 2 diabetes and cardiovascular disease.

From a preventive and public health point of view it is crucial that

• risk factors are identified at an early stage,
• in order to change and modify behaviour and lifestyle in high risk individuals.

Methods

Data from a community based study was used to assess

• the risk for type 2 diabetes,
• cardiovascular disease and
• prevalence of metabolic syndrome in middle-aged men.

In order to identify those with increased risk for type 2 diabetes and/or cardiovascular disease

• sensitivity and specificity analysis were performed, including
• calculation of positive and negative predictive values, and
• corresponding 95% CI for eleven different cut-off points,
  • with 1 cm intervals (92 to 102 cm), for waist circumference.

Results

A waist circumference ≥94 cm in middle-aged men,

• identified those with increased risk for type 2 diabetes
• and/or for cardiovascular disease

with a sensitivity of 84.4% (95% CI 76.4% to 90.0%), and a specificity of 78.2% (95% CI 68.4% to 85.5%). The positive predictive value was 82.9% (95% CI 74.8% to 88.8%), and negative predictive value 80.0% (95% CI 70.3% to 87.1%), respectively .

Conclusions

Measurement of waist circumference in middle-aged men

• is a reliable test to identify individuals at increased risk for type 2 diabetes and cardiovascular disease.

This measurement should be used more frequently in daily practice in primary care

• in order to identify individuals at risk and when planning health counselling and interventions.

Part 5.  How to use C-reactive protein in acute coronary care

Luigi M. Biasucci, Wolfgang Koenig, Johannes Mair, Christian Mueller, Mario Plebani, Bertil Lindahl, Nader Rifai,Per Venge,Christian Hamm, and the Study Group on Biomarkers in Cardiology of the Acute Cardiovascular Care Association of the European Society of Cardiology
Department of Cardiology B, Aarhus University Hospital, Tage Hansens Gade2, Aarhus DK-8000,Denmark; Germany, U.K., U.S., Italy
European Heart Journal Advance Access published Nov 7, 2013.  Current Opinion.  http://dx.doi.org/10.1093/eurheartj/eht435

Introduction

 C-reactive protein (CRP) is an acute phase protein and an established marker for detection, risk stratification, and monitoring of infections, and inflammatory and necrotic processes.. Because C-reactive protein is sensitive but not specific, its values must be nterpreted  in the clinical context. Inpatients with acute myocardial infarction (AMI), CRP increases within 4–6h of symptoms, peaks 2–4 days later,and returns to baseline after 7–10 days.

CRP has gained interest recently as a marker for risk stratification in acute coronary syndrome (ACS) when measured by high-sensitivity CRP assays. These assays have greater analytical sensitivity and reliably measure CRP concentrations within the reference range with low imprecision (5–10%). Because of evidence that atherosclerosis is an inflammatory disease, high-sensitivity CRP can be used as a biomarker of risk
in primary prevention and in patients with known cardiovascular disease. The aim of this review is to evaluate the use of CRP in patients with acute coronary disease.

The in-vitro stability of high-sensitivity C-reactive protein is excellent. Specific blood sampling conditions aren’t necessary.  However, retesting may be necessary with some assays if there is marked lipaemia.  Baseline and subsequent measures are in good for agreement for risk stratification despite biological variability of 30–60%.

The upper reference limit is method-dependent but usually 8mg/L for standard assays. The distribution of high-sensitivity CRP concentrations is skewed in both genders with a 50th percentile of_1.5mg/L (excluding women on hormone replacement therapy). Race differences have been reported. Most studies have reported no relationship with age,  but to circadian and seasonal variation. CRP concentrations are increased by smoking, obesity, and hormone replacement therapy and reduced by exercise, moderate alcohol drinking, and statin use. Correction for these factors is essential in reference range studies. CRP assays are not standardized. We recommend  the use of third-generation high-sensitivity CRP assays that combine features of standard and high-sensitivity CRP assays.  Required assay precision should be < 10% in the range of 3 and 10 mg/L.

Biochemical and analytical issues

Critical clinical concepts

(1) CRP concentrations are reported in mg/L
(2) CRP test results are method-dependent

•  classification of patients into risk categories is usually comparable

(3) Third generation CRP assay are recommended
(4) No specific patient preparation before blood sampling is necessary
(5) The in-vitro stability of CRP is high

This is only a portion of the published concensus document. What is relevant to this discussion is that the hs-CRP is an extremely valuable marker for inflammatory disease.  It is not ordered often enough because of the broad range of values that we have become accustomed to for years, and it is elevated in rheumatologic conditions, but even then, it is widely used in pediatrics because children may present with rapidly emergent sepsis with very minimal sympoms.
The hs-CRP has opened a window to subliminal inflammatory disease that is diabetes, with accompanied arteriolar endothelial inflammation.

Part 6.  Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony

Subjects: Diseases of the circulatory (Cardiovascular) system,
Specialties of internal medicine, Internal medicine, Medicine, Cardiovascular, Medicine (General), Health Sciences
Authors: Mirrakhimov Aibek E
Publisher: BioMed Central      Date of publication: Oct 2012   ISSN(s): 1475-2840
Published in: Cardiovascular Diabetology 2012; 11(1):132   Added to DOAJ: 2013-03-12
http://dx.doi.org/10.1186/1475-2840-11-132      http://www.cardiab.com/content/11/1/132

Keywords: COPD, Dysglycemia, Insulin resistance, Obesity, Metabolic syndrome, Diabetes mellitus endothelial dysfunction, Vasculopathy

Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus

• are common and underdiagnosed medical conditions.

It was predicted that chronic obstructive pulmonary disease

• will be the third leading cause of death worldwide by 2020.

The healthcare burden of this disease is even greater

• if we consider the significant impact of chronic obstructive pulmonary disease on
  • the cardiovascular morbidity and mortality.

Chronic obstructive pulmonary disease

• may be considered as a novel risk factor for new onset type 2 diabetes mellitus via

multiple pathophysiological alterations such as:

1. inflammation and oxidative stress,
2. insulin resistance,
3. weight gain and
4. alterations in metabolism of adipokines.

On the other hand, diabetes may act as an independent factor,

• negatively affecting pulmonary structure and function.

Diabetes is associated with an increased risk of

1. pulmonary infections,
2. disease exacerbations and
3. worsened COPD outcomes.

On the top of that, coexistent OSA

• may increase the risk for type 2 DM in some individuals.

The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and

• chronic obstructive pulmonary disease may be viewed as a risk factor for
• the new onset type 2 diabetes mellitus.

Conversely, both types of diabetes mellitus should be viewed as

• strong contributing factors for the development of obstructive lung disease.

Such approach can potentially improve the outcomes and medical control for both conditions,

• and, thus, decrease the healthcare burden of these major medical problems.

CONCLUSIONS

This discussion  presents a spectrum of cardiovascular risk associated with type 2 diabetes mellitus, with high risk for CVD, stroke, endothelial dysfunction, and an association with obesity, measured by waist circumference, and an underlying proinflammatory state that can be measured by CRP.

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