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Herpes simplex virus type 1 and Alzheimer’s disease: Increasing evidence for a major role of the virus

September 12, 2014 by 2012pharmaceutical

Herpes simplex virus type 1 and Alzheimer’s disease: Increasing evidence for a major role of the virus

Reporter: Aviva Lev-Ari, PhD, RN

 

The concept of a viral role in Alzheimer’s disease (AD), specifically of herpes simplex virus type 1 (HSV1), was first proposed several decades ago (Ball, 1982; Gannicliffe et al., 1986). Legitimizing the concept clearly depended on a positive answer to a number of test questions, the first of which was whether or not HSV1 is ever present in human brain. The subsequent discovery that HSV1 DNA resides in a high proportion of brains of elderly people in latent form (Jamieson et al., 1991)—both normals and AD patients—immediately made the concept more credible, but raised associated questions such as whether or not the virus is ever active in brain or is merely a passive resident there; whether on its own it is a causative factor in AD or it acts thus only with another factor, perhaps genetic; if active, what causes its activity; whether there is any link with the characteristic abnormal features of AD brains or their components, and whether, if indeed implicated in AD, antiviral agents would be useful for treating the disease. These questions were posed in a previous review (Wozniak and Itzhaki, 2010)—and strong evidence was presented that permitted the answer to each question to be “yes” or, very likely to be “yes”. The present review briefly summarizes the earlier evidence, and provides an update, which is especially timely in view of the subsequent steady increase in number of relevant publications.

 

Herpes simplex virus type 1 (HSV1), when present in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE), has been implicated as a major factor in Alzheimer’s disease (AD). It is proposed that virus is normally latent in many elderly brains but reactivates periodically (as in the peripheral nervous system) under certain conditions, for example stress, immunosuppression, and peripheral infection, causing cumulative damage and eventually development of AD.

 

Diverse approaches have provided data that explicitly support, directly or indirectly, these concepts. Several have confirmed HSV1 DNA presence in human brains, and the HSV1-APOE-ε4 association in AD. Further, studies on HSV1-infected APOE-transgenic mice have shown that APOE-e4 animals display a greater potential for viral damage. Reactivated HSV1 can cause direct and inflammatory damage, probably involving increased formation of beta amyloid (Aβ) and of AD-like tau (P-tau)—changes found to occur in HSV1-infected cell cultures.

 

Implicating HSV1 further in AD is the discovery that HSV1 DNA is specifically localized in amyloid plaques in AD. Other relevant, harmful effects of infection include the following: dynamic interactions between HSV1 and amyloid precursor protein (APP), which would affect both viral and APP transport; induction of toll-like receptors (TLRs) in HSV1-infected astrocyte cultures, which has been linked to the likely effects of reactivation of the virus in brain.

 

Several epidemiological studies have now shown, using serological data, an association between systemic infections and cognitive decline, with HSV1 particularly implicated. Genetic studies too have linked various pathways in AD with those occurring on HSV1 infection. In relation to the potential usage of antivirals to treat AD patients, acyclovir (ACV) is effective in reducing HSV1-induced AD-like changes in cell cultures, and valacyclovir, the bioactive form of ACV, might be most effective if combined with an antiviral that acts by a different mechanism, such as intravenous immunoglobulin (IVIG).

Source: journal.frontiersin.org

See on Scoop.it – Cardiovascular and vascular imaging

Posted in Neurodegenerative Diseases, virology | Leave a Comment »

FDA-Approved 3D Printed Face Implant is a First

September 12, 2014 by 2012pharmaceutical

FDA-Approved 3D Printed Face Implant is a First

Reporter: Aviva Lev-Ari, PhD, RN

 

3D printed organs, skulls and vertebrae are just a few of the ways 3D printing can literally be a part of us. On Tuesday, biomedical devices company Oxford Performance Materials (OPM) announced the latest addition to 3D printed body parts: a 3D printed face.

 

OPM has received official FDA approval for a 3D printed facial device that can be used on patients in need of facial reconstructive surgery. The 3D printed OsteoFab® Patient-Specific Facial Device (OPSFD), which is the first and only FDA cleared 3D printed polymeric facial implant, is entirely customizable. It is made of different 3D printed parts that are made to fit each individual patient’s anatomical features.

 

What is equally revolutionary about the 3D printed facial implant is the drastic reduction in price it brings to facial reconstructive surgery. As it is tailor-made to each patient, the OPSFD reduces overall cost of ownership of a facial implant by reducing operating time, hospital stay duration and the chance of procedure complications. It also minimizes time before surgery as the implant can be 3D printed quickly.

 

Scott DeFelice, the CEO of OPM, referred to the FDA’s approval of the OPSFD as a paradigm shift:

 

“There has been a substantial unmet need in personalized medicine for truly individualized – yet economical – solutions for facial reconstruction, and the FDA’s clearance of OPM’s latest orthopedic implant marks a new era in the standard of care for facial reconstruction. Until now, a technology did not exist that could treat the highly complex anatomy of these demanding cases.

 

With the clearance of our 3D printed facial device, we now have the ability to treat these extremely complex cases in a highly effective and economical way, printing patient-specific maxillofacial implants from individualized MRI or CT digital image files from the surgeon. This is a classic example of a paradigm shift in which technology advances to meet both the patient’s needs and the cost realities of the overall healthcare system.”

 

Oxford Performance Materials also developed the first and only 3D printed customizable skull implant, which was approved by the FDA in February 2013 and later used to replace 75% of a patient’s skull. According to the president of OPM’s biomedical division, the two implants can now be used together for more complex cases.

Source: www.inside3dp.com

See on Scoop.it – Cardiovascular and vascular imaging

Posted in 3D Printing for Medical Application | Leave a Comment »

Create a personalized high-performance computer by crossing the barriers between clouds

September 12, 2014 by 2012pharmaceutical

Create a personalized high-performance computer by crossing the barriers between clouds

Reporter: Aviva Lev-Ari, PhD, RN

 

The Information Technology Research Institute of the National Institute of Advanced Industrial Science and Technology has developed a technology with which once an environment to perform high-performance computing has been established, a virtual cluster-type computer can easily be built on a different cloud and made available for immediate use.

Generally, in high-performance computing, cluster-type computers where many computers are bundled and run as a single computer are used. However, their hardware configuration is not uniform. On the other hand, virtual computers that are not dependent on hardware configuration are provided in clouds, and by bundling them together, a virtual cluster-type computer can be created. However, in this case, the user had to re-install software or reset the settings for a different cloud. Therefore, a technology to build a virtual cluster-type computer based on the design concept of “Build Once, Run Everywhere” has been developed. Once the environment to run the application has been established it may be run on any cloud, be it a private, commercial, or other cloud. Furthermore, since there are no constraints on the number of virtual computers that can be incorporated into the cluster, when the computing power is insufficient, an even larger virtual cluster-type computer can be formed on another cloud that allows the use of even more virtual computers, but allowing it to be used in exactly the same manner.

 

A virtual cluster-type computer was formed on AIST’s private cloud, AIST Super Green Cloud (ASGC), and the ability to use it on Amazon EC2, a commercial cloud, was verified. With this technology, users and application fields that could not use high-performance computing previously can now use high-performance computing. Thus, the developed technology is expected to contribute to the enhancement of industrial competitiveness.

 

There are many research organizations and companies that require high-performance computing, such as in the development of automobiles and for drug discovery. Conventionally, each organization prepared cluster-type computers within their organization. This required the introduction of a system with even higher performance to solve problems exceeding its computing capacity. Further, it was not readily available for introduction when it was required.

In clouds now widely available today, computing performance can be increased through the addition of computers by bundling virtual computers to form a cluster-type computer. However, when the built environment is to be re-created on a different cloud, it required the software to be re-installed and the settings reconfigured, necessitating extra time, labor, and cost.

Furthermore, because initial introduction and operating costs for cluster-type computers are high, the environment for high-performance computing could not be maintained, especially for small- and medium-scale enterprises. Expansion of the fields in which high-performance computing can be applied in support of such users is required for the enhancement of industrial competitiveness.

 

AIST is conducting R&D aimed at achieving a high-performance computing infrastructure with both the convenience to run on any cluster-type computer once a high-performance computing application-executing environment has been created, and high computing performance. In the process, R&D was conducted under the concept of separating the application-executing environment from actual machines by virtualization using cloud technologies to establish cluster-type computers on various clouds as required. In addition, although a cloud is established with virtualization technology, in the field of high-performance computing, there has been an issue of a drop in computing performance when virtualized, which has hindered its popularization. Therefore, evaluation of the effects of virtualization when executing high-performance computing applications was conducted in detail and technologies to reduce the deterioration of performance caused by virtualization have been developed.

Source: phys.org

See on Scoop.it – Cardiovascular and vascular imaging

Posted in HealthCare IT, United States | Leave a Comment »

Scientists reset human stem cells to earliest developmental state equivalent to 7-9 days old embryo

September 12, 2014 by 2012pharmaceutical

Scientists have successfully ‘reset’ human pluripotent stem cells to the earliest developmental state – equivalent to cells found in an embryo before it implants in the womb (7-9 days old). These ‘pristine’ stem cells may mark the true starting point for human development, but have until now been impossible to replicate in the lab. fThe discovery, published in Cell, will lead to a better understanding of human development and could in future allow the production of safe and more reproducible starting materials for a wide range of applications including cell therapies.

Human pluripotent stem cells, which have the potential to become any of the cells and tissues in the body, can be made in the lab either from cells extracted from a very early stage embryo or from adult cells that have been induced into a pluripotent state.

However, scientists have struggled to generate human pluripotent stem cells that are truly pristine (also known as naïve). Instead, researchers have only been able to derive cells which have advanced slightly further down the developmental pathway. These bear some of the early hallmarks of differentiation into distinct cell types – they’re not a truly ‘blank slate’. This may explain why existing human pluripotent stem cell lines often exhibit a bias towards producing certain tissue types in the laboratory.

Now researchers led by the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute at the University of Cambridge, have managed to induce a ground state by rewiring the genetic circuitry in human embryonic and induced pluripotent stem cells. Their ‘reset cells’ share many of the characteristics of authentic naïve embryonic stem cells isolated from mice, suggesting that they represent the earliest stage of development.

“Capturing embryonic stem cells is like stopping the developmental clock at the precise moment before they begin to turn into distinct cells and tissues,” explains Professor Austin Smith, Director of the Stem Cell Institute, who co-authored the paper. “Scientists have perfected a reliable way of doing this with mouse cells, but human cells have proved more difficult to arrest and show subtle differences between the individual cells. It’s as if the developmental clock has not stopped at the same time and some cells are a few minutes ahead of others.”

The process of generating stem cells in the lab is much easier to control in mouse cells, which can be frozen in a state of naïve pluripotency using a protein called LIF. Human cells are not as responsive to LIF, so they must be controlled in a different way that involves switching key genes on and off. For this reason scientists have been unable to generate human pluripotent cells that are as primitive or as consistent as mouse embryonic stem cells.

The researchers overcame this problem by introducing two genes – NANOG and KLF2 – causing the network of genes that control the cell to reboot and induce the naïve pluripotent state. Importantly, the introduced genes only need to be present for a short time. Then, like other stem cells, reset cells can self-renew indefinitely to produce large numbers, are stable and can differentiate into other cell types, including nerve and heart cells.

By studying the reset cells, scientists will be able to learn more about how normal embryo development progresses and also how it can go wrong, leading to miscarriage and developmental disorders. The naïve state of the reset stem cells may also make it easier and more reliable to grow and manipulate them in the laboratory and may allow them to serve as a blank canvas for creating specialised cells and tissues for use in regenerative medicine.

Professor Smith adds: “Our findings suggest that it is possible to rewind the clock to achieve true ground state pluripotency in human cells. These cells may represent the real starting point for formation of tissues in the human embryo. We hope that in time they will allow us to unlock the fundamental biology of early development, which is impossible to study directly in people.” – See more at: http://www.cam.ac.uk/research/news/scientists-reset-human-stem-cells-to-earliest-developmental-state#sthash.4gxh2MI9.dpuf

Source: www.cam.ac.uk

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Posted in Uncategorized | Leave a Comment »

Masked smoothing using separable kernels for CT perfusion images

September 12, 2014 by 2012pharmaceutical

BMC Medical Imaging

Source: www.mdlinx.com

See on Scoop.it – Cardiovascular and vascular imaging

Posted in Uncategorized | Leave a Comment »

Lift Labs Acquisition by Google: A sign of Persistence of the BioTech Pursuit

September 11, 2014 by 2012pharmaceutical

Lift Labs Acquisition by Google: A sign of Persistence of the BioTech Pursuit

Reporter: Aviva Lev-Ari, PhD, RN  

Google Inc. Dives Deeper Into Biotech With Lift Labs Acquisition

9/11/2014 6:36:45 AM

September 11, 2014

By Mark Terry, BioSpace.com Breaking News Staff

Google Inc. (GOOGL) announced Wednesday that it has acquired San Francisco-based Lift Labs for an undisclosed amount as it doubles down on biotech.

Lift Labs is a medical technology and device company that manufactures a vibrating spoon and fork that makes it easier for individuals with tremors, like those seen in Parkinson’s disease, easier to eat.

The Lift Labs products, Liftware, retails for $295. It was developed with assistance from an NIH grant.

This follows recent news that a Google startup, Calico, had signed a collaboration agreement with pharmaceutical company AbbVie (ABBV). Calico is a biopharmaceutical company that focuses on drug development to deal with age-related illnesses, including neurodegeneration and cancer. The Lift Labs acquisition is an expansion into medical hardware, as opposed to drug R&D, but does emphasize Google’s continued expansion into the healthcare arena.

Lift Labs will join Google X’s Life Sciences team. Other health technology-related investments included sensor-enhanced contact lenses to help diabetic patients monitor their glucose levels.

“We’re also going to explore how their technology could be used in other ways to improve the understanding and management of neurodegenerative diseases such as Parkinson’s disease and essential tremor,” said Google in a statement.

The Liftware device utilizes a small onboard computer that detects and counteracts hand tremors. A spoon or other utensil attaches to one end. The company plans to develop other attachments, such as a key holder.

Lift Lab’s founder Anupam Pathak noted that they can envision a wide assortment of hand-held devices, including makeup applicators and handheld tools. “Once you start to lose the ability to function independently, there’s a huge emotional toll,” he said.

University of Michigan neurology professor Kelvin Chou, who has worked with Lift Labs on their technology, noted in a New York Times blog that the uses for assistance technology are varied and helpful.

“A lot of social interaction revolves around eating,” said Chou. “It’s embarrassing for them, and they feel like people are watching them all the time. I’ve had patients say ‘Someone came up to me and said I should stop drinking.’ Things like that.”

In the United States, there are between 50,000 and 60,000 new cases of Parkinson’s disease (PD) diagnosed each year. It is the 14th leading cause of death in the U.S., and afflicts approximately four to six million people worldwide. PD is a neurodegenerative brain disorders that progresses slowly and affects the brain cells that produce dopamine.

Essential Tremor (ET) is a separate disorder and typically presents as a bilateral tremor of hand and forearm. It can occur at any age, though it usually shows up in the mid-teens or between the ages of 50 and 65. Approximately half of ET patients have a family history of the condition. Treatments for Parkinson’s tremors are not effective for ET.

 

SOURCE

http://www.biospace.com/News/google-inc-dives-deeper-into-biotech-with-lift/346153?type=email&source=DD_091114#sthash.Mqv49Mr0.dpuf

Posted in Digital HealthCare – biotech & internet joint ventures | Leave a Comment »

Ion Torrent Platforms in Research @ Icahn institute for Genomics and Multiscale Biology at Mt. Sinai in Research of Genes Protecting from Rare Catastrophic Diseases

September 11, 2014 by 2012pharmaceutical

Ion Torrent Platforms @ Icahn institute for Genomics and Multiscale Biology at Mt. Sinai, in Research of Genes Protecting from Rare  Catastrophic Diseases

Reporter: Aviva Lev-Ari, PhD, RN

Mt. Sinai to Open NGS Facility, Initially Equip with Ion Torrent Platforms

September 11, 2014

NEW YORK (GenomeWeb) – The Icahn institute for Genomics and Multiscale Biology at Mt. Sinai is opening a new next-generation sequencing facility in Branford, Conn. The facility will be equipped with eight of Thermo Fisher Scientific’s Ion Proton systems and eight Ion Chef systems, along with the Torrent Suite Variant Caller and customized AmpliSeq panels.

Researchers at Mt. Sinai and Thermo Fisher collaborated to develop a custom AmpliSeq panel consisting of 26,000 amplicons that cover 700 genes known to increase the risk for inherited genetic diseases, cancer, cardiovascular disease, obesity, and other disorders.

The Mt. Sinai team plans to use the Ion Proton as part of its Resilience Project, a research project to better understand the genes and other factors that may protect individuals from developing rare, catastrophic diseases.

Robert Sebra, director of technology development and an assistant professor of genetics and genomic sciences at Mt. Sinai, said in a statement that the Proton’s “low per-sample cost, robustness across sample types, rapid end-to-end data generation, and the breadth of the AmpliSeq targeted custom panel for screening hundreds of targeted genes in a single sequencing assay indicated the platform as a highly efficient system for addressing the large volume and diversity of samples we intend to sequence in our new NGS lab.”

Eric Schadt, the founding director of the Icahn Institute for Genomics and Multiscale Biology, also said in the statement that the researchers plan to develop “a wide range of clinical tests to be run on the Proton” at the new sequencing facility, including an Ion AmpliSeq Cancer Hotspot Panel, which he said recently gained approval from the New York State Department of Health.

“As we scale up to processing large volumes of samples, we expect to rapidly advance our translational research findings in major disease areas such as cancer, rare inherited disorders, and characterization of risk across a broad spectrum of common human diseases,” he added.

SOURCE
http://www.genomeweb.com/sequencing/mt-sinai-open-ngs-facility-initially-equip-ion-torrent-platforms 

 

Posted in Gene Regulation, Gene Regulation and Evolution, Genome Biology | Leave a Comment »

Counting the numbers in the genome means shaping the outcome, that is phenotype

September 10, 2014 by Demet Sag, Ph.D., CRA, GCP

 

Demet Sag, Ph.D, CRA, GCP

Demet.sag@gmail.com

We learn how to count  when we start to speak one, two three…. Counting to balance check book.  Counting on people vs. counting people.  Counting from fly to human and life. It is a process we rely on counting things and counting on people. Both of them are necessary.

It is a common practice to count number of blood cells, hematocrit, and assume physiological responses for simple screening of a disease.

Counting X:A ratio is not just for flies what that means is that variations in human diseases also doing share similar signaling processing and create variations.  Counting GC%, comparing populations and developing biomarkers are all in the name of finding the cure.

Counting helps to program the cell to respond and produce proteins that is needed. Counting  polymorphisms, variations, mutations and alleles are important to measure disposition of the disease.  Make educational guess based on statistical analysis and bioinformatics.

The living systems regardless of their shape or size have their own counter / scale that includes gene control mechanism that may contain RNA binding proteins, DNA binding proteins, dimers, protein complexes or sensors to measure concentrations of molecules, hormones, elements, gases.

There can be one key gene but many others contribute for its function that is called transregulators either turn it on or turn it off that depends on the cues received from surrounding cells.  Thus, extending this simple rule we can explain  why predisposition of human diseases controlled or occurred differently in each person even though we all do carry the same blue print we do have variations on different locations of the genome. There are projects going around the world to count variations, analyze population genetics, determine pre-natal vs. natal outcomes. Thus, we have tons of data to analyze and to make sense.

As a result, these variations reflects on types of diagnostics tools and therapies.  Therefore, each individual may respond to the treatment differently. However, it is also possible inherited characteristics may shifted, lost or acquired  due to environmental factors, infectious diseases, stress, trauma, surgery and many more.

There is a counting mechanism in genome. This mechanism is actually “shared”.  When counting mechanism is mentioned people who took biology 101 immediately may say Drosophila melanogaster (fruit fly) determines its sex determination based on counting numbers of X:Y. Yet, the signaling process in the embryonic stem cell or sex determination is a common mechanism that we observe in cell differentiation and system biology.

The idea of using “a universal standard ruler” for measuring these shifts with three dimensional presentation DNA (x), RNA (y) and protein (z) responds to mainly  time (age), gender, origin/race/country can be possible. Data sharing and medical records are necessary but with respect to privacy and safety of people.

RNA binding proteins are important part of genome and central to many biological processes.

For example,neurodegenerative diseases are already complex to study but there are many efforts.  The Japanese study provided a study on CNS cell differentiation and counting mechanism.    Their intention was to understand the basic mechanisms of the generation of cellular diversity in the CNS, upon which therapeutic treatments for CNS injuries, degenerative diseases, and brain tumors. In rat animal studies they showed that generated rat monoclonal antibodies (Mab 14H1 and 14B8) that recognized an RNA-binding protein Musashi1.  The amino acid sequences at the epitope sites of these anti-Musashi1 Mabs were remarkably conserved among the human, mouse, and Xenopus proteins. Since cells committed to the oligodendroglial lineage were Musashi(-), it is advantageous to identify each cell and count cells in situ.

There are many examples of counting and role of RNA binding proteins through alternative splicing in immune response mechanisms, muscle cell differentiation, measuring an enzyme activity or analyzing evolution of plant development. This decides type of cell proliferation, creates number of receptors, proteins and actions.

During development alternative splicing occurs.  This also requires counting and balancing the act. RNA binding proteins has a big role in this. There are other factors of course.  Thus, establishment of  early differentiation under the inherited blue print displayed through counting. On the other hand, there can be a switch for a specific cellular response possibly for an immune response to fight against a disease or infection or against self due to acquired modifications on genome.

RNA binding proteins help to create diversity through gene expression control from transcription to post-translation that we count on throughout the life cycle at various developmental stages. Furthermore we should keep close attention to the viruses especially to RNA viruses and their metabolisms.  Microorganisms, fungi, yeast,  bacteria and viruses, do interact with their host to create living. Some of the diseases basically start from failure to defend host towards pathogen that leads into a disease such as a cancerous tumor, an autoimmune disease, a neurodegenerative disorder or a metabolic malfunction.

Furthermore, one can wonder about circulating RNAs with various shapes and sizes and their impact on gene expression control.  Their role is making customized responses but still they can be counted as well.

There are 79 clinical trials on RNA binding proteins.  One o these studies were on whole genome sequence analysis for schizophrenia. Furthermore determining the type of RNA-protein with high throughput sequencing is available, but  determining the precise interaction sites would help to identify underlying function in the genome and biological processes.

Kramer et al, (Nature Methods, 2014, doi:10.1038/nmeth.3092) provided an open-source software pipeline developed for this purpose, RNPxl, is available as part of the OpenMS (project.http://www.nature.com/nmeth/journal/vaop/ncurrent/carousel/nmeth.3092-F3.jpg)

How do we use the data to modulate cellular responses, count variations properly with genomic sequencing and make a clear understanding of physiological outcome for human health are the questions that we are after.  As we all know that RNA-protein complexes show crucial importance in many central biological processes. Therefore, we can modulate cells by synthesizing these data towards personalized medicine. Chemical and physical properties of these structures may identify these cells to target for selective elimination.  Next Gene Sequencing based on two main molecular technologies hybridization and polymerase chain reaction.  It is possible to make a sandwich of DNA, RNA and protein concurrently.

References:

An integrated map of genetic variation from 1,092 human genomes 

The 1000 Genomes Project Consortium,  Nature DOI: 10.1038/nature11632

Fly-FUCCI: A Versatile Tool for Studying Cell Proliferation in Complex Tissues

Norman Zielke, Jerome Korzelius, Monique van Straaten, Katharina Bender, Gregor F.P. Schuhknecht,

Devanjali Dutta, Jinyi Xiang, Bruce A. Edgar.

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Med Phys. 2013 August; 40(8): 081923. Published online 2013 July 31. doi: 10.1118/1.4813901

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PMID: 25201111

A potential regulatory loop between Lin28B:miR‑212 in androgen-independent prostate cancer.

Borrego-Diaz E, Powers BC, Azizov V, Lovell S, Reyes R, Chapman B, Tawfik O, McGregor D, Diaz FJ, Wang X, Veldhuizen PV.

Int J Oncol. 2014 Sep 9. doi: 10.3892/ijo.2014.2647. [Epub ahead of print]

PMID: 25201220

The RNA-Binding Protein DDX1 Promotes Primary MicroRNA Maturation and Inhibits Ovarian Tumor Progression.

Han C, Liu Y, Wan G, Choi HJ, Zhao L, Ivan C, He X, Sood AK, Zhang X, Lu X.

Cell Rep. 2014 Aug 27. pii: S2211-1247(14)00660-3. doi: 10.1016/j.celrep.2014.07.058. [Epub ahead of print]

PMID: 25176654

Hsp27 binding to the 3’UTR of bim mRNA prevents neuronal death during oxidative stress-induced injury – a novel cytoprotective mechanism.

Dávila D, Jiménez-Mateos EM, Mooney CM, Velasco G, Henshall DC, Prehn JH.

Mol Biol Cell. 2014 Sep 3. pii: mbc.E13-08-0495. [Epub ahead of print]

PMID: 25187648

Tombusvirus-yeast interactions identify conserved cell-intrinsic viral restriction factors.

Sasvari Z, Alatriste Gonzalez P, Nagy PD.

Front Plant Sci. 2014 Aug 11;5:383. doi: 10.3389/fpls.2014.00383. eCollection 2014. Review.

PMID: 25157258

Regulation of microRNA function in somatic stem cell proliferation and differentiation.

Shenoy A, Blelloch RH.

Nat Rev Mol Cell Biol. 2014 Sep;15(9):565-76. doi: 10.1038/nrm3854. Epub 2014 Aug 13.

PMID: 25118717

Flaviviral RNAs: weapons and targets in the war between virus and host.

Bidet K, Garcia-Blanco MA.

Biochem J. 2014 Sep 1;462(2):215-30. doi: 10.1042/BJ20140456.

PMID:25102029

Post-transcriptional gene regulation by RNA-binding proteins in vascular endothelial dysfunction.

Xin H, Deng K, Fu M.

Sci China Life Sci. 2014 Aug;57(8):836-44. doi: 10.1007/s11427-014-4703-5. Epub 2014 Aug 8.

PMID: 2510445

Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia.

Volpi S, Heaton C, Mack K, Hamilton JB, Lannan R, Wolfgang CD, Licamele L, Polymeropoulos MH, Lavedan C.

Mol Psychiatry. 2009 Nov;14(11):1024-31. doi: 10.1038/mp.2008.52. Epub 2008 Jun 3.

PMID:18521091

Emerging Significance of NLRs in Inflammatory Bowel Disease.

Davis BK, Philipson C, Hontecillas R, Eden K, Bassaganya-Riera J, Allen IC.

Inflamm Bowel Dis. 2014 Aug 22. [Epub ahead of print]

PMID:25153506

G3BP1, G3BP2 and CAPRIN1 are required for translation of interferon stimulated mRNAs and are targeted by a dengue virus non-coding RNA.

Bidet K, Dadlani D, Garcia-Blanco MA.

PLoS Pathog. 2014 Jul 3;10(7):e1004242. doi: 10.1371/journal.ppat.1004242. eCollection 2014 Jul.

PMID:24992036

 

Structure-guided design of fluorescent S-adenosylmethionine analogs for a high-throughput screen to target SAM-I riboswitch RNAs.

Hickey SF, Hammond MC.

Chem Biol. 2014 Mar 20;21(3):345-56. doi: 10.1016/j.chembiol.2014.01.004. Epub 2014 Feb 20.

PMID: 24560607

A truncated hnRNP A1 isoform, lacking the RGG-box RNA binding domain, can efficiently regulate HIV-1 splicing and replication.

Jean-Philippe J, Paz S, Lu ML, Caputi M.

Biochim Biophys Acta. 2014;1839(4):251-8. doi: 10.1016/j.bbagrm.2014.02.002. Epub 2014 Feb 14.

PMID: 24530421

Posttranscriptional Regulation of Intestinal Epithelial Tight Junction Barrier by RNA-binding Proteins and microRNAs.

Yang H, Rao JN, Wang JY.

Tissue Barriers. 2014 Jan 1;2(1):e28320. doi: 10.4161/tisb.28320. Epub 2014 Mar 19. Review.

PMID:24843843

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Germline Genes and Drug Targets: Medicine more Proactive and Disease Prevention more Effective.

September 10, 2014 by 2012pharmaceutical

Germline Genes and Drug Targets: Medicine more Proactive and Disease Prevention more Effective

 

Curators for a forthcoming article on Predictive Therapeutics:

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

Reporter for the content, below:

  • Aviva Lev-Ari, PhD, RN 

A Perspective on Predictive Therapeutics by Larry H Bernstein, MD, FCAP

The approach is novel.  I am quite versed in vit D metabolism and in retinol and retinoids.

The articles should not be ads, but should lay out a hypothesis, proof of concept, and extension to therapeutics.

The germ-line concept as an alternative approach to somatic cell genomics is powerful.  Somatic mutations I have thought for some time come late, and are part of a cascade of changes that lead to adaptive mutational expression.

What he is proposing with respect to the identification of SNPs associated with key germ-line targets is unexpected, and I can’t comment on it, but it would tie in somewhat with the surprising and rapid progress being made with stem cells.  But the success with stem cells still does not have to deal with an organ system in a living animal or person.  It’s a long way to Tipperari!

His attack to the problem is by identifying key differentiation related SNPs, and to address the targets with known INDISPENSIBLE metabolic and nontoxic agents for pharmacotherapy.

I would not go so far as the statement that all disease is related to germline genomic expression, if that is an extension of the hypothesis.  But it does bring together the functional concept of disordered metabolism related to germline SNP expression in a broader sense than just cancer, and perhaps related to immune tolerance, TLR receptors, and a number of chronic diseases.  It is an interesting divergence.

There is sufficient complexity in life processes that I can’t really conceptualize how he puts this all together.

About the Pioneer @ GenoMed, Inc.

 

Physician-scientist who identified angiotensin I-converting enzyme (ACE) as a “master” disease gene; President and CEO of GenoMed; St. Louis, MO

David W. Moskowitz, MD- Chairman, Chief Executive Officer, and Chief Medical Officer
Dr. Moskowitz majored in Chemistry (summa cum laude) at Harvard College, Biochemistry (first class honours) at Merton College, Oxford, and received an MD (cum laude) from the Harvard-MIT Division in Health Sciences and Technology (Harvard Medical School). He trained for 7 years in Internal Medicine, Biochemistry, and Nephrology at Washington University School of Medicine in St. Louis before spending 11 years on the faculty of St. Louis University School of Medicine. Since 1994, Dr. Moskowitz has experienced first hand the clinical effectiveness of knowing a disease-associated gene (the angiotensin converting enzyme, or ACE, gene). Dr. Moskowitz is a pioneer in the field of medical genomics, and has been recognized for his groundbreaking treatment of diseases associated with the angiotensin I-converting enzyme, such as chronic renal failure due to hypertension or type II diabetes.

VIEW VIDEO

http://www.genomed.com/about-us.html

GenoMed is a Next Generation DMtm company that uses medical genomics to improve patient outcomes. GenoMed is working to translate knowledge of medical genomics–the study of which genes cause disease–into clinical practice. We combine biotechnology with Disease Management (DM). We develop new and better drugs, we use existing drugs for new disease indications, and we uncover disease before symptoms arise. By studying disease genes, we hope to make medicine more proactive and disease prevention more effective.

 

Drug discovery: Once GenoMed identifies a disease gene without any existing therapy, the company pursues strategic alliances with large, research-oriented pharmaceutical companies to develop new drugs against the target.

Using existing drugs for new clinical indications: Occasionally, knowing a disease gene can make an existing drug more effective. For example, GenoMed has demonstrated that a proprietary regimen of an existing ACE inhibitor can dramatically delay the progression of end-stage kidney disease due to Type 2 diabetes or hypertension in both African American and Caucasian men, as well as the progression of peripheral vascular disease, and even emphysema. This is the first time an ACE inhibitor has been found to be useful for emphysema.

Gene-based diagnostic tests: Knowing the genes which cause a disease allows a physician to diagnose that disease before symptoms ever become visible. In clinical medicine, the earlier the diagnosis, the better the clinical outcome.

 

GenoMed was inspired by Dr. David Moskowitz’s research on the angiotensin I-converting enzyme (ACE) gene during the mid 1990s. His lab discovered that ACE was a “master” disease gene. ACE was found to be associated with about 160 common, serious diseases such as type 2 diabetes, common cancers (except for prostate and breast), and psychiatric diseases. Moskowitz, a nephrologist, treated 1,000 of his own patients based on his knowledge of diseases caused in part by ACE. His early efforts produced dramatic results — the rate of progression of kidney disease due to high blood pressure was reduced by an average of 300% in both African American and Caucasian male patients. Through this new treatment, patients who normally reached dialysis in 4 years were not predicted to reach end-stage kidney disease for 16 years. Patient outcomes for kidney failure due to type 2 diabetes, atherosclerotic peripheral vascular disease, and emphysema (COPD) were equally exciting. In February 2001 Moskowitz founded GenoMed with the help of industry veterans Jerry White, Richard Kranitz and Peter Brooks.

Competitive Position
Like the science of genomic medicine, GenoMed takes a targeted and efficient approach to finding and commercializing disease genes. Our past experience in medical genomics has helped us to identify a class of single nucleotide polymorphisms (SNPs) that we believe has strong associations with all common diseases. We use the least expensive, fastest throughput genotyping currently available in the world. Our ability to move much more quickly than larger, more bureaucratic corporations maximizes our intellectual property produced per dollar spent.

The medical industry is on an unsustainable course. Costs, already high, are still rising while outcomes mostly haven’t changed. The aging of the Baby Boomers threatens to bankrupt Medicare in the next few years. China and India can’t afford kidney dialysis for the hundreds of millions of people who need it. Only prevention can improve outcomes while simultaneously lowering costs. Fortunately, genomics lets us find the root causes of disease. GenoMed is inventing the field of preventive molecular medicine. We are also inventing a new business model for medicine.

GenoMed guarantees the best outcomes in the medical literature for diabetes, high blood pressure (also called “hypertension”), COPD (also called “emphysema”), sickle cell disease, or your money back! (more info…)

The best outcomes in the medical literature, or it’s free™.

SOURCE

http://www.genomed.com/

Help us make the world dialysis-free by 2020.

 

Technology and Approach

GenoMed’s primary scientific initiative consists of its SNPnet©. The SNPnet©™ is the set of single nucleotide polymorphisms (SNPs) GenoMed uses to locate disease genes. We use a fishing metaphor since finding disease genes is like fishing for a handful of letters in an ocean of three billion letters. Our SNPnet© is currently made up of over 80,000 SNPs and covers the entire human genome. Once the disease genes are identified, disease-associated SNPs will be placed onto a single DNA chip, the HealthChip®, for clinical diagnostic testing.

Targeted Diseases

Diseases with Published Superior Clinical Outcomes*:

  • Sickle Cell Disease
  • Kidney failure due to type 2 (“adult onset”) diabetes
  • Kidney failure due to high blood pressure
  • Emphysema (“COPD”)
  • Poor circulation due to high blood pressure

* see Moskowitz, “ACE Example”

If you would like information about subscribing to our Clinical Outcomes Improvement Program (COIP®) for one of the above diseases, then Contact GenoMed.

 

Diseases in Clinical Trials:

  • Cancer (of any organ, any stage, including leukemias and lymphomas)
  • HIV
  • SARS
  • Influenza
  • Hepatitis (A, B, and C)
  • Multiple sclerosis
  • Alopecia
  • Psoriasis (see Moskowitz, “Role of ACE”)
  • Chronic fatigue syndrome/fibromyalgia
  • Lupus
  • Rheumatoid Arthritis
  • Alzheimer’s Disease
  • Parkinson’s Disease
  • ALS (“Lou Gehrig’s Disease”)
  • Age-related macular degeneration
  • Glaucoma
  • West Nile virus (see Moskowitz, “Role of ACE”)

 

Pre-Clinical Research (looking for disease-predisposition genes):
Currently collections are underway or scheduled for the following diseases:

 

All Cancers
GenoMed would be delighted to discuss collaborations with qualified groups that are dedicated to solving specific diseases

 

Clinical Outcomes Improvement Program (COIP®)


PATIENTS

GenoMed invites patients to join its Clinical Outcomes Improvement Program (COIP®). GenoMed has so far published superior clinical outcomes for the following diseases: hypertension, type 2 diabetes, and emphysema. If you have one of these diseases, please contact us. An annual subscription to GenoMed’s COIP® costs $200. We would like to work with your current physician.

 

GenoMed is currently recruiting individuals for 2 clinical trials:

 

 Awards

 

    • • “Most Questions” Award, Gordon Research Conference on Angiotensin, Ventura, CA, Feb. 21-25, 2010.
      Moskowtize Award 1 Moskowitz Award 2
    • • 2006 Defender of Patient Safety Award, Missouri Watch, Jefferson City, MO, April 25, 2006.
  • • Finalist, St. Louis Health Hero (St. Louis Business Journal), November, 2005.

 

Publications

  1. From Pharmacogenomics to Improved Patient Outcomes: Angiotensin I-Converting Enzyme as an Example
  2. Is Angiotensin I-Converting Enzyme a “Master” Disease Gene?
  3. Is “Somatic” Angiotensin I-Converting Enzyme a Mechanosensor?
  4. Pathophysiologic Implications of Angiotensin I-Converting Enzyme as a Mechanosensor: Diabetes
  5. Why AT1R blockade makes sense for SARS
  6. The Central Role of Angiotensin I-Converting Enzyme in Vertebrate Pathophysiology
  7. Written evidence included in July 7, 2009 report on genomic medicine by the British House of Lords (view report)
  8. Are Blockbuster Drugs Still Possible in the Era of Personalized Medicine?
  9. A Modern-Day Tuskegee… and What’s Really Wrong with U.S. Health Care Today?

 SOURCE

http://www.genomed.com/companynews/publications.html

 


 

Posted in Computational Biology/Systems and Bioinformatics, Personalized and Precision Medicine & Genomic Research | Leave a Comment »

Biomarkers and risk factors for cardiovascular events, endothelial dysfunction, and thromboembolic complications

September 9, 2014 by larryhbern

Biomarkers and risk factors for cardiovascular events, endothelial dysfunction, and thromboembolic complications

Curator: Larry H Bernstein, MD, FCAP

 

 

Acute Coronary Syndrome

Predictive Cardiovascular and Circulation Biomarkers

Biomarkers are chemistry analytes measured in plasma, serum or whole blood that potentially identify injury or risk for injury.  They may be measured in the laboratory or at the bedside (point of care technology).  They may be measured as an enzyme (CK isoenzyme MB), a protein (troponins I & T), or as a micro RNA (miRNA).  In the last decade the discovery and use of cardiac biomarkers has moved toward very small quantities, even 100 times below the picogram range using Quanterix Simoa, compared with an enzyme immunoassay.

The time of sampling was based on time to appearance from time of damage, and the release of the biomarker is a stochastic process. The earliest studies of CK-MB appearance, peak height, and disappearance was by Burton Sobel and associates related to measuring the extent of damage, and determined that reperfusion had an effect.

There has been a nonlinear introduction of new biomarkers in that period, with an explosion of methods discovery and large studies to validate them in concert with clinical trials. The improvement of interventional methods, imaging methods, and the unraveling of patient characteristics associated with emerging cardiovascular disease is both cause for alarm (technology costs) and for raised expectations for both prevention, risk reduction, and treatment. What is strikingly missing is the kind of data analyses on the population database that could alleviate the burden of physician overload. It is an urgent requirement for the EHR, and it needs to be put in place to facilitate patient care.

 

Biomarkers: Diagnosis and Management, Present and Future

Curator: Larry H Bernstein, MD, FCAP
Biomarkers of Cardiovascular Disease : Molecular Basis and Practical Considerations.
RS Vasan .
Circulation. 2006;113:2335-2362. http://dx.doi.org/10.1161/CIRCULATIONAHA.104.482570
http://pharmaceuticalintelligence.com/2013/11/10/biomarkers-diagnosis-and-management/

sCD40L indicates soluble CD40 ligand; Fbg, fibrinogen; FFA, free fatty acid; ICAM, intercellular adhesion molecule; IL, interleukin; IMA, ischemia modified albumin; MMP, matrix metalloproteinases; MPO, myeloperoxidase; Myg, myoglobin; NT-proBNP, N-terminal proBNP; Ox-LDL, oxidized low-density lipoprotein; PAI-1, plasminogen activator inhibitor; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; TF, tissue factor; TNF, tumor necrosis factor; TNI, troponin I; TNT, troponin T; VCAM, vascular cell adhesion molecule; and VWF, von Willebrand factor.

 

Accurate Identification and Treatment of Emergent Cardiac Events  

Author: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/03/15/accurate-identification-and-treatment-of-emergent-cardiac-events/

The main issue that we have a consensus agreement that PLAQUE RUPTURE is not the only basis for a cardiac ischemic event. The introduction of  high sensitivity troponin tests has made it no less difficult after throwing out the receiver-operator characteristic curve (ROC) and assuming that any amount of cardiac troponin released from the heart is pathognomonic of an acute ischemic event.  This has resulted in a consensus agreement that

  • ctn measurement at a coefficient of variant (CV) measurement in excess of 2 Std dev of the upper limit of normal is a “red flag” signaling AMI? or other cardiomyopathic disorder

This is the catch.  The ROC curve established AMI in ctn(s) that were accurate for NSTEMI – (and probably not needed with STEMI or new Q-wave, not previously seen) –

  1. ST-depression
  2. T-wave inversion
  3. in the presence of other findings
  • suspicious for AMI

Wouldn’t it be nice if it was like seeing a robin on your lawn after a harsh winter?  Life isn’t like that.  When acute illness hits the patient may well present with ambiguous findings.   We are accustomed to relying on

  • clinical history
  • family history
  • co-morbidities, eg., diabetes, obesity, limited activity?, diet?
  • stroke and/or peripheral vascular disease
  • hypertension and/or renal vascular disease
  • aortic atherosclerosis or valvular heart disease

these are evidence, and they make up syndromic classes

  • Electrocardiogram – 12 lead EKG (as above)
  • Laboratory tests
  • isoenzyme MB of creatine kinase (CK)… which declines after 12-18 hours
  • isoenzyme-1 of LD if the time of appearance is > day-1 after initial symptoms (no longer used)
  1. cardiac troponin cTnI or cTnT
  • genome testing
  • advanced analysis of EKG

This may result in more consults for cardiologists, but it lays the ground for better evaluation of the patient, in the long run.

Perspectives on the Value of Biomarkers in Acute Cardiac Care and Implications for Strategic Management
Antoine Kossaify, … STAR-P Consortium
Biomarker Insights 2013:8 115–126.
http://dx.doi.org:/10.4137/BMI.S12703

In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care.

 Inverse Association between Cardiac Troponin-I and Soluble Receptor for Advanced Glycation End Products in Patients with Non-ST-Segment Elevation Myocardial Infarction

ED. McNair, CR. Wells, A.M. Qureshi, C Pearce, G Caspar-Bell, and K Prasad
Int J Angiol 2011;20:49–54
http://dx.doi.org/10.1055/s-0031-1272552

Interaction of advanced glycation end products (AGEs) with the receptor for advanced AGEs (RAGE) results in activation of nuclear factor kappa-B, release of cytokines, expression of adhesion molecules, and induction of oxidative stress. Oxygen radicals are involved in plaque rupture contributing to thromboembolism, resulting in acute coronary syndrome (ACS). Thromboembolism and the direct effect of oxygen radicals on myocardial cells cause cardiac damage that results in the release of cardiac troponin-I (cTnI) and other biochemical markers. The soluble RAGE (sRAGE) compete with RAGE for binding with AGE, thus functioning as a decoy and exerting a cytoprotective effect. Low levels of serum sRAGE would allow unopposed serum AGE availability for binding with RAGE, resulting in the generation of oxygen radicals and proinflammatory molecules that have deleterious consequences and promote myocardial damage. sRAGE may stabilize atherosclerotic plaques. It is hypothesized that low levels of sRAGE are associated with high levels of serum cTnI in patients with ACS.
The levels of cTnI were higher in NSTEMI patients (2.180.33 mg/mL) as compared with control subjects (0.0120.001 mg/mL). Serum sRAGE levels were negatively correlated with the levels of cTnI. In conclusion, the data suggest that low levels of serum sRAGE are associated with high serum levels of cTnI and that there is a negative correlation between sRAGE and cTnI.

Correlation of soluble receptor for advanced glycation end products (sRAGE) with cardiac troponin-I

Correlation of soluble receptor for advanced glycation end products (sRAGE) with cardiac troponin-I

 

Figure 1 Serum levels of soluble receptor for advanced glycation end products (sRAGE) in control subjects and in patients with non-ST-elevation myocardial infarction (NSTEMI). Results are expressed as meanstandard error. *p<0.05, control versus NSTEMI.

 

Serum levels of soluble receptor for advanced glycation end products

Serum levels of soluble receptor for advanced glycation end products

Figure 3 Correlation of soluble receptor for advanced glycation end products (sRAGE) with cardiac troponin-I (cTnI) in patients with non-ST-segment elevation myocardial infarction.

 

Heart Failure Complicating Non–ST-Segment Elevation Acute Coronary Syndrome

MC Bahit, RD. Lopes, RM. Clare, et al.
JACC: HtFail 2013; 1(3):223–9 .
http://dx.doi.org/10.1016/j.jchf.2013.02.007

This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS). Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization.

Other risk factors

Additive influence of genetic predisposition and conventional risk factors in the incidence of coronary heart disease: a population-based study in Greece
N Yiannakouris, M Katsoulis, A Trichopoulou, JM Ordovas, DTrichopoulos
BMJ Open 2014;4:e004387.
http://dx.doi.org:/10.1136/bmjopen-2013-004387

Genetic predisposition to CHD, operationalised through a multilocus GRS, and ConvRFs have essentially additive effects on CHD risk.

PTX3, A Prototypical Long Pentraxin, Is an Early Indicator of Acute Myocardial Infarction

G Peri, M Introna, D Corradi, G Iacuitti, S Signorini, et al.
Circulation. 2000;102:636-641
http://circ.ahajournals.org/content/102/6/636
http://dx.doi.org:/10.1161/01.CIR.102.6.636

PTX3 is a long pentraxin whose expression is induced by cytokines in endothelial cells, mononuclear phagocytes, and myocardium. PTX3 is present in the intact myocardium, increases in the blood of patients with AMI, and disappears from damaged myocytes. We suggest that PTX3 is an early indicator of myocyte irreversible injury in ischemic cardiomyopathy.

Early release of glycogen phosphorylase inpatients with unstable angina and transient ST-T alterations

J Mair, B Puschendorf, J Smidt, P Lechleitner, F Dienstl, et al.
BrHeartJ 1994;72:125-127.
http://www.ncbi.nlm.nih.gov/pubmed/7917682

Glycogen phosphorylase BB (molecular weight 96000 kDa as a monomer) is the predominant isotype in human myocardium where it occurs alongside the MM subtype. The release of glycogen phosphorylase from injured myocardium may reflect the burst in glycogenolysis initiated during acute myocardial ischaemia. This is supported by a rapid increase in serum concentrations of glycogen phosphorylase BB in patients with acute myocardial infarction before concentrations of creatine kinase, creatine kinase MB, myoglobin, and cardiac troponin T increase. Unstable angina, however, ranges from no myocardial cell damage to non-Q wave myocardial infarction.
All variables except for creatine kinase and creatine kinase MB activities were significantly higher on admission in patients with unstable angina and transient ST-T alterations than in patients without. However, glycogen phosphorylase BB concentration was the only marker that was significantly (p = 0-0001) increased above its discriminator value in most patients.

Endothelium and Vascular

Endothelial Dysfunction: An Early Cardiovascular Risk Marker in Asymptomatic Obese Individuals with Prediabetes
AK. Gupta, E Ravussin, DL. Johannsen, AJ. Stull, WT. Cefalu and WD. Johnson
Br J Med Med Res 2012; 2(3): 413-423.
http://www.ncbi.nlm.nih.gov/pubmed/22905340

Adults with desirable weight [n=12] and overweight [n=8] state, had normal fasting plasma glucose [Mean(SD)]: FPG [91.1(4.5), 94.8(5.8) mg/dL], insulin [INS, 2.3(4.4), 3.1(4.8) μU/ml], insulin sensitivity by homeostasis model assessment [HOMA-IR, 0.62(1.2), 0.80(1.2)] and desirable resting clinic blood pressure [SBP/DBP, 118(12)/74(5), 118(13)/76(8) mmHg]. Obese adults [n=22] had prediabetes [FPG, 106.5(3.5) mg/dL], hyperinsulinemia [INS 18.0(5.2) μU/ml], insulin resistance [HOMA-IR 4.59(2.3)], prehypertension [PreHTN; SBP/DBP 127(13)/81(7) mmHg] and endothelial dysfunction [ED; reduced RHI 1.7(0.3) vs. 2.4(0.3); all p<0.05]. Age-adjusted RHI correlated with BMI [r=-0.53; p<0.001]; however, BMI-adjusted RHI was not correlated with age [r=-0.01; p=0.89].

Association of digital vascular function with cardiovascular risk factors: a population study.
T Kuznetsova, E Van Vlierberghe, J Knez, G Szczesny, L Thijs, et al.
BMJ Open 2014; 4:e004399.
http://dx.doi.org:/10.1136/bmjopen-2013-004399

Our study is the first to implement the new photoplethysmography (PPG) technique to measure digital pulse amplitude hyperemic in a sample of a general population. The correlates of hyperaemic response were as expected and constitute an internal validation of the PPG technique in assessment of digital vascular function.

Thrombotic/Embolic Events

Risk marker associations with venous thrombotic events: a cross-sectional analysis 
BA Golomb, VT Chan, JO Denenberg, S Koperski,  & MH Criqui.
BMJ Open 2014;4:e003208.
http://dx.doi.org:/10.1136/bmjopen-2013-003208

To examine the interrelations among, and risk marker associations for, superficial and deep venous events—superficial venous thrombosis (SVT), deep venous thrombosis (DVT) and pulmonary embolism (PE). Significant correlates on multivariable analysis were, for SVT: female sex, ethnicity (African-American=protective), lower educational attainment, immobility and family history of varicose veins. For DVT and DVE, significant correlates included: heavy smoking, immobility and family history of DVEs (borderline for DVE). For PE, significant predictors included immobility and, in contrast to DVT, blood pressure (BP, systolic or diastolic). In women, estrogen use duration for hormone replacement therapy, in all and among estrogen users, predicted PE and DVE, respectively.

Endothelium and hemorheology
T Gori, S Dragoni, G Di Stolfo and S Forconi
Ann Ist Super Sanità 2007 | Vol. 43, No. 2: 124-129
http://www.ncbi.nlm.nih.gov/pubmed/22951621

The mechanisms underlying the regulation of its function are extremely complex, and are principally determined by physical forces imposed on the endothelium by the flowing blood. In the present paper, we describe the interactions between the rheological properties of blood and the vascular endothelium.The role of shear stress, viscosity, cell-cell interactions, as well as the molecular mechanisms that are important for the transduction of these signals are discussed both in physiology and in pathology, with a particular attention to the role of reactive oxygen species. In the final conclusions, we propose an hypothesis regarding the implications of changes in blood viscosity, and particularly on the significance of secondary hyperviscosity syndromes..

Fig. 1 | Endothelial “function” (i.e.,the production of protective autacoids by the vascular endothelium) and “dysfunction” (i.e., the involvement of the endothelium in vascular pathology). EDHF: En d o t h e l i um-De r i v e d Hyperpolarizing Factor; LDL:Low-Density Lipoprotein

Fig. 2 | Endothelial production of nitric oxide (NO) is stimulated by oscillatory shear stress, transmitted by the endothelial surface layer to the endothelial cells. NO: Nitric Oxide; NOS: Nitrous Oxide Systems; ESL: Endothelial Surface Layer

 

 

 

 

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