davidson first hematology 2015
TRANSCRIPT
![Page 1: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/1.jpg)
Biophysical Aspects of the Sanarelli-Shwartzman Phenomenon
Robert M. Davidson M.D. Ph.D. FAIS*
Ann Lauritzen, Stephanie Seneff,
Stephen D. Kette, Glyn Wainwright,
Anthony Samsel, and Sydney J. Bush
*Fellow, The American Institute of Stress
Physician and Medical Researcher, Kilgore, Texas, USA
Email: [email protected]
3rd International Conference on Hematology & Blood Disorders
November 2-4, 2015 Atlanta, Georgia USA
1
![Page 2: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/2.jpg)
DEFINITION:
UNIVERSAL NON-SPECIFIC MESENCHYMAL REACTION (UNMR)
• The UNMR refers to the different causes of an acceleration of metabolism of connective tissue of blood vessels as well as that of all organs studied [Hauss et al. 1962].
• Selye (1966) described a local or general intravascular coagulation that occurs in response to certain toxins or systemic stress [Selye, Thrombohemorrhagic Phenomena, 1966].
2
![Page 3: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/3.jpg)
DEFINITION:
Sanarelli-Shwartzman Phenomenon (SSP), a.k.a. Generalized Shwartzman Reaction (GSR)
• Activation of the coagulation system is thought to be the primary event in a clinical syndrome involving disseminated intravascular coagulation (DIC), a consumptive coagulopathy of the microvasculature, which can be localized or generalized, acute, subacute, or chronic.
• Fibrinolysis, if it occurs, is thought to be a secondary protective phenomenon [Bang et al. Thrombosis and Bleeding Disorders, 2014]
3
![Page 4: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/4.jpg)
The Major “Players" in Our Passion Play
Acid mucopolysaccharides
• Serine proteases
• Aryl sulfatases
• Transition metals
• Inflammatory stress
• Interfacial water stress
4
![Page 5: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/5.jpg)
TIME IS OF THE ESSENCE
A prompt response is often required: there’s not much time for de
novo protein synthesis and diffusion of substrates
• In the setting of acute bleeding: to achieve hemostasis and maintain organ
perfusion
• In the setting of critical care medicine: associated with inflammatory stress,
e.g., ARDS, DIC syndrome, severe trauma, acute coronary and
neurovascular syndromes
• In the setting severe infectious disease, e.g. septicemia, Purpura
fulminans, Hemorrhagic Fever viruses (Dengue, Ebola, etc.)
5
![Page 6: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/6.jpg)
Purpura Fulminans
“a rare syndrome of intravascular thrombosis and hemorrhagic infarction of the skin that is rapidly progressive and is accompanied by vascular collapse and disseminated intravascular coagulation. It may be classified as (1) neonatal, (2) idiopathic, or (3) acute infectious.”
The 4 primary features of acute infectious purpura fulminans are as follows:
• Large purpuric skin lesions • Fever • Hypotension • Disseminated intravascular coagulation (DIC)
SOURCE: http://emedicine.medscape.com/article/2202749-overview
6
![Page 7: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/7.jpg)
THE INITIAL COMMON PATHWAY
Exogenous Interfacial Water Stress (EIWS)
Inflammation
Disease
7
Davidson, Robert M.; Seneff, Stephanie. 2012. Entropy 14, no. 8: 1399-1442.
Davidson, R.M.; Lauritzen, A.; Seneff, S. 2013.Entropy 15, 3822-3876.
![Page 8: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/8.jpg)
Two Important Characteristics
of Inflammatory States
Low pH: 4.7 - 5.7 Tsai, et al (2014)
• cardiac ischemia • cancer • septicemia• trauma (fractures, hematomas)
High oxidative stress: Khansari et al (2009);
Reuter et al (2010); Kim et al (2013)
8
![Page 9: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/9.jpg)
The Redox Potential of Water is pH Dependent
“The redox potential increases as the pH decreases (increasing [H+])”. --- Martin Chaplin
9
http://www1.lsbu.ac.uk/water/water_redox.html
![Page 10: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/10.jpg)
Our Proposal for pH Dependent e(aq) Speciation
10
Mizuse, K. and Fujii, A. (2013). Characterization of a Solvent-Separated Ion-Radical Pair in Cationized Water Networks: Infrared
Photodissociation and Ar-Attachment Experiments for Water Cluster Radical Cations (H2O)n+ (n = 3–8). The Journal of Physical
Chemistry A, 117, 929-938.
Larsen, R.E., Glover, W.J. and Schwartz, B.J. (2010). Does the hydrated electron occupy a cavity? Science, 329, 65-69.
![Page 11: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/11.jpg)
ATP and PAPS are unstable in the setting of Inflammation
• pH instability of ATP in low pH range
“…but is rapidly hydrolysed at extreme pH.”
• pH instability of PAPS in low pH range
“…should be made up in pH 8.0 buffer and stored aliquoted at -70o
C.”
• Sulfotransferase (SULT) pH optima are typically neutral pH range to slightly alkaline
11
![Page 12: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/12.jpg)
Need for a Universal Sulfurylation Factor in Inflamed Tissue
• A prompt response is required for the GSP/SSP, DIC, Purpura Fulminans
• There is not enough time for de novo protein synthesis and diffusion of substrates, and/or
• To rescue PAPS and ATP from a "hydrolytic fate“ or a recycling, proofreading “mistake”
12
![Page 13: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/13.jpg)
Our Proposal for a Universal Sulfurylation
Factor
• Takebayashi, J., Kaji, H., Ichiyama, K., Makino, K., Gohda, E., Yamamoto, I. and Tai, A. (2007). Inhibition of free radical-induced erythrocyte
hemolysis by 2-O-substituted ascorbic acid derivatives. Free Radical Biology and Medicine, 43, 1156-1164.
• Verlangieri, A.J. and Mumma, R.O. (1973). In vivo sulfation of cholesterol by ascorbic acid 2-sulfate. Atherosclerosis, 17, 37-48.
• Cabral, J., Haake, P. and Kessler, K. (1998). Rearrangement of 3-Acyl Derivatives of L-Ascorbic Acid. Journal of Carbohydrate Chemistry, 17, 1321-1329.
WE PROPOSE: 2-O-sulfate L-ascorbate radical plays a central role in the "universal nonspecific mesenchymal reaction", which has also been referred to as the Sanarelli-Shwartzman phenomenon.
13
• Chiral
• Paramagnetic
• Quasi-aromatic
![Page 14: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/14.jpg)
Need for a Universal Phosphorylation Factor in Inflamed Tissue
• A great need also exists for an ultimate phosphorylation factor in inflamed tissue to
(a) rescue ATP from a "hydrolytic fate“, and
(b) rescue DNA/RNA from proofreading "errors".
14
![Page 15: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/15.jpg)
Proposed TBP TS for sulfuryl and phosphorylgroup transfer by Ascorbate derivative radicals
15
![Page 16: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/16.jpg)
“Flattening” the Free Energy Landscape for Biological Group Transfers, generally
• Having proposed chemical biological means by which the Ascorbate radical can catalyze sulfuryl and phosphoryl group transfer, under conditions of inflammatory stress, it soon became apparent that:
• Similar chemical biological means might exist by which the Ascorbate radical can also catalyze nitrosyl, acyl, and glycosyl group transfer, under conditions of inflammatory stress
16
![Page 17: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/17.jpg)
Copper-Ascorbate Complex
17
Source:
L. Amudat, Ph.D.Dissertation, 2010
![Page 18: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/18.jpg)
A NEW PARADIGM FOR HYPOTHESIS TESTING:
• Null hypothesis: The Cu1+ Ascorbate radical complex does NOT directly modulate miRNA synthesis by RNA polymerase III in human patients with cancer, i.e. under conditions of inflammatory stress (low pH and high oxidative stress).
• Application: Disproving the null hypothesis would allow us to assert that the Cu1+ Ascorbate radical complex directly modulates miRNA synthesis by RNA polymerase III in humans with cancer, perhaps as a sequela of a proofreading "error" or a sequela of dysregulating of a mesenchymal stem cell, under conditions of inflammatory stress.
18
![Page 19: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/19.jpg)
Fractones, Defined:
• Fractones have been referred to as stem cell “niches” and they are thought to regulate cytoskeletal assembly and organize the ECM of the heart, gut, brain, and bone marrow/RES. They have complex cytoarchitectures consisting of stem cells, progenitor cells, supporting cells, and laminin-rich basement membranes (Hochman-Mendez et al 2014).
• Frederic Mercier and his associates have studied neural stem cell niches and described fractones as:
“particulate extracellular matrix structures that I previously characterized in both the developing and adult brain”. --- F. Mercier (personal statement)
“In the neural stem cell niche of the adult brain, I have demonstrated that fractone-associated heparan sulfate proteoglycans serve as captors and activators of growth factors to regulate neural stem cell proliferation.”
Mercier, F., Kitasako, J.T. and Hatton, G.I. (2002). Anatomy of the brain neurogenic zones revisited: fractones and the fibroblast/macrophage network. J Comp Neurol, 451, 170-188.
19
![Page 20: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/20.jpg)
CNS Fractones Need Sulfur
• GAGs and HSPGs need a UNIVERSAL SULFURYLATION FACTOR, e.g. 2-O-sulfate-L-ascorbate radical might preempt and supercede PAPS/SULTS
• CNS fractones need BOTH ascorbate and sulfur
• HSPGs have been shown to be low in sulfur at autopsy of CNS fractones in Autism
Corley et al (2012); Mercier et al (2012); Meyza et al (2012); Pearson et al (2013); Mercier et al (2011)
20
![Page 21: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/21.jpg)
High-dose Intravenous Ascorbatein Critical Care Medicine
• High Dose Intravenous Ascorbate has become mainstream
• Evidence now exists to suggest an important role in both the prevention and management of critical care disease characterized by endothelial dysfunction [Oudemans-van Straaten, 2014; Rodemeister, 2014].
http://www.ccforum.com/content/18/4/460http://www.ccforum.com/content/18/4/461
21
![Page 22: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/22.jpg)
Early Reversal of Endothelial Dysfunction
22SOURCE: Oudemans-van Straaten, H.M., Spoelstra-de Man, A.M. and de Waard, M.C. (2014). Vitamin C revisited. Critical
care (London, England), 18, 460.
![Page 23: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/23.jpg)
Conclusion:
Ascorbate radical and putative 2-O-substituted L-Ascorbate derivative radicals,
(a) catalyze group transferreactions, and
(b) modulate redox kinetics.
The catalysis and modulation function for Vitamin C has supramolecular, epigenetic, biophysically-pleiotropic implications which apply to all aspects of medicine.
23
![Page 24: Davidson first hematology 2015](https://reader031.vdocuments.us/reader031/viewer/2022030211/58a3d1551a28ab98588b66e1/html5/thumbnails/24.jpg)
THANK YOU !
24