Marshall Protocol Knowledge Base - home:patients:assessing_literature

Animal models

anonymous@undisclosed.example.com (Anonymous) — Wed, 14 Sep 2022 20:53:53 +0000

09.01.2019		current
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-	======Animal models ======	+	====== Animal models ======
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		+	<relatedarticle> [[home:patients:assessing_literature:in_vitro_studies\|In vitro studies]] </article>

	Animal models have long been used to test theories of and therapies for chronic inflammatory diseases. Among the different animal models, the rodent may be the most widely used. Because they are quick to reach sexual maturity and are easily kept and bred in captivity, rodents have been praised as prime experimental subjects.		Animal models have long been used to test theories of and therapies for chronic inflammatory diseases. Among the different animal models, the rodent may be the most widely used. Because they are quick to reach sexual maturity and are easily kept and bred in captivity, rodents have been praised as prime experimental subjects.
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-	[{{ :home:patients:assessing_literature:mice.png?450\|According to a [[http://webarchive.nationalarchives.gov.uk/20110220142316/http://rds.homeoffice.gov.uk/rds/pdfs10/spanimals09.pdf\|2009 report]], "Statistics of Scientific Procedures on Living Animals," which examined research conducted in the United Kingdom, there has been a steady decrease in the number of scientific procedures using rats. (this graph page 12)}}]	+	[{{ :home:patients:assessing_literature:mice.png?450\|According to a [[https://webarchive.nationalarchives.gov.uk/20110220142316/https://rds.homeoffice.gov.uk/rds/pdfs10/spanimals09.pdf\|2009 report]], "Statistics of Scientific Procedures on Living Animals," which examined research conducted in the United Kingdom, there has been a steady decrease in the number of scientific procedures using rats. (this graph page 12)}}]


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	<relatedarticle> [[home:pathogenesis:innate_immunity\|Innate immune response and Th1 inflammation]]</article>		<relatedarticle> [[home:pathogenesis:innate_immunity\|Innate immune response and Th1 inflammation]]</article>

-	Multiple studies have demonstrated that the immune systems of rats and humans are inherently different. Molecular modeling research has revealed that the activity of the human innate immune system is controlled by the Vitamin D Receptor. In humans, the Vitamin D Receptor performs several fundamental roles. Not only does it control the activity of the innate immune system, but it transcribes 913 genes, and possibly more. It also controls the production of many of the antimicrobial peptides. These peptides kill bacteria, viruses, and fungi by a variety of mechanisms, including disrupting membranes, interfering with metabolism, and targeting components of the machinery inside the cell.(({{pubmed>long:17290304}}))(({{pubmed>long:15322146}}))	+	Multiple studies have demonstrated that the immune systems of rats and humans are inherently different. Molecular modeling research has revealed that the activity of the human innate immune system is controlled by the Vitamin D Receptor. In humans, the Vitamin D Receptor performs several fundamental roles. Not only does it control the activity of the innate immune system, but it transcribes 913 genes, and possibly more. It also controls the production of many of the antimicrobial peptides. These peptides kill bacteria, viruses, and fungi by a variety of mechanisms, including disrupting membranes, interfering with metabolism, and targeting components of the machinery inside the cell.(({{pmid>long:17290304}}))(({{pmid>long:15322146}}))

-	In contrast, the rat innate immune system is not controlled by the Vitamin D Receptor. It depends on a cascade of nitric oxide (an important signaling molecule) that functions in a manner yet to be fully understood. Rats do have Vitamin D Receptors, but they transcribe different genes than the human VDR. By using molecular modeling software, researchers at McGill University in Canada found many differences in the genes targeted by the rat and human Vitamin D Receptors. For example, the gene encoding a calcium binding protein called osteocalcin is “robustly” transcribed by the VDR in humans, but not in mice. In what proves to be a fundamental difference between mice and men, Manisha Brahmachary and team recently determined that the rat Vitamin D Receptor does not express the cathelicidin antimicrobial peptides (AMPs)--marking an important difference in the way the two species kill invading pathogens.(({{pubmed>long:17290304}})) This means that rats and humans respond differently to molecules or drugs that affect the VDR and subsequently the innate immune system.	+	In contrast, the rat innate immune system is not controlled by the Vitamin D Receptor. It depends on a cascade of nitric oxide (an important signaling molecule) that functions in a manner yet to be fully understood. Rats do have Vitamin D Receptors, but they transcribe different genes than the human VDR. By using molecular modeling software, researchers at McGill University in Canada found many differences in the genes targeted by the rat and human Vitamin D Receptors. For example, the gene encoding a calcium binding protein called osteocalcin is “robustly” transcribed by the VDR in humans, but not in mice. In what proves to be a fundamental difference between mice and men, Manisha Brahmachary and team recently determined that the rat Vitamin D Receptor does not express the cathelicidin antimicrobial peptides (AMPs)--marking an important difference in the way the two species kill invading pathogens.(({{pmid>long:17290304}})) This means that rats and humans respond differently to molecules or drugs that affect the VDR and subsequently the innate immune system.

-	According to Mestas //et al.//, there are significant differences between the way the rat and human immune systems develop, which affect “activation, and response to challenge, in both the innate and adaptive arms [of the immune system].” Such differences should not be surprising, as rats and humans diverged somewhere between 65 and 75 million years ago and differ hugely in both size and lifespan. According to Mestas, “They have also evolved in quite different ecological niches where widely different pathogenic challenges need to be met--after all, most of us do not live with our heads a half-inch off the ground.” Consequently, he argues that, “There has been a tendency to ignore differences and in many cases, perhaps, make the assumption that what is true in mice is necessarily true in humans. By making such assumptions we run the risk of overlooking vital aspects of human immunology that do not occur, or cannot be modeled, in mice.”(({{pubmed>long:14978070}}))	+	According to Mestas //et al.//, there are significant differences between the way the rat and human immune systems develop, which affect “activation, and response to challenge, in both the innate and adaptive arms [of the immune system].” Such differences should not be surprising, as rats and humans diverged somewhere between 65 and 75 million years ago and differ hugely in both size and lifespan. According to Mestas, “They have also evolved in quite different ecological niches where widely different pathogenic challenges need to be met--after all, most of us do not live with our heads a half-inch off the ground.” Consequently, he argues that, “There has been a tendency to ignore differences and in many cases, perhaps, make the assumption that what is true in mice is necessarily true in humans. By making such assumptions we run the risk of overlooking vital aspects of human immunology that do not occur, or cannot be modeled, in mice.”(({{pmid>long:14978070}}))
	===== Validity of murine models =====		===== Validity of murine models =====

-	While there are certainly exceptions,(({{pubmed>long:18364394}})) generally speaking the murine immune system tends not to be a valid approximation of the human immune system.	+	While there are certainly exceptions,(({{pmid>long:18364394}})) generally speaking the murine immune system tends not to be a valid approximation of the human immune system.

	In a systematic review comparing the treatment effects of animal experiments and clinical trials, Perel //et al.// review a number of examples where interventions used on animals are not duplicated in humans. These include head injury, antifibrinolytics in hemorrhage, thrombolysis in acute ischaemic stroke, tirilazad in acute ischaemic stroke, antenatal corticosteroids to prevent neonatal respiratory distress syndrome, and bisphosphonates to treat osteoporosis.		In a systematic review comparing the treatment effects of animal experiments and clinical trials, Perel //et al.// review a number of examples where interventions used on animals are not duplicated in humans. These include head injury, antifibrinolytics in hemorrhage, thrombolysis in acute ischaemic stroke, tirilazad in acute ischaemic stroke, antenatal corticosteroids to prevent neonatal respiratory distress syndrome, and bisphosphonates to treat osteoporosis.
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	<blockquote> Discordance between animal and human studies may be due to bias or to the failure of animal models to mimic clinical disease adequately.		<blockquote> Discordance between animal and human studies may be due to bias or to the failure of animal models to mimic clinical disease adequately.

-	//Pablo Perel et al.// (({{pubmed>long:17175568}}))</blockquote>	+	//Pablo Perel et al.// (({{pmid>long:17175568}}))</blockquote>


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-	* [[http://precedings.nature.com/documents/52/version/1\|Molecular static and dynamic analyses reveal flaw in murine model used by US FDA to detect drug carcinogenicity]]	+	* [[https://precedings.nature.com/documents/52/version/1\|Molecular static and dynamic analyses reveal flaw in murine model used by US FDA to detect drug carcinogenicity]]
-	* [[http://bacteriality.com/2007/11/07/mice/\|Of mice and men: Are the scientific studies you read accurate?]] {{:home:bacteriality.gif\|http://bacteriality.com/2007/10/28/interview6}}	+	* [[https://bacteriality.com/2007/11/07/mice/\|Of mice and men: Are the scientific studies you read accurate?]] {{:home:bacteriality.gif\|https://bacteriality.com/2007/10/28/interview6}}


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	{{tag>resource Assessing_Medical_Literature}}		{{tag>resource Assessing_Medical_Literature}}
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	===== Notes and comments =====		===== Notes and comments =====

-	obsolete links to Science journal, [[http://www.fda.gov/cder/foi/nda/2002/21-286_Benicar.htm\|acceptance testing]] removed --- //Sallie Q 08.21.2017//	+	obsolete links to Science journal, [[https://www.fda.gov/cder/foi/nda/2002/21-286_Benicar.htm\|acceptance testing]] removed --- //Sallie Q 08.21.2017//
	non-functioning link to 2009 article replaced with link to UK govt archive		non-functioning link to 2009 article replaced with link to UK govt archive
	* Legacy content		* Legacy content
-	* http://www.marshallprotocol.com/view_topic.php?id=4142&forum_id=37&jump_to=89011#p89011 s154	+	* https://www.marshallprotocol.com/view_topic.php?id=4142&forum_id=37&jump_to=89011#p89011 s154
	*		*

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-	<blockquote>http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1001192	+	<blockquote>https://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1001192

	"Human-Specific Evolution and Adaptation Led to Major Qualitative Differences in the Variable Receptors of Human and Chimpanzee Natural Killer Cells"		"Human-Specific Evolution and Adaptation Led to Major Qualitative Differences in the Variable Receptors of Human and Chimpanzee Natural Killer Cells"
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	ps: Thanks to Ragnar for the link :)		ps: Thanks to Ragnar for the link :)

-	pps: MHC - http://en.wikipedia.org/wiki/Major_histocompatibility_complex	+	pps: MHC - https://en.wikipedia.org/wiki/Major_histocompatibility_complex

	Joyce liked this --		Joyce liked this --
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	<blockquote>Parasites Unite!		<blockquote>Parasites Unite!

-	http://www.the-scientist.com/article/display/57935/	+	https://www.the-scientist.com/article/display/57935/

	What I like most :		What I like most :
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-		+	</nodisp>

Differences between in vitro, in vivo, and in silico studies

anonymous@undisclosed.example.com (Anonymous) — Wed, 14 Sep 2022 20:53:53 +0000

10.17.2018		current
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	====== Differences between in vitro, in vivo, and in silico studies ======		====== Differences between in vitro, in vivo, and in silico studies ======

		+	<relatedarticle> [[home:patients:assessing_literature:animal_models\|Animal models]] </article>

	There are three broad categories of experiments: //in vitro// studies, //in vivo// studies, and //in silico// studies. Each study type has conveniences and liabilities. Understanding the liabilities of study types offers insight into the validity of researchers' conclusions.		There are three broad categories of experiments: //in vitro// studies, //in vivo// studies, and //in silico// studies. Each study type has conveniences and liabilities. Understanding the liabilities of study types offers insight into the validity of researchers' conclusions.
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	<blockquote>Addressing this question is complicated by the fact that protein expression of culture-grown spirochetes does not fully resemble //Borrelia// in the host, i.e. the usefulness of protein lysates from culture-grown bacteria is limited as a source of antigen for ELISPOT analysis.		<blockquote>Addressing this question is complicated by the fact that protein expression of culture-grown spirochetes does not fully resemble //Borrelia// in the host, i.e. the usefulness of protein lysates from culture-grown bacteria is limited as a source of antigen for ELISPOT analysis.

-	//Stefan S. Tunev// (({{pubmed>long: 21637808}}))	+	//Stefan S. Tunev// (({{pmid>long: 21637808}}))
	</blockquote>		</blockquote>

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	Because of this, //in vitro// studies may lead to results that do not correspond to the circumstances occuring around a living organism.		Because of this, //in vitro// studies may lead to results that do not correspond to the circumstances occuring around a living organism.

-	Until the last several years, efforts to detect and identify microorganisms in the human body have depended almost exclusively on //in vitro// studies. As a result, many researchers began to assume that chronic diseases were not caused by microbes. The net effect of all this was that the understanding of pathogens in disease was driven by the study of well-known, easy-to-culture microbes--which, as it turns out, represent the vast minority of bacteria in the human body. By one estimate, 99.6% of the species in the human microbiota have not or cannot be characterized through //in vitro// techniques.(({{pubmed>long:9716951}}))	+	Until the last several years, efforts to detect and identify microorganisms in the human body have depended almost exclusively on //in vitro// studies. As a result, many researchers began to assume that chronic diseases were not caused by microbes. The net effect of all this was that the understanding of pathogens in disease was driven by the study of well-known, easy-to-culture microbes--which, as it turns out, represent the vast minority of bacteria in the human body. By one estimate, 99.6% of the species in the human microbiota have not or cannot be characterized through //in vitro// techniques.(({{pmid>long:9716951}}))

	Another example of a shortcoming of //in vitro// studies relates to concentrations of molecules, especially as they compete for nuclear receptors. For example, the vitamin D metabolite, 1,25-D, exerts its effects at 30 picograms per milliliter, or 0.000000000003 grams per milliliter.		Another example of a shortcoming of //in vitro// studies relates to concentrations of molecules, especially as they compete for nuclear receptors. For example, the vitamin D metabolite, 1,25-D, exerts its effects at 30 picograms per milliliter, or 0.000000000003 grams per milliliter.
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	//In silico// is an expression used to mean "performed on computer or via computer simulation." The expression //in silico// was first used in public in 1989 in the workshop "Cellular Automata: Theory and Applications" in Los Alamos, New Mexico. Pedro Miramontes, a mathematician from National Autonomous University of Mexico (UNAM), presented the report "DNA and RNA Physicochemical Constraints, Cellular Automata and Molecular Evolution." In his talk, Miramontes used the term "//in silico//" to characterize biological experiments carried out entirely in a computer.		//In silico// is an expression used to mean "performed on computer or via computer simulation." The expression //in silico// was first used in public in 1989 in the workshop "Cellular Automata: Theory and Applications" in Los Alamos, New Mexico. Pedro Miramontes, a mathematician from National Autonomous University of Mexico (UNAM), presented the report "DNA and RNA Physicochemical Constraints, Cellular Automata and Molecular Evolution." In his talk, Miramontes used the term "//in silico//" to characterize biological experiments carried out entirely in a computer.

-	Although //in silico// studies represent a relatively new avenue of inquiry, it has begun to be used widely in studies which predict how drugs interact with the body and with pathogens. For example, a 2009 study used software emulations to predict how certain drugs already on the market could treat multiple-drug-resistant and extensively drug-resistant strains of tuberculosis.((Kinnings SL, Liu N, Buchmeier N, Tonge PJ, Xie L, et al. 2009 [[http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000423#equal-contrib\|Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis]]. //PLoS Comput Biol// 5(7): e1000423. doi:10.1371/journal.pcbi.1000423))	+	Although //in silico// studies represent a relatively new avenue of inquiry, it has begun to be used widely in studies which predict how drugs interact with the body and with pathogens. For example, a 2009 study used software emulations to predict how certain drugs already on the market could treat multiple-drug-resistant and extensively drug-resistant strains of tuberculosis.((Kinnings SL, Liu N, Buchmeier N, Tonge PJ, Xie L, et al. 2009 [[https://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000423#equal-contrib\|Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis]]. //PLoS Comput Biol// 5(7): e1000423. doi:10.1371/journal.pcbi.1000423))


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	* Bacterial sequencing techniques – As an alternative to //in vitro// methods for identifying bacteria, various //in silico// methods which sequence bacterial DNA and RNA have been developed. The most commonly used use is polymerase chain reaction (PCR). PCR takes a single or few copies of a piece of DNA and increases it across several orders of magnitude, generating millions or more copies of a particular DNA sequence. PCR has allowed researchers to detect bacteria associated with a variety of conditions with increasingly high sensitivity.		* Bacterial sequencing techniques – As an alternative to //in vitro// methods for identifying bacteria, various //in silico// methods which sequence bacterial DNA and RNA have been developed. The most commonly used use is polymerase chain reaction (PCR). PCR takes a single or few copies of a piece of DNA and increases it across several orders of magnitude, generating millions or more copies of a particular DNA sequence. PCR has allowed researchers to detect bacteria associated with a variety of conditions with increasingly high sensitivity.
	* Molecular modeling – Part of the Marshall Pathogenesis is based on //in silico// work, demonstrating how drugs and other substances interact with the nuclear receptors of cells. In particular, Trevor Marshall, PhD, has used computer-based emulations to show that 25-D, one of the vitamin D metabolites, and Capnine, a substance produced by bacteria, turn off the Vitamin D Receptor. These conclusions have since been validated by clinical observations.		* Molecular modeling – Part of the Marshall Pathogenesis is based on //in silico// work, demonstrating how drugs and other substances interact with the nuclear receptors of cells. In particular, Trevor Marshall, PhD, has used computer-based emulations to show that 25-D, one of the vitamin D metabolites, and Capnine, a substance produced by bacteria, turn off the Vitamin D Receptor. These conclusions have since been validated by clinical observations.
-	* Whole cell simulations – As described [[http://www.rdmag.com/News/2011/03/Life-Sciences-Genomics-Researchers-Make-The-Leap-To-Whole-Cell-Simulations/\|here]], researchers have built a computer model of the crowded interior of a bacterial cell that—in a test of its response to sugar in its environment—accurately simulates the behavior of living cells.(({{pubmed>long:21423716}}))	+	* Whole cell simulations – As described [[https://www.rdmag.com/News/2011/03/Life-Sciences-Genomics-Researchers-Make-The-Leap-To-Whole-Cell-Simulations/\|here]], researchers have built a computer model of the crowded interior of a bacterial cell that—in a test of its response to sugar in its environment—accurately simulates the behavior of living cells.(({{pmid>long:21423716}}))

	===== Read more about study design =====		===== Read more about study design =====
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	===== Notes and comments =====		===== Notes and comments =====

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	* Legacy content		* Legacy content
-	* http://www.marshallprotocol.com/view_topic.php?id=4142&forum_id=37&jump_to=88745#p88745 s153	+	* https://www.marshallprotocol.com/view_topic.php?id=4142&forum_id=37&jump_to=88745#p88745 s153
-	* http://www.marshallprotocol.com/view_topic.php?id=3139&forum_id=37&jump_to=35262#p35262 s229	+	* https://www.marshallprotocol.com/view_topic.php?id=3139&forum_id=37&jump_to=35262#p35262 s229

-	===== References =====	+	===== References =====</nodisp>

Palliative vs. curative treatments

anonymous@undisclosed.example.com (Anonymous) — Wed, 14 Sep 2022 20:53:53 +0000

12.19.2018		current
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	* telmisartan - This ARB is a VDR antagonist (has the opposite action to olmesartan, which is a VDR agonist). It is a very strong immune suppressant.		* telmisartan - This ARB is a VDR antagonist (has the opposite action to olmesartan, which is a VDR agonist). It is a very strong immune suppressant.
	* interferon – Interferon therapy is immunosuppressive, reducing in number both cytokines and immune cells.		* interferon – Interferon therapy is immunosuppressive, reducing in number both cytokines and immune cells.
-	* corticosteroids – Patients with chronic disease may find that while taking corticosteroids, both symptoms and markers of the disease such X-rays or liver enzymes temporarily decrease. However, according to a comparative study(({{pubmed>long:9118698}})), 74% of patients relapse a significantly higher percentage of the time after trying to ease up their Prednisone, the first-line treatment for a number of chronic diseases, and:	+	* corticosteroids – Patients with chronic disease may find that while taking corticosteroids, both symptoms and markers of the disease such X-rays or liver enzymes temporarily decrease. However, according to a comparative study(({{pmid>long:9118698}})), 74% of patients relapse a significantly higher percentage of the time after trying to ease up their Prednisone, the first-line treatment for a number of chronic diseases, and:


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	<blockquote>Relapse... rarely occurred in patients who had not been treated with corticosteroids in the past. The striking difference in relapse rate between treated and untreated patients suggests that patients with disease that would later be severe and protracted were almost unerringly identified early in their course.... Corticosteroids contribute to the prolongation of the disease by delaying resolution.		<blockquote>Relapse... rarely occurred in patients who had not been treated with corticosteroids in the past. The striking difference in relapse rate between treated and untreated patients suggests that patients with disease that would later be severe and protracted were almost unerringly identified early in their course.... Corticosteroids contribute to the prolongation of the disease by delaying resolution.

-	//Jonathan E. Gottlieb et al.// (({{pubmed>long:9118698}}))	+	//Jonathan E. Gottlieb et al.//
	</blockquote>		</blockquote>

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	* soy – Soy contains phytoestrogens such as genistein, which act directly to inhibit innate immune function.		* soy – Soy contains phytoestrogens such as genistein, which act directly to inhibit innate immune function.
	* coffee – Coffee contains chlorogenic acid, an antioxidant and phenolic compound, which, in ways that are not yet fully clear, can suppress the immune response. Frequent consumers of coffee often point to caffeine as giving coffee its addictive quality, but the role of chlorogenic acid offers another way that coffee can offer temporary symptom relief.		* coffee – Coffee contains chlorogenic acid, an antioxidant and phenolic compound, which, in ways that are not yet fully clear, can suppress the immune response. Frequent consumers of coffee often point to caffeine as giving coffee its addictive quality, but the role of chlorogenic acid offers another way that coffee can offer temporary symptom relief.
-	* [[home:othertreatments:efas\|fish oil]] – In addition to containing high amounts of vitamin D, supplemental fish oil contains the omega 3 fatty acids, several of which have been shown to interfere with production of TNF-alpha, an important cytokine necessary for the response of the innate immune system.(({{pubmed>long:18063921}}))	+	* [[home:othertreatments:efas\|fish oil]] – In addition to containing high amounts of vitamin D, supplemental fish oil contains the omega 3 fatty acids, several of which have been shown to interfere with production of TNF-alpha, an important cytokine necessary for the response of the innate immune system.(({{pmid>long:18063921}}))


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	{{tag>resource Assessing_Medical_Literature Study_Design}}		{{tag>resource Assessing_Medical_Literature Study_Design}}

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	===== Notes and comments =====		===== Notes and comments =====

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	* Legacy content		* Legacy content
-	* http://www.marshallprotocol.com/view_topic.php?id=2495&forum_id=32&jump_to=42218#p42218 f227	+	* https://www.marshallprotocol.com/view_topic.php?id=2495&forum_id=32&jump_to=42218#p42218 f227
-	* http://www.marshallprotocol.com/view_topic.php?id=2495&forum_id=32&jump_to=29940#p29940 f225	+	* https://www.marshallprotocol.com/view_topic.php?id=2495&forum_id=32&jump_to=29940#p29940 f225

	===== References =====		===== References =====
-		+	</nodisp>