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Old 11-04-2016, 10:26 AM   #26
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I just found that recently dietary choline and betaine and serum TMAO
were linked to coronary heart disease.

some first snippets below


----------------------------------------------------------
Gut flora metabolism of phosphatidylcholine promotes
cardiovascular disease (Apr.2011)
-----------------------------------------------------
sex-specific association of CPS1 with CHD
-----------------------------------------------------
diatary choline and betain; association with subclinical markers of CVD
CHD,stroke,risk and incidence "Jackson Heart Study"




--------------------------------------------------

http://www.drperlmutter.com/wp-conte...-AJCN-2016.pdf
Conclusion: Egg or cholesterol intakes were not associated with
increased CAD risk, even in ApoE4 carriers (i.e., in highly suscep-
tible individuals).

Conclusions TMAO, a pro‐atherogenic metabolite formed by gut
microbes, predicts long‐term adverse event risk and incremental
prognostic value in patients with peripheral artery disease (PAD) PAD.
These findings point to the potential for TMAO to help improve selection
of high‐risk PAD patients with or without significant coronary artery
disease, who likely need more aggressive and specific dietary and
pharmacologic therapy.

Conclusion: These data suggest that higher phosphatidylcholine
consumption is associated with increased all-cause and CVD
mortality in the US population, especially in patients with diabetes,
independent of traditional risk factors. (~1.2 fold)

There is increasing appreciation that changes in microbiome composition
and function can promote long-term susceptibility for cardiometabolic risk.
Gut microbe-derived metabolites that are biologically active, such as
trimethylamine N-oxide (TMAO), are now recognized as contributors to
atherogenesis. This review summarizes our current understanding of the
role of TMAO in the pathogenesis of cardiometabolic diseases and will
discuss current findings, controversies, and further perspectives in this
new area of investigation. Better appreciation of the interactions
between dietary nutrient intake with gut microbiota-mediated
metabolism may provide clinical insights into defining individuals
at risk for disease progression in cardiometabolic diseases, as
well as additional potential therapeutic targets for reducing risks
for cardiometabolic disease progression.

--------------------------------
review:
http://biomarkers.imedpub.com/metabo...s.php?aid=9401

------------------------------------------

[can this lead to new insights on how/why CHD began in USA ~1920
and why it declined in Western industrialized countries ? ]
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Old 11-06-2016, 07:33 AM   #27
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so, the main culprit is now TMAO, cholesterol is not so important

timeline of TMAO,choline,betanine attention wrt. coronary disease :
http://magictour.free.fr/tmao01.GIF

https://en.wikipedia.org/wiki/Trimethylamine_N-oxide

----------------------------------------------
[HTML] Plasma phospholipid transfer protein activity is inversely associated with betaine
in diabetic and non-diabetic subjects
---------------------------------------------
Prognostic value of choline and betaine depends on intestinal microbiota-generated
metabolite trimethylamine-N-oxide. ... Nishida H, Nishida T. Phospholipid transfer
protein mediates transfer of not only phosphatidylcholine but also cholesterol from
phosphatidylcholine ...
--------------------------------------------
We found an inverted U-shaped association between TMAO levels and the
presence of coronary artery stenosis among HIV-infected men.
---------------------------------------------
Plasma Concentrations of Trimethylamine-N-oxide Are Directly Associated with
Dairy Food Consumption and Low-Grade Inflammation in a German Adult Population
----------------------------------------------
Plasma TMAO, choline, and betaine concentrations were measured using
LC-high resolution mass spectrometry
-----
C-reactive protein
---------------------------------------------------------
Meat, egg, or fish consumption was not associated with TMAO, choline, or betaine
concentrations (all P-trend ≥ 0.05). With increases in milk and other dairy food consumption,
the plasma TMAO concentration increased [geometric mean bottom quartile of milk consumption:
---------------------------------------------------------
Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels
-----------------------------------------------
. Inhibition of bacterial lyases prevents TMA and secondarily TMAO formation and
atherosclerosis in mice and provides strong evidence for the TMAO hypothesis.
find a potent "broad spectrum" bacterial lyase inhibitor
-------------------------------------------
][HTML] Plasma trimethylamine N-oxide, a gut microbe–generated phosphatidylcholine
metabolite, is associated with atherosclerotic burden
---------------------------------------------------
Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function
and Predicts Outcome in Chronic Kidney Disease
--------------------------------------
B vitamins plus vitamin D lowered plasma fasting TMAO compared to vitamin D.
-------------------------------------
agents that reduces the production of trimethylamine (TMA) or trimethylamine-n-oxide (TMAO) :
i) 3,3-dimethyl-1-butanol (DMB) or a DMB derivative or related compound,
ii) acetylsalicylic acid or derivative
iii) a flavin monooxygenase 3 (FMO3) inhibitor
iv) a gut TMA lyase inhibitor;
v) an antibiotic or antimicrobial
vi) a probiotic or prebiotic
vii) an antiplatelet agent
viii) a TMA and/or TMAO sequestering agent.
----------------------------------------------------
Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
------------------------------------------------
Fish protein increases circulating levels of trimethylamine‐N‐oxide and accelerates
aortic lesion formation in apoE null mice
-------------------------------------------------
Elevated trimethylamine-N-oxide (TMAO) is associated with poor prognosis in primary
sclerosing cholangitis patients with normal liver function
TMAO has further been shown to influence cholesterol metabolism, bile ... In several
studies TMAO has been associated with atherosclerosis and coronary artery disease
---------------------------------------------------
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709689/pdf/srep19188.pdf
The meta-analysis showed a significant reduction of Lp(a) levels following L-carnitine
supplementation. oral, but not intravenous
L-carnitine significantly reduced total cholesterol and showed borderline significant
reduction of LDL-C, while plasma HDL-C and triglycerides were not affected

----------------------------------------------------
Trimethylamine‐N‐oxide (TMAO) response to animal source foods varies among
healthy young men and is influenced by their gut microbiota composition: A …
----------------------------------------------------
Dietary phosphatidylcholine and risk of all-cause and cardiovascular-specific
mortality among US women and men1,2
-------------------------------------------------------
Conclusion: These data suggest that higher phosphatidylcholine consumption
is associated with increased all-cause and CVD mortality in the US population,
especially in patients with diabetes, independent of traditional risk factors.
-------------------------------------------------------
Gut Microbiota and Nonalcoholic Fatty Liver Disease:
-------------------------------------------------------
Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of
Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB
-------------------------------------------------------
L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate
with low aortic lesions in ... mice
-----------------------------------------------------------

=============================================

apparantly TMAO testing is not yet widely available, only
some few specialized labs offer it

6 Jan 2016 ... Kahn is the first physician in Michigan to offer TMAO testing, and offers this
advanced lab test at the Kahn Center for Cardiac Longevity, with ...

16 Feb 2016 ... CLEVELAND, Feb. 16, 2016 /PRNewswire/ -- Cleveland HeartLab Launches
Only Clinical Test for Measuring TMAO,

19 Oct 2016 ... "TMAO testing is available for clinical use

10 Feb 2015 it is hoped that TMAO testing will gain ground as an early predictor of atherosclerosis

29 Jan 2015 ... If more studies back its efficacy, TMAO testing may soon be like cholesterol
testing—a quick, easy way to assess your risk for heart disease

-==============================================
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Old 11-06-2016, 08:22 AM   #28
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From gsgs prior post ...
Quote:
Conclusion: These data suggest that higher phosphatidylcholine consumption
is associated with increased all-cause and CVD mortality in the US population,
especially in patients with diabetes, independent of traditional risk factors.
And phosphatidylcholine is currently sold as a health supplement .

..
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Old 11-06-2016, 08:31 AM   #29
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see also the part about L-carnitine above, it had healthy effects
but may also increase TMAO, depending presumably on the gut-flora

=============================================

Impact of L-carnitine on plasma lipoprotein(a) concentrations:
A systematic review and meta-analysis of randomized controlled trials
[2015]
-------------------------------------
The meta-analysis suggests that L-carnitine supplementation might be associated
with significant Lp(a) lowering. However, given the TMAO elevating effect of oral
L-carnitine supplementation, whether or not L-carnitine is a reasonable therapy
to reduce Lp(a) levels requires further long-term investigations with hard clinical
endpoints such as AMI, stroke and mortality risks. Prospective trials are required
to fully elucidate the clinical value of L-carnitine supplementation
--------------------------------------
[ In 1963, Kåre Berg discovered lipoprotein(a) [Lp(a)] in human plasma, a low-density
lipoprotein (LDL)-like lipoprotein particle with atherogenic and thrombotic properties1.
Lp(a) is composed by a central LDL-like lipoprotein core particle with apolipoprotein
B (apoB) covalently bound to glycoprotein apo(a), resulting in differing structure,
physical and chemical properties compared with LDL1,2. The levels of Lp(a) in human
plasma are genetically ]
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Old 11-06-2016, 05:51 PM   #30
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the interesting thing is, that I got the idea by myself,
that changes in the gut flora could be responsible for the emergence of the
CHD in USA in the 1920s. After reading about the history of milk pasteurization,
infant formula, availability of icecream, yoghourt., the timing of the
"epidemic" in USA,England, Western Europe --> Eastern Europe,
the 1975-US-death-decline-mystery, French paradoxon,
Quebec vs. Ontario delay, low incidence in middle America,
i.e. Guatemala, Singapore ethnicity differences, ...
the almost simultanous emergence of peptic ulcers(also
mainly in males)caused by HPylori bacteria,

So I searched directly for gut flora and CHD , and there it was.
But I still didn't find anything linking changes in the gut flora to the
_emergence_ , the natural history and timeline of CHD.
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Old 12-13-2016, 12:26 PM   #31
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from latest articles , Nov.2016
----------------------------------------------------------------
Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden
urinary excretion of TMAO
-----------------------------------------------------------------------
ongoing research Points to Key role of gut Microbes in Cardiovascular Health
http://circ.ahajournals.org/content/134/21/1687.full
no aspect of human biology that is free from the effects of gut microbes
identified 34 bacterial taxa associated with body mass index and blood lipids
--------------------------------------------------------------------------
https://www.jstage.jst.go.jp/article...57_16-414/_pdf
next-generation sequencing
order Lactobacillales was significantly increased; while the phylum Bacteroidetes was
significantly decreased in coronary artery disease (CAD)


{ good recent review , imo }

Bacterial taxa belonging to the families Clostridiaceae and
Peptostreptococcaceae were positively associated with
TMAO production in humans

the gut microbial enzyme TMA lyase is a key regulator that
metabolizes choline to TMA. They found that the molecule
3,3-dimethyl-1-butanol (DMB), which non-lethally inhibits
TMA production from cultured gut microbiota, decreased
TMAO levels in mice fed a high-choline diet

Oral administration of probiotics such as Lactobacillus
and Bididobacterium species has been demonstrated to sup-
press atherosclerotic lesion formation in mice.


Wu, et al demonstrated enterotypes were
strongly associated with long-term diets, particularly protein
and animal fat (Bacteroides) versus carbohydrates (Prevotel-
la).11)



--------------------------------------------------------------------
Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels
-----------------------------------------------------------------
http://circ.ahajournals.org/content/...1/A12622.short
systematic review
Conclusions: Higher blood TMAO levels were consistently and dose-dependently associated
with the development of MACE (major adverse cardiovascular events )
across diverse populations, independently of traditional risk factors.
-------------------------------------------------------------------
Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of
Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB
-----------------------------------------------------------------
Plasma Concentrations of Trimethylamine-N-oxide Are Directly Associated with
Dairy Food Consumption and Low-Grade Inflammation in a German Adult Population
-------------------------------------------------------------
L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low
aortic lesions in ApoE−/− transgenic mice expressing CETP
---------------------------------------------------------


===============
is measuring urinary TMAO feasable for privates ?
“the ingestion of fish raises urinary TMAO levels.”
Analysis of 16S rRNA genes indicated that high-TMAO producers (those with >20
% increase in urinary TMAO response to eggs and beef) had more Firmicutes
monitoring of plasma and urinary TMAO levels
reduce TMAO levels, including use of oral broad spectrum antibiotics,
promoting the growth of bacteria that utilize TMAO as substrate and the
development of target-specific molecules with varying level of success.

-----========================================

We quantified plasma and urinary levels of TMAO and plasma choline and
betaine levels by means of liquid chromatography and online tandem mass
spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled
eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants
before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics.

elevated TMAO level predicted an increased risk of major adverse cardiovascular events
after adjustment for traditional risk factors

Routine laboratory tests were performed, and samples were measured on the
Abbott Architect platform (Abbott Laboratories), except for testing of myeloperoxidase,
which was measured with the use of the CardioMPO test (Cleveland Heart Laboratories).
Creatinine clearance was estimated with the use of the Cockcroft–Gault equation.
TMAO was measured in plasma, as described below. Major adverse cardiovascular
events (defined as death from any cause, nonfatal myocardial infarction, and
nonfatal stroke) were ascertained and adjudicated for all participants during
3 years of follow-up.

An aliquot from each 24-hour urine collection was spun to precipitate any
potential cellular debris, and supernatants were stored at −80°C until analysis.
TMAO, trimethylamine, choline, betaine, and their d9-isotopologues were
quantified with the use of a stable-isotope-dilution assay and high-performance
liquid chromatography with on line electrospray ionization tandem mass
spectrometry on an AB SCIEX QTRAP 5500 mass spectrometer;
d4(1,1,2,2)-choline, d3(methyl)-trimethylamine-N-oxide, and
d3(methyl)-trimethylamine were used as internal standards
----------------------------------------
AB SCIEX LIGHTSIGHT SOFTWARE METABOLITE IDENTIFICATION v2.2 1038209 QTRAP 5500
$6,599.00 or Best Offer Free international shipping From Singapore
---------------------------------------
Complete and nice API 4500 QQQ and 5500 Qtrap available $250,000.00
or Best Offer Shipping not specified
---------------------------------------------------------
SCIEX 6500 QTRAP LC/MS $215,000.00
or Best Offer +$3,500.00 shipping From United States
-----------------------------------------
AB Sciex API 4000 QTRAP System $119,500.00
or Best Offer Shipping not specified
-------------------------------------


so presumably not so easy, not many labs can do it,
urine or blood


================================================== =


3,3-Dimethyl-1-butanol (DMB), a structural analog of choline, inhibits microbial
TMA formation in mice and in human feces, thereby reducing plasma TMAO
levels after choline or carnitine supplementation.[8] It is found in some balsamic
vinegars, red wines, and some cold-pressed extra virgin olive oils and grape seed oils.[8]

[8]
^ a b c d Wang, Zeneng; Roberts, Adam B.; Buffa, Jennifer A.; Levison, Bruce S.; Zhu,
Weifei; Org, Elin; Gu, Xiaodong; Huang, Ying; Zamanian-Daryoush, Maryam; Culley,
Miranda K.; DiDonato, Anthony J.; Fu, Xiaoming; Hazen, Jennie E.; Krajcik, Daniel;
DiDonato, Joseph A.; Lusis, Aldons J.; Hazen, Stanley L. (December 2015).
"Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment
of Atherosclerosis". Cell. 163 (7): 1585–1595. doi:10.1016/j.cell.2015.11.055. "
• A structural analog of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally
inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases,
and to both inhibit TMA production from physiologic polymicrobial cultures (e.g.,
intestinal contents, human feces) and reduce TMAO levels in mice fed a high-choline
or L-carnitine diet.
• DMB was detected in some balsamic vinegars, in red wines, and in some cold-pressed
extra virgin olive oils and grape seed oils"


http://scholar.google.de/scholar?cit... dt=0,5&hl=en

Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis
by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut …

olive oil, extra virgin olive oil, grape seed oil, yeast containing food, and red wine

pill or capsule Formula I (e.g., dimethylbutanol) prevent TMA
Formula I (capital i) or Formula (I)

could be this : http://www.ebay.com/itm/Siang-Pure-o...E#ht_858wt_621


=================================================
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Old 12-14-2016, 04:08 AM   #32
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http://nutritionfacts.org/video/carn...ao-connection/
video transcript [2013?] [lots of discussion there]
the same Dr. Michael Greger , from birdflubook.com who posted a lot
about H5N1 in 2006 , who had many important .pdfs about birdflu papers
when you were looking for references, and who I'm still linked with at facebook
https://drgreger.org
-----------------------------------------
Urine TMA/TMAO is a not uncommon test for the genetic disorder trimethylaminuria,
where the ratio, rather than absolute levels, is important – you may need to confirm
reporting if you want to experiment. A list of labs from around the world that will
perform this test:
http://breathandbodyodour.proboards....ead/450?page=1
190euro Uni-Heidelberg
---------------------------------------------
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Old 12-14-2016, 02:38 PM   #33
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Thanks gsgs,

Recently there was a article in the news about the relationship between gut microbiota, diet, TMAO levels and Parkinson's disease.. think it involved miss folding of a protein into lewd bodies,
eta;

Do Microbes in the Gut Trigger Parkinson’s Disease?
-------

----------------------
Cardio Effects of Garlic Elucidated
Posted on April 19, 2016, 6 a.m. in Cardio-Vascular GI-Digestive Other Vital Nutraceuticals & Nutrients

Allicin exerts cardiovascular effects via the gut, where the compound prevents metabolism of certain amino acids into trimethylamine N-oxide (TMAO)....
http://www.worldhealth.net/news/card...ic-elucidated/
--------------------

`

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Old 12-15-2016, 06:07 AM   #34
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hmm, can they measure TMAO levels or gut-bacterial DNA in diseased people
or tissues e.g. preserved in formalin or frozen in labs or permafrost ?

Would be interesting to see, how/whether that changed when CHD emerged
1920-1940

---------------------edit 2017/02/13---------------------
about garlic :
that dietary allicin may be capable of protecting the host
from producing TMAO when carnitine is consumed through its impact on gut
microbiota,” the study authors submit that: "Allicin and dietary fresh garlic
containing allicin may be used as functional foods for the prevention of atherosclerosis.”

wikipedia:
A great deal of low quality clinical research has been conducted to determine
the effect of garlic on preventing cardiovascular diseases and on various
biomarkers of cardiovascular health, but as of 2015, the results were
contradictory and it was not known if there are any effects.[33][34][35][36][37]

---------------------------------------
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