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NMN Restores Capillary Density and Blood Flow in Aging Mice

nmn nicotinamide mononucleotide endothelial function angiogenesis

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#1 Michael

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Posted 22 March 2018 - 08:15 PM


All:
 

Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging

Abhirup Das, George X. Huang, Michael S. Bonkowski, Alban Longchamp, Catherine Li, Michael B. Schultz, Lynn-Jee Kim, Brenna Osborne, Sanket Joshi, Yuancheng Lu, Jose Humberto Treviño-Villarreal, Myung-Jin Kang, Tzong-tyng Hung, Brendan Lee, Eric O. Williams, Masaki Igarashi, James R. Mitchell, Lindsay E. Wu, Nigel Turner, Zolt Arany, Leonard Guarente, David A. Sinclair
Cell 173(1)


  • •Reduced blood flow with age is due to loss of endothelial NAD+-SIRT1 activity
  • •NAD+ and H2S control muscle angiogenesis and increase endurance in old mice
  • •The NAD precursor NMN mimics and augments exercise by inhibiting NICD-Notch
  • •Neovascularization is as important as mitochondria for rejuvenating muscle



 


Summary

A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. ... Treatment of mice with ... (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a [dietary restriction (DR)] mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.




fx1.jpg

 


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#2 Harkijn

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Posted 22 March 2018 - 08:47 PM

This seems pretty sensational at first sight. Especially the combination of NMN and NaHS draws my attention. As most of us know Sulforaphane  causes the body to release H2S as for instance described here:

https://www.ncbi.nlm...pubmed/22005276


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#3 Michael

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Posted 22 March 2018 - 08:57 PM

As most of us know Sulforaphane  causes the body to release H2S as for instance described here:

https://www.ncbi.nlm...pubmed/22005276

 

Can you point to any studies showing that it does so in vivo after oral consumption, preferably in humans?

 

Taurine, on the other hand, does seem to raise H2S in humans, consistent with epidemiological and experimental evidence that it is cardioprotective.
 


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#4 Harkijn

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Posted 22 March 2018 - 09:08 PM

 

As most of us know Sulforaphane  causes the body to release H2S as for instance described here:

https://www.ncbi.nlm...pubmed/22005276

 

Can you point to any studies showing that it does so in vivo after oral consumption, preferably in humans?

 

Taurine, on the other hand, does seem to raise H2S in humans, consistent with epidemiological and experimental evidence that it is cardioprotective.
 

 

Well, what comes to mind is this one, though I am not at all sure if it fufills your requirements:

https://www.ncbi.nlm...es/PMC4785274/ 

It would require to plough through the huge Sulforaphane thread here on LC to find more appropriate data.


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#5 able

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Posted 22 March 2018 - 09:41 PM

Wow, very exciting.  Seems to realize the potential hinted at in the big Sinclair study that showed muscle of old mice looked like young.  Here, they actually performed like young mice.  

 

2 month of NMN results in old mice showing the endurance of young mice.  They conclude  it is the activation of Sirt1 increases capillary growth which is the key to youthful muscle performance, not the increased mitochondrial function.  Much to digest, but seems spectacular results.

 

Also note, most benefit incurred when combined with exercise - much more than NMN or exercise alone.

 

 

 

 

Some quotes below:

 

To restore NAD+ levels, we administered NMN to 18-month-old mice via drinking water for 2 months at 400 mg/kg/day 

 

NMN restored the number of capillaries and capillary density of the old mice to those typically seen in young mice 
 
but the most striking effect was a 56%–80% improvement in endurance, with lower post-exercise blood lactate 
 
NMN did not alter the capillarity or exercise capacity of sedentary animals younger than 12 months (not shown)
 
There was a strong effect, however, in young mice on NMN after endurance training for 1 month, resulting in 70% more capillaries than untreated sedentary mice, more than twice the effect of NMN alone 
 
 
Exogenous Hydrogen Sulfide Activates SIRT1 and Augments the Effects of NMN
 
As a signaling molecule, H2S shares many similarities with NAD+. It increases SIRT1 activity, protects against oxidative stress, and can promote angiogenesis 
Treatment of HUVECs with NaHS or NMN alone increased SIRT1 protein levels but the combination was even more potent (Figure 7A). 
 
In response to H2O2 treatment, NMN reduced the number of apoptotic ECs from 42% to 17% and, in combination with NaHS, reduced it to 11% (Figures 7F and S7E).
 
NMN also reduced apoptosis in HUVECs by 13% and the combination reduced it by 36% (Fig- ures 7G and S7F). 
 
Mice treated with NMN had 1.6-fold increase in time and distance run compared to untreated mice (Figure 7H), while the combination of NMN with NaHS treatment doubled their endurance. 
 
Interestingly, NMN supplementation had no effect on the capillary density of sedentary young to middle-aged mice. Only when coupled with exercise training or after ischemia did NMN improve these parameters. 
 
 
From the Summary:
Skeletal muscle is not the only tissue that requires adequate blood flow to maintain function. Heart, liver, bone, and the brain, for example, are critically dependent on blood flow. It will be interesting to test whether upregulation of the endothelial NAD+-H2S pathway improves the vasculature and blood flow into those tissues as well. If so, precursors to NAD+ and H2S may not only be effective agents for increasing the recovery from vessel blockages and enhancing the effects of exercise, but also for treating the most common of age-related diseases, if not aging itself. 

Edited by able, 22 March 2018 - 09:45 PM.

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#6 Michael

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Posted 22 March 2018 - 09:41 PM

 

 

As most of us know Sulforaphane  causes the body to release H2S as for instance described here:
https://www.ncbi.nlm...pubmed/22005276

 
Can you point to any studies showing that it does so in vivo after oral consumption, preferably in humans?

 

Well, what comes to mind is this one, though I am not at all sure if it fufills your requirements:
https://www.ncbi.nlm...es/PMC4785274/ 

 


All the evidence on SFN reviewed there is in vitro.



#7 stefan_001

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Posted 22 March 2018 - 10:02 PM

Wow that is an interesting study. Seems to match my personal experience that daily exercise in combination with NAD+ precurser (NR in my case) has the best results. It is still winter here and I often skipped using gloves (it gets here to -20 celcius), before I started on NR some of my fingers went numb even with the thickest gloves. That improvement in blood flow I have noticed.


Edited by stefan_001, 22 March 2018 - 10:03 PM.

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#8 tunt01

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Posted 22 March 2018 - 10:11 PM

Brian Kennedy (Buck Institute) wrote a preview here in the same issue of Cell of the Das paper and a related paper by Longchamp.

 

There appears to be an interesting Longchamp paper that demonstrates sulfur amino acid restriction (methionine, cysteine) also induce angiogenesis in a Hif1a independent manner.


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#9 tunt01

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Posted 22 March 2018 - 10:16 PM

If anyone knows a good video/primer on H2S signaling or angiogenesis, I would appreciate it.



#10 stefan_001

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Posted 22 March 2018 - 10:18 PM

So we are truly seeing proof here of reversing aspects of aging.

 

Also this is good to know:

The ability of NMN to promote angiogenesis raises the question
of whether it might stimulate tumor growth. Mice treated
with NMN or NR for extended periods show no evidence of
increased tumor burden (Mills et al., 2016; Zhang et al., 2016).
Indeed, during the course of our studies, no increase in tumor
burden was seen with NMN-treatment or in a DEN-induced
model of hepatocarcinoma (Figures S7J and S7K), although
more study is warranted.


Edited by stefan_001, 22 March 2018 - 10:19 PM.


#11 able

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Posted 22 March 2018 - 10:35 PM

Wow that is an interesting study. Seems to match my personal experience that daily exercise in combination with NAD+ precurser (NR in my case) has the best results. It is still winter here and I often skipped using gloves (it gets here to -20 celcius), before I started on NR some of my fingers went numb even with the thickest gloves. That improvement in blood flow I have noticed.

 

Yes, that is exactly what I have noticed also with NR and NMN.  I have more energy, and a bit more stamina in the gym, but as I continued, I have made more and more progress, getting back to the weights and running times I accomplished over 10 years ago.

 

Anecdotal, but lines up so perfectly with what I have been saying the last 2 years.

 

And yes, it does seem actual age reversal (in mice at least) - not just minor improvement in some metabolic markers.



#12 tunt01

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Posted 22 March 2018 - 10:44 PM

David Sinclair's video comment on this paper


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#13 stefan_001

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Posted 22 March 2018 - 10:51 PM

 

Wow that is an interesting study. Seems to match my personal experience that daily exercise in combination with NAD+ precurser (NR in my case) has the best results. It is still winter here and I often skipped using gloves (it gets here to -20 celcius), before I started on NR some of my fingers went numb even with the thickest gloves. That improvement in blood flow I have noticed.

 

Yes, that is exactly what I have noticed also with NR and NMN.  I have more energy, and a bit more stamina in the gym, but as I continued, I have made more and more progress, getting back to the weights and running times I accomplished over 10 years ago.

 

Anecdotal, but lines up so perfectly with what I have been saying the last 2 years.

 

And yes, it does seem actual age reversal (in mice at least) - not just minor improvement in some metabolic markers.

 

I am 3 years on NR end of the month and the progress continues. Same here on the energy. At times I am walking and I just want to go faster which I do and in the end I am running. I am happy when I see stairs so then I can dash up. I know sounds crazy especially considering I became 48 this week.
 


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#14 Michael

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Posted 22 March 2018 - 11:35 PM

These results were partially previewed in their "Battlefield Test" meeting abstract. As I noted at the time, one potential downside of this would be increased risk of cancer growth or invasion via angiogenesis. Flagging angiogenesis with age may be one of the reasons why cancer incidence plateaus late in current lifespans.


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#15 Michael

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Posted 22 March 2018 - 11:52 PM

Additional press over at the excellent health news site STAT. Snips of note:

 

 

Blood flow increased, and the animals’ endurance, measured by how long they could run on a treadmill before becoming exhausted, was 56 percent to 80 percent greater than that of untreated old mice: 1,400 feet compared to 780 feet. ...

 

New blood vessels could also be a mixed blessing. They support the growth of tumors, which is why anti-angiogenesis molecules have become cancer drugs. The scientists found no excess cancers in the mice given NMR [sic], but “more study is warranted,” they wrote. ...

 

Resveratrol is very, very good [at activating SIRT1 and extending lifespan] if you’re a mouse,” said Guarente, who cheerfully acknowledges buying a 10-year supply of micronized resveratrol. Most of it is still in his basement. “But the human trials were all over the place, which was unsettling,” he said. ...Thanks to negative studies, the jury is still out on whether anything related to sirtuins will extend lifespan, but the Cell study offers some hope for extending healthspan. If boosting NAD+ promotes blood vessel formation via SIRT1, it might “rescue muscle mass” that otherwise decreases as blood vessels atrophy, Guarente said. That could prevent the bone loss, frailty, and falls that can be fatal in old age. ...

 

Sinclair and his team are now studying whether raising NAD+ might also spur the creation of blood vessels in the brain. There and in other organs, said Sinclair, “the lack of oxygen and buildup of waste products” that results from loss of small blood vessels “sets off a downward spiral of disease and disability.” In the brain, that would include vascular dementia.

 

Sinclair takes NMN to boost NAD+ levels. “In someone my age [49], it’s probably harder to see immediate benefits,” he said, though he said he feels sharper and younger on it. After his 78-year-old father began taking NMN “he started climbing mountains and going whitewater rafting and looking forward to the next five years,” Sinclair said. “It might be psychological, but it isn’t hurting.”

 

Only rigorous human research can determine that. Metro International Biotech, a Michigan-based startup for which Sinclair consults, just finished a clinical trial of the safety of a proprietary version of NMN and hopes to start a trial of the molecule’s efficacy this year, Sinclair said.

 

One concern is that boosting sirtuins could backfire. An excess of the molecules, [The Buck Institute's Eric] Verdin said, can promote autoimmunity, which causes diseases such as Crohn’s and rheumatoid arthritis.

 

“That should give us pause about broad claims of what they can do,” he cautioned. “I worry sometimes that [with NAD+-boosting pills already on the market] the field is getting ahead of itself.”

 


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#16 able

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Posted 23 March 2018 - 01:00 AM

These results were partially previewed in their "Battlefield Test" meeting abstract. As I noted at the time, one potential downside of this would be increased risk of cancer growth or invasion via angiogenesis. Flagging angiogenesis with age may be one of the reasons why cancer incidence plateaus late in current lifespans.

 

In the Mills Long-term study, mice were given 100 or 300mg/kg NMN daily for 12 months (mid-life to old age) with no increased mortality.    Does that not give a clue to safety or cancer risk?

 

 

 

"It should be noted that NMN administration did not generate any obvious toxicity, serious side effects, or increased mortality rate throughout the 12-month-long intervention period"


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#17 tunt01

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Posted 23 March 2018 - 02:17 AM

In the Mills Long-term study, mice were given 100 or 300mg/kg NMN daily for 12 months (mid-life to old age) with no increased mortality.    Does that not give a clue to safety or cancer risk?

 

 

 

"It should be noted that NMN administration did not generate any obvious toxicity, serious side effects, or increased mortality rate throughout the 12-month-long intervention period"

 

 

 

I don't know enough about cancer to have a cognitive thought.  But the idea of persistent upregulation of SIRT1 and the downstream effect that it has on silencing p53, "guardian of the genome", kind of scares me.

 

There are a lot of overview/review papers on SIRT1 in cancer.  My gut reaction is to take NMN/NR in a pulsatile fashion at the tail end of a daily intermittent fast with periodic breaks in usage.

 

Lin, Z., & Fang, D. (2013). The Roles of SIRT1 in Cancer. Genes & Cancer4(3-4), 97-104. doi:10.1177/1947601912475079

 

 

EDIT:  We probably should have a SIRT1 cancer risk thread, maybe so that this thread doesn't get hijacked.


Edited by prophets, 23 March 2018 - 02:18 AM.

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#18 Michael

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Posted 23 March 2018 - 02:29 AM

Before we go too far down the NAD+ precursor-cancer rabbit hole, may I suggest we move that part of the discussion over to the existing thread on cancer and NAD+ precursors?


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#19 LawrenceW

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Posted 23 March 2018 - 03:08 PM

In your opinions would H2O2 be interchangeable and perform the same function as H2S in the dosing regimen described in this study?



#20 Michael

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Posted 23 March 2018 - 07:25 PM

In your opinions would H2O2 be interchangeable and perform the same function as H2S in the dosing regimen described in this study?

 

No — not remotely. Please don't start swallowing peroxide ;) .



#21 tunt01

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Posted 23 March 2018 - 07:50 PM

In your opinions would H2O2 be interchangeable and perform the same function as H2S in the dosing regimen described in this study?

 

You probably should be reaching for garlic.   First thing that pops into my head when I see Hydrogen Sulfide is garlic and Kyolic supplements.



#22 Michael

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Posted 23 March 2018 - 09:59 PM

 

In your opinions would H2O2 be interchangeable and perform the same function as H2S in the dosing regimen described in this study?

 

You probably should be reaching for garlic.   First thing that pops into my head when I see Hydrogen Sulfide is garlic and Kyolic supplements.

 

 

Hold that for the vampires, perhaps. This is all in vitro work; are you aware of any evidence of garlic/garlic supplements actually raising circulating H2S after oral consumption? The closest thing I'm aware of is this paper, which used 50 mg/kg pure S-allylcysteine (the main sulfur-containing bioactive in garlic) via i.p. injection; even if it works when taken orally (which seems likely:  this paper says "The bioavailability was 98.2, 103.0, and 87.2% in rats, mice, and dogs, respectively.," so I'd be surprised if human bioavailabiilty wasn't at least very high; (Kyolic claims SAC is 100% bioavailable, but gives "eminence-based medicine" instead of a scientific reference) — even so, there's only 0.322 mg SAC/kg in raw garlic (and 5.84 mg/kg in aged black garlic extract (ie, Kyolic)) per this web page, so you'd need an awful lot of it.

 

As I mentioned above, there is solid evidence in humans that taurine elevates circulating H2S. So does Calorie restriction, NB.


Edited by Michael, 23 March 2018 - 10:08 PM.

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#23 Harkijn

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Posted 24 March 2018 - 08:18 AM

We're in the danger of veering off topic now but for our background reading I would like to point to this short article about sulfide donors in a plant based 'diet'.

http://www.science.n...n-sulfide-donor

(Perhaps for another thread: I wonder if there is a contradiction between eating a diet rich in sulfide donors on the one hand and , on the other hand,  striving for restriction/moderation of sulfur containing molecules like methionine in order to activate the Transsulfuration Pathway.)



#24 stefan_001

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Posted 24 March 2018 - 08:27 AM

Some more about Taurine:

Our study demonstrated that the high dosage of taurine supplementation effectively mitigated the severity of pathological inflammation and white matter injury after ICH, and the mechanism may be related to upregulation of H2S content and reduced P2X7R expression.

https://link.springe...0726-017-2529-8

 

 


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#25 stefan_001

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Posted 24 March 2018 - 10:12 AM

I am going to try out Taurine + NAD+ booster (NR in my case) for a while. I would be surprised if I see strong differences but who knows - if the circulation improvement is universal I could imagine that my eyesight would improve somewhat. I am wondering if there is anybody on the board suffering from Hearth Failure and using NR, you may want to consider adding Taurine.

 

Skeletal muscle is not the only tissue that requires adequate
blood flow to maintain function. Heart, liver, bone, and the brain,
for example, are critically dependent on blood flow. It will be
interesting to test whether upregulation of the endothelial
NAD+-H2S pathway improves the vasculature and blood flow
into those tissues as well. If so, precursors to NAD+ and H2S
may not only be effective agents for increasing the recovery
from vessel blockages and enhancing the effects of exercise,
but also for treating the most common of age-related diseases,
if not aging itself.


Edited by stefan_001, 24 March 2018 - 10:14 AM.


#26 stefan_001

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Posted 24 March 2018 - 10:30 AM

BTW I think this may trigger a new chapter in sports performance enhancing substances.....



#27 Harkijn

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Posted 24 March 2018 - 01:35 PM

My eyesight could use some improvement too. Reading up on taurine today I see a lot of enthusiastic comments about taurine and vision.

A diet rich in sulfide donors supplemented with an NAD+precursor as well as lutein and zeaxanthin ( for years and years) has sofar not brought any improvement. So I will add taurine and place results on the NR experiences thread. The MD here 

http://renegadehealt...art-and-vision#

advises 500 - 1000 mg/day for general supplementation and up to 4000mg to addres a medical condition.


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#28 tunt01

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Posted 24 March 2018 - 01:56 PM

2000px-3-%284-%282-hydroxyethyl%29pipera

4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS)

 

 

Taurine.png

Taurine

 

Those of you interested in Taurine might want to take a look at EPPS.  Turnbuckle mentioned it in an Alzheimer's thread.  Taurine peaks in about 1.5 hrs after administration.  EPPS peaks in 3 days.  It seems to be like an extended life Taurine, though someone more fluent on the chemistry might have a better thought.

 

 

 


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#29 able

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Posted 15 April 2018 - 01:21 AM

Did they use the mice with faulty NNT gene in this study?  

 

 

 



#30 able

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Posted 15 April 2018 - 01:39 AM

Strange.  I was looking for info on the mice used, and found this chart in the supplementary info.

 

 

 

Attached File  nad-chart-liver-soleus.jpg   24.51KB   0 downloadsAttached File  nad-chart-liver-soleus2.jpg   21.73KB   0 downloads

 

 

 

 

 

 Seems quite significant that  after 8 weeks of supplementation, liver NAD looks to be over 5x higher in mice receiving NMN.  Soleus looks maybe 50% higher.

 

 

Isn't that quite a bit higher than some other studies have shown?  What am I missing here?


Edited by able, 15 April 2018 - 01:41 AM.






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