On Sep 13, 2:02=A0am, Kofi <k...@[EMAIL PROTECTED]
> wrote:
> This is a response I emailed one of the authors (Houston) of the paper,
> "Anemia of Chronic Disease: A harmful disorder or an adaptive,
> beneficial response?" <http://www.cmaj.ca/cgi/reprint/179/4/333.pdf>.
=A0
> I've edited my remarks somewhat to remove personal references and make
> them more readable. =A0Due to size, I will probably post any sup****ting
> research that's mentioned in dribbles over the next few days.
>
> In terms of a protective mechanism in anemia, I think the place you
> might want to look is HIF-1a. =A0EPO is downstream of HIF-1a and HIF-1a
> can be turned on via iron chelation. =A0Enough EPO itself might turn off
> HIF-1a via negative feedback. =A0Metallothionein also hangs off this
> pathway, as do some angiogenic factors - none of which are particularly
> beneficial for cancer (although, iron chelators like tannic acid are
> often used as chemotherapeutic agents). =A0Evidence from COPD suggests
EP=
O
> itself might be protective; in the right inflammatory environment, EPO
> doesn't increase red blood cell numbers [PMID 15795697, 15764763]. =A0
> Recent work has shown turning on HIF-1a in the gut blocks leaky gut
> syndrome (which, by the way, appears attached to cathelicidin, vitamin
> D3 and autophagy - all im****tant subjects with Crohn's). =A0Giving
someon=
e
> enough EPO or iron might downregulate HIF-1a in the gut lining.
>
> The more closely I scrutinize HIF-1a, the more im****tant it appears to
> be in a network regulating a range of activities from cellular
> glycolysis and mitochondrial stress response to innate immunity and
> general barrier function in certain cell types (which directly addresses
> your concerns about vascular permeability in sepsis). =A0I think you're
> right to point to infection rates and iron overload. =A0I suspect you've
> touched on a set of very deep relation****ps among antioxidant
> management, barrier function, innate immunity and iron movement. =A0
> There's also evidence of epigenetic regulation affecting several of the
> examples you cite like heart failure. =A0And EPO/anemia treatment may
not
> be the only medical intervention that backfires from misunderstanding
> these links - namely, broad spectrum antibiotics and glucocorticoids can
> also disrupt this delicate balance.
>
> I became interested in anemia because I've been using helminths provided
> by Ovamed to control my autoimmunity (with some, but limited, success).
=
=A0
> These helminth infections can induce anemia and I posit that this anemia
> - rather than being a nasty side-effect - is central to their beneficial
> function and activates the recently discovered, gut-protective HIF-1a
> pathway, limiting leaky gut and autoimmunity while also activating
> autophagy and synthesis of innate antimicrobials.
>
> Since helminth infections have been a common condition in human
> evolutionary history this means anemia has also been a common
> adaptation. =A0The human body may actually expect it as a regular
> occurrence. =A0Without it, certain chronic conditions could worsen in
way=
s
> for which the body is unprepared. =A0Protective barrier function could
be
> compromised as par for the course of modern living, perhaps accounting
> for the rash of allergies, asthma and rhinitis seen in modern society. =
=A0
> Hence you can see how my interest in anemia eventually brought this
> paper onto my radar.
>
> With regards to a feedback loop between EPO, hemoglobin and HIF-1a, I
> have no evidence that one exists. =A0It seems natural to posit at least
a=
n
> indirect loop, but that's not very scientific reasoning. =A0What little
I
> do have on the matter suggests a complicated relation****p. =A0Acellular
> hemoglobin can attenuate HIF-1a and EPO in a rat model while boosting
> HO-1 [PMID 18498252] - which provides interesting implications for blood
> substitutes and their effects on wound healing. =A0The transcriptional
> mechanism for the effect of hemoglobin on HIF-1a and EPO isn't entirely
> clear at this point.
>
> Perhaps cofactors are involved or there's a non-linear dose-response
> curve for EPO similar to naltrexone. =A0At a standard dose (50mg),
> naltrexone blocks the mu opioid receptor but at low doses like the one I
> take (4mg), it actually enhances receptor expression. =A0(If you're
> interested in the role gut bacteria play in pain perception and B cell
> production, I can send you a few notes; it goes something like
> lactobacillus/butyrate->mu opioid receptor->cannabinoids->B cell
> proliferation; it's an unpublished link, by the way; there are papers
> for each link in the chain but nothing tying it all together yet -
> especially with regards to the efficacy of low-dose naltrexone for
> Crohn's/M.S. or, say, how broad-spectrum antibiotics might induce
> autoimmunity).
>
> In published research, EPO doesn't always seem to elevate hemoglobin -
> at least there appear to be ways to raise EPO without affecting
> hemoglobin. =A0Aside from the citations on COPD, there's a more
> interesting paper on echinacea. =A0The herbal extract boosts EPO without
> affecting hemoglobin. =A0The authors of the paper, however, omitted any
> discussion linking EPO expression to innate immunity. =A0Given re****ts
of
> echinacea's immunity boosting ability, this is a tantalizing link in
> need of further exploration.
>
> In a small study, patients with chronic heart failure have higher EPO
> levels and lower hemoglobin than controls. =A0Patients with more severe
> cases had more severe differences from the norm but only NT-proBNP
> levels predicted mortality [PMID 18664018]. =A0Why "EPO resistance"
occur=
s
> and what it means is certainly an open question in the literature.
=A0(Se=
e
> below on HDACs and heart failure.)
>
> While there's no evidence yet linking EPO or anemia directly to innate
> immune factors like cathelicidin, there is evidence linking HIF-1a to
> cathelicidin production in keratinocytes [PMID 18323789], sometimes in a
> bi-directional manner [PMID 18412861] - putting HIF-1a itself partially
> under the regulation of the innate immune system, at least in the skin.
=
=A0
> Given that Vitamin D3 provokes cathelicidin synthesis (as does butyrate
> in some tissues), this would leave HIF-1a partially affected by the VDR
> (by the way, bile acids conjugate with bacteria-produced short chain
> fatty acids in the gut; some of the conjugates bind to the VDR and
> activate it without elevating calcium levels like Vitamin D3 does;
> there's a recent paper on lithocholic acid acetate/LCA propionate if
> you're interested in this).
>
> Cathelicidin has wide-ranging angiogenic, wound-healing [PMID 17805349],
> antimicrobial and antiinflammatory properties. =A0It's downstream of
> vitamin D3/HIF-1a/butyrate and tilts mast cell inflammation towards
> innate immunity [PMID 18239275]. =A0In general, cathelicidin
desensitizes
> the immune system to allergic response [PMID 18768846, 17237433] by
> altering TLR signaling (and given the involvement of CD44 here, I
> wouldn't be surprised to see cathelicidin turn out to be central to
> alopecia areata [PMID 12485450; see also PMID 12060392 and PMID
> 10998138]). =A0It's curious that helminths also ****ft mast cell function
> away from the spontaneous degranulation seen in allergy and other
> autoimmune conditions via IgG4 secretion
> <http://www.discover.com/issues/sep-93/features/ofparasitesandpo264/>).
=
=A0
> If I might take a moment to remark on trends in contem****ary medical
> research, digging in this cathelicidin/mast cell vein would certainly
> fit with recent examinations of the underappreciated role mast cells
> play in chronic inflammation and autoimmunity.
>
> Cathelicidin has antiviral properties so it probably inhibits certain
> kinds of cancer development, providing an additional antitumor property
> for HIF-1a beyond the p53 stability you mention. =A0I suspect
cathelicidi=
n
> has antifibrotic properties under certain cir***stances. =A0At least in
> some conditions where cathelicidin is absent or underexpressed, fibrosis
> does occur (e.g., cystic fibrosis [PMID 17727333]).
>
> Heme-oxygenase 1 (HO-1 / HSP32) catalyzes the conversion of heme into
> carbon monoxide and biliverdin. =A0HO-1 is induced during hypoxia and
> induced by VEGF-driven angiogenesis. =A0It's also one of the defensive
> genes induced by the Nrf2 response. =A0Animals without a Nrf2 response
> develop allergic/autoimmune syndromes. =A0I can't find the citation at
th=
e
> moment, but several heat shock proteins are induced by bacterial
> colonies in the gut. =A0HO-1 is a direct input into regulatory T-cells
an=
d
> can be triggered by glutamine in the gut (that glutamine activates Tregs
> is a supposition of mine; glutamine is beneficial for a number of
> autoimmune bowel conditions and glutamine is known to inhibit mTOR in
> the gut and induce HO-1; both HO-1 and mTOR inhibition activate Tregs;
> no one has yet drawn this final connection in the literature linking
> glutamine directly to Treg behavior but it's consistent with the data).
>
> HO-1 appears to be vital for barrier function. =A0In VEGF-induced
> angiogenesis, blocking HO-1 leaves the resulting vessels leaky.
=A0Unlike
> HO-1, cathelicidin does increase vascular permeability in the skin [PMID
> 16600571].
>
> If anemia does wind up boosting regulatory T-cell function (say, through
> HO-1), this might offer a benefit to heart attack patients whom often
> have autoantibodies directed against heart muscle. =A0Correcting anemia
> could then worsen any host attack on self tissue in heart muscle. =A0On
> the other hand, boosting Tregs in cancer is a very bad idea. =A0They
> ****eld tumors from the immune system - yet treating anemia in cancer, as
> you mention, has blown up in the past, accelerating tumor progression.
>
> With regards to studies on red blood cell transfusion in critical
> illness and mortality, did your analysis control for the age of the
> donated blood? =A0I don't have the reference handy, but there's a recent
> paper pointing to serious deterioration in donated blood after a few
> days. =A0Any study of blood transfusions and mortality will have to take
> account of the freshness of the transfused cells.
>
> Animal models ablating HIF-1alpha should shed light on its im****tance in
> chronic disease states, as could ablation of her downstream actions -
> metallothionein, cathelicidin, EPO, VEGF, etc. =A0If HIF-1alpha does
> account for the benefits of anemia then isolating the most im****tant
> pathways downstream of HIF-1alpha could provide much more refined
> benefits. =A0For instance, metallothionein is not just a
metals/pesticide=
s
> chelator but also an im****tant cellular stress response agent. =A0
> Molybdenum-based compounds might be found which efficiently induce it
> without triggering more hazardous side pathways in certain diseases. =A0
> Likewise if cathelicidin provides the main benefit then there may be
> vitamin D3 analogues (lithocholic acid proprionate?) that are more
> appropriate.
>
> If anemia's benefit does hinge on HIF-1alpha per se, that leaves us with
> several therapeutic implications - some of which would be quite
> inexpensive to apply in the developing world. =A0HIF-1alpha inducers
migh=
t
> provide broad benefits for certain chronic diseases. =A0That means
> hydroxylase inhibitors being developed for leaky gut may have wide
> application. =A0Green tea components (EGCG, tannic acid) and other
> polyphenol iron chelators might have broad benefits (provided there's a
> source of extract untainted by fluoride and metals). =A0Cobalt compounds
> could have applications if their cancer/liver risk could be minimized. =
=A0
> Methylcobalamin might fit that bill - but as a nutriceutical, few
> research dollars have been expended trying to explain, for instance,
> methyl-B12's benefit in neuropathy (Is it due to HIF-1a???).
=A0Sketching
> out this network might help avoid the detrimental hazards of EPO
> administration. =A0For instance, you might be able to break the feedback
> by applying EPO with an hypoxia mimetic of some type. =A0(I kind of
doubt
> this, though.)
>
> Hypoxia induces wide-ranging epigenetic alterations [PMID 18294659]. =A0
> It's possible anemia does the same, but since it's not widely assumed to
> be a beneficial adaptation it hasn't been studied like this.
=A0Epigeneti=
c
> changes might account for changes in cardiac output. =A0HDAC inhibition
> sensitizes the heart to calcium signals. =A0(There are interesting links
> among viral infections, metallothionein expression, cardiac
> metal/pesticide ac***ulation and heart failure. =A0I've written an
> internet article on this topic a few months back. =A0I contacted some of
> the researchers about the links but I heard nothing back from them.)
>
> What is anemia doing epigenetically? =A0I say that because I've already
> mapped out several interesting genes in my gut under HDAC regulation:
> metallothionein, defensins, cathelicidin, IDO, FoxP3 and the mu opioid
> receptor (which, in turn, regulates cannabinoid signaling which, in
> turn, may regulate B cell proliferation). =A0The circadian rhythm gene,
> Clock, is also an HDAC and circadian rhythms play a role in cancer
> development. =A0Circadian rhythms are frequently disrupted in severe
> allergy and infection (LPS fiddles with Clock).
>
> In tumors, HDAC inhibitors (and mTOR inhibitors) limit HIF-1a expression
> and reduce angiogenesis [PMID 18519793], however normal cells may not
> behave this way when exposed to HDAC inhibitors and, even if they do,
> the cascade may be different when initiated from a broad response to
> anemia.
>
> When you mentioned leaky vessels in sepsis, I thought about innate
> immunity once again. =A0Butyrate upregulates defensin production and has
> had a positive effect on the outcome of sepsis in animal studies. =A0If
> HIF-1a does indeed affect innate immunity in the rest of the body it
> might have a positive effect on sepsis too. =A0HIF-1a agonists coupled
> with vitamin D3 and butyrate might significantly improve survival in
> sepsis. =A0Anemia could have per se antimicrobial properties via its
iron
> sequestration. =A0This may represent a broad mammalian approach both to
> protecting tissue against oxidative stress and guarding against
> microbial infiltration. =A0Consider the effects on iron of other
mammalia=
n
> antimicrobials like lactotransferrin and lactoferrin.
>
> When you step back a moment from the problem of anemia per se and begin
> to look at the big picture of barrier function/innate immunity in
> chronic disease, two other suspect interventions come into focus besides
> EPO: antibiotics and glucocorticoids. =A0Glucocorticoids damage
> cathelicidin expression, at least in animals [PMID 18505188], and
> antibiotics destroys the friendly bacteria needed to maintain natural
> barrier function (via the butyrate/HDAC regulatory chain, HSPs, IL-10
> and other factors). =A0I think this is a fertile research area that's
bee=
n
> largely unexplored. =A0It's really time bacterial management in the
> western world ****fted to targeted phage therapy and quorum-sensing
> intervention instead of broad-spectrum assault.
>
> What are the long-term consequences of anemia? =A0There has long been
> evidence that mild iron deficiency reduces neurodegenerative risk and
> lengthens lifespan. =A0Several life extensionists give blood on a
regular
> basis for this reason. =A0There are connections here among the
> lifespan/aging-regulator klotho, ACE, Vitamin D3, mineral management,
> HIF-1a, metallothionein and thymosin beta 4 / Ac-SDKP. =A0I haven't had
> time to do the research to sketch it out. =A0There's been speculation
for
> years that certain ACE inhibitors might not improve mortality outcome
> because of the way they interfere with klotho.
>
> As I write this, it occurs to me that an HIF/glycolysis link might
> explain why intermittent fasting depletes B and T cell levels and is so
> effective for treating autoimmunity. =A0What is the effect of fasting on
> HIF-1alpha expression? =A0What's the relation****p with cholesterol and
> ketone production?
>
> Given the role autoantibodies play in anorexia/bulimia, it's possible
> anemia plays a protective role here as well. =A0Indeed it's possible
that
> fasting feels good in anorexia - however otherwise detrimental - because
> it's a crude attempt to shut down a harmful autoimmune reaction.
>
> Green tea extract is a PPARalpha agonist in some tissues. =A0It might
> behave the same way in the gut. =A0PPARalpha improves carnitine uptake
in
> some organs, which is downregulated in certain gut injuries.
=A0Carnitine
> is required for butyrate uptake, metabolization and utilization.
=A0Hence=
,
> PPARalpha agonists might be beneficial for Crohn's, IBD and the like -
> although I've never seen speculation per se in the literature. =A0
> PPARalpha also raises the pain threshold (as does carnitine, as does PKC
> inhibition... and carnitine does inhibit PKC, which might explain why;
> PKCtheta in particular is vital for regulatory T-cells; PKC inhibition
> also has fascinating consequences for mu opioid receptor
> tolerance/dependence).
>
> There's evidence PPARalpha is partially under the regulatory control of
> HIF-1alpha or at the very least hypoxia itself [PMID 14521756]. =A0
> PPARalpha and PPARgamma both act as selective breaks on angiogenesis via
> actions of VEGF receptors and signaling [PMID 15828227].
>
> Mice lacking prolyl hydroxylase PHD1 in skeletal muscle have decreased
> exercise tolerance and oxygen consumption but can remarkably tolerate
> ischemia in an HIF-2alpha- and PPARalpha-dependent fa****on [PMID
> 18316022]. =A0In fact, loss of PHD1 reprograms glucose metabolism from
> oxidative to more anaerobic ATP production through activation of a
> PPARalpha pathway. =A0Protection isn't through HIF-derived angiogenesis
o=
r
> erthyropoiesis or vasodilation but rather reduced oxidative stress from
> a ****ft in energy metabolism. =A0Protection relies on HIF-2alpha and was
> not observed in PHD2-deficient or PHD3-deficient mice [PMID 18176562]. =
=A0
> PPARalpha is necessary for the antitumor activity of PEDF (pigment
> epithelium-derived factor) [PMID 18497086]. =A0HIF-1alpha may be
involved
> in the hypoxia-induced suppression of fatty acid metabolism in
> cardiomyocytes by reducing the DNA binding activity of PPARalpha/RXR
> [PMID 17963722] and there's evidence that hypoxia mimetics reduce
> PPARalpha expression in murine hearts [PMID 11549245], ****fting the
> heart away from beta oxidation towards glucose during hypoxia. =A0In
some
> tissues, PPARs tend to rise with hypoxia [PMID 17156782].
>
> What's the body temperature of these chronic disease patients with mild
> anemia? =A0A ****ft in basal mitochondrial metabolism could lower body
> temperature and there is evidence that a dramatic lowering of
> temperature in isolated heart cell studies can further activate
> HIF-1alpha and HO-1, improving tissue survivability [PMID 17660400].
>
> A PPARgamma ligand modified with an unsaturated ketone can increase cell
> levels of HIF-1alpha [PMID 17658243] - unlike other PPARgamma agonists,
> which ameliorate allergic airway inflammation by reducing HIF-1alpha
> [PMID 16815147].
>
> The connection between PPARs and cancer is complex and confusing [PMID
> 18645611].
>
> There is evidence from old experiments in rat livers that PPARalpha
> ligands can regulate iron-binding proteins like lactoferrin and
> transferrin [PMID 12151626] but, by and large, I can find no evidence
> this relation****p has been thoroughly explored in humans.
>
> Fasting and calorie restriction elevate PPARalpha and carnitine
> concentrations. =A0Carnitine is needed for butyrate uptake and butyrate
> activates the FoxP3 gene needed for Treg function. =A0This is probably
on=
e
> reason fasting improves autoimmune conditions. =A0What's the effect of
> anemia on =A0carnitine content and/or PPARalpha? =A0Carnitine does
improv=
e
> EPO response [PMID 17962380], partly via HO-1. =A0Does it reduce the
> mortality associated with treating an adaptive anemia response to
> chronic disease? =A0Does EPO deplete carnitine in some manner when it's
> causing adverse events? =A0There's something going on here but it's not
> clear to me what it is.
>
> I think one of the places you want to keep your eye on is dermatology. =
=A0
> The skin is the easiest body barrier to study and experiment with and
> usually the most neglected. =A0Its study is often regarded as a mere
step
> up from cosmetic surgery, so in terms of a ****tfolio investment model
> for research, results from an inexpensive investment there can be highly
> profitable. =A0HIF-1a has recently been found to be im****tant to hair
> growth and cathelicidin defects play a wide range of roles in rosacea,
> psoriasis and acne. =A0I also suspect a role for cathelicidin in
baldness=
,
> an autoimmune condition which involves mast cell infiltration. =A0Hair
> follicle organs themselves contain some of the fastest dividing and
> self-renewing pluripotent stem cells in the human body. =A0Each organ
> recapitulates all the signals involved in the entire HPA axis and they
> are constantly regenerating the microvascular network around themselves.
=
=A0
> Something interesting always keeps popping up in the skin literature.
>
> Consider the role diet plays in chronic illness, especially if the gut
> barrier is leaky. =A0I've had to eliminate red meat from my diet.
=A0Live=
r
> is particularly bad. =A0The rich heme content does oxidize the gut
lining
> but red meat also contains opioid ligands. =A0Even on low-dose
naltrexone=
,
> I still have to avoid all the foods processed by digestion into natural
> opioids - red meat, wheat, milk (casein), rice and spinach. =A0I've also
> improved since avoiding turkey, I think because of its tryptophan
> content. =A0IDO degrades tryptophan and is activated by butyrate/HDAC
> inhibition. =A0Certain infections are known to manipulate IDO expression
> to their advantage.
>
> Have you considered that EPO might be damaging in mild anemia because it
> improves insulin sensitivity? =A0A course of EPO ameliorates insulin
> resistance, for instance decreasing plasma cell membrane glycoprotein 1
> (PC-1) expression to normal values [PMID 15209435]. =A0Yet, insulin
> resistance can be a protective strategy in the body, limiting the entry
> of insulin into cells and managing oxidative stress. =A0I'm not sure but
=
I
> think there may be something of interest in the DAF-16 fruit fly studies
> of longevity or the new IRS1(-/-) mouse [PMID 17928362]. =A0Female
> IRS1(-/-) mice are longer lived despite mild insulin resistance. =A0
> Lowering signaling through IRS2 can also enhance murine lifespan by 18%.
=
=A0
> Mice with specific IRS2 knockdown in the brain are overweight,
> hyperinsulinemic and glucose intolerant but more active compared to
> control mice, have greater glucose oxidation and have stable SOD2 levels
> in the hypothalamus during meals [PMID 17641201]. =A0The information on
> insulin sensitivity and human longevity is complex and the field is
> filled with controversy [PMID 18672019]. =A0Insulin resistance may
> represent an ongoing evolutionary adaptation that is shuffling resources
> away from muscles to the brain and from large numbers of cheap offspring
> to limited numbers of children requiring a greater investment [PMID
> 17437648].
>
> I haven't figured out yet where to stick this last bit of information. =
=A0
> Heparanase is an endo-beta-d-glucuronidase necessary to angiogenesis.
=A0
> Heparanase is overexpressed in the G.I. tract of Crohn's patients and
> Crohn's patients often benefit from heparin therapy, which inhibits
> heparanase. =A0There is a tantalizing allergy therapy that uses
> beta-glucuronidase injections coupled with antigens to induce tem****ary
> tolerance (of which there is almost nothing said in the online research
> literature). =A0I'm missing one or two links in the middle but I'm sure
> this set of facts is connected somehow and HIF-1a may be involved.
"What are the long-term consequences of anemia? There has long been
evidence that mild iron deficiency reduces neurodegenerative risk and
lengthens lifespan. Several life extensionists give blood on a
regular
basis for this reason. "
One needn't go anemic (hematocrit <35%) to receive the benefits
discussed. Phlebotomies, monitored by hematocrit testing, can safely
keep one in a range of subclinical lower hematocrit (35-39% men,
35-37% women), putting a constant pressure on the body to produce more
red blood cells and deny extra iron to storage in lysosome, in
hemosiderin, and as labile iron that can be involved in damage and
disease.
For example, my hematocrit is normally 41-42%. Each unit of blood
donation lowers it by 3%. Red Cross will not accept donations with
predonation crit below 38. So a donation will never take me below 35%.
If one keeps donating every 8 weeks, sooner or later they will use up
all stored iron and not be able to reach 38%. At this point they will
be deferred from donation and can try again in a a couple of weeks. As
soon as they reach 38 they can donate again, thus staying at a
slightly subnormal hematocrit, but not with too low a blood count that
causes them problems.
I have given 11 units on an 8 week period, still have 42 crit, so the
iron is still coming out, age 55. An elderly person of age 70+ may
have to unload 25 units or more to eliminate the iron stored up over a
lifetime. BTW, my ferritin became subnormal after the 3rd unit and
stayed that way, demonstrating ferritin is a useless marker for the
total amount of stored iron in the body. This iron is in long term
storage - hemosiderin, in lysosomes, and it can be mobilized and
removed, but only by making new red blood cells which is done only by
bleeding.
UK Red Cross only allows donations at 16 week periods, so for some
regions and for those ineligible to donate, phlebotomies in the
doctor's office are required. In this case, one can be bled down 500
cc every 2-4 weeks comfortably, achieving the goal of slightly
subnormal hematocrit quickly. Maintenance is the same as with the Red
Cross, rebleed as soon as one reaches 38-41 men, or 38-39 women.
Each one will vary with their comfort level at lower hematocrit, but
as long as crit is kept 2-3% lower than their baseline, any spare iron
will be used in producing new cells eg someone with 45 normal crit may
only need to keep levels to 42 to hold this iron reduction pressure.
However, if one is comfortable with a hematocrit of 35-38, then
negligible iron body stores are assured. If that is too low to be
comfortable for the level of physical activity required, then one can
hold crit higher, but needs to be 2+% below lowest recorded baseline
all the time.
JLC
|
