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From: B. Harris)
Subject: Re: Gamma-tocopherol
Date: 16 Apr 1997

In <01bc4a7f$93f76fa0$> "Martin
Banschbach" <> writes:

>Steve Harris:
>>    And if you believe the epidemiology, vitamin E supplements (alpha)
>> DO lower it.
>Yes, but not as well as the natural tocopherol mix does.

    Remains to be proven, of course, but I agree that this is the way
to bet (and I take, in the meantime, an E supplement with as much mixed
tocopherols in it as I can find).   Agree with you also that dietary E
effects on heart disease risk, when found, might just as well be gamma

>>    But that's not to say that there may not be worthwhile gamma
>>[tocopherol] effects for cancer, reperfusion injury, and septic shock
>>(where peroxynitrite has more of a pathogenic role).
>>                                            Steve Harris, M.D.
>You forgot chronic infection Steve.  Remember the C-reactive peptide data?
>Marty B.  "You are what you eat"

    I remember them, but that's chronic inflammation (which may or may
NOT be due to infection-- hasn't been proven).  The body is not all
knowing, and remember that chronic inflammation is also a result of
chronic injury.  In this case, you want to damp it down as much as you
can.  However, when it's a result of chronic infection, you are walking
a VERY fine line between damage due to the immune response, and damage
due to the organism, which inflammation fires the immune response
against.  Nature didn't make WBCs put out O2- and NO. and .O2NO- just
to make you age faster and hurt more!   These "nasty" chemicals one and
all serve a PURPOSE, not just for killing microbes, but for signalling
that microbes there there to be killed.  Interfere with this process at
your own peril-- for all the pain and damage you prevent, you also
screw up your own defense against germs.   In fact, I'm beginning to
wonder now at the immune stimulant properties of alpha-tocopherol.
Antioxidants are quite often immune suppressants, and indeed even
alpha-tocopherol at very large doses IS.  So how do more modest doses
stimulate the immune system?  One possibility is that they do so
PRECISELY by suppressing gamma tocopherol suppression of peroxynitrite
production.  THAT revs up inflammation against microbes where you want
it revved up.

   Now what about the inflammation associated with atherosclerosis.
Well, if it's not associated with an infection that needs to be fought,
it would be a good idea to damp it down by stepping on all the radicals
being made.  And antioxidants, as you know, interfer with many other
steps in atherogenesis, from platelet sticking to LDL modification.
But suppose (just suppose) that that protein C in atherogenesis is a
marker for suppression of something like CMV infection, which needs to
be done.  What happens if you screw this up?  You might get worse
problems.  Remember, Keshon cardiomyopathy, as we now know, is a result
of immune failure against a virus, due to lack of GSH, in turn due to
lack of Se.  It's quite possible that immune failure induced by TOO
much antioxidant activity might have similar nasty effects in the
cardiovascular system.  There are no guarantees until the research has
been done.  The idea that antioxidants are always good for you in any
amount, it a little simplistic.

                                              Steve Harris, M.D.

From: B. Harris)
Subject: NAC is Antiinflammatory, not Necessarily Immunosuppressive
Date: 24 May 1997

In <> "W. Fred Shaw" <>

Another George Carter Kervorkian favorite (NAC) bites the dust.

The Journal of Immunology: Volume: 158 Number: 11 Pages: 5418 -
5423 June 1, 1997

N-Acetylcysteine and alpha-Tocopherol Reverse the Inflammatory
Response in Activated Rat Kupffer Cells

   Comment: as George would be the first to tell you (listen to
him and you might learn something), the paper says nothing about
NAC and its role in AIDS.

   For those reading along who are educatable (may or may not
include F. Shaw), a little bit of annotation is in order.
"Inflammation" is a very large set of tissue changes which are
the body's chief response to infection and injury.  These effects
cause tissue changes which are quite familiar to any reader as
the four ancient signs of disease: rubor, calor, tumor, and dolor
(redness, heat, swelling, pain).  All of this is basically
triggered by a combination of breakdown products in damaged
tissue and bacterial wall molecules in infected tissue.  These
result in free-radical production, and triggering of immune
cells, respectively.  The immune cells in turn make more free-
radicals (which act as immune signals also), and lots of specific
protein signal molecules, too (interleukins, etc).   All these
cause other cells to change form and function in affected
tissues.  As a result of such changes, blood vessels dilate and
circulation increases (causing redness and heat), and capillaries
leak fluid into the tissue (causing swelling).  Certain cells
make bradykinins and substance P, which cause direct pain on
contact with nerves.

   The kind of response you see in the average badly sprained
ankle is the result.  As noted, this type of thing has three
major functions: 1) pain and swelling immobilize the tissue and
discourage further use and damage for a while.  2) Increased
circulation and other signals draw resources for healing, and
trigger fibroblasts to get to work repairing damage.  Finally, 3)
the increased circulation and free radicals draw neutrophils and
lymphocytes, which kill bacteria directly by eating them, and
also indirectly by pouring out toxic contents into the tissues--
a little like the Russian scorched-earth retreat before
Napoleon's and later Hitler's invading armies.

   This natural response works (obviously), but it's not perfect.
As a gerontologist who is also interested also in resuscitation
technology, I continually come up against several similar
problems in both my clinical work in humans and my research work
in rodents and canines:

1) Evolutionary mechanisms act on behalf of the problems of young
organisms, and ignore or malrespond to the problems of non-
reproductive older ones (for obvious reasons).  Thus, evolution
has designed inflammation (a marker for which is pain) to assume
that the inflamed tissue will heal eventually, after which the
inflammation turns off.  But what if the tissue is too old to
heal, or the damage is degeneration caused by wear and tear, as
on a joint or tooth?  In that case, it never will heal, and the
inflammation, which evolution has made no provision to turn off
if ineffective, will continue.  When this happens, the organism
experiences inflammation and pain for no particularly good
reason, and not only is this annoying, but the chronic
inflammation causes damage, which then results in further
inflammation.  A vicious cycle.

2) Evolutionary mechanisms don't know about antibiotics.  And
since inflammation does cause tissue damage, it sometime happens
that "unneeded" levels of inflammation in an infection that is
being dealt with by antibiotics, are as much of a problem, or
more of a problem, as damage caused by the infecting organism
itself.  An example is meningitis in children, where mortality is
improved in antibiotic treatment by giving steroids, which are
immune suppressive.  Much of the brain damage in antibiotic
treated bacterial meningitis in children is caused by
inflammation itself.

  A related problem is that evolution doesn't know when more
inflammation is a lost cause:  Spread of bacteria through the
body via the blood stream can result in an inflammatory response
throughout the body.  This can cause enough vasodilation to drop
blood pressure and stop the heart (septic shock).  Obviously this
is evolutionarily not a good response, but evolution has not
prepared any special cutoff for inflammation this widespread,
since without antibiotics it isn't survivable anyway.  Today,
with antibiotics, we'd like to stop it.  WE can kill the bac-
teria, if only we can let the body know not to destroy itself
trying to do the entire job by itself.

  The above problems also apply to widespread inflammation in
trauma.  For instance, there are inflammatory processes
triggerable in brain tissue, probably meant to help heal very
minor brain traumas.  When the brain is without blood flow for a
couple of minutes, however, all these processes are triggered
willy-nilly in the entire brain, resulting in larger blood flows
over the entire cortex, then swelling/edema which cuts off blood
flow (because the skull prevents brain expansion, so pressure
rises).  The result is brain death, something that happens
because mother nature has made no provision for return of brain
blood flow after circulatory arrest has occurred (evolution
doesn't "know" about CPR or heart-lung machines).  It is NOT true
that the brain "dies" after 6 minutes without blood flow.
Rather, times longer than this result in an inflammatory brain
response (including neurotransmitter cascade injury, which is a
special brain inflammatory response), which only later (hours to
days) causes brain death.  Block these events and resuscitation
becomes possible even after 15 minutes of clincal death at 37.5 C
(limits still being explored).

   The upshot of all this is that the proper amount of
inflammation in any severe medical problem is a horribly
complicated question, but it is NOT something that can
reflexively minimized or maximized.  Rather, it's a Goldilocks
problem.  You want not too much inflammation (since it causes
damage), but want also not too little (since it helps with
infection and healing).  And the optimal amount of inflammation
that is just right changes day by day, and is a function of other
treatments, and how well the body is doing in its battle.  Even
in traumatic inflammation, such as hypoxic brain injury,
interfering with the inflammatory cascade has problems, because
it *predisposes* to infection.

    For example, in a recent trial we resuscitated a dog success-
fully from 14.5 minutes of circulatory arrest and clinical death
at 37.5 C, only to have the animal die the next day of fulminant
aspiration pneumonia and sepsis, with a temp of 110 F reached in
less than 12 hours (this despite full and broad spectrum antibio-
tic coverage from the beginning of the procedure).  At autopsy
the combination of petechial hemorrhage with little inflammation
looked more like descriptions of Ebola than standard bacterial
sepsis.  Our drugs worked a little too well.  On the other hand,
animals in which we've avoided infection have done perfectly well
on inflammatory suppression, with normal behavior and learning,
when they should be brain-dead after such a severe ischemic

   The doctors of the future, as they gain better and better
control over inflammation-- a final common pathway of damage in
aging, trauma, and ischemia-- will be continuously facing the
consequences, in terms of loss of resistance to infection.

    Many of the considerations above apply to AIDS, in which
damage in infections may be done by inflammation itself (steroids
are helpful in PCP, as in childhood meningitis), but some
inflammation is obviously needed for an effective immune
response.  In addition, in AIDS things are made even more
complicated by the fact that activation of lymphocytes during an
immune response allows replication of the HIV virus.  Immune
modulation in AIDS is thus a double-edge sword in two ways (this
is true even of just cellular immune system modulation).

   Finally, the role of glutathione itself is peculiar in AIDS.
This molecule acts as an intermediate in the triggering of the
immune response by free radicals, as it triggers lymphocyte
activation and division after being itself triggered in
production by oxidation.  At the same time, glutathione
paradoxically inhibits HIV production in lymphocytes.  Is raising
glutathione in AIDS a good things to do?  Probably, but we still
don't know.  Looking at glutathione's role in modulating
inflammation in other processes (as in the paper above) won't
tell us, because the situation is too complicated.  Only somebody
like Fred Shaw could look at a paper like the one above, and
think he knew more about glutathione and AIDS than he did before.

                                Steve Harris, M.D.

From: B. Harris)
Subject: Re: arachidonic acid:  Where?
Date: Mon, 17 Nov 1997

In <>
(Syd Baumel) writes:

>This surplus of AA -- in conjunction with the unnatural paucity of
>linolenic acid-rich foods in the typical modern diet (and the shortage of
>long chain omega-3's in the diets of people who skimp on coldwater fish
>or seafood) -- has been blamed for many modern health evils by fat savvy
>scientists such as David Horrobin, Donald Rudin, and H. M. Sinclair.
>Unopposed by omega- 3's, the excess of AA results in a relative excess of
>2-series prostanoids (prostaglandins etc.), which tend to be inflammatory
>and thrombotic, and which have been strongly associated with anxiety and
>depression too (prostanoids are hormone-like biochemicals that only
>influence tissues/organs in their immediate vicinity). Apparently
>(according to a 1983 paper anyway) human adults are wired to make very
>little AA from its precursor dihomogammalinolenic acid (DGLA) (which we
>make from dietary linoleic acid), preferring instead to use the DGLA to
>make 1-series prostanoids, which are mood-elevating, antithrombotic "good
>guys." Possibly the high AA diet is saddling many people with a load of
>2- series prostanoids they weren't designed to handle, especially if
>counterbalancing omega-3's are in short supply (there's no shortage of
>the 1-series' father in our diet).

   I think we need to have a more balanced view of all this, however.
It's not like 2-series prostaglandins are evil and 1 and 3 series are
good, and that's the end of it (I'm in mind of the Pearson and Shaw
series of angels and devils in describing these systems).  The 2 series
is more closely involved in inflammation (infection control, etc) and
injury repair, is all.  For most causes of mortality before the age of
40, and indeed for most causes of mortality for most of humans through
most of history, this is the system you need.  Don't knock it.

   It's only with out modern sedentary lifestyles, sanitation,
antibiotics, and focus on age-related diseases that the other series of
prostaglandins begins to look better.  And, I agree that these are the
ones that need upregulation after 40.  Middle aged and elderly people
tend to clot up when they shouldn't, whereas younger people need all
the hemostasis and inflammation they can get.  But pleiotropic actions
of systems is an old story in evolutionary biology and medicine.  If
you find that what is good for you at 20 is no longer such a good thing
at 60, that doesn't mean that somehow your entire society has launched
into some conspiracy to feed you the wrong stuff.  Rather, it means
that what is the wrong stuff at a modern 60 is the right stuff for a
paleolithic 20, and that's what you're genetically engineered to like
(since nature cares more about your fitness at 20 than 60), and
therefore that's what your capitalistic economy, which provides what
people like, gives you.  Simple as that. <g>.

                                         Steve Harris, M.D.

From: B. Harris)
Subject: Re: arachidonic acid:  Where?
Date: Tue, 18 Nov 1997

In <3471DEEF.85C71242@notarealaddr.ess> Brian Manning Delaney
<bmdelaney@notarealaddr.ess> writes:

>> It's only with out modern sedentary lifestyles,
>> sanitation, antibiotics, and focus on age-related
>> diseases that the other series of prostaglandins
>> begins to look better. And, I agree that these
>> are the ones that need upregulation after 40.
>I wonder, though, what elderly EPA chompers are doing to
>their stroke risk (plus there's the prob of potentially
>delayed wound-healing, etc. -- nothing to worry about for
>most people, moi). I don't want to make too much of the
>epidemiological data on some heavy fish eaters, who suffer
>fewer heart attacks, but have more strokes (Medline ID:
>96165427) Other factors could be at play there. But I don't

   They have more hemorrhagic strokes, sure-- but more strokes overall?
 I doubt it, since the thrombotic kind are by far the most common.  You
probably can't increase one without decreasing the other.  However, you
can more easily make sure that the major risk factor for the
hemorrhagic kind (high BP) is controlled, than you can make sure that
all the multiple risks for thrombotic strokes are fixed.

   The piping gets rusty more often than it bursts.

                                     Steve Harris, M.D.

From: B. Harris)
Subject: Re: Too FEW free radicals?
Date: 14 Aug 1998 19:16:26 GMT

In <6r1l96$jkn$> writes:

>> So if these free radicals do play important roles, could it possibly be
>> that when *some* of us ingest too many anti-oxidants, we don't have
>> ENOUGH free radicals?  Perhaps we need a particular level or balance of
>> these things, and some of us need to avoid too many antioxidants?
>> Jeanette
>This is a very important topic and I sincerely hope that a person like
>Tom Matthews of LEF or others with knowledge about this would respond to
>your posting. I have also read about the immune cells using free radicals
>as weapons to fight off bacteria and viruses. Come on you anti-oxidant
>experts, lets have some answers on this!
>Ole ALstrup

   I don't have the answers-- these experiments involve challenging
animals with live viruses, etc, and are difficult to do.  Which is why
they haven't been done.  In some ways, life span experiments, in which
animals are housed AWAY from all infective agents, and either starved
or supplemented with radical scavengers, are easier.  But that's not
the real world.

   We know that some antioxidants (vitamin E) has an immune boosting
range (up to about 400-800 IU/day), and above that, an
anti-inflammatory range, which presumably would damp down infection
fighting capacity.  But the last is hard to prove.  And complicating
all of this is the fact that sometimes we WANT to tone down the body's
immune response to bacteria, if we are doing some of the job with an
antibiotic, since the immune response itself does damage.  The body,
ie, evolution, doesn't know we're in there helping, and sometimes needs
to be reminded not to be such a tiger.  OTOH, with many viruses and
perhaps also antibiotic resistant organisms, you might have to let the
body do all it can.

   This is going to be a VERY important topic in medicine over the next
few decades.  With nitric oxide sythesis blockers and new kinds of
NSAIDS and leukotriene modulators (not to mention all these good
vitamins, melatonin, etc, etc) we are going to gain an unprecidented
control over of the inflammatory response, and use it to control much
of the damage that results from ischemia and trauma, and even some of
the consequences of aging (which involve secondary inflammation after
damage is spontaneously done in aged tissues by simple mechanical
failure).  But the price we pay will be impaired ability to fight
infection.  That's not going to be a fun or easy trade-off.

                                      Steve Harris, M.D.

From: B. Harris)
Subject: Re: Genistein and blood clotting
Date: 28 Mar 1999 15:26:41 GMT

In <> Tom Matthews <> writes:

> wrote:
>> LEF's (The Life Extension Foundation) cancer protocol includes soy
>> extract product called Megasoy (700mg) which has very high genistein
>> content. The recommended daily dose provides approximately 2800 mg of
>> genistein. On the LEF's web page
>> there is the following warning:
>>     "Soy genistein may inhibit an enzyme that breaks down
>>     cyclooxygenase-2 (Cox-2). Cox-2 causes excess production
>>     of prostaglandin E2 in the body. Prostaglandin E2 can promote
>>     cancer cell growth and induce abnormal blood-clotting. Cancer
>>     patients should take a baby aspirin with their heavy meal
>>     each day to inhibit Cox-2. Other Cox-2 inhibitors include
>>     a daily dose of fish oil providing 2,400 mg of EPA and 1,800 mg
>>     of DHA, 2,000 mg of ginger extract, and 6,000 mg a day of garlic."

    This appears to be garbled somewhere.  COX-2 is not an enzyme that
breaks down cyclooxygenase.  COX-2 is one isoenzyme of cyclooxygenase,
which converts unsaturated fatty acids to prostaglandins.  Your body
contains COX-1 and COX-2, but in normal health there isn't much COX-2
activity except in kidneys and brain.  In inflammation, COX-2 is
inducibly expressed (it's the form of the enzyme that the body makes
more of, in order to increase inflammation, since most of the
prostaglandins produced by this enzyme, on AVERAGE, are inflammatory).
You don't take a baby aspirin to inhibit COX-2.  Platelets contain
COX-1, and they are the only cells permanently affected by such small
amounds of aspirin (your endothelial cells may be temporarily affected,
but they contain no COX-2 either, unless you have some kind of
endothelial disease).

   I know of no difference in the kinds of prostaglandins produced by
COX-1 vs. COX-2.  The only importance in the distinction between the
two iso-enzymes is where they are.  COX-1 is the enzyme in the normal
stomach, and it produces prostaglandins which are needed for stomach
production of mucus and protection from acid (this is not the only
mechanism).  That is why COX-2 inhibitors (such as the new drug
Celebra) are gentler on the stomach.  Fish oil, so far as I can tell,
inhibits neither COX-1 nor COX-2.  It is simply that the 3-series
prostaglandins produced by the action of these enzymes ON the fatty
acids (EPA, DHA) in fish oil are, ON AVERAGE, less inflammatory than
those 2-series prostaglandins produced by these enzymes from

                                         Steve Harris, M.D.

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