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ironjustice:
I am wondering if anyone has followed up on the theory of iron overload PREceding the thalassemia and its' contributing to the CAUSE of thalassemia as opposed to a SECONDARY result OF the thalassemia .. ?
As is evidenced in these two articles in which the lowering of the iron seems to lead to significant recovery in closely related disease states .. ?

"Complete recovery after iron chelation in aplastic anemia"

They treated this kid for five years .. aggressively .. and when and
ONLY when the kid was failing DUE TO their interventions / iron
buildup .. did they finally cure the kid / chelated the iron.

Removed the iron **totally** ..
IE: targeted the iron .. and the kid was cured.
---------

Complete hematopoietic recovery after continuous iron chelation
therapy in a patient with severe aplastic anemia with secondary
hemochromatosis.
Park SJ, Han CW
J Korean Med Sci 2008 Apr; 23(2):320-3.

A 16-yr-old male patient with hemochromatosis due to multiple packed
red blood cell transfusions was referred to our emergency center for
the treatment of severe aplastic anemia and dyspnea.
He was diagnosedwith aplastic anemia at 11-yr of age.
He had received continuous transfusions because an HLA-matched marrow
donor was unavailable.
Following a continuous, approximately 5-yr transfusion, he was noted
to develop hemochromatosis.
He had a dilated cardiomyopathy and required diuretics and digitalis,
multiple endocrine and liver dysfunction, generalized bleeding, and
skin pigmentation.
A total volume of red blood cell transfusion before deferoxamine
therapy was about 96,000 mL.
He received a regular iron chelation therapy (continuous intravenous
infusion of deferoxamine, 50 mg/kg/day for 5 days q 3-4 weeks) for
approximately seven years after the onset of multiple organ failures.
His cytopenia and organ dysfunctions began to be gradually recovered
since about 2002, following a 4-yr deferoxamine treatment.
He showed completely normal ranges of peripheral blood
cellcounts, heart size, and liver function two years ago.
He has notreceived any transfusions for the last four years.
This findingsuggests that a continuous deferoxamine infusion
may play a role inthe immune regulation in addition to iron
chelation effect.

Journal of Korean medical science
[J Korean Med Sci]

---------

"Iron restriction healed a leg ulcer."

Improvement of sickle cell anemia by iron-limited erythropoiesis.
Castro O, Poillon WN, Finke H, Massac E.
Center for Sickle Cell Disease, Howard University College of
Medicine,
Washington, D.C. 20059.
Am J Hematol. 1994 Oct;47(2):74-81. Links
Comment in:
Am J Hematol. 1995 Sep;50(1):68-9.

We report the hematologic and clinical features of four adult
patients
(Pts.) with sickle cell anemia and iron-limited erythropoiesis.
Two of the Pts. had spontaneous iron deficiency (chronic GI bleeding,
low-grade hemoglobinuria).
In the other two Pts. iron restriction was induced by periodic RBC
aphereses as part of a pilot protocol designed to decrease
intracellular HbS polymerization by MCHC reduction.
Iron-limited erythropoiesis was defined by reduction in red cell
indices (MCV range 60.4-67 fl) in the presence of low serum ferritin
(range < 10-20 ng/ml).
In these Pts. iron restriction did not cause clinically significant
worsening of the anemia (Hb 7.8-9.0 g/dl).
In two Pts. the anemia actually improved.
Other hematologic effects of iron restriction were: decreased MCHC,
reticulocyte count, RDW, and dense cells.
A reduced hemolytic rate was suggested by a lowering of serum
bilirubin and LDH.
In one of the Pts. the 51Cr RBC T1/2 survival increased from 12 to
16 days.
The intracellular HbS polymer fractions (fp) were determined at 25% O2
by Csat and with the use of the conservation of mass equation.
The baseline fp values ranged from 0.48-0.53.
After iron restriction they ranged from 0.33-0.48.
The fp decreased even though iron-limited erythropoiesis also lowered
the Hb F concentration in three of our Pts.
In one of the two Pts. with induced iron depletion, hospitalization
days for pain crises decreased from an average of 4.5 days/month (2
year baseline period) to an average of 0.5 days/month in the 3 year
follow-up after iron depletion.
The second patient with induced iron restriction experienced the rapid
healing of a leg ulcer.
Controlled iron restriction should be explored as a therapeutic
strategy in selected SS patients.

PMID: 7522396

ironjustice:
They have some real results with the oral chelator .. hydroxyurea .. and sooo again gives evidence of the iron PREceding the anemia .. ?

Oral liquid hydroxyurea promising for long-term use in babies with
sickle cell anemia
17 Jun 2005

Treating babies who have sickle cell anemia (SCA) with oral liquid
hydroxyurea appears to prevent the onset of long-term complications
triggered by this disease, according to results of a preliminary study
by investigators at St. Jude Children's Research Hospital.


The study's findings are important because the onset of damage caused
by SCA complications can occur as early as three months after birth.
Starting treatment before those complications begin could dramatically
reduce the chance of organ damage and premature death. A report on the
study appears in the June 14 online edition of Blood.


In SCA, a genetic mutation causes oxygen-carrying protein hemoglobin
(Hb) to form rigid cords in red blood cells, causing the cells to take
on a bent, sickled shape. The sickled cells clog small blood vessels,
causing pain and serious damage to the brain, kidneys, spleen and other
organs; and the subsequent premature death of the abnormal red cells
causes anemia. In the United States, SCA is found mostly among African
Americans.


Hydroxyurea increases the production of fetal hemoglobin (HbF), the
main oxygen transport protein in fetal red blood cells. Because HbF
prevents red blood cells from "sickling," clinicians have used
hydroxyurea for about a decade to reactivate HbF production in adults
and older children with SCA. In addition, hydroxyurea reduces the
severity of symptoms suffered by adolescents and adults with SCA, such
as lung infections, organ damage, stunted growth, impaired brain
development and acute chest syndrome (ACS). ACS refers to an infection
in the lungs that causes difficulty breathing, pain and other symptoms
and can be fatal.


The current St. Jude study was an extension of a previous clinical
trial, Hydroxyurea Safety and Organ Toxicity (HUSOFT), which was the
first in which young babies were treated with hydroxyurea. The original
HUSOFT study, published in 2001, demonstrated that short-term oral
liquid hydroxyurea therapy can be safe and effective in babies with
SCA. In the extension study, these infants were followed for up to six
years of therapy.


"Our results are promising and justify a larger multicenter clinical
trial to confirm that treating babies with hydroxyurea is safe and
effective," said Jane S. Hankins, M.D., a physician at the St. Jude
Comprehensive Sickle Cell Center and the study's lead author. "If a
larger trial supports our observations in the HUSOFT Extension, the
treatment of sickle cell anemia will undergo a significant change."


"This study is particularly encouraging because it suggests that we
can treat babies with hydroxyurea for several years without side
effects serious enough to limit the use of this drug," said Winfred
Wang, M.D., St. Jude Comprehensive Sickle Cell Center director. "Our
aim is to make sickle cell anemia a survivable disease that doesn't
significantly reduce a person's quality of life." Wang is the senior
author of the paper in Blood.


A two-year pilot study of 21 babies with SCA, the original HUSOFT was
designed to examine the feasibility of treating infants with liquid
hydroxyurea; to determine the toxicity of this drug in babies; to
assess hydroxyurea's effects on fetal Hb levels; and to observe if this
treatment could preserve spleen function. Patients received 20
milligrams/kilgrams of body weight/day (mg/kg/day) of hydroxyurea. All
21 patients who completed the initial study were enrolled by their
parents into the HUSOFT Extension study. In that study, the dose of
hydroxyurea was elevated from 20 to 30 mg/kg/day for an average of 4.0
years (range 2.1 - 6.0 years).


The aim of the HUSOFT Extension was to determine if this higher dose,
given for an extended period of time, provided significant long-term
benefits without causing unacceptable side effects in children ranging
in age from 2.6 to 4.4 years (median age 3.4 years).


After four years of hydroxyurea therapy, the concentrations of Hb, HbF
and the volume of red blood cells were significantly increased in the
children receiving hydroxyurea. Moreover, the HbF level often exceeded
20 percent of the total amount of Hb, Hankins said. "In children who
weren't treated with hydroxyurea, the level of HbF declined
significantly," she added. "The fact that HbF levels rose in babies
treated with hydroxyurea suggests that the drug is effective in babies,
as well as in adolescents and adults."


Babies receiving hydroxyurea also weighed more and were taller than
those untreated children 2 to 5 years old who had been observed in a
previous, long-term national study called the Cooperative Study for
Sickle Cell Disease. The average weight gain for babies in the St. Jude
study was more than 4.5 pounds per year; and the gain in height was
more than 3 inches, the researchers report.


"Hydroxyurea could also prove to be an effective way to improve the
care of sickle cell anemia patients who live in underprivileged areas
of the world," said Russell E. Ware, M.D., Ph.D., director of the
Hematology division of the Department of Hematology-Oncology at St.
Jude. "Treatment with hydroxyurea requires periodic checkups, but the
medication is relatively inexpensive and should be adaptable to
countries with limited resources," he said. Ware is a co-author of
the paper.


Other authors of the article include Zora Rogers (University of Texas,
Dallas); Lynn W. Wynn, MSN, PNP, CCRP (St. Jude); Peter A. Lane (Emory
University, Atlanta, GA); and J. Paul Scott (Medical College of
Wisconsin, Milwaukee).


This work was supported in part by a General Clinical Research Center
grant and ALSAC.


St. Jude Children's Research Hospital


St. Jude Children's Research Hospital is internationally recognized for
its pioneering work in finding cures and saving children with cancer
and other catastrophic diseases. Founded by late entertainer Danny
Thomas and based in Memphis, Tenn., St. Jude freely shares its
discoveries with scientific and medical communities around the world.
No family ever pays for treatments not covered by insurance, and
families without insurance are never asked to pay. St. Jude is
financially supported by ALSAC, its fund-raising organization. For more
information, please visit http://www.stjude.org.


Contact: Carrie Strehlau
carrie.streh...@stjude.org
901-495-2295
Marc Kusinitz, Ph.D.
marc.kusin...@stjude.org
901-495-5020


St. Jude Children's Research Hospital
http://www.stjude.org


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


Prevention of sickle cell crises with multiple phlebotomies.
Bouchair N, Manigne P, Kanfer A, Raphalen P, de Montalembert M, Hagege
I, Verschuur A, Maier-Redelsperger M, Girot R
Service de pediatrie, CHU,
Constantine, Algerie.


OBJECTIVES:
Sickle cell disease patients suffering from frequent painful crises
were submitted to phlebotomies in order to reduce hospitalization days
due to pain, through hemoglobin (Hb) level reduction and iron
deficiency in patients with an hemoglobin level equal to or above 9.5
g/dL.

PATIENTS:
Seven sickle cell disease patients (four SC, three SS), aged four to 24
years, were submitted to sequential phlebotomies during periods from 18
months to four years.

METHODS:
The number of hospitalization days for crises was considered.
The volumes and frequencies of phlebotomies were adjusted according to
the patients ages, the hemoglobin concentrations and the serum ferritin
levels.

RESULTS:
One hundred and forty-four hospitalization days were recorded in the
seven patients in the year preceding the treatment.
During the study period, the annual numbers of hospitalization days
were respectively 20, five, six and one.
Mean hemoglobin concentration was 10.7 g/dL before phlebotomies and 8.8
to 9.2 g/dL during the four years of treatment.
Mean corpuscular volume, mean corpuscular hemoglobin concentration and
serum ferritin were also reduced.
The volume of phlebotomies was 116 to 39 mL/kg/year according to the
patients.
COMMENTS AND CONCLUSION:
The striking decrease of the number of hospitalization days for all the
patients suggests a closed relationship between therapy and clinical
improvement.
The mechanism of this effect is probably multifactorial:
a) the concentration of Hb level is known to influence the blood
viscosity and its decrease always improved rheology in sickle cell
disease patients;
b) the mean corpuscular hemoglobin concentration is a critical factor
concerning the HbS molecule polymerization in sickle cell disease, and
its slight reduction may have an important biological effect.
We observed these two biological modifications in our patients and
suggest that they mediate the clinical effects.
The iron deficiency induced by phlebotomies has no evident deleterious
consequence either on height and weight in the children or on
intellectual performance in any patients.


Publication Types: * Clinical trial
PMID: 10761600, UI: 20224666
--------

Promising New Class of Antibiotics Causes Bacteria
to Commit Suicide
By Stuart Fox
Posted 12.17.2009

As bacteria continue to grow more resistant to a wide
range of antibiotics, doctors are searching furiously
for better ways to kill infectious microbes.
Enter hydroxyurea.
Researchers at MIT and Boston University have discovered
that hydroxyurea, normally a drug prescribed for
sickle-cell anemia or psoriasis, also causes bacteria to
create their own poisons and kill themselves.


In all cases, hydroxyurea prevents DNA transcription.
When used to treat psoriasis or sickle-cell anemia,
hydroxyurea simply slows down the production of sick
cells.
But when used against a bacterium, the cessation of
DNA transcription begins a chain reaction that ends
with the bacterium producing hydroxyl free radicals.
Those free radical are like molecular buzz saws, and
they quickly chop the bacterium apart from the inside
out.
In fact, many antibiotics currently in use also kill
bacteria by inducing hydroxyl free radical production,
but hydroxyurea does so in a totally novel way.
Thus, no bacteria on Earth has evolved any resistance
to it.
That lack of resistances means hydroxyurea can serve
either as an antibiotic on its own, or as a helper to
other, more widely resisted, antibiotics.


And with multiple-drug-resistant bacteria becoming a
bigger and bigger problem, any help is welcome.


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


Iron chelators hydroxyurea and bathophenanthroline
disulfonate inhibit DNA synthesis by different pathways.
Biochemistry and molecular biology international
1994;34(2):273-9.
1994: Alcaín F J; Löw H; Crane F L; Navas P
We previously showed that thrombin-stimulated DNA synthesis
in CCL 39 cells was inhibited by hydroxyurea (HU) and
bathophenanthroline disulfonate (BPS)
(Proc. Natl. Acad. Sci. USA, in press).
A clear difference exists between these two inhibitors.
Inhibition mediated by HU was immediate and must be present
in the culture medium.
BPS was equally effective when it was present in the medium
or after preincubation, but it required at least 12 h to
achieve maximal effect.
The permeable form 1,10 phenanthroline had the same inhibitory
effect in short-term incubations that BPS.
Moreover, 1,10 phenanthroline was cytotoxic in long-term
incubations indicating that the site of BPS inhibition was
outside the cell.
Further, long-term incubations with HU did not affect the
ability of the cell to reinitiate DNA synthesis after removal
of the chelator.

ironjustice:
This article raises the possibility thalassemia IS related to hemochromatosis.
Iron overload BEFORE / during disease process.

Reish O, Shefer-Kaufmann N, Shimshoni DC, Renbaum P, Orr-Urtreger A, Steiner H, Rapoport M, Levy-Lahad E, Altarescu G
Frequencies of C282Y and H63D alleles in the HFE gene among various Jewish ethnic groups in Israel: a change of concept required. [JOURNAL ARTICLE]
Genet Med 2010 Jan 15.



PURPOSE:: Hereditary hemochromatosis has not been fully evaluated in the non-Ashkenazi population and is considered to be relatively rare. After ascertaining three unrelated hereditary hemochromatosis families of North African Jewish origin with the HFE C282Y/C282Y genotype, we evaluated the C282Y and H63D allele frequencies among the different Jewish ethnic groups in Israel, in particular North African Jews.
METHODS:: Data were collected from three Israeli Medical Centers. North African, Oriental, Yemenite, and Sephardic Jewish healthy individuals were assessed for the C282Y and H63D alleles.
RESULTS:: The C282Y allele frequency was 1.02% (6/586 chromosomes), and the H63D allele frequency was 13.82% (81/586 chromosomes) in the North African Jewish group. The C282Y allele was not detected in the other non-Ashkenazi groups. The H63D allele frequency was 12.5% (38/304 chromosomes) in Oriental Jews, 14.9% (14/94 chromosomes) in Yemenite Jews, and 9.3% (11/118 chromosomes) in Sephardic Jews.
DISCUSSION:: Hereditary hemochromatosis is underrecognized among North African Jews, who have carrier frequencies of 1/58 and 1/4 for C282Y and H63D, respectively. HFE-hereditary hemochromatosis is not rare among this population as currently thought and merits increased awareness to prevent endpoint disease. The frequent occurrence of beta-thalassemia trait and HFE-H63D in non-Ashkenazi Jews raises the possibility of genetic interactions contributing to iron overload when coinherited and requires further evaluation.



--------------------------------------------------------------------------------
More from this journal
Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med]

Sharmin:
Dear Ironjustice,

Thank you for this article.  It would be great if "triggering" or "activating" the bone marrow could cure thalassemia.  In aplastic anemia, or perhaps in certain types of sickle cell anemia I can see how this can be helpful. 

In thalassemia major, and especially in beta zero patients this is next to impossible because these patients completely lack the genetic information to make red blood cells.  It is our genes that determine every function in our body.  Genes translate to the alignment of amino acids to make proteins which then make every cell in our body.  If the gene is missing there is no way on earth that our body can make the proteins that comprise red blood cells. 

In aplastic anemia the bone marrow is suppressed.  In thalassemia the bone marrow is not suppressed - and it will grow in order to expand its surface area in attempts to make more blood (which is what causes bone deformities and enlarged spleens in thalassemia).   

If we were dealing with a condition in which the bone marrow was suppressed then activating the bone marrow would be a goal.  That is not the problem in thalassemia so this research does not apply to thalassemia major. 

Some possiblities I have considered are adding spleen transplant or grafting donor tissue to an existing spleen to introduce the gene into a thalassemia major patient's body.  For one, this reduces rejection because once the spleen accepts the tissue the entire body is likely to.  Secondly, tissue from the spleen often finds its way into the bone marrow and begins to function.  As the spleen is capable of extra medullary hemopoesis - this may be a curative approach to thalassemia. 

Keep reasearching - you never know what you will find and what you may come up with,

Sharmin

ironjustice:
There may be more to it than what is imagined or proven ..

-----------

New Method Fixes Broken Proteins to Treat Genetic Diseases
ScienceDaily (Jan. 16, 2010) —
Researchers at Fox Chase Cancer Center have demonstrated how it could
be possible to treat genetic diseases by enhancing the natural ability
of cells to restore their own mutant proteins. In particular, they
found that drugs called proteosome inhibitors could provide one way of
manipulating cells into producing more of a so-called chaperone
protein, named Hsp70, which helps amino acid chains fold into their
proper protein form.


Their latest findings, presented in the journal PLoS Genetics, expand
their previous research from yeast models of disease to human cell
cultures and animal models. According to the researchers, if this
approach works in humans, it could be a way to turn certain
debilitating -- or even fatal -- genetic diseases into more treatable,
chronic conditions.


"Hsp70 pulls misfolded mutant proteins apart like a twisted rubber
bands and allows them to snap back into place, eventually a
significant percentage of these proteins will snap back into something
approaching a functional shape," says the study's leader, Warren
Kruger, Ph.D., professor in Fox Chase's Cancer Biology program. "If
this can be done in humans, it could represent a way of reducing the
severity -- or perhaps correcting -- certain hereditary diseases, even
some familial cancers."


Genetic diseases are often caused by a specific type of genetic
alteration called a missense mutation that makes cells add an
incorrect amino acid into the protein chain. Since the shape of a
protein depends on the specific arrangement of amino acids, even a
single error amid a gene's very long stretch of DNA can cause the
gene's protein product to become misshapen. Kruger and his colleagues
studied ways to reverse the functional effects of missense
mutationsfor three genetic diseases: two severe inherited metabolic
disorders (CBS deficiency and MTHFR deficiency) and one inherited
cancer syndrome (Li-Fraumeini).


In each case, the Fox Chase researchers found that it was possible to
restore the function of the mutant proteins by tricking the cell into
increasing levels of Hsp70. "We have shown that the more opportunities
we give Hsp70 proteins to try to 'fix' mutants, the more likely it is
that they will succeed," Kruger says.


While this approach has yet to be applied to clinical medicine, there
are several drugs that are known to induce Hsp70 in humans. Kruger
found that treating yeast and mammalian cells with a drug called
bortezomib elevated the amount of available Hsp70 and rescued mutant
proteins. Bortezomib is a member of a class of drugs called proteasome
inhibitors, which decreases the effectiveness of enzymes that cells
use to dispose of non-functioning proteins. Bortezemib (known under
the brand name Velcade) is currently used to treat patients with
multiple myeloma.


"We found that bortezomib can stabilize and restore mutants by
tripling the amount of available Hsp70," Kruger says. "While we do not
yet know the entiremechanism, we do know that bortezomib doesn't
rescue mutants in cells that lack the gene for Hsp70."


Kruger and his colleagues are currently studying how to best adapt
these findings to human disease.


"Of course, the big question we need to answer is one of safety --
what are the long term effects of sustained Hsp70 elevation?" Kruger
says. "The answer may be very disease-specific, one of how many mutant
proteins must be restored to reduce the severity of a given genetic
disease."


Funding for this research comes from grants from the National
Institutes of Health and the Commonwealth of Pennsylvania.


-----------


Blueberry supplemented diet reverses age-related decline in
hippocampal
HSP70 neuroprotection.
Neurobiol Aging. 2005 Apr 30;
Galli RL, Bielinski DF, Szprengiel A, Shukitt-Hale B, Joseph JA.
Neuroscience Laboratory, USDA-ARS Human Nutrition Research Center on
Aging at Tufts University, 711 Washington St., Boston, MA 02111, USA;
Department of Psychology, Simmons College, 300 The Fenway, Boston, MA
02115-5898, USA.


Dietary supplementation with antioxidant rich foods can decrease the
level of oxidative stress in brain regions and can ameliorate
age-related deficits in neuronal and behavioral functions. We examined
whether short-term supplementation with blueberries might enhance the
brain's ability to generate a heat shock protein 70 (HSP70) mediated
neuroprotective response to stress. Hippocampal (HC) regions from
young
and old rats fed either a control or a supplemented diet for 10 weeks
were subjected to an in vitro inflammatory challenge (LPS) and then
examined for levels of HSP70 at various times post LPS (30, 90 and
240min). While baseline levels of HSP70 did not differ among the
various groups compared to young control diet rats, increases in HSP70
protein levels in response to an in vitro LPS challenge were
significantly less in old as compared to young control diet rats at
the
30, 90 and 240min time points. However, it appeared that the blueberry
diet completely restored the HSP70 response to LPS in the old rats at
the 90 and 240min times. This suggests that a short-term blueberry
(BB)
intervention may result in improved HSP70-mediated protection against
a
number of neurodegenerative processes in the brain. Results are
discussed in terms of the multiplicity of the effects of the BB
supplementation which appear to range from
antioxidant/anti-inflammatory activity to signaling.


PMID: 15869824

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