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On Thu, 26 Mar 2009 19:07:43 -0700 (PDT), randall <...@aol.com
Hi,
http://ajp.amjpathol.org/cgi/content/abstract/174/4/1443
Keratinocyte but Not Endothelial Cell-Specific Overexpression of Tie2
Leads to the Development of Psoriasis
Julie A. Wolfram*, Doina Diaconu*, Denise A. Hatala*, Jessica
Rastegar*, Dorothy A. Knutsen*, Abigail Lowther*, David Askew*, Anita
C. Gilliam*, Thomas S. McCormick* and Nicole L. Ward*¶
From the Departments of Dermatology,* Pathology, Pediatrics, and
Neuroscience,¶ Case Western Reserve University, Cleveland; and The
Murdough Family Center for Psoriasis, University Hospitals, Case
Medical Center, Cleveland, Ohio
Psoriasis is initiated and maintained through a multifaceted interplay
between keratinocytes, blood vessels, gene expression, and the immune
system. One previous psoriasis model demonstrated that overexpression
of the angiopoietin receptor Tie2 in endothelial cells and
keratinocytes led to the development of a psoriasiform phenotype;
however, the etiological significance of overexpression in each cell
type alone was unclear. We have now engineered two new mouse models
whereby Tie2 expression is confined to either endothelial cells or
keratinocytes. Both lines of mice have significant increases in dermal
vasculature but only the KC-Tie2-overexpressing mice developed a
cutaneous psoriasiform phenotype. These mice spontaneously developed
characteristic hallmarks of human psoriasis, including extensive
acanthosis, increases in dermal CD4+ T cells, infiltrating epidermal
CD8+ T cells, dermal dendritic cells and macrophages, and increased
expression of cytokines and chemokines associated with psoriasis,
including interferon-, tumor necrosis factor-, and interleukins 1, 6,
12, 22, 23, and 17. Host-defense molecules, cathelicidin, β-defensin,
and S100A8/A9, were also up-regulated in the hyperproliferative skin.
All of the phenotypic traits were completely reversed without any
scarring following repression of the transgene and were significantly
improved following treatment with the anti-psoriasis systemic
therapeutic, cyclosporin A. Therefore, confining Tie2 overexpression
solely to keratinocytes results in a mouse model that meets the
clinical, histological, immunophenotypic, biochemical, and
pharmacological criteria required for an animal model of human
psoriasis
------------------------
http://www.ncbi.nlm.nih.gov/pubmed/19307725
Loss of serum response factor in keratinocytes results in
hyperproliferative skin disease in mice.
Koegel H, von Tobel L, Schäfer M, Alberti S, Kremmer E, Mauch C, Hohl
D, Wang XJ, Beer HD, Bloch W, Nordheim A, Werner S.
The transcription factor serum response factor (SRF) plays a crucial
role in the development of several organs. However, its role in the
skin has not been explored. Here, we show that keratinocytes in normal
human and mouse skin expressed high levels of SRF but that SRF
expression was strongly downregulated in the hyperproliferative
epidermis of wounded and psoriatic skin. Keratinocyte-specific
deletion within the mouse SRF locus during embryonic development
caused edema and skin blistering, and all animals died in utero.
Postnatal loss of mouse SRF in keratinocytes resulted in the
development of psoriasis-like skin lesions. These lesions were
characterized by inflammation, hyperproliferation, and abnormal
differentiation of keratinocytes as well as by disruption of the actin
cytoskeleton. Ultrastructural analysis revealed markedly reduced cell-
cell and cell-matrix contacts and loss of cell compaction in all
epidermal layers. siRNA-mediated knockdown of SRF in primary human
keratinocytes revealed that the cytoskeletal abnormalities and
adhesion defects were a direct consequence of the loss of SRF. In
contrast, the hyperproliferation observed in vivo was an indirect
effect that was most likely a consequence of the inflammation. These
results reveal that loss of SRF disrupts epidermal homeostasis and
strongly suggest its involvement in the pathogenesis of
hyperproliferative skin diseases, including psoriasis.
PMID: 19307725
http://www.ncbi.nlm.nih.gov/pubmed/19307064
Melanocyte as a possible key cell in the pathogenesis of psoriasis
vulgaris.
Brajac I, Kaštelan M, Prpić-Massari L, Periša D, Lončarek K, Malnar D.
Department of Dermatovenerology, University Hospital Center Rijeka,
Kresimirova 42, 51000 Rijeka, Croatia.
Current research in pathogenesis of psoriasis vulgaris suggests that
the inflammatory mechanisms are immune based and most likely initiated
and maintained by T cells. However, the question of lymphocyte being
an initiator of psoriatic events remains open so far. Clinical
observations such as plaque symmetry, stress-induced onset or
exacerbations, pruritus, and possibility of generalization, suggest a
role of the nervous system and neurogenic inflammation in
pathogenesis. A key to understanding the role of melanocyte in
psoriasis is their ability to act as regulatory cell in maintaining
epidermal homeo stasis. In suggested hypothetic event, melanocyte,
acting as a local "stress sensor", provide communicatory link between
CNS and skin. The disease probably begins with so far unknown signal
directed through neuronal network to the melanocyte, placed in the
center of epidermal unit. That signal governs keratinocyte cellular
activities and lead to reactive abnormal epidermal differentiation and
hyperproliferation. Increased proliferation of basal keratinocytes and
high metabolic demands creates angiogenesis in papillary dermis and
elongation of dermal papillae. Stimulated melanocytes and basal
keratinocytes become an important source of proinflammatory cytokines
that attract lymphocytes in dermis. In conclusion, according to our
hypothesis, lymphocyte infiltrate in psoriasis is secondary event
rather than vice versa as presented in the literature.
PMID: 19307064
Anti-psoriatic effects of indigo naturalis on the proliferation and
differentiation of keratinocytes with indirubin as the active
component.
Lin YK, Leu YL, Yang SH, Chen HW, Wang CT, Pang JH.
Department of Traditional Chinese Medicine, Center for Traditional
Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan;
Graduate Institute of Clinical Medical Sciences, College of Medicine,
Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan, 333,
Taiwan.
BACKGROUND: Indigo naturalis has shown efficacy in treating psoriasis
in our previous clinical studies. OBJECTIVES: To investigate the
potential effect of indigo naturalis on regulating keratinocyte
proliferation and differentiation. METHODS: Skin samples from six
patients were analyzed for proliferating cell nuclear antigen (PCNA)
and involucrin expression by immunohistochemical staining. In
addition, indigo naturalis extracts from 10 to 500mug/ml were added to
cultured keratinocytes and cell viability determined. Real-time RT-
PCR, Western blotting analysis and indirect immunofluorescent l
abeling were used to investigate the messenger (m)RNA and protein
expressions of PCNA and involucrin. Finally, high-performance liquid
chromatography (HPLC) was used to identify major components of indigo
naturalis and their in vitro effects compared. RESULTS:
Immunohistochemical results demonstrated decreased PCNA and increased
involucrin in psoriatic lesions after indigo naturalis treatment.
Cultured keratinocytes decreased after indigo naturalis treatment,
while G(0)/G(1) arrest was observed to dose-dependently increase.
Staining revealed decreased PCNA-stained nuclei and increased
cytosolic involucrin in treated keratinocytes. Decreased PCNA and
increased involucrin at both the mRNA and protein levels were
confirmed. Both major components, indirubin and indigo, could cause G
(0)/G(1) phase arrest; however, only indirubin modulated the
expressions of PCNA and involucrin similar to indigo naturalis.
CONCLUSIONS: Together, these findings indicate that the anti-psoriatic
effects of indigo naturalis are mediated, at least in part, by
modulating the proliferation and differentiation of keratinocytes,
with indirubin as the major active component.
PMID: 19303259
==========================================
http://www.ncbi.nlm.nih.gov/pubmed/19303464
Synergistic immunomopharmacological effects of N-alkylamides in
Echinacea purpurea herbal extracts.
Chicca A, Raduner S, Pellati F, Strompen T, Altmann KH, Schoop R,
Gertsch J.
ETH Zurich, Department of Chemistry and Applied Biosciences, CH-8093
Zürich, Switzerland.
Echinacea purpurea extracts are used in the production of standardized
herbal medicines for the prevention and treatment of upper respiratory
infections. Unsaturated N-alkylamide lipids, the main constituent of
E.purpurea and E. angustifolia preparations capable of activating the
cannabinoid receptor type-2 (CB(2)) have been suggested to play a role
as potential anti-inflammatory and immune-modulatory principles. Here
we show that ethanolic E. purpurea radix and herba extracts produce
synergistic pharmacological effects on the endocannabinoid system in
vitro. Superadditive action of N-alkylamide combinations were seen at
the level of intracellular calcium release as a function of CB(2)
receptor activation. Likewise, synergism of the radix and herba
tinctures was observed in experiments measuring LPS-stimulated
cytokine expression from human PBMCs. While the expression of the anti-
inflammatory cytokine IL-10 was significantly superstimulated, the
expression of the pro-inflammatory TNF-alpha protein was inhibited
more strongly upon combination of the extracts. We show that N-
alkylamides act in concert and exert pleiotropic effects modulating
the endocannabinoid system by simultaneously targeting the CB(2)
receptor, endocannabinoid transport and degradation.
PMID: 19303464
=================
http://www.pnas.org/content/102/2/355.full
CD98hc (SLC3A2) mediates integrin signaling
Chloe C. Feral*,
Naoyuki Nishiya*,
Csilla A. Fenczik*,
Heidi Stuhlmann*,
Marina Slepak*, and
Mark H. Ginsberg*,†,‡
*Department of Cell Biology, The Scripps Research Institute, La Jolla,
CA 92037; and †Department of Medicine, University of California, San
Diego, La Jolla, CA 92093
Edited by Barry S. Coller, The Rockefeller University, New York, NY
(received for review July 6, 2004)
Integrins regulate cellular behaviors th rough signaling pathways,
including Rho GTPases and kinases. CD98 heterodimers, comprised of a
heavy chain (CD98hc, SLC3A2) and one of several light chains, interact
with integrins through CD98hc. CD98hc overexpression leads to
anchorage-independent cell growth and tumorigenesis in 3T3 fibroblasts
and activates certain integrin-regulated signaling pathways. To
establish the biological function of CD98hc, we disrupted the gene and
analyzed CD98hc-null cells. Here we report that CD98hc contributes to
integrin-dependent cell spreading, cell migration, and protection from
apoptosis. Furthermore, CD98hc is required for efficient adhesion-
induced activation of Akt and Rac GTPase, major contributors to the
integrin-dependent signals involved in cell survival and cell
migration. CD98 promotes amino acid transport through its light
chains; however, a CD98hc mutant that interacts with β1 integrins, but
not CD98 light chains, restored integrin-dependent signaling and
protection from apoptosis. β1 integrins are involved in the
pathogenesis of certain cancers. CD98hc deletion markedly impaired the
ability of embryonic stem cells to form teratocarcinomas in mice;
teratocarcinoma formation was reconstituted by reexpression of CD98hc
or of the mutant that interacts exclusively with integrins. Thus,
CD98hc is an integrin-associated protein that mediates integrin-
dependent signals, which promote tumorigenesis.
=============
Should Obama go the way of al gore?
http://www.nolanchart.com/article6199.html
It's Time to Worry About Global COOLING
--------------------------------------------------------------------------------
Finally people will begin to understand that the earth is going
through a cooling stage, as it has for millions of years.
--------------------------------------------------------------------------------
by Kevin Roeten
(conservative)
Thursday, March 26, 2009
Solar scientists predict that, by 2020, the sun will be starting into
its weakest solar cycle of the past two centuries. They say this will
likely lead to unusually cool conditions on Earth. It is also
predicted that this cool period will go much longer than the normal 11
year cycle, as the Little Ice Age did. The climate threat is actually
cooling, especially to countries like Canada. On the northern limit to
agriculture in the world, very little cooling would likely destroy
much of its food crops.
The Little Ice Age, the coldest period in the past 1500 years,
corresponded perfectly with the Maunder Minimum. There was virtually
no sunspot activity for almost seven decades in the Maunder Minimum
(Willie Soon/ Harvard/Astrophysics). It turns out that for those 60-70
years the northern half of our globe was in a deep freeze. The New
York harbor froze, allowing walkers to journey from Manhattan to
Staten Island, and the Vikings abandoned Greenland--a once verdant
land that became tundra. In that Little Ice Age, Finland lost 1/3 of
its population and Iceland one half.
In the well-known 11-year "Schwabe" sunspot cycle, the output of the
sun varies by about 0.1%. Sunspots are violent storms on the surface
of the sun. Marine productivity and total irradiance match very well
with records that have been kept for centuries on visible sunspots.
Hundreds of studies of sunspots and earthly climate indicators (tree
rings in Russia's Kola Peninsula, to water levels of the Nile) show
exactly the same thing--that the sun drives climate change.
Even though it has been discovered that the sun is brighter now than
anytime in the past 8000 years, the increase in solar output was not
calculated to be sufficient to cause all of the past century's modest
warming. But that amplifier was discovered(starting in 2002) with
scientific papers from Veizer, Shaviv, Carslaw, and most recently
Svendsmark (Danish National Space Agency).
All these scientists have proven (particularly w/Svendsmark) that the
sun's protective solar wind (from sunspots) blows away deep-space
cosmic rays. With fewer sunspots there is less solar wind, more cosmic
rays, and more cloud formation from those cosmic rays. More cloud
formation means more cooling effect on the planet.
In a 2003 poll, 2/3 of more than 530 climate scientists from 27
countries did not believe greenhouse gases were the main reason for
global warming. It is now beyond 700 scientists. In fact, overlays of
CO2 variations show little correlation with earth's climate on long,
medium, and even short time scales. The science is nowhere near
settled.
Nigel Weiss (Mathematical Astrophysics/Cambridge) states that
"Variable behavior of the sun is an obvious explanation." He admits
that we are now living in a period of abnormally high solar activity,
and that these hyperactive periods do not last long (50-100 years),
then you get a crash. "It's a boom-bust system, and I would expect a
crash soon." And when the crash occurs, the Earth can cool
dramatically.
Dr. Kukla (Czechoslovakian Academy of Sciences) say he and many others
realize that global warming always precedes an ice age. Each lasts
about 100,000 years, punctuated by briefer, warmer periods called
interglacials. We are in an interglacial now. This ongoing cycle
closely matches cyclic variations in Earth's orbit around the sun.
Kukla says "The relationship is just too clear and consistent to allow
reasonable doubt. It's either that, or climate drives orbit, and that
just doesn't make sense."
No one knows when a "crash" will occur, but scientists expect it soon.
Mainly because the sun's polar field is now at its weakest since
measurements began in the 1950's. A deep crash last occurred in the
17th century--and it was the Little Ice Age, or the Maunder Minimum.
"Having a "crash" would certainly allow us to pin down the sun's true
level of influence on the earth's climate," concludes Dr. Weiss. "Then
we will be able to act on fact, rather than from fear."
It's not likely greenhouse "gassers" will be converted in 12 years.
They'll be busy looking for something humans have done to make it so
cold.
====================
http://www.aegis.com/pubs/amfar/2003/AM030701.html
Psoriasis: Yet Another Challenge for HIV/AIDS Patients
American Foundation for AIDS Research, July 2003
Jeff Getty
--------------------------------------------------------------------------------
Psoriasis has proved to be one of the most dramatic and intractable
skin ailments experienced by people with HIV. It commonly appears
first on the knees and elbows as itchy or burning inflamed reddish
patches that become covered with silvery gray scales or plaque. In
more severe cases, the malady can spread to 20% or more of the skin
surface and be quite uncomfortable. Psoriasis is not caused by a
contagious agent, though skin injury, including that caused by
infections, can trigger an episode. Systemic infections as well as
certain drugs represent environmental stress factors that can spark
psoriasis, too.
The plaque is composed of an overgrowth of skin cells that rapidly
mature and move to the surface, where they die and leave a scaly
surface on top of the eruption. Psoriasis is usually a mild-to-
moderate condition but can become severe and may be accompanied by
psoriatic arthritis.
About 3% of Americans have psoriasis. Dermatology and HIV specialists
agree that the prevalence of psoriasis among those with HIV is likely
similar to or just slightly higher than in the general population.
They also find that HIV can aggravate psoriasis. HIV-positive
individuals with exacerbated psoriasis are prone to developing new
systemic infections. Such psoriasis-induced infections, rare in
persons with psoriasis alone, can trigger still more extensive
psoriasis flare-ups.
When patients develop moderate to severe psoriasis, quality of life
deteriorates. According to the National Psoriasis Foundation,
afflicted individuals have described problems with employment, sexual
activity and suicidal thoughts. The Foundation reported that 81% of
psoriasis survey respondents felt embarrassed by the disease and most
thought the treatments to be ineffective. Some 54% reported depression
and many reported sleep disorders.
Most doctors agree that good antiviral coverage is the best treatment
for psoriasis and other HIV-related skin problems. Effective use of
HAART does not guarantee psoriasis will magically vanish, and standard
treatments for normal psoriasis may or may not produce results in HIV
patients.
HIV-related psoriasis is compounded by the fact that there are only a
few doctors in the country that specialize in this area. Most AIDS
care providers have little experience dealing with the condition.
Patients are commonly prescribed some type of topical cortisone or a
Vitamin D analog to reduce inflammation and then referred to a
dermatologist with little or no training in HIV. Often the overworked
dermatologists have little time to see these patients, and only
prescribe the same run-of-the-mill ointments and creams. Ultraviolet
light therapy three or more times weekly has become the automatic
backup when topical treatments fail to reduce the inflammation on
their own. Topical and oral retinoids are employed to reduce skin cell
maturation and proliferation.
A last resort is high potency immune-inhibiting therapy with
cyclosporin or methotrexate. Hydroxyurea is considered a safer
substitute in persons with HIV. It inhibits DNA production and already
is sometimes used to boost the anti-HIV potency of ddI and other
nucleoside analogs. (See box for an HIV-associated psoriasis treatment
algorithm.)
These therapies all have significant toxicities, which are enhanced in
persons with HIV. Since such persons already face a mountain of
disease- and drug-related problems, psoriasis can be quite
devastating. Unless a well-informed dermatologist is available, HIV-
related psoriasis could become part of a downward spiral of disease
progression.
The Psoriatic Paradox
No one knows the exact cause of psoriasis. Most authorities ascribe
the cause of psoriasis to overactive T-lymphocytes, whose inflammatory
secretions (cytokines) increase skin cell growth in a manner that
parallels wound healing. But HIV kills CD4+ T-lymphocytes, which
stimulate the other main kind of T-lymphocytes, the CD8+ killer cells.
In a review of the association between HIV and psoriasis, specialist
Eleanor Mallon (Imperial College School of Medicine, London)
concluded, "It is paradoxical that, while drugs that target T-
lymphocytes are effective in psoriasis (e.g., cyclosporin), the
condition should be exacerbated by HIV infection." (See E Mallon and
CB Bunker, "HIV-Associated Psoriasis" in AIDS Patient Care and STDs,
May 2000, pages 239-C46).
Although persons with HIV have depleted CD4 cell populations, their
immune systems are overactive in many respects. Dr. John Fung, a
leading transplant surgeon at the University of Pittsburgh, observed
that recent HIV-positive organ transplant recipients required greater -
C not smaller -C levels of immunosuppressive drugs to block organ
rejection. Dermatitis, folliculitis, joint pain and arthritis all are
common inflammatory symptoms associated with HIV infection.
Dr. Marcus Conant, a dermatologist and pioneer HIV specialist in San
Francisco, recalled that in the early days of AIDS when antiviral
medications were lacking, psoriasis was common in HIV populations,
suggesting that untreated HIV patients may have a higher incidence of
psoriasis. Research published in the 1980s about HIV and psoriasis
indicated that patients were dying within a year or so of their
psoriasis outbreaks. Reiter's syndrome and arthritic conditions were
also diagnosed in untreated HIV patients in the eighties and were more
common before HAART.
Too Much BLyS
These theories have led to current psoriasis treatments such as
cortisone and ultraviolet phototherapy. Acitretin (Soriatane) is a
standard systemic retinoid for severe psoriasis. It is often is used
in conjunction with ultraviolet light, reducing the doses and side
effects of both therapies while increasing overall effectiveness. The
effect is synergistic, with the UV therapy inhibiting lymphocyte
activation and the retinoid reducing skin cell proliferation.
Alefacept (Amevive), a new drug from Massachusetts-based Biogen, has
been approved for people who need something more than topical
psoriasis therapy. Amevive lowers the number and activity of memory/
effector T-lymphocytes. These CD4+ and CD8+ T-cells are the quick-
acting cells stored from past immune reactions. They are the most
numerous type detected in psoriasis lesions. In alefacept trials, 14%
to 21% of recipients largely resolved their chronic psoriasis after a
12-week course of treatment. Another 38% to 42% experienced major
improvement, compared with 10% to 18% in the placebo arm. The effect
remained for at least 12 weeks post-dosing.
The most common reason for discontinuing alefacept is a severe
depletion in CD4 cells. The drug is not recommended for people with
below normal CD4 counts, the characteristic condition of HIV
infection. It is not known if alefacept is safe for HIV-positive
patients, even those receiving successful anti-HIV therapy, because
Biogen has conducted no trials in such populations.
Studies continue on inhibiting lymphocyte activation with Embrel and
Remicade, two blockers of tumor necrosis factor (TNF) that are already
on the market for other uses. Meanwhile, immunologist Michael McCune
(University of California, San Francisco) suspects that some new and
undiscovered factor might be the common cause of several HIV-
associated inflammatory diseases.
McCune's suspicions arise from a paper published a paper last summer
by William Stohl (University of Southern California). Stohl identified
a new tumor necrosis factor in arthritis, lupus and HIV patients. The
factor, B lymphocyte simulator (BLyS) was present in high levels in
half of the HIV patients enrolled in the study. Stohl observed that
patients with high HIV levels also had more BLyS in their blood. This
mystery factor could be related to the skin disorders that affect
people with HIV.
An anti-BLyS biological drug has been developed and is being given to
lupus patients to test for safety. The research is still quite early,
but McCune and Stohl wonder if this drug might help people failing
anti-HIV treatment. So far, the drug has shown safety in animals and
in the first human lupus study. A request for funding an AIDS pilot
study has yet to be approved.
The National Psoriasis Foundation has published a helpful handbook for
psoriasis diagnosis and treatment, "Psoriasis: Treatment Options and
Patient Management." This handbook was the outcome of a consensus
meeting held in March 2002 on the latest understanding of the disease.
It can be obtained by contacting the National Psoriasis Foundation
(800-723-9166). The handbook discusses different types of psoriasis,
including HIV-related psoriasis, along with likely treatment
strategies.
My Journey to the Skin Boutique
I first became aware of my psoriasis problem last spring when a few
itchy, flaking patches of skin erupted into large annular sores that
began to take over huge portions of my back, trunk, arms and legs. My
initial onset was so severe that my doctor and I decided to use
prednisone to stop the onslaught. This worked, and I later weaned off
the prednisone, only to have the psoriasis slowly return to its former
severity. A dermatologist then prescribed the usual cortisone creams
and ointments. These had little or no effect.
At this point, I moved from the Bay Area to southern California and
began seeing a new physician. He referred me to a dermatologist who
ran a huge skin-care center in the desert south of Los Angeles.
I drove to the skin "boutique" and was amazed to find a large building
with an enormous waiting room full of black leather couches. On the
couches sat mostly senior citizens with a wide range of skin problems,
but mostly in search of Botox. I was taken into an exam room where I
was shown how an ultraviolet (UV) machine worked, and I signed up for
30 sessions. At this point, the doctor told me that psoriasis was
caused by T-cells attacking the skin. When I asked her which T-cells,
she said she did not know, but that it was definitely T-cells that
caused the disease. I did not attempt to introduce the psoriasis
pathogenesis debate at this time.
My first treatment began when I took off all my clothing and stepped
into a machine the size of an English phone booth. It was full of UV
lights, which were switched on for only one minute. I wore special UV-
blocking glasses and had sunscreen on my nose, face and ears. As
bright blue lights hummed, I closed my eyes for fear of blindness.
Then I stepped out and got dressed.
Convinced that the exercise had been useless, I began checking out and
noticed an older gentleman next to me. He was plunking down $600 for
his Botox injections. The man's face looked quite round and puffy, as
if a swarm of bees had stung it. I recall thinking to myself that
surely this was southern California at its height.
After two weeks of phototherapy, my psoriasis began clearing up for
the first time in a year. Almost 70% of it disappeared, and soon the
doctor began advising a maintenance dose of twice a week, which is my
current regimen.
I was initially shocked by the excess vanity of the patients at the
skin center, as well as by the concept of the skin boutique. I now
realize that much of the money from the vanity treatments likely helps
support research and buys equipment for the more serious psoriasis and
skin cancer conditions treated there. I do not believe that such a
center could survive on HMO dollars alone. So ultimately, I think that
the skin boutique approach might not be such a bad idea.
- JG
030710
AM030701
===================
http://www.eurekalert.org/pub_releases/2009-03/pl-pi031609.php
Preventium is 'where the prevention of breast and prostate cancer
begins'
LAS VEGAS --Dr. Ercole Cavalieri and Dr. Eleanor Rogen of the
University of Nebraska Medical Center, Eppley Institute for Research
in Cancer, located in Omaha, Nebraska, have identified the triggering
mechanism by which breast and prostate cancer cells begin. Preventium™
http://www.preventium.org is a recently developed dietary supplement
that promises to reduce people's risk for breast and prostate cancer.
Ercole Cavalieri, D.Sc. and research collaborator Eleanor Rogen, Ph.D.
say: "We have found the first step that starts a cell down the road to
becoming a cancer cell. By blocking this first step from happening, we
feel we can stop the development of breast and prostate cancer."
The researchers have discovered that certain estrogen derivates
(metabolites) can react with deoxyribonucleic acid (DNA) to cause
damage that may initiate the start of breast and prostate cancer.
Estrogen can initiate cancer when natural protective mechanisms
do20not function properly in the body, which then allows estrogen
metabolites to react with DNA. Since both men and women have naturally
occurring estrogen, the triggering mechanism for breast and prostate
cancer is identical. This research has been funded in part by nearly
$40 million in direct funding from the National Cancer Institute and
the U.S. Defense Department.
Drs. Cavalieri and Rogan are the first cancer researchers to study the
effects of Resveratrol on this process. New research establishes, that
to be effective, additional compounds must be added for optimal
effect. The combination of naturally occurring preventative agents
Resveratrol, N-Acetyl-L-Cysteine (NAC), Lipoic Acid and Melatonin
greatly enhances the body's natural protection mechanisms which, in
turn, decrease the triggering mechanism involved in the formation of
breast and prostate cancer cells. These compounds are available in a
recently developed dietary supplement called Preventium™.
###
Preventium, LLC, a Las Vegas, Nevada company, was formed in
association with our research scientists to assist women and men in
achieving and maintaining healthy, normal levels of estrogen
metabolites through the use of Preventium™. Supporting documentation
about the science and research is available upon request.
The above scientist and science have been published in the following
publications:
International Journal of Cancer
Cancer Prevention Research
Breast Cance r Basic and Clinical Research
Prostate
Journal of Steriod Biochemistry and Molecular Biology
Contacts
Preventium, LLC
John Raffanti, 702-809-9447
john...@preventium.org
===========================
http://www.examiner.com/x-1369-LA-Nutrition-Examiner~y2009m3d13-Grapes-gaurd-yo ur-gut
Grapes guard your guts
Here is just one more reason to eat your fruit and veggies:
Researchers at Clemson University found that compounds in grapes can
inhibit the bacteria Helicobacter pylori (H. pylori), a primary
culprit in the 2 million cases of gastritis in this country each year.
H. pylori is often acquired by ingesting contaminated food and water
and through person-to-person contact and is also associated with
peptic ulcers and gastric cancer.
Up until now, antibacterial drugs have been routinely administered to
treat the symptoms and provide temporary relief. But over time, the
body develops a resistance to these drugs and the risk of infection
returns.
But according to Science Daily, a recent study shows promise for using
diet and supplementation for fighting off harmful gut bacterium.
Here’s why: Grapes, particularly dark purple and black Muscadine
grapes, are a rich source of polyphenols and the potent antioxidant
resveratrol. The study shows that these compounds inhibit the growth
of H.pylori so that conditions like gastritis can be quelled. Unlike
antibiotics, your body won’t develop resistance to the healing
properties of grapes. While all kinds of grapes like red, purple and
green showed a protective benefit against the bacteria, the Muscadine
variety showed the most eff ective results.
If you’re not a big fan of grapes, are concerned about pesticide use,
or don’t have access to the Muscadine variety, look for a high grade
quality supplement that contains these powerful micronutrients. But
just make sure that you are not just solely relying on daily
supplements to give your body the nutrients it needs and instead
consider your daily supplement routine precisely as that – a
supplement to a diet that is full of a wide array of colorful fruits
and veggies.
======================
http://www.wickedlocal.com/cohasset/news/lifestyle/columnists/x1683620350/HEALT H-NOTES-Red-grapes-wine-and-a-miracle-drug
The latest miracle drug now being touted in newspapers, in blogs and
on the web, is Resveratrol. You’ve probably seen or heard about the
stuff and its ability to inhibit heart disease and cure some forms of
cancer. Like many such potions there’s a touch of truth in some of
what’s being said, but also much hype. Resveratrol (trans-3,5,4’-
trihydroxystilbene), an antioxidant compound while present in other
foods such as mulberries and peanuts, is found in the skins of red
grapes, particularly in Muscadine grapes used to make wines.
The Resveratrol content of wine is related to the length of time the
grape skins are present during the fermentatio n process. Thus the
concentration is significantly higher in red wine than in white wine,
because the skins are removed earlier during white wine production,
lessening the amount that is extracted.
Resveratrol is one of a class of antibiotic compounds produced as a
part of a plant’s defense system against disease. For example, in
response to an invading fungus, Resveratrol is formed to combat the
infestation. Since fungal infections are more common in cooler
climates, grapes grown in cooler climates have a higher concentration
of resveratrol, which came to scientific attention only four years
ago, as a possible explanation for the “French Paradox”— the low
incidence of heart disease among French people, who eat a relatively
high-fat diet but also consume red wine in abundance. Since wine is
the most notable dietary source, it is the object of much speculation
and research.
The most efficient way of administering Resveratrol in humans appears
to be buccal delivery, that is without swallowing, but by direct
absorption through the inside of the mouth. (Envision the way wine
tasters behave at tastings).
Many studies suggest that consuming alcohol (especially red wine) may
reduce the incidence of coronary heart disease. Alcohol can protect
cells against degradation of low-density lipoprotein and can be
considered by some to provide more effective protection than
conventionally used vitamins C and E. However, to date, most of the
research on Resveratrol’s antioxidant and anti-platelet properties has
been done in the laboratory using test-tube or tissue-culture
preparations. Further studies in animals and humans are necessary to
determine its effectiveness.
Resveratrol is also being studied in connection with its ability to
inhibit cancer cell growth, leading to questions about its ability to
simulate the effects of estrogen that also promotes growth of breast
cancer cells.
Laboratory tests may have clearly demonstrated that Resveratrol can
help prevent cardiovascular disease and cancer. But too much is not
known about the new compound:
· First, we know little about how rapidly the human system assimilates
Resveratrol by the heart and liver, and whether it is harmful.
· Second the research on Resveratrol has focused on its short-term
effects and on lab testing; a problem for many new products in these
rapidly changing times.
· Third, its role in breast cancer may significantly limit its use,
even for its “proven” benefits.
· Finally, if you are careful about overuse of red wine, it’s probably
better and a lot more pleasant to get the small amount of Resveratrol
you need through judicious use of red wine.
In spite of the proliferation of ads and media discussions about it,
there is really not enough information about Res veritrol for anyone
to consider regularly using it.
The entire article entitled Grape Expectations by Melissa Celery may
be found on the US Government web site: http://www.nih.gov.
Steve Bobo is a long-time member of the Cohasset Board of Health.
======================
http://news.biocompare.com/News/NewsStory/264271/NewsStory.html
Researchers Block Immune Cell Rush Behind Deadly Sepsis
Source: University of Rochester Medical Center
Wednesday, February 25, 2009
Work suggests how to eliminate bleeding risk from treatment
http://news.biocompare.com/News/NewsStory/264271/NewsStory.html
Researchers have found a way to block the ability of white blood cells
to sprint toward the sites of infection when such speed worsens the
damage done by sepsis, the often fatal, whole-body bacterial
infection, according to a study published today in the journal Blood.
The results recommend existing drugs as potential new treatments
against sepsis, and suggest improvements in the current treatment that
would increase its effect while eliminating a treatment-related risk
for internal bleeding.
A simple bacterial infection becomes sepsis, or "bl ood poisoning,"
when it gets bad enough to set off system-wide responses from the
body's immune defenses and blood-clotting system. It becomes septic
shock when bacteria, the toxins they produce and the body's
overwhelming immune response cause multiple organ failure. More than
30 percent of patients with severe sepsis die despite advances in
critical care, about 250,000 people per year. Physicians currently
rely on antibiotics and surgical drainage, but new options are
needed.
White blood cells called neutrophils fight infection by swarming
toward bacteria to engulf and destroy them with toxic molecules.
Because these same molecules also damage human cells, this phase of
the immune response is carefully contained and quickly shut down. The
massive rush of neutrophils seen in sepsis, however, can overcome
these restraints. In between infections, dormant neutrophils drift
with the bloodstream until they "realize" they are passing by the part
of a blood vessel wall closest to an infection. Proteins on the
neutraphil's surface called integrins then unfold and "grab" the
surface of the blood vessel wall, resisting the flow. The same
proteins then help the neutraphil crawl along the tissue scaffold
toward the infection site.
In the current study, a team of researchers at the University of
Rochester Medical Center demonstrated for the first time that the only
approved sepsis drug treatment, recombinant human activated protein C
(rhAPC), has its effect by interfering with specific integrins on
neutrophil surfaces, which k eeps the cells from moving. Importantly,
they also learned that a small protein piece of rhAPC, the "RGD"
peptide, is responsible for the treatment's effectiveness against
sepsis.
"Our results create the distinct possibility that several drugs
already approved as safe in humans may have a second use in sepsis,"
said Minsoo Kim, Ph.D., assistant professor of Microbiology and
Immunology within the David H. Smith Center for Vaccine Biology and
Immunology at the Medical Center, and lead author of the article.
"That is exciting because it could dramatically increase the pace at
which new treatments for sepsis arrive in the clinic."
While the standard approach for decades has been to try to kill
bacteria with antibiotics, some newer medications are designed to
lessen the body's inflammatory reaction to sepsis. Most of these
attempts have failed, but Drotrecogin alpha (brand name Xigris® from
Eli Lilly), a genetically engineered (recombinant) form human
activated protein C (rhAPC), was shown in a recent study to decrease
mortality by about six percent, from 31 percent to 25 percent, in
severe sepsis patients. Is the only FDA-approved drug for treating
severe sepsis and the drug used in the current study.
Before its approval for use in sepsis, rhAPC was known for its ability
to prevent blood clots, and researchers thought initially that this
ability explained its efficacy against sepsis. When other anti-
clotting agents failed to work the same way, however, researchers
began looking elsewhere. Rese arch published by Jerry Nick, M.D., and
colleagues at the National Jewish Medical and Research Center (Blood.
2004;104:3878-3885) was the first to suggest that the benefit of rhAPC
in sepsis might be explained by its effect on white blood cell
migration, not blood coagulation, and several papers followed to
confirm the idea. Until the current study, however, no one had been
able to show how.
Furthermore, the U.S. Food and Drug Administration earlier this month
announced that it was analyzing a report just published in the journal
Critical Care Medicine that found Xigris, because of its effect on
clotting, may increase the risk of dangerous bleeding in patients with
a recent history of hemorrhages. The company argues that the study was
flawed, and the drug's label is very clear about bleeding risk.
Whatever the case, Jiang and colleagues are excited because their
results argue that the part of Xigris that contributes to bleeding has
nothing to do with its effect on sepsis, and can be removed.
Halting the Great Migration
In a neutrophil at rest, integrins are kept in a "non-stick" state.
When the cell gets ready to move, however, integrins are quickly
activated on the cell's "foot," the area where the cell touches the
surface it wants to move across. Integrins bind to their partner
proteins on the surface, and the neutraphil's cell skeleton contracts
to pull itself over the leading-edge integrins. Previous studies in
Kim's lab suggest that, without precise, integrin-mediat ed changes
that enable the front end to gain traction, and the tail end to let
go, immune cells could not migrate. He studied T cells in his earlier
experiment, but the current results suggest the same processes are in
play in neutrophils. In the current study, the research team showed
for the first time that rhAPC has an effect on sepsis because it
directly binds to β1 and β3 integrins on the surface of neutrophils
and prevents those integrins from grabbing the surface.
Just as importantly, the team proved that human rhAPC contains the
"RGD" three-amino acid chain. This peptide is a key component of
several human proteins (e.g. fibronectin) over which neutrophils crawl
because it has the right shape to be grabbed by integrin. In the case
of rhAPC, its RGD chains grab neutraphil integrins first, taking away
their ability to gain traction on surfaces. When the current research
team changed the shape of the RGD sequence in rhAPC, the medication
could neither bind to integrin nor interfere with the migration of
neutrophils toward infection sites. In addition, treatment of septic
mice with a single dose of the RGD peptide delivered the same
improvement in survival as a dose of whole rhAPC, about 30 percent.
Kim's team tracked the ability of neutrophils to migrate across a
glass plate coated with fibronectin. The team placed the neutrophils
on the surface and then hit them with a type of molecule produced by
bacteria, and toward which neutrophils swarm. The results show that,
although neutrophils could sense the bacterial product and had a
"desire" in chemical terms to move toward it, they could not in the
presence of rhAPC.
Along with Kim, the work was led by Pranita Sarangi, Young-min Hyun,
Joseph Hollenbaugh and David Topham within the Department of
Microbiology and Immunology at the Medical Center, and by Hung-Li
Chung and James McGrath in the Department of Biomechanical
Engineering.
Gwendolyn Elphick, Alfred Ayala and Jonathan Reichner led the research
at the Department of Surgery at Rhode Island Hospital, as did Walter
Biffl in the Department of Surgery at Denver Health Medical Center and
Alireza Rezaie in the Department of Biochemistry and Molecular Biology
at the Saint Louis University School of Medicine. The work was
supported by the National Institutes of Health.
"If, as suggested by our results and the literature, the effects of
rhAPC on sepsis are attributable to reduced neutrophil migration, then
anti-integrin agents represent a new class of drug candidates for
sepsis," Kim said. "An RGD peptide already in clinical trials for
cancer has potential against sepsis. We are also using molecular
biology techniques to look for protein fragments similar to RGD, but
with even greater ability to attach to and shut down activated
integrins, and having shed the rhAPC anti-clotting functions that
create bleeding risk."
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