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A Retrovirus Implicated in Primary Biliary Cirrhosis
What are PBC and PSC, and how
do they differ?
By David Rhodes
When my son was diagnosed with primary sclerosing cholangitis
(PSC) and ulcerative colitis (UC) in the summer of 2003, I set about
chronic cholestatic liver diseases. Both are
reading everything I could find about this (and related) liver and
presumed to have an autoimmune basis.
inflammatory bowel diseases. Of the thousands of research abstracts I
have read over the last 6 months, I was particularly impressed by
destruction of bile ducts leading to chronic
several authored by Dr. Andrew Mason (currently located at the
cholestasis and liver cirrhosis. This is often
University of Alberta; formerly of Tulane University, New Orleans)
on the possible involvement of a retrovirus in primary biliary cirrhosis
portal hypertension and liver failure. Both
(PBC). It seemed to me that Dr. Mason's studies represent a
significant breakthrough in the understanding of the "trigger"
mechanism of a cholestatic disease; advances that may eventually help
in understanding the cause(s) of PSC. In this article I briefly
diseases are currently treated in their early
stages with ursodeoxycholic acid (UDCA).
PBC has long been thought to be an autoimmune disease (1).
PBC involves progressive destruction of the
However, several lines of evidence indicate that an infectious agent
small, interlobular bile ducts. It affects
might be involved in triggering the disease in genetically susceptible
individuals (1). PBC has been documented in unrelated care providers
and in non-related family members, and in one study it was associated
with a particular water supply (reviewed in 1). Several unusual
typically exhibit antimitochondrial anti-
geographical clusters of the disease have recently been documented
(7). PBC frequently recurs after liver transplantation (1). A hallmark
of PBC is the occurrence of antimitochondrial antibodies primarily
directed against the pyruvate dehydrogenase complex. These
being the pyruvate dehydrogenase complex.
antibodies begin to reappear on the biliary epithelial cells of thetransplanted allograft following transplantation (1). A variety of
organisms have been considered as possible causes of PBC, including
stricturing of the intrahepatic and extra-
viruses, bacteria and fungi, but a retrovirus has recently taken center
stage (1). Retroviruses are infectious particles built on RNA rather
than DNA. The most infamous retrovirus is HIV, the virus that causes
AIDS. Other diseases thought to be caused by retroviruses include
breast cancer and Sjogren's syndrome.
imately 75% of patients with PSC also haveinflammatory bowel disease (IBD), mostly
Mason and colleagues first showed that serum of PBC patients had
reactivity to certain proteins characteristic of retroviruses (2). Mason
and colleagues then obtained evidence that a transmissible factor can
typically exhibit perinuclear antineutrophil
promote the appearance of antimitochondrial antibodies in normal
cytoplasmic antibodies and/or other auto-
biliary epithelial cells. Biliary epithelial cells extracted from normal
liver were co-cultivated with homogenized lymph nodes from PBCpatients. Normal biliary epithelial cells developed pyruvate
dehydrogenase antibodies 5 to 7 days after incubation with
homogenized lymph nodes from PBC patients (5). This effect could
advances in understanding the causes of one
be halted by either ultra-centrifugation or by gamma irradiation of the
may assist in understanding the causes of
supernatants prior to incubation, suggesting that the lymph nodes of
patients with PBC harbor a transmissible, particulate agent with aradiation-sensitive nucleic acid genome (5). The agent appears to be
capable of replicating and producing the characteristic antibodies of
PBC in biliary epithelial cells (1).
cholangitis. Clin. Liver Dis. 3: 529-570.
Electron microscopy studies also revealed virus-like particles in the
extracellular space of biliary epithelial cells of PBC patients (5). Eachparticle was approximately 110 to 120 nm in diameter and had an
1. Mason A, Nair S (2002) Primary biliary
oval, eccentric nuclear dense core, compatible with viral particles (5).
cirrhosis: new thoughts on patho-physiology and treatment. Curr.
More recently, a betaretrovirus has been cloned and sequenced from
the lymphoid tissue of PBC patients (4). The retrovirus has strikingnucleotide homology with mouse mammary tumor virus (MMTV) and
with retrovirus sequences derived from human breast cancer samples
(4). The human betaretrovirus nucleic acid sequences cloned from
PBC patients contain five sequences encoding proteins characteristic
of retroviruses, including the superantigen (Sag) protein (4). The
Detection of retroviral antibodies in primary
retroviral superantigen may be responsible, in part, for triggering an
biliary cirrhosis and other idiopathic biliary
inflammatory cascade leading to autoantibody production, and
cholangiocyte destruction (6). Because MMTV viral replication isregulated by the female hormone progesterone (5), this may provide
an explanation for the predominantly female incidence of PBC.
A, Carman W, Neuberger J (1998)Expression of pyruvate-dehydrogenase
These findings add further impetus to ongoing trials of anti-retroviral
complex PDC-E2 on biliary epithelial cells
therapies in PBC (1). Mason and colleagues have initiated small pilot
trials of treatment of PBC patients with lamivudine or Combivir (a
biliary cirrhosis. Lancet 352: 1595-1596.
combination of lamivudine and zidovudine) (1). Significantimprovements in serum aspartate aminotransferase (AST), alanine
aminotransferase (ALT), and alkaline phosphatase (Alk Phos) levels
were observed in patients after 6 months of Combivir treatment (1). A
human betaretrovirus proviral genome from
reduction in serum liver biochemistry was seen in most patients taking
patients with primary biliary cirrhosis.
Combivir, but not lamivudine alone (1). A reduction of serum
antimitochondrial antibody levels in the majority of patients followingtreatment also raises the possibility that antiretroviral therapy has an
effect on the pathogenesis of the disease (1).
A, Joplin R, O'Donnell B, Aitken J, CarmanW, Neuberger J, Mason A (2003) Does a
Poupon and Poupon (6) have recently called attention to the need for a
clinical trial to further test the effectiveness of anti-retroviral therapy
biliary cirrhosis? Proc. Natl. Acad. Sci.
in PBC. They urge that patients enrolled in such a trial will need to
have a high concentration of viral sequences in blood or peripheralblood cells, and should be in an early stage of the disease (6).
6. Poupon R, Poupon RE (2004) Retrovirusinfection as a trigger for primary biliary
How are these studies relevant to PSC? In 1998, Mason and
colleagues also detected retroviral antibodies in patients with primarysclerosing cholangitis (2). As far as I am aware, these findings have
not been pursued as tenaciously as they have been in PBC. I eagerly
await follow-up investigations of the possible involvement of a
retrovirus (or other infectious agents) in the pathogenesis of PSC.
Geographic clusters of primary biliarycirrhosis. Clin. Dev. Immunol. 10: 127-131.
David Rhodes is a member of the U.S.-based "Primary Sclerosing Cholangitis Support Group":http://health.groups.yahoo.com/group/psc-support/
He maintains a website with links to a large number of www resources and research abstracts on PSC, UC andallied diseases:http://home.insightbb.com/~rhodesdavid/
David is a Professor in the Department of Horticulture and Landscape Architecture at Purdue University, WestLafayette, IN, U.S.A.
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