·
Recent data suggest that activation of the
complement pathway may contribute to ischemia-reperfusion injury.[34] The complement system is involved in host defense and
is an important mechanism of immune injury ( Chapter 6 ). Some IgM antibodies have a propensity to deposit in ischemic
tissues, for unknown reasons, and when blood flow is resumed, complement
proteins bind to the antibodies, are activated, and cause cell injury and
inflammation. Knockout mice lacking several complement proteins are resistant
to this type of injury.
·
Lipoxins
are a recent addition to the family of bioactive products generated from AA,
and transcellular biosynthetic mechanisms (involving
two cell populations) are key to their production.
Leukocytes, particularly neutrophils, produce
intermediates in lipoxin synthesis, and these are
converted to lipoxins by platelets interacting with
the leukocytes. Lipoxins A4 and B4 (LXA4, LXB4) are
generated by the action of platelet 12-lipoxygenase on neutrophil-derived
LTA4 ( Fig. 2-17 ). Cell-cell contact enhances transcellular metabolism, and blocking adhesion inhibits lipoxin production. The principal actions of lipoxins are to inhibit leukocyte recruitment and the
cellular components of inflammation. They inhibit neutrophil
chemotaxis and adhesion to endothelium.[55] There is an inverse relationship between the amount of
lipoxin and leukotrienes
formed, suggesting that the lipoxins may be
endogenous negative regulators of leukotriene action
and may thus play a role in the resolution of inflammation.
A new class of arachidonic
acid-derived mediators, called resolvins,
have been identified in experimental animals treated with aspirin.[54] These
mediators inhibit leukocyte recruitment and activation, in part by inhibiting
the production of cytokines. Thus, the anti-inflammatory activity of aspirin is
likely attributable to its ability to inhibit cyclooxygenases
(see below) and, perhaps, to stimulate the production of resolvins.
·
A recently discovered peptide (25 amino acids,
synthesized by liver cells) named hepcidin appears to play an important role in iron
metabolism. It down-regulates the intestinal absorption and placental transfer
of iron and also the release of iron from macrophages, possibly by interaction
with ferroportin.
When plasma levels of iron are high, synthesis of hepcidin
increases; the opposite occurs when plasma levels of iron are low. It may play
an important role in hemochromatosis (see below) and
also in the iron deficiency anemia seen in chronic inflammatory conditions.
Another recently discovered protein named hemojuvelin may act by modulating the
expression of hepcidin.
·
recent studies, mostly
in mice, have implicated another CD4+ T-cell subset, the "TH17" cells, in immune reactions. The
signature cytokine of this subset is IL-17, which is a potent inducer of
inflammation. It may be that TH17 cells are important contributors to
inflammatory diseases, such as Crohn disease and multiple sclerosis.
·
peripheral blood cells
of SLE patients show evidence of overproduction of the cytokine IFN-a and of increased responses to this cytokine. IFN-a is an antiviral cytokine produced during the early innate
immune response to many viruses. The relevance of the "interferon
signature" to the development of SLE is intriguing but remains
unexplained. Persistent activation of B cells by self nucleoproteins engaging
Toll-like receptors has also been invoked as a mechanism of autoantibody
production.
·
cancer stem cells, sometimes called tumor-initiating cells, were identified in breast cancer, glioblastoma multiforme (a brain tumor), and acute myeloid leukemia.
Cancer stem cells constitute fewer than 2% of the cells in breast tumors and
0.1% to 1.0% of cells in acute myeloid leukemia.
·
Recent data has
confirmed the adverse effects of HRT on endometrial and breast cancers but does
not support the view that HRT offers protection against ischemic heart disease.
·
The pluripotency
of ES cells may be related to the expression of unique transcription
factors in these cells, such as a recently described homeobox
protein called Nanog (named after Tir na n'Og, the Celtic land of the ever-young). Recent studies
also implicate the Wnt-ß-catenin signaling
in maintaining pluripotency.
·
in addition to the
numerous structural malformations, patients with the 22q11.2 deletion syndrome are at a particularly high risk
for psychotic illnesses, such as schizophrenia
and bipolar disorders.
·
ICAT
(isotope-coding affinity tags) used in PROTEOMICs does not rely on
electrophoresis for protein separation. In ICAT, proteins in the test and
control samples are labeled with light or heavy isotopes. The differentially
labeled proteins are then identified and quantified by mass spectrometry. A
variation of proteomic analysis has been used to obtain protein profiles in the
blood of cancer patients without identification of individual proteins.
·
Recent studies have revealed that endosymbiotic rickettsia-like Wolbachia bacteria infect filarial nematodes
and might contribute to pathogenesis of disease.] Wolbachia
appear to be needed for nematode development and reproduction, since
antibiotics that eradicate Wolbachia impair nematode
survival and fertility. It has been hypothesized that LPS from Wolbachia may stimulate inflammatory responses.
doxycycline treatment has been
shown to block reproduction of O. volvus for up to 24
months. Doxycycline kills Wolbachia, which are
symbiotic bacteria that live inside adult O. volvulus
and are required for worm fertility, similar to filarial nematodes.
·
Recent studies indicate other untoward effects
of chronic hypervitaminosis
A. Vitamin A stimulates osteoclast
formation, thus leading to increased bone resorption and osteoporosis and predisposition to
fractures. This is particularly true in older individuals, who are prone to
osteoporosis.
·
The major abnormality in "new" BPD is a decrease in alveolar number, referred
to as alveolar hypoplasia.
Thus, the current view is that BPD is caused by an arrested development of alveolar septation
at the saccular stage.
·
Chinese Herbs
Nephropathy: A syndrome of chronic tubulointerstitial nephritis caused by aristolochic acid, a supplement found in some formulations of
herbal remedies, has been recognized recently. The drug causes a distinctive
picture of renal failure with histopathologic
features of interstitial fibrosis with a relative paucity of infiltrating
interstitial leukocytes. As with analgesic nephropathy, there is an increased
incidence of carcinoma in the kidney and urinary tract.
·
Recently, elevated tissue and serum levels of inhibin, an
ovarian product, have been associated with granulosa
cell tumors. This biomarker may be useful for identifying granulosa and other sex cord stromal
tumors, and for monitoring patients under therapy for these neoplasms.
·
mechanism recently
proposed for PREECLAMPSIA involves circulating soluble fms-like tyrosine kinase (sFlt1),
which binds both placental growth factor (PIGF) and vascular endothelial growth
factor (VEGF). Normally, serum sFlt1 increases, and PIGF and VEGF decrease near
term, reflecting a reduction in angiogenic activity.
In preeclampsia, decreased angiogenesis occurs much earlier than in normal
pregnancy. The premature application of an antiangiogenic
"brake" may, thus, be a key factor in the initiation of preeclampsia.
·
The AGE inhibitor
aminoguanidine has recently been shown to
retard the progression of nephropathy in type 1 diabetics.
·
Stem cells are located in sites called niches,[17] which
differ among various tissues ( Fig. 3-5 ). For instance, in the
gastrointestinal tract,[18] they are located at the
isthmus of stomach glands and at the base of the crypts of the colon (each
colonic crypt is the clonal product of a single stem
cell). Niches have been identified in other tissues, such as the bulge area of
hair follicles and the limbus of the cornea.
·
Another surprising revelation from the recent
progress in genomics is that, on average, any two individuals share 99.9% of
their DNA sequences. Thus, the remarkable
diversity of humans is encoded in about 0.1% of our DNA. The secrets
to disease predisposition and response to environmental agents and drugs must
therefore reside within these variable regions. Although small as compared to
the total nucleotide sequences, this 0.1% represents about 3 million base
pairs. The most common form of DNA variations in the human genome is the single
nucleotide polymorphism (SNP). Typically, the SNPs are biallelic
(i.e., only two choices exist at a given site within the population), and they
may occur anywhere in the genome—within exons, introns, or intergenic regions.
Less than 1% of SNPs occur in coding regions. These could of course alter the
gene product and give rise to a disease. Much more commonly, however, the SNP
is just a marker that is co-inherited with a disease-causing gene, due to
physical proximity. Another way of expressing this is to say that the SNP and
the genetic factor are in linkage disequilibrium. Much effort is ongoing to
make SNP maps of the human genome so that we can decipher genetic determinants
of disease.[5] Just as genomics involves the study of all the DNA sequences,
proteomics concerns itself with the measurement of all proteins expressed in a
cell or tissue. Currently, progress in proteomics is lagging behind genomics,
because the methodology to identify hundreds of distinct proteins
simultaneously is not fully developed, but much effort continues.
·
In 1961, Lyon[55]
outlined the X-inactivation, or what is commonly known as the Lyon hypothesis. It states that (1) only one
of the X chromosomes is genetically active, (2) the other X of either
maternal or paternal origin undergoes heteropyknosis
and is rendered inactive, (3) inactivation of either the maternal or paternal X
occurs at random among all the cells of the blastocyst
on or about the 16th day of embryonic life, and (4) inactivation of the same
X chromosome persists in all the cells derived from each precursor cell.
Thus, the great preponderance of normal females are in reality mosaics and have
two populations of cells, one with an inactivated maternal X and the other with
an inactivated paternal X. Herein lies the explanation of why females have the
same dosage of X-linked active genes as have males. The inactive X can be seen
in the interphase
nucleus as a darkly staining small mass in contact with the nuclear membrane
known as the Barr body, or X chromatin.
The molecular basis of X inactivation is just beginning to be understood. It
involves a unique gene called Xist, whose product is a noncoding
RNA that is retained in the nucleus, where it "coats" the inactive X
chromosome and initiates a gene-silencing process by chromatin modification and
DNA methylation. The
Xist allele is turned off in the active X.
Although it was initially thought
that all the genes on the inactive X are "shut off," more recent
molecular studies have revealed that many genes escape X inactivation. Recent
studies suggest that 21% of genes on Xp, and a
smaller number (3%) on Xq, escape X inactivation.
At least some of the genes that are expressed from both X chromosomes are
important for normal growth and development. This notion is supported by the
fact that patients with monosomy of the X chromosome
(Turner syndrome: 45,X) have severe somatic and gonadal abnormalities. If a single dose of X-linked genes
were sufficient, no detrimental effect would be expected in such cases.
Furthermore, although one X chromosome is inactivated in all cells during embryogenesis,
it is selectively reactivated in oogonia before the
first meiotic division. Thus, it seems that both X chromosomes are required
for normal oogenesis.