Pathology Updates

·         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.