Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.

/pdf/mendelian-randomization-can-genetic-epidemiology-contribute-vb0zjyrtxf.pdf

‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?

[Crohn's disease].

The neurotrophins are a small group of dimeric proteins that profoundly affect the development of the nervous system of vertebrates. Recent studies have established clear correlations between the survival requirements for different neurotrophins of functionally distinct subsets of sensory neurons. The biological role of the neurotrophins is not limited to the prevention of programmed cell death of specific groups of neurons during development. Neurotrophin-3 in particular seems to act on neurons well before the period of target innervation and of normally occuning cell death. In animals lacking functional neurotrophin or receptor genes, neuronal numbers do not seem to be massively reduced in the CNS, unlike in the PNS. Finally, rapid actions of neurotrophins on synaptic efficacy, as well as the regulation of their mRNAs by electrical activity, suggest that neurotrophins might play important roles in regulating neuronal connectivity in the developing and in the adult central nervous system.

Physiology of the neurotrophins

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The induction of pain: an integrative review

50 Years of Image Analysis

Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo.

Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: Evidence for a regulatory function of nerve growth factor in vivo

Carbamylation of proteins through reactive cyanate has been demonstrated to predict an increased cardiovascular risk. Cyanate is formed in vivo by breakdown of urea and at sites of inflammation by the phagocyte protein myeloperoxidase. Because myeloperoxidase (MPO) associates with high-density lipoprotein (HDL) in human atherosclerotic intima, we examined in the present study whether cyanate specifically targets HDL. Mass spectrometry analysis revealed that protein carbamylation is a major posttranslational modification of HDL. The carbamyllysine content of lesion-derived HDL was more than 20-fold higher in comparison with 3-chlorotyrosine levels, a specific oxidation product of MPO. Notably, the carbamyllysine content of lesion-derived HDL was five- to eightfold higher when compared with lesion-derived low-density lipoprotein (LDL) or total lesion protein and increased with lesion severity. The carbamyllysine content of HDL, but not of LDL, correlated with levels of 3-chlorotyrosine, suggesting ...

Protein carbamylation renders high-density lipoprotein dysfunctional

Effects of the cyclo-oxygenase (COX)-1 inhibitor SC-560 and the COX-2 inhibitors rofecoxib and DFU were investigated in the normal stomach and after acid challenge.


In healthy rats, neither SC-560 nor rofecoxib (20 mg kg−1 each) given alone damaged the mucosa. Co-treatment with SC-560 and rofecoxib, however, induced severe lesions comparable to indomethacin (20 mg kg−1) whereas co-administration of SC-560 and DFU (20 mg kg−1 each) had no comparable ulcerogenic effect 5 h after dosing.


SC-560 (20 mg kg−1) inhibited gastric 6-keto-prostaglandin (PG) F1α by 86±5% and platelet thromboxane (TX) B2 formation by 89±4% comparable to indomethacin (20 mg kg−1). Rofecoxib (20 mg kg−1) did not inhibit gastric and platelet eicosanoids.


Intragastric HCl elevated mucosal mRNA levels of COX-2 but not COX-1. Dexamethasone (2 mg kg−1) prevented the up-regulation of COX-2.


After acid challenge, SC-560 (5 and 20 mg kg−1) induced dose-dependent injury. Rofecoxib (20 mg kg−1), DFU (5 mg kg−1) and dexamethasone (2 mg kg−1) given alone were not ulcerogenic but aggravated SC-560-induced damage. DFU augmented SC-560 damage 1 but not 5 h after administration whereas rofecoxib increased injury after both treatment periods suggesting different time courses.


Gastric injurious effects of rofecoxib and DFU correlated with inhibition of inflammatory PGE2.


The findings show that in the normal stomach lesions only develop when both COX-1 and COX-2 are inhibited. In contrast, during acid challenge inhibition of COX-1 renders the mucosa more vulnerable suggesting an important role of COX-1 in mucosal defence in the presence of a potentially noxious agent. In this function COX-1 is supported by COX-2. In the face of pending injury, however, COX-2 cannot maintain mucosal integrity when the activity of COX-1 is suppressed.





Keywords: Cyclo-oxygenase-1, cyclo-oxygenase-2, gastric damage, rofecoxib, DFU, SC-560, gastric 6-keto-prostaglandin F1α, platelet thromboxane, inflammatory prostaglandin E2, non-steroidal anti-inflammatory drugs


Introduction
Two isoforms of cyclo-oxygenase (COX), the key enzyme in prostaglandin (PG) and thromboxane (TX) biosynthesis, referred to as COX-1 and COX-2, have been identified. Each enzyme is encoded by a separate gene (Hla & Neilson, 1992) and has a distinct pattern of expression and biological function. COX-1 is expressed constitutively and high levels can be detected in most tissues (O'Neill & Ford-Hutchinson, 1993). In contrast, levels of COX-2 mRNA and protein are usually low or undetectable under basal conditions but are rapidly elevated during inflammation or mitogenic stimulation (Raz et al., 1989; Kujubu et al., 1991). The COX isoforms are the primary target enzymes for non-steroidal anti-inflammatory drugs (NSAIDs). It was postulated that inhibition of COX-2 mediates the anti-inflammatory and chemopreventive effects of NSAIDs without relevant influence on homeostasis reactions, whereas inhibition of COX-1 is responsible for the NSAID-associated side effects in the gastrointestinal tract, cardiovascular system and kidney (Vane & Botting, 1995). This concept was corroborated by studies showing that e.g. the severity of gastrointestinal side effects that occur during NSAID therapy correlates with the COX-1 selectivity of the drugs (Warner et al., 1999). Furthermore, it was demonstrated that selective COX-2 inhibitors do not induce gastric mucosal damage in experimental animals (Futaki et al., 1993; Masferrer et al., 1994; Riendeau et al., 1997; Schmassmann et al., 1998; Chan et al., 1999) and cause significantly less gastrointestinal side effects in humans than standard NSAIDs that inhibit both COX-1 and COX-2 (Laine et al., 1999; Langman et al., 1999; Simon et al., 1999).

In contrast to the initial hypothesis, recent findings suggest that COX-2 contributes to prostaglandin biosynthesis in physiological situations. Thus, COX-2 is expressed constitutively in the brain (Lukiw & Bazan, 1997), kidney (Harris, 1996) and pancreatic islets (Robertson, 1998). A physiological role of COX-2 is supported by the finding that COX-2 deficient mice have defects in renal function (Morham et al., 1995), female reproductive physiology (Lim et al., 1997), and regulation of bone resorption (Raisz, 1999). Moreover, in healthy humans, urinary excretion of 6-keto-PGF1α and the metabolite 2,3 dinor 6-keto-PGF1α was significantly suppressed by the COX-2 inhibitor celecoxib implicating a major role for COX-2 in the biosynthesis of renal and systemic PGI2 under physiological conditions (McAdam et al., 1999). In rats, COX-2 inhibitors counteracted the gastroprotective effects of a mild irritant (Gretzer et al., 1998) or luminal perfusion with peptone (Ehrlich et al., 1998) and markedly aggravated gastric damage induced by ischaemia-reperfusion (Maricic et al., 1999). COX-2 inhibitors delayed the healing of gastric ulcers in mice (Mizuno et al., 1997) and rats (Schmassmann et al., 1998) and inhibited angiogenesis, epithelial cell proliferation and maturation of the granulation tissue in chronic gastric ulcers (Schmassmann et al., 1998). Furthermore, in a rat colitis model, COX-2 inhibitors were demonstrated to cause exacerbation of colonic inflammation (Reuter et al., 1996). On the other hand, in the rat stomach chronic administration of endotoxin increased the expression of both COX-1 and COX-2 mRNA but only the non-selective COX inhibitor indomethacin and not a selective COX-2 inhibitor counteracted the protective effect of endotoxin (Ferraz et al., 1997). Hence, both COX-1 and COX-2 were found to mediate gastrointestinal defence reactions in certain pathophysiological situations.

Standard NSAIDs cause profound inhibition of gastric mucosal prostaglandin formation and induce gastric mucosal injury in experimental animals and humans. As selective COX-2 inhibitors have a markedly reduced capacity to exert gastrotoxic effects, it was postulated that in the healthy stomach COX-1 is the exclusive COX isoform responsible for the maintenance of mucosal integrity (Vane & Botting, 1995; Warner et al., 1999) with COX-2 contributing to mucosal defence only under pathophysiological conditions. This hypothesis seemed to be supported by the finding that a selective COX-1 inhibitor (Smith et al., 1998) but not selective COX-2 inhibitors (Mizuno et al., 1997; Schmassmann et al., 1998; Gretzer et al., 1998; Ehrlich et al., 1998; Maricic et al., 1999) cause measurable inhibition of gastric mucosal prostaglandin formation. The present study investigates in rats the effects of the selective COX-1 inhibitor [5-(4-chlorophenyl)-1 - (4 - methoxyphenyl) - 3 -trifluoromethylpyrazole] (SC-560) (Smith et al., 1998) and the selective COX-2 inhibitors 4-[4-(methylsulphonyl)phenyl]-3-phenyl-2(5H)-furanone (rofecoxib) (Chan et al., 1999) and 5,5-dimethyl -3 -(3 -fluorophenyl) - 4 - (4 - methylsulphonyl)phenyl -2(5II)-furanone (DFU) (Riendeau et al., 1997) on gastric mucosal integrity in the normal rat stomach and after intraluminal acid instillation. The doses of the COX-2 inhibitors used in our experiments were selected with respect to the reported anti-inflammatory effects of rofecoxib (Chan et al., 1999) and DFU (Riendeau et al., 1997) in various models of inflammation in rats. The findings of this study show that in the normal stomach mucosal damage only develops when both COX-1 and COX-2 are inhibited. A similar conclusion has recently been reached using other COX-2 inhibitors in combination with SC-560 by Wallace et al. (2000). In contrast to normal gastric mucosa, in acid-challenged gastric mucosa selective inhibition of COX-1 is sufficient to produce mucosal injury that is further increased by simultaneous COX-2 inhibition. Some of this work has been previously published in abstract form (Gretzer et al., 2000).

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0703955

Rufina Schuligoi

Papers

Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo.

Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: Evidence for a regulatory function of nerve growth factor in vivo

Protein carbamylation renders high-density lipoprotein dysfunctional

Effects of specific inhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the rat stomach with normal mucosa and after acid challenge.

E-type prostanoid receptor 4 (EP4) in disease and therapy