Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Effect of infliximab on small bowel stenoses in patients with Crohn's disease

AIM: To assess prospectively small bowel stenoses in Crohn's disease (CD) patients treated with infliximab using Small Intestine Contrast Ultrasonography (SICUS). METHODS: Twenty patients (M 12, age, 42.7 +/- 11.8 years), 15 of whom showed obstructive symptoms indicating the presence of small bowel stenosis, and 5 without stenosis, were treated with infliximab (5 mg/kg at A 0, 2, 6 and 5 mg/kg every 8 A thereafter) for steroid refractoriness, fistulizing disease, or to avoid high-risk surgery. SICUS was performed at the induction phase and at regular time intervals during the follow-up period of 34.7 +/- 16.1 mo (range 7-58). Small bowel stenoses were detected by SICUS, endoscopy and MRI. RESULTS: In no case was progression of stenoses or the appearance of new ones seen. Of the 15 patients with stenosis, 5 stopped treatment after the induction phase (2 for no response, 3 for drug intolerance, one of whom showed complete regression of one stenosis). Among the remaining 10 patients, a complete regression of 8 stenoses (1 stenosis in 5 patients and 3 stenoses in one patient) was observed after 6-22 infliximab infusions. CONCLUSION: In patients with CD treated with infliximab we observed: (a) No progression of small bowel stenosis and no appearance of new ones, (b) Complete regression of 1/22 stenosis after the induction phase and of 8/15 (53.3%) stenosis after 6-22 infusions during maintenance therapy. (c) 2008 WJG. All rights reserved

[The efficacy of slow-release diltiazem in the treatment of stable angina of effort: a comparison between diltiazem and placebo].

The efficacy of a new slow release (SR) diltiazem preparation was assessed in 10 patients with stable effort angina. A double-blind, placebo controlled, randomized, crossover protocol was carried out comparing the effects of diltiazem 60 mg tid and diltiazem SR 120 mg bid on clinical and ergometric parameters. Exercise test was carried out 3 and 12 hours after the last dose of diltiazem or diltiazem SR respectively. Both drug preparations reduced the incidence of positive test, increased the exercise time and the time of onset of ischemic ST depression. The beneficial effects of the drugs appeared to be due to a reduction in myocardial oxygen consumption at the same workload as shown by the lesser value of pressure rate product at submaximal exercise. In conclusion, diltiazem SR at 12 hours after the last administration has the same effectiveness of diltiazem 60 mg at 3 hours

IL-1beta-511 and IL-1RN*2 polymorphisms in inflammatory bowel disease: An Italian population study and meta-analysis of European studies.

Several studies have tried to find possible associations between genetic polymorphisms and inflammatory bowel disease prevalence and/or phenotype. Our objectives were to test the frequency and phenotypic association of two polymorphisms of the interleukin-1 pathway, IL-1beta-511 and IL-1RN*2, in inflammatory bowel disease patients and controls from an Italian population, and to compare our data with previously published similar studies in Europe.We screened 290 inflammatory bowel disease patients (178 ulcerative colitis and 112 Crohn's disease) and 106 controls for IL-1beta-511 and IL-1RN*2 polymorphisms by polymerase chain reaction (PCR)-based methods. The prevalence of the IL-1beta-511 and IL-1RN*2 polymorphisms in European inflammatory bowel disease patients was calculated by a meta-analysis of previously published studies using the Mantel-Haenszel method.No correlation between the IL-1 polymorphisms and inflammatory bowel disease prevalence was found in our study population. Crohn's disease patients with the IL-1beta-511 mutation had a higher rate of complicated disease. A trend for an association between the IL-1RN*2 mutation and a higher risk for inflammatory bowel disease has been found only in studies with Northern European populations.The IL-1beta-511 mutation can be associated with complex disease behaviour in Italian Crohn's disease patients. The IL-1RN*2 mutation may play a role in Northern European people with inflammatory bowel disease

Polymorphisms of TNF-alpha but not MDR-1influence response to medical therapy in pediatric onset inflammatory bowel disease

AIM: We investigated the contribution of variants of tumour necrosis factor (TNF)-alpha and MDR1 genes in the predisposition and response to medical therapy in a large pediatric cohort of patients with Crohn disease (CD) and ulcerative colitis (UC). PATIENTS AND METHODS: In this study, 200 patients with CD, 186 patients with UC, 434 parents (217 trios), and 347 healthy unrelated controls were investigated. Single-nucleotide polymorphisms -G308A and -C857T of the TNF-alpha gene and C3435T of the MDR1 gene were investigated and correlated with clinical subphenotypes and efficacy of medical therapy. RESULTS: The frequency of the -308A allele of the TNF-alpha gene was significantly increased in both patients with CD (15%; odds ratio [OR] = 2.79; P < 0.01) and patients with UC (11%; OR = 1.96; P < 0.003) compared with controls (6%). Carriers of this allele were 27% in CD (OR = 2.94; P < 0.01) and 19% in UC (OR = 1.86; P = 0.015) compared with 11% in healthy controls. No significant difference was found for both the -C857T and C3435T single-nucleotide polymorphisms. With the genotype/phenotype analysis, no correlation in patients with UC with the MDR1 gene was found. CD carriers of the -308A allele had a higher frequency of surgical resection (35% vs 20%; OR = 2.1; P = 0.035) and more frequent resistance to steroids (22% vs 8%; OR = 0.29; P = 0.032) compared with noncarriers. These findings were confirmed by stepwise logistic regression. CONCLUSIONS: In our pediatric cohort, the promoter -308A polymorphism of TNF-alpha but not the MDR1 gene is significantly involved in the predisposition to both CD and UC. This polymorphism carries a significant reduction in response to steroid therapy, probably leading to a more frequent need for surgical resection

Polymorphisms of tumor necrosis factor-alpha but not MDR1 influence response to medical therapy in pediatric-onset inflammatory bowel disease

Abstract AIM: We investigated the contribution of variants of tumour necrosis factor (TNF)-alpha and MDR1 genes in the predisposition and response to medical therapy in a large pediatric cohort of patients with Crohn disease (CD) and ulcerative colitis (UC). PATIENTS AND METHODS: In this study, 200 patients with CD, 186 patients with UC, 434 parents (217 trios), and 347 healthy unrelated controls were investigated. Single-nucleotide polymorphisms -G308A and -C857T of the TNF-alpha gene and C3435T of the MDR1 gene were investigated and correlated with clinical subphenotypes and efficacy of medical therapy. RESULTS: The frequency of the -308A allele of the TNF-alpha gene was significantly increased in both patients with CD (15%; odds ratio [OR] = 2.79; P < 0.01) and patients with UC (11%; OR = 1.96; P < 0.003) compared with controls (6%). Carriers of this allele were 27% in CD (OR = 2.94; P < 0.01) and 19% in UC (OR = 1.86; P = 0.015) compared with 11% in healthy controls. No significant difference was found for both the -C857T and C3435T single-nucleotide polymorphisms. With the genotype/phenotype analysis, no correlation in patients with UC with the MDR1 gene was found. CD carriers of the -308A allele had a higher frequency of surgical resection (35% vs 20%; OR = 2.1; P = 0.035) and more frequent resistance to steroids (22% vs 8%; OR = 0.29; P = 0.032) compared with noncarriers. These findings were confirmed by stepwise logistic regression. CONCLUSIONS: In our pediatric cohort, the promoter -308A polymorphism of TNF-alpha but not the MDR1 gene is significantly involved in the predisposition to both CD and UC. This polymorphism carries a significant reduction in response to steroid therapy, probably leading to a more frequent need for surgical resection