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Human Situation (human + situation)
Selected AbstractsLong-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2009K. Pels ABSTRACT Background, The optimal duration of clopidogrel treatment following percutaneous coronary intervention (PCI) and the patient population that would benefit most are still unknown. In a porcine coronary injury model, we tested two different durations of clopidogrel treatment on severely or moderately injured arteries and examined the arterial response to injury. To understand the molecular mechanism, we also investigated the effects on transcription factors nuclear factor-kappaB (NF-,B) and activator protein 1 (AP-1). Materials and methods, In 24 cross-bred pigs, one coronary artery was only moderately injured by percutaneous transluminal coronary angioplasty (PTCA) and one coronary artery was severely injured by PTCA and subsequent beta-irradiation (Brachy group). Animals received 325 mg aspirin daily for 3 months and 75 mg clopidogrel daily for either 28 days [short-term (ST) clopidogrel group] or 3 months [long-term (LT) clopidogrel group]. Results, After 3 months, the number of proliferating cells per cross-section differed significantly between ST and LT in both injury groups (PTCAST 90·2 ± 10·3 vs. PTCALT 19·2 ± 4·7, P < 0·05; BrachyST 35·8 ± 8·4 vs. BrachyLT 7·5 ± 2·0, P < 0·05). Similar results were seen for inflammatory cells (CD3+ cells): PTCAST 23·5 ± 3·55 vs. PTCALT 4·67 ± 0·92, P < 0·05; BrachyST 83·17 ± 11·17 vs. BrachyLT 20 ± 4·82, P < 0·05). Long-term administration also reduced the activity of NF-,B and AP-1 by 62,64% and 42,58%, respectively. However, the effects of different durations of clopidogrel administration on artery dimensions were not statistically significant. Conclusions, Regarding inflammation and transcription factor activity at the PCI site, long-term clopidogrel administration is superior to short-term administration, especially in severely injured arteries. Transferring our results to the human situation, patients with more severely diseased arteries may benefit from a prolonged clopidogrel medication after PCI. [source] Immunoregulatory effects of adenosine 5,-triphosphate on cytokine release from stimulated whole bloodEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2005Els L. R. Swennen Abstract In vitro studies suggest that extracellular nucleotides and nucleosides may be important regulators of inflammatory and immune responses. Most studies with adenosine 5,-triphosphate (ATP) have been performed in cell lines, which are remote from the human situation. The purpose of the present study was to determine the effects of ATP on TNF-,, IL-6 and IL-10 release in stimulated whole blood. Blood samples were drawn from healthy volunteers and incubated with ATP and lipopolysaccharide (LPS) + phytohemagglutinin (PHA) for 24,h. Contrary to expectations, ATP at 100,,M and 300,,M induced a reduction in TNF-, secretion by 32±8% (mean ± SEM) and 65±4%, respectively. Furthermore, these ATP concentrations induced an increase in IL-10 secretion by 48±5% and 62±7% in whole blood. The ATP analogue adenosine 5,-O-(3-thiotriphosphate) (ATP-,-S) and adenosine 5,-diphosphate (ADP) also inhibited TNF-, release, but only ADP showed a stimulatory effect on IL-10. Co-treatment with adenosine deaminase did not reverse the ATP effect on TNF-, and IL-10. These results show, for the first time, that ATP inhibits the inflammatory response in stimulated whole blood as indicated by inhibition of TNF-, and stimulation of IL-10 release and that this effect is predominantly mediated by ATP and not by adenosine. [source] Review of the potential photo-cocarcinogenicity of topical calcineurin inhibitorsJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 6 2005Position statement of the European Dermatology Forum ABSTRACT, Topical Calcineurin Inhibitors (TCIs) used for the treatment of atopic eczema modify the immune regulatory function of the skin and may have the potential to enhance immunosuppressive ultraviolet (UV) effects. Current recommendations on UV protection in eczema patients treated with PCIs are inconsistent and have given rise to uncertainty and anxiety in patients. Therefore, the European Dermatology Forum (EDF) developed a position statement which reviews critically the available data with regard to the problem, especially analysing and commenting the limitations of rodent models for the human situation. There is no conclusive evidence from rodent trials to indicate that long-term application of TCIs is photococarcinogenic. There is a need for further studies to investigate the validity of mouse models as well as long-term cohort studies in patients using TCIs. Available data suggest that long-term application of TCIs is safe, that there is no evidence of increased skin cancer risk and that it is ethical to treat patients with TCIs when indicated. [source] Iron and inflammatory bowel diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2001B. Oldenburg Both anaemia of iron deficiency and anaemia of chronic disease are frequently encountered in inflammatory bowel disease. Anaemia of iron deficiency is mostly due to inadequate intake or loss of iron. Anaemia of chronic disease probably results from decreased erythropoiesis, secondary to increased levels of proinflammatory cytokines, reactive oxygen metabolites and nitric oxide. Assessment of the iron status in a condition associated with inflammation, such as inflammatory bowel disease, is difficult. The combination of serum transferrin receptor with ferritin concentrations, however, allows a reliable assessment of the iron deficit. The best treatment for anaemia of chronic disease is the cure of the underlying disease. Erythropoietin reportedly may increase haemoglobin levels in some of these patients. The anaemia of iron deficiency is usually treated with oral iron supplements. Iron supplementation may lead to an increased inflammatory activity through the generation of reactive oxygen species. To date, data from studies in animal models of inflammatory bowel disease support the theoretical disadvantage of iron supplementation in this respect. The results, however, cannot easily be extrapolated to the human situation, because the amount of supplemented iron in these experiments was much higher than the dose used in patients with iron deficiency. [source] Gastroschisis: International epidemiology and public health perspectives,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 3 2008Eduardo E. Castilla Abstract Gastroschisis offers the intriguing epidemiological situation of a pandemic, strongly associated with very low maternal age. Identifying gastroschisis, and distinguishing it from the other abdominal wall defects, is theoretically easy but difficult in practice. The baseline birth prevalence of gastroschisis before the pandemic was approximately 1 in 50,000 births and has increased since between 10- and 20-fold. In many populations worldwide, it is still increasing. Such increasing prevalence and the association with very low maternal age are well proven, but the interaction between these two findings remains unknown. Geographic gradients (decreasing prevalence from North to South) are clear in Continental Europe and suggestive in Britain and Ireland. Gastroschisis seems more frequent in Caucasians compared to African Blacks and Orientals, and in Northern compared to Southern Europeans. These observations indicate the need for investigating gene,environment interactions. Since the global human situation is marked by inequalities among as well as within countries, the medical care and public health impact of gastroschisis varies widely among regions and social strata. The postnatal benefits of prenatal diagnosis of gastroschisis include family awareness; adequate planning of delivery with alerted obstetrical, pediatric, and surgical staff; optimal risk categorization, and personalized protocol for action. The increasing prevalence of gastroschisis combined with improved medical techniques to reduce morbidity and mortality are also increasing the burden and costs of this anomaly on health systems. © 2008 Wiley-Liss, Inc. [source] Mechanisms involved in the chemoprevention of flavonoidsBIOFACTORS, Issue 1-4 2000Marie-HÉLÉNe Siess Flavonoids, widespread in edible plants, have been studied extensively for their anticarcinogenic properties. However, only few studies have been done with these constituents being administered by the dietary route. In our research, the effects of feeding rats with flavone, flavanone, tangeretin, and quercetin were investigated on two steps of aflatoxin B1 (AFB1)-induced hepatocarcinogenesis (initiation and promotion). Nonpolar flavonoids such as flavone, flavanone and tangeretin administered through the initiation period, decreased the number of ,-glutamyl transpeptidase-preneoplastic foci. In the same conditions of administration, quercetin, a polyhydroxylated flavonoid, showed no protective effect. Moreover, feeding rats with flavanone during the phenobarbital-induced promotion step significantly reduced the areas of placental glutathione S-transferase preneoplastic foci. Quercetin, flavone, and tangeretin, administered in the same conditions, caused no significant effect. Therefore flavanone act as an anti-initiator as well as an anti-promotor. Several mechanisms were involved in the anti-initiating effects of flavone, flavanone, and tangeretin: enhancement of enzymes involved in the detoxication of AFB1 (glutathione S-transferase, UDP-glucuronyl transferase), increase of the formation of AFB1 -glutathione conjugates and inhibition of the binding of AFB1 to DNA. Although the relevance of these data to the human situation remains to be demonstrated, they confirm that several flavonoids administered by the dietary route possess promising chemoprotective effects. [source] Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodentsCANCER SCIENCE, Issue 6 2004Mami Takahashi Studies of colon carcinogenesis in animal models are very useful to elucidate mechanisms and provide pointers to potential prevention approaches in the human situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM), we have documented frequent mutations of specific genes. K-ras mutations at codon 12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large adenocarcinomas. In addition, mutations of the ,-catenin gene in its GSK-3, phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of p-catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of ,-catenin is a major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene mutations of ,-catenin and altered cellular localization of the protein are also features of AOM-induced colon tumors in mice. Expression of enzymes associated with inflammation, such as inducible nitric oxide synthase (INOS) and the inducible type of cyclooxyge-nase (COX), COX-2, is increased in AOM-induced rat colon carcinogenesis, and overproduction of nitric oxide (NO) and prostaglandins is considered to be involved in colon tumor development. We have demonstrated that increased expression of INOS is an early and important event occurring in step with ,-catenin alteration in rat colon carcinogenesis. Activation of K-ras was also found to be involved in up-regulation of INOS in the presence of inflammatory stimuli. In addition, expression levels of prostaglandin E2 (PGE2) receptors may be altered in colon cancers. For example, the EP, and EP2 subtypes have been shown to be up-regulated and EP3 down-regulated in AOM-induced colon cancers in rats and mice. EP, and EP4 appear to be involved in ACF formation, while alteration in EP2 and EP3 is considered to contribute to later steps in colon carcinogenesis. Increased expression of some other gene products, such as the targets of Wnt/,-catenin signaling, have also been reported. The further accumulation of data with this chemically-induced animal colon carcinogenesis model should provide useful information for understanding colorectal neoplasia in man. [source] | |||||||||||||