Early and mid-term results of a prospective observational study comparing emergency endovascular aneurysm repair with open surgery in both ruptured and unruptured acute abdominal aortic aneurysms.

The aim of the paper is to prospectively describe early and mid-term outcomes for emergency endovascular aneurysm repair (eEVAR) versus open surgery in acute abdominal aortic aneurysms (aAAAs), both unruptured (symptomatic) and ruptured. We enrolled all consecutive patients treated for aAAA at our center between April 2002 and April 2008. The main outcome parameters were 30-day, 6- and 12-month mortality (all-cause and aneurysm-related). Two hundred forty patients were enrolled in the study. In the unruptured aAAA group (n = 111), 47 (42%) underwent eEVAR. The 30-day, 6- and 12-month mortality rates were 6, 13 and 15% in the eEVAR group versus 11% (NS), 13% (NS) and 16% (NS) in the open group, respectively. In the ruptured aAAA group (n = 129), 25 (19%) underwent eEVAR (mortality rates: 20, 28 and 36%, respectively) compared with 104 (81%) patients who underwent open surgery (mortality rates: 45% (P = 0.021), 60% (P = 0.004) and 63% (P = 0.014), respectively). In conclusion, the present study showed a reduced 30-day, 6- and 12-month mortality of eEVAR compared with open surgery in all patients with aAAA, mainly due to a lower mortality in the ruptured aAAA group. Late aneurysm-related mortality occurred only in the eEVAR group.

Treatment for intermittent claudication and the effects on walking distance and quality of life.

The objective of the study was to provide an overview of the most common treatments for intermittent claudication and to determine the effectiveness in improving walking distance and quality of life based on a combination of direct and indirect evidence. We included trials that compared: angioplasty, surgery, exercise therapy or no treatment for intermittent claudication. Outcome measurements were walking distance (maximum, pain-free) and quality of life (physical, mental). We used a network meta-analysis model for the combination of direct and indirect evidence. We included 42 studies, presenting 3106 participants. The network meta-analysis showed that supervised exercise therapy (Δ = 1.62, P < 0.01), angioplasty (Δ = 1.89, P < 0.01) and surgery (Δ = 2.72, P = 0.02) increased walking distance significantly more than no treatment. Furthermore, supervised exercise therapy (Δ = 0.60, P < 0.01), angioplasty (Δ = 0.91, P = 0.01) and surgery (Δ = 1.07, P < 0.01) increased physical quality of life more than no treatment. However, in the sensitivity analysis, only supervised exercise therapy had additional value over no symptomatic treatment (Δ = 0.66, P < 0.01). In conclusion, this network meta-analysis indicates that supervised exercise therapy is more effective in both increasing walking distance and physical quality of life, compared with no treatment. Angioplasty and surgery also increase walking distance, compared with no treatment, but results for physical quality of life are less convincing.

Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease.

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumour necrosis factor (TNF)-α, a known agonist of the mitogen-activated protein kinase (MAPK) pathway, is a key cytokine in this process. We aimed first to determine whether p38 MAPK is activated in IBD inflamed mucosa, and then studied the effect of four different p38α inhibitory compounds on MAPK phosphorylation and secretion of proinflammatory cytokines by IBD lamina propria mononuclear cells (LPMCs) and organ culture biopsies. In vivo phospho-p38α and p38α expression was evaluated by immunoblotting on intestinal biopsies from inflamed areas of patients affected by Crohn's disease and ulcerative colitis, and from normal mucosa of sex- and age-matched control subjects. Both mucosal biopsies and isolated LPMCs were incubated with four different p38α selective inhibitory drugs. TNF-α, interleukin (IL)-1ß and IL-6 were measured in the organ and cell culture supernatants by enzyme-linked immunosorbent assay. We found higher levels of phospho-p38α in the inflamed mucosa of IBD patients in comparison to controls. All the p38α inhibitory drugs inhibited p38α phosphorylation and secretion of TNF-α, IL-1ß and IL-6 from IBD LPMCs and biopsies. Activated p38α MAPK is up-regulated in the inflamed mucosa of patients with IBD. Additionally, all the p38α selective inhibitory drugs significantly down-regulated the activation of the MAPK pathway and the secretion of proinflammatory cytokines.

From the Cochrane library: Ginkgo biloba for intermittent claudication.

BACKGROUND: Patients with intermittent claudication suffer from pain in the muscles of the legs during exercise that is relieved by a short rest. Ginkgo biloba extract is a vasoactive agent used for symptomatic relief in intermittent claudication. In this article a meta-analysis is discussed that assessed the effect of Ginkgo biloba on walking capacity in patients with intermittent claudication. PATIENTS AND METHODS: The Cochrane Peripheral Vascular Diseases Group searched their Trials Register and the Cochrane Central Register of Controlled Trials in The Cochrane Library. Furthermore MEDLINE/PUBMED (until May 2008) and EMBASE (until May 2008) were searched and manufacturers of Ginkgo biloba extract were contacted. Randomized controlled trials of Ginkgo biloba extract versus placebo in people with intermittent claudication were included. Two authors independently assessed trials for selection, assessed study quality and extracted data. To standardize walking distance or time, caloric expenditures were used to correct for the different treadmill protocols. RESULTS: Eleven trials involving 477 participants compared Ginkgo biloba with placebo and assessed the absolute claudication distance (maximal walking distance). At the end of the study the absolute claudication distance increased with an overall effect size of 3.57 kilocalories ( p = 0.06), for treatment with Ginkgo biloba, compared to placebo. This translates to an increase of 64.5 meters (confidence interval -1.8 to 130.7) on a flat treadmill with an average speed of 3.2 km/h. CONCLUSIONS: There is no evidence that Ginkgo biloba has a clinically significant benefit for patients with intermittent claudication.

Predictors of walking distance after supervised exercise therapy in patients with intermittent claudication.

OBJECTIVE: To identify predictor variables for results after supervised exercise therapy (SET), and to develop a clinical prediction model that aims to predict a target walking distance for individual patients. DESIGN: Retrospective analyses on prospectively collected data. MATERIALS: Patients with intermittent claudication who participated in a SET programme. METHODS: SET was conducted according to the guidelines of the Royal Dutch Society for Physiotherapy. The main outcome measurement was the absolute claudication distance (ACD) after 6 months of SET. Linear regression analyses were conducted to identify independent predictor variables for ACD. RESULTS: In this cohort, 437 patients were analysed. Independent predictor variables for post-treatment ACD were baseline ACD (P<0.001), smoking behaviour (P=0.012) and body-mass index (P=0.041). A better baseline ACD was associated with a longer post-treatment ACD whereas current smoking and a higher body-mass index were associated with a shorter post-treatment ACD. The final regression equation included baseline ACD, age, body-mass index, smoking and pulmonary disease, and was translated into several clinical prediction models. However, only 24.8-33.6% of the patients had an ACD within the calculated target range. CONCLUSIONS: Predictive variables for post-treatment ACD after SET are baseline ACD, age, body-mass index, pulmonary disease and smoking behaviour. However, translating the regression equation into a clinical prediction model did not lead to a valid model for use in clinical practice.

Supervised exercise versus non-supervised exercise for reducing weight in obese adults.

AIM: The prevalence of obesity is rising. Because obesity is positively associated with many health related risks and negatively associated with life expectancy this is a threat to public health. Physical exercise is a well known method to lose fat mass. Due to shame of their appearance, bad general condition and social isolation, starting and continuing physical exercise tends to be problematic for obese adults. A supervised training program could be useful to overcome such negative factors. In this study we hypothesized that offering a supervised exercise program for obese adults would lead to greater benefits in body fat and total body mass reduction than a non-specific oral advice to increase their physical activity. METHODS: Thirty-four participants were randomised to a supervised exercise program group (N.=17) and a control group (N.=17). Fifteen candidates in the intervention group and 12 in the control group appeared for baseline measurements and bought an all inclusive sports pass to a health club for Euro 10, per month. The control group just received the oral advice to increase their physical activity at their convenience. The supervised exercise group received biweekly exercise sessions of 2 hours with an estimated energy expenditure of 2 500 kJ per hour. Both groups received no dietary advice. RESULTS: After 4 months the overall decrease in body mass in the intervention group was 8.0 kg (SD 6.2) and the decrease in body fat was 6.2 kg (SD 4.5). The control group lost 2.8 kg overall (SD 4.2) and the decrease in body fat was 1.7 kg (SD 3.1). Correction for differences between groups in gender and age by multiple linear regression analysis showed significantly greater loss of total body mass (P = 0.001) and fat mass (P =0.002) in the intervention group compared with the control group. CONCLUSIONS: Stimulation of physical activity alone seems to result in a slight short term body mass and fat mass reduction in obese adults who are eager to lose weight. Supervised exercise under supervision of a qualified fitness instructor leads to a larger decrease.

Validation of the Dutch version of the Walking Impairment Questionnaire.

OBJECTIVES: The Walking Impairment Questionnaire (WIQ) is a frequently used questionnaire to evaluate patients with intermittent claudication (IC). The aim of this study is to validate the Dutch WIQ for the European situation using the metric system. DESIGN: Validation study. MATERIALS: After translation and cultural adaptation of the WIQ, 130 patients with IC completed the Dutch WIQ, the RAND-36, and the EuroQol questionnaire. Walking distances were determined by treadmill testing. METHODS: Correlations between the WIQ, the two quality of life questionnaires, and walking distances were calculated to determine validity. Reliability and internal consistency were determined using the intraclass correlation coefficient (ICC) and Cronbach's alpha, respectively. RESULTS: Significant correlations were found between the WIQ and the absolute claudication distance (ACD) (0.52), EuroQol (0.33) and seven domains of the RAND-36. Test-retest reliability expressed by the ICC was 0.89. The internal consistency determined by Cronbach's alpha was 0.92 for the total WIQ score. Furthermore, a lower WIQ score corresponds to a shorter ACD. CONCLUSIONS: This study shows that the Dutch version of the WIQ using the European metric system is a valid, reliable and clinically relevant instrument for assessing walking impairment in patients with intermittent claudication.

[From the Cochrane Library: increased walking distance through supervised exercise therapy in patients with intermittent claudication]. / Uit de Cochrane Library: langere loopafstand door gesuperviseerde looptherapie bij patiënten met claudicatio intermittens.

Intermittent claudication is the most important symptom of peripheral arterial disease. Walking is the main treatment for intermittent claudication and is usually prescribed as a single recommendation to 'go home and walk'. A recent Cochrane systematic review of 7 randomised trials and 1 controlled trial compared a supervised walking regimen with non-supervised exercise therapy. Supervised exercise therapy showed statistically significant benefits compared with non-supervised exercise therapy. Further research is needed to determine the clinical relevance of this difference, with a focus on quality of life. Long-term results with supervised exercise therapy should be studied in future trials.

Blockade of transforming growth factor beta upregulates T-box transcription factor T-bet, and increases T helper cell type 1 cytokine and matrix metalloproteinase-3 production in the human gut mucosa.

BACKGROUND AND AIMS: The role of transforming growth factor beta (TGFbeta) in inhibiting T cell function in the normal gut has been studied in animal models. However, the impact of TGFbeta inhibition on T cells in the normal human gut remains poorly understood. The effect of TGFbeta blockade in normal intestinal biopsies grown ex vivo and lamina propria mononuclear cells (LPMCs) on T-bet, a T-box transcription factor required for T helper cell type (Th)1 differentiation, interferon gamma (IFN gamma) production, T cell apoptosis and matrix metalloproteinase (MMP)-3 production has therefore been tested. METHODS: TGFbeta transcripts were determined by quantitative reverse transcription-PCR in laser-captured gut epithelium and lamina propria. Biopsies and LPMCs were cultured with anti-TGFbeta neutralising antibody. After 24 h culture, T-bet was determined by immunoblotting, and T cell apoptosis was assessed by flow cytometry. IFN gamma, tumour necrosis factor alpha (TNFalpha), interleukin (IL) 2, IL6, IL8, IL10, IL12p70 and IL17 were measured by ELISA. MMP-3 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were assessed by immunoblotting. RESULTS: A higher number of TGFbeta transcripts was found in the lamina propria than in the epithelium in normal gut. T-bet expression was significantly higher in biopsies and LPMCs cultured with anti-TGFbeta antibody than in those cultured with control antibody. TGFbeta blockade downregulated T cell apoptosis, and induced a significant increase in IFN gamma, TNFalpha, IL2, IL6, IL8 and IL17 production. A higher expression of MMP-3, but not TIMP-1, was observed in the tissue and supernatant of biopsies treated with anti-TGFbeta antibody. CONCLUSIONS: The findings support a crucial role for TGFbeta in dampening T cell-mediated tissue-damaging responses in the human gut.

Supervised exercise therapy for intermittent claudication.

PURPOSE OF THE REVIEW: Although exercise therapy is considered to be of significant benefit to people with intermittent claudication, almost half of those affected do not undertake any exercise therapy. The purpose of this review is to evaluate the effects of supervised exercise therapy (SET) for people with intermittent claudication. MATERIALS AND METHODS: SET will be compared with non-supervised exercise therapy programs and the superiority of SET will be demonstrated. The development and implementation of a new community-based concept of SET will be addressed, whereas the first results of this new concept will be presented and compared with the results of SET programs provided in clinical settings, as described in literature. MAIN RESULTS: SET programs have significant benefits compared with non-supervised programs. Community-based SET has both economic and logistic advantages over clinic-based SET. Furthermore, community-based SET programs seems to be as effective as SET provided in a clinic-based setting and is a promising approach to providing conservative treatment for patients with intermittent claudication. CONCLUSIONS: SET in a community-based setting should ideally be the initial standard of care for patients with intermittent claudication. However, a study of the cost-effectiveness should be awaited.

Expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel diseases.

BACKGROUND/AIMS: Matrix metalloproteinases are major contributors in the breakdown and reconstitution of basement membranes and extracellular matrix in pathophysiological processes. We assessed the expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel disease. PATIENTS/METHODS: Resected tissue specimens from patients with Crohn's disease or ulcerative colitis and control tissue from patients with a colorectal carcinoma were used for enzyme-linked immunosorbent assay, zymography, activity assay, reverse transcription polymerase chain reaction and immunohistochemistry to evaluate the expression of these matrix metalloproteinases. RESULTS: Matrix metalloproteinase-2 and more strongly matrix metalloproteinase-9 protein and mRNA were markedly increased in inflammatory bowel disease tissues, with the highest levels in severely inflamed tissues. Immunohistochemistry showed that matrix metalloproteinase-2 was present in the extracellular matrix of the submucosa, with a lower but more generalised expression in the severely inflamed regions. Matrix metalloproteinase-9 was most prominent in polymorphonuclear leukocytes and was increased, also in activity, in all inflammatory bowel disease tissues. An increased matrix metalloproteinase-9 expression in the extracellular matrix was observed in relation to the severity of inflammation. CONCLUSIONS: Matrix metalloproteinases-2 and -9 are enhanced in the intestinal tissue and seem to be actively involved in the inflammatory and remodelling processes in inflammatory bowel disease, without major differences between CD and UC.

Review article: oxidative stress as a pathogenic factor in inflammatory bowel disease--radicals or ridiculous?

Virtually all inflammatory mediators investigated to date seem to be dysregulated in the inflamed intestinal mucosa of patients with inflammatory bowel disease. However, which of these are actually involved in the initiation and perpetuation of intestinal tissue damage is still not fully understood. Amongst these mediators are the reactive oxygen metabolites, produced in large amounts by the massively infiltrating leucocytes. These reactive oxygen metabolites are believed to constitute a major tissue-destructive force and may contribute significantly to the pathogenesis of inflammatory bowel disease. This paper provides a concise overview of reactive oxygen metabolite biochemistry, the types of cell and tissue damage potentially inflicted by them, and the endogenous antioxidants which should prevent these harmful effects. An up-to-date summary of the available human experimental data suggests that reactive oxygen metabolite-mediated injury is important in both the primary and downstream secondary pathophysiological mechanisms underlying intestinal inflammation. Nonetheless, how the individual components of the mucosal antioxidant enzymatic cascade respond to inflammatory conditions is a neglected area of research. This particular aspect of intestinal mucosal oxidative stress therefore merits further study, in order to provide a sound, scientific basis for the design of antioxidant-directed treatment strategies for inflammatory bowel disease patients.

Metallothionein in human gastrointestinal cancer.

Metallothionein (MT) is a small thiol-rich metalloprotein with antioxidant properties, involved in tumour pathophysiology and therapy resistance. In order to assess the contribution of MT in gastrointestinal carcinogenesis, this study examined both the MT content by radioimmunoassay and the MT localization by immunohistochemistry in pairs of neoplastic and normal-appearing human gastrointestinal tissues. In addition, the relationship between MT expression and major clinicopathological parameters was assessed. The MT concentration of gastric carcinomas and of colorectal adenomas, carcinomas, and liver metastases was found to be significantly lower than that of corresponding normal-appearing tissue. A relatively high MT content, however, was found to be associated with the villous character of colorectal adenomas and with the Dukes' stage of colorectal carcinomas, indicating a relationship between MT level and malignant potential. Immunohistochemical evaluation showed a fairly good correlation with these quantitative data. MT was found to be expressed at a low level and in a patchy pattern in the gastrointestinal neoplastic and metastatic tissues, whereas in normal-appearing gastrointestinal mucosa MT was uniformly distributed in the cytoplasm and/or nucleus of apical cells. Although in the gastric cancer patients no association was found between the MT concentration and the clinicopathological parameters, the strong MT expression in areas with intestinal metaplasia, known to have neoplastic potential, further points to a relationship between this antioxidant metalloprotein and the malignant character of cells. Gastrointestinal neoplasms are apparently accompanied by a low level and decreased expression of MT, but those with a relatively high level seem to have an increased malignant potential. Further studies will be required to determine the clinical relevance of these observations.

Superoxide dismutases in the human colorectal cancer sequence.

PURPOSE: The oxidant-antioxidant balance within tissues is thought to contribute to the development and progression of cancer. Previous investigations have indicated changes in this balance during the colorectal oncogenic process that merit further investigation. The aim of the present study was to evaluate whether the human colorectal cancer sequence is accompanied by changes in the protein and activity levels of the antioxidant enzymes manganese- and copper/zinc-superoxide dismutase (Mn-SOD and Cu/Zn-SOD). PATIENTS AND METHODS: SOD levels were assessed in colorectal adenomas, carcinomas, and liver metastases and were compared with those in the corresponding normal tissues (n = 35 in each group). Mn- and Cu/Zn-SOD expression was first evaluated semiquantitatively by electrophoretic activity analysis, immunoblotting, and immunohistochemistry and was subsequently quantified by enzyme-linked immunosorbent assays (ELISAs) and spectrophotometric activity assays. RESULTS: The semiquantitative analyses showed enhanced Mn-SOD levels, primarily localized in (neoplastic) epithelial cells, in carcinomas, and in liver metastases as compared with adenomas and normal mucosa, whereas no consistent pattern was observed for Cu/Zn-SOD. Normal liver tissue expressed the highest levels of both SODs. The quantitative SOD analyses confirmed these observations and revealed that carcinomas and liver metastases expressed 2-4 times more Mn-SOD protein and enzymatic activity (0.0005 < P < 0.01) than did the normal mucosa. Adenomas expressed intermediate Mn-SOD levels, which increased significantly with the diameter and tended to increase with the grade of dysplasia and presence of a villous component. In contrast, adenomas, carcinomas, and the corresponding normal mucosa were found to have a similar Cu/Zn-SOD content, whereas liver metastases contained significantly (P < 0.02) more Cu/Zn-SOD as compared with these tissues. In addition, the Cu/Zn-SOD content was not related to any histopathological characteristic of the carcinomas or adenomas. CONCLUSIONS: Our study indicates that the development of neoplasia in the human colorectum is accompanied by major changes in the level and activity of Mn-SOD. This observation illustrates that Mn-SOD might have a functional role in human colorectal carcinogenesis.

Antioxidants and mucosa protectives: realistic therapeutic options in inflammatory bowel disease?

Oxidative damage is involved in the pathogenic process of idiopathic chronic inflammatory bowel disease. Although specific intervention in the oxidative cascade showed promising results in animal models and preliminary patient trials, the clinical efficacy of antioxidants still has to be established. Mucosa protection, for example by dietary fatty acids, seems to attenuate the intestinal inflammatory process as well but awaits definite clinical proof for the treatment of inflammatory bowel disease.