Genetic association studies of interleukin-13 receptor alpha1 subunit gene polymorphisms in asthma and atopy.

Interleukin (IL)-13 plays a central role in asthma pathogenesis by binding to the IL-13 receptor, which is a heterodimer composed of the IL-13 receptor alpha1 subunit (IL-13Ralpha1) and IL-4Ralpha. The genetic diversity at the IL-13Ralpha1 gene (IL13RA1) locus on chromosome Xq24 was characterised and the association of identified polymorphisms with asthma and atopy phenotypes examined. The promoter and coding region of IL13RA1 were screened for common genetic variants, and polymorphisms found were genotyped in a large cohort of 341 asthmatic Caucasian families (each containing at least two asthmatic siblings) and 182 nonasthmatic control subjects. Genetic association was determined using case-control and transmission disequilibrium test analyses. Two common polymorphisms were identified, a newly found thymidine (T) to guanine (G) transition of nucleotide -281 (-281T>G) single nucleotide polymorphism in the IL13RA1 promoter and the previously described 1365A>G variant in the IL13RA1 proximal 3' untranslated region. No significant association of either -281T>G or 1365A>G with risk of asthma or atopy phenotypes was found, apart from a suggestive association between the IL13RA1 -281T/1365A haplotype and raised total serum immunoglobulin E levels in adult female asthmatics. These findings indicate that the interleukin-13 receptor alpha1 subunit gene -281T>G and 1365A>G polymorphisms do not contribute to asthma susceptibility or severity, although the interleukin-13 receptor alpha1 subunit gene locus might be involved in the control of immunoglobulin E production.     

Is infrainguinal bypass grafting successful following failed angioplasty?

OBJECTIVES: Angioplasty is often used in the management of lower limb ischaemia and can reduce the need for infrainguinal bypass in some patients. There is an associated failure rate with this technique and bypass surgery is often used in this situation as a secondary limb salvage procedure. We aimed to evaluate the outcome of infrainguinal bypass grafting following failed attempt at angioplasty. METHODS: All cases of infrainguinal bypass at a single centre over a seven year period were identified and notes reviewed. Cases were divided into four groups according to their indication for surgery; acute ischaemia, chronic critical ischaemia, failed angioplasty and an 'other' group including aneurysmal disease and claudicants. The failed angioplasty group was compared with the other three groups. Survival analysis was performed using Kaplan Meier curves and groups compared in terms of long term patency and survival. RESULTS: Primary patency was 61.2% in the failed angioplasty group at 12 months compared with 60.6% in the other groups (P=1.11). There was also no significant difference in primary patency at 60 months (50% vs 40.6%, P=0.26). Survival at 12 months was also comparable between the groups (failed angioplasty group 74.2% compared with 77.3% in the other groups, P=0.662) as was 60 months survival (33.3% and 35.4% respectively, P=0.166). DISCUSSION: In this study, outcome of infrainguinal bypass following failed angioplasty was comparable to outcome of surgery performed for another indication. This paper supports the use of distal bypass surgery for limb salvage in cases where minimal access techniques have failed.     

Ischaemia-reperfusion injury and regional inflammatory responses in abdominal aortic aneurysm repair.

OBJECTIVES: The inflammatory response to abdominal aortic aneurysm repair is likely to result in response to an ischaemia-reperfusion injury (IRI) to the lower-limbs and gastrointestinal tract. This paper reviews the pathogenesis of the inflammatory response to abdominal aortic aneurysm repair, with specific reference to the levels of evidence in the current literature regarding the potential origin of the inflammatory response. DESIGN: Review article. METHODS: The current literature (1966 to August 2003) was reviewed specifically for all articles employing techniques of regional blood sampling from the venous drainage of the lower limbs or gastrointestinal tract during abdominal aortic aneurysm repair. RESULTS: Ten relevant studies were identified. These demonstrated that regional blood sampling techniques could be easily performed, and provided useful information regarding the potential sites of origin of the inflammatory response. CONCLUSIONS: Regional blood sampling techniques provide useful information regarding the potential sites of origin of the inflammatory response. Current evidence suggests that both the lower limbs and gastrointestinal tract are clearly important in their roles, however more work is now required to compare directly the roles and contributions of the lower limbs and gastrointestinal tract to the inflammatory response during abdominal aortic aneurysm repair.     

Characterisation of Interleukin-8 and Monocyte Chemoattractant Protein-1 Expression within the Abdominal Aortic Aneurysm and their Association with Mural Inflammation

ObjectivesAbdominal aortic aneurysms (AAAs) are characterised by chronic transmural inflammation. This study investigated the expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) within the AAA, and their relationship with mural inflammation.MethodsBiopsies were obtained from 25 AAAs, 15 abdominal aortas, and 10 atherosclerotic thoracic aortas. IL-8 and MCP-1 expression was measured in homogenised specimens by ELISA. Infiltrate composition and localised expression of IL-8 and MCP-1 were determined through immunohistochemistry.ResultsELISA analysis demonstrated that IL-8 and MCP-1 were raised in the AAA compared to the controls [(IL-8, AAA vs. abdominal aorta: >28-fold, P < .001; AAA vs. thoracic aorta: >28-fold, P < .001) (MCP-1, AAA vs. abdominal aorta: 9-fold, P < .001; AAA vs. thoracic aorta: 19-fold, P < .001)]. Immunohistochemistry revealed that IL-8 was localised to the inflammatory infiltrate, which consisted predominantly of CD3⁺ T- and CD20⁺ B-lymphocytes. MCP-1 was predominantly expressed by CD68⁺ macrophages. Increasing IL-8 expression was associated with an increase in mural inflammation, and an increase in CD3⁺ T-lymphocytes of CD4⁺ phenotype within the infiltrate population.ConclusionPathways involving IL-8 and MCP-1 may be involved in AAA pathogenesis. IL-8 may be directly involved in the chemotaxis of T_H-lymphocytes into the AAA wall.     

Prosthetic patch infection after carotid endarterectomy.

OBJECTIVES and DESIGN: prospective audit of the management and outcome of prosthetic patch infection after carotid endarterectomy (CEA) at Leicester Royal Infirmary plus review of the literature. RESULTS: 8/936 CEA patients (0.85%) developed a prosthetic patch infection. Responsible organisms included MRSA (n=3), Staphylococcus epidermidis(n=2), haemolytic Streptococcus (n=1), Staphylococcus aureus(n=1) and Pseudomonas (n=1). Early wound complications preceded 4/5 infections presenting within 9 weeks of surgery. In addition to systemic antibiotics and debridement, management included patch removal and: (i) carotid ligation (n=3), vein patch repair (n=1), vein bypass (n=3). One patient had antibiotic irrigation of the in-situpatch. No patient died, one suffered a disabling postoperative stroke and two had temporary cranial nerve injuries. Including this series, a literature review identified 43 prosthetic patch infections, 91% culturing Staphylococci or Streptococci. Cumulative freedom from perioperative stroke/death or re-infection was 65% at 2 years. Patients treated by patch excision and autologous venous reconstruction had the best outcome with a cumulative freedom from perioperative stroke/death or re-infection of 91% at 2 years. CONCLUSION: prosthetic patch infection after CEA is rare. This study emphasises the importance of close surveillance of early wound complications. Surgical decision-making, especially the safety of carotid ligation, was facilitated by access to transcranial Doppler.     

The value of urgent carotid surgery for crescendo transient ischemic attacks

OBJECTIVE: This study audited operative risk in patients undergoing urgent carotid surgery for crescendo transient ischemic attacks (TIAs). METHODS: Interrogation of the vascular unit database (January 1992 to July 2004) identified 42 patients operated on urgently for crescendo TIAs, which were defined as>or=3 TIAs within the preceding 7 days. Stroke, death, and any major cardiac events were analyzed. RESULTS: Thirty-nine patients underwent conventional endarterectomy, and three underwent interposition vein bypass. Crescendo TIA patients had sustained a median of five TIAs (range, 3 to 20) in the 7 days before surgery. Three patients died or had a stroke after surgery, for a combined stroke/death rate of 7%. This compares with 2.4% in 1000 patients undergoing elective carotid endarterectomy in this unit during the same time period. The combined stroke/death/major cardiac event rate was 14% (n=6). CONCLUSIONS: The combined risk of neurologic and cardiac complications after urgent carotid surgery for crescendo TIA is higher than that expected after elective cases but is still acceptable considering the natural history of patients with unstable neurologic symptoms.