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Medical education has traditionally focused on the learners, the educators, and the curriculum, while tending to overlook the role of the designed environment. Experience indicates, however, that processes and outcomes of medical education are sensitive to the qualities and disposition of the spaces in which it occurs. This includes the clinical education within the patient care environment, termed the clinical learning environment (CLE). Recognition of this has informed the design of some new clinical learning spaces for the past decade. Competency-based clinical education can drive design requirements that differ materially from those associated with general purpose educational or clinical spaces. In this article, we outline two conceptual frameworks: (i) materialist spatiality and (ii) actor-network theory and consider how they can guide the design of spaces to support competency-based medical education and to guide the evaluation and discussion of the educational impacts of the spaces once built. We illustrate the use of these frameworks through discussion of the educational ambitions that underpinned the design of some recent clinical educational spaces. We close with practical points for consideration by educators and designers.

Introduction Les patients cancereux ont un risque augmente d'evenements thromboemboliques veineux. Certaines substances utilisees lors de chimiotherapies ont egalement ete associees au developpement de thromboses. Les cas rapportes d'episodes ischemiques arteriels aigus chez des patients cancereux sont rares. Methodes Les patients operes chirurgicalement pour une ischemie aigue associee a une tumeur maligne dans un centre hospitalo-universitaire etaient identifies sur une periode de 10 ans. Les caracteristiques demographiques des patients, les types de cancer, l'utilisation de chimiotherapies, le site de la thrombose, les traitements et les resultats etaient notes. Resultats Quatre cents dix-neuf patients etaient operes pour une ischemie aigue arterielle. Parmi eux, 16 patients (3,8%) avaient un cancer associe. Les sites les plus frequents de cancer etaient le tractus urogenital (n = 5) et les poumons (n = 5). Huit patients (50%) avaient ete diagnostiques de leur cancer recemment, et quatre (25%) de ces cancers etaient decouverts fortuitement apres l'episode d'ischemie aigue. Quatre patients (25%) developpaient une ischemie aigue lors d'une chimiotherapie. L'artere femorale superficielle etait le site le plus frequent d'occlusion (50%), suivie par les arteres brachiales (18%) et poplitees (12%). Tous les patients avaient une thrombo-embolectomie, mais deux (12%) patients necessitaient un pontage secondaire. Six patients (37%) perdaient leur membre, et la mortalite intra-hospitaliere etait de 12%. L'histologie revelait que toutes les occlusions etaient dues a une maladie thromboembolique, sans cellule tumorale identifiee. Lors du suivi, 44% de patients etaient vivants a 1 an. Conclusion Le cancer et la chimiotherapie peuvent predisposer les patients a l'ischemie aigue arterielle. Au contraire d'autres rapports qui retrouvaient que cet evenement etait preterminal et mieux traite par des mesures palliatives, dans cette serie, un diagnostic et une intervention precoces permettaient un sauvetage de membre et la survie du patient.

0% (95% CI 0%-5%) 4.0cm - 4.9cm 1% (95% CI 0%-5%) 5.0cm - 5.9cm 11% (95% CI 1%-21%) 6.0cm - 6.9cm 26% (95% CI 7%-46%)

Objective. We hypothesize that treatment with Pravastatin, a HMG CoA reductase inhibitor would improve flow-mediated dilation (FMD), a nitric oxide dependent phenomenon and the earliest detectable marker of endothelial dysfunction, in asymptomatic patients with type-1 diabetes. Materials and methods. FMD of the brachial artery in response to reactive hyperaemia was measured using high-resolution ultrasonograghy. Young male patients with type-1 diabetes (n=9) were compared with age matched non-diabetic controls (n=8). Results. The FMD response in the control group was a median increase in diameter of 7.9 (range 3.8–12.6)%. In the diabetic group the FMD response was impaired when compared with controls with a median increase only of 4.4 (range 3.7–5.8)% (p

Introduction. Thermal preconditioning has previously been shown to attenuate ischemia-reperfusion induced injuries, possible due to increased expression of heat shock proteins (HSP). The model of thermal preconditioning used, however, was not clinically relevant as preconditioning was to 41°C, leading to cellular damage. Our aim was thus to establish a novel and clinically applicable method of preconditioning. Materials and Methods. Twenty-six male Sprague-Dawley rats were split into three groups (nine control, nine ischemia-reperfusion, and eight preconditioned followed by ischemia-reperfusion). To precondition the animals, they were anesthetized and, using a water bath, their core temperature was raised by 1°C for 15 min once a day for five successive days. I/R injury consisted of 30 min of aortic cross-clamping followed by 120 min of reperfusion; control animals had a laparotomy only. Indicators of lung injury were tissue myeloperoxidase, broncho-alveolar lavage protein concentration, and tissue edema. Tissue heat shock protein expression was detected by Western blot analysis. Results. Lower torso ischemia-reperfusion causes significant lung injury versus control, with raised levels of myeloperoxidase 4.53 iu/g to 7.88 iu/g (P < 0.05), raised B.A.L. protein concentration 419 μg/ml to 684 μg/ml (P < 0.05) and altered wet dry ratio 4.63 to 5.50. Clinically relevant thermal preconditioning attenuates all of these parameters back to control levels: myeloperoxidase 3.87 iu/g (P < 0.05 vs I/R), B.A.L. to 284 μg/ml (P < 0.01 vs I/R) and wet dry ratio to 4.44 (P < 0.05 vs I/R). Western blot demonstrated increased expression of H.S.P. 72 in the preconditioned group versus control and I/R alone. Western blot demonstrated increased expression of HSP72 in the preconditioned group vs control and I/R alone. Conclusions. We conclude that clinically applicable thermal preconditioning can attenuate ischemia-reperfusion induced lung injury, possibly through increased expression of HSP72.

Background An increased plasma level of homocysteine has been proposed as an independent risk factor for atherosclerosis; this review examines the evidence. Methods A Medline search was undertaken for English language articles on homocysteine and vascular disease. Further papers were identified by cross-referencing from the reference lists of relevant major articles. Results Although much interest has been generated about homocysteine and atherosclerotic disease, contradictory data exist regarding its role in disease progression. There is insufficient current evidence to regard increased homocysteine level as a causative factor in atherosclerotic disease. Conclusion It is not known whether lowering plasma homocysteine concentration will reduce cardiovascular risk in the long term. Until such data become available, there is no evidence for the widespread use of folic acid therapy to reduce cardiovascular disease risk.

Taurine is a semiessential amino acid and naturally occurring antioxidant. One of its main roles is to protect tissues against attack by chlorinated oxidants particularly hypochlorous acid (HOCl). It is found in high concentrations in neutrophils and previous studies showed it possesses potent antimicrobial properties and attenuates high glucose induced endothelial cell apoptosis. In humans taurine has been shown to up-regulate constitutive nitric oxide synthase (cNOS), a known cytoprotector. No reported studies to date have looked at the possible therapeutic role of taurine in preventing diabetic endothelial dysfunction. We therefore hypothesised that taurine would attenuate the microvascular changes associated with hyperglycaemia in an animal model through alteration of leucocyte–endothelial interactions. Male Sprague Dawley rats were randomised into control, hyperglycaemia, and taurine + hyperglycaemia groups. Taurine was gavaged (200 mg/kg) for 5 d prior to the experiment. Hyperglycaemia was established by intravenous infusion of 50% glucose. Blood glucose reached a steady state of 3 times baseline at 30 min. Using intravital microscopy leukocyte rolling, adhesion and transendothelial migration was determined in mesenteric postcapillary venules for 3 h. Intracellular adhesion molecule-1 (ICAM-1) was immunohistochemically graded using a scoring system to determine the expression in mesenteric tissue. Taurine pretreatment significantly attenuates leukocyte-endothelial adhesion and transendothelial migration following acute hyperglycaemia but not leukocyte rolling velocity. The mechanism by which taurine protects against these effects is in part by inhibition of ICAM-1 expression1. Table 1. Results at 120 min (n = 5/group) Control Hyperglycaemia Taurine + Hyperglycaemia Data are expressed as mean (SEM). Analysis with anova and post Scheffe hoc test. *P

The purpose of this study was to determine if prereatment with taurolidine, a known anti-endotoxin agent, would attenuate the hemodynamic and respiratory responses associated with endotoxin induced lung injury in a large animal model in a randomized controlled study under license from the Department of Health. All animals underwent a general anesthetic. Vascular catheters were placed in the femoral artery and in the femoral vein. A Swan-Ganz Catheter was inserted for measurement of pulmonary artery pressure. Animals were randomized into three groups: Control, with measurements taken at baseline and half hourly up to 90 min; Endotoxin, receiving 5microg/Kg E. coli endotoxin intravenously after baseline measurements; and Endotoxin + Taurolidine, receiving 5g of taurolidine via intraperitoneal infusion 1 h before endotoxin administration. Main outcome measures were mean systemic arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), arterial oxygen tension (pO2), serum endotoxin concentration, and pulmonary myeloperoxidase. Endotoxin induced a significant lung injury characterized by an increase in pulmonary artery pressure, hypoxia, and systemic hypotension. Pretreatment with intraperitoneal taurolidine significantly attenuated these hemodynamic and respiratory changes. Serum endotoxin concentration was also significantly reduced as was lung myeloperoxidase. The data suggest that taurolidine may have a therapeutic role in preventing the lung injury seen in endotoxemia.

Objectives to elicit whether pre-treatment with pravastatin will prevent or ameliorate the acute lung injury that occurs following lower torso ischaemia–reperfusion (IR) in an experimental animal model. Materials and methods male Sprague–Dawley rats were randomised into three groups (n=7/group). The control group underwent a sham laparotomy and aortic dissection. The second group underwent infrarenal aortic cross clamping for 30 min followed by reperfusion for 120 min. The third group pre-treated with pravastatin sodium (0.4 mg/kg/day over 5 days) were again subjected to an ischaemia–reperfusion (IR) injury. The parameters used to assess lung injury included: Wet to dry lung weight ratio (W:D), myeloperoxidase activity (MPO), protein concentration (BALprot) and neutrophil count (BAL PMN) of bronchoaveolar lavage fluid. Western blotting was used to determine the expression of constitutive endothelial nitric oxide synthase (ecNOS) within lung tissue. Results IR causes an acute lung injury as indicated by statistically significant differences in W:D lung weight ratios, MPO activity, neutrophil count and BALprotein concentration in the IR group over that of controls. Pre-treatment with pravastatin attenuated this neutrophil infiltration and microvascular leakage. The pravastatin group showed a marked increased expression of ecNOS over that of the IR group and controls. Conclusion this data indicates that pre-treatment with pravastatin protects against ischaemia–reperfusion induced lung injury in an experimental animal model. We believe that its mechanism of action involves an upregulation of ecNOS, which increases basal expression of nitric oxide providing protective effects on the pulmonary circulation against microvascular injury.

An early event in endotoxin-induced tissue injury is adhesion and migration of leukocytes through the endothelium. This is a three-stage process, initially low-grade selectin-mediated adhesion, seen as a decrease in rolling velocity, followed by integrin-mediated adhesion and transmigration. Thermotolerance has been shown to reduce tissue injury and mortality induced by endotoxin. The aim of this study was to investigate the effect of thermotolerance on leukocyte-endothelial interactions. Intravital video microscopy was used to examine hemodynamic parameters, leukocyte rolling, adhesion, and migration in rat mesenteric postcapillary venules. Sprague-Dawley rats were randomized into control, lipopolysaccharide (LPS), and thermotolerance + LPS groups. Thermotolerance was induced 18 h prior to administration of LPS by elevating core body temperature to 41 + 0.5 degrees C for 15 min. LPS (055:B5 15 mg/kg) was administered via the jugular vein after baseline recording. Leukocyte rolling velocity and the number of adherent and migrated leukocytes were measured by intravital microscopy at baseline 0 min and 10, 30, 60, and 90 min after LPS administration. Heat shock protein 72 (HSP72) expression in tissues was determined by Western immunoblotting. The results indicated that LPS administration significantly decreased leukocyte rolling velocity during endotoxemia and increased leukocyte adhesion (10.3 +/- 1.67, 13.2 +/- 1.40, and 10.0 +/- 1.57/100 microm) and migration (5.7 +/- 1.02 and 8.3 +/- 1.76/field) at 30, 60, and 90 min after LPS injection (P0.01 vs baseline and control group). Thermotolerance maintained leukocyte rolling velocity and significantly reduced leukocyte adhesion (5.7 +/- 0.88 and 4.0 +/- 0.68/100 microm) and migration (2.8 +/- 0.32 and 3.0 +/- 0.68/field) at 30 and 60 min after LPS administration (P0.01 and 0.05 vs LPS group). Expression of HSP72 was induced in mesentery, gut, and lung by thermotolerance. This study indicates that thermotolerance attenuated LPS-induced microvascular injury by decreasing leukocyte-endothelial adhesion and migration.

Background. Adhesion of polymorphonuclear leukocytes (PMN) to endothelial cells and subsequent transendothelial migration are an early key events in the inflammatory response and play an important part in the pathogenesis of septic shock, contributing to vascular and tissue injury. Taurine (2-aminoethanesulfonic acid) is a sulphur-containing β amino acid. It is a known antioxidant, possesses antimicrobial properties, and has previously been shown to be protective to the endothelium both in vivo and in vitro. The aim of this study was to determine if pretreatment with taurinewould attenuate the lipopolysaccharide (LPS)-induced increase in leukocyte-endothelial interactions and microvascular permeability during endotoxemia. Materials and methods. Male Sprague-Dawley rats (300–350 g) were randomized into three groups: (1) Control, (2) LPS, and (3) LPS + Taurine groups. Taurine was administered orally as a 4% solution. Endotoxemia was induced using Escherichia Coli endotoxin (Serotype 0.55 B5)—15 mg/kg via a slow intravenous infusion. Using mesenteric postcapillary venules (28–32-μm diameter) the number of adherent and migrated leukocytes and their rolling velocity were measured by intravital microscopy at baseline and subsequently at 10, 30, 60, and 90 min post administration of LPS. Results. Following administration of LPS there was a reduction in leukocyte rolling velocity at 30, 60 and 90 min. This was accompanied by a significant increase in the number of adherent leukocytes at 10, 30, 60 and 90 min. Transendothelial migration was significantly increased at 90 min. Taurine significantly attenuated the LPS-induced reduction in leukocyte rolling velocity at 10 and 30 min and the number of adherent leukocytes at all time points. Taurine also attenuated the LPS-induced increase in transendothelial migration at 90 min. Conclusions. These results demonstrate that taurine ameliorates endotoxin-induced leukocyte-endothelial cell interactions associated with sepsis, thereby suggesting that taurine may have a therapeutic role in the preventionof endothelial damage in sepsis.

Background: The therapeutic efficacy of interleukin-2 (IL-2) has been limited by a dose-dependent vascular leak syndrome. This may be related to neutrophil-mediated endothelial injury. Taurine has been shown to decrease this injury in vitro. This study investigates the role of taurine in preventing IL-2-induced lung injury, and the role of neutrophil-endothelial interactions in mediating this injury. Methods:Study 1: Sprague-Dawley rats (n = 12/groups) were randomised to controls, IL-2-treated (1 × 106 units), and IL-2-treated with taurine (4% solution, orally for 48 h prior to IL-2 therapy). Lung injury was measured by extravascular lung water (wet/dry weight) and bronchoalveolar lavage protein concentration. Neutrophil infiltration was evaluated by measuring myeloperoxidase activity and bronchoalveolar lavage neutrophil concentration. Study 2: Rats (n = 10/group) were randomised into the same groups as study 1. Neutrophil-endothelial interactions in mesenteric vessels were assessed by intravital microscopy at half-hourly intervals. Results: Taurine reduced IL-2-induced acute lung injury as reflected by a decrease in wet-to-dry lung weight ratio from 7.2 ± 0.5 in the IL-2 group to 4.7 ± 0.3 in the taurine group (p < 0.05), and a decrease in bronchoalveolar neutrophil concentration from 823 ± 19.5 in the IL-2 group to 538 ± 18 in the taurine group (p < 0.05). Intravital microscopy demonstrated that IL-2 increased leucocyte adhesion and migration in mesenteric vessels, and that this was significantly reduced by taurine. Conclusion: These data suggest that taurine prevents IL-2-induced tissue injury in part by decreasing neutrophil-endothelial interactions.

Background Ischaemia–reperfusion injury is mediated by neutrophil–endothelial interaction. Induction of heat shock proteins attenuates neutrophil–endothelial interactions. The aim of this study was to determine whether thermal preconditioning could have a protective effect on neutrophil-mediated lung injury in an animal model of lower torso ischaemia–reperfusion. Methods Sprague-Dawley rats were randomized into: control, ischaemia–reperfusion, and ischaemia–reperfusion preconditioned with hyperthermia groups. Ischaemia–reperfusion injury was induced by infrarenal aortic clamping for 30 min and reperfusion for 120 min. Thermotolerance was induced by raising the core body temperature to 40·5–41·5°C for 15 min, 18 h before ischaemia–reperfusion. Wet:dry lung (W:D) weight ratio, bronchoalveolar lavage protein (BALprot) concentration, tissue myeloperoxidase (MPO) activity and bronchoalveolar lavage polymorphonuclear neutrophil (BAL PMN) count were measured. Heat shock protein 72 (hsp72) expression in lung, intestine and mesentery was measured using Western immunoblotting. Results Ischaemia–reperfusion resulted in a significant increase in tissue oedema (W:D weight ratio) and BALprot concentration. In addition there was a marked increase in tissue neutrophil infiltration (MPO activity, BAL PMN concentration). Preconditioning with hyperthemia resulted in increased expression of hsp72 and significantly reduced tissue oedema and neutrophil infiltration. Conclusion Thermal preconditioning protects against neutrophil-mediated ischaemia–reperfusion-induced lung injury, possibly by increasing the expression of heat shock proteins.

Mortality rates for patients undergoing surgery for ruptured abdominal aortic aneurysm (RAAA) remain high. The high cost of providing care for these patients mandates that proposed treatment protocols be evaluated for their cost-effectiveness. This study assessed costs related to outcome in different groups of patients with RAAA. From July 1987 to December 1993, 140 patients underwent emergency surgery for RAAA. Complete data on preoperative haemodynamic status, blood transfusion requirements, intensive care unit (ICU) stay and other hospital costs was available for 94 patients. Seventy-seven males (mean age 71.6(6)) and 17 females (mean age 77.2(6)) underwent surgery. Known risk factors including age (< 0r >70 years), shock on admission (systolic blood pressure (BP) < or >90 mm Hg), sex, and acute renal failure were analysed. For the purpose of comparison, costs (£) were assessed by the ESRI (Economic and Social Research Institute of Ireland) based on 1992 prices. The overall survival rate was 48%; 53% among males and 24% among females (p70 years old presenting with haemodynamic instability had significantly longer hospital and ICU stays than younger male patients. The average cost per RAAA survival (£12 945) in this series is not prohibitive, and the greater cost in high risk groups should not discourage intervention.

Background The aims of this study were to evaluate the effects of aortic clamping and unclamping on neutrophil and monocyte activation and release of plasma mediators in 2() patients undergoing elective aortic aneurysm surgery, and to correlate these findings with pulmonary haemodynamics and gas exchange. Methods Simultaneous arterial and mixed venous samples were obtained during and after aortic damping and unclamping. Results Neutrophil respiratory burst activity in mixed venous samples increased significantly during the period of aortic clamping. An initial increase in neutrophil CD11b expression in venous blood 5 min after clamp removal was followed by a significant decrease in level of expression. Plasma tumour necrosis factor levels increased at the end of the cross-clamp period and reached a maximum 60 min following reperfusion. There was a significant and sustained rise in plasma thromboxane B 2 levels following clamp removal. This increase correlated with the development of increased pulmonary vascular resistance. Conclusion This study confirms the central role played by activated neutrophils in the early stages of reperfusion injury and also suggests a role for plasma mediators in mediating cardiopulmonary dysfunction during major vascular surgery.

Lower torso revascularisation following ischaemia results in a systemic inflammatory response. Endothelial barrier function is disrupted by neutrophil-derived proteases and oxidants. Taurine, an amino acid found in large quantities in neutrophils, is a powerful endogeneous anti-oxidant. The aims of this study were to investigate the systemic effects of reperfusion following lower limb revascularisation and to evaluate the role of taurine administration in preventing this injury. A rat model of aortic occlusion (30 min) followed by 2 h of reperfusion was used. Animals were randomised to one of three groups ( n = 10 per group): control; ischaemia reperfusion untreated (IR) and taurine-treated. Taurine (4% solution) was administrated orally for 48 h prior to the experiment. Neutrophil infiltration and microvascular permeability were assessed by measuring tissue myeloperoxidase activity and wet/dry weights respectively in lung, liver, kidney, and in cardiac and skeletal muscle. Statistical analysis was by means of analysis of variance (ANOVA). Reperfusion resulted in pulmonary and renal microvascular injury as assessed by organ oedema. Hepatic tissue, skeletal and cardiac muscle were unaffected by lower limb revascularisation. Taurine was effective in preventing neutrophil-mediated pulmonary but not renal microvascular injury. These data suggest that, whilst reperfusion-induced pulmonary injury is predominantly neutrophilmediated, agents other than neutrophil-derived oxidative metabolites, capable of independently causing organ injury through direct endothelial damage, are produced during reperfusion.

Objectives The number of operations performed per surgeon is thought to determine the quality of carotid endarterectomy (CEA) surgery. The advent of carotid artery stenting (CAS) threatens to reduce the volume of CEA. This paper assesses CEA and the effects of the introduction of CAS service on outcomes. Design Retrospective cohort study. Methods Clinical data and results of CEA were reviewed retrospectively for the treatment of carotid stenosis, between January 1988 and December 2010. CEA patients were grouped into those treated before and after the introduction of CAS to our hospital in 2001. Results 757 patients underwent a CEA between 1988 and 2010. The perioperative stroke rate prior to the introduction of CAS was 4.9%, and 3.3% after stent introduction in 2001. In this latter period, 85.5% had symptomatic stenosis which suggests that the patients were not low risk. The major adverse event rate (inclusive of death and myocardial infarction) post introduction of CAS from 2001 to 2010 was 4.1%. There was no correlation between post-operative stroke/MAE and procedure volume, despite the trend of decreasing CEA numbers over time. Conclusion The introduction of carotid artery stenting has led to a decrease in carotid endarterectomy volume. However, outcomes in our high risk patient population are acceptable. Therefore, CEA remains the procedure of choice for carotid artery revascularization.

Thermotolerance describes the process in which hyperthermia induces a transient resistance of the stressed cells to subsequent episodes of oxidative stress. The aims of this study were first, to assess the effect of ischemia-reperfusion (IR) injury on renal function and the expression of the ICAM-1 receptor and MHC antigens, and second, to evaluate the protective effects of thermotolerance on IR induced renal injury and its potential for decreasing allograft rejection, by decreasing alloantigen expression. Sprague-Dawley rats were randomized into three groups: control, IR, and hyperthermia + IR (HIR) (n=8 per group). Thermotolerance was induced 18 hr prior to IR by increasing the core body temperature to 41 degrees C+/-0.5 degrees C for 15 min. After left uninephrectomy, IR was induced by clamping the right renal pedicle for 45 min, followed by 2 hr reperfusion. Myeloperoxidase (MPO) activity was used as an indicator of renal neutrophil influx. Kidney edema was assessed using the weight difference between left and right kidneys. Renal function was evaluated by measuring serum creatinine and urea 2 hr following clamp removal. Immunocytochemistry was used to measure expression of ICAM-1 and MHC antigen. Renal function was significantly impaired by IR with serum creatinine and urea levels of 131.5+/-5.01 microM and 11.2+/-0.71 mM, respectively, compared with controls of 67.9+/-5.11 microM and 8.1+/-0.36 mM, P

The aim of this study was to determine whether glyceryl trinitrate (GTN) has a protective effect on neutrophil- mediated lung injury in a model of aortic occlusion (30 min) and reperfusion (120 min). Sprague-Dawley rats were randomized into control (n = 11), ischaemia-reperfusion (IR) (n = 12), and IR treated with GTN (2 μg kg−1 min−1) during reperfusion (n = 10). Myeloperoxidase (MPO) activity measured pulmonary neutrophil influx. Pulmonary endothelial permeability was measured by wet:dry weight ratio, bronchoalveolar lavage (BAL) protein and neutrophil counts. Neutrophil superoxide release was measured by flow cytometry in a further IR versus GTN experiment (n = 6 in each group). The significant increase in MPO activity produced by IR to a level of 7·99 units g−1 was prevented by GTN which reduced the level to 4·73 units g−1. The increase in pulmonary microvascular leakage after reperfusion was also prevented by GTN: BAL protein without GTN was 992 μg ml−1 and with GTN 579 μg ml−1; BAL neutrophil count without GTN was 3219 cells mm−3 and with GTN 820 cells mm−3; the wet:dry lung weight ratio without GTN was 3·8 and with GTN 3·3. Neutrophil superoxide release increased significantly after 40 min of reperfusion in the untreated IR group (P < 0·05). This increase was prevented in the GTN-treated group. GTN administration had no effect on plasma thromboxane production during revascularization. These data suggest that GTN administration during the reperfusion phase has the potential to decrease pulmonary microvascular injury.

This study evaluated the effect of varying the synthesis of nitric oxide with sodium nitroprusside or N-nitro-L-arginine methyl ester (L-NAME) in a pancreatitis-lung injury model. Rats (n = 45) were randomized to control or caerulein-induced pancreatitis groups, treated with saline, sodium nitroprusside (0·4 μg/kg) or l-NAME (10 mg/kg). Myeloperoxidase activity was used as a measure of neutrophil infiltration. Wet to dry (W:D) lung weight and bronchoalveolar lavage (BAL) protein concentrations were used to assess vascular leakage. Pancreatitis was shown to induce pulmonary neutrophil influx: mean(s.e.m.) myeloperoxidase activity 6·79(0·5) units/g in caerulein-treated animals versus 2·08(0·5) units/g in controls (P < 0·001). Animals with pancreatitis showed increased microvascular leakage compared with controls (mean(s.e.m.) W:D lung weight 7·01(0·5) versus 2·85(0·2), P < 0·001; BAL protein concentration 2539(222) versus 347(32) μg/ml, P < 0·001). Compared with the saline-treated pancreatitis group, these changes were reduced by sodium nitroprusside (mean(s.e.m.) myeloperoxidase activity to 2·5(0·4) units/g, P < 0·001; W:D lung weight to 3·8(0·37), P < 0·001; BAL protein concentration 1389(182) μg/ml, P < 0·05). L-NAME exacerbated the pancreatitis-induced pulmonary oedema (W:D lung weight increased to 11·96(0·6), P < 0·001), protein leakage (BAL protein concentration rose to 3707(309) μg/ml, P < 0·05) and neutrophil infiltration (myeloperoxidase activity increased to 9·01(0·3) units/g, P < 0·05). These data suggest that, in vivo, nitric oxide inhibits pancreatitis-induced lung injury, possibly in part by inhibiting pulmonary neutrophil influx.

Popliteal and femoral aneurysms can be treated by endoluminal graft stenting, instead of conventional surgery. Results in four cases suggest, however, that long-term results do not justify an endovascular approach.

Fiona Godlee challenges the Royal College of Surgeons in Ireland (RCSI) in relation to the detention and trial of healthcare professionals in Bahrain.1 We here clarify our position on this issue. RCSI is a not for profit medical educational institution that has consistently espoused the fundamental principles of independence and non-discrimination in providing medical care to patients, advancing healthcare in the Republic of Ireland and elsewhere, and educating healthcare professionals to the highest ethical and professional standards. Such ethical principles inform all our actions everywhere. With regard to the current situation in Bahrain, we welcome the Bahraini authorities’ decision on 5 October 2011 to set aside the verdicts of the military court, as well as the announcement that the accused healthcare professionals will be retried in civilian courts …

Background Cancer patients have an increased risk of venous thromboembolic events. Certain chemotherapeutic agents have also been associated with the development of thrombosis. Reported cases of acute arterial ischemic episodes in cancer patients are rare. Methods Patients who underwent surgery for acute limb ischemia associated with malignancy in a university teaching hospital over a 10-year period were identified. Patient demographics, cancer type, chemotherapy use, site of thromboembolism, treatment and outcome were recorded. Results Four hundred nineteen patients underwent surgical intervention for acute arterial ischemia, 16 of these patients (3.8%) had associated cancer. Commonest cancer sites were the urogenital tract ( n = 5) and the lungs ( n = 5). Eight patients (50%) had been recently diagnosed with cancer, and four (25%) of these cancers were incidental findings after presentation with acute limb ischemia. Four patients (25%) developed acute ischemia during chemotherapy. The superficial femoral artery was the most frequent site of occlusion (50%), followed by the brachial (18%) and popliteal (12%) arteries. All patients underwent thromboembolectomy, but two (12%) patients subsequently required a bypass procedure. Six patients (37%) had limb loss, and in-patient mortality was 12%. Histology revealed that all occlusions were due to thromboembolism, with no tumor cells identified. At follow-up, 44% of patients were found to be alive after 1 year. Conclusion Cancer and chemotherapy can predispose patients to acute arterial ischemia. Unlike other reports that view this finding as a preterminal event most appropriately treated by palliative measures, in this series, early diagnosis and surgical intervention enabled limb salvage and patient survival.

Curriculum reform poses significant challenges for medical schools across the globe. This paper describes the reforms that took place at the medical school of the Royal College of Surgeons in Ireland (RCSI) between 2005 and 2008 and the institutional self review process that accompanied these reforms.Although fully accredited with the Irish Medical Council the RCSI sought additional detailed review of all aspects of its undergraduate medical program. Five medical educationalists were invited to visit the College in 2005 and again in 2008 to act as 'critical friends' and guide the self review using the World Federation for Medical Education (WFME) standards which had recently been adopted in Ireland.The process of institutional self review (as opposed to more high stakes accreditation) can bring about significant reform, especially when supported by a panel of 'critical friends' working alongside faculty to help guide and support sustained curriculum reform. The WFME standards continue to provide a useful framework to consider all medical education activities within a medical school engaged in continuous renewal. Adequate preparation for such reviews is critical to the success of such an undertaking and should be supported by a comprehensive communication strategy and project plan.

Peripheral arterial disease (PAD) and type 2 diabetes mellitus (DM) are both associated with excessive vascular calcification and elevated levels of inflammatory markers IL-6 and hsCRP. The recently identified Osteoprotegerin(OPG)/RANKL/TRAIL pathway has been implicated in vascular calcification, but data on levels in PAD and effect of co-existent DM are lacking.4 groups of patients were recruited - 26 with PAD and DM, 35 with DM alone, 22 with PAD alone, and 21 healthy individuals. Serum OPG, RANKL, TRAIL, hsCRP and IL-6 were measured using commercial ELISA assays. Presence and severity of PAD was defined using ankle brachial index (ABI).Serum OPG (7.4±0.3 vs.5.8±0.2 pmol/l, p0.0001), TRAIL (95.5±5.2 ng/ml vs. 76.2±4.4 ng/ml, p=0.006), hsCRP (2.6±0.3 vs. 1.8±0.3 mg/l, p=0.048), and IL-6 (4.1±0.4 vs. 2.9±0.4 pg/ml, p=0.06) were higher in patients with PAD. There was no difference in RANKL. Only OPG was significantly higher in PAD and DM (7.2±0.3 pmol/l) and PAD alone (7.7±0.4 pmol/l) compared to DM only (5.8±0.3 pmol/l) and healthy controls (5.6±0.4 pmol/l), p0.01, but OPG was no higher in those with DM plus PAD versus those with PAD alone (p0.3). Only OPG was associated with PAD severity, correlating negatively with ABI (r=-0.26, p=0.03), independent of age, gender, glycaemic status, hsCRP and IL-6.PAD is associated with higher serum OPG, regardless of the co-existence of DM. This finding, in addition to its correlation with severity of PAD, suggests that OPG may be a novel marker for the presence and severity of PAD, possibly by reflecting the degree of underlying vascular calcification.

Background To avoid ischemic necrosis, compartment syndrome is a surgical emergency treated with decompression once identified. A potentially lethal, oxidant-driven reperfusion injury occurs after decompression. N-acetylcysteine is an antioxidant with the potential to attenuate the reperfusion injury. Questions/purposes We asked whether N-acetylcysteine could preserve striated muscle contractility and modify neutrophil infiltration and activation after simulated compartment syndrome release. Materials and Methods Fifty-seven rats were randomized to control, simulated compartment syndrome, and simulated compartment syndrome plus N-acetylcysteine groups. We isolated the rodent cremaster muscle on its neurovascular pedicle and placed it in a pressure chamber. Chamber pressure was elevated above critical closing pressure for 3 hours to simulate compartment syndrome. Experiments were concluded at three times: 1 hour, 24 hours, and 7 days after decompression of compartment syndrome. We assessed twitch and tetanic contractile function and tissue myeloperoxidase activity. Ten additional rats were randomized to control and N-acetylcysteine administration after which neutrophil respiratory burst activity was assessed. Results The simulated compartment syndrome decreased muscle contractility and increased muscle tissue myeloperoxidase activity compared with controls. Treatment with N-acetylcysteine preserved twitch and tetanic contractility. N-acetylcysteine did not alter neutrophil infiltration (myeloperoxidase activity) acutely but did reduce infiltration at 24 hours, even when given after decompression. N-acetylcysteine reduced neutrophil respiratory burst activity. Conclusion N-acetylcysteine administration before or after simulated compartment syndrome preserved striated muscle contractility, apparently by attenuating neutrophil activation and the resultant oxidant injury. Clinical Relevance Our data suggest a potential role for N-acetylcysteine in the attenuation of muscle injury after release of compartment syndrome and possibly in the prophylaxis of compartment syndrome.

Summary Objectives There is lack of consensus regarding concurrent vs. staged approaches, and the prioritisation of staged procedures in cases presenting with colorectal carcinoma (CRC) and abdominal aortic aneurysm (AAA) synchronously. We aim to present our experience, review the literature on this therapeutic dilemma and examine the role of endovascular aortic repair (EVAR). Design, materials and methods An observational study of the experience of two centres and a systematic review of the published literature. Results Twenty-four patients were identified from the prospective databases of two tertiary referral centres between 2001 and 2006. Intervention for both malignancy and aneurysm was performed in 13 patients. In 10 patients, cancer resection was performed initially and was followed by open aneurysm repair ( n =3) or EVAR ( n =7). Two patients (AAA diameters: 7.0 and 8.0cm) underwent EVAR prior to colonic resection. One patient was selected for synchronous surgery. There were no interval AAA ruptures, graft infection or postoperative mortalities. Literature review identified 269 such cases; of these 101 were treated by combined surgery. In staged surgery, there were nine interval aneurysmal ruptures and one aortic graft infection. Conclusions In our experience, staged management can be undertaken, without interval aneurysmal rupture. EVAR has an evolving role in preventing delay in CRC management, in high-risk patients, and during combined intervention.

Background The pathogenesis of interleukin (IL) 2-induced vascular leak syndrome may be related to neutrophil-mediated endothelial injury. Nitric oxide inhibits neutrophil superoxide anion synthesis and adherence to endothelial cells. The role of systemic nitric oxide in preventing IL-2-induced lung injury was studied in an experimental model. Methods Sprague-Dawley rats (seven per group) were randomized to control, IL-2 treatment (1 × 106 units), and IL-2 with sodium nitroprusside 0.2 mg/kg. Lung injury was measured by estimation of extravascular lung water (wet:dry weight) and bronchoalveolar lavage (BAL) protein concentration, and by histological findings. Neutrophil infiltration was evaluated by measuring myeloperoxidase activity and BAL neutrophil concentration. Results IL-2 produced significant lung damage characterized by leucocyte sequestration (increased myeloperoxidase and BAL neutrophil concentrations), pulmonary congestion and microvascular protein leakage (increased wet: dry weight ratio and BAL protein concentration). This injury was reduced significantly by the addition of sodium nitroprusside, the nitric oxide donor. Conclusion Nitric oxide reduces IL-Zinduced lung injury.

Background The aim of this study was to investigate whether inhibition of hydroxymethylglutaryl co-enzyme A reductase attenuates leucocyte–endothelial cell interactions and alters expression of endothelial constitutive nitric oxide synthase (ecNOS) and inducible nitric oxide synthase (iNOS) following exposure to endotoxin. Methods Male Sprague–Dawley rats were randomized into control, lipopolysaccharide (LPS) and pravastatin + LPS groups (seven per group). Pravastatin sodium was gavaged at 0·4 mg per kg per day for 5 days, after which LPS 15 mg/kg was administered via the jugular vein. Intravital microscopy was used to determine leucocyte–endothelial cell interactions. Results Following the administration of LPS there was a significant reduction in leucocyte rolling velocity at 10 min (mean(s.e.m.) 69(3) versus 102(6) per cent of baseline value; P = 0·041), an increase in the number of adherent leucocytes at 10 min (4·5(0·5) versus 2·8(0·3) per 100 µm; P = 0·044) and an increase in the number of leucocytes undergoing transendothelial migration at 30 min (4·2(0·4) versus 1·7(0·4) per field; P = 0·008) compared with controls. Pretreatment with pravastatin significantly attenuated LPS-induced leucocyte–endothelial cell interactions (rolling velocity 89(6) per cent at 10 min, P = 0·038; adherent leucocytes 3·0(0·5) per 100 µm at 10 min, P = 0·038; migrating leucocytes 1·9(0·5) per field at 30 min, P = 0·001). This endothelial protection was associated with maintenance of ecNOS and reduced iNOS expression within mesenteric tissues. Conclusion These data show that pravastatin produces anti-inflammatory effects in response to injurious stimuli by attenuation of leucocyte–endothelial cell interactions.

We have previously demonstrated that clinically applicable thermal preconditioning induces heat shock protein 72 (HSP72) and protects against a subsequent ischemia-reperfusion (I/R) injury in an animal model. A core component of I/R injuries is the interaction between activated leukocytes and endothelial cells. We hypothesized that the effects of clinically applicable thermal preconditioning are mediated through attenuation of this leukocyte-endothelial (L-E) interaction.Twenty-one male Sprague Dawley rats were divided into control, I/R, and preconditioning plus I/R groups. Preconditioning was done under general anesthesia and the animals' temperature raised by 1 degrees C for 15 minutes in a water bath. This was repeated once a day for 5 successive days. I/R injury was caused by occlusion of the superior mesenteric artery for 10 minutes followed by 1 hour of reperfusion. L-E interactions were analyzed using intravital microscopy of a mesenteric vessel in vivo. L-E interactions were determined using leukocyte velocity (which decreases as cells interact), and number of adherent and migrated leukocytes. HSP72 was assessed by Western blot.Ischemia-reperfusion caused a decrease in leukocyte rolling velocity at all timepoints (p0.05 versus controls). Preconditioning attenuated the effects of I/R, and leukocyte rolling velocity was significantly improved versus I/R (p0.05) to levels similar to those in controls. Similarly, the number of adherent and migrating leukocytes increased significantly (p0.05) after I/R versus control at all time points, and preconditioning attenuated these to control levels, (p0.05 versus I/R) at both the 30- and 60-minute postischemia time points. Upregulation of HSP72 was demonstrated on Western blot.These results demonstrate that the benefit of clinically applicable thermal preconditioning is at least partially because of an immunomodulatory role in attenuating leukocyte-endothelial interactions associated with an increased expression of HSP 72.

Background— Endothelial dysfunction initiated by monocyte-endothelial interactions has previously been observed in many vasculopathies, including chronic cigarette smoking. Taurine, a semiessential amino acid, and vitamin C, a naturally occurring antioxidant, have previously been shown to have endothelial protective effects when exposed to proinflammatory insults. Therefore, we hypothesized that taurine and vitamin C would restore endothelial function in young smokers by modifying monocyte-endothelial interactions. Methods and Results— Endothelial-dependent vasodilatation was assessed in vivo using duplex ultrasonography, and monocyte-endothelial interactions were assessed in vitro using endothelial cell culture (human umbilical vein endothelial cells [HUVECs]) with monocyte-conditioned medium (MCM). Endothelial-dependent vasodilatation was significantly impaired in young smokers compared with nonsmokers. Pretreatment of young smokers for 5 days with 2 g/d vitamin C and, more significantly, with 1.5 g/d taurine attenuated this response. MCM taken from smokers impaired the release of nitric oxide and increased the levels of endothelin-1 release from HUVECs. When HUVECs were cultured with MCM from smokers who had been treated with taurine, the levels of nitric oxide and endothelin-1 returned toward control levels. This was attributed to an upregulation in endothelial nitric oxide synthase expression. Conclusions— These observations suggest that taurine supplementation has a beneficial impact on macrovascular endothelial function, and an investigation of its effect on altered endothelial function in dyslipidemic states is warranted.

Objectives: intimal hyperplasia (IH) is a major cause of re-stenosis post-vascular intervention. Induction of heat shock proteins (HSPs), by thermal pre-conditioning, reduces IH. Our aim was to investigate the effect of the pharmacological HSP inducer herbimycin A on IH in the rat carotid balloon injury model. Materials and Methods: thirty male Sprague–Dawley rats were randomized into three groups. All groups underwent balloon injury to the left carotid artery. Stress proteins were induced 18 h pre-operatively by heat shock or herbimycin A. Two weeks post-operatively, animals were sacrificed and carotid intima/media area ratio (I/M ratio) calculated using computerized planimetry. Neo-intimal proliferation was assessed immunohistochemically with PCNA (proliferating cell nuclear antigen). Western blot and immunohistochemistry for arterial HSP70 and HSP27 were performed. Results: heat stress and herbimycin significantly reduced the I/M ratio (p < 0.05 vs balloon injury alone). Neo-intimal proliferation was significantly reduced in the heat stress and herbimycin groups (p < 0.05 vs balloon injury alone). Heat stress induced arterial HSP70 and HSP27. Herbimycin A increased arterial HSP27. Conclusion: herbimycin A significantly attenuates IH after balloon injury. HSP27 may be the HSP involved in mediating this response. Pharmacological inducers of HSPs may have a therapeutic role to play in preventing re-stenosis post-vascular intervention.Eur J Vasc Endovasc Surg 25, 40–47 (2003)

BACKGROUND Lung carcinoma usually is advanced at the time of presentation and frequently shows metastatic spread. In recent times, prognostic factors such as c-erbB-2 in patients with breast carcinoma have provided useful information and beneficial therapeutic targets. The objective of this study was to evaluate angiogenesis, immune function, and telomerase expression in patients with nonsmall cell lung carcinoma (NSCLC) to determine their prognostic significance. METHODS Immunohistochemistry was used to evaluate the expression of human telomerase reverse transcriptase (hTERT; n = 115 patients), interleukin-2r (IL-2r; n = 40 patients), microvessel density (MVD; n = 81 patients), and vascular endothelial growth factor (VEGF; n = 61 patients). Three-year survival follow-up information was available for most patients, and a comprehensive review of clinicopathologic features was carried out. RESULTS Fifty percent of tumors showed nuclear staining for hTERT, 55% of tumors showed some degree of lymphocyte IL-2r expression, 33% of tumors were recorded with an MVD that was higher than average, and VEGF staining was detected in 85% of tumors. None of the parameters measured had an impact on survival. hTERT expression was correlated with lymph node status. Lymph node status and tumor size were identified as independent prognostic factors. CONCLUSIONS This study failed to identify a marker of prognosis for patients with NSCLC other than tumor size and lymph node status in this population. Telomerase expression was associated with metastases, raising the possibility that this enzyme is involved in the metastatic process. Tumor cell VEGF expression was identified frequently: This growth factor may have potential as a target for antiangiogenic therapy. Lung carcinoma typically is the result of large numbers of mutations. Further understanding of the biologic implications of these mutations will lead to the development of effective prognostic markers and treatments for patients with NSCLC. Cancer 2001;92:2648–57. © 2001 American Cancer Society.

To find out if pretreatment with taurine would reduce the severity of endotoxin-induced acute lung injury in a large animal model.Randomised controlled study under licence from the Department of Health.Department of Surgical Research, Ireland.15 male Suffolk sheep.Vascular catheters were placed in the femoral artery and vein and a Swan-Ganz catheter in the external jugular vein under general anaesthetic. Animals were randomized into three groups: control with measurements taken at baseline and half hourly up to 90 minutes; endotoxin, given Escherichia coli endotoxin intravenously after baseline measurements and taurine given 300 mg/kg 1 hour before endotoxin was given.Mean systemic arterial pressure, mean pulmonary arterial pressure, arterial oxygen tension (PO2), pulmonary myeloperoxidase activity, and neutrophil respiratory burst activity.Endotoxin induced a severe lung injury characterised by a decrease in mean systemic blood pressure and an increase in pulmonary artery pressure, hypoxia, and an increase in pulmonary myeloperoxidase activity. Pretreatment with intravenous taurine significantly reduced these haemodynamic changes. It reduced pulmonary myeloperoxidase activity and peripheral neutropenia and increased neutrophil respiratory burst activity.This data suggest that taurine may have a therapeutic role in preventing the lung injury seen in endotoxaemia.

Background Programmed cell death, or apoptesis, is a distinct, managed form of cell death. It is fundamentally different from necrosis. It is a genetically controlled, energy-dependent method of cellular deletion without inflammation. In the cardiovascular system, apoptosis occurs as a primary and secondary event in disease pathogenesis. This review addresses our current understanding of the initiation, propagation and significance of apoptosis in the cardiovascular system, as well as assessing therapeutic potentials arising therefrom. Methods A Medline search was performed and relevant publications reviewed. Further articles were obtained from the references of these publications. Results and conclusions Apoptotic cell death is a key element in the pathogenesis and progression of ischaemia-reperfusion (IR) injury, cardiac failure, myocardial infarction, atherosclerosis, endothelial dysfunction and the clinical syndromes which these situations produce. Our increased understanding of the role of apoptosis in the pathogenesis of cardiovascular disease offers potential to develop new therapeutic strategies.

Background. Respiratory complications continue to be a major cause of morbidity and mortality following major vascular surgery. The recent UK Small Aneurysm Trial cited preoperative respiratory function as the major predictor of outcome following elective aortic surgery. Aim. The aim of this study was to investigate the effect of aortic clamping and revascularization on diaphragmatic muscle function in a small animal model and to evaluate the role of preoperative treatment with recombinant human growth hormone (rhGH) in preventing diaphragmatic muscle dysfunction. Methods. Male Sprague-Dawley rats (n = 18) were randomized into one of three groups: control (n = 6) underwent laparotomy only; IR (n = 6) had a laparotomy with infrarenal cross-clamping for 30 min followed by lower torso revascularization for 2 h; IR + rhGH (n = 6) were treated with rhGH (Genotropin 0.3 IU/kg/day) for 5 days before laparotomy and aortic cross-clamping for 30 min followed by lower torso revascularization for 2 h. Diaphragmatic muscle contractile function was assessed ex vivo using electrical field stimulation in a tissue bath. Results. Two hours of IR injury resulted in a significant impairment in diaphragmatic twitch (Control, 242.01 + 38.45 g; IR, 108.55 + 7.15 g). This impairment was prevented by pretreatment with rhGH (rhGH, 319.14 + 30.71 g; P < 0.01). Tetanic function was also significantly impaired by ischemia reperfusion injury (control, 605 + 77.63 g; IR, 228.12 + 14.38 g). Again, pretreatment with rhGH prevented this deterioration (IR + rhGH, 704.39 + 45.69 g; P < 0.05) compared with controls. Conclusion. The results of this study suggest that preoperative administration of rhGH may have a role in preventing the diaphragmatic dysfunction associated with infrarenal aortic cross-clamping and revascularization.

Ischemia/reperfusion (I/R) results in endothelial dysfunction, seen as loss of endothelium-dependent vasodilatation. In prolonged ischemia, this can result in marked vasospasm or no reflow in the microvasculature. Thermotolerance (T) attenuates I/R-induced microvascular injury. The aim of this study was to investigate the effect of thermotolerance on I/R-induced vasomotor changes and "no reflow." Sprague-Dawley rats were randomized into an ischemia/reperfusion group (I/R group) and a group in which thermotolerance (41 + 0.5 degrees C for 15 min 18 h prior to I/R) was induced (T + I/R group). IR injury was established by occlusion of the superior mesenteric and celiac vascular pedicle for 30 min, followed by 60 min of reperfusion. Vasomotor function [arteriolar constriction:dilatation (C:D) ratio] measured by response to acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) and "no-reflow" phenomenon were determined in mesenteric arterioles by intravital microscopy. Data are expressed as means +/- SEM and were analyzed using ANOVA and chi(2) test. I/R caused a significant decrease in endothelium-dependent vasodilatation (C:D = 1.37+/-0.31 in IR group vs. 2.06+/-0.20 in baseline, P0.01) and no reflow in arterioles in 16 of 28 unheated rats. Endothelium-independent dilatation was not altered by I/R. Thermotolerance attenuated this impairment of endothelium-dependent dilatation (P0.01 vs. IR; C:D = 1.95+/-0.19) and reduced no-reflow phenomenon to 4 of 16 rats (P0.05 vs. IR). This study demonstrated that thermotolerance preserves endothelial vasomotor function and markedly reduces "no reflow" in arterioles.

To assess the efficacy of the cytoprotective B-amino acid taurine in prevention of skeletal muscle dysfunction secondary to ischaemia-reperfusion (IR) injury.Randomised controlled animal study.Biomedical research laboratory, teaching hospital, Republic of Ireland.96 Sprague Dawley rats.Rats were randomised into three groups (n = 24/group): control (sham); ischaemia-reperfusion (untreated); and ischaemia-reperfusion + taurine. A further 24 rats were given taurine alone. The rat cremaster skeletal muscle model of four hours of ischaemia followed by reperfusion was used. Taurine 4%wt/vol was given in the animals' water throughout the experiment, beginning 48 hours before the ischaemia was initiated.8 rats were killed from each group and muscle contractile function was assessed using electrical field stimulation in a tissue bath at 24 hrs, 48 hrs and 7 days.Ischaemia followed by 24 hours, 48 hours or 7 days of reperfusion resulted in significant reduction in both muscle twitch and tetanic contractile function (p0.05). This was reversed by taurine, which resulted in significant preservation of twitch and tetanic contractility at all time points including one week of reperfusion (p0.05). There was no difference in muscle function between muscle treated with taurine after ischaemia-reperfusion and control muscle, with the same operation but without ischaemia, from 48 hours onwards.These data show that pharmaceutical use of the endogenous amino acid taurine, unlike many-other agents, protects electrophysiological function in skeletal muscle against both early and late ischaemia-reperfusion injury.

Surgical myotomy is the mainstay of treatment for oesophageal achalasia. Minimally invasive surgical techniques, if feasible, reduce patient morbidity and mortality. In this study we review our experience of thoracoscopic Heller's myotomy. Thoracoscopic myotomy was undertaken in 9 patients (male = 3; female = 6, mean age = 37). All patients presented with dysphagia of 1 to 8 yr duration. Diagnosis was based on barium swallow and manometry. Two patients had previous dilatations and 1 had a transabdominal myotomy. All patients had a 5 port thoracoscopic technique. Thoracoscopic Heller's myotomy was completed in 8 out of 9 patients. In 1 patient extensive oesophagitis and peri-oesophagitis precluded both a thoracoscopic and an open myotomy, and oesophagectomy was subsequently performed. The mean duration of surgery was 142 min. Completion of myotomy and mucosal integrity was confirmed by intraoperative gastroscopy. All patients had an uneventful post-operative recovery. The mean hospital stay was 4 days. All patients are now asymptomatic, with documented weight gain. No patients have reflux oesophagitis symptoms. Our preliminary experience would suggest that thoracoscopic Heller's myotomy is a safe alternative to open surgery, with satisfactory results and reduced hospital stay.

Objectives: to determine whether pharmacological induction of heat shock proteins (HSPs) by herbimycin-A (a tyrosine-kinase inhibitor) would protect against neutrophil-mediated lung injury in an animal model of lower torso ischaemia-reperfusion. Materials and methods: Sprague-Dawley rats were randomised into three groups: the control group underwent midline laparotomy only; the ischaemia-reperfusion (IR) group underwent laparotomy and clamping of the infrarenal abdominal aorta for 30 min followed by 2 h of reperfusion; the third group (HerbIR) was pretreated with herbimycin-A 18 h prior to IR insult. Wet to dry lung weight ratio (W:D), bronchoalveolar lavage protein concentration (BALprot), tissue myeloperoxidase activity (MPO) and bronchoalveolar lavage neutrophil count (BALPMN) were measured. Heat shock protein 72 (HSP72) expression in lung, intestine, mesentery and liver was measured using Western immunoblotting. Results: IR resulted in acute lung injury with tissue oedema (W:D) and neutrophil infiltration (PMO, BALPMN). Herbimycin-A, in vivo, induced HSP expression and attenuated neutrophil infiltration (MPO, BALPMN). Conclusion: these data indicate that herbimycin-A protects against ischaemia-reperfusion induced pulmonary neutrophil infiltration, possibly by increasing the expression of heat shock proteins.

Leukocyte-endothelial interaction is a pivotal step in the pathogenesis of ischemia-reperfusion (I/R) injury. Exposure of cells to a subcritical heat stress may protect cells from subsequent I/R injury, through induction of a 72-kDa heat shock protein (HSP72). The aim of this study was to investigate the effect of thermotolerance on leukocyte adherence and migration during an I/R period in rat mesenteric postcapillary venules. Sprague-Dawley rats were randomized into control (sham I/R), I/R, and thermotolerance+I/R groups. Thermotolerance was induced 18 hr prior to I/R, which was in turn established by occlusion of the superior mesenteric vascular pedicle for 10 mins, followed by 60 mins of reperfusion. The blood flow, leukocyte rolling velocity, and the number of adherent and migrated leukocytes in postcapillary venules were measured by intravital microscopy. I/R significantly decreased the rolling velocity of leukocytes; increased the number of adherent leukocytes at 10, 30, and 60 mins after reperfusion; and also increased the number of migrated leukocytes at 60 mins after reperfusion. Thermotolerance induction expression of HSP72 in pulmonary, intestinal, and mesenteric tissues was determined by Western immunoblotting. Thermotolerance significantly prevented the I/R-induced decrease in rolling velocity of leukocytes, the increase in the number of adherent leukocytes at 30 and 60 mins, and the increase in the number of migrated leukocytes at 60 mins. This results suggest that thermotolerance attenuates I/R injury by modulating leukocyte-endothelial interaction in vivo, possibly by increasing tissue expression of HSP72.

Aortic occlusion and revascularization (I-R) may lead to lung injury dependent on activated neutrophil adherence. Nitric oxide (NO) inhibits neutrophil adherence to endothelial cells. We studied the effect of increasing or decreasing NO levels with sodium nitroprusside (SNP) or N-nitro-L-arginine methyl ester (L-NAME) in an I-R lung injury model of 30 min ischemia followed by 120 min reperfusion. Sprague-Dawley rats (10/group) were randomized to controls, I-R, I-R treated with L-NAME (10 mg/ml/hr), and I-R treated with SNP (0.2 mg/ml/hr). Myeloperoxidase activity (MPO) was used as a measure of pulmonary neutrophil influx. Pulmonary endothelial permeability was measured by wet:dry weight ratio and bronchoalveolar lavage protein (BAL prot) and neutrophil counts (BAL PMN). Aortic occlusion and revascularization led to significant increases in pulmonary neutrophil influx (6.1 +/- 0.1 MPO u/g vs 3.05 +/- 0.4 MPO u/g in the control group, P < 0.001) and microvascular leakage; BAL prot (347 +/- 32 mg/ml in controls vs 454 +/- 16 mg/ml in the I-R group, P < 0.05); and BAL PMN (0.7 +/- 0.05 in controls vs 1.8 +/- 0.07 PMN/ml in the I-R group, P < 0.001). These changes were exacerbated further by administration of L-NAME (MPO = 8.9 +/- 0.7; BAL prot = 581 +/- 40 mg/ml; BAL PMN = 2.7 +/- 0.16 PMN/ml). Sodium nitroprusside therapy attenuated the I-R-induced lung injury (3.5 +/- 0.4 MPO u/g, P < 0.05 vs I-R; BAL prot = 330 +/- 61 mg/ml; BAL PMN = 0.9 +/- 0.1 PMN/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Ischaemic nerve injury has been suggested as the mechanism for post-tourniquet limb paralysis. As hypothermia has been shown to prolong ischaemia time in many tissues, we tested the hypothesis that cold protection would reduce tourniquet induced neural injury. In 16 male Wistar rats a tourniquet was applied to the right hind limb for 3 h. In eight rats both hind limbs were maintained at room temperature (27 degrees C) while the limb temperature was decreased to 4 degrees C by application of cold polyglycol gel packs in the remaining eight animals. Motor nerve conduction velocity (MNCV) and the amplitude of muscle motor units (AMMU) in response to nerve stimulation were measured at 0 h, 1 h and 1 week post-tourniquet release. Application of the tourniquet for 3 h abolished nerve conduction in all animals. Hypothermia resulted in a significant improvement in AMMU (5.8 +/- vs. 0.6 +/- 0.4 mv, p less than 0.05) at 1 h and in MNCV (26.6 +/- 1.6 vs. 8.1 +/- 4.4 ms-1, p less than 0.05) and AMMU (18.5 +/- 2.0 vs. 9.7 +/- 4.5 mv, p less than 0.05) at 1 week. Hypothermia without ischaemia also reduced MNCV (44.2 +/- 9.4 vs. 74.3 +/- 8.9 ms-1, p less than 0.05) and AMMU (28.1 +/- 2.8 vs. 36.3 +/- 8.4 mv, N.S.). These data indicate that hypothermia reduces normal MNCV and protects nerve function during tourniquet ischaemia. These results support the ischaemic hypothesis for post-tourniquet nerve injury. Cold protection may have clinical applications for surgical procedures performed with tourniquet ischaemia.

This study assesses the changes in the microvasculature of peripheral nerves in acute large vessel ischaemic neuropathy. An animal model of large vessel ligation, producing an ischaemic neuropathy was used: the presence and extent of the neuropathy was documented by clinical examination and nerve conduction studies. The nerve microcirculation, the "vasa nervorum" was examined using casting materials, methyl methacrylate and silicone rubber, which were in turn examined by light microscopy and scanning electron microscopy. In all, ten animals were used, all of whom showed clinical evidence of an ischaemic neuropathy 1 week post-ligation. This ischaemic neuropathy was confirmed by nerve conduction studies. Corrosion casts were produced in five of the ten animals. Examination of these casts showed that all five had an area of underfilling of the microcirculation in the region of the proximal tibial nerve with good filling of vessels proximal and distal to this, indicating that in generalised hypoperfusion states such as large vessel ligation, the area of poorest perfusion (and thus maximal damage) is not the distal vascular field, but a probable "watershed zone" between two adjacent nutrient vessels to the nerve.

Pravastatin attenuates changes in serum creatinine, renal haemodynamics (renal flux and glomerular filtration rate [GFR]) and architectural distortion. It had no systemic effects on weight loss or serum lipid levels suggesting that reno-protection occurs locally and independent of lipid lowering.

The above data demonstrate that the endothelial dysfunction (FMD) previously demonstrated correlates with endothelial injury (vWF) and platelet abnormalities. These are early and possibly synergistic alterations in young smokers that contribute to the development of atherogenesis.