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3.  Supervised Exercise vs Primary Stenting for Claudication Due to Aortoiliac Peripheral Artery Disease: 6-Month Outcomes from the CLEVER Study 
Circulation  2011;125(1):130-139.
Claudication is a common and disabling symptom of peripheral artery disease that can be treated with medication, supervised exercise or stent revascularization.
We randomly assigned 111 patients with aortoiliac peripheral artery disease to receive one of three treatments: optimal medical care [OMC], OMC plus supervised exercise [(SE], or OMC plus stent revascularization [ST]. The primary endpoint was the change in peak walking time (PWT) on a graded treadmill test at 6 months as compared with baseline. Secondary endpoints included free-living step activity, quality of life (QOL) using the Walking Impairment Questionnaire (WIQ) and Peripheral Artery Questionnaire (PAQ), and cardiovascular risk factors.
At six month follow-up, change in PWT (the primary endpoint) was greatest for SE, intermediate for ST, and least with OMC (mean change vs. baseline 5.8±4.6, 3.7±4.9, and 1.2±2.6 minutes, respectively; p<0.001 for the comparison of SE vs. OMC; p=0.02 for ST vs. OMC; and p=0.04 for SE vs. ST). Although disease-specific quality of life as assessed by the WIQ and PAQ also improved with both SE and ST compared with OMC, for most scales the extent of improvement was greater with ST than SE. Free-living step activity increased more with ST than with either SE or OMC alone (114±274 vs. 73±139 vs. −6±109 steps/hour) but these differences were not statistically significant.
Supervised exercise treatment results in superior treadmill walking performance than stent placement, even for those with aortoiliac PAD. The contrast between better walking performance for SE and better patient-reported QOL for ST warrants further study.
PMCID: PMC3374869  PMID: 22090168
4.  Three horizontal muscle surgery for large-angle infantile esotropia: validation of a table of amounts of surgery 
Eye  2011;25(11):1435-1441.
To validate a table of amounts of three horizontal muscle surgery in patients with large-angle infantile esotropia (≥60 prism dioptres, PD).
A prospective interventional case series reporting the postoperative alignment of 51 patients (27 male, 24 female) over a 15-year period was conducted. Surgery amounts were according to a published table developed on a previous patient cohort (n=49), using bilateral medial rectus recession with graded unilateral lateral rectus resection. Kaplan–Meier life-table survival curves were formulated for success to orthotropia (±10 PD) after one and subsequent horizontal muscle surgeries for up to 8 years follow-up.
The median preoperative deviation was 65 PD (range 60–80 PD) and median age at surgery was 11.8 months (range 5.1 months–3.6 years). Surgical success to orthotropia (±10 PD) after one surgery was 100% at 2 months, 95.7% at 6 months, 91.3% at 12 months, 77.8% at 4 years, and 73.6% at 8 years. Postoperative failure requiring further horizontal surgery occurred in 17.6% (residual esotropia 4, consecutive exotropia 5).
Our second cohort has reproduced the success rate of the previous cohort (77.8% vs 77.1% at 4 years). If the published table of surgical amounts is used, three horizontal muscle surgery in large-angle infantile esotropia (≥60 PD) appears to have a good long-term success rate, and does not lead to the high rates of either residual esotropia or consecutive exotropia reported by others in the literature.
PMCID: PMC3213649  PMID: 21818127
infantile esotropia; strabismus; surgery
7.  Validity of synthetic bone as a substitute for osteoporotic cadaveric femoral heads in mechanical testing 
Bone & Joint Research  2012;1(4):50-55.
The objective of this study was to determine if a synthetic bone substitute would provide results similar to bone from osteoporotic femoral heads during in vitro testing with orthopaedic implants. If the synthetic material could produce results similar to those of the osteoporotic bone, it could reduce or eliminate the need for testing of implants on bone.
Pushout studies were performed with the dynamic hip screw (DHS) and the DHS Blade in both cadaveric femoral heads and artificial bone substitutes in the form of polyurethane foam blocks of different density. The pushout studies were performed as a means of comparing the force displacement curves produced by each implant within each material.
The results demonstrated that test material with a density of 0.16 g/cm3 (block A) produced qualitatively similar force displacement curves for the DHS and qualitatively and quantitatively similar force displacement curves for the DHS Blade, whereas the test material with a density of 0.08 g/cm3 (block B) did not produce results that were predictive of those recorded within the osteoporotic cadaveric femoral heads.
This study demonstrates that synthetic material with a density of 0.16 g/cm3 can provide a good substitute for cadaveric osteoporotic femoral heads in the testing of implants. However we do recognise that no synthetic material can be considered as a definitive substitute for bone, therefore studies performed with artificial bone substrates may need to be validated by further testing with a small bone sample in order to produce conclusive results.
PMCID: PMC3626209  PMID: 23610671
Intertrochanteric fracture; Biomechanical study; Artificial bone substitute; DHS; DHS Blade; Osteoporotic Bone
8.  Differential stimulation of monocytic cells results in distinct populations of microparticles 
Microparticles (MPs), small vesicles shed from stimulated cells, permit cross-talk between cells within a particular environment. Their composition is thought to reflect their cell of origin, and differs according to whether they are produced by stimulation or by apoptosis. Whether MP properties vary according to stimulus is not yet known.
We studied the characteristics of MPs produced from monocytic THP-1 cells upon stimulation with lipopolysaccharide or a soluble P-selectin chimera, using proteomics, flow cytometry, western blotting, and electron microscopy.
Utilizing a novel criterion of calcein-AM staining to define MPs, we found that MP populations were similar with respect to size, presence and organization of cytoskeleton, and expression of certain antigens. The MPs shared the same level of procoagulant activity. We found that MPs also have distinct characteristics, depending on stimuli. These include differences in phosphatidylserine expression and expression of proteins from specific subcellular locations such as the mitochondria, and of unique antigens such as leukocyte-associated immunoglobin-like-receptor (LAIR)-1, which was found only upon stimulation with the soluble P-selectin chimera.
We found that the properties of MPs depend on the stimulus that produced them. This supports the concept that monocytic MPs differentially modulate thrombosis, inflammation and immune regulation according to stimulus.
PMCID: PMC3242443  PMID: 19548909
LPS; microparticles; monocytes; phosphatidylserine; proteomics; P-selectin
9.  Engineering Silicone Rubbers for In vitro Studies: Creating AAA Models and ILT Analogues with Physiological Properties 
In vitro studies of abdominal aortic aneurysm (AAA) have been widely reported. Frequently mock artery models with intraluminal thrombus (ILT) analogues are used to mimic the AAA in vivo. While the models used may be physiological, their properties are frequently either not reported or investigated.
Method of Approach
This study is concerned with the testing and characterisation of previously used vessel analogue materials and the development of new materials for the manufacture of AAA models. These materials were used in conjunction with a previously validated injection moulding technique to manufacture AAA models of ideal geometry. To determine the model properties (stiffness (β) and compliance) the diameter change of each AAA model was investigated under incrementally increasing internal pressures and compared to published in vivo studies to determine if the models behaved physiologically. A FEA study was implemented to determine if the pressure – diameter change behaviour of the models could be predicted numerically. ILT analogues were also manufactured and characterised. Ideal models were manufactured with ILT analogue internal to the aneurysm region and the effect of the ILT analogue on the model compliance and stiffness was investigated.
The wall materials had similar properties to aortic tissue at physiological pressures (Einit 2.22MPa and 1.57MPa (aortic tissue: 1.8MPa)). ILT analogues had similar Young’s modulus to the medial layer of ILT (0.24 and 0.33MPa (ILT: 0.28MPa)). All models had aneurysm sac compliance in the physiological range (2.62 – 8.01×10-4/mmHg (AAA in vivo: 1.8 – 9.4×10-4/mmHg)). The necks of our AAA models had similar stiffness to healthy aortas (20.44 – 29.83 (healthy aortas in vivo: 17.5±5.5)). Good agreement was seen between the diameter changes due to pressurisation in the experimental and FEA wall models with a maximum error of 7.3% at 120mmHg. It was also determined that the inclusion of ILT analogue in the sac of our models could have an effect on the compliance of the model neck.
Ideal AAA models with physiological properties were manufactured. The behaviour of these models due to pressurisation was predicted using FEA, validating this technique for the future design of realistic, physiological AAA models. Addition of ILT analogues in the aneurysm sac was shown to affect neck behaviour. This could have implications for endovascular AAA repair due to the importance of the neck for stent-graft fixation.
PMCID: PMC2882675  PMID: 20524746
Abdominal aortic aneurysm; mock artery models; realistic properties
10.  Vessel Asymmetry as an Additional Diagnostic Tool in the Assessment of Abdominal Aortic Aneurysms 
Abdominal aortic aneurysm rupture (AAA) is believed to occur when the local mechanical stress exceeds the local mechanical strength of the wall tissue. Based on this hypothesis, the knowledge of the stress acting on the wall of an unruptured aneurysm could be useful in determining the risk of rupture. The role of asymmetry has previously been identified in idealised AAA models, and is now studied using realistic AAAs in the current work.
Fifteen patient-specific AAAs were studied to estimate the relationship between wall stress and geometrical parameters. 3D AAA models were reconstructed from CT scan data. The stress distribution on the AAA wall was evaluated by the finite element method, and peak wall stress was compared to both diameter and centreline asymmetry. A simple method of determining asymmetry was adapted and developed. Statistical analyses were also performed to determine potential significance of results.
Mean von Mises peak wall stress ± standard deviation was shown to be 0.4505 ± 0.14 MPa, with a range of 0.3157 – 0.9048 MPa. Posterior wall stress increases with anterior centreline asymmetry. Peak stress increased by 48% and posterior wall stress increased by 38% when asymmetry was introduced into a realistic AAA model.
The relationship between posterior wall stress and AAA asymmetry showed that excessive bulging of one surface results in elevated wall stress on the opposite surface. Assessing the degree of bulging and asymmetry that is experienced in an individual AAA may be of benefit to surgeons in the decision making process, and may provide a useful adjunct to diameter as a surgical intervention guide.
PMCID: PMC2666821  PMID: 19028061
11.  Sphenopalatine artery ligation under local anesthesia: A report of two cases and review of the literature 
Epistaxis is the commonest emergency in otorhinolaryngology. Over the last decade endoscopic sphenopalatine artery (SPA) ligation has become a popular treatment option for posterior epistaxis and has been shown to be the most effective and cost-efficient definitive treatment for posterior epistaxis. SPA ligation is usually performed under general anesthesia. The majority of epistaxis patients are elderly, frail and have multiple medical conditions. These patients are therefore not always amenable to general anesthesia. In this article we describe two cases where posterior epistaxis was successfully treated with sphenopalatine artery ligation under local anesthesia and should be considered suitable for patients with severe posterior epistaxis who are not fit for a general anesthetic.
PMCID: PMC3417940  PMID: 22915861
epistaxis; sphenopalatine artery ligation; local anesthesia
12.  Atrioventricular block after transcatheter closure of perimembranous ventricular septal defects 
Heart  2006;92(9):1295-1297.
To look at the presentation, treatment and outcome of patients who developed atrioventricular block after transcatheter closure of a perimembranous ventricular septal defect (PMVSD) with the Amplatzer PMVSD device.
Three tertiary referral centres for paediatric cardiology in two countries.
All three patients presented within 10 days of the procedure. All three patients were treated with intravenous steroids. A permanent pacemaker was inserted in all patients but no pacemaker required activation after two months.
Complete atrioventricular block occurring in the weeks after device occlusion of a PMVSD appears to resolve quickly. Continued involvement in multicentre device databases is required to monitor safety.
PMCID: PMC1861195  PMID: 16449504
13.  Mannose-binding lectin plays a critical role in myocardial ischaemia and reperfusion injury in a mouse model of diabetes 
Diabetologia  2008;51(8):1544-1551.
Diabetic patients are at increased risk of cardiomyopathy, acute myocardial infarction and loss of cardiac progenitor cells (CPCs), but the aetiology is poorly understood. We hypothesised a significant role for mannose-binding lectin (MBL) in cardiomyopathies associated with hyperglycaemia.
The role of MBL in myocardial ischaemia and reperfusion (MI/R) injury was investigated in wild-type (WT) and MBL-null mice following 2 weeks of streptozotocin-induced hyperglycaemia.
Hyperglycaemic WT mice presented with significantly decreased left ventricular ejection fractions and increased serum troponin I levels and myocardial inflammation compared with non-diabetic WT mice following MI/R. Hyperglycaemic MBL-null mice or insulin-treated diabetic WT mice were significantly protected from MI/R injury compared with diabetic WT mice. In an additional study using diabetic WT mice, echocardiographic measurements demonstrated signs of dilative cardiomyopathy, whereas heart:body weight ratios suggested hypertrophic cardiac remodelling after 2 weeks of hyperglycaemia. Immunohistochemical analysis of CPCs showed significantly lower numbers in diabetic WT hearts compared with non-diabetic hearts. Insulin-treated diabetic WT or untreated diabetic MBL-null mice were protected from dilative cardiomyopathy, hypertrophic remodelling and loss of CPCs.
These data demonstrate that MBL may play a critical role in diabetic MI/R injury. Further, the absence of MBL appears to inhibit hypertrophic remodelling and hyperglycaemia-induced loss of CPCs after just 2 weeks of hyperglycaemia in mice.
PMCID: PMC2542900  PMID: 18493734
Animal; Complement; Mannose-binding lectin; Type 1 diabetes
14.  Non‐response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS‐3) in patients with chronic hepatitis C, viral genotype 1 
Gut  2006;55(4):529-535.
Interferon α (IFN‐α) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown.
To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN‐α therapy and to determine hepatic expression of factors inhibiting IFN‐α signalling in obese and non‐obese subjects with chronic HCV.
A total of 145 subjects were analysed to determine host factors associated with non‐response to antiviral therapy. Treatment comprised IFN‐α or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time‐polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS‐3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment.
Non‐response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p<0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index ⩾ 30 kg/m2 (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS‐3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS‐3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS‐3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non‐responders compared with responders (p = 0.014).
In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN‐α.
PMCID: PMC1856185  PMID: 16299039
insulin resistance; tumour necrosis factor; phosphoenolpyruvate carboxy kinase; suppressor of cytokine signalling; obesity; antiviral therapy; hepatitis C
15.  Improving the management and referral of patients with transient ischaemic attacks: a change strategy for a health community 
Rapid referral and management of patients with transient ischaemic attacks is a key component in the national strategy for stroke prevention. However, patients with transient ischaemic attacks are poorly identified and undertreated.
Design and setting
Before and after evaluation of quality improvement programme with controlled comparison in three primary care trusts reflecting diverse populations and organisational structures in an urban district in the North of England.
Key measures for improvement
The proportion of patients receiving antiplatelet drugs and safe driving advice on referral to a speciality clinic, and the numbers of referrals, adjusted for age, to the specialist clinic before and after the improvement programme.
Strategies for change
Interviews with patient and professionals to identify gaps and barriers to good practice; development of evidence based guidelines for the management of patients with transient ischaemic attacks; interactive multidisciplinary workshops for each primary care trust with feedback of individual audit results of referral practice; outreach visits to teams who were unable to attend the workshops; referral templates and desktop summaries to provide reminders of the guidelines to clinicians; incorporation of standards into professional contracts.
Effects of change
A significant improvement occurred in identification and referral of patients with transient ischaemic attacks to specialist clinics, with a 41% increase in referrals from trained practices compared with control practices. There were also significant improvements in the early treatment and safety advice provided to patients before referral.
Lessons learnt
A strategic approach to effective quality improvement across a diverse health community is feasible and achievable. Careful planning with patient and professional involvement to develop a tailored and multifaceted quality improvement programme to implement evidence based practice can work in very different primary care settings. Key components of the effectiveness of the model include contextual analysis, strong professional support, clear recommendations based on robust evidence, simplicity of adoption, good communication, and use of established networks and opinion leaders.
PMCID: PMC2564006  PMID: 16456203
quality improvement report; stroke prevention; clinical guidelines; transient ischaemic attacks; implementation of change
16.  Perioperative serum inflammatory response and the development of atrial fibrillation after coronary artery bypass surgery 
Heart  2005;91(11):1475-1476.
PMCID: PMC1769158  PMID: 16230451
adhesion molecules; atrial fibrillation; C reactive protein; coronary artery bypass surgery; inflammation
17.  BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum 
Gut  2004;53(8):1137-1144.
Background and aims: Mutations in BRAF have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP).
Methods: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as “sessile serrated adenoma” (SSA). All tumours were screened for BRAF activating mutations.
Results: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001).
Conclusions: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this “serrated” pathway.
PMCID: PMC1774130  PMID: 15247181
BRAF; colorectal cancer; serrated pathway; CpG island methylator phenotype; microsatellite instability
18.  Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer 
Gut  2004;53(4):573-580.
Aim: Hyperplastic polyps (HP) of the colorectum have traditionally been regarded as non-neoplastic lesions. Recent data implicate HP in the pathogenesis of colorectal cancers (CRC) characterised by extensive DNA methylation and microsatellite instability. The aim of this study was to identify morphological and molecular features that may characterise subtypes of HP with potential for neoplastic progression.
Materials and methods: HP (22) clustering around distal CRC (group I) were compared with HP (58) in subjects with hyperplastic polyposis (group II). DNA methylation was tested in methylated in tumour (MINT) loci (1, 2, 12, 31) and genes HPP1, MGMT, p14ARF, p16INK4a, and hMLH1.
Results: Group II HP showed significantly more methylation than group I HP at all loci except MINT1 and MGMT. Group I showed the lowest frequency of DNA methylation but the highest frequency of K-ras mutation. Group II HP (termed HP variant) had the morphological features of the recently described “sessile serrated adenomas”. Methylation of hMLH1 was found most frequently in group II polyps that included foci of dysplasia (7/10) and in no group I lesions.
Conclusion: The findings support the existence of morphological and molecular heterogeneity among HP and highlight a subset that is likely to have significant malignant potential.
PMCID: PMC1774017  PMID: 15016754
hyperplastic polyposis; CpG methylation; colon cancer; microsatellite instability
19.  APC mutation and tumour budding in colorectal cancer 
Journal of Clinical Pathology  2003;56(1):69-73.
Aim: To determine the frequency of tumour budding and somatic APC mutation in a series of colorectal cancers stratified according to DNA microsatellite instability (MSI) status.
Material/Methods: Ninety five colorectal cancers were genotyped for APC mutation in the mutation cluster region (exon 15) and scored for the presence of tumour budding at the invasive margin in haematoxylin and eosin stained sections. A subset was immunostained for β catenin and p16.
Results: The frequency of both somatic APC mutation and tumour budding increased pari passu in cancers stratified as sporadic MSI high (MSI-H), hereditary non-polyposis colorectal cancer (HNPCC), MSI low (MSI-L), and microsatellite stable (MSS). Both budding and APC mutation were significantly less frequent in sporadic MSI-H cancers than in MSI-L or MSS cancers. Tumour buds were characterised by increased immunostaining for both β catenin and p16.
Conclusion: Tumour budding is associated with an adverse prognosis. The lack of budding in MSI-H colorectal cancer may account for the improved prognosis of this subset and may be explained by an intact WNT signalling pathway and/or inactivated p16INK4a.
PMCID: PMC1769852  PMID: 12499439
colon; rectum; cancer; budding; APC gene; mutation; microsatellite instability
20.  Mucin gene expression in the ileoanal reservoir is altered and may be relevant to the risk of inflammation and dysplasia 
Gut  2002;51(3):386-391.
Background: Adaptive colonic phenotypic change of the ileal mucosa is a feature of the ileoanal reservoir (IAR) with time, as described by mucin glycoprotein and histological analysis. Mucin gene expression is altered in colorectal neoplasia and inflammatory bowel disease but little is known of its expression in the IAR.
Aims: To examine the changes in mucin gene expression contributing to mucosal protection of the IAR against a background of known changes occurring in inflammatory disease and colorectal neoplasia.
Patients: Paraffin embedded specimens from 29 “W” and 11 “J” ileoanal reservoirs were studied. Colonic and ileal control tissue was obtained from normal resection margins.
Methods: Mucin mRNA was detected by in situ hybridisation using [35S]dATP labelled oligonucleotide probes. Mucin core protein was detected by immunohistochemistry.
Results: There was no change in mRNA expression of MUC1–4 in the IAR compared with ileal controls but there was a decrease in the protein product of MUC1 and MUC3. No mRNA transcripts of MUC5AC, 5B, or 6 were detected but protein product of MUC5AC and MUC6 was detected. Both cases of MUC6 positivity and 1/5 cases of MUC5AC positivity were confined to the ulcer associated cell lineage. No dysplasia was detected.
Conclusions: There is a change in the pattern of the membrane associated mucins MUC1 and MUC3, part of which is in keeping with changes described in colorectal neoplasia. A small number of cases demonstrated mucin gene changes (MUC5AC) which are seen in early neoplasia and this may provide a valuable monitor for such changes in IAR surveillance.
PMCID: PMC1773360  PMID: 12171961
mucin gene; ileoanal reservoir; dysplasia; colonic phenotypic change
21.  Risk stratification in unstable angina and non-Q wave myocardial infarction using soluble cell adhesion molecules 
Heart  2001;85(6):623-627.
OBJECTIVE—To assess prospectively the prognostic value of soluble cellular adhesion molecules (CAMs) in patients with unstable angina and non-Q wave myocardial infarction and to compare their prognostic accuracy with that of C reactive protein (CRP).
DESIGN AND SETTING—Prospective observational study of patients presenting acutely with unstable angina and non-Q wave myocardial infarction to a single south Dublin hospital.
METHODS—Patients with Braunwald IIIA unstable angina and non-Q wave myocardial infarction had serum samples taken at presentation before initiation of antithrombotic treatment and were followed for six months. The primary end point was the occurrence of major adverse cardiovascular events (recurrent unstable angina, non-fatal myocardial infarction, and cardiovascular death) at six months. Concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble endothelial selectin, and soluble platelet selectin were measured using an enzyme linked immunosorbent assay technique. CRP was measured with an immunophelometric assay.
RESULTS—91 patients (73 men and 18 women, mean (SD) age 61 (11) years) were studied; 27 patients (30%) had major adverse cardiac events during the six months of follow up. Concentration of CRP were significantly raised in patients who had an ischaemic event (mean (SEM) 11.5 (6.4) mg/l v 5.4 (2.5) mg/l, p < 0.001). Concentrations of sVCAM-1 were also significantly raised in the ischaemic event group (979 (30) ng/ml v 729 (22) ng/ml, p < 0.001). Both sVCAM-1 and CRP concentrations correlated strongly with the occurrence of an adverse event. The sensitivity of CRP > 3 mg/l and sVCAM-1 > 780 ng/ml for predicting future events was > 90%. There was no difference in concentrations of sICAM-1, soluble endothelin selectin, or soluble platelet selectin between event and non-event groups.
CONCLUSION—Raised concentrations of sVCAM-1 and CRP are predictive of an increased risk of major adverse cardiovascular events six months after presentation with unstable angina and non-Q wave myocardial infarction. These findings suggest that the intensity of the vascular inflammatory process at the time of presentation is a determinant of clinical outcome in unstable coronary artery disease. 

Keywords: cell adhesion molecules; risk stratification; unstable angina
PMCID: PMC1729754  PMID: 11359739
22.  Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status 
Gut  2001;48(3):360-366.
BACKGROUND—The presence of high level DNA microsatellite instability (MSI-H) in colorectal cancer is associated with an improved prognosis, as is the presence of tumour infiltrating lymphocytes (TILs). It is not clear if TILs contribute directly to the survival advantage associated with MSI-H cancers through activation of an antitumour immune response.
AIMS—To correlate TIL and apoptosis rates in colorectal cancer stratified by MSI status.
METHODS—The distribution of TILs was characterised and quantified in a selected series of 102 sporadic colorectal cancers classified according to levels of MSI as 32 MSI-H, 30 MSI-low (MSI-L), and 40 microsatellite stable (MSS). Archival blocks were immunostained using the T cell markers CD3 and CD8, and the B cell marker CD20. Apoptosis of malignant epithelial cells was quantified by immunohistochemistry with the M30 CytoDEATH antibody.
RESULTS—Positive staining with anti-CD3 and negative staining with anti-CD20 identified virtually all TILs as T cells. The majority of CD3+ TILs (>75%) also stained with anti-CD8. TILs were most abundant in MSI-H colorectal cancers in which 23/32 (72%) scored as TIL positive. Only 5/40 (12.5%) MSS tumours and 9/30 (30%) MSI-L cancers were TIL positive (p<0.0001). MSI-H cancers showed a twofold higher rate of apoptosis (mean (SD) 3.52 (0.34)%) than the MSS cancers (1.53 (0.23)%) while the MSI-L subgroup had an intermediate level (2.52 (0.35)%) (p<0.0001). Overall, there was a small (r=0.347) but significant linear correlation between CD3+ and M30+ random apoptosis counts (p<0.001). However, TILs and apoptosis showed little colocalisation.
CONCLUSIONS—While TILs might be expected to explain the increased apoptotic rate and improved prognosis of MSI-H cancers, it is likely that TILs and apoptosis are independent characteristics of MSI-H cancers.

Keywords: colorectal cancer; DNA microsatellite instability; tumour infiltrating lymphocytes; apoptosis
PMCID: PMC1760146  PMID: 11171826
23.  The experience and training of British general surgeons in trauma surgery for the abdomen, thorax and major vessels. 
BACKGROUND: The report Better Carefor the Severely Injured [London: The Royal College of Surgeons of England and the British Orthopaedic Association; 2000] states that an experienced general surgeon trained in the techniques required to perform life-saving emergency surgery is vital in the management of major trauma. The experience and training of general surgeons in the UK in the management of trauma to the abdomen, thorax and major vessels has never been assessed. METHOD: Postal questionnaire sent to UK general surgical consultants and Higher Surgical Trainees (HSTs). RESULTS: A total of 854 (48%) questionnaires were completed. Of respondents, 85% believe that major trauma should be directed to hospitals that provide a dedicated trauma service. Of non-vascular specialists, 43% felt their training was adequate to manage vascular trauma and only one-third of general surgical consultants felt adequately prepared to manage acute cardiothoracic injuries. The median number of trauma laparotomies undertaken annually was 2 for blunt injury and 1 for penetrating injury. Of HSTs, 21% had not performed a splenectomy for trauma and 44% had no experience of packing for liver injuries. CONCLUSIONS: There is limited experience and training in the surgical management of torso trauma in the UK. Implementation of the recommendations from Better Care for the Severely Injured will be hampered unless steps are taken to maximise experience and improve training.
PMCID: PMC2504212  PMID: 12484581
24.  Massive abdominal and pelvic myxoma in Carney's syndrome 
Journal of Clinical Pathology  2000;53(7):558-560.
Note in proof: since the writing of this report, the patient has had a massive recurrence of abdominal myxoma (confirmed histologically).
This report describes a massive abdominal and pelvic myxoma in a patient with Carney's syndrome. A 38 year old woman presented with abdominal distension and a palpable mass, and at operation a large pelvic and abdominal tumour was identified and resected. The surgical specimen consisted of a lobulated mass, which on cut section had a uniform gelatinous consistency. The mass surrounded both ovaries, the appendix, and the upper part of the uterus, but macroscopically did not appear to involve these organs. Histological examination showed plump stellate and spindle shaped cells set in an abundant myxoid stroma, in keeping with a myxoma. Immunohistochemical staining revealed positivity of tumour cells for vimentin, but no reactivity to desmin, α-smooth muscle actin, S-100 protein, CD34, or AE1/AE3. This is the first documented case of massive adominal and pelvic myxoma in a patient with Carney's syndrome. Clinicians and pathologists should be aware that myxomas in Carney's syndrome can rarely involve unusual sites other than the skin and heart.
Key Words: abdomen • pelvis • myxoma • Carney's syndrome • immunohistochemistry
PMCID: PMC1731236  PMID: 10961183
25.  Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum 
Gut  2000;47(1):43-49.
AIM—Colorectal cancer has been described in association with hyperplastic polyposis but the mechanism underlying this observation is unknown. The aim of this study was to characterise foci of dysplasia developing in the polyps of subjects with hyperplastic polyposis on the basis of DNA microsatellite status and expression of the DNA mismatch repair proteins hMLH1, hMSH2, and hMSH6.
MATERIALS AND METHODS—The material was derived from four patients with hyperplastic polyposis and between one and six synchronous colorectal cancers. Normal (four), hyperplastic (13), dysplastic (13), and malignant (11) samples were microdissected and a PCR based approach was used to identify mutations at 10 microsatellite loci, TGFβIIR, IGF2R, BAX, MSH3, and MSH6. Microsatellite instability-high (MSI-H) was diagnosed when 40% or more of the microsatellite loci showed mutational bandshifts. Serial sections were stained for hMLH1, hMSH2, and hMSH6.
RESULTS—DNA microsatellite instability was found in 1/13 (8%) hyperplastic samples, in 7/13 (54%) dysplastic foci, and in 8/11 (73%) cancers. None of the MSI-low (MSI-L) samples (one hyperplastic, three dysplastic, two cancers) showed loss of hMLH1 expression. All four MSI-H dysplastic foci and six MSI-H cancers showed loss of hMLH1 expression. Loss of hMLH1 in MSI-H but not in MSI-L lesions showing dysplasia or cancer was significant (p< 0.001, Fisher's exact test). Loss of hMSH6 occurred in one MSI-H cancer and one MSS focus of dysplasia which also showed loss of hMLH1 staining.
CONCLUSION—Neoplastic changes in hyperplastic polyposis may occur within a hyperplastic polyp. Neoplasia may be driven by DNA instability that is present to a low (MSI-L) or high (MSI-H) degree. MSI-H but not MSI-L dysplastic foci are associated with loss of hMLH1 expression. At least two mutator pathways drive neoplasia in hyperplastic polyposis. The role of the hyperplastic polyp in the histogenesis of sporadic DNA microsatellite unstable colorectal cancer should be examined.

Keywords: colon; hyperplastic polyposis; DNA mismatch repair; microsatellite instability
PMCID: PMC1727952  PMID: 10861263

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