The role of endothelial cells and their progenitors in intimal hyperplasia.

Intimal hyperplasia leading to restenosis is the major process that limits the success of cardiovascular intervention. The emergence of vascular progenitor cells and, in particular, endothelial progenitor cells has led to great interest in their potential therapeutic value in preventing intimal hyperplasia. We review the mechanism of intimal hyperplasia and highlight the important attenuating role played by a functional endothelium. The role of endothelial progenitor cells in maintaining endothelial function is reviewed and we describe how reduced progenitor cell number and function and reduced endothelial function lead to an increased risk of intimal hyperplasia. We review other potential sources of endothelial cells, including monocytes, mesenchymal stem cells and tissue resident stem cells. Endothelial progenitor cells have been used in clinical trials to reduce the risk of restenosis with varied success. Progenitor cells have huge therapeutic potential to prevent intimal hyperplasia but a more detailed understanding of vascular progenitor cell biology is necessary before further clinical trials are commenced.

Quality of life after surgical reduction for severe primary lymphoedema of the limbs and genitalia.

BACKGROUND: The aim was to assess the quality of life (QoL) of patients who had surgery for primary lymphoedema. METHODS: A QoL questionnaire was administered to patients who had surgery between 1981 and 2003 (retrospective group) and between 2003 and 2006 (prospective group). RESULTS: The response rate was 70.3 per cent (109 of 155 patients): 88 patients had limb reduction (78, retrospective; ten, prospective) and 21 had genital reduction (13, retrospective; eight, prospective). Forty-nine patients (63 per cent) who had limb reduction studied retrospectively reported satisfaction with the procedure and most of these would opt for surgery again. In the prospectively studied group, nine of ten patients reported improved limbs, and seven would opt for surgery again. Nineteen of 21 patients who had genital reduction would choose to have surgery again if needed (11 of the retrospectively assessed group and all of the prospective group). Patients' perception that surgery was worthwhile was greater in both of the prospectively assessed groups (P = 0.013). CONCLUSION: Surgery for severe lymphoedema improved QoL at early assessment. This, however, may not be sustained. Genital reduction appeared to provide greater benefit than limb reduction.

Hereditary palmoplantar keratoderma associated with primary (congenital) lymphedema.

The palmoplantar keratodermas are a heterogenous group of hereditary disorders of keratinization. They are characterized by epidermal thickening and a yellow waxy appearance of the palms and soles. Genetic studies have linked various forms of palmoplantar keratoderma to markers on chromosomes one, twelve, and seventeen, and several genes have been identified. Primary lymphedema is occasionally present at birth (congenital lymphedema or Milroy's disease), but more commonly develops at puberty (lymphedema praecox). Genetic studies have linked various autosomal dominant forms of primary lymphedema (Milroy's disease and lymphedema distichiasis), to genes on chromosomes five and sixteen respectively. We report a case of palmoplantar keratoderma in a child with congenital lymphedema. To our knowledge, this has not been previously described and may represent a new phenotype for future genetic study.

Adenovirus-mediated VEGF gene therapy enhances venous thrombus recanalization and resolution.

OBJECTIVE: Rapid thrombus recanalization reduces the incidence of post-thrombotic complications. This study aimed to discover whether adenovirus-mediated transfection of the vascular endothelial growth factor gene (ad.VEGF) enhanced thrombus recanalization and resolution. METHODS AND RESULTS: In rats, thrombi were directly injected with either ad.VEGF (n=40) or ad.GFP (n=37). Thrombi in SCID mice (n=12) were injected with human macrophages transfected with ad.VEGF or ad.GFP. Thrombi were analyzed at 1 to 14 days. GFP was found mainly in the vein wall and adventitia by 3 days, but was predominantly found in cells within the body of thrombus by day 7. VEGF levels peaked at 4 days (376+/-299 pg/mg protein). Ad.VEGF treatment reduced thrombus size by >50% (47.7+/-5.1 mm(2) to 22.0+/-4.0 mm(2), P=0.0003) and increased recanalization by >3-fold (3.9+/-0.69% to 13.6+/-4.1%, P=0.024) compared with controls. Ad.VEGF treatment increased macrophage recruitment into the thrombus by more than 50% (P=0.002). Ad.VEGF-transfected macrophages reduced thrombus size by 30% compared with controls (12.3+/-0.89 mm(2) to 8.7+/-1.4 mm(2), P=0.04) and enhanced vein lumen recanalization (3.39+/-0.34% to 5.07+/-0.57%, P=0.02). CONCLUSIONS: Treatment with ad.VEGF enhanced thrombus recanalization and resolution, probably as a consequence of an increase in macrophage recruitment.

Mobile phones, in combination with a computer locator system, improve the response times of emergency medical services in central London.

INTRODUCTION: The aim of this study was to determine whether mobile phones and mobile phone locating devices are associated with improved ambulance response times in central London. PATIENTS AND METHODS: All calls from the London Ambulance Service database since 1999 were analysed. In addition, 100 consecutive patients completed a questionnaire on mobile phone use whilst attending the St Thomas's Hospital Emergency Department in central London. RESULTS: Mobile phone use for emergencies in central London has increased from 4007 (5% of total) calls in January 1999 to 21,585 (29%) in August 2004. Ambulance response times for mobile phone calls were reduced after the introduction of the mobile phone locating system (mean 469 s versus 444 s; P = 0.0195). The proportion of mobile phone calls made from mobile phones for life-threatening emergencies was higher after injury than for medical emergencies (41% versus 16%, P = 0.0063). Of patients transported to the accident and emergency department by ambulance, 44% contacted the ambulance service by mobile phone. Three-quarters of calls made from outside the home or work-place were by mobile phone and 72% of patients indicated that it would have taken longer to contact the emergency services if they had not used a mobile. CONCLUSIONS: Since the introduction of the mobile phone locating system, there has been an improvement in ambulance response times. Mobile locating systems in urban areas across the UK may lead to faster response times and, potentially, improved patient outcomes.

Imaging of deep vein thrombosis.

BACKGROUND: Deep vein thrombosis of the leg affects 1-2 per cent of the population with an annual incidence of 0.5-1 per 1000. It presents with non-specific symptoms and signs making clinical diagnosis difficult. Techniques to image and diagnose this condition are advancing rapidly. METHODS AND RESULTS: A literature review from 1980 to 2007 was undertaken using PubMed, The Cochrane Library, Medline and Embase. The most frequently used diagnostic test is duplex ultrasonography which is accurate above the knee and has a low cost, but is limited by inaccuracy when assessing the pelvic and distal veins and in diagnosing a new thrombosis in the post-thrombotic limb. Magnetic resonance imaging (MRI) and sonographic elasticity imaging are more recent techniques that have shown promise in overcoming these limitations. However, their availability is currently restricted because they are expensive. Computed tomography (CT) is sensitive, specific and provides good imaging of the pelvis. It has the advantage that it can be performed at the same time as CT pulmonary angiography. CONCLUSION: MRI has some specific advantages over duplex ultrasonography, but requires refinement before it can be used clinically. Venography or CT venography should be considered when duplex scanning is inadequate.

Effect of collagen turnover and matrix metalloproteinase activity on healing of venous leg ulcers.

BACKGROUND: The presence of fibrous tissue in poorly healing venous leg ulcers suggests abnormal collagen metabolism. The aim was to determine whether there were differences in collagen turnover and matrix metalloproteinase (MMP) activity between ulcers that healed, those that did not heal and normal skin. METHODS: Biopsies were taken from the ulcers of 12 patients whose venous ulcers went on to heal and 15 patients whose ulcers failed to heal despite 12 months of compression bandaging. Biopsies were taken from 15 normal controls. Collagen turnover (collagen III N-terminal propeptide (PIIINP) and degraded collagen), and total MMP, MMP-1 and MMP-3 activities were measured. RESULTS: PIIINP and degraded collagen levels were higher in ulcers that healed compared with lesions that failed to heal (P = 0.005 and P < 0.001 respectively) and normal skin (P = 0.003 and P < 0.001). MMP-1 activity was also higher in healing ulcers than resistant ulcers (P < 0.001) and normal skin (P < 0.001). Significantly more total MMP activity was present in all ulcers than in normal skin (P < 0.001), but there was no difference in total MMP (and MMP-3 activity) between ulcers that healed and those that did not. CONCLUSION: Rapidly healing venous leg ulcers had increased collagen turnover and MMP-1 activity, which appeared to differentiate them from those that failed to heal within 12 months.

Effect of statins on proteolytic activity in the wall of abdominal aortic aneurysms.

BACKGROUND: The aim of this study was to examine the effect of statin treatment on the activity of proteases in the wall of abdominal aortic aneurysms (AAAs). METHODS: The activities of matrix metalloproteinases (MMPs) 9 and 3, cathepsins B, H, K, L and S, and the cystatin C level were measured in extracts of AAA wall taken from 82 patients undergoing AAA repair; 21 patients were receiving statin treatment before surgery. All values were standardized against soluble protein (SP) concentration in the extract, and reported as median (interquartile range) or mean(s.e.m.). RESULTS: The two groups had similar demographics. Reduced activity of MMP-9 (43 (34-56) versus 80 (62-110) pg per mg SP; P < 0.001), cathepsin H (183 (117-366) versus 321 (172-644) nmol 4-methylcoumarin-7-amide released per mg SP; P = 0.016) and cathepsin L (102 (51-372) versus 287 (112-816) micromol 7-amino-4-trifluoromethylcoumarin released per mg SP; P = 0.020) was found in the statin-treated aortas compared with AAAs from patients not taking a statin. The statin-treated group had lower MMP-3 activity, but this did not reach statistical significance (P = 0.053). Cystatin C levels were higher in statin-treated aortas than in controls (41.3(3.1) versus 28.9(2.1) ng per mg SP; P = 0.003). CONCLUSION: Statins decreased the activity of proteases that have been implicated in aneurysm disease.

Tissue and urinary haemosiderin in chronic leg ulcers.

OBJECTIVE: The aim of this study was to assess the relationship between urinary and tissue haemosiderin in chronic leg ulcers, and its value as a diagnostic test for venous ulceration. METHODS: 45 patients with chronic leg ulcers were recruited to the study (24 venous, 6 ischaemic, 6 lymphoedematous, 5 rheumatoid and 4 sickle cell). Punch biopsy of the ulcer edge was taken and early morning urine samples were collected. Positive Prussian-blue urinary haemosiderin granules were measured with a haemocytometer following Perls' staining. The percentage area of histological section staining positively with Perls' was measured using image analysis. RESULTS: 84 urine samples and 46 ulcer biopsies were collected. Urinary haemosiderin was present in 92% of venous ulcer patients, but was absent in the ischaemic ulcer patients (p<0.0001). Significantly more urinary haemosiderin granules were detected in venous ulcer patients compared with patients who had lymphoedema (p<0.05). Tissue haemosiderin was detected in all ulcer types investigated. No correlation was found between the amounts of haemosiderin deposited in the tissue and the amount found in urine (r(2)=0.06). CONCLUSIONS: Haemosiderin is present in the urine of most patients with venous ulcers but not in ischaemia ulcers.

Excision and meshed skin grafting for leg ulcers resistant to compression therapy.

BACKGROUND: The aim of this study was to determine the success of excision and meshed skin grafting for chronic leg ulcers. The effects of different ulcer aetiology and ulcer size on outcome were also assessed. METHODS: All patients who had excision and mesh grafting for chronic leg ulceration between January 1996 and December 2004 at St Thomas' Hospital were reviewed. Recurrence was classified as any breakdown of the ulcer during follow-up. RESULTS: Sixty-two patients with 100 chronic leg ulcers underwent operation. Seventy-two of the ulcers were venous and the median ulcer size was 36 (range 1.5-192) cm2. Only three patients left the hospital with their ulcers unhealed, but ulcers had recurred in 28 (28 per cent) by 2 months. A further 17 ulcers recurred later, with just over half (55 per cent) remaining healed by 5 years. There was no difference between the recurrence rates of venous ulcers and ulcers of other aetiologies (P=0.980), or large (more than 10 cm2) and small ulcers (P=0.686). CONCLUSION: Wide local excision and meshed skin grafting benefitted over half of these patients with refractory leg ulcers. Recurrence was most likely to occur in the first 2 months and, provided that ulcers were healed at this time, there was a low rate of further breakdown.

A painless method of ultrasonically assisted debridement of chronic leg ulcers: a pilot study.

OBJECTIVES: Devitalized tissue in a recalcitrant leg ulcer is common and may impede healing. The aim of this study was to evaluate the use of a non-invasive low frequency ultrasound device to debride chronic leg ulcers as an adjunct to compression bandages therapy. METHODS: 19 patients with leg ulceration of at least 6 months were recruited. Low frequency ultrasound at 25kHz was delivered by a portable Sonaca--180 via a handheld probe, using normal saline as the irrigation/coupling medium. The ultrasound was applied for 10-20 seconds per probe head area onto the ulcer. Each leg underwent treatment at an interval of 2-3 weeks with compression bandages reapplied at the end of the treatment. Serial colour photographs were taken to evaluate the response at each visit. RESULTS: Each patient received on average 5.7 treatments each ranged from 5-20 minutes depending on the ulcer size. Symptomatic relief (pain and odour reduction) was achieved in 6 patients. 7 patients achieved complete ulcer healing (mean ulcer size=4.72+/-SD 1.872cm(2)) but no response was observed in 8 patients. There were no major complications of the treatment which was relatively painless. CONCLUSIONS: The application of low frequency ultrasound debridement may heal some recalcitrant ulcers when standard compression regimens have failed. It is cheap and does not require admission. The role of simple wound cleansing requires further investigation.

Development of simultaneous anastomotic false aneurysms at both ends of an autologous vein graft caused by methicillin-resistent Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus (MRSA) infection is a well recognised problem, especially in vascular surgical patients with synthetic bypass grafts. This is to our knowledge the first report in the literature of the development of anastomotic false aneurysms at both ends of an autologous vein graft, as a result of MRSA infection within the vascular wall.

Peripheral arterial embolism: prevalence, outcome, and the role of echocardiography in management.

The aims of this study were to review the prevalence and outcome of all surgically treated upper and lower limb emboli presenting to one vascular unit in the last 3 years and to compare transthoracic with transesophageal echocardiography for defining the source of the embolus. All patients who underwent surgical embolectomy for acute limb ischemia from January 2001 to June 2004 were reviewed. Transthoracic and transesophageal echocardiography were carried out on a subset of consecutive unselected patients. Forty-two patients, with a mean age of 80 years, underwent surgical embolectomy from January 2001 to June 2004 (M/F 1:1.8): 27 for lower limb ischemia and 15 for upper limb ischemia. Two thirds of these patients were found to be in atrial fibrillation at presentation (n = 28), of whom less than a third were receiving anticoagulants or antiplatelet agents (n = 8). The mean hospital stay was 15 days with 36 patients (86%) being fully anticoagulated before discharge from hospital. The 30-day mortality rate was 11% (n = 3/27) with 5 patients requiring fasciotomies (12%) and 3 patients requiring an amputation of the lower limb (11%). Postoperatively, 34 patients (81%) had transthoracic echocardiography (TTE), which demonstrated a source or potential source for thrombus in 19 (56%). Fifteen patients (36%) had transesophageal echocardiography (TEE), which changed the subsequent management in 3 patients. All patients in whom TEE altered clinical management would have required this investigation if standard clinical guidelines were followed. TEE did not identify any additional patients with cardiac embolic sources that were not detected by TTE. Arterial limb emboli are still prevalent, but limb salvage and mortality rates appear to be improving. Despite clear guidelines on anticoagulation for patients in atrial fibrillation, many are not receiving appropriate treatment. Transthoracic echocardiography is a good screening tool for detecting a potential cardiac source for peripheral embolism, with transesophageal echocardiography being reserved for specific indications.

The modernisation of the surgical house officer.

INTRODUCTION: There have been considerable changes in the junior doctors' hours and working patterns over the last 4 years. The aim of this study was to assess the effect of these changes on the house officers' surgical experience and to obtain their opinions on the 'Hospital at Night' system, which has recently been introduced at our large teaching hospital. METHODS: A questionnaire was filled out by surgical house officers at the end of their surgical posts in 2001. The same questionnaire was then repeated for house officers completing the same posts in 2005. RESULTS: Pre-registration house officers now see less acute surgical admissions (mean 5 patients in 3 months in 2005 compared with 35 in 2001; P < 0.0001) and spend less time attending theatre than four years ago (mean 12 sessions in 3 months in 2001 compared with 6 in 2005). Despite the reduction in hours, they are still managing to attend educational sessions. Nine out of ten house officers felt that the 'Hospital at Night' system was unsatisfactory. They were unable to see and clerk acute surgical admissions or go to theatre because they were providing cross cover for other specialties. CONCLUSIONS: The full shift system and the introduction of the 'Hospital at Night' team have led to a reduction in acute surgical experience for surgical house officers. The General Medical Council recommendations for reducing non-educational tasks have not been fulfilled despite the evolving role of nurse practitioners.

Endothelial progenitor cells are recruited into resolving venous thrombi.

BACKGROUND: The purpose of this study was to determine whether endothelial cells of bone marrow origin are involved in thrombus recanalization. METHODS AND RESULTS: Irradiated mice were reconstituted with bone marrow from transgenic donors expressing green fluorescent protein (GFP) linked to the Tie2 promoter. Thrombi were formed in 2 groups of 6 mice. GFP-expressing cells were located and quantified in sections of the thrombi taken after 7 and 14 days. The cell markers Mac-3, F4/80, CD68 (macrophage), and vascular endothelial growth factor receptor 2 (VEGFR2; endothelial cells) were used to determine colocalization with GFP expression in tissue sections and peritoneal macrophages. The markers CD34 and VEGFR2 were used to quantify changes in circulating endothelial cells by flow cytometry of blood from 3 cohorts of wild-type animals that had either a thrombus induced (n=18), a sham operation (n=18), or no operation (n=10). The number of GFP-expressing cells was found to increase by approximately 3-fold in thrombi formed in transplanted animals between 7 and 14 days after induction (P=0.0022). No GFP-expressing cells were found lining the new vascular channels that formed at either time interval, but many of the GFP-expressing cells also expressed Mac-3, CD68, and VEGFR2. Approximately twice as many circulating CD34+/VEGFR2+ cells were found by day 3 in animals with thrombus compared with sham controls (CD45-, P=0.046 and CD45(+), P=0.016). CONCLUSIONS: Bone marrow-derived, Tie2-expressing cells were recruited into the thrombus during resolution but did not line the new vessels. Many of these cells expressed a macrophage phenotype and may represent a population of plastic stem cells that orchestrate thrombus recanalization.

Sequential cohort study of Dacron patch closure following carotid endarterectomy.

BACKGROUND: Carotid endarterectomy reduces the risk of stroke and death in patients with severe carotid artery stenosis. This study examined whether the technique used to close the arteriotomy influenced the rate of perioperative transient ischaemic attack (TIA), stroke or death. METHODS: A cohort of 236 patients undergoing carotid endarterectomy at a single centre was studied; 117 patients had primary closure of the arteriotomy and 119 patients in a sequential series had closure with a Dacron patch. A standard endarterectomy with completion intraoperative duplex imaging and digital subtraction angiography was used throughout. RESULTS: Patch closure was associated with a significant reduction in the 30-day combined death, stroke and TIA rate: 10.3 per cent for primary closure versus 2.5 per cent for patch closure (P = 0.017). The risk of any cerebral event (stroke or TIA) was also significantly reduced (7.7 versus 1.7 per cent; P = 0.033). Residual stenosis on completion angiography was more common after primary closure (24.6 versus 7.4 per cent; P = 0.003). CONCLUSION: Dacron patch closure had a higher technical success rate on completion imaging and was associated with a significant reduction in the risk of perioperative stroke, TIA and death.

Complications of reperfusion in acute aortic artery occlusion following saddle embolization originating from an atrial myxoma.

A 58-year-old man presented to the hospital with an 8-hour history of acute-onset bilateral lower limb ischemia. A large saddle embolus had occluded the aorta and could not be removed by balloon endarterectomy through the femoral arteries. Successful open aortic and femoral thromboembolectomy followed by extensive fasciotomies was accompanied by severe reperfusion injury. Life-threatening hyperkalemia was associated with three episodes of intraoperative ventricular fibrillation and ventricular tachycardia requiring cardiac massage and defibrillation. A dextrose-insulin-bicarbonate infusion was required to correct the hyperkalemia. Rhabdomyolysis developed at 24 hours, causing marked myoglobinuria and acute renal failure, which required hemofiltration. Histology of the recovered embolus confirmed an atrial myxoma, and when the patient had fully recovered, open cardiac surgery was carried out to resect the tiny stump of residual myxoma. Rhabdomyolysis associated with a myxomatous saddle embolus has not been previously reported. This case highlights the need for pre- and perioperative measures to be taken to overcome hyperkalemia and acute renal failure when revascularizing acute, massive, prolonged ischemia of the lower body.