The Scottish-Finnish-Swedish PARTNER study of taprostene versus placebo treatment in patients with critical limb ischemia.

AIM: Atherosclerotic peripheral arterial disease is a major health problem in the western world, often manifested as intermittent claudication, affecting 10-20% males above 60 years. Ischemic complications can lead to rest pain, ulceration and gangrene. The treatment of choice for critical limb ischemia (CLI) is vascular reconstruction or endovascular interventions. Medical management with vasodilator antiplatelet prostaglandins, could be considered in patients unsuitable for surgery. Long term follow-up on previous prostaglandin studies has been insufficient to evaluate amputation rates. Hence this study evaluated safety and longer term efficacy of taprostene sodium, a prostacyclin (PGI2) analogue in CLI. The aim of this study was to determine whether Taprostene sodium, a PGI2 analogue, was a safe and effective treatment for CLI. METHODS: This paper reports the data from the Scottish-Finnish-Swedish PARTNER Study Group which consisted of a double-blind placebo controlled multi-centre study evaluating Taprostene compared to placebo. The primary endpoints were pain relief and early ulcer healing response at the end of the four week infusion phase and amputation at six months follow-up. The patients were randomly allocated to receive taprostene or placebo in a two to one randomization of active versus placebo. A total of 111 patients with CLI were recruited. Taprostene was given twice a day over two 2 hour periods for four weeks. The early response was evaluated at the end of the four week infusion phase. In patients with rest pain without ulceration, a positive response was complete pain relief without any requirement for analgesic therapy. However in patients with ulceration, a positive response was defined as a decrease in the ulcer size by >30%. Amputation scores were compared at the end of the 6 months follow-up period for all participants. RESULTS: Seventy-four patients received taprostene and 37 placebo. Overall, 61 male patients were enrolled in the study along with 50 females with 11% more women in the taprostene (active) group. For both patients with and without ulcers there was no statistically significant difference noted in the early response between those receiving taprostene and those receiving placebo infusion. The percentage of patients without any amputations was 43% in the taprostene group compared to 38% in the control group at the end of six months; however, these results were not statistically significant. CONCLUSION: Although a reasonable number of patients enrolled in the study it has not been possible to demonstrate any statistically significant benefit of taprostene over placebo. This may be due to more patients with risk factors for peripheral artery disease (PAD) such as hypertension, diabetes mellitus and cigarette smoking in the actively treated group and also due the increased number of women in the active group who are known to generally respond less favourably to antiplatelet agents.

Cystic adventitial disease: a trap for the unwary.

Cystic adventitial disease is an uncommon condition. A case of cystic adventitial disease of the popliteal artery is reported in a young man who has been followed up for 14 years after surgical treatment. Early recognition and treatment of the condition will prevent progression to popliteal thrombosis and critical ischaemia. However, diagnosis of the condition is difficult. Characteristic features in the presenting history, such as fluctuation in severity of symptoms, sudden onset after vigorous activity and delayed recovery time after cessation of exercise are identified, which should help the clinician avoid misdiagnosis and delayed diagnosis of the condition. The clinician is also warned of the associated misleading clinical features such as the presence of normal peripheral pulses and normal ankle pressures in some cases of CAD.

An unusual presentation of a rare nerve cell tumour.

We present a rare case of a schwannoma in a pre/para-aortic position resembling a thrombosed saccular abdominal aortic aneurysm.

Carotid endarterectomy in patients aged 75 and over: early results and late outcome.

BACKGROUND: The mean age of patients in the European Carotid Surgery Trial with greater than 70% stenosis was 62 years. With changing demographics older patients are increasingly being referred for carotid endarterectomy (CEA). OBJECTIVES: To assess the complications and survival (stroke-free and overall) of patients over the age of 75 undergoing CEA. METHODS: Analysis of a database, clinical records and cause of death of patients undergoing CEA in a single regional unit over a 7 year period (1/4/1993 until 1/4/2000), with follow-up to April 2002. The rates of further neurological events were obtained from the Scottish Morbidity Record 1 (SMR 1) of hospital discharges. Patients referred from outside the region were excluded. Differences between groups were assessed by the Chi-squared test, with Yates correction and log-rank tests. RESULTS: Of the 235 patients undergoing CEAs, 55 (23%) were 75 years or older. The post-operative neurological complication rate was 1.7% in the under 75's and 5.4% in the older group (p < 0.05). The 30 day mortality was 1.1% (two patients) and 1.8% (one patient) respectively. The Kaplan-Meier estimated survival for the under 75's and older were 93 and 75% at 3 years and 80 and 59% at 5 years respectively (p < 0.001). The Kaplan-Meier estimated neurological event-free 5 year survival for the under 75's and older patients were 96 and 82% respectively (p < 0.001). CONCLUSION: CEA in patients aged 75 years and over is associated with a significantly increased risk of stroke and death. CEA may not benefit elderly patients with a reduced life expectancy.

Management of synchronous infrarenal aortic disease and large bowel cancer: a North-east of Scotland experience.

OBJECTIVES: to review our experience of combined aortic and colonic surgery. DESIGN: retrospective review. METHODS: synchronous aortic and colorectal procedures were identified from prospective computerised audit and archival vascular records. Clinical parameters were used as surrogates for measuring clinical outcome. RESULTS: six patients (F:M=2:1), median age 75.6 years (range 70-80 years) were identified with infrarenal aortic pathology (5 aneurysms, median AP diameter 6 cm, 1 occluded aortoiliac segment) and colonic carcinoma. All carcinomas were Dukes stage B and moderately well differentiated. Synchronous aortic and colonic resections were performed in five cases, bypass for aortoiliac occlusion was deferred in preference to colonic resection in one case. Operating time ranged between 3-6.5 hours (median 4 h), transfusion requirements 2-5 units (median 3 units). One anastomotic dehiscence was reported. With follow-up between 6 months to 6 years all patients remain alive; no patient has re-presented with graft sepsis or symptomatic tumour recurrence. CONCLUSION: synchronous resections of aortic and colonic lesion may be a treatment option in selected cases.

Xenobiotic metabolism in rat, dog, and human precision-cut liver slices, freshly isolated hepatocytes, and vitrified precision-cut liver slices.

Human, rat, and dog phase I and phase II xenobiotic metabolism in precision-cut liver slices and freshly isolated hepatocytes was compared using a range of substrates. Carbamazepine (50 microM) and styrene (2 mM) were used as probes to study the maintenance of cytochrome P450 and epoxide hydrolase-mediated metabolism in male Sprague-Dawley rat, precision-cut liver slices and hepatocytes. Carbamazepine metabolism in both models resulted in the formation of the bioactive 10,11-epoxide (KM = 766 microM and Vmax = 2.5 pmol/min/mg protein in precision-cut slices). Epoxide formation was higher (2.4-fold) in hepatocytes than slices. Styrene was deactivated to styrene diol at a higher rate in hepatocytes (9.7-fold) than slices. The lower rate of metabolism in slices compared with hepatocytes confirms our previous observations using testosterone, 7-ethoxycoumarin, 1-chloro-2,4-dinitrobenzene and 2-(5'-chloro-2'-phosphoryloxyphenyl)-6-chloro-4-(3H)-quinazolinone in the rat. Testosterone 6 beta-hydroxylation in human liver slices was similar to cultured hepatocytes, but lower than in freshly isolated hepatocytes. 7-Ethoxycoumarin O-deethylation was higher in freshly isolated human hepatocytes, as was the ratio of glucuronide to 7-hydroxycoumarin. Testosterone hydroxylations, 7-ethoxycoumarin O-deethylation, and 1-chloro-2,4-dinitrobenzene conjugation were also lower in male beagle dog slices, compared with freshly isolated hepatocytes. Attempts at long-term preservation of dog liver slices using vitrification and storage for up to 9 days at -196 degrees C resulted in the retention of phase I and phase II metabolism, although conjugation was lower than in freshly prepared slices. Xenobiotic metabolism in short-term incubations is consistently lower in dog and rat precision-cut slices than in freshly isolated hepatocytes; whereas, in humans, this quantitative difference is partly hidden by the large interindividual variation.

Prospective audit of discharge summary errors.

During an 8-month interval of prospective audit, 63 of 637 (10 per cent) vascular discharge summaries were found to contain 94 errors. These comprised 11 (12 per cent) general errors, 21 (22 per cent) diagnostic errors, 19 (20 per cent) operative data errors, 19 (20 per cent) cases of incorrect clinical text information, 14 (15 per cent) missed complications and 10 (11 per cent) concerning follow-up arrangements. Overall, 2 per cent of consultant discharge summaries contained errors compared with 7 per cent for the senior registrar, 10 per cent for registrars and 17 per cent for senior house officers. Given that the majority of discharge summaries are currently prepared by junior staff, this study suggests that verification of the accuracy of clinical and management data should be an essential component of departmental audit meetings.

Major lower limb amputation for vascular disease in the Grampian area: the outcome of rehabilitation.

The outcome of lower limb amputation in the Grampian Region has been studied. In the years 1990-1991, 93 patients had 104 amputations for vascular disease. Rehabilitation was supervised by a multidisciplinary team. The amputation level was: unilateral and below-knee (BKA), 55 patients; unilateral and above-knee (AKA), 27 patients; and bilateral (BA) in 11 patients. At a median follow-up of 27 months, survivors who had had a limb fitted were sent a questionnaire to assess their physical mobility. The response rate was 95%. There were 33 (60%) survivors in the BKA group. Fourteen patients (25%) indicated good mobility and seven (13%) indicated fair mobility. There were five (19%) survivors in the AKA group, only one of whom described fair mobility with a prosthetic limb. There were 5 (46%) survivors of BA. Two described good and one fair mobility. Although vascular amputees have a high mortality rate, physical mobility tends to be good in those fitted with a prosthesis after BKA.

Abdominal aortic aneurysm: a 12-year experience in the Grampian region, Scotland.

All the 638 new hospital cases of abdominal aortic aneurysm (AAA) diagnosed in the Grampian region of Scotland, over the 12-year period between January 1980 and December 1991, were studied. Information was obtained from the Scottish Morbidity Record Form 1 (SMR1). The number of AAA cases has risen from 19 in 1980 to 84 in 1991 totalling 638 cases in the 12-year study period. Of these, 29% were women, a percentage which remained fairly constant for each year of the study. The mean age of the study population was 73.8 years; higher in women (74.7 in intact and 76.6 in ruptured cases) than in men (71 in intact and 73.1 in ruptured cases). There was a significant increase in the percentage of patients over the age of 75 years (from 31.6% in 1980 to 41.7% in 1991) which was very marked in men (from 25% to 40%). This may indicate that ageing of the population is partly responsible for the apparent increased incidence of the disease. Ruptured AAA constituted 36.5% of all cases of which 76.4% were men. The rate of ruptured cases has dropped from 73.7% in 1980 to 32.1% in 1991 probably owing to operating on more elective cases. Analysis of hospital fatality, including unoperated cases, showed a fatality rate of 8.4% for intact cases as opposed to 46.3% for ruptured cases. Allowing for improved diagnostic techniques and clinical awareness of the disease, the figures suggest a true increase in the incidence of AAA in the Grampian region.

Cryopreservation of human adult hepatocytes for use in drug metabolism and toxicity studies.

1. Human hepatocytes were cryopreserved for up to 14 days at -80 degrees C and the cryoprotection offered by different media investigated in terms of post-thaw cell viability and function. 2. Optimal cryoprotection was offered by a solution containing dimethylsulphoxide, propylene glycol, acetamide and polyethylene glycol 8000 in Leibowitz L15 medium. 3. The cytochrome P450 content and activities of the microsomal P450 dependent mixed function oxidase system were well maintained at above 70% of fresh cell values throughout the cryopreservation period. However, the activities of the cytosolic enzymes studied, glutathione S-transferase and glutathione reductase, were not well maintained; they declined to < 40% of fresh cell values after storage of cells for 14 days at -80 degrees C. The membrane environment may protect microsomal enzymes from denaturation by freeze-thaw damage. 4. After cryopreservation, viability of human hepatocytes was higher than that of rat hepatocytes preserved under identical conditions. For human cells maximum post-cryopreservation viability was 67% after 24 h at -80 degrees C; this declined to 49% after 14 days storage at -80 degrees C. In addition post-cryopreservation human hepatocytes remained > 70% viable when incubated at 37 degrees C in suspension compared with only 46% of rat hepatocytes. This indicates that human hepatocytes can withstand freeze-thaw damage better than those from rat. 5. The results of this study define optimal conditions for cryopreserving human hepatocytes. Although microsomal enzyme activities are retained post-cryopreservation, the decrease in viability of thawed cells upon incubation at 37 degrees C suggests that caution should be exercized when using cryopreserved cells to study integrated drug metabolizing pathways in man in vitro.

Axillofemoral bypass as a limb salvage procedure in high risk patients with aortoiliac disease.

Thirty-eight patients presenting with severe limb ischaemia and considered unfit for major aortic reconstruction underwent axillofemoral bypass as a limb salvage procedure. Four patients (11 per cent) died, including two who had presented with bilateral ischaemia secondary to acute aortic occlusion. The operative mortality rate for patients presenting with rest pain or ulceration/gangrene was 6 per cent. Cumulative 5-year survival and limb salvage were 44 per cent and 86 per cent respectively. Graft occlusion was the principal cause of worsening symptoms during follow-up (5-year primary patency of 68 per cent) and accounted for all major amputations of the operated limb. Axillounifemoral grafts had a significantly worse 5-year patency (50 per cent) than axillobifemoral grafts (80 per cent, P less than 0.05) and three of five patients who developed worsening symptoms in the non-operated limb died or required a major limb amputation as a consequence. Axillofemoral bypass is a valuable alternative to major aortic reconstruction in elderly patients and allows a greater proportion to be offered reconstruction than would otherwise be possible.

Aortoiliac endarterectomy: an 11-year review.

Fifty-seven patients underwent aortoiliac endarterectomy over an 11-year period, the majority (86 per cent) for disabling claudication. No patient died within 30 days of surgery, but nine patients suffered significant complications. The cumulative survival rate was 98 per cent at 1 year, and was 94 and 78 per cent at 5 and 10 years respectively. Cumulative operated segment patency rates were 92 per cent at 5 years and 68 per cent at 10 years. There was no significant difference in survival rates between patients who smoked after surgery and those who did not, but smokers had significantly worse rates for cumulative patency, limb failure and symptom status than non-smokers. Twenty-seven patients developed worsening symptoms during follow-up and 24 patients required secondary vascular intervention. Fourteen patients subsequently required aortofemoral bypass and the largest single cause of operated segment failure was recurrent disease in the external iliac artery. Our evidence suggests that, while aortoiliac endarterectomy should be considered in young patients with localized disease not involving the external iliac artery, those who do not fit these criteria should be considered for primary aortofemoral bypass. Regardless of the choice of operation, the chance of success is jeopardized if the patient continues to smoke.

Purification and characterization of an anticonvulsant-induced human cytochrome P-450 catalysing cyclosporin metabolism.

A form of human hepatic microsomal cytochrome P-450 (P450hA7) with subunit Mr 50,400 has been purified from an epileptic who had been receiving long-term treatment with anticonvulsant drugs. P450hA7 metabolized the immunosuppressant drug cyclosporin A and the dihydropyridine calcium channel antagonist nifedipine, but did not metabolize a similar dihydropyridine drug, nicardipine, nor a series of alkoxyresorufin model substrates. The hepatic microsomal concentration of P450hA7 was higher in five individuals who had been receiving long-term anticonvulsant treatment than in any of 21 individuals who had not been similarly treated. The mean P450hA7 concentration in the treated individuals was 5-fold higher than the mean concentration in the untreated individuals. It is concluded that P450hA7 is a member of the cytochrome P450III family which is induced by anticonvulsant drugs in man.

Morbidity and mortality after aortofemoral grafting for peripheral limb ischaemia.

Over a 10-year period, aortofemoral grafting was employed in the revascularization of 484 limbs in 245 patients with peripheral limb ischaemia. Six patients (2.4%) died in the postoperative period, the most common cause of death being myocardial infarction. Forty-three patients (18%) developed significant non-fatal complications within 30 days of operation, half of whom required further surgery as a consequence. Thirty-seven patients suffered late graft-related complications of which graft thrombosis was the most common. Immediate graft patency was 98.4%, cumulative patency was 95% and 87% at 1 and 5 years respectively. False aneurysm formation was encountered in 3.3% of patients, deep graft sepsis in 1.6% and the phenomenon of 'non-healing' of grafts in 1.2%. Cumulative survival following elective surgery was 97% and 84% at 1 and 5 years respectively, and 89% and 72% for those undergoing limb salvage procedures.

Graft occlusion following aortofemoral bypass for peripheral ischaemia.

Over a 10-year period, 241 patients with non-aneurysmal aortoiliac disease underwent aortofemoral bypass to 476 limbs. Four patients (1.7 per cent) occluded their grafts within 30 days of surgery, while 25 (10.4 per cent) suffered late graft occlusion. Postoperative occlusions were associated with significant morbidity and only one patient avoided major limb amputation or death. Overall, 46 episodes of graft thrombosis involving 51 graft limbs were encountered, the most common underlying cause being pre-existing or progressive multilevel distal occlusive disease. The overall cumulative graft patency rates were 95 and 87 per cent at 1 and 5 years respectively. Cumulative 5-year patency was significantly higher in patients presenting with claudication (91 per cent) than in patients presenting with rest pain (77 per cent) or ulceration and/or gangrene (71 per cent). Patients with evidence of multilevel distal occlusive disease at the time of aortic surgery had a significantly higher incidence of occlusion compared with those in whom there was no significant distal disease. In 35 episodes of occlusion (76 per cent), surgery was undertaken to restore limb blood flow, being successful in all but one case, with the most commonly performed procedure being graft limb thrombectomy. Seven of 28 patients (25 per cent) ultimately required major limb amputation and three patients died as a direct consequence of graft thrombosis.