Biomedical subjects
Publications and source records attributed to J A Dormandy.
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The efficacy of regional thrombolysis for treating leg ischaemia is well established, but the duration of infusion and the frequent complications remain major disadvantages. By delivering recombinant human tissue type plasminogen activator (rt-PA) as pulsed intra-thrombus 5-mg aliquots combined with catheter manipulation to maintain an intra-thrombus location, the average time taken to achieve thrombolysis in 20 consecutive patients with infra-aortic occlusions was 109 min. Immediate thrombolysis was achieved in every case. Pulsed delivery of high dose rt-PA significantly accelerates thrombolysis, decreases dose and reduces costs.
Two patients with acutely thrombosed femorofemoral bypass grafts are presented. Recombinant human tissue-type plasminogen activator (rt-PA) was used successfully in thrombolysis of the occluded grafts. Utilizing a new technique the grafts were punctured directly and bolus doses of rt-PA administered.
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A prospective study of 1969 patients with intermittent claudication receiving placebo medication for a minimum of 1 year is reported. Patients were carefully monitored and only four patients were lost to follow-up. Annual mortality was 4.3%. Thirty-six patients developed a definite myocardial infarction, 27 a major stroke, 32 required a major amputation and 111 required surgical or radiological intervention for deteriorating ischaemia of the leg. The entry characteristics of the patients were analysed as a predictor of serious cardiovascular events. The most sensitive predictors of total mortality were age, history of coronary heart disease and an ankle/arm pressure ratio below 0.5. Of the laboratory measurements performed only the initial white cell count was a significant predictor of myocardial infarction, stroke and vascular deaths.
OBJECTIVE: To compare low (0.5 ng/kg/min) and standard dose (2 ng/kg/min) iloprost (a stable carbacyclin analogue of prostacyclin) in patients with Raynaud's phenomenon secondary to connective tissue disorders. DESIGN: Double blind, random allocation, three six hour infusions on consecutive days. Follow up period eight weeks. SETTING: Rheumatology units, five teaching hospitals. PATIENTS: 55 Patients with Raynaud's phenomenon (greater than seven attacks per week), 32 secondary to well documented classical progressive systemic sclerosis (American Rheumatism Association criteria), 11 CREST syndrome, 5 mixed connective tissue disease, 1 rheumatoid arthritis, 1 Sjögren's syndrome, 1 childhood dermatomyositis, and 4 abnormal nailfold capillaroscopy and antibody profiles but no definite diagnosis. INTERVENTIONS: All other treatment for Raynaud's phenomenon was discontinued two weeks before entry. 28 Patients were randomly allocated to receive the low dose, 27 the standard dose. Differing dilutions allowed infusion rates to be started at 10 ml/h with increments of 10 ml/h every 15 minutes until infusion rates reached 0.5 ng/kg/min and 2 ng/kg/min respectively. MAIN OUTCOME MEASURE(s)--Reduction in frequency, duration, and severity of attacks of Raynaud's phenomenon. Assessment of ulcer and ischaemic lesion healing. RESULTS: Both dosage regimens were equally effective in reducing severity, frequency, and duration of Raynaud's attacks. Ulcer healing occurred to similar degree in both treatment groups (standard dose 44%, low dose 39%). Low dose was associated with significantly fewer side effects. CONCLUSIONS: Both dosage regimens reduce severity of Raynaud's phenomenon and encourage ulcer healing. Low dose was associated with fewer side effects and was better tolerated by the patients.
Recent studies have shown that the response of granulocytes to stimulation is increased by the presence of platelets. Using an assay based on counting aggregates with a Coulter Counter, we found that heparinized or citrated platelet-rich plasma directly caused aggregation of isolated granulocytes. Platelets themselves were frequently present within the granulocyte aggregates. The degree of aggregation depended on the platelet:granulocyte ratio, and increased over a 2--5 min period of mixing, with a slower increase thereafter. Aggregation was calcium-dependent, increased by stimulation of the platelets with ADP or collagen but not serotonin, and only slightly reduced by a thrombin inhibitor (hirudin, at concentrations up to 0.9 U/ml). A similar adhesive interaction in vivo might be relevant to thrombotic and ischaemic pathology.
In order to investigate the involvement of white blood cells (WBC) in ischaemia, we have used micropore filtration techniques to measure the flow properties of cells from patients with severe leg ischaemia, before and after therapy (amputation or pharmacological). Compared to age-matched controls, WBC from patients had impaired ability to flow through 8 microns and 5 microns pore filters. This applied to fractionated granulocytes and mononuclear cells, as well as to unfractionated mixed WBC. WBC from blood drawn from the ischaemic leg had worse filterability than those from arm blood of the same patients. Judging from WBC morphology, the percentage of active WBC was higher in samples drawn from ischaemic patients compared to controls. After amputation of the ischaemic leg, significant improvement was observed, so that the WBC were no longer significantly different from controls. The flow abnormalities may reflect activation of WBC by factors released in the ischaemic tissue. A cycle of WBC trapping, activation, tissue damage and further activation and trapping could contribute to the worsening of tissue ischaemia. Pharmacological intervention in this degenerative cycle might be possible, and our preliminary data show that Trental infusion (600 mg over 6 hours) improves the filterability of granulocytes from severely ischaemic patients.
Interest in white cell (WBC) rheology has largely been directed towards hypotensive conditions. However, as capillary flow is dependent on the relative arteriovenous pressure gradient, we investigated the dynamics of WBC flow in patients with venous hypertension. Three groups of matched subjects were studied: normal controls, patients with primary varicose veins, and patients with deep venous insufficiency confirmed by foot volumetry and Doppler studies. A venous cannula inserted at the level of the medial malleolus allowed blood samples to be taken at time 0 (supine) and then at 15, 30, 45, and 60 minutes after sitting up. Further samples were taken after subjects resumed a supine position. After 60 minutes sitting the haematocrit of blood leaving the foot increased by 9.6% in controls and 25.6% in patients with venous insufficiency. The difference in the behaviour of WBC was more marked. Controls showed a 5.0% decrease in the relative number of WBC after 60 minutes sitting compared to 28% decrease in patients with venous insufficiency. On resuming a supine position there was a significant increase in the number of WBC leaving the foot and this "wash-out" appeared to be delayed in the two patient groups. Platelets showed a corresponding fall when the foot was dependent but there appeared to be no washout after elevation.
OBJECTIVE: To determine the effect of oxpentifylline on the healing of venous ulcers of the leg. DESIGN: Double blind, randomised, prospective, placebo controlled, parallel group study. SETTING: Four outpatient clinics treating leg ulcers in England and the Republic of Ireland. PATIENTS: 80 Consecutive patients with clinical evidence of venous ulceration of the leg in whom appreciable arterial disease was excluded by the ratio of ankle to brachial systolic pressure being greater than 0.8. INTERVENTIONS: All patients received either oxpentifylline 400 mg three times a day by mouth or a matching placebo for six months (or until their reference ulcer healed if this occurred sooner) in addition to a locally standardised method of compression bandaging. MAIN OUTCOME MEASURES: The primary end point was complete healing of the reference ulcer within six months. The secondary end point was the change in the area of the ulcer over the six month observation period. RESULTS: Complete healing of the reference ulcer occurred in 23 of the 38 patients treated with oxpentifylline and in 12 of the 42 patients treated with a placebo. Life table analysis showed that the proportion of ulcers healed at six months was 64% in the group treated with oxpentifylline compared with 34% in the group treated with a placebo (log rank test chi 2 = 4.78, p = 0.03), which was significant (odds ratio = 1.81, 95% confidence interval 1.20 to 2.71). CONCLUSION: Oxpentifylline used in conjunction with compression bandaging improves the healing of venous ulcers of the leg.
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Although changes in the mechanical properties of infected red cells may contribute to the pathophysiology of malaria, such changes have not previously been described in detail. In this study, the physical properties of individual cells from both clinical and cultured samples infected with Plasmodium falciparum were tested using micropipette aspiration techniques. Cells containing ring forms took about 50% longer to enter 3 microns pipettes compared with nonparasitised cells, and there was a similar increase in the critical pressure required to induce cell entry. These abnormalities were similar in clinical and cultured samples. More mature cultured parasites (ie, trophozoites and schizonts containing pigment) caused much greater loss of deformability, with entry time and pressure increased four to sixfold. The decrease in deformability of the ring forms was attributable to a deficit in cell surface area/volume ratio (based on micropipette measurement of the surface area and volume of individual cells) and slight stiffening of the cell membrane (shear elastic modulus increased 13%, as measured by pipette aspiration of small membrane tongues). Measurement of the rate of cell shape recovery indicated that the membrane of parasitised cells was not more viscous. The main factor in the drastic loss of deformability of the trophozoites and schizonts was the presence of the large very resistant parasite itself. Otherwise, the cell surface area/volume deficit was slightly less and membrane rigidification slightly greater compared with ring forms. The above abnormalities should cause the trophozoites and schizonts to have great difficulty in traversing splenic or marrow sinuses and could contribute to microvascular occlusion and sequestration. On the other hand, the ring forms may be expected to circulate relatively unhindered.
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PURPOSE: The effects of ketanserin on primary or secondary Raynaud's phenomenon due to connective tissue disease were studied in a large, international group of patients. PATIENTS AND METHODS: The study population consisted of 222 patients from 10 countries. After a run-in period of one month of placebo therapy, patients were randomly assigned in a double-blind manner to receive ketanserin 40 mg three times daily (n = 113) or placebo (n = 109) for three months. Total finger blood flow was measured in 41 patients in a warm and cool room before and during treatment. Vasospastic episodes were assessed by diaries and global evaluations. RESULTS: A significant reduction of 34% in frequency of episodes occurred with ketanserin, compared to 18% with placebo (p = 0.011). There was a 1% reduction in duration of episodes with ketanserin therapy, compared to a 2% increase with placebo therapy, but this finding was not statistically significant (p = 0.29). No difference was observed in severity of attacks. Global evaluations by investigators (p = 0.03) and patients (p less than 0.01) showed an overall benefit with ketanserin compared to that seen with placebo. Patients with primary or secondary Raynaud's phenomenon responded similarly to treatment. No changes in total finger blood flow were found. CONCLUSION: Ketanserin significantly improves the subjective symptoms of patients with primary or secondary Raynaud's phenomenon and is an appropriate agent to use in this disease when conservative measures fail.