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Aim: To review the radiology-led ultrasound (US) surveillance programme for the detection of hepatocellular carcinoma (HCC) in cirrhotic patients in a UK tertiary-referral centre., Materials and Methods: The radiology information system was searched for patients who had undergone US for surveillance of cirrhosis from September 2009 to May 2013. Patient demographics and cirrhosis aetiology were documented. Data including numbers of surveillance scans, abnormal findings suspicious for HCC, subsequent radiological investigations, numbers of HCC and survival for HCC patients were recorded. Service performance data, such as rates of attendance and rebooking, were also recorded., Results: Eight hundred and four patients entered surveillance and 2,366 surveillance US examinations were performed; 368 (46%) underwent follow-up (6-monthly US). Abnormalities leading to further radiological investigations were found in 81 patients. Reasons for incomplete surveillance included non-attendance and radiology failure to re-book appointments. HCC was diagnosed in 22 patients. Fourteen had HCC diagnosed on a surveillance scan, eight had HCC diagnosed on a scan performed for other reasons. Patients diagnosed with HCC on a surveillance scan were more likely to be treated with curative intent and had longer survival., Conclusion: Even with a radiology-led recall service for HCC surveillance, the proportion of patients receiving scans 6-monthly was low, due in part to the lack of organisational support that is available for other screening programmes. This study gives a realistic representation of the implementation of surveillance in a UK hospital at the current time and of the rates of HCC proceeding to treatment., (Copyright © 2016. Published by Elsevier Ltd.)

The British Heart Foundation sponsors the Michael Davies Young Investigator Award, and at its presentation in the Spring of 2009 two collaborators of Michael Davies spoke regarding their experiences on the Plaque Vulnerability project with him. This was to provide the winner and other nominees for the award, and colleagues at the meeting, descriptions of collaborating with Michael to sustain more than his name in association with the award. This article is an expansion of the personal reminiscences given at the time as a tribute to him, and to provide an inside story of how collaboration with such a prominent cardiac pathologist worked., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

We investigate the flow dynamics and oscillatory behaviour of wall shear stress (WSS) vectors in intracranial aneurysms using high resolution numerical simulations. We analyse three representative patient-specific internal carotid arteries laden with aneurysms of different characteristics: (i) a wide-necked saccular aneurysm, (ii) a narrower-necked saccular aneurysm, and (iii) a case with two adjacent saccular aneurysms. Our simulations show that the pulsatile flow in aneurysms can be subject to a hydrodynamic instability during the decelerating systolic phase resulting in a high-frequency oscillation in the range of 20-50 Hz, even when the blood flow rate in the parent vessel is as low as 150 and 250 ml min(-1) for cases (iii) and (i), respectively. The flow returns to its original laminar pulsatile state near the end of diastole. When the aneurysmal flow becomes unstable, both the magnitude and the directions of WSS vectors fluctuate at the aforementioned high frequencies. In particular, the WSS vectors around the flow impingement region exhibit significant spatio-temporal changes in direction as well as in magnitude.

Mural thrombi are composed dominantly of platelets and develop under a blood flow. Portions can break off and are carried in the blood flow as emboli. Thrombus growth rates are affected by the velocity of the blood flow, but they do not simply increase with it, they exhibit a maximum, with subsequent decrease. Whereas this variation indicates an interaction of biochemical and physical processes, studies have concentrated widely on understanding only the biochemical processes. Here we show results of simulation of thrombus formation in 3D flows by accounting for the movements of individual platelets. Each platelet follows prescribed rules for interactions while the local flow around the thrombus continuously adjusts to the growing structure of the thrombus, also when embolization occurs. With an activation delay time assigned to each platelet we demonstrate the dependence of thrombus growth rate on blood velocity as found experimentally by Begent and Born [Begent N, Born GV (1970) Nature 227:926-930]. With activated platelets having mutual tensile action sustainable up to a prescribed distance we achieve thrombus growth faster than with shorter maximum distances that make a thrombus less porous; when the prescribed maximum distance is large enough the thrombus shape is not like a "hill" but like a "carpet." We find that thrombus growth rate is enhanced by modest pulsatility but less so when pulsations are amplified in part because of more embolization.

Infertility is common in women with end-stage liver disease. Successful liver transplant (LT), however, can restore childbearing potential. Controversy exists regarding the most appropriate immunosuppressive regimen and timing of conception following LT. We report the outcomes of a review of all pregnancies occurring following LT at King's College Hospital, London, from 1988 to 2004. Seventy-one pregnancies were recorded in 45 women. Tacrolimus (60%) and cyclosporin A (38%) were the predominant primary immunosuppressive agents used. Median age at conception was 29 years (range, 19-42), with a median time from LT to conception of 40 months (range, 1-111). There were 50 live births, and no maternal or fetal deaths related to pregnancy. There were no graft losses. Median gestation was 37 weeks (range, 24-42) with a median birth weight of 2,690 g (range, 554-4,260). Caesarean section was performed in 40% of pregnancies. Complications included pregnancy-induced hypertension in 20%, preeclampsia in 13%, acute cellular rejection in 17%, and renal impairment in 11%. There was no statistically significant difference in complication rates observed between immunosuppressive groups. Pregnancies occurring within 1-year posttransplant had an increased incidence of prematurity, low birth weight, and acute cellular rejection compared to those occurring later than 1 year. In conclusion, this study confirms that favorable outcomes of pregnancy post-LT can be expected for the majority of patients. However, delaying pregnancy until after 1-year post-LT is advisable, since doing so maybe associated with a lower risk of prematurity., (Copyright 2006 AASLD)

A three-dimensional model with simplified geometry for the branched coronary artery is presented. The bifurcation is defined by an analytical intersection of two cylindrical tubes lying on a sphere that represents an idealized heart surface. The model takes into account the repetitive variation of curvature and motion to which the vessel is subject during each cardiac cycle, and also includes the phase difference between arterial motion and blood flowrate, which may be nonzero for patients with pathologies such as aortic regurgitation. An arbitrary Lagrangian Eulerian (ALE) formulation of the unsteady, incompressible, three-dimensional Navier-Stokes equations is employed to solve for the flow field, and numerical simulations are performed using the spectral/hp element method. The results indicate that the combined effect of pulsatile inflow and dynamic geometry depends strongly on the aforementioned phase difference. Specifically, the main findings of this work show that the time-variation of flowrate ratio between the two branches is minimal (less than 5%) for the simulation with phase difference angle equal to 90 degrees, and maximal (51%) for 270 degrees. In two flow pulsatile simulation cases for fixed geometry and dynamic geometry with phase angle 270 degrees, there is a local minimum of the normalized wall shear rate amplitude in the vicinity of the bifurcation, while in other simulations a local maximum is observed.

Beginning in 1969, Pierre Galletti and his colleagues established a laboratory at Brown University, which, initially and for many years, was involved with artificial lungs. Various projects budded out of this, including the following: the establishment of standards for oxygenator performance, which anticipated Food and Drug Administration requirements; studies of thrombosis and other pathologies, which could be reduced by design changes; long-term, pumpless arterio-venous (A-V) bypass; early hybrid pancreas and other artificial organs; implantable lungs; and spin off companies. The current report outlines the history, philosophy, collaborations, and major results of the laboratory, as well as how the principal investigators simultaneously moved into research areas outside of artificial lungs in the late 1980s.

Relatively little attention has been given to vessel wall mechanics in interaction with the pulsatile fluid motion of blood in the epicardial coronary arteries which are prone to atherosclerotic plaque development. Theories for lipid transport by convective effects, while appealing in many ways, do not serve to explain the predominantly bounded, elliptic profiles of atherosclerotic plaques when examined en face at gross autopsy. This paper outlines how structural-mechanical concepts relating to plaque shapes (starting from the shapes available even with isometric shell peeling to create the cavities typical of early plaques) can be combined with understanding of the blood pressure distribution which develops in the vicinity of a predominantly T-junction in a blood vessel to modulate and interact in shape formation by cyclic, local flexure. This provides a foundation for a rational hypothesis to be tested in vivo with bi-plane angiography and vessel wall imaging, e.g., intravascular ultrasound, to better assess the roles of solid and fluid mechanics in the localization of plaques.

Plaque rupture has become identified as a critical step in the evolution of arterial plaques, especially as clinically significant events occur in critical arteries. It has become common in the past dozen years or so to consider which plaques are vulnerable, even though not yet ruptured. Thrombotic events have remained significant, but in a context where they are seen as being triggered often by plaque rupture. Weaving together considerations from structural mechanics, fluid mechanics, plaque morphology, epidemiological pathology, micromechanical measurements of arterial wall tissues, and emerging information on the complex roles of the matrix metalloproteinases, this critical review draws attention to the relative paucity of data (i) on the mechanical behavior of small test portions of arterial tissues and (ii) on the relation of plaque locations to local vessel curvature and curvature flexure. This is especially important in the epicardial arteries, where combination of biplane angiograms and intravascular ultrasound (both becoming increasingly available in digital recordings) offer opportunities for clinical investigation, allied to biomechanics, to an extent previously not possible. Improved imaging and local tissue property assessments provide related opportunities for the carotid bifurcation. The discussion includes a proposal for developing an assessment scale for plaque vulnerability.

The main strategy of gene therapy has traditionally been focused on gene augmentation. This approach typically involves the introduction of an expression system designed to express a specific protein in the transfected cell. Both the basic and clinical sciences have generated enough information to suggest that gene therapy would eventually alter the fundamental practice of modern medicine. However, despite progress in the field, widespread clinical applications and success have not been achieved. The myriad deficiencies associated with gene augmentation have resulted in the development of alternative approaches to treat inherited and acquired genetic disorders. One, derived primarily from the pioneering work of homologous recombination, is gene repair. Simply stated, the process involves targeting the mutation in situ for gene correction and a return to normal gene function. Site-specific genetic repair has many advantages over augmentation although it too is associated with significant limitations. This review outlines the advantages and disadvantages of gene correction. In particular, we discuss technologies based on chimeric RNA/DNA oligonucleotides, single-stranded and triplex-forming oligonucleotides, and small fragment homologous replacement. While each of these approaches is different, they all share a number of common characteristics, including the need for efficient delivery of nucleic acids to the nucleus. In addition, we review the potential application of a novel and exciting nonviral gene augmentation strategy--the Sleeping Beauty transposon system.

We are now approaching the reality of success in gene therapy as our knowledge of the genetic basis of disease continues to grow, coupled with improved delivery methods for therapeutic nucleic acid molecules. It is apparent that gene therapy can be divided into two specific and very different approaches in which gene replacement, or augmentation, is differentiated from gene repair. In fact, gene augmentation is characterized by the delivery of the coding sequence of the gene of interest in an expression cassette. In contrast, gene repair differs in that the process targets for correction of the mutation responsible for the genetic disorder. The in situ repair of a gene has many advantages over conventional replacement methods. This review will concentrate on the various strategies currently available for gene repair. The potential benefits of correction versus augmentation will be addressed and possible future developments outlined.

Cyclosporine is a potent suppresser of cell-mediated immunity that is mainly used in organ transplantation to prevent rejection. It is also being used increasingly outside of transplantation and probably is the only new treatment to have made an impact in acute ulcerative colitis (UC) resistant to steroid therapy. We describe a case of Nocardia asteroides lung abscess in a patient treated with cyclosporine for acute steroid resistant UC that was successfully managed with antibiotics and by discontinuing cyclosporine. With increasing use of cyclosporine for acute UC it is to be anticipated that opportunistic infections such as Nocardia will be more frequently encountered in the future.

Background/aim: Azathioprine is standard therapy for maintenance of remission in patients with autoimmune hepatitis. However, approximately 15% of patients are intolerant of therapy and 10% do not respond to it. There is a need for alternative therapies. We describe here the results of mycophenolate mofetil therapy in patients with autoimmune hepatitis., Patients: We studied seven patients with type 1 AIH (six female). Three were intolerant of azathioprine and had elevated transaminases and liver histology showing active disease despite prednisolone therapy. Four had been on a dose of 2 mg per kg of azathioprine without complete normalisation of ALT, and had liver biopsies showing active disease. All were treated with mycophenolate 1 g bd and were followed for a median of 46 months (21-59). End points were improvement in histological inflammation, ALT and prednisolone dose., Results: Five of the seven (71%) patients had normal transaminases after 3 months of treatment. The steroid dose fell from a median of 20 mg per day to 2 mg per day at 9 months (p=0.0001) and the hepatic activity index fell from median 11 to 3 (p=0.001) after 7 months of therapy. One patient required dose reduction because of a fall in white cell count. No other adverse effects were seen., Conclusions: Mycophenolate mofetil is effective and well tolerated in patients with type 1 AIH who are intolerant of, or do not respond to, azathioprine.

Aim: To determine the effect of Helicobacter pylori eradication with omeprazole and amoxycillin, with or without metronidazole, on the 12-month course of duodenal ulcer disease., Methods: In a randomized; double-blind study, conducted in 19 hospitals, 105 H. pylori positive duodenal ulcer patients were healed and symptom-free following either omeprazole dual therapy (omeprazole 40 mg o.m.+amoxycillin 500 mg t.d.s., OA, eradication rate 46%, n = 52) or omeprazole triple therapy (omeprazole 40 mg o.m.+amoxycillin 500 mg t.d.s.+metronidazole 400 mg t.d.s., OAM, eradication rate 92%, n = 53) for 2 weeks, followed by 2 weeks of omeprazole 20 mg o.m. and a 12-month untreated follow-up period, after which time all patients were endoscoped. Endoscopic and symptomatic relapse rates, and effect on H. pylori status measured using 13C-urea breath test, were determined., Results: During the 12-month untreated follow-up period, the life-table endoscopic relapse rates were 12% (95% CI: 2-22%) and 2% (95% CI: 0-6%) for OA and OAM patients, respectively. By 12 months, life-table symptomatic relapse rates were 22% (95% CI: 13-37%) and 19% (95% CI: 8-30%) for OA and OAM, respectively. In the 12 months untreated follow-up period, 2/69 (3%, 95% CI: 0-7%) patients rendered H. pylori negative had an endoscopic relapse at the end of the 12-month follow-up period, compared with 5/31 (16%, 95% CI: 3-29%) patients remaining H. pylori positive (P = 0.03 between H. pylori positive and negative groups). Twelve of 69 (17%, 95% CI: 8-26%) patients rendered H. pylori negative relapsed symptomatically, compared with 9/31 (29%, 95% CI: 13-45%) patients remaining H. pylori positive (P = N.S. between groups). There was a significant improvement in epigastric pain (P = 0.0001), nausea and vomiting (P < 0.05) between entry to the study and 1, 6 and 12 months post-treatment for both treatment groups., Conclusions: OAM eradicates H. pylori in significantly more patients than OA, but successful H. pylori eradication with either OAM or OA predisposes to low endoscopic and symptomatic relapse rates for duodenal ulcer patients when followed up for 12 months.

Background: As many as 50% of patients with reflux symptoms have no endoscopic evidence of oesophagitis. This multicentre study was designed to assess symptom relief after omeprazole 20 mg once daily in patients with symptoms typical of gastro-oesophageal reflux disease but without endoscopic evidence of oesophagitis., Methods: Patients (n = 209) were randomized in a double-blind study to receive either omeprazole 20 mg once daily (n = 98) or placebo (n = 111) for 4 weeks. Symptoms were assessed at clinic visits and using daily diary cards, with patient-completed questionnaires providing additional data on symptoms and on psychological disturbance., Results: On completion, symptom relief favoured omeprazole: 57% of patients on omeprazole were free of heartburn (vs. 19% on placebo), 75% were free of regurgitation (47%) and 43% were completely asymptomatic (14%), each with P < 0.0001. Fewer patients in the omeprazole group required alginate/antacid relief medication (P < 0.05). Symptom relief (time to first heartburn-free day) was more rapid with omeprazole (2 vs. 5 days on placebo; P < 0.01). A greater reduction in anxiety occurred in the omeprazole group (P < 0.05)., Conclusion: Omeprazole 20 mg once daily is effective in providing relief of the symptoms typical of gastro-oesophageal reflux disease in patients with essentially normal oesophageal mucosa.

This study determined the optimal maintenance dose of omeprazole in reflux oesophagitis. One hundred and ninety three patients rendered asymptomatic and healed after four or eight weeks omeprazole were randomised double blind to 10 mg omeprazole once daily (n = 60 evaluable), 20 mg omeprazole once daily (n = 68), or placebo (n = 62) for one year or until symptomatic relapse. Each omeprazole regimen was superior to placebo in preventing both symptomatic relapse (life table analysis, p < 0.001) and endoscopically verified relapse (p < 0.001). At 12 months, the life table endoscopic remission rates (proportions of patients without grade > or = 2 oesophagitis) were: 50% (95% confidence intervals 34 to 66%) with 10 mg omeprazole once daily, 74% (62 to 86%) with 20 mg omeprazole once daily, and 14% (2 to 26%) with placebo. At 12 months, the life table symptomatic remission rates (proportions of patients asymptomatic or with mild symptoms) were: 77% (64 to 89%) with 10 mg omeprazole once daily, 83% (73 to 93%) with 20 mg omeprazole once daily, and 34% (16 to 52%) with placebo. Both 10 mg and 20 mg omeprazole once daily were effective in prolonging the remission of reflux oesophagitis: 10 mg may be appropriate to start longterm treatment, though the existence of a dose response relation means that 20 mg once daily may be effective in patients for whom 10 mg once daily is suboptimal.

The dominant problem in the design of an intracorporeal oxygenator is achieving gas transfer rates sufficient for physiological needs in the space available with acceptably low flow resistance to blood. Design problems still to be solved, when configurations with sufficient gas transfer effectiveness are well identified, are biological tolerance (including adequate blood compatibility), ease of manufacture, and prolonged function.

The woven tubes membrane oxygenator is a suitable configuration for the intracorporeal membrane oxygenator because of a high gas exchange performance and a compact packing of tubing. In this study the oxygen transfer performance of woven tubes was evaluated by an in vitro experiment with an external perfusion mode; the blood flow is outside of the tubes in order to reveal the feasibility of designing the intravascular oxygenator (IVOX) by the woven tubes. The oxygen transfer efficiency of the external perfusion mode is superior to that with the internal perfusion mode because of the larger convective mixing effect on the external surface of the tubes. Thus the use of the external perfusion mode results in the shorter necessary tube length for the rated condition, which enables making the oxygenator unit more compact. All of these features encourage the adoption of the woven tubes for use in the intravascular oxygenator.

In a double-blind, randomized, parallel-group clinical trial, 340 asthmatic patients aged 12-70 years received budesonide 400 micrograms once daily in the morning, budesonide 400 micrograms once daily in the evening, budesonide 200 micrograms twice daily or placebo, for 12 weeks in addition to inhaled short-acting beta 2-agonists used as required (p.r.n.). Budesonide was given as Pulmicort Turbohaler. Peak expiratory flow rate (PEFR) increased by 20 to 30 1 min-1 in each of the active treatment groups, significantly more than in the placebo group (P < 0.01). There were no significant differences between the active treatment groups. Symptom improvement and decreased beta 2-agonist use reflected the PEFR data. Incidences of adverse events in the active treatment groups were similar to those observed in the placebo group. Budesonide 400 micrograms given once daily morning or evening is equieffective with the same total daily dose given twice daily in the treatment of mild to moderate stable asthmatics.

Unstable plaques are undergoing thrombosis which, in most instances, is due to fissuring and rupture of the plaque cap. This process (deep intimal injury) is a complication of plaques with a lipid-rich core. The cap tear allows blood to enter the core from the lumen, leading initially to intraplaque thrombosis and, subsequently, in some cases intraluminal thrombosis. Cap tears reflect the interplay between the force exerted on the tissue and its inherent mechanical strength. Factors which elevate and concentrate circumferential wall stress on the cap during systole include an increasing proportion of the total plaque volume occupied by the lipid core, thinning of the cap and a loss of internal collagen struts within the core. Factors which lead to an inherent reduction in the mechanical strength of cap tissue include a reduction in collagen and glycosaminoglycan concentrations, an increase in the number and density of macrophages, and a concomitant reduction in smooth muscle cells in the cap tissue. It is therefore possible to define a vulnerable plaque as one in which the lipid core is disproportionately large, the cap thin, and in which monocytes preponderate over smooth muscle cells.

This study was designed to establish whether 40 mg omeprazole once daily exhibits sufficient additional efficacy over that of 20 mg omeprazole once daily in patients with symptomatic reflux oesophagitis requiring more than an initial 4-week course of 20 mg omeprazole once daily (o.m.) to warrant routine use of the higher dose. Three hundred and thirteen patients were randomized to receive either 20 mg omeprazole (4 weeks) then 20 mg (second 4 weeks if not both healed and symptom-free after 4 weeks), or 20 mg omeprazole (4 weeks) then 40 mg omeprazole o.m. (second 4 weeks). One hundred and twenty-seven patients were healed and symptom-free after 4 weeks and left the study at that point. Taking the second treatment period in isolation, the healing rate (64% vs. 45%, P < 0.02) and relief of heartburn (72% vs. 60%, P < 0.002) were greater among patients receiving 40 mg omeprazole o.m., demonstrating the existence of a dose-response relationship for omeprazole. However, on completion, there were no significant differences between the patients randomized to the 20/20 mg (healed 65%, asymptomatic 69%) or the 20/40 mg (healed 74%, asymptomatic 74%: both not significant differences compared with 20/20 mg) regimens. The magnitude of the difference in efficacy between 20 and 40 mg omeprazole in symptomatic reflux oesophagitis is insufficient to warrant the routine use of 40 mg in patients requiring more than 4 weeks' treatment with 20 mg omeprazole o.m.; continued treatment with 20 mg omeprazole for 4-8 weeks is the preferred option.

Objective: To assess the size of the lipid pool and the number of smooth muscle cells and monocyte/macrophages in human aortic plaques that were intact and to compare the results with those in aortic plaques undergoing ulceration and thrombosis., Design: The lipid pool was measured as a percentage of the total cross sectional area of the plaque. Immunohistochemistry was used to identify cell types (monocytes/macrophages (M phi) by EBM11 and HAM56, smooth muscle cells by alpha actin). The area of the tissue occupied by each cell type was measured by quantitative microscopy in the peripheral (shoulder) area of the plaque and the plaque cap. Absolute counts of each cell type were expressed as the ratio of SMC:M phi., Material: Aortas were obtained at necropsy from men aged less than 69 years who died suddenly (within 6 hours of the onset of symptoms) of ischaemic heart disease. 155 plaques from 13 aortas were studied. Four aortas showed intact plaques only (group A, n = 31). Nine aortas showed both intact plaques (group B, n = 79) and plaques that were undergoing thrombosis (group C, n = 45)., Results: In 41 (91.1%) of the 45 plaques undergoing thrombosis (group C) lipid pools occupied more than 40% of the cross sectional area of the plaque. Only 12 (10.9%) of the 110 intact plaques (groups A + B) had lipid pools of this size. The mean size of the lipid pool in plaques of groups A, B, and C was 12.7%, 27.3% and 56.7% respectively. Compared with intact plaques those undergoing thrombosis contained a smaller volume of smooth muscle cells (2.8% v 11.8%) and a larger volume of monocyte/macrophages (13.7% v 2.9%) in the plaque cap. The ratio of the number of smooth muscle cells to monocytes/macrophages was 7.8 in group A plaques, 4.1 in group B plaques, and 1.0 in group C plaques. This gradient was the result of an absolute increase in monocyte/macrophages and an absolute decrease in smooth muscle cells., Conclusions: In the aorta ulceration and thrombosis were characteristic of plaques with a high proportion of their volume occupied by extracellular lipid, and in which there was a shift toward a preponderance of monocyte/macrophages compared with smooth muscle cells in the cap.

The tearing of the cap of atheromatous plaques is the commonest cause of thrombosis in human coronary arteries. It has been proposed that tearing arises because of structural weakening of the cap's connective tissue around the tear. To test this hypothesis we compared the mechanical properties of the intact edges of torn plaque caps and unbroken caps. Owing to limitations in plaque size, a purpose-built tensometer was developed to study stress-strain relationships of the small connective tissue specimens. The design of the tensometer is reported and was shown to detect accurately, minor differences in connective tissues and to generate complete stress-curves with computer-assisted image analysis.

Measurements of total collagen, of the ratio of collagen types III/(I+III) and of sulphated glycosaminoglycans (GAGs) were compared with mechanical strength for individual ulcerated and non-ulcerated human aortic plaque caps and with intima adjacent to the plaques. The distributions of the collagen type ratio were similar for both ulcerated and non-ulcerated plaque caps but different from that of the adjacent intima. The proportions of different collagen types were not related to fracture stress and are thus unlikely to affect the potential to ulcerate. The distributions of the sulphated GAGs showed lower amounts for the plaque caps compared with the nearby intima, with the centres of ulcerated plaque caps having the lowest values. Total collagen had higher values in the peripheries of plaque caps compared with the nearby intima, but was distinctly lower in the centres of ulcerated plaque caps. Plaque caps appeared to require a higher collagen content than adjacent intima to support a given level of mechanical strength, suggesting that while collagen production had occurred in the plaque caps it was not as efficiently organized to resist fracture as a similar amount of collagen in the adjacent intima. Ulcerated plaque caps are notable for much larger transverse (centre vs. periphery) gradients of connective tissue constituents than for non-ulcerated plaque caps. The development of these transverse gradients may be a critical aspect in determining the propensity of a plaque to ulcerate.

The immediate cause of arterial, predominantly coronary thrombosis is almost always cracking or fissuring of the cap of an atheromatous plaque. This exposes collagen and lipids to the flowing blood and thereby initiates thrombotic platelet aggregation, almost immediately followed by coagulation. The thrombi tend to extend into the arterial lumen, causing obstruction to blood flow and clinical symptoms and signs. Evidence for this sequence of events comes, inter alia, from angiograms of patients with unstable angina and developing myocardial infarction. Direct angioscopy in life is also visualising mural thrombi over fissured plaques in atheromatous coronary arteries. We are investigating the initial development of atheromatous plaques liable to fissuring. The cap over such plaques covers a "lipid pool". We have discovered that one factor promoting the uptake of lipid, in the form of plasma low-density lipoprotein, is the concentration of circulating catecholamines (Cardona-Sanclemente LE, Gorog P, Born GVR (1992) J Physiol London, in press). We are also investigating the immediate cause(s) of plaque fissure. We have evidence for a complex interaction of different determinants, including the concentration of macrophages, presumably as foam cells, in the plaque caps (Lendon CL, Davies MJ, Born BVR, Richardson PD (1991) Atherosclerosis 87: 87).

A serpentine gas exchange unit was built with cylindrical tubular microporous membranes featuring periodic arcs with a fixed curvature ratio (ratio of tube radius to radius of curvature) of 1/14 and circular angles between 30 and 360 deg. Oxygen transfer was measured under steady and pulsatile blood flow conditions in vitro and ex vivo to assess the design features which most effectively augment gas transfer. Under steady blood flow conditions, oxygen transfer increased with circular angles beyond 70 deg. Under pulsatile conditions, a wide range of geometrical and fluid mechanical parameters could be combined to enhance gas transfer performance, which eventually depended upon the secondary Reynolds number and the Womersley parameter.

The density of macrophages, identified by the antibody EBMII, in human aortic plaque caps was counted. A contiguous strip of cap tissue was tested mechanically. Aortic plaque caps which had undergone rupture (ulceration) at one end (n = 18) were compared with caps of intact plaques (n = 22). The caps of ruptured plaques showed a significant increase in macrophage density, an increased extensibility and decreased maximum stress (force per unit area) at fracture when compared with caps from intact plaques.

A randomized, parallel group, double-blind multi-centre study was carried out in 342 patients with symptomatic seasonal allergic rhinitis to assess the efficacy and tolerability of intranasal budesonide administered either as a single morning dose of 400 micrograms or as a 200 micrograms twice-daily dose, morning and evening, for 4 weeks. Both treatments improved the symptoms of seasonal allergic rhinitis; specific nasal symptom scores recorded daily by the patient being reduced. The proportions of patients symptom free after 4-weeks' treatment were 46% in the 400 micrograms once-daily group and 54% in the 200 micrograms twice-daily group, with total daily symptom scores recorded by diary cards reduced by 79% and 80%, respectively. The differences between the groups were not statistically significant. Sub-group analysis of patients allergic to grass pollen (n = 166) showed similar total symptom scores at each level of grass pollen exposure (no significant difference between treatment groups). Patients assessed both treatments to be effective (no significant difference between groups), with 65% of patients questioned stating a preference for a once-daily treatment given equal symptom control. Both treatments were equally well tolerated and few side-effects were reported.

A double-blind, parallel-group, multi-centre study was carried out in 248 patients with symptomatic seasonal allergic rhinitis to assess the effectiveness and tolerability of intranasal aqueous budesonide given as a single daily dose each morning of 400 micrograms compared with the conventional dosage regimen of 200 micrograms twice daily. After a 1-week run-in period during which only oral terfenadine was allowed for intolerable symptom relief, symptomatic patients were allocated at random to receive budesonide in one or other dosage regimen for 3 weeks. The results of assessments made by the physician at clinic visits and by patients recording daily data on diary record cards showed that specific nasal symptom incidence and severity were significantly (p less than 0.001) reduced in both treatment groups. The proportions of patients symptom-free at 3 weeks were 40% in the 400 micrograms once daily and 45% in the 200 micrograms twice daily group; in addition, mean nasal symptom scores from the daily diary cards were significantly (p less than 0.001) reduced in both groups, with a reduction in total symptom scores of 53% and 60%, respectively. The differences between the groups were not statistically significant. Total symptom scores were significantly (p less than 0.01) reduced in both dosage groups at all levels of pollen exposure. Patients rated treatment overall as being highly effective, mean scores being very similar in both groups, and tolerability was similar and good whether budesonide was given as a 400 micrograms once daily dose or as 200 micrograms twice daily. Assuming equal symptom control, 74% of patients stated they would prefer once daily to twice daily treatment.

Beta 2-agonist therapy effectively relieves asthmatic symptoms, but an improvement in patient lifestyle has not been demonstrated. This open study in which patients acted as their own controls, assessed the efficacy and acceptability of intermittent symptom-related use of terbutaline inhaled via 'Turbohaler', and its influence on the lifestyle of 1133 inhaler-naive, mild asthmatics treated in general practice. A 1-week run-in period was followed by 4-weeks' treatment with inhaled terbutaline (500 micrograms as required). Peak expiratory flow rate (PEFR) and 'Turbohaler' technique were assessed at clinic visits. Diary cards, completed daily, assessed: the number of terbutaline inhalations, the relief obtained after use, the severity of asthma symptoms (cough, morning wheeze, nocturnal wheeze and wheeze on activity), and lifestyle indices (sleep disturbance, work/school days lost, limitation of normal activity). After terbutaline treatment, PEFR increased by 54 +/- 2 l/min (p less than 0.001), the severity of asthma symptoms was almost halved (p less than 0.001), with over two-thirds (65% to 76%) of patients reporting improvements in each variable, and the adverse effect of asthma on lifestyle was at least halved (p less than 0.001). Improvements in lung function, asthma symptoms and lifestyle were comparable for all sub-groups: adults (greater than 16 years), school-age children (6 to 16 years) and preschool children (less than or equal to 5 years). This study not only confirmed the efficacy and acceptability of intermittent symptom-related use of terbutaline inhaled via 'Turbohaler', but also demonstrated that its use enhanced patients' lifestyles.

One hundred and one hypertensive patients [diastolic pressure (dBP) 95-110 mm Hg after greater than or equal to 6 weeks with no antihypertensive therapy] were randomized to receive, double-blind, felodipine-ER 5 mg once daily (n = 49) or placebo (n = 52) for 2 weeks. Twenty-four hours post-dose, felodipine-ER 5 mg o.m. reduced dBP by a mean of 11 mm Hg; in contrast, dBP fell in the placebo group by 3 mm Hg (p less than 0.001). If the target dBP of less than or equal to 90 mm Hg was not attained at 2 weeks, the dose of felodipine-ER (or placebo) was doubled; if the target was not attained after a further 2 weeks, the doses were doubled again, to 20 mg felodipine-ER or placebo. If the target was achieved after 2 or 4 weeks, patients remained on that dose; the double-blind period for all patients was 6 weeks. After 6 weeks, the mean reduction in dBP in the felodipine-ER group was 14 mm Hg, significantly (p less than 0.001) greater than in the placebo group (8 mm Hg). Blood pressure "control" was defined prospectively as a seated dBP less than or equal to 90 mm Hg: after 6 weeks, 67% of patients receiving felodipine-ER compared with 27% on placebo had a controlled blood pressure (p less than 0.001). The figures after 2 weeks were 45% on 5 mg felodipine-ER and 21% on placebo (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

An open, multi-centre, general practice study was carried out in 1661 asthmatic patients to assess the efficacy, in terms of symptom relief and changes in lifestyle, of budesonide and to record objective lung function changes and any adverse events. After a 1-week run-in period on any pre-trial anti-asthma medication, patients received either 200 micrograms or 400 micrograms budesonide twice daily by metered dose inhaler for 4 weeks. Peak expiratory flow rate (PEFR) was measured by the doctor on entry, after the run-in, and at the end of the study and patients were asked to complete diary cards on a daily basis to record compliance, bronchodilator usage and the severity of cough, wheeze and sleep disturbance, and weekly to record 5 lifestyle assessments, e.g. physical activity. Analysis of data from the clinic visits and 1375 completed diary cards showed that PEFR increased significantly from 321 +/- 3 l/min at the end of the run-in to 368 +/- 3 l/min at the end of the trial; 77% of patients had an improved PEFR. Bronchodilator use decreased significantly from 4.2 +/- 0.1 times/day during the run-in period to 3.0 +/- 0.1 times/day at the end of the study; 65% of patients used less bronchodilator. Significant improvements were recorded in all the symptoms and lifestyle indices monitored; 76% of patients improved in at least 5 of the 11 assessments. Treatment-emergent adverse events occurred in 103 (6%) of patients: none was classified as serious or unexpected. No sub-group of patients was identified in which the results were at variance from the full sample. It is concluded that budesonide improves patients' lifestyle and ability to carry out normal activities, as well as improving PEFR and reducing bronchodilator use, in mild to moderately severe asthmatics treated in general practice.

The aim of this study was to compare duodenal ulcer healing and symptom relief after two and four weeks treatment with omeprazole or cimetidine in groups of patients treated in general practice and as hospital out-patients. It was a randomised, double-blind, parallel group study with stratification for trial centre (hospital or GP). Endoscopy was performed at entry, after two weeks and, if unhealed at two weeks, after four weeks. All endoscopies were carried out in hospitals. In all, 189 patients were randomised (98 omeprazole, 91 cimetidine), 79 (42 per cent) of which by GPs, to either omeprazole 20 mg om (n = 41) or cimetidine 800 mg nocte (n = 38) for two to four weeks. After two weeks, ulcer healing occurred in 56 per cent (omeprazole) and 29 per cent (cimetidine) (p less than 0.05) of patients treated by GPs, and 67 per cent (omeprazole) and 36 per cent (cimetidine) (p less than 0.005) of those treated as hospital out-patients. Similar differences in healing rates were seen after four weeks. Omeprazole produces faster duodenal ulcer healing than cimetidine whether patients are treated as hospital out-patients or by GPs.

Experiments were performed to study the rheological response of human blood at hematocrit ratios of 0 to 0.45 in axial oscillatory flow in a tube of uniform bore. Three principal regimes of flow were identified, depending on the amplitude of oscillation. At the highest amplitudes (and therefore the largest range of shear rates in the blood) there was turbulent motion and the friction coefficient increased in proportion to the square of the hematocrit. At small amplitudes the friction decreased with increase in amplitude, the rate of decrease increasing with hematocrit. At intermediate amplitudes the friction increased in proportion to the square of the hematocrit. Glutaraldehyde fixation of the red cells caused increase in the friction, and reduced the rate of decrease of friction with amplitude at small amplitudes. With a stenosis of very modest degree and span the friction in normal blood increased disproportionately, and a small blind hole in the lumen of the stenosis caused additional and disproportionate increase in friction.

Blood flow was measured in the descending thoracic aorta of the anaesthetised dog using a perivascular flow probe and electromagnetic flowmeter. Blood velocity was measured in the same vessel with an intravascular velocity probe and electromagnetic flowmeter. Changes in blood pressure, flow and velocity, were induced by intravenous administration of noradrenaline, angiotensin, isoprenaline and aminophylline. If the velocity probe was within the cuff of the flow probe, percentage changes in flow and velocity were comparable, but if the velocity probe was "upstream" or "downstream" from the cuff, discrepancies between percentage drug-induced changes in flow and velocity were of the order of 30% and, in 12 out of 80 observations, in opposite directions. Measuring absolute flow with the velocity-sensitive device produced variable results showing a systematic underestimate of flow estimated from velocity, compared with flow measured with the perivascular probe. It is concluded that the measurement of blood flow and changes in blood flow, with the intravascular velocity probe, is liable to produce inaccurate data.