Outcome in Men with a Screen-detected Abdominal Aortic Aneurysm Who are not Fit for Intervention.

OBJECTIVE/BACKGROUND: Abdominal aortic aneurysm (AAA) screening in Gloucestershire has been ongoing for 25 years. The aim of this study was to review the outcome of a cohort of men with a large (> 5.4 cm) screen-detected AAA who did not have early intervention for their AAA. METHODS: A prospectively maintained database was interrogated for a 10-year interval from 2001 to 2011. Men who did not have their large AAA repaired within 3 months of the diagnosis were identified. The reasons for initial nonintervention and subsequent outcomes were identified from a combination of hospital case notes and general practitioner records. RESULTS: Of 334 men referred, 59 (median age 71 years, range 62-83 years) did not have intervention within 3 months (initial nonintervention rate 17.6%). The reasons included placed back on surveillance after assessment (n = 34); immediately discharged (n = 12); required further investigations (n = 5); died before complete assessment (n = 3); and incomplete follow-up (n = 5). Sixteen men had delayed AAA repair with no perioperative mortality. Overall mortality in the study was 14/34 (nine from ruptured AAA, the rest from medical conditions). Two further men survived repair of a ruptured AAA. The overall rate of ruptured AAA was 11/59 (18.6%). CONCLUSION: Information from studies such as these can be used to help plan treatment of men with a large AAA and to compare performance of vascular units.

The effect of structure and a secondary carbon source on the microbial degradation of chlorophenoxy acids.

Pseudomonas putida, Aspergillus niger, Bacillus subtilis, Pseudomonas fluorescens, Sphingomonas herbicidovorans and Rhodococcus rhodochrous growing on glucose in a medium containing one of three chlorophenoxy acids at a concentration of 0.1 g L(-1) (clofibric acid, (R)-2-(4-chloro-2-methylphenoxy)propionic acid (mecoprop or MCPP) and 4-chloro-2-methylphenoxyacetic acid (MCPA)) degraded these compounds to varying degrees; from nonmeasurable to almost complete removal. These results with the addition of glucose (2.5 g L(-1)) as an easy to use carbon source indicated the formation of metabolites different from results reported in the literature for growth studies in which the chlorophenoxy acid was the sole carbon source. The metabolite, 4-chloro-2-methylphenol, which had been reported previously, was only observed in trace amounts for MCPP and MCPA in the presence of S. herbicidovorans and glucose. In addition, three other compounds (M1, M3 and M4) were observed. It is suggested that these unidentified metabolites resulted from ring opening of the metabolite 4-chloro-2-methylphenol (M2). The rate of biodegradation of the chlorophenoxy acids was influenced by the degree of steric hindrance adjacent to the internal oxygen bond common to all three compounds. The most hindered compound, clofibric acid, was converted to ethyl clofibrate by R. rhodochrous but was not degraded by any microorganisms studied. The more accessible internal oxygen bonds of the other two chlorophenoxy acids, MCPP and MCPA, were readily broken by S. herbicidovorans.

Novel uses for statins in surgical patients.

BACKGROUND: Aside from their cholesterol-lowering effects statins are known to have a range of other 'pleiotropic' effects. We present an overview of the basic science behind these effects and then review clinical trials and the current role of statins relevant to modern surgical practice. METHODS: A systematic review of the literature was performed using the keywords surgery and the MeSH term for statins. All clinical studies relating to statin use in surgical patients were evaluated. An overview of the literature on statin use and cardiac outcomes was performed. CONCLUSIONS: Statins are safe and have a wide range of pleiotropic effects relevant to surgical practice. Strongest evidence for their clinical use comes in primary cardiac risk reduction in many types of vascular surgery. There is a large body of evidence showing their benefit perioperatively in high-risk vascular and cardiac surgery but the picture is less clear for low-risk patients. Further studies are needed to evaluate exact dosage regimes and timing of administration. Novel uses of their anti-inflammatory properties in sepsis and vasomotor properties in subarachnoid haemorrhage are being further investigated by randomised trials.

Role of medical intervention in slowing the growth of small abdominal aortic aneurysms.

Abdominal aortic aneurysm is a common-but preventable-cause of death in elderly men; 4% of men at the age of 65 years have an aorta >3 cm in diameter. Continued expansion runs the risk of aneurysm rupture, a condition that is fatal in all but 15% of individuals. A national screening programme has commenced that aims to reduce the number of deaths from aneurysm rupture by 50%. The programme will detect a large number of men with a small aneurysm who are not in imminent danger of rupture, but who will join a regular ultrasound programme of surveillance. If the aneurysm expansion rate could be reduced, fewer men would be at risk of aneurysm rupture, and fewer would need elective aneurysm repair. A considerable amount is known about the pathophysiology of aneurysm growth. Exploring pharmacological means to delay or reduce aneurysm growth could make a considerable contribution to any screening programme. A number of case control studies have suggested that some antihypertensive drugs, non-steroidal anti-inflammatory drugs, antibiotics, and statins may reduce aneurysm growth rates. Data from controlled studies have provided less secure conclusions. Use of these medications, together with lifestyle modification such as stopping smoking, could become standard advice to men with a small aortic aneurysm. Further studies of novel agents and larger controlled trials of existing drugs are warranted.

Entrapment syndromes.

Entrapment syndromes represent a pathological process that vascular specialists encounter infrequently. However symptomatic patients are often young with impaired quality of life and successful treatment can produce great benefit, making knowledge of these conditions essential. The purpose of this review was to bring together the entrapment syndromes to understand and gain consensus on the aetiology, pathogenesis, diagnosis and modern management of these rare and interesting vascular disorders. This includes entrapment syndromes of the popliteal artery, superior mesenteric artery, coeliac artery, renal vein and iliac vein.

Endovascular stenting of large popliteal artery aneurysm is feasible!

INTRODUCTION: Endovascular stenting has been successfully employed in management of aortic aneurysms; however, its utility in managing popliteal aneurysms remains questionable. This is because of the non-availability of long term data about graft patency rates. CASE PRESENTATION: We report a case of large popliteal artery aneurysm stenting in a patient with significant co-morbidities and high risk for open surgical repair. He underwent successful endovascular stenting of a popliteal artery aneurysm measuring 6.4x9.7 cm extending for approximately 11.0 cm in length with Hemobahn grafts. The graft was patent at 12 months of follow up with complete exclusion of the aneurysm. CONCLUSIONS: Popliteal stents can be successfully used in treating large popliteal artery aneurysms in patients unfit for open repair.

Plasticizers and related toxic degradation products in wastewater sludges.

Plasticizers can persist during the treatment of wastewaters in sewage treatment plants (STPs) and can be discharged in effluents and/or accumulated in sewage sludges. For example, di-2-ethylhexyl phthalate (DEHP) is a common plasticizer that is now considered a priority pollutant and is known to accumulate in sludges. This may add constraints to the exploitation of the beneficial uses of sludges that contain significant quantities of plasticizers. Recently, it was demonstrated in studies with pure cultures that the biodegradation of plasticizers including DEHP and di-ethylhexyl adipate (DEHA) generates toxic metabolites including 2-ethylhexanoic acid, 2-ethylhexanol, and 2-ethylhexanal. However, the environmental impacts and fate of the degradation products arising from plasticizers are unknown. Therefore, this work investigated the concentrations of DEHP and DEHA and their metabolites in the sludges from several STPs in Quebec, Canada. DEHP and DEHA were found in concentrations ranging from 15 to 346 mg kg(-1) and 4 to 743 mg kg(-1), respectively, in primary, secondary, digested, dewatered or dried sludges. Metabolites were detected in almost all sludges, except those that had undergone a drying process at high temperature. It is concluded that sludges can represent significant sources of plasticizers and their toxic metabolites in the environment.

Plasticizers and their degradation products in the process streams of a large urban physicochemical sewage treatment plant.

The plasticizers bis (2-ethylhexyl) phthalate (BEHP), bis (2-ethylhexyl) terephthalate (BEHTP) and bis (2-ethylhexyl) adipate (BEHA) were found in significant quantities in the influents, process streams, treated effluent and solid residues of a large physicochemical treatment plant in Montreal, Canada. Of these plasticizers, BEHA was the most abundant in the influent but most was removed during primary treatment. Evidence indicated that significant biodegradation occurred within the sewers and during treatment resulting in the formation of three biodegradation products that had been reported in earlier laboratory studies; namely, 2-ethylhexanol, 2-ethylhexanal and 2-ethylhexanoic acid. Significantly greater concentrations of 2-ethylhexanal were found in process streams than had been reported in earlier laboratory work. This was attributed to the fact that there were fewer opportunities for losses of this volatile compound over the course of wastewater treatment. The plasticizers were removed from the aqueous phase to varying degrees during treatment, with most ending up in the solid residues. All three metabolites and the parent plasticizers were observed in the effluent and most were found in the solids that were analyzed. Results suggest that the treatment plant does not effectively remove plasticizers from the influent and represents a significant source of these compounds and their degradation products in the environment.

Primary varicose veins: altered transcription of VEGF and its receptors (KDR, flt-1, soluble flt-1) with sapheno-femoral junction incompetence.

OBJECTIVE: Loss of regulation of vascular endothelial growth factor (VEGF) production and action disturbs vascular homeostasis leading to pathology. Primary varicose veins (VVs) demonstrate aberrant production/release of VEGF. Our aim was to examine transcription of genes for VEGF (VEGF(121)/VEGF(165)) and its receptors (KDR, flt-1, s.flt-1) in VVs, in relation to underlying venous incompetence. MATERIALS AND METHODS: Samples of varicose (n=83, 18 patients) or normal (n=14, five subjects) great saphenous vein were divided into segments, determined by anatomical position from the sapheno-femoral junction (SFJ). SFJ and segmental incompetence were determined from duplex scans. Gene transcripts were amplified by RT-PCR, analysed by scanning densitometry, and the levels of transcription determined by ratio to control gene GADPH-3 (GAP-3). RESULTS: VEGF(121)/(165), KDR and flt-1 transcription was elevated in VVs overall (p<0.001), and in VVs with an incompetent SFJ (p<0.001), but not when the SFJ was functional; s.flt-1 was unaltered. Notably, gene transcription was unaffected by segmental position, or incompetence. Position below the SFJ correlated with increased transcription of s.flt-1 when the SFJ was incompetent (p<0.04), and s.flt-1 and VEGF(121) when the segment was incompetent (p<0.03). CONCLUSIONS: SFJ incompetence is associated with altered transcription of VEGF and its receptors reflecting an aetiological mechanism or later stage of disease development. Altered VEGF(121) and s.flt-1 transcription may be an early event in varicogenesis.

Primary varicose veins: the sapheno-femoral junction, distribution of varicosities and patterns of incompetence.

OBJECTIVE: to determine the patterns of long saphenous vein (LSV) disease in primary varicose veins (VVs). DESIGN: a retrospective analysis of venous duplex scans performed on patients referred for treatment of primary VVs. METHODS: analysis was made of sapheno-femoral junction (SFJ) incompetence, non-SFJ incompetence, segmental and perforating vein incompetence, distribution of varicosities, deep venous insufficiency, and short saphenous incompetence. RESULTS: four hundred and eighty-one patients were assessed (median age 50 (range 12-98) years; male:female ratio 1:1.95), comprising 706 limbs. Forty-six per cent of limbs had a competent SFJ, 64% of which had no incompetent perforating vessels associated. Disease was more widespread when the SFJ was incompetent. Varicosities were most common in the calf, occurring at or below the level of incompetence within the LSV. Incompetent segments occurred most commonly above-knee. There was no obvious correlation between incompetent perforators and distribution of varicosities, or incompetent segments. Short saphenous incompetence and non-SFJ groin recurrence were associated more with a competent SFJ, the converse being true for the Giacomini vein. CONCLUSION: primary VVs develop in isolated segments of the superficial venous system (without connection to the deep system) at, or distal to, the underlying main trunk incompetence, suggesting a process of "spreading incompetence" from one focal point, producing varicosities (mainly in tributaries).

Biodegradation of plasticizers by Rhodococcus rhodochrous.

Rhodococcus rhodochrous was grown in the presence of one of three plasticizers: bis 2-ethylhexyl adipate (BEHA), dioctyl phthalate (DOP) or dioctyl terephthalate (DOTP). None of the plasticizers were degraded unless another carbon source, such as hexadecane, was also present. When R. rhodochrous was grown with hexadecane as a co-substrate, BEHA was completely degraded and the DOP was degraded slightly. About half of the DOTP was degraded, if hexadecane were present. In all of these growth studies, the toxicity of the media, which was assessed using the Microtox assay, increased as the organism degraded the plasticizer. In each case, there was an accumulation of one or two intermediates in the growth medium as the toxicity increased. One of these was identified as 2-ethylhexanoic acid and it was observed for all three plasticizers. Its concentration increased until degradation of the plasticizers had stopped and it was always present at the end of the fermentation. The other intermediate was identified as 2-ethylhexanol and this was only observed for growth in the presence of BEHA. The alcohol was observed early in the growth studies with BEHA and had disappeared by the end of the experiment. Both the 2-ethylhexanol and 2-ethylhexanoic acid were shown to be toxic and their presence explained the increase of toxicity as the fermentations proceeded. The appearance of these intermediates was consistent with similar degradation mechanisms for all three plasticizers involving hydrolysis of the ester bonds followed by oxidation of the released alcohol.

Conformationally restricted indolopiperidine derivatives as potent CCR2B receptor antagonists.

The preparation and biological evaluation of a series of indolopiperidine CCR2B receptor antagonists possessing a conformationally restricted C-5 linker chain in combination with a restricted piperidine ring are described. Compared to the parent compound 1, analogue 8 shows a dramatic improvement in selectivity against a range of 5-HT and dopaminergic receptors.

Potent inhibition of a recombinant low voltage-activated Ca(2+) channel by SB-209712.

T-type Ca(2+) currents were recorded in 2 mM Ca(2+) from HEK293 cells stably expressing the low voltage-activated Ca(2+) channel sub-unit alpha(1I). These currents were inhibited by the known Ca(2+) channel antagonist mibefradil with an IC(50) close to 1 microM. SB-209712 (1,6,bis¿1-[4-(3-phenylpropyl)piperidinyl]¿hexane), a compound originally developed as a high voltage-activated Ca(2+) channel blocker, proved to be a more potent T-type channel antagonist, exhibiting an IC(50) in the region of 500 nM. The antagonism produced by SB-209712 was reversed following drug removal and the observed antagonism exhibited little or no voltage-dependence with respect to either holding or test potential. These data indicate that SB-209712 is amongst the most potent known non-peptide T-type channel antagonists and thus may have some use in understanding the role of these channels in cellular function.

CCR2B receptor antagonists: conversion of a weak HTS hit to a potent lead compound.

A weak HTS hit at the CCR2B receptor has been converted into a potent antagonist by array SAR studies. Selectivity over the closely related CCR5 receptor is also achieved.

Toluene removal in an automated cyclical bioreactor.

A control scheme was developed for the automation of toluene removal in a cyclical bioreactor. Toluene was added to the self-cycling fermentor by diffusion across a silicone membrane. Transient dissolved oxygen, carbon dioxide evolution, and oxidation-reduction potential (ORP) were screened as potential control variables. Through experimentation, ORP was deemed most effective. Control algorithms based on real-time estimates of the first and second derivatives of the ORP signal were tested. Although both approaches resulted in stable operation of the reactor, average toluene removal efficiencies of 95% were realized when control was based on the second derivative. This was significantly higher than the 77% efficiencies obtained when the control scheme centered on the first derivative of the transient ORP signal. The system developed was self-regulating, ensuring that a high toluene removal rate, on the order of 1.1 g h(-1), was maintained from cycle to cycle.

Modeling of biological processes using self-cycling fermentation and genetic algorithms.

Self-cycling fermentation (SCF) was coupled with a genetic algorithm (GA) to provide a simple system for evaluating biological models. The SCF provided the necessary system excitation and data "richness" required to completely define the fitted biological models. The solution scheme based on the GA avoided the computational difficulties often associated with calculus-based nonlinear regression techniques, resulting in rapid and accurate convergence. After validating the mathematical approach, data from the SCF obtained under denitrifying conditions were fitted successfully to an established model using the GA. Finally, data obtained in the SCF for the removal of phenol were used to compare multiple models. This work suggests that the SCF, in conjunction with the GA, provides a coherent system that can facilitate the characterization of biological systems.

Alzheimer's disease: correlation of the suppression of beta-amyloid peptide secretion from cultured cells with inhibition of the chymotrypsin-like activity of the proteasome.

Peptide aldehyde inhibitors of the chymotrypsin-like activity of the proteasome (CLIP) such as N-acetyl-Leu-Leu-Nle-H (or ALLN) have been shown previously to inhibit the secretion of beta-amyloid peptide (A beta) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on A beta formation of a much wider range of peptide-based inhibitors of CLIP than published previously. The inhibitors tested included several peptide boronates, some of which proved to be the most potent peptide-based inhibitors of beta-amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress A beta formation from cells correlated extremely well with their potency as CLIP inhibitors. Thus, we conclude that the proteasome may be involved either directly or indirectly in A beta formation.

Propagating front in an excited granular layer.

A partial monolayer of approximately 20 000 uniform spherical steel beads, vibrated vertically on a flat plate, shows remarkable ordering transitions and cooperative behavior just below 1g maximum acceleration. We study the stability of a quiescent disordered or "amorphous" state formed when the acceleration is switched off in the excited "gaseous" state. The transition from the amorphous state back to the gaseous state upon increasing the plate's acceleration is generally subcritical: An external perturbation applied to one bead initiates a propagating front that produces a rapid transition. We measure the front velocity as a function of the applied acceleration. This phenomenon is explained by a model based on a single vibrated particle with multiple attractors that is perturbed by collisions. A simulation shows that a sufficiently high rate of interparticle collisions can prevent trapping in the attractor corresponding to the nonmoving ground state.

Velocity statistics in excited granular media.

We present an experimental study of velocity statistics for a partial layer of inelastic colliding beads driven by a vertically oscillating boundary. Over a wide range of parameters (accelerations 3-8 times the gravitational acceleration), the probability distribution P(v) deviates measurably from a Gaussian for the two horizontal velocity components. It can be described by P(v) approximately exp(-mid R:v/v(c)mid R:(1.5)), in agreement with a recent theory. The characteristic velocity v(c) is proportional to the peak velocity of the boundary. The granular temperature, defined as the mean square particle velocity, varies with particle density and exhibits a maximum at intermediate densities. On the other hand, for free cooling in the absence of excitation, we find an exponential velocity distribution. Finally, we examine the sharing of energy between particles of different mass. The more massive particles are found to have greater kinetic energy. (c) 1999 American Institute of Physics.

The effects of SB 206284A, a novel neuronal calcium-channel antagonist, in models of cerebral ischemia.

The effects of SB 206284A, 1-[7-(4-benzyloxyphenoxy)heptyl] piperidine hydrochloride, have been investigated in vitro on calcium and sodium currents in rat-cultured dorsal root ganglion (DRG) neurones and potassium-mediated calcium influx in rat synaptosomes. Cardiovascular hemodynamic effects in both anesthetized and conscious rats, and neuroprotective activity in in vivo cerebral ischemia models were also investigated. In the rat DRG cells, SB 206284A caused almost complete block of the sustained inward Ca2+ current (IC50 = 2.4 microM), suggesting that the compound is an effective blocker of slowly inactivating, high-voltage calcium current. SB 206284A reduced locomotor hyperactivity in the gerbil bilateral carotid artery occlusion model without affecting ischemia-induced damage in the hippocampal CA1 region. In the rat middle cerebral artery occlusion model, SB 206284A reduced lesion volume in the posterior forebrain, and in the rat photochemical cortical lesion model, lesion volume was reduced even when treatment was delayed until 4 hours after occlusion. At neuroprotective doses, SB 206284A had no cardiovascular effects. These findings show that SB 206284A is a novel calcium channel antagonist that shows neuroprotective properties.