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With the long-term goal of developing a gene-based treatment for osteoarthritis (OA), we performed studies to evaluate the equine joint as a model for adeno-associated virus (AAV)-mediated gene transfer to large, weight-bearing human joints. A self-complementary AAV2 vector containing the coding regions for human interleukin-1-receptor antagonist (hIL-1Ra) or green fluorescent protein was packaged in AAV capsid serotypes 1, 2, 5, 8 and 9. Following infection of human and equine synovial fibroblasts in culture, we found that both were only receptive to transduction with AAV1, 2 and 5. For these serotypes, however, transgene expression from the equine cells was consistently at least 10-fold higher. Analyses of AAV surface receptor molecules and intracellular trafficking of vector genomes implicate enhanced viral uptake by the equine cells. Following delivery of 1 × 10(11) vector genomes of serotypes 2, 5 and 8 into the forelimb joints of the horse, all three enabled hIL-1Ra expression at biologically relevant levels and effectively transduced the same cell types, primarily synovial fibroblasts and, to a lesser degree, chondrocytes in articular cartilage. These results provide optimism that AAV vectors can be effectively adapted for gene delivery to large human joints affected by OA.

Summary Reasons for performing study: Sildenafil, a phosphodiesterase-5 inhibitor vasodilator, increases cGMP concentrations by inhibiting enzymatic degradation. Marketed to treat erectile dysfunction in men, it also reduces pulmonary arterial pressure (PAP). Because it reduces PAP, sildenafil may enhance performance and/or prevent exercise induced-pulmonary haemorrhage (EIPH). Objective: To determine if sildenafil citrate administration altered commonly measured indices of performance or reduced EIPH in exercised horses. Methods: Thirteen athletically conditioned Thoroughbred horses (2 mares and 11 geldings, age 3–12 years) were administered sildenafil citrate or placebo in 2 crossover design exercise testing studies. In a step-wise test to exhaustion, inspired/expired gas analysis, blood lactate, heart rate, runtime and bronchoalveolar lavage (BAL) cytology were measured. In a 13 m/s test to exhaustion, blood lactate, heart rate, runtime, BAL cytology and pulmonary arterial pressure were measured. Data were analysed with paired and unpaired t tests, one-way ANOVA and Tukey's pair-wise multiple comparison and Friedman repeated measure analysis of variance on ranks. Results: The administration of sildenafil did not alter mean inspired/expired gas measurements, plasma lactate concentrations or acute pulmonary haemorrhage in either exercise test or pulmonary arterial pressure measurement in the 13 m/s trial. Heart rates in both stress tests were significantly different at submaximal speeds and during the early recovery period. Run time was not affected by sildenafil administration in the step-wise trial (P = 0.622) or in the 13 m/s trial (P = 0.059). Conclusions: Sildenafil did not alleviate pulmonary haemorrhage or enhance performance-related indices in these trials. Sildenafil administration altered cardiovascular adaptation to intense exercise as evidenced by altered heart rates at submaximal speeds and post exercise. The effect of these alterations on other performance perimeters was not evident.

Partial hospitalization is a service modality that some have suggested is incompatible with both evidence-based and recovery-oriented treatment. The purpose of this study was to examine the accuracy of this assumption. Toward this end, a specific partial hospitalization program was examined using administrative data, self-reports regarding recovery orientation, and fidelity ratings from independent assessors. Findings support that the partial hospitalization program studied has reasonable lengths of stay, provides recovery-oriented services, and has implemented evidence-based practices. We conclude that partial hospitalization programs have the potential to become part of an evidence-based and recovery-oriented system.

Adrenergic activity accompanies intense exercise and mediates physiological and metabolic responses to exercise. Guanabenz, an antihypertensive drug marketed for human usage, depresses brain vasomotor and cardioaccelerator centres, blocks peripherally adrenergic neurons and is reportedly used as a calming agent in horses but little is known of its effects in the species.To determine if guanabenz induces measurable signs of adrenergic suppression on fit Thoroughbred horses undergoing intense exercise.In a random crossover design, 12 exercise conditioned Thoroughbred horses each received guanabenz (0.08 mg/kg bwt i.v.) and placebo at 3-week intervals. An incremental exercise test to exhaustion on a treadmill followed treatment by 1 h. Heart rate, oxygen consumption, carbon dioxide production, plasma lactate, catecholamines, adrenocorticotropic hormone (ACTH) and cortisol, and time to fatigue were monitored. Statistical analysis was performed using mixed-effects linear modelling.Mean heart rate during the exercise period was lower in guanabenz-treated horses (P = 0.04). Mean concentrations of plasma cortisol (P = 0.02) and adrenaline (P = 0.03) were lower for guanabenz-treated horses during the exercise period. Mean run time was slightly but not significantly longer for guanabenz-treated horses, (P = 0.053). No significant effects of guanabenz administration were found for oxygen consumption, carbon dioxide production nor for plasma lactate, noradrenaline and ACTH concentrations.Guanabenz administration induced signs of adrenergic suppression including plasma cortisol and adrenaline concentrations and heart rate and may enhance endurance, but did not eliminate increases in hormone concentrations induced by exercise. Clear determination of a positive performance effect of adrenaline, but not noradrenaline, suppression is needed before clinical significance can be determined.

Objective—To determine the effects of a dose of caffeine (2.5 mg/kg, IV) administered to physically fit Thoroughbreds during incremental exercise testing to fatigue on a treadmill. Animals—10 conditioned Thoroughbreds. Procedure—Horses were randomly assigned to receive caffeine or a control solution. Each horse received both treatments in a crossover design with a 3-week interval between treatments. Each horse was administered caffeine (2.5 mg/kg) or an equivalent amount of a control solution IV. One hour after injection, each horse performed an incremental exercise test to exhaustion. Hematologic values, heart rate, oxygen consumption, carbon dioxide production, plasma lactate concentration, urine and serum concentrations of caffeine and metabolites, and time until exhaustion were monitored. Statistical analysis was performed by use of a mixed-effects linear model. Results—Significant differences in measured values when horses were treated with caffeine or the control solution were not detected. Conclusions and Clinical Relevance—A dose of caffeine (2.5 mg/kg, IV) appears to have no effect on any performance variable of physically fit Thoroughbreds during incremental exercise testing to fatigue. (Am J Vet Res 2005;66:569–573)

Objectives: To estimate the economic efficiency of tight blood pressure control, with angiotensin converting enzyme inhibitors or beta blockers, compared with less tight control in hypertensive patients with type 2 diabetes. Design: Cost effectiveness analysis incorporating within trial analysis and estimation of impact on life expectancy through use of the within trial hazards of reaching a defined clinical end point. Use of resources driven by trial protocol and use of resources in standard clinical practice were both considered. Setting: 20 hospital based clinics in England, Scotland, and Northern Ireland. Subjects: 1148 hypertensive patients with type 2 diabetes from UK prospective diabetes study randomised to tight control of blood pressure (n=758) or less tight control (n=390). Main outcome measure: Cost effectiveness ratios based on (a) use of healthcare resources associated with tight control and less tight control and treatment of complications and (b) within trial time free from diabetes related end points, and life years gained. Results: Based on use of resources driven by trial protocol, the incremental cost effectiveness of tight control compared with less tight control was cost saving. Based on use of resources in standard clinical practice, incremental cost per extra year free from end points amounted to £1049 (costs and effects discounted at 6% per year) and £434 (costs discounted at 6% per year and effects not discounted). The incremental cost per life year gained was £720 (costs and effects discounted at 6% per year) and £291 (costs discounted at 6% per year and effects not discounted). Conclusions: Tight control of blood pressure in hypertensive patients with type 2 diabetes substantially reduced the cost of complications, increased the interval without complications and survival, and had a cost effectiveness ratio that compares favourably with many accepted healthcare programmes.

Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features, and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would die differed markedly from those who would survive. The different profiles of proteins and metabolites clustered into fatty acid transport and β-oxidation, gluconeogenesis and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of seven metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.

Objective—To determine effects of leukotriene (LT) C4 on ion transport across equine tracheal epithelium. Sample—Tracheal epithelium from cadavers of 24 horses considered free of respiratory tract disease. Procedures—Mucosae were mounted into Ussing chambers, and short-circuit current (Isc) was monitored over time. Effects of LTC4 were examined for various conditions, including addition of amiloride (10μM) to the mucosal bath solution, addition of bumetanide (10μM) to the serosal bath solution, addition of barium (1mM) to the serosal bath solution, and substitution of gluconate for chloride and HEPES for bicarbonate in bath solutions. Electrolyte transport was assessed via 22Na and 36Cl isotope fluxes. Results—Addition of LTC4 (50nM) to the serosal bath solution caused an increase in Isc for basal conditions and a larger increase after pretreatment with amiloride. The increase was negated in part by the addition of bumetanide to the serosal bath solution and further reduced by substitution of HEPES for bicarbonate in bath solutions. Remaining current was reduced to values less than those before treatment with LTC4 by the addition of barium to the serosal solution. There was a small increase in Isc after the addition of amiloride and substitution of gluconate for chloride. Radioisotope flux indicated that addition of LTC4 to the serosal bath solution increased chloride secretion and reduced sodium absorption. Conclusions and Clinical Relevance—LTC4 stimulated chloride secretion through a predominately bumetanide-sensitive pathway, with a smaller contribution from a bicarbonate-dependent pathway. Thus, LTC4 appears to be a potential mediator of airway hypersecretion in horses.

End of project report It is now well established that rape-seed oil can provide a sustainable source of renewable fuel for diesel engines. The main problem is a high viscosity and vaporisation temperature, which could lead to pumping, atomisation and combustion difficulties. These problems can be overcome in either of two ways: by further processing of the oil to improve its pumping and combustion properties (usually achieved by esterification and layer separation to produce biodiesel) or by some peripheral modifications to the engine to allow it to cope with the more viscous fuel. Engine conversion kits for this purpose are widely available. The second option has attractions in Ireland, at least in the short-term, for a number of reasons. Plants can be established quickly, and so could make an immediate if small contribution to the achievement of Ireland’s substitution target in the Transport Biofuels Directive (Commission of European Communities, 2003). The small operating scale of coldpressing oil extraction plants could be achieved without undue difficulty, and the capital investment required to launch such a project is relatively low. In the event of a biodiesel plant being established at some stage in the future, the option of sourcing some of the oil requirement from these extraction plants would still be available. This study was commissioned by Sustainable Energy Ireland. The complete report has been published on their web-site (www.sei.ie).

End of Project Report The three separate components with parallel objectives to this programme were to: 1. Develop technologies for conserving and optimally feeding alternative/complimentary feedstuffs to grass silage. 2. Quantify the use and re-use of plastic sheeting or film used to seal ensiled feedstuffs or mulch maize, and evaluate some new options. 3. Develop computer programs that will facilitate investigating prototype models of forage-based beef production systems.

Despite ongoing controversy, there has never been a large-scale, prospective study of the cognitive effects of electroconvulsive therapy (ECT). We conducted a prospective, naturalistic, longitudinal study of clinical and cognitive outcomes in patients with major depression treated at seven facilities in the New York City metropolitan area. Of 751 patients referred for ECT with a provisional diagnosis of a depressive disorder, 347 patients were eligible and participated in at least one post-ECT outcome evaluation. The primary outcome measures, Modified Mini-Mental State exam scores, delayed recall scores from the Buschke Selective Reminding Test, and retrograde amnesia scores from the Columbia University Autobiographical Memory Interview-SF (AMI-SF), were evaluated shortly following the ECT course and 6 months later. A substantial number of secondary cognitive measures were also administered. The seven sites differed significantly in cognitive outcomes both immediately and 6 months following ECT, even when controlling for patient characteristics. Electrical waveform and electrode placement had marked cognitive effects. Sine wave stimulation resulted in pronounced slowing of reaction time, both immediately and 6 months following ECT. Bilateral (BL) ECT resulted in more severe and persisting retrograde amnesia than right unilateral ECT. Advancing age, lower premorbid intellectual function, and female gender were associated with greater cognitive deficits. Thus, adverse cognitive effects were detected 6 months following the acute treatment course. Cognitive outcomes varied across treatment facilities and differences in ECT technique largely accounted for these differences. Sine wave stimulation and BL electrode placement resulted in more severe and persistent deficits.

peer-reviewed This study involved an evaluation of the changes in grain yield, nutritive value, ensilability and harvesting losses of intensively managed winter cereals harvested during the advancing stages of ripening. Five cereal crops (barley cv. Regina and wheat cv. Madrigal in 2001; barley cv. Regina, wheat cv. Falstaff and triticale cv. Fidelio in 2002) were assessed. Twenty plots per crop were arranged in a randomised complete block design, with five times of harvest (four for barley in 2002) and four replicate blocks per harvest. Dry matter (DM) yields changed relatively little between harvest dates, but fresh yields declined (P < 0.001) over time due to the moisture loss associated with ripening. Time-course changes in indices of nutritive value, such as concentrations of crude protein, starch and ash, and organic matter digestibility, were relatively small and did not follow a consistent pattern. Ensilability indices, such as DM and watersoluble carbohydrate concentrations and buffering capacity, indicated that satisfactory fermentations were likely if such crops were ensiled; buffering capacity, generally declining with advancing maturity. Harvesting losses were not clearly related to growth stage at harvest. It is concluded that winter cereal grain (barley, wheat and triticale) DM yields and quality were relatively constant as ripening progressed from DM concentrations of around 550 to >800 g/kg. One of the authors (P.S.) was in receipt of a Teagasc Walsh Fellowship.

End of Project Report The use of recovered vegetable oil (RVO) and tallow as vehicle fuels was investigated. Two options were considered; use in unprocessed form in specially adapted engines, and the production of biodiesel for use in unmodified engines. Two vehicles were modified to allow the use of RVO as fuel. Their performance in terms of power and fuel economy was acceptable, but fuel filter blockage problems would need to be resolved and long-term effects on engine life investigated before this approach could be recommended. Tallow with high free-fatty-acid content was esterified by a two-stage process that could be used in a simple plant and produce biodiesel of reasonable quality. High ester yields were obtained in laboratory and pilot-scale trials. Problems of layer separation remain to be resolved, and the process needs to be streamlined to allow a high throughput to be achieved. In comparing the costs of these fuels with each other and with mineral diesel, allowance must be made for any differences in fuel economy and for the cost of engine conversion kits. Including these items, the use of RVO in a converted engine would have a slightly lower cost than its use as biodiesel. Biodiesel from tallow is likely to be more expensive than from RVO if either ester yield or plant capacity is significantly reduced.

Background Clinical trials indicate that electroconvulsive therapy (ECT) is the most effective treatment for major depression, but its effectiveness in community settings has not been examined. Methods In a prospective, naturalistic study involving 347 patients at seven hospitals, clinical outcomes immediately after ECT and over a 24-week follow-up period were examined in relation to patient characteristics and treatment variables. Results The sites differed markedly in patient features and ECT administration but did not differ in clinical outcomes. In contrast to the 70%–90% remission rates expected with ECT, remission rates, depending on criteria, were 30.3%–46.7%. Longer episode duration, comorbid personality disorder, and schizoaffective disorder were associated with poorer outcome. Among remitters, the relapse rate during follow-up was 64.3%. Relapse was more frequent in patients with psychotic depression or comorbid Axis I or Axis II disorders. Only 23.4% of ECT nonremitters had sustained remission during follow-up. Conclusions The remission rate with ECT in community settings is substantially less than that in clinical trials. Providers frequently end the ECT course with the view that patients have benefited fully, yet formal assessment shows significant residual symptoms. Patients who do not remit with ECT have a poor prognosis; this underscores the need to achieve maximal improvement with this modality.

End of Project Report Trials were carried out over a three-year period in Oak Park to compare airinduction with conventional nozzles for weed control in sugar beet. Two makes of low-drift nozzle (Bubble Jet and DriftBETA) were compared with conventional fans. All nozzles were used at a pressure of 3 bar. Two sizes (015 and 03) of each type of nozzle were used, to allow volumes of 110 and 220 litres per hectare to be applied. These nozzles were used to apply two-spray programmes to sugar-beet crops. In four of the weed control trials, tank mixes of products with some residual action (Progress, Goltix, Venzar and Debut) were used. In the other two trials, a contact-only spray (Betanal E) was used. The aim was to see how the nozzles behaved with contact-only sprays as well as those with more complex modes of action. Spray drift was also measured with the size 03 nozzles. Spray drift reductions from 37% to 64% were measured when the air-induction nozzles were compared with conventional fans. In general, the tank mix programme gave better weed control than the contact-only treatments. Within programmes, differences between the application methods were significant in two trials. In both of these, the conventional nozzles gave the best results. Looking at the mean results of the tank-mix trials, two trends were suggested: higher water volumes gave slightly better weed control, and the effect of the coarser sprays was slight. With the contact-only sprays, the decline in performance with the coarser sprays was more emphatic, and the lower volumes appeared to give slightly better control. It is concluded that in calm conditions conventional fan or cone nozzles should continue to be used, but that air-induction nozzles are a valuable fall-back when it is necessary to spray in a moderate breeze. In these situations, and with the normal tank-mix programmes, small nozzle sizes applying very low volumes should be avoided. Makes of air-induction nozzle which give very coarse spray should also be avoided.

End of Project Report Field and farm trials were carried out between 1996 and 2000 to determine the efficacy of the NegFry and Met. Éireann decision support systems (DSS) in controlling late blight of potatoes compared with routine fungicide treatments. The trials were also used to determine the potential of the systems to reduce fungicide inputs. Hardi International

End of Project Report The mapping of within-field crop yield variations offers a basis for the adjustment of input application rates to match yield potential. The aim of this project was to examine available yield mapping components and systems, and to assess the benefits that could accrue from yield mapping. The work also included site investigations of possible causes of yield reduction, and an evaluation of the potential increase in profitability from variable-rate N application. Yield mapping requires the continuous measurement of harvester position and grain yield. Accurate positioning was achieved with systems which received a remote correction signal via communications satellite. A grain flow meter in the clean grain elevator gave low errors in conditions where the deflector plate could be kept clean. The production of useful yield maps was sometimes limited by rainy weather leading to wet crops, lodging, and big variations in harvest conditions within the field. Difficulties are also presented by small, irregularly-shaped fields. The level of within-field variation in cereal yields (25% of the field area at least 21% below the mean) suggests that there is scope for identifying low-yielding areas and either taking corrective action or applying reduced inputs. An analysis of the results of N fertiliser trials suggests a potential gain from about £20/ha in sugar beet to less than £10/ha in spring barley if N application rate could be varied to apply the optimum amount to each area within a field. All the costs of application map development and variable-rate application would need to fall below these gains to justify the use of the technology. To allow further use to be made of yield maps, it is desirable that the factors responsible for yield reduction be identified, in particular those which recur each year. In the present study, soil chemical analysis and compaction affected yield in only a small proportion of cases. Differences between maps from successive years have been small. It is concluded that the immediate financial benefits from the use of this technology will be small. However, in a future where the recording, justification and minimisation of inputs such as pesticides and fertiliser will grow in significance, and where the cost of the equipment and software will continue to fall, yield mapping and variable-rate input application will find a useful role.

End of Project Report The aim of this work was to see whether the introduction of diploid varieties, with their more erect leaf growth, would require any adjustment of the traditional plant spacing and row width recommendations for sugar beet. Five trials were carried out in 1996-98 in which the diploid variety Celt was sown at three row widths: 51, 56 and 61 cm. At each row width, seed spacings were adjusted to give four plant densities between 30,000 and 89,000 plants/ha. In four of the trials, field establishment was between 75 and 90%. In these trials, there was a slight increase in sugar yield with population up to 75,000 plants/ha, and little or no change above this level. There was a slight increase in extractability at higher populations, but not sufficient to have a significant effect on extractable sugar yield. In one trial where plant establishment was reduced by very cold weather, yield and sugar content continued to increase up to the highest plant count of 65,000 plants/ha. Over the five trials, there were no yield or quality differences between 51- and 56-cm rows. There was a reduction of 3.5% in extractable sugar yield in 61-cm rows, though this reached statistical significance in only one trial. Taking into account the high emergence that is normally achieved with diploid varieties, these results suggest that no change should be made to the seed spacings currently recommended for triploid varieties. For those using 61-cm rows, a small yield increase could probably be achieved by reducing row width. Teagasc acknowledges the support of Irish Sugar plc and Sugar Beet Levy Farmer Funds in the financing of this project

End of Project Report As part of a programme to assess bio-diesel production from low-cost materials, the availability of waste oils and fats in Ireland and the EU was assessed, and the behaviour of their esters in vehicles was measured. The utilisation of beef tallow from BSE risk organisms was given special attention. Esterification of high-FFA tallow required the use of excess methanol and base catalyst. Acidification, followed by glycerol separation and secondary acid-catalysed esterification, brought ester yields up to acceptable levels. The high melting point of the ester restricted its use in vehicles to low proportions in mixes with mineral diesel. Fuels made up from low-cost esters behaved well in vehicle trials, even where there was a high level of dilution of the engine oil. The only problems arose from inadequate low-temperature properties and from suspended solids in the tallow ester. Within the EU, there are sufficient waste oils and fats available to greatly increase bio-diesel production. In Ireland, there is sufficient for a small production unit.