VenUS III: a randomised controlled trial of therapeutic ultrasound in the management of venous leg ulcers.

OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of low-dose ultrasound delivered in conjunction with standard care against standard care alone in the treatment of hard-to-heal venous ulcers. DESIGN: A multicentre, pragmatic, two-armed randomised controlled trial with an economic evaluation. SETTING: Community nurse services; community leg ulcer clinics; hospital outpatient leg ulcer clinics, among both urban and rural settings in England, Scotland, Northern Ireland and Ireland. PARTICIPANTS: Patients with a venous leg ulcer of > 6 months' duration or > 5 cm2 and an ankle-brachial pressure index of ≥ 0.8. In total, 337 patients were recruited to the study. INTERVENTIONS: Participants in the intervention group received low-dose ultrasound (0.5 W/cm2) delivered at 1 MHz, pulsed pattern of 1 : 4, applied to periulcer skin (via a water-based contact gel) weekly for up to 12 weeks alongside standard care. Standard care consisted of low-adherent dressings and compression therapy, renewed as recommended by the patient's nurse and modified if required to reflect changes in ulcer and skin condition. The output of the ultrasound machines was checked every 3 months to confirm intervention fidelity. MAIN OUTCOME MEASURES: The primary end point was time to healing of the largest eligible ulcer (reference ulcer). Secondary outcomes were time to healing of all ulcers, proportion of patients healed, percentage and absolute change in ulcer size, proportion of time patients were ulcer free, cost of treatments, health-related quality of life (HRQoL), adverse events, withdrawal and loss to follow-up. RESULTS: There was a small, and statistically not significant, difference in the median time to complete ulcer healing of all ulcers in favour of standard care [median 328 days, 95% confidence interval (CI) 235 days, inestimable] compared with ultrasound (median 365 days, 95% CI 224 days, inestimable). There was no difference between groups in the proportion of patients with ulcers healed at 12 months (72/168 in ultrasound vs 78/169 standard care), nor in the change in ulcer size at 4 weeks. There was no evidence of a difference in recurrence of healed ulcers. There was no difference in HRQoL [measured using the Short Form questionnaire-12 items (SF-12)] between the two groups. There were more adverse events with ultrasound than with standard care. Ultrasound therapy as an adjuvant to standard care was found not to be a cost-effective treatment when compared with standard care. The mean cost of ultrasound was £197.88 (bias-corrected 95% CI -£35.19 to £420.32) higher than standard care per participant per year. There was a significant relationship between ulcer healing and area and duration at baseline. In addition, those centres with high recruitment rates had the highest healing rates. CONCLUSIONS: Low-dose ultrasound, delivered weekly during dressing changes, added to the package of current best practice (dressings, compression therapy) did not increase ulcer healing rates, affect quality of life (QoL) or reduce recurrence. It was associated with higher costs and more adverse events. There is no evidence that adding low-dose ultrasound to standard care for 'hard-to-heal' ulcers aids healing, improves QoL or reduces recurrence. It increases costs and adverse events. The relationship between ulcer healing rates and patient recruitment is worthy of further study. TRIAL REGISTRATION: Current Controlled Trials ISRCTN21175670. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 13. See the HTA programme website for further project information.

Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA.

OBJECTIVES: To review the evidence for the efficacy and safety of biological agents in patients with rheumatoid arthritis (RA) to provide data to develop treatment recommendations by the European League Against Rheumatism (EULAR) Task Force. METHODS: Medline, Embase and Cochrane databases were searched for relevant articles on infliximab (IFX), etanercept (ETN), adalimumab (ADA), certolizumab-pegol (CZP), golimumab (GLM), anakinra (ANA), abatacept (ABT), rituximab (RTX) and tocilizumab (TCZ) published between 1962 and February 2009; published abstracts from the 2007-2008 American College of Rheumatology (ACR) and EULAR conference were obtained. RESULTS: 87 articles and 40 abstracts were identified. In methotrexate (MTX) naïve patients, biological therapy with IFX, ETN, ADA, GLM or ABT has been shown to improve clinical outcomes (level of evidence 1B). In MTX/other synthetic disease-modifying antirheumatic drug (DMARD) failures all nine biological agents confer benefit (1B), with lower efficacy noted for ANA. RTX, ABT, TCZ and GLM demonstrate efficacy in tumour necrosis factor inhibitor (TNFi) failures (1B). Less evidence exists for switching between IFX, ETN and ADA (3B). Biological and MTX combination therapy is more efficacious than a biological agent alone (1B). A safety review shows no increased malignancy risk compared with conventional DMARDs (3B). TNFi are generally associated with an increased risk of serious bacterial infection, particularly within the first 6 months of treatment initiation; increased tuberculosis (TB) rates with TNFi are highest with the monoclonal antibodies (3B). CONCLUSIONS: There is good evidence for the efficacy of biological agents in patients with RA. Safety data confirm an increased risk of bacterial infection and TB with TNFi compared with conventional DMARDs.

VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers.

OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of larval therapy with a standard debridement technique (hydrogel). DESIGN: A pragmatic, three-arm, randomised controlled trial with an economic evaluation. SETTING: Community nursing services, community leg ulcer clinics and hospital outpatient leg ulcer clinics. A range of urban and rural settings. PARTICIPANTS: Patients with venous or mixed venous/arterial ulcers (minimum ankle brachial pressure index of 0.6) where a minimum of 25% of ulcer area was covered by slough and/or necrotic material. INTERVENTIONS: Loose larval therapy and bagged larval therapy compared with hydrogel. MAIN OUTCOME MEASURES: The primary end point was complete healing of the largest eligible ulcer. The primary outcome was time to complete healing of the reference ulcer. Secondary outcomes were: time to debridement, cost of treatments, health-related quality of life (including ulcer-related pain), bacterial load, presence of methicillin-resistant Staphylococcus aureus and staff and patient attitudes to and beliefs about larval therapy. RESULTS: Between July 2004 and May 2007 the trial recruited 267 people aged 20-94 years at trial entry. There were more female (n = 158) than male (n = 109) participants and most ulcers were classified by the nurse as having an area greater than 5 cm(2). The time to healing for the three treatment arms was compared using the log rank test. The difference in time to healing in the three treatments was not statistically significant at the 5% level. Adjustment was then made for stratification and prespecified prognostic factors (centre, baseline ulcer area, ulcer duration and type of ulcer) using a Cox proportional hazards model. No difference was found in healing rates between the loose and bagged larvae groups. Results for larvae (loose and bagged pooled) compared with hydrogel showed no evidence of a difference in time to healing. When the same analytical steps were used to investigate time to debridement, larvae-treated ulcers debrided significantly more rapidly than hydrogel-treated ulcers; however, the difference in time to debridement between loose and bagged larvae was not significant. The adjusted analysis reported the hazard of debriding at any time for those in loose and bagged larvae groups as approximately twice that of the hydrogel group. No differences in health-related quality of life or bacteriology were observed between trial arms. Larval therapy was associated with significantly more ulcer-related pain than hydrogel. Our base-case economic evaluation showed large decision uncertainty associated with the cost-effectiveness of larval therapy compared with hydrogel, suggesting that larval therapy and hydrogel therapy have similar costs and effects in the treatment of sloughy and/or necrotic leg ulcers. CONCLUSIONS: Larval therapy significantly reduced the time to debridement of sloughy and/or necrotic, chronic venous and mixed venous/arterial leg ulcers, compared with hydrogel; however, larval therapy did not significantly increase the rate of healing of the ulcers. It was impossible to distinguish between larval therapy and hydrogel in terms of cost-effectiveness. Future research should investigate the association of debridement and healing and the value of debridement as a clinical outcome for patients and clinicians. To inform decision-makers' selection of debriding agents where debridement is the treatment goal, decision analytic modelling of all alternative debridement treatments is required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55114812.

Population tobacco control interventions and their effects on social inequalities in smoking: systematic review.

OBJECTIVE: To assess the effects of population tobacco control interventions on social inequalities in smoking. DATA SOURCES: Medical, nursing, psychological, social science and grey literature databases, bibliographies, hand-searches and contact with authors. STUDY SELECTION: Studies were included (n = 84) if they reported the effects of any population-level tobacco control intervention on smoking behaviour or attitudes in individuals or groups with different demographic or socioeconomic characteristics. DATA EXTRACTION: Data extraction and quality assessment for each study were conducted by one reviewer and checked by a second. DATA SYNTHESIS: Data were synthesised using graphical ("harvest plot") and narrative methods. No strong evidence of differential effects was found for smoking restrictions in workplaces and public places, although those in higher occupational groups may be more likely to change their attitudes or behaviour. Smoking restrictions in schools may be more effective in girls. Restrictions on sales to minors may be more effective in girls and younger children. Increasing the price of tobacco products may be more effective in reducing smoking among lower-income adults and those in manual occupations, although there was also some evidence to suggest that adults with higher levels of education may be more price-sensitive. Young people aged under 25 are also affected by price increases, with some evidence that boys and non-white young people may be more sensitive to price. CONCLUSIONS: Population-level tobacco control interventions have the potential to benefit more disadvantaged groups and thereby contribute to reducing health inequalities.

Thyroid hormone concentrations in captive and free-ranging West Indian manatees (Trichechus manatus).

Because thyroid hormones play a critical role in the regulation of metabolism, the low metabolic rates reported for manatees suggest that thyroid hormone concentrations in these animals may also be reduced. However, thyroid hormone concentrations have yet to be examined in manatees. The effects of captivity, diet and water salinity on plasma total triiodothyronine (tT(3)), total thyroxine (tT(4)) and free thyroxine (fT(4)) concentrations were assessed in adult West Indian manatees (Trichechus manatus). Free-ranging manatees exhibited significantly greater tT(4) and fT(4) concentrations than captive adults, regardless of diet, indicating that some aspect of a captive existence results in reduced T(4) concentrations. To determine whether this reduction might be related to feeding, captive adults fed on a mixed vegetable diet were switched to a strictly sea grass diet, resulting in decreased food consumption and a decrease in body mass. However, tT(4) and fT(4) concentrations were significantly elevated over initial values for 19 days. This may indicate that during periods of reduced food consumption manatees activate thyroid-hormone-promoted lipolysis to meet water and energetic requirements. Alterations in water salinity for captive animals did not induce significant changes in thyroid hormone concentrations. In spite of lower metabolic rates, thyroid hormone concentrations in captive manatees were comparable with those for other terrestrial and marine mammals, suggesting that the low metabolic rate in manatees is not attributable to reduced circulating thyroid hormone concentrations.

Effects of capture on adrenal steroid and vasopressin concentrations in free-ranging bottlenose dolphins (Tursiops truncatus).

Marine mammals are routinely caught in the wild in an effort to monitor their health. However, capture-associated stress could potentially bias various biochemical parameters used to monitor the health of these wild caught animals. Therefore, the effects of capture were quantified by measuring plasma adrenal steroids and arginine vasopressin (AVP) in free-ranging bottlenose dolphins (Tursiops truncatus) (n=31). Total capture and restraint times were also correlated to hormone concentrations to quantify the effects of capture. Significant, positive correlations between corticosterone and cortisol (R=0.752; P<0.0001), and between corticosterone and aldosterone (R=0.441; P=0.045) were demonstrated. Significant correlations between capture and restraint time and hormone levels were not observed. Animals restrained for less than 20 min exhibited hormone levels similar to those for animals restrained for more than 20 min. The positive correlations among the adrenal steroids suggest that release of these steroids was stimulated by adrenocorticotropin (ACTH). The lack of a correlation between cortisol and AVP indicates that AVP did not influence ACTH-induced cortisol release in this situation. The study suggests that (1) a typical hypothalamic-pituitary-adrenal axis is present in these animals, and (2) the relatively short capture and restraint times did not induce a significant neuroendocrine stress response.

Comparison of elements in bottlenose dolphins stranded on the beaches of Texas and Florida in the Gulf of Mexico over a one-year period.

We analyzed tissue samples from bottlenose dolphins (Tursiops truncatus) that had stranded on beaches in Texas and Florida over a 1-year period starting in September 1991. The concentrations of 10 elements plus methyl mercury (MeHg) were determined in brain, kidney, and liver, and we examined these results for differences based upon age, site, sex, and tissue type. A strong inverse relationship between total mercury (Hg) and the percentage that was MeHg was found in liver, kidney, and brain tissue, presumably due to demethylation of MeHg. A threshold concentration was found for total Hg in brain tissue, indicating that most Hg was present as MeHg up to about 8 years of age. Increases in total Hg after this age were accompanied by an increase in the ratio of total Hg to MeHg, indicating demethylation. Strong relationships were found between total Hg in liver and age and between total Hg and selenium in liver, which have been observed before in many fish- and squid-eating marine mammals. The only difference based on sex of the animals was observed for MeHg, which was higher in females and contrary to the pattern often observed for organic contaminants. Several elements (copper, Hg, lead, zinc) exhibited intersite differences, which were not consistent. Bottlenose dolphin from Florida exhibited the highest levels of MeHg and total Hg, while animals from Texas exhibited the highest levels of lead, copper, and zinc. The essential elements copper and zinc were expected to be the same for the Texas and Florida animals; however, observed differences may indicate population differences in basic physiological levels, dietary intake, or health status.

Estimation of water turnover rates of captive West Indian manatees (Trichechus manatus) held in fresh and salt water.

The ability of West Indian manatees (Trichechus manatus) to move between fresh and salt water raises the question of whether manatees drink salt water. Water turnover rates were estimated in captive West Indian manatees using the deuterium oxide dilution technique. Rates were quantified in animals using four experimental treatments: (1) held in fresh water and fed lettuce (N=4), (2) held in salt water and fed lettuce (N=2), (3) acutely exposed to salt water and fed lettuce (N=4), and (4) chronically exposed to salt water with limited access to fresh water and fed sea grass (N=5). Animals held in fresh water had the highest turnover rates (145+/-12 ml kg-1 day-1) (mean +/- s.e.m.). Animals acutely exposed to salt water decreased their turnover rate significantly when moved into salt water (from 124+/-15 to 65+/-15 ml kg-1 day-1) and subsequently increased their turnover rate upon re-entry to fresh water (146+/-19 ml kg-1 day-1). Manatees chronically exposed to salt water had significantly lower turnover rates (21+/-3 ml kg-1 day-1) compared with animals held in salt water and fed lettuce (45+/-3 ml kg-1 day-1). Manatees chronically exposed to salt water and fed sea grass had very low turnover rates compared with manatees held in salt water and fed lettuce, which is consistent with a lack of mariposia. Manatees in fresh water drank large volumes of water, which may make them susceptible to hyponatremia if access to a source of Na+ is not provided.

Osmoregulation in wild and captive West Indian manatees (Trichechus manatus).

The ability of West Indian manatees (Trichechus manatus latirostris and Trichechus manatus manatus) to inhabit both freshwater and marine habitats presents an interesting model to study osmoregulation in sirenians. Blood samples were analyzed from manatees held in fresh- and saltwater and from wild animals captured in fresh-, brackish, and saltwater for concentrations of aldosterone, arginine vasopressin, plasma renin activity, Na+, K+, Cl-, and osmolality. Two separate experiments were also conducted on captive animals to evaluate osmoregulatory responses to acute saltwater exposure and freshwater deprivation. Spurious differences were observed in plasma electrolyte and osmolality among the captive and wild groups. Wild brackish water animals exhibited the highest vasopressin concentrations, while wild freshwater manatees had the highest aldosterone levels. A significant correlation between mean vasopressin and osmolality was demonstrated for captive and wild animals. When freshwater animals were acutely exposed to saltwater, osmolality, Na+, and Cl- increased 5.5%, 8.0%, and 14%, respectively, while aldosterone decreased 82.6%. Saltwater animals deprived of freshwater exhibited an almost twofold increase in aldosterone during the deprivation period and a fourfold decrease when freshwater was again provided. Within this group, osmolality increased significantly by 3.4% over the course of the study; however, electrolytes did not change. The lack of consistent differences in electrolyte and osmolality among wild and captive groups suggests that manatees are good osmoregulators regardless of the environment. The high aldosterone levels in wild freshwater animals may indicate a need to conserve Na+, while the high vasopressin levels in wild brackish-water manatees suggest an antidiuretic state to conserve water. Vasopressin levels appear to be osmotically mediated in manatees as in other mammals.

Morbilliviral epizootic in bottlenose dolphins of the Gulf of Mexico.

Morbillivirus infection was diagnosed in 35/67 bottlenose dolphins (Tursiops truncatus) from the Gulf of Mexico that stranded from October 1993 through April 1994 in Alabama, Mississippi, and Texas (USA) during periods of increased dolphin strandings in each of the 3 states. Diagnosis was based on histologic lesions, immunohistochemical demonstration of mobilliviral antigen, and detection of morbilliviral RNA by a reverse transcriptase polymerase chain reaction (RT-PCR) test performed on formalin-fixed, paraffin-embedded tissue (5 dolphins), on histologic lesions and detection of morbilliviral RNA by RT-PCR performed on formalin-fixed, paraffin-embedded tissue (1 dolphin), and on detection of morbilliviral RNA by RT-PCR performed on unfixed lung samples collected from carcasses with advanced postmortem autolysis (29 dolphins). Histologic lesions included proliferative interstitial pneumonia with syncytial cells and eosinophilic intranuclear and intracytoplasmic inclusion bodies, lymphoid depletion and syncytial cells with eosinophilic intranuclear inclusion bodies in lymph nodes, eosinophilic intracytoplasmic inclusion bodies in transitional epithelium of urinary bladder, and a syncytial cell with eosinophilic intranuclear inclusion bodies in epidermis. Concomitant pulmonary aspergillosis was diagnosed histologically in 4 dolphins. This is the 5th reported morbilliviral epizootic of aquatic mammals and the 2nd involving bottlenose dolphins in the United States.

Insulation and thermal balance of fasting harp and grey seal pups.

1. Harp and grey seal pups were examined during the post-weaning period to quantify their thermoregulatory abilities and thermal limits. 2. Deep body temperatures of harp seals (37.8 +/- 0.8 degrees C) were not significantly different from those of grey seals (38.9 +/- 0.4 degrees C). 3. As blubber depth declined during the fast, temperature gradients extended increasingly deeper into the muscle layer potentially decreasing heat loss. 4. Blubber conductivity (approximately 0.18 W/m/degrees C) did not vary regionally within an animal, or between animals or species. 5. Calculated lethal cold limits in air were between -85.4 degrees C and -116.1 degrees C, suggesting that fasting, weaned pups can easily cope with temperatures they would normally experience.

Sealpox in captive grey seals (Halichoerus grypus) and their handlers.

Histopathologic, ultrastructural, and negative-staining studies indicated that nodular lesions on the flippers, head, and necks of recently weaned, captive grey seals (Halichoerus grypus) were similar to sealpox lesions reported from several other species of seals. Virions associated with the nodules were characteristic of the parapoxvirus subgroup of pox viruses. Two of the three persons handling the seals developed nodular lesions similar to "milker's nodules," the characteristic lesion in persons infected with parapoxvirus. The clinical course of the parapoxvirus infection in both the grey seals and their handlers is described. It was concluded that although sealpox is transmissible to man, the mild clinical manifestations place it in the nuisance category of zoonotic diseases.