Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis. METHODS: We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18-65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348. FINDINGS: 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was significantly lower in patients in the simvastatin group (0·288% per year [SD 0·521]) than in those in the placebo group (0·584% per year [0·498]). The adjusted difference in atrophy rate between groups was -0·254% per year (95% CI -0·422 to -0·087; p=0·003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]). INTERPRETATION: High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing. FUNDING: The Moulton Foundation [charity number 1109891], Berkeley Foundation [268369], the Multiple Sclerosis Trials Collaboration [1113598], the Rosetrees Trust [298582] and a personal contribution from A Pidgley, UK National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme.

Ungulate herbivory alters leaf functional traits and recruitment of regenerating aspen.

Herbivory by ungulates can affect forest regeneration success, but its long-term impacts on tree function and recruitment are less studied. We evaluated strategies of resistance, tolerance and vertical escape against ungulate herbivory by evaluating leaf traits (photosynthesis, morphology and chemistry) and growth rates of aspen in the presence and absence of ungulate herbivores 1, 2, 3 and 26 years after fires initiated aspen suckering. Over the initial 3-year period, ~60% of aspen stems in unfenced plots showed evidence of being browsed by ungulates. After 3 years, aspen in unfenced plots had smaller leaves, were 50% shorter, and had 33% lower nonstructural carbohydrate concentrations and 33% greater concentrations of condensed tannins, when compared with fenced aspen. Aspen exposed to ungulate herbivory over a 26-year period maintained smaller leaves, had lower annual radial growth rates and were still below the critical height threshold of 2 m required to escape ungulate herbivory for successful recruitment. In contrast, the average height of aspen protected from ungulates was approaching 6 m. Over the 26-year period leaves in unfenced plots had 41% lower nonstructural carbohydrate concentrations and greater expression of defense compounds-condensed tannins (63%) and phenolic glycosides (102%)-than leaves in fenced plots. Photosynthetic rates were slightly higher in aspen that experienced ungulate browsing, suggesting that changes in leaf anatomy and chemistry due to ungulate herbivory did not interfere with photosynthesis. Our data suggest that ungulate browsing increases investment in chemical defense, lowers nonstructural carbohydrate concentrations and reduces leaf area, which decreases the recruitment potential of regenerating aspen.

Postfire soil water repellency in piñon-juniper woodlands: Extent, severity, and thickness relative to ecological site characteristics and climate.

Wildfires can create or intensify water repellency in soil, limiting the soil's capacity to wet and retain water. The objective of this research was to quantify soil water repellency characteristics within burned piñon-juniper woodlands and relate this information to ecological site characteristics. We sampled soil water repellency across forty-one 1,000 m2 study plots within three major wildfires that burned in piñon-juniper woodlands. Water repellency was found to be extensive-present at 37% of the total points sampled-and strongly related to piñon-juniper canopy cover. Models developed for predicting SWR extent and severity had R2adj values of 0.67 and 0.61, respectively; both models included piñon-juniper canopy cover and relative humidity the month before the fire as coefficient terms. These results are important as they suggest that postfire water repellency will increase in the coming years as infilling processes enhance piñon-juniper canopy cover. Furthermore, reductions in relative humidity brought about by a changing climate have the potential to link additively with infilling processes to increase the frequency and intensity of wildfires and produce stronger water repellency over a greater spatial extent. In working through these challenges, land managers can apply the predictive models developed in this study to prioritize fuel control and postfire restoration treatments.