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Rayleigh wave ellipticity measurements from seismic ambient noise recorded on the Greenland Ice Sheet (GrIS) show complex and anomalous behavior at wave periods sensitive to ice (T < 3–4 s). To understand these complex observations, we compare them with synthetic ellipticity measurements obtained from synthetic ambient noise computed for various seismic velocity and attenuation models, including surface wave overtone effects. We find that in dry snow conditions within the interior of the GrIS, to first order the anomalous ellipticity observations can be explained by ice models associated with the accumulation and densification of snow into firn. We also show that the distribution of ellipticity measurements is strongly sensitive to seismic attenuation and the thermal structure of the ice. Our results suggest that Rayleigh wave ellipticity is well suited for monitoring changes in firn properties and thermal composition of the Greenland and Antarctic ice sheets in a changing climate. Plain Language Summary: Surface meltwater is increasingly being routed and distributed through the Greenland Ice Sheet (GrIS) changing the mechanical and thermal properties of the ice and resulting in accelerated ice flow. Here we observe complex and anomalous Rayleigh wave ellipticity measurements at periods sensitive to the ice structure. We compare our observations with ellipticity measurements made on simulated seismic noise for various seismic velocity and attenuation models. We demonstrate that in the interior of the GrIS the ellipticity is sensitive to the accumulation and densification of snow as it compacts into glacier ice. The variation in the measurements is strongly sensitive to the thermal structure of the ice sheet which we estimate to be warmer than about −10°. These results demonstrate that Rayleigh wave ellipticity is well suited for monitoring changes in firn properties and thermal composition of the Greenland and Antarctic ice sheets in a changing climate. Key Points: Densification of snow into firn has a first order effect on ellipticity measurements at periods sensitive to the iceThe distribution of ellipticity measurements is sensitive to the thermal composition of the iceEllipticity is a promising method for long term monitoring of ice properties and thickness beneath the seismic station [ABSTRACT FROM AUTHOR]

The JUpiter ICy moons Explorer (JUICE) of the European Space Agency will investigate Jupiter and its icy moons Europa, Ganymede, and Callisto, with the aim to better understand the origin and evolution of our Solar System and the emergence of habitable worlds around gas giants. The Particle Environment Package (PEP) on board JUICE is designed to measure neutrals and ions and electrons at thermal, suprathermal, and radiation belt energies (eV to MeV). In the vicinity of Callisto, PEP will characterize the plasma environment, the outer parts of Callisto's atmosphere and ionosphere and their interaction with Jupiter's dynamic magnetosphere. Roughly 20 Callisto flybys with closest approaches between 200 and 5,000 km altitude are planned over the course of the JUICE mission. In this article, we review the state of the art regarding Callisto's ambient environment and magnetospheric interaction with recent modeling efforts for Callisto's atmosphere and ionosphere. Based on this review, we identify science opportunities for the PEP observations to optimize scientific insight gained from the foreseen JUICE flybys. These considerations will inform both science operation planning of PEP and JUICE and they will guide future model development for Callisto's atmosphere, ionosphere, and their interaction with the plasma environment. Key Points: Particle Environment Package (PEP) on JUpiter ICy moons Explorer (JUICE) will provide in situ and remote measurements of Callisto's atmosphere and its space environment during ∼20 flybysWe investigate operation plans and instrument capabilities to optimize science return from PEP observationsThe interactions of the atmosphere with the space environment and surface are complex and must be further analyzed in preparation for JUICE [ABSTRACT FROM AUTHOR]

The Pre‐Industrial climate model simulation is intended as an equilibrium control experiment that uses constant external forcing, yet in the Coupled Model Intercomparison Project Phase 6 (CMIP6) model HadGEM3‐GC31‐LL a distinct change in climate state occurs around year 500 of the 2000 year simulation. The global mean near surface air temperature increases by almost 0.5 K associated with a reduction in southern hemisphere sea ice area of almost 20%. Here we show this step change in the state of the climate to be a consequence of the onset of deep convection in the Weddell and Ross Sea gyres. The delayed onset of convection in the gyres is a consequence of a positive, downward, top‐of‐atmosphere radiative balance, and continual ocean heat up‐take during the model spin‐up and the initial pre‐industrial control simulation. Consequently, model spin‐up strategy should be revised to initialize pre‐industrial simulations that are in energy balance. Plain Language Summary: The Pre‐industrial control simulation of climate models is a reference for climate change simulations. Consequently it should simulate a stable climate. However, if the model is not in radiative equilibrium, the ocean continually accumulates heat, becoming unstable at high latitudes and generating large climate fluctuations. This results in a control simulation that is not a steady state. Consequently the methodologies used to initialize and formulate climate models should be revised to ensure a steady state is achieved. Key Points: The long timescales associated with deep ocean heat uptake suggests simulations may not be equilibriated before forcing is perturbedSouthern Ocean venting of heat reduces sea ice cover and increases global mean temperature, leading to a warmer climate stateNet top‐of‐atmosphere energy imbalance can have implications for the methodologies used for climate model spin‐up [ABSTRACT FROM AUTHOR]

We investigate a possible negative ion feature observed by the Cassini Plasma Spectrometer (CAPS) during a flyby of Saturn's moon Dione that occurred on 7 April 2010. By examining possible particle trajectories, we find that the observed particles are consistent with negative pickup ions originating near the moon's surface. We find that the mass of the negative pickup ions is in the range of 15–25 u and tentatively identify this species as O−, likely resulting from ionization and subsequent pickup from Dione's O2‐CO2 exosphere. Our estimates show that the negative ion density is ~3 × 10−3 cm−3. This is comparable to, but slightly smaller than, that previously reported for the density of O2+ pickup ions for the same flyby, indicating that negative pickup ions may represent a major loss channel for Dione's exosphere. Key Points: Analysis of data from the Cassini Plasma Spectrometer confirms negative pickup ions originating from Saturn's moon DioneThe negative pickup ions are consistent with O− originating from Dione's exosphereDensity estimates indicate that negative pickup ions may represent a significant loss channel for Dione's exosphere [ABSTRACT FROM AUTHOR]

The inner boundary of Saturn's electron radiation belts, near the planet's A ring (∼2.27 Rs), is studied using Cassini's proximal orbit measurements. We find that variable convective flows transport energetic electrons to the A ring, which absorbs them instantaneously, forming the inner belt boundary. These flows are also responsible for a variable and longitudinally asymmetric boundary configuration. Prenoon, the boundary oscillates toward and away from the A ring with a 2‐week period. Postnoon, it maps persistently near the F ring (∼2.32 Rs) and coexists with localized MeV electron intensity enhancements (microbelts). We propose that the microbelts contain electrons in drift resonance with corotation, trapped in local time‐confined trajectories, which result from the aforementioned convective flows. The microbelts' collocation with the F ring implies either a local, secondary electron production due to galactic cosmic ray collisions with F ring dust or an enhanced resonant electron trapping due to an electrodynamic interaction between the F ring and Saturn's magnetosphere. Plain Language Summary: The material density of Saturn's main rings is large enough to instantaneously remove even the highest energy particles of the planet's radiation belts that come in contact with them. Even though this interaction does not sound trivial, Cassini observations indicate the opposite. The transition between Saturn's electron radiation belts and the Saturn's A ring, the outermost component of the main rings, was crossed 45 times during Cassini's final orbits. In all cases, the expected signature of electron depletion by the rings was observed but only twice this depletion mapped on the outer edge of the A ring. All other times, it was found several thousand kilometers away from its expected location. On certain areas in the afternoon sector of the radiation belts, the dropout was preceded by an unexpected, sharp increase of high‐energy electron intensities, which we named microbelts. Both the microbelts and the electron depletions map closer to Saturn's F ring, a highly structured, narrow ring of Saturn. The study investigates the topological properties of the microbelts and the electron belt depletion to demonstrate that the ring belts transition likely combines complex electron flows and a local F ring‐driven electron source that make its structure much more complex than ever anticipated. Key Points: The radial transport of energetic electrons onto Saturn's rings is dominated by convectionThe F ring contains regions of MeV electron pileup evolving separately from Saturn's electron beltsThe F ring may be both a source and a sink of energetic electrons [ABSTRACT FROM AUTHOR]

Background: There are few controlled studies of the effect of different doses of vitamin D3 on bone mineral density (BMD).Objectives: We conducted a randomized placebo-controlled trial of increasing doses of vitamin D3 in 163 Caucasian and 31 African American women with serum 25-hydroxyvitamin D (25OHD) ≤50 nmol/L. This is an analysis of secondary outcome BMD to see if there is an association between percent change in BMD and dose of vitamin D3.Methods: Participants were randomly assigned to placebo, vitamin D3 400, 800, 1600, 2400, 3200, 4000, or 4800 IU/day; calcium supplements, average 600mg, were given to provide a total calcium intake of 1200 mg/d. The primary outcome was 12-month serum 25OHD level. Analysis methods include ANOVA and Pearson correlations.Results: The mean percent increase (±SD) in BMD at 12 months for all women was small; total body, 0.62% (± 2.72), femoral neck 0.59% (±3.58) and spine 0.43% (±2.80). There was no difference in BMD or serum N-telopeptide in response to vitamin D by dose or race. The increase in total body, spine and hip BMD in elderly women given vitamin D doses between 400 and 4800 IU daily and calcium supplementation is small, unrelated to dose or 12-month serum 25OHD, free 25OHD or 1,25(OH)2D. There was no evidence of a threshold change in BMD with increasing serum 25OHD or free 25OHD in this population.Conclusions: We found no significant effect of daily vitamin D dose ranging from 400 to 4800 IU/day on BMD or serum N-terminal telopeptides in elderly women with initially low serum 25OHD. [ABSTRACT FROM AUTHOR]

Abstract: Saturn's largest icy moon, Rhea, hosts a tenuous surface‐sputtered exosphere composed primarily of molecular oxygen and carbon dioxide. In this Letter, we examine Cassini Plasma Spectrometer velocity space distributions near Rhea and confirm that Cassini detected nongyrotropic fluxes of outflowing CO 2 + during both the R1 and R1.5 encounters. Accounting for this nongyrotropy, we show that these possess comparable along‐track densities of ∼2 × 10−3 cm−3. Negatively charged pickup ions, also detected during R1, are surprisingly shown as consistent with mass 26 ± 3 u which we suggest are carbon‐based compounds, such as CN−, C 2 H −, C 2 −, or HCO−, sputtered from carbonaceous material on the moon's surface. The negative ions are calculated to possess along‐track densities of ∼5 × 10−4 cm−3 and are suggested to derive from exogenic compounds, a finding consistent with the existence of Rhea's dynamic CO2 exosphere and surprisingly low O2 sputtering yields. These pickup ions provide important context for understanding the exospheric and surface ice composition of Rhea and of other icy moons which exhibit similar characteristics. [ABSTRACT FROM AUTHOR]

Background and purpose Intracerebral hemorrhage ( ICH) is a devastating cerebrovascular disorder with high morbidity and mortality. Minocycline is a matrix metalloproteinase-9 ( MMP-9) inhibitor that may attenuate secondary mechanisms of injury in ICH. The feasibility and safety of minocycline in ICH patients were evaluated in a pilot, double-blinded, placebo-controlled randomized clinical trial. Methods Patients with acute onset (<12 h from symptom onset) ICH and small initial hematoma volume (<30 ml) were randomized to high-dose (10 mg/kg) intravenous minocycline or placebo. The outcome events included adverse events, change in serial National Institutes of Health Stroke Scale score assessments, hematoma volume and MMP-9 measurements, 3-month functional outcome (modified Rankin score) and mortality. Results A total of 20 patients were randomized to minocycline ( n = 10) or placebo ( n = 10). The two groups did not differ in terms of baseline characteristics. No serious adverse events or complications were noted with minocycline infusion. The two groups did not differ in any of the clinical and radiological outcomes. Day 5 serum MMP-9 levels tended to be lower in the minocycline group (372 ± 216 ng/ml vs. 472 ± 235 ng/ml; P = 0.052). Multiple linear regression analysis showed that minocycline was associated with a 217.65 (95% confidence interval −425.21 to −10.10, P = 0.041) decrease in MMP-9 levels between days 1 and 5. Conclusions High-dose intravenous minocycline can be safely administered to patients with ICH. Larger randomized clinical trials evaluating the efficacy of minocycline and MMP-9 inhibition in ICH patients are required. [ABSTRACT FROM AUTHOR]

Background and purpose The Beagley-Gibson ( BG) grading system utilizes microtopographical skin changes to generate an individualized, objective estimate of cumulative, lifetime ultraviolet radiation ( UVR) exposure. However, predictors of BG grade are ill-defined, particularly in older populations. The aim of this cross-sectional study was to describe the factors associated with skin damage as measured by the BG method in 835 community-dwelling older adults. Methods Study participants aged 53-83 years had silicone casts taken from the dorsum of both hands and graded by the BG method. Lifetime sun exposure, skin phenotypic traits and smoking status were assessed by questionnaire. 25-hydroxyvitamin D and melanin density were measured using radioimmunoassay and spectrophotometry, respectively. Ordered logistic regression was used to compute a single odds ratio ( OR) by taking BG grade as the outcome variable. Results Higher 25-hydroxyvitamin D was associated with increasing BG grade ( OR = 1.39, P = 0.02) in adjusted analysis. Age ( OR = 1.14, P < 0.001), occupational sun exposure ( OR = 1.62, P < 0.001), ability to tan ( OR = 1.40, P < 0.001), melanin density ( OR=0.79, P = 0.001), lifetime leisure time sun exposure ( OR = 1.21, P = 0.004), current smoking ( OR = 1.82, P = 0.007), propensity to sunburn ( OR = 1.18, P = 0.016), and waist-hip ratio ( OR = 1.10, P = 0.02) were independent predictors of BG grade. Hair colour, number of sunburns, body mass index and gender were not independent predictors of BG grade. Conclusions Beagley-Gibson skin cast grade is a biologically relevant marker of UVR exposure in older adults influenced by both intrinsic and extrinsic factors. [ABSTRACT FROM AUTHOR]

Objective: To determine the associations between body adiposity and change in serum 25-(OH)D levels over 2.6 years, and if these associations are mediated by metabolic and inflammatory factors in older adults.Methods: This is a longitudinal study of 859 randomly selected subjects (mean 62 years, range 51-80, 49% women). Serum 25-hydroxyvitamin D [25-(OH)D] was assessed by radioimmunoassay at baseline and 2.6 years later. Baseline serum level of leptin was assessed by radioimmunoassay and interleukin (IL)-6 by a chemiluminescent immunoassay in the first 183 subjects.Results: In multivariable analyses, body mass index, trunk fat percentage and waist-to-hip ratio were significant predictors of increased incident vitamin D deficiency [a 25-(OH)D < 50 nmol L⁻¹ at follow-up when ≥50 nmol L⁻¹ at baseline] and decreased recovery of vitamin D deficiency [a 25-(OH)D ≥ 50 nmol L⁻¹ at follow-up when < 50 nmol L⁻¹ at baseline]. Change in 25-(OH)D levels per annum was also independently predicted by baseline leptin (β: -0.09/unit, 95% CI: -0.17, -0.03), IL-6 (β: -0.68/quartile, 95% CI: -1.35, -0.02) and total cholesterol/high-density lipoprotein (HDL) ratio (β: -0.51, 95% CI: -0.88, -0.14). The associations between body adiposity measures and change in 25-(OH)D completely disappeared after adjustment for leptin, diminished after adjustment for IL-6, but remained unchanged after adjustment for total cholesterol/HDL ratio. All associations were independent of season and sun exposure.Conclusions: Body fat is not simply a passive reservoir for 25-(OH)D. In addition to season and sun exposure, 25-(OH)D levels appear to be determined by metabolic and, to a lesser extent, inflammatory factors, and these appear to mediate the effects of adiposity on change in 25-(OH)D. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Large-scale expansion of no-take closures within the Great Barrier Reef has not enhanced fisheries production," by W. J. Fletcher and colleagues in the 2015 issue.

An abstract of the article "Three cases of cervical distortion secondary to incarceration of a retroverted gravid uterus: ultrasound features and management challenges" by I. Babic is presented.

Background Post-operative recurrence of Crohn's disease is an important management challenge, with 2-year recurrence rates defined by clinical, endoscopic and radiological parameters of up to 77%, 64% and 49%. Clinical and severe endoscopic recurrence vary widely in controlled trials from 13% to 36% and 22% to 56% with thiopurine treatment or 0% and 9% with infliximab treatment respectively at 1 year. Aims To provide a review of the evidence for thiopurine or anti- TNF use in post-operative Crohn's disease, and to assess the ability to identify those patients at highest risk of recurrent disease. Methods A literature search was undertaken using Medline, Embase and Cochrane databases to identify studies using search terms 'thiopurine', 'azathioprine', 'mercaptopurine', 'Infliximab', 'adalimumab', 'Anti- TNF', 'Crohn's disease', 'post-operative' and 'recurrence'. Results Trials to examine this important area have proved difficult to execute, with recruitment and retention of patients posing major challenges to randomised clinical trials. There have been four RCTs of 433 patients of thiopurine therapy (with three meta-analyses of these data), and one of anti- TNF therapy involving 24 patients. Overall the efficacy data for thiopurine use in this setting are inconclusive, and other than smoking, there are no consistent predictors of post-operative relapse. Conclusions At present, evidence for routine use of thiopurine treatment in post-operative Crohn's disease is heterogeneous and unconvincing. Stratification by risk of relapse emerges as a key challenge in post-operative management that needs to be addressed, using clinical parameters and emerging biomarkers. The evidence for prophylactic anti- TNF use is limited though promising, with its routine use guided by early assessment of relapse. [ABSTRACT FROM AUTHOR]

Objective Foot pain is a common complaint in adults. Increased BMI and fat mass have been linked only to foot pain prevalence. Therefore, a longitudinal study to examine the relationship between body composition and incident foot pain over 3 years was conducted. Design and Methods Sixty-one community dwelling participants from a previous study of musculoskeletal health, who did not have foot pain at study inception in 2008, were invited to take part in this follow-up study in 2011. Current foot pain was determined using the Manchester Foot Pain and Disability Index, and body composition was measured using dual X-ray absorptiometry at study baseline. Results Of the 51 respondents (84% response rate, 37 females and 14 males), there were 11 who developed foot pain. BMI ranged from underweight to morbidly obese (17-44 kg/m2), mean 27.0 ± 6.0 kg/m2. Incident foot pain was positively associated with both fat mass (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.03-1.20) and fat-mass index (OR 1.28, 95% CI 1.04-1.57) in multivariate analysis. Conclusions Fat mass is a predictor of incident foot pain. This study supports the notion that incident foot pain in overweight individuals is associated with fat mass rather than body mass alone. [ABSTRACT FROM AUTHOR]

Sedimentation is a substantial threat to aquatic ecosystems and a primary cause of habitat degradation on near-shore coral reefs. Although numerous studies have demonstrated major impacts of sedimentation and turbidity on corals, virtually nothing is known of the sensitivity of reef fishes. Planktivorous fishes are an important trophic group that funnels pelagic energy sources into reef ecosystems. These fishes are visual predators whose foraging is likely to be impaired by turbidity, but the threshold for such effects and their magnitude are unknown. This study examined the effect of sediment-induced turbidity on foraging in four species of planktivorous damselfishes (Pomacentridae) of the Great Barrier Reef, including inshore and offshore species that potentially differ in tolerance for turbidity. An experimental flow tunnel was used to quantify their ability to catch mobile and immobile planktonic prey under different levels of turbidity and velocity in the range encountered on natural and disturbed reefs. Turbidity of just 4 NTU (nephelometric turbidity units) reduced average attack success by up to 56%, with higher effect sizes for species with offshore distributions. Only the inshore species (Neopomacentrus bankieri), which frequently encounters this turbidity on coastal reefs, could maintain high prey capture success. At elevated turbidity similar to that found on disturbed reefs (8 NTU), attack success was reduced in all species examined by up to 69%. These reductions in attack success led to a 21-24% decrease in foraging rates for all mid to outer-shelf species, in spite of increasing attack rates at high turbidity. Although effects of turbidity varied among species, it always depended heavily on prey mobility and ambient velocity. Attack success was up to 14 times lower on mobile prey, leaving species relatively incapable of foraging on anything but immobile prey at high turbidity. Effects of turbidity were particularly prominent at higher velocities, as attack success was overall 20-fold lower and foraging rates 3.3-fold lower at flow velocities >30 cm/s relative to <10 cm/s. Given that many planktivorous reef fishes predominantly occupy exposed, high-flow habitats, these results provide a reasonable explanation for the lack of planktivores on inshore coral reefs and warn that the performance of visual predators could be impaired at turbidity levels of only 4 NTU. [ABSTRACT FROM AUTHOR]

Phosphodiesterases ( PDEs) are critical regulatory enzymes in cyclic nucleotide signaling. PDEs have diverse expression patterns within the central nervous system ( CNS), show differing affinities for cyclic adenosine monophosphate ( cAMP) and cyclic guanosine monophosphate ( cGMP), and regulate a vast array of behaviors. Here, we investigated the expression profile of the PDE8 gene family members Pde8a and Pde8b in the mouse brain. We find that Pde8a expression is largely absent in the CNS; by contrast, Pde8b is expressed in select regions of the hippocampus, ventral striatum, and cerebellum. Behavioral analysis of mice with Pde8b gene inactivation ( PDE8B KO) demonstrate an enhancement in contextual fear, spatial memory, performance in an appetitive instrumental conditioning task, motor-coordination, and have an attenuation of age-induced motor coordination decline. In addition to improvements observed in select behaviors, we find basal anxiety levels to be increased in PDE8B KO mice. These findings indicate that selective antagonism of PDE8B may be an attractive target for enhancement of cognitive and motor functions; however, possible alterations in affective state will need to be weighed against potential therapeutic value. [ABSTRACT FROM AUTHOR]

Objective To investigate health researchers' attitudes to involving the public in research. Background Public involvement in research is encouraged by the Department of Health in the UK. Despite this, the number of health researchers actively involving the public in research appears to be limited. There is little research specifically addressing the attitudes of health researchers towards involving the public: how they interpret the policy, what motivates and de-motivates them and what their experiences have been to date. Design A qualitative research design, using semi-structured telephone interviews. Setting and participants Fifteen purposively sampled UK-based University health researchers were the participants. Interviews were conducted over the telephone. Findings The participants suggested varying constructions of public involvement in research. Arguments based on moral and political principles and consequentialist arguments for involving the public in research were offered and most participants highlighted the potential benefits of involving the public. However, feelings of apprehension expressed by some participants imply that a number of researchers may still be uncomfortable with involving the public, as it presents a different way of working. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the associations between serum levels of vitamin D, sunlight exposure, and knee cartilage loss cross-sectionally and longitudinally in older adults. METHODS: A total of 880 randomly selected subjects (mean age 61 years [range 51-79 years], 50% women) were studied at baseline, and 353 of these subjects were studied 2.9 years later. Serum levels of 25-hydroxyvitamin D (25[OH]D) were assessed by radioimmunoassay, and sunlight exposure was assessed by questionnaire. T1-weighted fat-suppressed magnetic resonance imaging (MRI) of the right knee was performed to determine knee cartilage volume and defects. Knee radiographic osteoarthritis (OA) and knee pain were also assessed. RESULTS: The mean 25(OH)D serum level was 52.8 nmoles/liter at baseline (range 13-119 nmoles/liter). Winter sunlight exposure and serum 25(OH)D level were both positively associated with medial and lateral tibial cartilage volume, and a serum 25(OH)D level <50 nmoles/liter was associated with increased medial tibiofemoral joint space narrowing (all P < 0.05). Longitudinally, baseline serum 25(OH)D level predicted change in both medial and lateral tibial cartilage volume (beta = +0.04% per annum per nmole/liter for both; P < 0.05), and change in serum 25(OH)D level was positively associated with change in medial tibial cartilage volume. These associations were consistent in subjects with radiographic OA and knee pain and/or in women, but not in men or in subjects without radiographic OA or knee pain. CONCLUSION: Sunlight exposure and serum 25(OH)D levels are both associated with decreased knee cartilage loss (assessed by radiograph or MRI). This is best observed using the whole range of 25(OH)D levels rather than predefined cut points and implies that achieving vitamin D sufficiency may prevent and/or retard cartilage loss in knee OA. [ABSTRACT FROM AUTHOR]

Background and purpose:M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M1 mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs.Experimental approach:In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology.Key results:Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration.Conclusions and implications:These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.British Journal of Pharmacology (2008) 154, 1104–1115; doi:10.1038/bjp.2008.152; published online 5 May 2008 [ABSTRACT FROM AUTHOR]

The ATP-binding cassette A1 (ABCA1) protein regulates plasma high-density lipoprotein (HDL) levels. Mutations in ABCA1 can cause HDL deficiency and increase the risk of premature coronary artery disease. Single nucleotide polymorphisms (SNPs) in ABCA1 are associated with variation in plasma HDL levels. We investigated the prevalence of mutations and common SNPs in ABCA1 in 154 low-HDL individuals and 102 high-HDL individuals. Mutations were identified in five of the low-HDL subjects, three having novel variants (I659V, R2004K, and A2028V) and two with a previously identified variant (R1068H). Analysis of four SNPs in the ABCA1 gene promoter (C-564T, G-407C, G-278C, and C-14T) identified the C-14T SNP and the TCCT haplotype to be over-represented in low-HDL individuals. The R1587K SNP was over-represented in low-HDL individuals, and the V825I and I883M SNPs over-represented in high-HDL individuals. We conclude that sequence variation in ABCA1 contributes significantly to variation in HDL levels. [ABSTRACT FROM AUTHOR]

Background and Purpose: Oxidative stress may be involved in the development of abdominal aortic aneurysms (AAAs). Previous studies indicate that antioxidants protect against AAA formation during chronic angiotensin (Ang) II infusion in apolipoprotein E-deficient (ApoE(0)) mice. We here examine if these protective effects also occurred in aged ApoE(0) mice.Experimental Approach: Male ApoE(0) mice (50-60 weeks) were randomly divided into 4 groups: saline, Ang II (1000 ng kg(-1) min(-1) for 4 weeks), Ang II plus antioxidants (0.1% vitamin E in food plus 0.1% vitamin C in drinking water), and Ang II plus losartan (30 mg kg(-1) day(-1)).Key Results: Exogenous Ang II increased systolic blood pressure by 40 mmHg and resulted in the formation of pseudoaneurysms (rupture and extramural haematoma) in the abdominal aorta in 50% of animals. True aneurysmal dilatation was rarely observed. Antioxidants decreased systemic oxidative stress (plasma malondialdehyde), but had only minor effects on aortic rupture, relative to the complete prevention by losartan. Immunohistochemistry revealed strong matrix metalloproteinase-9 (MMP-9) expression in atherosclerotic plaques and at the sites of rupture. Antioxidants did not affect tumour necrosis factor-alpha-stimulated MMP-9 release from U937 cells. In addition, antioxidants had little effects on Ang II-induced renal dysfunction.Conclusions and Implications: In contrast to previous findings in younger mice, antioxidants had only minor effects on Ang II-induced aortic rupture in aged mice. Our results demonstrate that the pathological features of the aneurysmal remodelling induced by Ang II in old ApoE(0) mice are distinct from those of human AAA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The significance of asymptomatic knee cartilage defects in healthy individuals is not known. The aim of this study was to examine the association between cartilage defects in the knee and cartilage volume both cross-sectionally and longitudinally in healthy, middle-age adults. METHODS: Eighty-six healthy men and women (mean +/- SD age 53.8 +/- 8.8 years) underwent T1-weighted fat-suppressed magnetic resonance imaging of their dominant knees at baseline and at the 2-year followup visit. Knee cartilage volume was measured. Cartilage defects were scored according to a grading system (0-4) and as present (a defect score of > or = 2) or absent in the medial and lateral tibiofemoral compartments. RESULTS: Cartilage defects in the medial and lateral tibiofemoral compartments were very common (in 61% and 43% of subjects, respectively). Those with cartilage defects had a 25% reduction in medial tibial cartilage volume, a 15% reduction in lateral tibial cartilage volume, and a 19% reduction in total femoral cartilage volume relative to those with no cartilage defects in cross-sectional analyses (all P < 0.05). In the medial tibiofemoral compartment, the annual loss of tibial cartilage in those with cartilage defects was 2.5% (95% confidence interval [95% CI] 2.2%, 3.1%) compared with an annual loss of tibial cartilage of 1.3% (95% CI 0.5%, 2.0%) in those with no defects (P = 0.028), independent of other known risk factors for osteoarthritis (OA). CONCLUSION: These data suggest that the presence of asymptomatic, non-full-thickness medial tibiofemoral cartilage defects identifies healthy individuals most likely to lose knee cartilage in the absence of radiographic knee OA. Thus, interventions aimed at reducing or reversing cartilage defects may reduce the risk of subsequent knee OA. [ABSTRACT FROM AUTHOR]

1. Patterns of torpor, arousal and activity in free-living Greater Horseshoe Bats, Rhinolophus ferrumequinum (Schreber), were investigated during the hibernation period by using temperature-sensitive radio-transmitters. 2. Torpor bouts varied between 0·1 and 11·8 days, with individual means ranging from 1·3 to 7·4 days. Torpor bout duration decreased with increasing ambient temperature. 3. Activity duration varied from 37 min to 54 h 24 min, with individual means ranging from 2 : 29 to 8 : 58 h. Activity duration increased with ambient temperatures above approximately 10 °C. 4. Ten of 11 bats synchronized their arousals with dusk. The circadian rhythm of one bat showed a free-running pattern over a period of about 5 weeks. Arousals were more highly synchronized, and closer to dusk, in individuals with lower body condition. 5. That bats forage in mild weather is supported by the strong synchronization of arousals with dusk, especially in bats with low body condition. 6. Patterns of torpor and subsequent activity are consistent with predictions that torpor lasts until a critical metabolic or water imbalance is achieved. Because metabolism and water loss are temperature-dependent, torpor bout duration decreases with increasing temperature. The imbalance is corrected during subsequent activity, which is relatively constant in duration until a temperature threshold of 10 °C, above which increasing levels of foraging lead to longer activity bouts. [ABSTRACT FROM AUTHOR]

This review discusses the feasibility of an HIV vaccine and describes the history, efficacy and potential to succeed of old and new vaccine concepts. [ABSTRACT FROM AUTHOR]

We investigated intraspecific differences in evening emergence time of northern bats Eptesicus nilssonii, greater horseshoe bats Rhinolophus ferrumequinum and lesser horseshoe bats R. hipposideros. Significant differences in emergence time were associated with presumed variation in predation risk, related to light intensity, and energetic benefits of early emergence, caused by differences in age, reproductive state (energetic demands), and body condition. Females of both species emerged progressively later as pregnancy advanced, perhaps because of decreased flight performance, and earlier as lactation proceeded, probably because of increased energy demands and low reserves. Bats under energetic stress, due to persistent low ambient temperatures during pregnancy, or when body reserves were low, emerged relatively early, and hence appeared to take higher risks, than other bats. Young bats emerged much later than the adults at first, but progressively earlier as their flight skills improved. Lesser horseshoe bats emerged later at exposed roost exits than in more protected situations. The results largely corroborate the hypothesis that emergence time, and therefore feeding performance, of insectivorous bats is constrained at bright light conditions, possibly by predation risk (from birds), and modified by energetic considerations. [ABSTRACT FROM AUTHOR]