Preliminary study of proton magnetic resonance spectroscopy to assess bone marrow adiposity in the third metacarpus or metatarsus in Thoroughbred racehorses

Background: Magnetic resonance spectroscopy (MRS) has been used to investigate metabolic changes within human bone. It may be possible to use MRS to investigate bone metabolism and fracture risk in the distal third metacarpal/tarsal bone (MC/MTIII) in racehorses. Objectives: To determine the feasibility of using MRS as a quantitative imaging technique in equine bone by using the 1H spectra for the MC/MTIII to calculate fat content (FC). Study Design: Observational cross-sectional study Methods: Limbs from Thoroughbred racehorses were collected from horses that died or were subjected to euthanasia on racecourses. Each limb underwent magnetic resonance imaging (MRI) at 3T followed by single-voxel MRS at 3 regions of interest (ROI) within MC/MTIII (lateral condyle, medial condyle, proximal bone marrow (PBM)). Percentage FC was calculated at each ROI. Each limb underwent computed tomography (CT) and bone mineral density (BMD) was calculated for the same ROIs. All MR and CT images were graded for sclerosis. Histology slides were graded for sclerosis and proximal marrow space was calculated. Pearson or Spearman correlations were used to assess the relationship between BMD, FC and marrow space. Kruskall-Wallis tests were used to check for differences between sclerosis groups for BMD or FC. Results: Eighteen limbs from 10 horses were included. A negative correlation was identified for mean BMD and FC for the lateral condyle (correlation coefficient =-0.60, p=0.01) and PBM (correlation coefficient =-0.5, p=0.04). There was a significant difference between median BMD for different sclerosis grades in the condyles on both MRI and CT. A significant difference in FC was identified between sclerosis groups in the lateral condyle on MRI and CT . Main Limitations: Small sample size. Conclusions: 1H Proton MRS is feasible in the equine MC/MTIII. Further work is required to evaluate the use of this technique to predict fracture risk in racehorses

Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control

Signature of effective mass in crackling noise asymmetry

Crackling noise is a common feature in many dynamic systems [1-9], the most familiar instance of which is the sound made by a sheet of paper when crumpled into a ball. Although seemingly random, this noise contains fundamental information about the properties of the system in which it occurs. One potential source of such information lies in the asymmetric shape of noise pulses emitted by a diverse range of noisy systems [8-12], but the cause of this asymmetry has lacked explanation [1]. Here we show that the leftward asymmetry observed in the Barkhausen effect [2] - the noise generated by the jerky motion of domain walls as they interact with impurities in a soft magnet - is a direct consequence of a magnetic domain wall's negative effective mass. As well as providing a means of determining domain wall effective mass from a magnet's Barkhausen noise our work suggests an inertial explanation for the origin of avalanche asymmetries in crackling noise phenomena more generally.Comment: 13 pages, 4 figures, to appear in Nature Physic

Impact of Scottish smoke-free legislation on smoking quit attempts and prevalence

<p><b>Objectives:</b> In Scotland, legislation was implemented in March 2006 prohibiting smoking in all wholly or partially enclosed public spaces. We investigated the impact on attempts to quit smoking and smoking prevalence.</p> <p><b>Methods:</b> We performed time series models using Box-Jenkins autoregressive integrated moving averages (ARIMA) on monthly data on the gross ingredient cost of all nicotine replacement therapy (NRT) prescribed in Scotland in 2003–2009, and quarterly data on self-reported smoking prevalence between January 1999 and September 2010 from the Scottish Household Survey.</p> <p><b>Results:</b> NRT prescription costs were significantly higher than expected over the three months prior to implementation of the legislation. Prescription costs peaked at £1.3 million in March 2006; £292,005.9 (95% CI £260,402.3, £323,609, p<0.001) higher than the monthly norm. Following implementation of the legislation, costs fell exponentially by around 26% per month (95% CI 17%, 35%, p<0.001). Twelve months following implementation, the costs were not significantly different to monthly norms. Smoking prevalence fell by 8.0% overall, from 31.3% in January 1999 to 23.7% in July–September 2010. In the quarter prior to implementation of the legislation, smoking prevalence fell by 1.7% (95% CI 2.4%, 1.0%, p<0.001) more than expected from the underlying trend.</p> <p><b>Conclusions:</b> Quit attempts increased in the three months leading up to Scotland's smoke-free legislation, resulting in a fall in smoking prevalence. However, neither has been sustained suggesting the need for additional tobacco control measures and ongoing support.</p&gt

Supersymmetric 3-branes on smooth ALE manifolds with flux

We construct a new family of classical BPS solutions of type IIB supergravity describing 3-branes transverse to a 6-dimensional space with topology R^2*ALE. They are characterized by a non-trivial flux of the supergravity 2-forms through the homology 2-cycles of a generic smooth ALE manifold. Our solutions have two Killing spinors and thus preserve N=2 supersymmetry. They are expressed in terms of a quasi harmonic function H (the ``warp factor''), whose properties we study in the case of the simplest ALE, namely the Eguchi-Hanson manifold. The equation for H is identified as an instance of the confluent Heun equation. We write explicit power series solutions and solve the recurrence relation for the coefficients, discussing also the relevant asymptotic expansions. While, as in all such N=2 solutions, supergravity breaks down near the brane, the smoothing out of the vacuum geometry has the effect that the warp factor is regular in a region near the cycle. We interpret the behavior of the warp factor as describing a three-brane charge ``smeared'' over the cycle and consider the asymptotic form of the geometry in that region, showing that conformal invariance is broken even when the complex type IIB 3-form field strength is assumed to vanish. We conclude with a discussion of the basic features of the gauge theory dual.Comment: latex, 36 pages (26 + appendix). Some statements on the gauge dual made more precise. Final version to appear on NP

Orientifolds and the Refined Topological String

We study refined topological string theory in the presence of orientifolds by counting second-quantized BPS states in M-theory. This leads us to propose a new integrality condition for both refined and unrefined topological strings when orientifolds are present. We define the SO(2N) refined Chern-Simons theory which computes refined open string amplitudes for branes wrapping Seifert three-manifolds. We use the SO(2N) refined Chern-Simons theory to compute new invariants of torus knots that generalize the Kauffman polynomials. At large N, the SO(2N) refined Chern-Simons theory on the three-sphere is dual to refined topological strings on an orientifold of the resolved conifold, generalizing the Gopakumar-Sinha-Vafa duality. Finally, we use the (2,0) theory to define and solve refined Chern-Simons theory for all ADE gauge groups

Sunscreens - Which and what for?

It is well established that sun exposure is the main cause for the development of skin cancer. Chronic continuous UV radiation is believed to induce malignant melanoma, whereas intermittent high-dose UV exposure contributes to the occurrence of actinic keratosis as precursor lesions of squamous cell carcinoma as well as basal cell carcinoma. Not only photocarcinogenesis but also the mechanisms of photoaging have recently become apparent. In this respect the use of sunscreens seemed to prove to be more and more important and popular within the last decades. However, there is still inconsistency about the usefulness of sunscreens. Several studies show that inadequate use and incomplete UV spectrum efficacy may compromise protection more than previously expected. The sunscreen market is crowded by numerous products. Inorganic sunscreens such as zinc oxide and titanium oxide have a wide spectral range of activity compared to most of the organic sunscreen products. It is not uncommon for organic sunscreens to cause photocontact allergy, but their cosmetic acceptability is still superior to the one given by inorganic sunscreens. Recently, modern galenic approaches such as micronization and encapsulation allow the development of high-quality inorganic sunscreens. The potential systemic toxicity of organic sunscreens has lately primarily been discussed controversially in public, and several studies show contradictory results. Although a matter of debate, at present the sun protection factor (SPF) is the most reliable information for the consumer as a measure of sunscreen filter efficacy. In this context additional tests have been introduced for the evaluation of not only the protective effect against erythema but also protection against UV-induced immunological and mutational effects. Recently, combinations of UV filters with agents active in DNA repair have been introduced in order to improve photoprotection. This article reviews the efficacy of sunscreens in the prevention of epithelial and nonepithelial skin cancer, the effect on immunosuppression and the value of the SPF as well as new developments on the sunscreen market. Copyright (C) 2005 S. Karger AG, Basel

Cytochrome P450 CYP1B1 activity in renal cell carcinoma

Renal cell carcinoma (RCC) is the most common malignancy of the kidney and has a poor prognosis due to its late presentation and resistance to current anticancer drugs. One mechanism of drug resistance, which is potentially amenable to therapeutic intervention, is based on studies in our laboratory. CYP1B1 is a cytochrome P450 enzyme overexpressed in a variety of malignant tumours. Our studies are now elucidating a functional role for CYP1B1 in drug resistance. Cytochrome P450 reductase (P450R) is required for optimal metabolic activity of CYP1B1. Both CYP1B1 and P450R can catalyse the biotransformation of anticancer drugs at the site of the tumour. In this investigation, we determined the expression of CYP1B1 and P450R in samples of normal kidney and RCC (11 paired normal and tumour and a further 15 tumour samples). The O-deethylation of ethoxyresorufin to resorufin was used to measure CYP1B1 activity in RCC. Cytochrome P450 reductase activity was determined by following the reduction of cytochrome c at 550 nm. The key finding of this study was the presence of active CYP1B1 in 70% of RCC. Coincubation with the CYP1B1 inhibitor alpha-naphthoflavone (10nM) inhibited this activity. No corresponding CYP1B1 activity was detected in any of the normal tissue examined (n = 11). Measurable levels of active P450R were determined in all normal (n = 11) and tumour samples (n = 26). The presence of detectable CYP1B1, which is capable of metabolising anticancer drugs in tumour cells, highlights a novel target for therapeutic intervention

Association between critical care admission and 6-month functional outcome after spontaneous intracerebral haemorrhage

BACKGROUND: There is uncertainty about the clinical benefit of admission to critical care after spontaneous intracerebral haemorrhage (ICH). PURPOSE: We investigated factors associated with critical care admission after spontaneous ICH and evaluated associations between critical care and 6-month functional outcome. METHODS: We included 825 patients with acute spontaneous non-traumatic ICH, recruited to a prospective multicenter observational study. We evaluated the characteristics associated with critical care admission and poor 6-month functional outcome (modified Rankin Scale, mRS > 3) using univariable (chi-square test and Wilcoxon rank-sum test, as appropriate) and multivariable analysis. RESULTS: 286 patients (38.2%) had poor 6-month functional outcome. Seventy-seven (9.3%) patients were admitted to critical care. Patients admitted to critical care were younger (p < 0.001), had lower GCS score (p < 0.001), larger ICH volume (p < 0.001), more often had intraventricular extension (p = 0.008) and underwent neurosurgery (p < 0.001). Critical care admission was associated with poor functional outcome at 6 months (39/77 [50.7%] vs 286/748 [38.2%]; p = 0.034); adjusted OR 2.43 [95%CI 1.36-4.35], p = 0.003), but not with death (OR 1.29 [95%CI 0.71-2.35; p = 0.4). In ordinal logistic regression, patients admitted to critical care showed an OR 1.47 (95% CI 0.98-2.20; p = 0.07) for a shift in the 6-month modified Rankin Scale. CONCLUSIONS: Admission to critical care is associated with poor 6-month functional outcome after spontaneous ICH but not with death. Patients admitted to critical care were a priori more severely affected. Although adjusted for main known predictors of poor outcome, our findings could still be confounded by unmeasured factors. Establishing the true effectiveness of critical care after ICH requires a randomised trial with clinical outcomes and quality of life assessments

Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin

Pathological processes involved in the initiation of rheumatoid synovitis remain unclear. We undertook the present study to identify immune and stromal processes that are present soon after the clinical onset of rheumatoid arthritis ( RA) by assessing a panel of T cell, macrophage, and stromal cell related cytokines and chemokines in the synovial fluid of patients with early synovitis. Synovial fluid was aspirated from inflamed joints of patients with inflammatory arthritis of duration 3 months or less, whose outcomes were subsequently determined by follow up. For comparison, synovial fluid was aspirated from patients with acute crystal arthritis, established RA and osteoarthritis. Rheumatoid factor activity was blocked in the synovial fluid samples, and a panel of 23 cytokines and chemokines measured using a multiplex based system. Patients with early inflammatory arthritis who subsequently developed RA had a distinct but transient synovial fluid cytokine profile. The levels of a range of T cell, macrophage and stromal cell related cytokines ( e. g. IL-2, IL-4, IL-13, IL-17, IL-15, basic fibroblast growth factor and epidermal growth factor) were significantly elevated in these patients within 3 months after symptom onset, as compared with early arthritis patients who did not develop RA. In addition, this profile was no longer present in established RA. In contrast, patients with non-rheumatoid persistent synovitis exhibited elevated levels of interferon-gamma at initiation. Early synovitis destined to develop into RA is thus characterized by a distinct and transient synovial fluid cytokine profile. The cytokines present in the early rheumatoid lesion suggest that this response is likely to influence the microenvironment required for persistent RA