Evaluation of the influence of kyphosis and scoliosis on intervertebral disc extrusion in French bulldogs

Although thoracic vertebral malformations with kyphosis and scoliosis are often considered incidental findings on diagnostic imaging studies of screw-tailed brachycephalic breeds, they have been suggested to interfere with spinal biomechanics and intervertebral disc degeneration. It is however unknown if an abnormal spinal curvature also predisposes dogs to develop clinically relevant intervertebral disc herniations. The aim of this study was to evaluate if the occurrence of thoracic vertebral malformations, kyphosis or scoliosis would be associated with a higher prevalence of cervical or thoracolumbar intervertebral disc extrusion in French bulldogs

Efficacy of Fluoxetine, Riluzole and Amiloride in treating neuropathic pain associated with secondary progressive multiple sclerosis. Pre-specified analysis of the MS-SMART double-blind randomised placebo-controlled trial

BACKGROUND: Evidence-based treatment of pain in people with MS presents a major unmet need. OBJECTIVE: We aimed to establish if use of Fluoxetine, Riluzole or Amiloride improved neuropathic pain outcomes in comparison to placebo, in adults with secondary progressive MS participating in a trial of these putative neuroprotectants. METHODS: In pre-specified secondary analyses of the MS SMART phase-2b double-blind randomised controlled trial (NCT01910259), we analyzed reports of neuropathic pain, overall pain, and pain interference. Multivariate analyses included adjustment for baseline pain severity. Additionally, we explored associations of pain severity with clinical and MRI brain imaging variables. RESULTS: 445 Participants were recruited from 13 UK neuroscience centres. We found no statistically significant benefit of active intervention on any rating of neuropathic pain, or pain overall. Compared to placebo, adjusted mean difference in pain intensity was 0.38 (positive values favouring placebo, 95%CI -0.30 to 1.07, p = 0.27) for Amiloride; 0.52 (-0.17 to 1.22, p = 0.14) for Fluoxetine; and 0.40 (-0.30 to 1.10, p = 0.26) for Riluzole. Pain severity was positively correlated with depressive symptoms (Spearman correlation 0.19, 95%CI 0.10-0.28) and fatigue (Rho 0.30, 95%CI 0.20-0.39). CONCLUSION: Use of Fluoxetine, Riluzole or Amiloride was not associated with improvement in neuropathic pain symptoms, in comparison to placebo

A 50% Reduction of Excitability but Not of Intercellular Coupling Affects Conduction Velocity Restitution and Activation Delay in the Mouse Heart

Computer simulations suggest that intercellular coupling is more robust than membrane excitability with regard to changes in and safety of conduction. Clinical studies indicate that SCN5A (excitability) and/or Connexin43 (Cx43, intercellular coupling) expression in heart disease is reduced by approximately 50%. In this retrospective study we assessed the effect of reduced membrane excitability or intercellular coupling on conduction in mouse models of reduced excitability or intercellular coupling. Epicardial activation mapping of LV and RV was performed on Langendorff-perfused mouse hearts having the following: 1) Reduced excitability: Scn5a haploinsufficient mice; and 2) reduced intercellular coupling: Cx43(CreER(T)/fl) mice, uninduced (50% Cx43) or induced (10% Cx43) with Tamoxifen. Wild type (WT) littermates were used as control. Conduction velocity (CV) restitution and activation delay were determined longitudinal and transversal to fiber direction during S(1)S(1) pacing and S(1)S(2) premature stimulation until the effective refractory period. In both animal models, CV restitution and activation delay in LV were not changed compared to WT. In contrast, CV restitution decreased and activation delay increased in RV during conduction longitudinal but not transverse to fiber direction in Scn5a heterozygous animals compared to WT. In contrast, a 50% reduction of intercellular coupling did not affect either CV restitution or activation delay. A decrease of 90% Cx43, however, resulted in decreased CV restitution and increased activation delay in RV, but not LV. Reducing excitability but not intercellular coupling by 50% affects CV restitution and activation delay in RV, indicating a higher safety factor for intercellular coupling than excitability in R

Gender-dependent differences in plasma matrix metalloproteinase-8 elevated in pulmonary tuberculosis.

Tuberculosis (TB) remains a global health pandemic and greater understanding of underlying pathogenesis is required to develop novel therapeutic and diagnostic approaches. Matrix metalloproteinases (MMPs) are emerging as key effectors of tissue destruction in TB but have not been comprehensively studied in plasma, nor have gender differences been investigated. We measured the plasma concentrations of MMPs in a carefully characterised, prospectively recruited clinical cohort of 380 individuals. The collagenases, MMP-1 and MMP-8, were elevated in plasma of patients with pulmonary TB relative to healthy controls, and MMP-7 (matrilysin) and MMP-9 (gelatinase B) were also increased. MMP-8 was TB-specific (p<0.001), not being elevated in symptomatic controls (symptoms suspicious of TB but active disease excluded). Plasma MMP-8 concentrations inversely correlated with body mass index. Plasma MMP-8 concentration was 1.51-fold higher in males than females with TB (p<0.05) and this difference was not due to greater disease severity in men. Gender-specific analysis of MMPs demonstrated consistent increase in MMP-1 and -8 in TB, but MMP-8 was a better discriminator for TB in men. Plasma collagenases are elevated in pulmonary TB and differ between men and women. Gender must be considered in investigation of TB immunopathology and development of novel diagnostic markers

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

The "Ram Effect": A "Non-Classical" Mechanism for Inducing LH Surges in Sheep

During spring sheep do not normally ovulate but exposure to a ram can induce ovulation. In some ewes an LH surge is induced immediately after exposure to a ram thus raising questions about the control of this precocious LH surge. Our first aim was to determine the plasma concentrations of oestradiol (E2) E2 in anoestrous ewes before and after the "ram effect" in ewes that had a "precocious" LH surge (starting within 6 hours), a "normal" surge (between 6 and 28h) and "late» surge (not detected by 56h). In another experiment we tested if a small increase in circulating E2 could induce an LH surge in anoestrus ewes. The concentration of E2 significantly was not different at the time of ram introduction among ewes with the three types of LH surge. "Precocious" LH surges were not preceded by a large increase in E2 unlike "normal" surges and small elevations of circulating E2 alone were unable to induce LH surges. These results show that the "precocious" LH surge was not the result of E2 positive feedback. Our second aim was to test if noradrenaline (NA) is involved in the LH response to the "ram effect". Using double labelling for Fos and tyrosine hydroxylase (TH) we showed that exposure of anoestrous ewes to a ram induced a higher density of cells positive for both in the A1 nucleus and the Locus Coeruleus complex compared to unstimulated controls. Finally, the administration by retrodialysis into the preoptic area, of NA increased the proportion of ewes with an LH response to ram odor whereas treatment with the α1 antagonist Prazosin decreased the LH pulse frequency and amplitude induced by a sexually active ram. Collectively these results suggest that in anoestrous ewes NA is involved in ram-induced LH secretion as observed in other induced ovulators

Diffractive Higgs Production by AdS Pomeron Fusion

The double diffractive Higgs production at central rapidity is formulated in terms of the fusion of two AdS gravitons/Pomerons first introduced by Brower, Polchinski, Strassler and Tan in elastic scattering. Here we propose a simple self-consistent holographic framework capable of providing phenomenologically compelling estimates of diffractive cross sections at the LHC. As in the traditional weak coupling approach, we anticipate that several phenomenological parameters must be tested and calibrated through factorization for a self-consistent description of other diffractive process such as total cross sections, deep inelastic scattering and heavy quark production in the central region.Comment: 53 pages, 8 figure

Positive and negative well-being and objectively measured sedentary behaviour in older adults: evidence from three cohorts

Background: Sedentary behaviour is related to poorer health independently of time spent in moderate to vigorous physical activity. The aim of this study was to investigate whether wellbeing or symptoms of anxiety or depression predict sedentary behaviour in older adults. Method: Participants were drawn from the Lothian Birth Cohort 1936 (LBC1936) (n = 271), and the West of Scotland Twenty-07 1950s (n = 309) and 1930s (n = 118) cohorts. Sedentary outcomes, sedentary time, and number of sit-to-stand transitions, were measured with a three-dimensional accelerometer (activPAL activity monitor) worn for 7 days. In the Twenty-07 cohorts, symptoms of anxiety and depression were assessed in 2008 and sedentary outcomes were assessed ~ 8 years later in 2015 and 2016. In the LBC1936 cohort, wellbeing and symptoms of anxiety and depression were assessed concurrently with sedentary behaviour in 2015 and 2016. We tested for an association between wellbeing, anxiety or depression and the sedentary outcomes using multivariate regression analysis. Results: We observed no association between wellbeing or symptoms of anxiety and the sedentary outcomes. Symptoms of depression were positively associated with sedentary time in the LBC1936 and Twenty-07 1950s cohort, and negatively associated with number of sit-to-stand transitions in the LBC1936. Meta-analytic estimates of the association between depressive symptoms and sedentary time or number of sit-to-stand transitions, adjusted for age, sex, BMI, long-standing illness, and education, were β = 0.11 (95% CI = 0.03, 0.18) and β = − 0.11 (95% CI = − 0.19, −0.03) respectively. Conclusion: Our findings indicate that depressive symptoms are positively associated with sedentary behavior. Future studies should investigate the causal direction of this association

Longitudinal Metabolite Changes in Progressive Multiple Sclerosis: A Study of 3 Potential Neuroprotective Treatments

BACKGROUND: 1 H-magnetic resonance spectroscopy (1 H-MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N-acetyl-aspartate (tNAA), total creatine (tCr), myo-inositol (mIns), total-choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS). PURPOSE: To assess the effect on neurometabolites from three candidate drugs after 96-weeks as seen by 1 H-MRS and their association with clinical disability in SPMS. STUDY-TYPE: Longitudinal. POPULATION: 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]. FIELD STRENGTH/SEQUENCE: 3-Tesla. Chemical-shift-imaging 2D-point-resolved-spectroscopy (PRESS), 3DT1. ASSESSMENT: Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine-hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96-weeks. STATISTICAL TESTS: Paired t-test was used to analyze metabolite changes in the placebo arm over 96-weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96-weeks assessed using multiple linear regression models. P-value<0.05 was considered statistically significant. RESULTS: In the placebo arm, tCho increased in GM (mean difference = -0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (β = -0.21); in the riluzole arm, GM Glx (β = -0.25) and Glx/tCr (β = -0.29) were reduced. Baseline tNAA(β = 0.22) and tNAA/tCr (β = 0.23) in NAWM were associated with 9HPT scores at 96-weeks. DATA CONCLUSION: 1 H-MRS demonstrated altered membrane turnover over 96-weeks in the placebo group. It also distinguished changes in neuro-metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 4