Pharmacologic inhibition of S-nitrosoglutathione reductase protects against experimental asthma in BALB/c mice through attenuation of both bronchoconstriction and inflammation

BACKGROUND: S-nitrosoglutathione (GSNO) serves as a reservoir for nitric oxide (NO) and thus is a key homeostatic regulator of airway smooth muscle tone and inflammation. Decreased levels of GSNO in the lungs of asthmatics have been attributed to increased GSNO catabolism via GSNO reductase (GSNOR) leading to loss of GSNO- and NO- mediated bronchodilatory and anti-inflammatory actions. GSNOR inhibition with the novel small molecule, N6022, was explored as a therapeutic approach in an experimental model of asthma. METHODS: Female BALB/c mice were sensitized and subsequently challenged with ovalbumin (OVA). Efficacy was determined by measuring both airway hyper-responsiveness (AHR) upon methacholine (MCh) challenge using whole body plethysmography and pulmonary eosinophilia by quantifying the numbers of these cells in the bronchoalveolar lavage fluid (BALF). Several other potential biomarkers of GSNOR inhibition were measured including levels of nitrite, cyclic guanosine monophosphate (cGMP), and inflammatory cytokines, as well as DNA binding activity of nuclear factor kappa B (NFκB). The dose response, onset of action, and duration of action of a single intravenous dose of N6022 given from 30 min to 48 h prior to MCh challenge were determined and compared to effects in mice not sensitized to OVA. The direct effect of N6022 on airway smooth muscle tone also was assessed in isolated rat tracheal rings. RESULTS: N6022 attenuated AHR (ED(50) of 0.015 ± 0.002 mg/kg; Mean ± SEM) and eosinophilia. Effects were observed from 30 min to 48 h after treatment and were comparable to those achieved with three inhaled doses of ipratropium plus albuterol used as the positive control. N6022 increased BALF nitrite and plasma cGMP, while restoring BALF and plasma inflammatory markers toward baseline values. N6022 treatment also attenuated the OVA-induced increase in NFκB activation. In rat tracheal rings, N6022 decreased contractile responses to MCh. CONCLUSIONS: The significant bronchodilatory and anti-inflammatory actions of N6022 in the airways are consistent with restoration of GSNO levels through GSNOR inhibition. GSNOR inhibition may offer a therapeutic approach for the treatment of asthma and other inflammatory lung diseases. N6022 is currently being evaluated in clinical trials for the treatment of inflammatory lung disease

Multicenter Study of Predictors of Disease Course in Alzheimer Disease (the "Predictors Study"). I. Study Design, Cohort Description, and Intersite Comparisons

Clinicians should be able to provide the patient with Alzheimer disease (AD) and the family with an accurate prediction of what to expect, but the variability in the rate of disease progression precludes this. In several previous studies, specific clinical signs such as muscular rigidity, myoclonus, and hallucinations or delusions were associated with rapid progression to a more severe stage of dementia or death. The 'Predictors Study,' a longitudinal study at three independent sites, was designed to develop a predictor model of the natural history of Alzheimer disease. The study was conducted at three study sites, New York, Baltimore, and Boston in a cohort of 224 patients with early probable AD. This article describes the design and implementation of the Predictors Study, and compares features of the study cohort at baseline across sites. Patients were all at the mild stage of disease at entry and were relatively comparable across sites. Extrapyramidal signs and delusions were common, but myoclonus was rarely observed

Pesticide exposure and self-reported incident depression among wives in the Agricultural Health Study

Depression in women is a public health problem. Studies have reported positive associations between pesticides and depression, but few studies were prospective or presented results for women separately

Suicide and Pesticide Use among Pesticide Applicators and Their Spouses in the Agricultural Health Study

Background: An association may exist between pesticide exposure and suicide

Ovarian cancer symptom awareness and anticipated delayed presentation in a population sample

Background: While ovarian cancer is recognised as having identifiable early symptoms, understanding of the key determinants of symptom awareness and early presentation is limited. A population-based survey of ovarian cancer awareness and anticipated delayed presentation with symptoms was conducted as part of the International Cancer Benchmarking Partnership (ICBP). Methods: Women aged over 50 years were recruited using random probability sampling (n = 1043). Computer-assisted telephone interviews were used to administer measures including ovarian cancer symptom recognition, anticipated time to presentation with ovarian symptoms, health beliefs (perceived risk, perceived benefits/barriers to early presentation, confidence in symptom detection, ovarian cancer worry), and demographic variables. Logistic regression analysis was used to identify the contribution of independent variables to anticipated presentation (categorised as < 3 weeks or ≥ 3 weeks). Results: The most well-recognised symptoms of ovarian cancer were post-menopausal bleeding (87.4%), and persistent pelvic (79.0%) and abdominal (85.0%) pain. Symptoms associated with eating difficulties and changes in bladder/bowel habits were recognised by less than half the sample. Lower symptom awareness was significantly associated with older age (p ≤ 0.001), being single (p ≤ 0.001), lower education (p ≤ 0.01), and lack of personal experience of ovarian cancer (p ≤ 0.01). The odds of anticipating a delay in time to presentation of ≥ 3 weeks were significantly increased in women educated to degree level (OR = 2.64, 95% CI 1.61 – 4.33, p ≤ 0.001), women who reported more practical barriers (OR = 1.60, 95% CI 1.34 – 1.91, p ≤ 0.001) and more emotional barriers (OR = 1.21, 95% CI 1.06 – 1.40, p ≤ 0.01), and those less confident in symptom detection (OR = 0.56, 95% CI 0.42 – 0.73, p ≤ 0.001), but not in those who reported lower symptom awareness (OR = 0.99, 95% CI 0.91 – 1.07, p = 0.74). Conclusions: Many symptoms of ovarian cancer are not well-recognised by women in the general population. Evidence-based interventions are needed not only to improve public awareness but also to overcome the barriers to recognising and acting on ovarian symptoms, if delays in presentation are to be minimised

Pesticide Exposure and Depression among Male Private Pesticide Applicators in the Agricultural Health Study

Background: Pesticide exposure may be positively associated with depression. Few previous studies have considered the episodic nature of depression or examined individual pesticides

Classification performance of sEMG and kinematic parameters for distinguishing between non-lame and induced lameness conditions in horses

Despite its proven research applications, it remains unknown whether surface electromyography (sEMG) can be used clinically to discriminate non-lame from lame conditions in horses. This study compared the classification performance of sEMG absolute value (sEMGabs) and asymmetry (sEMGasym) parameters, alongside validated kinematic upper-body asymmetry parameters, for distinguishing non-lame from induced fore- (iFL) and hindlimb (iHL) lameness. Bilateral sEMG and 3D-kinematic data were collected from clinically non-lame horses (n=8) during in-hand trot. iFL and iHL (2-3/5 AAEP) were induced on separate days using a modified horseshoe, with baseline data initially collected each day. sEMG signals were DC-offset removed, high-pass filtered (40Hz), and full-wave rectified. Normalized, average rectified value (ARV) was calculated for each muscle and stride (sEMGabs), with the difference between right and left-side ARV representing sEMGasym. Asymmetry parameters (MinDiff, MaxDiff, Hip Hike) were calculated from poll, withers, and pelvis vertical displacement. Receiver-operating-characteristic (ROC) and area under the curve (AUC) analysis determined the accuracy of each parameter for distinguishing baseline from iFL or iHL. Both sEMG parameters performed better for detecting iHL (0.97≥AUC≥0.48) compared to iFL (0.77≥AUC≥0.49). sEMGabs performed better (0.97≥AUC≥0.49) than sEMGasym (0.76≥AUC≥0.48) for detecting both iFL and iHL. Like previous studies, MinDiff Poll and Pelvis asymmetry parameters (MinDiff, MaxDiff, Hip Hike) demonstrated excellent discrimination for iFL and iHL, respectively (AUC>0.95). Findings support future development of multivariate lameness-detection approaches that combine kinematics and sEMG. This may provide a more comprehensive approach to diagnosis, treatment, and monitoring of equine lameness, by measuring the underlying functional cause(s) at a neuromuscular level

Reliability of surface electromyographic (sEMG) measures of equine axial and appendicular muscles during overground trot

The reliability of surface electromyography (sEMG) has not been adequately demonstrated in the equine literature and is an essential consideration as a methodology for application in clinical gait analysis. This observational study investigated within-session, intra-subject (stride-to-stride) and inter-subject reliability, and between-session reliability of normalised sEMG activity profiles, from triceps brachii (triceps), latissimus dorsi (latissimus), longissimus dorsi (longissimus), biceps femoris (biceps), superficial gluteal (gluteal) and semitendinosus muscles in n = 8 clinically non-lame horses during in-hand trot. sEMG sensors were bilaterally located on muscles to collect data during two test sessions (session 1 and 2) with a minimum 24-hour interval. Raw sEMG signals from ten trot strides per horse and session were DC-offset removed, high-pass filtered (40 Hz), full-wave rectified, and low-pass filtered (25 Hz). Signals were normalised to peak amplitude and percent stride before calculating intra- and inter-subject ensemble average sEMG profiles across strides for each muscle and session. sEMG profiles were assessed using waveform similarity statistics: the coefficient of variation (CV) to assess intra- and inter-subject reliability and the adjusted coefficient of multiple correlation (CMC) to evaluate between-session reliability. Across muscles, CV data revealed that intra-horse sEMG profiles within- and between-sessions were comparatively more reliable than inter-horse profiles. Bilateral gluteal, semitendinosus, triceps and longissimus (at T14 and L1) and right biceps showed excellent between-session reliability with group-averaged CMCs > 0.90 (range 0.90–0.97). Bilateral latissimus and left biceps showed good between-session reliability with group-averaged CMCs > 0.75 (range 0.78–0.88). sEMG profiles can reliably describe fundamental muscle activity patterns for selected equine muscles within a test session for individual horses (intra-subject). However, these profiles are more variable across horses (inter-subject) and between sessions (between-session reliability), suggesting that it is reasonable to use sEMG to objectively monitor the intra-individual activity of these muscles across multiple gait evaluation sessions at in-hand trot

Fractionation of sulfide phases controls the chalcophile metal budget of arc magmas: evidence from the Chilas complex, Kohistan arc, Pakistan

Some arc magmas lead to the formation of porphyry deposits in the relatively shallow upper crust (<5 km). Porphyry deposits are major sources of Cu and an important Au source but lack significant amounts of platinum group elements (PGE). Sulfide phases control the behavior of chalcophile elements and affect the potential to form ore deposits either by remaining in the mantle residue or by fractionating from arc magmas at lower crustal levels, although in detail the role of sulfide saturation in the lower crust remains poorly understood. Lower crustal cumulate rocks from the 85 Ma Chilas Complex of the Kohistan arc, Pakistan, provide insight into processes that occur at depth in arcs. Here we provide Cu, Ni, Au, and PGE concentrations and Os isotope ratios of the Chilas Complex in order to constrain the extent of sulfide saturation in the lower crust and the effect of sulfide saturation on the metal budget of evolved melts that ascend to the upper crust. The Chilas rock suite contains less than 0.17 wt % sulfides and low PGE concentrations. In situ laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) measurements of the sulfide inclusions in silicate minerals show enrichment in several chalcophile elements (up to 34 wt % Cu, 23 ppm Au, 245 ppm Pd, and 20 ppm Pt), whereas iridium group PGE (IPGE- Os, Ir, Ru) are mainly below detection limits. The metal content of the parental melt was modeled based on the elemental concentrations of the sulfides. The modeled parental arc magmas contain 70 to 140 ppm Cu, 0.2 to 1.5 ppb Au, and 1.2 to 8 ppb Pd, but low concentrations of IPGE, suggesting that IPGE were likely retained in the mantle source. Mass balance calculations show that segregation of a sulfide melt in the lower crust could further deplete the melt by more than 95% in Pd and Pt, 33 to 85% in Au, and 13 to 60% in Cu. Thus, magmas that ascend to the upper crust would contain very low concentrations of Au (< 0.2 ppb) and Pd (< 0.04 ppb), but they would retain sufficient concentration of Cu (~45–57 ppm) to form porphyry Cu deposits upon emplacement in the upper crust, as is commonly observed in arc settings

Adaptations in equine appendicular muscle activity and movement occur during induced fore- and hindlimb lameness: An electromyographic and kinematic evaluation

The relationship between lameness-related adaptations in equine appendicular motion and muscle activation is poorly understood and has not been studied objectively. The aim of this study was to compare muscle activity of selected fore- and hindlimb muscles, and movement of the joints they act on, between baseline and induced forelimb (iFL) and hindlimb (iHL) lameness. Three-dimensional kinematic data and surface electromyography (sEMG) data from the fore- (triceps brachii, latissimus dorsi) and hindlimbs (superficial gluteal, biceps femoris, semitendinosus) were bilaterally and synchronously collected from clinically non-lame horses ( n = 8) trotting over-ground (baseline). Data collections were repeated during iFL and iHL conditions (2-3/5 AAEP), induced on separate days using a modified horseshoe. Motion asymmetry parameters and continuous joint and pro-retraction angles for each limb were calculated from kinematic data. Normalized average rectified value (ARV) and muscle activation onset, offset and activity duration were calculated from sEMG signals. Mixed model analysis and statistical parametric mapping, respectively, compared discrete and continuous variables between conditions (α= 0.05). Asymmetry parameters reflected the degree of iFL and iHL. Increased ARV occurred across muscles following iFL and iHL, except non-lame side forelimb muscles that significantly decreased following iFL. Significant, limb-specific changes in sEMG ARV, and activation timings reflected changes in joint angles and phasic shifts of the limb movement cycle following iFL and iHL. Muscular adaptations during iFL and iHL are detectable using sEMG and primarily involve increased bilateral activity and phasic activation shifts that reflect known compensatory movement patterns for reducing weightbearing on the lame limb. With further research and development, sEMG may provide a valuable diagnostic aid for quantifying the underlying neuromuscular adaptations to equine lameness, which are undetectable through human observation alone