INCREASED STRIATAL VULNERABILITY TO 3-NITROPROPIONIC ACID IN MALE, BUT NOT FEMALE, MICE LACKING INTERLEUKIN-1R1

Interleukin-1β (IL-1β), classically considered as a pro-inflammatory cytokine, has proven essential to cellular defense in nearly all tissues (Kaur et al., 2014, Ren and Torres, 2009). In brain, studies suggest that IL-1β has pleiotrophic effects. It acts as a neuromodulator, has been implicated in the pathogenic processes associated with a number of CNS diseases, but has also been shown to provide protection to the injured CNS. With respect to the latter, IL-1β signalling appears to mitigate pathology and motor symptoms in a mouse model of Huntington’s disease (HD), a progressive neurodegenerative condition that targets the striatum. Specifically, HD mice bred onto an IL-1R1 null background demonstrate greater pathological striatal HTT aggregation that coincides with increased severity of motor symptoms (Wang et al., 2010). Of interest for this thesis, mitochondrial dysfunction and subsequent reactive oxygen species (ROS) generation appear to precipitate neuropathology in HD (Emerit et al., 2004). Also of interest, is research from this laboratory demonstrating that IL-1β can protect neural cells against oxidant-induced injury (He et al., 2015) (Chowdhury, unpublished observations). Thus, in this thesis, I explored whether IL-1β signalling could protect against oxidative stress-generated brain damage in vivo by employing a chemical model of HD. Toward this end, both male and female mice (16-18 wks) that were either null or wild-type for the IL-1β signalling receptor, IL-1R1, were treated systemically with 3-nitropropionic acid (3-NP), a phyto/fungal mitochondrial toxin (Pedraza-Chaverrí et al., 2009), for a total cumulative dose of 920mg/kg. Comparisons of the histological striatal injury and extent of behavioral symptomatology were made. Motor symptoms —including reduced general locomotor activity, hind limb and truncal dystonia, and postural instability —increased progressively with increasing days of dosage with 3-NP, in both sexes regardless of genotype, demonstrating no observable difference in response during treatment. Despite this, histological analysis of the striatum, measured over seven levels ranging from +1.22 to -0.18 from bregma, revealed that IL-1R1 null male, but not female, mice had a greater incidence of striatal lesions that were also larger in size compared to their wild-type littermate controls. These results indicate that endogenous IL-1β signalling mitigated 3-NP induced structural, but not functional, striatal injury in male but not female mice

Does wage rank affect employees' well-being?

How do workers make wage comparisons? Both an experimental study and an analysis of 16,000 British employees are reported. Satisfaction and well-being levels are shown to depend on more than simple relative pay. They depend upon the ordinal rank of an individual's wage within a comparison group. “Rank” itself thus seems to matter to human beings. Moreover, consistent with psychological theory, quits in a workplace are correlated with pay distribution skewness

The influence of decision-making in tree ring-based climate reconstructions.

Tree-ring chronologies underpin the majority of annually-resolved reconstructions of Common Era climate. However, they are derived using different datasets and techniques, the ramifications of which have hitherto been little explored. Here, we report the results of a double-blind experiment that yielded 15 Northern Hemisphere summer temperature reconstructions from a common network of regional tree-ring width datasets. Taken together as an ensemble, the Common Era reconstruction mean correlates with instrumental temperatures from 1794-2016 CE at 0.79 (p < 0.001), reveals summer cooling in the years following large volcanic eruptions, and exhibits strong warming since the 1980s. Differing in their mean, variance, amplitude, sensitivity, and persistence, the ensemble members demonstrate the influence of subjectivity in the reconstruction process. We therefore recommend the routine use of ensemble reconstruction approaches to provide a more consensual picture of past climate variability

2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults

The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted for the period beginning March 2008 through April 2010. Searches were limited to studies, reviews, and other evidence conducted in human subjects and published in English. Key search words included, but were not limited to, African Americans, Asian Americans, albuminuria, asymptomatic, asymptomatic screening and brachial artery reactivity, atherosclerosis imaging, atrial fibrillation, brachial artery testing for atherosclerosis, calibration, cardiac tomography, compliance, carotid intima-media thickness (IMT), coronary calcium, coronary computed tomography angiography (CCTA), C-reactive protein (CRP), detection of subclinical atherosclerosis, discrimination, endothelial function, family history, flow-mediated dilation, genetics, genetic screening, guidelines, Hispanic Americans, hemoglobin A, glycosylated, meta-analysis, Mexican Americans, myocardial perfusion imaging (MPI), noninvasive testing, noninvasive testing and type 2 diabetes, outcomes, patient compliance, peripheral arterial tonometry (PAT), peripheral tonometry and atherosclerosis, lipoprotein-associated phospholipase A2, primary prevention of coronary artery disease (CAD), proteinuria, cardiovascular risk, risk scoring, receiver operating characteristics (ROC) curve, screening for brachial artery reactivity, stress echocardiography, subclinical atherosclerosis, subclinical and Framingham, subclinical and Multi-Ethnic Study of Atherosclerosis (MESA), and type 2 diabetes. Additionally, the writing committee reviewed documents related to the subject matter previously published by the ACCF and AHA, American Diabetes Association (ADA), European Society of Cardiology, and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) 7. References selected and published in this document are representative and not all-inclusive

2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted for the period beginning March 2008 through April 2010. Searches were limited to studies, reviews, and other evidence conducted in human subjects and published in English. Key search words included, but were not limited to, African Americans, Asian Americans, albuminuria, asymptomatic, asymptomatic screening and brachial artery reactivity, atherosclerosis imaging, atrial fibrillation, brachial artery testing for atherosclerosis, calibration, cardiac tomography, compliance, carotid intima-media thickness (IMT), coronary calcium, coronary computed tomography angiography (CCTA), C-reactive protein (CRP), detection of subclinical atherosclerosis, discrimination, endothelial function, family history, flow-mediated dilation, genetics, genetic screening, guidelines, Hispanic Americans, hemoglobin A, glycosylated, meta-analysis, Mexican Americans, myocardial perfusion imaging (MPI), noninvasive testing, noninvasive testing and type 2 diabetes, outcomes, patient compliance, peripheral arterial tonometry (PAT), peripheral tonometry and atherosclerosis, lipoprotein-associated phospholipase A2, primary prevention of coronary artery disease (CAD), proteinuria, cardiovascular risk, risk scoring, receiver operating characteristics (ROC) curve, screening for brachial artery reactivity, stress echocardiography, subclinical atherosclerosis, subclinical and Framingham, subclinical and Multi-Ethnic Study of Atherosclerosis (MESA), and type 2 diabetes. Additionally, the writing committee reviewed documents related to the subject matter previously published by the ACCF and AHA, American Diabetes Association (ADA), European Society of Cardiology, and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) 7. References selected and published in this document are representative and not all-inclusive

Kepler Planet-Detection Mission: Introduction and First Results

The Kepler mission was designed to determine the frequency of Earth-sized planets in and near the habitable zone of Sun-like stars. The habitable zone is the region where planetary temperatures are suitable for water to exist on a planet’s surface. During the first 6 weeks of observations, Kepler monitored 156,000 stars, and five new exoplanets with sizes between 0.37 and 1.6 Jupiter radii and orbital periods from 3.2 to 4.9 days were discovered. The density of the Neptune-sized Kepler-4b is similar to that of Neptune and GJ 436b, even though the irradiation level is 800,000 times higher. Kepler-7b is one of the lowest-density planets (~0.17 gram per cubic centimeter) yet detected. Kepler-5b, -6b, and -8b confirm the existence of planets with densities lower than those predicted for gas giant planets

Multirater Agreement of the Causes of Anterior Cruciate Ligament Reconstruction Failure

BackgroundAnterior cruciate ligament (ACL) reconstruction failure occurs in up to 10% of cases. Technical errors are considered the most common cause of graft failure despite the absence of validated studies. Limited data are available regarding the agreement among orthopaedic surgeons regarding the causes of primary ACL reconstruction failure and accuracy of graft tunnel placement.HypothesisExperienced knee surgeons have a high level of interobserver reliability in the agreement about the causes of primary ACL reconstruction failure, anatomic graft characteristics, and tunnel placement.Study designCohort study (diagnosis); Level of evidence, 3.MethodsTwenty cases of revision ACL reconstruction were randomly selected from the Multicenter ACL Revision Study (MARS) database. Each case included the patient's history, standardized radiographs, and a concise 30-second arthroscopic video taken at the time of revision demonstrating the graft remnant and location of the tunnel apertures. All 20 cases were reviewed by 10 MARS surgeons not involved with the primary surgery. Each surgeon completed a 2-part questionnaire dealing with each surgeon's training and practice, as well as the placement of the femoral and tibial tunnels, condition of the primary graft, and the surgeon's opinion as to the causes of graft failure. Interrater agreement was determined for each question with the kappa coefficient and the prevalence-adjusted, bias-adjusted kappa (PABAK).ResultsThe 10 reviewers have been in practice an average of 14 years and have performed at least 25 ACL reconstructions per year, and 9 were fellowship trained in sports medicine. There was wide variability in agreement among knee experts as to the specific causes of ACL graft failure. When participants were specifically asked about technical error as the cause for failure, interobserver agreement was only slight (PABAK = 0.26). There was fair overall agreement on ideal femoral tunnel placement (PABAK = 0.55) but only slight agreement on whether a femoral tunnel was too anterior (PABAK = 0.24) and fair agreement on whether it was too vertical (PABAK = 0.46). There was poor overall agreement for ideal tibial tunnel placement (PABAK = 0.17).ConclusionThis study suggests that more objective criteria are needed to accurately determine the causes of primary ACL graft failure as well as the ideal femoral and tibial tunnel placement in patients undergoing revision ACL reconstruction

Subsequent Surgery After Revision Anterior Cruciate Ligament Reconstruction: Rates and Risk Factors From a Multicenter Cohort

BackgroundWhile revision anterior cruciate ligament reconstruction (ACLR) can be performed to restore knee stability and improve patient activity levels, outcomes after this surgery are reported to be inferior to those after primary ACLR. Further reoperations after revision ACLR can have an even more profound effect on patient satisfaction and outcomes. However, there is a current lack of information regarding the rate and risk factors for subsequent surgery after revision ACLR.PurposeTo report the rate of reoperations, procedures performed, and risk factors for a reoperation 2 years after revision ACLR.Study designCase-control study; Level of evidence, 3.MethodsA total of 1205 patients who underwent revision ACLR were enrolled in the Multicenter ACL Revision Study (MARS) between 2006 and 2011, composing the prospective cohort. Two-year questionnaire follow-up was obtained for 989 patients (82%), while telephone follow-up was obtained for 1112 patients (92%). If a patient reported having undergone subsequent surgery, operative reports detailing the subsequent procedure(s) were obtained and categorized. Multivariate regression analysis was performed to determine independent risk factors for a reoperation.ResultsOf the 1112 patients included in the analysis, 122 patients (11%) underwent a total of 172 subsequent procedures on the ipsilateral knee at 2-year follow-up. Of the reoperations, 27% were meniscal procedures (69% meniscectomy, 26% repair), 19% were subsequent revision ACLR, 17% were cartilage procedures (61% chondroplasty, 17% microfracture, 13% mosaicplasty), 11% were hardware removal, and 9% were procedures for arthrofibrosis. Multivariate analysis revealed that patients aged &lt;20 years had twice the odds of patients aged 20 to 29 years to undergo a reoperation. The use of an allograft at the time of revision ACLR (odds ratio [OR], 1.79; P = .007) was a significant predictor for reoperations at 2 years, while staged revision (bone grafting of tunnels before revision ACLR) (OR, 1.93; P = .052) did not reach significance. Patients with grade 4 cartilage damage seen during revision ACLR were 78% less likely to undergo subsequent operations within 2 years. Sex, body mass index, smoking history, Marx activity score, technique for femoral tunnel placement, and meniscal tearing or meniscal treatment at the time of revision ACLR showed no significant effect on the reoperation rate.ConclusionThere was a significant reoperation rate after revision ACLR at 2 years (11%), with meniscal procedures most commonly involved. Independent risk factors for subsequent surgery on the ipsilateral knee included age &lt;20 years and the use of allograft tissue at the time of revision ACLR

Invisible interpretations: reflections on the digital humanities and intellectual history

Much has been made of the digital humanities, yet it remains an underexplored field in relation to intellectual history. This paper aims to add to the little literature which does exist by offering a survey of the ideas and issues facing would-be practitioners. This includes: an overview of what the digital humanities are; reflections on what they offer intellectual history and how they may be problematic in regard to, first, accessing texts, and second, analysing source material; a conclusion with three reflections on future best practices – to be sceptical of digital sources, to be reflective of methodologies and how they may need to be modified when engaging with the digital humanities, and to embrace more directly the methodological, statistical, and technical aspects behind digital humanities. The aim is not to provide all the answers – at this stage that is impossible – but to be part of an emerging and ongoing discussion