DNA and Protein Sequence Analysis of Neuronal Markers Neuronal Nuclei (Neun) and Doublecortin (Dcx) in the Northern Pacific Rattlesnake (\u3ci\u3eCrotalus oreganus\u3c/i\u3e) and Western Fence Lizard (\u3ci\u3eSceloporus occidentalis\u3c/i\u3e).

Neuronal Nuclei (NeuN) and Doublecortin (DCX) are neuron specific proteins that are used in histological studies of brain structure in a variety of vertebrate taxa.Antibodies against NeuN (anti-NeuN) bind to the Fox-3 protein, an RNA binding protein common in mature neurons. Anti-DCX labels a microtubule-associated protein expressed in actively dividing neural progenitor cells and migrating neurons. The DCX gene encodes a protein that is well conserved across mammalian, avian, and a few reptilian species, therefore anti-DCX staining has been used successfully across a range of vertebrate taxa. Successful neuronal staining using anti-NeuN has been demonstrated in mammals, birds, and the Testudines order (turtles). However, herpetologists who study neurobiology in squamates have had limited success with anti-NeuN and anti-DCX binding to their respective antigens. All commercially available anti-NeuN and anti-DCX antiserums were designed to mammalian antigens, and significant differences in tertiary structure divergence at the epitope where these antibodies bind may explain the failure of anti-NeuN and anti-DCX immunohistochemistry in many squamate species. This study aims to characterize evolutionary differences in gene and protein structure between two species of reptiles (Crotalus oreganus and Sceloporus occidentalis) and mammals. We sequenced the Fox-3 and DCX coding sequences using polymerase chain reaction (PCR) and Sanger sequencing, which allowed us to build phylogenetic trees comparing Fox-3 and DCX deduced protein structures. By identifying structural differences linked to evolutionary variation, new polyclonal antibodies specifically targeting Fox-3 and DCX in reptile brains can be developed to facilitate future investigations of neurogenesis and brain structure in squamate reptiles

Impact of Hospital Admission for Patients with Transient Ischemic Attack

OBJECTIVES: To determine the impact of admission among transient ischemic attack (TIA) patients in the emergency department (ED). STUDY DESIGN: Retrospective cohort study using national Veterans Health Administration data (2008). METHODS: We first analyzed whether admitted patients were discharged from the hospital with a diagnosis of TIA. We then analyzed whether admission was associated with a composite outcome (new stroke, new myocardial infarction, or death in the year after TIA) using multivariate logistic regression modeling with propensity score matching. RESULTS: Among 3623 patients assigned a diagnosis of TIA in the ED, 2118 (58%) were admitted to the hospital or placed in observation compared with 1505 (42%) who were discharged from the ED. Among the 2118 patients who were admitted, 903 (43% of admitted group) were discharged from the hospital with a diagnosis of TIA, and 548 (26% of admitted group) were discharged with a diagnosis of stroke. Admitted patients were more likely than nonadmitted patients to receive processes of care (i.e., brain imaging, carotid imaging, echocardiography). In matched analyses using propensity scores, the 1-year composite outcome in the admitted group (15.3%) was not lower than the discharged group (13.3%, OR 1.17 [.94-1.46], P = .17). CONCLUSIONS: Less than half of patients admitted with a diagnosis of TIA retained that diagnosis at hospital discharge. Although admitted patients were more likely to receive diagnostic procedures, we did not identify improvements in outcomes among admitted patients; however, evaluating care for patients with TIA is limited by the reliability of secondary data analysis

Systematic reviews in the prevention of research waste in emergency medicine randomized controlled trials

Before a randomized controlled trial (RCT) is performed, systematic reviews (SR) of the topic need to be cited to ensure new, meaningful information is being added. Studies that do not do this can cause wasted resources such as funding and time. We analyzed RCTs in the top emergency medicine journals for indication of SR citations. We searched PubMed for studies that were published between 01/01/2014 and 12/31/2017.This search resulted in 615 studies. Of those 615 studies, we found that 275 of them fulfilled the requirements of a RCT. The bibliographies of the 275 studies were analyzed for evidence of SR citation. If a SR citation was present, we determined if information from the citation was used to justify the RCT. Of the 275 studies, we found that 66%, 95%, and 74% studies did not use SR citations as justification or did not have SR citations at all in the introduction, methods, and discussion sections respectively. The average sample size of each RCT was 294 participants. 40% of the studies did not report the type of funding, and 20% of studies received funding from government resources. The most common trial type was a parallel group trial contributing to 69% of our studies.The results from this study reveal that there is a lack of justification for RCTs in emergency medicine research due to the underutilization of meaningful SR citations. Trialists in emergency medicine should be more proactive in citing SRs in their studies to prevent wasted resources

Evaluation of systematic review utilization in the development of OB-GYN randomized controlled trials

Introduction: The issue of research waste has been raised due to the fact that 85% of funding for biomedical research has been improperly utilized. A prominent issue is the frequency of randomized controlled trials (RCTs) being conducted without prior consultation of existing support, such as systematic reviews (SRs). Meticulous monitoring is necessary to ensure that clinical recommendations are being made with confidence in high-quality biomedical practices. The aim of this study was to survey Obstetric and Gynecology journals to analyze their published articles for citation of SR for justification of conducting the RCT.Methods: We conducted a search of PubMed for RCTs published between January 1, 2014 and December 31, 2017, in the top ten Obstetric and Gynecology journals. Each included study was evaluated to determine the number of SRs cited within the introduction, methods, and discussion sections. We further analyzed whether the SR was cited verbatim or indirectly, number of participants, type of intervention being studied, funding source, type of trial, and how the outcome was perceived.Results: Of the 720 articles from our initial search, 458 (63.61%) met inclusion criteria. Of the 458 included studies, 279 (60.92%) cited an SR in the introduction, 34 (7.42%) cited an SR in the methods, and 207 (45.2%) cited an SR in the discussion as justification for conducting the study.Conclusion: A large portion of the RCTs being published in clinical Obstetrics and Gynecology journals are not citing SRs as justification for conducting their studies, which may be leading to an increase in research waste

BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization

<p>Abstract</p> <p>Background</p> <p>BACE1 is a key enzyme in the generation of the Aβ peptide that plays a central role in the pathogenesis of Alzheimer's disease. While BACE1 is an attractive therapeutic target, its normal physiological function remains largely unknown. Examination of BACE1^-/-mice can provide insight into this function and also help anticipate consequences of BACE1 inhibition. Here we report a seizure-susceptibility phenotype that we have identified and characterized in BACE1^-/-mice.</p> <p>Results</p> <p>We find that electroencephalographic recordings reveal epileptiform abnormalities in some BACE1^-/-mice, occasionally including generalized tonic-clonic and absence seizures. In addition, we find that kainic acid injection induces seizures of greater severity in BACE1^-/-mice relative to BACE1^+/+littermates, and causes excitotoxic cell death in a subset of BACE1^-/-mice. This hyperexcitability phenotype is variable and appears to be manifest in approximately 30% of BACE1^-/-mice. Finally, examination of the expression and localization of the voltage-gated sodium channel α-subunit Na_v1.2 reveals no correlation with BACE1 genotype or any measure of seizure susceptibility.</p> <p>Conclusions</p> <p>Our data indicate that BACE1 deficiency predisposes mice to spontaneous and pharmacologically-induced seizure activity. This finding has implications for the development of safe therapeutic strategies for reducing Aβ levels in Alzheimer's disease. Further, we demonstrate that altered sodium channel expression and axonal localization are insufficient to account for the observed effect, warranting investigation of alternative mechanisms.</p

Prevalence of Deep Surgical Site Infection After Repair of Periarticular Knee Fractures: A systematic review and meta-analysis

Importance Surgical management of periarticular knee fractures can be challenging, and adverse outcomes may be severe. Recent literature indicates that the rate of periarticular knee surgical site infection (SSI) may range from 2% to 88% depending on the fracture site. Objective To examine the prevalence of deep SSI and the rate of septic arthritis after surgical repair of fractures around the knee. Data Sources The electronic databases MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from their inception to July 1, 2018. Study Selection Eligible studies had to specifically report deep SSI rates and include fractures in the distal femur, patella, tibial plateau, or proximal tibia. Risk factors that were associated with increased the risk of deep SSI were also examined. Data Extraction and Synthesis This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were extracted by multiple investigators. Comprehensive Meta-Analysis software was used for the pooling of data, using either random-effects or fixed-effects models, with respect to the degree of statistical heterogeneity present. Data analyses were conducted in October 2018. Main Outcomes and Measures The primary outcome was overall prevalence of deep SSI after periarticular knee fracture repair. The secondary outcomes were the overall prevalence of septic arthritis, risk factors associated with deep SSI, and the most commonly cultured bacteria specimens found periarticular knee infections. Results Of 6928 articles screened, 117 articles met inclusion criteria and were included in analysis. Among 11 432 patients included in analysis, 653 patients (5.7%) experienced deep SSIs, most commonly among patients with proximal tibia fractures (56 of 872 patients [6.4%]). Among studies that included information on septic arthritis, 38 of 1567 patients (2.4%) experienced septic arthritis. The 2 most commonly reported bacteria were methicillin-resistant Staphylococcus aureus, found in 67 SSIs, and methicillin-susceptible S aureus, found in 53 SSIs. Sixty-two studies (53.0%) in the sample received a Coleman Methodological Score of poor (<50 points). Conclusions and Relevance Deep SSIs occurred in nearly 6% of periarticular knee fracture repairs, and 2.4% of SSIs were associated with septic arthritis. Surgeons managing these injuries should be vigilant when wounds are not pristine. Efforts should be made to elevate the quality of research conducted not only in this subject but also in orthopedic surgery as a whole

Using Administrative Databases to Calculate Framingham Scores within a Large Healthcare Organization

Background and Purpose—Framingham calculators are typically implemented in 1-on-1 settings to determine if a patient is at high risk for development of cardiovascular disease in the next 10 years. Because health care administrative datasets are including more clinical information, we explored how well administrative data-derived Framingham scores could identify persons who would have stroke develop in the next year. Methods—Using a nested case-control design, we compared all 313 persons who had a first-time stroke at 5 Veterans Administration Medical Centers with a random sample of 25 361 persons who did not have a first-time stroke in 2008. We compared Framingham scores and risk using administrative data available at the end of 2007. Results—Stroke patients had higher risk profile than controls: older age, higher systolic blood pressure and total cholesterol, more likely to have diabetes, cardiovascular disease, left ventricular hypertrophy, and more likely to use treatment for blood pressure (P<0.05). The mean Framingham generalized cardiovascular disease score (18.0 versus 14.5) as well as the mean Framingham stroke-specific score (13.2 versus 10.2) was higher for stroke cases than controls (both P<0.0001). The c-statistic for the generalized cardiovascular disease score was 0.68 (95% CI, 0.65–0.70) and for the stroke score was 0.64 (95% CI, 0.62–0.67). Conclusions—Persons who had a stroke develop in the next year had a worse Framingham risk profile, as determined by administrative data. Future studies should examine how to improve the stroke predictive tools and to identify the appropriate populations and uses for applying stroke risk predictive tools

Prion protein interacts with bace1 and differentially regulates its activity towards wild type and swedish mutant amyloid precursor protein

In Alzheimer disease amyloid-β (Aβ) peptides derived from the amyloid precursor protein (APP) accumulate in the brain. Cleavage of APP by the β-secretase BACE1 is the rate-limiting step in the production of Aβ. We have reported previously that the cellular prion protein (PrP(C)) inhibited the action of BACE1 toward human wild type APP (APP(WT)) in cellular models and that the levels of endogenous murine Aβ were significantly increased in PrP(C)-null mouse brain. Here we investigated the molecular and cellular mechanisms underlying this observation. PrP(C) interacted directly with the prodomain of the immature Golgi-localized form of BACE1. This interaction decreased BACE1 at the cell surface and in endosomes where it preferentially cleaves APP(WT) but increased it in the Golgi where it preferentially cleaves APP with the Swedish mutation (APP(Swe)). In transgenic mice expressing human APP with the Swedish and Indiana familial mutations (APP(Swe,Ind)), PrP(C) deletion had no influence on APP proteolytic processing, Aβ plaque deposition, or levels of soluble Aβ or Aβ oligomers. In cells, although PrP(C) inhibited the action of BACE1 on APP(WT), it did not inhibit BACE1 activity toward APP(Swe). The differential subcellular location of the BACE1 cleavage of APP(Swe) relative to APP(WT) provides an explanation for the failure of PrP(C) deletion to affect Aβ accumulation in APP(Swe,Ind) mice. Thus, although PrP(C) exerts no control on cleavage of APP(Swe) by BACE1, it has a profound influence on the cleavage of APP(WT), suggesting that PrP(C) may be a key protective player against sporadic Alzheimer disease

Medication Responsiveness of Motor Symptoms in a Population-Based Study of Parkinson Disease

We assessed degree of Parkinson disease motor symptom improvement with medication among subjects enrolled in an ongoing, population-based study in Central California. The motor section of the unified Parkinson disease rating scale (UPDRS) was performed on subjects in both OFF and ON medication states, and difference between these scores was used as an indicator of symptomatic benefit. Higher OFF minus ON scores correlated with more severe baseline symptoms. There was equivalent improvement on the motor UPDRS scale for subjects divided according to medication classes used: levodopa alone 7.3 points, levodopa plus other medications 8.5 points, and dopamine agonists but not levodopa 6.1 points. In addition, there was no difference in the magnitude of improvement when subjects were divided according to Parkinson disease subtype, defined as tremor dominant, akinetic-rigid, or mixed. In this community-based sample, these values are within the range of a clinically important difference as defined by previous studies