Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

<p>Abstract</p> <p>Background</p> <p>Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified <it>R</it>-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic <it>R</it>-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice.</p> <p>Results</p> <p>A four-month preventative treatment regimen with <it>R</it>-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of <it>R</it>-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning.</p> <p>Conclusion</p> <p>We have found that chronic administration of <it>R</it>-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its ability to selectively target Aβ42 production and improve cognitive impairments in transgenic APP mice, as well as promising data from a phase 2 human clinical trial, future studies are needed to investigate the utility of <it>R</it>-flurbiprofen as an AD therapeutic and its possible mechanisms of action.</p

Unnecessary use of fluoroquinolone antibiotics in hospitalized patients

<p>Abstract</p> <p>Background</p> <p>Fluoroquinolones are among the most commonly prescribed antimicrobials and are an important risk factor for colonization and infection with fluoroquinolone-resistant gram-negative bacilli and for <it>Clostridium difficile </it>infection (CDI). In this study, our aim was to determine current patterns of inappropriate fluoroquinolone prescribing among hospitalized patients, and to test the hypothesis that longer than necessary treatment durations account for a significant proportion of unnecessary fluoroquinolone use.</p> <p>Methods</p> <p>We conducted a 6-week prospective, observational study to determine the frequency of, reasons for, and adverse effects associated with unnecessary fluoroquinolone use in a tertiary-care academic medical center. For randomly-selected adult inpatients receiving fluoroquinolones, therapy was determined to be necessary or unnecessary based on published guidelines or standard principles of infectious diseases. Adverse effects were determined based on chart review 6 weeks after completion of therapy.</p> <p>Results</p> <p>Of 1,773 days of fluoroquinolone therapy, 690 (39%) were deemed unnecessary. The most common reasons for unnecessary therapy included administration of antimicrobials for non-infectious or non-bacterial syndromes (292 days-of-therapy) and administration of antimicrobials for longer than necessary durations (234 days-of-therapy). The most common syndrome associated with unnecessary therapy was urinary tract infection or asymptomatic bacteriuria (30% of all unnecessary days-of-therapy). Twenty-seven percent (60/227) of regimens were associated with adverse effects possibly attributable to therapy, including gastrointestinal adverse effects (14% of regimens), colonization by resistant pathogens (8% of regimens), and CDI (4% of regimens).</p> <p>Conclusions</p> <p>In our institution, 39% of all days of fluoroquinolone therapy were unnecessary. Interventions that focus on improving adherence with current guidelines for duration of antimicrobial therapy and for management of urinary syndromes could significantly reduce overuse of fluoroquinolones.</p

A genome-wide association study of myasthenia gravis

IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody–positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8114394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10(−8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the over all case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10(−8); odds ratio, 1.37; 95% CI, 1.25–1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10(−8); odds ratio, 2.31; 95% CI, 2.02 – 2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10(−9); odds ratio, 1.41; 95% CI, 1.29–1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10(−12); odds ratio, 1.56; 95% CI, 1.44–1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P = 7.02 × 10(−18); odds ratio, 4.27; 95% CI, 3.92–4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P = 2.52 × 10(−11); odds ratio, 4.0; 95% CI, 3.57–4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Emergence of a Cue Strategy Preference on the Water Maze Task in Aged C57B6 × SJL F1 Hybrid Mice

The effects of age on cue learning, spatial reference memory, and strategy preference were assessed in B6 × SJL F1 mice by using the Morris water maze. This mouse strain is of particular interest because it is the background strain for a common transgenic model of Alzheimer's disease, the Tg2576 mouse, which develops plaques and other neurobiological markers of pathology beginning at 8 mo and increasing in severity with advanced age. In the current study, 12- and 23-mo-old C57B6 × SJL F1 mice were serially trained in cue and place versions of the Morris water maze task. At the completion of training, mice received a strategy probe test in which place (hidden) and cue (visible) strategies were in competition. Cue and spatial learning ability was maintained between 12 and 23 mo of age; however, on the strategy preference probe test, the 23-mo-old mice exhibited a significant bias toward the selection of a cue strategy. There was no relationship between strategy preference in the probe test and spatial learning ability, but the 23-mo-old mice did exhibit a strong trend toward shorter latencies during visible platform training, possibly reflecting the enhanced function of striatal-based neural systems in aging. These data demonstrate that 23-mo-old C57B6 × SJL F1 mice are capable of effective place learning, but if a place strategy is pitted against the use of a cue strategy, the use of a cue strategy predominates in the aged mice. The strategy preference observed here may reflect an emergence of differential processing in underlying brain circuitry with age in the B6 × SJL F1 mouse strain

The Neonatal-Perinatal Medicine fellowship application webinar series: a novel approach to helping applicants succeed

Abstract Background In 2022, 13,586 candidates applied to subspecialty fellowships. Formal resources to inform candidates on subspecialty-specific fellowship application are limited. Candidates rely on residency application experience, informal advice, and online research for navigating the application process. Thus, a need exists for formal subspecialty-specific fellowship application guidance. The American Academy of Pediatrics Organization of Neonatal-Perinatal Medicine Training Program Directors (ONTPD) and Trainees and Early Career Neonatologists (TECaN) created a webinar-based curriculum to help educate trainees about the application process and recruit diverse fellowship applicants. Methods In 2022, ONTPD and TECaN co-hosted and implemented a four-part national webinar series focused on different aspects of the Neonatal-Perinatal Medicine (NPM) fellowship application and interview processes. Webinars were advertised through list-servs and social media, conducted in two time zones, and recorded for asynchronous viewing. Registration, demographic data, and questions for webinar panelists were collected via electronic survey. Program evaluation data was collected after each webinar and following the fellowship match. Results In the 2022 appointment year, 310 candidates participated in the NPM fellowship match and 250 individuals registered for the webinar series. A quarter (26%) of registrants identified as underrepresented in medicine. Most registrants reported minimal or no knowledge of the fellowship application (64%, 158/248) and interview (81%, 201/248) processes. The majority of registrants (70%, 173/248) were planning on applying to fellowship in 2022, and 91% of post-webinar respondents (43/47) felt the webinars were moderately or extremely helpful, a finding that was sustained beyond the match (37/42). Almost all respondents rated the quality of the webinars as good or higher and were likely or very likely to recommend them to peers (39/42). There was considerable variability amongst respondents in the number of fellowship programs applied to, interviewed at, and ranked, and factors influencing rank list. Conclusion We describe a virtual curriculum to prepare trainees for the NPM fellowship application and interview process. This webinar series provides needed education to fellowship candidates, bridges the gap between candidate knowledge and program director expectations, is generalizable to other specialties, and can be replicated with minimal resources

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice-1

<p><b>Copyright information:</b></p><p>Taken from "Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice"</p><p>BMC Neuroscience 2007;8():54-54.</p><p>Published online 24 Jul 2007</p><p>PMCID:PMC1948891.</p><p></p> mice from the three water mazes are plotted as percent control. The mean Aβ levels +/- the standard error from control mice are shown below each graph. The absolute values (pmoles/gram tissue) of formic acid soluble Aβ40 and Aβ42 levels from individual animals are plotted against one another to show the distribution of individual animals from experimental groups. "Preventative 1 and Preventative 2" refers to two different experiments examining the effects of 4 months of administration of -flurbiprofen to Tg2576 mice. "Therapeutic" refers to 2 weeks administration of -flurbiprofen