Mutations in neuroligin-3 in male mice impact behavioral flexibility but not relational memory in a touchscreen test of visual transitive inference

Cognitive dysfunction including disrupted behavioral flexibility is central to neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). A cognitive measure that assesses relational memory, and the ability to flexibly assimilate and transfer learned information is transitive inference. Transitive inference is highly conserved across vertebrates and disrupted in cognitive disorders. Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility. We first refined a rodent touchscreen assay to measure visual transitive inference, then assessed two mouse models of Nlgn3 dysfunction (Nlgn3−/y and Nlgn3R451C). Deep analysis of touchscreen behavioral data at a trial level established we could measure trajectories in flexible responding and changes in processing speed as cognitive load increased. We show that gene mutations in Nlgn3 do not disrupt relational memory, but significantly impact flexible responding. Our study presents the first analysis of reaction times in a rodent transitive inference test, highlighting response latencies from the touchscreen system are useful indicators of processing demands or decision-making processes. These findings expand our understanding of how dysfunction of key components of synaptic signaling complexes impact distinct cognitive processes disrupted in neurodevelopmental disorders, and advance our approaches for dissecting rodent behavioral assays to provide greater insights into clinically relevant cognitive symptoms

Volume-based referral for cardiovascular procedures in the United States: a cross-sectional regression analysis

BACKGROUND: We sought to estimate the numbers of patients affected and deaths avoided by adopting the Leapfrog Group's recommended hospital procedure volume minimums for coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI). In addition to hospital risk-adjusted mortality standards, the Leapfrog Group recommends annual hospital procedure minimums of 450 for CABG and 400 for PCI to reduce procedure-associated mortality. METHODS: We conducted a retrospective analysis of a national hospital discharge database to evaluate in-hospital mortality among patients who underwent PCI (n = 2,500,796) or CABG (n = 1,496,937) between 1998 and 2001. We calculated the number of patients treated at low volume hospitals and simulated the number of deaths potentially averted by moving all patients to high volume hospitals under best-case conditions (i.e., assuming the full volume-associated reduction in mortality and the capacity to move all patients to high volume hospitals with no related harms). RESULTS: Multivariate adjusted odds of in-hospital mortality were higher for patients treated in low volume hospitals compared with high volume hospitals for CABG (OR 1.16, 95% CI 1.10–1.24) and PCI (OR 1.12, 95% CI 1.05–1.20). A policy of hospital volume minimums would have required moving 143,687 patients for CABG and 87,661 patients for PCI from low volume to high volume hospitals annually and prevented an estimated 619 CABG deaths and 109 PCI deaths. Thus, preventing a single death would have required moving 232 CABG patients or 805 PCI patients from low volume to high volume hospitals. CONCLUSION: Recommended hospital CABG and PCI volume minimums would prevent 728 deaths annually in the United States, fewer than previously estimated. It is unclear whether a policy requiring the movement of large numbers of patients to avoid relatively few deaths is feasible or effective

Suppression of ABCE1-mediated mRNA translation limits N-MYC-driven cancer progression

The ability of the N-MYC transcription factor to drive cancer progression is well demonstrated in neuroblastoma, the most common extracranial pediatric solid tumor, where MYCN amplification heralds a poor prognosis, with only 11% of high-risk patients surviving past 5 years. However, decades of attempts of direct inhibition of N-MYC or its paralogues has led to the conclusion that this protein is “undruggable.” Therefore, targeting pathways upregulated by N-MYC signaling presents an alternative therapeutic approach. Here, we show that MYCN-amplified neuroblastomas are characterized by elevated rates of protein synthesis and that high expression of ABCE1, a translation factor directly upregulated by N-MYC, is itself a strong predictor of poor clinical outcome. Despite the potent ability of N-MYC in heightening protein synthesis and malignant characteristics in cancer cells, suppression of ABCE1 alone selectively negated this effect, returning the rate of translation to baseline levels and significantly reducing the growth, motility, and invasiveness of MYCN-amplified neuroblastoma cells and patient-derived xenograft tumors in vivo. The growth of nonmalignant cells or MYCN-nonamplified neuroblastoma cells remained unaffected by reduced ABCE1, supporting a therapeutic window associated with targeting ABCE1. Neuroblastoma cells with c-MYC overexpression also required ABCE1 to maintain cell proliferation and translation. Taken together, ABCE1-mediated translation constitutes a critical process in the progression of N-MYC-driven and c-MYC-driven cancers that warrants investigations into methods of its therapeutic inhibition

A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through Gq/11and Gi/oto stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-functionCASRmutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca2+iresponses. We report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing CaSRR680Gin HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+iresponses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11and Gi/oand was mediated instead by a noncanonical pathway involving β-arrestin proteins. Homology modeling and mutagenesis studies showed that the R680G CaSR mutation selectively enhanced β-arrestin signaling by disrupting a salt bridge formed between Arg680and Glu767, which are located in CaSR transmembrane domain 3 and extracellular loop 2, respectively. Thus, our results demonstrate CaSR signaling through β-arrestin and the importance of the Arg680-Glu767salt bridge in mediating signaling bias

Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and meta-analysis

: EPHPP quality rating scores (DOCX 38 kb

Characteristics of optimum falls prevention exercise programmes for community-dwelling older adults using the FITT principle

peer-reviewedThis review aims to identify the optimal exercise intervention characteristics for falls prevention among community-dwelling adults aged 60 years and over. Articles for inclusion were sourced by searching the Academic Search Premier, AMED, Biomedical Reference Collection: Expanded, CINAHL Plus, MEDLINE and SPORTDiscus databases with the key words ‘falls’, ‘prevention’, ‘exercise’ and ‘community’ and via reference lists of relevant articles. Only articles of level 1 or level 2 evidence (Howick et al. 2011) were included. Other inclusion criteria included recording falls incidence as an outcome measure, examining a community-dwelling population aged 60 years or over and implementing exercise as a single intervention in at least one group. Exercise programme characteristics from 31 articles were examined according to their frequency, intensity, time and type and their effects on falls incidence were reviewed. Exercising for a minimum of 1 h/week for at least 40 h over the course of an intervention is required to successfully reduce falls incidence. The optimal exercise frequency is three times per week, but the optimal duration per bout remains unclear. Specific balance training of sufficiently challenging intensity is a vital programme component, and strength training is most effective when combined with balance training. Flexibility and endurance training may also be included as part of a comprehensive programme. A combination of group and individual home exercise may be most effective for preventing falls and promoting exercise adherence

Variations in clinical decision-making between cardiologists and cardiac surgeons; a case for management by multidisciplinary teams?

OBJECTIVE: To assess variations in decisions to revascularise patients with coronary heart disease between general cardiologists, interventional cardiologists and cardiac surgeons DESIGN: Six cases of coronary heart disease were presented at an open meeting in a standard format including clinical details which might influence the decision to revascularise. Clinicians (n = 53) were then asked to vote using an anonymous electronic system for one of 5 treatment options: medical, surgical (CABG), percutaneous coronary intervention (PCI) or initially medical proceeding to revascularisation if symptoms dictated. Each case was then discussed in an open forum following which clinicians were asked to revote. Differences in treatment preference were compared by chi squared test and agreement between groups and between voting rounds compared using Kappa. RESULTS: Surgeons were more likely to choose surgery as a form of treatment (p = 0.034) while interventional cardiologists were more likely to choose PCI (p = 0.056). There were no significant differences between non-interventional and interventional cardiologists (p = 0.13) in their choice of treatment. There was poor agreement between all clinicians in the first round of voting (Kappa 0.26) but this improved to a moderate level of agreement after open discussion for the second vote (Kappa 0.44). The level of agreement among surgeons (0.15) was less than that for cardiologists (0.34) in Round 1, but was similar in Round 2 (0.45 and 0.45 respectively) CONCLUSION: In this case series, there was poor agreement between cardiac clinical specialists in the choice of treatment offered to patients. Open discussion appeared to improve agreement. These results would support the need for decisions to revascularise to be made by a multidisciplinary panel

Design and Implementation of Degenerate Microsatellite Primers for the Mammalian Clade

Microsatellites are popular genetic markers in molecular ecology, genetic mapping and forensics. Unfortunately, despite recent advances, the isolation of de novo polymorphic microsatellite loci often requires expensive and intensive groundwork. Primers developed for a focal species are commonly tested in a related, non-focal species of interest for the amplification of orthologous polymorphic loci; when successful, this approach significantly reduces cost and time of microsatellite development. However, transferability of polymorphic microsatellite loci decreases rapidly with increasing evolutionary distance, and this approach has shown its limits. Whole genome sequences represent an under-exploited resource to develop cross-species primers for microsatellites. Here we describe a three-step method that combines a novel in silico pipeline that we use to (1) identify conserved microsatellite loci from a multiple genome alignments, (2) design degenerate primer pairs, with (3) a simple PCR protocol used to implement these primers across species. Using this approach we developed a set of primers for the mammalian clade. We found 126,306 human microsatellites conserved in mammalian aligned sequences, and isolated 5,596 loci using criteria based on wide conservation. From a random subset of ∼1000 dinucleotide repeats, we designed degenerate primer pairs for 19 loci, of which five produced polymorphic fragments in up to 18 mammalian species, including the distinctly related marsupials and monotremes, groups that diverged from other mammals 120–160 million years ago. Using our method, many more cross-clade microsatellite loci can be harvested from the currently available genomic data, and this ability is set to improve exponentially as further genomes are sequenced

Patient complexity in quality comparisons for glycemic control: An observational study

<p>Abstract</p> <p>Background</p> <p>Patient complexity is not incorporated into quality of care comparisons for glycemic control. We developed a method to adjust hemoglobin A1c levels for patient characteristics that reflect complexity, and examined the effect of using adjusted A1c values on quality comparisons.</p> <p>Methods</p> <p>This cross-sectional observational study used 1999 national VA (US Department of Veterans Affairs) pharmacy, inpatient and outpatient utilization, and laboratory data on diabetic veterans. We adjusted individual A1c levels for available domains of complexity: age, social support (marital status), comorbid illnesses, and severity of disease (insulin use). We used adjusted A1c values to generate VA medical center level performance measures, and compared medical center ranks using adjusted versus unadjusted A1c levels across several thresholds of A1c (8.0%, 8.5%, 9.0%, and 9.5%).</p> <p>Results</p> <p>The adjustment model had R²= 8.3% with stable parameter estimates on thirty random 50% resamples. Adjustment for patient complexity resulted in the greatest rank differences in the best and worst performing deciles, with similar patterns across all tested thresholds.</p> <p>Conclusion</p> <p>Adjustment for complexity resulted in large differences in identified best and worst performers at all tested thresholds. Current performance measures of glycemic control may not be reliably identifying quality problems, and tying reimbursements to such measures may compromise the care of complex patients.</p

Impact of treatment policies on patient outcomes and resource utilization in acute cholecystitis in Japanese hospitals

BACKGROUND: Although currently available evidence predominantly recommends early laparoscopic cholecystectomy (LC) for the treatment of acute cholecystitis, this strategy has not been widely adopted in Japan. Herein, we describe a hospital-based study of patients with acute cholecystitis in 9 Japanese teaching hospitals in order to evaluate the impact of different institutional strategies in treating acute cholecystitis on overall patient outcomes and medical resource utilization. METHODS: From an administrative database and chart review, we identified 228 patients diagnosed with acute cholecystitis who underwent cholecystectomy between April 2001 and June 2003. In order to examine the relationship between hospitals' propensity to perform LC and patient outcomes and/or medical resource utilization, we divided the hospitals into three groups according to the observed to expected ratio of performing LC (LC propensity), and compared the postoperative complication rate, length of hospitalization (LOS), and medical charges. RESULTS: No hospital adopted the policy of early surgery, and the mean overall LOS among the subjects was 30.9 days. The use of laparoscopic surgery varied widely across the hospitals; the adjusted rates of LC to total cholecystectomies ranged from 9.5% to 77%. Although intra-operative complication rate was significantly higher among patients whom LC was initially attempted when compared to those whom OC was initially attempted (9.7% vs. 0%), there was no significant association between LC propensity and postoperative complication rates. Although the postoperative time to oral intake and postoperative LOS was significantly shorter in hospitals with high use of LC, the overall LOS did not differ among hospital groups with different LC propensities. Medical charges were not associated with LC propensity. CONCLUSION: Under the prevailing policy of delayed surgery, in terms of the postoperative complication rate and medical resource utilization, our study did not show the superiority of LC in treating acute cholecystitis patients. The timing of surgery and discharge was mainly determined by the institutional policy in Japan, rather than by the clinical course of the patient; however, considering the substantially less postoperative pain and shorter recovery time of LC compared to OC, LC should be actively applied for the treatment of acute cholecystitis. If the policy of early surgery were universally applied, the advantage of LC over OC may be more clearly demonstrated