PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS

The Drosophila DmGluRA is required for social interaction and memory

Metabotropic glutamate receptors (mGluRs) have well-established roles in cognition and social behavior in mammals. Whether or not these roles have been conserved throughout evolution from invertebrate species is less clear. Mammals have eight mGluRs whereas Drosophila has a single DmGluRA, which has both Gi and Gq coupled signaling activity. We have utilized Drosophila to examine the role of DmGluRA in social behavior and various phases of memory. We have found that flies that are homozygous or heterozygous for loss of function mutations of DmGluRA have impaired social behavior in male Drosophila. Futhermore, flies that are heterozygous for loss of function mutations of DmGluRA have impaired learning during training, immediate-recall memory, short-term memory, and long-term memory as young adults. This work demonstrates a role for mGluR activity in both social behavior and memory in Drosophila

Near fatal posterior reversible encephalopathy syndrome complicating chronic liver failure and treated by induced hypothermia and dialysis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Posterior reversible encephalopathy syndrome is a clinico-neuroradiological entity characterized by headache, vomiting, altered mental status, blurred vision and seizures with neuroimaging studies demonstrating white-gray matter edema involving predominantly the posterior region of the brain.</p> <p>Case presentation</p> <p>We report a 47-year-old Caucasian man with liver cirrhosis who developed posterior reversible encephalopathy syndrome following an upper gastrointestinal hemorrhage and who was managed with induced hypothermia for control of intracranial hypertension and continuous veno-venous hemodiafiltration for severe hyperammonemia.</p> <p>Conclusion</p> <p>We believe this is the first documented case report of posterior reversible encephalopathy syndrome associated with cirrhosis as well as the first report of the use of induced hypothermia and continuous veno-venous hemodiafiltration in this setting.</p

Post-stroke infection: A systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p><b>s</b>troke is the main cause of disability in high-income countries, and ranks second as a cause of death worldwide. Patients with acute stroke are at risk for infections, but reported post-stroke infection rates vary considerably. We performed a systematic review and meta-analysis to estimate the pooled post-stroke infection rate and its effect on outcome.</p> <p>Methods</p> <p>MEDLINE and EMBASE were searched for studies on post-stroke infection. Cohort studies and randomized clinical trials were included when post-stroke infection rate was reported. Rates of infection were pooled after assessment of heterogeneity. Associations between population- and study characteristics and infection rates were quantified. Finally, we reviewed the association between infection and outcome.</p> <p>Results</p> <p>87 studies were included involving 137817 patients. 8 studies were restricted to patients admitted on the intensive care unit (ICU). There was significant heterogeneity between studies (P < 0.001, I²= 97%). The overall pooled infection rate was 30% (24-36%); rates of pneumonia and urinary tract infection were 10% (95% confidence interval [CI] 9-10%) and 10% (95%CI 9-12%). For ICU studies, these rates were substantially higher with 45% (95% CI 38-52%), 28% (95%CI 18-38%) and 20% (95%CI 0-40%). Rates of pneumonia were higher in studies that specifically evaluated infections and in consecutive studies. Studies including older patients or more females reported higher rates of urinary tract infection. Pneumonia was significantly associated with death (odds ratio 3.62 (95%CI 2.80-4.68).</p> <p>Conclusions</p> <p>Infection complicated acute stroke in 30% of patients. Rates of pneumonia and urinary tract infection after stroke were 10%. Pneumonia was associated with death. Our study stresses the need to prevent infections in patients with stroke.</p

Profiles in patient safety: When an error occurs

Medical error is now clearly established as one of the most significant problems facing the American health care system. Anecdotal evidence, studies of human cognition, and analysis of high-reliability organizations all predict that despite excellent training, human error is unavoidable. When an error occurs and is recognized, providers have a duty to disclose the error. Yet disclosure of error to patients, families, and hospital colleagues is a difficult and/or threatening process for most physicians. A more thorough understanding of the ethical and social contract between physicians and their patients as well as the professional milieu surrounding an error may improve the likelihood of its disclosure. Key among these is the identification of institutional factors that support disclosure and recognize error as an unavoidable part of the practice of medicine. Using a case-based format, this article focuses on the communication of error with patients, families, and colleagues and grounds error disclosure in the cultural milieu of medial ethics

Integrating Quality Improvement With Graduate Medical Education: Lessons Learned From the AIAMC National Initiatives

Quality and safety initiatives (QI) are national priorities for health care, yet the role of residents in QI has not always been clear. In academic medical centers, residents and fellows play a critical role in patient care and, as such, their integration into QI presents a unique opportunity to affect change. The Alliance for Independent Academic Medical Centers (AIAMC) began a national campaign in 2007 to harness the potential of infusing graduate medical education (GME) with QI, through their AIAMC National Initiative: Improving Patient Care Through Medical Education. This article describes the National Initiatives (NIs) and the reflections of NI participants, including their reflections on the goals they set for integrating GME with QI, the barriers they encountered along the way, and their advice to others beginning the challenge. These reflections provide some insight into the pathways of promoting organizational change and offer practical insight and inspiring advice for others embarking on the journey

Derivation and initial application of a standard population for out-of-hospital cardiac arrest (SPOHCA)

Aim: While adjusting data for age, sex, race and/or socio-economic status is well established in out-of-hospital cardiac arrest (OHCA) research, there are shortcomings to reporting and comparing population-based OHCA outcomes. The purpose of this study was to derive a case-based standard population specific to EMS treated adult OHCA (SPOHCA) in the U.S., and demonstrate its application.\ud \ud Methods: The proposed SPOHCA was developed from three sources of multi-site OHCA data: the Cardiac Arrest Registry to Enhance Survival (CARES); the National EMS Information System (NEMSIS); and a published report from the Resuscitation Outcomes Consortium (ROC). OHCA data from a single EMS system were then used to demonstrate the application of SPOHCA. We report raw survival, population-based survival adjusted to the U.S. population, and the new SPOHCA-adjusted survival.\ud \ud Results: Observed raw survival was 12.3%. Adjustment to the demographic make-up of the adult U.S. population produced an adjusted incidence of 94.2 OHCA per 100,000 p-y, with a survival rate of 9.8 per 100,000 p-y. Using the proposed SPOHCA to adjust survival data produced an adjusted survival rate of 12.4%.\ud \ud Conclusion: A case-based standard population provides for more practical interpretation of reported OHCA outcomes. We encourage a more widespread effort involving multiple stakeholders to further explore the effects of adjusting OHCA outcomes using the proposed SPOHCA instead of population-based demographics

Getting doctors to clean their hands: lead the followers

BACKGROUND: Despite ample evidence that hand hygiene (HH) can reduce nosocomial infections, physician compliance remains low. The authors hypothesised that attending physician role modelling and peer pressure among internal medicine teams would impact HH adherence. METHODS: Nine teams were covertly observed. Team member entry and exit order, and adherence to HH were recorded secretly. The mean HH percentage across encounters was estimated by compliance of the first person entering and exiting an encounter, and by the attending physician\u27s HH compliance. RESULTS: 718 HH opportunities prior to contact and 744 opportunities after contact were observed. If the first person entering a patient encounter performed HH, the mean compliance of other team members was 64%, but was only 45% if the first person failed to perform HH (p=0.002). When the attending physician performed HH upon entering the patient encounter, the mean HH compliance was 66%, but only 42% if the attending physician did not perform HH (p\u3c0.001). Similar results were seen on exiting the room. The effects of the first person were not driven solely by the attending physician\u27s HH behaviour because the attending physician was first or second to enter 57% of the encounters and exit 44% of the encounters. CONCLUSIONS: If the first person entering a patient room performs HH, then others were more likely to perform HH too, implying that peer pressure impacts team member HH compliance. The attending physician\u27s behaviour also influenced team members regardless of whether the attending physician was the first to enter or exit an encounter, implying that role modelling impacts the HH behaviour of learners. These findings should be used when designing HH improvement programmes targeting physicians