Electrical and Network Neuronal Properties Are Preferentially Disrupted in Dorsal, But Not Ventral, Medial Entorhinal Cortex in a Mouse Model of Tauopathy.

The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal-ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30-80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia. SIGNIFICANCE STATEMENT: The medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia.

A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity.

Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer's disease, progressive supranuclear palsy, Pick's disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as 'tau propagation' and may explain the stereotypic progression of tau pathology in the brains of Alzheimer's disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.

Intraoperative liposomal bupivacaine for skin graft donor site analgesia: A retrospective cohort study.

INTRODUCTION: Burn injury and reconstructive operations often result in severe pain, particularly at skin graft donor sites. Traditional local anesthetics administered intraoperatively control pain at donor sites, but the duration of action is short. Liposomal bupivacaine, a novel local anesthetic, can provide sustained-release analgesia for 72h. The primary aim of this study was to describe the efficacy of liposomal bupivacaine for postoperative donor site pain control for patients undergoing skin graft procedures. METHODS: A retrospective cohort study was performed on patients who received a donor site liposomal bupivacaine field block and was compared to a matched control. Patients rated donor site pain on post-operative day 0 and 1, and stated whether the donor or graft site was more painful. RESULTS: Fifty-eight patients were included. Twenty-nine patients received liposomal bupivacaine. Eighty-six percent of patients in the treatment group rated donor site pain as three or less on postoperative day 0 and 1, compared to 3.4% in the control (p<0.0001). Also, 76% of patients in the treatment group stated donor site pain was less than graft site pain, compared to 3.4% in the control (p<0.0001). CONCLUSION: Patients who received liposomal bupivacaine reported less postoperative donor site pain and found the donor site to be less bothersome without major complications. Liposomal bupivacaine may be a safe and promising agent for prolonging postoperative analgesia and minimizing donor site pain.

Automated external defibrillators and simulated in-hospital cardiac arrests.

OBJECTIVE: To test the hypothesis that pediatric residents would have shorter time to attempted defibrillation using automated external defibrillators (AEDs) compared with manual defibrillators (MDs). STUDY DESIGN: A prospective, randomized, controlled trial of AEDs versus MDs was performed. Pediatric residents responded to a simulated in-hospital ventricular fibrillation cardiac arrest and were randomized to using either an AED or MD. The primary end point was time to attempted defibrillation. RESULTS: Sixty residents, 21 (35%) interns, were randomized to 2 groups (AED = 30, MD = 30). Residents randomized to the AED group had a significantly shorter time to attempted defibrillation [median, 60 seconds (interquartile range, 53 to 71 seconds)] compared with those randomized to the MD group [median, 103 seconds (interquartile range, 68 to 288 seconds)] (P < .001). All residents in the AED group attempted defibrillation at <5 minutes compared with 23 (77%) in the MD group (P = .01). CONCLUSIONS: AEDs improve the time to attempted defibrillation by pediatric residents in simulated cardiac arrests. Further studies are needed to help determine the role of AEDs in pediatric in-hospital cardiac arrests.

The exploration of rotenone as a toxin for inducing Parkinson's disease in rats, for application in BBB transport and PK-PD experiments.

INTRODUCTION: In search for a suitable rat model to study potentially affected blood-brain barrier (BBB) transport mechanisms in the course of Parkinsons disease (PD) progression, experiments were performed to characterise Parkinsons disease markers following subcutaneous (SC) and intracerebral (IC) infusion of the toxin rotenone in the rat. METHODS: Studies were performed using Male Lewis rats. SC infusion of rotenone (3 mg/kg/day) was performed via an osmotic minipump. IC infusion of rotenone occurred directly into the right medial forebrain bundle at three different dosages. At different times following rotenone infusion, behaviour, histopathology (tyrosine hydroxylase and alpha-synuclein immunocytochemistry), peripheral organ pathology (adrenals, heart, kidney, liver, lung, spleen and stomach) were assessed. In part of the SC and IC rats, BBB transport profiles of the permeability marker sodium fluorescein were determined using microdialysis. RESULTS: SC rotenone failed to produce dopaminergic lesions and led to extensive peripheral organ toxicity. BBB permeability for fluorescein following SC rotenone was changed, however due peripheral toxicity. In contrast, IC rotenone produced a progressive lesion of the nigrostrial dopaminergic pathway over 28 days with no associated peripheral toxicity. IC rotenone also exhibited a large increase in amphetamine induced rotational behaviour. In addition, a few IC rats showed alpha-synuclein immunoreactivity and aggregation. Following IC rotenone, no changes in BBB permeability were detected after 14 days. DISCUSSION: SC rotenone only produced peripheral toxicity. IC rotenone appeared to create a progressive lesion of the rat nigrostrial pathway, and may therefore be a more appropriate model of Parkinson's disease progression, compared with the most commonly used 6-OH-DA rat model.

What is a clinical pearl and what is its role in medical education?

BACKGROUND: Despite the advent of evidence-based medicine, clinical pearls, verbal and published, remain a popular and important part of medical education. AIMS: The purpose of this study was to establish a definition of a clinical pearl and to determine criteria for an educationally sound clinical pearl. METHODS: The authors searched the Medline database for material dealing with clinical pearls, examined and discussed the information found, and formulated a consensus opinion regarding the definition and criteria. RESULTS: Clinical pearls are best defined as small bits of free standing, clinically relevant information based on experience or observation. They are part of the vast domain of experience-based medicine, and can be helpful in dealing with clinical problems for which controlled data do not exist. CONCLUSIONS: While there are no universally accepted criteria for preparing or evaluating a clinical pearl, we propose some rational guidelines for both.

Impact of the final adjective in the Medical Student Performance Evaluation on determination of applicant desirability.

BACKGROUND: The Medical Student Performance Evaluation (MSPE) is a primary source of information used by residency programs in their selection of trainees. The MSPE contains a narrative description of the applicant's performance during medical school. In 2002, the Association of American Medical Colleges' guideline for preparation of the MSPE recommended inclusion of a comparative summative assessment of the student's overall performance relative to his/her peers (final adjective). OBJECTIVE: We hypothesize that the inclusion of a final adjective in the MSPE affects a reviewer's assessment of the applicant's desirability more than the narrative description of performance and designed a study to evaluate this hypothesis. DESIGN: Fifty-six faculty members from the Departments of Pediatrics and Medicine with experience reviewing MSPEs as part of the intern selection process reviewed two pairs of mock MSPE letters. In each pair, the narrative in one letter was superior to that in the other. Two final adjectives describing relative class ranks were created. Each subject was first presented with a pair of letters with mismatched final adjective (study), i.e., the letter with the stronger narrative was presented with the weaker final adjective and vice versa. The subject was then presented with a second pair of letters without final adjectives (control). Subjects ranked the relative desirability of the two applicants in each pair. RESULTS: The proportion of rankings congruent with the strength of the narratives under study and control conditions were compared. Subjects were significantly less likely to rank the applicants congruent with the strength of the narratives when the strength of the final adjectives conflicted with the strength of the narrative; 42.9% of study letters were ranked congruent with the narrative versus 82.1% of controls (p = 0.0001). CONCLUSION: The MSPE final adjective had a greater impact than the narrative description of performance on the determination of applicant desirability. ABBREVIATIONS: MSPE: Medical Student Performance Evaluation; AAMC: Association of American Medical Colleges; BCM: Baylor College of Medicine.

A theory-informed, process-oriented Resident Scholarship Program.

BACKGROUND: The Accreditation Council for Graduate Medical Education requires residency programs to provide curricula for residents to engage in scholarly activities but does not specify particular guidelines for instruction. We propose a Resident Scholarship Program that is framed by the self-determination theory (SDT) and emphasize the process of scholarly activity versus a scholarly product. METHODS: The authors report on their longitudinal Resident Scholarship Program, which aimed to support psychological needs central to SDT: autonomy, competence, and relatedness. By addressing those needs in program aims and program components, the program may foster residents' intrinsic motivation to learn and to engage in scholarly activity. To this end, residents' engagement in scholarly processes, and changes in perceived autonomy, competence, and relatedness were assessed. RESULTS: Residents engaged in a range of scholarly projects and expressed positive regard for the program. Compared to before residency, residents felt more confident in the process of scholarly activity, as determined by changes in increased perceived autonomy, competence, and relatedness. Scholarly products were accomplished in return for a focus on scholarly process. CONCLUSIONS: Based on our experience, and in line with the SDT, supporting residents' autonomy, competence, and relatedness through a process-oriented scholarship program may foster the curiosity, inquisitiveness, and internal motivation to learn that drives scholarly activity and ultimately the production of scholarly products.

Amphetamine promotes task-dependent recovery following focal cortical ischaemic lesions in the rat.

This study investigated the effect of amphetamine (AMP) on skilled forelimb use following focal cortical ischaemic lesions in the rat. Unilateral lesions were produced by a novel method of intracortical microinjection of endothelin-1 (ET-1), intended to principally target the forelimb representation zone in primary motor-primary somatosensory cortex. Lesions were placed in the hemisphere contralateral to the preferred limb and produced deficits in skilled forelimb use on two tasks: the paw reach (PR) test and the foot fault (FF) test. Beginning on post-lesion day (D) 2, animals received injections of 2 mg/kg AMP and were injected every third day until D26. Animals were tested both during, and 24 h after, AMP administration. AMP facilitated recovery of skilled forelimb use on the PR test when assessed during drug-free test sessions. No such effect was seen on the FF test. These results demonstrate that sub-acute administration of AMP following a unilateral focal ischaemic lesion of FL can facilitate task-dependent recovery of skilled forelimb use in the rat. They also demonstrate that different behavioural tasks measuring superficially similar behavioural outputs may show different sensitivities to such drug effects.

Learning across the explicit, implicit, and extra-curricula: an exploratory study of the relative proportions of residents' perceived learning in clinical areas at three pediatric residency programs.

PURPOSE: This exploratory multisite study investigated relative proportions of residents' perceived learning across the explicit, implicit (typically called hidden or informal), and extra-curricula for six Clinical Learning Environment Review (CLER) focus areas-patient safety, health care quality, care transitions, supervision, fatigue management, and professionalism-using qualitative and numeric data. METHOD: In April through June 2013, the authors recruited and interviewed third-year categorical pediatric residents from three sites. For each CLER focus area, the authors asked residents to think aloud while they assigned a total of 60 points to the explicit, implicit, and extra-curricula, according to where they perceived their learning occurred. All interviews were audio taped and transcribed verbatim. The authors coded qualitative data from interviews using the constant comparative method, scrutinized qualitative data for themes, and reviewed qualitative and numeric data. RESULTS: A total of 28/79 (35%) residents participated. Residents perceived learning to occur most often in the implicit curriculum for five of the six CLER focus areas; the one exception being health care quality, which predominantly took place in the explicit curriculum. In the implicit curriculum, role modeling and "learning by doing" were frequently reported modes of learning. The explicit curriculum was perceived as an important baseline for understanding clinical areas. Relatively less learning was perceived to occur in the extra-curriculum. CONCLUSIONS: The authors believe that recognizing learning in "other-than-explicit" curricula could broaden the medical education community's understanding of the purview of the medical education curriculum and help educators tap into underused educational opportunities for important clinical topics.

The neuronal nitric oxide synthase inhibitor, TRIM, as a neuroprotective agent: effects in models of cerebral ischaemia using histological and magnetic resonance imaging techniques.

Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are subsequently dismissed as relatively ineffective when entered into large-scale clinical trials. Many pre-clinical studies of potential neuroprotective candidates evaluate efficacy in only one or possibly two different models of ischaemia. In this study we examined the effects of 1,2-trifluoromethylphenyl imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor, in three models of cerebral ischaemia (global gerbil, global rat and focal rat). In addition, to follow the progression of the pathology, we also compared traditional histology methods with more advanced magnetic resonance imaging (MRI) as endpoint measures for neurological damage and neuroprotection. TRIM (50 mg/kg i.p.) prevented ischaemia-induced hippocampal damage following global ischaemia in gerbils when administered before or immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. Further studies indicated that the compound (administered at 50 mg/kg, i.p., immediately after occlusion) also protected in a rat four-vessel occlusion (4-VO) model using both histological and diffusion-weighted (DW) imaging techniques. In a final study, TRIM (50 mg/kg i.p. 30 min after occlusion) provided a significant reduction in infarct volume at 4 and 24 h as measured using diffusion-weighted (DW) and proton density (PD)-weighted magnetic resonance imaging (MRI). This was confirmed using histological techniques. These studies confirm that nNOS inhibitors may have utility in stroke and provide evidence that combined magnetic resonance and histological methods can provide a powerful method of assessing neuronal damage in rodent models of cerebral ischaemia.

Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson's disease.

Recent developments in the molecular biology and pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and evidence suggests that they play important roles in plasticity and cognitive processes. Activation of AMPA receptors also increases neuronal activation and activity-dependent signalling, which may increase brain-derived neurotrophic factor (BDNF) expression and enhance cell proliferation in the brain. We therefore hypothesised that an AMPA receptor potentiator may provide neurotrophic effects in rodent models of Parkinson's disease. In the present studies we report that the potent and selective AMPA receptor potentiator, R,S-N-2-(4-(4-Cyanophenyl)phenyl)propyl 2-propanesulfonamide (LY404187), provides both functional, neurochemical and histological protection against unilateral infusion of 6-hydroxydopamine into the substantia nigra or striatum of rats. The compound also reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice. Interestingly, we were also able to observe large functional and histological effects when we delayed treatment until after cell death had occurred (3 or 6 days after 6-hydroxydopamine infusion), supporting a neurotrophic mechanism of action. In addition, LY404187 provided a dose-dependent increase in growth-associated protein-43 expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new therapy to halt the progression and perhaps repair the degeneration in Parkinson's disease.

Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson's disease.

The aim of the present studies was to examine the ability of a potent, systemically active, selective Group II mGlu receptor (mGluR2/3) agonist, 1R,4R,5S,6R-2-oxa-4-minobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) to provide both functional relief and neuroprotection in rodent models of Parkinson's disease (PD). In functional studies, intracerebroventricular administration of LY379268 (1, 5, 10, 20 nmol/2 microl) produced a dose-dependent increase in locomotor activity in the reserpine (5 mg/kg ip)-treated rat. In contrast, systemic administration of LY379268 (0.1, 1, 10 mg/kg ip) did not reverse reserpine-induced akinesia and failed to effect rotational behaviour 1 month after unilateral lesioning of the nigrostriatal tract by 6-hydroxydopamine (6-OHDA; 4 microg infused into the substantia nigra (SN)). In neuroprotective studies, animals were treated with LY379268 (10 mg/kg/day ip) either for 7 days following 6-OHDA injection into the SN (4 microg) or for 21 days following 6-OHDA injection into the striatum (10 microg) before measurement of tyrosine hydroxylase immunoreactivity in the striatum and/or SN as an index of neuroprotection. LY379268 provided some protection against nigral infusion of 6-OHDA and also some functional improvement and correction of dopamine turnover was observed. The compound also provided significant protection in the striatum and some protection in the SN against striatal infusion of 6-OHDA. These data suggest that activation of Group II mGlu receptors can provide some protection in models of PD, while their role in providing functional improvement is less clear.

Third place winner. Three-year-old female with intermittent ovarian torsion.

We report an atypical case of ovarian torsion, an uncommon cause of abdominal pain in a very young girl. She presented with intermittent episodes of groin and thigh pain over a 10-week period. The child had minimal objective findings at the time of each evaluation. Despite the delay in diagnosis, the ovary was preserved. Despite its rarity, ovarian torsion must be considered in the differential diagnosis of abdominal pain in young girls.

Etomidate versus pentobarbital for sedation of children for head and neck CT imaging.

OBJECTIVES: We compare etomidate to pentobarbital for sedation of children for head and neck computed tomography imaging. METHODS: We performed a prospective, randomized, double-blinded trial of patients aged 6 months to 6 years enrolled from the emergency department or radiology department at a large urban children's hospital. The primary outcome measure was sedation success rate. RESULTS: A total of 61 patients were enrolled in the study (27 etomidate group, 34 pentobarbital group) at 2 different dosing regimens for etomidate. The final analysis group included 17 etomidate patients and 33 pentobarbital patients. The success rate for the etomidate group was 57% at total doses of up to 0.3 mg/kg (n = 7) and 76% at total doses of up to 0.4 mg/kg (n = 17), in contrast to a success rate of 97% for pentobarbital at a total dose of up to 5 mg/kg (n = 33). The success rate for pentobarbital was significantly greater than the final etomidate group (P = 0.04; difference in proportions 20.5%, 95% CI 1.9% to 44.4%). Patients receiving etomidate had significantly shorter induction times (P = 0.02; difference of means 2.1 minutes, 95% CI 0.35 to 3.86), sedation times (P < 0.001; difference of means 31.3 minutes, 95% CI 24.0 to 38.5), and total examination times (P < 0.001; difference of means 53.1 minutes, 95% CI 40.8 to 65.3). Significantly more parents in the etomidate group perceived their child to be back to baseline by discharge from the hospital (P < 0.001; difference of proportions 60.7, 95% CI 29.1 to 92.4) and expressed fewer concerns about their child's behavior after discharge (P = 0.024; difference of proportions 28.6, 95% CI 6.5 to 50.7). CONCLUSIONS: At the dosing used in this study, pentobarbital is superior to etomidate when comparing success rates for sedation. However, among the successful sedations, the duration of sedation was shorter in the etomidate group than in the pentobarbital group. Pentobarbital is associated with more frequent side effects and parental concerns compared to etomidate.

Well-defined "clickable" copolymers prepared via one-pot synthesis.

Well-defined "clickable" homo- and co-polymers were synthesised using a living polymerisation technique. Specifically propargyl methacrylate was successfully homo- and co-polymerised using group transfer polymerisation, GTP. This one-pot synthesis was performed without the need to protect the acetylenic group. Finally it was confirmed that the acetylenic functional group was unaffected by the polymerisation by clicking with azide 4-azidobenzoic acid.