Early existence and biochemical evolution characterise acutely synaptotoxic PrPSc.

Although considerable evidence supports that misfolded prion protein (PrPSc) is the principal component of "prions", underpinning both transmissibility and neurotoxicity, clear consensus around a number of fundamental aspects of pathogenesis has not been achieved, including the time of appearance of neurotoxic species during disease evolution. Utilizing a recently reported electrophysiology paradigm, we assessed the acute synaptotoxicity of ex vivo PrPSc prepared as crude homogenates from brains of M1000 infected wild-type mice (cM1000) harvested at time-points representing 30%, 50%, 70% and 100% of the terminal stage of disease (TSD). Acute synaptotoxicity was assessed by measuring the capacity of cM1000 to impair hippocampal CA1 region long-term potentiation (LTP) and post-tetanic potentiation (PTP) in explant slices. Of particular note, cM1000 from 30% of the TSD was able to cause significant impairment of LTP and PTP, with the induced failure of LTP increasing over subsequent time-points while the capacity of cM1000 to induce PTP failure appeared maximal even at this early stage of disease progression. Evidence that the synaptotoxicity directly related to PrP species was demonstrated by the significant rescue of LTP dysfunction at each time-point through immuno-depletion of >50% of total PrP species from cM1000 preparations. Moreover, similar to our previous observations at the terminal stage of M1000 prion disease, size fractionation chromatography revealed that capacity for acute synpatotoxicity correlated with predominance of oligomeric PrP species in infected brains across all time points, with the profile appearing maximised by 50% of the TSD. Using enhanced sensitivity western blotting, modestly proteinase K (PK)-resistant PrPSc was detectable at very low levels in cM1000 at 30% of the TSD, becoming robustly detectable by 70% of the TSD at which time substantial levels of highly PK-resistant PrPSc was also evident. Further illustrating the biochemical evolution of acutely synaptotoxic species the synaptotoxicity of cM1000 from 30%, 50% and 70% of the TSD, but not at 100% TSD, was abolished by digestion of immuno-captured PrP species with mild PK treatment (5µg/ml for an hour at 37°C), demonstrating that the predominant synaptotoxic PrPSc species up to and including 70% of the TSD were proteinase-sensitive. Overall, these findings in combination with our previous assessments of transmitting prions support that synaptotoxic and infectious M1000 PrPSc species co-exist from at least 30% of the TSD, simultaneously increasing thereafter, albeit with eventual plateauing of transmitting conformers.

A Virtual Wellness and Learning Communities Program for Medical Students during the COVID-19 Pandemic.

OBJECTIVES: Numerous studies have demonstrated the high risk for burnout and mental illness in medical students. Because of the coronavirus disease 2019 (COVID-19) pandemic, our medical school transitioned to an all-virtual learning environment from March to June 2020, which raised concerns among student leaders and administrators, as reduced interpersonal attachments have known associations with decreased mental health. In an effort to facilitate student well-being during the pandemic, the Virtual Wellness and Learning Communities (VWLC) program was established. VWLC consisted of hour-long events that offered students the opportunity to engage with their peers online. METHODS: More than 20 events and workshops were conducted from March to June 2020, including trivia nights, song and guitar performances, sketching, video editing tutorials, chess lessons, yoga, and personal investing tips. An institutional review board-approved survey to assess the efficacy of the VWLC program was sent to medical student participants and nonparticipants. RESULTS: The overall response rate of this study was 43% (53/123). The response rate for students who attended a VWLC event was 51% (33/65), and the response rate for students who did not attend a VWLC event was 34% (20/58). Of all of the respondents, 85% (45/53) reported a decreased sense of connectivity with peers because of the pandemic, and 40% (21/53) reported a decrease in their sense of wellness. After attending a VWLC event, 79% (26/33) reported an increased sense of peer connectivity, 61% (20/33) reported improved wellness, and 55% (18/33) believed that these events should continue postpandemic to supplement in-person programming. Those who did not attend a virtual event stated that the main barriers to attending were unfamiliarity with attendees and screen fatigue. CONCLUSIONS: The COVID-19 pandemic has worsened medical student well-being and sense of community. VWLC programming may be an effective strategy for promoting medical student wellness and community while social distancing during the COVID-19 pandemic. To our knowledge, this is the first virtual wellness program for promotion of medical student mental health during the COVID-19 pandemic to be described in the literature.

PrPSc Oligomerization Appears Dynamic, Quickly Engendering Inherent M1000 Acute Synaptotoxicity.

Prion diseases are neurodegenerative disorders pathogenically linked to cellular prion protein (PrPC) misfolding into abnormal conformers (PrPSc), with PrPSc underpinning both transmission and synaptotoxicity. Although the biophysical features of PrPSc required to induce acute synaptic dysfunction remain incompletely defined, we recently reported that acutely synaptotoxic PrPSc appeared to be oligomeric. We herein provide further insights into the kinetic and requisite biophysical characteristics of acutely synaptotoxic ex vivo PrPSc derived from the brains of mice dying from M1000 prion disease. Pooled fractions of M1000 PrPSc located within the molecular weight range approximating monomeric PrP (mM1000) generated through size exclusion chromatography were found to harbor acute synaptotoxicity equivalent to preformed oligomeric fractions (oM1000). Subsequent investigation showed mM1000 corresponded to PrPSc rapidly concatenating in physiological buffer to exist as predominantly, closely associated, small oligomers. The oligomerization of PrP in mM1000 could be substantially mitigated by treatment with the antiaggregation compound epigallocatechin gallate, thereby maintaining the PrPSc as primarily nonoligomeric with completely abrogated acute synaptotoxicity; moreover, despite epigallocatechin gallate treatment, pooled oM1000 remained oligomeric and acutely synaptotoxic. A similar tendency to rapid formation of oligomers was observed for PrPC when monomeric fractions derived from size exclusion chromatography of normal brain homogenates (mNBH) were pooled, but neither mNBH nor preformed higher-order NBH complexes (oNBH) were acutely synaptotoxic. Oligomers formed from mNBH could be reduced to mainly monomers (<100 kDa) after enzymatic digestion of nucleic acids, whereas higher-order PrP assemblies derived from pooled mM1000, oM1000, and oNBH resisted such treatment. Collectively, these findings support that oligomerization of PrPSc into small multimeric assemblies appears to be a critical biophysical feature for engendering inherent acute synaptotoxicity, with preformed oligomers found in oM1000 appearing to be stable, tightly self-associated ensembles that coexist in dynamic equilibrium with mM1000, with the latter appearing capable of rapid aggregation, albeit initially forming smaller, weakly self-associated, acutely synaptotoxic oligomers.

The role of lipids in α-synuclein misfolding and neurotoxicity.

The misfolding and aggregation of α-synuclein (αsyn) in the central nervous system is associated with a group of neurodegenerative disorders referred to as the synucleinopathies. In addition to being a pathological hallmark of disease, it is now well-established that upon misfolding, αsyn acquires pathogenic properties, such as neurotoxicity, that can contribute to disease development. The mechanisms that produce αsyn misfolding and the molecular events underlying the neuronal damage caused by these misfolded species are not well-defined. A consistent observation that may be relevant to αsyn's pathogenicity is its ability to associate with lipids. This appears important not only to how αsyn aggregates, but also to the mechanism by which the misfolded protein causes intracellular damage. This review discusses the current literature reporting a role of lipids in αsyn misfolding and neurotoxicity in various synucleinopathy disorders and provides an overview of current methods to assess protein misfolding and pathogenicity both in vitro and in vivo.

Prion acute synaptotoxicity is largely driven by protease-resistant PrPSc species.

Although misfolding of normal prion protein (PrPC) into abnormal conformers (PrPSc) is critical for prion disease pathogenesis our current understanding of the underlying molecular pathophysiology is rudimentary. Exploiting an electrophysiology paradigm, herein we report that at least modestly proteinase K (PK)-resistant PrPSc (PrPres) species are acutely synaptotoxic. Brief exposure to ex vivo PrPSc from two mouse-adapted prion strains (M1000 and MU02) prepared as crude brain homogenates (cM1000 and cMU02) and cell lysates from chronically M1000-infected RK13 cells (MoRK13-Inf) caused significant impairment of hippocampal CA1 region long-term potentiation (LTP), with the LTP disruption approximating that reported during the evolution of murine prion disease. Proof of PrPSc (especially PrPres) species as the synaptotoxic agent was demonstrated by: significant rescue of LTP following selective immuno-depletion of total PrP from cM1000 (dM1000); modestly PK-treated cM1000 (PK+M1000) retaining full synaptotoxicity; and restoration of the LTP impairment when employing reconstituted, PK-eluted, immuno-precipitated M1000 preparations (PK+IP-M1000). Additional detailed electrophysiological analyses exemplified by impairment of post-tetanic potentiation (PTP) suggest possible heightened pre-synaptic vulnerability to the acute synaptotoxicity. This dysfunction correlated with cumulative insufficiency of replenishment of the readily releasable pool (RRP) of vesicles during repeated high-frequency stimulation utilised for induction of LTP. Broadly comparable results with LTP and PTP impairment were obtained utilizing hippocampal slices from PrPC knockout (PrPo/o) mice, with cM1000 serial dilution assessments revealing similar sensitivity of PrPo/o and wild type (WT) slices. Size fractionation chromatography demonstrated that synaptotoxic PrP correlated with PK-resistant species >100kDa, consistent with multimeric PrPSc, with levels of these species >6 ng/ml appearing sufficient to induce synaptic dysfunction. Biochemical analyses of hippocampal slices manifesting acute synaptotoxicity demonstrated reduced levels of multiple key synaptic proteins, albeit with noteworthy differences in PrPo/o slices, while such changes were absent in hippocampi demonstrating rescued LTP through treatment with dM1000. Our findings offer important new mechanistic insights into the synaptic impairment underlying prion disease, enhancing prospects for development of targeted effective therapies.

A charcot-marie-tooth type 1B kindred associated with hemifacial spasm and trigeminal neuralgia.

INTRODUCTION: Charcot-Marie-Tooth (CMT) phenotypes can be distinguished by electrophysiology and genetic analysis but few can be identified by their clinical characteristics. Distinctive phenotypes are useful in identifying affected individuals and providing additional clues about the mechanism of the neuropathy. Cranial neuropathies are uncommon features of CMT, and few reports of familial hemifacial spasm (HFS) and trigeminal neuralgia (TN) have been published. METHODS: Sixty-three members of a large CMT 1B kindred were assessed for signs of peripheral neuropathy and cranial neuropathies then tested for the G163R mutation in the myelin protein zero (MPZ) gene. RESULTS: Of 27 individuals with the G163R mutation in MPZ, 10 had HFS or TN. Co-existing HFS and TN were found in 3 of these and 4 had bilateral HFS or TN. CONCLUSIONS: This kindred exhibits a distinct CMT phenotype characterized by the development of HFS or TN decades after clinical signs of hereditary neuropathy are manifest. Muscle Nerve, 2019.

Does video recording inhibit crime suspects? Evidence from a fully randomized field experiment.

In partnership with a small city police department, we randomly informed or did not inform 122 crime suspects that their interrogations were being video-recorded. Coding of all sessions indicated that camera-informed suspects spoke as often and as much as did those who were not informed; they were as likely to waive Miranda at the outset and later; they were as likely to make admissions and confessions, not just denials; and they were perceived no differently by detectives on a range of dimensions. Looking at distal outcomes, we observed no differences in ultimate case dispositions. In terms of policy and practice, results did not support the hypothesis that recording-even when transparent, as required in 2-party consent states-inhibits suspects or alters case dispositions. At least for now, this conclusion is empirically limited to situations in which cameras are concealed and to interrogations that do not involve juveniles, homicides, or drug crimes, which we a priori excluded from our sample. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Fibromyalgia syndrome and small fiber, early or mild sensory polyneuropathy.

INTRODUCTION: Pain mechanisms in fibromyalgia syndrome (FMS) are not clearly understood. Growing evidence appears to suggest a role for small fiber polyneuropathy (SFPN) in some FMS patients, as measured by epidermal nerve fiber density (ENFD). We aimed to better characterize and distinguish the subset of patients with both fibromyalgia and small fiber, early or mild sensory polyneuropathy (FM-SFSPN). METHODS: 155 FMS patients with neuropathic symptoms completed a Short Form McGill Questionnaire and visual analog scale in addition to having skin biopsies, nerve conduction studies (NCS), and serologic testing. RESULTS: Sural and medial plantar (MP) response amplitudes correlated with ENFD, with markers of metabolic syndrome being more prevalent in this subset of patients. Pain intensity and quality did not distinguish patients. DISCUSSION: The FM-SFSPN subset of patients may be identified through sural and MP sensory NCS and/or skin biopsy but cannot be identified by pain features and intensity. Muscle Nerve 58: 625-630, 2018.

Risky Teen Driving in a Rural Southern State.

OBJECTIVE: Alabama is one of the five US states with the highest teen driving mortality. We recruited teen drivers to participate in a questionnaire regarding high-risk driving behaviors. METHODS: Teens were recruited from a large county school system to participate in a voluntary anonymous survey. Questions were taken in part from the National Youth Risk Behavior Survey. Descriptive statistics and odds ratios with 95% confidence intervals were calculated. RESULTS: A total of 1023 teen drivers participated (46% boys, 47% African American, 39% white, 6% Latino, and 7% other). In all, 526 students (52%) reported inconsistent seat belt use. Half of the teens surveyed reported using a cellular telephone while driving within the past 30 days (51%); 10% admitted to driving after drinking alcoholic beverages in the past 30 days, with 23% saying they had ridden with a driver who had been drinking. CONCLUSIONS: High-risk teen driving behaviors were reported by many of the participants in our study. The majority of teens surveyed do not routinely wear seatbelts. Common misperceptions still exist regarding seatbelts and should be a focus of future education. Future research should focus on parental behaviors and correcting misperceptions of young drivers.

Police reports of mock suspect interrogations: A test of accuracy and perception.

A 2-phased experiment assessed the accuracy and completeness of police reports on mock interrogations and their effects on people's perceptions. In Phase 1, 16 experienced officers investigated a mock crime scene, interrogated 2 innocent suspects-1 described by the experimenter as more suspicious than the other-and filed an incident report. All 32 sessions were covertly recorded; the recordings were later used to assess the reports. In Phase 2, 96 lay participants were presented with a brief summary of the case and then either read 1 police report, read 1 verbatim interrogation transcript, or listened to an audiotape of a session. Results showed that (a) Police and suspects diverged in their perceptions of the interrogations; (b) Police committed frequent errors of omission in their reports, understating their use of confrontation, maximization, leniency, and false evidence; and (c) Phase 2 participants who read a police report, compared to those who read a verbatim transcript, perceived the process as less pressure-filled and were more likely to misjudge suspects as guilty. These findings are limited by the brevity and low-stakes nature of the task and by the fact that no significant effects were obtained for our suspicion manipulation, suggesting a need for more research. Limitations notwithstanding, this study adds to a growing empirical literature indicating the need for a requirement that all suspect interrogations be electronically recorded. To provide a more objective and accurate account of what transpired, this study also suggests the benefit of producing verbatim transcripts. (PsycINFO Database Record

Pathogenic mechanisms of prion protein, amyloid-ß and α-synuclein misfolding: the prion concept and neurotoxicity of protein oligomers.

Proteinopathies represent a group of diseases characterized by the unregulated misfolding and aggregation of proteins. Accumulation of misfolded protein in the central nervous system (CNS) is associated with neurodegenerative diseases, such as the transmissible spongiform encephalopathies (or prion diseases), Alzheimer's disease, and the synucleinopathies (the most common of which is Parkinson's disease). Of these, the pathogenic mechanisms of prion diseases are particularly striking where the transmissible, causative agent of disease is the prion, or proteinaceous infectious particle. Prions are composed almost exclusively of PrPSc ; a misfolded isoform of the normal cellular protein, PrPC , which is found accumulated in the CNS in disease. Today, mounting evidence suggests other aggregating proteins, such as amyloid-ß (Aß) and α-synuclein (α-syn), proteins associated with Alzheimer's disease and synucleinopathies, respectively, share similar biophysical and biochemical properties with PrPSc that influences how they misfold, aggregate, and propagate in disease. In this regard, the definition of a 'prion' may ultimately expand to include other pathogenic proteins. Unifying knowledge of folded proteins may also reveal common mechanisms associated with other features of disease that are less understood, such as neurotoxicity. This review discusses the common features Aß and α-syn share with PrP and neurotoxic mechanisms associated with these misfolded proteins. Several proteins are known to misfold and accumulate in the central nervous system causing a range of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and the prion diseases. Prions are transmissible misfolded conformers of the prion protein, PrP, which seed further generation of infectious proteins. Similar effects have recently been observed in proteins associated with Alzheimer's disease and the synucleinopathies, leading to the proposition that the definition of a 'prion' may ultimately expand to include other pathogenic proteins. Unifying knowledge of misfolded proteins may also reveal common mechanisms associated with other features of disease that are less understood, such as neurotoxicity.

The management and treatment of children with Fabry disease: A United States-based perspective.

Fabry disease is an inherited X-linked disorder that presents during childhood in male and female patients. Young patients may initially experience pain, hypohidrosis, and gastrointestinal symptoms. Other manifestations of Fabry disease, such as renal and cardiac disease, manifest later in adolescence or adulthood. In the pediatric population, renal damage is typically subclinical and identifiable only through biopsy. Specialists from the United States with expertise in Fabry disease convened during 2013-2014 in order to develop these consensus guidelines about the management and treatment of children with Fabry disease. The presence of symptoms in boys and girls of any age is an indication to begin therapy. Early treatment before the onset of potentially irreversible vital organ pathology is ideal. Asymptomatic children with Fabry mutations should be followed closely for the development of renal, cardiac, neurological, or gastrointestinal signs, symptoms, or laboratory changes, which would warrant treatment initiation. A comprehensive care plan should be implemented by the treating physicians to guide the management of children with Fabry disease.

Health psychology: supporting the self-management of long-term conditions.

This article considers how knowledge of health psychology can help nurses support patients in managing their long-term conditions. The concept of 'self-management' is defined and the need for self-efficacy-the patient's confidence in their ability to manage-and social support is highlighted. Patients' 'illness perceptions', or beliefs about the nature of their condition, also have an impact on their self-management. This is discussed in particular relation to adherence to treatment. A distinction is made between intentional and non-intentional non-adherence. Understanding of the many factors, other than lack of knowledge, that influence self-management success will help nurses and patients work together to develop an effective self-management plan.

Using health psychology to help patients: promoting healthy choices.

This article describes behaviour change techniques that nurses can use to help individual patients to make and stick to healthy choices. These include helping patients to set goals that are specific, measureable, achievable, relevant and timely (SMART), promoting self-monitoring and providing feedback and motivational interviewing. The process for delivering these techniques is described and the evidence for them discussed. Simply providing brief advice and follow up can lead to behaviour change, even in people who have not expressed a desire to change. The techniques are designed to be brief and feasible to use in routine practice. Using them can help nurses to apply the NHS policy of Making Every Contact Count so that their patients achieve long-term benefit.

Using health psychology techniques to manage chronic physical symptoms.

Chest pain and palpitations, non-malignant pain, breathlessness and fatigue often endure despite the receipt of appropriate nursing and medical care. This is distressing for patients, impacts on their quality of life and ability to function and is associated with high healthcare usage and costs. The cognitive behavioural approach offers nurses a model to understand how people's perceptions and beliefs and their emotional, behavioural and physiological reactions are linked. Common 'thinking errors' which can exacerbate symptom severity and impact are highlighted. Understanding of this model may help nurses to help patients cope better with their symptoms by helping them to come up with alternative more helpful beliefs and practices. Many Improving Access to Psychological Therapy services offer support to people with chronic physical symptoms and nurses are encouraged to sign post patients to them.

Using health psychology to help patients: promoting wellbeing.

This article explores the construct of wellbeing. Research concerning the relationship between subjective wellbeing and health is discussed. Key components of wellbeing that are important to health include 'sense of coherence', 'optimism' and 'benefit finding and post-traumatic growth'. A range of positive psychology interventions that aim to increase positive thoughts, feelings and emotions in order to improve wellbeing have been developed. Mindfulness-based approaches to improving wellbeing are especially popular and are evidence based. These focus on helping the individual to develop an awareness of the present with acceptance and attention. Instead of trying to change uncomfortable thoughts or feelings, the individual practices accepting these, without judgement. Nurses can draw on the information in this article to provide evidence-based advice and guidance to help improve their patients' and their own wellbeing.

Using health psychology to help patients: common mental health disorders and psychological distress.

This article provides an overview of how health psychology can be used by nurses to help patients experiencing common mental health problems and psychological distress. Mental health problems are common and are associated with poor outcomes, especially for patients with comorbid physical health conditions. Mental health problems are associated with unhealthy behaviours such as smoking, physical inactivity, overeating and excessive alcohol use, which will result in poorer outcomes for patients. Consideration of a patient's psychological health is therefore important for all nurses providing holistic care. Awareness of the symptoms of psychological distress, good communication skills and simple screening instruments can be used by nurses to assess patients' mental health. The cognitive and behavioural risk factors associated with depression and anxiety are also explored, as an understanding of these can help nurses to provide appropriate care.

Using health psychology to help patients: theories of behaviour change.

Behaviour change theories and related research evidence highlight the complexity of making and sticking to health-related behaviour changes. These theories make explicit factors that influence behaviour change, such as health beliefs, past behaviour, intention, social influences, perceived control and the context of the behaviour. Nurses can use this information to understand why a particular patient may find making recommended health behaviour changes difficult and to determine factors that may help them. This article outlines five well-established theories of behaviour change: the health belief model, the theory of planned behaviour, the stages of change model, self-determination theory, and temporal self-regulation theory. The evidence for interventions that are informed by these theories is then explored and appraised. The extent and quality of evidence varies depending on the type of behaviour and patients targeted, but evidence from randomised controlled trials indicates that interventions informed by theory can result in behaviour change.

Prion infection impairs cholesterol metabolism in neuronal cells.

Conversion of prion protein (PrP(C)) into a pathological isoform (PrP(Sc)) during prion infection occurs in lipid rafts and is dependent on cholesterol. Here, we show that prion infection increases the abundance of cholesterol transporter, ATP-binding cassette transporter type A1 (ATP-binding cassette transporter type A1), but reduces cholesterol efflux from neuronal cells leading to the accumulation of cellular cholesterol. Increased abundance of ABCA1 in prion disease was confirmed in prion-infected mice. Mechanistically, conversion of PrP(C) to the pathological isoform led to PrP(Sc) accumulation in rafts, displacement of ABCA1 from rafts and the cell surface, and enhanced internalization of ABCA1. These effects were abolished with reversal of prion infection or by loading cells with cholesterol. Stimulation of ABCA1 expression with liver X receptor agonist or overexpression of heterologous ABCA1 reduced the conversion of prion protein into the pathological form upon infection. These findings demonstrate a reciprocal connection between prion infection and cellular cholesterol metabolism, which plays an important role in the pathogenesis of prion infection in neuronal cells.

Glycosaminoglycan sulfation determines the biochemical properties of prion protein aggregates.

Prion diseases are transmissible neurodegenerative disorders associated with the conversion of the cellular prion protein, PrP(C), to a misfolded isoform called PrP(Sc). Although PrP(Sc) is a necessary component of the infectious prion, additional factors, or cofactors, have been shown to contribute to the efficient formation of transmissible PrP(Sc). Glycosaminoglycans (GAGs) are attractive cofactor candidates as they can be found associated with PrP(Sc) deposits, have been shown to enhance PrP misfolding in vitro, are found in the same cellular compartments as PrP(C) and have been shown to be disease modifying in vivo. Here we investigated the effects of the sulfated GAGs, heparin and heparan sulfate (HS), on disease associated misfolding of full-length recombinant PrP. More specifically, the degree of sulfation of these molecules was investigated for its role in modulating the disease-associated characteristics of PrP. Both heparin and HS induced a ß-sheet conformation in recombinant PrP that was associated with the formation of aggregated species; however, the biochemical properties of the aggregates formed in the presence of heparin or HS varied in solubility and protease resistance. Furthermore, these properties could be modified by changes in GAG sulfation, indicating that subtle changes in the properties of prion disease cofactors could initiate disease associated misfolding.