Neuroprotection by acrolein sequestration through exogenously applied scavengers and endogenous enzymatic enabling strategies in mouse EAE model.

We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in MS pathology. In this study, we found that the acrolein scavenger hydralazine (HZ), when applied from the day of induction, can suppress acrolein and alleviate motor and sensory deficits in a mouse experimental autoimmune encephalomyelitis (EAE) model. Furthermore, we also demonstrated that HZ can alleviate motor deficits when applied after the emergence of MS symptoms, making potential anti-acrolein treatment a more clinically relevant strategy. In addition, HZ can reduce both acrolein and MPO, suggesting a connection between acrolein and inflammation. We also found that in addition to HZ, phenelzine (PZ), a structurally distinct acrolein scavenger, can mitigate motor deficits in EAE when applied from the day of induction. This suggests that the likely chief factor of neuroprotection offered by these two structurally distinct acrolein scavengers in EAE is their common feature of acrolein neutralization. Finally, up-and-down regulation of the function of aldehyde dehydrogenase 2 (ALDH2) in EAE mice using either a pharmacological or genetic strategy led to correspondent motor and sensory changes. This data indicates a potential key role of ALDH2 in influencing acrolein levels, oxidative stress, inflammation, and behavior in EAE. These findings further consolidate the critical role of aldehydes in the pathology of EAE and its mechanisms of regulation. This is expected to reinforce and expand the possible therapeutic targets of anti-aldehyde treatment to achieve neuroprotection through both endogenous and exogenous manners.

The Effects of a News Literacy Video and Real-Time Corrections to Video Misinformation Related to Sunscreen and Skin Cancer.

Given concerns about the persuasive power of video misinformation on social media for health topics, we test two techniques - exposure to a news literacy video and user corrections - to limit the effects on misperceptions. An online sample of American adults from August of 2019 was randomly assigned to view two simulated Facebook videos. The first video manipulated the presence of news literacy concepts. The second video either promoted sunscreen use or made inaccurate claims regarding its dangers; scrolling comments either debunked or did not address the sunscreen misinformation in the video. Our results demonstrate that video misinformation heightened beliefs in sunscreen myths and reduced acceptance of sunscreen facts and intentions to wear sunscreen compared to a promotional video. Real-time user corrections were partially successful in reducing the effects of the misinformation video on beliefs but not intentions. Additionally, exposure to a news literacy video did not inoculate people to the misinformation. We discuss the implications of these findings for best practices regarding correcting video misinformation on health topics.

Systemic Acrolein Elevations in Mice With Experimental Autoimmune Encephalomyelitis and Patients With Multiple Sclerosis.

Demyelination and axonal injury are the key pathological processes in multiple sclerosis (MS), driven by inflammation and oxidative stress. Acrolein, a byproduct and instigator of oxidative stress, has been demonstrated as a neurotoxin in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, due to the invasive nature of acrolein detection using immunoblotting techniques, the investigation of acrolein in MS has been limited to animal models. Recently, detection of a specific acrolein-glutathione metabolite, 3-HPMA, has been demonstrated in urine, enabling the noninvasive quantification of acrolein for the first time in humans with neurological disorders. In this study, we have demonstrated similar elevated levels of acrolein in both urine (3-HPMA) and in spinal cord tissue (acrolein-lysine adduct) in mice with EAE, which can be reduced through systemic application of acrolein scavenger hydralazine. Furthermore, using this approach we have demonstrated an increase of 3-HPMA in both the urine and serum of MS patients relative to controls. It is expected that this noninvasive acrolein detection could facilitate the investigation of the role of acrolein in the pathology of MS in human. It may also be used to monitor putative therapies aimed at suppressing acrolein levels, reducing severity of symptoms, and slowing progression as previously demonstrated in animal studies.

"You get old. You get invisible": Social isolation and the challenge of communicating with aging women.

Social isolation is a problem facing many older women. Isolation can contribute to poor health as adults age without social support. Increased and tailored communication offers service organizations more opportunities to provide social support to these adults. This research examines perceptions of aging to explore communication behaviors, barriers, and opportunities for improved communication and service provision for aging women. Using data from focus groups and interviews, this study finds that participants from community organizations rely on word of mouth and traditional media to communicate with their aging constituents, despite opportunities to use digital communication and to develop communication plans for this population.

Elevated axonal membrane permeability and its correlation with motor deficits in an animal model of multiple sclerosis.

BACKGROUND: It is increasingly clear that in addition to myelin disruption, axonal degeneration may also represent a key pathology in multiple sclerosis (MS). Hence, elucidating the mechanisms of axonal degeneration may not only enhance our understanding of the overall MS pathology, but also elucidate additional therapeutic targets. The objective of this study is assess the degree of axonal membrane disruption and its significance in motor deficits in EAE mice. METHODS: Experimental Autoimmune Encephalomyelitis was induced in mice by subcutaneous injection of myelin oligodendrocyte glycoprotein/complete Freud's adjuvant emulsion, followed by two intraperitoneal injections of pertussis toxin. Behavioral assessment was performed using a 5-point scale. Horseradish Peroxidase Exclusion test was used to quantify the disruption of axonal membrane. Polyethylene glycol was prepared as a 30% (w/v) solution in phosphate buffered saline and injected intraperitoneally. RESULTS: We have found evidence of axonal membrane disruption in EAE mice when symptoms peak and to a lesser degree, in the pre-symptomatic stage of EAE mice. Furthermore, polyethylene glycol (PEG), a known membrane fusogen, significantly reduces axonal membrane disruption in EAE mice. Such PEG-mediated membrane repair was accompanied by significant amelioration of behavioral deficits, including a delay in the emergence of motor deficits, a delay of the emergence of peak symptom, and a reduction in the severity of peak symptom. CONCLUSIONS: The current study is the first indication that axonal membrane disruption may be an important part of the pathology in EAE mice and may underlies behavioral deficits. Our study also presents the initial observation that PEG may be a therapeutic agent that can repair axolemma, arrest axonal degeneration and reduce motor deficits in EAE mice.

School Administrator Perceptions of Cyberbullying Facilitators and Barriers to Preventive Action: A Qualitative Study.

BACKGROUND: Schools are often held responsible for preventing or addressing cyberbullying, yet little is known about school administrator perceptions of cyberbullying and the challenges they face in addressing this public health issue. AIMS: The goal of this study is to examine school administrators' perceptions of the facilitators of cyberbullying and barriers to primary and secondary prevention strategies. METHOD: Public school administrators ( N = 36) participated in in-depth interviews about bullying and discussed their experiences with cyberbullying and their perceptions of cyberbullying facilitators and barriers to prevention. RESULTS: Three main themes arose from the analysis: (1) cyberbullying as a major challenge; (2) facilitators of cyberbullying and barriers to preventive action, including parents and technology; and (3) prevention efforts, including unclear jurisdiction for action, primary versus secondary prevention efforts, and technology attributes that facilitate school response to bullying. DISCUSSION: Although administrators perceive cyberbullying as a major challenge facing their schools, they are often unsure about appropriate primary and secondary prevention efforts. Relationships with parents and police complicate response and prevention as schools attempt to navigate unclear jurisdiction. Additionally, technology presents a challenge to schools because it is seen as an enabler of cyberbullying, a facilitator of prevention, and a necessary part of education efforts. CONCLUSION: Lack of research on prevention strategies, parents' knowledge and attitudes, and confusion about responsibility for addressing cyberbullying are barriers to action. Findings suggest administrators could benefit from additional clarity on which strategies are most effective for primary prevention of cyberbullying, and that prevention strategies should proactively involve parents to promote effective collaboration with schools.

Acute systemic accumulation of acrolein in mice by inhalation at a concentration similar to that in cigarette smoke.

Cigarette smoke is an important environmental factor associated with a wide array of public health concerns. Acrolein, a component of tobacco smoke and a known toxin to various cell types, may be a key pathological factor mediating the adverse effects linked with tobacco smoke. Although acrolein is known to accumulate in the respiratory system after acute nasal exposure, it is not clear if it accumulates systemically, and less is known in the nervous system. The aim of this study was to assess the degree of acrolein accumulation in the circulation and in the spinal cord following acute acrolein inhalation in mice. Using a laboratory-fabricated inhalation chamber, we found elevated urinary 3-HPMA, an acrolein metabolite, and increased acrolein adducts in the spinal cord after weeks of nasal exposure to acrolein at a concentration similar to that in tobacco smoke. The data indicated that acrolein is absorbed into the circulatory system and some enters the nervous system. It is expected that these findings may facilitate further studies to probe the pathological role of acrolein in the nervous system resulting from smoke and other external sources.

Acrolein detection: potential theranostic utility in multiple sclerosis and spinal cord injury.

Oxidative stress has been implicated as a major pathological process underlying CNS disease and trauma. More specifically, acrolein, an unsaturated aldehyde, produced by way of lipid peroxidation, has been shown to play a crucial role in initiating and perpetuating detrimental effects associated with multiple sclerosis and spinal cord injury. In light of these findings, quantification of acrolein levels both systemically and locally could allow for the use of acrolein as a biomarker to aid in diagnosis and guide treatment regimens. The three main approaches currently available are acrolein derivatization followed by LC/GC-MS, application of an acrolein antibody and subsequent immunoblotting, and the 3-hydroxypropylmercapturic acid-based method. Of these three strategies, the 3-hydroxypropylmercapturic acid-based method is the least invasive allowing for rapid translation of acrolein detection into a clinical setting.

New insights in the pathogenesis of multiple sclerosis--role of acrolein in neuronal and myelin damage.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by an inappropriate inflammatory reaction resulting in widespread myelin injury along white matter tracts. Neurological impairment as a result of the disease can be attributed to immune-mediated injury to myelin, axons and mitochondria, but the molecular mechanisms underlying the neuropathy remain incompletely understood. Incomplete mechanistic knowledge hinders the development of therapies capable of alleviating symptoms and slowing disease progression in the long-term. Recently, oxidative stress has been implicated as a key component of neural tissue damage prompting investigation of reactive oxygen species (ROS) scavengers as a potential therapeutic option. Despite the establishment of oxidative stress as a crucial process in MS development and progression, ROS scavengers have had limited success in animal studies which has prompted pursuit of an alternative target capable of curtailing oxidative stress. Acrolein, a toxic ß-unsaturated aldehyde capable of initiating and perpetuating oxidative stress, has been suggested as a viable point of intervention to guide the development of new treatments. Sequestering acrolein using an FDA-approved compound, hydralazine, offers neuroprotection resulting in dampened symptom severity and slowed disease progression in experimental autoimmune encephalomyelitis (EAE) mice. These results provide promise for therapeutic development, indicating the possible utility of neutralizing acrolein to preserve and improve neurological function in MS patients.

Determination of urine 3-HPMA, a stable acrolein metabolite in a rat model of spinal cord injury.

Acrolein has been suggested to be involved in a variety of pathological conditions. The monitoring of acrolein is of significant importance in delineating the pathogenesis of various diseases. Aimed at overcoming the reactivity and volatility of acrolein, we describe a specific and stable metabolite of acrolein in urine, N-acetyl-S-3-hydroxypropylcysteine (3-HPMA), as a potential surrogate marker for acrolein quantification. Using the LC/MS/MS method, we demonstrated that 3-HPMA was significantly elevated in a dose-dependent manner when acrolein was injected into rats IP or directly into the spinal cord, but not when acrolein scavengers were co-incubated with acrolein solution. A nonlinear mathematic relationship is established between acrolein injected directly into the spinal cord and a correlated dose-dependent increase of 3-HPMA, suggesting the increase of 3-HPMA becomes less apparent as the level of injected acrolein increases. The elevation of 3-HPMA was further detected in the rat spinal cord injury, a pathological condition known to be associated with elevated endogenous acrolein. This finding was further validated by concomitant confirmation of increased acrolein-lysine adducts using established dot immunoblotting techniques. The noninvasive nature of measuring 3-HPMA concentrations in urine allows for long-term monitoring of acrolein in the same animal and ultimately in human clinical studies. Due to wide spread involvement of acrolein in human health, the benefits of this study have the potential to enhance human health significantly.

Differential effects of anesthetics on cocaine's pharmacokinetic and pharmacodynamic effects in brain.

Most studies of the effect of cocaine on brain activity in laboratory animals are preformed under anesthesia, which could potentially affect the physiological responses to cocaine. Here we assessed the effects of two commonly used anesthetics [alpha-chloralose (alpha-CHLOR) and isofluorane (ISO)] on the effects of acute cocaine (1 mg/kg i.v.) on cerebral blood flow (CBF), cerebral blood volume (CBV), and tissue hemoglobin oxygenation (S(t)O(2)) using optical techniques and cocaine's pharmacokinetics (PK) and binding in the rat brain using (PET) and [(11)C]cocaine. We showed that acute cocaine at a dose abused by cocaine abusers decreased CBF, CBV and S(t)O(2) in rats anesthetized with ISO, whereas it increased these parameters in rats anesthetized with alpha-CHLOR. Importantly, in ISO-anesthetized animals cocaine-induced changes in CBF and S(t)O(2) were coupled, whereas for alpha-CHLOR these measures were uncoupled. Moreover, the clearance of [(11)C]cocaine from the brain was faster for ISO (peak half-clearance 15.8 +/- 2.8 min) than for alpha-CHLOR (27.5 +/- 0.6 min), and the ratio of specific to non-specific binding of [(11)C]cocaine in the brain was higher for ISO- (3.37 +/- 0.32) than for alpha-CHLOR-anesthetized rats (2.24 +/- 0.4). For both anesthetics, cocaine-induced changes in CBF followed the fast uptake of [(11)C]cocaine in the brain (peaking at approximately 2.5-4 min), but only for ISO did the duration of the CBV and S(t)O(2) changes correspond to the rate of [(11)C]cocaine's clearance from the brain. These results demonstrate that anesthetics influence cocaine's hemodynamic and metabolic changes in the brain, and its binding and PK, which highlights the need to better understand the interactions between anesthetics and pharmacological challenges in brain functional imaging studies.

Quantification of cocaine-induced cortical blood flow changes using laser speckle contrast imaging and Doppler optical coherence tomography.

We present a dual-imaging technique combining laser speckle contrast imaging and spectral-domain Doppler optical coherence tomography to enable quantitative characterization of local cerebral blood flow (CBF) changes in rat cortex in response to drug stimulus (e.g., cocaine) at high spatiotemporal resolutions. To examine the utility of this new technique, animal experiments were performed to study the influences of anesthetic regimes (e.g., isoflurane, alpha-chloralose) on the pharmadynamic effects of acute cocaine challenge. The results showed that cocaine-evoked CBF patterns (e.g., increases in alpha-chloralose and decreases in isoflurane regimes) were quantitatively characterized, thus rendering it a potentially useful tool for imaging studies of brain functions.

Development and implementation of an education and credentialing programme to provide safe paediatric procedural sedation in emergency departments.

OBJECTIVE: In the conduct of paediatric procedural sedation (PPS) within the ED the combination of powerful drugs, variable competency levels and high staff turnover carry the potential for sedation-associated adverse events. Yet, currently, there is no set programme for education and accreditation of ED staff in PPS. We set out to develop such a programme. METHODS: We outline the development process of a comprehensive multidisciplinary PPS programme and present its key educational elements (sedation manual, lecture, treatment order form and checklist, parent information handout) and credentialing through multiple-choice questions and competency assessments. We describe issues associated with the implementation of the programme at a metropolitan mixed ED and the ED of a major tertiary paediatric centre. RESULTS: Since its inception a total of 294 emergency staff have either completed or have partially completed the programme. Staff feedback showed that the majority of staff scored the elements of the programme as very good to excellent, and felt that their sedation skills had improved and their practice was safer. The development and implementation of the PPS programme raised many issues and posed a number of challenges. We describe the strategies we used to overcome such challenges and barriers. CONCLUSION: We present the development and implementation of a comprehensive PPS programme for emergency staff. As a result of the multicentre development process involving a community and a tertiary paediatric ED the programme will likely have broad applicability in different types of ED caring for children.

Evaluation of the impact of a paediatric procedural sedation credentialing programme on quality of care.

OBJECTIVES: The aim of the present study is to describe changes in documentation, risk assessment and patient care resulting from implementation of a credentialing process for medical and nursing staff in paediatric procedural sedation (PPS) in two EDs - one an urban mixed ED and the other a specialist paediatric ED. METHODS: Chart review of 100 patients undergoing PPS prior to and 100 patients following introduction of the PPS programme. Information was extracted from medical records and sedation checklists. Demographics, drugs used, procedure performed and elements of the pre-procedural, intra-procedural and post-procedural care were compared pre- and post implementation of the PPS programme. RESULTS: Significant improvements in the post-implementation period compared with pre-implementation were seen in: frequency of documentation of informed consent (87 vs 15%, P < 0.0001); evidence of performance of a pre-procedural risk assessment (87 vs 1%, P < 0.0001); and appropriate recording of vital signs (58 vs 27%, P < 0.0001). Improvements were also noted in documentation of weight, allergies, fasting status and recording of drug orders. There were no adverse events recorded in the pre-programme period and 6 recorded in the post-programme period. CONCLUSION: The implementation of a PPS credentialing programme into these two EDs resulted in significant improvements in risk assessment, monitoring and documentation of important information related to safe PPS. These improvements should result in improved quality and safety of PPS.