A Case of Life-Threatening Postpartum Necrotizing Pancreatitis Requiring Gastrocystostomy With Serial Pancreatic Necrosectomies.

We present a life-threatening case of postpartum acute necrotizing pancreatitis. The patient is a 37-year-old female with no past medical history who delivered a healthy baby boy via cesarean section. Twenty days later, she presented to the emergency department with acute onset of nausea, non-bloody vomiting, abdominal bloating, and epigastric pain radiating to the back. Less than 24 hours later, she progressed into septic shock despite aggressive resuscitation, requiring vasopressor support in the ICU. Initial CT imaging showed multiple patchy hypodensities throughout the pancreas consistent with severe necrotizing pancreatitis. Her hospitalization was further complicated by difficulty obtaining source control of her infection, Clostridium difficile, and nutritional deficiencies that resulted in gross anasarca. She was discharged from the hospital on day 59 after undergoing multiple percutaneous drain placements, IV antibiotics, and endoscopic gastrocystostomy with four pancreatic necrosectomies. Since discharge, the patient has required readmission twice for complications from her pancreatitis.

How should artificial intelligence be used in Australian health care? Recommendations from a citizens' jury.

OBJECTIVE: To support a diverse sample of Australians to make recommendations about the use of artificial intelligence (AI) technology in health care. STUDY DESIGN: Citizens' jury, deliberating the question: "Under which circumstances, if any, should artificial intelligence be used in Australian health systems to detect or diagnose disease?" SETTING, PARTICIPANTS: Thirty Australian adults recruited by Sortition Foundation using random invitation and stratified selection to reflect population proportions by gender, age, ancestry, highest level of education, and residential location (state/territory; urban, regional, rural). The jury process took 18 days (16 March - 2 April 2023): fifteen days online and three days face-to-face in Sydney, where the jurors, both in small groups and together, were informed about and discussed the question, and developed recommendations with reasons. Jurors received extensive information: a printed handbook, online documents, and recorded presentations by four expert speakers. Jurors asked questions and received answers from the experts during the online period of the process, and during the first day of the face-to-face meeting. MAIN OUTCOME MEASURES: Jury recommendations, with reasons. RESULTS: The jurors recommended an overarching, independently governed charter and framework for health care AI. The other nine recommendation categories concerned balancing benefits and harms; fairness and bias; patients' rights and choices; clinical governance and training; technical governance and standards; data governance and use; open source software; AI evaluation and assessment; and education and communication. CONCLUSIONS: The deliberative process supported a nationally representative sample of citizens to construct recommendations about how AI in health care should be developed, used, and governed. Recommendations derived using such methods could guide clinicians, policy makers, AI researchers and developers, and health service users to develop approaches that ensure trustworthy and responsible use of this technology.

Facilitating public involvement in research about healthcare AI: A scoping review of empirical methods.

OBJECTIVE: With the recent increase in research into public views on healthcare artificial intelligence (HCAI), the objective of this review is to examine the methods of empirical studies on public views on HCAI. We map how studies provided participants with information about HCAI, and we examine the extent to which studies framed publics as active contributors to HCAI governance. MATERIALS AND METHODS: We searched 5 academic databases and Google Advanced for empirical studies investigating public views on HCAI. We extracted information including study aims, research instruments, and recommendations. RESULTS: Sixty-two studies were included. Most were quantitative (N = 42). Most (N = 47) reported providing participants with background information about HCAI. Despite this, studies often reported participants' lack of prior knowledge about HCAI as a limitation. Over three quarters (N = 48) of the studies made recommendations that envisaged public views being used to guide governance of AI. DISCUSSION: Provision of background information is an important component of facilitating research with publics on HCAI. The high proportion of studies reporting participants' lack of knowledge about HCAI as a limitation reflects the need for more guidance on how information should be presented. A minority of studies adopted technocratic positions that construed publics as passive beneficiaries of AI, rather than as active stakeholders in HCAI design and implementation. CONCLUSION: This review draws attention to how public roles in HCAI governance are constructed in empirical studies. To facilitate active participation, we recommend that research with publics on HCAI consider methodological designs that expose participants to diverse information sources.

Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

Surge of Midazolam Use in the Midst of Lorazepam Shortage.

BACKGROUND: Lorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several off-label indications including aggression, alcohol withdrawal, panic disorder, chemotherapy-associated anticipatory nausea, and catatonia. Recent increases in demand, manufacturing changes, and quality control issues have resulted in a shortage of injectable and oral lorazepam, prompting clinicians to use alternatives. One such alternative is midazolam, a drug that has been used primarily in the intensive care unit and anesthesia settings. PROCEDURES: This article examines the significant pharmacologic differences between lorazepam and midazolam. In addition, this article provides dosage guidelines based on the current scientific knowledge and recommendations for conversion equivalencies. RESULTS: The clinical preference for lorazepam can be attributed to its simpler metabolism with no active metabolites, better suitability for patients with less severe hepatic and renal impairment, less risk of adverse reactions, fewer drug-drug interactions, and greater desirability for special populations. In periods of shortages, midazolam has been shown to be effective for a number of off-label uses. To manage conditions that have not been extensively studied, clinicians may opt to use conversion equivalencies, with the caveat that guidelines may vary greatly between institutions and online sources; therefore, it would be best to start low and titrate slowly. CONCLUSIONS: Our goal is to aid clinicians in safely and effectively prescribing midazolam during the shortage of injectable lorazepam so that patients are provided the same effects and benefits.

Measures of socioeconomic advantage are not independent predictors of support for healthcare AI: subgroup analysis of a national Australian survey.

Objectives: Applications of artificial intelligence (AI) have the potential to improve aspects of healthcare. However, studies have shown that healthcare AI algorithms also have the potential to perpetuate existing inequities in healthcare, performing less effectively for marginalised populations. Studies on public attitudes towards AI outside of the healthcare field have tended to show higher levels of support for AI among socioeconomically advantaged groups that are less likely to be sufferers of algorithmic harms. We aimed to examine the sociodemographic predictors of support for scenarios related to healthcare AI.Methods: The Australian Values and Attitudes toward AI survey was conducted in March 2020 to assess Australians' attitudes towards AI in healthcare. An innovative weighting methodology involved weighting a non-probability web-based panel against results from a shorter omnibus survey distributed to a representative sample of Australians. We used multinomial logistic regression to examine the relationship between support for AI and a suite of sociodemographic variables in various healthcare scenarios.Results: Where support for AI was predicted by measures of socioeconomic advantage such as education, household income and Socio-Economic Indexes for Areas index, the same variables were not predictors of support for the healthcare AI scenarios presented. Variables associated with support for healthcare AI included being male, having computer science or programming experience and being aged between 18 and 34 years. Other Australian studies suggest that these groups may have a higher level of perceived familiarity with AI.Conclusion: Our findings suggest that while support for AI in general is predicted by indicators of social advantage, these same indicators do not predict support for healthcare AI.

Paper Charts: A Continued Barrier to Psychiatric Care in the Midst of a Broken and Fragmented Mental Health System.

ABSTRACT: The use of electronic medical records (EMRs) has increased dramatically over the last 15 years. However, psychiatry has lagged. EMRs are not being used by many mental health professionals. There are many reasons, including financial burden, lack of technological support, stigma, disaggregation of upfront costs, indirect benefits, and concerns about privacy and Health Insurance Portability and Accountability Act compliance. Obtaining paper records is a lengthy process, making continuity of care and emergency care challenging. Even when records are made available, it is common for information to be incomplete. The objective of this article is to highlight how the continued use of paper charts may decrease the quality and timeliness of psychiatric care provided and to discuss the psychiatry-specific issues created by EMRs. A case illustrating the disruption of care by continued use of paper charts in psychiatric facilities is presented. The growing use of EMR creates new challenges that affect psychiatry in ways other fields are not affected. These challenges include confidentiality issues, the frequent change/spectrum of diagnoses, determining how much information should be recorded in a note, and what the implications are of the information recorded. This article will discuss the use of EMRs in psychiatry, as well as encourage medical students and residents to take a deeper dive into psychiatry-specific issues regarding the use of EMR. EMR use may have a profound impact on our patient outcomes, health care delivery system, shorter inpatient stay, as well as reduce health care costs.

Filling the gap between evidence, policy and practice: are 45 and Up Study researchers planning for impact?

AIM: To improve health outcomes, policy and practice decisions should be guided by relevant and timely evidence. High-quality, large-scale population data could play an essential role in supporting evidence-based decision making. The 45 and Up Study is a long-term, large-scale cohort study with more 250 000 participants aged 45 years and over from New South Wales (NSW), Australia. Data collected by the Study is accessible to researchers, government and non-governmental bodies. The study aimed to identify the proportion of researchers using data from the Study who intended to have an impact and achieved impact; the types of impact they intended and achieved; and the pathways through which they achieved it. METHODS: Using data extracted from the application, progress and final report documents for 25 projects using 45 and Up Study data from January 2011 until December 2017, we a) determined the proportion of projects that intended to have policy or practice impact and b) described the type of policy and practice impact achieved. RESULTS: We found that 88% (n = 22) of projects intended to have a policy or practice impact. Of those, 68% (n = 15) planned to influence or inform a policy or program, and 41% (n = 9) planned to share findings at conferences or in journals. Almost half of projects with intended impact (45%, n = 10) did not state how they planned to achieve impact. Approximately 16% of all projects (n = 4) reported achieving an impact on policy or services. The type of impact achieved by all four of these projects was influencing, informing or changing a policy or program. One of these four projects also achieved a change to legislation or regulation. CONCLUSIONS: Further strategies to promote a targeted approach to impact planning in research projects using datasets such as the 45 and Up Study would help guide researchers in achieving impact.

Clinical and radiographic phenotypes of patients with multifocal subcortical versus cortical cerebral infarcts.

BACKGROUND AND PURPOSE: Infarct topology is a key determinant in classification of a stroke as potentially embolic, with cortical and multifocal lesions being presumed embolic. Whether isolated subcortical multifocal infarcts are likely embolic has not been well studied. METHODS: A prospective, single-center cohort study of consecutive patients with acute multifocal strokes confirmed on diffusion-weighting imaging (DWI) was queried, and patients compared according to the presence of isolated subcortical infarct topology versus cortical ± subcortical topology. Descriptive statistics and multivariable logistic regression were used to determine independent predictors of cryptogenic, subcortical infarcts. RESULTS: Of 1739 patients screened, 743 had complete diagnostic testing with DWI evidence of acute infarction, 183 (24.6%) of whom had a multifocal stroke pattern. Isolated subcortical involvement was disproportionate among patients with ESUS (64.9%) when compared to patients with cardioembolic (24.3%) or large vessel disease (10.8%, p<0.01). Following multivariable adjustment, independent predictors of isolated subcortical multifocal infarction were milder strokes (OR 0.94, 95%CI 0.89-0.98) and higher grade Fazekas score (OR 2.32, 95%CI 1.02-5.29), while cardioembolism (OR 0.30, 95%CI 0.08-1.13) and large vessel disease (OR 0.27, 95%CI 0.08-0.91) remained inversely associated (as compared to ESUS). CONCLUSIONS: These data suggest that multifocal subcortical infarctions are less likely to have an associated proximal embolic source than multifocal infarctions with cortical involvement. The strong association with chronic microvascular disease suggests this topology is more consistent with acute-on-chronic microvascular injury rather than an occult embolic source.

Embolic infarct topology differs between atrial fibrillation subtypes and embolic stroke of undetermined source.

BACKGROUND: The lack of superiority of anticoagulation over antiplatelet therapy in embolic stroke of undetermined source (ESUS) may be in part due to the misclassification of radiographic ESUS patterns as cardioembolic. In this imaging analysis, we sought to differentiate clinical and radiographic patterns of ESUS patients from patterns in patients with a highly probable cardioembolic source. MATERIALS & METHODS: A prospective registry of consecutive adults with acute infarction on diffusion-weighted magnetic resonance imaging was queried. Patients with infarctions due to small vessel disease, large vessel disease, and other causes were excluded. Multivariable logistic regression was used to identify independent predictors of two potentially embolic patterns: (1) multifocal and (2) cortical lesions, comparing patients with ESUS against those with atrial fibrillation (AF). RESULTS: Among 1243 screened patients, 343 (27.6%) experienced strokes due to ESUS or AF. Prior to the index stroke, patients with AF as compared to ESUS were older (median 75 vs. 65, p<0.01) and had more heart failure (25.9% vs. 8.4%, p<0.01). The odds of multifocal infarction were the same between patients with ESUS and both AF subtypes (p>0.05), however, cortical involvement was more associated with both AF versus ESUS (77.7% vs. 65.7%, P=0.02). A higher Fazekas grade of white matter disease was inversely associated with cortical infarction among included patients (aOR 0.77, 95% CI 0.62-0.96). CONCLUSION: Cortical infarctions were twice as common among patients with AF versus ESUS. Subcortical infarct topography was strongly associated with chronic microvascular ischemic changes and therefore may not represent embolic phenomena. Larger-scale investigations are warranted to discern whether large or multifocal subcortical infarcts ought to be excluded from the ESUS designation.

Assessing the effect of COVID-19 stay-at -home orders on firearm injury in Maryland.

This study sought to characterize frequency and demographic characteristics of firearm injury and penetrating trauma in Maryland over the first year of the pandemic, by comparing these characteristics to those of the three years prior to stay-at-home order issuance. Patients were identified in the Maryland Health Services Cost Review Commission database using ICD-10 codes for firearm injury by all intents and assaults by penetrating trauma. Cases from July 1, 2017 to March 31, 2020 ("pre-stay-at-home") were compared to those from April 1, 2020 to March 31, 2021 ("post-stay-at-home") using descriptive statistics. There was no significant change overall in frequency or demographics of firearm injury or penetrating trauma in the year after stay-at-home orders were issued. Youth between ages 15 and 24, overwhelmingly male, comprise a disproportionately high percentage of firearm injuries and assaults, and most penetrating trauma occurs in urban environments where Black non-Hispanic youth and children of low socioeconomic status are at high risk. Our study also found unintentional firearm injury among adults was significantly increased during the pandemic. While increased unintentional firearm injury among adults was the major significant change found in our study, the persistence of firearm injury, particularly in youth, racial and ethnic minority groups, and those in urban environments, should be deeply concerning. Stay-at-home policies did not keep youth safer from firearm injury. With continued high rates of firearm injury and the national debate over how to prevent these incidents, increased education and comprehensive strategies for prevention are needed.

Public views on ethical issues in healthcare artificial intelligence: protocol for a scoping review.

BACKGROUND: In recent years, innovations in artificial intelligence (AI) have led to the development of new healthcare AI (HCAI) technologies. Whilst some of these technologies show promise for improving the patient experience, ethicists have warned that AI can introduce and exacerbate harms and wrongs in healthcare. It is important that HCAI reflects the values that are important to people. However, involving patients and publics in research about AI ethics remains challenging due to relatively limited awareness of HCAI technologies. This scoping review aims to map how the existing literature on publics' views on HCAI addresses key issues in AI ethics and governance. METHODS: We developed a search query to conduct a comprehensive search of PubMed, Scopus, Web of Science, CINAHL, and Academic Search Complete from January 2010 onwards. We will include primary research studies which document publics' or patients' views on machine learning HCAI technologies. A coding framework has been designed and will be used capture qualitative and quantitative data from the articles. Two reviewers will code a proportion of the included articles and any discrepancies will be discussed amongst the team, with changes made to the coding framework accordingly. Final results will be reported quantitatively and qualitatively, examining how each AI ethics issue has been addressed by the included studies. DISCUSSION: Consulting publics and patients about the ethics of HCAI technologies and innovations can offer important insights to those seeking to implement HCAI ethically and legitimately. This review will explore how ethical issues are addressed in literature examining publics' and patients' views on HCAI, with the aim of determining the extent to which publics' views on HCAI ethics have been addressed in existing research. This has the potential to support the development of implementation processes and regulation for HCAI that incorporates publics' values and perspectives.

Mapping precision public health definitions, terminology and applications: a scoping review protocol.

INTRODUCTION: Precision public health is an emerging and evolving field. Academic communities are divided regarding terminology and definitions, and what the scope, parameters and goals of precision public health should include. This protocol summarises the procedure for a scoping review which aims to identify and describe definitions, terminology, uses of the term and concepts in current literature. METHODS AND ANALYSIS: A scoping review will be undertaken to gather existing literature on precision public health. We will search CINAHL, PubMed, Scopus, Web of Science and Google Scholar, and include all documents published in English that mention precision public health. A critical discourse analysis of the resulting papers will generate an account of precision public health terminology, definitions and uses of the term and the use and meaning of language. The analysis will occur in stages: first, descriptive information will be extracted and descriptive statistics will be calculated in order to characterise the literature. Second, occurrences of the phrase 'precision public health' and alternative terms in documents will be enumerated and mapped, and definitions collected. The third stage of discourse analysis will involve analysis and interpretation of the meaning of precision public health, including the composition, organisation and function of discourses. Finally, discourse analysis of alternative phrases to precision public health will be undertaken. This will include analysis and interpretation of what alternative phrases to precision public health are used to mean, how the phrases relate to each other and how they are compared or contrasted to precision public health. Results will be grouped under headings according to how they answer the research questions. ETHICS AND DISSEMINATION: No ethical approval will be required for the scoping review. Results of the scoping review will be used as part of a doctoral thesis, and may be published in journals, conference proceedings or elsewhere.

Reporting of screening and diagnostic AI rarely acknowledges ethical, legal, and social implications: a mass media frame analysis.

BACKGROUND: Healthcare is a rapidly expanding area of application for Artificial Intelligence (AI). Although there is considerable excitement about its potential, there are also substantial concerns about the negative impacts of these technologies. Since screening and diagnostic AI tools now have the potential to fundamentally change the healthcare landscape, it is important to understand how these tools are being represented to the public via the media. METHODS: Using a framing theory approach, we analysed how screening and diagnostic AI was represented in the media and the frequency with which media articles addressed the benefits and the ethical, legal, and social implications (ELSIs) of screening and diagnostic AI. RESULTS: All the media articles coded (n = 136) fit into at least one of three frames: social progress (n = 131), economic development (n = 59), and alternative perspectives (n = 9). Most of the articles were positively framed, with 135 of the articles discussing benefits of screening and diagnostic AI, and only 9 articles discussing the ethical, legal, and social implications. CONCLUSIONS: We found that media reporting of screening and diagnostic AI predominantly framed the technology as a source of social progress and economic development. Screening and diagnostic AI may be represented more positively in the mass media than AI in general. This represents an opportunity for health journalists to provide publics with deeper analysis of the ethical, legal, and social implications of screening and diagnostic AI, and to do so now before these technologies become firmly embedded in everyday healthcare delivery.

Role of PDGF-A-Activated ERK Signaling Mediated FAK-Paxillin Interaction in Oligodendrocyte Progenitor Cell Migration.

Oligodendrocyte progenitor cells (OPCs) originate from the sub-ventricular zone of the developing brain. They migrate and proliferate to occupy the white matter tracts of the central nervous system and transform into myelinating oligodendrocytes. Along their route of migration, OPCs are guided and controlled by several growth factors and chemokines. PDGF-A (platelet-derived growth factor), a growth factor, serves as a monogenic and mitogenic cue during the process and activates intracellular signaling pathways inside the cell. Activation of extracellular signal regulated kinase (ERK) signaling is one of the mechanisms by which PDGF-A induces the migration of OPCs. However, the mechanisms governing the PDGF-A-induced ERK-driven OPCs migration are still unclear. In the current study, we investigated further the role of PDGF-A-induced ERK signaling in OPC migration. First, we confirmed the role of PDGF-A-activated ERK signaling in OPC migration using the pharmacological inhibitor U0126, or siRNA-mediated suppression of ERK expression. Then, we demonstrated that PDGF-A-induced actin reorganization and interaction of focal adhesion kinase (FAK), Paxillin, and pERK signals are impaired in OPCs treated with the MEK inhibitor U0126. Thus, our findings demonstrated that PDGF-A induces OPC migration in an ERK-dependent mechanism via regulation of actin reorganization and FAK-Paxillin interaction.

MeCP2 in central nervous system glial cells: current updates.

avMethyl­CpG binding protein 2 (MeCP2) is an epigenetic regulator, which preferentially binds to methylated CpG dinucleotides in DNA. MeCP2 mutations have been linked to Rett syndrome, a neurodevelopmental disorder characterized by severe intellectual disability in females. Earlier studies indicated that loss of MeCP2 function in neuronal cells was the sole cause of Rett syndrome. Subsequent studies have linked MeCP2 expression in CNS glial cells to Rett syndrome pathogenesis. In this review, we have discussed the role of MeCP2 in glial subtypes, astrocytes, oligodendrocytes and microglia, and how loss of MeCP2 function in these cells has a profound influence on both glial and neuronal function.

MeCP2 overexpression inhibits proliferation, migration and invasion of C6 glioma by modulating ERK signaling and gene expression.

MethylCpG binding protein-2 (MeCP2) is an epigenetic regulator and essential for brain development. MeCP2 mutations are associated with a spectrum of neuro-developmental disorders that vary depending on the patient gender, most notably Rett Syndrome. MeCP2 is essential for normal neuronal maturation, and glial cell function in the brain. Besides, its role in neurodevelopmental disorders, MeCP2 is involved in many cancers such as breast, colorectal, lung, liver, and prostate cancer. Glioma is the most lethal form of brain cancer. Studies have shown that dysfunctional epigenetic regulation plays a crucial role in glioma progression. Further, previous studies have suggested a role for MeCP2 in glioma pathogenesis. In this study, we show that MeCP2 may play a critical role in the suppression of glioma progression. Stable overexpression of MeCP2in C6 glioma cells inhibits proliferation, migration, invasion, and adhesion. Moreover, MeCP2 overexpression inhibits pERKand BDNF expression while inducing GFAP expression in C6 glioma. These findings suggest that MeCP2 may play a crucial role in suppression of glioma progression.

Stable individual differences predict eye movements to the left, but not handedness or line bisection.

When observers view an image, their initial eye movements are not equally distributed but instead are often biased to the left of the picture. This pattern has been linked to pseudoneglect, the spatial bias to the left that is observed in line bisection and a range of other perceptual and attentional tasks. Pseudoneglect is often explained according to the dominance of the right-hemisphere in the neural control of attention, a view bolstered by differences between left- and right-handed participants in both line bisection and eye movements. We re-examined this observation in eighty participants (half of whom reported being left handed) who completed a computerised line bisection task and viewed a series of images. We failed to replicate the previously-reported effect of handedness on eye movements in image viewing, with both groups showing a large average bias to the left on the first saccade. While there was a modest effect of handedness on line bisection, there was no correlation between the two tasks. Stable individual differences, as well as a shorter latency on the initial saccade, were robust predictors of an initial saccade to the left. Therefore, while there seems to be a reflexive and idiosyncratic drive to look to the left, it is not well accounted for by handedness and may have different mechanisms from other forms of pseudoneglect.

Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases.

Matrix metalloproteinases (MMPs) have numerous physiological functions and share a highly similar catalytic domain. Differential dynamical information on the closely related human MMP-8, -13, and -14 was integrated onto the benzoxazinone molecular template. An in silico library of 28,099 benzoxazinones was generated and evaluated in the context of the molecular-dynamics information. This led to experimental evaluation of 19 synthesized compounds and identification of selective inhibitors, which have potential utility in delineating the physiological functions of MMPs. Moreover, the approach serves as an example of how dynamics of closely related active sites may be exploited to achieve selective inhibition by small molecules and should find applications in other enzyme families with similar active sites.

pERK1/2 Peripheral Recruitment and Filopodia Protrusion Augment Oligodendrocyte Progenitor Cell Migration: Combined Effects of PDGF-A and Fibronectin.

Oligodendrocyte progenitor cell (OPC) migration is critical for effective myelination of the central nervous system. Not only during normal myelination but also during remyelination, the growth factors (GFs) and extracellular matrix (ECM) protein affect the OPC migration. Studies showed the altered levels of GFs and ECM in the demyelinating lesions. In our earlier studies, we have shown that the effect of platelet-derived growth factor alpha (PDGF-A) on OPC migration is dose- and time-dependent. In that we have shown that the physiological concentration (1 ng/ml) of PDGF-A was unable to induce OPC migration at transient exposure (30 min). However, the involvement of ECM in the regulation of PDGF-A mediated OPC migration was not clear. In the present study, we have used fibronectin (FN) as ECM. PDGF-A and FN have similar and overlapping intracellular signaling pathways including the extracellular regulated kinases 1 and 2 (ERK1/2). Here we demonstrate how physiological concentration of PDGF-A combines with FN to augment OPC migration in vitro. The present study is first of its kind to show the importance of the synergistic effects of PDGF-A and FN on peripheral recruitment of phosphorylated/activated ERK1/2 (pERK1/2), actin-pERK1/2 co-localization, and filopodia formation, which are essential for the enhanced OPC migration. These findings were further confirmed by ERK1/2 inhibition studies, using the pharmacological inhibitor U0126. An understanding of these complex interactions may lead to additional strategies for transplanting genetically modified OPCs to repair widespread demyelinated lesions.