Mechanisms Mediating Adaptive Presynaptic Muting Induction

Neurons are responsible for information processing within the nervous system, so strong perturbations of neuronal function have far-reaching consequences within the neural network. Damage in response to excess excitation, as occurs during stroke or seizure, is known as excitotoxicity. One method utilized by neurons for reducing excitotoxicity within an overly activated neuronal network is to arrest excitatory neurotransmitter release from presynaptic terminals. The mechanisms responsible for inducing this presynaptic silencing: or muting ), however, have been elusive. In order to elucidate the signals responsible, I used molecular techniques in defined networks of cultured neurons from the mammalian hippocampus, a well-studied brain region known to be important for learning and memory but susceptible to excitotoxic damage. Calcium serves as a signal transducer during excitotoxicity and many forms of synaptic plasticity, but the signaling cascades in presynaptic silencing were previously unknown. In neurons individually depolarized via heterologous ion channel activation, I showed that calcium influx led to cell death while channel expression led to synaptic depression, although muting was not confirmed. Calcium, however, was not necessary for presynaptic muting after strong depolarization. Instead, inhibitory G-protein signaling induced silencing through cyclic adenosine monophosphate: cAMP) reduction but surprisingly not via activation of likely candidate receptors. This cAMP reduction contributed to loss of proteins important for vesicle fusion at the presynaptic terminal. I also found that astrocytes, support cells in the nervous system that have garnered attention recently for their ability to modulate neuronal function, were required for the proper development of presynaptic muting in hippocampal neurons. Soluble factors released by astrocytes were permissive, but not instructive, for silencing induction. Thrombospondins were identified as the astrocyte-derived factors responsible for muting competence in neurons, and they act through binding to the a2d-1 subunit of voltage-gated calcium channels. cAMP-activated protein kinase A exhibited dysfunctional behavior in the absence of thrombospondins, potentially explaining the presynaptic muting deficit in an astrocyte-deficient environment. Together these results clarify the molecular mechanisms responsible for an underappreciated form of neuroprotective synaptic plasticity and provide potential therapeutic targets for a number of disorders expressing excitotoxic damage

The Impact of an At-Risk Program in an Elementary School

The purpose of this project is to examine the effect:, of an elementary At-Risk Program. Challengers. over a nine month period. The intent of this. program was lo increase student self-concept and academic achievement measured by grade point averages. Identification of students who participated in this study was done by a needs assessment survey completed by the teachers. The needs assessment survey includes identifying characteristics for students at-risk. The control group consisted of students who were identified as at-risk , but did not participate in the program. Data collection included scores on the Pier-Harris Self Concept Scale and teacher input on academic achievement scores. Research found a significant difference in self-esteem scores, but not grade point averages of students participating in the program

The temporal nature of legitimation:the case of IFRS8

Legitimation can operate on an episodic or continual basis [Suchman, M.C. (1995). Managing legitimacy: Strategic and institutional approaches. Academy of Management Review, 20(3), 571-610]. We examine the temporal legitimation of the International Accounting Standards Board (IASB)'s actions during the adoption and review of International Financial Reporting Standard (IFRS) 8 Operating Segments. We conceptualise the controversy surrounding IFRS8 as an episode when the IASB sought segmental reporting convergence with the US standard, Statement of Financial Accounting Standard 131. Interpreting evidence from 15 (20) semi-structured interviews undertaken in 2009 (2011), before (after) entities reported under IFRS8, reveals its adoption precipitated an episodic legitimacy threat from selected audiences to the actions of the IASB. We discuss the IASB's attempt to influence legitimation for this episode through commitment to a post-implementation review [IFRS Foundation. (2011). Post implementation reviews: Plan for developing the framework for conducting post-implementation reviews. IASB Board meeting February 2011. Retrieved July 27, 2011, from http://www.ifrs.org/NR/rdonlyres/ 3E1502E4-F1E8-4907-838B-FFB20C7268ED/0/PIR02111st2ndb04obs.pdf] of IFRS8. Interpreting legitimacy concerns across diverse audiences about specific actions of the IASB (the introduction of IFRS8) enables us to draw conclusions about the resilience of the IASB as a standard setting organisation, in itself

Mental health problems: Are they or are they not a risk factor for dropout from drug treatment? A systematic review of the evidence

Background: A sizeable number of recent studies investigating whether clients with substance misuse and mental health problems (dual diagnosis clients) are at heightened risk of dropout from drug treatment have been published. It is timely that their findings are brought together in a comprehensive review of the current evidence. Aims: The aim of the review is to examine whether dually diagnosed clients are less likely to be retained in drug treatment than clients without mental health problems, and, if so, whether this varies for clients diagnosed with different types of mental health problems. Methods: The review considers peer-reviewed research published after 1 January 1990, which was located using the literature databases Medline and PsycInfo. Predefined search terms were used. Further papers were identified from the bibliographies of relevant publications. Findings: 58 studies (84% from the USA) met the inclusion criteria for the review. The findings suggest that for most clients, having a past history of mental health problems does not influence the likelihood of being retained in drug treatment. The body of evidence regarding concurrent mental health problems is contradictory. On the whole, the majority of studies suggest that neither presence nor severity of depressive, anxiety, or other Axis-I disorders is related to retention, but these findings are not entirely unequivocal, as a few studies report strong positive or negative associations between depression and anxiety disorders and retention. Few researchers looked separately at psychotic spectrum disorders hence no conclusions could be drawn. The presence of most personality disorders also did not appear to affect treatment tenure, with the exception of antisocial personality disorder, for which the evidence points towards a greater risk of dropout. Conclusions: The balance of evidence suggests that, overall, dual diagnosis clients with Axis-I disorders who seek treatment in drug treatment services are retained as well as clients without dual diagnosis. Subgroups of clients who appear more vulnerable to premature dropout include those with antisocial personality disorder. Methodological shortcomings of the reviewed studies and resulting implications for this review and future research are discussed

Challenges for the childcare market: the implications of COVID-19 for childcare providers in England

The closures of childcare providers to most families during the COVID-19 crisis have underlined the importance of access to childcare, both to support paid work and to help shape young children’s environment. However, the crisis has had severe consequences for the finances of childcare providers, which were already weak in several parts of the sector going into the crisis. Despite a range of government support programmes, many providers lost income during lockdown. In the medium term, a longer-lasting fall in demand for childcare or an increase in costs related to social distancing could seriously hamper financial sustainability in the sector going forward. In this report, we assess the consequences of the pandemic – and the resulting public health response – for the finances of early years childcare providers

Expression of cannabinoid receptors in human osteoarthritic cartilage: implications for future therapies

Introduction: Cannabinoids have shown to reduce joint damage in animal models of arthritis and reduce matrix metalloproteinase expression in primary human steoarthritic (OA) chondrocytes. The actions of cannabinoids are mediated by a number of receptors, including cannabinoid receptors 1 and 2 (CB1 and CB2), Gprotein-coupled receptors 55 and 18 (GPR55 and GPR18), transient receptor potential vanilloid-1 (TRPV1), and peroxisome proliferator-activated receptors alpha and gamma (PPARa and PPARc). However, to date very few studies have investigated the expression and localization of these receptors in human chondrocytes, and expression during degeneration, and thus their potential in clinical applications is unknown. Methods: Human articular cartilage from patients with symptomatic OA was graded histologically and the expression and localization of cannabinoid receptors within OA cartilage and underlying bone were determined immunohistochemically. Expression levels across regions of cartilage and changes with degeneration were investigated. Results: Expression of all the cannabinoid receptors investigated was observed with no change with grade of degeneration seen in the expression of CB1, CB2, GPR55, PPARa, and PPARc. Conversely, the number of chondrocytes within the deep zone of cartilage displaying immunopositivity for GPR18 and TRPV1 was significantly decreased in degenerate cartilage. Receptor expression was higher in chondrocytes than in osteocytes in the underlying bone. Conclusions: Chondrocytes from OA joints were shown to express a wide range of cannabinoid receptors even in degenerate tissues, demonstrating that these cells could respond to cannabinoids. Cannabinoids designed to bind to receptors inhibiting the catabolic and pain pathways within the arthritic joint, while avoiding psychoactive effects, could provide potential arthritis therapies. Key words: articular cartilage; cannabinoid receptors; cannabinoids; osteoarthriti

Impact of appropriate pharmaceutical therapy for chronic conditions on direct medical costs and workplace productivity: A review of the literature

This paper presents the findings of a literature review investigating the economic impact of appropriate pharmaceutical therapy in treating four prevalent chronic conditions - asthma, diabetes, heart failure, and migraine. The goal of the review was to identify high-quality studies examining the extent to which appropriate pharmaceutical therapy impacts overall medical expenditure (direct costs) and workplace productivity (indirect costs). The working hypothesis in conducting the review was that the costs of pharmaceuticals for the selected chronic conditions are offset by savings in direct and indirect costs in other areas. The literature provides evidence that appropriate drug therapy improves the health status and quality of life of individuals with chronic illnesses while reducing costs associated with utilization of emergency room, inpatient, and other medical services. A growing body of evidence also suggests that workers whose chronic conditions are effectively controlled with medications are more productive. For employers, the evidence translates into potential direct and indirect cost savings. The findings also confirm the importance of pharmaceutical management as a cornerstone of disease management

The Role of Multiple Sclerosis as a Risk Factor for the Development of Osteoporosis

Background: Osteoporosis is the most common bone disease in the United States, and it is particularly common among women with multiple sclerosis (MS). However, despite this association, the temporal relationship between these two conditions has not been previously studied. Data from the Women’s Health Initiative provides a unique opportunity to examine the risk of developing osteoporosis over time in individuals diagnosed with MS. Objective: The purpose of this study is to refine the relationship between MS and osteoporosis, clarifying the impact of environmental and pharmacologic factors on each condition, as well as addressing treatment and preventative efforts for a patient population at a greater potential risk for osteoporosis. Methods: The study sample, derived from the Women’s Health Initiative, included 449 women who reported an MS diagnosis at baseline and 161,359 women without MS who comprised a control group. Baseline measures of self-reported osteoporosis, age, smoking status, steroid and anti-inflammatory use, and supplementary as well as dietary calcium and vitamin D were compared. MS patients reporting osteoporosis at baseline were removed, resulting in 355 women with MS to monitor for time to incident osteoporosis. Survival analyses were performed on follow-up data gathered annually between 1993 and 2005 to factor out significant associations of additional factors. Proportions of participants on osteoporosis-related medications as well as latency to use were compared between the multiple sclerosis and control cohorts. Results: At baseline, women with MS are nearly three times as likely to report osteoporosis (p Conclusions: A higher prevalence of osteoporosis at baseline suggests MS may significantly increase the risk of osteoporosis in premenopausal women. In contrast, environmental and pharmacologic variables appear to have a more significant role in the post-menopausal population. While osteoporosis was treated similarly between both groups, the point for intervention or prevention of osteoporosis in MS patients may be earlier in the disease course