Once-Weekly Exenatide as Adjunct Treatment of Type 1 Diabetes Mellitus in Patients Receiving Continuous Subcutaneous Insulin Infusion Therapy

Objective The use of once-weekly exenatide in type 2 diabetes mellitus is well supported, but little is known about its effectiveness in type 1 diabetes. The objective of this study was to determine the clinical efficacy of once-weekly exenatide on glycemic control in patients with type 1 diabetes when added to basal-bolus insulin therapy. Methods For this retrospective study, patients with type 1 diabetes, aged 18 years and older, receiving continuous subcutaneous insulin infusion, using a continuous glucose monitoring device or regularly measuring blood glucose levels and receiving 2 mg of exenatide once weekly for at least 3 months were included. Demographic information, glycated hemoglobin (A1C), body weight, body mass index, systolic and diastolic blood pressures, total daily insulin dose, basal and bolus insulin doses, 28-day continuous subcutaneous insulin infusion glucose average and incidence of hypoglycemia were collected at baseline and 3 months after beginning therapy with once-weekly exenatide. Results An electronic medical record search identified 11 patients with type 1 diabetes who met the inclusion criteria. Comparing baseline and 3 months after initiation of once-weekly exenatide revealed reductions of 0.6% in A1C (p=0.013), 3.7% in body weight (p=0.008), 1.7 kg/m2 in body mass index (p=0.003), 13% in total daily insulin dose (p=0.011) and 9.3 units in bolus insulin dose (p=0.015). Conclusions This study revealed that the addition of once-weekly exenatide to insulin therapy for type 1 diabetes patients leads to significant improvements in A1C, body weight, body mass index and insulin doses

Environmental Toxins Linked to Neurodegeneration and Autism Activate the Brain’s Immune System

Microglia are the primary immune cells of the central nervous system and become activated in response to noxious stimuli, leading to a cycle of inflammation and cell death that has been implicated in the development of Parkinson’s disease and autism. This study examines the effects of environmental toxins, at levels commonly found in humans, on microglial cell survival and activation. The toxins used in this study include polybrominated diphenyl ether (PBDE) flame retardants, the food additive propionic acid (PPA), and the organochlorine pesticide dieldrin. These chemicals have been linked to neuronal damage, although their effects on microglial cells have not been fully studied. Our results indicate that microglial cell survival could be decreased by as much as 50% due to exposure to these toxins, without the production of certain cytokines produced by lipopolysaccharide (LPS)-induced activation. These effects are significant as further understanding of the role of microglia in neuronal damage could provide a pharmacologic target for future drug development as well as elucidate the pathology of neurodegenerative diseases

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

The Sir Jimmy Savile Scandal: Child Sexual Abuse and Institutional Denial at the BBC

This study advances research on scandal through an empirical examination of one of the most extraordinary UK institutional child sexual abuse (CSA) scandals in the post-war period. Sir Jimmy Savile (1926–2011) was a BBC celebrity, showbiz friend of the establishment and philanthropist. In October 2012, one year after his death, an ITV documentary alleged that Savile was also a prolific sexual predator who for decades had exploited his BBC status to abuse teenage girls. As we demonstrate, this incendiary documentary triggered a news media feeding frenzy that in less than one week destroyed Savile’s reputation and thrust the BBC – the institution that made him a star – into a multi-faceted, globally reported CSA scandal. This study has four purposes. First, we propose a model of institutional CSA scandals that can account for critical transitions between key phases in the scandal process. Second, we apply this model to analyse the transition between the ‘latent’ and ‘activated’ phases of the Savile scandal. This transition corresponded with a dramatic transformation in the inferential structuring of Savile from ‘national treasure’, who had devoted decades to working with children, to ‘prolific sexual predator’, who spent decades abusing them. Third, we demonstrate how the BBC’s denial of responsibility for Savile’s sexual offending and its subsequent institutional cover-up triggered a ‘trial by media’ which in turn initiated the next phase in the scandal’s development – ‘amplification’. Finally, we consider the significance of our analysis of the Sir Jimmy Savile scandal for understanding the activation and development of scandals more generally

Cultural and Media Identity Among Latvian Migrants in Germany

This chapter explores how transnational media and culture impacts on the identity formation of recent Latvian migrants in Germany. In the context of the EU, Germany opened its labour market to the new EU countries rather late, when compared to other ‘old’ EU countries. This has had an effect on the composition of the group of Latvian migrants going to Germany, and their identities. In the light of this, this chapter examines how Latvian migrants in Germany feel and experience their belonging to Latvia and its culture. It analyses the social and communicative practices crucial for the development of belonging, including the rootedness in the country where they live and the cultural references that are important for them. The evidence for the analysis in this chapter comes from in-depth interviews, open media diaries and network maps of Latvian migrants in Germany. The chapter situates the description of evidence in the framework of cultural identity concepts and discusses the role of culture and media in the process of building migrant identity. The chapter argues that culture is shaping the transnational self-perception of Latvian migrants in Germany – as it provides collective narratives of imagined common frames of references, and confirms feelings of belonging and distinction

Antiinflammatory and immunomodulating properties of fungal metabolites

We discuss current information on the ability of extracts and isolated metabolites from mushrooms to modulate immune responses. This can result in a more enhanced innate and acquired disease resistance. The major immunomodulating effects of these active substances derived from mushrooms include mitogenicity and activation of immune effector cells, such as lymphocytes, macrophages, and natural killer cells, resulting in the production of cytokines, including interleukins (ILs), tumor necrosis factor alpha (TNF)-¿, and interferon gamma (INF)-¿. In particular, the ability of selective mushroom extracts to modulate the differentiation capacity of CD4+ T cells to mature into TH1 and/or TH2 subsets will be discussed. As a consequence these extracts will have profound effects in particular diseases, like chronic autoimmune TH1-mediated or allergic TH2-mediated diseases. Immunosuppressive effects by mushroom components have also been observed. The therapeutic effects of mushrooms, such as anticancer activity, suppression of autoimmune diseases, and allergy have been associated with their immunomodulating effects. However, further studies are needed to determine the molecular mechanisms of the immunomodulating effects of mushrooms metabolites both individually and in complex mixtures, for example, extract

La gestión del agua durante El Argar: el caso de La Bastida (Totana, Murcia)

Prehistoric hydraulic structures offer the most reliable way to gain knowledge on a critical resource for subsistence. The functional (catchment, storage, distribution), spatial and technological analysis of these structures show differences amongst local groups and entire societies regarding water use and policies. Moreover, they set out the objective background for making economic and political inferences on the societies that used them. In this paper, a large water reservoir (pond) excavated in the site of La Bastida (Totana, Murcia, Spain) is presented. Also, an assessment on its role in the settlement organisation together with a contextualisation in relation to other contemporary and older hydraulic structures in soth-east Iberia are made.Las estructuras hidráulicas prehistóricas proporcionan los medios más fiables para conocer la gestión de un recurso básico para la subsistencia. El análisis de su función (acopio, almacenamiento, distribución) y ubicación, unido al de sus características tecnológicas en tanto artefactos, permiten conocer diferencias entre grupos locales y sociedades respecto alos usos y políticas del agua. Además, enmarcan y limitan las inferencias económico-políticas sobre la sociedad que utilizó dichas estructuras. En este artículo se presenta el hallazgo de una balsa de grandes dimensiones excavada en el yacimiento argárico de La Bastida (Totana, Murcia, España), se valora su relevancia en el marco del asentamiento y se contextualiza en referencia a otras estructuras de control hídrico sincrónicasy previas en el sureste de la península ibé

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

Microglial activation and chronic neurodegeneration

Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurode-generative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.g., lipopolysaccharide or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss with time. Although the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson’s disease. We review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype