Abstract Although an association between air pollution and adverse systemic health effects has been known for years, the effect of pollutants on neurodevelopment has been underappreciated. Recent ...evidence suggests a possible link between air pollution and neurocognitive impairment and behavioral disorders in children, however, the exact nature of this relationship remains poorly understood. Infants and children are uniquely vulnerable due to the potential for exposure in both the fetal and postnatal environments during critical periods in development. Carbon monoxide (CO), a common component of indoor and outdoor air pollution, can cross the placenta to gain access to the fetal circulation and the developing brain. Thus, CO is of particular interest as a known neurotoxin and a potential public health threat. Here we review overt CO toxicity and the policies regulating CO exposure, detail the evidence suggesting a potential link between CO-associated ambient air pollution, tobacco smoke, and learning and behavioral abnormalities in children, describe the effects of subclinical CO exposure on the brain during development, and provide mechanistic insight into a potential connection between CO exposure and neurodevelopmental outcome. CO can disrupt a number of critical processes in the developing brain, providing a better understanding of how this specific neurotoxin may impair neurodevelopment. However, further investigation is needed to better define the effects of perinatal CO exposure on the immature brain. Current policies regarding CO standards were established based on evidence of cardiovascular risk in adults with pre-existing comorbidities. Thus, recent and emerging data highlighted in this review regarding CO exposure in the fetus and developing child may be important to consider when the standards and guidelines are evaluated and revised in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Geological data indicate that there were major variations in Antarctic ice sheet volume and extent during the early to mid-Miocene. Simulating such large-scale changes is problematic because of a ...strong hysteresis effect, which results in stability once the ice sheets have reached continental size. A relatively narrow range of atmospheric CO₂ concentrations indicated by proxy records exacerbates this problem. Here, we are able to simulate large-scale variability of the early to mid-Miocene Antarctic ice sheet because of three developments in our modeling approach. (i) We use a climate–ice sheet coupling method utilizing a high-resolution atmospheric component to account for ice sheet–climate feedbacks. (ii) The ice sheet model includes recently proposed mechanisms for retreat into deep subglacial basins caused by ice-cliff failure and ice-shelf hydrofracture. (iii) We account for changes in the oxygen isotopic composition of the ice sheet by using isotope-enabled climate and ice sheet models. We compare our modeling results with ice-proximal records emerging from a sedimentological drill core from the Ross Sea (Andrill-2A) that is presented in a companion article. The variability in Antarctic ice volume that we simulate is equivalent to a seawater oxygen isotope signal of 0.52–0.66‰, or a sea level equivalent change of 30–36 m, for a range of atmospheric CO₂ between 280 and 500 ppm and a changing astronomical configuration. This result represents a substantial advance in resolving the long-standing model data conflict of Miocene Antarctic ice sheet and sea level variability.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The clinical signs grouped under the concept of apathy are a common feature of prefrontal and basal ganglia lesions or dysfunctions and can therefore help to improve our understanding of the ...functional anatomy of the prefrontal–basal ganglia system. Apathy is here defined as a quantitative reduction of voluntary, goal-directed behaviors. The underlying mechanisms responsible for apathy can be divided into three subtypes of disrupted processing: ‘emotional–affective’, ‘cognitive’ and ‘auto-activation’. Apathy due to the disruption of ‘emotional–affective’ processing refers to the inability to establish the necessary linkage between emotional–affective signals and the ongoing or forthcoming behavior. It may be related to lesions of the orbital–medial prefrontal cortex or to the related subregions (limbic territory) within the basal ganglia (e.g. ventral striatum, ventral pallidum). Apathy due to the disruption of ‘cognitive’ processing refers to difficulties in elaborating the plan of actions necessary for the ongoing or forthcoming behavior. It may be related to lesions of the dorsolateral prefrontal cortex and the related subregions (associative territory) within the basal ganglia (e.g. dorsal caudate nucleus). The disruption of ‘auto-activation’ processing refers to the inability to self-activate thoughts or self-initiate actions contrasting with a relatively spared ability to generate externally driven behavior. It is responsible for the most severe form of apathy and in most cases the lesions affect bilaterally the associative and limbic territories of the internal portion of the globus pallidus. It characterizes the syndrome of ‘auto-activation deficit’ (also known as ‘psychic akinesia’ or ‘athymormia’). This syndrome implies that direct lesions of the basal ganglia output result in a loss of amplification of the relevant signal, consequently leading to a diminished extraction of this signal within the frontal cortex. Likewise, apathy occurring in Parkinson's disease could be interpreted as secondary to the loss of spatial and temporal focalization of the signals transferred to the frontal cortex. In both situations (direct basal ganglia lesions and nigro-striatal dopaminergic loss), the capacity of the frontal cortex to select, initiate, maintain and shift programs of actions is impaired.
This trial showed clinically significant responses in spleen size and quality of life among patients with myelofibrosis receiving ruxolitinib, a JAK1 and JAK2 inhibitor. The agent has some ...myelotoxicity, but this study showed a survival advantage with ruxolitinib.
Myelofibrosis, a myeloproliferative neoplasm, is manifested by abnormal blood counts (anemia, thrombocytosis or thrombocytopenia, and leukocytosis or leukopenia), splenomegaly, and debilitating symptoms (e.g., fatigue, weakness, abdominal pain, cachexia, weight loss, pruritus, night sweats, and bone pain), which are thought to be caused by the combined effects of massive splenomegaly and elevated levels of proinflammatory cytokines.
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Survival ranges from approximately 2 to 11 years, depending on defined prognostic factors.
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Traditional therapeutic options, including splenectomy, have limited benefit.
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Although allogeneic stem-cell transplantation may cure myelofibrosis, few patients are eligible for this treatment.
Although the gain-of-function mutation in the gene encoding Janus kinase . . .
The new division of labor Levy, Frank; Murnane, Richard J
2004, 2012., 20121126, 2012, 2004-01-01, 20040101
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Die Autoren gehen von der Tatsache aus, dass sich die Situation auf dem Arbeitsmarkt in den letzten Jahren grundlegend verändert hat: Selbst nach einer Rezession werden die durch die Automatisierung ...oder die Verlagerung in Niedriglohnländer verloren gegangenen Arbeitsplätze nicht wieder entstehen. Analysiert werden die Einflüsse der Informationstechnik auf die Arbeitsplatzstruktur, insbesondere die Möglichkeiten der Problemlösung und Kommunikation. Es wird dabei die These abgeleitet, dass komplexe Kommunikation nach wie vor eine Domäne menschlichen Handels sein wird, und Computer auf diesem Gebiet keine Alternative darstellen. Die Gesellschaft muss sich auf diese Veränderungen einzustellen, indem eine Arbeitsteilung zwischen automatisierten Jobs und gut bezahlten und hochqualifizierten Arbeitsplätze akzeptiert und gestaltet wird. Arbeitsplätze, deren Schwerpunkt auf komplexen Problemlösungen sowie auf interpersonaler Kommunikation liegt, werden in großer Zahl entstehen. Die Untersuchung enthält quantitative Daten. Forschungsmethode: deskriptive Studie. (IAB).
Exposure to carbon monoxide (CO) during general anesthesia can result from volatile anesthetic degradation by carbon dioxide absorbents and rebreathing of endogenously produced CO. Although adherence ...to the Anesthesia Patient Safety Foundation guidelines reduces the risk of CO poisoning, patients may still experience subtoxic CO exposure during low-flow anesthesia. The consequences of such exposures are relatively unknown. In contrast to the widely recognized toxicity of high CO concentrations, the biologic activity of low concentration CO has recently been shown to be cytoprotective. As such, low-dose CO is being explored as a novel treatment for a variety of different diseases. Here, we review the concept of anesthesia-related CO exposure, identify the sources of production, detail the mechanisms of overt CO toxicity, highlight the cellular effects of low-dose CO, and discuss the potential therapeutic role for CO as part of routine anesthetic management.
Mitochondrial dysfunction is thought to play an important role in the pathogenesis of many different disease states. It has been proposed that an acquired defect in oxidative phosphorylation prevents ...cells from using molecular oxygen for adenosine triphosphate production and potentially causes sepsis-induced organ dysfunction. This concept, termed cytopathic hypoxia, however, has been difficult to prove because impaired oxidative phosphorylation has never been shown to cause sepsis-induced organ failure or to be a reversible phenomenon. Presented here is are view of oxidative phosphorylation, evidence of defective electron-transport-chain function in the heart and other organ systems during sepsis, and support for a link between mitochondrial dysfunction and pathologic metabolic down-regulation.
Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1−/y mouse have a ...mitochondrial inner membrane leak contributing to a “leak metabolism.” In human Fragile X syndrome (FXS) fibroblasts and in Fmr1−/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase β subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.
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•ATP synthase c-subunit leak in Fragile X causes aberrant metabolism•Changes in ATP synthase component stoichiometry regulate protein synthesis rate•Inhibition of the leak normalizes synaptic spine morphology and Fragile X behavior
Lack of FMRP in Fragile X neurons is associated with a leak in the ATP synthase, the blockade of which normalizes cellular and behavioral disease phenotypes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autism spectrum disorder (ASD), the fastest growing developmental disability in the United States, represents a group of neurodevelopmental disorders characterized by impaired social interaction and ...communication as well as restricted and repetitive behavior. The underlying cause of autism is unknown and therapy is currently limited to targeting behavioral abnormalities. Emerging studies suggest a link between mitochondrial dysfunction and ASD. Here, we review the evidence demonstrating this potential connection. We focus specifically on biochemical links, genetic-based associations, non-energy related mechanisms, and novel therapeutic strategies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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