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Sample records for mediates cerebellar long-term

  1. A stochastic signaling network mediates the probabilistic induction of cerebellar long-term depression.

    PubMed

    Antunes, Gabriela; De Schutter, Erik

    2012-07-04

    Many cellular processes involve a small number of molecules and undergo stochastic fluctuations in their levels of activity. Cerebellar long-term depression (LTD) is a form of synaptic plasticity expressed as a reduction in the number of synaptic AMPA receptors (AMPARs) in Purkinje cells. We developed a stochastic model of the LTD signaling network, including a PKC-ERK-cPLA(2) positive feedback loop and mechanisms of AMPAR trafficking, and tuned the model to replicate calcium uncaging experiments. The signaling network activity in single synapses switches between two discrete stable states (LTD and non-LTD) in a probabilistic manner. The stochasticity of the signaling network causes threshold dithering and allows at the macroscopic level for many different and stable mean magnitudes of depression. The probability of LTD occurrence in a single spine is only modulated by the concentration and duration of the signal used to trigger it, and inputs with the same magnitude can give rise to two different responses; there is no threshold for the input signal. The stochasticity is intrinsic to the signaling network and not mostly dependent on noise in the calcium input signal, as has been suggested previously. The activities of the ultrasensitive ERK and of cPLA(2) undergo strong stochastic fluctuations. Conversely, PKC, which acts as a noise filter, is more constantly activated. Systematic variation of the biochemical population size demonstrates that threshold dithering and the absence of spontaneous LTD depend critically on the number of molecules in a spine, indicating constraints on spine size in Purkinje cells.

  2. Inhibition promotes long-term potentiation at cerebellar excitatory synapses

    PubMed Central

    Binda, F.; Dorgans, K.; Reibel, S.; Sakimura, K.; Kano, M.; Poulain, B.; Isope, P.

    2016-01-01

    The ability of the cerebellar cortex to learn from experience ensures the accuracy of movements and reflex adaptation, processes which require long-term plasticity at granule cell (GC) to Purkinje neuron (PN) excitatory synapses. PNs also receive GABAergic inhibitory inputs via GCs activation of interneurons; despite the involvement of inhibition in motor learning, its role in long-term plasticity is poorly characterized. Here we reveal a functional coupling between ionotropic GABAA receptors and low threshold CaV3 calcium channels in PNs that sustains calcium influx and promotes long-term potentiation (LTP) at GC to PN synapses. High frequency stimulation induces LTP at GC to PN synapses and CaV3-mediated calcium influx provided that inhibition is intact; LTP is mGluR1, intracellular calcium store and CaV3 dependent. LTP is impaired in CaV3.1 knockout mice but it is nevertheless recovered by strengthening inhibitory transmission onto PNs; promoting a stronger hyperpolarization via GABAA receptor activation leads to an enhanced availability of an alternative Purkinje-expressed CaV3 isoform compensating for the lack of CaV3.1 and restoring LTP. Accordingly, a stronger hyperpolarization also restores CaV3-mediated calcium influx in PNs from CaV3.1 knockout mice. We conclude that by favoring CaV3 channels availability inhibition promotes LTP at cerebellar excitatory synapses. PMID:27641070

  3. Systems biology perspectives on cerebellar long-term depression.

    PubMed

    Ogasawara, Hideaki; Doi, Tomokazu; Kawato, Mitsuo

    2008-01-01

    Long-term depression (LTD) at parallel fiber-Purkinje cell (PF-PC) synapses is thought to be the cellular correlate of cerebellar associative learning. The molecular processes are, in brief, phosphorylation of AMPA-type glutamate receptors (AMPARs) and their subsequent removal from the surface of the PF-PC synapse. In order to elucidate the fundamental mechanisms for cerebellar LTD and further the understanding of its computational role, we have investigated its systems biology and proposed the following hypotheses, some of which have already been experimentally verified: (1) due to the mitogen-activated protein kinase (MAPK)-protein kinase C (PKC) positive feedback loop, phosphorylation of AMPARs is an all-or-none event; (2) the inositol 1,4,5-triphosphate receptor detects concurrent PF and climbing fiber inputs, forming the cellular basis for associative learning, and (3) the local concentration of nitric oxide in the PC dendrite reflects the relevance of a given context, enabling context-dependent selection of learning modules within the cerebellum. In this review, we first introduce theoretical studies on cerebellar LTD, mainly focusing on our own published work, followed by a discussion of the effects of stochasticity, localization, diffusion, and scaffolding. Neurons embody two features that are apparently contradictory, yet necessary for synaptic memory: stability and plasticity. We will also present models for explaining how neurons solve this dilemma. In the final section, we propose a conceptual model in which a cascade of excitable dynamics with different time scales, i.e., Ca(2+)-induced Ca(2+) release, the MAPK-PKC positive feedback loop, and protein kinase Mzeta (PKMzeta)-induced PKMzeta synthesis, provides a mechanism for stable memory that is still amenable to modifications. Copyright 2008 S. Karger AG, Basel.

  4. Calcium as a trigger for cerebellar long-term synaptic depression.

    PubMed

    Finch, Elizabeth A; Tanaka, Keiko; Augustine, George J

    2012-09-01

    Cerebellar long-term depression (LTD) is a form of long-term synaptic plasticity that is triggered by calcium(Ca2+) signals in the postsynaptic Purkinje cell. This Ca2+comes both from IP3-mediated release from intracellular Ca2+ stores, as well as from Ca2+ influx through voltage-gated Ca2+ channels. The Ca2+ signal that triggers LTD occurs locally within dendritic spines and is due to supralinear summation of signals coming from these two Ca2+ sources. The properties of this postsynaptic Ca2+signal can explain several features of LTD, such as its associativity, synapse specificity, and dependence on thetiming of synaptic activity, and can account for the slow kinetics of LTD expression. Thus, from a Ca2+ signaling perspective, LTD is one of the best understood forms of synaptic plasticity.

  5. Hyperpolarization induces a long-term increase in the spontaneous firing rate of cerebellar Golgi cells.

    PubMed

    Hull, Court A; Chu, YunXiang; Thanawala, Monica; Regehr, Wade G

    2013-04-03

    Golgi cells (GoCs) are inhibitory interneurons that influence the cerebellar cortical response to sensory input by regulating the excitability of the granule cell layer. While GoC inhibition is essential for normal motor coordination, little is known about the circuit dynamics that govern the activity of these cells. In particular, although GoC spontaneous spiking influences the extent of inhibition and gain throughout the granule cell layer, it is not known whether this spontaneous activity can be modulated in a long-term manner. Here we describe a form of long-term plasticity that regulates the spontaneous firing rate of GoCs in the rat cerebellar cortex. We find that membrane hyperpolarization, either by mGluR2 activation of potassium channels, or by somatic current injection, induces a long-lasting increase in GoC spontaneous firing. This spike rate plasticity appears to result from a strong reduction in the spike after hyperpolarization. Pharmacological manipulations suggest the involvement of calcium-calmodulin-dependent kinase II and calcium-activated potassium channels in mediating these firing rate increases. As a consequence of this plasticity, GoC spontaneous spiking is selectively enhanced, but the gain of evoked spiking is unaffected. Hence, this plasticity is well suited for selectively regulating the tonic output of GoCs rather than their sensory-evoked responses.

  6. Hyperpolarization induces a long-term increase in the spontaneous firing rate of cerebellar Golgi cells

    PubMed Central

    Hull, Court; Chu, YunXiang; Thanawala, Monica; Regehr, Wade G.

    2013-01-01

    Golgi cells (GoCs) are inhibitory interneurons that influence the cerebellar cortical response to sensory input by regulating the excitability of the granule cell layer. While GoC inhibition is essential for normal motor coordination, little is known about the circuit dynamics that govern the activity of these cells. In particular, while GoC spontaneous spiking influences the extent of inhibition and gain throughout the granule cell layer, it is not known whether this spontaneous activity can be modulated in a long-term manner. Here we describe a form of long-term plasticity that regulates the spontaneous firing rate of GoCs in the rat cerebellar cortex. We find that membrane hyperpolarization, either by mGluR2 activation of potassium channels, or by somatic current injection, induces a long-lasting increase in GoC spontaneous firing. This spike rate plasticity appears to result from a strong reduction in the spike afterhyperpolarization (AHP). Pharmacological manipulations suggest the involvement of calcium-calmodulin dependent kinase II (CaMKII) and calcium-activated potassium channels in mediating these firing rate increases. As a consequence of this plasticity, GoC spontaneous spiking is selectively enhanced, but the gain of evoked spiking is unaffected. Hence this plasticity is well-suited for selectively regulating the tonic output of GoCs rather than their sensory-evoked responses. PMID:23554471

  7. The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK.

    PubMed

    Lippiello, Pellegrino; Hoxha, Eriola; Speranza, Luisa; Volpicelli, Floriana; Ferraro, Angela; Leopoldo, Marcello; Lacivita, Enza; Perrone-Capano, Carla; Tempia, Filippo; Miniaci, Maria Concetta

    2016-02-01

    The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum.

  8. Alcohol Impairs Long-Term Depression at the Cerebellar Parallel Fiber–Purkinje Cell Synapse

    PubMed Central

    Belmeguenai, Amor; Botta, Paolo; Weber, John T.; Carta, Mario; De Ruiter, Martijn; De Zeeuw, Chris I.; Valenzuela, C. Fernando; Hansel, Christian

    2008-01-01

    Acute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cerebellum and affects synaptic transmission and plasticity at excitatory climbing fiber (CF) to Purkinje cell synapses. However, it has not been examined thus far how acute ethanol application affects long-term depression (LTD) and long-term potentiation (LTP) at excitatory parallel fiber (PF) to Purkinje cell synapses, which are assumed to mediate forms of cerebellar motor learning. To examine ethanol effects on PF synaptic transmission and plasticity, we performed whole cell patch-clamp recordings from Purkinje cells in rat cerebellar slices. We found that ethanol (50 mM) selectively blocked PF–LTD induction, whereas it did not change the amplitude of excitatory postsynaptic currents at PF synapses. In contrast, ethanol application reduced voltage-gated calcium currents and type 1 metabotropic glutamate receptor (mGluR1)–dependent responses in Purkinje cells, both of which are involved in PF–LTD induction. The selectivity of these effects is emphasized by the observation that ethanol did not impair PF–LTP and that PF–LTP could readily be induced in the presence of the group I mGluR antagonist AIDA or the mGluR1a antagonist LY367385. Taken together, these findings identify calcium currents and mGluR1-dependent signaling pathways as potential ethanol targets and suggest that an ethanol-induced blockade of PF–LTD could contribute to the motor coordination deficits resulting from alcohol consumption. PMID:18922952

  9. Changes in cortical, cerebellar and basal ganglia representation after comprehensive long term unilateral hand motor training.

    PubMed

    Walz, A D; Doppl, K; Kaza, E; Roschka, S; Platz, T; Lotze, M

    2015-02-01

    We were interested in motor performance gain after unilateral hand motor training and associated changes of cerebral and cerebellar movement representation tested with functional magnetic resonance imaging (fMRI) before and after training. Therefore, we trained the left hand of strongly right-handed healthy participants with a comprehensive training (arm ability training, AAT) over two weeks. Motor performance was tested for the trained and non-trained hand before and after the training period. Functional imaging was performed for the trained and the non-trained hand separately and comprised force modulation with the fist, sequential finger movements and a fast writing task. After the training period the performance gain of tapping movements was comparable for both hand sides, whereas the motor performance for writing showed a higher training effect for the trained hand. fMRI showed a reduction of activation in supplementary motor, dorsolateral prefrontal cortex, parietal cortical areas and lateral cerebellar areas during sequential finger movements over time. During left hand writing lateral cerebellar hemisphere also showed reduced activation, while activation of the anterior cerebellar hemisphere was increased. An initially high anterior cerebellar activation magnitude was a predictive value for high training outcome of finger tapping and visual guided movements. During the force modulation task we found increased activation in the striate. Overall, a comprehensive long-term training of the less skillful hand in healthy participants resulted in relevant motor performance improvements, as well as an intermanual learning transfer differently pronounced for the type of movement tested. Whereas cortical motor area activation decreased over time, cerebellar anterior hemisphere and striatum activity seem to represent increasing resources after long-term motor training.

  10. Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation

    PubMed Central

    van Beugen, Boeke J.; Qiao, Xin; Simmons, Dana H.; De Zeeuw, Chris I.

    2014-01-01

    Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites. In the presence of CX546 in the bath, PF-evoked calcium transients were enhanced and prolonged, suggesting that CX546 not only enhances synaptic transmission, but also boosts dendritic calcium signaling at cerebellar synapses. In contrast to previous observations in the hippocampus, however, CX546 applied during cerebellar recordings facilitates long-term depression (LTD) rather than LTP at PF synapses. These findings show that ampakines selectively modify the LTP–LTD balance depending on the brain area and type of synapse, and may provide tools for the targeted regulation of synaptic memories. PMID:25403454

  11. Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation.

    PubMed

    van Beugen, Boeke J; Qiao, Xin; Simmons, Dana H; De Zeeuw, Chris I; Hansel, Christian

    2014-12-01

    Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites. In the presence of CX546 in the bath, PF-evoked calcium transients were enhanced and prolonged, suggesting that CX546 not only enhances synaptic transmission, but also boosts dendritic calcium signaling at cerebellar synapses. In contrast to previous observations in the hippocampus, however, CX546 applied during cerebellar recordings facilitates long-term depression (LTD) rather than LTP at PF synapses. These findings show that ampakines selectively modify the LTP-LTD balance depending on the brain area and type of synapse, and may provide tools for the targeted regulation of synaptic memories.

  12. Long-term supratentorial brain structure and cognitive function following cerebellar tumour resections in childhood.

    PubMed

    Moberget, T; Andersson, S; Lundar, T; Due-Tønnessen, B J; Heldal, A; Endestad, T; Westlye, L T

    2015-03-01

    The cerebellum is connected to extensive regions of the cerebrum, and cognitive deficits following cerebellar lesions may thus be related to disrupted cerebello-cerebral connectivity. Moreover, early cerebellar lesions could affect distal brain development, effectively inducing long-term changes in brain structure and cognitive function. Here, we characterize supratentorial brain structure and cognitive function in 20 adult patients treated for cerebellar tumours in childhood (mean age at surgery: 7.1 years) and 26 matched controls. Relative to controls, patients showed reduced cognitive function and increased grey matter density in bilateral cingulum, left orbitofrontal cortex and the left hippocampus. Within the patient group, increased grey matter density in these regions was associated with decreased performance on tests of processing speed and executive function. Further, diffusion tensor imaging revealed widespread alterations in white matter microstructure in patients. While current ventricle volume (an index of previous hydrocephalus severity it patients) was associated with grey matter density and white matter microstructure in patients, this could only partially account for the observed group differences in brain structure and cognitive function. In conclusion, our results show distal effects of cerebellar lesions on cerebral integrity and wiring, likely caused by a combination of neurodegenerative processes and perturbed neurodevelopment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Systemic inflammation combined with neonatal cerebellar haemorrhage aggravates long-term structural and functional outcomes in a mouse model.

    PubMed

    Tremblay, Sophie; Pai, Alex; Richter, Lindsay; Vafaei, Rod; Potluri, Praneetha; Ellegood, Jacob; Lerch, Jason P; Goldowitz, Daniel

    2017-07-27

    Despite the increased recognition of cerebellar injury in survivors of preterm birth, the neurodevelopmental consequences of isolated cerebellar injury have been largely unexplored and our current understanding of the functional deficits requires further attention in order to translate knowledge to best practices. Preterm infants are exposed to multiple stressors during their postnatal development including perinatal cerebellar haemorrhage (CBH) and postnatal infection, two major risk factors for neurodevelopmental impairments. We developed a translational mouse model of CBH and/or inflammation to measure the short- and long-term outcomes in cerebellar structure and function. Mice exposed to early combined insults of CBH and early inflammatory state (EIS) have a delay in grasping acquisition, neonatal motor deficits and deficient long-term memory. CBH combined with late inflammatory state (LIS) does not induce neonatal motor problems but leads to poor fine motor function and long-term memory deficits at adulthood. Early combined insults result in poor cerebellar growth from postnatal day 15 until adulthood shown by MRI, which are reflected in diminished volumes of cerebellar structures. There are also decreases in volumes of gray matter and hippocampus. Cerebellar microgliosis appears 24h after the combined insults and persists until postnatal day 15 in the cerebellar molecular layer and cerebellar nuclei in association with a disrupted patterning of myelin deposition, a delay of oligodendrocyte maturation and reduced white matter cerebellar volume. Together, these findings reveal poor outcomes in developing brains exposed to combined cerebellar perinatal insults in association with cerebellar hypoplasia, persistence of microgliosis and alterations of cerebellar white matter maturation and growth. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Distinct cerebellar engrams in short-term and long-term motor learning.

    PubMed

    Wang, Wen; Nakadate, Kazuhiko; Masugi-Tokita, Miwako; Shutoh, Fumihiro; Aziz, Wajeeha; Tarusawa, Etsuko; Lorincz, Andrea; Molnár, Elek; Kesaf, Sebnem; Li, Yun-Qing; Fukazawa, Yugo; Nagao, Soichi; Shigemoto, Ryuichi

    2014-01-07

    Cerebellar motor learning is suggested to be caused by long-term plasticity of excitatory parallel fiber-Purkinje cell (PF-PC) synapses associated with changes in the number of synaptic AMPA-type glutamate receptors (AMPARs). However, whether the AMPARs decrease or increase in individual PF-PC synapses occurs in physiological motor learning and accounts for memory that lasts over days remains elusive. We combined quantitative SDS-digested freeze-fracture replica labeling for AMPAR and physical dissector electron microscopy with a simple model of cerebellar motor learning, adaptation of horizontal optokinetic response (HOKR) in mouse. After 1-h training of HOKR, short-term adaptation (STA) was accompanied with transient decrease in AMPARs by 28% in target PF-PC synapses. STA was well correlated with AMPAR decrease in individual animals and both STA and AMPAR decrease recovered to basal levels within 24 h. Surprisingly, long-term adaptation (LTA) after five consecutive daily trainings of 1-h HOKR did not alter the number of AMPARs in PF-PC synapses but caused gradual and persistent synapse elimination by 45%, with corresponding PC spine loss by the fifth training day. Furthermore, recovery of LTA after 2 wk was well correlated with increase of PF-PC synapses to the control level. Our findings indicate that the AMPARs decrease in PF-PC synapses and the elimination of these synapses are in vivo engrams in short- and long-term motor learning, respectively, showing a unique type of synaptic plasticity that may contribute to memory consolidation.

  15. Association of Progressive Cerebellar Atrophy With Long-term Outcome in Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis.

    PubMed

    Iizuka, Takahiro; Kaneko, Juntaro; Tominaga, Naomi; Someko, Hidehiro; Nakamura, Masaaki; Ishima, Daisuke; Kitamura, Eiji; Masuda, Ray; Oguni, Eiichi; Yanagisawa, Toshiyuki; Kanazawa, Naomi; Dalmau, Josep; Nishiyama, Kazutoshi

    2016-06-01

    Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder that occurs with IgG antibodies against the GluN1 subunit of NMDAR. Some patients develop reversible diffuse cerebral atrophy (DCA), but the long-term clinical significance of progressive brain and cerebellar atrophy is unknown. To report the long-term clinical implications of DCA and cerebellar atrophy in anti-NMDAR encephalitis. A retrospective observational study and long-term imaging investigation was conducted in the Department of Neurology at Kitasato University. Fifteen patients with anti-NMDAR encephalitis admitted to Kitasato University Hospital between January 1, 1999, and December 31, 2014, were included; data analysis was conducted between July 15, 2015, and January 18, 2016. Neurologic examination, immunotherapy, and magnetic resonance imaging (MRI) studies were performed. Long-term MRI changes in association with disease severity, serious complications (eg, pulmonary embolism, septic shock, and rhabdomyolysis), treatment, and outcome. The clinical outcome of 15 patients (median age, 21 years, [range, 14-46 years]; 10 [67%] female) was evaluated after a median follow-up of 68 months (range, 10-179 months). Thirteen patients (87%) received first-line immunotherapy (intravenous high-dose methylprednisolone, intravenous immunoglobulin, and plasma exchange alone or combined), and 4 individuals (27%) also received cyclophosphamide; 2 patients (13%) did not receive immunotherapy. In 5 patients (33%), ovarian teratoma was found and removed. Serious complications developed in 4 patients (27%). Follow-up MRI revealed DCA in 5 patients (33%) that, in 2 individuals (13%), was associated with progressive cerebellar atrophy. Long-term outcome was good in 13 patients (87%) and poor in the other 2 individuals (13%). Although cerebellar atrophy was associated with poor long-term outcome (2 of 2 vs 0 of 13 patients; P = .01), other features, such as DCA without cerebellar atrophy

  16. Mediation in long-term care facilities: a pilot project.

    PubMed

    Persson, Diane; Castro, Carmen

    2008-06-01

    To describe the development and implementation of a mediation model appropriate for long-term care facilities. The recruitment and training of mediators; the role of the ombudsman; and approaches to educating facility staff, families, and residents are described. Disputes identified as suitable for mediation include care disputes, resident-to-resident issues, and family matters. Pilot project results indicate cases that reach mediation generally come to a mutual agreement that is upheld over time. Only a small number of cases referred for mediation are actually mediated. A main barrier to using mediation as an option is lack of knowledge of its availability and potential benefits. Intensive outreach within facilities is essential if residents, families, and staff are to recognize and refer cases. Mediation must be considered broadly as an approach, not as a single process. Mediation can help to involve residents and families in constructive decision making that improves care, and could be a part of the overall dispute resolution system in long-term care.

  17. ERK1/2 but not p38 MAP kinase is essential for the long-term depression in mouse cerebellar slices.

    PubMed

    Ito-Ishida, Aya; Kakegawa, Wataru; Yuzaki, Michisuke

    2006-09-01

    Mitogen-activated protein kinase (MAPK) cascade is essential for synaptic plasticity and learning. In the hippocampus, three different MAPK subfamilies, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK and c-Jun NH2-terminal protein kinase (JNK), selectively regulate activity-dependent glutamate receptor trafficking during long-term potentiation (LTP), long-term depression (LTD), and depotentiation after LTP, respectively. Although LTP and LTD at cerebellar parallel fibre (PF)-Purkinje cell synapses are thought to be controlled by glutamate receptor trafficking, the involvement of MAPK subfamilies has not been systemically studied in cerebellar slice preparations. To clarify the role of the MAPK cascade in cerebellar LTD, we performed biochemical and electrophysiological analyses using ICR mouse cerebellar slices. Immunoblot analyses using phosphorylation-specific antibodies for MAPKs revealed that among the three MAPKs, ERK1/2 was specifically activated by phorbol ester, which could induce LTD in cerebellar slices. In addition, U0126, a specific inhibitor of the MAPK kinase-ERK1/2 pathway, abrogated the induction of LTD in cerebellar slices, whereas SB203580 and SP600125, specific inhibitors of p38 MAPK and JNK, respectively, had no effect. Although metabotropic glutamate receptor 1 (mGluR1) has been suggested as a possible downstream target of ERK1/2 in cell-culture preparations, mGluR1-activated slow excitatory postsynaptic currents (EPSCs) were not affected by U0126 treatment in slices. These findings indicate that unlike hippocampal LTD mediated by p38 MAPK, glutamate receptor trafficking during cerebellar LTD was regulated by a distinct mechanism involving ERK1/2 in slice preparations.

  18. Nitric Oxide Regulates Input Specificity of Long-Term Depression and Context Dependence of Cerebellar Learning

    PubMed Central

    Ogasawara, Hideaki; Doi, Tomokazu; Doya, Kenji; Kawato, Mitsuo

    2007-01-01

    Recent studies have shown that multiple internal models are acquired in the cerebellum and that these can be switched under a given context of behavior. It has been proposed that long-term depression (LTD) of parallel fiber (PF)–Purkinje cell (PC) synapses forms the cellular basis of cerebellar learning, and that the presynaptically synthesized messenger nitric oxide (NO) is a crucial “gatekeeper” for LTD. Because NO diffuses freely to neighboring synapses, this volume learning is not input-specific and brings into question the biological significance of LTD as the basic mechanism for efficient supervised learning. To better characterize the role of NO in cerebellar learning, we simulated the sequence of electrophysiological and biochemical events in PF–PC LTD by combining established simulation models of the electrophysiology, calcium dynamics, and signaling pathways of the PC. The results demonstrate that the local NO concentration is critical for induction of LTD and for its input specificity. Pre- and postsynaptic coincident firing is not sufficient for a PF–PC synapse to undergo LTD, and LTD is induced only when a sufficient amount of NO is provided by activation of the surrounding PFs. On the other hand, above-adequate levels of activity in nearby PFs cause accumulation of NO, which also allows LTD in neighboring synapses that were not directly stimulated, ruining input specificity. These findings lead us to propose the hypothesis that NO represents the relevance of a given context and enables context-dependent selection of internal models to be updated. We also predict sparse PF activity in vivo because, otherwise, input specificity would be lost. PMID:17222054

  19. PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression.

    PubMed

    Anggono, Victor; Koç-Schmitz, Yeliz; Widagdo, Jocelyn; Kormann, Jan; Quan, Annie; Chen, Chih-Ming; Robinson, Phillip J; Choi, Se-Young; Linden, David J; Plomann, Markus; Huganir, Richard L

    2013-08-20

    The dynamic trafficking of AMPA receptors (AMPARs) into and out of synapses is crucial for synaptic transmission, plasticity, learning, and memory. The protein interacting with C-kinase 1 (PICK1) directly interacts with GluA2/3 subunits of the AMPARs. Although the role of PICK1 in regulating AMPAR trafficking and multiple forms of synaptic plasticity is known, the exact molecular mechanisms underlying this process remain unclear. Here, we report a unique interaction between PICK1 and all three members of the protein kinase C and casein kinase II substrate in neurons (PACSIN) family and show that they form a complex with AMPARs. Our results reveal that knockdown of the neuronal-specific protein, PACSIN1, leads to a significant reduction in AMPAR internalization following the activation of NMDA receptors in hippocampal neurons. The interaction between PICK1 and PACSIN1 is regulated by PACSIN1 phosphorylation within the variable region and is required for AMPAR endocytosis. Similarly, the binding of PICK1 to the ubiquitously expressed PACSIN2 is also regulated by the homologous phosphorylation sites within the PACSIN2-variable region. Genetic deletion of PACSIN2, which is highly expressed in Purkinje cells, eliminates cerebellar long-term depression. This deficit can be fully rescued by overexpressing wild-type PACSIN2, but not by a PACSIN2 phosphomimetic mutant, which does not bind PICK1 efficiently. Taken together, our data demonstrate that the interaction of PICK1 and PACSIN is required for the activity-dependent internalization of AMPARs and for the expression of long-term depression in the cerebellum.

  20. Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia.

    PubMed

    Benussi, Alberto; Dell'Era, Valentina; Cotelli, Maria Sofia; Turla, Marinella; Casali, Carlo; Padovani, Alessandro; Borroni, Barbara

    Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. The present study investigated whether a two-weeks' treatment with cerebellar anodal tDCS could improve symptoms in patients with neurodegenerative cerebellar ataxia and could modulate cerebello-motor connectivity, at short and long term. We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia. Each patient underwent a clinical evaluation pre- and post-anodal tDCS or sham stimulation. A follow-up evaluation was performed at one and three months. Cerebello-motor connectivity was evaluated using transcranial magnetic stimulation (TMS) at baseline and at follow-up. Patients who underwent anodal tDCS showed a significant improvement in all performance scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale, 9-hole peg test, 8-m walking time) and in cerebellar brain inhibition compared to patients who underwent sham stimulation. A two-weeks' treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression.

    PubMed

    Gallimore, Andrew R; Aricescu, A Radu; Yuzaki, Michisuke; Calinescu, Radu

    2016-01-01

    The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins-glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)-regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process.

  2. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression

    PubMed Central

    Gallimore, Andrew R.; Aricescu, A. Radu; Yuzaki, Michisuke; Calinescu, Radu

    2016-01-01

    The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins–glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)–regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process. PMID:26807999

  3. DHHC8-dependent PICK1 palmitoylation is required for induction of cerebellar long-term synaptic depression.

    PubMed

    Thomas, Gareth M; Hayashi, Takashi; Huganir, Richard L; Linden, David J

    2013-09-25

    The palmitoyl acyltransferase (PAT) DHHC8 is implicated in synaptic regulation but few DHHC8 substrates are known. Here we report that DHHC8 binds and palmitoylates the PDZ domain-containing protein PICK1 at a cysteine residue that is essential for long-term synaptic depression (LTD) in cultured mouse cerebellar Purkinje neurons. Cerebellar LTD is palmitoylation-dependent and induction of LTD requires DHHC8. Furthermore, PICK1 is a critical DHHC8 substrate whose palmitoylation is necessary for LTD. These results identify the first DHHC8 substrate required for a specific form of synaptic plasticity and provide new insights into synaptic roles of palmitoylation.

  4. Auditory-perceptual speech analysis in children with cerebellar tumours: a long-term follow-up study.

    PubMed

    De Smet, Hyo Jung; Catsman-Berrevoets, Coriene; Aarsen, Femke; Verhoeven, Jo; Mariën, Peter; Paquier, Philippe F

    2012-09-01

    Mutism and Subsequent Dysarthria (MSD) and the Posterior Fossa Syndrome (PFS) have become well-recognized clinical entities which may develop after resection of cerebellar tumours. However, speech characteristics following a period of mutism have not been documented in much detail. This study carried out a perceptual speech analysis in 24 children and adolescents (of whom 12 became mute in the immediate postoperative phase) 1-12.2 years after cerebellar tumour resection. The most prominent speech deficits in this study were distorted vowels, slow rate, voice tremor, and monopitch. Factors influencing long-term speech disturbances are presence or absence of postoperative PFS, the localisation of the surgical lesion and the type of adjuvant treatment. Long-term speech deficits may be present up to 12 years post-surgery. The speech deficits found in children and adolescents with cerebellar lesions following cerebellar tumour surgery do not necessarily resemble adult speech characteristics of ataxic dysarthria. Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  5. Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses via cannabinoid signaling.

    PubMed

    Rinaldo, Lorenzo; Hansel, Christian

    2013-07-02

    Muscarinic acetylcholine receptors (mAChRs) are known to modulate synaptic plasticity in various brain areas. A signaling pathway triggered by mAChR activation is the production and release of endocannabinoids that bind to type 1 cannabinoid receptors (CB1R) located on synaptic terminals. Using whole-cell patch-clamp recordings from rat cerebellar slices, we have demonstrated that the muscarinic agonist oxotremorine-m (oxo-m) blocks the induction of presynaptic long-term potentiation (LTP) at parallel fiber (PF)-Purkinje cell synapses in a CB1R-dependent manner. Under control conditions, LTP was induced by delivering 120 PF stimuli at 8 Hz. In contrast, no LTP was observed when oxo-m was present during tetanization. PF-LTP was restored when the CB1R antagonist N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) was coapplied with oxo-m. Furthermore, the suppressive effect of oxo-m on PF-LTP was abrogated by the GDP analog GDP-β-S (applied intracellularly), the phospholipase C inhibitor U-73122, and the diacylglycerol lipase inhibitor tetrahydrolipstatin (THL), suggesting that cannabinoid synthesis results from the activation of Gq-coupled mAChRs present on Purkinje cells. The oxo-m-mediated suppression of LTP was also prevented in the presence of the M3 receptor antagonist DAU 5884, and was absent in M1/M3 receptor double-KO mice, identifying M3 receptors as primary oxo-m targets. Our findings allow for the possibility that cholinergic signaling in the cerebellum--which may result from long-term depression (LTD)-related disinhibition of cholinergic neurons in the vestibular nuclei--suppresses presynaptic LTP to prevent an up-regulation of transmitter release that opposes the reduction of postsynaptic responsiveness. This modulatory capacity of mAChR signaling could promote the functional penetrance of LTD.

  6. Long-term follow-up clinical courses of cerebellar hemangioblastoma in von hippel-lindau disease : two case reports and a literature review.

    PubMed

    Lee, Seung Hwan; Park, Bong Jin; Kim, Tae Sung; Lim, Young Jin

    2010-09-01

    Although cerebellar hemangioblastomas are histopathologically benign, they yield a degree of malignant clinical behavior in long-term follow-up. We present two cases of long-term progression of renal cell carcinoma, which had been diagnosed as renal cysts during treatment for cerebellar hemangioblastoma. A 14-year-old male with von Hippel-Lindau disease was admitted for a cerebellar hemangioblastoma with multiple spinal hemangioblastomas and a renal cyst. After primary total resection of the cerebellar hemangioblastoma, the patient required two further surgeries after 111 and 209 months for a recurrent cerebellar hemangioblastoma. Furthermore, he underwent radical nephrectomy as his renal cyst had progressed to renal cell carcinoma 209 months after initial diagnosis. A 26-year-old male presented with multiple cerebellar hemangioblastomas associated with von Hippel-Lindau disease and accompanied by multiple spinal hemangioblastomas and multiple cystic lesions in the liver, kidney, and pancreas. He underwent primary resection of the cerebellar hemangioblastoma in association with craniospinal radiation for multiple intracranial/spinal masses. Unexpectedly, a malignant glioma developed 83 months after discovery of the cerebellar hemangioblastoma. At the same time, renal cell carcinoma, which had developed from an initial renal cyst, was diagnosed, and a radical nephrectomy was performed. In the view of long term clinical course, cerebellar hemangioblastoma associated with von Hipple-Lindau disease may redevelop even after primary total resection. In addition, associated lesions such as renal cysts may also progress to malignancy after the passing of a sufficient length of time.

  7. Long-Term Follow-Up Clinical Courses of Cerebellar Hemangioblastoma in von Hippel-Lindau Disease : Two Case Reports and a Literature Review

    PubMed Central

    Lee, Seung Hwan; Kim, Tae Sung; Lim, Young Jin

    2010-01-01

    Although cerebellar hemangioblastomas are histopathologically benign, they yield a degree of malignant clinical behavior in long-term follow-up. We present two cases of long-term progression of renal cell carcinoma, which had been diagnosed as renal cysts during treatment for cerebellar hemangioblastoma. A 14-year-old male with von Hippel-Lindau disease was admitted for a cerebellar hemangioblastoma with multiple spinal hemangioblastomas and a renal cyst. After primary total resection of the cerebellar hemangioblastoma, the patient required two further surgeries after 111 and 209 months for a recurrent cerebellar hemangioblastoma. Furthermore, he underwent radical nephrectomy as his renal cyst had progressed to renal cell carcinoma 209 months after initial diagnosis. A 26-year-old male presented with multiple cerebellar hemangioblastomas associated with von Hippel-Lindau disease and accompanied by multiple spinal hemangioblastomas and multiple cystic lesions in the liver, kidney, and pancreas. He underwent primary resection of the cerebellar hemangioblastoma in association with craniospinal radiation for multiple intracranial/spinal masses. Unexpectedly, a malignant glioma developed 83 months after discovery of the cerebellar hemangioblastoma. At the same time, renal cell carcinoma, which had developed from an initial renal cyst, was diagnosed, and a radical nephrectomy was performed. In the view of long term clinical course, cerebellar hemangioblastoma associated with von Hipple-Lindau disease may redevelop even after primary total resection. In addition, associated lesions such as renal cysts may also progress to malignancy after the passing of a sufficient length of time. PMID:21082056

  8. Enhanced AMPA Receptor Function Promotes Cerebellar Long-Term Depression Rather than Potentiation

    ERIC Educational Resources Information Center

    van Beugen, Boeke J.; Qiao, Xin; Simmons, Dana H.; De Zeeuw, Chris I.; Hansel, Christian

    2014-01-01

    Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar…

  9. Enhanced AMPA Receptor Function Promotes Cerebellar Long-Term Depression Rather than Potentiation

    ERIC Educational Resources Information Center

    van Beugen, Boeke J.; Qiao, Xin; Simmons, Dana H.; De Zeeuw, Chris I.; Hansel, Christian

    2014-01-01

    Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar…

  10. The long-term structural plasticity of cerebellar parallel fiber axons and its modulation by motor learning

    PubMed Central

    Carrillo, Jennifer; Cheng, Shao-Ying; Ko, Kwang Woo; Jones, Theresa A.; Nishiyama, Hiroshi

    2013-01-01

    Presynaptic axonal varicosities, like postsynaptic spines, are dynamically added and eliminated even in mature neuronal circuitry. To study the role of this axonal structural plasticity in behavioral learning, we performed two-photon in vivo imaging of cerebellar parallel fibers (PFs) in adult mice. PFs make excitatory synapses on Purkinje cells (PCs) in the cerebellar cortex, and long-term potentiation and depression at PF-PC synapses are thought to play crucial roles in cerebellar-dependent learning. Time-lapse vital imaging of PFs revealed that, under a control condition (no behavioral training), approximately 10% of PF varicosities appeared and disappeared over a period of 2 weeks without changing the total number of varicosities. The fraction of dynamic PF varicosities significantly diminished during training on an acrobatic motor skill learning task, owing largely to reduced addition of new varicosities. Thus, this form of motor learning was associated with greater structural stability of PFs and a slight decrease in the total number of varicosities. Together with prior findings that the number of PF-PC synapses increases during similar training, our results suggest that acrobatic motor skill learning involves a reduction of some PF inputs and a strengthening of others, probably via the conversion of some pre-existing PF varicosities into multisynaptic terminals. PMID:23658170

  11. The long-term structural plasticity of cerebellar parallel fiber axons and its modulation by motor learning.

    PubMed

    Carrillo, Jennifer; Cheng, Shao-Ying; Ko, Kwang Woo; Jones, Theresa A; Nishiyama, Hiroshi

    2013-05-08

    Presynaptic axonal varicosities, like postsynaptic spines, are dynamically added and eliminated even in mature neuronal circuitry. To study the role of this axonal structural plasticity in behavioral learning, we performed two-photon in vivo imaging of cerebellar parallel fibers (PFs) in adult mice. PFs make excitatory synapses on Purkinje cells (PCs) in the cerebellar cortex, and long-term potentiation and depression at PF-PC synapses are thought to play crucial roles in cerebellar-dependent learning. Time-lapse vital imaging of PFs revealed that, under a control condition (no behavioral training), ∼10% of PF varicosities appeared and disappeared over a period of 2 weeks without changing the total number of varicosities. The fraction of dynamic PF varicosities significantly diminished during training on an acrobatic motor skill learning task, largely because of reduced addition of new varicosities. Thus, this form of motor learning was associated with greater structural stability of PFs and a slight decrease in the total number of varicosities. Together with prior findings that the number of PF-PC synapses increases during similar training, our results suggest that acrobatic motor skill learning involves a reduction of some PF inputs and a strengthening of others, probably via the conversion of some preexisting PF varicosities into multisynaptic terminals.

  12. Psychosocial Mediators of Long-Term Abstinence Following Smoking Cessation.

    ERIC Educational Resources Information Center

    Horwitz, Michael B.; And Others

    It is well known that many smokers who quit during cessation programs relapse soon after leaving treatment. To investigate the relationship of health locus of control, social support, nonsmoking areas, and objecting to another person's smoking to relapse and long-term maintenance of nonsmoking, male (N=70) and female (N=149) subjects participated…

  13. Cerebellar pilocytic astrocytoma in childhood: Investigating the long-term impact of surgery on cognitive performance and functional outcome.

    PubMed

    Pletschko, Thomas; Felnhofer, Anna; Lamplmair, Doris; Dorfer, Christian; Czech, Thomas; Chocholous, Monika; Slavc, Irene; Leiss, Ulrike

    2017-10-02

    Previous studies differ regarding the long-term effects of surgically removed pediatric cerebellar pilocytic astrocytomas (CPA). Thus, the aim of this study was to investigate the long-term impact on neurocognitive and functional outcome and to analyze age as an influencing factor. Fourteen CPA patients were compared to the age norm and to a group of 14 high-achieving peers regarding cognitive functioning, health-related quality of life (HRQoL), and stress regulation. Mean follow-up time after diagnosis was 13.29 years (range: 3-21 years). Patients showed satisfactory academic achievement and did not differ from the norm except for the bodily dimension of HRQoL. However, there were marked differences in specific neurocognitive functions between patients and high achievers. Age at diagnosis did not influence neurocognitive outcome. CPA patients treated with surgery only seem to have a favorable long-term outcome, yet, in comparison with high achievers specific cognitive impairments become apparent.

  14. Long-Term Spatiotemporal Reconfiguration of Neuronal Activity Revealed by Voltage-Sensitive Dye Imaging in the Cerebellar Granular Layer

    PubMed Central

    Gandolfi, Daniela; Mapelli, Jonathan; D'Angelo, Egidio

    2015-01-01

    Understanding the spatiotemporal organization of long-term synaptic plasticity in neuronal networks demands techniques capable of monitoring changes in synaptic responsiveness over extended multineuronal structures. Among these techniques, voltage-sensitive dye imaging (VSD imaging) is of particular interest due to its good spatial resolution. However, improvements of the technique are needed in order to overcome limits imposed by its low signal-to-noise ratio. Here, we show that VSD imaging can detect long-term potentiation (LTP) and long-term depression (LTD) in acute cerebellar slices. Combined VSD imaging and patch-clamp recordings revealed that the most excited regions were predominantly associated with granule cells (GrCs) generating EPSP-spike complexes, while poorly responding regions were associated with GrCs generating EPSPs only. The correspondence with cellular changes occurring during LTP and LTD was highlighted by a vector representation obtained by combining amplitude with time-to-peak of VSD signals. This showed that LTP occurred in the most excited regions lying in the core of activated areas and increased the number of EPSP-spike complexes, while LTD occurred in the less excited regions lying in the surround. VSD imaging appears to be an efficient tool for investigating how synaptic plasticity contributes to the reorganization of multineuronal activity in neuronal circuits. PMID:26294979

  15. Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice.

    PubMed

    Aiba, A; Kano, M; Chen, C; Stanton, M E; Fox, G D; Herrup, K; Zwingman, T A; Tonegawa, S

    1994-10-21

    mGluR1 mutant mice are viable but show characteristic cerebellar symptoms such as ataxic gait and intention tremor. The anatomy of the cerebellum is not overtly disturbed. Excitatory synaptic transmission from parallel fibers (PFs) to Purkinje cells and that from climbing fibers (CFs) to Purkinje cells appear to be functional, and voltage-gated Ca2+ channels of Purkinje cells are normal. Both PF and CF synapses display normal short-term synaptic plasticity to paired stimuli. By marked contrast, long-term depression (LTD) is clearly deficient and conditioned eyeblink response is impaired. We conclude that mGluR1 is required for the induction of LTD and that the ataxic behavior and impaired eyeblink conditioning of the mGluR1 mutant mice are primarily due to deficient LTD.

  16. The effect of gallium nitride on long-term culture induced aging of neuritic function in cerebellar granule cells.

    PubMed

    Chen, Chi-Ruei; Young, Tai-Horng

    2008-04-01

    Gallium nitride (GaN) has been developed for a variety of microelectronic and optical applications due to its unique electric property and chemical stability. In the present study, n-type and p-type GaN were used as substrates to culture cerebellar granule neurons to examine the effect of GaN on cell response for a long-term culture period. It was found that GaN could rapidly induce cultured neurons to exhibit a high phosphorylated Akt level after 20h of incubation. It was assumed that the anti-apoptotic effect of Akt phosphorylation could be correlated with cell survival, neurite growth and neuronal function for up to 35 days of incubation. Morphological studies showed GaN induced larger neuronal aggregates and neurite fasciculation to exhibit a dense fiber network after 8 days of incubation. Western blot analysis and immunocytochemical characterization showed that GaN still exhibited the expression of neurite growth and function, such as high levels of GAP-43, synapsin I and synaptophysin even after 35 days of incubation. In addition, survival of cerebellar granule neurons on GaN was improved by the analysis of lactate dehydrogenase (LDH) release from damaged cells. These results indicated that neuronal connections were formed on GaN by a gradual process from Akt activation and cell aggregation to develop neurite growth, fasciculation and function. Therefore, GaN offers a good model system to identify a well-characterized pattern of neuronal behavior for a long-term culture period, consistent with the development of a neurochip requiring the integration of biological system and semiconductor material.

  17. A model of long-term memory storage in the cerebellar cortex: a possible role for plasticity at parallel fiber synapses onto stellate/basket interneurons.

    PubMed

    Kenyon, G T

    1997-12-09

    By evoking changes in climbing fiber activity, movement errors are thought to modify synapses from parallel fibers onto Purkinje cells (pf*Pkj) so as to improve subsequent motor performance. Theoretical arguments suggest there is an intrinsic tradeoff, however, between motor adaptation and long-term storage. Assuming a baseline rate of motor errors is always present, then repeated performance of any learned movement will generate a series of climbing fiber-mediated corrections. By reshuffling the synaptic weights responsible for any given movement, such corrections will degrade the memories for other learned movements stored in overlapping sets of synapses. The present paper shows that long-term storage can be accomplished by a second site of plasticity at synapses from parallel fibers onto stellate/basket interneurons (pf*St/Bk). Plasticity at pf*St/Bk synapses can be insulated from ongoing fluctuations in climbing fiber activity by assuming that changes in pf*St/Bk synapses occur only after changes in pf*Pkj synapses have built up to a threshold level. Although climbing fiber-dependent plasticity at pf*Pkj synapses allows for the exploration of novel motor strategies in response to changing environmental conditions, plasticity at pf*St/Bk synapses transfers successful strategies to stable long-term storage. To quantify this hypothesis, both sites of plasticity are incorporated into a dynamical model of the cerebellar cortex and its interactions with the inferior olive. When used to simulate idealized motor conditioning trials, the model predicts that plasticity develops first at pf*Pkj synapses, but with additional training is transferred to pf*St/Bk synapses for long-term storage.

  18. A Model of Induction of Cerebellar Long-Term Depression Including RKIP Inactivation of Raf and MEK

    PubMed Central

    Hepburn, Iain; Jain, Anant; Gangal, Himanshu; Yamamoto, Yukio; Tanaka-Yamamoto, Keiko; De Schutter, Erik

    2017-01-01

    We report an updated stochastic model of cerebellar Long Term Depression (LTD) with improved realism. Firstly, we verify experimentally that dissociation of Raf kinase inhibitor protein (RKIP) from Mitogen-activated protein kinase kinase (MEK) is required for cerebellar LTD and add this interaction to an earlier published model, along with the known requirement of dissociation of RKIP from Raf kinase. We update Ca2+ dynamics as a constant-rate influx, which captures experimental input profiles accurately. We improve α-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor interactions by adding phosphorylation and dephosphorylation of AMPA receptors when bound to glutamate receptor interacting protein (GRIP). The updated model is tuned to reproduce experimental Ca2+ peak vs. LTD amplitude curves at four different Ca2+ pulse durations as closely as possible. We find that the updated model is generally more robust with these changes, yet we still observe some sensitivity of LTD induction to copy number of the key signaling molecule Protein kinase C (PKC). We predict natural variability in this number by stochastic diffusion may influence the probabilistic LTD response to Ca2+ input in Purkinje cell spines and propose this as an extra source of stochasticity that may be important also in other signaling systems. PMID:28220061

  19. Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity

    PubMed Central

    Kakizawa, Sho; Kishimoto, Yasushi; Hashimoto, Kouichi; Miyazaki, Taisuke; Furutani, Kazuharu; Shimizu, Hidemi; Fukaya, Masahiro; Nishi, Miyuki; Sakagami, Hiroyuki; Ikeda, Atsushi; Kondo, Hisatake; Kano, Masanobu; Watanabe, Masahiko; Iino, Masamitsu; Takeshima, Hiroshi

    2007-01-01

    Functional crosstalk between cell-surface and intracellular ion channels plays important roles in excitable cells and is structurally supported by junctophilins (JPs) in muscle cells. Here, we report a novel form of channel crosstalk in cerebellar Purkinje cells (PCs). The generation of slow afterhyperpolarization (sAHP) following complex spikes in PCs required ryanodine receptor (RyR)-mediated Ca2+-induced Ca2+ release and the subsequent opening of small-conductance Ca2+-activated K+ (SK) channels in somatodendritic regions. Despite the normal expression levels of these channels, sAHP was abolished in PCs from mutant mice lacking neural JP subtypes (JP-DKO), and this defect was restored by exogenously expressing JPs or enhancing SK channel activation. The stimulation paradigm for inducing long-term depression (LTD) at parallel fiber–PC synapses adversely established long-term potentiation in the JP-DKO cerebellum, primarily due to the sAHP deficiency. Furthermore, JP-DKO mice exhibited impairments of motor coordination and learning, although normal cerebellar histology was retained. Therefore, JPs support the Ca2+-mediated communication between voltage-gated Ca2+ channels, RyRs and SK channels, which modulates the excitability of PCs and is fundamental to cerebellar LTD and motor functions. PMID:17347645

  20. Long-term potentiation of the responses to parallel fiber stimulation in mouse cerebellar cortex in vivo.

    PubMed

    Wang, X; Chen, G; Gao, W; Ebner, T

    2009-09-01

    that high frequency PF stimulation generates long-term potentiation of PF-PC synapses in vivo. This novel form of LTP is generated primarily postsynaptically and is mediated by mGluR(1) receptors.

  1. Long-Term Potentiation of the Responses to Parallel Fiber Stimulation in Mouse Cerebellar Cortex in Vivo

    PubMed Central

    Wang, X.; Chen, G.; Gao, W.; Ebner, T.

    2009-01-01

    that high frequency PF stimulation generates long-term potentiation of PF–PC synapses in vivo. This novel form of LTP is generated primarily postsynaptically and is mediated by mGluR1 receptors. PMID:19409215

  2. The Mediating Role of Insight for Long-Term Improvements in Psychodynamic Therapy

    ERIC Educational Resources Information Center

    Johansson, Paul; Hoglend, Per; Ulberg, Randi; Amlo, Svein; Marble, Alice; Bogwald, Kjell-Petter; Sorbye, Oystein; Sjaastad, Mary Cosgrove; Heyerdahl, Oscar

    2010-01-01

    Objective: According to psychoanalytic theory, interpretation of transference leads to increased insight that again leads to improved interpersonal functioning over time. In this study, we performed a full mediational analysis to test whether insight gained during treatment mediates the long-term effects of transference interpretation in dynamic…

  3. Lgr4 Protein Deficiency Induces Ataxia-like Phenotype in Mice and Impairs Long Term Depression at Cerebellar Parallel Fiber-Purkinje Cell Synapses*

    PubMed Central

    Guan, Xin; Duan, Yanhong; Zeng, Qingwen; Pan, Hongjie; Qian, Yu; Li, Dali; Cao, Xiaohua; Liu, Mingyao

    2014-01-01

    Cerebellar dysfunction causes ataxia characterized by loss of balance and coordination. Until now, the molecular and neuronal mechanisms of several types of inherited cerebellar ataxia have not been completely clarified. Here, we report that leucine-rich G protein-coupled receptor 4 (Lgr4/Gpr48) is highly expressed in Purkinje cells (PCs) in the cerebellum. Deficiency of Lgr4 leads to an ataxia-like phenotype in mice. Histologically, no obvious morphological changes were observed in the cerebellum of Lgr4 mutant mice. However, the number of PCs was slightly but significantly reduced in Lgr4−/− mice. In addition, in vitro electrophysiological analysis showed an impaired long term depression (LTD) at parallel fiber-PC (PF-PC) synapses in Lgr4−/− mice. Consistently, immunostaining experiments showed that the level of phosphorylated cAMP-responsive element-binding protein (Creb) was significantly decreased in Lgr4−/− PCs. Furthermore, treatment with forskolin, an adenylyl cyclase agonist, rescued phospho-Creb in PCs and reversed the impairment in PF-PC LTD in Lgr4−/− cerebellar slices, indicating that Lgr4 is an upstream regulator of Creb signaling, which is underlying PF-PC LTD. Together, our findings demonstrate for first time an important role for Lgr4 in motor coordination and cerebellar synaptic plasticity and provide a potential therapeutic target for certain types of inherited cerebellar ataxia. PMID:25063812

  4. Lgr4 protein deficiency induces ataxia-like phenotype in mice and impairs long term depression at cerebellar parallel fiber-Purkinje cell synapses.

    PubMed

    Guan, Xin; Duan, Yanhong; Zeng, Qingwen; Pan, Hongjie; Qian, Yu; Li, Dali; Cao, Xiaohua; Liu, Mingyao

    2014-09-19

    Cerebellar dysfunction causes ataxia characterized by loss of balance and coordination. Until now, the molecular and neuronal mechanisms of several types of inherited cerebellar ataxia have not been completely clarified. Here, we report that leucine-rich G protein-coupled receptor 4 (Lgr4/Gpr48) is highly expressed in Purkinje cells (PCs) in the cerebellum. Deficiency of Lgr4 leads to an ataxia-like phenotype in mice. Histologically, no obvious morphological changes were observed in the cerebellum of Lgr4 mutant mice. However, the number of PCs was slightly but significantly reduced in Lgr4(-/-) mice. In addition, in vitro electrophysiological analysis showed an impaired long term depression (LTD) at parallel fiber-PC (PF-PC) synapses in Lgr4(-/-) mice. Consistently, immunostaining experiments showed that the level of phosphorylated cAMP-responsive element-binding protein (Creb) was significantly decreased in Lgr4(-/-) PCs. Furthermore, treatment with forskolin, an adenylyl cyclase agonist, rescued phospho-Creb in PCs and reversed the impairment in PF-PC LTD in Lgr4(-/-) cerebellar slices, indicating that Lgr4 is an upstream regulator of Creb signaling, which is underlying PF-PC LTD. Together, our findings demonstrate for first time an important role for Lgr4 in motor coordination and cerebellar synaptic plasticity and provide a potential therapeutic target for certain types of inherited cerebellar ataxia. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. DNA Methylation Mediates the Discriminatory Power of Associative Long-Term Memory in Honeybees

    PubMed Central

    Biergans, Stephanie D.; Jones, Julia C.; Treiber, Nadine; Galizia, C. Giovanni; Szyszka, Paul

    2012-01-01

    Memory is created by several interlinked processes in the brain, some of which require long-term gene regulation. Epigenetic mechanisms are likely candidates for regulating memory-related genes. Among these, DNA methylation is known to be a long lasting genomic mark and may be involved in the establishment of long-term memory. Here we demonstrate that DNA methyltransferases, which induce and maintain DNA methylation, are involved in a particular aspect of associative long-term memory formation in honeybees, but are not required for short-term memory formation. While long-term memory strength itself was not affected by blocking DNA methyltransferases, odor specificity of the memory (memory discriminatory power) was. Conversely, perceptual discriminatory power was normal. These results suggest that different genetic pathways are involved in mediating the strength and discriminatory power of associative odor memories and provide, to our knowledge, the first indication that DNA methyltransferases are involved in stimulus-specific associative long-term memory formation. PMID:22724000

  6. DNA methylation mediates the discriminatory power of associative long-term memory in honeybees.

    PubMed

    Biergans, Stephanie D; Jones, Julia C; Treiber, Nadine; Galizia, C Giovanni; Szyszka, Paul

    2012-01-01

    Memory is created by several interlinked processes in the brain, some of which require long-term gene regulation. Epigenetic mechanisms are likely candidates for regulating memory-related genes. Among these, DNA methylation is known to be a long lasting genomic mark and may be involved in the establishment of long-term memory. Here we demonstrate that DNA methyltransferases, which induce and maintain DNA methylation, are involved in a particular aspect of associative long-term memory formation in honeybees, but are not required for short-term memory formation. While long-term memory strength itself was not affected by blocking DNA methyltransferases, odor specificity of the memory (memory discriminatory power) was. Conversely, perceptual discriminatory power was normal. These results suggest that different genetic pathways are involved in mediating the strength and discriminatory power of associative odor memories and provide, to our knowledge, the first indication that DNA methyltransferases are involved in stimulus-specific associative long-term memory formation.

  7. Debra, a protein mediating lysosomal degradation, is required for long-term memory in Drosophila.

    PubMed

    Kottler, Benjamin; Lampin-Saint-Amaux, Aurélie; Comas, Daniel; Preat, Thomas; Goguel, Valérie

    2011-01-01

    A central goal of neuroscience is to understand how neural circuits encode memory and guide behavior changes. Many of the molecular mechanisms underlying memory are conserved from flies to mammals, and Drosophila has been used extensively to study memory processes. To identify new genes involved in long-term memory, we screened Drosophila enhancer-trap P(Gal4) lines showing Gal4 expression in the mushroom bodies, a specialized brain structure involved in olfactory memory. This screening led to the isolation of a memory mutant that carries a P-element insertion in the debra locus. debra encodes a protein involved in the Hedgehog signaling pathway as a mediator of protein degradation by the lysosome. To study debra's role in memory, we achieved debra overexpression, as well as debra silencing mediated by RNA interference. Experiments conducted with a conditional driver that allowed us to specifically restrict transgene expression in the adult mushroom bodies led to a long-term memory defect. Several conclusions can be drawn from these results: i) debra levels must be precisely regulated to support normal long-term memory, ii) the role of debra in this process is physiological rather than developmental, and iii) debra is specifically required for long-term memory, as it is dispensable for earlier memory phases. Drosophila long-term memory is the only long-lasting memory phase whose formation requires de novo protein synthesis, a process underlying synaptic plasticity. It has been shown in several organisms that regulation of proteins at synapses occurs not only at translation level of but also via protein degradation, acting in remodeling synapses. Our work gives further support to a role of protein degradation in long-term memory, and suggests that the lysosome plays a role in this process.

  8. Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1.

    PubMed

    Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

    2014-12-23

    Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities.

  9. Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

    PubMed Central

    Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

    2014-01-01

    Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities. DOI: http://dx.doi.org/10.7554/eLife.05151.001 PMID:25535838

  10. Resilience and rejection sensitivity mediate long-term outcomes of parental divorce.

    PubMed

    Schaan, Violetta K; Vögele, Claus

    2016-11-01

    Increasing divorce rates leave more and more children to deal with the separation of their parents. Recent research suggests that children of divorced parents more often experience psychological and physical symptoms than children of non-divorced parents. The processes that mediate the relationship between parental divorce and ill-health, however, are still elusive. This study investigated the mediating role of psychological factors such as resilience and rejection sensitivity on the long-term consequences of parental divorce in young adults. One hundred and ninety-nine participants (mean age 22.3 years) completed an online survey, including measures of mental health, childhood trauma, resilience, and rejection sensitivity. Participants with divorced parents (33 %) reported increased levels of psychological symptoms, childhood trauma, rejection sensitivity, and lower levels of resilience. The association between parental divorce and mental health was fully mediated by resilience, rejection sensitivity, and childhood trauma. The mediation model explained up to 44 % of the total variance in mental health symptoms. Resilience and rejection sensitivity are crucial factors for successful coping with the experience of parental separation. Prevention programs that help to boost children's resilience might help to reduce the long-term effects of parental divorce on their attachment style (e.g., rejection sensitivity), thereby improving their mental health on the long run. Furthermore, the results call for parental awareness and counseling to target and reduce the observed increased level of childhood trauma. Limitations concern the cross-sectional and retrospective design of the study.

  11. Interparental violence and children's long-term psychosocial adjustment: the mediating role of parenting practices.

    PubMed

    Gámez-Guadix, Manuel; Almendros, Carmen; Carrobles, José Antonio; Muñoz-Rivas, Marina

    2012-03-01

    The objectives of this study were: (a) to examine the direct and indirect relationships among witnessing interparental violence, parenting practices, and children's long-term psychosocial adjustment; (b) to analyze the possible gender differences in the relationships specified. The sample consisted of 1295 Spanish university students (M age = 21.21, SD = 4.04). We performed statistical analyses using structural equation modeling. The results showed that witnessing parental violence as a child is related to poor long-term psychosocial adjustment during the child's adult years. Furthermore, we found that parenting practices fully mediated the relation between witnessing interparental violence and the child's long-term adjustment. The multigroup analyses showed that most of the relations among the variables did not differ significantly by gender. However, the relation between harsh discipline and antisocial behavior was stronger for males, whereas the relation between harsh discipline and depressive symptoms was stronger for females. Finally, we discuss the implications of these findings for the clinicians and specialists who plan and develop intervention programs for populations at risk.

  12. Gene insertion and long-term expression in lung mediated by the Sleeping Beauty transposon system.

    PubMed

    Belur, Lalitha R; Frandsen, Joel L; Dupuy, Adam J; Ingbar, David H; Largaespada, David A; Hackett, Perry B; Scott McIvor, R

    2003-09-01

    Gene transfer to the lung could provide important new treatments for chronic and acquired lung diseases such as cystic fibrosis, alpha1-antitrypsin deficiency, emphysema, and cancer. DNA-mediated gene transfer to the lung has been previously demonstrated, but anticipated effectiveness has been limited by low gene transfer efficiencies and by transient expression of the transgene. Here, we combine plasmid-based gene transfer with the integrating capacity of the nonviral Sleeping Beauty (SB) transposon vector system to mediate gene insertion and long-term gene expression in mouse lung. We observed transgene expression after 24 h in lungs of all animals injected with the luciferase transposon (pT/L), but expression for up to 3 months required codelivery of a plasmid encoding the Sleeping Beauty transposase. We also observed long-term expression in pT/L-injected animals transgenic for SB transposase. Transgene expression was localized to the alveolar region of the lung, with transfection including mainly type II pneumocytes. We used a linker-mediated PCR technique to recover transposon flanking sequences, demonstrating transposition of pT/L into mouse chromosomal DNA of the lung.

  13. Garcinia kola aqueous suspension prevents cerebellar neurodegeneration in long-term diabetic rat - a type 1 diabetes mellitus model.

    PubMed

    Farahna, Mohammed; Seke Etet, Paul F; Osman, Sayed Y; Yurt, Kıymet K; Amir, Naheed; Vecchio, Lorella; Aydin, Isınsu; Aldebasi, Yousef H; Sheikh, Azimullah; Chijuka, John C; Kaplan, Süleyman; Adem, Abdu

    2017-01-04

    The development of compounds able to improve metabolic syndrome and mitigate complications caused by inappropriate glycemic control in type 1 diabetes mellitus is challenging. The medicinal plant with established hypoglycemic properties Garcinia kola Heckel might have the potential to mitigate diabetes mellitus metabolic syndrome and complications. We have investigated the neuroprotective properties of a suspension of G. kola seeds in long-term type 1 diabetes mellitus rat model. Wistar rats, made diabetic by single injection of streptozotocin were monitored for 8 months. Then, they were administered with distilled water or G. kola oral aqueous suspension daily for 30 days. Body weight and glycemia were determined before and after treatment. After sacrifice, cerebella were dissected out and processed for stereological quantification of Purkinje cells. Histopathological and immunohistochemical analyses of markers of neuroinflammation and neurodegeneration were performed. Purkinje cell counts were significantly increased, and histopathological signs of apoptosis and neuroinflammation decreased, in diabetic animals treated with G. kola compared to diabetic rats given distilled water. Glycemia was also markedly improved and body weight restored to non-diabetic control values, following G. kola treatment. These results suggest that G. kola treatment improved the general condition of long-term diabetic rats and protected Purkinje cells partly by improving the systemic glycemia and mitigating neuroinflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. On the long-term effects of methyl isocyanate on cell-mediated immunity in Bhopal gas-exposed long-term survivors and their offspring.

    PubMed

    Senthilkumar, Chinnu Sugavanam; Sah, Nand Kishore; Ganesh, Narayanan

    2017-04-01

    Methyl isocyanate (MIC) is a toxic industrial chemical that is documented as a potent respiratory toxicant. We investigated cell-mediated immunity (CMI) in the MIC-exposed long-term survivors and their offspring born after the Bhopal gas-leak tragedy in 1984. Several earlier reports show inconsistency in the assessment of immunological effects of MIC on the human population. In these studies, important factors including lifestyle attributes were overlooked. We incorporated these factors also in our study of the basic cell-mediated immune function in the Bhopal MIC-affected population. Twenty-seven years after exposure, we assessed the circulating T-lymphocyte frequency using E-Rosette assay. A total of 46 MIC-exposed healthy long-term survivors and their offspring were studied vis-a-vis parallel gender-age group-matched unexposed controls from Bhopal and various other regions of India. The influence of several lifestyle variabilities (smoking, alcohol intake, and tobacco chewing) on T-lymphocyte frequency was also taken into consideration. Our observations suggest that Erythrocyte-Rosette-forming cell (E-RFC) distribution frequency is largely insignificant in the MIC-affected population as compared to controls ( p > 0.05). In the MIC-affected tobacco chewers, there was a trend of suppression in CMI (relative decrease = 10.3%) as compared to nonchewers. Overall, our results show negligible long-term effect of MIC on CMI measured in terms of E-RFC frequency. These observations are not in agreement with earlier findings that immunosuppressive effects of MIC exposure persist in the T-cells of the affected population. However, atypical lymphocytes were frequently observed as E-RFC in the exposed females when compared to all other subgroups. Hematopoietic disorders (atypical lymphocytosis) in the MIC-affected population along with previous reports on the cytogenetic and humoral immune system linking cancer risk and chronic obstructive pulmonary disease (COPD) are

  15. Chronic Deep Cerebellar Stimulation Promotes Long-Term Potentiation, Microstructural Plasticity, and Reorganization of Perilesional Cortical Representation in a Rodent Model

    PubMed Central

    Cooperrider, Jessica; Furmaga, Havan; Plow, Ela; Park, Hyun-Joo; Chen, Zhihong; Kidd, Grahame; Baker, Kenneth B.; Gale, John T.

    2014-01-01

    Control over postinjury CNS plasticity is a major frontier of science that, if conquered, would open new avenues for treatment of neurological disorders. Here we investigate the functional, physiological, and structural changes in the cerebral cortex associated with chronic deep brain stimulation of the cerebellar output, a treatment approach that has been shown to improve postischemia motor recovery in a rodent model of cortical infarcts. Long–Evans rats were pretrained on the pasta-matrix retrieval task, followed by induction of focal cortical ischemia and implantation of a macroelectrode in the contralesional lateral cerebellar nucleus. Animals were assigned to one of three treatment groups pseudorandomly to balance severity of poststroke motor deficits: REGULAR stimulation, BURST stimulation, or SHAM. Treatment initiated 2 weeks post surgery and continued for 5 weeks. At the end, animals were randomly selected for perilesional intracortical microstimulation mapping and tissue sampling for Western blot analysis or contributed tissue for 3D electron microscopy. Evidence of enhanced cortical plasticity with therapeutically effective stimulation is shown, marked by greater perilesional reorganization in stimulation- treated animals versus SHAM. BURST stimulation was significantly effective for promoting distal forepaw cortical representation. Stimulation-treated animals showed a twofold increase in synaptic density compared with SHAM. In addition, treated animals demonstrated increased expression of synaptic markers of long-term potentiation and plasticity, including synaptophysin, NMDAR1, CaMKII, and PSD95. These findings provide a critical foundation of how deep cerebellar stimulation may guide plastic reparative reorganization after nonprogressive brain injury and indicate strong translational potential. PMID:24990924

  16. Metabotropic glutamate receptor-mediated long-term depression: molecular mechanisms.

    PubMed

    Gladding, Clare M; Fitzjohn, Stephen M; Molnár, Elek

    2009-12-01

    The ability to modify synaptic transmission between neurons is a fundamental process of the nervous system that is involved in development, learning, and disease. Thus, synaptic plasticity is the ability to bidirectionally modify transmission, where long-term potentiation and long-term depression (LTD) represent the best characterized forms of plasticity. In the hippocampus, two main forms of LTD coexist that are mediated by activation of either N-methyl-d-aspartic acid receptors (NMDARs) or metabotropic glutamate receptors (mGluRs). Compared with NMDAR-LTD, mGluR-LTD is less well understood, but recent advances have started to delineate the underlying mechanisms. mGluR-LTD at CA3:CA1 synapses in the hippocampus can be induced either by synaptic stimulation or by bath application of the group I selective agonist (R,S)-3,5-dihydroxyphenylglycine. Multiple signaling mechanisms have been implicated in mGluR-LTD, illustrating the complexity of this form of plasticity. This review provides an overview of recent studies investigating the molecular mechanisms underlying hippocampal mGluR-LTD. It highlights the role of key molecular components and signaling pathways that are involved in the induction and expression of mGluR-LTD and considers how the different signaling pathways may work together to elicit a persistent reduction in synaptic transmission.

  17. Interleukin-1 mediates long-term hippocampal dentate granule cell loss following postnatal viral infection.

    PubMed

    Orr, Anna G; Sharma, Anup; Binder, Nikolaus B; Miller, Andrew H; Pearce, Bradley D

    2010-05-01

    Viral infections of the developing CNS can cause long-term neuropathological sequela through undefined mechanisms. Proinflammatory cytokines such as IL-1beta have gained attention in mediating neurodegeneration in corticohippocampal structures due to a variety of insults in adults, though there is less information on the developing brain. Little is known concerning the spatial-temporal pattern of IL-1beta induction in the developing hippocampus following live virus infection, and there are few studies addressing the long-term consequences of this cytokine induction. We report that infection of rats with lymphocytic choriomeningitis virus on postnatal day 4 induces IL-1beta protein in select regions of the hippocampus on 6, 15, 21, and 45 days after infection. This infection resulted in a 71% reduction of dentate granule cell neurons by the time the rats reached mid-adulthood. We further investigated the causative role of IL-1 in this dentate granule cell loss by blocking IL-1 activity using an IL-1ra-expressing adenoviral vector administered at the time of infection. Blockade of IL-1 abrogated the infection-associated neuron loss in this vivo model. Considering that IL-1 can be triggered by multiple perinatal insults, our findings suggest that early therapy with anti-inflammatory agents that block IL-1 may be effective for reducing adulthood neuropathology.

  18. Long-term results of a pilot study of low dose cranial-spinal irradiation for cerebellar medulloblastoma

    SciTech Connect

    Brand, W.N.; Schneider, P.A.; Tokars, R.P.

    1987-11-01

    Between May 1974 and March 1983, 44 children with histologically verified cerebellar medulloblastoma were seen for post-operative cranial-spinal irradiation following attempted total tumor removal. Six patients were excluded from review because they received all or part of their treatment at another institution (3 patients) or did not complete the planned course of irradiation (3 patients). All of the 38 remaining patients were treated by a previously described technique on a 4 MeV Linear Accelerator with 55 Gy delivered to the primary tumor site. Prior to December 1978, 19 consecutive children (Group A) had spinal prophylactic doses of 30-40 Gy and brain prophylactic doses of 40-50 Gy. After the date, 25 Gy was given to the cranial-spinal axis of 19 consecutive children (Group B). This lower dose was arbitrarily selected with the hope of reducing morbidity in treated survivors and achieving the same tumor control. Risk factors that define good and poor prognosis were evaluated for each group, and there were no differences noted. Myelography and CSF cytology were not routinely performed. Follow-up for the 38 patients ranges from 20 months to 124 months. For the low risk patients, survival (12/15 or 80%) was independent of cranial-spinal radiation dose (Group A 6/8, Group B 6/7). For the high risk patients survival was poor (9/23 or 39%), not dependent on cranial-spinal radiation dose (Group A 5/11, Group B 4/12), and associated with failure at the primary site (10/14), often with CSF seeding (8/10). The other 4 failures include 2 who had moved outside the United States (details of failure are unknown), 1 with supratentorial, CSF seeding and distant metastases, and 1 with distant metastasis only.

  19. Insulin induces long-term depression of VTA dopamine neurons via an endocannabinoid-mediated mechanism

    PubMed Central

    Labouèbe, Gwenaël; Liu, Shuai; Dias, Carine; Zou, Haiyan; Wong, Jovi C.Y.; Karunakaran, Subashini; Clee, Susanne M.; Phillips, Anthony; Boutrel, Benjamin; Borgland, Stephanie L.

    2014-01-01

    The prevalence of obesity has drastically increased over the last few decades. Exploration into how hunger and satiety signals influence the reward system can help us to understand non-homeostatic mechanisms of feeding. Evidence suggests that insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce a long-term depression (LTD) of excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high fat meal, which elevates endogenous insulin levels, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior and conditioned place preference for food. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces salience of food-related cues. PMID:23354329

  20. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling.

    PubMed

    Puighermanal, Emma; Marsicano, Giovanni; Busquets-Garcia, Arnau; Lutz, Beat; Maldonado, Rafael; Ozaita, Andrés

    2009-09-01

    Cognitive impairment is one of the most important negative consequences associated with cannabis consumption. We found that CB1 cannabinoid receptor (CB1R) activation transiently modulated the mammalian target of rapamycin (mTOR)/p70S6K pathway and the protein synthesis machinery in the mouse hippocampus, which correlated with the amnesic properties of delta9-tetrahydrocannabinol (THC). In addition, non-amnesic doses of either the mTOR blocker rapamycin or the protein synthesis inhibitor anisomycin abrogated the amnesic-like effects of THC, pointing to a mechanism involving new protein synthesis. Moreover, using pharmacological and genetic tools, we found that THC long-term memory deficits were mediated by CB1Rs expressed on GABAergic interneurons through a glutamatergic mechanism, as both the amnesic-like effects and p70S6K phosphorylation were reduced in GABA-CB1R knockout mice and by NMDA blockade.

  1. Presynaptic long-term depression mediated by Gi/o-coupled receptors

    PubMed Central

    Atwood, Brady K.; Lovinger, David M.; Mathur, Brian N.

    2014-01-01

    Long-term depression (LTD) of the efficacy of synaptic transmission is now recognized as an important mechanism for regulation of information storage and control of actions, as well as synapse, neuron, and circuit development. Studies of LTD mechanisms have focused mainly on postsynaptic AMPA receptor trafficking. However, the focus has now expanded to include presynaptically expressed plasticity; the predominant form being initiated by presynaptically expressed Gi/o-coupled metabotropic receptor (Gi/o-GPCR) activation. Several forms of LTD involving activation of different presynaptic Gi/o-GPCRs as a “common pathway” are described. Here, we review the literature on presynaptic Gi/o-GPCR-mediated LTD, discuss known mechanisms, gaps in our knowledge, and evaluate if all Gi/o-GPCR are capable of inducing presynaptic LTD. PMID:25160683

  2. Presynaptic long-term depression mediated by Gi/o-coupled receptors.

    PubMed

    Atwood, Brady K; Lovinger, David M; Mathur, Brian N

    2014-11-01

    Long-term depression (LTD) of the efficacy of synaptic transmission is now recognized as an important mechanism for the regulation of information storage and the control of actions, as well as for synapse, neuron, and circuit development. Studies of LTD mechanisms have focused mainly on postsynaptic AMPA-type glutamate receptor trafficking. However, the focus has now expanded to include presynaptically expressed plasticity, the predominant form being initiated by presynaptically expressed Gi/o-coupled metabotropic receptor (Gi/o-GPCR) activation. Several forms of LTD involving activation of different presynaptic Gi/o-GPCRs as a 'common pathway' are described. We review here the literature on presynaptic Gi/o-GPCR-mediated LTD, discuss known mechanisms, gaps in our knowledge, and evaluate whether all Gi/o-GPCRs are capable of inducing presynaptic LTD.

  3. Postsynaptic Signals Mediating Induction of Long-Term Synaptic Depression in the Entorhinal Cortex

    PubMed Central

    Kourrich, Saïd; Glasgow, Stephen D.; Caruana, Douglas A.; Chapman, C. Andrew

    2008-01-01

    The entorhinal cortex receives a large projection from the piriform cortex, and synaptic plasticity in this pathway may affect olfactory processing. In vitro whole cell recordings have been used here to investigate postsynaptic signalling mechanisms that mediate the induction of long-term synaptic depression (LTD) in layer II entorhinal cortex cells. To induce LTD, pairs of pulses, using a 30-millisecond interval, were delivered at 1 Hz for 15 minutes. Induction of LTD was blocked by the NMDA receptor antagonist APV and by the calcium chelator BAPTA, consistent with a requirement for calcium influx via NMDA receptors. Induction of LTD was blocked when the FK506 was included in the intracellular solution to block the phosphatase calcineurin. Okadaic acid, which blocks activation of protein phosphatases 1 and 2a, also prevented LTD. Activation of protein phosphatases following calcium influx therefore contributes to induction of LTD in layer II of the entorhinal cortex. PMID:18670611

  4. Reassessment of long-term depression in cerebellar Purkinje cells in mice carrying mutated GluA2 C terminus

    PubMed Central

    Yamaguchi, Kazuhiko; Itohara, Shigeyoshi; Ito, Masao

    2016-01-01

    Long-term depression (LTD) of synaptic transmission from parallel fibers (PFs) to a Purkinje cell (PC) in the cerebellum has been considered to be a core mechanism of motor learning. Recently, however, discrepancies between LTD and motor learning have been reported in mice with a mutation that targeted the expression of PF–PC LTD by blocking AMPA-subtype glutamate receptor internalization regulated via the phosphorylation of AMPA receptors. In these mice, motor learning behavior was normal, but no PF–PC LTD was observed. We reexamined slices obtained from these GluA2 K882A and GluA2 Δ7 knockin mutants at 3–6 mo of age. The conventional protocols of stimulation did not induce LTD in these mutant mice, as previously reported, but surprisingly, LTD was induced using certain modified protocols. Such modifications involved increases in the number of PF stimulation (from one to two or five), replacement of climbing fiber stimulation with somatic depolarization (50 ms), filling a patch pipette with a Cs+-based solution, or extension of the duration of conjunction. We also found that intracellular infusion of a selective PKCα inhibitor (Gö6976) blocked LTD induction in the mutants, as in WT, suggesting that functional compensation occurred downstream of PKCα. The possibility that LTD in the mutants was caused by changes in membrane resistance, access resistance, or presynaptic property was excluded. The present results demonstrate that LTD is inducible by intensified conjunctive stimulations even in K882A and Δ7 mutants, indicating no contradiction against the LTD hypothesis of motor learning. PMID:27551099

  5. Long-term administration of Delta9-tetrahydrocannabinol desensitizes CB1-, adenosine A1-, and GABAB-mediated inhibition of adenylyl cyclase in mouse cerebellum.

    PubMed

    Selley, Dana E; Cassidy, Michael P; Martin, Billy R; Sim-Selley, Laura J

    2004-11-01

    Cannabinoid CB(1) receptors in the cerebellum mediate the inhibitory effects of Delta(9)-tetrahydrocannabinol (THC) on motor coordination. Intracellular effects of CB(1) receptors include inhibition of adenylyl cyclase via activation of G(i/o) proteins. There is evidence for the convergence of other neuronal receptors, such as adenosine A(1) and GABA(B), with the cannabinoid system on this signaling pathway to influence motor function. Previous studies have shown that brain CB(1) receptors are desensitized and down-regulated by long-term THC treatment, but few studies have examined the effects of long-term THC treatment on downstream effector activity in brain. Therefore, these studies examined the relationship between CB(1), adenosine A(1), and GABA(B) receptors in cerebella of mice undergoing prolonged treatment with vehicle or THC at the level of G protein activation and adenylyl cyclase inhibition. In control cerebella, CB(1) receptors produced less than additive inhibition of adenylyl cyclase with GABA(B) and A(1) receptors, indicating that these receptors are localized on overlapping populations of cells. Long-term THC treatment produced CB(1) receptor down-regulation and desensitization of both cannabinoid agonist-stimulated G protein activation and inhibition of forskolin-stimulated adenylyl cyclase. However, G protein activation by GABA(B) or A(1) receptors was unaffected. It is noteworthy that heterologous attenuation of GABA(B) and A(1) receptor-mediated inhibition of adenylyl cyclase was observed, even though absolute levels of basal and forskolin- or G(s)-stimulated activity were unchanged. These results indicate that long-term THC administration produces a disruption of inhibitory receptor control of cerebellar adenylyl cyclase and suggest a potential mechanism of cross-tolerance to the motor incoordinating effects of cannabinoid, GABA(B), and A(1) agonists.

  6. Dendritic morphogenesis of cerebellar Purkinje cells through extension and retraction revealed by long-term tracking of living cells in vitro.

    PubMed

    Tanaka, M; Yanagawa, Y; Obata, K; Marunouchi, T

    2006-08-25

    Cerebellar Purkinje cells have the most elaborate dendritic trees among the neurons in the CNS. To investigate the dynamic aspects of dendritic morphogenesis of Purkinje cells, we performed a long-term analysis of living cells in cerebellar cell cultures derived from glutamate decarboxylase 67-green fluorescent protein mice. Most Purkinje cells had several primary dendrites during the 25-day culture period. Repeated observation of green fluorescent protein-expressing Purkinje cells over a period of 10-25 days in vitro demonstrated that not only extension, but also retraction of primary dendrites occurred during this culture period. Interestingly, both extension and retraction of primary dendrites were active between 10 and 15 days in vitro, and retraction of a primary dendrite occurred concomitantly with elongation of other primary dendrites in the same cell. Analysis of the morphological characteristics of the retracted primary dendrites demonstrated that shorter and less branched primary dendrites tended to retract. Furthermore, treatment with an inhibitor of calcium/calmodulin-dependent protein kinase II reduced the number of primary dendrites specifically during 5-15 days in vitro, the culture period when the extension and retraction of primary dendrites occurred actively. Blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-type glutamate receptors also reduced the number of primary dendrites during the same culture period, while inhibition of glutamate transporters increased the number. These findings suggest that the final morphology of Purkinje cells is achieved not only through extension, but also through retraction of their dendrites, and that calcium/calmodulin-dependent protein kinase II and neuronal activity are involved in this dendritic morphogenesis.

  7. Mediators of the Long-Term Impact of Child Sexual Abuse: Perceived Stigma, Betrayal, Powerlessness, and Self-Blame.

    ERIC Educational Resources Information Center

    Coffey, Patricia; And Others

    1996-01-01

    This study tested 192 women who had been sexually abused as children, to see if perceived stigma, betrayal, powerlessness, and self-blame mediated long-term effects of child sexual abuse. Levels of psychological distress experienced by adult survivors of abuse were found to be mediated by feelings of stigma and self-blame. (Author/PB)

  8. Out of Place: Mediating Health and Social Care in Ontario's Long-Term Care Sector

    ERIC Educational Resources Information Center

    Daly, Tamara

    2007-01-01

    The paper discusses two reforms in Ontario's long-term care. The first is the commercialization of home care as a result of the implementation of a "managed competition" delivery model. The second is the Ministry of Health and Long-Term Care's privileging of "health care" over "social care" through changes to which…

  9. Out of Place: Mediating Health and Social Care in Ontario's Long-Term Care Sector

    ERIC Educational Resources Information Center

    Daly, Tamara

    2007-01-01

    The paper discusses two reforms in Ontario's long-term care. The first is the commercialization of home care as a result of the implementation of a "managed competition" delivery model. The second is the Ministry of Health and Long-Term Care's privileging of "health care" over "social care" through changes to which…

  10. Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis.

    PubMed

    Dong, Zhifang; Han, Huili; Li, Hongjie; Bai, Yanrui; Wang, Wei; Tu, Man; Peng, Yan; Zhou, Limin; He, Wenting; Wu, Xiaobin; Tan, Tao; Liu, Mingjing; Wu, Xiaoyan; Zhou, Weihui; Jin, Wuyang; Zhang, Shu; Sacktor, Todd Charlton; Li, Tingyu; Song, Weihong; Wang, Yu Tian

    2015-01-01

    Long-term potentiation (LTP) of synaptic strength between hippocampal neurons is associated with learning and memory, and LTP dysfunction is thought to underlie memory loss. LTP can be temporally and mechanistically classified into decaying (early-phase) LTP and nondecaying (late-phase) LTP. While the nondecaying nature of LTP is thought to depend on protein synthesis and contribute to memory maintenance, little is known about the mechanisms and roles of decaying LTP. Here, we demonstrated that inhibiting endocytosis of postsynaptic α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) prevents LTP decay, thereby converting it into nondecaying LTP. Conversely, restoration of AMPAR endocytosis by inhibiting protein kinase Mζ (PKMζ) converted nondecaying LTP into decaying LTP. Similarly, inhibition of AMPAR endocytosis prolonged memory retention in normal animals and reduced memory loss in a murine model of Alzheimer's disease. These results strongly suggest that an active process that involves AMPAR endocytosis mediates the decay of LTP and that inhibition of this process can prolong the longevity of LTP as well as memory under both physiological and pathological conditions.

  11. Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation

    PubMed Central

    Gao, Virginia; Suzuki, Akinobu; Magistretti, Pierre J.; Lengacher, Sylvain; Pollonini, Gabriella; Steinman, Michael Q.; Alberini, Cristina M.

    2016-01-01

    Emotionally relevant experiences form strong and long-lasting memories by critically engaging the stress hormone/neurotransmitter noradrenaline, which mediates and modulates the consolidation of these memories. Noradrenaline acts through adrenergic receptors (ARs), of which β2-adrenergic receptors (βARs) are of particular importance. The differential anatomical and cellular distribution of βAR subtypes in the brain suggests that they play distinct roles in memory processing, although much about their specific contributions and mechanisms of action remains to be understood. Here we show that astrocytic rather than neuronal β2ARs in the hippocampus play a key role in the consolidation of a fear-based contextual memory. These hippocampal β2ARs, but not β1ARs, are coupled to the training-dependent release of lactate from astrocytes, which is necessary for long-term memory formation and for underlying molecular changes. This key metabolic role of astrocytic β2ARs may represent a novel target mechanism for stress-related psychopathologies and neurodegeneration. PMID:27402767

  12. A novel model for studies of blood-mediated long-term responses to cellular transplants

    PubMed Central

    Lindblom, Susanne; Hong, Jaan; Nilsson, Bo; Korsgren, Olle; Ronquist, Gunnar

    2015-01-01

    Aims Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h. Methods Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability. Results Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen. Conclusion A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions. PMID:25322825

  13. Long-Term Effects of a Universal Family Intervention: Mediation Through Parent-Adolescent Conflict

    PubMed Central

    Jensen, M.; Wong, J.J.; Gonzales, N.A.; Dumka, L.E.; Millsap, R.; Coxe, S.

    2014-01-01

    Objective This randomized trial of a family-focused preventive intervention for Mexican American middle schoolers examined internalizing, externalizing, and substance use outcomes in late adolescence, five years after completing the intervention. Parent-adolescent conflict was tested as a mediator of these effects. The role of parent and adolescent acculturation in these pathways was also examined. Method 498 7th grade adolescents and their primary female caregivers were randomized to receive either a 9-week, multi-component intervention or a brief workshop control group. Assessments were conducted at pre-test, two year follow-up (9th grade), and five year follow-up (when most participants were in the 12th grade). Results The Bridges program significantly reduced mother-adolescent conflict measured in the 9th grade, with conflict mediating program effects on internalizing and externalizing symptoms, adolescent substance use, and diagnosed internalizing disorder in late adolescence. Mother and child acculturation were both significantly predictive of late adolescence outcomes. Contrary to hypotheses, neither mother nor child acculturation emerged as a significant predictor of mother-adolescent conflict, and the interaction of mother and adolescent acculturation was similarly not related to mother-adolescent conflict. Intervention effects were largely consistent across different levels of acculturation. Conclusions These findings provide support for the efficacy of family-focused intervention during early adolescence, both in reducing mental health problems and substance use in the long term, as well as in impacting parent-adolescent conflict processes that appear to play an important role in the development of later adjustment problems. PMID:24730357

  14. SCOP/PHLPP1β mediates circadian regulation of long-term recognition memory

    PubMed Central

    Shimizu, Kimiko; Kobayashi, Yodai; Nakatsuji, Erika; Yamazaki, Maya; Shimba, Shigeki; Sakimura, Kenji; Fukada, Yoshitaka

    2016-01-01

    Learning and memory depend on the time of day in various organisms, but it is not clear whether and how the circadian clock regulates memory performance. Here we show that consolidation of long-term recognition memory is a circadian-regulated process, which is blunted by disruption of the hippocampal clock. We focused on SCOP, a key molecule regulating hippocampus-dependent long-term memory for objects. The amounts of SCOP and its binding partner K-Ras in the hippocampal membrane rafts exhibit robust circadian changes, and SCOP knockdown in the hippocampal CA1 impairs long-term memory at night. Circadian changes in stimulus-dependent activation of ERK in the hippocampal neurons are dependent on the SCOP levels in the membrane rafts, while Scop knockout abrogates the activation rhythm. We conclude that long-term memory formation is regulated by the circadian clock through SCOP dynamics in the membrane rafts of the hippocampal CA1. PMID:27686624

  15. Long-term social recognition memory is mediated by oxytocin-dependent synaptic plasticity in the medial amygdala.

    PubMed

    Gur, Rotem; Tendler, Alex; Wagner, Shlomo

    2014-09-01

    Recognition of specific individuals is fundamental to mammalian social behavior and is mediated in most mammals by the main and accessory olfactory systems. Both these systems innervate the medial amygdala (MeA), where activity of the neuropeptide oxytocin is thought to mediate social recognition memory (SRM). The specific contribution of the MeA to SRM formation and the specific actions of oxytocin in the MeA are unknown. We used the social discrimination test to evaluate short-term and long-term SRM in adult Sprague-Dawley male rats (n = 38). The role of protein synthesis in the MeA was investigated by local application of the protein synthesis blocker anisomycin (n = 11). Synaptic plasticity was assessed in vivo by recording the MeA evoked field potential responses to stimulation of the main (n = 21) and accessory (n = 56) olfactory bulbs before and after theta burst stimulation. Intracerebroventricular administration of saline, oxytocin, or oxytocin receptor antagonist was used to measure the effect of oxytocin on synaptic plasticity. Anisomycin application to the MeA prevented the formation of long-term SRM. In addition, the responses of MeA neurons underwent long-term depression (LTD) after theta burst stimulation of the accessory olfactory bulb, but not the main accessory bulb, in an oxytocin-dependent manner. No LTD was found in socially isolated rats, which are known to lack long-term SRM. Finally, accessory olfactory bulb stimulation before SRM acquisition blocked long-term SRM, supporting the involvement of LTD in the MeA in formation of long-term SRM. Our results indicate that long-term SRM in rats involves protein synthesis and oxytocin-dependent LTD in the MeA. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  16. Zinc-mediated attenuation of hippocampal mossy fiber long-term potentiation induced by forskolin.

    PubMed

    Ando, Masaki; Oku, Naoto; Takeda, Atsushi

    2010-11-01

    The rise in presynaptic calcium induced by high-frequency stimulation activates the calcium-calmodulin-sensitive adenylyl cyclase (AC) 1 followed by the induction of long-term potentiation (LTP) at the hippocampal mossy fiber-CA3 synapse. Zinc is released with glutamate from mossy fiber terminals. However, the role of the zinc in mossy fiber LTP is controversial. In the present study, the mechanism of zinc-mediated attenuation of mossy fiber LTP was examined in that induced by forskolin, an AC activator. Mossy fiber LTP induced by tetanic stimulation (100 Hz for 1 s) was attenuated in the presence of 5 microM ZnCl(2), whereas that induced by forskolin under test stimulation (0.1 Hz) was not attenuated. Forskolin-induced mossy fiber LTP was attenuated by perfusion with 100 microM ZnCl(2) prior to the induction. However, the zinc (100 microM) pre-perfusion did not attenuate mossy fiber LTP induced by Sp-cAMPS, an activator of protein kinase A, under test stimulation. Zinc is necessary to be taken up into mossy fiber boutons for effectively inhibiting AC activity. In hippocampal slices labeled with ZnAF-2 DA, a membrane-permeable zinc indicator, intracellular ZnAF-2 signal was increased during tetanic stimulation in the presence of 5 microM ZnCl(2), but not under test stimulation. Intracellular ZnAF-2 signal was increased under test stimulation in the presence of 100 microM ZnCl(2). These results suggest that zinc taken up into mossy fibers attenuates forskolin-induced mossy fiber LTP via inhibition of AC activity. The significance of endogenous zinc uptake by mossy fibers is discussed focused on tetanus-induced mossy fiber LTP.

  17. Long-Term Effects of Child Corporal Punishment on Depressive Symptoms in Young Adults: Potential Moderators and Mediators

    ERIC Educational Resources Information Center

    Turner, Heather A.; Muller, Paul A.

    2004-01-01

    Based on a sample of 649 students from 3 New England colleges, this study examined the long-term effects of childhood corporal punishment on symptoms of depression and considered factors that may moderate or mediate the association. Similar to national studies, approximately 40% of the sample reported experiencing some level of corporal punishment…

  18. Enhanced photovoltaic properties and long-term stability in plasmonic dye-sensitized solar cells via noncorrosive redox mediator.

    PubMed

    Jung, Heesuk; Koo, Bonkee; Kim, Jae-Yup; Kim, Taehee; Son, Hae Jung; Kim, BongSoo; Kim, Jin Young; Lee, Doh-Kwon; Kim, Honggon; Cho, Jinhan; Ko, Min Jae

    2014-11-12

    We demonstrate the localized surface plasmon resonance (LSPR) effect, which can enhance the photovoltaic properties of dye-sensitized solar cells (DSSCs), and the long-term stability of size-controlled plasmonic structures using a noncorrosive redox mediator. Gold nanoparticles (Au NPs) were synthesized with a phase transfer method based on ligand exchange. This synthetic method is advantageous because the uniformly sized Au NPs, can be mass produced and easily applied to DSSC photoanodes. The plasmonic DSSCs showed an 11% improvement of power conversion efficiency due to the incorporation of 0.07 wt % Au NPs, compared to the reference DSSCs without Au NPs. The improved efficiency was primarily due to the enhanced photocurrent generation by LSPR effect. With the cobalt redox mediator, the long-term stability of the plasmonic structures also significantly increased. The plasmonic DSSCs with cobalt(II/III) tris(2,2'-bipyridine) ([Co(bpy)3](2+/3+)) redox mediator maintained the LSPR effect with stable photovoltaic performance for 1000 h. This is, to our knowledge, the first demonstration of the long-term stability of plasmonic nanostructures in plasmonic DSSCs based on liquid electrolytes. As a result, the enhanced long-term stability of plasmonic NPs via a noncorrosive redox mediator will increase the feasibility of plasmonic DSSCs.

  19. Long-Term Effects of Child Corporal Punishment on Depressive Symptoms in Young Adults: Potential Moderators and Mediators

    ERIC Educational Resources Information Center

    Turner, Heather A.; Muller, Paul A.

    2004-01-01

    Based on a sample of 649 students from 3 New England colleges, this study examined the long-term effects of childhood corporal punishment on symptoms of depression and considered factors that may moderate or mediate the association. Similar to national studies, approximately 40% of the sample reported experiencing some level of corporal punishment…

  20. Gating of long-term depression by Ca2+/calmodulin-dependent protein kinase II through enhanced cGMP signalling in cerebellar Purkinje cells

    PubMed Central

    Kawaguchi, Shin-ya; Hirano, Tomoo

    2013-01-01

    Long-term depression (LTD) at parallel fibre synapses on a cerebellar Purkinje cell has been regarded as a cellular basis for motor learning. Although Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the LTD induction as an important Ca2+-sensing molecule, the underlying signalling mechanism remains unclear. Here, we attempted to explore the potential signalling pathway underlying the CaMKII involvement in LTD using a systems biology approach, combined with validation by electrophysiological and FRET imaging experiments on a rat cultured Purkinje cell. Model simulation predicted the following cascade as a candidate mechanism for the CaMKII contribution to LTD: CaMKII negatively regulates phosphodiesterase 1 (PDE1), subsequently facilitates the cGMP/protein kinase G (PKG) signalling pathway and down-regulates protein phosphatase 2A (PP-2A), thus supporting the LTD-inducing positive feedback loop consisting of mutual activation of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). This model suggestion was corroborated by whole-cell patch clamp recording experiments. In addition, FRET measurement of intracellular cGMP concentration revealed that CaMKII activation causes sustained increase of cGMP, supporting the signalling mechanism of LTD induction by CaMKII. Furthermore, we found that activation of the cGMP/PKG pathway by nitric oxide (NO) can support LTD induction without activation of CaMKII. Thus, this study clarified interaction between NO and Ca2+/CaMKII, two important factors required for LTD. PMID:23297306

  1. The mediating effects of job satisfaction on turnover intention for long-term care nurses in Taiwan.

    PubMed

    Kuo, Huai-Ting; Lin, Kuan-Chia; Li, I-Chuan

    2014-03-01

    This study explores the mediating effects of job satisfaction on work stress and turnover intention among long-term care nurses in Taiwan. Healthcare institutions face a nursing shortage, and it is important to examine the factors that influence turnover intention among nurses. Excessive levels of work stress may lead to employee dissatisfaction and a significant inverse relationship between work stress and job satisfaction, including subsequent effects on turnover among nurses. However, little is known about the mediating role of job satisfaction on work stress and turnover intention among long-term care nurses. A cross-sectional survey and a correlation design were used. Multistage linear regression was used to test the mediation model. This study showed that job satisfaction significantly mediated the relationship between work stress and turnover intention. Thirty-eight percent of the variance in turnover intention explained by work stress was accounted for by the mediation pathway. The results of this study showed that higher job satisfaction significantly decreased work stress and turnover intention among long-term care nurses. This study provides nursing administrators with a resource to build a supportive environment to increase nurses' job satisfaction and to decrease their stress and turnover. © 2013 John Wiley & Sons Ltd.

  2. Long-Term Neuropsychological Profiles and Their Role as Mediators of Adaptive Functioning after Traumatic Brain Injury in Early Childhood.

    PubMed

    Treble-Barna, Amery; Zang, Huaiyu; Zhang, Nanhua; Taylor, H Gerry; Yeates, Keith Owen; Wade, Shari

    2017-01-15

    The objectives of the study were to characterize long-term neuropsychological outcomes following traumatic brain injury (TBI) sustained during early childhood, and determine whether identified neuropsychological impairments mediated the effect of TBI on long-term adaptive functioning. Participants included 16 children with severe TBI, 42 children with moderate TBI, and 72 children with orthopedic injuries (OI) sustained between ages 3 and 7 years. Children completed neuropsychological tests and caregivers completed a structured interview of child adaptive functioning at 6.9 (±1.10) years post-injury. Profile analysis and multiple mediator modeling were employed. Children with severe TBI demonstrated poorer fluid reasoning and inhibitory control than both children with moderate TBI and OI, as well as slower processing speed than the OI group. Both fluid reasoning and processing speed were significant independent mediators of the effect of severe TBI on adaptive functioning. No neuropsychological measure significantly mediated the effect of moderate TBI on adaptive functioning. Children sustaining early severe TBI demonstrate persisting neuropsychological impairments into adolescence and young adulthood. The impact of severe TBI on children's long-term adaptive functioning is mediated in part by its effects on fluid reasoning and processing speed.

  3. PKG-Mediated MAPK Signaling Is Necessary for Long-Term Operant Memory in "Aplysia"

    ERIC Educational Resources Information Center

    Michel, Maximilian; Green, Charity L.; Eskin, Arnold; Lyons, Lisa C.

    2011-01-01

    Signaling pathways necessary for memory formation, such as the mitogen-activated protein kinase (MAPK) pathway, appear highly conserved across species and paradigms. Learning that food is inedible (LFI) represents a robust form of associative, operant learning that induces short- (STM) and long-term memory (LTM) in "Aplysia." We investigated the…

  4. GABA-Mediated Presynaptic Inhibition Is Required for Precision of Long-Term Memory

    ERIC Educational Resources Information Center

    Cullen, Patrick K.; Dulka, Brooke N.; Ortiz, Samantha; Riccio, David C.; Jasnow, Aaron M.

    2014-01-01

    Though much attention has been given to the neural structures that underlie the long-term consolidation of contextual memories, little is known about the mechanisms responsible for the maintenance of memory precision. Here, we demonstrate a rapid time-dependent decline in memory precision in GABA [subscript B(1a)] receptor knockout mice. First, we…

  5. PKG-Mediated MAPK Signaling Is Necessary for Long-Term Operant Memory in "Aplysia"

    ERIC Educational Resources Information Center

    Michel, Maximilian; Green, Charity L.; Eskin, Arnold; Lyons, Lisa C.

    2011-01-01

    Signaling pathways necessary for memory formation, such as the mitogen-activated protein kinase (MAPK) pathway, appear highly conserved across species and paradigms. Learning that food is inedible (LFI) represents a robust form of associative, operant learning that induces short- (STM) and long-term memory (LTM) in "Aplysia." We investigated the…

  6. GABA-Mediated Presynaptic Inhibition Is Required for Precision of Long-Term Memory

    ERIC Educational Resources Information Center

    Cullen, Patrick K.; Dulka, Brooke N.; Ortiz, Samantha; Riccio, David C.; Jasnow, Aaron M.

    2014-01-01

    Though much attention has been given to the neural structures that underlie the long-term consolidation of contextual memories, little is known about the mechanisms responsible for the maintenance of memory precision. Here, we demonstrate a rapid time-dependent decline in memory precision in GABA [subscript B(1a)] receptor knockout mice. First, we…

  7. Mediators of a long-term movement abnormality in a Drosophila melanogaster model of classic galactosemia

    PubMed Central

    Ryan, Emily L.; DuBoff, Brian; Feany, Mel B.; Fridovich-Keil, Judith L.

    2012-01-01

    SUMMARY Despite neonatal diagnosis and life-long dietary restriction of galactose, many patients with classic galactosemia grow to experience significant long-term complications. Among the more common are speech, cognitive, behavioral, ovarian and neurological/movement difficulties. Despite decades of research, the pathophysiology of these long-term complications remains obscure, hindering prognosis and attempts at improved intervention. As a first step to overcome this roadblock we have begun to explore long-term outcomes in our previously reported GALT-null Drosophila melanogaster model of classic galactosemia. Here we describe the first of these studies. Using a countercurrent device, a simple climbing assay, and a startle response test to characterize and quantify an apparent movement abnormality, we explored the impact of cryptic GALT expression on phenotype, tested the role of sublethal galactose exposure and galactose-1-phosphate (gal-1P) accumulation, tested the impact of age, and searched for potential anatomical defects in brain and muscle. We found that about 2.5% residual GALT activity was sufficient to reduce outcome severity. Surprisingly, sublethal galactose exposure and gal-1P accumulation during development showed no effect on the adult phenotype. Finally, despite the apparent neurological or neuromuscular nature of the complication we found no clear morphological differences between mutants and controls in brain or muscle, suggesting that the defect is subtle and/or is physiologic rather than structural. Combined, our results confirm that, like human patients, GALT-null Drosophila experience significant long-term complications that occur independently of galactose exposure, and serve as a proof of principle demonstrating utility of the GALT-null Drosophila model as a tool for exploring genetic and environmental modifiers of long-term outcome in GALT deficiency. PMID:22736462

  8. Mediators of a long-term movement abnormality in a Drosophila melanogaster model of classic galactosemia.

    PubMed

    Ryan, Emily L; DuBoff, Brian; Feany, Mel B; Fridovich-Keil, Judith L

    2012-11-01

    Despite neonatal diagnosis and life-long dietary restriction of galactose, many patients with classic galactosemia grow to experience significant long-term complications. Among the more common are speech, cognitive, behavioral, ovarian and neurological/movement difficulties. Despite decades of research, the pathophysiology of these long-term complications remains obscure, hindering prognosis and attempts at improved intervention. As a first step to overcome this roadblock we have begun to explore long-term outcomes in our previously reported GALT-null Drosophila melanogaster model of classic galactosemia. Here we describe the first of these studies. Using a countercurrent device, a simple climbing assay, and a startle response test to characterize and quantify an apparent movement abnormality, we explored the impact of cryptic GALT expression on phenotype, tested the role of sublethal galactose exposure and galactose-1-phosphate (gal-1P) accumulation, tested the impact of age, and searched for potential anatomical defects in brain and muscle. We found that about 2.5% residual GALT activity was sufficient to reduce outcome severity. Surprisingly, sublethal galactose exposure and gal-1P accumulation during development showed no effect on the adult phenotype. Finally, despite the apparent neurological or neuromuscular nature of the complication we found no clear morphological differences between mutants and controls in brain or muscle, suggesting that the defect is subtle and/or is physiologic rather than structural. Combined, our results confirm that, like human patients, GALT-null Drosophila experience significant long-term complications that occur independently of galactose exposure, and serve as a proof of principle demonstrating utility of the GALT-null Drosophila model as a tool for exploring genetic and environmental modifiers of long-term outcome in GALT deficiency.

  9. Lentiviral Vectors Mediate Long-Term and High Efficiency Transgene Expression in HEK 293T cells

    PubMed Central

    Mao, Yingying; Yan, Renhe; Li, Andrew; Zhang, Yanling; Li, Jinlong; Du, Hongyan; Chen, Baihong; Wei, Wenjin; Zhang, Yi; Sumners, Colin; Zheng, Haifa; Li, Hongwei

    2015-01-01

    . Surprisingly, neither the HS4 insulator nor the UCOE sequence improved the GFP expression level or stability. Clonal cell lines with HCV E1 gene were generated from LV-CMV-E1 vector-infected 293T cells. A representative recombinant cell line maintained stable E1expression for at least 9 weeks without significant difference in morphology compared with untreated 293T cells. Conclusion: The results suggest that all five vectors can stably transduce 293T cells, producing long term transgene expression with different efficiencies. However, neither the insulator nor the UCOE improved the GFP expression. The vectors containing the promoter CMV or CMV (β-globin intron) generated the highest gene expressions, manifesting as more favorable candidates for recombinant protein production in HEK293T cells. PMID:26005375

  10. Long-term exposure to PGE2 causes homologous desensitization of receptor-mediated activation of protein kinase A.

    PubMed

    Malty, Ramy Habashy; Hudmon, Andy; Fehrenbacher, Jill C; Vasko, Michael R

    2016-07-11

    Acute exposure to prostaglandin E2 (PGE2) activates EP receptors in sensory neurons which triggers the cAMP-dependent protein kinase A (PKA) signaling cascade resulting in enhanced excitability of the neurons. With long-term exposure to PGE2, however, the activation of PKA does not appear to mediate persistent PGE2-induced sensitization. Consequently, we examined whether homologous desensitization of PGE2-mediated PKA activation occurs after long-term exposure of isolated sensory neurons to the eicosanoid. Sensory neuronal cultures were harvested from the dorsal root ganglia of adult male Sprague-Dawley rats. The cultures were pretreated with vehicle or PGE2 and used to examine signaling mechanisms mediating acute versus persistent sensitization by exposure to the eicosanoid using enhanced capsaicin-evoked release of immunoreactive calcitonin gene-related peptide (iCGRP) as an endpoint. Neuronal cultures chronically exposed to vehicle or PGE2 also were used to study the ability of the eicosanoid and other agonists to activate PKA and whether long-term exposure to the prostanoid alters expression of EP receptor subtypes. Acute exposure to 1 μM PGE2 augments the capsaicin-evoked release of iCGRP, and this effect is blocked by the PKA inhibitor H-89. After 5 days of exposure to 1 μM PGE2, administration of the eicosanoid still augments evoked release of iCGRP, but the effect is not attenuated by inhibition of PKA or by inhibition of PI3 kinases. The sensitizing actions of PGE2 after acute and long-term exposure were attenuated by EP2, EP3, and EP4 receptor antagonists, but not by an EP1 antagonist. Exposing neuronal cultures to 1 μM PGE2 for 12 h to 5 days blocks the ability of PGE2 to activate PKA. The offset of the desensitization occurs within 24 h of removal of PGE2 from the cultures. Long-term exposure to PGE2 also results in desensitization of the ability of a selective EP4 receptor agonist, L902688 to activate PKA, but does not alter the ability of

  11. Nitric oxide-dependent long-term depression but not endocannabinoid-mediated long-term potentiation is crucial for visual recognition memory

    PubMed Central

    Tamagnini, Francesco; Barker, Gareth; Warburton, E Clea; Burattini, Costanza; Aicardi, Giorgio; Bashir, Zafar I

    2013-01-01

    Synaptic plasticity in perirhinal cortex is essential for recognition memory. Nitric oxide and endocannabinoids (eCBs), which are produced in the postsynaptic cell and act on the presynaptic terminal, are implicated in mechanisms of long-term potentiation (LTP) and long-term depression (LTD) in other brain regions. In this study, we examine these two retrograde signalling cascades in perirhinal cortex synaptic plasticity and in visual recognition memory in the rat. We show that inhibition of NO-dependent signalling prevented both carbachol- and activity (5 Hz)-dependent LTD but not activity (100 Hz theta burst)-dependent LTP in the rat perirhinal cortex in vitro. In contrast, inhibition of the eCB-dependent signalling prevented LTP but not the two forms of LTD in vitro. Local administration into perirhinal cortex of the nitric oxide synthase inhibitor NPA (2 μm) disrupted acquisition of long-term visual recognition memory. In contrast, AM251 (10 μm), a cannabinoid receptor 1 antagonist, did not impair visual recognition memory. The results of this study demonstrate dissociation between putative retrograde signalling mechanisms in LTD and LTP in perirhinal cortex. Thus, LTP relies on cannabinoid but not NO signalling, whilst LTD relies on NO- but not eCB-dependent signalling. Critically, these results also establish, for the first time, that NO- but not eCB-dependent signalling is important in perirhinal cortex-dependent visual recognition memory. PMID:23671159

  12. ENDOCANNABINOID-MEDIATED LONG-TERM PLASTICITY REQUIRES cAMP/PKA SIGNALING AND RIM1α

    PubMed Central

    Chevaleyre, Vivien; Heifets, Boris D.; Kaeser, Pascal S.; Südhof, Thomas C.; Castillo, Pablo E.

    2007-01-01

    SUMMARY Endocannabinoids (eCB) have emerged as key activity-dependent signals that, by activating presynaptic cannabinoid receptors (CB1) coupled to Gi/o protein, can mediate short-term and long-term synaptic depression (LTD). While the presynaptic mechanisms underlying eCB-dependent short-term depression have been identified, the molecular events linking CB1 receptors to LTD are unknown. Here we show in the hippocampus that long-term, but not short-term, eCB-dependent depression of inhibitory transmission requires presynaptic cAMP/PKA signaling. We further identify the active zone protein RIM1α as a key mediator of both CB1 receptor effects on the release machinery, as well as eCB-dependent LTD in the hippocampus. Moreover, we show that eCB-dependent LTD in the amygdala and hippocampus shares major mechanistic features. These findings reveal for the first time the signaling pathway by which CB1 receptors mediate long-term effects of eCBs in two crucial brain structures. Further, our results highlight a conserved mechanism of presynaptic plasticity in the brain. PMID:17553427

  13. Long-term rebamipide and diquafosol in two cases of immune-mediated dry eye.

    PubMed

    Yamane, Mio; Ogawa, Yoko; Fukui, Masaki; Kamoi, Mizuka; Saijo-Ban, Yumiko; Yaguchi, Saori; Mukai, Shin; Kawakita, Tetsuya; Simmura, Shigeto; Tsubota, Kazuo

    2015-04-01

    Two new drugs with mucin-inducing and secretion-promotive effects, rebamipide and diquafosol, were recently approved as topical dry-eye treatments. We report two cases in which the long-term use of mucin-inducing eye drops improved chronic ocular graft-versus-host disease (cGVHD)-related dry eye and ocular cicatricial pemphigoid (OCP)-like disease. Case 1. A 61-year-old woman had cGVHD-related dry eye that resisted traditional medications. Next, we use topical diquafosol in addition to conventional treatments. The patient used diquafosol for 6 months without experiencing any side effects. The symptoms, including dry-eye sensation, ocular pain, foreign body sensation, and photophobia, as well as ocular surface findings including fluorescein and rose bengal scores and tear break-up time (TBUT), partly improved. To further improve the clinical signs and symptoms and decrease chronic inflammation, rebamipide was added to diquafosol. The symptoms, TBUT, and fluorescein and rose bengal scores markedly improved after long-term dual treatment without any side effects for 6 months. Case 2. A 77-year-old woman had OCP-like disease with dry eye. The patient did not improve using the currently available conventional treatments. Next, we use topical rebamipide in addition to conventional treatments. Symptoms including asthenopia, dry-eye sensation, ocular pain, and dull sensation, as well as fluorescein and rose bengal scores and TBUT, partly improved. Specifically, functional visual acuity was markedly improved after commencement of rebamipide. To further improve the clinical signs and symptoms and increase tear film stability and tear film volume, diquafosol was added to rebamipide. The combination of diquafosol and rebamipide worked for the patient. Improvements were seen in several symptoms, fluorescein and rose bengal scores, Schirmer test value, and TBUT without any side effects for 12 months. Long-term treatment with topical rebamipide and diquafosol can improve dry eye

  14. Mediators of the long-term impact of child sexual abuse: perceived stigma, betrayal, powerlessness, and self-blame.

    PubMed

    Coffey, P; Leitenberg, H; Henning, K; Turner, T; Bennett, R T

    1996-05-01

    Using a community sample of 192 adult women who had been sexually abused during childhood, the present study tested the hypothesis that perceived stigma, betrayal, powerlessness, and self-blame mediate the long-term effects of child sexual abuse. A path analysis indicated that the level of psychological distress currently experienced by adult women who had been sexually abused in childhood was mediated by feelings of stigma and self-blame. This result provides partial support for Finkelhor and Browne's (1985) traumagenic dynamics model of child sexual abuse. The limitations of the study are discussed.

  15. Out of place: mediating health and social care in Ontario's long-term care sector.

    PubMed

    Daly, Tamara

    2007-01-01

    The paper discusses two reforms in Ontario's long-term care. The first is the commercialization of home care as a result of the implementation of a "managed competition" delivery model. The second is the Ministry of Health and Long-Term Care's privileging of "health care" over "social care" through changes to which types of home care and home support services receive public funding. It addresses the effects of these reforms on the state–non-profit relationship, and the shifting balance between public funding of health and social care. At a program level, and with few exceptions, homemaking services have been cut from home care, and home support services are more medicalized. With these changes, growing numbers of people no longer eligible to receive publicly funded home care services look for other alternatives: they draw available resources from home support, they draw on family and friend networks, they hire privately and pay out of pocket, they leave home and enter an institution, or they do without.

  16. The Role of Lactate-Mediated Metabolic Coupling between Astrocytes and Neurons in Long-Term Memory Formation

    PubMed Central

    Steinman, Michael Q.; Gao, Virginia; Alberini, Cristina M.

    2016-01-01

    Long-term memory formation, the ability to retain information over time about an experience, is a complex function that affects multiple behaviors, and is an integral part of an individual’s identity. In the last 50 years many scientists have focused their work on understanding the biological mechanisms underlying memory formation and processing. Molecular studies over the last three decades have mostly investigated, or given attention to, neuronal mechanisms. However, the brain is composed of different cell types that, by concerted actions, cooperate to mediate brain functions. Here, we consider some new insights that emerged from recent studies implicating astrocytic glycogen and glucose metabolisms, and particularly their coupling to neuronal functions via lactate, as an essential mechanism for long-term memory formation. PMID:26973477

  17. Long-term Rebamipide and Diquafosol in Two Cases of Immune-Mediated Dry Eye

    PubMed Central

    Yamane, Mio; Ogawa, Yoko; Fukui, Masaki; Kamoi, Mizuka; Saijo-Ban, Yumiko; Yaguchi, Saori; Mukai, Shin; Kawakita, Tetsuya; Simmura, Shigeto; Tsubota, Kazuo

    2015-01-01

    ABSTRACT Purpose Two new drugs with mucin-inducing and secretion-promotive effects, rebamipide and diquafosol, were recently approved as topical dry-eye treatments. We report two cases in which the long-term use of mucin-inducing eye drops improved chronic ocular graft-versus-host disease (cGVHD)–related dry eye and ocular cicatricial pemphigoid (OCP)-like disease. Case Reports Case 1. A 61-year-old woman had cGVHD-related dry eye that resisted traditional medications. Next, we use topical diquafosol in addition to conventional treatments. The patient used diquafosol for 6 months without experiencing any side effects. The symptoms, including dry-eye sensation, ocular pain, foreign body sensation, and photophobia, as well as ocular surface findings including fluorescein and rose bengal scores and tear break-up time (TBUT), partly improved. To further improve the clinical signs and symptoms and decrease chronic inflammation, rebamipide was added to diquafosol. The symptoms, TBUT, and fluorescein and rose bengal scores markedly improved after long-term dual treatment without any side effects for 6 months. Case 2. A 77-year-old woman had OCP-like disease with dry eye. The patient did not improve using the currently available conventional treatments. Next, we use topical rebamipide in addition to conventional treatments. Symptoms including asthenopia, dry-eye sensation, ocular pain, and dull sensation, as well as fluorescein and rose bengal scores and TBUT, partly improved. Specifically, functional visual acuity was markedly improved after commencement of rebamipide. To further improve the clinical signs and symptoms and increase tear film stability and tear film volume, diquafosol was added to rebamipide. The combination of diquafosol and rebamipide worked for the patient. Improvements were seen in several symptoms, fluorescein and rose bengal scores, Schirmer test value, and TBUT without any side effects for 12 months. Conclusions Long-term treatment with topical

  18. Upregulation of CREB-mediated transcription enhances both short- and long-term memory.

    PubMed

    Suzuki, Akinobu; Fukushima, Hotaka; Mukawa, Takuya; Toyoda, Hiroki; Wu, Long-Jun; Zhao, Ming-Gao; Xu, Hui; Shang, Yuze; Endoh, Kengo; Iwamoto, Taku; Mamiya, Nori; Okano, Emiko; Hasegawa, Shunsuke; Mercaldo, Valentina; Zhang, Yue; Maeda, Ryouta; Ohta, Miho; Josselyn, Sheena A; Zhuo, Min; Kida, Satoshi

    2011-06-15

    Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity. These transgenic lines improved not only LTM but also long-lasting long-term potentiation in the CA1 area in the hippocampus. However, we also observed enhanced short-term memory (STM) in contextual fear-conditioning and social recognition tasks. Enhanced LTM and STM could be dissociated behaviorally in these four lines of transgenic mice, suggesting that the underlying mechanism for enhanced STM and LTM are distinct. LTM enhancement seems to be attributable to the improvement of memory consolidation by the upregulation of CREB transcriptional activity, whereas higher basal levels of BDNF, a CREB target gene, predicted enhanced shorter-term memory. The importance of BDNF in STM was verified by microinfusing BDNF or BDNF inhibitors into the hippocampus of wild-type or transgenic mice. Additionally, increasing BDNF further enhanced LTM in one of the lines of transgenic mice that displayed a normal BDNF level but enhanced LTM, suggesting that upregulation of BDNF and CREB activity cooperatively enhances LTM formation. Our findings suggest that CREB positively regulates memory consolidation and affects memory performance by regulating BDNF expression.

  19. Long-term fasting decreases mitochondrial avian UCP-mediated oxygen consumption in hypometabolic king penguins

    PubMed Central

    Rey, Benjamin; Halsey, Lewis G.; Dolmazon, Virginie; Rouanet, Jean-Louis; Roussel, Damien; Handrich, Yves; Butler, Patrick J.; Duchamp, Claude

    2008-01-01

    In endotherms, regulation of the degree of mitochondrial coupling affects cell metabolic efficiency. Thus it may be a key contributor to minimizing metabolic rate during long periods of fasting. The aim of the present study was to investigate whether variation in mitochondrial avian uncoupling proteins (avUCP), as putative regulators of mitochondrial oxidative phosphorylation, may contribute to the ability of king penguins (Aptenodytes patagonicus) to withstand fasting for several weeks. After 20 days of fasting, king penguins showed a reduced rate of whole animal oxygen consumption (V̇o2; −33%) at rest, together with a reduced abundance of avUCP and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1-α) mRNA in pectoralis muscle (−54%, −36%, respectively). These parameters were restored after the birds had been refed for 3 days. Furthermore, in recently fed, but not in fasted penguins, isolated muscle mitochondria showed a guanosine diphosphate-inhibited, fatty acid plus superoxide-activated respiration, indicating the presence of a functional UCP. It was calculated that variation in mitochondrial UCP-dependent respiration in vitro may contribute to nearly 20% of the difference in resting V̇o2 between fed or refed penguins and fasted penguins measured in vivo. These results suggest that the lowering of avUCP activity during periods of long-term energetic restriction may contribute to the reduction in metabolic rate and hence the ability of king penguins to face prolonged periods of fasting. PMID:18495832

  20. Long-term fasting decreases mitochondrial avian UCP-mediated oxygen consumption in hypometabolic king penguins.

    PubMed

    Rey, Benjamin; Halsey, Lewis G; Dolmazon, Virginie; Rouanet, Jean-Louis; Roussel, Damien; Handrich, Yves; Butler, Patrick J; Duchamp, Claude

    2008-07-01

    In endotherms, regulation of the degree of mitochondrial coupling affects cell metabolic efficiency. Thus it may be a key contributor to minimizing metabolic rate during long periods of fasting. The aim of the present study was to investigate whether variation in mitochondrial avian uncoupling proteins (avUCP), as putative regulators of mitochondrial oxidative phosphorylation, may contribute to the ability of king penguins (Aptenodytes patagonicus) to withstand fasting for several weeks. After 20 days of fasting, king penguins showed a reduced rate of whole animal oxygen consumption (Vo2; -33%) at rest, together with a reduced abundance of avUCP and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1-alpha) mRNA in pectoralis muscle (-54%, -36%, respectively). These parameters were restored after the birds had been refed for 3 days. Furthermore, in recently fed, but not in fasted penguins, isolated muscle mitochondria showed a guanosine diphosphate-inhibited, fatty acid plus superoxide-activated respiration, indicating the presence of a functional UCP. It was calculated that variation in mitochondrial UCP-dependent respiration in vitro may contribute to nearly 20% of the difference in resting Vo2 between fed or refed penguins and fasted penguins measured in vivo. These results suggest that the lowering of avUCP activity during periods of long-term energetic restriction may contribute to the reduction in metabolic rate and hence the ability of king penguins to face prolonged periods of fasting.

  1. The Hidden Complexity of Long-Term Care: how context mediates knowledge translation and use of best practices.

    PubMed

    Cammer, Allison; Morgan, Debra; Stewart, Norma; McGilton, Katherine; Rycroft-Malone, Jo; Dopson, Sue; Estabrooks, Carole

    2014-12-01

    Context is increasingly recognized as a key factor to be considered when addressing healthcare practice. This study describes features of context as they pertain to knowledge use in long-term care (LTC). As one component of the research program Translating Research in Elder Care, an in-depth qualitative case study was conducted to examine the research question "How does organizational context mediate the use of knowledge in practice in long-term care facilities?" A representative facility was chosen from the province of Saskatchewan, Canada. Data included document review, direct observation of daily care practices, and interviews with direct care, allied provider, and administrative staff. The Hidden Complexity of Long-Term Care model consists of 8 categories that enmesh to create a context within which knowledge exchange and best practice are executed. These categories range from the most easily identifiable to the least observable: physical environment, resources, ambiguity, flux, relationships, and philosophies. Two categories (experience and confidence, leadership and mentoring) mediate the impact of other contextual factors. Inappropriate physical environments, inadequate resources, ambiguous situations, continual change, multiple relationships, and contradictory philosophies make for a complicated context that impacts care provision. A hidden complexity underlays healthcare practices in LTC and each care provider must negotiate this complexity when providing care. Attending to this complexity in which care decisions are made will lead to improvements in knowledge exchange mechanisms and best practice uptake in LTC settings. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Long-Term Follow-up of Foamy Viral Vector-Mediated Gene Therapy for Canine Leukocyte Adhesion Deficiency

    PubMed Central

    Bauer, Thomas R; Tuschong, Laura M; Calvo, Katherine R; Shive, Heather R; Burkholder, Tanya H; Karlsson, Eleanor K; West, Robert R; Russell, David W; Hickstein, Dennis D

    2013-01-01

    The development of leukemia following gammaretroviral vector-mediated gene therapy for X-linked severe combined immunodeficiency disease and chronic granulomatous disease (CGD) has emphasized the need for long-term follow-up in animals treated with hematopoietic stem cell gene therapy. In this study, we report the long-term follow-up (4–7 years) of four dogs with canine leukocyte adhesion deficiency (CLAD) treated with foamy viral (FV) vector-mediated gene therapy. All four CLAD dogs previously received nonmyeloablative conditioning with 200 cGy total body irradiation followed by infusion of autologous, CD34+ hematopoietic stem cells transduced by a FV vector expressing canine CD18 from an internal Murine Stem Cell Virus (MSCV) promoter. CD18+ leukocyte levels were >2% following infusion of vector-transduced cells leading to ongoing reversal of the CLAD phenotype for >4 years. There was no clinical development of lymphoid or myeloid leukemia in any of the four dogs and integration site analysis did not reveal insertional oncogenesis. These results showing disease correction/amelioration of disease in CLAD without significant adverse events provide support for the use of a FV vector to treat children with leukocyte adhesion deficiency type 1 (LAD-1) in a human gene therapy clinical trial. PMID:23531552

  3. Parenting and Family Stress as Mediators of the Long-Term Effects of Child Abuse.

    ERIC Educational Resources Information Center

    Wind, Tiffany Weissmann; Silvern, Louise

    1994-01-01

    Data on child physical/sexual abuse, family stress histories, perceived parental warmth, and current psychological functioning were gathered from 259 working women. Multiple regression analyses showed that parental warmth strongly influenced or mediated the relationship of intrafamilial child abuse to depression and self-esteem levels. However,…

  4. Layer-specific endocannabinoid-mediated long-term depression of GABAergic neurotransmission onto principal neurons in mouse visual cortex.

    PubMed

    Sun, Wenjuan; Wang, Laijian; Li, Shuo; Tie, Xiaoxiu; Jiang, Bin

    2015-08-01

    Visually induced endocannabinoid-mediated long-term depression of GABAergic neurotransmission (iLTD) mediates the maturation of GABAergic release in layer 2/3 of visual cortex. Here we examined whether the maturation of GABAergic transmission in other layers of visual cortex also requires endocannabinoids. The developmental plasticity of GABAergic neurotransmission onto the principal neurons in different layers of mouse visual cortex was examined in cortical slices by whole-cell recordings of inhibitory postsynaptic currents evoked by presynaptic inhibitory inputs. Theta burst stimulation of GABAergic inputs induced an endocannabinoid-mediated long-term depression of GABAergic neurotransmission onto pyramidal cells in layer 2/3 from postnatal day (P)10 to 30 and in layer 5 from P10 to 40, whereas that of GABAergic inputs did not induce iLTD onto star pyramidal neurons in layer 4 at any time postnatally, indicating that this plasticity is laminar-specific. The developmental loss of iLTD paralleled the maturation of GABAergic inhibition in both layer 2/3 and layer 5. Visual deprivation delayed the developmental loss of iLTD in layers 3 and 5 during a critical period, while 2 days of light exposure eliminated iLTD in both layers. Furthermore, the GABAergic synapses in layers 2/3 and 5 did not normally mature in the type 1 cannabinoid receptor knock-out mice, whereas those in layer 4 did not require endocannabinoid receptor for maturation. These results suggest that visually induced endocannabinoid-dependent iLTD mediates the maturation of GABAergic release in extragranular layer rather than in granular layer of mouse visual cortex.

  5. Apical Organelle Secretion by Toxoplasma Controls Innate and Adaptive Immunity and Mediates Long-Term Protection.

    PubMed

    Sloves, Pierre-Julien; Mouveaux, Thomas; Ait-Yahia, Saliha; Vorng, Han; Everaere, Laetitia; Sangare, Lamba Omar; Tsicopoulos, Anne; Tomavo, Stanislas

    2015-11-01

    Apicomplexan parasites have unique apical rhoptry and microneme secretory organelles that are crucial for host infection, although their role in protection against Toxoplasma gondii infection is not thoroughly understood. Here, we report a novel function of the endolysosomal T. gondii sortilin-like receptor (TgSORTLR), which mediates trafficking to functional apical organelles and their subsequent secretion of virulence factors that are critical to the induction of sterile immunity against parasite reinfection. We further demonstrate that the T. gondii armadillo repeats-only protein (TgARO) mutant, which is deficient only in apical secretion of rhoptries, is also critical in mounting protective immunity. The lack of TgSORTLR and TgARO proteins completely inhibited T-helper 1-dependent adaptive immunity and compromised the function of natural killer T-cell-mediated innate immunity. Our findings reveal an essential role for apical secretion in promoting sterile protection against T. gondii and provide strong evidence for rhoptry-regulated discharge of antigens as a key effector for inducing protective immunity.

  6. Parenting and family stress as mediators of the long-term effects of child abuse.

    PubMed

    Wind, T W; Silvern, L

    1994-05-01

    Child abuse is known to be associated with a variety of adult psychological difficulties. However, the level and types of such difficulties may be influenced by variation in other nonabusive aspects of the child-rearing context. This study examines whether variation in perceived parental warmth and in nonabusive family stressors influenced the strength of relationships of women's psychological difficulties to their childhood sexual and/or physical abuse. Child abuse, family stress histories, and perceived parental warmth, as well as current psychological functioning was gathered from a community sample of 259 working women. Perceived parental warmth, childhood stress, and abuse were each separately associated with current functioning. However, as expected, multiple regression analyses showed that parental warmth strongly influenced or mediated the relationship of intrafamilial child abuse to depression and self-esteem levels. In contrast, abuse was associated to PTSD independently of variation in perceived parenting. Finally, parenting mediated initial relationships of childhood stress to each of the adjustment measures. The Discussion focuses on the possibility that there may be several developmental pathways that lead to the array of symptoms associated with child abuse. Some symptoms, such as PTSD, may be most influenced by the abuse itself, while others, such as depression, and low self-esteem may be more impacted by lack of parental warmth. Treatment implications are discussed.

  7. Long-term T-cell-mediated immunologic memory to hepatitis B vaccine in young adults following neonatal vaccination.

    PubMed

    Saffar, Hiva; Saffar, Mohammed Jafar; Ajami, Abolghasem; Khalilian, Ali Reza; Shams-Esfandabad, Kian; Mirabi, Araz Mohammad

    2014-09-01

    The long-term duration of cell-mediated immunity induced by neonatal hepatitis B virus (HBV) vaccination is unknown. Study was designed to determine the cellular immunity memory status among young adults twenty years after infantile HB immunization. Study subjects were party selected from a recent seroepidemiologic study in young adults, who had been vaccinated against HBV twenty years earlier. Just before and ten to 14 days after one dose of HBV vaccine booster injection, blood samples were obtained and sera concentration of cytokines (interleukin 2 and interferon) was measured. More than twofold increase after boosting was considered positive immune response. With regard to the serum level of antibody against HBV surface antigen (HBsAb) before boosting, the subjects were divided into four groups as follow: GI, HBsAb titer < 2; GII, titer 2 to 9.9; GIII, titer 10 to 99; and GIV, titers ≥ 100 IU/L. Mean concentration level (MCL) of each cytokines for each group at preboosting and postboosting and the proportion of responders in each groups were determined. Paired descriptive statistical analysis method (t test) was used to compare the MCL of each cytokines in each and between groups and the frequency of responders in each group. Before boosting, among 176 boosted individuals, 75 (42.6%) had HBsAb 10 IU/L and were considered seroprotected. Among 101 serosusceptible persons, more than 80% of boosted individuals showed more than twofold increase in cytokines concentration, which meant positive HBsAg-specific cell-mediated immunity. MCL of both cytokines after boosting in GIV were decreased more than twofold, possibly because of recent natural boosting. Findings showed that neonatal HBV immunization was efficacious in inducing long-term immunity and cell-mediated immune memory for up to two decades, and booster vaccination are not required. Further monitoring of vaccinated subjects for HBV infections are recommended.

  8. Long-Term T-Cell-Mediated Immunologic Memory to Hepatitis B Vaccine in Young Adults Following Neonatal Vaccination.

    PubMed Central

    Saffar, Hiva; Saffar, Mohammed Jafar; Ajami, Abolghasem; Khalilian, Ali Reza; Shams-Esfandabad, Kian; Mirabi, Araz Mohammad

    2014-01-01

    Background: The long-term duration of cell-mediated immunity induced by neonatal hepatitis B virus (HBV) vaccination is unknown. Objectives: Study was designed to determine the cellular immunity memory status among young adults twenty years after infantile HB immunization. Patients and Methods: Study subjects were party selected from a recent seroepidemiologic study in young adults, who had been vaccinated against HBV twenty years earlier. Just before and ten to 14 days after one dose of HBV vaccine booster injection, blood samples were obtained and sera concentration of cytokines (interleukin 2 and interferon) was measured. More than twofold increase after boosting was considered positive immune response. With regard to the serum level of antibody against HBV surface antigen (HBsAb) before boosting, the subjects were divided into four groups as follow: GI, HBsAb titer < 2; GII, titer 2 to 9.9; GIII, titer 10 to 99; and GIV, titers ≥ 100 IU/L. Mean concentration level (MCL) of each cytokines for each group at preboosting and postboosting and the proportion of responders in each groups were determined. Paired descriptive statistical analysis method (t test) was used to compare the MCL of each cytokines in each and between groups and the frequency of responders in each group. Results: Before boosting, among 176 boosted individuals, 75 (42.6%) had HBsAb 10 IU/L and were considered seroprotected. Among 101 serosusceptible persons, more than 80% of boosted individuals showed more than twofold increase in cytokines concentration, which meant positive HBsAg-specific cell-mediated immunity. MCL of both cytokines after boosting in GIV were decreased more than twofold, possibly because of recent natural boosting. Conclusions: Findings showed that neonatal HBV immunization was efficacious in inducing long-term immunity and cell-mediated immune memory for up to two decades, and booster vaccination are not required. Further monitoring of vaccinated subjects for HBV infections

  9. Morphogenetic and chemical stability of long-term maintained Agrobacterium-mediated transgenic Catharanthus roseus plants.

    PubMed

    Verma, Priyanka; Sharma, Abhishek; Khan, Shamshad Ahmad; Mathur, Ajay Kumar; Shanker, Karuna

    2015-01-01

    Transgenic Catharanthus roseus plants (transgenic Dhawal [DT] and transgenic Nirmal [NT]) obtained from the Agrobacterium tumefaciens and Agrobacterium rhizognenes-mediated transformations, respectively, have been maintained in vitro for 5 years. Plants were studied at regular intervals for various parameters such as plant height, leaf size, multiplication rate, alkaloid profile and presence of marker genes. DT plant gradually lost the GUS gene expression and it was not detected in the fifth year while NT plant demonstrated the presence of genes rolA, rolB and rolC even in the fifth year, indicating the more stable nature of Ri transgene. Vindoline content in the DT was two times more than in non-transformed control plants. Alkaloid and tryptophan profiles were almost constant during the 5 years. The cluster analysis revealed that the DT plant is more close to the control Nirmal plant followed by NT plant.

  10. Dose optimization for long-term rAAV-mediated RNA interference in the nigrostriatal projection neurons.

    PubMed

    Ulusoy, Ayse; Sahin, Gurdal; Björklund, Tomas; Aebischer, Patrick; Kirik, Deniz

    2009-09-01

    Short-hairpin RNA (shRNA)-mediated gene knockdown is a powerful tool for targeted gene silencing and an emerging novel therapeutic strategy. Recent publications, however, reported unexpected toxicity after utilizing viral-mediated shRNA knockdown in vivo. Thus, it is currently unclear whether shRNA-mediated knockdown strategy can be used as a safe and efficient tool for gene silencing. In this study, we have generated rAAV vectors expressing shRNAs targeting the rat tyrosine hydroxylase (TH) mRNA (shTH) for testing the efficacy of in vivo TH knockdown in the nigral dopaminergic neurons. At high titers, not only the shTH vectors but also the scrambled and green fluorescence protein (GFP)-only controls caused cell death. In a dose-response study, we identified a dose window leading to >60% decrease in TH(+) neurons without any change in vesicular monoamine transporter-2 (VMAT2) expression. Moreover, using the safe and efficient dose, we showed that dopamine (DA) synthesis rate was significantly reduced and this lead to emergence of motor deficits in the shTH-expressing rats. Interestingly, these animals showed very robust and long-lasting recovery after a single systemic L-3,4-dihydroxyphenylalanine (L-DOPA) administration beyond what can be achieved in 6-hydroxydopamine (6-OHDA)-lesioned rats. Our results have implications for both mechanistic and therapeutic studies utilizing long-term shRNA-mediated gene silencing in the nigrostriatal projection system.

  11. Ethanol Acutely Inhibits Ionotropic Glutamate Receptor-mediated Responses and Long-Term Potentiation in the Developing CA1 Hippocampus

    PubMed Central

    Puglia, Michael P.; Valenzuela, C. Fernando

    2011-01-01

    Background Developmental ethanol (EtOH) exposure damages the hippocampus, causing long-lasting alterations in learning and memory. Alterations in glutamatergic synaptic transmission and plasticity may play a role in the mechanism of action of EtOH. This signaling is fundamental for synaptogenesis, which occurs during the third-trimester of human pregnancy (first 12 days of life in rats). Methods Acute coronal brain slices were prepared from 7–9 day-old rats. Extracellular and patch-clamp electrophysiological recording techniques were used to characterize the acute effects of EtOH on α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated responses and long-term potentiation (LTP) in the CA1 hippocampal region. Results EtOH (40 and 80 mM) inhibited AMPAR- and NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs). EtOH (80 mM) also reduced AMPAR-mediated fEPSPs in presence of an inhibitor of Ca2+ permeable AMPARs. The effect of 80 mM EtOH on NMDAR-mediated fEPSPs was significantly greater in presence of Mg2+. EtOH (80 mM) neither affected the paired-pulse ratio of AMPAR-mediated fEPSPs nor the presynaptic volley. The paired-pulse ratio of AMPAR-mediated excitatory postsynaptic currents was not affected either, and the amplitude of these currents was inhibited to a lesser extent than that of fEPSPs. EtOH (80 mM) inhibited LTP of AMPAR-mediated fEPSPs. Conclusions Acute EtOH exposure during the third-trimester equivalent of human pregnancy inhibits hippocampal glutamatergic transmission and LTP induction, which could alter synapse refinement and ultimately contribute to the pathophysiology of fetal alcohol spectrum disorder. PMID:20102565

  12. Natural Killer T Cell-Targeted Immunotherapy Mediating Long-term Memory Responses and Strong Antitumor Activity.

    PubMed

    Dashtsoodol, Nyambayar; Shigeura, Tomokuni; Tashiro, Takuya; Aihara, Minako; Chikanishi, Toshihiro; Okada, Hiromi; Hanada, Keigo; Sano, Hirokazu; Kurogi, Akihiko; Taniguchi, Masaru

    2017-01-01

    Current tumor therapies, including immunotherapies, focus on passive eradication or at least reduction of the tumor mass. However, cancer patients quite often suffer from tumor relapse or metastasis after such treatments. To overcome these problems, we have developed a natural killer T (NKT) cell-targeted immunotherapy focusing on active engagement of the patient's immune system, but not directly targeting the tumor cells themselves. NKT cells express an invariant antigen receptor α chain encoded by Trav11 (Vα14)-Traj18 (Jα18) gene segments in mice and TRAV10 (Vα24)-TRAJ18 (Jα18) in humans and recognize glycolipid ligand in conjunction with a monomorphic CD1d molecule. The NKT cells play a pivotal role in the orchestration of antitumor immune responses by mediating adjuvant effects that activate various antitumor effector cells of both innate and adaptive immune systems and also aid in establishing a long-term memory response. Here, we established NKT cell-targeted therapy using a newly discovered NKT cell glycolipid ligand, RK, which has a stronger capacity to stimulate both human and mouse NKT cells compared to previous NKT cell ligand. Moreover, RK mediates strong adjuvant effects in activating various effector cell types and establishes long-term memory responses, resulting in the continuous attack on the tumor that confers long-lasting and potent antitumor effects. Since the NKT cell ligand presented by the monomorphic CD1d can be used for all humans irrespective of HLA types, and also because NKT cell-targeted therapy does not directly target tumor cells, this therapy can potentially be applied to all cancer patients and any tumor types.

  13. The mediating effects of depressive symptoms on nutritional status of older adults in long-term care facilities.

    PubMed

    Li, I-C; Kuo, H-T; Lin, Y-C

    2013-07-01

    To test whether depressive symptoms mediate the effects of activities of daily living (ADLs) on nutritional status of older adults living in long-term care (LTC) facilities in Taiwan. A cross-sectional study. Seventy-three community-based LTC facilities in northern Taiwan. This study sampled 306 adults ranging in age from 65 to 97 years who were free of acute infection or disease and who were able to communicate. Nutritional status was assessed by the Mini-Nutritional Assessment (MNA) scale and depressive symptoms were assessed by the short form of the Geriatric Depressive Scale (GDS-SF). MNA scores revealed that 65% of the subjects were at risk for malnutrition (17 to 23.5 points). In addition, depressive symptoms partially mediated the relationship between ADLs and nutritional status, with 10.7% of the effect of depressive symptoms on nutritional status going through the mediator. Interventions to reduce depressive symptoms among institutionalized older adults should focus on improving nutritional status rather than promoting ADLs, which are believed to be difficult to change.

  14. Administration of memantine during ethanol withdrawal in neonatal rats: effects on long-term ethanol-induced motor incoordination and cerebellar Purkinje cell loss.

    PubMed

    Idrus, Nirelia M; McGough, Nancy N H; Riley, Edward P; Thomas, Jennifer D

    2011-02-01

    Alcohol consumption during pregnancy can damage the developing fetus, illustrated by central nervous system dysfunction and deficits in motor and cognitive abilities. Binge drinking has been associated with an increased risk of fetal alcohol spectrum disorders, likely due to increased episodes of ethanol withdrawal. We hypothesized that overactivity of the N-methyl-D-aspartate (NMDA) receptor during ethanol withdrawal leads to excitotoxic cell death in the developing brain. Consistent with this, administration of NMDA receptor antagonists (e.g., MK-801) during withdrawal can attenuate ethanol's teratogenic effects. The aim of this study was to determine whether administration of memantine, an NMDA receptor antagonist, during ethanol withdrawal could effectively attenuate ethanol-related deficits, without the adverse side effects associated with other NMDA receptor antagonists. Sprague-Dawley pups were exposed to 6.0 g/kg ethanol or isocaloric maltose solution via intubation on postnatal day 6, a period of brain development equivalent to a portion of the 3rd trimester. Twenty-four and 36 hours after ethanol, subjects were injected with 0, 10, or 15 mg/kg memantine, totaling doses of 0, 20, or 30 mg/kg. Motor coordination was tested on a parallel bar task and the total number of cerebellar Purkinje cells was estimated using unbiased stereology. Alcohol exposure induced significant parallel bar motor incoordination and reduced Purkinje cell number. Memantine administration significantly attenuated both ethanol-associated motor deficits and cerebellar cell loss in a dose-dependent manner. Memantine was neuroprotective when administered during ethanol withdrawal. These data provide further support that ethanol withdrawal contributes to fetal alcohol spectrum disorders. Copyright © 2010 by the Research Society on Alcoholism.

  15. Endocannabinoids Mediate Muscarinic Acetylcholine Receptor-Dependent Long-Term Depression in the Adult Medial Prefrontal Cortex.

    PubMed

    Martin, Henry G S; Bernabeu, Axel; Lassalle, Olivier; Bouille, Clément; Beurrier, Corinne; Pelissier-Alicot, Anne-Laure; Manzoni, Olivier J

    2015-01-01

    Cholinergic inputs into the prefrontal cortex (PFC) are associated with attention and cognition; however there is evidence that acetylcholine also has a role in PFC dependent learning and memory. Muscarinic acetylcholine receptors (mAChR) in the PFC can induce synaptic plasticity, but the underlying mechanisms remain either opaque or unresolved. We have characterized a form of mAChR mediated long-term depression (LTD) at glutamatergic synapses of layer 5 principal neurons in the adult medial PFC. This mAChR LTD is induced with the mAChR agonist carbachol and inhibited by selective M1 mAChR antagonists. In contrast to other cortical regions, we find that this M1 mAChR mediated LTD is coupled to endogenous cannabinoid (eCB) signaling. Inhibition of the principal eCB CB1 receptor blocked carbachol induced LTD in both rats and mice. Furthermore, when challenged with a sub-threshold carbachol application, LTD was induced in slices pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184, suggesting that the eCB 2-arachidonylglyerol (2-AG) mediates M1 mAChR LTD. Yet, when endogenous acetylcholine was released from local cholinergic afferents in the PFC using optogenetics, it failed to trigger eCB-LTD. However coupling patterned optical and electrical stimulation to generate local synaptic signaling allowed the reliable induction of LTD. The light-electrical pairing induced LTD was M1 mAChR and CB1 receptor mediated. This shows for the first time that connecting excitatory synaptic activity with coincident endogenously released acetylcholine controls synaptic gain via eCB signaling. Together these results shed new light on the mechanisms of synaptic plasticity in the adult PFC and expand on the actions of endogenous cholinergic signaling.

  16. Dose Optimization for Long-term rAAV-mediated RNA Interference in the Nigrostriatal Projection Neurons

    PubMed Central

    Ulusoy, Ayse; Sahin, Gurdal; Björklund, Tomas; Aebischer, Patrick; Kirik, Deniz

    2009-01-01

    Short-hairpin RNA (shRNA)–mediated gene knockdown is a powerful tool for targeted gene silencing and an emerging novel therapeutic strategy. Recent publications, however, reported unexpected toxicity after utilizing viral-mediated shRNA knockdown in vivo. Thus, it is currently unclear whether shRNA-mediated knockdown strategy can be used as a safe and efficient tool for gene silencing. In this study, we have generated rAAV vectors expressing shRNAs targeting the rat tyrosine hydroxylase (TH) mRNA (shTH) for testing the efficacy of in vivo TH knockdown in the nigral dopaminergic neurons. At high titers, not only the shTH vectors but also the scrambled and green fluorescence protein (GFP)–only controls caused cell death. In a dose–response study, we identified a dose window leading to >60% decrease in TH+ neurons without any change in vesicular monoamine transporter-2 (VMAT2) expression. Moreover, using the safe and efficient dose, we showed that dopamine (DA) synthesis rate was significantly reduced and this lead to emergence of motor deficits in the shTH-expressing rats. Interestingly, these animals showed very robust and long-lasting recovery after a single systemic L-3,4-dihydroxyphenylalanine (L-DOPA) administration beyond what can be achieved in 6-hydroxydopamine (6-OHDA)–lesioned rats. Our results have implications for both mechanistic and therapeutic studies utilizing long-term shRNA-mediated gene silencing in the nigrostriatal projection system. PMID:19584816

  17. Endocannabinoids Mediate Muscarinic Acetylcholine Receptor-Dependent Long-Term Depression in the Adult Medial Prefrontal Cortex

    PubMed Central

    Martin, Henry G. S.; Bernabeu, Axel; Lassalle, Olivier; Bouille, Clément; Beurrier, Corinne; Pelissier-Alicot, Anne-Laure; Manzoni, Olivier J.

    2015-01-01

    Cholinergic inputs into the prefrontal cortex (PFC) are associated with attention and cognition; however there is evidence that acetylcholine also has a role in PFC dependent learning and memory. Muscarinic acetylcholine receptors (mAChR) in the PFC can induce synaptic plasticity, but the underlying mechanisms remain either opaque or unresolved. We have characterized a form of mAChR mediated long-term depression (LTD) at glutamatergic synapses of layer 5 principal neurons in the adult medial PFC. This mAChR LTD is induced with the mAChR agonist carbachol and inhibited by selective M1 mAChR antagonists. In contrast to other cortical regions, we find that this M1 mAChR mediated LTD is coupled to endogenous cannabinoid (eCB) signaling. Inhibition of the principal eCB CB1 receptor blocked carbachol induced LTD in both rats and mice. Furthermore, when challenged with a sub-threshold carbachol application, LTD was induced in slices pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184, suggesting that the eCB 2-arachidonylglyerol (2-AG) mediates M1 mAChR LTD. Yet, when endogenous acetylcholine was released from local cholinergic afferents in the PFC using optogenetics, it failed to trigger eCB-LTD. However coupling patterned optical and electrical stimulation to generate local synaptic signaling allowed the reliable induction of LTD. The light—electrical pairing induced LTD was M1 mAChR and CB1 receptor mediated. This shows for the first time that connecting excitatory synaptic activity with coincident endogenously released acetylcholine controls synaptic gain via eCB signaling. Together these results shed new light on the mechanisms of synaptic plasticity in the adult PFC and expand on the actions of endogenous cholinergic signaling. PMID:26648844

  18. Serotonin-mediated synapsin expression is necessary for long-term facilitation of the Aplysia sensorimotor synapse.

    PubMed

    Hart, Anne K; Fioravante, Diasinou; Liu, Rong-Yu; Phares, Gregg A; Cleary, Leonard J; Byrne, John H

    2011-12-14

    Serotonin (5-HT)-induced long-term facilitation (LTF) of the Aplysia sensorimotor synapse depends on enhanced gene expression and protein synthesis, but identification of the genes whose expression and regulation are necessary for LTF remains incomplete. In this study, we found that one such gene is synapsin, which encodes a synaptic vesicle-associated protein known to regulate short-term synaptic plasticity. Both synapsin mRNA and protein levels were increased by 5-HT. Upregulation of synapsin protein occurred in presynaptic sensory neurons at neurotransmitter release sites. To investigate the molecular mechanisms underlying synapsin regulation, we cloned the promoter region of Aplysia synapsin, and found that the synapsin promoter contained a cAMP response element (CRE), raising the possibility that the transcriptional activator CRE-binding protein 1 (CREB1) mediates 5-HT-induced regulation of synapsin. Indeed, binding of CREB1 to the synapsin promoter was increased following treatment with 5-HT. Furthermore, increased acetylation of histones H3 and H4 and decreased association of histone deacetylase 5 near the CRE site are consistent with transcriptional activation by CREB1. RNA interference (RNAi) targeting synapsin mRNA blocked the 5-HT-induced increase in synapsin protein levels and LTF; in the absence of 5-HT treatment, basal synapsin levels were unaffected. These results indicate that the 5-HT-induced regulation of synapsin levels is necessary for LTF and that this regulation is part of the cascade of synaptic events involved in the consolidation of memory.

  19. Endocannabinoid-mediated long-term depression of afferent excitatory synapses in hippocampal pyramidal cells and GABAergic interneurons.

    PubMed

    Péterfi, Zoltán; Urbán, Gabriella M; Papp, Orsolya I; Németh, Beáta; Monyer, Hannah; Szabó, Gábor; Erdélyi, Ferenc; Mackie, Ken; Freund, Tamás F; Hájos, Norbert; Katona, István

    2012-10-10

    Although endocannabinoids have emerged as essential retrograde messengers in several forms of synaptic plasticity, it remains controversial whether they mediate long-term depression (LTD) of glutamatergic synapses onto excitatory and inhibitory neurons in the hippocampus. Here, we show that parvalbumin- and somatostatin/metabotropic glutamate receptor 1(a) (mGlu(1a))-positive GABAergic interneurons express diacylglycerol lipase-α (DGL-α), a synthesizing enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), albeit at lower levels than principal cells. Moreover, this lipase accumulates postsynaptically around afferent excitatory synapses in all three cell types. To address the role of retrograde 2-AG signaling in LTD, we investigated two forms: (1) produced by postsynaptic spiking paired with subsequent presynaptic stimulation or (2) induced by group I mGlu activation by (S)-3,5-dihydroxyphenylglycine (DHPG). Neither form of LTD was evoked in the presence of the mGlu(5) antagonist MPEP [2-methyl-6-(phenylethynyl)-pyridine], the DGL inhibitor THL [N-formyl-l-leucine (1S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester], or the intracellularly applied Ca(2+) chelator BAPTA in CA1 pyramidal cells, fast-spiking interneurons (representing parvalbumin-containing cells) and interneurons projecting to stratum lacunosum-moleculare (representing somatostatin/mGlu(1a)-expressing interneurons). Both forms of LTD were completely absent in CB(1) cannabinoid receptor knock-out mice, whereas pharmacological blockade of CB(1) led to inconsistent results. Notably, in accordance with their lower DGL-α level, a higher stimulation frequency or higher DHPG concentration was required for LTD induction in interneurons compared with pyramidal cells. These findings demonstrate that hippocampal principal cells and interneurons produce endocannabinoids to mediate LTD in a qualitatively similar, but quantitatively different manner. The shifted induction threshold implies that

  20. Can individual conditions during childhood mediate or moderate the long-term cognitive effects of poor economic environments at birth?

    PubMed

    Fritze, Thomas; Doblhammer, Gabriele; van den Berg, Gerard J

    2014-10-01

    Recent analyses revealed that the business cycle at the time of birth influences cognitive functioning at older ages, and that those individuals born during economic boom periods on average display better cognitive functioning later in life. The current study examines the impact of childhood conditions on late-life cognitive functioning and investigates whether they mediate or moderate the effects of the business cycle at the time of birth. The underlying purpose is to find potential starting points for societal interventions that may counterbalance the negative long-term outcomes of adverse living conditions early in life. We use data from 7935 respondents at ages 60+ in eleven European countries from the first three waves of the Survey of Health, Ageing and Retirement in Europe (SHARE). The survey data was collected in 2004, 2006/07, and 2008/09. Country fixed-effects models are used to examine the impact of macro-economic deviations in the year of birth and the indicators of childhood circumstances on late-life cognitive functioning. This study shows that the effects of boom and recession periods at birth are not simply mediated or moderated by living conditions during childhood. Conditions at birth have biological long-run effects on late-life cognitive functioning. Individuals born during boom periods display signs of having better cognitive functioning later in life, whereas recessions negatively influence cognition. Furthermore, a series of childhood conditions in and of themselves influence late-life cognition. Good childhood cognition, high education as well as a high social status, favourable living arrangements, and good health have a positive impact. Policy interventions should aim at a better access to school or measures to improve the economic and social situations of disadvantaged households. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo

    PubMed Central

    Hu, Neng-Wei; Nicoll, Andrew J.; Zhang, Dainan; Mably, Alexandra J.; O’Malley, Tiernan; Purro, Silvia A.; Terry, Cassandra; Collinge, John; Walsh, Dominic M.; Rowan, Michael J.

    2014-01-01

    NMDA-type glutamate receptors (NMDARs) are currently regarded as paramount in the potent and selective disruption of synaptic plasticity by Alzheimer’s disease amyloid β-protein (Aβ). Non-NMDAR mechanisms remain relatively unexplored. Here we describe how Aβ facilitates NMDAR-independent long-term depression of synaptic transmission in the hippocampus in vivo. Synthetic Aβ and Aβ in soluble extracts of Alzheimer’s disease brain usurp endogenous acetylcholine muscarinic receptor-dependent long-term depression, to enable long-term depression that required metabotropic glutamate-5 receptors (mGlu5Rs). We also find that mGlu5Rs are essential for Aβ-mediated inhibition of NMDAR-dependent long-term potentiation in vivo. Blocking Aβ binding to cellular prion protein with antibodies prevents the facilitation of long-term depression. Our findings uncover an overarching role for Aβ-PrPC-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary. PMID:24594908

  2. Singlet oxygen explicit dosimetry to predict long-term local tumor control for Photofrin-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Penjweini, Rozhin; Kim, Michele M.; Ong, Yi Hong; Zhu, Timothy C.

    2017-02-01

    Although photodynamic therapy (PDT) is an established modality for the treatment of cancer, current dosimetric quantities do not account for the variations in PDT oxygen consumption for different fluence rates (φ). In this study we examine the efficacy of reacted singlet oxygen concentration ([1O2]rx) to predict long-term local control rate (LCR) for Photofrin-mediated PDT. Radiation-induced fibrosarcoma (RIF) tumors in the right shoulders of female C3H mice are treated with different in-air fluences of 225-540 J/cm2 and in-air fluence rate (φair) of 50 and 75 mW/cm2 at 5 mg/kg Photofrin and a drug-light interval of 24 hours using a 1 cm diameter collimated laser beam at 630 nm wavelength. [1O2]rx is calculated by using a macroscopic model based on explicit dosimetry of Photofrin concentration, tissue optical properties, tissue oxygenation and blood flow changes during PDT. The tumor volume of each mouse is tracked for 90 days after PDT and Kaplan-Meier analyses for LCR are performed based on a tumor volume <=100 mm3, for the four dose metrics light fluence, photosensitizer photobleaching rate, PDT dose and [1O2]rx. PDT dose is defined as a temporal integral of photosensitizer concentration and Φ at a 3 mm tumor depth. φ is calculated throughout the treatment volume based on Monte-Carlo simulation and measured tissue optical properties. Our preliminary studies show that [1O2]rx is the best dosimetric quantity that can predict tumor response and correlate with LCR. Moreover, [1O2]rx calculated using the blood flow changes was in agreement with [1O2]rx calculated based on the actual tissue oxygenation.

  3. Singlet oxygen explicit dosimetry to predict long-term local tumor control for BPD-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Kim, Michele M.; Penjweini, Rozhin; Ong, Yi Hong; Zhu, Timothy C.

    2017-02-01

    Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence, photosensitizer photobleaching rate, and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (Φ) effects are not accounted for, which has a large effect on the oxygen consumption rate. In this preclinical study, reacted singlet oxygen [1O2]rx was investigated as a dosimetric quantity for PDT outcome. The ability of [1O2]rx to predict the long-term local tumor control rate (LCR) for BPD-mediated PDT was examined. Mice bearing radioactivelyinduced fibrosarcoma (RIF) tumors were treated with different in-air fluences (250, 300, and 350 J/cm2) and in-air ϕ (75, 100, and150 mW/cm2) with a BPD dose of 1 mg/kg and a drug-light interval of 3 hours. Treatment was delivered with a collimated laser beam of 1 cm diameter at 690 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and BPD concentration was used to calculate [1O2]rx. Φ was calculated for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Kaplan-Meier analyses for LCR were done for an endpoint of tumor volume <= 100 mm3 using four dose metrics: light fluence, photosensitizer photobleaching rate, PDT dose, and [1O2]rx. PDT dose was defined as the product of the timeintegral of photosensitizer concentration and Φ at a 3 mm tumor depth. Preliminary studies show that [1O2]rx better correlates with LCR and is an effective dosimetric quantity that can predict treatment outcome.

  4. Histological long-term outcomes from acute antibody-mediated rejection following ABO-compatible liver transplantation.

    PubMed

    Del Bello, Arnaud; Danjoux, Marie; Congy-Jolivet, Nicolas; Lavayssière, Laurence; Esposito, Laure; Muscari, Fabrice; Kamar, Nassim

    2017-04-01

    Acute antibody-mediated rejection (aAMR) is an unusual complication after orthotopic ABO-compatible liver transplantation. To date, the clinical and histological long-term outcomes after aAMR are not well known. Herein, we describe nine cases of aAMR that occurred in our liver-transplant center between 2008 and 2016, with an initial and reevaluation liver biopsy available for reexamination. Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, caused by preformed donor-specific antibodies. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), associated with polyclonal antibodies (three patients) or intravenous immunoglobulins (three patients). At the last follow up (i.e. 21 [4-90] months post-aAMR), seven patients were alive, including two patients with normal liver tests. Grafts' survival was 66%. A liver biopsy performed at 11.5 (5-48.5) months after the first biopsy showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). In this study, a B-cell-depleting agent seemed to improve the prognosis of aAMR in selected cases, but several patients kept active lesions antibody-mediated rejection. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  5. Long-term exposure to dieldrin reduces gamma-aminobutyric acid type A and N-methyl-D-aspartate receptor function in primary cultures of mouse cerebellar granule cells.

    PubMed

    Babot, Zoila; Vilaró, M Teresa; Suñol, Cristina

    2007-12-01

    The organochlorine pesticide dieldrin is a persistent organic pollutant that accumulates in the fatty tissue of living organisms. In mammals, it antagonizes the GABA(A) receptor, producing convulsions after acute exposure. Although accumulation in human brain has been reported, little is known about the effects of long-term exposure to dieldrin in the nervous system. Homeostatic control of the balance between excitation and inhibition has been reported when neuronal activity is chronically altered. We hypothesized that noncytotoxic concentrations of dieldrin could decrease glutamatergic neurotransmission as a consequence of a prolonged reduction in GABA(A) receptor function. Long-term exposure of primary cerebellar granule cell cultures to 3 microM dieldrin reduced the GABA(A) receptor function to 55% of control, as measured by the GABA-induced (36)Cl(-) uptake. This exposure produced a significant reduction (approximately 35%) of the NMDA-induced increase in [Ca(2+)](i) and of the [(3)H]MK-801 binding, which was not accompanied by a reduction in the NMDA receptor subunit NR1, as determined by Western blot. Consistent with the decreased NMDA receptor function, dieldrin-treated cultures were insensitive to an excitotoxic stimulus induced by exposure to high potassium. In summary, we report that the chronic reduction of GABA(A) receptor function induced by dieldrin decreases the number of functional NMDA receptors, which may be attributable to a mechanism of synaptic scaling. These effects could underlie neural mechanisms involved in cognitive impairment produced by low-level exposure to dieldrin. (c) 2007 Wiley-Liss, Inc.

  6. The indirect association of job strain with long-term sickness absence through bullying: a mediation analysis using structural equation modeling.

    PubMed

    Janssens, Heidi; Braeckman, Lutgart; De Clercq, Bart; Casini, Annalisa; De Bacquer, Dirk; Kittel, France; Clays, Els

    2016-08-22

    In this longitudinal study the complex interplay between both job strain and bullying in relation to sickness absence was investigated. Following the "work environment hypothesis", which establishes several work characteristics as antecedents of bullying, we assumed that job strain, conceptualized by the Job-Demand-Control model, has an indirect relation with long-term sickness absence through bullying. The sample consisted of 2983 Belgian workers, aged 30 to 55 years, who participated in the Belstress III study. They completed a survey, including the Job Content Questionnaire and a bullying inventory, at baseline. Their sickness absence figures were registered during 1 year follow-up. Long-term sickness absence was defined as at least 15 consecutive days. A mediation analysis, using structural equation modeling, was performed to examine the indirect association of job strain through bullying with long-term sickness absence. The full structural model was adjusted for several possible confounders: age, gender, occupational group, educational level, company, smoking habits, alcohol use, body mass index, self-rated health, baseline long-term sickness absence and neuroticism. The results support the hypothesis: a significant indirect association of job strain with long-term sickness absence through bullying was observed, suggesting that bullying is an intermediate variable between job strain and long-term sickness absence. No evidence for the reversed pathway of an indirect association of bullying through job strain was found. Bullying was observed as a mediating variable in the relation between job strain and sickness absence. The results suggest that exposure to job strain may create circumstances in which a worker risks to become a target of bullying. Our findings are generally in line with the work environment hypothesis, which emphasizes the importance of organizational work factors in the origin of bullying. This study highlights that remodeling jobs to reduce

  7. Long-Term Care

    MedlinePlus

    ... this page please turn Javascript on. Long-Term Care What Is Long-Term Care? Long-term care involves a variety of services ... the Escape (Esc) button on your keyboard.) Most Care Provided at Home Long-term care is provided ...

  8. Temperature and food mediate long-term thermotactic behavioral plasticity by association-independent mechanisms in C. elegans.

    PubMed

    Chi, Cynthia A; Clark, Damon A; Lee, Stella; Biron, David; Luo, Linjiao; Gabel, Christopher V; Brown, Jeffrey; Sengupta, Piali; Samuel, Aravinthan D T

    2007-11-01

    Thermotactic behavior in the nematode Caenorhabditis elegans exhibits long-term plasticity. On a spatial thermal gradient, C. elegans tracks isotherms near a remembered set-point (T(S)) corresponding to its previous cultivation temperature. When navigating at temperatures above its set-point (T>T(S)), C. elegans crawls down spatial thermal gradients towards the T(S) in what is called cryophilic movement. The T(S) retains plasticity in the adult stage and is reset by approximately 4 h of sustained exposure to a new temperature. Long-term plasticity in C. elegans thermotactic behavior has been proposed to represent an associative learning of specific temperatures conditioned in the presence or absence of bacterial food. Here, we use quantitative behavioral assays to define the temperature and food-dependent determinants of long-term plasticity in the different modes of thermotactic behavior. Under our experimental conditions, we find that starvation at a specific temperature neither disrupts T(S) resetting toward the starvation temperature nor induces learned avoidance of the starvation temperature. We find that prolonged starvation suppresses the cryophilic mode of thermotactic behavior. The hen-1 and tax-6 genes have been reported to affect associative learning between temperature and food-dependent cues. Under our experimental conditions, mutation in the hen-1 gene, which encodes a secreted protein with an LDL receptor motif, does not significantly affect thermotactic behavior or long-term plasticity. Mutation in the tax-6 calcineurin gene abolishes thermotactic behavior altogether. In summary, we do not find evidence that long-term plasticity requires association between temperature and the presence or absence of bacterial food.

  9. Long-term nicotine exposure dampens LPS-induced nerve-mediated airway hyperreactivity in murine airways.

    PubMed

    Xu, Yuan; Cardell, Lars-Olaf

    2017-09-01

    Nicotine is a major component of cigarette smoke. It causes addiction and is used clinically to aid smoke cessation. The aim of the present study is to investigate the effect of nicotine on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and to explore the potential involvement of neuronal mechanisms behind nicotine's effects in murine models in vivo and in vitro. BALB/c mice were exposed to nicotine in vivo via subcutaneous Alzet osmotic minipumps containing nicotine tartate salt solution (24 mg·kg(-1)·day(-1)) for 28 days. LPS (0.1 mg/ml, 20 µl) was administered intranasally for 3 consecutive days during the end of this period. Lung functions were measured with flexiVent. For the in vitro experiments, mice tracheae were organcultured with either nicotine (10 μM) or vehicle (DMSO, 0.1%) for 4 days. Contractile responses of the tracheal segments were measured in myographs following electric field stimulation (EFS; increasing frequencies of 0.2 to 12.8 Hz) before and after incubation with 10 µg/ml LPS for 1 h. Results showed that LPS induced AHR to methacholine in vivo and increased contractile responses to EFS in vitro. Interestingly, long-term nicotine exposure markedly dampened this LPS-induced AHR both in vitro and in vivo. Tetrodotoxin (TTX) inhibited LPS-induced AHR but did not further inhibit nicotine-suppressed AHR in vivo. In conclusion, long-term nicotine exposure dampened LPS-induced AHR. The effect of nicotine was mimicked by TTX, suggesting the involvement of neuronal mechanisms. This information might be used for evaluating the long-term effects of nicotine and further exploring of how tobacco products interact with bacterial airway infections. Copyright © 2017 the American Physiological Society.

  10. Nitromusk and Polycyclic Musk Compounds as Long-Term Inhibitors of Cellular Xenobiotic Defense Systems Mediated by Multidrug Transporters

    PubMed Central

    Luckenbach, Till; Epel, David

    2005-01-01

    Synthetic musk compounds, widely used as fragrances in consumer products, have been detected in human tissue and, surprisingly, in aquatic organisms such as fish and mollusks. Although their persistence and potential to bioaccumulate are of concern, the toxicity and environmental risks of these chemicals are generally regarded as low. Here, however, we show that nitromusks and polycyclic musks inhibit the activity of multidrug efflux transporters responsible for multixenobiotic resistance (MXR) in gills of the marine mussel Mytilus californianus. The IC10 (concentration that inhibits 10%) values for the different classes of musks were in the range of 0.09–0.39 μM, and IC50 values were 0.74–2.56 μM. The immediate consequence of inhibition of efflux transporters is that normally excluded xenobiotics will now be able to enter the cell. Remarkably, the inhibitory effects of a brief 2-hr exposure to musks were only partially reversed after a 24- to 48-hr recovery period in clean seawater. This unexpected consequence of synthetic musks—a long-term loss of efflux transport activity—will result in continued accumulation of normally excluded toxicants even after direct exposure to the musk has ended. These findings also point to the need to determine whether other environmental chemicals have similar long-term effects on these transporters. The results are relevant to human health because they raise the possibility that exposure to common xenobiotics and pharmaceuticals could cause similar long-term inhibition of these transporters and lead to increased exposure to normally excluded toxicants. PMID:15626642

  11. Acute neuregulin-1 signaling influences AMPA receptor mediated responses in cultured cerebellar granule neurons

    PubMed Central

    Fenster, Catherine; Vullhorst, Detlef; Buonanno, Andres

    2012-01-01

    Neuregulin-1 (NRG1) is a trophic and differentiation factor that signals through ErbB receptor tyrosine kinases to regulate nervous system development. Previous studies have demonstrated that NRG1 affects plasticity at glutamatergic synapses in principal glutamatergic neurons of the hippocampus and frontal cortex; however, immunohistochemical and genetic analyses strongly suggest these effects are indirect and mediated via ErbB4 receptors on GABAergic interneurons. Here, we used cultured cerebellar granule cells (CGCs) that express ErbB4 to analyze the cell-autonomous effects of NRG1 stimulation on glutamatergic function. These cultures have the advantage that they are relatively homogenous and consist primarily of granule neurons that express ErbB4. We show that acute NRG1 treatment does not affect whole-cell AMPA or NMDA receptor (NMDAR) mediated currents in CGCs at 10–12 days in vitro. NRG1 also does not affect the frequency or amplitude of spontaneous AMPAR or NMDAR mediated miniature excitatory post-synaptic currents (mEPSCs). To further investigate the effects of NRG1 on activity-dependent plasticity of glutamatergic synapses in CGCs, we characterized the effects of activation of synaptic NMDAR with high-glyine/0 Mg2+ on AMPAR-mEPSC frequency and amplitude. We show that high-glycine induces a form of chemical long-term potentiation (chemLTP) in CGCs characterized by an increase in AMPAR-mEPSC frequency but not amplitude. Moreover, NRG1 induces a decrease in AMPAR-mEPSC frequency following chemLTP, but does not affect AMPAR-mEPSC amplitude. CGCs in our cultures conditions express low levels of GluR1, in contrast to dissociated hippocampal cultures, but do express the long isoform of GluR4. This study provides first evidence that (1) high-glycine can induce plasticity at glutamatergic synapses in CGCs, and (2) that acute NRG1/ErbB-signaling can regulate glutamatergic plasticity in CGCs. Taken together with previous reports, our results suggest that, similar

  12. Acute neuregulin-1 signaling influences AMPA receptor mediated responses in cultured cerebellar granule neurons.

    PubMed

    Fenster, Catherine; Vullhorst, Detlef; Buonanno, Andres

    2012-01-04

    Neuregulin-1 (NRG1) is a trophic and differentiation factor that signals through ErbB receptor tyrosine kinases to regulate nervous system development. Previous studies have demonstrated that NRG1 affects plasticity at glutamatergic synapses in principal glutamatergic neurons of the hippocampus and frontal cortex; however, immunohistochemical and genetic analyses strongly suggest these effects are indirect and mediated via ErbB4 receptors on GABAergic interneurons. Here, we used cultured cerebellar granule cells (CGCs) that express ErbB4 to analyze the cell-autonomous effects of NRG1 stimulation on glutamatergic function. These cultures have the advantage that they are relatively homogenous and consist primarily of granule neurons that express ErbB4. We show that acute NRG1 treatment does not affect whole-cell AMPA or NMDA receptor (NMDAR) mediated currents in CGCs at 10-12 days in vitro. NRG1 also does not affect the frequency or amplitude of spontaneous AMPAR or NMDAR mediated miniature excitatory post-synaptic currents (mEPSCs). To further investigate the effects of NRG1 on activity-dependent plasticity of glutamatergic synapses in CGCs, we characterized the effects of high-glyine/0 Mg(2+) (which activates synaptic NMDARs) on AMPAR-mEPSC frequency and amplitude. We show that high-glycine induces a form of chemical long-term potentiation (chemLTP) in CGCs characterized by an increase in AMPAR-mEPSC frequency but not amplitude. Moreover, NRG1 induces a decrease in AMPAR-mEPSC frequency following chemLTP, but does not affect AMPAR-mEPSC amplitude. CGCs in our cultures conditions express low levels of GluR1, in contrast to dissociated hippocampal cultures, but do express the long isoform of GluR4. This study provides first evidence that (1) high-glycine can induce plasticity at glutamatergic synapses in CGCs, and (2) that acute NRG1/ErbB-signaling can regulate glutamatergic plasticity in CGCs. Taken together with previous reports, our results suggest that, similar

  13. Short- and long-term regulation of adenylyl cyclase activity by delta-opioid receptor are mediated by Galphai2 in neuroblastoma N2A cells.

    PubMed

    Zhang, Lei; Tetrault, Joan; Wang, Wei; Loh, Horace H; Law, Ping-Yee

    2006-06-01

    Activation of the opioid receptor results in short-term inhibition of intracellular cAMP levels followed by receptor desensitization and subsequent increase of cAMP above the control level (adenylyl cyclase superactivation). Using adenovirus to deliver pertussis toxin-insensitive mutants of the alpha-subunits of G(i/o) that are expressed in neuroblastoma Neuro2A cells (Galpha(i2), Galpha(i3), and Galpha(o)), we examined the identities of the G proteins involved in the short- and long-term action of the delta-opioid receptor (DOR). Pertussis toxin pretreatment completely abolished the ability of [d-Pen(2), d-Pen(5)]-enkephalin (DPDPE) to inhibit forskolin-stimulated intracellular cAMP production. Expression of the C352L mutant of Galpha(i2), and not the C351L mutants of Galpha(i3) or Galpha(o), rescued the short-term effect of DPDPE after pertussis toxin treatment. The ability of Galpha(i2) in mediating DOR inhibition of adenylyl cyclase activity was also reflected in the ability of Galpha(i2), not Galpha(i3) or Galpha(o), to coimmunoprecipitate with DOR. Coincidently, after long-term DPDPE treatment, pertussis toxin treatment eliminated the antagonist naloxone-induced superactivation of adenylyl cyclase activity. Again, only the C352L mutant of Galpha(i2) restored the adenylyl cyclase superactivation after pertussis toxin treatment. More importantly, the C352L mutant of Galpha(i2) remained associated with DOR after long-term agonist and pertussis toxin treatment whereas the wild-type Galpha(i2) did not. These data suggest that Galpha(i2) serves as the signaling molecule in both DOR-mediated short- and long-term regulation of adenylyl cyclase activity.

  14. Divergent short- and long-term effects of acute stress in object recognition memory are mediated by endogenous opioid system activation.

    PubMed

    Nava-Mesa, Mauricio O; Lamprea, Marisol R; Múnera, Alejandro

    2013-11-01

    Acute stress induces short-term object recognition memory impairment and elicits endogenous opioid system activation. The aim of this study was thus to evaluate whether opiate system activation mediates the acute stress-induced object recognition memory changes. Adult male Wistar rats were trained in an object recognition task designed to test both short- and long-term memory. Subjects were randomly assigned to receive an intraperitoneal injection of saline, 1 mg/kg naltrexone or 3 mg/kg naltrexone, four and a half hours before the sample trial. Five minutes after the injection, half the subjects were submitted to movement restraint during four hours while the other half remained in their home cages. Non-stressed subjects receiving saline (control) performed adequately during the short-term memory test, while stressed subjects receiving saline displayed impaired performance. Naltrexone prevented such deleterious effect, in spite of the fact that it had no intrinsic effect on short-term object recognition memory. Stressed subjects receiving saline and non-stressed subjects receiving naltrexone performed adequately during the long-term memory test; however, control subjects as well as stressed subjects receiving a high dose of naltrexone performed poorly. Control subjects' dissociated performance during both memory tests suggests that the short-term memory test induced a retroactive interference effect mediated through light opioid system activation; such effect was prevented either by low dose naltrexone administration or by strongly activating the opioid system through acute stress. Both short-term memory retrieval impairment and long-term memory improvement observed in stressed subjects may have been mediated through strong opioid system activation, since they were prevented by high dose naltrexone administration. Therefore, the activation of the opioid system plays a dual modulating role in object recognition memory. Copyright © 2013 Elsevier Inc. All rights

  15. NPY-Induced Phase Shifts of PER2::LUC Rhythms are Mediated by Long-Term Suppression of Neuronal Excitability in a Phase-Specific Manner

    PubMed Central

    Besing, Rachel C.; Hablitz, Lauren M.; Paul, Jodi R.; Johnson, Russell L.; Prosser, Rebecca A.; Gamble, Karen L.

    2013-01-01

    Endogenous circadian rhythms are entrained to the 24-h light/dark cycle by both light and nonphotic stimuli. During the day, nonphotic stimuli, such as novel-wheel induced exercise, produce large phase advances. Neuropeptide Y (NPY) release from the thalamus onto suprachiasmatic nucleus (SCN) neurons at least partially mediates this nonphotic signal. We examined the hypothesis that NPY-induced phase advances are accompanied by suppression of PER2 and are mediated by long-term depression of neuronal excitability in a phase-specific manner. First, we found that NPY-induced phase advances in PER2::LUC SCN cultures are largest when NPY (2.35 µM) is given in the early part of the day (circadian time [CT] 0–6). In addition, PER2::LUC levels in NPY-treated (compared to vehicle-treated) samples were suppressed beginning 6–7 h after treatment. Similar NPY application to organotypic Per1::GFP SCN cultures resulted in long-term suppression of spike rate of GFP+ cells when slices were treated with NPY during the early or middle of the day (zeitgeber time [ZT] 2 or 6), but not during the late day (ZT 10). Furthermore, 1-h bath application of NPY to acute SCN brain slices decreased general neuronal activity measured through extracellular recordings. Finally, NPY-induced phase advances of PER2::LUC rhythms were blocked by latent depolarization with 34.5 mM [K+] 3 h after NPY application. These results suggest that NPY-induced phase advances may be mediated by long-term depression of neuronal excitability. This model is consistent with findings in other brain regions that NPY-induced persistent hyperpolarization underlies mechanisms of energy homeostasis, anxiety-related behavior, and thalamocortical synchronous firing. PMID:22324550

  16. Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model.

    PubMed

    Kucerova, L; Skolekova, S; Demkova, L; Bohovic, R; Matuskova, M

    2014-10-01

    Mesenchymal stromal cells (MSC) can be exploited as cellular delivery vehicles for the enzymes converting non-toxic prodrugs to toxic substances. Because of their inherent chemoresistance, they exert potent bystander and antitumor effect. Here we show that the human adipose tissue-derived MSC expressing fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) in combination with 5-fluorocytosine (5FC) mediated a long-term tumor-free survival in the 83.3% of tumor-bearing animals. CD-MSC/5FC treatment induced cytotoxicity against model human melanoma cells EGFP-A375. Only 4% of the therapeutic CD-MSC cells eliminated >98.5% of the tumor cells in vitro. Long-term tumor-free survival was confirmed in 15 out of the 18 animals. However, repeatedly used CD-MSC/5FC therapeutic regimen generated more aggressive and metastatic variant of the melanoma cells EGFP-A375/Rel3. These cells derived from the refractory xenotransplants exhibited increased resistance to the CD-MSC/5FC treatment, altered cell adhesion, migration, tumorigenic and metastatic properties. However, long-term curative effect was achieved by the augmentation of the CD-MSC/5FC regimen along with the inhibition of c-Met/hepatocyte growth factor signaling axis in this aggressive melanoma derivative. In summary, the CD-MSC/5FC regimen can be regarded as a very effective antitumor approach to achieve long-term tumor-free survival as demonstrated on a mouse model of aggressive human melanoma xenografts.

  17. CA1 Pyramidal Cell Theta-Burst Firing Triggers Endocannabinoid-Mediated Long-Term Depression at Both Somatic and Dendritic Inhibitory Synapses

    PubMed Central

    Younts, Thomas J.; Chevaleyre, Vivien

    2013-01-01

    Endocannabinoids (eCBs) are retrograde lipid messengers that, by targeting presynaptic type 1 cannabinoid receptors (CB1Rs), mediate short- and long-term synaptic depression of neurotransmitter release throughout the brain. Short-term depression is typically triggered by postsynaptic, depolarization-induced calcium rises, whereas long-term depression is induced by synaptic activation of Gq/11 protein-coupled receptors. Here we report that a physiologically relevant pattern of postsynaptic activity, in the form of theta-burst firing (TBF) of hippocampal CA1 pyramidal neurons, can trigger long-term depression of inhibitory transmission (iLTD) in rat hippocampal slices. Paired recordings between CA1 interneurons and pyramidal cells, followed by post hoc morphological reconstructions of the interneurons' axon, revealed that somatic and dendritic inhibitory synaptic inputs equally expressed TBF-induced iLTD. Simultaneous recordings from neighboring pyramidal cells demonstrated that eCB signaling triggered by TBF was highly restricted to only a single, active cell. Furthermore, pairing submaximal endogenous activation of metabotropic glutamate or muscarinic acetylcholine receptors with submaximal TBF unmasked associative iLTD. Although CB1Rs are also expressed at Schaffer-collateral excitatory terminals, long-term plasticity under various recording conditions was spared at these synapses. Consistent with this observation, TBF also shifted the balance of excitation and inhibition in favor of excitatory throughput, thereby altering information flow through the CA1 circuit. Given the near ubiquity of burst-firing activity patterns and CB1R expression in the brain, the properties described here may be a general means by which neurons fine tune the strength of their inputs in a cell-wide and cell-specific manner. PMID:23966696

  18. Long-term Smoking Mediated Down-regulation of Smad3 Induces Resistance to Carboplatin in Non-Small Cell Lung Cancer12

    PubMed Central

    Samanta, Debangshu; Kaufman, Jacob; Carbone, David P; Datta, Pran K

    2012-01-01

    While numerous cell signaling pathways are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the Smad-dependent transforming growth factor β pathway on the therapeutic outcome. Previous reports suggested that patients with lung cancer who continue to smoke while receiving chemotherapy have a poorer outcome than their nonsmoking counterparts do. In our previous study, we showed that long-term cigarette smoke condensate (CSC)-mediated down-regulation of Smad3 induces tumorigenesis. The objective of this study was to determine the mechanism of function of Smad3 in chemoresistance induced by CSC in human lung cell lines, namely, A549 and HPL1A. Long-term CSC treatment increases the half-maximal inhibitory concentration (IC50) of carboplatin and makes cells resistant to carboplatin. The increase in IC50 of long-term CSC-treated cells is due to the reduced induction in apoptosis by carboplatin. The increase in IC50 and decrease in apoptosis in long-term CSC-treated cells is correlated with the expression of Bcl2. We have determined that Bcl2 is both necessary and sufficient to make the cells resistant to carboplatin. We have also shown that Smad3 acts upstream to regulate the expression of Bcl2 specifically and, thus, sensitivity of the cells to carboplatin. This is supported by the inverse correlation between the expressions of Smad3 and Bcl2 in human lung tumors. Collectively, these data suggest that loss of Smad3 expression in CSC-treated cells induces resistance to carboplatin by upregulating the expression of Bcl2. This study explains, at least in part, the higher chemoresistance rate observed in smokers. PMID:22904681

  19. Long-term persistence of hepatitis B surface antigen and antibody induced by DNA-mediated immunization results in liver and kidney lesions in mice.

    PubMed

    Zi, Xiao-Yuan; Yao, Yu-Cheng; Zhu, Hai-Ying; Xiong, Jun; Wu, Xiu-Ju; Zhang, Nan; Ba, Yue; Li, Wen-Lin; Wang, Xin-Ming; Li, Jian-Xiu; Yu, Hong-Yu; Ye, Xu-Ting; Lau, Joseph T Y; Hu, Yi-Ping

    2006-04-01

    DNA-mediated immunization has been recognized as a new approach for prevention and treatment of hepatitis B virus (HBV) infection. However, the side effects of this approach have not been well described. Here we report that DNA-mediated immunization by intramuscular injection of plasmid DNA encoding HBV surface antigen (HBsAg) induced long-term persistence of HBsAg and HBsAg-specific antibody (anti-HBs) in the sera of the immunized BALB/c mice and resulted in liver and kidney lesions. The lesions persisted for 6 months after injection. Lesions were also found in normal mice injected with the sera from immunized mice, and in HBV-transgenic mice injected with anti-HBs antibody, or sera from immunized mice. Furthermore, lesions were accompanied by deposition of circulating immune complex (CIC) of HBsAg and anti-HBs antibody in the damaged organs. These results indicate that long-term persistence of HBsAg and anti-HBs in the immunized mice can result in deposited CIC in liver and kidney, and in development of lesions. The use of DNA containing mammalian replication origins, such as the plasmids used in this study, is not appropriate for human vaccines due to safety concerns relating to persistence of DNA; nevertheless, the safety of DNA-mediated immunization protocols still needs to be carefully evaluated before practical application.

  20. Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain.

    PubMed

    Ashok, Iyaswamy; Sheeladevi, Rathinasamy

    2014-01-01

    Aspartame, an artificial sweetener, is very widely used in many foods and beverages. But there are controversies about its metabolite which is marked for its toxicity. Hence it is believed to be unsafe for human use. Previous studies have reported on methanol exposure with involvements of free radicals on excitotoxicity of neuronal apoptosis. Hence, this present study is proposed to investigate whether or not chronic aspartame (FDA approved Daily Acceptable Intake (ADI),40 mg/kg bwt) administration could release methanol, and whether or not it can induce changes in brain oxidative stress status and gene and protein expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax and caspase-3 in the rat brain region. To mimic the human methanol metabolism, Methotrexate (MTX)-treated Wistar strain male albino rats were used and after the oral administration of aspartame, the effects were studied along with controls and MTX-treated controls. Aspartame exposure resulted with a significant increase in the enzymatic activity in protein carbonyl, lipid peroxidation levels, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase and catalase activity in (aspartame MTX)-treated animals and with a significant decrease in reduced glutathione, glutathione reductase and protein thiol, pointing out the generation of free radicals. The gene and protein expression of pro apoptotic marker Bax showed a marked increase whereas the anti-apoptotic marker Bcl-2 decreased markedly indicating the aspartame is harmful at cellular level. It is clear that long term aspartame exposure could alter the brain antioxidant status, and can induce apoptotic changes in brain.

  1. Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain

    PubMed Central

    Ashok, Iyaswamy; Sheeladevi, Rathinasamy

    2014-01-01

    Aspartame, an artificial sweetener, is very widely used in many foods and beverages. But there are controversies about its metabolite which is marked for its toxicity. Hence it is believed to be unsafe for human use. Previous studies have reported on methanol exposure with involvements of free radicals on excitotoxicity of neuronal apoptosis. Hence, this present study is proposed to investigate whether or not chronic aspartame (FDA approved Daily Acceptable Intake (ADI),40 mg/kg bwt) administration could release methanol, and whether or not it can induce changes in brain oxidative stress status and gene and protein expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax and caspase-3 in the rat brain region. To mimic the human methanol metabolism, Methotrexate (MTX)-treated Wistar strain male albino rats were used and after the oral administration of aspartame, the effects were studied along with controls and MTX-treated controls. Aspartame exposure resulted with a significant increase in the enzymatic activity in protein carbonyl, lipid peroxidation levels, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase and catalase activity in (aspartame MTX)-treated animals and with a significant decrease in reduced glutathione, glutathione reductase and protein thiol, pointing out the generation of free radicals. The gene and protein expression of pro apoptotic marker Bax showed a marked increase whereas the anti-apoptotic marker Bcl-2 decreased markedly indicating the aspartame is harmful at cellular level. It is clear that long term aspartame exposure could alter the brain antioxidant status, and can induce apoptotic changes in brain. PMID:25009784

  2. Reactive Oxygen Species-mediated Loss of Phenotype of Parvalbumin Interneurons Contributes to Long-term Cognitive Impairments After Repeated Neonatal Ketamine Exposures.

    PubMed

    Zhang, Hui; Sun, Xiao-Ru; Wang, Jing; Zhang, Zhen-Zhen; Zhao, Hong-Ting; Li, Hui-Hui; Ji, Mu-Huo; Li, Kuan-Yu; Yang, Jian-Jun

    2016-11-01

    Ketamine, a common anesthetic used for pediatric patients, has been shown to induce neurotoxicity and alter adolescent behaviors in rats when administered during neonatal period. However, the mechanisms underlying this kind of neurotoxicity remain largely to be determined. Herein, we studied whether the reactive oxygen species (ROS) due to the increased NOX2 mediates loss of phenotype of PV interneurons and thus contributes to long-term cognitive impairments after repeated ketamine exposures. Sprague-Dawley male rat pups received a daily administration of ketamine intraperitoneally (75 mg/kg) from postnatal day 6 (P6) to P8 for three consecutive days. For the interventional study, pups were treated with a NADPH oxidase inhibitor, apocynin (Apo). Learning and memory abilities were tested by the open field, fear conditioning, and Morris water maze on P40, P42-44, and P50-56, respectively. For histological and biochemical assays, a separate cohort of rats was killed on P9 or P60, and the brain tissues were harvested. Our results showed the upregulation of 8-OHdG and gp91/NOX2 and downregulation of PV and glutamic acid decarboxylase 67 (GAD67) after repeated ketamine exposures, which co-occurred with the long-term cognitive impairments as evidenced by the decreased freezing time to context. However, Apo treatment attenuated these abnormalities. Our results suggest that oxidative damage, probably due to the increased NOX2, mediates loss of phenotype of PV interneurons and thus contributes to long-term cognitive impairments after repeated ketamine exposures. Moreover, the inhibition of NADPH oxidase may protect against cognitive dysfunction.

  3. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans

    PubMed Central

    Meydani, Simin N.; Das, Sai K.; Pieper, Carl F.; Lewis, Michael R.; Klein, Sam; Dixit, Vishwa D.; Gupta, Alok K.; Villareal, Dennis T.; Bhapkar, Manjushri; Huang, Megan; Fuss, Paul J.; Roberts, Susan B.; Holloszy, John O.; Fontana, Luigi

    2016-01-01

    Calorie restriction (CR) inhibits inflammation and slows aging in many animal species, but in rodents housed in pathogen-free facilities, CR impairs immunity against certain pathogens. However, little is known about the effects of long-term moderate CR on immune function in humans. In this multi-center, randomized clinical trial to determine CR's effect on inflammation and cell-mediated immunity, 218 healthy non-obese adults (20-50 y), were assigned 25% CR (n=143) or an ad-libitum (AL) diet (n=75), and outcomes tested at baseline, 12, and 24 months of CR. CR induced a 10.4% weight loss over the 2-y period. Relative to AL group, CR reduced circulating inflammatory markers, including total WBC and lymphocyte counts, ICAM-1 and leptin. Serum CRP and TNF-α concentrations were about 40% and 50% lower in CR group, respectively. CR had no effect on the delayed-type hypersensitivity skin response or antibody response to vaccines, nor did it cause difference in clinically significant infections. In conclusion, long-term moderate CR without malnutrition induces a significant and persistent inhibition of inflammation without impairing key in vivo indicators of cell-mediated immunity. Given the established role of these pro-inflammatory molecules in the pathogenesis of multiple chronic diseases, these CR-induced adaptations suggest a shift toward a healthy phenotype. PMID:27410480

  4. Long-term impact of parental divorce on intimate relationship quality in adulthood and the mediating role of psychosocial resources.

    PubMed

    Mustonen, Ulla; Huurre, Taina; Kiviruusu, Olli; Haukkala, Ari; Aro, Hillevi

    2011-08-01

    The purpose of this 16-year prospective follow-up study was to investigate the association between parental divorce in childhood and intimate relationship quality in adulthood. The mediating role of psychosocial resources (parent-child relationships at 16 years, self-esteem and social support at 32 years) in this association was also studied. All 16 year olds of one Finnish city completed questionnaires at school and were followed up by postal questionnaires at 32 years of age (n = 1,471). Results showed that women and men from divorced families were more often divorced or separated at the age of 32 years than those from nondivorced families. However, parental divorce was associated with poorer intimate relationship quality only among women. Women from divorced families also had poorer relationships with their father and mother in adolescence, and they had lower self-esteem and satisfaction with social support in adulthood than women from intact families. No such associations were found among men. The impact of parental divorce on intimate relationship quality among women was partially mediated by mother-daughter relationship, self-esteem, and satisfaction with social support. The mediating role of mother-daughter relationship was not direct, however, but was mediated via self-esteem and satisfaction with social support. Our findings indicate that parental divorce affects daughters more than sons. In the context of parental divorce, the mother-daughter relationship in adolescence is important for the development of later psychosocial resources and, via them, for intimate relationship quality.

  5. Coping self-efficacy perceptions as a mediator between acute stress response and long-term distress following natural disasters.

    PubMed

    Benight, Charles C; Harper, Michelle L

    2002-06-01

    The mediating effect of coping self-efficacy (CSE) perceptions between acute stress responses (ASR) and 1-year distress following two disasters was tested. Between 3 and 8 weeks after the second disaster and again at 1 year, 46 residents completed questionnaires. Posttraumatic Stress Disorder (PTSD) symptoms and global distress served as outcomes. Multiple regression demonstrated that ASR and Time I CSE were significant predictors of both Time 1 outcomes. Time 1 PTSD symptoms and Time 2 CSE were significant factors for Time 2 PTSD symptoms. Gender was significant for Time 2 PTSD symptoms, but not for Time 2 global distress. Longitudinally, Time 1 CSE predicted Time 2 PTSD symptoms, but not general distress. CSE mediated between ASR and both psychological outcomes at Time 2. Coping self-efficacy perceptions provide a possible intervention target.

  6. Mediators and moderators of long-term effects of violent video games on aggressive behavior: practice, thinking, and action.

    PubMed

    Gentile, Douglas A; Li, Dongdong; Khoo, Angeline; Prot, Sara; Anderson, Craig A

    2014-05-01

    Although several longitudinal studies have demonstrated an effect of violent video game play on later aggressive behavior, little is known about the psychological mediators and moderators of the effect. To determine whether cognitive and/or emotional variables mediate the effect of violent video game play on aggression and whether the effect is moderated by age, sex, prior aggressiveness, or parental monitoring. Three-year longitudinal panel study. A total of 3034 children and adolescents from 6 primary and 6 secondary schools in Singapore (73% male) were surveyed annually. Children were eligible for inclusion if they attended one of the 12 selected schools, 3 of which were boys' schools. At the beginning of the study, participants were in third, fourth, seventh, and eighth grades, with a mean (SD) age of 11.2 (2.1) years (range, 8-17 years). Study participation was 99% in year 1. The final outcome measure was aggressive behavior, with aggressive cognitions (normative beliefs about aggression, hostile attribution bias, aggressive fantasizing) and empathy as potential mediators. Longitudinal latent growth curve modeling demonstrated that the effects of violent video game play are mediated primarily by aggressive cognitions. This effect is not moderated by sex, prior aggressiveness, or parental monitoring and is only slightly moderated by age, as younger children had a larger increase in initial aggressive cognition related to initial violent game play at the beginning of the study than older children. Model fit was excellent for all models. Given that more than 90% of youths play video games, understanding the psychological mechanisms by which they can influence behaviors is important for parents and pediatricians and for designing interventions to enhance or mitigate the effects.

  7. Inferior Olivary TMEM16B Mediates Cerebellar Motor Learning.

    PubMed

    Zhang, Yang; Zhang, Zhushan; Xiao, Shaohua; Tien, Jason; Le, Son; Le, Trieu; Jan, Lily Y; Yang, Huanghe

    2017-08-30

    Ca(2+)-activated ion channels shape membrane excitability and Ca(2+) dynamics in response to cytoplasmic Ca(2+) elevation. Compared to the Ca(2+)-activated K(+) channels, known as BK and SK channels, the physiological importance of Ca(2+)-activated Cl(-) channels (CaCCs) in neurons has been largely overlooked. Here we report that CaCCs coexist with BK and SK channels in inferior olivary (IO) neurons that send climbing fibers to innervate cerebellar Purkinje cells for the control of motor learning and timing. Ca(2+) influx through the dendritic high-threshold voltage-gated Ca(2+) channels activates CaCCs, which contribute to membrane repolarization of IO neurons. Loss of TMEM16B expression resulted in the absence of CaCCs in IO neurons, leading to markedly diminished action potential firing of IO neurons in TMEM16B knockout mice. Moreover, these mutant mice exhibited severe cerebellar motor learning deficits. Our findings thus advance the understanding of the neurophysiology of CaCCs and the ionic basis of IO neuron excitability. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Long-term correction of hemophilia A mice following lentiviral mediated delivery of an optimized canine factor VIII gene.

    PubMed

    Staber, J M; Pollpeter, M J; Anderson, C-G; Burrascano, M; Cooney, A L; Sinn, P L; Rutkowski, D T; Raschke, W C; McCray, P B

    2017-09-14

    Current therapies for hemophilia A include frequent prophylactic or on-demand intravenous factor treatments which are costly, inconvenient and may lead to inhibitor formation. Viral vector delivery of factor VIII (FVIII) cDNA has the potential to alleviate the debilitating clotting defects. Lentiviral-based vectors delivered to murine models of hemophilia A mediate phenotypic correction. However, a limitation of lentiviral-mediated FVIII delivery is inefficient transduction of target cells. Here, we engineer a feline immunodeficiency virus (FIV) -based lentiviral vector pseudotyped with the baculovirus GP64 envelope glycoprotein to mediate efficient gene transfer to mouse hepatocytes. In anticipation of future studies in FVIII-deficient dogs, we investigated the efficacy of FIV-delivered canine FVIII (cFVIII). Codon-optimization of the cFVIII sequence increased activity and decreased blood loss as compared to the native sequence. Further, we compared a standard B-domain deleted FVIII cDNA to a cDNA including 256 amino acids of the B-domain with 11 potential asparagine-linked oligosaccharide linkages. Restoring a partial B-domain resulted in modest reduction of endoplasmic reticulum (ER) stress markers. Importantly, our optimized vectors achieved wild-type levels of phenotypic correction with minimal inhibitor formation. These studies provide insights into optimal design of a therapeutically relevant gene therapy vector for a devastating bleeding disorder.Gene Therapy advance online publication, 14 September 2017; doi:10.1038/gt.2017.67.

  9. Tissue requirements for establishing long-term CD4+ T cell-mediated immunity following Leishmania donovani infection.

    PubMed

    Bunn, Patrick T; Stanley, Amanda C; de Labastida Rivera, Fabian; Mulherin, Alexander; Sheel, Meru; Alexander, Clare E; Faleiro, Rebecca J; Amante, Fiona H; Montes De Oca, Marcela; Best, Shannon E; James, Kylie R; Kaye, Paul M; Haque, Ashraful; Engwerda, Christian R

    2014-04-15

    Organ-specific immunity is a feature of many infectious diseases, including visceral leishmaniasis caused by Leishmania donovani. Experimental visceral leishmaniasis in genetically susceptible mice is characterized by an acute, resolving infection in the liver and chronic infection in the spleen. CD4+ T cell responses are critical for the establishment and maintenance of hepatic immunity in this disease model, but their role in chronically infected spleens remains unclear. In this study, we show that dendritic cells are critical for CD4+ T cell activation and expansion in all tissue sites examined. We found that FTY720-mediated blockade of T cell trafficking early in infection prevented Ag-specific CD4+ T cells from appearing in lymph nodes, but not the spleen and liver, suggesting that early CD4+ T cell priming does not occur in liver-draining lymph nodes. Extended treatment with FTY720 over the first month of infection increased parasite burdens, although this associated with blockade of lymphocyte egress from secondary lymphoid tissue, as well as with more generalized splenic lymphopenia. Importantly, we demonstrate that CD4+ T cells are required for the establishment and maintenance of antiparasitic immunity in the liver, as well as for immune surveillance and suppression of parasite outgrowth in chronically infected spleens. Finally, although early CD4+ T cell priming appeared to occur most effectively in the spleen, we unexpectedly revealed that protective CD4+ T cell-mediated hepatic immunity could be generated in the complete absence of all secondary lymphoid tissues.

  10. Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling.

    PubMed

    Lao-Peregrín, Cristina; Ballesteros, Jesús Javier; Fernández, Miriam; Zamora-Moratalla, Alfonsa; Saavedra, Ana; Gómez Lázaro, María; Pérez-Navarro, Esther; Burks, Deborah; Martín, Eduardo D

    2016-07-25

    Caffeine has cognitive-enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor-independent form of LTP (CAF LTP) in the CA1 region of the hippocampus by promoting calcium-dependent secretion of BDNF, which subsequently activates TrkB-mediated signaling required for the expression of CAF LTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction of CAF LTP, a process that requires cytosolic free Ca(2+) . Consistent with the involvement of IRS2 signals in caffeine-mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2(-/-) mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3-kinase (PI3K) pathway. These findings indicate that TrkB-IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine.

  11. Long Term Prognosis

    MedlinePlus

    ... TERM PROGNOSIS The long-term outlook of pediatric cardiomyopathy continues to be unpredictable because it occurs with ... a child also depends on the type of cardiomyopathy and the stage the disease is first diagnosed. ...

  12. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness.

    PubMed

    Acland, Gregory M; Aguirre, Gustavo D; Bennett, Jean; Aleman, Tomas S; Cideciyan, Artur V; Bennicelli, Jeannette; Dejneka, Nadine S; Pearce-Kelling, Susan E; Maguire, Albert M; Palczewski, Krzysztof; Hauswirth, William W; Jacobson, Samuel G

    2005-12-01

    The short- and long-term effects of gene therapy using AAV-mediated RPE65 transfer to canine retinal pigment epithelium were investigated in dogs affected with disease caused by RPE65 deficiency. Results with AAV 2/2, 2/1, and 2/5 vector pseudotypes, human or canine RPE65 cDNA, and constitutive or tissue-specific promoters were similar. Subretinally administered vectors restored retinal function in 23 of 26 eyes, but intravitreal injections consistently did not. Photoreceptoral and postreceptoral function in both rod and cone systems improved with therapy. In dogs followed electroretinographically for 3 years, responses remained stable. Biochemical analysis of retinal retinoids indicates that mutant dogs have no detectable 11-cis-retinal, but markedly elevated retinyl esters. Subretinal AAV-RPE65 treatment resulted in detectable 11-cis-retinal expression, limited to treated areas. RPE65 protein expression was limited to retinal pigment epithelium of treated areas. Subretinal AAV-RPE65 vector is well tolerated and does not elicit high antibody levels to the vector or the protein in ocular fluids or serum. In long-term studies, wild-type cDNA is expressed only in target cells. Successful, stable restoration of rod and cone photoreceptor function in these dogs has important implications for treatment of human patients affected with Leber congenital amaurosis caused by RPE65 mutations.

  13. Long-Term Restoration of Rod and Cone Vision by Single Dose rAAV-Mediated Gene Transfer to the Retina in a Canine Model of Childhood Blindness

    PubMed Central

    Acland, Gregory M.; Aguirre, Gustavo D.; Bennett, Jean; Aleman, Tomas S.; Cideciyan, Artur V.; Bennicelli, Jeannette; Dejneka, Nadine S.; Pearce-Kelling, Susan E.; Maguire, Albert M.; Palczewski, Krzysztof; Hauswirth, William W.; Jacobson, Samuel G.

    2010-01-01

    The short- and long-term effects of gene therapy using AAV-mediated RPE65 transfer to canine retinal pigment epithelium were investigated in dogs affected with disease caused by RPE65 deficiency. Results with AAV 2/2, 2/1, and 2/5 vector pseudotypes, human or canine RPE65 cDNA, and constitutive or tissue-specific promoters were similar. Subretinally administered vectors restored retinal function in 23 of 26 eyes, but intravitreal injections consistently did not. Photoreceptoral and postreceptoral function in both rod and cone systems improved with therapy. In dogs followed electroretinographically for 3 years, responses remained stable. Biochemical analysis of retinal retinoids indicates that mutant dogs have no detectable 11-cis-retinal, but markedly elevated retinyl esters. Subretinal AAV-RPE65 treatment resulted in detectable 11-cis-retinal expression, limited to treated areas. RPE65 protein expression was limited to retinal pigment epithelium of treated areas. Subretinal AAV-RPE65 vector is well tolerated and does not elicit high antibody levels to the vector or the protein in ocular fluids or serum. In long-term studies, wild-type cDNA is expressed only in target cells. Successful, stable restoration of rod and cone photoreceptor function in these dogs has important implications for treatment of human patients affected with Leber congenital amaurosis caused by RPE65 mutations. PMID:16226919

  14. Long-Term Prevention of Congenital Thrombotic Thrombocytopenic Purpura in ADAMTS13 Knockout Mice by Sleeping Beauty Transposon-Mediated Gene Therapy.

    PubMed

    Verhenne, Sebastien; Vandeputte, Nele; Pareyn, Inge; Izsvák, Zsuzsanna; Rottensteiner, Hanspeter; Deckmyn, Hans; De Meyer, Simon F; Vanhoorelbeke, Karen

    2017-05-01

    Severe deficiency in the von Willebrand factor-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) because of mutations in the ADAMTS13 gene can lead to acute episodes of congenital thrombotic thrombocytopenic purpura (TTP), requiring prompt treatment. Current treatment consists of therapeutic or prophylactic infusions of fresh frozen plasma. However, lifelong treatment with plasma products is a stressful therapy for TTP patients. Here, we describe the use of the nonviral sleeping beauty (SB) transposon system as a gene therapeutic approach to realize lifelong expression of ADAMTS13 and subsequent protection against congenital TTP. We demonstrated that hydrodynamic tail vein injection of the SB100X system expressing murine ADAMTS13 in Adamts13(-/-) mice resulted in long-term expression of supraphysiological levels of transgene ADAMTS13 over a period of 25 weeks. Stably expressed ADAMTS13 efficiently removed the prothrombotic ultralarge von Willebrand factor multimers present in the circulation of Adamts13(-/-) mice. Moreover, mice stably expressing ADAMTS13 were protected against TTP. The treated mice did not develop severe thrombocytopenia or did organ damage occur when triggered with recombinant von Willebrand factor, and this up to 20 weeks after gene transfer. These data demonstrate the feasibility of using SB100X-mediated gene therapy to achieve sustained expression of transgene ADAMTS13 and long-term prophylaxis against TTP in Adamts13(-/-) mice. © 2017 American Heart Association, Inc.

  15. Long-term effects of rapamycin treatment on insulin mediated phosphorylation of Akt/PKB and glycogen synthase activity

    SciTech Connect

    Varma, Shailly; Shrivastav, Anuraag; Changela, Sheena; Khandelwal, Ramji L.

    2008-04-01

    Protein kinase B (Akt/PKB) is a Ser/Thr kinase that is involved in the regulation of cell proliferation/survival through mammalian target of rapamycin (mTOR) and the regulation of glycogen metabolism through glycogen synthase kinase 3{beta} (GSK-3{beta}) and glycogen synthase (GS). Rapamycin is an inhibitor of mTOR. The objective of this study was to investigate the effects of rapamycin pretreatment on the insulin mediated phosphorylation of Akt/PKB phosphorylation and GS activity in parental HepG2 and HepG2 cells with overexpression of constitutively active Akt1/PKB-{alpha} (HepG2-CA-Akt/PKB). Rapamycin pretreatment resulted in a decrease (20-30%) in the insulin mediated phosphorylation of Akt1 (Ser 473) in parental HepG2 cells but showed an upregulation of phosphorylation in HepG2-CA-Akt/PKB cells. Rictor levels were decreased (20-50%) in parental HepG2 cells but were not significantly altered in the HepG2-CA-Akt/PKB cells. Furthermore, rictor knockdown decreased the phosphorylation of Akt (Ser 473) by 40-60% upon rapamycin pretreatment. GS activity followed similar trends as that of phosphorylated Akt and so with rictor levels in these cells pretreated with rapamycin; parental HepG2 cells showed a decrease in GS activity, whereas as HepG2-CA-Akt/PKB cells showed an increase in GS activity. The changes in the levels of phosphorylated Akt/PKB (Ser 473) correlated with GS and protein phoshatase-1 activity.

  16. Seladin-1 is a fundamental mediator of the neuroprotective effects of estrogen in human neuroblast long-term cell cultures.

    PubMed

    Luciani, Paola; Deledda, Cristiana; Rosati, Fabiana; Benvenuti, Susanna; Cellai, Ilaria; Dichiara, Francesca; Morello, Matteo; Vannelli, Gabriella Barbara; Danza, Giovanna; Serio, Mario; Peri, Alessandro

    2008-09-01

    Estrogen exerts neuroprotective effects and reduces beta-amyloid accumulation in models of Alzheimer's disease (AD). A few years ago, a new neuroprotective gene, i.e. seladin-1 (for selective AD indicator-1), was identified and found to be down-regulated in AD vulnerable brain regions. Seladin-1 inhibits the activation of caspase-3, a key modulator of apoptosis. In addition, it has been demonstrated that the seladin-1 gene encodes 3beta-hydroxysterol Delta24-reductase, which catalyzes the synthesis of cholesterol from desmosterol. We have demonstrated previously that in fetal neuroepithelial cells, 17beta-estradiol (17betaE2), raloxifene, and tamoxifen exert neuroprotective effects and increase the expression of seladin-1. The aim of the present study was to elucidate whether seladin-1 is directly involved in estrogen-mediated neuroprotection. Using the small interfering RNA methodology, significantly reduced levels of seladin-1 mRNA and protein were obtained in fetal neuroepithelial cells. Seladin-1 silencing determined the loss of the protective effect of 17betaE2 against beta-amyloid and oxidative stress toxicity and caspase-3 activation. A computer-assisted analysis revealed the presence of half-palindromic estrogen responsive elements upstream from the coding region of the seladin-1 gene. A 1490-bp region was cloned in a luciferase reporter vector, which was transiently cotransfected with the estrogen receptor alpha in Chinese hamster ovarian cells. The exposure to 17betaE2, raloxifene, tamoxifen, and the soy isoflavones genistein and zearalenone increased luciferase activity, thus suggesting a functional role for the half-estrogen responsive elements of the seladin-1 gene. Our data provide for the first time a direct demonstration that seladin-1 may be considered a fundamental mediator of the neuroprotective effects of estrogen.

  17. Contrapuntal role of ABA: does it mediate stress tolerance or plant growth retardation under long-term drought stress?

    PubMed

    Sreenivasulu, Nese; Harshavardhan, Vokkaliga T; Govind, Geetha; Seiler, Christiane; Kohli, Ajay

    2012-09-15

    Recent developments in defining the functional basis of abscisic acid in regulating growth, development and stress response have provided essential components for its actions. We are yet to envision the impact of how differential levels of ABA influence plant growth across life cycle. Here we reviewed the information arising from the recent unprecedented advancement made in the field of ABA signaling operative under calcium-dependent and calcium-independent pathways mediating the transcriptional reprogramming under short-term stress response. Advancement made in the field of ABA receptors and transporters has started to fill major gaps in our understanding of the ABA action. However, ABA just not only regulates guard cell movement but impacts other reproductive tissue development through massive transcriptional reprogramming events affecting various stages of the plant life cycle. Therefore many questions still remain unanswered. One such intriguing question is the contradictory role of ABA known to mediate two opposite faces of the coin: regulating abiotic stress tolerance and imparting growth retardation. In this review, we critically assessed the impact of substantial elevated levels of ABA on impairment of photosynthesis and growth alteration and its subsequent influence on seed yield formation. Excess biosynthesis of ABA under stress may deprive the same precursor pool necessary for chlorophyll biosynthesis pathway, thereby triggering growth retardation. Further, we emphasized the importance of ABA homeostasis for integrating stress cues towards coordinating sustainable plant growth. Also we provided a pertinent background on ABA biosynthesis and degradation pathway manipulation to highlight the genes and processes used in genetic engineering of plants for changed ABA content. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Different regulatory and cytotoxic CD4+ T lymphocyte profiles in renal transplants with antibody-mediated chronic rejection or long-term good graft function.

    PubMed

    Giaretta, Fulvia; Bussolino, Stefania; Beltramo, Silvia; Fop, Fabrizio; Rossetti, Maura; Messina, Maria; Cantaluppi, Vincenzo; Ranghino, Andrea; Basso, Elisa; Camussi, Giovanni; Segoloni, Giuseppe Paolo; Biancone, Luigi

    2013-01-01

    Comparative analysis of the different subsets of CD4(+) T-lymphocytes may provide hints on the immunologic mechanisms operating in the long-term fate of a kidney transplant. We analyzed peripheral regulatory CD4(+) T cells (Tregs) and CD4(+) cytotoxic T lymphocytes (CTLs) in antibody-mediated chronic rejection (AMCR), in middle-term kidney transplants (2-4 years, MTKT) with good graft function and rejection-free history, in long-term kidney transplants (>15 years, LTKT) and in normal healthy subjects (NHS). Transplant groups with good prognosis (MTKT and LTKT) displayed a significant lower amount of CD4(+)CD25(high) T lymphocytes than NHS, with a trend of a higher percentage in AMCR than in MTKT and LTKT. However, CD4(+)CD25(high) Foxp3(+) cells were significantly higher in LTKT and MTKT than AMCR. Characterization of CD4(+)CD25(high) T cells showed a marked increase of intracellular CTLA-4 in the AMCR group in respect to the other transplant groups, while the expression of the surface molecule seemed to follow a reverse trend. In addition, CD27, a costimulatory receptor involved in long-term T cell survival and prevention of immune tolerance, is significantly reduced in CD4(+)CD25(high) and CD4(+)Foxp3(+) T cells in the LTKT in respect to the other transplant groups. CD4(+)CD25(high)CD45RO(+) and CD4(+)Foxp3(+)CD45RO(+) regulatory T cells with memory function were increased in LTKT compared to NHS and for the latter also in AMCR group. Finally, CD4(+)CTLs that were quantified on the basis of granzyme A expression, were more represented in AMCR patients in comparison to the other groups. Strikingly, CD27 in the CD4(+)CTLs was suppressed in LTKT and MTKT and markedly expressed in AMCR group. No significant differences in the expression of CD28 were observed among different groups. In conclusion, different profiles of Tregs and CD4(+)CTL populations correlate with different long-term conditions of kidney-transplanted patients, suggesting their role in the development

  19. Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain

    PubMed Central

    Semple, Bridgette D; Trivedi, Alpa; Gimlin, Kayleen; Noble-Haeusslein, Linda J

    2014-01-01

    While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary pathogenesis in adult models of brain ischemia and spinal cord injury, no studies to date have examined this protease in the context of the injured immature brain, where there is notable vulnerability resulting from inadequate antioxidant reserves and prolonged exposure to infiltrating neutrophils. We thus reasoned that NE may be a key determinant of secondary pathogenesis, and as such, adversely influence long-term neurological recovery. To address this hypothesis, wild-type (WT) and NE knockout (KO) mice were subjected to a controlled cortical impact at post-natal day 21, approximating a toddler-aged child. To determine if NE is required for neutrophil infiltration into the injured brain, and whether this protease contributes to vasogenic edema, we quantified neutrophil numbers and measured water content in the brains of each of these genotypes. While leukocyte trafficking was indistinguishable between genotypes, vasogenic edema was markedly attenuated in the NE KO. To determine if early pathogenesis is dependent on NE, indices of cell death (TUNEL and activated caspase-3) were quantified across genotypes. NE KO mice showed a reduction in these markers of cell death in the injured hippocampus, which corresponded to greater preservation of neuronal integrity as well as reduced expression of heme oxygenase-1, a marker of oxidative stress. WT mice, treated with a competitive inhibitor of NE at 2, 6 and 12 h post-injury, likewise showed a reduction in cell death and oxidative stress compared to vehicle-treated controls. We next examined the long-term behavioral and structural consequences of NE deficiency. NE KO mice showed an improvement in long-term spatial memory retention and amelioration of injury-induced hyperactivity. However, volumetric and stereological analyses found comparable tissue loss in the injured cortex and hippocampus independent of genotype. Further

  20. Assessment of endothelial dysfunction by flow-mediated dilatation in men on long-term androgen deprivation therapy for prostate cancer.

    PubMed

    Gilbert, Stephen E; Tew, Garry A; Bourke, Liam; Winter, Edward M; Rosario, Derek J

    2013-09-01

    What is the central question of this study? Androgen deprivation therapy (ADT) for prostate cancer has been linked with increased cardiovascular risk, but the mechanisms are unclear. Is there evidence that endothelial dysfunction, as evidenced by reduced flow-mediated dilatation (FMD), is associated with ADT? What is the main finding and its importance? Reduction in FMD with preservation of glyceryl trinitrate-mediated dilatation indicates endothelial dysfunction in men with prostate cancer on long-term ADT compared with well-matched control subjects. Vascular endothelial dysfunction associated with long-term ADT for prostate cancer might explain the observed epidemiological increases in adverse cardiovascular events. Assessment of FMD may be useful in the monitoring of cardiovascular risk in men with prostate cancer on ADT. Androgen deprivation therapy (ADT) in men with prostate cancer has been linked to an increased incidence of cardiovascular events and mortality, but the underpinning mechanisms are unclear. Endothelial dysfunction is considered a precursor for cardiovascular disease. Previous studies have reported variably on the association between ADT and endothelial function. This blinded case-control study examined endothelial function, using high-resolution ultrasound to measure flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-mediated-dilatation in the brachial artery, in 20 men with prostate cancer (69 ± 7 years old) treated by ADT (median duration 22 months, range 6-133 months) and 20 men without prostate cancer (69 ± 5 years old) matched for age, physical activity, coexistent cardiovascular disease and body mass index. The magnitude of dilatation was calculated traditionally and allometrically scaled, adjusting for baseline diameter. There were no differences between groups for resting vascular measures (means ± SD). Flow-mediated dilatation was lower in men on ADT than in control subjects (3.9 ± 2.1 versus 5.9 ± 3.8% for traditional

  1. Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria

    PubMed Central

    Freeman, Brandi D.; Martins, Yuri C.; Akide-Ndunge, Oscar B.; Bruno, Fernando P.; Wang, Hua; Tanowitz, Herbert B.; Spray, David C.; Desruisseaux, Mahalia S.

    2016-01-01

    Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria. PMID:27031954

  2. Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria.

    PubMed

    Freeman, Brandi D; Martins, Yuri C; Akide-Ndunge, Oscar B; Bruno, Fernando P; Wang, Hua; Tanowitz, Herbert B; Spray, David C; Desruisseaux, Mahalia S

    2016-03-01

    Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

  3. Cytotoxic immune response blunts long-term transgene expression after efficient retroviral-mediated hepatic gene transfer in rat.

    PubMed

    Aubert, Dominique; Ménoret, Séverine; Chiari, Estelle; Pichard, Virginie; Durand, Sophie; Tesson, Laurent; Moullier, Philippe; Anegon, Ignacio; Ferry, Nicolas

    2002-04-01

    Vectors derived from oncoretroviruses can transduce a small proportion of hepatocytes when injected in the regenerating liver. Transgene expression may be sustained for months without immune response. In striking contrast, we observed a rapid extinction when the intravenous injection of a high input of nuclear beta-galactosidase (beta-gal) expression vector, one day after partial hepatectomy, led to a significant proportion of transduced cells in the liver. Extinction was associated with liver inflammation on tissue sections and appearance of antibodies against the transgene product, while vector genomes became undetectable in liver tissue by PCR. These observations suggested the elimination of transduced cells by an immune response. Transgenic rats tolerant for cytoplasmic beta-gal, or normal rats depleted in CD8 T lymphocytes, steadily expressed the beta-gal vector. In the spleen of normal rats, we detected cytotoxic cells directed against cells expressing beta-gal after the injection of the beta-gal vector. In jaundiced Gunn rats deficient in bilirubin glucuronosyl transferase (BGT1) and treated with a human BGT1 cDNA expression vector, we observed the same kinetics of extinction as well as the appearance of anti-BGT1 antibodies. This study demonstrates that retrovirus-mediated gene transfer may induce cytotoxic T lymphocytes specifically directed against transgene-expressing cells.

  4. Hijacking multivesicular bodies enables long-term and exosome-mediated long-distance action of anthrax toxin.

    PubMed

    Abrami, Laurence; Brandi, Lucia; Moayeri, Mahtab; Brown, Michael J; Krantz, Bryan A; Leppla, Stephen H; van der Goot, F Gisou

    2013-11-27

    Anthrax lethal toxin is a classical AB toxin comprised of two components: protective antigen (PA) and lethal factor (LF). Here, we show that following assembly and endocytosis, PA forms a channel that translocates LF, not only into the cytosol, but also into the lumen of endosomal intraluminal vesicles (ILVs). These ILVs can fuse and release LF into the cytosol, where LF can proteolyze and disable host targets. We find that LF can persist in ILVs for days, fully sheltered from proteolytic degradation, both in vitro and in vivo. During this time, ILV-localized LF can be transmitted to daughter cells upon cell division. In addition, LF-containing ILVs can be delivered to the extracellular medium as exosomes. These can deliver LF to the cytosol of naive cells in a manner that is independent of the typical anthrax toxin receptor-mediated trafficking pathway, while being sheltered from neutralizing extracellular factors of the immune system. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune-System-Mediated Protection and Subsequent Long-Term Adaptive Immunity

    PubMed Central

    Wong, Chinn Yi; Mifsud, Edin J.; Edenborough, Kathryn M.; Sekiya, Toshiki; Tan, Amabel C. L.; Mercuri, Francesca; Rockman, Steve; Chen, Weisan; Turner, Stephen J.; Doherty, Peter C.; Kelso, Anne; Brown, Lorena E.; Jackson, David C.

    2015-01-01

    ABSTRACT The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R4Pam2Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R4Pam2Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R4Pam2Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8+ T cell responses are also induced by the use of R4Pam2Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8+ T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity. PMID:26507227

  6. Flt3-L gene therapy enhances immunocytokine-mediated antitumor effects and induces long-term memory.

    PubMed

    Neal, Zane C; Sondel, Paul M; Bates, Mary Kay; Gillies, Stephen D; Herweijer, Hans

    2007-11-01

    Therapeutic treatment with hu14.18-IL-2 immunocytokine (IC) or Flt3-L (FL) protein is initially effective at resolving established intradermal NXS2 neuroblastoma tumors in mice. However, many treated animals develop recurrent disease. We previously found that tumors recurring following natural killer (NK) mediated IC treatment show augmented MHC class I expression, while the tumors that recurred following T cell dependent Flt3-L treatment exhibited decreased MHC class I expression. We hypothesized that this divergent MHC modulation on recurrent tumors was due to therapy-specific immunoediting. We further postulated that combining IC and Flt3-L treatments might decrease the likelihood of recurrent disease by preventing MHC modulation as a mechanism for immune escape. We now report that combinatorial treatment of FL plus hu14.18-IL-2 IC provides greater antitumor benefit than treatment with either alone, suppressing development of recurrent disease. We administered FL by gene therapy using a clinically relevant approach: hydrodynamic limb vein (HLV) delivery of DNA for transgene expression by myofibers. Delivery of FL DNA by HLV injection in mice resulted in systemic expression of >10 ng/ml of FL in blood at day 3, and promoted up to a fourfold and tenfold increase in splenic NK and dendritic cells (DCs), respectively. Furthermore, the combination of FL gene therapy plus suboptimal IC treatment induced a greater expansion in the absolute number of splenic NK and DCs than achieved by individual component treatments. Mice that received combined FL gene therapy plus IC exhibited complete and durable resolution of established NXS2 tumors, and demonstrated protection from subsequent rechallenge with NXS2 tumor.

  7. Avoidant coping and self-efficacy mediate relationships between perceived social constraints and symptoms among long-term breast cancer survivors.

    PubMed

    Adams, Rebecca N; Mosher, Catherine E; Cohee, Andrea A; Stump, Timothy E; Monahan, Patrick O; Sledge, George W; Cella, David; Champion, Victoria L

    2017-07-01

    Many breast cancer survivors feel constrained in discussing their cancer experience with others. Limited evidence suggests that social constraints (e.g., avoidance and criticism) from loved ones may negatively impact breast cancer survivors' global health, but research has yet to examine relationships between social constraints and common physical symptoms. Informed by social cognitive processing theory, this study examined whether perceived social constraints from partners and healthcare providers (HCPs) were associated with fatigue, sleep disturbance, and attentional functioning among long-term breast cancer survivors (N = 1052). In addition, avoidant coping and self-efficacy for symptom management were examined as potential mediators of these relationships. Long-term breast cancer survivors (mean years since diagnosis = 6) completed questionnaires assessing social constraints from partners and HCPs, avoidant coping, self-efficacy for symptom management, and symptoms (i.e., fatigue, sleep disturbance, and attentional functioning). Structural equation modeling was used to evaluate the hypothesized relationships among variables in two models: one focused on social constraints from partners and one focused on social constraints from HCPs. Both models demonstrated good fit. Consistent with theory and prior research, greater social constraints from both partners and HCPs were associated with greater symptom burden (i.e., greater fatigue and sleep disturbance, poorer attentional functioning). In addition, all relationships were mediated by avoidant coping and self-efficacy for symptom management. Findings are consistent with social cognitive processing theory and suggest that symptom management interventions may be enhanced by addressing the impact of social constraints from survivors' partners and HCPs on their coping and self-efficacy. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  8. Receptor-mediated toxicity of human amylin fragment aggregated by short- and long-term incubations with copper ions.

    PubMed

    Caruso, Giuseppe; Distefano, Donatella A; Parlascino, Paolo; Fresta, Claudia G; Lazzarino, Giuseppe; Lunte, Susan M; Nicoletti, Vincenzo G

    2017-01-01

    Human amylin (hA1-37) is a polypeptide hormone secreted in conjunction with insulin from the pancreatic β-cells involved in the pathogenesis of type 2 diabetes mellitus (T2DM). The shorter fragment hA17-29 than full-length peptide is capable to form amyloids "in vitro". Here, we monitored the time course of hA17-29 β-amyloid fibril and oligomer formation [without and with copper(II)], cellular toxicity of different amyloid aggregates, and involvement of specific receptors (receptor for advanced glycation end-products, RAGE; low-affinity nerve growth factor receptor, p75-NGFR) in aggregate toxicity. Fibril and oligomer formation of hA17-29 incubated at 37 °C for 0, 48, and 120 h, without or with copper(II), were measured by the thioflavin T fluorescence assay and ELISA, respectively. Toxicity of hA17-29 aggregates and effects of anti-RAGE and anti-p75-NGFR antibodies were evaluated on neuroblastoma SH-SY5Y viability. Fluorescence assay of hA17-29 indicates an initial slow rate of soluble fibril formation (48 h), followed by a slower rate of insoluble aggregate formation (120 h). The highest quantity of oligomers was recorded when hA17-29 was pre-aggregated for 48 h in the presence of copper(II) showing also the maximal cell toxicity (-44% of cell viability, p < 0.01 compared to controls). Anti-RAGE or anti-p75-NGFR antibodies almost abolished cell toxicity of hA17-29 aggregates. These results indicate that copper(II) influences the aggregation process and hA17-29 toxicities are especially attributable to oligomeric aggregates. hA17-29 aggregate toxicity seems to be mediated by RAGE and p75-NGFR receptors which might be potential targets for new drugs in T2DM treatment.

  9. MicroRNA-mediated responses to long-term magnesium-deficiency in Citrus sinensis roots revealed by Illumina sequencing.

    PubMed

    Liang, Wei-Wei; Huang, Jing-Hao; Li, Chun-Ping; Yang, Lin-Tong; Ye, Xin; Lin, Dan; Chen, Li-Song

    2017-08-24

    Magnesium (Mg)-deficiency occurs most frequently in strongly acidic, sandy soils. Citrus are grown mainly on acidic and strong acidic soils. Mg-deficiency causes poor fruit quality and low fruit yield in some Citrus orchards. For the first time, we investigated Mg-deficiency-responsive miRNAs in 'Xuegan' (Citrus sinensis) roots using Illumina sequencing in order to obtain some miRNAs presumably responsible for Citrus Mg-deficiency tolerance. We obtained 101 (69) miRNAs with increased (decreased) expression from Mg-starved roots. Our results suggested that the adaptation of Citrus roots to Mg-deficiency was related to the several aspects: (a) inhibiting root respiration and related gene expression via inducing miR158 and miR2919; (b) enhancing antioxidant system by down-regulating related miRNAs (miR780, miR6190, miR1044, miR5261 and miR1151) and the adaptation to low-phosphorus (miR6190); (c) activating transport-related genes by altering the expression of miR6190, miR6485, miR1044, miR5029 and miR3437; (d) elevating protein ubiquitination due to decreased expression levels of miR1044, miR5261, miR1151 and miR5029; (e) maintaining root growth by regulating miR5261, miR6485 and miR158 expression; and (f) triggering DNA repair (transcription regulation) by regulating miR5176 and miR6485 (miR6028, miR6190, miR6485, miR5621, miR160 and miR7708) expression. Mg-deficiency-responsive miRNAs involved in root signal transduction also had functions in Citrus Mg-deficiency tolerance. We obtained several novel Mg-deficiency-responsive miRNAs (i.e., miR5261, miR158, miR6190, miR6485, miR1151 and miR1044) possibly contributing to Mg-deficiency tolerance. These results revealed some novel clues on the miRNA-mediated adaptation to nutrient deficiencies in higher plants.

  10. Similar cation channels mediate protection from cerebellar exitotoxicity by exercise and inheritance.

    PubMed

    Ben-Ari, Shani; Ofek, Keren; Barbash, Shahar; Meiri, Hanoch; Kovalev, Eugenia; Greenberg, David Samuel; Soreq, Hermona; Shoham, Shai

    2012-03-01

    Exercise and inherited factors both affect recovery from stroke and head injury, but the underlying mechanisms and interconnections between them are yet unknown. Here, we report that similar cation channels mediate the protective effect of exercise and specific genetic background in a kainate injection model of cerebellar stroke. Microinjection to the cerebellum of the glutamatergic agonist, kainate, creates glutamatergic excito\\xE2\\x80\\x90toxicity characteristic of focal stroke, head injury or alcoholism. Inherited protection and prior exercise were both accompanied by higher cerebellar expression levels of the Kir6.1 ATP-dependent potassium channel in adjacent Bergmann glia, and voltage-gated KVbeta2 and cyclic nucleotide-gated cation HCN1 channels in basket cells. Sedentary FVB/N and exercised C57BL/6 mice both expressed higher levels of these cation channels compared to sedentary C57BL/6 mice, and were both found to be less sensitive to glutamate toxicity. Moreover, blocking ATP-dependent potassium channels with Glibenclamide enhanced kainate-induced cell death in cerebellar slices from the resilient sedentary FVB/N mice. Furthermore, exercise increased the number of acetylcholinesterase-positive fibres in the molecular layer, reduced cerebellar cytokine levels and suppressed serum acetylcholinesterase activity, suggesting anti-inflammatory protection by enhanced cholinergic signalling. Our findings demonstrate for the first time that routine exercise and specific genetic backgrounds confer protection from cerebellar glutamatergic damages by similar molecular mechanisms, including elevated expression of cation channels. In addition, our findings highlight the involvement of the cholinergic anti-inflammatory pathway in insult-inducible cerebellar processes. These mechanisms are likely to play similar roles in other brain regions and injuries as well, opening new venues for targeted research efforts.

  11. Assessing the value of post-processed state-of-the-art long-term weather forecast ensembles for agricultural water management mediated by farmers' behaviours

    NASA Astrophysics Data System (ADS)

    Li, Yu; Giuliani, Matteo; Castelletti, Andrea

    2016-04-01

    Recent advances in modelling of coupled ocean-atmosphere dynamics significantly improved skills of long-term climate forecast from global circulation models (GCMs). These more accurate weather predictions are supposed to be a valuable support to farmers in optimizing farming operations (e.g. crop choice, cropping and watering time) and for more effectively coping with the adverse impacts of climate variability. Yet, assessing how actually valuable this information can be to a farmer is not straightforward and farmers' response must be taken into consideration. Indeed, in the context of agricultural systems potentially useful forecast information should alter stakeholders' expectation, modify their decisions, and ultimately produce an impact on their performance. Nevertheless, long-term forecast are mostly evaluated in terms of accuracy (i.e., forecast quality) by comparing hindcast and observed values and only few studies investigated the operational value of forecast looking at the gain of utility within the decision-making context, e.g. by considering the derivative of forecast information, such as simulated crop yields or simulated soil moisture, which are essential to farmers' decision-making process. In this study, we contribute a step further in the assessment of the operational value of long-term weather forecasts products by embedding these latter into farmers' behavioral models. This allows a more critical assessment of the forecast value mediated by the end-users' perspective, including farmers' risk attitudes and behavioral patterns. Specifically, we evaluate the operational value of thirteen state-of-the-art long-range forecast products against climatology forecast and empirical prediction (i.e. past year climate and historical average) within an integrated agronomic modeling framework embedding an implicit model of the farmers' decision-making process. Raw ensemble datasets are bias-corrected and downscaled using a stochastic weather generator, in

  12. Long-term luciferase expression monitored by bioluminescence imaging after adeno-associated virus-mediated fetal gene delivery in rhesus monkeys (Macaca mulatta).

    PubMed

    Tarantal, Alice F; Lee, C Chang I

    2010-02-01

    The safety and efficiency of fetal adeno-associated virus (AAV) gene delivery in rhesus monkeys and long-term monitoring of transgene expression by bioluminescence imaging (BLI) were evaluated. Early second-trimester fetal monkeys were administered AAV2/5, AAV2/9, or AAV2/10 vector supernatant preparations expressing firefly luciferase under the control of the cytomegalovirus promoter, using an intrathoracic (n = 6) or intramyocardial (n = 6) approach and established ultrasound-guided techniques. Postnatal BLI was performed monthly up to 6 months postnatal age (n = 12) and then every 3 months thereafter to monitor transgene expression up to 24 months postnatal age (27 months after gene transfer; n = 6). All AAV serotypes showed greater than 1.0 x 10(9) photons/sec at all time points evaluated with limited biodistribution to nontargeted anatomical sites. The highest levels of bioluminescence (photons per second) observed were noted with AAV2/9 and AAV2/10 when the three vector constructs were compared. To correlate in vivo findings at the tissue level, specimens were collected from selected animals and analyzed. Three-dimensional reconstruction showed that firefly luciferase expression was consistent with imaging and morphometric measures. These findings suggest that (1) high levels of AAV-mediated firefly luciferase expression can be found after fetal AAV gene transfer and without any evidence of adverse effects; (2) the intercostal muscles, myocardium, and muscular component of the diaphragm of developing fetuses are readily transduced with AAV2/5, AAV2/9, or AAV2/10; and (3) postnatal outcomes and long-term luciferase expression can be effectively monitored by BLI in young rhesus monkeys.

  13. KRAS(G12D)-mediated oncogenic transformation of thyroid follicular cells requires long-term TSH stimulation and is regulated by SPRY1.

    PubMed

    Zou, Minjing; Baitei, Essa Y; Al-Rijjal, Roua A; Parhar, Ranjit S; Al-Mohanna, Futwan A; Kimura, Shioko; Pritchard, Catrin; BinEssa, Huda; Alanazi, Azizah A; Alzahrani, Ali S; Akhtar, Mohammed; Assiri, Abdullah M; Meyer, Brian F; Shi, Yufei

    2015-11-01

    KRAS(G12D) can cause lung cancer rapidly, but is not sufficient to induce thyroid cancer. It is not clear whether long-term serum thyroid stimulating hormone (TSH) stimulation can promote KRAS(G12D)-mediated thyroid follicular cell transformation. In the present study, we investigated the effect of long-term TSH stimulation in KRAS(G12D) knock-in mice and the role of Sprouty1 (SPRY1) in KRAS(G12D)-mediated signaling. We used TPO-KRAS(G12D) mice for thyroid-specific expression of KRAS(G12D) under the endogenous KRAS promoter. Twenty TPO-KRAS(G12D) mice were given anti-thyroid drug propylthiouracil (PTU, 0.1% w/v) in drinking water to induce serum TSH and 20 mice were without PTU treatment. Equal number of wild-type littermates (TPO-KRAS(WT)) was given the same treatment. The expression of SPRY1, a negative regulator of receptor tyrosine kinase (RTK) signaling, was analyzed in both KRAS(G12D)-and BRAF(V600E)-induced thyroid cancers. Without PTU treatment, only mild thyroid enlargement and hyperplasia were observed in TPO-KRAS(G12D) mice. With PTU treatment, significant thyroid enlargement and hyperplasia occurred in both TPO-KRAS(G12D) and TPO-KRAS(WT) littermates. Thyroids from TPO-KRAS(G12D) mice were six times larger than TPO-KRAS(WT) littermates. Distinct thyroid histology was found between TPO-KRAS(G12D) and TPO-KRAS(WT) mice: thyroid from TPO-KRAS(G12D) mice showed hyperplasia with well-maintained follicular architecture whereas in TPO-KRAS(WT) mice this structure was replaced by papillary hyperplasia. Among 10 TPO-KRAS(G12D) mice monitored for 14 months, two developed follicular thyroid cancer (FTC), one with pulmonary metastasis. Differential SPRY1 expression was demonstrated: increased in FTC and reduced in papillary thyroid cancer (PTC). The increased SPRY1 expression in FTC promoted TSH-RAS signaling through PI3K/AKT pathway whereas downregulation of SPRY1 by BRAF(V600E) in PTC resulted in both MAPK and PI3K/AKT activation. We conclude that chronic TSH

  14. Myosin II ATPase Activity Mediates the Long-Term Potentiation-Induced Exodus of Stable F-Actin Bound by Drebrin A from Dendritic Spines

    PubMed Central

    Mizui, Toshiyuki; Sekino, Yuko; Yamazaki, Hiroyuki; Ishizuka, Yuta; Takahashi, Hideto; Kojima, Nobuhiko; Kojima, Masami; Shirao, Tomoaki

    2014-01-01

    The neuronal actin-binding protein drebrin A forms a stable structure with F-actin in dendritic spines. NMDA receptor activation causes an exodus of F-actin bound by drebrin A (DA-actin) from dendritic spines, suggesting a pivotal role for DA-actin exodus in synaptic plasticity. We quantitatively assessed the extent of DA-actin localization to spines using the spine-dendrite ratio of drebrin A in cultured hippocampal neurons, and found that (1) chemical long-term potentiation (LTP) stimulation induces rapid DA-actin exodus and subsequent DA-actin re-entry in dendritic spines, (2) Ca2+ influx through NMDA receptors regulates the exodus and the basal accumulation of DA-actin, and (3) the DA-actin exodus is blocked by myosin II ATPase inhibitor, but is not blocked by myosin light chain kinase (MLCK) or Rho-associated kinase (ROCK) inhibitors. These results indicate that myosin II mediates the interaction between NMDA receptor activation and DA-actin exodus in LTP induction. Furthermore, myosin II seems to be activated by a rapid actin-linked mechanism rather than slow MLC phosphorylation. Thus the myosin-II mediated DA-actin exodus might be an initial event in LTP induction, triggering actin polymerization and spine enlargement. PMID:24465547

  15. Myosin II ATPase activity mediates the long-term potentiation-induced exodus of stable F-actin bound by drebrin A from dendritic spines.

    PubMed

    Mizui, Toshiyuki; Sekino, Yuko; Yamazaki, Hiroyuki; Ishizuka, Yuta; Takahashi, Hideto; Kojima, Nobuhiko; Kojima, Masami; Shirao, Tomoaki

    2014-01-01

    The neuronal actin-binding protein drebrin A forms a stable structure with F-actin in dendritic spines. NMDA receptor activation causes an exodus of F-actin bound by drebrin A (DA-actin) from dendritic spines, suggesting a pivotal role for DA-actin exodus in synaptic plasticity. We quantitatively assessed the extent of DA-actin localization to spines using the spine-dendrite ratio of drebrin A in cultured hippocampal neurons, and found that (1) chemical long-term potentiation (LTP) stimulation induces rapid DA-actin exodus and subsequent DA-actin re-entry in dendritic spines, (2) Ca(2+) influx through NMDA receptors regulates the exodus and the basal accumulation of DA-actin, and (3) the DA-actin exodus is blocked by myosin II ATPase inhibitor, but is not blocked by myosin light chain kinase (MLCK) or Rho-associated kinase (ROCK) inhibitors. These results indicate that myosin II mediates the interaction between NMDA receptor activation and DA-actin exodus in LTP induction. Furthermore, myosin II seems to be activated by a rapid actin-linked mechanism rather than slow MLC phosphorylation. Thus the myosin-II mediated DA-actin exodus might be an initial event in LTP induction, triggering actin polymerization and spine enlargement.

  16. Long-term aerosol-mediated changes in cloud radiative forcing of deep clouds at the top and bottom of the atmosphere over the Southern Great Plains

    NASA Astrophysics Data System (ADS)

    Yan, Hongru; Li, Zhanqing; Huang, Jianping; Cribb, Maureen; Liu, Jianjun

    2014-07-01

    Aerosols can alter the macro- and micro-physical properties of deep convective clouds (DCCs) and their radiative forcing (CRF). This study presents what is arguably the first long-term estimate of the aerosol-mediated changes in CRF (AMCRF) for deep cloud systems derived from decade-long continuous ground-based and satellite observations, model simulations, and reanalysis data. Measurements were made at the US Department of Energy's Atmospheric Radiation Measurement Program's Southern Great Plains (SGP) site. Satellite retrievals are from the Geostationary Operational Environmental Satellite. Increases in aerosol loading were accompanied by the thickening of DCC cores and the expansion and thinning of anvils, due presumably to the aerosol invigoration effect (AIV) and the aerosol microphysical effect. Meteorological variables dictating these cloud processes were investigated. Consistent with previous findings, the AIV is most significant when the atmosphere is moist and unstable with weak wind shear. Such aerosol-mediated systematic changes in DCC core thickness and anvil size alter CRF at the top of atmosphere (TOA) and at the surface. Using extensive observations, ~300 DCC systems were identified over a 10 years period at the SGP site (2000-2011) and analyzed. Daily mean AMCRF at the TOA and at the surface are 29.3 W m-2 and 22.2 W m-2, respectively. This net warming effect due to changes in DCC microphysics offsets the cooling resulting from the first aerosol indirect effect.

  17. Long-term aerosol-mediated changes in cloud radiative forcing of deep clouds at the top and bottom of the atmosphere over the Southern Great Plains

    NASA Astrophysics Data System (ADS)

    Yan, Hongru; Li, Zhanqing; Huang, Jianping; Cribb, Maureen; Liu, Jianjun

    2014-02-01

    Aerosols can alter the macro- and micro-physical properties of deep convective clouds (DCC) and their radiative forcing (CRF). This study presents what is arguably the first long-term estimate of the aerosol-mediated changes in CRF (AMCRF) for deep cloud systems derived from decade-long continuous ground-based and satellite observations, model simulations and reanalysis data. Measurements were made at the US Department of Energy's Atmospheric Radiation Measurement Program's Southern Great Plains (SGP) site. Satellite retrievals are from the Geostationary Operational Environmental Satellite (GOES). Increases in aerosol loading were accompanied by the thickening of DCC cores and the expansion and thinning of anvils, due presumably to the aerosol invigoration effect (AIV) and the aerosol microphysical effect (AME). Meteorological variables dictating these cloud processes were investigated. Consistent with previous findings, the AIV is most significant when the atmosphere is moist and unstable with weak wind shear. Such aerosol-mediated systematic changes in DCC core thickness and anvil size alter CRF at the top of atmosphere (TOA) and at the surface. Using extensive observations, ~300 DCC systems were identified over a 10 yr period at the SGP site (2000-2011) and analyzed. Daily mean AMCRF at the TOA and at the surface are 29.3 W m-2 and 22.2 W m-2, respectively. This net warming effect due to changes in DCC microphysics offsets the cooling resulting from the first aerosol indirect effect.

  18. Long-term survival of cardiac allografts induced by cyclophosphamide combined with CTLA4Ig-gene transfer mediated by adenoviral vector.

    PubMed

    Wang, G M; Ma, J B; Jin, Y Z; Feng, Y G; Hao, J; Gao, X; Xie, S S

    2006-11-01

    There is a need to achieve donor-specific tolerance in clinical organ transplantation, where potential benefits remain overshadowed by chronic rejection and the side-effects of long-term immunosuppressive therapy. It is known that the mature immune system in mice can be reprogrammed to accept a foreign graft as if it was "self". The AdCTLA4Ig-mediated gene transfer (SC) + cyclophosphamide (CP) treatment alone prolongs allograft survival but does not induce tolerance. However, in our study, the AdCTLA4Ig-mediated gene transfer combined with SC + CP treatment yielded significantly prolonged mean survival times (149.7 +/- 18.0 days), while those in the untreated or AdLacZ treated mice were rejected in normal fashion (5.3 +/- 0.5 and 5.2 +/- 0.4 days, respectively), and survival in the AdCTLA4Ig or SC + CP treated groups were 45.7 +/- 9.6 or 50.2 +/- 5.3 days, respectively. In conclusion, a protocol of AdCTLA4Ig + SC + CP improved the survival of DA-->LEW cardiac allografts.

  19. A BTLA-mediated bait-and-switch strategy permits Listeria expansion in CD8α+ DCs to promote long term T cell responses

    PubMed Central

    Yang, Xuanming; Zhang, Xunmin; Sun, Yonglian; Tu, Tony; Fu, May Lynne; Miller, Mendy; Fu, Yang-Xin

    2014-01-01

    SUMMARY Listeria monocytogenes infected CD8α+ DCs in the spleen are essential for CD8+ T cell generation. CD8α+ DCs are also necessary for Listeria expansion and dissemination within the host. The mechanisms that regulate CD8α+ DCs to allow Listeria expansion are unclear. We find that activating the B and T lymphocyte attenuator (BTLA), a co-inhibitory receptor on CD8α+ DCs, suppresses, while blocking BTLA enhances both the primary and memory CD8 T cell responses against Listeria. Btla−/− mice have lower effector and memory CD8+ T cells while paradoxically also being more resistant to Listeria. Although bacterial entry into Btla−/− CD8α+ DCs is unaffected, Listeria fails to expand within these cells. BTLA signaling limits Fas/FasL-mediated suppression of Listeria expansion within CD8α+ DCs to more effectively alert adaptive immune cells. This study uncovers a BTLA-mediated strategy used by the host that permits Listeria proliferation to enable increasing T cell responses for long-term protection. PMID:25011109

  20. Abnormal GABA-mediated and cerebellar inhibition in women with the fragile X premutation.

    PubMed

    Conde, Virginia; Palomar, Francisco J; Lama, María José; Martínez, Raquel; Carrillo, Fátima; Pintado, Elizabeth; Mir, Pablo

    2013-03-01

    The fragile X syndrome is a mutation-driven developmental disorder caused by a repetition over 200 times of the CGG trinucleotide situated in the 5'-untranslated region of the fragile X mental retardation 1 gene (FMR1). The interval between 55 and 199 CGG repeats, which is over the normal range but below full mutation, is named fragile X premutation. Recent studies have focused on the asymptomatic state of fragile X premutation carriers and their potentially relevant preclinical features. However, the underlying neurological mechanisms leading to altered functions in fragile X premutation carriers are still poorly understood. In this study, we wanted to test the hypothesis that asymptomatic women who carry the fragile X premutation present GABAergic and cerebellar abnormalities compared with healthy women without the premutation. We performed noninvasive brain stimulation protocols on both asymptomatic fragile X premutation carriers and controls comprising of measures of GABAA- and GABAB-mediated intracortical inhibition, afferent inhibition, and cerebello-motor functional interactions. Premutation carriers presented an absence of cerebellar inhibition over primary motor cortex as well as a reduced GABAA-mediated intracortical and afferent inhibition compared with healthy nonpremutated controls. These alterations are most probably dependent on a dysfunctional GABAergic mechanism associated with the fragile X premutation condition as previously found in CGG-repeat animal models. Furthermore, the lack of cerebello-motor inhibition could be related to the cerebellar structural abnormalities previously found in carriers of the premutation.

  1. Abdominal wall integrity after open abdomen: long-term results of vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM).

    PubMed

    Willms, A; Schaaf, S; Schwab, R; Richardsen, I; Bieler, D; Wagner, B; Güsgen, C

    2016-12-01

    The open abdomen has become a standard technique in the management of critically ill patients undergoing surgery for severe intra-abdominal conditions. Negative pressure and mesh-mediated fascial traction are commonly used and achieve low fistula rates and high fascial closure rates. In this study, long-term results of a standardised treatment approach are presented. Fifty-five patients who underwent OA management for different indications at our institution from 2006 to 2013 were enrolled. All patients were treated under a standardised algorithm that uses a combination of vacuum-assisted wound closure and mesh-mediated fascial traction. Structured follow-up assessments were offered to patients and included a medical history, a clinical examination and abdominal ultrasonography. The data obtained were statistically analysed. The fascial closure rate was 74 % in an intention-to-treat analysis and 89 % in a per-protocol analysis. The fistula rate was 1.8 %. Thirty-four patients attended follow-up. The median follow-up was 46 months (range 12-88 months). Incisional hernias developed in 35 %. Patients with hernias needed more operative procedures (10.3 vs 3.4, p = 0.03) than patients without hernia formation. A Patient Observer Scar Assessment Scale (POSAS) of 31.1 was calculated. Patients with symptomatic hernias (NAS of 2-10) had a significantly lower mean POSAS score (p = 0.04). Vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM) seem to result in low complication rates and high fascial closure rates. Abdominal wall reconstruction, which is a challenging and complex procedure and causes considerable patient discomfort, can thus be avoided in the majority of cases. Available results are based on studies involving only a small number of cases. Multi-centre studies and registry-based data are therefore needed to validate these findings.

  2. Traveling waves in developing cerebellar cortex mediated by asymmetrical Purkinje cell connectivity.

    PubMed

    Watt, Alanna J; Cuntz, Hermann; Mori, Masahiro; Nusser, Zoltan; Sjöström, P Jesper; Häusser, Michael

    2009-04-01

    Correlated network activity is important in the development of many neural circuits. Purkinje cells are among the first neurons to populate the cerebellar cortex, where they sprout exuberant axon collaterals. We used multiple patch-clamp recordings targeted with two-photon microscopy to characterize monosynaptic connections between the Purkinje cells of juvenile mice. We found that Purkinje cell axon collaterals projected asymmetrically in the sagittal plane, directed away from the lobule apex. On the basis of our anatomical and physiological characterization of this connection, we constructed a network model that robustly generated waves of activity that traveled along chains of connected Purkinje cells. Consistent with the model, we observed traveling waves of activity in Purkinje cells in sagittal slices from young mice that require GABA(A) receptor-mediated transmission and intact Purkinje cell axon collaterals. These traveling waves are absent in adult mice, suggesting they have a developmental role in wiring the cerebellar cortical microcircuit.

  3. Brain-derived neurotrophic factor-mediated retrograde signaling required for the induction of long-term potentiation at inhibitory synapses of visual cortical pyramidal neurons.

    PubMed

    Inagaki, Tsuyoshi; Begum, Tahamina; Reza, Faruque; Horibe, Shoko; Inaba, Mie; Yoshimura, Yumiko; Komatsu, Yukio

    2008-06-01

    High-frequency stimulation (HFS) induces long-term potentiation (LTP) at inhibitory synapses of layer 5 pyramidal neurons in developing rat visual cortex. This LTP requires postsynaptic Ca2+ rise for induction, while the maintenance mechanism is present at the presynaptic site, suggesting presynaptic LTP expression and the necessity of retrograde signaling. We investigated whether the supposed signal is mediated by brain-derived neurotrophic factor (BDNF), which is expressed in pyramidal neurons but not inhibitory interneurons. LTP did not occur when HFS was applied in the presence of the Trk receptor tyrosine kinase inhibitor K252a in the perfusion medium. HFS produced LTP when bath application of K252a was started after HFS or when K252a was loaded into postsynaptic cells. LTP did not occur in the presence of TrkB-IgG scavenging BDNF or function-blocking anti-BDNF antibody in the medium. In cells loaded with the Ca2+ chelator BAPTA, the addition of BDNF to the medium enabled HFS to induce LTP without affecting baseline synaptic transmission. These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB, leading to LTP. Because BDNF, expressed activity dependently, regulates the maturation of cortical inhibition, inhibitory LTP may contribute to this developmental process, and hence experience-dependent functional maturation of visual cortex.

  4. Long-term changes in food availability mediate the effects of temperature on growth, development and survival in striped marsh frog larvae: implications for captive breeding programmes.

    PubMed

    Courtney Jones, Stephanie K; Munn, Adam J; Penman, Trent D; Byrne, Phillip G

    2015-01-01

    Food availability and temperature are known to trigger phenotypic change, but the interactive effects between these factors are only beginning to be considered. The aim of this study was to examine the independent and interactive effects of long-term stochastic food availability and water temperature on larval survivorship, growth and development of the striped marsh frog, Limnodynastes peronii. Larval L. peronii were reared in conditions of either constant or stochastic food availability and in water at three different temperatures (18, 22 and 26°C), and effects on survival, growth and development were quantified. Over the experimental period, larval growth rate was highest and survivorship lowest at the warmest temperature. However, changes in food availability mediated the effects of temperature, with slower larval growth and higher survivorship in stochastic food availability treatments. Tadpoles in the stochastic food availability treatments did not reach metamorphosis during the experimental period, suggesting that developmental stasis may have been induced by food restriction. Overall, these results demonstrate that changes in food availability alter the effects of water temperature on survival, growth and development. From an applied perspective, understanding how environmental factors interact to cause phenotypic change may assist with amphibian conservation by improving the number of tadpoles generated in captive breeding programmes.

  5. Long-term changes in food availability mediate the effects of temperature on growth, development and survival in striped marsh frog larvae: implications for captive breeding programmes

    PubMed Central

    Courtney Jones, Stephanie K.; Munn, Adam J.; Penman, Trent D.; Byrne, Phillip G.

    2015-01-01

    Food availability and temperature are known to trigger phenotypic change, but the interactive effects between these factors are only beginning to be considered. The aim of this study was to examine the independent and interactive effects of long-term stochastic food availability and water temperature on larval survivorship, growth and development of the striped marsh frog, Limnodynastes peronii. Larval L. peronii were reared in conditions of either constant or stochastic food availability and in water at three different temperatures (18, 22 and 26°C), and effects on survival, growth and development were quantified. Over the experimental period, larval growth rate was highest and survivorship lowest at the warmest temperature. However, changes in food availability mediated the effects of temperature, with slower larval growth and higher survivorship in stochastic food availability treatments. Tadpoles in the stochastic food availability treatments did not reach metamorphosis during the experimental period, suggesting that developmental stasis may have been induced by food restriction. Overall, these results demonstrate that changes in food availability alter the effects of water temperature on survival, growth and development. From an applied perspective, understanding how environmental factors interact to cause phenotypic change may assist with amphibian conservation by improving the number of tadpoles generated in captive breeding programmes. PMID:27293714

  6. Immunological ignorance allows long-term gene expression after perinatal recombinant adeno-associated virus-mediated gene transfer to murine airways.

    PubMed

    Carlon, Marianne S; Vidović, Dragana; Dooley, James; da Cunha, Marina Mori; Maris, Michael; Lampi, Youlia; Toelen, Jaan; Van den Haute, Chris; Baekelandt, Veerle; Deprest, Jan; Verbeken, Erik; Liston, Adrian; Gijsbers, Rik; Debyser, Zeger

    2014-06-01

    Gene therapy of the lung has the potential to treat life-threatening diseases such as cystic fibrosis and α(1)-antitrypsin or surfactant deficiencies. A major hurdle for successful gene therapy is the development of an immune response against the transgene and/or viral vector. We hypothesized that by targeting the airways in the perinatal period, induction of an immune response against the vector particle could be prevented because of immaturity of the immune system, in turn allowing repeated gene transfer later in adult life to ensure long-term gene expression. Therefore, we readministered recombinant adeno-associated viral vector serotype 5 (rAAV2/5) to mouse airways 3 and 6 months after initial perinatal gene transfer. Our findings demonstrate that perinatal rAAV2/5-mediated gene transfer to the airways avoids a strong immune response. This immunological ignorance allows the readministration of an autologous vector later in adult life, resulting in efficient and stable gene transfer up to 7 months, without evidence of a decrease in transgene expression. Together, these data provide a basis to further explore perinatal gene therapy for pulmonary conditions with adequate gene expression up to 7 months.

  7. Rescue of Cyclic AMP Mediated Long Term Potentiation Impairment in the Hippocampus of Mecp2 Knockout (Mecp2(-/y) ) Mice by Rolipram.

    PubMed

    Balakrishnan, Saju; Niebert, Marcus; Richter, Diethelm W

    2016-01-01

    Rett syndrome (RTT) patients experience learning difficulties and memory loss. Analogous deficits of hippocampal plasticity are reported in mouse models of RTT. To elucidate the underlying pathophysiology, we studied long term potentiation (LTP) at the CA3 to CA1 synapses in the hippocampus in acute brain slices from WT and Mecp2(-/y) mice, by either activating cAMP dependent pathway or using high frequency stimulation, by means of patch clamp. We have observed that, the NMDA channel current characteristics remain unchanged in the Mecp2(-/y) mice. The adenylyl cyclase (AC) agonist forskolin evoked a long lasting potentiation of evoked EPSCs in WT CA1 neurons, but only minimally enhanced the EPSCs in the Mecp2(-/y) mice. This weaker potentiation in Mecp2 (-/) (y) mice was ameliorated by application of phosphodiesterase 4 inhibitor rolipram. The hyperpolarization activated cyclic nucleotide gated channel current (I h) was potentiated to similar extent by forskolin in both phenotypes. Multiple tetanus induced cAMP-dependent plasticity was also impaired in the Mecp2 (-/) (y) mice, and was also partially rescued by rolipram. Western blot analysis of CA region of Mecp2 (-/) (y) mice hippocampus revealed more than twofold up-regulation of protein kinase A (PKA) regulatory subunits, while the expression of the catalytic subunit remained unchanged. We hypothesize that the overexpressed PKA regulatory subunits buffer cAMP and restrict the PKA mediated phosphorylation of target proteins necessary for LTP. Blocking the degradation of cAMP, thereby saturating the regulatory subunits alleviated this defect.

  8. Adenosine monophosphate activated protein kinase (AMPK), a mediator of estradiol-induced apoptosis in long-term estrogen deprived breast cancer cells.

    PubMed

    Chen, Haiyan; Wang, Ji-Ping; Santen, Richard J; Yue, Wei

    2015-06-01

    Estrogens stimulate growth of hormone-dependent breast cancer but paradoxically induce tumor regress under certain circumstances. We have shown that long-term estrogen deprivation (LTED) enhances the sensitivity of hormone dependent breast cancer cells to estradiol (E2) so that physiological concentrations of estradiol induce apoptosis in these cells. E2-induced apoptosis involve both intrinsic and extrinsic pathways but precise mechanisms remain unclear. We found that exposure of LTED MCF-7 cells to E2 activated AMP activated protein kinase (AMPK). In contrast, E2 inhibited AMPK activation in wild type MCF-7 cells where E2 prevents apoptosis. As a result of AMPK activation, the transcriptional activity of FoxO3, a downstream factor of AMPK, was up-regulated in E2 treatment of LTED. Increased activity of FoxO3 was demonstrated by up-regulation of three FoxO3 target genes, Bim, Fas ligand (FasL), and Gadd45α. Among them, Bim and FasL mediate intrinsic and extrinsic apoptosis respectively and Gadd45α causes cell cycle arrest at the G2/M phase. To further confirm the role of AMPK in apoptosis, we used AMPK activator AICAR in wild type MCF-7 cells and examined apoptosis, proliferation and expression of Bim, FasL, and Gadd45α. The effects of AICAR on these parameters recapitulated those observed in E2-treated LTED cells. Activation of AMPK by AICAR also increased expression of Bax in MCF-7 cells and its localization to mitochondria, which is a required process for apoptosis. These results reveal that AMPK is an important factor mediating E2-induced apoptosis in LTED cells, which is implicative of therapeutic potential for relapsing breast cancer after hormone therapy.

  9. Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM.

    PubMed

    Amor, Veronique; Feinberg, Konstantin; Eshed-Eisenbach, Yael; Vainshtein, Anya; Frechter, Shahar; Grumet, Martin; Rosenbluth, Jack; Peles, Elior

    2014-04-09

    Clustering of Na(+) channels at the nodes of Ranvier is coordinated by myelinating glia. In the peripheral nervous system, axoglial contact at the nodes is mediated by the binding of gliomedin and glial NrCAM to axonal neurofascin 186 (NF186). This interaction is crucial for the initial clustering of Na(+) channels at heminodes. As a result, it is not clear whether continued axon-glial contact at nodes of Ranvier is required to maintain these channels at the nodal axolemma. Here, we report that, in contrast to mice that lack either gliomedin or NrCAM, absence of both molecules (and hence the glial clustering signal) resulted in a gradual loss of Na(+) channels and other axonal components from the nodes, the formation of binary nodes, and dysregulation of nodal gap length. Therefore, these mice exhibit neurological abnormalities and slower nerve conduction. Disintegration of the nodes occurred in an orderly manner, starting with the disappearance of neurofascin 186, followed by the loss of Na(+) channels and ankyrin G, and then βIV spectrin, a sequence that reflects the assembly of nodes during development. Finally, the absence of gliomedin and NrCAM led to the invasion of the outermost layer of the Schwann cell membrane beyond the nodal area and the formation of paranodal-like junctions at the nodal gap. Our results reveal that axon-glial contact mediated by gliomedin, NrCAM, and NF186 not only plays a role in Na(+) channel clustering during development, but also contributes to the long-term maintenance of Na(+) channels at nodes of Ranvier.

  10. Long-Term Maintenance of Na+ Channels at Nodes of Ranvier Depends on Glial Contact Mediated by Gliomedin and NrCAM

    PubMed Central

    Amor, Veronique; Feinberg, Konstantin; Eshed-Eisenbach, Yael; Vainshtein, Anya; Frechter, Shahar; Grumet, Martin; Rosenbluth, Jack

    2014-01-01

    Clustering of Na+ channels at the nodes of Ranvier is coordinated by myelinating glia. In the peripheral nervous system, axoglial contact at the nodes is mediated by the binding of gliomedin and glial NrCAM to axonal neurofascin 186 (NF186). This interaction is crucial for the initial clustering of Na+ channels at heminodes. As a result, it is not clear whether continued axon-glial contact at nodes of Ranvier is required to maintain these channels at the nodal axolemma. Here, we report that, in contrast to mice that lack either gliomedin or NrCAM, absence of both molecules (and hence the glial clustering signal) resulted in a gradual loss of Na+ channels and other axonal components from the nodes, the formation of binary nodes, and dysregulation of nodal gap length. Therefore, these mice exhibit neurological abnormalities and slower nerve conduction. Disintegration of the nodes occurred in an orderly manner, starting with the disappearance of neurofascin 186, followed by the loss of Na+ channels and ankyrin G, and then βIV spectrin, a sequence that reflects the assembly of nodes during development. Finally, the absence of gliomedin and NrCAM led to the invasion of the outermost layer of the Schwann cell membrane beyond the nodal area and the formation of paranodal-like junctions at the nodal gap. Our results reveal that axon-glial contact mediated by gliomedin, NrCAM, and NF186 not only plays a role in Na+ channel clustering during development, but also contributes to the long-term maintenance of Na+ channels at nodes of Ranvier. PMID:24719088

  11. Effects of Aluminium on Long-Term Memory in Rats and on SIRT1 Mediating the Transcription of CREB-Dependent Gene in Hippocampus.

    PubMed

    Yan, Dongying; Jin, Cuihong; Cao, Yang; Wang, Lulu; Lu, Xiaobo; Yang, Jinghua; Wu, Shengwen; Cai, Yuan

    2017-10-01

    Epidemiological investigations have shown that aluminium (Al) is an important neurotoxicant which can be absorbed by organisms via various routes. Previous studies have confirmed that exposure to Al could cause neurodegenerative diseases, decline CREB phosphorylation and then down-regulate the transcription and protein expression of its target genes including BDNF. However, recent studies revealed that CREB activation alone was far from enough to activate the expression of long-term memory (LTM)-related genes; there might be other regulatory factors involved in this process. Several studies showed that TORC1 might be involved in regulating the transcription of downstream target genes as well. Also, TORC1 could be mediated by SIRT1 during the formation of LTM. However, the role of CREB regulating system in Al-induced LTM impairment was still not utterly elucidated till now. This study was designed to establish the rat model of subchronic Al exposure to observe the neuroethology, regulatory factor levels and molecular biological alterations in hippocampal cells. The results showed that, with the increasing AlCl3 dose, blood Al content increased gradually; morphology of the hippocampus and neuronal ultrastructure were aberrant; in the Morris water maze test, the escape latency and distance travelled became longer, swimming traces turned more complicated in the place navigation test; intracellular Ca(2+) , cAMP levels declined significantly in AlCl3 -treated rats, followed by abated nuclear translocation of TORC1 and decreased SIRT1, TORC1 and pCREB levels. These results indicate that SIRT1 and TORC1 might play an important mediating role in Al-induced LTM impairment. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  12. Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial.

    PubMed

    Pickles, Andrew; Le Couteur, Ann; Leadbitter, Kathy; Salomone, Erica; Cole-Fletcher, Rachel; Tobin, Hannah; Gammer, Isobel; Lowry, Jessica; Vamvakas, George; Byford, Sarah; Aldred, Catherine; Slonims, Vicky; McConachie, Helen; Howlin, Patricia; Parr, Jeremy R; Charman, Tony; Green, Jonathan

    2016-11-19

    It is not known whether early intervention can improve long-term autism symptom outcomes. We aimed to follow-up the Preschool Autism Communication Trial (PACT), to investigate whether the PACT intervention had a long-term effect on autism symptoms and continued effects on parent and child social interaction. PACT was a randomised controlled trial of a parent-mediated social communication intervention for children aged 2-4 years with core autism. Follow-up ascertainment was done at three specialised clinical services centres in the UK (London, Manchester, and Newcastle) at a median of 5·75 years (IQR 5·42-5·92) from the original trial endpoint. The main blinded outcomes were the comparative severity score (CSS) from the Autism Diagnostic Observation Schedule (ADOS), the Dyadic Communication Assessment Measure (DCMA) of the proportion of child initiatiations when interacting with the parent, and an expressive-receptive language composite. All analyses followed the intention-to-treat principle. PACT is registered with the ISRCTN registry, number ISRCTN58133827. 121 (80%) of the 152 trial participants (59 [77%] of 77 assigned to PACT intervention vs 62 [83%] of 75 assigned to treatment as usual) were traced and consented to be assessed between July, 2013, and September, 2014. Mean age at follow-up was 10·5 years (SD 0·8). Group difference in favour of the PACT intervention based on ADOS CSS of log-odds effect size (ES) was 0·64 (95% CI 0·07 to 1·20) at treatment endpoint and ES 0·70 (95% CI -0·05 to 1·47) at follow-up, giving an overall reduction in symptom severity over the course of the whole trial and follow-up period (ES 0·55, 95% CI 0·14 to 0·91, p=0·004). Group difference in DCMA child initiations at follow-up showed a Cohen's d ES of 0·29 (95% CI -0.02 to 0.57) and was significant over the course of the study (ES 0·33, 95% CI 0·11 to 0·57, p=0·004). There were no group differences in the language composite at follow-up (ES 0·15, 95% CI -0

  13. Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges

    PubMed Central

    2013-01-01

    Background Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein. Results Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin’s suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor. Conclusions A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod’s innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and

  14. Evidence for inflammation-mediated memory dysfunction in gastropods: putative PLA2 and COX inhibitors abolish long-term memory failure induced by systemic immune challenges.

    PubMed

    Hermann, Petra M; Park, Deborah; Beaulieu, Emily; Wildering, Willem C

    2013-08-06

    Previous studies associate lipid peroxidation with long-term memory (LTM) failure in a gastropod model (Lymnaea stagnalis) of associative learning and memory. This process involves activation of Phospholipase A2 (PLA2), an enzyme mediating the release of fatty acids such as arachidonic acid that form the precursor for a variety of pro-inflammatory lipid metabolites. This study investigated the effect of biologically realistic challenges of L. stagnalis host defense response system on LTM function and potential involvement of PLA2, COX and LOX therein. Systemic immune challenges by means of β-glucan laminarin injections induced elevated H2O2 release from L. stagnalis circulatory immune cells within 3 hrs of treatment. This effect dissipated within 24 hrs after treatment. Laminarin exposure has no direct effect on neuronal activity. Laminarin injections disrupted LTM formation if training followed within 1 hr after injection but had no behavioural impact if training started 24 hrs after treatment. Intermediate term memory was not affected by laminarin injection. Chemosensory and motor functions underpinning the feeding response involved in this learning model were not affected by laminarin injection. Laminarin's suppression of LTM induction was reversed by treatment with aristolochic acid, a PLA2 inhibitor, or indomethacin, a putative COX inhibitor, but not by treatment with nordihydro-guaiaretic acid, a putative LOX inhibitor. A systemic immune challenge administered shortly before behavioural training impairs associative LTM function in our model that can be countered with putative inhibitors of PLA2 and COX, but not LOX. As such, this study establishes a mechanistic link between the state of activity of this gastropod's innate immune system and higher order nervous system function. Our findings underwrite the rapidly expanding view of neuroinflammatory processes as a fundamental, evolutionary conserved cause of cognitive and other nervous system disorders.

  15. Viral-mediated Zif268 expression in the prefrontal cortex protects against gonadectomy-induced working memory, long-term memory, and social interaction deficits in male rats.

    PubMed

    Dossat, Amanda M; Jourdi, Hussam; Wright, Katherine N; Strong, Caroline E; Sarkar, Ambalika; Kabbaj, Mohamed

    2017-01-06

    In humans, some males experience reductions in testosterone levels, as a natural consequence of aging or in the clinical condition termed hypogonadism, which are associated with impaired cognitive performance and mood disorder(s). Some of these behavioral deficits can be reversed by testosterone treatment. Our previous work in rats reported that sex differences in the expression of the transcription factor Zif268, a downstream target of testosterone, within the medial prefrontal cortex (mPFC) mediates sex differences in social interaction. In the present study, we aimed to examine the effects of gonadectomy (GNX) in male rats on mPFC Zif268 expression, mood and cognitive behaviors. We also examined whether reinstitution of Zif268 in GNX rats will correct some of the behavioral deficits observed following GNX. Our results show that GNX induced a downregulation of Zif268 protein in the mPFC, which was concomitant with impaired memory in the y-maze and spontaneous object recognition test, reduced social interaction time, and depression-like behaviors in the forced swim test. Reinstitution of mPFC Zif268, using a novel adeno-associated-viral (AAV) construct, abrogated GNX-induced working memory and long-term memory impairments, and reductions in social interaction time, but not GNX-induced depression-like behaviors. These findings suggest that mPFC Zif268 exerts beneficial effects on memory and social interaction, and could be a potential target for novel treatments for behavioral impairments observed in hypogonadal and aged men with declining levels of gonadal hormones.

  16. Rescue of Cyclic AMP Mediated Long Term Potentiation Impairment in the Hippocampus of Mecp2 Knockout (Mecp2-/y) Mice by Rolipram

    PubMed Central

    Balakrishnan, Saju; Niebert, Marcus; Richter, Diethelm W.

    2016-01-01

    Rett syndrome (RTT) patients experience learning difficulties and memory loss. Analogous deficits of hippocampal plasticity are reported in mouse models of RTT. To elucidate the underlying pathophysiology, we studied long term potentiation (LTP) at the CA3 to CA1 synapses in the hippocampus in acute brain slices from WT and Mecp2-/y mice, by either activating cAMP dependent pathway or using high frequency stimulation, by means of patch clamp. We have observed that, the NMDA channel current characteristics remain unchanged in the Mecp2-/y mice. The adenylyl cyclase (AC) agonist forskolin evoked a long lasting potentiation of evoked EPSCs in WT CA1 neurons, but only minimally enhanced the EPSCs in the Mecp2-/y mice. This weaker potentiation in Mecp2-/y mice was ameliorated by application of phosphodiesterase 4 inhibitor rolipram. The hyperpolarization activated cyclic nucleotide gated channel current (Ih) was potentiated to similar extent by forskolin in both phenotypes. Multiple tetanus induced cAMP-dependent plasticity was also impaired in the Mecp2-/y mice, and was also partially rescued by rolipram. Western blot analysis of CA region of Mecp2-/y mice hippocampus revealed more than twofold up-regulation of protein kinase A (PKA) regulatory subunits, while the expression of the catalytic subunit remained unchanged. We hypothesize that the overexpressed PKA regulatory subunits buffer cAMP and restrict the PKA mediated phosphorylation of target proteins necessary for LTP. Blocking the degradation of cAMP, thereby saturating the regulatory subunits alleviated this defect. PMID:26869885

  17. Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias.

    PubMed

    Mitoma, Hiroshi; Adhikari, Keya; Aeschlimann, Daniel; Chattopadhyay, Partha; Hadjivassiliou, Marios; Hampe, Christiane S; Honnorat, Jérôme; Joubert, Bastien; Kakei, Shinji; Lee, Jongho; Manto, Mario; Matsunaga, Akiko; Mizusawa, Hidehiro; Nanri, Kazunori; Shanmugarajah, Priya; Yoneda, Makoto; Yuki, Nobuhiro

    2016-04-01

    In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias.

  18. Maturation and long-term hypoxia-induced acclimatization responses in PKC-mediated signaling pathways in ovine cerebral arterial contractility.

    PubMed

    Goyal, Ravi; Mittal, Ashwani; Chu, Nina; Arthur, Rebecca Afiba; Zhang, Lubo; Longo, Lawrence D

    2010-11-01

    In the developing fetus, cerebral arteries (CA) show striking differences in signal transduction mechanisms compared with the adult, and these differences are magnified in response to high-altitude long-term hypoxia (LTH). In addition, in the mature organism, cerebrovascular acclimatization to LTH may be associated with several clinical problems, the mechanisms of which are unknown. Because PKC plays a key role in regulating CA contractility, in fetal and adult cerebral arteries, we tested the hypothesis that LTH differentially regulates the PKC-mediated Ca(2+) sensitization pathways and contractility. In four groups of sheep [fetal normoxic (FN), fetal hypoxic (FH), adult normoxic (AN), and adult hypoxic (AH)], we examined, simultaneously, responses of CA tension and intracellular Ca(2+) concentration and measured CA levels of PKC, ERK1/2, RhoA, 20-kDa myosin light chain, and the 17-kDa PKC-potentiated myosin phosphatase inhibitor CPI-17. The PKC activator phorbol 12,13-dibutyrate (PDBu) produced robust contractions in all four groups. However, PDBu-induced contractions were significantly greater in AH CA than in the other groups. In all CA groups except AH, in the presence of MEK inhibitor (U-0126), the PDBu-induced contractions were increased a further 20-30%. Furthermore, in adult CA, PDBu led to increased phosphorylation of ERK1, but not ERK2; in fetal CA, the reverse was the case. PDBu-stimulated ERK2 phosphorylation also was significantly greater in FH than FN CA. Also, although RhoA/Rho kinase played a significant role in PDBu-mediated contractions of FN CA, this was not the case in FH or either adult group. Also, whereas CPI-17 had a significant role in adult CA contractility, this was not the case for the fetus. Overall, in ovine CA, the present study demonstrates several important maturational and LTH acclimatization changes in PKC-induced contractile responses and downstream pathways. The latter may play a key role in the pathophysiologic disorders

  19. Maturation and long-term hypoxia-induced acclimatization responses in PKC-mediated signaling pathways in ovine cerebral arterial contractility

    PubMed Central

    Goyal, Ravi; Mittal, Ashwani; Chu, Nina; Arthur, Rebecca Afiba; Zhang, Lubo

    2010-01-01

    In the developing fetus, cerebral arteries (CA) show striking differences in signal transduction mechanisms compared with the adult, and these differences are magnified in response to high-altitude long-term hypoxia (LTH). In addition, in the mature organism, cerebrovascular acclimatization to LTH may be associated with several clinical problems, the mechanisms of which are unknown. Because PKC plays a key role in regulating CA contractility, in fetal and adult cerebral arteries, we tested the hypothesis that LTH differentially regulates the PKC-mediated Ca2+ sensitization pathways and contractility. In four groups of sheep [fetal normoxic (FN), fetal hypoxic (FH), adult normoxic (AN), and adult hypoxic (AH)], we examined, simultaneously, responses of CA tension and intracellular Ca2+ concentration and measured CA levels of PKC, ERK1/2, RhoA, 20-kDa myosin light chain, and the 17-kDa PKC-potentiated myosin phosphatase inhibitor CPI-17. The PKC activator phorbol 12,13-dibutyrate (PDBu) produced robust contractions in all four groups. However, PDBu-induced contractions were significantly greater in AH CA than in the other groups. In all CA groups except AH, in the presence of MEK inhibitor (U-0126), the PDBu-induced contractions were increased a further 20–30%. Furthermore, in adult CA, PDBu led to increased phosphorylation of ERK1, but not ERK2; in fetal CA, the reverse was the case. PDBu-stimulated ERK2 phosphorylation also was significantly greater in FH than FN CA. Also, although RhoA/Rho kinase played a significant role in PDBu-mediated contractions of FN CA, this was not the case in FH or either adult group. Also, whereas CPI-17 had a significant role in adult CA contractility, this was not the case for the fetus. Overall, in ovine CA, the present study demonstrates several important maturational and LTH acclimatization changes in PKC-induced contractile responses and downstream pathways. The latter may play a key role in the pathophysiologic disorders

  20. Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression.

    PubMed

    Niere, Farr; Wilkerson, Julia R; Huber, Kimberly M

    2012-04-25

    Group 1 metabotropic glutamate receptor (mGluR)-stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in the mouse model of fragile X syndrome, Fmr1 knock-out (KO) mice. Fmr1 encodes fragile X mental retardation protein (FMRP), a dendritic RNA binding protein that functions, in part, as a translational suppressor. It is unknown whether and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP, which contributes to translational activation of some target mRNAs. Here, we report that PP2A and dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid (5 min) increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, but mGluR-triggered Arc synthesis is absent. Lentiviral-mediated expression of wild-type FMRP in Fmr1 KO neurons suppresses basal dendritic Arc levels and mGluR-LTD, and restores rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady-state dendritic Arc levels but does not rescue mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses dendritic Arc nor supports mGluR-induced Arc synthesis. Accordingly, S500D-FMRP expression in Fmr1 KO neurons suppresses mGluR-LTD, whereas S500A-FMRP has no effect. These data support a model in which phosphorylated FMRP functions to suppress steady-state translation of Arc and LTD. Upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated, which contributes to rapid new synthesis of Arc and mGluR-LTD.

  1. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non obese humans

    USDA-ARS?s Scientific Manuscript database

    Calorie restriction (CR) inhibits inflammation and slows aging in many animal species, but in rodents housed in pathogen-free facilities, CR impairs immunity against certain pathogens. However, little is known about the effects of long-term moderate CR on immune function in humans. In this multi-cen...

  2. Long-term testing

    SciTech Connect

    Ferber, M.; Graves, G.A. Jr.

    1994-12-31

    Land-based gas turbines are significantly different from automotive gas turbines in that they are designed to operate for 50,000 h or greater (compared to 5,000--10,000 h). The primary goal of this research is to determine the long-term survivability of ceramic materials for industrial gas turbine applications. Research activities in this program focus on the evaluation of the static tensile creep and stress rupture (SR) behavior of three commercially available structural ceramics which have been identified by the gas turbine manufacturers as leading candidates for use in industrial gas turbines. For each material investigated, a minimum of three temperatures and four stresses will be used to establish the stress and temperature sensitivities of the creep and SR behavior. Because existing data for many candidate structural ceramics are limited to testing times less than 2,000 h, this program will focus on extending these data to times on the order of 10,000 h, which represents the lower limit of operating time anticipated for ceramic blades and vanes in gas turbine engines. A secondary goal of the program will be to investigate the possibility of enhancing life prediction estimates by combining interrupted tensile SR tests and tensile dynamic fatigue tests in which tensile strength is measured as a function of stressing rate. The third goal of this program will be to investigate the effects of water vapor upon the SR behavior of the three structural ceramics chosen for the static tensile studies by measuring the flexural strength as a function of stressing rate at three temperatures.

  3. Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage

    PubMed Central

    Prestori, Francesca; Bonardi, Claudia; Mapelli, Lisa; Lombardo, Paola; Goselink, Rianne; De Stefano, Maria Egle; Gandolfi, Daniela; Mapelli, Jonathan; Bertrand, Daniel; Schonewille, Martijn; De Zeeuw, Chris; D’Angelo, Egidio

    2013-01-01

    The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation. PMID:23741401

  4. Mitigation of cerebellar neuropathy in globoid cell leukodystrophy mice by AAV-mediated gene therapy.

    PubMed

    Lin, Dar-Shong; Hsiao, Chung-Der; Lee, Allan Yueh-Luen; Ho, Che-Sheng; Liu, Hsuan-Liang; Wang, Tuen-Jen; Jian, Yuan-Ren; Hsu, Jui-Cheng; Huang, Zon-Darr; Lee, Tsung-Han; Chiang, Ming-Fu

    2015-10-15

    Globoid cell leukodystrophy (GLD) is an autosomal recessive, lysosomal storage disease caused by deficiency of the enzyme galactocerebrosidase (GALC). The absence of GALC activity leads to the accumulation of the toxic substance psychosine and the preferential loss of myelinating cells in the central and peripheral nervous systems. Profound demyelination, astrogliosis and axonopathy are the hallmarks of the pathogenesis of GLD, and cerebellar ataxia is one of the dominant manifestations in adolescents and adults affected with GLD. To date, studies regarding cerebellar degeneration in GLD are limited. In this study, the efficacy of cerebellum-targeted gene therapy on the cerebellar neuropathology in twitcher mice (a murine model of GLD) has been validated. We observed degeneration of Purkinje cells, Bergmann glia, and granule cells in addition to astrocytosis and demyelination in the cerebellum of the twitcher mice. Ultrastructural analysis revealed dark cell degeneration and disintegration of the cellular composition of Purkinje cells in untreated twitcher mice. In addition, the expressions of neurotrophic factors CNTF, GDNF and IGF-I were up-regulated and the expression of BDNF was down-regulated. Intracerebellar-mediated gene therapy efficiently corrected enzymatic deficiency by direct transduction to Purkinje cells and cross-correction in other cell types in the cerebellum, leading to the amelioration of both neuroinflammation and demyelination. The population, dendritic territory, and axonal processes of Purkinje cells remained normal in the cerebellum of treated twitcher mice, where radial fibers of Bergmann glia spanned the molecular layer and collateral branches ensheathed the dendritic processes of Purkinje cells. Moreover, the aberrant expressions of neurotrophic factors were mitigated in the cerebellum of treated twitcher mice, indicating the preservation of cellular function in addition to maintaining the neuronal architecture. The life span of the

  5. Disturbed mitotic progression and genome segregation are involved in cell transformation mediated by nano-TiO2 long-term exposure

    SciTech Connect

    Huang Shing; Chueh Pinju; Lin Yunwei; Shih Tungsheng; Chuang Showmei

    2009-12-01

    Titanium dioxide (TiO2) nano-particles (< 100 nm in diameter) have been of interest in a wide range of applications, such as in cosmetics and pharmaceuticals because of their low toxicity. However, recent studies have shown that TiO2 nano-particles (nano-TiO2) induce cytotoxicity and genotoxicity in various lines of cultured cells as well as tumorigenesis in animal models. The biological roles of nano-TiO2 are shown to be controversial and no comprehensive study paradigm has been developed to investigate their molecular mechanisms. In this study, we showed that short-term exposure to nano-TiO2 enhanced cell proliferation, survival, ERK signaling activation and ROS production in cultured fibroblast cells. Moreover, long-term exposure to nano-TiO2 not only increased cell survival and growth on soft agar but also the numbers of multinucleated cells and micronucleus (MN) as suggested in confocal microscopy analysis. Cell cycle phase analysis showed G2/M delay and slower cell division in long-term exposed cells. Most importantly, long-term TiO2 exposure remarkably affected mitotic progression at anaphase and telophase leading to aberrant multipolar spindles and chromatin alignment/segregation. Moreover, PLK1 was demonstrated as the target for nano-TiO2 in the regulation of mitotic progression and exit. Notably, a higher fraction of sub-G1 phase population appeared in TiO2-exposed cells after releasing from G2/M synchronization. Our results demonstrate that long-term exposure to nano-TiO2 disturbs cell cycle progression and duplicated genome segregation, leading to chromosomal instability and cell transformation.

  6. Lipid signalling mediated by PLD/PA modulates proline and H2O2 levels in barley seedlings exposed to short- and long-term chilling stress.

    PubMed

    Peppino Margutti, Micaela; Reyna, Matias; Meringer, María Verónica; Racagni, Graciela E; Villasuso, Ana Laura

    2017-04-01

    Phospholipase D (PLD) hydrolyses phospholipids to yield phosphatidic acid (PA) and a head group, and is involved in responses to a variety of environmental stresses, including chilling and freezing stress. Barley responses to chilling stress (induced by incubating seedlings at 4 °C) are dynamic and the duration of stress, either short (0-180 min) or long-term (24-36 h) had a significant impact on the response. We investigated the roles of PLD/PA in responses of barley (Hordeum vulgare) seedlings to short and long-term chilling stress, based on regulation of proline and reactive oxygen species (ROS) levels. Short-term chilling stress caused rapid and transient increases in PLD activity, proline level, and ROS levels in young leaves. PLD has the ability to catalyse the transphosphatidylation reaction leading to formation of phosphatidylalcohol (preferentially, to PA). Pre-treatment of seedlings with 1-butanol significantly increased proline synthesis but decreased ROS (H2O2) formation. These observations suggest that PLD is a negative regulator of proline synthesis, whereas PA/PLD promote ROS signals. Exogenous PA pre-treatment reduced the proline synthesis but enhanced H2O2 formation. Effects of long-term chilling stress on barley seedlings differed from those of short-term chilling stress. E.g., PLD activity was significantly reduced in young leaves and roots, whereas proline synthesis and ROS signals were increased in roots. Exogenous ROS application enhanced proline level while exogenous proline application reduced ROS level and modulated some effects of long-term chilling stress. Our findings suggest that PLD contributes to signalling pathways in responses to short-term chilling stress in barley seedling, through regulation of the balance between proline and ROS levels. In contrast, reduced PLD activity in the response to long-term chilling stress did not affect proline level. Increased ROS levels may reflect an antioxidant system that is affected by

  7. LKB1 Regulates Cerebellar Development by Controlling Sonic Hedgehog-mediated Granule Cell Precursor Proliferation and Granule Cell Migration

    PubMed Central

    Men, Yuqin; Zhang, Aizhen; Li, Haixiang; Jin, Yecheng; Sun, Xiaoyang; Li, Huashun; Gao, Jiangang

    2015-01-01

    The Liver Kinase B1 (LKB1) gene plays crucial roles in cell differentiation, proliferation and the establishment of cell polarity. We created LKB1 conditional knockout mice (LKB1Atoh1 CKO) to investigate the function of LKB1 in cerebellar development. The LKB1Atoh1 CKO mice displayed motor dysfunction. In the LKB1Atoh1 CKO cerebellum, the overall structure had a larger volume and morelobules. LKB1 inactivationled to an increased proliferation of granule cell precursors (GCPs), aberrant granule cell migration and overproduction of unipolar brush cells. To investigate the mechanism underlying the abnormal foliation, we examined sonic hedgehog signalling (Shh) by testing its transcriptional mediators, the Gli proteins, which regulate the GCPs proliferation and cerebellar foliation during cerebellar development. The expression levels of Gli genes were significantly increased in the mutant cerebellum. In vitro assays showed that the proliferation of cultured GCPs from mutant cerebellum significantly increased, whereas the proliferation of mutant GCPs significantly decreased in the presence of a Shh inhibitor GDC-0049. Thus, LKB1 deficiency in the LKB1Atoh1 CKO mice enhanced Shh signalling, leading to the excessive GCP proliferation and the formation of extra lobules. We proposed that LKB1 regulates cerebellar development by controlling GCPs proliferation through Shh signalling during cerebellar development. PMID:26549569

  8. Long-term environmental stewardship.

    SciTech Connect

    Nagy, Michael David

    2010-08-01

    The purpose of this Supplemental Information Source Document is to effectively describe Long-Term Environmental Stewardship (LTES) at Sandia National Laboratories/New Mexico (SNL/NM). More specifically, this document describes the LTES and Long-Term Stewardship (LTS) Programs, distinguishes between the LTES and LTS Programs, and summarizes the current status of the Environmental Restoration (ER) Project.

  9. Long-term urethral catheterisation.

    PubMed

    Turner, Bruce; Dickens, Nicola

    This article discusses long-term urethral catheterisation, focusing on the relevant anatomy and physiology, indications for the procedure, catheter selection and catheter care. It is important that nurses have a good working knowledge of long-term catheterisation as the need for this intervention will increase with the rise in chronic health conditions and the ageing population.

  10. Presynaptic long-term plasticity

    PubMed Central

    Yang, Ying; Calakos, Nicole

    2013-01-01

    Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long-term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity. PMID:24146648

  11. Transduced CD34+ cells from adrenoleukodystrophy patients with HIV-derived vector mediate long-term engraftment of NOD/SCID mice.

    PubMed

    Benhamida, Sonia; Pflumio, Françoise; Dubart-Kupperschmitt, Anne; Zhao-Emonet, Jing Chao; Cavazzana-Calvo, Marina; Rocchiccioli, Francis; Fichelson, Serge; Aubourg, Patrick; Charneau, Pierre; Cartier, Nathalie

    2003-03-01

    X-linked adrenoleukodystrophy (ALD), an inherited demyelinating disorder of the central nervous system, can be corrected by allogeneic bone marrow transplantation, likely due to the turnover of brain macrophages that are bone marrow derived. ALD is characterized by an accumulation of very long chain fatty acids (VLCFA) due to the deficiency of an ATP binding cassette transporter that imports these fatty acids in peroxisomes. Murine retroviral transduction results in metabolic correction of ALD CD34(+) cells in vitro but reinfusion of these cells into ALD patients would not provide clinical benefit owing to the absence of selective advantage conferred by transgene expression. High-efficiency transduction of ALD CD34(+) peripheral blood mobilized cells was achieved using an HIV-based vector driving ALD gene expression under the elongation factor 1 alpha promoter and a protocol without prestimulation of CD34(+) cells with cytokines prior to transduction to preserve their stem cell properties. Efficient expression of the ALD gene was demonstrated in monocytes/macrophages derived from cultures of transduced ALD CD34(+) cells and in long-term culture initiating cells. VLCFA metabolism was corrected in transduced CD34(+), CFU-derived, and LTC-derived cells, indicating that the vector-encoded ALD protein was fully functional. Transplantation of transduced ALD CD34(+) cells into NOD/SCID mice resulted in long-term expression of ALD protein in monocytes/macrophages derived from engrafted stem cells.

  12. Cerebellar learning mechanisms

    PubMed Central

    Freeman, John H.

    2014-01-01

    The mechanisms underlying cerebellar learning are reviewed with an emphasis on old arguments and new perspectives on eyeblink conditioning. Eyeblink conditioning has been used for decades a model system for elucidating cerebellar learning mechanisms. The standard model of the mechanisms underlying eyeblink conditioning is that there two synaptic plasticity processes within the cerebellum that are necessary for acquisition of the conditioned response: 1) long-term depression (LTD) at parallel fiber-Purkinje cell synapses and 2) long-term potentiation (LTP) at mossy fiber-interpositus nucleus synapses. Additional Purkinje cell plasticity mechanisms may also contribute to eyeblink conditioning including LTP, excitability, and entrainment of deep nucleus activity. Recent analyses of the sensory input pathways necessary for eyeblink conditioning indicate that the cerebellum regulates its inputs to facilitate learning and maintain plasticity. Cerebellar learning during eyeblink conditioning is therefore a dynamic interactive process which maximizes responding to significant stimuli and suppresses responding to irrelevant or redundant stimuli. PMID:25289586

  13. Metabotropic glutamate receptor, mGlu5, mediates enhancements of hippocampal long-term potentiation after environmental enrichment in young and old mice.

    PubMed

    Buschler, Arne; Manahan-Vaughan, Denise

    2017-03-15

    The metabotropic glutamate (mGlu) receptor, mGlu5, is of particular relevance for hippocampal function. It is critically required for the expression of long-term potentiation (LTP) and long-term depression (LTD), regulates neuronal oscillations, maintains the stability of place fields and is required for hippocampus-dependent memory. MGlu5-dysfunctions are associated with profound cognitive deficits in humans, and mGlu5 has been targeted as a putative cognitive enhancer. Cognitive enhancement, by means of environmental enrichment (EE) in rodents, results in improved hippocampal synaptic plasticity and memory. Here, we explored whether mGlu5 contributes to these enhancements. MGlu5-antagonism dose-dependently impaired the early phase of LTP (>4 h) in the CA1 region of young(3-4 month old) mice. Late-LTP (>24 h) was also impaired. LTP (>24 h) elicited in old (10-14 month old) mice displayed reduced sensitivity to mGlu5 antagonism. Short-term potentiation (STP, < 2 h) that was elicited by weaker afferent stimulation was unaffected by mGlu5-antagonism in both age-groups. EE significantly amplified STP (<2 h) in old and young animals, but did not increase the duration of synaptic potentiation, or promote induction of LTP. The improvement in STP was prevented by mGlu5-antagonism, in both young and old animals. These results indicate that modifications of the synapse that underlie improvements of LTP by EE require the contribution of mGlu5. Strikingly, although LTP in old mice does not critically depend on mGlu5, improvements in synaptic potentiation resulting from EE are mGlu5-dependent in old mice. Regarded in light of the known role for mGlu5 in hippocampal function and pathophysiology, these data suggest that mGlu5 regulation of synaptic information storage is pivotal to optimal hippocampal function. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Different NMDA receptor subtypes mediate induction of long-term potentiation and two forms of short-term potentiation at CA1 synapses in rat hippocampus in vitro

    PubMed Central

    Volianskis, Arturas; Bannister, Neil; Collett, Valerie J; Irvine, Mark W; Monaghan, Daniel T; Fitzjohn, Stephen M; Jensen, Morten S; Jane, David E; Collingridge, Graham L

    2013-01-01

    Potentiation at synapses between CA3 and the CA1 pyramidal neurons comprises both transient and sustained phases, commonly referred to as short-term potentiation (STP or transient LTP) and long-term potentiation (LTP), respectively. Here, we utilized four subtype-selective N-methyl-d-aspartate receptor (NMDAR) antagonists to investigate whether the induction of STP and LTP is dependent on the activation of different NMDAR subtypes. We find that the induction of LTP involves the activation of NMDARs containing both the GluN2A and the GluN2B subunits. Surprisingly, however, we find that STP can be separated into two components, the major form of which involves activation of NMDARs containing both GluN2B and GluN2D subunits. These data demonstrate that synaptic potentiation at CA1 synapses is more complex than is commonly thought, an observation that has major implications for understanding the role of NMDARs in cognition. PMID:23230236

  15. Suitability of invertebrate and vertebrate cells in a portable impedance-based toxicity sensor: temperature mediated impacts on long-term survival.

    PubMed

    Curtis, T M; Collins, A M; Gerlach, B D; Brennan, L M; Widder, M W; van der Schalie, W H; Vo, N T K; Bols, N C

    2013-10-01

    Using ECIS (electric cell-substrate impedance sensing) to monitor the impedance of vertebrate cell monolayers provides a sensitive measure of toxicity for a wide range of chemical toxicants. One major limitation to using a cell-based sensor for chemical toxicant detection in the field is the difficulty in maintaining cell viability over extended periods of time prior to use. This research was performed to identify cell lines suitable for ECIS-based toxicity sensing under field conditions. A variety of invertebrate and vertebrate cell lines were screened for their abilities to be stored for extended periods of time on an enclosed fluidic biochip with minimal maintenance. Three of the ten cell lines screened exhibited favorable portability characteristics on the biochips. Interestingly, all three cell lines were derived from ectothermic vertebrates, and the storage temperature that allowed long-term cell survival on the enclosed fluidic biochips was also at the lower end of reported body temperature for the organism, suggesting that reduced cellular metabolism may be essential for longterm survival on the biochip. Future work with the ectothermic vertebrate cells will characterize their sensitivity to a wide range of chemical toxicants to determine if they are good candidates for use in a field portable toxicity sensor.

  16. Alzheimer amyloid beta-peptide A-beta25-35 blocks adenylate cyclase-mediated forms of hippocampal long-term potentiation.

    PubMed

    Bisel, Blaine E; Henkins, Kristen M; Parfitt, Karen D

    2007-02-01

    Progressive memory loss and deposition of amyloid beta (Abeta) peptides throughout cortical regions are hallmarks of Alzheimer's disease (AD). Several studies in mice and rats have shown that overexpression of amyloid precursor protein (APP) or pretreatment with Abeta peptide fragments results in the inhibition of hippocampal long-term potentiation (LTP) as well as impairments in learning and memory of hippocampal-dependent tasks. For these studies we have investigated the effects of the Abeta(25-35) peptide fragment on LTP induced by adenylate cyclase stimulation followed immediately by application of Mg(++)-free aCSF ("chemLTP"). Treatment of young adult slices with the Abeta(25-35) peptide had no significant effect on basal synaptic transmission in area CA1, but treatment with the peptide for 20 min before inducing chemLTP with isoproterenol (ISO; 1 microM) or forskolin (FSK;10 microM) + Mg(++)-free aCSF resulted in complete blockade of LTP. In contrast, normal ISO-chemLTP was observed after treatment with the control peptide Abeta(35-25). The ability of the Abeta(25-35) peptide fragment to block this and other forms of synaptic plasticity may help elucidate the mechanisms underlying hippocampal deficits observed in animal models of AD and/or AD individuals.

  17. Ganglioside inhibition of glutamate-mediated protein kinase C translocation in primary cultures of cerebellar neurons

    SciTech Connect

    Vaccarino, F.; Guidotti, A.; Costa, E.

    1987-12-01

    In primary cultures of cerebellar granule cells, protein kinase C (PKC) translocation and activation can be triggered by the stimulation of excitatory amino acid neurotransmitter receptors. Glutamate evokes a dose-related translocation of 4-..beta..-(/sup 3/H)phorbol 12,13-dibutyrate /(/sup 3/H)-P(BtO)/sub 2// binding sites from the cytosol to the neuronal membrane and stimulates the incorporation of /sup 32/P into a number of membrane proteins, particularly protein bands in the range of 80, 50, and 40 kDa. The glutamate-evoked PKC translocation is Mg/sup 2 +/ sensitive, is prevented by 2-amino-5-phosphonovalerate and phencyclidine, is not inhibited by nitrendipine (a voltage-dependent Ca/sup 2 +/-channel-blocker) but is abolished by the removal of Ca/sup 2 +/ from the incubation medium, suggesting that glutamate-mediated Ca/sup 2 +/ influx is operative in the redistribution of PKC. Exposure of granule cells to the gangliosides trisialosylgangliotetraglycosylceramide (GT1b) of monosialosylgangliotetraglycosylceramide (GM1) inhibits the translocation and activation of PKC evoked by glutamate. These glycosphingolipids fail to interfere with glutamate binding to its high-affinity recognition site of with the (/sup 3/H)P(BtO)/sub 2/ binding, nor do they affect the Ca/sup 2 +/ influx. These gangliosides may prevent PKC translocation by interfering with the PKC binding to the neuronal membrane phosphatidylserine.

  18. Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway.

    PubMed

    Wang, Yi; Wei, Wei; Wang, Yuan; Dong, Jing; Song, Binbin; Min, Hui; Teng, Weiping; Chen, Jie

    2013-09-01

    Neurotoxicity of iodine deficiency-induced hypothyroidism during developmental period results in serious impairments of brain function, such as learning and memory. These impairments are largely irreversible, and the underlying mechanisms remain unclear. In addition to hypothyroidism, iodine deficiency may cause hypothyroxinemia, a relatively subtle form of thyroid hormone deficiency. Neurotoxicity of developmental hypothyroxinemia also potentially impairs learning and memory. However, more direct evidence of the associations between developmental hypothyroxinemia and impairments of learning and memory should be provided, and the underlying mechanisms remain to be elucidated. Thus, in the present study, we investigated the effects of developmental hypothyroxinemia and hypothyroidism on long-term potentiation (LTP), a widely accepted cellular model of learning and memory, in the hippocampal CA1 region. The activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway - a pathway closely associated with synaptic plasticity and learning and memory - was also investigated. Wistar rats were treated with iodine deficient diet or methimazole (MMZ) to induce developmental hypothyroxinemia or hypothyroidism. The results showed that developmental hypothyroxinemia caused by mild iodine deficiency and developmental hypothyroidism caused by severe iodine deficiency or MMZ significantly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and

  19. Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss.

    PubMed

    Freund, Ronald K; Gibson, Emily S; Potter, Huntington; Dell'Acqua, Mark L

    2016-05-01

    Alzheimer's disease (AD) is characterized by neurofibrillary tangles, amyloid plaques, and neurodegeneration. However, this pathology is preceded by increased soluble amyloid beta (Aβ) 1-42 oligomers that interfere with the glutamatergic synaptic plasticity required for learning and memory, includingN-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). In particular, soluble Aβ(1-42) acutely inhibits LTP and chronically causes synapse loss. Many mechanisms have been proposed for Aβ-induced synaptic dysfunction, but we recently found that Aβ(1-42) inhibits the microtubule motor protein Eg5/kinesin-5. Here we compared the impacts of Aβ(1-42) and monastrol, a small-molecule Eg5 inhibitor, on LTP in hippocampal slices and synapse loss in neuronal cultures. Acute (20-minute) treatment with monastrol, like Aβ, completely inhibited LTP at doses >100 nM. In addition, 1 nM Aβ(1-42) or 50 nM monastrol inhibited LTP #x223c;50%, and when applied together caused complete LTP inhibition. At concentrations that impaired LTP, neither Aβ(1-42) nor monastrol inhibited NMDAR synaptic responses until #x223c;60 minutes, when only #x223c;25% inhibition was seen for monastrol, indicating that NMDAR inhibition was not responsible for LTP inhibition by either agent when applied for only 20 minutes. Finally, 48 hours of treatment with either 0.5-1.0μM Aβ(1-42) or 1-5μM monastrol reduced the dendritic spine/synapse density in hippocampal cultures up to a maximum of #x223c;40%, and when applied together at maximal concentrations, no additional spine loss resulted. Thus, monastrol can mimic and in some cases occlude the impact of Aβon LTP and synapse loss, suggesting that Aβinduces acute and chronic synaptic dysfunction in part through inhibiting Eg5. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  20. Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway

    SciTech Connect

    Wang, Yi; Wei, Wei; Wang, Yuan; Dong, Jing; Song, Binbin; Min, Hui; Teng, Weiping; Chen, Jie

    2013-09-01

    Neurotoxicity of iodine deficiency-induced hypothyroidism during developmental period results in serious impairments of brain function, such as learning and memory. These impairments are largely irreversible, and the underlying mechanisms remain unclear. In addition to hypothyroidism, iodine deficiency may cause hypothyroxinemia, a relatively subtle form of thyroid hormone deficiency. Neurotoxicity of developmental hypothyroxinemia also potentially impairs learning and memory. However, more direct evidence of the associations between developmental hypothyroxinemia and impairments of learning and memory should be provided, and the underlying mechanisms remain to be elucidated. Thus, in the present study, we investigated the effects of developmental hypothyroxinemia and hypothyroidism on long-term potentiation (LTP), a widely accepted cellular model of learning and memory, in the hippocampal CA1 region. The activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway – a pathway closely associated with synaptic plasticity and learning and memory – was also investigated. Wistar rats were treated with iodine deficient diet or methimazole (MMZ) to induce developmental hypothyroxinemia or hypothyroidism. The results showed that developmental hypothyroxinemia caused by mild iodine deficiency and developmental hypothyroidism caused by severe iodine deficiency or MMZ significantly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and

  1. Rb silencing mediated by the down-regulation of MeCP2 is involved in cell transformation induced by long-term exposure to hydroquinone.

    PubMed

    Liu, Linhua; Ling, Xiaoxuan; Wu, Minhua; Chen, Jialong; Chen, Shaoqiao; Tan, Qiang; Chen, Jiansong; Liu, Jiaxian; Zou, Fei

    2017-02-01

    Hydroquinone (HQ), a metabolite of benzene, is a well-known human carcinogen; however, its molecular mechanisms of action remain unclear. MeCP2 has been traditionally described as a transcriptional repressor, though growing evidence indicates that it also activates gene expression. Here, we investigated whether some epigenetic machinery genes are aberrantly expressed as target tumor suppressor genes in HQ-transformed TK6 lymphoblastoid cells. Our results showed that treatment with 5-Aza-2'-deoxycytidine or trichostatin A enhanced the expression of Rb, resulting in cell arrest in G1-phase, and subsequently, an increase in apoptosis and a decrease in cell growth. Moreover, we hypothesised that Rb was silenced by the down-regulation of MeCP2 in HQ-transformed cells, resulting in the dynamic expression of Rb and epigenetic machinery proteins in HQ-transformed cells at different time points. The expression of Rb and MeCP2 in patients with B-cell non-Hodgkin's lymphoma (B-NHL) showed that positive staining for MeCP2 or Rb was significantly lower in B-NHL tumor tissues, and these changes were significantly and negatively correlated with the grade of B-NHL. The restoration of MeCP2 in HQ-transformed cells enhanced the expression of Rb, promoted cell apoptosis, and inhibited cell growth. The changes in the expression patterns of MeCP2 and Rb were inversely correlated with the degree of DNA methylation. A ChiP assay revealed that MeCP2 proteins were recruited to the Rb promoter with lower 5'-methylcytosine levels. In conclusion, we demonstrated that the down-regulation of MeCP2 silences Rb, a process involved in cell transformation resulting from long-term exposure to HQ. © 2016 Wiley Periodicals, Inc.

  2. Mindfulness facets as differential mediators of short and long-term effects of Mindfulness-Based Cognitive Therapy in diabetes outpatients: Findings from the DiaMind randomized trial.

    PubMed

    Haenen, Sharon; Nyklíček, Ivan; van Son, Jenny; Pop, Victor; Pouwer, François

    2016-06-01

    There is increasing evidence that mindfulness-based interventions reduce psychological distress in various medical populations. However, it has hardly been studied if these effects are mediated by an increase in mindfulness. The aim of this study was to examine mediating effects of various mindfulness facets on effects of a Mindfulness Based Cognitive Therapy (MBCT) on perceived stress and mood. Outpatients with diabetes types 1 and 2 and low levels of emotional wellbeing were randomized into a group receiving MBCT (n=70) or a waiting-list control group (n=69). Primary outcomes were mood and perceived stress. Before, after and at follow-up (6months post intervention) relevant questionnaires were completed. Mediation analysis using bootstrap resampling indicated that increases in total mindfulness and the facets observing and nonreactivity mediated the effects of the intervention on depressed and angry mood, anxiety (only observing), and perceived stress (only nonreactivity) from pre- to post-intervention. In contrast, from post-intervention to follow-up, besides total mindfulness the facets of acting with awareness and nonjudging mediated the effects on depressed, anxious, and angry mood, while only nonjudging mediated the effects on perceived stress. The findings indicate that increases in levels of mindfulness mediate the effects of the Mindfulness-Based Cognitive Therapy in patients with diabetes. It is notable that different facets may be important for immediate change versus long-term outcome. These findings might be relevant for post-intervention care. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L. L.

    2003-10-01

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival of a given organism. The development and maintenance of vestibular connections are controlled by environmental gravitational stimulation as well as genetically controlled molecular interactions. This paper describes the effects of hypergravity on axonal growth and dendritic morphology, respectively. Two aspects of this vestibular adaptation are examined: (1) How does long-term exposure to hypergravity affect the development of vestibular axons? (2) How does short-term exposure to extremely rapid changes in gravity, such as those that occur during shuttle launch and landing, affect dendrites of the vestibulocerebellar system? To study the effects of longterm exposures to altered gravity, embryonic rats that developed in hypergravity were compared to microgravity-exposed and control rats. Examination of the vestibular projections from epithelia devoted to linear and angular acceleration revealed that the terminal fields segregate differently in rat embryos that gestated in each of the gravitational environments.To study the effects of short-term exposures to altered gravity, mice were exposed briefly to strong vestibular stimuli and the vestibulocerebellum was examined for any resulting morphological changes. My data show that these stimuli cause intense vestibular excitation of cerebellar Purkinje cells, which induce up-regulation of clathrin-mediated endocytosis and other morphological changes that are comparable to those seen in long-term depression. This system provides a basis for studying how the vestibular environment can modify cerebellar function, allowing animals to adapt to new environments.

  4. Fine Motor Skill Mediates Visual Memory Ability with Microstructural Neuro-correlates in Cerebellar Peduncles in Prematurely Born Adolescents.

    PubMed

    Thomas, Alyssa R; Lacadie, Cheryl; Vohr, Betty; Ment, Laura R; Scheinost, Dustin

    2017-01-19

    Adolescents born preterm (PT) with no evidence of neonatal brain injury are at risk of deficits in visual memory and fine motor skills that diminish academic performance. The association between these deficits and white matter microstructure is relatively unexplored. We studied 190 PTs with no brain injury and 92 term controls at age 16 years. The Rey-Osterrieth Complex Figure Test (ROCF), the Beery visual-motor integration (VMI), and the Grooved Pegboard Test (GPT) were collected for all participants, while a subset (40 PTs and 40 terms) underwent diffusion-weighted magnetic resonance imaging. PTs performed more poorly than terms on ROCF, VMI, and GPT (all P < 0.01). Mediation analysis showed fine motor skill (GPT score) significantly mediates group difference in ROCF and VMI (all P < 0.001). PTs showed a negative correlation (P < 0.05, corrected) between fractional anisotropy (FA) in the bilateral middle cerebellar peduncles and GPT score, with higher FA correlating to lower (faster task completion) GPT scores, and between FA in the right superior cerebellar peduncle and ROCF scores. PTs also had a positive correlation (P < 0.05, corrected) between VMI and left middle cerebellar peduncle FA. Novel strategies to target fine motor skills and the cerebellum may help PTs reach their full academic potential.

  5. Acquisition of contextual discrimination involves the appearance of a RAS-GRF1/p38 mitogen-activated protein (MAP) kinase-mediated signaling pathway that promotes long term potentiation (LTP).

    PubMed

    Jin, Shan-Xue; Arai, Junko; Tian, Xuejun; Kumar-Singh, Rajendra; Feig, Larry A

    2013-07-26

    RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and RAC GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway.

  6. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L.

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival. We are studying two aspects of this vestibular adaptation: (1) How does long-term exposure to microgravity and hypergravity affect the development of vestibular afferents? (2) How does short- term exposure to extremely rapid changes in gravity, such as those that occur during launch and landing, affect the vestibular system. During space flight the gravistatic receptors in the otolith organs are effectively unloaded. In hypergravity conditions they are overloaded. However, the angular acceleration receptors of the semicircular canals receive relatively normal stimulation in both micro- and hypergravity.Rat embryos exposed to microgravity from gestation day 10 (prior to vestibular function) until gestation day 20 (vestibular system is somewhat functional) showed that afferents from the posterior vertical canal projecting to the medial vestibular nucleus developed similarly in microgravity, hypergravity, and in controls . However, afferents from the saccule showed delayed development in microgravity as compared to development in hypergravity and in controls. Cerebellar plasticity is crucial for modification of sensory-motor control and learning. Thus we explored the possibility that strong vestibular stimuli would modify cerebellar motor control (i.e., eye movement, postural control, gut motility) by altering the morphology of cerebellar Purkinje cells. To study the effects of short-term exposures to strong vestibular stimuli we focused on structural changes in the vestibulo-cerebellum that are caused by strong vestibular stimuli. Adult mice were exposed to various combinations of constant and/or rapidly changing angular and linear accelerations for 8.5 min (the time length of shuttle launch). Our data shows that these stimuli cause intense excitation of cerebellar Purkinje cells, inducing up-regulation of clathrin-mediated endocytosis

  7. Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

    PubMed Central

    Coronas-Samano, Guillermo; Baker, Keeley L.; Tan, Winston J. T.; Ivanova, Alla V.; Verhagen, Justus V.

    2016-01-01

    Insufficient advances in the development of effective therapeutic treatments of sporadic Alzheimer's Disease (sAD) to date are largely due to the lack of sAD-relevant animal models. While the vast majority of models do recapitulate AD's hallmarks of plaques and tangles by virtue of tau and/or beta amyloid overexpression, these models do not reflect the fact that in sAD (unlike familial AD) these genes are not risk factors per se and that other mechanisms like oxidative stress, metabolic dysregulation and inflammation play key roles in AD etiology. Here we characterize and propose the Fus1 KO mice that lack a mitochondrial protein Fus1/Tusc2 as a new sAD model. To establish sAD relevance, we assessed sAD related deficits in Fus1 KO and WT adult mice of 4–5 months old, the equivalent human age when the earliest cognitive and olfactory sAD symptoms arise. Fus1 KO mice showed oxidative stress (increased levels of ROS, decreased levels of PRDX1), disruption of metabolic homeostasis (decreased levels of ACC2, increased phosphorylation of AMPK), autophagy (decreased levels of LC3-II), PKC (decreased levels of RACK1) and calcium signaling (decreased levels of Calb2) in the olfactory bulb and/or hippocampus. Mice were behaviorally tested using objective and accurate video tracking (Noldus), in which Fus1 KO mice showed clear deficits in olfactory memory (decreased habituation/cross-habituation in the short and long term), olfactory guided navigation memory (inability to reduce their latency to find the hidden cookie), spatial memory (learning impairments on finding the platform in the Morris water maze) and showed more sleep time during the diurnal cycle. Fus1 KO mice did not show clear deficits in olfactory perception (cross-habituation), association memory (passive avoidance) or in species-typical behavior (nest building) and no increased anxiety (open field, light-dark box) or depression/anhedonia (sucrose preference) at this relatively young age. These neurobehavioral

  8. Long-Term Effects of the Implementation of State-Wide Exit Exams: A Multilevel Regression Analysis of Mediation Effects of Teaching Practices on Students' Motivational Orientations

    ERIC Educational Resources Information Center

    Maag Merki, Katharina; Oerke, Britta

    2017-01-01

    This study extends previous research investigating the effects of state-wide exit exams by studying the change from a class-based to a state-wide exit exam system over 5 years, using multilevel analyses and examining mediating effects of teachers' practices on students' motivational orientations. In this multi-cohort study, we analyzed in…

  9. Cerebellar mutism syndrome and its relation to cerebellar cognitive and affective function: Review of the literature

    PubMed Central

    Yildiz, Ozlem; Kabatas, Serdar; Yilmaz, Cem; Altinors, Nur; Agaoglu, Belma

    2010-01-01

    Tumors of the cerebellum and brainstem account for half of all brain tumors in children. The realization that cerebellar lesions produce clinically relevant intellectual disability makes it important to determine whether neuropsychological abnormalities occur in long-term survivors of pediatric cerebellar tumors. Little is known about the neurobehavioral sequale resulting specifically from the resection of these tumors in this population. We therefore reviewed neuropsychological findings associated with postoperative cerebellar mutism syndrome and discuss the further implications for cerebellar cognitive function. PMID:20436742

  10. Long-term Effects of Parents' Education on Children's Educational and Occupational Success: Mediation by Family Interactions, Child Aggression, and Teenage Aspirations.

    PubMed

    Dubow, Eric F; Boxer, Paul; Huesmann, L Rowell

    2009-07-01

    We examine the prediction of individuals' educational and occupational success at age 48 from contextual and personal variables assessed during their middle childhood and late adolescence. We focus particularly on the predictive role of the parents' educational level during middle childhood, controlling for other indices of socioeconomic status and children's IQ, and the mediating roles of negative family interactions, childhood behavior, and late adolescent aspirations. Data come from the Columbia County Longitudinal Study, which began in 1960 when all 856 third graders in a semi-rural county in New York State were interviewed along with their parents; participants were reinterviewed at ages 19, 30, and 48 (Eron et al, 1971; Huesmann et al., 2002). Parents' educational level when the child was 8 years old significantly predicted educational and occupational success for the child 40 years later. Structural models showed that parental educational level had no direct effects on child educational level or occupational prestige at age 48 but had significant indirect effects that were independent of the other predictor variables' effects. These indirect effects were mediated through age 19 educational aspirations and age 19 educational level. These results provide strong support for the unique predictive role of parental education on adult outcomes 40 years later and underscore the developmental importance of mediators of parent education effects such as late adolescent achievement and achievement-related aspirations.

  11. Variation in short-term and long-term responses of photosynthesis and isoprenoid-mediated photoprotection to soil water availability in four Douglas-fir provenances

    PubMed Central

    Junker, Laura Verena; Kleiber, Anita; Jansen, Kirstin; Wildhagen, Henning; Hess, Moritz; Kayler, Zachary; Kammerer, Bernd; Schnitzler, Jörg-Peter; Kreuzwieser, Jürgen; Gessler, Arthur; Ensminger, Ingo

    2017-01-01

    For long-lived forest tree species, the understanding of intraspecific variation among populations and their response to water availability can reveal their ability to cope with and adapt to climate change. Dissipation of excess excitation energy, mediated by photoprotective isoprenoids, is an important defense mechanism against drought and high light when photosynthesis is hampered. We used 50-year-old Douglas-fir trees of four provenances at two common garden experiments to characterize provenance-specific variation in photosynthesis and photoprotective mechanisms mediated by essential and non-essential isoprenoids in response to soil water availability and solar radiation. All provenances revealed uniform photoprotective responses to high solar radiation, including increased de-epoxidation of photoprotective xanthophyll cycle pigments and enhanced emission of volatile monoterpenes. In contrast, we observed differences between provenances in response to drought, where provenances sustaining higher CO2 assimilation rates also revealed increased water-use efficiency, carotenoid-chlorophyll ratios, pools of xanthophyll cycle pigments, β-carotene and stored monoterpenes. Our results demonstrate that local adaptation to contrasting habitats affected chlorophyll-carotenoid ratios, pool sizes of photoprotective xanthophylls, β-carotene, and stored volatile isoprenoids. We conclude that intraspecific variation in isoprenoid-mediated photoprotective mechanisms contributes to the adaptive potential of Douglas-fir provenances to climate change. PMID:28071755

  12. Variation in short-term and long-term responses of photosynthesis and isoprenoid-mediated photoprotection to soil water availability in four Douglas-fir provenances

    DOE PAGES

    Junker, Laura Verena; Kleiber, Anita; Jansen, Kirstin; ...

    2017-01-10

    For long-lived forest tree species, the understanding of intraspecific variation among populations and their response to water availability can reveal their ability to cope with and adapt to climate change. Dissipation of excess excitation energy, mediated by photoprotective isoprenoids, is an important defense mechanism against drought and high light when photosynthesis is hampered. We used 50-year-old Douglas-fir trees of four provenances at two common garden experiments to characterize provenance-specific variation in photosynthesis and photoprotective mechanisms mediated by essential and non-essential isoprenoids in response to soil water availability and solar radiation. All provenances revealed uniform photoprotective responses to high solar radiation,more » including increased de-epoxidation of photoprotective xanthophyll cycle pigments and enhanced emission of volatile monoterpenes. In contrast, we observed differences between provenances in response to drought, where provenances sustaining higher CO2 assimilation rates also revealed increased water-use efficiency, carotenoid-chlorophyll ratios, pools of xanthophyll cycle pigments, β-carotene and stored monoterpenes. Our results demonstrate that local adaptation to contrasting habitats affected chlorophyll-carotenoid ratios, pool sizes of photoprotective xanthophylls, β-carotene, and stored volatile isoprenoids. We conclude that intraspecific variation in isoprenoid-mediated photoprotective mechanisms contributes to the adaptive potential of Douglas-fir provenances to climate change.« less

  13. Variation in short-term and long-term responses of photosynthesis and isoprenoid-mediated photoprotection to soil water availability in four Douglas-fir provenances.

    PubMed

    Junker, Laura Verena; Kleiber, Anita; Jansen, Kirstin; Wildhagen, Henning; Hess, Moritz; Kayler, Zachary; Kammerer, Bernd; Schnitzler, Jörg-Peter; Kreuzwieser, Jürgen; Gessler, Arthur; Ensminger, Ingo

    2017-01-10

    For long-lived forest tree species, the understanding of intraspecific variation among populations and their response to water availability can reveal their ability to cope with and adapt to climate change. Dissipation of excess excitation energy, mediated by photoprotective isoprenoids, is an important defense mechanism against drought and high light when photosynthesis is hampered. We used 50-year-old Douglas-fir trees of four provenances at two common garden experiments to characterize provenance-specific variation in photosynthesis and photoprotective mechanisms mediated by essential and non-essential isoprenoids in response to soil water availability and solar radiation. All provenances revealed uniform photoprotective responses to high solar radiation, including increased de-epoxidation of photoprotective xanthophyll cycle pigments and enhanced emission of volatile monoterpenes. In contrast, we observed differences between provenances in response to drought, where provenances sustaining higher CO2 assimilation rates also revealed increased water-use efficiency, carotenoid-chlorophyll ratios, pools of xanthophyll cycle pigments, β-carotene and stored monoterpenes. Our results demonstrate that local adaptation to contrasting habitats affected chlorophyll-carotenoid ratios, pool sizes of photoprotective xanthophylls, β-carotene, and stored volatile isoprenoids. We conclude that intraspecific variation in isoprenoid-mediated photoprotective mechanisms contributes to the adaptive potential of Douglas-fir provenances to climate change.

  14. Long-term parenteral nutrition

    PubMed Central

    Ladefoged, Karin; Jarnum, Stig

    1978-01-01

    Nineteen patients (11 women and eight men) aged 20-68 received long-term parenteral nutrition, mostly at home, for six to 63 months (mean 19 months). Indications for LTPN were extensive, active Crohn's disease in three patients, intestinocutaneous fistulas in three, and short-bowel syndrome in the remaining 13 patients. Subclavian or intra-atrial (Broviac) catheters were most commonly used, for which the average life was four and seven months respectively. Complications of long-term parenteral nutrition included pneumothorax in four out of 48 subclavian vein punctures. Catheter-induced thrombosis of central veins was shown by phlebography 17 times in nine patients, and eight episodes of total occlusion occurred. Two of these patients had pulmonary infarction. Nineteen episodes of catheter sepsis occurred in 11 patients, but only one was fatal. Complications related to intestinal disease included intra-abdominal abscesses and intestinal fistulas, and disturbances of liver function. Five patients died, though in only two was death related to long-term parenteral nutrition. One of these patients died from catheter sepsis, the other had subdural haematoma possibly caused by anticoagulant treatment. Eight of the 14 surviving patients still needed parenteral nutrition. All received a disability pension, but six had an acceptable quality of life with almost normal social activities. Despite problems such as difficulties in maintaining standardised infusion programmes, it was concluded that long-term parenteral nutrition at home is practicable and consistent with an acceptable quality of life. ImagesFIG 2 PMID:98199

  15. Differential effects of short- and long-term bupivacaine treatment on α1-adrenoceptor-mediated contraction of isolated rat aorta rings and the reversal effect of lipid emulsion

    PubMed Central

    Guo, Hao; Zhang, He-fei; Xu, Wen-qi; Du, Qian; Zhao, Jing; Ren, Lei-ming

    2015-01-01

    Aim: Arterial function is significantly influenced by bupivacaine at both clinically relevant concentrations and toxic concentrations, but the underlying mechanisms are not fully understood. In the present study we investigated the role of α1-adrenoceptors in bupivacaine effects on isolated rat aortas. Methods: Isolated aortic rings were prepared from rats and suspended in an organ bath. Phenylephrine (Phe)-induced vasoconstriction and acetylcholine (ACh)-induced vasodilation were recorded through an isometric force transducer connected to a data acquisition system. Results: Administration of bupivacaine (30–300 μmol/L) produced mild vasoconstriction, and this response declined with repeated administrations. Treatment of the aortic rings with bupivacaine (3–30 μmol/L) for 20 min enhanced Phe-induced vasoconstriction, while treatment for 40 min suppressed Phe-induced vasoconstriction. Both the short- and long-term bupivacaine treatment suppressed ACh-induced vasodilation. Incubation of the aortic rings with 0.2%–0.6% lipid emulsion (LE) for 100 min significantly increased the pD2 and Emax values of Phe-induced vasoconstriction, and incubation with 0.4% LE for 100 min reversed the inhibition of bupivacaine on vasoconstriction induced by Phe (30 μmol/L). In contrast, incubation with LE suppressed ACh-induced vasodilation, even at a lower concentration and with a 5-min incubation. Conclusion: Bupivacaine exerts dual effects on α1-adrenoceptor-mediated vasoconstriction of isolated rat aortic rings: short-term treatment enhances the response, while long-term treatment inhibits it; the inhibition may be reversed via long-term incubation with LE. PMID:26073324

  16. Controlling fibrous capsule formation through long-term down-regulation of collagen type I (COL1A1) expression by nanofiber-mediated siRNA gene silencing

    PubMed Central

    Rujitanaroj, Pim-on; Jao, Brian; Yang, Junghoon; Wang, Feng; Anderson, James M.; Wang, Jun; Chew, Sing Yian

    2012-01-01

    The foreign body reaction often interferes with the long-term functionality and performance of implanted biomedical devices through fibrous capsule formation. While many implant modification techniques have been adopted in attempts to control fibrous encapsulation, the outcomes remained sub-optimal. Nanofiber scaffold-mediated RNA interference may serve as an alternative approach through the localized and sustained delivery of siRNA at implant sites. In this study, we investigated the efficacy of siRNA-PCLEEP (poly(caprolactone-co-ethylethylene phosphate) nanofibers in controlling fibrous capsule formation through the down-regulation of Collagen type I (COL1A1) in vitro and in vivo. By encapsulating complexes of COL1A1 siRNA with a transfection reagent (Transit TKO) or cell penetrating peptides (CPPs), CADY or MPG, within the nanofibers (550–650 nm in diameter), a sustained release of siRNA was obtained for at least 28 days (loading efficiency ~ 60–67%). Scaffold-mediated transfection significantly enhanced cellular uptake of oligonucleotides and prolonged in vitro gene silencing duration by at least 2–3 times as compared to conventional bolus delivery of siRNA (14 days vs 5–7 days by bolus delivery). In vivo subcutaneous implantation of siRNA scaffolds revealed a significant decrease in fibrous capsule thickness at weeks 2 and 4 as compared to plain nanofibers (p < 0.05). Taken together, the results demonstrated the efficacy of scaffold-mediated siRNA gene-silencing in providing effective long-term control of fibrous capsule formation. PMID:23036951

  17. Developmental enhancement of alpha2-adrenoceptor-mediated suppression of inhibitory synaptic transmission onto mouse cerebellar Purkinje cells.

    PubMed

    Hirono, M; Matsunaga, W; Chimura, T; Obata, K

    2008-09-22

    Noradrenaline (NA) modulates glutamatergic and GABAergic transmission in various areas of the brain. It is reported that some alpha2-adrenoceptor subtypes are expressed in the cerebellar cortex and alpha2-adrenoceptors may play a role in motor coordination. Our previous study demonstrated that the selective alpha2-adrenoceptor agonist clonidine partially depresses spontaneous inhibitory postsynaptic currents (sIPSCs) in mouse cerebellar Purkinje cells (PCs). Here we found that the inhibitory effect of clonidine on sIPSCs was enhanced during postnatal development. The activation of alpha2-adrenoceptors by clonidine did not affect sIPSCs in PCs at postnatal days (P) 8-10, when PCs showed a few sIPSCs and interneurons in the molecular layer (MLIs) did not cause action potential (AP). In the second postnatal week, the frequency of sIPSCs increased temporarily and reached a plateau at P14. By contrast, MLIs began to fire at P11 with the firing rate gradually increasing thereafter and reaching a plateau at P21. In parallel with this rise in the rate of firing, the magnitude of the clonidine-mediated inhibition of sIPSCs increased during postnatal development. Furthermore, the magnitude of the clonidine-mediated firing suppression in MLIs, which seemed to be mediated by a reduction in amplitude of the hyperpolarization-activated nonselective cation current, I(h), was constant across development. Both alpha2A- and alpha2B-, but not alpha2C-, adrenoceptors were strongly expressed in MLIs at P13, and P31. Therefore, the developmental enhancement of the clonidine-mediated inhibition of sIPSCs is attributed to an age-dependent increase in AP-derived sIPSCs, which can be blocked by clonidine. Thus, presynaptic activation of alpha2-adrenoceptors inhibits cerebellar inhibitory synaptic transmission after the second postnatal week, leading to a restriction of NA signaling, which is mainly mediated by alpha1- and beta2-adrenoceptors in the adult cerebellar neuronal circuit.

  18. Long-term data archiving

    SciTech Connect

    Moore, David Steven

    2009-01-01

    Long term data archiving has much value for chemists, not only to retain access to research and product development records, but also to enable new developments and new discoveries. There are some recent regulatory requirements (e.g., FDA 21 CFR Part 11), but good science and good business both benefit regardless. A particular example of the benefits of and need for long term data archiving is the management of data from spectroscopic laboratory instruments. The sheer amount of spectroscopic data is increasing at a scary rate, and the pressures to archive come from the expense to create the data (or recreate it if it is lost) as well as its high information content. The goal of long-term data archiving is to save and organize instrument data files as well as any needed meta data (such as sample ID, LIMS information, operator, date, time, instrument conditions, sample type, excitation details, environmental parameters, etc.). This editorial explores the issues involved in long-term data archiving using the example of Raman spectral databases. There are at present several such databases, including common data format libraries and proprietary libraries. However, such databases and libraries should ultimately satisfy stringent criteria for long term data archiving, including readability for long times into the future, robustness to changes in computer hardware and operating systems, and use of public domain data formats. The latter criterion implies the data format should be platform independent and the tools to create the data format should be easily and publicly obtainable or developable. Several examples of attempts at spectral libraries exist, such as the ASTM ANDI format, and the JCAMP-DX format. On the other hand, proprietary library spectra can be exchanged and manipulated using proprietary tools. As the above examples have deficiencies according to the three long term data archiving criteria, Extensible Markup Language (XML; a product of the World Wide Web

  19. Combined meningococcal serogroup A and W135 outer-membrane vesicles activate cell-mediated immunity and long-term memory responses against non-covalent capsular polysaccharide A.

    PubMed

    Romeu, Belkis; Lastre, Miriam; García, Luis; Cedré, Bárbara; Mandariote, Aleida; Fariñas, Mildrey; Oliva, Reynaldo; Rosenqvist, Einar; Pérez, Oliver

    2014-01-01

    Outer-membrane vesicles (OMVs) have inherent adjuvant properties, and many vaccines use OMV as vaccine components. Utilizing the adjuvant properties of OMV could lead to the formulation of vaccines that are less expensive and potentially more immunogenic than covalently conjugated polysaccharide vaccines. We evaluated the adjuvant effect in Balb/c mice of combinations of OMV from Neisseria meningitidis serogroup A and W135 as compared to that of the non-covalently conjugated capsular polysaccharide A. Both antigens were adsorbed onto aluminum hydroxide. The mice were given a booster dose of plain polysaccharide A to stimulate an immunologic memory response. Subclasses determination and cytokine assays demonstrated the capacity of OMV to induce a IgG2a/IgG2b isotype profile and IFN-γ production, suggesting the induction of a Th1 pattern immune response. Lymphoproliferative responses to OMVs were high, with affinity maturation of antibodies observed. Bactericidal titers after the booster dose were also observed. Memory B cells and long-term memory T cells were also detected. The results of this study indicate that combined meningococcal serogroup A and W135 OMV can activate cell-mediated immunity and induce a long-term memory response.

  20. Role of protein kinase C (PKC) in short- and long-term cellular responses: inhibition of agonist-mediated calcium transients and down-regulation of PKC

    SciTech Connect

    Fabbro, D.; Mazurek, N.; Borner, C.; Conscience, J.F.; Erne, P.

    1988-01-01

    Active tumor promoters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or membrane-diffusible synthetic diacylglycerols such as 1,2-dioctanoyl-sn-glycerol (DiC8), which specifically activate protein kinase C (PKC), inhibited the agonist-mediated rise in cytosolic calcium ((Ca2+)i) in a mast cell line (PB-3c) and human platelets. TPA inhibition of agonist-mediated calcium transient in platelets was readily reversed by the PKC inhibitor staurosporine. In contrast to DiCs, only active tumor promoters induced a time- and dose-dependent translocation of cytosolic PKC to membranes as determined both enzymatically or by immunoblotting. However, the concentration of TPA required to induce a half-maximal subcellular redistribution of immunodetectable PKC activity was an order of magnitude greater than the half-maximal dose required to inhibit the intracellular rise in (Ca2+)i. Thus, activation of PKC seems not to be exclusively coupled to its translocation to membranes, suggesting that translocation of PKC is mainly involved in the down-regulation of PKC. Down-regulation of immunoprecipitable PKC was studied in various human breast cancer cell lines that display differential growth inhibitory responses toward the tumor promoter. TPA induced translocation of (35S)methionine-prelabeled cytosolic 80 kDa PKC to membranes followed by complete degradation of the enzyme (t1/2 = 2 h) without affecting PKC synthesis. During prolonged TPA exposure, 20-80% of total 80 kDa PKC of control cells was still synthetized as a membrane-bound 74/80 kDa PKC doublet. Although both proteins lacked PKC activity and phorbol ester binding, they revealed structural similarity with the active 80 kDa PKC form of untreated cells.

  1. Neural correlates of cerebellar-mediated timing during finger tapping in children with fetal alcohol spectrum disorders

    PubMed Central

    du Plessis, Lindie; Jacobson, Sandra W.; Molteno, Christopher D.; Robertson, Frances C.; Peterson, Bradley S.; Jacobson, Joseph L.; Meintjes, Ernesta M.

    2014-01-01

    Objectives Classical eyeblink conditioning (EBC), an elemental form of learning, is among the most sensitive indicators of fetal alcohol spectrum disorders. The cerebellum plays a key role in maintaining timed movements with millisecond accuracy required for EBC. Functional MRI (fMRI) was used to identify cerebellar regions that mediate timing in healthy controls and the degree to which these areas are also recruited in children with prenatal alcohol exposure. Experimental design fMRI data were acquired during an auditory rhythmic/non-rhythmic finger tapping task. We present results for 17 children with fetal alcohol syndrome (FAS) or partial FAS, 17 heavily exposed (HE) nonsyndromal children and 16 non- or minimally exposed controls. Principal observations Controls showed greater cerebellar blood oxygen level dependent (BOLD) activation in right crus I, vermis IV–VI, and right lobule VI during rhythmic than non-rhythmic finger tapping. The alcohol-exposed children showed smaller activation increases during rhythmic tapping in right crus I than the control children and the most severely affected children with either FAS or PFAS showed smaller increases in vermis IV–V. Higher levels of maternal alcohol intake per occasion during pregnancy were associated with reduced activation increases during rhythmic tapping in all four regions associated with rhythmic tapping in controls. Conclusions The four cerebellar areas activated by the controls more during rhythmic than non-rhythmic tapping have been implicated in the production of timed responses in several previous studies. These data provide evidence linking binge-like drinking during pregnancy to poorer function in cerebellar regions involved in timing and somatosensory processing needed for complex tasks requiring precise timing. PMID:25844307

  2. [Endogenous opioid system as a mediator of acute and long-term adaptation to stress. Prospects for clinical use of opioid peptides].

    PubMed

    Lishmanov, Iu B; Maslov, L N; Naryzhnaia, N V; Pei, J M; Kolar, F; Zhang, Y; Portnichenko, A G; Wang, N

    2012-01-01

    It has been well established that opioid peptides (OPs) affect various hormonal systems. Opioids exhibit stress-limiting and gastro-protective effects in stressed animals, acting via mu- and delta-opioid receptors (OR). Peripheral mu-OR stimulation by endogenous and exogenous opioids increases cardiac tolerance to pathological consequences of stress. Enhancement ofprostacyclin synthesis, decrease of thromboxane production as well as suppression of lipid peroxidation can be directly responsible for cardioprotective effects of OPs in stressed animals. Adaptive responses are accompanied by increased OP levels in blood and tissues. Reduction of ventricular arrhythmias induced by repeated short-term immobilization stress is mediated via mu-OR stimulation by endogenous opioids, while delta-OR account for an antiarrhythmic effect of adaptation to chronic intermittent hypobaric hypoxia. The mechanism of infarct size-limiting effect of continuous normobaric hypoxia involves both mu- and delta-OR stimulation. Peptide OR agonists can be considered in future clinical practice for treatment of withdrawal syndrome, stress-related cardiac disease or myocardial injury caused by ischemia-reperfusion insult.

  3. The Long-Term Effectiveness of the Family Check-up on Peer Preference: Parent-Child Interaction and Child Effortful Control as Sequential Mediators.

    PubMed

    Chang, Hyein; Shaw, Daniel S; Shelleby, Elizabeth C; Dishion, Thomas J; Wilson, Melvin N

    2017-05-01

    We examined the longitudinal effects of the Family Check-Up (FCU) intervention beginning in toddlerhood on children's peer preference at school-age. Specifically, a sequential mediational model was proposed in which the FCU was hypothesized to promote peer preference (i.e., higher acceptance and lower rejection by peers) in middle childhood through its positive effects on parent-child interaction and child effortful control in early childhood. Participants were 731 low-income families (49 % female). Qualities of parent-child interaction were observed during structured activities at 2 to 5 years, child effortful control was assessed using behavioral tasks at 5 years, and peer acceptance and rejection were rated by teachers at 7.5 to 10.5 years. Results indicated that the FCU indirectly predicted peer preference by sequentially improving parent-child interaction and child effortful control. The findings are discussed with respect to implications for understanding mechanisms by which early parenting-focused programs may enhance child functioning across time and context.

  4. Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation.

    PubMed

    Artola, A; Singer, W

    1993-11-01

    In many brain areas, including the cerebellar cortex, neocortex, hippocampus, striatum and nucleus accumbens, brief activation of an excitatory pathway can produce long-term depression (LTD) of synaptic transmission. In most preparations, induction of LTD has been shown to require a minimum level of postsynaptic depolarization and a rise in the intracellular Ca2+ concentration [Ca2+]i in the postsynaptic neurone. Thus, induction conditions resemble those described for the initiation of associative long-term potentiation (LTP). However, data from structures susceptible to both LTD and LTP suggest that a stronger depolarization and a greater increase in [Ca2+]i are required to induce LTP than to initiate LTD. The source of Ca2+ appears to be less critical for the differential induction of LTP and LTD than the amplitude of the Ca2+ surge, since the activation of voltage- and ligand-gated Ca2+ conductances as well as the release from intracellular stores have all been shown to contribute to both LTD and LTP induction. LTD is induceable even at inactive synapses if [Ca2+]i is raised to the appropriate level by antidromic or heterosynaptic activation, or by raising the extracellular Ca2+ concentration [Ca2+]o. These conditions suggest a rule (called here the ABS rule) for activity-dependent synaptic modifications that differs from the classical Hebb rule and that can account for both homosynaptic LTD and LTP as well as for heterosynaptic competition and associativity.

  5. Cytokines related to three major types of cell-mediated immunity in short- and long-term exposures to lead compounds.

    PubMed

    Dobrakowski, Michał; Boroń, Marta; Czuba, Zenon P; Kasperczyk, Aleksandra; Machoń-Grecka, Anna; Kasperczyk, Sławomir

    2016-11-01

    Many investigators have posited on the significant influence of lead on the immune system function. However, available data on this topic are not conclusive. Therefore, a study was undertaken to examine associations between lead exposure and levels of cytokines related to the T-helper (TH)-1, TH2, and TH17 types of immune response in humans. For these analyses, three population groups were examined: the first consisted of male workers exposed to lead for a short period of time (36-44 days); the second included male workers chronically exposed to lead (13 ± 10 years); and a control group that was composed of male administrative workers with blood lead levels (BLL) < 10 μg/dl. BLL were determined for all study subjects. Thereafter, serum samples were analyzed for the levels of interleukin (IL)-2 (IL-2), IL-4, IL-5, IL-12, IL-13, IL-17A, and interferon (IFN)-γ using a multi-analyte system. The results indicated that the levels of IFNγ IL-2, IL-12 (related to TH1 cells), IL-4, IL-5, IL-13 (related to TH2 cells), and IL-17A (related to TH17 cells) did not change after a short-term exposure to lead (compared to baseline). However, the levels of all of these cytokines were significantly higher in workers chronically exposed to lead than in the controls by 82%, 32%, 81%, 22%, 70%, 42%, and 17% (IFNγ, IL-2, IL-12, IL-4, IL-5, IL-13, IL-17A, respectively). From these studies, we conclude that in humans, a short-term exposure to lead does not affect levels of cytokines related to the TH1-, TH2-, and TH17-mediated immune responses, while chronic exposure modifies their levels. Taken together, these modifications do not evidence an ability of lead to promote specifically one type of immune response in an exposed host.

  6. ERBB3-mediated regulation of Bergmann glia proliferation in cerebellar lamination

    PubMed Central

    Sathyamurthy, Anupama; Yin, Dong-Min; Barik, Arnab; Shen, Chengyong; Bean, Jonathan C.; Figueiredo, Dwight; She, Jin-Xiong; Xiong, Wen-Cheng; Mei, Lin

    2015-01-01

    Cortical lamination is crucial for the assembly of cerebellar circuitry. In this process, granule neurons (GNs) migrate along Bergmann glia (BG), which are specialized astroglial cells, from the external granule layer to the internal granule layer. However, the molecular mechanisms underlying BG development are not well understood. Here, we show that GFAP::Cre;Erbb3F/F mice, which lack Erbb3 in both radial glia and neurons, exhibit impairments in balance and motor coordination. Cerebellar lamination is aberrant, with misplaced Purkinje neurons and GN clusters. These phenotypes were not observed in Math1::CreERT2;Erbb3F/F mice, where the Erbb3 gene was deleted in GNs, suggesting involvement of non-neuronal Erbb3 in cerebellar lamination. Mechanistic studies indicate that ERBB3 is crucial for the proliferation of BG, which are required for GN migration. These observations identify a crucial role for ERBB3 in cerebellar lamination and reveal a novel mechanism that regulates BG development. PMID:25564653

  7. Localization of the Cerebellar Cortical Zone Mediating Acquisition of Eyeblink Conditioning in Rats

    PubMed Central

    Steinmetz, Adam B.; Freeman, John H.

    2014-01-01

    Delay eyeblink conditioning is established by paired presentations of a conditioned stimulus (CS) such as a tone or light and an unconditioned stimulus (US) that elicits eyelid closure before training. The CS and US inputs converge on Purkinje cells in the cerebellar cortex. The cerebellar cortex plays a substantial role in acquisition of delay eyeblink conditioning in rabbits and rodents, but the specific area of the cortex that is necessary for acquisition in rodents has not been identified. A recent study identified an eyeblink microzone in the mouse cerebellar cortex at the base of the primary fissure (Heiney, Kim, Augustine, & Medina, 2014). There is no evidence that the cortex in this eyeblink microzone plays a role in rodent eyeblink conditioning but it is a good candidate region. Experiment 1 examined the effects of unilateral (ipsilateral to the US) lesions of lobule HVI, the lateral anterior lobe, or the base of the primary fissure on eyeblink conditioning in rats. Lesions of either the anterior lobe or lobule HVI impaired acquisition, but lesions of the base of the primary fissure produced the largest deficit. Experiment 2 used reversible inactivation with muscimol to demonstrate that inactivation of the putative eyeblink microzone severely impaired acquisition and had only a modest effect on retention of eyeblink conditioning. The findings indicate that the base of the primary fissure is the critical zone of the cerebellar cortex for acquisition of eyeblink conditioning in rats. PMID:24931828

  8. CLIPPERS and the need for long-term immunosuppression.

    PubMed

    Abkur, Tarig M; Kearney, Hugh; Hennessy, Michael J

    2017-02-01

    Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is a rare chronic inflammatory disorder of the central nervous system. Herein, we describe the case of a 62-year-old female who presented with right sided facial tingling, gait ataxia and diplopia. Neuroimaging revealed pontine curvilinear enhancing lesions with extension into cerebellar peduncles, characteristic of CLIPPERS. This report discusses the differential diagnosis and the importance of prolonged immunomodulatory treatment for this rare neuro-inflammatory disorder. Long-term immunosuppression appears to be mandatory in order to achieve sustained remission and prevent disability related to atrophy of the structures involved in repeated attacks.

  9. Long-term oxygen therapy.

    PubMed

    Christopher, Kent L; Porte, Phillip

    2011-02-01

    This article provides an overview of the status of long-term oxygen therapy (LTOT). In the United States, payment cutbacks are occurring as a result of congressionally mandated competitive bidding and capped rental programs. These Medicare programs are discussed. These legislative and regulatory changes may result in reduced patient access to appropriate oxygen-delivery systems that meet medical needs, including optimal ambulation. Prescribing LTOT is addressed in this article, as is the need for adequate patient education. The importance of appropriate monitoring and reassessment is presented. The use of an LTOT collaborative care model is discussed. Although the new intermittent flow oxygen-delivery systems have potential benefits, there is consensus that each patient should be tested on the specific device because of variability in delivery and patient response. Feasible locations for patient education and monitoring are identified.

  10. Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

    PubMed Central

    Costa, Lara; Sardone, Lara M.; Lacivita, Enza; Leopoldo, Marcello; Ciranna, Lucia

    2015-01-01

    Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of Fragile X Syndrome

  11. Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome.

    PubMed

    Costa, Lara; Sardone, Lara M; Lacivita, Enza; Leopoldo, Marcello; Ciranna, Lucia

    2015-01-01

    Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of Fragile X Syndrome.

  12. Asthma Medicines: Long-Term Control

    MedlinePlus

    ... Size Email Print Share Asthma Medicines: Long-term Control Page Content Article Body Corticosteroids Synthetic versions of ... form, they are used exclusively for long-term control; they are not very effective for acute symptoms. ...

  13. Consumer Direction in Long-Term Care.

    ERIC Educational Resources Information Center

    Generations, 2000

    2000-01-01

    Issue includes 17 theme articles on long-term care, covering legal issues, federal role, state programs, demonstration programs, family caregivers, home health care, home care workers, culturally appropriate long-term care, financial support, and cognitive impairments. (SK)

  14. A left cerebellar pathway mediates language in prematurely-born young adults.

    PubMed

    Constable, R Todd; Vohr, Betty R; Scheinost, Dustin; Benjamin, Jennifer R; Fulbright, Robert K; Lacadie, Cheryl; Schneider, Karen C; Katz, Karol H; Zhang, Heping; Papademetris, Xenophon; Ment, Laura R

    2013-01-01

    Preterm (PT) subjects are at risk for developmental delay, and task-based studies suggest that developmental disorders may be due to alterations in neural connectivity. Since emerging data imply the importance of right cerebellar function for language acquisition in typical development, we hypothesized that PT subjects would have alternate areas of cerebellar connectivity, and that these areas would be responsible for differences in cognitive outcomes between PT subjects and term controls at age 20 years. Nineteen PT and 19 term control young adults were prospectively studied using resting-state functional MRI (fMRI) to create voxel-based contrast maps reflecting the functional connectivity of each tissue element in the grey matter through analysis of the intrinsic connectivity contrast degree (ICC-d). Left cerebellar ICC-d differences between subjects identified a region of interest that was used for subsequent seed-based connectivity analyses. Subjects underwent standardized language testing, and correlations with cognitive outcomes were assessed. There were no differences in gender, hand preference, maternal education, age at study, or Peabody Picture Vocabulary Test (PPVT) scores. Functional connectivity (FcMRI) demonstrated increased tissue connectivity in the biventer, simple and quadrangular lobules of the L cerebellum (p<0.05) in PTs compared to term controls; seed-based analyses from these regions demonstrated alterations in connectivity from L cerebellum to both R and L inferior frontal gyri (IFG) in PTs compared to term controls. For PTs but not term controls, there were significant positive correlations between these connections and PPVT scores (R IFG: r=0.555, p=0.01; L IFG: r=0.454, p=0.05), as well as Verbal Comprehension Index (VCI) scores (R IFG: r=0.472, p=0.04). These data suggest the presence of a left cerebellar language circuit in PT subjects at young adulthood. These findings may represent either a delay in maturation or the engagement of

  15. Long Term Surface Salinity Measurements

    NASA Technical Reports Server (NTRS)

    Schmitt, Raymond W.; Brown, Neil L.

    2005-01-01

    Our long-term goal is to establish a reliable system for monitoring surface salinity around the global ocean. Salinity is a strong indicator of the freshwater cycle and has a great influence on upper ocean stratification. Global salinity measurements have potential to improve climate forecasts if an observation system can be developed. This project is developing a new internal field conductivity cell that can be protected from biological fouling for two years. Combined with a temperature sensor, this foul-proof cell can be deployed widely on surface drifters. A reliable in-situ network of surface salinity sensors will be an important adjunct to the salinity sensing satellite AQUARIUS to be deployed by NASA in 2009. A new internal-field conductivity cell has been developed by N Brown, along with new electronics. This sensor system has been combined with a temperature sensor to make a conductivity - temperature (UT) sensor suitable for deployment on drifters. The basic sensor concepts have been proven on a high resolution CTD. A simpler (lower cost) circuit has been built for this application. A protection mechanism for the conductivity cell that includes antifouling protection has also been designed and built. Mr. A.Walsh of our commercial partner E-Paint has designed and delivered time-release formulations of antifoulants for our application. Mr. G. Williams of partner Clearwater Instrumentation advised on power and communication issues and supplied surface drifters for testing.

  16. AB055. Long term NIV

    PubMed Central

    Siopi, Dimitra

    2016-01-01

    During the last decades, non-invasive mechanical ventilation has evolved into one of the most evidence-based areas of respiratory medicine, with many indications in acute or chronic respiratory failure. From the first application of negative pressure models during poliomyelitis epidemics to the new sophisticated positive pressure models, and the development of the “intelligent ventilators”, there has been a long time course. Undoubtedly the spur was given by better understanding of respiratory physiology during sleep and the shift of healthcare towards a chronic base. Novel randomized controlled trials (RCTs) established the use of NIV in acute respiratory failure due to exacerbations of COPD, as well as acute pulmonary edema and weaning from invasive mechanical ventilation. Long-term NIV has been used in neuromuscular diseases for many decades, first in Duchenne muscular dystrophy, and then spreading to other disorders of this category, increasing survival in inherited neuromuscular diseases. NIV should be initiated early in the course of the disease, when symptomatic nocturnal hypoventilation is detected. Combined with cough augmentation (physiotherapy, insufflation-exsufflation devices) and percutaneous gastrostomy feeding, it can delay tracheostomy and invasive ventilation. In ALS patients NIV improves the quality of life and increases survival, especially when there is no bulbar involvement. The right time to initiate ventilation in this group of patients is not well established since it is difficult to detect signs and symptom of respiratory impairment. Patients seem to benefit from an early application of NIV, and their personal decisions should always be considered before any intervention. In patients with chest wall disorders NIV—despite the fact that RCTs are lacking—has proved its value in many uncontrolled trials and numerous reports. It seems to improve the work of breathing, sleep architecture, nocturnal and daytime arterial blood gases. The

  17. Stapedectomy - long-term report.

    PubMed

    Shea, J J

    1982-01-01

    The long-term results with large fenestra stapedectomy with vein graft and Teflon piston are compared with results with the small fenestra stapedectomy with teflon piston directly into the vestibule. There were 1,943 operations in the former group and 2,155 in the latter when compared in 1970. One hundred consecutive patients from the beginning of each group with follow-up to present were compared. Results were generally the same with no great change in 15 and 20 years as compared to those at 5 years. The complication of perilymph fistula was caused by creating an opening in the footplate much larger than the prosthesis and was eliminated by interposing a living oval window seal if the opening was much larger than the prosthesis and a flap of lining membrane from the promontory when it was not. Other factors that influence a good result are discussed, including the type and the diameter of the piston used, the type of living oval window seal and the method of attachment to the incus. The small fenestra operation was found to be superior to the large, not only for the hearing gain achieved, but the case of performance and the freedom from complications due to migration of the prosthesis and/or the oval window seal. At present we have done about all that can be done for the conductive components. What remains is the sensorineural component which our studies indicate may be due to an autoimmune response.

  18. Long-term corrosion studies

    SciTech Connect

    Gdowski, G.

    1998-05-29

    The scope of this activity is to assess the long-term corrosion properties of metallic materials under consideration for fabricating waste package containers. Three classes of metals are to be assessed: corrosion resistant, intermediate corrosion resistant, and corrosion allowance. Corrosion properties to be evaluated are general, pitting and crevice corrosion, stress-corrosion cracking, and galvanic corrosion. The performance of these materials will be investigated under conditions that are considered relevant to the potential emplacement site. Testing in four aqueous solutions, and vapor phases above them, and at two temperatures are planned for this activity. (The environmental conditions, test metals, and matrix are described in detail in Section 3.0.) The purpose and objective of this activity is to obtain the kinetic and mechanistic information on degradation of metallic alloys currently being considered for waste package containers. This information will be used to provide assistance to (1) waste package design (metal barrier selection) (E-20-90 to E-20-92), (2) waste package performance assessment activities (SIP-PA-2), (3) model development (E-20-75 to E-20-89). and (4) repository license application.

  19. Anti-Yo Mediated Paraneoplastic Cerebellar Degeneration Associated with Pseudobulbar Affect in a Patient with Breast Cancer

    PubMed Central

    Martin, Allison N.; Jones, David E.; Brenin, David R.; Lapides, David A.

    2017-01-01

    Paraneoplastic cerebellar degeneration (PCD) is a rare anti-Yo mediated paraneoplastic syndromes rarely that is infrequently associated with breast cancer. We present a case of a 52-year-old female presenting with diplopia, gait instability, dysarthria, dysphagia, nystagmus, and, most notably, new onset paroxysmal episodes of uncontrollable crying concerning for pseudobulbar affect (PBA). Serologic testing showed anti-Yo antibodies. The patient was found to have stage IIIA breast cancer as the inciting cause of the paraneoplastic syndrome. The patient was treated with neoadjuvant chemotherapy, modified radical mastectomy, adjuvant Herceptin, and pertuzumab. She was given IVIG for paraneoplastic syndrome, antidepressants, and dextromethorphan-quinidine (Nuedexta), the first FDA-approved therapy for PBA. With multimodality therapy, she demonstrated significant improvement in neurologic and mood symptoms associated with PCD and PBA. PMID:28377827

  20. Long-Term Planning in Higher Education.

    ERIC Educational Resources Information Center

    United Nations Educational, Scientific and Cultural Organization, Bangkok (Thailand). Principal Regional Office for Asia and the Pacific.

    This report presents the concepts and issues discussed at a Regional Symposium on Long-term Planning in Higher Education held in Dhaka, Bangladesh, September 21-30, 1986. Chapter 1 explores some fundamental issues about the rationale for the objectives of long-term planning. It defines long-term planning in higher education, considers its…

  1. Long Term TOA - M Data and Information

    Atmospheric Science Data Center

    2015-06-30

    A Long-Term TOA and Constrained Surface Radiation Budget Project A Long-Term TOA and Constrained Surface Readiation Budget Dataset Using Merged CERES, ... and apply the knowledge to existing data to develop long-term (nearly 30 years) consistent and calibrated data product (TOA irradiances ...

  2. 5-HT2 presynaptic receptors mediate inhibition of glutamate release from cerebellar mossy fibre terminals.

    PubMed

    Maura, G; Carbone, R; Guido, M; Pestarino, M; Raiteri, M

    1991-09-17

    'Giant' synaptosomes originating from mossy fibre terminals and having sedimentation properties different from those of standard synaptosomes were obtained from rat cerebellum. Exposure of superfused giant synaptosomes to 15 mM KCl caused the release of endogenous glutamate in a largely (about 80%) calcium-dependent manner. The K(+)-evoked overflow of glutamate was inhibited in a concentration-dependent manner by 5-hydroxytryptamine (5-HT) and by the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), but not by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The effects of 5-HT and DOI were quite potent, already reaching significant inhibition (about 25%) at 10 nM. The 5-HT2 receptor antagonist ketanserin counteracted the inhibitory effect of 5-HT. In cerebellar slices, ketanserin increased on its own the calcium-dependent K(+)-evoked release of glutamate and this effect was not prevented by tetrodotoxin (TTX). The results support the idea that cerebellar mossy fibres use glutamate as a transmitter and show that the release of glutamate can be inhibited via presynaptic heteroreceptors of the 5-HT2 type probably localized on the mossy fibre terminals.

  3. Long-term Aβ exposure augments mCa2+-independent mROS-mediated depletion of cardiolipin for the shift of a lethal transient mitochondrial permeability transition to its permanent mode in NARP cybrids: a protective targeting of melatonin.

    PubMed

    Hsiao, Chia-Wei; Peng, Tsung-I; Peng, Alexander C; Reiter, Russel J; Tanaka, Masashi; Lai, Yiu-Kay; Jou, Mei-Jie

    2013-01-01

    Mitochondrial dysfunction is a hallmark of amyloid β-peptide (Aβ)-induced neurodegeneration of Alzheimer's disease (AD). This study investigated whether mtDNA T8993G mutation-induced complex V inhibition, clinically associated with neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP), is a potential risk factor for AD and the pathological link for long-term exposure of Aβ-induced mitochondrial toxicity and apoptosis in NARP cybrids. Using noninvasive fluorescence probe-coupled laser scanning imaging microscopy and NARP cybrids harboring 98% mutant genes along with its parental 143B osteosarcoma cells, we demonstrated that Aβ-augmented mitochondrial Ca(2+) (mCa(2+))-independent mitochondrial reactive oxygen species (mROS) formation for a cardiolipin (CL, a major mitochondrial protective phospholipid)-dependent lethal modulation of the mitochondrial permeability transition (MPT). Aβ augmented not only the amount but also the propagation rate of mROS-induced mROS formation to significantly depolarize mitochondrial membrane potential (∆Ψ(m)) and reduce mCa(2+) stress. Aβ-augmented mROS oxidized and depleted CL, thereby enhances mitochondrial fission and movement retardation, which promoted the NARP-augmented lethal transient-MPT (t-MPT) to switch to its irreversible mode of permanent-MPT (p-MPT). Interestingly, melatonin, a multiple mitochondrial protector, markedly reduced Aβ-augmented mROS formation and therefore significantly reduced mROS-mediated depolarization of ∆Ψ(m), fission of mitochondria and retardation of mitochondrial movement to stabilize CL and hence the MPT. In the presence of melatonin, Aβ-promoted p-MPT was reversed to a protective t-MPT, which preserved ∆Ψ(m) and lowered elevated mCa(2+) to sublethal levels for an enhanced mCa(2+)-dependent O(2) consumption. Thus, melatonin may potentially rescue AD patients associated with NARP symptoms.

  4. Hippocampal Focal Knockout of CBP Affects Specific Histone Modifications, Long-Term Potentiation, and Long-Term Memory

    PubMed Central

    Barrett, Ruth M; Malvaez, Melissa; Kramar, Eniko; Matheos, Dina P; Arrizon, Abraham; Cabrera, Sara M; Lynch, Gary; Greene, Robert W; Wood, Marcelo A

    2011-01-01

    To identify the role of the histone acetyltransferase (HAT) CREB-binding protein (CBP) in neurons of the CA1 region of the hippocampus during memory formation, we examine the effects of a focal homozygous knockout of CBP on histone modifications, gene expression, synaptic plasticity, and long-term memory. We show that CBP is critical for the in vivo acetylation of lysines on histones H2B, H3, and H4. CBP's homolog p300 was unable to compensate for the loss of CBP. Neurons lacking CBP maintained phosphorylation of the transcription factor CREB, yet failed to activate CREB:CBP-mediated gene expression. Loss of CBP in dorsal CA1 of the hippocampus resulted in selective impairments to long-term potentiation and long-term memory for contextual fear and object recognition. Together, these results suggest a necessary role for specific chromatin modifications, selectively mediated by CBP in the consolidation of memories. PMID:21508930

  5. Hippocampal focal knockout of CBP affects specific histone modifications, long-term potentiation, and long-term memory.

    PubMed

    Barrett, Ruth M; Malvaez, Melissa; Kramar, Eniko; Matheos, Dina P; Arrizon, Abraham; Cabrera, Sara M; Lynch, Gary; Greene, Robert W; Wood, Marcelo A

    2011-07-01

    To identify the role of the histone acetyltransferase (HAT) CREB-binding protein (CBP) in neurons of the CA1 region of the hippocampus during memory formation, we examine the effects of a focal homozygous knockout of CBP on histone modifications, gene expression, synaptic plasticity, and long-term memory. We show that CBP is critical for the in vivo acetylation of lysines on histones H2B, H3, and H4. CBP's homolog p300 was unable to compensate for the loss of CBP. Neurons lacking CBP maintained phosphorylation of the transcription factor CREB, yet failed to activate CREB:CBP-mediated gene expression. Loss of CBP in dorsal CA1 of the hippocampus resulted in selective impairments to long-term potentiation and long-term memory for contextual fear and object recognition. Together, these results suggest a necessary role for specific chromatin modifications, selectively mediated by CBP in the consolidation of memories.

  6. Alteration of AMPA Receptor-Mediated Synaptic Transmission by Alexa Fluor 488 and 594 in Cerebellar Stellate Cells123

    PubMed Central

    2016-01-01

    Abstract The fluorescent dyes, Alexa Fluor 488 and 594 are commonly used to visualize dendritic structures and the localization of synapses, both of which are critical for the spatial and temporal integration of synaptic inputs. However, the effect of the dyes on synaptic transmission is not known. Here we investigated whether Alexa Fluor dyes alter the properties of synaptic currents mediated by two subtypes of AMPA receptors (AMPARs) at cerebellar stellate cell synapses. In naive mice, GluA2-lacking AMPAR-mediated synaptic currents displayed an inwardly rectifying current–voltage (I–V) relationship due to blockade by cytoplasmic spermine at depolarized potentials. We found that the inclusion of 100 µm Alexa Fluor dye, but not 10 µm, in the pipette solution led to a gradual increase in the amplitude of EPSCs at +40 mV and a change in the I–V relationship from inwardly rectifying to more linear. In mice exposed to an acute stress, AMPARs switched to GluA2-containing receptors, and 100 µm Alexa Fluor 594 did not alter the I–V relationship of synaptic currents. Therefore, a high concentration of Alexa Fluor dye changed the I–V relationship of EPSCs at GluA2-lacking AMPAR synapses. PMID:27280156

  7. Alteration of AMPA Receptor-Mediated Synaptic Transmission by Alexa Fluor 488 and 594 in Cerebellar Stellate Cells.

    PubMed

    Maroteaux, Matthieu; Liu, Siqiong June

    2016-01-01

    The fluorescent dyes, Alexa Fluor 488 and 594 are commonly used to visualize dendritic structures and the localization of synapses, both of which are critical for the spatial and temporal integration of synaptic inputs. However, the effect of the dyes on synaptic transmission is not known. Here we investigated whether Alexa Fluor dyes alter the properties of synaptic currents mediated by two subtypes of AMPA receptors (AMPARs) at cerebellar stellate cell synapses. In naive mice, GluA2-lacking AMPAR-mediated synaptic currents displayed an inwardly rectifying current-voltage (I-V) relationship due to blockade by cytoplasmic spermine at depolarized potentials. We found that the inclusion of 100 µm Alexa Fluor dye, but not 10 µm, in the pipette solution led to a gradual increase in the amplitude of EPSCs at +40 mV and a change in the I-V relationship from inwardly rectifying to more linear. In mice exposed to an acute stress, AMPARs switched to GluA2-containing receptors, and 100 µm Alexa Fluor 594 did not alter the I-V relationship of synaptic currents. Therefore, a high concentration of Alexa Fluor dye changed the I-V relationship of EPSCs at GluA2-lacking AMPAR synapses.

  8. Long-term solar-terrestrial observations

    NASA Technical Reports Server (NTRS)

    1988-01-01

    The results of an 18-month study of the requirements for long-term monitoring and archiving of solar-terrestrial data is presented. The value of long-term solar-terrestrial observations is discussed together with parameters, associated measurements, and observational problem areas in each of the solar-terrestrial links (the sun, the interplanetary medium, the magnetosphere, and the thermosphere-ionosphere). Some recommendations are offered for coordinated planning for long-term solar-terrestrial observations.

  9. Long-Term Persistence of Cell-Mediated and Humoral Responses to A(H1N1)pdm09 Influenza Virus Vaccines and the Role of the AS03 Adjuvant System in Adults during Two Randomized Controlled Trials

    PubMed Central

    Clément, Frédéric; Willekens, Julie; Dewé, Walthère; Walravens, Karl; Vaughn, David W.; Leroux-Roels, Geert

    2017-01-01

    ABSTRACT We investigated the role of AS03A (here AS03), an α-tocopherol oil-in-water emulsion-based adjuvant system, on the long-term persistence of humoral and cell-mediated immune responses to A(H1N1)pdm09 influenza vaccines. In two studies, a total of 261 healthy adults (≤60 years old) were randomized to receive two doses of AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin (HA) or nonadjuvanted vaccine containing 15 μg of hemagglutinin (in study A) or 3.75 μg of hemagglutinin (in study B) 21 days apart. Hemagglutination inhibition (HI) antibody, memory B-cell, and CD4+/CD8+ T-cell responses were characterized up to 1 year following dose 1. We also assessed the effects of age and seasonal influenza vaccination history. AS03-adjuvanted (3.75 μg HA) vaccine and nonadjuvanted vaccine at 15 μg but not at 3.75 μg HA elicited HI antibody responses persisting at levels that continued to meet European licensure criteria through month 12. At month 12, the geometric mean titer for AS03-adjuvanted vaccine was similar to that for nonadjuvanted (15-μg) vaccine in study A (1:86 and 1:88, respectively) and higher than that for nonadjuvanted (3.75-μg) vaccine in study B (1:77 and 1:35, respectively). A(H1N1)pdm09-specific CD4+ T-cell and B-cell responses were stronger in AS03-adjuvanted groups and persisted only in these groups for 12 months at levels exceeding prevaccination frequencies. Advancing age and a seasonal vaccination history tended to reduce HI antibody and memory B-cell responses and, albeit less consistently, CD4+ T-cell responses. Thus, AS03 seemed to enhance the persistence of humoral and cell-mediated responses to A(H1N1)pdm09 vaccine, allowing for antigen sparing and mitigating potential negative effects of age and previous seasonal vaccination. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00968539 and NCT00989287.) PMID:28446441

  10. Self-complementary adeno-associated virus serotype 6 mediated knockdown of ADAMTS4 induces long-term and effective enhancement of aggrecan in degenerative human nucleus pulposus cells: A new therapeutic approach for intervertebral disc disorders

    PubMed Central

    Shenegelegn Mern, Demissew; Tschugg, Anja; Hartmann, Sebastian; Thomé, Claudius

    2017-01-01

    -mediated knockdown of ADAMTS4 showed no impact on cell viability and expression levels of other inflammatory catabolic proteins. Thus, our results are promising and may help to design long-term and less immunogenic gene therapeutic approaches in IVD disorders, which usually need prolonged therapeutic period between weeks and months. PMID:28207788

  11. Concept Formation Skills in Long-Term Cochlear Implant Users

    ERIC Educational Resources Information Center

    Castellanos, Irina; Kronenberger, William G.; Beer, Jessica; Colson, Bethany G.; Henning, Shirley C.; Ditmars, Allison; Pisoni, David B.

    2015-01-01

    This study investigated if a period of auditory sensory deprivation followed by degraded auditory input and related language delays affects visual concept formation skills in long-term prelingually deaf cochlear implant (CI) users. We also examined if concept formation skills are mediated or moderated by other neurocognitive domains (i.e.,…

  12. Concept Formation Skills in Long-Term Cochlear Implant Users

    ERIC Educational Resources Information Center

    Castellanos, Irina; Kronenberger, William G.; Beer, Jessica; Colson, Bethany G.; Henning, Shirley C.; Ditmars, Allison; Pisoni, David B.

    2015-01-01

    This study investigated if a period of auditory sensory deprivation followed by degraded auditory input and related language delays affects visual concept formation skills in long-term prelingually deaf cochlear implant (CI) users. We also examined if concept formation skills are mediated or moderated by other neurocognitive domains (i.e.,…

  13. [Perspectives in long-term care insurance].

    PubMed

    Pick, P

    2007-03-01

    Twelve years after its introduction, long-term care insurance is back on the agenda and up for political reform. This paper shows why long-term care insurance needs to be reformed. The two central aspects on which reform projects focus are addressed: firstly, the structural improvement of nursing care and long-term care insurance and, secondly, the creation of a sustained financing. The principal conclusion is that, while there is a broad consensus about the structural improvement of long-term care insurance, opinions differ widely in the matter of its sustained financing. As a consequence, a coherent financing concept has yet to emerge.

  14. Drebrin-mediated microtubule–actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection

    PubMed Central

    Trivedi, Niraj; Stabley, Daniel R.; Cain, Blake; Howell, Danielle; Laumonnerie, Christophe; Ramahi, Joseph S.; Temirov, Jamshid; Kerekes, Ryan A.; Gordon-Weeks, Phillip R.; Solecki, David J.

    2017-01-01

    Neuronal migration from a germinal zone to a final laminar position is essential for the morphogenesis of neuronal circuits. While it is hypothesized that microtubule–actomyosin crosstalk is required for a neuron's ‘two-stroke' nucleokinesis cycle, the molecular mechanisms controlling such crosstalk are not defined. By using the drebrin microtubule–actin crosslinking protein as an entry point into the cerebellar granule neuron system in combination with super-resolution microscopy, we investigate how these cytoskeletal systems interface during migration. Lattice light-sheet and structured illumination microscopy reveal a proximal leading process nanoscale architecture wherein f-actin and drebrin intervene between microtubules and the plasma membrane. Functional perturbations of drebrin demonstrate that proximal leading process microtubule–actomyosin coupling steers the direction of centrosome and somal migration, as well as the switch from tangential to radial migration. Finally, the Siah2 E3 ubiquitin ligase antagonizes drebrin function, suggesting a model for control of the microtubule–actomyosin interfaces during neuronal differentiation. PMID:28230156

  15. Drebrin-mediated microtubule–actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection

    DOE PAGES

    Trivedi, Niraj; Stabley, Daniel R.; Cain, Blake; ...

    2017-02-23

    Neuronal migration from a germinal zone to a final laminar position is essential for the morphogenesis of neuronal circuits. While it is hypothesized that microtubule–actomyosin crosstalk is required for a neuron’s ‘two-stroke’ nucleokinesis cycle, the molecular mechanisms controlling such crosstalk are not defined. By using the drebrin microtubule–actin crosslinking protein as an entry point into the cerebellar granule neuron system in combination with super-resolution microscopy, we investigate how these cytoskeletal systems interface during migration. Lattice light-sheet and structured illumination microscopy reveal a proximal leading process nanoscale architecture wherein f-actin and drebrin intervene between microtubules and the plasma membrane. Functional perturbationsmore » of drebrin demonstrate that proximal leading process microtubule–actomyosin coupling steers the direction of centrosome and somal migration, as well as the switch from tangential to radial migration. Finally, the Siah2 E3 ubiquitin ligase antagonizes drebrin function, suggesting a model for control of the microtubule–actomyosin interfaces during neuronal differentiation.« less

  16. Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells.

    PubMed

    Jiménez, Andrés; Jordà, Elvira G; Verdaguer, Ester; Pubill, David; Sureda, Francesc X; Canudas, Anna M; Escubedo, Elena; Camarasa, Jordi; Camins, Antoni; Pallàs, Mercè

    2004-04-15

    The neurotoxic action of the abuse drugs methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) on cerebellar granule neurones (CGNs) culture was examined. Treatment for 48 h with METH or MDMA (1-5 mM) induced a higher decrease in viability than 24 h treatment. z.VAD.fmk (100 microM) but not MK-801 nor NBQX recovered control viability values. In both cases, cell death was characterised as apoptotic rather than necrotic by morphology cell observation. Apoptosis measured by flow cytometry indicated an increase in the hypodiploid population after 48 h treatment with METH and MDMA. Apoptosis was reverted by the presence of z.VAD.fmk (100 microM) but not by 10 microM MK-801 or NBQX. Similar results were obtained by analysing nuclear chromatine condensation. These results ruled out excitotoxic participation in amphetamine derivative-induced neurotoxicity in CGNs. Participation of radical oxygen species (ROS) was evaluated using alpha-tocopherol (1-15 microM) and cytometric studies. The co-treatment with 4 mM METH or MDMA for 48 h partially reverted neurotoxic action and apoptotic features, indicating ROS implication in CGNs death by amphetamine derivatives. Alteration of mitochondrial function induced cytochrome C (Cyt C) release after 48-h treatment with METH and MDMA (4 mM). There was also indication of caspase-3-like activation, measured by immunoanalysis and biochemically. Finally, neurodegenerative action caused by amphetamine derivatives may be prevented by using caspase inhibitors.

  17. The direction of the postural response to a vestibular perturbation is mediated by the cerebellar vermis.

    PubMed

    Lam, Chris K; Tokuno, Craig D; Staines, W Richard; Bent, Leah R

    2016-12-01

    When an electrical stimulus is applied to perturb the vestibular system, a postural response is generated orthogonal to head orientation. It has previously been shown that there is a convergence of neck proprioceptive and vestibular input within the cerebellum to provide a head-on-body reference frame (Manzoni et al. in Neuroscience 93:1095-1107, 1999). The objective of this experiment was to determine whether the direction of the postural response to a vestibular perturbation is modulated when function of the cerebellar vermis is temporarily depressed. Twenty participants were randomly assigned to a SHAM group (paired-pulse transcranial magnetic stimulation) or a TEST group (continuous theta burst stimulation). Stochastic vestibular stimulation (SVS) was applied to standing subjects with their head facing forward or over their left shoulder. Cumulant density traces were established between the SVS and shear force over 180°, and the peak amplitude determined the direction of sway. There were no significant changes in sway direction when the head was facing forward for either stimulation (TEST or SHAM; p = 0.889) or when the head was facing over the shoulder for the SHAM condition (p = 0.954). There was, however, a significant change in sway direction when the head was turned with a depressed cerebellum (p = 0.018); from the expected antero-posterior direction, orthogonal to head orientation, to one slightly more mediolateral with respect to the feet. These results suggest the cerebellum plays a role in the integration of input to generate an appropriately directed postural response relative to the head position.

  18. Virtual Models of Long-Term Care

    ERIC Educational Resources Information Center

    Phenice, Lillian A.; Griffore, Robert J.

    2012-01-01

    Nursing homes, assisted living facilities and home-care organizations, use web sites to describe their services to potential consumers. This virtual ethnographic study developed models representing how potential consumers may understand this information using data from web sites of 69 long-term-care providers. The content of long-term-care web…

  19. Virtual Models of Long-Term Care

    ERIC Educational Resources Information Center

    Phenice, Lillian A.; Griffore, Robert J.

    2012-01-01

    Nursing homes, assisted living facilities and home-care organizations, use web sites to describe their services to potential consumers. This virtual ethnographic study developed models representing how potential consumers may understand this information using data from web sites of 69 long-term-care providers. The content of long-term-care web…

  20. Long Term Preservation of Digital Information.

    ERIC Educational Resources Information Center

    Lorie, Raymond A.

    The preservation of digital data for the long term presents a variety of challenges from technical to social and organizational. The technical challenge is to ensure that the information, generated today, can survive long term changes in storage media, devices, and data formats. This paper presents a novel approach to the problem. It distinguishes…

  1. Long-Term Nutrition: A Clinician's Guide to Successful Long-Term Enteral Access in Adults.

    PubMed

    Bechtold, Matthew L; Mir, Fazia A; Boumitri, Christine; Palmer, Lena B; Evans, David C; Kiraly, Laszlo N; Nguyen, Douglas L

    2016-09-22

    Long-term nutrition support requires long-term enteral access. To ensure the success of long-term enteral access, many factors need to be taken into consideration. This article represents a guide to placing and maintaining access in patients requiring long-term nutrition and addresses many of the common questions regarding long-term enteral access, such as indications, types of access, feeding after access placed, and recognition and treatment of potential complications. This guide will help the clinician establish and maintain access to maximize nutrition in patients requiring long-term nutrition.

  2. Paying for long-term care.

    PubMed Central

    Estes, C L; Bodenheimer, T

    1994-01-01

    Everyone agrees that insurance for long-term care is inadequate in the United States. Disagreement exists, however, on whether such insurance should be provided through the private or public sector. Private insurance generally uses the experience-rating principle that persons with higher risk of illness are charged higher premiums. For private insurance for long-term care, this principle creates a dilemma. Most policies will be purchased by the elderly; yet, because the elderly have a high risk of needing long-term care, only about 20% of them can afford the cost of premiums. A public-private partnership by which the government partially subsidizes private long-term-care insurance is unlikely to resolve this dilemma. Only a social insurance program for long-term care can provide universal, affordable, and equitable coverage. PMID:8128712

  3. [Cerebellar hypoplasias].

    PubMed

    Safronova, Marta Maia; Barbot, Clara; Resende Pereira, Jorge

    2010-01-01

    Cerebellar hypoplasias are cerebellar malformations with small but completely formed cerebellum. They can be divided in focal and in diffuse or generalized. It is sometimes difficult to make distinction between cerebellar atrophy (progressive condition) and hipoplasia (not progressive condition). Focal hypoplasias are restricted to one cerebellar hemisphere or to the vermis. Diffuse hypoplasias refer to both cerebellar hemispheres and vermis. If there is associated IVth ventricle enlargement, hypoplasias occur in the context of Dandy-Walker complex, a continuum of posterior fossa cystic anomalies. A revision of cerebellar hypoplasias and associated pathology is done, illustrated with 22 cases tha include focal and diffuse cerebellar hypoplasias, Dandy-Walker malformations and its variant, persistent Blake's pouch cyst, megacisterna magna, PEHO síndrome (progressive encephalopathy with oedema, hipsarrhythmia and optic atrophy), Joubert syndrome, congenital disorder of glycosylation type Ia, pontocerebellar hipoplasias Barth type I and II, diffuse subcortical heterotopia. The imaging finding of structural cerebellar anomalies frequently leads to diagnostic incertainty as the anomalies are mostly unspecific, implying an extenuating analytical and genetic workup. Their knowledge and classification may be useful to decide the patient adjusted laboratorial workup.

  4. Purkinje cell stripes and long-term depression at the parallel fiber-Purkinje cell synapse

    PubMed Central

    Hawkes, Richard

    2014-01-01

    The cerebellar cortex comprises a stereotyped array of transverse zones and parasagittal stripes, built around multiple Purkinje cell subtypes, which is highly conserved across birds and mammals. This architecture is revealed in the restricted expression patterns of numerous molecules, in the terminal fields of the afferent projections, in the distribution of interneurons, and in the functional organization. This review provides an overview of cerebellar architecture with an emphasis on attempts to relate molecular architecture to the expression of long-term depression (LTD) at the parallel fiber-Purkinje cell (pf-PC) synapse. PMID:24734006

  5. Bestrophin1 Channels are Insensitive to Ethanol and Do not Mediate Tonic GABAergic Currents in Cerebellar Granule Cells.

    PubMed

    Diaz, Marvin R; Wadleigh, Aya; Hughes, Benjamin A; Woodward, John J; Valenzuela, C Fernando

    2011-01-01

    The granule cell layer of the cerebellum functions in spatio-temporal encoding of information. Granule cells (GCs) are tonically inhibited by spillover of GABA released from Golgi cells and this tonic inhibition is facilitated by acute ethanol. Recently, it was demonstrated that a specialized Ca(2+)-activated anion-channel, bestrophin1 (Best1), found on glial cells, can release GABA that contributes up to 50-75% of the tonic GABAergic current. However, it is unknown if ethanol has any actions on Best1 function. Using whole-cell electrophysiology, we found that recombinant Best1 channels expressed in HEK-293 cells were insensitive to 40 and 80 mM ethanol. We attempted to measure the Best1-mediated component of the tonic current in slices using 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). We confirmed that this agent blocks recombinant Best1 channels. Unexpectedly, we found that NPPB significantly potentiated the tonic current and the area and decay of GABA(A)-mediated spontaneous inhibitory post-synaptic currents (IPSCs) in GCs in rodent slices under two different recording conditions. To better isolate the Best1-dependent tonic current component, we blocked the Golgi cell component of the tonic current with tetrodotoxin and found that NPPB similarly and significantly potentiated the tonic current amplitude and decay time of miniature IPSCs. Two other Cl(-)-channel blockers were also tested: 4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate (DIDS) showed no effect on GABAergic transmission, while niflumic acid (NFA) significantly suppressed the tonic current noise, as well as the mIPSC frequency, amplitude, and area. These data suggest that acute ethanol exposure does not modulate Best1 channels and these findings serve to challenge recent data indicating that these channels participate in the generation of tonic GABAergic currents in cerebellar GCs.

  6. Bestrophin1 Channels are Insensitive to Ethanol and Do not Mediate Tonic GABAergic Currents in Cerebellar Granule Cells

    PubMed Central

    Diaz, Marvin R.; Wadleigh, Aya; Hughes, Benjamin A.; Woodward, John J.; Valenzuela, C. Fernando

    2012-01-01

    The granule cell layer of the cerebellum functions in spatio-temporal encoding of information. Granule cells (GCs) are tonically inhibited by spillover of GABA released from Golgi cells and this tonic inhibition is facilitated by acute ethanol. Recently, it was demonstrated that a specialized Ca2+-activated anion-channel, bestrophin1 (Best1), found on glial cells, can release GABA that contributes up to 50–75% of the tonic GABAergic current. However, it is unknown if ethanol has any actions on Best1 function. Using whole-cell electrophysiology, we found that recombinant Best1 channels expressed in HEK-293 cells were insensitive to 40 and 80 mM ethanol. We attempted to measure the Best1-mediated component of the tonic current in slices using 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). We confirmed that this agent blocks recombinant Best1 channels. Unexpectedly, we found that NPPB significantly potentiated the tonic current and the area and decay of GABAA-mediated spontaneous inhibitory post-synaptic currents (IPSCs) in GCs in rodent slices under two different recording conditions. To better isolate the Best1-dependent tonic current component, we blocked the Golgi cell component of the tonic current with tetrodotoxin and found that NPPB similarly and significantly potentiated the tonic current amplitude and decay time of miniature IPSCs. Two other Cl−-channel blockers were also tested: 4′-diisothiocyanatostilbene-2,2′-disulfonic acid disodium salt hydrate (DIDS) showed no effect on GABAergic transmission, while niflumic acid (NFA) significantly suppressed the tonic current noise, as well as the mIPSC frequency, amplitude, and area. These data suggest that acute ethanol exposure does not modulate Best1 channels and these findings serve to challenge recent data indicating that these channels participate in the generation of tonic GABAergic currents in cerebellar GCs. PMID:22275879

  7. Hospital diversification into long-term care.

    PubMed

    Shah, A; Fennell, M; Mor, V

    2001-01-01

    In the 1990s, acute care hospitals in the United States encountered an unstable operating environment created by a series of transformations in the health care delivery system and long-term-care market. Confronted with an array of economic pressures and demographic changes, hospitals were motivated to engage in long-term-care diversification, such as establishing a long-term-care unit or providing home health services, as a means of entering new markets and ensuring financial stability. This article examines the organizational, market, and community factors associated with this strategic activity among a national sample of urban and rural hospitals.

  8. Cerebellar ataxias.

    PubMed

    Manto, Mario; Marmolino, Daniele

    2009-08-01

    The term 'cerebellar ataxias' encompasses the various cerebellar disorders encountered during daily practice. Patients exhibit a cerebellar syndrome and can also present with pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. The clinical diagnosis of subtypes of ataxias is complicated by the salient overlap of the phenotypes between genetic subtypes. The identification of the causative mutations of many hereditary ataxias and the development of relevant animal models bring hope for effective therapies in neurodegenerative ataxias. We describe the current classification of cerebellar ataxias and underline the recent discoveries in molecular pathogenesis. Cerebellar disorders can be divided into sporadic forms and inherited diseases. Inherited ataxias include autosomal recessive cerebellar ataxias, autosomal dominant cerebellar ataxias/spinocerebellar ataxia) and episodic ataxias, and X-linked ataxias. From a motor control point of view, the leading theories of ataxia are based on neural representations or 'internal models' to emulate fundamental natural processes such as body motion. Recent molecular advances have direct implications for research and daily practice. We provide a framework for the diagnosis of ataxias. For the first time, the therapeutic agents under investigation are targeted to deleterious pathways.

  9. Long Term Effects of Food Poisoning

    MedlinePlus

    ... develop chronic arthritis. Brain and nerve damage A Listeria infection can lead to meningitis, an inflammation of ... brain. If a newborn infant is infected with Listeria , long-term consequences may include mental retardation, seizures, ...

  10. Mental Health in Long Term Care Settings.

    ERIC Educational Resources Information Center

    Shore, Herbert

    1978-01-01

    There are many ways in which long-term care facilities attempt to cope with the mental health problems of the elderly. The author reviews five factors crucial to effective care for the aged in these facilities. (Author/RK)

  11. Roadmap to Long-Term Monitoring Optimization

    EPA Pesticide Factsheets

    This roadmap focuses on optimization of established long-term monitoring programs for groundwater. Tools and techniques discussed concentrate on methods for optimizing the monitoring frequency and spatial (three-dimensional) distribution of wells ...

  12. Long-term-care legal update.

    PubMed

    Fiesta, J

    1998-04-01

    As more nurses move from the acute care setting to long-term-care and home health care, different practice issues arise. To maximize liability protection, nurses must understand the legal issues unique to each delivery system.

  13. Evidence-based long term care design.

    PubMed

    Calkins, Margaret P

    2009-01-01

    Research on the impact of the built environment in long-term care settings continues to grow. This article focuses on work conducted and published since 2000, when an earlier review on research on dementia and design was published. The vast majority of research that addressed neurological conditions in residents in long-term care settings (assisted living and nursing homes) relates to Alzheimer's disease and related dementias.

  14. Long Term Outcomes after Pediatric Liver Transplantation

    PubMed Central

    2013-01-01

    Long term outcomes after liver transplantation are major determinants of quality of life and of the value of this heroic treatment. As short term outcomes are excellent, our community is turning to take a harder look at long term outcomes. The purpose of this paper is to review these outcomes, and highlight proposed treatments, as well as pressing topics needing to be studied. A systemic review of the English literature was carried in PubMed, covering all papers addressing long term outcomes in pediatric liver transplant from 2000-2013. Late outcomes after pediatric liver transplant affect the liver graft in the form of chronic liver dysfunction. The causes include rejection particularly humoral rejection, but also de novo autoimmune hepatitis, and recurrent disease. The metabolic syndrome is a major factor in long term cardiovascular complication risk. Secondary infections, kidney dysfunction and malignancy remain a reality of those patients. There is growing evidence of late cognitive and executive function delays affecting daily life productivity as well as likely adherence. Finally, despite a good health status, quality of life measures are comparable to those of children with chronic diseases. Long term outcomes are the new frontier in pediatric liver transplantation. Much is needed to improve graft survival, but also to avoid systemic morbidities from long term immunosuppression. Quality of life is a new inclusive measure that will require interventions and innovative approaches respectful not only on the patients but also of their social circle. PMID:24511516

  15. Cerebellar Degeneration

    MedlinePlus

    ... is a process in which neurons in the cerebellum - the area of the brain that controls coordination ... body, can cause neurons to die in the cerebellum. Neurological diseases that feature cerebellar degeneration include: ischemic ...

  16. Ethanol acutely modulates mGluR1-dependent long-term depression in cerebellum.

    PubMed

    Su, Li-Da; Sun, Cheng-Long; Shen, Ying

    2010-07-01

    Acute and chronic ethanol exposure produces profound impairments in motor functioning. Individuals with lower sensitivity to the acute motor impairing effects of ethanol have an increased risk of developing alcohol dependence and abuse, and infants with subtle delays in motor coordination development may have an increased risk for subsequently developing alcoholism. Thus, understanding the mechanism by which ethanol disrupts motor functioning is very important. Parasagittal slices of the cerebellar vermis (250 microM thick) were prepared from P17 to 20 Sprague-Dawley rats. Whole-cell recordings of Purkinje cells were obtained with an Axopatch 200B amplifier. Parallel fiber-Purkinje cell synaptic currents were sampled at 1 kHz and digitized at 10 kHz, and synaptic long-term depression (LTD) was observed in either external or internal application of ethanol for comparison. We determined whether ethanol acutely affects parallel fiber LTD using whole-cell patch-clamp recordings from Purkinje cells. Application of ethanol both externally (50 mM) and internally (17 and 10 mM) significantly suppressed mGluR-mediate slow currents. Short-term external ethanol exposure (50 but not 17 mM) during tetanus blocked mGluR-dependent parallel fiber LTD. Furthermore, internal 17 and 10 mM ethanol completely inhibited this LTD. The results of the current study demonstrate that ethanol acutely suppresses parallel fiber LTD and may influence the mGluR-mediated slow current intracellularly. This study, plus previous evidence by Carta and colleagues (2006) and Belmeguenai and colleagues (2008), suggests significant actions of ethanol on mGluR-mediated currents and its dependent plasticity in brain.

  17. Long-term exposure to PM2.5 lowers influenza virus resistance via down-regulating pulmonary macrophage Kdm6a and mediates histones modification in IL-6 and IFN-β promoter regions.

    PubMed

    Ma, Jing-Hui; Song, Shao-Hua; Guo, Meng; Zhou, Ji; Liu, Fang; Peng, Li; Fu, Zhi-Ren

    2017-11-18

    Atmospheric particulates, especially PM2.5, not only damage the respiratory system, but also play important roles in pulmonary immunity. China is influenced by atmospheric diffusion conditions, industrial manufacturers, and heating and discharging. PM2.5 levels in the air rise substantially in the winter, which is also a period of flu high-incidence. Although an epidemiological link exists between PM2.5 and flu, we do not understand how long-term PM2.5 inhalation affects pulmonary immunity and the influenza virus response. Our study has prepared an in vivo PM2.5 mouse pharyngeal wall drop-in model and has found that PM2.5 exposure leads to mouse inflammatory injuries and furthers influenza A infection. Our results suggest that short-term exposure to PM2.5 significantly enhances the survival rate of influenza A-contaminated mice, while long-term PM2.5 inhalation lowers the capacity of pulmonary macrophages to secrete IL-6 and IFN-β. A disorder in the pulmonary innate defense system results in increased death rates following influenza infection. On a macromolecular level, this mechamism involves Kdm6a down-regulation after long-term exposure to PM 2.5 and a resultant increase in H3K4 and H3K9 methylation in IL-6 and IFN-β promoter regions. In summary, PM2.5 causes injuries of lung tissue cells and downregulates immune defense mechanisms in the lung. Copyright © 2017. Published by Elsevier Inc.

  18. Anti-Yo antibody-mediated paraneoplastic cerebellar degeneration in a female patient with pleural malignant mesothelioma.

    PubMed

    Tanriverdi, Ozgur; Meydan, Nezih; Barutca, Sabri; Ozsan, Nazan; Gurel, Duygu; Veral, Ali

    2013-05-01

    Paraneoplastic cerebellar degeneration is a rare non-metastatic complication of malignancies. It presents with acute or subacute onset of ataxia, dysarthria and intention tremor. Paraneoplastic cerebellar degeneration is most commonly associated with malignancies of the ovary, breast and lung. The anti-Yo (anti-Purkinje cells) antibodies that specifically damage the Purkinje cells of the cerebellum are found in the serum and cerebrospinal fluid. Anti-Yo-related paraneoplastic cerebellar degeneration is most commonly found in women with gynecological and breast cancers, but it is reported in other malignancies. Patients with paraneoplastic syndromes most often present with neurologic symptoms before an underlying cancer is detected. We report a case of anti-Yo-related paraneoplastic cerebellar degeneration associated with pleural malignant mesothelioma in a 51-year-old female patient. She presented to our department with a 2-week history after the last chemotherapy of progressive dizziness related to head movement, nausea, vomiting, ataxia and unsteady gait. A western blot assay was negative for anti-Hu, anti-Ri, anti-Ma2, anti-CV2 and anti-amphiphysin paraneoplastic antibody markers but positive for anti-Yo. In conclusion, we report a case of paraneoplastic cerebellar degeneration in a patient with pleural malignant mesothelioma because of the rarity of this neurologic presentation after the diagnosis of malignant mesothelioma and of the association with anti-Yo antibodies.

  19. Long-term symptom relief after septoplasty.

    PubMed

    Sundh, Carolina; Sunnergren, Ola

    2015-10-01

    The results for long-term symptom relief after septoplasty are contradictory in reviewed publications but the findings suggest that results are unsatisfactory. In this study, we analyzed and compared short- and long-term symptom relief after septoplasty and factors possibly associated with symptom relief. 111 patients that underwent septoplasty between 2008 and 2010 were included in the study. Medical charts were reviewed for preoperative characteristics and assessments. Data on short-term symptom relief (6 months) were retrieved from the Swedish National Quality Registry for Septoplasty; data on long-term symptom relief (34-70 months) were collected through a questionnaire. Upon the 34-70 month follow-up, 53% of the patients reported that symptoms either remained or had worsened and 83% reported nasal obstruction. Degree of symptom relief was significantly higher among patients not reporting nasal obstruction than among patients reporting nasal obstruction at long-term follow-up. The proportion of patients that reported "my symptoms are gone" declined from 53% after 6 months to 18% after 34-70 months. None of the factors taken into consideration, age at surgery, gender, follow-up time, primary operation/reoperation, history of nasal trauma, self-reported allergy, rhinometric obstruction, or same sided rhinometric, clinical and subjective nasal obstruction were associated with symptom relief. The long-term results after septoplasty are unsatisfactory. A majority of patients report that their symptoms remain after septoplasty.

  20. Representational Specificity of Within-Category Phonetic Variation in the Long-Term Mental Lexicon

    ERIC Educational Resources Information Center

    Ju, Min; Luce, Paul A.

    2006-01-01

    This study examines the potential encoding in long-term memory of subphonemic, within-category variation in voice onset time (VOT) and the degree to which this encoding of subtle variation is mediated by lexical competition. In 4 long-term repetition-priming experiments, magnitude of priming was examined as a function of variation in VOT in words…

  1. Representational Specificity of Within-Category Phonetic Variation in the Long-Term Mental Lexicon

    ERIC Educational Resources Information Center

    Ju, Min; Luce, Paul A.

    2006-01-01

    This study examines the potential encoding in long-term memory of subphonemic, within-category variation in voice onset time (VOT) and the degree to which this encoding of subtle variation is mediated by lexical competition. In 4 long-term repetition-priming experiments, magnitude of priming was examined as a function of variation in VOT in words…

  2. Long-term outcomes of autoimmune pancreatitis

    PubMed Central

    Ikeura, Tsukasa; Miyoshi, Hideaki; Shimatani, Masaaki; Uchida, Kazushige; Takaoka, Makoto; Okazaki, Kazuichi

    2016-01-01

    Autoimmune pancreatitis (AIP) has been considered a favorable-prognosis disease; however, currently, there is limited information on natural course of AIP during long-term follow-up. Recently published studies regarding the long-term outcomes of AIP has demonstrated the developments of pancreatic stone formation, exocrine insufficiency, and endocrine insufficiency are observed in 5%-41%, 34%-82%, and 38%-57% of patients having the disease. Furthermore, the incidence rate of developing pancreatic cancer ranges from 0% to 4.8% during the long-term follow-up. The event of death from AIP-related complications other than accompanying cancer is likely to be rare. During follow-up of AIP patients, careful surveillance for not only relapse of the disease but also development of complications at regular intervals is needed. PMID:27678359

  3. Valuing a long-term care facility.

    PubMed

    Mellen, C M

    1992-10-01

    The business valuation industry generally uses at least one of three basic approaches to value a long-term care facility: the cost approach, sales comparison approach, or income approach. The approach that is chosen and the resulting weight that is applied to it depend largely on the circumstances involved. Because a long-term care facility is a business enterprise, more weight usually is given to the income approach which factors into the estimate of value both the tangible and intangible assets of the facility.

  4. Keratoprosthesis: a long-term review.

    PubMed Central

    Barnham, J. J.; Roper-Hall, M. J.

    1983-01-01

    A keratoprosthesis (KP), is an artificial cornea which is inserted into an opacified cornea in an attempt to restore useful vision or, less commonly, to make the eye comfortable in painful keratopathy. Results o a retrospective study of 35 patients, with 55 KP insertions, are reviewed with regard to visual acuity, length of time vision is maintained, retention time, and complication. Overall there were a number of long-term real successes, eith retention of the KP and maintenance of improved vision in eyes not amenable to conventional treatment. Careful long-term follow-up was needed, with further surgical procedures often being necessary. Images PMID:6860613

  5. Long-term Outcomes after Severe Shock

    PubMed Central

    Pratt, Cristina M.; Hirshberg, Eliotte L.; Jones, Jason P.; Kuttler, Kathryn G.; Lanspa, Michael J.; Wilson, Emily L.; Hopkins, Ramona O.; Brown, Samuel M.

    2014-01-01

    Background Severe shock is a life-threatening condition with very high short-term mortality. Whether the long-term outcomes among survivors of severe shock are similar to long-term outcomes of other critical illness survivors is unknown. We therefore sought to assess long-term survival and functional outcomes among 90-day survivors of severe shock and determine whether clinical predictors were associated with outcomes. Methods Seventy-six patients who were alive 90 days after severe shock (received ≥1 mcg/kg/min of norepinephrine equivalent) were eligible for the study. We measured three-year survival and long-term functional outcomes using the Medical Outcomes Study 36-Item Short-Form Health Survey, the EuroQOL 5-D-3L, the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised and an employment instrument. We also assessed the relationship between in-hospital predictors and long-term outcomes. Results The mean long-term survival was 5.1 years: 82% (62/76) of patients survived, of whom 49 were eligible for follow-up. Patients who died were older than patients who survived. Thirty-six patients completed a telephone interview a mean of five years after hospital admission. The patients’ Physical Functioning scores were below US population norms (p<0.001), whereas mental health scores were similar to population norms. Nineteen percent of the patients had symptoms of depression, 39% had symptoms of anxiety and 8% had symptoms of posttraumatic stress disorder. Thirty-six percent were disabled, and 17% were working full time. Conclusions Early survivors of severe shock had a high three-year survival rate. Patients’ long term physical and psychological outcomes were similar to those reported for cohorts of less severely ill ICU survivors. Anxiety and depression were relatively common, but only a few patients had symptoms of posttraumatic stress disorder. This study supports the observation that acute illness severity does not determine long-term

  6. [Fetal pain: immediate and long term consequences].

    PubMed

    Houfflin Debarge, Véronique; Dutriez, Isabelle; Pusniak, Benoit; Delarue, Eléonore; Storme, Laurent

    2010-06-01

    Several situations are potentially painful for fetuses, such as malformations and invasive procedures. Nociceptive pathways are known to be functional at 26 weeks. Even if it is not possible to evaluate the fetal experience of pain, it is essential to examine its immediate and long-term consequences. As early as the beginning of the second trimester, hemodynamic and hormonal responses are observed following fetal nociceptive stimulation, In experimental studies, long-term changes have been noted in the corticotrop axis, subsequent responses to pain, and behavior after perinatal nociceptive stimulation.

  7. Long-term outcomes after severe shock.

    PubMed

    Pratt, Cristina M; Hirshberg, Eliotte L; Jones, Jason P; Kuttler, Kathryn G; Lanspa, Michael J; Wilson, Emily L; Hopkins, Ramona O; Brown, Samuel M

    2015-02-01

    Severe shock is a life-threatening condition with very high short-term mortality. Whether the long-term outcomes among survivors of severe shock are similar to long-term outcomes of other critical illness survivors is unknown. We therefore sought to assess long-term survival and functional outcomes among 90-day survivors of severe shock and determine whether clinical predictors were associated with outcomes. Seventy-six patients who were alive 90 days after severe shock (received ≥1 μg/kg per minute of norepinephrine equivalent) were eligible for the study. We measured 3-year survival and long-term functional outcomes using the Medical Outcomes Study 36-Item Short-Form Health Survey, the EuroQOL 5-D-3L, the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised, and an employment instrument. We also assessed the relationship between in-hospital predictors and long-term outcomes. The mean long-term survival was 5.1 years; 82% (62 of 76) of patients survived, of whom 49 were eligible for follow-up. Patients who died were older than patients who survived. Thirty-six patients completed a telephone interview a mean of 5 years after hospital admission. The patients' Physical Functioning scores were below U.S. population norms (P < 0.001), whereas mental health scores were similar to population norms. Nineteen percent of the patients had symptoms of depression, 39% had symptoms of anxiety, and 8% had symptoms of posttraumatic stress disorder. Thirty-six percent were disabled, and 17% were working full-time. Early survivors of severe shock had a high 3-year survival rate. Patients' long-term physical and psychological outcomes were similar to those reported for cohorts of less severely ill intensive care unit survivors. Anxiety and depression were relatively common, but only a few patients had symptoms of posttraumatic stress disorder. This study supports the observation that acute illness severity does not determine long-term outcomes. Even extremely

  8. Long-Term Memory and Learning

    ERIC Educational Resources Information Center

    Crossland, John

    2011-01-01

    The English National Curriculum Programmes of Study emphasise the importance of knowledge, understanding and skills, and teachers are well versed in structuring learning in those terms. Research outcomes into how long-term memory is stored and retrieved provide support for structuring learning in this way. Four further messages are added to the…

  9. Long-Term Memory and Learning

    ERIC Educational Resources Information Center

    Crossland, John

    2011-01-01

    The English National Curriculum Programmes of Study emphasise the importance of knowledge, understanding and skills, and teachers are well versed in structuring learning in those terms. Research outcomes into how long-term memory is stored and retrieved provide support for structuring learning in this way. Four further messages are added to the…

  10. Professionalism in Long-Term Care Settings

    ERIC Educational Resources Information Center

    Lubinski, Rosemary

    2006-01-01

    Speech-language pathologists who serve elders in a variety of long-term care settings have a variety of professional skills and responsibilities. Fundamental to quality service is knowledge of aging and communication changes and disorders associated with this process, institutional alternatives, and the changing nature of today's elders in…

  11. Long-Term Impacts of Educational Interventions

    ERIC Educational Resources Information Center

    Deming, David James

    2010-01-01

    The school accountability movement has led to a marked increase in the use of standardized test scores to measure school and teacher productivity, yet little is known about the correlation between test score gains and improvements in long-term outcomes. In the first chapter of my dissertation, I study the impact of a school choice policy in…

  12. Long-term studies of dopamine agonists.

    PubMed

    Hubble, Jean P

    2002-02-26

    Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

  13. Long Term Care Aide. Course Outline.

    ERIC Educational Resources Information Center

    Wilbee, Judy

    This course outline is intended to assist the instructor in the development of a curriculum for a long-term care aide program by specifying one component of the curriculum--the objectives. These objectives, or competencies expected as outcomes for student performance on completion of the program, describe the capabilities an individual must…

  14. Long-term lysimeter data on evapotranspiration

    USDA-ARS?s Scientific Manuscript database

    Long term crop evapotranspiration (ET) data measured using large weighing lysimeters have only been gathered in a few places in the world, yet are of great importance for ground truthing of many models of plant water use, mesoscale climate, remote sensing estimation of ET, climate change and climate...

  15. Who Recommends Long-Term Care Matters

    ERIC Educational Resources Information Center

    Kane, Robert L.; Bershadsky, Boris; Bershadsky, Julie

    2006-01-01

    Purpose: Making good consumer decisions requires having good information. This study compared long-term-care recommendations among various types of health professionals. Design and Methods: We gave randomly varied scenarios to a convenience national sample of 211 professionals from varying disciplines and work locations. For each scenario, we…

  16. Professionalism in Long-Term Care Settings

    ERIC Educational Resources Information Center

    Lubinski, Rosemary

    2006-01-01

    Speech-language pathologists who serve elders in a variety of long-term care settings have a variety of professional skills and responsibilities. Fundamental to quality service is knowledge of aging and communication changes and disorders associated with this process, institutional alternatives, and the changing nature of today's elders in…

  17. Evaluating Long-Term Disability Insurance Plans.

    ERIC Educational Resources Information Center

    Powell, Jan

    1992-01-01

    This report analyzes the factors involved in reviewing benefits and services of employer-sponsored group long-term disability plans for higher education institutions. Opening sections describe the evolution of disability insurance and its shape today. Further sections looks at the complex nature of "value" within a plan, relationship…

  18. LONG TERM HYDROLOGICAL IMPACT ASSESSMENT (LTHIA)

    EPA Science Inventory

    LTHIA is a universal Urban Sprawl analysis tool that is available to all at no charge through the Internet. It estimates impacts on runoff, recharge and nonpoint source pollution resulting from past or proposed land use changes. It gives long-term average annual runoff for a lan...

  19. Long-Term Stability of Tutor Performance.

    ERIC Educational Resources Information Center

    Dolmans, Diana H. J. M.; And Others

    1996-01-01

    Examined the extent to which tutor ratings remained stable in the long term by evaluating 291 ratings of 140 tutors at Maastricht University in the Netherlands between 1992 and 1995. The results indicated that, if the aggregated score and overall judgement are used to interpret the precision of individual scores, four and two occasions,…

  20. Urethroplasty for hypospadias: long-term results.

    PubMed

    Glassman, C N; Machlus, B J; Kelalis, P P

    1980-06-01

    A retrospective study of patients who had undergone multi-staged hypospadias repair at the Mayo Clinic was undertaken to identify long-term problems associated with this surgery. Patients were queried concerning their satisfaction with quality of urinary stream; penile erection and ejaculation; sexual function and fertility; and cosmetic appearance.

  1. LONG TERM HYDROLOGICAL IMPACT ASSESSMENT (LTHIA)

    EPA Science Inventory

    LTHIA is a universal Urban Sprawl analysis tool that is available to all at no charge through the Internet. It estimates impacts on runoff, recharge and nonpoint source pollution resulting from past or proposed land use changes. It gives long-term average annual runoff for a lan...

  2. Very Long Term Memory for Tacit Knowledge.

    ERIC Educational Resources Information Center

    Allen, Rhianon; Reber, Arthur S.

    1980-01-01

    Very long-term memory for abstract materials was examined for subjects who had served in a synthetic grammar learning experiment two years earlier. Knowledge of these grammars was retained. The form and structure of knowledge and the manner in which it is put to use remained similar to the original. (Author/RD)

  3. Long-term opioid therapy reconsidered.

    PubMed

    Von Korff, Michael; Kolodny, Andrew; Deyo, Richard A; Chou, Roger

    2011-09-06

    In the past 20 years, primary care physicians have greatly increased prescribing of long-term opioid therapy. However, the rise in opioid prescribing has outpaced the evidence regarding this practice. Increased opioid availability has been accompanied by an epidemic of opioid abuse and overdose. The rate of opioid addiction among patients receiving long-term opioid therapy remains unclear, but research suggests that opioid misuse is not rare. Recent studies report increased risks for serious adverse events, including fractures, cardiovascular events, and bowel obstruction, although further research on medical risks is needed. New data indicate that opioid-related risks may increase with dose. From a societal perspective, higher-dose regimens account for the majority of opioids dispensed, so cautious dosing may reduce both diversion potential and patient risks for adverse effects. Limiting long-term opioid therapy to patients for whom it provides decisive benefits could also reduce risks. Given the warning signs and knowledge gaps, greater caution and selectivity are needed in prescribing long-term opioid therapy. Until stronger evidence becomes available, clinicians should err on the side of caution when considering this treatment.

  4. Long-term fixed income market structure

    NASA Astrophysics Data System (ADS)

    Grilli, Luca

    2004-02-01

    Long-term fixed income market securities present a strong positive correlation in daily returns. By using a metrical approach and considering “modified” time series, I show how it is possible to show a more complex structure which depends strictly on the maturity date.

  5. Long-term function after restorative proctocolectomy.

    PubMed

    Wheeler, J M D; Banerjee, A; Ahuja, N; Jewell, D P; Mortensen, N J McC

    2005-05-01

    Early functional outcome after restorative proctocolectomy and formation of an ileoanal pouch is known to be good, but there are minimal data on the long-term function of the pouch. The aim of this study was to look at the long-term functional outcome in patients who had undergone restorative proctocolectomy and formation of an ileoanal pouch. A total of 151 consecutive patients (96 males, 55 females) who underwent ileoanal pouch surgery between April 1983 and May 1993 were identified. Functional outcomes from the previous 12 months were appraised by a standardized questionnaire. The median age at surgery was 31 years (range, 6-63 years), with a median follow-up of 142 months (range, 100-221 months). Eighteen patients have had their pouches excised, with another patient being defunctioned. Therefore 19 patients (13 percent) had suffered pouch failure. Altogether, 115 patients were available for follow-up, and 98 patients (85 percent) returned questionnaires. The median pouch-emptying frequency was five times (range, 1-17) during the day and one time (range, 0-6) at night. A total of 74 percent of patients had perfect continence during the day. Most of the patients had no life-style restrictions related to the pouch, and 98 percent of patients would recommend a pouch to others. Long-term functional outcome after ileoanal pouch surgery is good in most patients. For patients requiring proctocolectomy, ileoanal pouch surgery can now be recommended as an excellent long-term option.

  6. Long-Term Impacts of Educational Interventions

    ERIC Educational Resources Information Center

    Deming, David James

    2010-01-01

    The school accountability movement has led to a marked increase in the use of standardized test scores to measure school and teacher productivity, yet little is known about the correlation between test score gains and improvements in long-term outcomes. In the first chapter of my dissertation, I study the impact of a school choice policy in…

  7. Long-Term Stability of Tutor Performance.

    ERIC Educational Resources Information Center

    Dolmans, Diana H. J. M.; And Others

    1996-01-01

    Examined the extent to which tutor ratings remained stable in the long term by evaluating 291 ratings of 140 tutors at Maastricht University in the Netherlands between 1992 and 1995. The results indicated that, if the aggregated score and overall judgement are used to interpret the precision of individual scores, four and two occasions,…

  8. Who Recommends Long-Term Care Matters

    ERIC Educational Resources Information Center

    Kane, Robert L.; Bershadsky, Boris; Bershadsky, Julie

    2006-01-01

    Purpose: Making good consumer decisions requires having good information. This study compared long-term-care recommendations among various types of health professionals. Design and Methods: We gave randomly varied scenarios to a convenience national sample of 211 professionals from varying disciplines and work locations. For each scenario, we…

  9. Long-term disability in anxiety disorders.

    PubMed

    Hendriks, Sanne M; Spijker, Jan; Licht, Carmilla M M; Hardeveld, Florian; de Graaf, Ron; Batelaan, Neeltje M; Penninx, Brenda W J H; Beekman, Aartjan T F

    2016-07-19

    This longitudinal study aims to investigate differences in long-term disability between social anxiety disorder (SAD), panic disorder with agoraphobia (PDA), panic disorder without agoraphobia (PD), generalized anxiety disorder (GAD) and multiple anxiety disorders (multiple AD), focusing on the effects of different course trajectories (remission, recurrence and chronic course) and specific symptom dimensions (anxiety arousal and avoidance behaviour). Data were used from participants with no psychiatric diagnosis (healthy controls, n = 647) or with a current anxiety disorder (SAD, n = 191; PDA, n = 90; PD, n = 84; GAD, n = 110; multiple AD, n = 480). Severity of anxiety arousal and avoidance behaviour symptoms was measured using the Beck Anxiety Inventory and the Fear Questionnaire. The World Health Organization Disability Assessment Schedule II was used to measure disability. Long-term disability was most prevalent in participants with SAD and multiple AD, and lowest in PDA and PD. GAD had an intermediate position. Anxiety arousal and avoidance behaviour were associated with more long-term disability in anxiety disorders than course trajectories. Various anxiety disorders have different disability levels over 4 years of time, therefore diagnostic distinction is important for treatment focus. Anxiety arousal and avoidance behaviour are major predictors for long-term disability in anxiety disorders.

  10. Long-Term Stability of Social Participation

    ERIC Educational Resources Information Center

    Hyyppa, Markku T.; Maki, Juhani; Alanen, Erkki; Impivaara, Olli; Aromaa, Arpo

    2008-01-01

    The long-term stability of social participation was investigated in a representative urban population of 415 men and 579 women who had taken part in the nationwide Mini-Finland Health Survey in the years 1978-1980 and were re-examined 20 years later. Stability was assessed by means of the following tracking coefficients: kappa, proportion of…

  11. Long-Term Care Research and Policy

    ERIC Educational Resources Information Center

    Kemper, Peter

    2003-01-01

    This article provides a framework for understanding how long-term care (LTC) research contributes to policy, develops a typology of research contributions to policy with examples of each type, and suggests ways to ensure that contributions continue in the future. The article draws on in-depth interviews with LTC experts working at the interface…

  12. The long term characteristics of greenschist

    NASA Astrophysics Data System (ADS)

    Jang, Bo-An

    2016-04-01

    The greenschist in the Jinping II Hydropower Station in southwest China exhibits continuous creep behaviour because of the geological conditions in the region. This phenomenon illustrates the time-dependent deformation and progressive damage that occurs after excavation. In this study, the responses of greenschist to stress over time were determined in a series of laboratory tests on samples collected from the access tunnel walls at the construction site. The results showed that the greenschist presented time-dependent behaviour under long-term loading. The samples generally experienced two stages: transient creep and steady creep, but no accelerating creep. The periods of transient creep and steady creep increased with increasing stress levels. The long-term strength of the greenschist was identified based on the variation of creep strain and creep rate. The ratio of long-term strength to conventional strength was around 80% and did not vary much with confining pressures. A quantitative method for predicting the failure period of greenschist, based on analysis of the stress-strain curve, is presented and implemented. At a confining pressure of 40 MPa, greenschist was predicted to fail in 5000 days under a stress of 290 MPa and to fail in 85 days under the stress of 320 MPa, indicating that the long-term strength identified by the creep rate and creep strain is a reliable estimate.

  13. The Long-Term Effect of the Periconception Period on the Embryo's Epigenetic Profile and Phenotype: The Role of Maternal Disease Such as Diabetes and How the Effect Is Mediated (Example from a Rabbit Model).

    PubMed

    Fischer, Bernd; Schindler, Maria; Mareike Pendzialek, S; Gürke, Jacqueline; Haucke, Elisa; Grybel, Katarzyna Joanna; Thieme, René; Santos, Anne Navarrete

    2017-01-01

    Maternal metabolic diseases such as diabetes mellitus with diabetogenic hypoinsulinemia and hyperglycemia change periconceptional developmental conditions in utero. In preimplantation rabbit embryos, all major metabolic pathways are affected. Alterations in protein, lipid and glucose metabolism, adipokines, advanced glycation end products (AGEs) and reactive oxygen species (ROS) are described in this review. The embryonic metabolism is characterized by a high plasticity which enables survival of most preimplantation embryos under the non-physiological developmental conditions in diabetic mothers. Adiponectin, for example, compensates for the missing insulin-driven glucose supply and stimulates intracellular lipid accumulation in embryonic cells. AGEs and ROS are clear indicators of metabolic stress. The price paid for survival, however, needs to be taken into consideration. It is an increase in lipogenesis and proteinogenesis, leading to metabolic stress and with potentially negative long-term health effects.

  14. Lithium-mediated long-term neuroprotection in neonatal rat hypoxia-ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells

    PubMed Central

    Li, Hongfu; Li, Qian; Du, Xiaonan; Sun, Yanyan; Wang, Xiaoyang; Kroemer, Guido; Blomgren, Klas; Zhu, Changlian

    2011-01-01

    The aim of this study was to evaluate the long-term effects of lithium treatment on neonatal hypoxic-ischemic brain injury, inflammation, and neural stem/progenitor cell (NSPC) proliferation and survival. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2 mmol/kg lithium chloride was injected intraperitoneally immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-hour intervals for 7 days. Animals were killed 6, 24, 72 hours, or 7 weeks after HI. Lithium reduced total tissue loss by 69%, from 89.4±14.6 mm3 in controls (n=15) to 27.6±6.2 mm3 in lithium-treated animals (n=14) 7 weeks after HI (P<0.001). Microglia activation was inhibited by lithium treatment, as judged by Iba-1 and galectin-3 immunostaining, and reduced interleukin-1β and CCL2 levels. Lithium increased progenitor, rather than stem cell, proliferation in both nonischemic and ischemic brains, as judged by 5-bromo-2-deoxyuridine labeling 24 and 72 hours as well as by phospho-histone H3 and brain lipid-binding protein labeling 7 weeks after HI. Lithium treatment also promoted survival of newborn NSPCs, without altering the relative levels of neuronal and astroglial differentiation. In summary, lithium conferred impressive, morphological long-term protection against neonatal HI, at least partly by inhibiting inflammation and promoting NSPC proliferation and survival. PMID:21587270

  15. Workshop on long-term contraceptives.

    PubMed

    1996-01-01

    The National Population Council Secretariat (NPCS) of Ghana held a three-day workshop on long-term contraceptives in 1996 in collaboration with the Ministry of Health, the Association of Voluntary Surgical Contraception, and the Johns Hopkins Population Communication Services. The session was funded by USAID. The executive director of NPCS, Dr. Richard Turkson, said that the slow rate of contraceptive acceptance was an obstacle to population control despite political concern that rapid population growth exerted an adverse impact on the economy. Only 10% of married women were using long-term or permanent methods of contraception. The hope was voiced that the participants would devise practical and cost-effective education, information, and communication (IEC) strategies to boost the demand for long-term contraceptive methods among sexually active people in Ghana. It was essential that these strategies and activities were based on a realist assessment of the demographic and social situation of the country. The examination of case studies in cultures similar to Ghana would also offer valuable lessons. The factors that hinder the acceptance of long-term methods include misconceptions, myths, and false rumors rooted in a general lack of knowledge among the people. Participants were urged to come up with strategies to counter these problems, and service providers were encouraged to improve their knowledge about contraceptive methods and counseling skills. Male involvement in contraception was also advocated. Statistics show that most Ghanians practicing contraception were using short-term methods such as foaming tablets, pills, and condoms. However, it is necessary to shift to long-term methods such as injectables, implants, and sterilization in order to achieve significant reductions in fertility.

  16. Long-term biological investigations in space.

    PubMed

    Lotz, R G; Fuchs, H; Bertsche, U

    1975-01-01

    Missions in space within the next two decades will be of longer duration than those carried out up to the present time, and the effects of such long-term flights on biological organisms are unknown. Results of biological experiments that have been performed to date cannot be extrapolated to results in future flights because of the unknown influence of adaptation over a long period of time. Prior experiments with Axolotl, fishes, and vertebrates by our research team (in part with sounding rockets) showed that these specimens did not appear to be suitable for long-term missions on which minimization of expense, technique, and energy is required. Subsequent investigations have shown the suitability of the leech (Hirudo medicinalis), which consumes blood of mammals up to ten times its own weight (1 g) and can live more than 2 years without further food supply. Emphasis in the experiments with Hirudo medicinalis is placed on metabolic rhythm and motility. Resorption and diffusion in tissue, development, and growth under long-term effects of cosmic proton radiation and zero-gravity are other focal points. The constancy of cellular life in the mature animals is a point in favor of these specimens. We have also taken into account the synergistic effects of the space environment on the problems just mentioned. The life-support system constructed for the leech has been tested successfully in four sounding rocket flights and, on that basis, has been prepared for a long-term mission. Long-term investigations out of the terrestrial biosphere will provide us with information concerning the degree of adaptation of certain physiological and biochemical functions and as to what extent biological readjustment or repair processes can occur under the specific stress conditions of space flight.

  17. Long-Term Hearing Results After Ossiculoplasty.

    PubMed

    Cox, Matthew D; Trinidade, Aaron; Russell, James Shep; Dornhoffer, John L

    2017-04-01

    To determine if the OOPS index is predictive of long-term hearing results after ossiculoplasty. Case series with retrospective chart review. Tertiary care otology practice. Adult and pediatric patients (3-88 years of age). Ossiculoplasty with cartilage tympanoplasty, with or without mastoidectomy. Primary outcome measures included short-term hearing results (pure-tone average air-bone gap [PTA-ABG] measured between 60 days and 1 year after surgery), long-term hearing results (PTA-ABG measured ≥5 years after surgery), and the rate of successful ABG closure to ≤20 dB. Secondary measures included the need for revision surgery, delayed tympanic membrane graft failure, worsening conductive hearing loss (after an initially satisfactory hearing result), and recurrence of cholesteatoma. There was no significant difference between adults and children for short-term hearing results (average post-op PTA-ABG was 18.9 dB vs. 19.8 dB, respectively; p = 0.544), long-term hearing results (average final PTA-ABG was 19.3 dB vs. 19.4 dB, respectively; p = 0.922), or rate of ABG closure to less than 20 dB (63.1% vs. 58.0%, p = 0.282). Spearman's rank-order correlation (ρ) identified a strong positive correlation between OOPS index score and average post-operative PTA-ABG (ρ = 0.983; p < 0.001; 2-tailed), as well as average long-term PTA-ABG (ρ = 0.950, p < 0.001; 2-tailed). The OOPS index makes it possible to accurately prognosticate hearing outcomes in adult and pediatric patients undergoing ossiculoplasty in both the short term and the long term.

  18. Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression.

    PubMed

    Stein, Valentin; House, David R C; Bredt, David S; Nicoll, Roger A

    2003-07-02

    Previous studies have shown that overexpression of the protein PSD-95 (postsynaptic density-95) selectively enhances AMPA receptor-mediated synaptic responses in hippocampal pyramidal cells. To determine whether this effect is related to synaptic plasticity at these synapses, we examined whether PSD-95 expression mimics long-term potentiation (LTP), and also whether it influences LTP and long-term depression (LTD) in hippocampal slice cultures. Using simultaneous recording from transfected or infected cells and control pyramidal cells, we found that PSD-95, similar to LTP, increases the amplitude and frequency of miniature EPSCs. It also converts silent synapses to functional synapses, as does LTP. In addition, LTP is completely occluded in cells expressing PSD-95, whereas LTD is greatly enhanced. These results suggest that common mechanisms are involved in controlling synaptic AMPA receptors by PSD-95 and synaptic plasticity.

  19. Crossed Cerebellar Diaschisis

    PubMed Central

    Han, Shuguang; Wang, Xiaopeng; Xu, Kai; Hu, Chunfeng

    2016-01-01

    Abstract Crossed cerebellar diaschisis (CCD) describes a depression of oxidative metabolism glucose and blood flow in the cerebellum secondary to a supratentorial lesion in the contralateral cerebral hemisphere. PET/MR has the potential to become a powerful tool for demonstrating and imaging intracranial lesions .We herein report 3 cases of CCD imaging using a tri-modality PET/CT–MR set-up for investigating the value of adding MRI rather than CT to PET in clinical routine. We describe 3 patients with CCD and neurological symptoms in conjunction with abnormal cerebral fluorodeoxyglucose (FDG) positron emission tomography/computed tomography-magnetic resonance imaging (PET/CT–MR) manifestations including arterial spin-labeling (ASL) and T2-weighted images. In all, 18FDG-PET/CT detected positive FDG uptake in supratentorial lesions, and hypometabolism with atrophy in the contralateral cerebellum. More than that, hybrid PET/MRI provided a more accurate anatomic localization and ASL indicated disruption of the cortico-ponto-cerebellar pathway. Using pathology or long-term clinical follow-up to confirm the PET and ASL findings, the supratentorial lesions of the 3 patients were respectively diagnosed with cerebral infarction, recurrent glioma, and metastasis. The reports emphasize the significance of multimodality radiological examinations. Multimodality imaging contributes to proper diagnosis, management, and follow-up of supratentorial lesions with CCD. PMID:26765477

  20. Different Molecular Mechanisms Mediate Direct or Glia-Dependent Prion Protein Fragment 90-231 Neurotoxic Effects in Cerebellar Granule Neurons.

    PubMed

    Thellung, Stefano; Gatta, Elena; Pellistri, Francesca; Villa, Valentina; Corsaro, Alessandro; Nizzari, Mario; Robello, Mauro; Florio, Tullio

    2017-05-25

    Glia over-stimulation associates with amyloid deposition contributing to the progression of central nervous system neurodegenerative disorders. Here we analyze the molecular mechanisms mediating microglia-dependent neurotoxicity induced by prion protein (PrP)90-231, an amyloidogenic polypeptide corresponding to the protease-resistant portion of the pathological prion protein scrapie (PrP(Sc)). PrP90-231 neurotoxicity is enhanced by the presence of microglia within neuronal culture, and associated to a rapid neuronal [Ca(++)] i increase. Indeed, while in "pure" cerebellar granule neuron cultures, PrP90-231 causes a delayed intracellular Ca(++) entry mediated by the activation of NMDA receptors; when neuron and glia are co-cultured, a transient increase of [Ca(++)] i occurs within seconds after treatment in both granule neurons and glial cells, then followed by a delayed and sustained [Ca(++)] i raise, associated with the induction of the expression of inducible nitric oxide synthase and phagocytic NADPH oxidase. [Ca(++)] i fast increase in neurons is dependent on the activation of multiple pathways since it is not only inhibited by the blockade of voltage-gated channel activity and NMDA receptors but also prevented by the inhibition of nitric oxide and PGE2 release from glial cells. Thus, Ca(++) homeostasis alteration, directly induced by PrP90-231 in cerebellar granule cells, requires the activation of NMDA receptors, but is greatly enhanced by soluble molecules released by activated glia. In glia-enriched cerebellar granule cultures, the activation of inducible nitric oxide (iNOS) and NADPH oxidase represents the main mechanism of toxicity since their pharmacological inhibition prevented PrP90-231 neurotoxicity, whereas NMDA blockade by D(-)-2-amino-5-phosphonopentanoic acid is ineffective; conversely, in pure cerebellar granule cultures, NMDA blockade but not iNOS inhibition strongly reduced PrP90-231 neurotoxicity. These data indicate that amyloidogenic peptides

  1. Long-term consequences of foodborne infections.

    PubMed

    Batz, Michael B; Henke, Evan; Kowalcyk, Barbara

    2013-09-01

    Foodborne infections with Campylobacter, E. coli O157:H7, Listeria monocytogenes, Salmonella, Shigella, Toxoplasma gondii, and other pathogens can result in long-term sequelae to numerous organ systems. These include irritable bowel syndrome, inflammatory bowel disease, reactive arthritis, hemolytic uremic syndrome, chronic kidney disease, Guillain-Barré Syndrome, neurological disorders from acquired and congenital listeriosis and toxoplasmosis, and cognitive and developmental deficits due to diarrheal malnutrition or severe acute illness. A full understanding of the long-term sequelae of foodborne infection is important both for individual patient management by clinicians, as well as to inform food safety and public health decision making. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Case presentation: long-term treatment.

    PubMed

    Glucksman, Myron L

    2013-01-01

    The long-term (14 years) psychodynamic psychotherapy and pharmacotherapy of a depressed, suicidal, self-mutilating female patient is described. Her diagnoses included Chronic Posttraumatic Stress Disorder, Borderline Personality Disorder, and Recurrent Major Depression. Treatment was punctuated with repeated hospitalizations for self-mutilation (cutting) and suicidal ideation. A major determinant for her psychopathology was sexual abuse by her father from ages 6 to 14. This resulted in feelings of guilt and rage that she repressed and acted out through self-mutilating and suicidal behavior. A prolonged negative transference gradually became ambivalent, then positive. This was associated with her internalization of the healing qualities of the therapeutic relationship. She also gained insight into the reasons for her need to punish herself. Her initial self-representation as unworthy and bad was transformed into perceiving herself as a worthwhile, loving person. This case illustrates the role of long-term treatment for a complex, life-threatening, psychiatric disorder.

  3. Modeling long-term collider performance

    SciTech Connect

    Ritson, D. Superconducting Super Collider Lab., Dallas, TX )

    1991-07-01

    A model for the SSC arcs is described with multipole lattice field errors agglomerated into 32 lattice points, and with first order lattice errors and modulation provided by discrete transfer elements. Numerical solutions for long term dynamic aperture studies are obtained by multipole kick-drift tracking. The CPU time required to track through one turn is minimal, and comparable to that required to implement a one-turn fifth-order Taylor series map. Comparisons with tracking results using a fine grained representation of the lattice are made, and found to be satisfactory. The effects of tune modulation are studied and can substantially degrade long-term dynamic aperture. The effects of small relativistic momentum corrections, usually neglected for the large momenta at the SSC, are shown to have negligible influence on tracking results. 5 refs., 7 figs.

  4. Alcohol Withdrawal and Cerebellar Mitochondria.

    PubMed

    Jung, Marianna E

    2015-08-01

    Cerebellar disorders trigger the symptoms of movement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca(2+) level and a decrease in a Ca(2+)-binding protein, both of which result in the excessive entry of Ca(2+) to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellum under the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondria-targeting research may help develop a powerful new

  5. [Ambulatory long-term EEG monitors].

    PubMed

    John, K; Komärek, V; Lehovský, M

    1990-06-01

    Ambulatory EEG monitoring is indicated in patients with attacks of uncertain origin. The method is useful to distinguish non-epileptic and epileptic attacks and to differentiate the kind of epileptic seizures which is important for the choice of antiepileptic drugs and for prognosis. It is necessary to describe in detail behaviour and seizures of patient during monitoring. EEG long term monitoring is only useful if attacks were seen frequently, at least once or twice a week.

  6. LOP - Long-Term Orbit Predictor

    NASA Technical Reports Server (NTRS)

    Kwok, Johnny H.

    1992-01-01

    Long-Term Orbit Preditor (LOP) trajectory-propagation computer program is useful tool in analysis of lifetime of orbiting spacecraft. Suitable for studying planetary-orbit missions with reconnaissance (flyby) and exploratory (mapping) trajectories. Includes sample data for study of drift cycle of geosynchronous station, strategy for radar mapping of Venus, frozen orbit about Mars, and orbit characterized by repeating ground trace. Executed faster than such programs based on Cowell's method. Written in FORTRAN 77.

  7. Long term economic relationships from cointegration maps

    NASA Astrophysics Data System (ADS)

    Vicente, Renato; Pereira, Carlos de B.; Leite, Vitor B. P.; Caticha, Nestor

    2007-07-01

    We employ the Bayesian framework to define a cointegration measure aimed to represent long term relationships between time series. For visualization of these relationships we introduce a dissimilarity matrix and a map based on the sorting points into neighborhoods (SPIN) technique, which has been previously used to analyze large data sets from DNA arrays. We exemplify the technique in three data sets: US interest rates (USIR), monthly inflation rates and gross domestic product (GDP) growth rates.

  8. Long-term sequelae of electrical injury

    PubMed Central

    Wesner, Marni L.; Hickie, John

    2013-01-01

    Abstract Objective To summarize the current evidence-based knowledge about the long-term sequelae of injuries from electrical current. Quality of evidence MEDLINE was searched for English-language articles published in the past 20 years using the following search terms: electrical, injuries, wound, trauma, accident, sequelae, long-term, follow-up, and aftereffects. For obvious reasons, it is unethical to randomly study electrical injury in controlled clinical trials. By necessity, this topic is addressed in less-rigorous observational and retrospective work and case studies. Therefore, the strength of the literature pertaining to the long-term sequelae of electrical injury is impaired by the necessity of retrospective methods and case studies that typically describe small cohorts. Main message There are 2 possible consequences of electrical injury: the person either survives or dies. For those who survive electrical injury, the immediate consequences are usually obvious and often require extensive medical intervention. The long-term sequelae of the electrical injury might be more subtle, pervasive, and less well defined, but can include neurologic, psychological, and physical symptoms. In the field of compensation medicine, determining causation and attributing outcome to an injury that might not result in objective clinical findings becomes a considerable challenge. Conclusion The appearance of these consequences of electrical injury might be substantially delayed, with onset 1 to 5 or more years after the electrical injury. This poses a problem for patients and health care workers, making it hard to ascribe symptoms to a remote injury when they might not arise until well after the incident event. PMID:24029506

  9. Breakthroughs in long term care design.

    PubMed

    Hiatt, L

    1991-01-01

    In summary, here is what design is trying to accomplish in long term care facilities: Functional access; Privacy as entitlement; Sensory optimization to improve vision and hearing; Reduced walking and wheeling distances that still allow people to be mobile; Effective or functional placement of space and equipment; The option of smaller scale, so neither residents nor staff feel like they are hanging out with a unit full of, perhaps 68, people all the time; Flexibility and adaptability

  10. Long-term course of opioid addiction.

    PubMed

    Hser, Yih-Ing; Evans, Elizabeth; Grella, Christine; Ling, Walter; Anglin, Douglas

    2015-01-01

    Opioid addiction is associated with excess mortality, morbidities, and other adverse conditions. Guided by a life-course framework, we review the literature on the long-term course of opioid addiction in terms of use trajectories, transitions, and turning points, as well as other factors that facilitate recovery from addiction. Most long-term follow-up studies are based on heroin addicts recruited from treatment settings (mostly methadone maintenance treatment), many of whom are referred by the criminal justice system. Cumulative evidence indicates that opioid addiction is a chronic disorder with frequent relapses. Longer treatment retention is associated with a greater likelihood of abstinence, whereas incarceration is negatively related to subsequent abstinence. Over the long term, the mortality rate of opioid addicts (overdose being the most common cause) is about 6 to 20 times greater than that of the general population; among those who remain alive, the prevalence of stable abstinence from opioid use is low (less than 30% after 10-30 years of observation), and many continue to use alcohol and other drugs after ceasing to use opioids. Histories of sexual or physical abuse and comorbid mental disorders are associated with the persistence of opioid use, whereas family and social support, as well as employment, facilitates recovery. Maintaining opioid abstinence for at least five years substantially increases the likelihood of future stable abstinence. Recent advances in pharmacological treatment options (buprenorphine and naltrexone) include depot formulations offering longer duration of medication; their impact on the long-term course of opioid addiction remains to be assessed.

  11. Long-Term Potentiation in the CA1 Hippocampus Induced by NR2A Subunit-Containing NMDA Glutamate Receptors Is Mediated by Ras-GRF2/Erk Map Kinase Signaling

    PubMed Central

    Jin, Shan-xue; Feig, Larry A.

    2010-01-01

    Background NMDA-type glutamate receptors (NMDARs) are major contributors to long-term potentiation (LTP), a form of synaptic plasticity implicated in the process of learning and memory. These receptors consist of calcium-permeating NR1 and multiple regulatory NR2 subunits. A majority of studies show that both NR2A and NR2B-containing NMDARs can contribute to LTP, but their unique contributions to this form of synaptic plasticity remain poorly understood. Methodology/Principal Findings In this study, we show that NR2A and NR2B-containing receptors promote LTP differently in the CA1 hippocampus of 1-month old mice, with the NR2A receptors functioning through Ras-GRF2 and its downstream effector, Erk Map kinase, and NR2B receptors functioning independently of these signaling molecules. Conclusions/Significance This study demonstrates that NR2A-, but not NR2B, containing NMDA receptors induce LTP in pyramidal neurons of the CA1 hippocamus from 1 month old mice through Ras-GRF2 and Erk. This difference add new significance to the observation that the relative levels of these NMDAR subtypes is regulated in neurons, such that NR2A-containing receptors become more prominent late in postnatal development, after sensory experience and synaptic activity. PMID:20661302

  12. Infective endocarditis: determinants of long term outcome

    PubMed Central

    Netzer, R O M; Altwegg, S C; Zollinger, E; Täuber, M; Carrel, T; Seiler, C

    2002-01-01

    Objective: To evaluate predictors of long term prognosis in infective endocarditis. Design: Retrospective cohort study. Setting: Tertiary care centre. Patients: 212 consecutive patients with infective endocarditis between 1980 and 1995 Main outcome measures: Overall and cardiac mortality; event-free survival; and the following events: recurrence, need for late valve surgery, bleeding and embolic complications, cerebral dysfunction, congestive heart failure. Results: During a mean follow up period of 89 months (range 1–244 months), 56% of patients died. In 180 hospital survivors, overall and cardiac mortality amounted to 45% and 24%, respectively. By multivariate analysis, early surgical treatment, infection by streptococci, age < 55 years, absence of congestive heart failure, and > 6 symptoms or signs of endocarditis during active infection were predictive of improved overall long term survival. Independent determinants of event-free survival were infection by streptococci and age < 55 years. Event-free survival was 17% at the end of follow up both in medically–surgically treated patients and in medically treated patients. Conclusions: Long term survival following infective endocarditis is 50% after 10 years and is predicted by early surgical treatment, age < 55 years, lack of congestive heart failure, and the initial presence of more symptoms of endocarditis. PMID:12067947

  13. Long-term OH variability of Miras

    NASA Astrophysics Data System (ADS)

    Etoka, S.; Le Squeren, A. M.

    2000-10-01

    We present here the results and interpretation of a long-term OH variability program conducted with the French {Nançay} Radiotelescope from 1980 to 1995. It concerns seven Mira stars: R Aql, RS Vir, S CrB, R LMi, RR Aql, U Her and UX Cyg. This study deals with the three OH maser lines observed in the Miras at 1612, 1665 and 1667 MHz. These OH variable stars have periods ranging from 290 to 580 days. The study presents the first insight of the long-term temporal behaviour of OH integrated flux variations as well as spectral component variations. The main aims are to determine the temporal behaviour of the OH maser emission and the longevity and variability of the spectral components. We find that the shapes of the OH curve are closer to the IR than the optical shapes and that the emissions at 1665 and 1667 MHz have a very similar behaviour while the emission at 1612 MHz behaves differently. The 1612 MHz emission shows smoother temporal variations and greater component longevity than the main line emission, leading to the conclusion that the 1612 MHz emission is coming from an outer part of the circumstellar shell and is more saturated than the main line emission. The study also shows the existence of inhomogeneities, especially differences between the front and back parts of the shell can be seen, and that OH variability curves undergo long term variations over several cycles.

  14. Electrodes for long-term esophageal electrocardiography.

    PubMed

    Niederhauser, Thomas; Haeberlin, Andreas; Marisa, Thanks; Jungo, Michael; Goette, Josef; Jacomet, Marcel; Abacherli, Roger; Vogel, Rolf

    2013-09-01

    The emerging application of long-term and high-quality ECG recording requires alternative electrodes to improve the signal quality and recording capability of surface skin electrodes. The esophageal ECG has the potential to overcome these limitations but necessitates novel recorder and lead designs. The electrode material is of particular interest, since the material has to ensure conflicting requirements like excellent biopotential recording properties and inertness. To this end, novel electrode materials like PEDOT and silver-PDMS as well as established electrode materials such as stainless steel, platinum, gold, iridium oxide, titanium nitride, and glassy carbon were investigated by long-term electrochemical impedance spectroscopy and model-based signal analysis using the derived in vitro interfacial properties in conjunction with a dedicated ECG amplifier. The results of this novel approach show that titanium nitride and iridium oxide featuring microstructured surfaces did not degrade when exposed to artificial acidic saliva. These materials provide low electrode potential drifts and insignificant signal distortion superior to surface skin electrodes making them compatible with accepted standards for ambulatory ECG. They are superior to the noble and polarizable metals such as platinum, silver, and gold that induced more signal distortions and are superior to esophageal stainless steel electrodes that corrode in artificial saliva. The study provides rigorous criteria for the selection of electrode materials for prolonged ECG recording by combining long-term in vitro electrode material properties with ECG signal quality assessment.

  15. Long-term prophylaxis in bipolar disorder.

    PubMed

    Taylor, Matthew J; Goodwin, Guy M

    2006-01-01

    Bipolar disorder is a major cause of disability, and the prevention of relapse is a key management goal. Pharmacological interventions, effectively delivered through enhanced clinical care, are central to long-term management. This article summarises the available evidence for a range of pharmacological options, and provides guidance on common issues in clinical management in line with current practice guidelines. The use of medications for long-term prophylaxis should be considered in all patients meeting criteria for bipolar I disorder. Increasing high-quality evidence from randomised trials informs management decisions relating to both novel agents, such as lamotrigine and olanzapine, and longer-established therapies, such as lithium and valproate, in monotherapy. Medications taken long-term in bipolar disorder differ in the extent to which they protect against manic and depressive relapse. Consequently, the emerging challenge is to understand how combination treatments can enhance efficacy and effectiveness based on data from controlled trials rather than random polypharmacy. Clinical care can be enhanced with effective education about the illness, and the use of strategies to improve treatment adherence and the recognition and management of stressors or prodromal symptoms. Where available, a range of specific psychological interventions can be effective as an adjunct to medication. When discontinuation of prophylaxis is necessary, gradual tapering of dose over weeks or months is recommended.

  16. Long term therapy of generalized anxiety disorder.

    PubMed

    Rouillon, Frédéric

    2004-04-01

    Generalized anxiety disorder (GAD) is a common (lifetime prevalence: 5.1%), recurrent condition, which often heralds other psychiatric disorders, notably depression. As by definition it is a disorder progressing over months, treatment should be designed on a long term basis. And yet, few studies have been conducted beyond the classical 6-8 weeks characterizing the acute treatment phase. This is especially true of anxiolytics, but also of antidepressants, with the exception of paroxetine and venlafaxine, which are the only drugs approved in this indication in Western countries. The efficacy of psychotherapy, notably relaxation and cognitive-behavioral therapy, is established in the treatment of GAD, but its preferred indications and possible combination with antidepressants are still to be specified. Long term, not to say very long term studies of GAD, as well as depression, will still be required in the future to improve its management and specify therapeutic modalities (combination treatment, optimal duration, continuous or intermittent therapy, choice of psychotherapeutic techniques or agents, em leader ). Early and adequately prolonged treatment should not only result in more numerous remission periods, but also in decreased frequency of co-morbidities whether depressive, addictive, or of another nature, and should also reduce the social impact of GAD.

  17. Titanium for long-term tritium storage

    SciTech Connect

    Heung, L.K.

    1994-12-01

    Due to the reduction of nuclear weapon stockpile, there will be an excess of tritium returned from the field. The excess tritium needs to be stored for future use, which might be several years away. A safe and cost effective means for long term storage of tritium is needed. Storing tritium in a solid metal tritide is preferred to storing tritium as a gas, because a metal tritide can store tritium in a compact form and the stored tritium will not be released until heat is applied to increase its temperature to several hundred degrees centigrade. Storing tritium as a tritide is safer and more cost effective than as a gas. Several candidate metal hydride materials have been evaluated for long term tritium storage. They include uranium, La-Ni-Al alloys, zirconium and titanium. The criteria used include material cost, radioactivity, stability to air, storage capacity, storage pressure, loading and unloading conditions, and helium retention. Titanium has the best combination of properties and is recommended for long term tritium storage.

  18. The role of the human cerebellum in short- and long-term habituation of postural responses.

    PubMed

    Schwabe, Achim; Drepper, Johannes; Maschke, Matthias; Diener, Hans Christoph; Timmann, Dagmar

    2004-02-01

    The aim of the present study was to investigate the role of the human cerebellum in short-term (STH) and long-term habituation (LTH) of postural responses to repeated platform perturbations. Ten cerebellar patients and ten age- and sex-matched healthy controls participated. Twenty backward platform translations were applied on each of 5 consecutive days. Changes of postural response size within each day were assessed to determine STH and changes across days to determine LTH. Both controls and cerebellar patients showed a significant reduction of postural response size within each day (i.e. STH). No significant reduction of postural response size was observed across days (i.e. no LTH). Both controls and cerebellar patients, however, showed a tendency of response size to increase across days suggesting long-term sensitization. The amount of changes within and across days did not significantly differ between groups. The present findings suggest that changes of postural response size to repeated perturbations do not depend upon the integrity of the cerebellum.

  19. Visuokinesthetic Perception of Hand Movement is Mediated by Cerebro–Cerebellar Interaction between the Left Cerebellum and Right Parietal Cortex

    PubMed Central

    Hagura, Nobuhiro; Oouchida, Yutaka; Aramaki, Yu; Okada, Tomohisa; Matsumura, Michikazu; Sadato, Norihiro

    2009-01-01

    Combination of visual and kinesthetic information is essential to perceive bodily movements. We conducted behavioral and functional magnetic resonance imaging experiments to investigate the neuronal correlates of visuokinesthetic combination in perception of hand movement. Participants experienced illusory flexion movement of their hand elicited by tendon vibration while they viewed video-recorded flexion (congruent: CONG) or extension (incongruent: INCONG) motions of their hand. The amount of illusory experience was graded by the visual velocities only when visual information regarding hand motion was concordant with kinesthetic information (CONG). The left posterolateral cerebellum was specifically recruited under the CONG, and this left cerebellar activation was consistent for both left and right hands. The left cerebellar activity reflected the participants' intensity of illusory hand movement under the CONG, and we further showed that coupling of activity between the left cerebellum and the “right” parietal cortex emerges during this visuokinesthetic combination/perception. The “left” cerebellum, working with the anatomically connected high-order bodily region of the “right” parietal cortex, participates in online combination of exteroceptive (vision) and interoceptive (kinesthesia) information to perceive hand movement. The cerebro–cerebellar interaction may underlie updating of one's “body image,” when perceiving bodily movement from visual and kinesthetic information. PMID:18453537

  20. [Memory transfer in cerebellar motor learning].

    PubMed

    Nagao, Soichi

    2012-01-01

    Most of our motor skills are acquired through learning. Experiments of gain adaptation of ocular reflexes have consistently suggested that the memory of adaptation is initially formed in the cerebellar cortex, and is transferred to the cerebellar (vestibular) nuclei for consolidation to long-term memory after repetitions of training. We have recently developed a new system to evaluate the motor learning in human subjects using prism adaptation of hand reaching movement, by referring to the prism adaptation of dart throwing of Martin et al. (1996). In our system, the subject views the small target presented in the touch-panel screen, and touches it with his/her finger without direct visual feedback. After 15-30 trials of touching wearing prisms, an adaptation occurs in healthy subjects: they became able to touch the target correctly. Meanwhile, such an adaptation was impaired in patients of cerebellar disease. We have proposed a model of human prism adaptation that the memory of adaptation is initially encoded in the cerebellar cortex, and is later transferred to the cerebellar nuclei after repetitions of training. The memory in the cerebellar cortex may be formed and extinguished independently of the memory maintained in the cerebellar nuclei, and these two memories work cooperatively.

  1. Cerebellar Ataxia.

    PubMed

    Perlman

    2000-05-01

    There is nothing more discouraging than for a patient to be given a specific diagnosis, then to be told that there is nothing that can be done. Physicians are equally disheartened to see exponential progress being made in the understanding of the pathophysiology of a complex disorder but few direct benefits resulting for their patients. Over the past 5 years, molecular genetic research has completely revolutionized the way in which the progressive cerebellar ataxias are classified and diagnosed, but it has yet to produce effective gene-based, neuroprotective, or neurorestorative therapies. The treatment of cerebellar ataxia remains primarily a neurorehabilitation challenge, employing physical, occupational, speech, and swallowing therapy; adaptive equipment; driver safety training; and nutritional counseling. Modest additional gains are seen with the use of medications that can improve imbalance, incoordination, or dysarthria (amantadine, buspirone, acetazolamide); cerebellar tremor (clonazepam, propranolol); and cerebellar or central vestibular nystagmus (gabapentin, baclofen, clonazepam). Many of the progressive cerebellar syndromes have associated features involving other neurologic systems (eg, spasticity, dystonia or rigidity, resting or rubral tremor, chorea, motor unit weakness or fatigue, autonomic dysfunction, peripheral or posterior column sensory loss, neuropathic pain or cramping, double vision, vision and hearing loss, dementia, and bowel, bladder, and sexual dysfunction), which can impede the treatment of the ataxic symptoms or can worsen with the use of certain drugs. Treatment of the associated features themselves may in turn worsen the ataxia either directly (as side effects of medication) or indirectly (eg, relaxation of lower limb spasticity that was acting as a stabilizer for an ataxic gait). Secondary complications of progressive ataxia can include deconditioning or immobility, weight loss or gain, skin breakdown, recurrent pulmonary and

  2. Timber beams subjected to long - term loading

    NASA Astrophysics Data System (ADS)

    Sógel, K.

    2010-09-01

    Wood is a significant structural material, which is often used for timber bearing structures. Elements of timber structures must especially satisfy safety requirements, which are expressed by the ultimate limit states in the established standards. The structure must also satisfy the serviceability limit states. Local and global deformations make it impossible for the structure to serve the purpose it was designed for. It is important to take the deflections and their possible increase into account in the design to provide a structure which can be used during the whole period of service. Based on earlier examinations, it is known that a timber element over the course of long-term loading shows creep behavior. The structure of wood is able to adapt to the conditions of the surrounding environment. The properties of wood are especially affected by the relative humidity of the air and then by the type, intensity and duration of the loading. The most important factors affecting the serviceability of timber structures are volume changes caused by humidity and additional deflections caused by the effects of long-term loading. These phenomena emphasize the importance of serviceability limit states for timber structures. The paper deals with a long-term experimental investigation of timber girders that are currently often used. The aim was to obtain the deflection curves and mark the time dependence and the final deflections. The paper will also define the approximations for simulating the time-dependent deflections and obtain the creep coefficients for calculating the final deflections of the girders investigated.

  3. Long-Term Recency in Anterograde Amnesia

    PubMed Central

    Talmi, Deborah; Caplan, Jeremy B.; Richards, Brian; Moscovitch, Morris

    2015-01-01

    Amnesia is usually described as an impairment of a long-term memory (LTM) despite an intact short-term memory (STM). The intact recency effect in amnesia had supported this view. Although dual-store models of memory have been challenged by single-store models based on interference theory, this had relatively little influence on our understanding and treatment of amnesia, perhaps because the debate has centred on experiments in the neurologically intact population. Here we tested a key prediction of single-store models for free recall in amnesia: that people with amnesia will exhibit a memory advantage for the most recent items even when all items are stored in and retrieved from LTM, an effect called long-term recency. People with amnesia and matched controls studied, and then free-recalled, word lists with a distractor task following each word, including the last (continual distractor task, CDFR). This condition was compared to an Immediate Free Recall (IFR, no distractors) and a Delayed Free Recall (DFR, end-of-list distractor only) condition. People with amnesia demonstrated the full long-term recency pattern: the recency effect was attenuated in DFR and returned in CDFR. The advantage of recency over midlist items in CDFR was comparable to that of controls, confirming a key prediction of single-store models. Memory deficits appeared only after the first word recalled in each list, suggesting the impairment in amnesia may emerge only as the participant’s recall sequence develops, perhaps due to increased susceptibility to output interference. Our findings suggest that interference mechanisms are preserved in amnesia despite the overall impairment to LTM, and challenge strict dual-store models of memory and their dominance in explaining amnesia. We discuss the implication of our findings for rehabilitation. PMID:26046770

  4. Long-Term Recency in Anterograde Amnesia.

    PubMed

    Talmi, Deborah; Caplan, Jeremy B; Richards, Brian; Moscovitch, Morris

    2015-01-01

    Amnesia is usually described as an impairment of a long-term memory (LTM) despite an intact short-term memory (STM). The intact recency effect in amnesia had supported this view. Although dual-store models of memory have been challenged by single-store models based on interference theory, this had relatively little influence on our understanding and treatment of amnesia, perhaps because the debate has centred on experiments in the neurologically intact population. Here we tested a key prediction of single-store models for free recall in amnesia: that people with amnesia will exhibit a memory advantage for the most recent items even when all items are stored in and retrieved from LTM, an effect called long-term recency. People with amnesia and matched controls studied, and then free-recalled, word lists with a distractor task following each word, including the last (continual distractor task, CDFR). This condition was compared to an Immediate Free Recall (IFR, no distractors) and a Delayed Free Recall (DFR, end-of-list distractor only) condition. People with amnesia demonstrated the full long-term recency pattern: the recency effect was attenuated in DFR and returned in CDFR. The advantage of recency over midlist items in CDFR was comparable to that of controls, confirming a key prediction of single-store models. Memory deficits appeared only after the first word recalled in each list, suggesting the impairment in amnesia may emerge only as the participant's recall sequence develops, perhaps due to increased susceptibility to output interference. Our findings suggest that interference mechanisms are preserved in amnesia despite the overall impairment to LTM, and challenge strict dual-store models of memory and their dominance in explaining amnesia. We discuss the implication of our findings for rehabilitation.

  5. Long-term management of prolactinomas.

    PubMed

    Schlechte, Janet A

    2007-08-01

    Prolactinomas are a frequent cause of gonadal dysfunction and infertility, especially in young women. The regulation of prolactin secretion and the efficacy of dopamine agonists in the therapy of prolactinomas are well established. The current challenges in management of prolactinomas are related to follow-up after successful therapy. Issues and questions to be addressed in this approach to long-term management of prolactinomas include the frequency of radiographic monitoring, effect of pregnancy and menopause, safety of estrogen in women taking oral contraceptives, and the potential for discontinuation of dopamine agonist therapy.

  6. Human Behaviour in Long-Term Missions

    NASA Technical Reports Server (NTRS)

    1997-01-01

    In this session, Session WP1, the discussion focuses on the following topics: Psychological Support for International Space Station Mission; Psycho-social Training for Man in Space; Study of the Physiological Adaptation of the Crew During A 135-Day Space Simulation; Interpersonal Relationships in Space Simulation, The Long-Term Bed Rest in Head-Down Tilt Position; Psychological Adaptation in Groups of Varying Sizes and Environments; Deviance Among Expeditioners, Defining the Off-Nominal Act in Space and Polar Field Analogs; Getting Effective Sleep in the Space-Station Environment; Human Sleep and Circadian Rhythms are Altered During Spaceflight; and Methodological Approach to Study of Cosmonauts Errors and Its Instrumental Support.

  7. Long-Term Wind Power Variability

    SciTech Connect

    Wan, Y. H.

    2012-01-01

    The National Renewable Energy Laboratory started collecting wind power data from large commercial wind power plants (WPPs) in southwest Minnesota with dedicated dataloggers and communication links in the spring of 2000. Over the years, additional WPPs in other areas were added to and removed from the data collection effort. The longest data stream of actual wind plant output is more than 10 years. The resulting data have been used to analyze wind power fluctuations, frequency distribution of changes, the effects of spatial diversity, and wind power ancillary services. This report uses the multi-year wind power data to examine long-term wind power variability.

  8. Transverse dimension and long-term stability.

    PubMed

    Vanarsdall, R L

    1999-09-01

    This article emphasizes the critical importance of the skeletal differential between the width of the maxilla and the width of the mandible. Undiagnosed transverse discrepancy leads to adverse periodontal response, unstable dental camouflage, and less than optimal dentofacial esthetics. Hundreds of adult retreatment patients corrected for significant maxillary transverse deficiency using surgically assisted maxillary expansion (similar to osseous distraction) has produced excellent stability. Eliciting tooth movement for children (orthopedics, lip bumper, Cetlin plate) in all three planes of space by muscles, eruption, and growth, develops the broader arch form (without the mechanical forces of fixed or removable appliances) and has also demonstrated impressive long term stability.

  9. Terminating a long-term clinical trial.

    PubMed

    Klimt, C R; Canner, P L

    1979-05-01

    Long-term trials often include more than one active treatment group. These may be discontinued independently if found ineffective or possibly harmful. Certain subgroups of patients may be discovered, in the course of a clinical trial, who do not respond satisfactorily and are, therefore, excluded during the course of a trial. Yet anouther kind of termination comes when we have a therapeutic breakthrough or when hope has to be abandoned for demonstrating beneficial effects for one, several, or all treatments included in a trial. Examples from the authors' experience are presented, as are successful and unsuccessful techniques in managing terminations of various types.

  10. Terminating a long-term clinical trial.

    PubMed

    Klimt, C R

    1981-05-01

    Long-term clinical trials often include more than one active treatment group. These may be discontinued independently if found to be ineffective or possibly harmful. Certain subgroups of patients may be discovered, in the course of a clinical trial, who do not respond satisfactorily and are, therefore, excluded during the course of a trial. Yet another kind of termination comes when we have a therapeutic breakthrough or when hope has to be abandoned for demonstrating beneficial effects for one, several, or all treatments included in a trial. Examples from the authors' experience are presented, as are successful and unsuccessful techniques in managing terminations of various types.

  11. A long-term climatology of medicanes

    NASA Astrophysics Data System (ADS)

    Cavicchia, Leone; von Storch, Hans; Gualdi, Silvio

    2014-09-01

    Medicanes, intense and destructive mesoscale cyclones exhibiting several similarities with tropical hurricanes, are known to struck occasionally the Mediterranean Sea. Thanks to a high-resolution dynamical downscaling effort, we are able to study for the first time the long-term climatology of those rare storms in a systematic way. The distribution of medicanes frequency in space and time is discussed, and the environmental factors responsible for their formation are investigated. We find that medicanes develop in those areas of the Mediterranean region where intrusions of cold air in the upper troposphere can produce configurations of thermodynamical disequilibrium of the atmosphere similar to those associated with the formation of tropical cyclones.

  12. Performance considerations in long-term spaceflight

    NASA Technical Reports Server (NTRS)

    Akins, F. R.

    1979-01-01

    Maintenance of skilled performance during extended space flight is of critical importance to both the health and safety of crew members and to the overall success of mission goals. An examination of long term effects and performance requirements is therefore a factor of immense importance to the planning of future missions. Factors that were investigated include: definition of performance categories to be investigated; methods for assessing and predicting performance levels; in-flight factors which can affect performance; and factors pertinent to the maintenance of skilled performance.

  13. PI3K signalling in GnRH actions on dispersed goldfish pituitary cells: relationship with PKC-mediated LH and GH release and regulation of long-term effects on secretion and total cellular hormone availability.

    PubMed

    Pemberton, Joshua G; Orr, Michael E; Stafford, James L; Chang, John P

    2014-09-01

    Goldfish pituitary cells are exposed to two GnRHs, salmon (s)GnRH and chicken (c)GnRH-II. Phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) both participate in acute sGnRH- and cGnRH-II-stimulated LH and GH release. Using goldfish pituitary cells, we examined the relationship between PI3K and PKC in acute LH and GH secretion, and PI3K involvement in chronic hormone release and total LH and GH availability. The PI3K inhibitor LY294002 did not affect PKC agonists-induced LH or GH release, and PKC agonists did not alter PI3K p85 phosphorylation, suggesting PKC activation is not upstream of PI3K in acute hormone release. In 2, 6, 12 and 24h treatments, LY294002 did not affect LH release but stimulated total LH availability at 6h. sGnRH stimulatory actions on LH release and total availability at 12 and 24h, and cGnRH-II effects on these parameters at 6h were inhibited by LY294002. LY294002 enhanced basal GH release at 2 and 6h, but reduced total GH at 12 and 24h. Increased GH release was seen following 6, 12 and 24h of sGnRH, and 2, 6 and 24h of cGnRH-II treatment but total GH availability was only elevated by 24h cGnRH-II treatment. Whereas LY294002 inhibited GH release responses to sGnRH at 12h and cGnRH-II at 6h, it attenuated cGnRH-II-elicited, but not sGnRH-induced, effects on total GH. These results indicate that PI3K differentially modulates long-term basal and GnRH-stimulated hormone release, and total hormone availability, in a time-, cell-type-, and GnRH isoform-selective manner. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. The Long-Term Impact of High School Civics Curricula on Political Knowledge, Democratic Attitudes and Civic Behaviors: A Multi-Level Model of Direct and Mediated Effects through Communication. CIRCLE Working Paper #65

    ERIC Educational Resources Information Center

    Hutchens, Myiah J.; Eveland, William P., Jr.

    2009-01-01

    This report examines the effects of exposure to various elements of a civics curriculum on civic participation, two forms of political knowledge, internal political efficacy, political cynicism, news elaboration, discussion elaboration and various forms of interpersonal and mediated political communication behaviors. The data are based on a…

  15. Long-term habituation of the C-start escape response in zebrafish larvae.

    PubMed

    Roberts, Adam C; Pearce, Kaycey C; Choe, Ronny C; Alzagatiti, Joseph B; Yeung, Anthony K; Bill, Brent R; Glanzman, David L

    2016-10-01

    The cellular and molecular basis of long-term memory in vertebrates remains poorly understood. Knowledge regarding long-term memory has been impeded by the enormous complexity of the vertebrate brain, particularly the mammalian brain, as well as by the relative complexity of the behavioral alterations examined in most studies of long-term memory in vertebrates. Here, we demonstrate a long-term form of nonassociative learning-specifically, long-term habituation (LTH)-of a simple reflexive escape response, the C-start, in zebrafish larvae. The C-start is triggered by the activation of one of a pair of giant neurons in the zebrafish's hindbrain, the Mauthner cells. We show that LTH of the C-start requires the activity of NMDA receptors and involves macromolecular synthesis. We further show that the long-term habituated reflex can by rapidly dishabituated by a brief tactile stimulus. Our results set the stage for rigorous, mechanistic investigations of the long-term memory for habituation of a reflexive behavioral response, one that is mediated by a relatively simple, neurobiologically tractable, neural circuit. Moreover, the demonstration of NMDAR and transcriptionally dependent LTH in a translucent vertebrate organism should facilitate the use of optical recording, and optogenetic manipulation, of neuronal activity to elucidate the cellular basis of a long-term vertebrate memory. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Long-Term Care Policy: Singapore's Experience.

    PubMed

    Chin, Chee Wei Winston; Phua, Kai-Hong

    2016-01-01

    Singapore, like many developed countries, is facing the challenge of a rapidly aging population and the increasing need to provide long-term care (LTC) services for elderly in the community. The Singapore government's philosophy on care for the elderly is that the family should be the first line of support, and it has relied on voluntary welfare organizations (VWOs) or charities for the bulk of LTC service provision. For LTC financing, it has emphasized the principles of co-payment and targeting of state support to the low-income population through means-tested government subsidies. It has also instituted ElderShield, a national severe disability insurance scheme. This paper discusses some of the challenges facing LTC policy in Singapore, particularly the presence of perverse financial incentives for hospitalization, the pitfalls of over-reliance on VWOs, and the challenges facing informal family caregivers. It discusses the role of private LTC insurance in LTC financing, bearing in mind demand- and supply-side failures that have plagued the private LTC insurance market. It suggests the need for more standardized needs assessment and portable LTC benefits, with reference to the Japanese Long-Term Care Insurance program, and also discusses the need to provide more support to informal family caregivers.

  17. Sleep facilitates long-term face adaptation

    PubMed Central

    Ditye, Thomas; Javadi, Amir Homayoun; Carbon, Claus-Christian; Walsh, Vincent

    2013-01-01

    Adaptation is an automatic neural mechanism supporting the optimization of visual processing on the basis of previous experiences. While the short-term effects of adaptation on behaviour and physiology have been studied extensively, perceptual long-term changes associated with adaptation are still poorly understood. Here, we show that the integration of adaptation-dependent long-term shifts in neural function is facilitated by sleep. Perceptual shifts induced by adaptation to a distorted image of a famous person were larger in a group of participants who had slept (experiment 1) or merely napped for 90 min (experiment 2) during the interval between adaptation and test compared with controls who stayed awake. Participants' individual rapid eye movement sleep duration predicted the size of post-sleep behavioural adaptation effects. Our data suggest that sleep prevented decay of adaptation in a way that is qualitatively different from the effects of reduced visual interference known as ‘storage’. In the light of the well-established link between sleep and memory consolidation, our findings link the perceptual mechanisms of sensory adaptation—which are usually not considered to play a relevant role in mnemonic processes—with learning and memory, and at the same time reveal a new function of sleep in cognition. PMID:23986109

  18. Craniopharyngioma in Children: Long-term Outcomes

    PubMed Central

    STEINBOK, Paul

    2015-01-01

    The survival rate for childhood craniopharyngioma has been improving, with more long-term survivors. Unfortunately it is rare for the patient to be normal, either from the disease itself or from the effects of treatment. Long-term survivors of childhood craniopharyngioma suffer a number of impairments, which include visual loss, endocrinopathy, hypothalamic dysfunction, cerebrovascular problems, neurologic and neurocognitive dysfunction. Pituitary insufficiency is present in almost 100%. Visual and hypothalamic dysfunction is common. There is a high risk of metabolic syndrome and increased risk of cerebrovascular disease, including stroke and Moyamoya syndrome. Cognitive, psychosocial, and emotional problems are prevalent. Finally, there is a higher risk of premature death among survivors of craniopharyngioma, and often this is not from tumor recurrence. It is important to consider craniopharyngioma as a chronic disease. There is no perfect treatment. The treatment has to be tailored to the individual patient to minimize dysfunction caused by tumor and treatments. So “cure” of the tumor does not mean a normal patient. The management of the patient and family needs multidisciplinary evaluation and should involve ophthalmology, endocrinology, neurosurgery, oncology, and psychology. Furthermore, it is also important to address emotional issues and social integration. PMID:26345668

  19. Long-term Trend of Sunspot Numbers

    NASA Astrophysics Data System (ADS)

    Gao, P. X.

    2016-10-01

    Using the Hilbert-Huang Transform method, we investigate the long-term trend of yearly mean total sunspot numbers in the time interval of 1700-2015, which come from the World Data Center—the sunspot Index and long-term solar observations. The main findings of this study are summarized below. (1) From the adaptive trend, which is extracted from the yearly mean total sunspot numbers, we can find that the value gradually increases during the time period 1700-1975, then decreases gradually from 1975 to 2015. (2) The Centennial Gleissberg Cycle is extracted from the yearly mean total sunspot numbers and confirms that a new grand minimum is in progress; the Dalton Minimum, the Gleissberg Minimum, and low level of solar activity during solar cycle 24 (the part of the new grand minimum) all can be understood as minima of the Centennial Gleissberg Cycle. (3) Based on the adaptive (overall) trend, and the 100-year and longer timescale trend of yearly mean total sunspot numbers, we can infer that the level of solar activity during the new grand minimum may be close to that during the Gleissberg Minimum, slightly higher than that during the Dalton Minimum, and significantly higher than that during the Maunder Minimum. Our results do not support the suggestion that a new grand minimum, somewhat resembling the Maunder Minimum, is in progress.

  20. Sleep facilitates long-term face adaptation.

    PubMed

    Ditye, Thomas; Javadi, Amir Homayoun; Carbon, Claus-Christian; Walsh, Vincent

    2013-10-22

    Adaptation is an automatic neural mechanism supporting the optimization of visual processing on the basis of previous experiences. While the short-term effects of adaptation on behaviour and physiology have been studied extensively, perceptual long-term changes associated with adaptation are still poorly understood. Here, we show that the integration of adaptation-dependent long-term shifts in neural function is facilitated by sleep. Perceptual shifts induced by adaptation to a distorted image of a famous person were larger in a group of participants who had slept (experiment 1) or merely napped for 90 min (experiment 2) during the interval between adaptation and test compared with controls who stayed awake. Participants' individual rapid eye movement sleep duration predicted the size of post-sleep behavioural adaptation effects. Our data suggest that sleep prevented decay of adaptation in a way that is qualitatively different from the effects of reduced visual interference known as 'storage'. In the light of the well-established link between sleep and memory consolidation, our findings link the perceptual mechanisms of sensory adaptation--which are usually not considered to play a relevant role in mnemonic processes--with learning and memory, and at the same time reveal a new function of sleep in cognition.

  1. Clinical review: Long-term noninvasive ventilation

    PubMed Central

    Robert, Dominique; Argaud, Laurent

    2007-01-01

    Noninvasive positive ventilation has undergone a remarkable evolution over the past decades and is assuming an important role in the management of both acute and chronic respiratory failure. Long-term ventilatory support should be considered a standard of care to treat selected patients following an intensive care unit (ICU) stay. In this setting, appropriate use of noninvasive ventilation can be expected to improve patient outcomes, reduce ICU admission, enhance patient comfort, and increase the efficiency of health care resource utilization. Current literature indicates that noninvasive ventilation improves and stabilizes the clinical course of many patients with chronic ventilatory failure. Noninvasive ventilation also permits long-term mechanical ventilation to be an acceptable option for patients who otherwise would not have been treated if tracheostomy were the only alternative. Nevertheless, these results appear to be better in patients with neuromuscular/-parietal disorders than in chronic obstructive pulmonary disease. This clinical review will address the use of noninvasive ventilation (not including continuous positive airway pressure) mainly in diseases responsible for chronic hypoventilation (that is, restrictive disorders, including neuromuscular disease and lung disease) and incidentally in others such as obstructive sleep apnea or problems of central drive. PMID:17419882

  2. Long term changes in the polar vortices

    NASA Astrophysics Data System (ADS)

    Braathen, Geir O.

    2015-04-01

    As the amount of halogens in the stratosphere is slowly declining and the ozone layer slowly recovers it is of interest to see how the meteorological conditions in the vortex develop over the long term since such changes might alter the foreseen ozone recovery. In conjunction with the publication of the WMO Antarctic and Arctic Ozone Bulletins, WMO has acquired the ERA Interim global reanalysis data set for several meteorological parameters. This data set goes from 1979 - present. These long time series of data can be used for several useful studies of the long term development of the polar vortices. Several "environmental indicators" for vortex change have been calculated, and a climatology, as well as trends, for these parameters will be presented. These indicators can act as yardsticks and will be useful for understanding past and future changes in the polar vortices and how these changes affect polar ozone depletion. Examples of indicators are: vortex mean temperature, vortex minimum temperature, vortex mean PV, vortex "importance" (PV*area), vortex break-up time, mean and maximum wind speed. Data for both the north and south polar vortices have been analysed at several isentropic levels from 350 to 850 K. A possible link between changes in PV and sudden stratospheric warmings will be investigated, and the results presented.

  3. Long-term Caspian Sea level change

    NASA Astrophysics Data System (ADS)

    Chen, J. L.; Pekker, T.; Wilson, C. R.; Tapley, B. D.; Kostianoy, A. G.; Cretaux, J.-F.; Safarov, E. S.

    2017-07-01

    Caspian Sea level (CSL) has undergone substantial fluctuations during the past several hundred years. The causes over the entire historical period are uncertain, but we investigate here large changes seen in the past several decades. We use climate model-predicted precipitation (P), evaporation (E), and observed river runoff (R) to reconstruct long-term CSL changes for 1979-2015 and show that PER (P-E + R) flux predictions agree very well with observed CSL changes. The observed rapid CSL increase (about 12.74 cm/yr) and significant drop ( -6.72 cm/yr) during the periods 1979-1995 and 1996-2015 are well accounted for by integrated PER flux predictions of +12.38 and -6.79 cm/yr, respectively. We show that increased evaporation rates over the Caspian Sea play a dominant role in reversing the increasing trend in CSL during the past 37 years. The current long-term decline in CSL is expected to continue into the foreseeable future, under global warming scenarios.

  4. Long term efficacy of a pen injector.

    PubMed

    Dinneen, S F; Cronin, C C; O'Sullivan, D J

    1991-09-01

    We assessed the long term efficacy of Novopen as a form of insulin administration. Records were obtained on 48 patients who were treated with Novopen between January '86 and October '88. Six patients were excluded due to insufficient data. The study group of 42 patients comprised 22 females and 20 males of average age 33 years (range 17-66). Mean Hb.A1 rose from 10.6% to 12.1% after Novopen therapy, a rise of 14.1%. This rise is both clinically and statistically significant (p less than 0.001; 99% confidence limits 0.59-2.78). Increases in weight and insulin dose were also noted, but did not reach statistical significance. The majority of patients felt Novopen was superior to twice daily insulin in terms of ease of administration (81%) and flexibility of lifestyle (95%), and all who were using Novopen wished to continue with it. More than 50% of patients admitted to altering their dietary habits while using Novopen. Despite continuing patient satisfaction with this form of insulin administration, its long-term use may be associated with sub-optimal metabolic control.

  5. Climate Predictability and Long Term Memory

    NASA Astrophysics Data System (ADS)

    Zhu, X.; Blender, R.; Fraedrich, K.; Liu, Z.

    2010-09-01

    The benefit of climate Long Term Memory (LTM) for long term prediction is assessed using data from a millennium control simulation with the atmosphere ocean general circulation model ECHAM5/MPIOM. The forecast skills are evaluated for surface temperature time series at individual grid points. LTM is characterised by the Hurst exponent in the power-law scaling of the fluctuation function which is determined by detrended fluctuation analysis (DFA). LTM with a Hurst exponent close to 0.9 occurs mainly in high latitude oceans, which are also characterized by high potential predictability. Climate predictability is diagnosed in terms of potentially predictable variance fractions. Explicit prediction experiments for various time steps are conducted on a grid point basis using an auto-correlation (AR1) predictor: in regions with LTM, prediction skills are beyond that expected from red noise persistence; exceptions occur in some areas in the southern oceans and over the northern hemisphere continents. Extending the predictability analysis to the fully forced simulation shows large improvement in prediction skills.

  6. Long-term phenotypic evolution of bacteria.

    PubMed

    Plata, Germán; Henry, Christopher S; Vitkup, Dennis

    2015-01-15

    For many decades comparative analyses of protein sequences and structures have been used to investigate fundamental principles of molecular evolution. In contrast, relatively little is known about the long-term evolution of species' phenotypic and genetic properties. This represents an important gap in our understanding of evolution, as exactly these proprieties play key roles in natural selection and adaptation to diverse environments. Here we perform a comparative analysis of bacterial growth and gene deletion phenotypes using hundreds of genome-scale metabolic models. Overall, bacterial phenotypic evolution can be described by a two-stage process with a rapid initial phenotypic diversification followed by a slow long-term exponential divergence. The observed average divergence trend, with approximately similar fractions of phenotypic properties changing per unit time, continues for billions of years. We experimentally confirm the predicted divergence trend using the phenotypic profiles of 40 diverse bacterial species across more than 60 growth conditions. Our analysis suggests that, at long evolutionary distances, gene essentiality is significantly more conserved than the ability to utilize different nutrients, while synthetic lethality is significantly less conserved. We also find that although a rapid phenotypic evolution is sometimes observed within the same species, a transition from high to low phenotypic similarity occurs primarily at the genus level.

  7. Long term perfusion system supporting adipogenesis

    PubMed Central

    Abbott, Rosalyn D.; Raja, Waseem K.; Wang, Rebecca Y.; Stinson, Jordan A.; Glettig, Dean L.; Burke, Kelly A.; Kaplan, David L.

    2015-01-01

    Adipose tissue engineered models are needed to enhance our understanding of disease mechanisms and for soft tissue regenerative strategies. Perfusion systems generate more physiologically relevant and sustainable adipose tissue models, however adipocytes have unique properties that make culturing them in a perfusion environment challenging. In this paper we describe the methods involved in the development of two perfusion culture systems (2D and 3D) to test their applicability for long term in vitro adipogenic cultures. It was hypothesized that a silk protein biomaterial scaffold would provide a 3D framework, in combination with perfusion flow, to generate a more physiologically relevant sustainable adipose tissue engineered model than 2D cell culture. Consistent with other studies evaluating 2D and 3D culture systems for adipogenesis we found that both systems successfully model adipogensis, however 3D culture systems were more robust, providing the mechanical structure required to contain the large, fragile adipocytes that were lost in 2D perfused culture systems. 3D perfusion also stimulated greater lipogenesis and lipolysis and resulted in decreased secretion of LDH compared to 2D perfusion. Regardless of culture configuration (2D or 3D) greater glycerol was secreted with the increased nutritional supply provided by perfusion of fresh media. These results are promising for adipose tissue engineering applications including long term cultures for studying disease mechanisms and regenerative approaches, where both acute (days to weeks) and chronic (weeks to months) cultivation are critical for useful insight. PMID:25843606

  8. Long-term experience with indapamide.

    PubMed

    Beling, S; Vukovich, R A; Neiss, E S; Zisblatt, M; Webb, E; Losi, M

    1983-07-01

    Indapamide, 2.5 mg administered once daily for periods up to 36 months, was found to be safe and effective for the long-term control of mild to moderate hypertension. The effects of hydrochlorothiazide, 50 mg, and indapamide, 2.5 mg, were studied in two randomized, double-blind, multicenter trials. Data from the two multicenter trials (20 study sites) were pooled for purposes of comparison. Significant reductions in systolic and diastolic blood pressure, with patients in both supine and standing positions, occurred in both groups within the first 8 weeks of treatment. This effect was maintained throughout the active treatment period. Success, as determined by the therapeutic success rate (percentage of patients with decreases of standing phase V diastolic blood pressure of at least 10 mm Hg or to below 90 mm Hg), occurred in 53% of the patients given hydrochlorothiazide and in 56% of the indapamide-treated patients. During the study period, the nature, frequency, and severity of adverse reactions were similar for both groups. There was no clinically significant difference between the treatment groups for the laboratory assessments. Patients who completed the multicenter trials were eligible for participation in an ongoing long-term extension study of the safety of indapamide. Data are available for periods up to 36 months and demonstrate neither augmentation of clinical or laboratory adverse effects nor any potentially harmful indicators that could be attributed to prolonged treatment.

  9. Long Term Changes in the Polar Vortices

    NASA Astrophysics Data System (ADS)

    Braathen, Geir O.

    2016-04-01

    As the amount of halogens in the stratosphere is slowly declining and the ozone layer slowly recovers it is of interest to see how the meteorological conditions in the vortex develop over the long term since such changes might alter the foreseen ozone recovery. In conjunction with the publication of the WMO Antarctic and Arctic Ozone Bulletins, WMO has acquired the ERA Interim global reanalysis data set for several meteorological parameters. This data set goes from 1979 - present. These long time series of data can be used for several useful studies of the long term development of the polar vortices. Several "environmental indicators" for vortex change have been calculated, and a climatology, as well as trends, for these parameters will be presented. These indicators can act as yardsticks and will be useful for understanding past and future changes in the polar vortices and how these changes affect polar ozone depletion. Examples of indicators are: vortex mean temperature, vortex minimum temperature, vortex mean PV, vortex "importance" (PV*area), vortex break-up time, mean and maximum wind speed. Data for both the north and south polar vortices have been analysed at several isentropic levels from 350 to 850 K. A possible link between changes in PV and sudden stratospheric warmings will be investigated, and the results presented. The unusual meteorological conditions of the 2015 south polar vortex and the 2010/11 and 2015/16 north polar vortices will be compared to other recent years.

  10. Long term effects of Escherichia coli mastitis.

    PubMed

    Blum, Shlomo E; Heller, Elimelech D; Leitner, Gabriel

    2014-07-01

    Escherichia coli is one of the most frequently diagnosed causes of bovine mastitis, and is typically associated with acute, clinical mastitis. The objective of the present study was to evaluate the long term effects of intramammary infections by E. coli on milk yield and quality, especially milk coagulation. Twenty-four Israeli Holstein cows diagnosed with clinical mastitis due to intramammary infection by E. coli were used in this study. Mean lactation number, days in milk (DIM) and daily milk yield (DMY) at the time of infection was 3.3 ± 1.3, 131.7 days ± 78.6 and 45.7 L ± 8.4, respectively. DMY, milk constituents, somatic cells count (SCC), differential leukocytes count and coagulation parameters were subsequently assessed. Two patterns of inflammation were identified: 'short inflammation', characterized by <15% decrease in DMY and <30 days until return to normal (n = 5), and 'long inflammation', characterized by >15% decrease in DMY and >30 days to reach a new maximum DMY (n = 19). The estimated mean loss of marketable milk during the study was 200 L/cow for 'short inflammation' cases, and 1,500 L/cow for 'long inflammation' ones. Significant differences between 'short' and 'long inflammation' effects were found in almost all parameters studied. Long-term detrimental effects on milk quality were found regardless of clinical or bacteriological cure of affected glands.

  11. Childhood adoption: long-term effects in adulthood.

    PubMed

    Smyer, M A; Gatz, M; Simi, N L; Pedersen, N L

    1998-01-01

    Clinicians and researchers have characterized early life experiences as permanent and stable influences on the personality and subsequent life experiences of an individual. Recent conceptualizations have suggested that personal and environmental factors influencing development are not deterministic. Multiple pathways into adulthood are possible. Adoption is one potential early life stressor that may illustrate the usefulness of such conceptualizations for assessing long-term effects in adulthood. Previous studies of adoption have characterized the effects of adoption into adolescence and young adulthood. The purpose of this study was to provide an initial assessment of the long-term impact of adoption. The participants were taken from the Swedish Adoption/Twin Study of Aging. From the original sample, we identified a subsample of 60 pairs of twins who were separated and reared apart, with one member being raised by a biological parent or parents and the other by an adoptive parent or parents with no biological relationship. A series of univariate and multivariate analyses were undertaken to assess the elements associated with being reared in either an adoptive home or the home of biological parent(s). The results suggest few significant effects of adoption on the adult adjustment of adoptees. In particular, the results reflect the important mediating role of childhood socioeconomic status, suggesting that the stress of adoption itself is mediated by the type of rearing environment provided by the adoption process.

  12. Response to abdominal hysterectomy with bilateral salpingo-oophorectomy in postmenopausal woman with anti-yo antibody mediated paraneoplastic cerebellar degeneration.

    PubMed

    Bhargava, Amita; Bhushan, Bharat; Kasundra, Gaurav M; Shubhakaran, Khichar; Pujar, Guruprasad S; Banakar, Basavaraj

    2014-07-01

    Paraneoplastic cerebellar degeneration (PCD) is a rare neurological disorder characterized by a widespread loss of Purkinje cells associated with a progressive pancerebellar dysfunction. PCD often precedes the cancer diagnosis by months to years. Here, we report a case of 44-year old postmenopausal woman who presented with PCD symptoms and high levels of anti-Yo antibodies titer since 8 months. We failed to conclude any neoplastic focus after thorough laboratory and imaging study. She minimally responded to methylprednisolone and immunoglobulin therapies. Despite therapy she was severely disabled. Planned abdominal hysterectomy with bilateral salpingo-oophorectomy (AHBSO) was done, histology revealed grade IIA borderline serous papillary carcinoma of ovary. Her neurological deficit responded dramatically to AHBSO. It is first case report who emphasize the response of AHBSO with presentation of anti-Yo antibody-mediated PCD and hidden nidus in post menopausal women.

  13. B lymphocyte-directed immunotherapy promotes long-term islet allograft survival in nonhuman primates.

    PubMed

    Liu, Chengyang; Noorchashm, Hooman; Sutter, Jennifer A; Naji, Mina; Prak, Eline Luning; Boyer, Jean; Green, Taryn; Rickels, Michael R; Tomaszewski, John E; Koeberlein, Brigitte; Wang, Zhonglin; Paessler, Michelle E; Velidedeoglu, Ergun; Rostami, Susan Y; Yu, Ming; Barker, Clyde F; Naji, Ali

    2007-11-01

    We found that an induction immunotherapy regimen consisting of rabbit anti-thymocyte globulin (Thymoglobulin) and the monoclonal antibody to CD20 rituximab (Rituxan) promoted long-term islet allograft survival in cynomolgus macaques maintained on rapamycin monotherapy. B lymphocyte reconstitution after rituximab-mediated depletion was characterized by a preponderance of immature and transitional cells, whose persistence was associated with long-term islet allograft survival. Development of donor-specific alloantibodies was abrogated only in the setting of continued rapamycin monotherapy.

  14. Managing soils for long-term productivity

    PubMed Central

    Syers, J. K.

    1997-01-01

    Meeting the goal of long-term agricultural productivity requires that soil degradation be halted and reversed. Soil fertility decline is a key factor in soil degradation and is probably the major cause of declining crop yields. There is evidence that the contribution of declining soil fertility to soil degradation has been underestimated.
    Sensitivity to soil degradation is implicit in the assessment of the sustainability of land management practices, with wide recognition of the fact that soils vary in their ability to resist change and recover subsequent to stress. The concept of resilience in relation to sustainability requires further elaboration and evaluation.
    In the context of soil degradation, a decline in soil fertility is primarily interpreted as the depletion of organic matter and plant nutrients. Despite a higher turnover rate of organic matter in the tropics there is no intrinsic difference between the organic matter content of soils from tropical and temperate regions. The level of organic matter in a soil is closely related to the above and below ground inputs. In the absence of adequate organic material inputs and where cultivation is continuous, soil organic matter declines progressively. Maintaining the quantity and quality of soil organic matter should be a guiding principle in developing management practices.
    Soil microbial biomass serves as an important reservoir of nitrogen (N), phosphorus (P) and sulphur (S), and regulates the cycling of organic matter and nutrients. Because of its high turnover rate, microbial biomass reacts quickly to changes in management and is a sensitive indicator for monitoring and predicting changes in soil organic matter. Modelling techniques have been reasonably successful in predicting changes in soil organic matter with different organic material inputs, but there is little information from the tropics.
    Nutrient depletion through harvested crop components and residue removal, and by leaching and soil

  15. Neurotoxicity testing during long-term studies.

    PubMed

    Ivens, I

    1990-01-01

    Several tests and methods for the investigation of neurotoxicity were performed with female Wistar rats for up to 187 days. The methods were validated by testing 10 rats treated with beta,beta'-iminodipropionitrile (IDPN) and 10 control rats. Cage side observation of the animals revealed signs of altered behavior and motor dysfunction of the IDPN-treated rats. Results of a neuromuscular screen indicated changes in gait, righting reflex, grip strength and performance of the negative geotropism test. Investigation of the animals in activity monitors and on the accelerating rotarod showed changes of several parameters. The motor nerve conduction velocity, measured 6 months after the first treatment, was reduced by 6.7 meters per second in the IDPN group compared to controls. From the results of the tests it can be concluded that the methods chosen can be used during long-term studies but may be most useful for animals not older than 12 months.

  16. Long term cryogenic storage facility systems study

    NASA Technical Reports Server (NTRS)

    Schuster, John R.

    1987-01-01

    The Long Term Cryogenic Storage Facility Systems Study (LTCSFSS) is a Phase A study of a large capacity propellant depot for the space based, cryogenic orbital transfer vehicle. The study is being performed for Marshall Space Flight Center by General Dynamics Space Systems Division and has five principal objectives: (1) Definition of preliminary concept designs for four storage facility concepts; (2) Selection of preferred concepts through the application of trade studies to candidate propellant management system components; (3) Preparation of a conceptual design for an orbital storage facility; (4) Development of supporting research and technology requirements; and (5) Development of a test program to demonstrate facility performance. The initial study has been completed, and continuation activities are just getting under way to provide greater detail in key areas and accommodate changes in study guidelines and assumptions.

  17. Reducing long-term reservoir performance uncertainty

    SciTech Connect

    Lippmann, M.J.

    1988-04-01

    Reservoir performance is one of the key issues that have to be addressed before going ahead with the development of a geothermal field. In order to select the type and size of the power plant and design other surface installations, it is necessary to know the characteristics of the production wells and of the produced fluids, and to predict the changes over a 10--30 year period. This is not a straightforward task, as in most cases the calculations have to be made on the basis of data collected before significant fluid volumes have been extracted from the reservoir. The paper describes the methodology used in predicting the long-term performance of hydrothermal systems, as well as DOE/GTD-sponsored research aimed at reducing the uncertainties associated with these predictions. 27 refs., 1 fig.

  18. Long-term monitoring for closed sites

    SciTech Connect

    Golchert, N.W.; Sedlet, J.; Veluri, V.R.

    1985-01-01

    A procedure is presented for planning and implementing a long-term environmental monitoring program for closed low-level radioactive waste disposal sites. The initial task in this procedure is to collect the available information on the legal/regulatory requirements, site and area characteristics, source term, pathway analysis, and prior monitoring results. This information is coupled with parameters such as half-life and retardation factors to develop a monitoring program. As examples, programs are presented for a site that has had little or no waste migration, and for sites where waste has been moved by suface water, by ground water, and by air. Sampling techniques and practices are discussed relative to how a current program would be structured and projections are made on techniques and practices expected to be available in the future. 8 refs., 2 figs.

  19. Emotional behavior in long-term marriage.

    PubMed

    Carstensen, L L; Gottman, J M; Levenson, R W

    1995-03-01

    In exploring the emotional climate of long-term marriages, this study used an observational coding system to identify specific emotional behaviors expressed by middle-aged and older spouses during discussions of a marital problem. One hundred and fifty-six couples differing in age and marital satisfaction were studied. Emotional behaviors expressed by couples differed as a function of age, gender, and marital satisfaction. In older couples, the resolution of conflict was less emotionally negative and more affectionate than in middle-aged marriages. Differences between husbands and wives and between happy and unhappy marriages were also found. Wives were more affectively negative than husbands, whereas husbands were more defensive than wives, and unhappy marriages involved greater exchange of negative affect than happy marriages.

  20. Long Term Hydrological (Radiological) Site Monitoring Data

    EPA Pesticide Factsheets

    Quality Data Asset includes all current and historical data on the quality of water with regard to the presence of water pollutants of all kinds regulated by the Clean Water Act. Under the new Interagency Agreement with the Department of Energy (DOE), the Radiation & Indoor Environments National Laboratory (R&IE), Office of Radiation and Indoor Air (ORIA), EPA, located in Las Vegas, NV, conducts a Long-Term Hydrological Monitoring Program (LTHMP) providing laboratory sampling/analysis and Quality Assurance and Control to measure radioactivity concentrations in the water sources near the sites of former underground nuclear explosions. The results of the LTHMP provide assurance that radioactive material from the tests have not migrated into water supplies.

  1. Long-term U. S. energy outlook

    SciTech Connect

    Friesen, G.

    1984-01-01

    Each year Chase Econometrics offers its clients a brief summary of the assumptions underlying the long-term energy forecast for the U.S. To illustrate the uncertainty involved in forecasting for the period to the year 2000, they choose to compare forecasts with some recent projections prepared by the Department of Energy's Office of Policy, Planning and Analysis for the annual National Energy Policy Plan supplement. Particular emphasis is placed on Scenario B, which is the mid-range reference case. As the introduction to the supplement emphasizes, the NEPP projections should not be considered a statement of the policy goals of the Reagan Administration. They represent an analysis of the possible evolution of U.S. energy markets, given current information and existing policies. The purpose of providing Scenario B as a reference case as well as Scenarios A and C as alternate cases is to show the sensitivity of oil price projections to small swings in energy demand.

  2. Advanced long term cryogenic storage systems

    NASA Technical Reports Server (NTRS)

    Brown, Norman S.

    1987-01-01

    Long term, cryogenic fluid storage facilities will be required to support future space programs such as the space-based Orbital Transfer Vehicle (OTV), Telescopes, and Laser Systems. An orbital liquid oxygen/liquid hydrogen storage system with an initial capacity of approximately 200,000 lb will be required. The storage facility tank design must have the capability of fluid acquisition in microgravity and limit cryogen boiloff due to environmental heating. Cryogenic boiloff management features, minimizing Earth-to-orbit transportation costs, will include advanced thick multilayer insulation/integrated vapor cooled shield concepts, low conductance support structures, and refrigeration/reliquefaction systems. Contracted study efforts are under way to develop storage system designs, technology plans, test article hardware designs, and develop plans for ground/flight testing.

  3. Long term performance of radon mitigation systems

    SciTech Connect

    Prill, R.; Fisk, W.J.

    2002-03-01

    Researchers installed radon mitigation systems in 12 houses in Spokane, Washington and Coeur d'Alene, Idaho during the heating season 1985--1986 and continued to monitor indoor radon quarterly and annually for ten years. The mitigation systems included active sub-slab ventilation, basement over-pressurization, and crawlspace isolation and ventilation. The occupants reported various operational problems with these early mitigation systems. The long-term radon measurements were essential to track the effectiveness of the mitigation systems over time. All 12 homes were visited during the second year of the study, while a second set 5 homes was visited during the fifth year to determine the cause(s) of increased radon in the homes. During these visits, the mitigation systems were inspected and measurements of system performance were made. Maintenance and modifications were performed to improve system performance in these homes.

  4. Withdrawal from long-term benzodiazepine treatment.

    PubMed Central

    Petursson, H; Lader, M H

    1981-01-01

    Long-term, normal-dose benzodiazepine treatment was discontinued in 16 patients who were suspected of being dependent on their medication. The withdrawal was gradual, placebo-controlled, and double-blind. All the patients experienced some form of withdrawal reaction, which ranged from anxiety and dysphoria to moderate affective and perceptual changes. Symptom ratings rose as the drugs were discontinued, but usually subsided to prewithdrawal levels over the next two to four weeks. Other features of the withdrawal included disturbance of sleep and appetite and noticeable weight loss. Electroencephalography showed appreciable reduction in fast-wave activity as the drugs were withdrawn, and an improvement in psychological performance was recorded by the Digit Symbol Substitution Test. Because of the risk of dependence on benzodiazepines these agents should probably not be given as regular daily treatment for chronic anxiety. PMID:6114776

  5. [Enteral nutrition through long-term jejunostomy].

    PubMed

    Fernández, T; Neira, P; Enríquez, C

    2008-01-01

    We present the case of a female patient suffering a peritonitis episode after subtotal gastrectomy due to gastric neoplasm in relation to lesser curvature necrosis extending to the anterior esophageal wall. This an uncommon andsevere complication that made mandatory further aggressive surgery: transection of the abdominal esophagus, transection of the gastric stump, and cervical esophagostomy with creation of a jejunostomy with a needle catheter for feeding. This digestive tube access technique is generally used during major abdominal post-surgery until oral intake is reestablished. Our patient has been 187 days with this therapy since reconstruction of the GI tract was ruled out due to tumoral infiltration of the colon and tumor recurrence at the gastrohepatic omentum. To date, there has been no complication from permanence and/or long-term use of this technique.

  6. [Childhood liver transplantation. Long-term results].

    PubMed

    Jara, Paloma; Hierro, Loreto

    2010-05-01

    Liver transplantation allows long-term survival (10 years or more) in 75% of children receiving transplants before 2000. The risk of mortality after the first year is 4-10% in the next 10-20 years. Chronic rejection affects 6%. The need for late retransplantation is 3-5%. However, the follow-up of these patients involves the management of diverse problems in the graft (immunological, biliary, vascular) and others related to the use of immunosuppressants (renal dysfunction, lymphoproliferative syndrome). The transition from pediatric to adult care generates special needs. Adolescence and young adulthood are associated with a lack of compliance. Adult specialists should be aware of the special features of the original diagnosis and the surgical techniques used in childhood transplantation. Final quality of life is good overall but is lower than that in healthy young persons.

  7. Long-term leaching of photovoltaic modules

    NASA Astrophysics Data System (ADS)

    Nover, Jessica; Zapf-Gottwick, Renate; Feifel, Carolin; Koch, Michael; Metzger, Jörg W.; Werner, Jürgen H.

    2017-08-01

    Some photovoltaic module technologies use toxic materials. We report long-term leaching on photovoltaic module pieces of 5 × 5 cm2 size. The pieces are cut out from modules of the four major commercial photovoltaic technologies: crystalline and amorphous silicon, cadmium telluride as well as from copper indium gallium diselenide. To simulate different environmental conditions, leaching occurs at room temperature in three different water-based solutions with pH 3, 7, and 11. No agitation is performed to simulate more representative field conditions. After 360 days, about 1.4% of lead from crystalline silicon module pieces and 62% of cadmium from cadmium telluride module pieces are leached out in acidic solutions. The leaching depends heavily on the pH and the redox potential of the aqueous solutions and it increases with time. The leaching behavior is predictable by thermodynamic stability considerations. These predictions are in good agreement with the experimental results.

  8. Technology for long-term care.

    PubMed

    Tak, Sunghee H; Benefield, Lazelle E; Mahoney, Diane Feeney

    2010-01-01

    Severe staff shortages in long-term care (LTC) make it difficult to meet the demands of the growing aging population. Further, technology-savvy Baby Boomers are expected to reshape the current institutional environments toward gaining more freedom and control in their care and lives. Voices from business, academia, research, advocacy organizations, and government bodies suggest that innovative technological approaches are the linchpin that may prepare society to cope with these projected demands. In this article, we review the current state of aging-related technology, identify potential areas for efficacy testing on improving the quality of life of LTC residents in future research, and discuss barriers to implementation of LTC technology. Finally, we present a vision of future technology use that could transform current care practices.

  9. Radiation risk during long-term spaceflight.

    PubMed

    Petrov, V M

    2002-01-01

    Cosmonauts' exposure to cosmic rays during long-term spaceflight can cause unfavorable effects in health and risk for the crew members' lives. All unfavorable effects induced by exposure should be taken into consideration for the risk estimation. They should include both the acute deterministic effects and delayed effects called stochastic. On the ground the limitation of unfavorable consequences of acute exposure is achieved by means of establishing dose limits. But in space applications this approach can't be acceptable. Establishing a fixed dose limit is adequate to introducing indefinite reserve coefficient and therefore ineffective usage of spacecraft resource. The method of radiation risk calculation caused by acute and delayed effects of cosmonauts' exposure is discussed and substantiated in the report. Peculiarities of the impact of permanent radiation sources (galactic cosmic rays and trapped radiation) and the variable one (solar cosmic rays) are taken into consideration. c2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.

  10. Long-term control of root growth

    SciTech Connect

    Burton, F.G.; Cataldo, D.A.; Cline, J.F.; Skiens, W.E.

    1992-05-26

    A method and system for long-term control of root growth without killing the plants bearing those roots involves incorporating a 2,6-dinitroaniline in a polymer and disposing the polymer in an area in which root control is desired. This results in controlled release of the substituted aniline herbicide over a period of many years. Herbicides of this class have the property of preventing root elongation without translocating into other parts of the plant. The herbicide may be encapsulated in the polymer or mixed with it. The polymer-herbicide mixture may be formed into pellets, sheets, pipe gaskets, pipes for carrying water, or various other forms. The invention may be applied to other protection of buried hazardous wastes, protection of underground pipes, prevention of root intrusion beneath slabs, the dwarfing of trees or shrubs and other applications. The preferred herbicide is 4-difluoromethyl-N,N-dipropyl-2,6-dinitro-aniline, commonly known as trifluralin. 7 figs.

  11. Long-term control of root growth

    DOEpatents

    Burton, Frederick G.; Cataldo, Dominic A.; Cline, John F.; Skiens, W. Eugene

    1992-05-26

    A method and system for long-term control of root growth without killing the plants bearing those roots involves incorporating a 2,6-dinitroaniline in a polymer and disposing the polymer in an area in which root control is desired. This results in controlled release of the substituted aniline herbicide over a period of many years. Herbicides of this class have the property of preventing root elongation without translocating into other parts of the plant. The herbicide may be encapsulated in the polymer or mixed with it. The polymer-herbicide mixture may be formed into pellets, sheets, pipe gaskets, pipes for carrying water, or various other forms. The invention may be applied to other protection of buried hazardous wastes, protection of underground pipes, prevention of root intrusion beneath slabs, the dwarfing of trees or shrubs and other applications. The preferred herbicide is 4-difluoromethyl-N,N-dipropyl-2,6-dinitro-aniline, commonly known as trifluralin.

  12. Long-term dynamics of Typha populations

    USGS Publications Warehouse

    Grace, J.B.; Wetzel, R.G.

    1998-01-01

    The zonation of Typha populations in an experimental pond in Michigan was re-examined 15 years after the original sampling to gain insight into the long-term dynamics. Current distributions of Typha populations were also examined in additional experimental ponds at the site that have been maintained for 23 years. The zonation between T. latifolia and T. angustifolia in the previously studied pond 15 years after the initial sampling revealed that the density and distribution of shoots had not changed significantly. Thus, it appears that previously reported results (based on 7- year old populations) have remained consistent over time. Additional insight into the interaction between these two taxa was sought by comparing mixed and monoculture stands in five experimental ponds that have remained undisturbed for their 23-year history. The maximum depth of T. latifolia, the shallow- water species, was not significantly reduced when growing in the presence of the more flood tolerant T. angustifolia. In contrast, the minimum depth of T. angustifolia was reduced from 0 to 37 cm when in the presence of T. latifolia. When total populations were compared between monoculture and mixed stands, the average density of T. angustifolia shoots was 59.4 percent lower in mixed stands while the density of T. latifolia was 32 percent lower, with T. angustifolia most affected at shallow depths (reduced by 92 percent) and T. latifolia most affected at the deepest depths (reduced by 60 percent). These long-term observations indicate that competitive displacement between Typha taxa has remained stable over time.

  13. Reconstructing the long-term aa index

    NASA Astrophysics Data System (ADS)

    Clilverd, Mark A.; Clarke, Ellen; Ulich, Thomas; Linthe, Joachim; Rishbeth, Henry

    2005-07-01

    The robustness of the aa geomagnetic index is of critical importance to the debate about the previously reported doubling of the solar coronal magnetic field in the last 100 years, inferred from an increasing trend in this index. To test the trend in aa, we have reconstructed the aa index using two long-running European stations (Sodankylä from 1914 and Niemegk from 1890) to provide data for the northern component of the index that are independent of data from the UK observatories used in the "official" aa index. Both the fully "reconstructed" aa series, based on Sodankylä (67°N, L = 5.2 RE) and Niemegk (52°N, L = 2.3 RE) data in combination with the official aa Southern Hemisphere data, confirm the increasing trend in the index. The Niemegk-based index shows little solar cycle variation in its deviation from the official index, probably because of the midlatitude location of the station. The high-latitude station, Sodankylä, is more affected by active geomagnetic conditions during solar maximum because of the proximity of the auroral oval to the station. Nevertheless, its index also clearly confirms the increasing trend in the aa index and hence supports the idea of a long-term increase in solar coronal magnetic field strength. As an added test, we reconstructed the aa index from a single site using data from two long-running UK stations, Eskdalemuir and Lerwick, applying a technique known as interhourly variation (IHV) proposed by Svalgaard et al. (2004). The resulting series is designed to be primarily sensitive to solar wind conditions. Both the reconstructed aaIHV also showed an increasing trend with time and high consistency with the official aa index. Overall, we conclude that the robustness of the trend in the aa index supports the idea of a long-term increase in solar coronal magnetic field strength.

  14. Posterior urethral valves: long-term outcome.

    PubMed

    Caione, Paolo; Nappo, Simona Gerocarni

    2011-10-01

    Posterior urethral valves represent the most common cause of bladder outlet obstruction in infancy that impairs renal and bladder function. Long-term outcome of patients with previous PUV is evaluated. Patients over 18 years of age, treated from 1982 to 1995 before the age of 3 years were considered. Previous surgery, renal function, bladder activity, urinary incontinence, and fertility/sexual activity were evaluated. Clinical interview, creatinine clearance, uroflowmetry with ultrasound post-void urine residue, and self-administered questionnaire were recorded. Out of 45 identified records, 24 patients (53.3%) accepted to be enrolled (age 18-34 years, mean 23 years). The mean follow-up was 19.5 years (16-30 years). Out of the 21 excluded patients, 20 did not reply to the clinical interview and 1 died at age of 6 years. All the 24 patients had early endoscopic section of PUV; nine also received transient ureterocutaneostomy or vesicostomy. Ureteroneocystostomy was performed in five patients and ureterocystoplasty with unilateral nephrectomy in two. At follow-up chronic renal failure was detected in 13 patients (54.1%) and 9 (37.5%) had arterial hypertension. End-stage renal disease developed in five patients (20.8%): three had successful renal transplantation and two were in dialysis. Lower urinary tract symptoms were present in seven patients (29.1%). No significant fertility deficit and sexual dysfunction were observed in 23 patients, while 1 patient was azoospermic. No paternity was reported so far. Long-term outcome of patients with previously treated PUV is mandatory. Kidney, bladder, and sexual functions should be monitored till adulthood to verify any modified behaviour.

  15. Long term results of pneumatic retinopexy

    PubMed Central

    Ellakwa, Amin F

    2012-01-01

    Background Rhegmatogenous retinal detachment is a commonly encountered retinal problem where rapid treatment can prevent irreversible vision loss. Pneumatic retinopexy (PR) is a simple, minimally invasive procedure for retinal reattachment. Purpose This study aimed to assess the long-term anatomical and functional outcome of pneumatic retinopexy in primary rhegmatogenous retinal detachment. Patients and methods A prospective interventional study was performed. Subjects with rhegmatogenous retinal detachment who underwent pneumatic retinopexy from May 2006 to May 2007 at Menoufiya University Hospital were included in this study with at least 3 years follow-up. Results A total of 40 cases were included in the study. The mean age of patients was 44.25 ± 10.85 years. Reattachment of the retina was achieved in 100% of cases. In 75% of cases, the primary intervention was successful. However, the retina redetached in 20% of these during the first 6 months, requiring reinjection or another procedure. Three years after the first intervention, follow-up measurement of the mean visual acuity of the eyes without reoperation was 0.40 ± 0.21 while the mean visual acuity of the eyes which needed additional operations was 0.22 ± 0.13. Conclusion Sixty percent of the cases obtained long-term retinal reattachment with a single operation success (SOS), with good visual recovery and less morbidity than other more invasive procedures like scleral buckling or pars plana vitrectomy, translating to higher productivity for the patient. This procedure, being quicker than the alternatives, also saves the surgeon’s time, making PR a good choice for managing primary rhegmatogenous retinal detachment in developing countries. PMID:22275808

  16. Managing Records for the Long Term - 12363

    SciTech Connect

    Montgomery, John V.; Gueretta, Jeanie

    2012-07-01

    The U.S. Department of Energy (DOE) is responsible for managing vast amounts of information documenting historical and current operations. This information is critical to the operations of the DOE Office of Legacy Management. Managing legacy records and information is challenging in terms of accessibility and changing technology. The Office of Legacy Management is meeting these challenges by making records and information management an organizational priority. The Office of Legacy Management mission is to manage DOE post-closure responsibilities at former Cold War weapons sites to ensure the future protection of human health and the environment. These responsibilities include environmental stewardship and long-term preservation and management of operational and environmental cleanup records associated with each site. A primary organizational goal for the Office of Legacy Management is to 'Preserve, Protect, and Share Records and Information'. Managing records for long-term preservation is an important responsibility. Adequate and dedicated resources and management support are required to perform this responsibility successfully. Records tell the story of an organization and may be required to defend an organization in court, provide historical information, identify lessons learned, or provide valuable information for researchers. Loss of records or the inability to retrieve records because of poor records management processes can have serious consequences and even lead to an organisation's downfall. Organizations must invest time and resources to establish a good records management program because of its significance to the organization as a whole. The Office of Legacy Management will continue to research and apply innovative ways of doing business to ensure that the organization stays at the forefront of effective records and information management. DOE is committed to preserving records that document our nation's Cold War legacy, and the Office of Legacy

  17. Dynamics of long-term genomic selection

    PubMed Central

    2010-01-01

    Background Simulation and empirical studies of genomic selection (GS) show accuracies sufficient to generate rapid gains in early selection cycles. Beyond those cycles, allele frequency changes, recombination, and inbreeding make analytical prediction of gain impossible. The impacts of GS on long-term gain should be studied prior to its implementation. Methods A simulation case-study of this issue was done for barley, an inbred crop. On the basis of marker data on 192 breeding lines from an elite six-row spring barley program, stochastic simulation was used to explore the effects of large or small initial training populations with heritabilities of 0.2 or 0.5, applying GS before or after phenotyping, and applying additional weight on low-frequency favorable marker alleles. Genomic predictions were from ridge regression or a Bayesian analysis. Results Assuming that applying GS prior to phenotyping shortened breeding cycle time by 50%, this practice strongly increased early selection gains but also caused the loss of many favorable QTL alleles, leading to loss of genetic variance, loss of GS accuracy, and a low selection plateau. Placing additional weight on low-frequency favorable marker alleles, however, allowed GS to increase their frequency earlier on, causing an initial increase in genetic variance. This dynamic led to higher long-term gain while mitigating losses in short-term gain. Weighted GS also increased the maintenance of marker polymorphism, ensuring that QTL-marker linkage disequilibrium was higher than in unweighted GS. Conclusions Losing favorable alleles that are in weak linkage disequilibrium with markers is perhaps inevitable when using GS. Placing additional weight on low-frequency favorable alleles, however, may reduce the rate of loss of such alleles to below that of phenotypic selection. Applying such weights at the beginning of GS implementation is important. PMID:20712894

  18. Behavioral and systemic consequences of long-term inflammatory challenge.

    PubMed

    Fischer, Christina W; Elfving, Betina; Lund, Sten; Wegener, Gregers

    2015-11-15

    Inflammatory reactions are involved in a diversity of diseases, including major depressive disorder. Cytokines act as intercellular signaling molecules and mediators of inflammation between the periphery and the brain. Within the brain, evidence from animal studies of acute inflammation has shown that elevated cytokine levels are linked to behavioral responses of sickness and depression-like behavior. Although chronic inflammation is more translational to human depression than acute studies, little is known on central cytokine expression and associated behavioral responses following chronic immune challenges. The present study assessed behavioral changes and a selection of cytokines in the brain and in the blood in rats randomized to receive a single or 8week administration with either lipopolysaccharide (LPS, 600μg/kg, i.p.) or saline. Acute and long-term LPS treatments caused similar sickness and depression-like behavior. Chronic LPS administration did not have an effect on blood cytokine levels, indicating endotoxin tolerance, whereas increased fasting blood glucose was observed, indicating insulin resistance, a metabolic consequence of chronic inflammation. While a single LPS injection produced a generalized cytokine response in the brain, long-term LPS administration produced a specific central cytokine response with increased interleukin (IL)-1β and interferon (IFN)-γ. These cytokines can explain the behavioral changes observed, and could indicate microglia activation, although future studies are needed to uncover this assumption. Taken together, although the behavioral outcome was similar between acute and chronic LPS administration, the central cytokine response was distinct. As the long-term LPS paradigm also posed a metabolic demand, this setting may reflect a more translational insight into inflammatory reactions in human depression, and could prove useful for assessing cytokine down-stream effects and experimental antidepressant drug products.

  19. Short-term information processing, long-term responses: Insights by mathematical modeling of signal transduction. Early activation dynamics of key signaling mediators can be predictive for cell fate decisions.

    PubMed

    Schneider, Annette; Klingmüller, Ursula; Schilling, Marcel

    2012-07-01

    How do cells interpret information from their environment and translate it into specific cell fate decisions? We propose that cell fate is already encoded in early signaling events and thus can be predicted from defined signal properties. Specifically, we hypothesize that the time integral of activated key signaling molecules can be correlated to cellular behavior such as proliferation or differentiation. The identification of these decisive key signal mediators and their connection to cell fate is facilitated by mathematical modeling. A possible mechanistic linkage between signaling dynamics and cellular function is the directed control of gene regulatory networks by defined signals. Targeted experiments in combination with mathematical modeling can increase our understanding of how cells process information and realize distinct cell fates. Copyright © 2012 WILEY Periodicals, Inc.

  20. Strength and timing of motor responses mediated by rebound firing in the cerebellar nuclei after Purkinje cell activation

    PubMed Central

    Witter, Laurens; Canto, Cathrin B.; Hoogland, Tycho M.; de Gruijl, Jornt R.; De Zeeuw, Chris I.

    2013-01-01

    The cerebellum refines the accuracy and timing of motor performance. How it encodes information to perform these functions is a major topic of interest. We performed whole cell and extracellular recordings of Purkinje cells (PCs) and cerebellar nuclei neurons (CNs) in vivo, while activating PCs with light in transgenic mice. We show for the first time that graded activation of PCs translates into proportional CN inhibition and induces rebound activity in CNs, which is followed by graded motor contractions timed to the cessation of the stimulus. Moreover, activation of PC ensembles led to disinhibition of climbing fiber activity, which coincided with rebound activity in CNs. Our data indicate that cessation of concerted activity in ensembles of PCs can regulate both timing and strength of movements via control of rebound activity in CNs. PMID:23970855

  1. The Starkey project: long-term research for long-term management solutions.

    Treesearch

    Thomas M. Quigley; Michael J. Wisdom

    2004-01-01

    The Starkey Project is a unique, long-term research program designed to study the effects of key resource uses of national forests on mule deer (Odocoileus hemionus) and elk (Cervus elaphus) habitats and populations located at the Starkey Experimental Forest and Range (Starkey). The purpose of the project was to fill knowledge...

  2. Long-term trajectories and service needs for military families.

    PubMed

    Link, Patrick E; Palinkas, Lawrence A

    2013-12-01

    The deployment of US military personnel to recent conflicts has been a significant stressor for their families; yet, we know relatively little about the long-term family effects of these deployments. Using data from prior military service eras, we review our current understanding of the long-term functioning and needs of military families. These data suggest that overseas deployment, exposure to combat, experiencing or participating in violence during war deployment, service member injury or disability, and combat-related post-traumatic stress disorder (PTSD) all have profound impacts on the functioning of military families. We offer several recommendations to address these impacts such as the provision of family-centered, trauma-informed resources to families of veterans with PTSD and veterans who experienced high levels of combat and war violence. Recent efforts to address the needs of caregivers of veterans should be evaluated and expanded, as necessary. We should also help military families plan for predictable life events likely to challenge their resilience and coping capacities. Future research should focus on the following: factors that mediate the relationship between PTSD, war atrocities, caregiver burden, and family dysfunction; effective family-centered interventions that can be scaled-up to meet the needs of a dispersed population; and system-level innovations necessary to ensure adequate access to these interventions.

  3. A neural model of cerebellar learning for arm movement control: cortico-spino-cerebellar dynamics.

    PubMed

    Contreras-Vidal, J L; Grossberg, S; Bullock, D

    1997-01-01

    A neural network model of opponent cerebellar learning for arm movement control is proposed. The model illustrates how a central pattern generator in cortex and basal ganglia, a neuromuscular force controller in spinal cord, and an adaptive cerebellum cooperate to reduce motor variability during multijoint arm movements using mono- and bi-articular muscles. Cerebellar learning modifies velocity commands to produce phasic antagonist bursts at interpositus nucleus cells whose feed-forward action overcomes inherent limitations of spinal feedback control of tracking. Excitation of alpha motoneuron pools, combined with inhibition of their Renshaw cells by the cerebellum, facilitate movement initiation and optimal execution. Transcerebellar pathways are opened by learning through long-term depression (LTD) of parallel fiber-Purkinje cell synapses in response to conjunctive stimulation of parallel fibers and climbing fiber discharges that signal muscle stretch errors. The cerebellar circuitry also learns to control opponent muscles pairs, allowing cocontraction and reciprocal inhibition of muscles. Learning is stable, exhibits load compensation properties, and generalizes better across movement speeds if motoneuron pools obey the size principle. The intermittency of climbing fiber discharges maintains stable learning. Long-term potentiation (LTP) in response to uncorrelated parallel fiber signals enables previously weakened synapses to recover. Loss of climbing fibers, in the presence of LTP, can erode normal opponent signal processing. Simulated lesions of the cerebellar network reproduce symptoms of cerebellar disease, including sluggish movement onsets, poor execution of multijoint plans, and abnormally prolonged endpoint oscillations.

  4. The histone deacetylase HDAC4 regulates long-term memory in Drosophila.

    PubMed

    Fitzsimons, Helen L; Schwartz, Silvia; Given, Fiona M; Scott, Maxwell J

    2013-01-01

    A growing body of research indicates that pharmacological inhibition of histone deacetylases (HDACs) correlates with enhancement of long-term memory and current research is concentrated on determining the roles that individual HDACs play in cognitive function. Here, we investigate the role of HDAC4 in long-term memory formation in Drosophila. We show that overexpression of HDAC4 in the adult mushroom body, an important structure for memory formation, resulted in a specific impairment in long-term courtship memory, but had no affect on short-term memory. Overexpression of an HDAC4 catalytic mutant also abolished LTM, suggesting a mode of action independent of catalytic activity. We found that overexpression of HDAC4 resulted in a redistribution of the transcription factor MEF2 from a relatively uniform distribution through the nucleus into punctate nuclear bodies, where it colocalized with HDAC4. As MEF2 has also been implicated in regulation of long-term memory, these data suggest that the repressive effects of HDAC4 on long-term memory may be through interaction with MEF2. In the same genetic background, we also found that RNAi-mediated knockdown of HDAC4 impairs long-term memory, therefore we demonstrate that HDAC4 is not only a repressor of long-term memory, but also modulates normal memory formation.

  5. 17 CFR 256.224 - Other long-term debt.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... SYSTEM OF ACCOUNTS FOR MUTUAL SERVICE COMPANIES AND SUBSIDIARY SERVICE COMPANIES, PUBLIC UTILITY HOLDING COMPANY ACT OF 1935 6. Long-Term Debt § 256.224 Other long-term debt. This account shall include all long...

  6. 17 CFR 256.224 - Other long-term debt.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... SYSTEM OF ACCOUNTS FOR MUTUAL SERVICE COMPANIES AND SUBSIDIARY SERVICE COMPANIES, PUBLIC UTILITY HOLDING COMPANY ACT OF 1935 6. Long-Term Debt § 256.224 Other long-term debt. This account shall include all long...

  7. Treatment for childhood cancer -- long-term risks

    MedlinePlus

    ... ency/patientinstructions/000849.htm Treatment for childhood cancer - long-term risks To use the sharing features on this ... has. Being aware of your child's risk of long-term health problems can help you follow-up with ...

  8. 22 CFR 228.12 - Long-term leases.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... SERVICES FINANCED BY USAID Conditions Governing Source and Nationality of Commodity Procurement Transactions for USAID Financing § 228.12 Long-term leases. Any commodity obtained under a long-term lease...

  9. 22 CFR 228.18 - Long-term leases.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... USAID Conditions Governing Source and Nationality of Commodity and Service Procurement Transactions for USAID Financing § 228.18 Long-term leases. Any commodity obtained under a long-term lease agreement as...

  10. 22 CFR 228.18 - Long-term leases.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... USAID Conditions Governing Source and Nationality of Commodity and Service Procurement Transactions for USAID Financing § 228.18 Long-term leases. Any commodity obtained under a long-term lease agreement as...

  11. 22 CFR 228.18 - Long-term leases.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... USAID Conditions Governing Source and Nationality of Commodity and Service Procurement Transactions for USAID Financing § 228.18 Long-term leases. Any commodity obtained under a long-term lease agreement as...

  12. 22 CFR 228.12 - Long-term leases.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... SERVICES FINANCED BY USAID Conditions Governing Source and Nationality of Commodity Procurement Transactions for USAID Financing § 228.12 Long-term leases. Any commodity obtained under a long-term lease...

  13. Cerebellar Synaptic Plasticity and the Credit Assignment Problem.

    PubMed

    Jörntell, Henrik

    2016-04-01

    The mechanism by which a learnt synaptic weight change can contribute to learning or adaptation of brain function is a type of credit assignment problem, which is a key issue for many parts of the brain. In the cerebellum, detailed knowledge not only of the local circuitry connectivity but also of the topography of different sources of afferent/external information makes this problem particularly tractable. In addition, multiple forms of synaptic plasticity and their general rules of induction have been identified. In this review, we will discuss the possible roles of synaptic and cellular plasticity at specific locations in contributing to behavioral changes. Focus will be on the parts of the cerebellum that are devoted to limb control, which constitute a large proportion of the cortex and where the knowledge of the external connectivity is particularly well known. From this perspective, a number of sites of synaptic plasticity appear to primarily have the function of balancing the overall level of activity in the cerebellar circuitry, whereas the locations at which synaptic plasticity leads to functional changes in terms of limb control are more limited. Specifically, the postsynaptic forms of long-term potentiation (LTP) and long-term depression (LTD) at the parallel fiber synapses made on interneurons and Purkinje cells, respectively, are the types of plasticity that mediate the widest associative capacity and the tightest link between the synaptic change and the external functions that are to be controlled.

  14. LONG-TERM MONITORING SENSOR NETWORK

    SciTech Connect

    Stephen P. Farrington; John W. Haas; Neal Van Wyck

    2003-10-16

    Long-term monitoring (LTM) associated with subsurface contamination sites is a key element of Long Term Stewardship and Legacy Management across the Department of Energy (DOE) complex. However, both within the DOE and elsewhere, LTM is an expensive endeavor, often exceeding the costs of the remediation phase of a clean-up project. The primary contributors to LTM costs are associated with labor. Sample collection, storage, preparation, analysis, and reporting can add a significant financial burden to project expense when extended over many years. Development of unattended, in situ monitoring networks capable of providing quantitative data satisfactory to regulatory concerns has the potential to significantly reduce LTM costs. But survival and dependable operation in a difficult environment is a common obstacle to widespread use across the DOE complex or elsewhere. Deploying almost any sensor in the subsurface for extended periods of time will expose it to chemical and microbial degradation. Over the time-scales required for in situ LTM, even the most advanced sensor systems may be rendered useless. Frequent replacement or servicing (cleaning) of sensors is expensive and labor intensive, offsetting most, if not all, of the cost savings realized with unattended, in situ sensors. To enable facile, remote monitoring of contaminants and other subsurface parameters over prolonged periods, Applied Research Associates, Inc has been working to develop an advanced LTM sensor network consisting of three key elements: (1) an anti-fouling sensor chamber that can accommodate a variety of chemical and physical measurement devices based on electrochemical, optical and other techniques; (2) two rapid, cost effective, and gentle means of emplacing sensor packages either at precise locations directly in the subsurface or in pre-existing monitoring wells; and (3) a web browser-based data acquisition and control system (WebDACS) utilizing field-networked microprocessor-controlled smart

  15. Robotics for Long-Term Monitoring

    SciTech Connect

    Shahin, Sarkis; Duran, Celso

    2002-07-01

    While long-term monitoring and stewardship means many things to many people, DOE has defined it as The physical controls, institutions, information, and other mechanisms needed to ensure protection of people and the environment at sites where DOE has completed or plans to complete cleanup (e.g., landfill closures, remedial actions, and facility stabilization). Across the United States, there are thousands of contaminated sites with multiple contaminants released from multiple sources where contaminants have transported and commingled. The U.S. government and U.S. industry are responsible for most of the contamination and are landowners of many of these contaminated properties. These sites must be surveyed periodically for various criteria including structural deterioration, water intrusion, integrity of storage containers, atmospheric conditions, and hazardous substance release. The surveys, however, are intrusive, time-consuming, and expensive and expose survey personnel to radioactive contamination. In long-term monitoring, there's a need for an automated system that will gather and report data from sensors without costly human labor. In most cases, a SCADA (Supervisory Control and Data Acquisition) unit is used to collect and report data from a remote location. A SCADA unit consists of an embedded computer with data acquisition capabilities. The unit can be configured with various sensors placed in different areas of the site to be monitored. A system of this type is static, i.e., the sensors, once placed, cannot be moved to other locations within the site. For those applications where the number of sampling locations would require too many sensors, or where exact location of future problems is unknown, a mobile sensing platform is an ideal solution. In many facilities that undergo regular inspections, the number of video cameras and air monitors required to eliminate the need for human inspections is very large and far too costly. HCET's remote harsh

  16. Long-term Changes in Tropospheric Ozone

    NASA Astrophysics Data System (ADS)

    Oltmans, S.; Lefohn, A.; Galbally, I.; Scheel, E.; Bodeker, G.; Brunke, E.; Claude, H.; Tarasick, D.; Simmonds, P.; Anlauf, K.; Schmidlin, F.; Akagi, K.; Redondas, A.

    2006-05-01

    Tropospheric ozone measurements from a selected network of surface and ozonesonde sites are used to give a broad geographic picture of long-term variations. The picture of long-term tropospheric ozone changes is a varied one in terms of both the sign and magnitude of trends and in the possible causes for the changes. At mid latitudes of the S.H. three time series of ~20 years in length agree in showing increases that are strongest in the austral spring (August-October). Profile measurements show this increase extending through the mid troposphere but not into the highest levels of the troposphere. In the N.H. in the Arctic a period of declining ozone in the troposphere through the 1980s into the mid 1990s has reversed and the overall change is small. The decadal-scale variations in the troposphere in this region are related in part to changes in the lowermost stratosphere. At mid latitudes in the N.H., continental Europe and Japan showed significant increases in the 1970s and 1980s. Over North America rises in the 1970s are less than those seen in Europe and Japan, suggesting significant regional differences. In all three of these mid latitude, continental regions tropospheric ozone amounts appear to have leveled off or in some cases declined in the more recent decades. Over the North Atlantic three widely separated sites show significant increases since the late 1990s that may have peaked in recent years. In the N.H. tropics both the surface record and the ozonesondes in Hawaii show a significant increase in the autumn months in the most recent decade compared to earlier periods that drives the overall increase seen in the 30 year record. This appears to be related to a shift in the transport pattern during this season with more frequent flow from higher latitudes in the latest decade. The pattern of change, with the largest increases in the N.H. coming prior to the mid 1980s, suggests that increased positive radiative forcing due to tropospheric ozone was felt

  17. Evaluating Long-Term Care Through the Humanbecoming Lens.

    PubMed

    Hart, Judith D

    2015-10-01

    The author describes evaluating long-term care from the humanbecoming perspective. Three core ideas are presented related to dignity and living quality, and how the humanbecoming perspective can be incorporated into long-term care evaluations that make a difference to the residents, caregivers, management, and to the outcomes of long-term care. This approach from the humanbecoming perspective can enrich evaluative information, influence long-term care outcomes, and ensure human dignity for all concerned.

  18. AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL.

    PubMed

    Sondhi, D; Peterson, D A; Giannaris, E L; Sanders, C T; Mendez, B S; De, B; Rostkowski, A B; Blanchard, B; Bjugstad, K; Sladek, J R; Redmond, D E; Leopold, P L; Kaminsky, S M; Hackett, N R; Crystal, R G

    2005-11-01

    Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal, autosomal recessive disease resulting from mutations in the CLN2 gene with consequent deficiency in its product tripeptidyl peptidase I (TPP-I). In the central nervous system (CNS), the deficiency of TPP-I results in the accumulation of proteins in lysosomes leading to a loss of neurons causing progressive neurological decline, and death by ages 10-12 years. To establish the feasibility of treating the CNS manifestations of LINCL by gene transfer, an adeno-associated virus 2 (AAV2) vector encoding the human CLN2 cDNA (AAV2CUhCLN2) was assessed for its ability to establish therapeutic levels of TPP-I in the brain. In vitro studies demonstrated that AAV2CUhCLN2 expressed CLN2 and produced biologically active TPP-I protein of which a fraction was secreted as the pro-TPP-I precursor and was taken up by nontransduced cells (ie, cross-correction). Following AAV2-mediated CLN2 delivery to the rat striatum, enzymatically active TPP-I protein was detected. By immunohistochemistry TPP-I protein was detected in striatal neurons (encompassing nearly half of the target structure) for up to 18 months. At the longer time points following striatal administration, TPP-I-positive cell bodies were also observed in the substantia nigra, frontal cerebral cortex and thalamus of the injected hemisphere, and the frontal cerebral cortex of the noninjected hemisphere. These areas of the brain contain neurons that extend axons into the striatum, suggesting that CNS circuitry may aid the distribution of the gene product. To assess the feasibility of human CNS delivery, a total of 3.6 x 10(11) particle units of AAV2CUhCLN2 was administered to the CNS of African green monkeys in 12 distributed doses. Assessment at 5 and 13 weeks demonstrated widespread detection of TPP-I in neurons, but not glial cells, at all regions of injection. The distribution of TPP-I-positive cells was similar between the two time points at all injection

  19. Long-term effects of weight loss with a very-low carbohydrate, low saturated fat diet on flow mediated dilatation in patients with type 2 diabetes: A randomised controlled trial.

    PubMed

    Wycherley, Thomas P; Thompson, Campbell H; Buckley, Jonathan D; Luscombe-Marsh, Natalie D; Noakes, Manny; Wittert, Gary A; Brinkworth, Grant D

    2016-09-01

    Very-low carbohydrate diets can improve glycaemic control in patients with type 2 diabetes (T2DM). However, compared to traditional higher carbohydrate, low fat (HighCHO) diets, they have been associated with impaired endothelial function (measured by flow mediated dilatation [FMD]) that is possibly related to saturated fat. This study aimed to examine the effects of a 12-month hypocaloric very-low carbohydrate, low saturated fat (LowCHO) diet compared to an isocaloric HighCHO diet. One hundred and fifteen obese patients with T2DM (age:58.4 ± 0.7 [SEM] yr, BMI:34.6 ± 0.4 kg/m(2), HbA1c:7.33 [56.3 mmol/mol] ± 0.10%) were randomised to consume an energy restricted LowCHO diet (Carb:Pro:Fat:Sat-Fat 14:28:58: < 10% energy; n = 58) or isocaloric HighCHO diet (53:17:30: < 10%; n = 57) whilst undertaking exercise (60 min, 3/wk). Bodyweight, HbA1c and FMD were assessed. Seventy eight participants completed the intervention (LowCHO = 41, HighCHO = 37). Both groups experienced similar reductions in weight and HbA1c (-10.6 ± 0.7 kg, -1.05 ± 0.10%; p < 0.001 time, p ≥ 0.48 time × diet). FMD did not change (p = 0.11 time, p = 0.20 time × diet). In patients with obesity and T2DM, HighCHO diet and LowCHO diet have similar effects on endothelial function. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Long-term Variability of Beach Cusps

    NASA Astrophysics Data System (ADS)

    Pianca, C.; Holman, R. A.; Siegle, E.

    2016-02-01

    The most curious morphological features observed on beaches are the cusps. Due to their rhythmic spacing, beach cusps have attracted many observers and many, often contradictory, theories as to their form. Moreover, most of the research about beach cusps has focused on their formation. Few had available long time series to study such things as the variability of alongshore and cross-shore position and spacing on the cusp field, the presence, longevity and interactions between higher and lower sets of cusps, and the processes by which cusp fields extend, shrink or change length scale. The purpose of this work is to use long-term data sets of video images from two study sites, an intermediate (Duck, USA, 26 years) and a reflective beach (Massaguaçu, Brazil, 3 years), to investigate the temporal and spatial changes of cusps conditions. Time-evolving shoreline data were first extracted using an algorithm called ASLIM (Pianca et al 2015). Cusps were then identified based on the band-passed variability of time exposure image data about this shoreline as a function of elevation relative to MSL. The identified beaches cusps will be analyzed for cusp spacing, positions (upper or lower cusps), alongshore variability, merging events, percentage of cusp events, patterns of the events and time scales of variability. Finally, the relationship of these characteristics to environmental conditions (wave, tides, beach conditions) will be studied.

  1. Long-term adequacy of metal resources

    USGS Publications Warehouse

    Singer, D.A.

    1977-01-01

    Although the earth's crust contains vast quantities of metals, extraction technologies and associated costs are inextricably bound to three fundamental geological factors - the amount of metal available in the earth's crust in each range of grades, the mineralogical form and chemical state of the metal, and the spatial distribution of the metal. The energy required to recover a given amount of metal increases substantially as grade declines. Most metal is produced from sulphide or oxide minerals, whereas most metal in the crust may be locked in the structures of the more refractory silicates. Recovery from silicate minerals could require orders of magnitude more energy than that used at present as also could exploitation of small, widely scattered or thin, deeply buried deposits. Although specific information on the fundamental factors is not available, each factor must in turn tend to further restrict exploitation. Independence of average grade and tonnage for many deposit types further reduces the availability of rock as a source of metal. In the long term, effects of these factors will be large increases in price for many metals. ?? 1977.

  2. Long term results of childhood dysphonia treatment.

    PubMed

    Mackiewicz-Nartowicz, Hanna; Sinkiewicz, Anna; Bielecka, Arleta; Owczarzak, Hanna; Mackiewicz-Milewska, Magdalena; Winiarski, Piotr

    2014-05-01

    The aim of this study was to assess the long term results of treatment and rehabilitation of childhood dysphonia. This study included a group of adolescents (n=29) aged from 15 to 20 who were treated due to pediatric hyperfunctional dysphonia and soft vocal fold nodules during their pre-mutational period (i.e. between 5 and 12 years of age). The pre-mutational therapy was comprised of proper breathing pattern training, voice exercises and psychological counseling. Laryngostroboscopic examination and perceptual analysis of voice were performed in each patient before treatment and one to four years after mutation was complete. The laryngostroboscopic findings, i.e. symmetry, amplitude, mucosal wave and vocal fold closure, were graded with NAPZ scale, and the GRBAS scale was used for the perceptual voice analysis. Complete regression of the childhood dysphonia was observed in all male patients (n=14). Voice disorders regressed completely also in 8 out of 15 girls, but symptoms of dysphonia documented on perceptual scale persisted in the remaining seven patients. Complex voice therapy implemented in adolescence should be considered as either the treatment or preventive measure of persistent voice strain, especially in girls. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  3. Long-term corrosion testing pan.

    SciTech Connect

    Wall, Frederick Douglas; Brown, Neil R.

    2008-08-01

    This document describes the testing and facility requirements to support the Yucca Mountain Project long-term corrosion testing needs. The purpose of this document is to describe a corrosion testing program that will (a) reduce model uncertainty and variability, (b) reduce the reliance upon overly conservative assumptions, and (c) improve model defensibility. Test matrices were developed for 17 topical areas (tasks): each matrix corresponds to a specific test activity that is a subset of the total work performed in a task. A future document will identify which of these activities are considered to be performance confirmation activities. Detailed matrices are provided for FY08, FY09 and FY10 and rough order estimates are provided for FY11-17. Criteria for the selection of appropriate test facilities were developed through a meeting of Lead Lab and DOE personnel on October 16-17, 2007. These criteria were applied to the testing activities and recommendations were made for the facility types appropriate to carry out each activity. The facility requirements for each activity were assessed and activities were identified that can not be performed with currently available facilities. Based on this assessment, a total of approximately 10,000 square feet of facility space is recommended to meet all future testing needs, given that all testing is consolidated to a single location. This report is a revision to SAND2007-7027 to address DOE comments and add a series of tests to address NWTRB recommendations.

  4. Long-term data storage in diamond.

    PubMed

    Dhomkar, Siddharth; Henshaw, Jacob; Jayakumar, Harishankar; Meriles, Carlos A

    2016-10-01

    The negatively charged nitrogen vacancy (NV(-)) center in diamond is the focus of widespread attention for applications ranging from quantum information processing to nanoscale metrology. Although most work so far has focused on the NV(-) optical and spin properties, control of the charge state promises complementary opportunities. One intriguing possibility is the long-term storage of information, a notion we hereby introduce using NV-rich, type 1b diamond. As a proof of principle, we use multicolor optical microscopy to read, write, and reset arbitrary data sets with two-dimensional (2D) binary bit density comparable to present digital-video-disk (DVD) technology. Leveraging on the singular dynamics of NV(-) ionization, we encode information on different planes of the diamond crystal with no cross-talk, hence extending the storage capacity to three dimensions. Furthermore, we correlate the center's charge state and the nuclear spin polarization of the nitrogen host and show that the latter is robust to a cycle of NV(-) ionization and recharge. In combination with super-resolution microscopy techniques, these observations provide a route toward subdiffraction NV charge control, a regime where the storage capacity could exceed present technologies.

  5. Long-term physiological consequences of pneumonectomy.

    PubMed

    Deslauriers, Jean; Ugalde, Paula; Miro, Santiago; Deslauriers, Deborah R; Ferland, Sylvie; Bergeron, Sébastien; Lacasse, Yves; Provencher, Steeve

    2011-01-01

    Ever since the first successful pneumonectomy for lung cancer was performed in 1933, a number of largely historical reports have attempted to look at the physiological consequences of this operation in order to define patient long-term functional status. The pertinence of these contributions is, however, limited because most were performed in patients who had their pneumonectomy for benign diseases or were carried out in small and heterogeneous populations. Thus, several surgical myths and beliefs such as phrenic nerve interruption at the time of operation might be desirable, marked hyperinflation of the residual lung is associated with reduced lung function, and patients develop pulmonary hypertension over time and have poor exercise tolerance have persisted over the years. Our findings based on a study of 100 patients evaluated 5 or more years after surgery (mean follow-up time, 9.1 ± 2.8 years [5.0-14.7 years]) show that most patients can adjust to living with only one lung and are thus able to live a near-normal life. Although diaphragmatic paralysis is characterized by significant alterations in respiratory function, hyperinflation of the residual lung is beneficial. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Long-term predictions using natural analogues

    SciTech Connect

    Ewing, R.C.

    1995-09-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10{sup 3}-10{sup 5} years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., {open_quotes}natural analogues{close_quotes}) provide perhaps the only means of partial {open_quotes}validation,{close_quotes} as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10{sup 3}-10{sup 8} years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the {open_quotes}validation{close_quotes} of performance assessments.

  7. Long-term corrosion testing plan.

    SciTech Connect

    Wall, Frederick Douglas; Brown, Neil R.

    2009-02-01

    This document describes the testing and facility requirements to support the Yucca Mountain Project long-term corrosion testing program. The purpose of this document is to describe a corrosion testing program that will (a) reduce model uncertainty and variability, (b) reduce the reliance upon overly conservative assumptions, and (c) improve model defensibility. Test matrices were developed for 17 topical areas (tasks): each matrix corresponds to a specific test activity that is a subset of the total work performed in a task. A future document will identify which of these activities are considered to be performance confirmation activities. Detailed matrices are provided for FY08, FY09 and FY10 and rough order estimates are provided for FY11-17. Criteria for the selection of appropriate test facilities were developed through a meeting of Lead Lab and DOE personnel on October 16-17, 2007. These criteria were applied to the testing activities and recommendations were made for the facility types appropriate to carry out each activity. The facility requirements for each activity were assessed and activities were identified that can not be performed with currently available facilities. Based on this assessment, a total of approximately 10,000 square feet of facility space is recommended to accommodate all future testing, given that all testing is consolidated to a single location. This report is a revision to SAND2008-4922 to address DOE comments.

  8. Long-term treatment outcome in acromegaly.

    PubMed

    Holdaway, I M; Rajasoorya, C R; Gamble, G D; Stewart, A W

    2003-08-01

    A number of groups have developed guidelines to indicate whether an individual with acromegaly has been cured by treatment. However, studies to date do not provide a robust definition of biochemical remission of the disorder based on correlation with long-term outcome. Available data suggest that those with a random serum growth hormone (GH) level of <2.5 microg/l, or a glucose-suppressed GH level of <1 microg/l following treatment have mortality figures indistinguishable from the general population. However, the confidence limits for these mortality estimates are quite wide. It remains possible that growth hormone levels lower than 1 microg/l for random samples, or even lower when using ultrasensitive GH assays, may indicate superior outcome, but this remains to be confirmed. There are limited data relating serum insulin-like growth factor-I (IGF-I) levels to outcome, although normalisation of serum IGF-I clearly improves outcome compared with continued elevation of measurements after treatment. Current evidence suggests that a post-treatment random serum GH <2.5 microg/l and a normal serum IGF-I value defines biochemical cure. Available data suggest that achieving similar growth hormone levels after treatment also reduces the prevalence of chronic complications of the disorder, which is subsequently reflected in improved mortality.

  9. Dental hygienists and long-term care.

    PubMed

    Ablah, C R; Pickard, R B

    1998-01-01

    This study examined the willingness of dental hygienists to work in long-term care (LTC) facilities providing oral health care to the elderly. In August 1995, a mail survey of all 839 licensed and practicing dental hygienists in Kansas was conducted. Respondents were asked about their reasons for choosing dental hygiene as a career, perceptions of the adequacy of their education, satisfaction with their work, interest in working with elderly patients, and whether general supervision would influence their willingness to practice in LTC settings. Response rate was 69 percent, with 582 usable questionnaires returned. Data were analyzed using descriptive statistics and chi-square tests of significance. The results showed an overwhelming majority (94 percent) of respondents would be willing to work, at least on occasion, in a LTC facility. However, few were interested in full-time geriatric practice. Those indicating a willingness to practice regularly with the elderly, at least part time, were typically less experienced in their field and more likely to perceive their education as having adequately prepared them to care for older patients. The findings demonstrate dental hygienists' willingness to provide dental care for older adults. To optimize this resource, appropriate education is needed so that students and current practitioners master the distinctive skills necessary to care for this population.

  10. Long-Term Consequences of Neonatal Injury

    PubMed Central

    Beggs, Simon

    2015-01-01

    The maturation of the central nervous system’s (CNS’s) sensory connectivity is driven by modality-specific sensory input in early life. For the somatosensory system, this input is the physical, tactile interaction with the environment. Nociceptive circuitry is functioning at the time of birth; however, there is still considerable organization and refinement of this circuitry that occurs postnatally, before full discrimination of tactile and noxious input is possible. This fine-tuning involves separation of tactile and nociceptive afferent input to the spinal cord’s dorsal horn and the maturation of local and descending inhibitory circuitry. Disruption of that input in early postnatal life (for example, by tissue injury or other noxious stimulus), can have a profound influence on subsequent development, and consequently the mature functioning of pain systems. In this review, the impact of neonatal surgical incision on nociceptive circuitry is discussed in terms of the underlying developmental neurobiology. The changes are complex, occurring at multiple anatomical sites within the CNS, and including both neuronal and glial cell populations. The altered sensory input from neonatal injury selectively modulates neuronal excitability within the spinal cord, disrupts inhibitory control, and primes the immune system, all of which contribute to the adverse long-term consequences of early pain exposure. PMID:26174217

  11. Intermediate- and long-term earthquake prediction.

    PubMed

    Sykes, L R

    1996-04-30

    Progress in long- and intermediate-term earthquake prediction is reviewed emphasizing results from California. Earthquake prediction as a scientific discipline is still in its infancy. Probabilistic estimates that segments of several faults in California will be the sites of large shocks in the next 30 years are now generally accepted and widely used. Several examples are presented of changes in rates of moderate-size earthquakes and seismic moment release on time scales of a few to 30 years that occurred prior to large shocks. A distinction is made between large earthquakes that rupture the entire downdip width of the outer brittle part of the earth's crust and small shocks that do not. Large events occur quasi-periodically in time along a fault segment and happen much more often than predicted from the rates of small shocks along that segment. I am moderately optimistic about improving predictions of large events for time scales of a few to 30 years although little work of that type is currently underway in the United States. Precursory effects, like the changes in stress they reflect, should be examined from a tensorial rather than a scalar perspective. A broad pattern of increased numbers of moderate-size shocks in southern California since 1986 resembles the pattern in the 25 years before the great 1906 earthquake. Since it may be a long-term precursor to a great event on the southern San Andreas fault, that area deserves detailed intensified study.

  12. Intermediate- and long-term earthquake prediction.

    PubMed Central

    Sykes, L R

    1996-01-01

    Progress in long- and intermediate-term earthquake prediction is reviewed emphasizing results from California. Earthquake prediction as a scientific discipline is still in its infancy. Probabilistic estimates that segments of several faults in California will be the sites of large shocks in the next 30 years are now generally accepted and widely used. Several examples are presented of changes in rates of moderate-size earthquakes and seismic moment release on time scales of a few to 30 years that occurred prior to large shocks. A distinction is made between large earthquakes that rupture the entire downdip width of the outer brittle part of the earth's crust and small shocks that do not. Large events occur quasi-periodically in time along a fault segment and happen much more often than predicted from the rates of small shocks along that segment. I am moderately optimistic about improving predictions of large events for time scales of a few to 30 years although little work of that type is currently underway in the United States. Precursory effects, like the changes in stress they reflect, should be examined from a tensorial rather than a scalar perspective. A broad pattern of increased numbers of moderate-size shocks in southern California since 1986 resembles the pattern in the 25 years before the great 1906 earthquake. Since it may be a long-term precursor to a great event on the southern San Andreas fault, that area deserves detailed intensified study. Images Fig. 1 PMID:11607658

  13. Transuranic waste: long-term planning

    SciTech Connect

    Young, K.C.

    1985-07-01

    Societal concerns for the safe handling and disposal of toxic waste are behind many of the regulations and the control measures in effect today. Transuranic waste, a specific category of toxic (radioactive) waste, serves as a good example of how regulations and controls impact changes in waste processing - and vice versa. As problems would arise with waste processing, changes would be instituted. These changes improved techniques for handling and disposal of transuranic waste, reduced the risk of breached containment, and were usually linked with regulatory changes. Today, however, we face a greater public awareness of and concern for toxic waste control; thus, we must anticipate potential problems and work on resolving them before they can become real problems. System safety analyses are valuable aids in long-term planning for operations involving transuranic as well as other toxic materials. Examples of specific system safety analytical methods demonstrate how problems can be anticipated and resolution initiated in a timely manner having minimal impacts upon allocation of resource and operational goals. 7 refs., 1 fig.

  14. The long-term variability of Vega

    NASA Astrophysics Data System (ADS)

    Butkovskaya, V.; Plachinda, S.; Valyavin, G.; Baklanova, D.; Lee, B.-C.

    2011-12-01

    Over the time of 60 years Vega (α Lyrae = HD 172167, A0V) has been generally accepted as a standard star in the near-infrared, optical, and ultraviolet regions. But is the spectrophotometric standard Vega really non-variable star? Researchers give very different answers to this question. We aim to search a periodicity in our results of spectropolarimetric study of Vega, namely periodic variations in equivalent width of the spectral lines and longitudinal magnetic field measurements. High-accuracy spectropolarimetric observations of Vega have been performed during 26 nights from 1997 to 2010 using the Coudé spectrograph of the 2.6-m Shain reflector at the Crimean Astrophysical Observatory (CrAO, Ukraine) and during 4 nights in 2007 and 2008 using the echelle spectrograph BOES at the Bohyunsan Optical Astronomy Observatory (BOAO, South Korea). The long-term (year-to-year) variability of Vega was confirmed. It was concluded that this variability does not have magnetic nature. The paper is dedicated to the memory of V.P. Merezhin.

  15. Economic efficiency, IRPs and long term contracts

    SciTech Connect

    Sutherland, R.J.

    1993-04-30

    There is no market failure that warrants utility regulation of the construction of new generating plants, the supply of energy efficiency or the purchase of fuel under contract. The natural monopoly problem applies to the distribution of electricity and gas, not to generation, energy conservation, or gas purchases. Utility regulation magnifies a market failure, which is the principal agent problem. Regulatory allowance of utilities signing long term fixed price contracts and undertaking conservation measures result in costs and risks being shifted to ratepayers that would not occur under competitive market conditions. Economic efficiency would be enhanced if cost of service regulation of electric and gas utilities were replaced by a competitive market process for the construction of new power plants, utility conservation programs and contracts to purchase fuel. Conservation measures could be supplied by energy service companies. Gas merchants could provide gas and energy conservation directly to ultimate customers, if they had access to LDC pipelines. With a competitive market established to sell gas and energy services, contracts and conservation measures would not require cost-of- service regulation.

  16. Long-Term Soft Denture Lining Materials

    PubMed Central

    Chladek, Grzegorz; Żmudzki, Jarosław; Kasperski, Jacek

    2014-01-01

    Long-term soft denture lining (LTSDL) materials are used to alleviate the trauma associated with wearing complete dentures. Despite their established clinical efficacy, the use of LTSDLs has been limited due to the unfavorable effects of the oral environment on some of their mechanical and performance characteristics. The unresolved issue of LTSDL colonization by Candida albicans is particularly problematic. Silicone-based LTSDL (SLTSDL) materials, which are characterized by more stable hardness, sorption and solubility than acrylic-based LTSDLs (ALTSDLs), are currently the most commonly used LTSDLs. However, SLTSDLs are more prone to debonding from the denture base. Moreover, due to their limitations, the available methods for determining bond strength do not fully reflect the actual stability of these materials under clinical conditions. SLTSDL materials exhibit favorable viscoelastic properties compared with ALTSDLs. Furthermore, all of the lining materials exhibit an aging solution-specific tendency toward discoloration, and the available cleansers are not fully effective and can alter the mechanical properties of LTSDLs. Future studies are needed to improve the microbiological resistance of LTSDLs, as well as some of their performance characteristics. PMID:28788163

  17. Long-term data storage in diamond

    PubMed Central

    Dhomkar, Siddharth; Henshaw, Jacob; Jayakumar, Harishankar; Meriles, Carlos A.

    2016-01-01

    The negatively charged nitrogen vacancy (NV−) center in diamond is the focus of widespread attention for applications ranging from quantum information processing to nanoscale metrology. Although most work so far has focused on the NV− optical and spin properties, control of the charge state promises complementary opportunities. One intriguing possibility is the long-term storage of information, a notion we hereby introduce using NV-rich, type 1b diamond. As a proof of principle, we use multicolor optical microscopy to read, write, and reset arbitrary data sets with two-dimensional (2D) binary bit density comparable to present digital-video-disk (DVD) technology. Leveraging on the singular dynamics of NV− ionization, we encode information on different planes of the diamond crystal with no cross-talk, hence extending the storage capacity to three dimensions. Furthermore, we correlate the center’s charge state and the nuclear spin polarization of the nitrogen host and show that the latter is robust to a cycle of NV− ionization and recharge. In combination with super-resolution microscopy techniques, these observations provide a route toward subdiffraction NV charge control, a regime where the storage capacity could exceed present technologies. PMID:27819045

  18. Long-term potentiation: peeling the onion.

    PubMed

    Nicoll, Roger A; Roche, Katherine W

    2013-11-01

    Since the discovery of long-term potentiation (LTP), thousands of papers have been published on this phenomenon. With this massive amount of information, it is often difficult, especially for someone not directly involved in the field, not to be overwhelmed. The goal of this review is to peel away as many layers as possible, and probe the core properties of LTP. We would argue that the many dozens of proteins that have been implicated in the phenomenon are not essential, but rather modulate, often in indirect ways, the threshold and/or magnitude of LTP. What is required is NMDA receptor activation followed by CaMKII activation. The consequence of CaMKII activation is the rapid recruitment of AMPA receptors to the synapse. This recruitment is independent of AMPA receptor subunit type, but absolutely requires an adequate pool of surface receptors. An important unresolved issue is how exactly CaMKII activation leads to modifications in the PSD to allow rapid enrichment. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.

  19. Neurological long term consequences of deep diving.

    PubMed Central

    Todnem, K; Nyland, H; Skeidsvoll, H; Svihus, R; Rinck, P; Kambestad, B K; Riise, T; Aarli, J A

    1991-01-01

    Forty commercial saturation divers, mean age 34.9 (range 24-49) years, were examined one to seven years after their last deep dive (190-500 metres of seawater). Four had by then lost their divers' licence because of neurological problems. Twenty seven (68%) had been selected by neurological examination and electroencephalography before the deep dives. The control group consisted of 100 men, mean age 34.0 (range 22-48) years. The divers reported significantly more symptoms from the nervous system. Concentration difficulties and paraesthesia in feet and hands were common. They had more abnormal neurological findings by neurological examination compatible with dysfunction in the lumbar spinal cord or roots. They also had a larger proportion of abnormal electroencephalograms than the controls. The neurological symptoms and findings were highly significantly correlated with exposure to deep diving (depth included), but even more significantly correlated to air and saturation diving and prevalence of decompression sickness. Visual evoked potentials, brainstem auditory evoked potentials, and magnetic resonance imaging of the brain did not show more abnormal findings in the divers. Four (10%) divers had had episodes of cerebral dysfunction during or after the dives; two had had seizures, one had had transitory cerebral ischaemia and one had had transitory global amnesia. It is concluded that deep diving may have a long term effect on the nervous system of the divers. PMID:2025592

  20. Long-term in vivo pineal microdialysis.

    PubMed

    Sun, Xing; Liu, Tiecheng; Deng, Jie; Borjigin, Jimo

    2003-09-01

    This study describes the development of a new technique for long-term measurement of daily 5-hydroxytryptamine (5-HT) and melatonin contents in the pineal gland of freely moving rats. The technique features a number of novel improvements over previous protocols. It allows visualization of the pineal gland for accurate targeting of the guide cannula, which minimizes bleeding; incurs no direct injury to the surrounding brain tissues; and causes no interference with the sympathetic innervation from the superior cervical ganglia. Robust releases of melatonin and indole precursors were continuously monitored quantitatively and reproducibly for more than 2 wk in the same animal. In addition, effects of pharmacological agents on in vivo pineal circadian rhythms can be studied reproducibly over time, and gene expression profiles can be correlated with physiological consequences in single animals. Using these approaches, it is found that beta-adrenergic activation leads to decreased release of 5-HT, and that increased cAMP signaling in vivo results in activation of N-acetyltransferase gene induction and melatonin production. These studies will enhance the understanding of signaling pathways that regulate pineal 5-HT and melatonin synthesis and secretion.

  1. [Long-term stability of orthodontic treatment].

    PubMed

    Kuijpers-Jagtman, A M; Al Yami, E A; van 't Hof, M A

    2000-04-01

    Aim of this study was to assess long-term stability of orthodontic treatment in a sample of 1016 patients until 10 years postretention. Treatment outcome was measured with the PAR-index at 6 different stages. The mean age of the patients was 12.0 +/- 3.1 year at the start of treatment to 26.3 +/- 2.9 year 10 years postretention. The results show that 67% of the orthodontic treatment result, as measured with the PAR-index, was maintained 10 years postretention. The PAR-scores for the midline and the open bite remained about the same over the years. However, the scores for the lateral occlusion, overjet, reversed overjet, overbite, and contact point displacement of the upper and lower front teeth increased gradually over time. Nearly 50% of the total relapse took place the first two years after retention. The largest change was found for the position of the lower incisors. Ten years postretention their position was even worse than at the start of treatment.

  2. Legislation on Long-Term Care Insurance. Report No. 11.

    ERIC Educational Resources Information Center

    Wisconsin State Legislative Council, Madison.

    This report presents Wisconsin state legislation on long-term care insurance. Part I summarizes key provisions of six 1987 assembly bills concerned with long-term care insurance. Part II describes activities of the Wisconsin State Legislative Council's Special Committee on Long-Term Health Care Insurance. Part III provides background information…

  3. 3 CFR - Long-Term Gulf Coast Restoration Support Plan

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 3 The President 1 2011-01-01 2011-01-01 false Long-Term Gulf Coast Restoration Support Plan Presidential Documents Other Presidential Documents Memorandum of June 30, 2010 Long-Term Gulf Coast... help the Gulf Coast and its people recover from this tragedy. A long-term plan to restore the unique...

  4. Protein kinase M ζ and the maintenance of long-term memory.

    PubMed

    Zhang, Yang; Zong, Wei; Zhang, Lei; Ma, Yuanye; Wang, Jianhong

    2016-10-01

    Although various molecules have been found to mediate the processes of memory acquisition and consolidation, the molecular mechanism to maintain memory still remains elusive. In recent years, a molecular pathway focusing on protein kinase Mζ (PKMζ) has become of interest to researchers because of its potential role in long-term memory maintenance. PKMζ is an isoform of protein kinase C (PKC) and has a related structure that influences its function in maintaining memory. Considerable evidence has been gathered on PKMζ activity, including loss of function studies using PKMζ inhibitors, such as PKMζ inhibitory peptide (ZIP), suggesting PKMζ plays an important role in long-term memory maintenance. This review provides an overview of the role of PKMζ in long-term memory and outlines the molecular structure of PKMζ, the molecular mechanism of PKMζ in long-term memory maintenance and future directions of PKMζ research. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Temporal dynamics of cerebellar and motor cortex physiological processes during motor skill learning.

    PubMed

    Spampinato, D; Celnik, P

    2017-01-16

    Learning motor tasks involves distinct physiological processes in the cerebellum (CB) and primary motor cortex (M1). Previous studies have shown that motor learning results in at least two important neurophysiological changes: modulation of cerebellar output mediated in-part by long-term depression of parallel fiber-Purkinje cell synapse and induction of long-term plasticity (LTP) in M1, leading to transient occlusion of additional LTP-like plasticity. However, little is known about the temporal dynamics of these two physiological mechanisms during motor skill learning. Here we use non-invasive brain stimulation to explore CB and M1 mechanisms during early and late motor skill learning in humans. We predicted that early skill acquisition would be proportional to cerebellar excitability (CBI) changes, whereas later stages of learning will result in M1 LTP-like plasticity modifications. We found that early, and not late into skill training, CBI changed. Whereas, occlusion of LTP-like plasticity over M1 occurred only during late, but not early training. These findings indicate a distinct temporal dissociation in the physiological role of the CB and M1 when learning a novel skill. Understanding the role and temporal dynamics of different brain regions during motor learning is critical to device optimal interventions to augment learning.

  6. Temporal dynamics of cerebellar and motor cortex physiological processes during motor skill learning

    PubMed Central

    Spampinato, D.; Celnik, P.

    2017-01-01

    Learning motor tasks involves distinct physiological processes in the cerebellum (CB) and primary motor cortex (M1). Previous studies have shown that motor learning results in at least two important neurophysiological changes: modulation of cerebellar output mediated in-part by long-term depression of parallel fiber-Purkinje cell synapse and induction of long-term plasticity (LTP) in M1, leading to transient occlusion of additional LTP-like plasticity. However, little is known about the temporal dynamics of these two physiological mechanisms during motor skill learning. Here we use non-invasive brain stimulation to explore CB and M1 mechanisms during early and late motor skill learning in humans. We predicted that early skill acquisition would be proportional to cerebellar excitability (CBI) changes, whereas later stages of learning will result in M1 LTP-like plasticity modifications. We found that early, and not late into skill training, CBI changed. Whereas, occlusion of LTP-like plasticity over M1 occurred only during late, but not early training. These findings indicate a distinct temporal dissociation in the physiological role of the CB and M1 when learning a novel skill. Understanding the role and temporal dynamics of different brain regions during motor learning is critical to device optimal interventions to augment learning. PMID:28091578

  7. Serotonin induces long-term depression at corticostriatal synapses.

    PubMed

    Mathur, Brian N; Capik, Nicole A; Alvarez, Veronica A; Lovinger, David M

    2011-05-18

    The striatum has important roles in motor control and action learning and, like many brain regions, receives multiple monoaminergic inputs. We have examined serotonergic modulation of rat and mouse corticostriatal neurotransmission and find that serotonin (5-HT) activates 5-HT(1b) receptors resulting in a long-term depression (LTD) of glutamate release and striatal output that we have termed 5-HT-LTD. 5-HT-LTD is presynaptically mediated, cAMP pathway dependent, and inducible by endogenous striatal 5-HT, as revealed by application of a selective 5-HT reuptake inhibitor. 5-HT-LTD is mutually occlusive with dopamine/endocannabinoid-dependent LTD, suggesting that these two forms of LTD act on the same corticostriatal terminals. Thus, serotonergic and dopaminergic mechanisms exist that may interact to persistently sculpt corticostriatal circuits, potentially influencing action learning and striatal-based disorders.

  8. Dopamine controls persistence of long-term memory storage.

    PubMed

    Rossato, Janine I; Bevilaqua, Lia R M; Izquierdo, Iván; Medina, Jorge H; Cammarota, Martín

    2009-08-21

    The paradigmatic feature of long-term memory (LTM) is its persistence. However, little is known about the mechanisms that make some LTMs last longer than others. In rats, a long-lasting fear LTM vanished rapidly when the D1 dopamine receptor antagonist SCH23390 was injected into the dorsal hippocampus 12 hours, but not immediately or 9 hours, after the fearful experience. Conversely, intrahippocampal application of the D1 agonist SK38393 at the same critical post-training time converted a rapidly decaying fear LTM into a persistent one. This effect was mediated by brain-derived neurotrophic factor and regulated by the ventral tegmental area (VTA). Thus, the persistence of LTM depends on activation of VTA/hippocampus dopaminergic connections and can be specifically modulated by manipulating this system at definite post-learning time points.

  9. Notch is required for long-term memory in Drosophila.

    PubMed

    Presente, Asaf; Boyles, Randy S; Serway, Christine N; de Belle, J Steven; Andres, Andrew J

    2004-02-10

    A role for Notch in the elaboration of existing neural processes is emerging that is distinct from the increasingly well understood function of this gene in binary cell-fate decisions. Several research groups, by using a variety of organisms, have shown that Notch is important in the development of neural ultrastructure. Simultaneously, Presenilin (Psn) was identified both as a key mediator of Notch signaling and as a site of genetic lesions that cause early-onset Alzheimer's disease. Here we demonstrate that Notch loss of function produces memory deficits in Drosophila melanogaster. The effects are specific to long-term memory, which is thought to depend on ultrastructural remodeling. We propose that Notch plays an important role in the neural plasticity underlying consolidated memory.

  10. Notch is required for long-term memory in Drosophila

    PubMed Central

    Presente, Asaf; Boyles, Randy S.; Serway, Christine N.; de Belle, J. Steven; Andres, Andrew J.

    2004-01-01

    A role for Notch in the elaboration of existing neural processes is emerging that is distinct from the increasingly well understood function of this gene in binary cell-fate decisions. Several research groups, by using a variety of organisms, have shown that Notch is important in the development of neural ultrastructure. Simultaneously, Presenilin (Psn) was identified both as a key mediator of Notch signaling and as a site of genetic lesions that cause early-onset Alzheimer's disease. Here we demonstrate that Notch loss of function produces memory deficits in Drosophila melanogaster. The effects are specific to long-term memory, which is thought to depend on ultrastructural remodeling. We propose that Notch plays an important role in the neural plasticity underlying consolidated memory. PMID:14752200

  11. Lanthanum-mediated modification of GABAA receptor deactivation, desensitization and inhibitory synaptic currents in rat cerebellar neurons.

    PubMed

    Zhu, W J; Wang, J F; Corsi, L; Vicini, S

    1998-09-15

    1. We investigated La3+ effects on recombinant and native gamma-aminobutyric acid A (GABAA) receptors using rapid agonist applications and on inhibitory synaptic currents (IPSCs) in granule and stellate neurons of rat cerebellar slices. 2. Rapid desensitization of currents elicited by 200 ms pulses of 1 mM GABA to small lifted cells transfected with alpha1beta3gamma2 cDNAs was greatly decreased by the coapplication of 100 microM LaCl3. 3. GABA responses were unaffected when coapplication lasted only 2 ms. In contrast, with LaCl3 pre-perfusion, a significant slowing of deactivation in response to 2 ms applications was observed. LaCl3 pre-perfusion also prolonged the duration of responses to 20 mM taurine. 4. Outside-out patches excised from cells transfected with alpha1beta3gamma2 subunit cDNAs were briefly exposed to a saturating concentration of GABA, eliciting a transient activation of single channel currents with a main conductance of 30 pS. Opening and burst durations increased by pre-equilibration of patches with LaCl3. 5. LaCl3 depressed the peak amplitude without affecting the slow deactivation and desensitization of GABA responses in cells transfected with alpha6beta3gamma2 and alpha6beta3delta cDNAs. No significant difference in La3+ modulation of GABA-gated currents was observed between alpha1beta3gamma2 and alpha1beta3delta receptors. 6. The effects of LaCl3 on deactivation and desensitization of GABA responses observed in nucleated patches excised from rat cerebellar granule and stellate neurons were comparable to those in the cells transfected with alpha1beta3gamma2 cDNAs. In addition, La3+ clearly prolonged the spontaneous IPSC time course without changing the amplitude. 7. Our results indicate that La3+ has a dual action on GABA-gated currents: it decreases desensitization and increases channel opening duration. These actions depend on receptor subunit composition and contribute to the prolongation of IPSCs.

  12. Scientific Understanding from Long Term Observations: Insights from the Long Term Ecological Research (LTER) Program

    NASA Astrophysics Data System (ADS)

    Gosz, J.

    2001-12-01

    The network dedicated to Long Term Ecological Research (LTER) in the United States has grown to 24 sites since it was formed in 1980. Long-term research and monitoring are performed on parameters thatare basic to all ecosystems and are required to understand patterns, processes, and relationship to change. Collectively, the sites in the LTER Network provide opportunities to contrast marine, coastal, and continental regions, the full range of climatic gradients existing in North America, and aquatic and terrestrial habitats in a range of ecosystem types. The combination of common core areas and long-term research and monitoring in many habitats have allowed unprecedented abilities to understand and compare complex temporal and spatial dynamics associated with issues like climate change, effects of pollution, biodiversity and landuse. For example, McMurdo Dry Valley in the Antarctic has demonstrated an increase in glacier mass since 1993 which coincides with a period of cooler than normal summers and more than average snowfall. In contrast, the Bonanza Creek and Toolik Lake sites in Alaska have recorded a warming period unprecedented in the past 200 years. Nitrogen deposition effects have been identified through long-term watershed studies on biogeochemical cycles, especially at Coweeta Hydrological Lab, Harvard Forest, and the Hubbard Brook Experimental Forest. In aquatic systems, such as the Northern Temperate Lakes site, long-term data revealed time lags in effects of invaders and disturbance on lake communities. Biological recovery from an effect such as lake acidification was shown to lag behind chemical recovery. The long-term changes documented over 2 decades have been instrumental in influencing management practices in many of the LTER areas. In Puerto Rico, the Luquillo LTER demonstrated that dams obstruct migrations of fish and freshwater shrimp and water abstraction at low flows can completely obliterate downstream migration of juveniles and damage

  13. The neuronal response at extended timescales: long-term correlations without long-term memory

    PubMed Central

    Soudry, Daniel; Meir, Ron

    2014-01-01

    Long term temporal correlations frequently appear at many levels of neural activity. We show that when such correlations appear in isolated neurons, they indicate the existence of slow underlying processes and lead to explicit conditions on the dynamics of these processes. Moreover, although these slow processes can potentially store information for long times, we demonstrate that this does not imply that the neuron possesses a long memory of its input, even if these processes are bidirectionally coupled with neuronal response. We derive these results for a broad class of biophysical neuron models, and then fit a specific model to recent experiments. The model reproduces the experimental results, exhibiting long term (days-long) correlations due to the interaction between slow variables and internal fluctuations. However, its memory of the input decays on a timescale of minutes. We suggest experiments to test these predictions directly. PMID:24744724

  14. The interaction between cell adhesion molecule L1, matrix metalloproteinase 14, and adenine nucleotide translocator at the plasma membrane regulates L1-mediated neurite outgrowth of murine cerebellar neurons.

    PubMed

    Loers, Gabriele; Makhina, Tatjana; Bork, Ute; Dörner, Andrea; Schachner, Melitta; Kleene, Ralf

    2012-03-14

    We have identified the adenine nucleotide translocator (ANT) isoforms ANT1 and ANT2 that are present in the plasma membrane of mouse cerebellar neurons as novel binding partners of the cell adhesion molecule L1. The direct interaction between ANT and L1 is mediated by sites within the fibronectin type III domains of L1 and the first and third extracellular loops of the ANT proteins. We also show that L1 interacts with the ANT binding partner matrix metalloprotease 14 (MMP14) and that the ANT proteins bind directly to the L1 interaction partner glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Moreover, we provide evidence that the functional interplay between L1, ANT proteins, MMP14, and GAPDH at the plasma membrane mediates L1-induced neurite outgrowth of cerebellar neurons. Disruption of this interplay by ANT inhibitors, ANT-derived synthetic peptides, and/or function-blocking MMP14 and ANT antibodies leads to alterations in L1-dependent neurite outgrowth. Stimulation of L1-mediated signaling in cerebellar neurons triggers transient ATP secretion via ANT proteins and leads to transient src family-dependent tyrosine phosphorylation of L1, ANT1, ANT2, and MMP14. Thus, our results indicate that plasma membrane-localized ANT1 and ANT2 regulate L1-mediated neurite outgrowth in conjunction with MMP14.

  15. α6-Containing GABAA Receptors Are the Principal Mediators of Inhibitory Synapse Strengthening by Insulin in Cerebellar Granule Cells.

    PubMed

    Accardi, Michael V; Brown, Patricia M G E; Miraucourt, Loïs S; Orser, Beverley A; Bowie, Derek

    2015-07-01

    Activity-dependent strengthening of central synapses is a key factor driving neuronal circuit behavior in the vertebrate CNS. At fast inhibitory synapses, strengthening is thought to occur by increasing the number of GABAA receptors (GABARs) of the same subunit composition to preexisting synapses. Here, we show that strengthening of mouse cerebellar granule cell GABAergic synapses occurs by a different mechanism. Specifically, we show that the neuropeptide hormone, insulin, strengthens inhibitory synapses by recruiting α6-containing GABARs rather than accumulating more α1-containing receptors that are resident to the synapse. Because α6-receptors are targeted to functionally distinct postsynaptic sites from α1-receptors, we conclude that only a subset of all inhibitory synapses are strengthened. Together with our recent findings on stellate cells, we propose a general mechanism by which mature inhibitory synapses are strengthened. In this scenario, α1-GABARs resident to inhibitory synapses form the hardwiring of neuronal circuits with receptors of a different composition fulfilling a fundamental, but unappreciated, role in synapse strengthening. Copyright © 2015 the authors 0270-6474/15/359676-13$15.00/0.

  16. Modeling Maintenance of Long-Term Potentiation in Clustered Synapses: Long-Term Memory without Bistability

    PubMed Central

    Smolen, Paul

    2015-01-01

    Memories are stored, at least partly, as patterns of strong synapses. Given molecular turnover, how can synapses maintain strong for the years that memories can persist? Some models postulate that biochemical bistability maintains strong synapses. However, bistability should give a bimodal distribution of synaptic strength or weight, whereas current data show unimodal distributions for weights and for a correlated variable, dendritic spine volume. Thus it is important for models to simulate both unimodal distributions and long-term memory persistence. Here a model is developed that connects ongoing, competing processes of synaptic growth and weakening to stochastic processes of receptor insertion and removal in dendritic spines. The model simulates long-term (>1 yr) persistence of groups of strong synapses. A unimodal weight distribution results. For stability of this distribution it proved essential to incorporate resource competition between synapses organized into small clusters. With competition, these clusters are stable for years. These simulations concur with recent data to support the “clustered plasticity hypothesis” which suggests clusters, rather than single synaptic contacts, may be a fundamental unit for storage of long-term memory. The model makes empirical predictions and may provide a framework to investigate mechanisms maintaining the balance between synaptic plasticity and stability of memory. PMID:25945261

  17. Modeling maintenance of long-term potentiation in clustered synapses: long-term memory without bistability.

    PubMed

    Smolen, Paul

    2015-01-01

    Memories are stored, at least partly, as patterns of strong synapses. Given molecular turnover, how can synapses maintain strong for the years that memories can persist? Some models postulate that biochemical bistability maintains strong synapses. However, bistability should give a bimodal distribution of synaptic strength or weight, whereas current data show unimodal distributions for weights and for a correlated variable, dendritic spine volume. Thus it is important for models to simulate both unimodal distributions and long-term memory persistence. Here a model is developed that connects ongoing, competing processes of synaptic growth and weakening to stochastic processes of receptor insertion and removal in dendritic spines. The model simulates long-term (>1 yr) persistence of groups of strong synapses. A unimodal weight distribution results. For stability of this distribution it proved essential to incorporate resource competition between synapses organized into small clusters. With competition, these clusters are stable for years. These simulations concur with recent data to support the "clustered plasticity hypothesis" which suggests clusters, rather than single synaptic contacts, may be a fundamental unit for storage of long-term memory. The model makes empirical predictions and may provide a framework to investigate mechanisms maintaining the balance between synaptic plasticity and stability of memory.

  18. A security/safety survey of long term care facilities.

    PubMed

    Acorn, Jonathan R

    2010-01-01

    What are the major security/safety problems of long term care facilities? What steps are being taken by some facilities to mitigate such problems? Answers to these questions can be found in a survey of IAHSS members involved in long term care security conducted for the IAHSS Long Term Care Security Task Force. The survey, the author points out, focuses primarily on long term care facilities operated by hospitals and health systems. However, he believes, it does accurately reflect the security problems most long term facilities face, and presents valuable information on security systems and practices which should be also considered by independent and chain operated facilities.

  19. LONG TERM IN SITU DISPOSAL ENGINEERING STUDY

    SciTech Connect

    ADAMS; CARLSON; BROCKMAN

    2003-07-23

    Patent application pulled per Ken Norris (FH General Counsel). The objective of this study is to devise methods, produce conceptual designs, examine and select alternatives, and estimate costs for the demonstration of long-term (300-year) in situ disposal of an existing waste disposal site. The demonstration site selected is the 216-A-24 Crib near the 200 East Area. The site contains a fission product inventory and has experienced plant, animal, and inadvertent than intrusion. Of the potential intrusive events and transport pathways at the site, potential human intrusion has been given primary consideration in barrier design. Intrusion by wind, plants, and animals has been given secondary consideration. Groundwater modeling for a number of barrier configurations has been carried out to help select a barrier that will minimize water infiltration and waste/water contact time. The estimated effective lifetime and cost of 20 barrier schemes, using a variety of materials, have been evaluated. The schemes studied include single component surface barriers, multicomponent barriers, and massively injected grout barriers. Five barriers with high estimated effective lifetimes and relatively low costs have been selected for detailed evaluation. They are basalt riprap barriers, massive soil barriers, salt basin barriers, multi-component fine/coarse barriers, and cemented basalt barriers. A variety of materials and configurations for marking the site have also been considered. A decision analysis was completed to select a barrier scheme for demonstration. The analysis indicated that the basalt riprap alternative would be the preferred choice for a full-scale demonstration. The recommended approach is to demonstrate the basalt riprap barrier at the 216-A-24 Crib as soon as possible. Methods and costs of assessing effectiveness of the demonstration are also described. Preliminary design modifications and costs for applying the five selected barrier schemes to other site types are

  20. Long-term Behavior of DNAPL Residuals

    NASA Astrophysics Data System (ADS)

    Liu, Y.; Illangasekare, T.; Kitanidis, P. K.

    2012-12-01

    Understanding and being able to predict the long-term behavior of DNAPL (i.e., TCE) residuals in the source zone are significant in the evaluation of plume spreading. We apply both theoretical analysis and pore-scale simulations to investigate the mass transfer and the effect of reductive dechlorination, in which the contaminant behaves as electron acceptor. At the upfront of the source zone, where the boundary layer has not fully developed, the mass transfer increases as a power-law function of the Peclet number, and is enhanced by biodegradation. These results are consistent with past findings. Under certain conditions, further downstream inside the source zone, the rate of dissolution is slower due to the diluted mass from upstream. Widely applied first-order biodegradation implicitly assumes that the reaction solely depends on the concentration of the contaminant. However, in the slow dilution region, the limitation of electron donor on biodegradation is not negligible. For the reaction between an electron donor and an electron acceptor with intrinsic second-order kinetics, the late-time bio-reaction demonstrates a first-order decay macroscopically with respect to the mass of electron donor, not with respect to that of the contaminant. The late-time decay rate only depends on the intrinsic rate and the solubility of the contaminant. During the intermediate time, affecting by both the concentrations of electron donor and electron acceptor, the first-order decay is not valid. We show that the electron donor decays as exp(-t^2), instead of exp(-t). Moreover, the intermediate-time decay rate is a function of the spatial distribution of DNAPL residuals and the initial conditions.he relationship of the Sherwood number and Peclet number (Comparison of pore-scale simulations and best-fitting curve) he decay of electron donor as a function of t^2

  1. Long term cultivation of larger benthic Foraminifera

    NASA Astrophysics Data System (ADS)

    Wöger, Julia; Eder, Wolfgang; Kinoshita, Shunichi; Antonino, Briguglio; Carles, Ferrandes-Cañadell; Hohenegger, Johann

    2015-04-01

    Benthic Foraminifera are used in a variety of applications employing numerous different methods, i.e. ecological monitoring, studying the effects of ocean acidification, reconstructing palaeo-bathymetry or investigating palaeo-salinity and palaeo-temperature to name only a few. To refine our understanding of ecological influences on larger benthic foraminiferal biology and to review inferences from field observations, culture experiments have become an indispensable tool. While culture experiments on smaller benthic foraminifera have become increasingly frequent in the past century, reports of the cultivation of symbiont bearing larger Foraminifera are rare. Generally, cultivation experiments can be divided into two groups: Culturing of populations and cultivation of single specimens allowing individual investigation. The latter differ form the former by several restrictions resulting from the need to limit individual motility without abridging microenvironmental conditions in the Foraminiferans artificial habitat, necessary to enable the individual to development as unfettered as possible. In this study we present first experiences and preliminary results of the long-term cultivation of larger benthic Foraminifera conducted at the 'Tropical Biosphere Research Station Sesoko Island, University of the Ryukyus', Japan, trying to reproduce natural conditions as closely as possible. Individuals of three species of larger benthic Foraminifera (Heterostegina depressa, Palaeonummulites venosus and Operculina complanata) have been cultured since April 2014. At the time of the general assembly the cultivation experiments will have been going on for more than one year, with the aim to investigate growth rates, longevities and reproduction strategies for comparison with results statistically inferred from application of the of the 'natural laboratory' method. The most important factor influencing foraminiferal health and development was found to be light intensity and light

  2. A molecular brake controls the magnitude of long-term potentiation.

    PubMed

    Wang, Yubin; Zhu, Guoqi; Briz, Victor; Hsu, Yu-Tien; Bi, Xiaoning; Baudry, Michel

    2014-01-01

    Overexpression of suprachiasmatic nucleus circadian oscillatory protein (SCOP), a negative ERK regulator, blocks long-term memory encoding. Inhibition of calpain-mediated SCOP degradation also prevents the formation of long-term memory, suggesting rapid SCOP breakdown is necessary for memory encoding. However, whether SCOP levels also control the magnitude of long-term synaptic plasticity is unknown. Here we show that following synaptic activity-induced SCOP degradation, SCOP is rapidly replaced via mTOR-mediated protein synthesis. We further show that early SCOP degradation is specifically catalysed by μ-calpain, whereas late SCOP resynthesis is mediated by m-calpain. We propose that μ-calpain promotes long-term potentiation induction by degrading SCOP and activating ERK, whereas m-calpain activation limits the magnitude of potentiation by terminating the ERK response via enhanced SCOP synthesis. This unique braking mechanism could account for the advantages of spaced versus massed training in the formation of long-term memory.

  3. The inferior olive is essential for long-term maintenance of a simple motor skill.

    PubMed

    Chen, Xiang Yang; Wang, Yu; Chen, Yi; Chen, Lu; Wolpaw, Jonathan R

    2016-10-01

    The inferior olive (IO) is essential for operant down-conditioning of the rat soleus H-reflex, a simple motor skill. To evaluate the role of the IO in long-term maintenance of this skill, the H-reflex was down-conditioned over 50 days, the IO was chemically ablated, and down-conditioning continued for up to 102 more days. H-reflex size just before IO ablation averaged 62(±2 SE)% of its initial value (P < 0.001 vs. initial). After IO ablation, H-reflex size rose to 75-80% over ∼10 days, remained there for ∼30 days, rose over 10 days to above its initial value, and averaged 140(±14)% for the final 10 days of study (P < 0.01 vs. initial). This two-stage loss of down-conditioning maintenance correlated with IO neuronal loss (r = 0.75, P < 0.01) and was similar to the loss of down-conditioning that follows ablation of the cerebellar output nuclei dentate and interpositus. In control (i.e., unconditioned) rats, IO ablation has no long-term effect on H-reflex size. These results indicate that the IO is essential for long-term maintenance of a down-conditioned H-reflex. With previous data, they support the hypothesis that IO and cortical inputs to cerebellum combine to produce cerebellar plasticity that produces sensorimotor cortex plasticity that produces spinal cord plasticity that produces the smaller H-reflex. H-reflex down-conditioning appears to depend on a hierarchy of plasticity that may be guided by the IO and begin in the cerebellum. Similar hierarchies may underlie other motor learning.

  4. The inferior olive is essential for long-term maintenance of a simple motor skill

    PubMed Central

    Wang, Yu; Chen, Yi; Chen, Lu; Wolpaw, Jonathan R.

    2016-01-01

    The inferior olive (IO) is essential for operant down-conditioning of the rat soleus H-reflex, a simple motor skill. To evaluate the role of the IO in long-term maintenance of this skill, the H-reflex was down-conditioned over 50 days, the IO was chemically ablated, and down-conditioning continued for up to 102 more days. H-reflex size just before IO ablation averaged 62(±2 SE)% of its initial value (P < 0.001 vs. initial). After IO ablation, H-reflex size rose to 75–80% over ∼10 days, remained there for ∼30 days, rose over 10 days to above its initial value, and averaged 140(±14)% for the final 10 days of study (P < 0.01 vs. initial). This two-stage loss of down-conditioning maintenance correlated with IO neuronal loss (r = 0.75, P < 0.01) and was similar to the loss of down-conditioning that follows ablation of the cerebellar output nuclei dentate and interpositus. In control (i.e., unconditioned) rats, IO ablation has no long-term effect on H-reflex size. These results indicate that the IO is essential for long-term maintenance of a down-conditioned H-reflex. With previous data, they support the hypothesis that IO and cortical inputs to cerebellum combine to produce cerebellar plasticity that produces sensorimotor cortex plasticity that produces spinal cord plasticity that produces the smaller H-reflex. H-reflex down-conditioning appears to depend on a hierarchy of plasticity that may be guided by the IO and begin in the cerebellum. Similar hierarchies may underlie other motor learning. PMID:27535367

  5. Long term effects of oral contraception.

    PubMed

    Koetsawang, S; Chiemprasert, T; Premyodhin, M

    1972-01-01

    This study attempts to assess the long-term effects of oral contraceptives on Asian women. At the Family Planning Clinic, Siniray Hospital, Thailand, 181 of the more than 800 women who had used oral contraceptives for more than 4 years prior to May 31, 1971, were studied. All had completed premedical examinations before beginning the drugs. In addition to being studied for changes in body weight, blood pressure, hematocrit, liver function, thyroid function, oral glucose tolerance, and blood urea nitrogen, they were interviewed on their experience with oral contraception. Most were between ages 25-29 years, had only primary education, were housewives, and more than half were in the lower income group. Living children ranged from 1 to 10 with 52.5% having 4 or more. They had been started on a variety or oral contraceptives but in the last 2 years all were given Ovral (norgestrel .5 mg with ethinyl estradiol .05 mg). A total of 10,830 cycles were recorded. Only 9 requested anotehr method. Culdoscopic tubal sterilization was done on 6 and 3 discontinued because they wanted to get pregnant. All had heard rumors of adverse effects but few believed them because 89.3% had no adverse effects. 81.2% said they were in better physical and mental condition because of absence of pregnancy and a majority reported better socioeconomic status. Neurotic complaints were noted in 6.1%. Libido was unchanged in a majority, decreased in a few, but rarely increased. Weight gain of 2.5 kg or more was present in 68%. Slight increase in blood pressure was noted in 17.1%, mostly in those starting with increased pressure. Hematocrit values changed only slightly may have been due to other causes. Liver function tests showed prolonged bromsulphthalein retention in a considerable number. Thyroid function tests were normal except for increased TBG level in 17.8%. Carbohydrate metabolism remained normal in all but a few. Pretreatment glucose tolerance tests not been recorded. Normal findings were

  6. LOP- LONG-TERM ORBIT PREDICTOR

    NASA Technical Reports Server (NTRS)

    Kwok, J. H.

    1994-01-01

    The Long-Term Orbit Predictor (LOP) trajectory propagation program is a useful tool in lifetime analysis of orbiting spacecraft. LOP is suitable for studying planetary orbit missions with reconnaissance (flyby) and exploratory (mapping) trajectories. Sample data is included for a geosynchronous station drift cycle study, a Venus radar mapping strategy, a frozen orbit about Mars, and a repeat ground trace orbit. LOP uses the variation-of-parameters method in formulating the equations of motion. Terms involving the mean anomaly are removed from numerical integrations so that large step sizes, on the order of days, are possible. Consequently, LOP executes much faster than programs based on Cowell's method, such as the companion program ASAP (the Artificial Satellite Analysis Program, NPO-17522, also available through COSMIC). The program uses a force model with a gravity field of up to 21 by 21, lunisolar perturbation, drag, and solar radiation pressure. The input includes classical orbital elements (either mean or oscillating), orbital elements of the sun relative to the planet, reference time and dates, drag coefficients, gravitational constants, planet radius, rotation rate. The printed output contains the classical elements for each time step or event step, and additional orbital data such as true anomaly, eccentric anomaly, latitude, longitude, periapsis altitude, and the rate of change per day of certain elements. Selected output is additionally written to a plot file for postprocessing by the user. LOP is written in FORTRAN 77 for bat