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Sample records for oligomers impair long-term

  1. Impaired Right Ventricular Function in Long-Term Lymphoma Survivors.

    PubMed

    Murbraech, Klaus; Holte, Espen; Broch, Kaspar; Smeland, Knut B; Holte, Harald; Rösner, Assami; Lund, May Brit; Dalen, Håvard; Kiserud, Cecilie; Aakhus, Svend

    2016-06-01

    Cardiotoxicity from anthracyclines or cardiac radiation therapy is detrimental to left ventricular (LV) function. However, the long-term effects on right ventricular (RV) performance are largely unknown. The aim of this study was to investigate the long-term impact of cardiotoxic treatment on RV function among adult cancer survivors. Adult lymphoma survivors (LSs) who underwent autologous hematopoietic stem cell transplantation in Norway from 1987 to 2008 were invited to undergo cardiovascular evaluation by echocardiography and cardiopulmonary exercise testing. In total, 274 LSs participated. The mean age was 56 ± 12 years, and the mean follow-up time since lymphoma diagnosis was 13 ± 6 years. Echocardiographic parameters were compared with those of age- and gender-matched control subjects from an existing large Norwegian database. RV systolic dysfunction was indicated by two or more abnormal RV systolic parameters according to current recommendations. LV systolic dysfunction was indicated by LV global longitudinal strain > -17%. All parameters of RV systolic function were impaired in LSs compared with control subjects (P < .01 for all). The most pronounced difference was observed for tricuspid annular plane systolic excursion: 22.9 ± 4.1 versus 27.1 ± 4.2 mm. Greater cardiotoxic treatment burden was associated with larger RV functional impairment. Tricuspid annular plane systolic excursion correlated with peak oxygen consumption (r = 0.23, P = .001). RV systolic performance was associated with LV systolic function (r = 0.49, P < .001 for tricuspid annular plane systolic excursion vs LV global longitudinal strain), but a greater proportion of patients had LV dysfunction (30.8%) compared with RV dysfunction (6.2%) (P < .001). RV systolic function was impaired in LSs. The association between RV and LV function indicates a global, long-term cardiotoxic effect. However, RV dysfunction was less prevalent than LV dysfunction. Copyright

  2. Long-Term Cognitive Impairment in Kleine-Levin Syndrome

    PubMed Central

    Uguccioni, Ginevra; Lavault, Sophie; Chaumereuil, Charlotte; Golmard, Jean-Louis; Gagnon, Jean-François; Arnulf, Isabelle

    2016-01-01

    Study Objectives: In Kleine-Levin syndrome (KLS), episodes of hypersomnia, cognitive, and behavioral disturbances alternate with asymptomatic periods. Because 50% of patients report decreased academic performances, we evaluated their cognitive status during asymptomatic periods, determinants of deficits, and changes during follow-up. Methods: The cognitive assessment during asymptomatic periods in all consecutive patients with typical KLS and healthy controls included the non-verbal intelligence quotient (Raven Progressive Matrices), the Trail Making Test, the Stroop Color-Word Test, the Wechsler Memory Test, verbal fluencies, the Free and Cued Learning Memory Test, and the Rey-Osterreith Complex Figure. Cognitive status was reevaluated after 0.5 to 2 y in 44 patients. Results: At baseline, compared with the 42 controls, the 122 patients with KLS exhibited lower non-verbal intelligence quotient, speed of processing, attention, and reduced retrieval strategies in episodic memory. Higher episode frequency, shorter episode duration, shorter time since last episode, deeper sleep, and megaphagia during episodes predicted impaired memory. The visuoconstructional abilities and non-verbal memory were intact. After a mean follow-up of 1.7 ± 1.0 y, the episode frequency decreased from 4.6 ± 4.8 to 1.7 ± 1.9/y. The logical reasoning and attention improved, the processing speed remained low, and the retrieval strategies in verbal memory further worsened. Conclusions: In this field study, one-third of patients with KLS have long-term cognitive deficits affecting retrieval and processing speed. Cognitive function should be systematically tested in patients with KLS, which appears important to help patients in their academic studies. Citation: Uguccioni G, Lavault S, Chaumereuil C, Golmard JL, Gagnon JF, Arnulf I. Long-term cognitive impairment in kleine-levin syndrome. SLEEP 2016;39(2):429–438. PMID:26414895

  3. Long-Term Cognitive Impairment in Kleine-Levin Syndrome.

    PubMed

    Uguccioni, Ginevra; Lavault, Sophie; Chaumereuil, Charlotte; Golmard, Jean-Louis; Gagnon, Jean-François; Arnulf, Isabelle

    2016-02-01

    In Kleine-Levin syndrome (KLS), episodes of hypersomnia, cognitive, and behavioral disturbances alternate with asymptomatic periods. Because 50% of patients report decreased academic performances, we evaluated their cognitive status during asymptomatic periods, determinants of deficits, and changes during follow-up. The cognitive assessment during asymptomatic periods in all consecutive patients with typical KLS and healthy controls included the non-verbal intelligence quotient (Raven Progressive Matrices), the Trail Making Test, the Stroop Color-Word Test, the Wechsler Memory Test, verbal fluencies, the Free and Cued Learning Memory Test, and the Rey-Osterreith Complex Figure. Cognitive status was reevaluated after 0.5 to 2 y in 44 patients. At baseline, compared with the 42 controls, the 122 patients with KLS exhibited lower non-verbal intelligence quotient, speed of processing, attention, and reduced retrieval strategies in episodic memory. Higher episode frequency, shorter episode duration, shorter time since last episode, deeper sleep, and megaphagia during episodes predicted impaired memory. The visuoconstructional abilities and non-verbal memory were intact. After a mean follow-up of 1.7 ± 1.0 y, the episode frequency decreased from 4.6 ± 4.8 to 1.7 ± 1.9/y. The logical reasoning and attention improved, the processing speed remained low, and the retrieval strategies in verbal memory further worsened. In this field study, one-third of patients with KLS have long-term cognitive deficits affecting retrieval and processing speed. Cognitive function should be systematically tested in patients with KLS, which appears important to help patients in their academic studies. © 2016 Associated Professional Sleep Societies, LLC.

  4. Dopaminergic neurotransmission dysfunction induced by amyloid-β transforms cortical long-term potentiation into long-term depression and produces memory impairment.

    PubMed

    Moreno-Castilla, Perla; Rodriguez-Duran, Luis F; Guzman-Ramos, Kioko; Barcenas-Femat, Alejandro; Escobar, Martha L; Bermudez-Rattoni, Federico

    2016-05-01

    Alzheimer's disease (AD) is a neurodegenerative condition manifested by synaptic dysfunction and memory loss, but the mechanisms underlying synaptic failure are not entirely understood. Although dopamine is a key modulator of synaptic plasticity, dopaminergic neurotransmission dysfunction in AD has mostly been associated to noncognitive symptoms. Thus, we aimed to study the relationship between dopaminergic neurotransmission and synaptic plasticity in AD models. We used a transgenic model of AD (triple-transgenic mouse model of AD) and the administration of exogenous amyloid-β (Aβ) oligomers into wild type mice. We found that Aβ decreased cortical dopamine levels and converted in vivo long-term potentiation (LTP) into long-term depression (LTD) after high-frequency stimulation delivered at basolateral amygdaloid nucleus-insular cortex projection, which led to impaired recognition memory. Remarkably, increasing cortical dopamine and norepinephrine levels rescued both high-frequency stimulation -induced LTP and memory, whereas depletion of catecholaminergic levels mimicked the Aβ-induced shift from LTP to LTD. Our results suggest that Aβ-induced dopamine depletion is a core mechanism underlying the early synaptopathy and memory alterations observed in AD models and acts by modifying the threshold for the induction of cortical LTP and/or LTD. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. N-Terminal pyroglutamate formation of Aβ38 and Aβ40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation.

    PubMed

    Schlenzig, Dagmar; Rönicke, Raik; Cynis, Holger; Ludwig, Hans-Henning; Scheel, Eike; Reymann, Klaus; Saido, Takaomi; Hause, Gerd; Schilling, Stephan; Demuth, Hans-Ulrich

    2012-06-01

    Pyroglutamate (pGlu)-modified amyloid peptides have been identified in sporadic and familial forms of Alzheimer's disease (AD) and the inherited disorders familial British and Danish Dementia (FBD and FDD). In this study, we characterized the aggregation of amyloid-β protein Aβ37, Aβ38, Aβ40, Aβ42 and ADan species in vitro, which were modified by N-terminal pGlu (pGlu-Aβ3-x, pGlu-ADan) or possess the intact N-terminus (Aβ1-x, ADan). The pGlu-modification confers rapid formation of oligomers and short fibrillar aggregates. In accordance with these observations, the pGlu-modified Aβ38, Αβ40 and Αβ42 species inhibit hippocampal long term potentiation of synaptic response, but pGlu-Aβ3-42 showing the highest effect. Among the unmodified Aβ peptides, only Aβ1-42 exhibites such propensity, which was similar to pGlu-Aβ3-38 and pGlu-Aβ3-40. Likewise, the amyloidogenic peptide pGlu-ADan impaired synaptic potentiation more pronounced than N-terminal unmodified ADan. The results were validated using conditioned media from cultivated HEK293 cells, which express APP variants favoring the formation of Aβ1-x, Aβ3-x or N-truncated pGlu-Aβ3-x species. Hence, we show that the ability of different amyloid peptides to impair synaptic function apparently correlates to their potential to form oligomers as a common mechanism. The pGlu-modification is apparently mediating a higher surface hydrophobicity, as shown by 1-anilinonaphtalene-8-sulfonate fluorescence, which enforces potential to interfere with neuronal physiology.

  6. Post-learning REM sleep deprivation impairs long-term memory: reversal by acute nicotine treatment.

    PubMed

    Aleisa, A M; Alzoubi, K H; Alkadhi, K A

    2011-07-15

    Rapid eye movement sleep deprivation (REM-SD) is associated with spatial learning and memory impairment. During REM-SD, an increase in nicotine consumption among habitual smokers and initiation of tobacco use by non-smokers have been reported. We have shown recently that nicotine treatment prevented learning and memory impairments associated with REM-SD. We now report the interactive effects of post-learning REM-SD and/or nicotine. The animals were first trained on the radial arm water maze (RAWM) task, then they were REM-sleep deprived using the modified multiple platform paradigm for 24h. During REM-SD period, the rats were injected with saline or nicotine (1mg/kg s.c. every 12h: a total of 3 injections). The animals were tested for long-term memory in the RAWM at the end of the REM-SD period. The 24h post-learning REM-SD significantly impaired long-term memory. However, nicotine treatment reversed the post-learning REM-SD-induced impairment of long-term memory. On the other hand, post-learning treatment of normal rats with nicotine for 24h enhanced long-term memory. These results indicate that post-learning acute nicotine treatment prevented the deleterious effect of REM-SD on cognitive abilities.

  7. 40 CFR 51.306 - Long-term strategy requirements for reasonably attributable visibility impairment.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... every 3 years until the date of submission of the State's first plan addressing regional haze visibility... and regional haze visibility impairment, and the State must submit the first such coordinated long... first regional haze plan. In addition, the plan must provide for review of the long-term strategy as...

  8. Long-term reproductive impairment in a seabird after the Prestige oil spill.

    PubMed

    Barros, Alvaro; Alvarez, David; Velando, Alberto

    2014-01-01

    Large oil spills are dramatic perturbations on marine ecosystems, and seabirds are one of the worst affected organisms in such events. It has been argued that oil spills may have important long-term consequences on marine organisms, but supporting evidence remains scarce. The European shag (Phalacrocorax aristotelis) was strongly impacted at population level by the Prestige oil spill, the biggest spillage in the eastern North Atlantic. In this paper, we report on the long-term consequences on reproduction of this coastal seabird, using temporal and spatial replicated data (before-after-control-impact design). Our study revealed long-term reproductive impairment during at least the first 10 years since the Prestige oil spill. Annual reproductive success did not differ before the impact, but after the impact it was reduced by 45% in oiled colonies compared with unoiled ones. This is a rare documentation of long-term effects after a major oil spill, highlighting the need for long-term monitoring in order to assess the real impact of this type of disturbance on marine organisms.

  9. Long-term reproductive impairment in a seabird after the Prestige oil spill

    PubMed Central

    Barros, Álvaro; Álvarez, David; Velando, Alberto

    2014-01-01

    Large oil spills are dramatic perturbations on marine ecosystems, and seabirds are one of the worst affected organisms in such events. It has been argued that oil spills may have important long-term consequences on marine organisms, but supporting evidence remains scarce. The European shag (Phalacrocorax aristotelis) was strongly impacted at population level by the Prestige oil spill, the biggest spillage in the eastern North Atlantic. In this paper, we report on the long-term consequences on reproduction of this coastal seabird, using temporal and spatial replicated data (before–after–control–impact design). Our study revealed long-term reproductive impairment during at least the first 10 years since the Prestige oil spill. Annual reproductive success did not differ before the impact, but after the impact it was reduced by 45% in oiled colonies compared with unoiled ones. This is a rare documentation of long-term effects after a major oil spill, highlighting the need for long-term monitoring in order to assess the real impact of this type of disturbance on marine organisms. PMID:24789139

  10. Stress administered prior to encoding impairs neutral but enhances emotional long-term episodic memories.

    PubMed

    Payne, Jessica D; Jackson, Eric D; Hoscheidt, Siobhan; Ryan, Lee; Jacobs, W Jake; Nadel, Lynn

    2007-12-01

    Stressful events frequently comprise both neutral and emotionally arousing information, yet the impact of stress on emotional and neutral events is still not fully understood. The hippocampus and frontal cortex have dense concentrations of receptors for stress hormones, such as cortisol, which at high levels can impair performance on hippocampally dependent memory tasks. Yet, the same stress hormones can facilitate memory for emotional information, which involves interactions between the hippocampus and amygdala. Here, we induced psychosocial stress prior to encoding and examined its long-term effects on memory for emotional and neutral episodes. The stress manipulation disrupted long-term memory for a neutral episode, but facilitated long-term memory for an equivalent emotional episode compared with a control condition. The stress manipulation also increased salivary cortisol, catecholamines as indicated by the presence of alpha-amylase, heart rate, and subjectively reported stress. Stressed subjects reported more false memories than nonstressed control subjects, and these false memories correlated positively with cortisol levels, providing evidence for a relationship between stress and false memory formation. Our results demonstrate that stress, when administered prior to encoding, produces different patterns of long-term remembering for neutral and emotional episodes. These differences likely emerge from differential actions of stress hormones on memory-relevant regions of the brain.

  11. The Association of Reamed Intramedullary Nailing and Long-Term Cognitive Impairment

    PubMed Central

    Richards, Justin E; Guillamondegui, Oscar D; Archer, Kristin R; Jackson, James C; Ely, E Wesley; Obremskey, William T

    2013-01-01

    Objectives To examine the association of reamed intramedullary nailing (IMN) and long-term cognitive impairment in trauma intensive care unit (TICU) survivors. Design Prospective observational cohort. Setting Academic Level-1 Trauma Center. Patients 173 patients with multiple trauma (Injury Severity Score (ISS) >15) who presented to a Level I TICU from July 2006 to July 2007 without evidence of intrancranial hemorrhage (ICH) Intervention None Main Outcome Measure Twelve-month cognitive impairment defined a priori as 2 neuropsychological test scores 1.5 SD below the mean or 1 neuropsychological test score 2 SD below the mean. Results 108/173 patients (62.4%) were evaluated 12-months after injury with a comprehensive battery of neuropsychological tests. There were 18 patients who received a reamed IMN and 14/18 (78%) of these patients had cognitive deficit at follow-up. Fracture treatment with a reamed IMN was associated with long-term impairment (27.4% vs. 8.2%, p= 0.03). Multivariable logistic regression found that a reamed IMN (OR: 3.2, 95% CI: 0.95-10.9; p=0.06) was a moderate risk factor for the development of cognitive impairment 12-months after injury, after controlling for ISS, level of education, intra-operative hypotension, and duration of mechanical ventilation. Conclusions Fracture fixation with a reamed IMN is moderately associated with cognitive impairment in this cohort of multiple trauma patients without ICH at 1-year post-injury. Orthopaedic trauma research should continue to investigate a potential association of acute fracture management and long-term cognitive outcome. PMID:22089759

  12. Severe Malarial Anemia is Associated With Long-term Neurocognitive Impairment

    PubMed Central

    Bangirana, Paul; Opoka, Robert O.; Boivin, Michael J.; Idro, Richard; Hodges, James S.; Romero, Regilda A.; Shapiro, Elsa; John, Chandy C.

    2014-01-01

    Background. Cerebral malaria (CM) is associated with long-term neurocognitive impairment in children ≥5 years of age. No prospective studies to date have assessed neurocognitive impairment in children with CM <5 years of age, or in children with severe malarial anemia (SMA), a form of severe malaria estimated to affect as many as 5 million children annually. Methods. Children <5 years of age presenting to Mulago Hospital, Kampala, Uganda, with CM (n = 80) or SMA (n = 86) were assessed for overall cognitive ability, attention, and associative memory 1 week after discharge and 6 and 12 months later. The z scores for each domain were computed based on scores of 61 healthy community children (CC), who were also tested at enrollment and 6 and 12 months later. Groups were compared using mixed linear models, adjusted for age, weight for age, and child's education. Results. At 12 months, children with CM had lower adjusted scores than CC in cognitive ability (P < .001), attention (P = .02), and associative memory, (P = .002). Children with SMA had lower scores than CC in cognitive ability (P = .01) but not attention or associative memory. Cognitive ability scores in children with CM and SMA did not differ significantly. Conclusions. In children <5 years of age, SMA is associated with long-term impairment in cognitive ability, whereas CM is associated with additional impairment in the areas of attention and associative memory. SMA may be a major contributor to long-term neurocognitive impairment in children in sub-Saharan Africa. PMID:24771329

  13. WASP-1, a canonical Wnt signaling potentiator, rescues hippocampal synaptic impairments induced by Aβ oligomers.

    PubMed

    Vargas, Jessica Y; Ahumada, Juan; Arrázola, Macarena S; Fuenzalida, Marco; Inestrosa, Nibaldo C

    2015-02-01

    Amyloid-β (Aβ) oligomers are a key factor in Alzheimer's disease (AD)-associated synaptic dysfunction. Aβ oligomers block the induction of hippocampal long-term potentiation (LTP) in rodents. The activation of Wnt signaling prevents Aβ oligomer-induced neurotoxic effects. The compound WASP-1 (Wnt-activating small molecule potentiator-1), has been described as a synergist of the ligand Wnt-3a, enhancing the activation of Wnt/β-catenin signaling. Herein, we report that WASP-1 administration successfully rescued Aβ-induced synaptic impairments both in vitro and in vivo. The activation of canonical Wnt/β-catenin signaling by WASP-1 increased synaptic transmission and rescued hippocampal LTP impairments induced by Aβ oligomers. Additionally, intra-hippocampal administration of WASP-1 to the double transgenic APPswe/PS1dE9 mouse model of AD prevented synaptic protein loss and reduced tau phosphorylation levels. Moreover, we found that WASP-1 blocked Aβ aggregation in vitro and reduced pathological tau phosphorylation in vivo. These results indicate that targeting canonical Wnt signaling with WASP-1 could have value for treating AD.

  14. Acute pentobarbital treatment impairs spatial learning and memory and hippocampal long-term potentiation in rats.

    PubMed

    Wang, Wei; Tan, Tao; Tu, Man; He, Wenting; Dong, Zhifang; Han, Huili

    2015-10-01

    Reports of the effects of pentobarbital on learning and memory are contradictory. Some studies have not shown any interference with learning and memory, whereas others have shown that pentobarbital impairs memory and that these impairments can last for long periods. However, it is unclear whether acute local microinjections of pentobarbital affect learning and memory, and if so, the potential mechanisms are also unclear. Here, we reported that the intra-hippocampal infusion of pentobarbital (8.0mM, 1μl per side) significantly impaired hippocampus-dependent spatial learning and memory retrieval. Moreover, in vitro electrophysiological recordings revealed that these behavioral changes were accompanied by impaired hippocampal CA1 long-term potentiation (LTP) and suppressed neuronal excitability as reflected by a decrease in the number of action potentials (APs). These results suggest that acute pentobarbital application causes spatial learning and memory deficits that might be attributable to the suppression of synaptic plasticity and neuronal excitability.

  15. Different impairment of immune and inflammation functions in short and long-term after ischemic stroke

    PubMed Central

    Li, Wen-Xing; Qi, Fei; Liu, Jia-Qian; Li, Gong-Hua; Dai, Shao-Xing; Zhang, Tao; Cheng, Fei; Liu, Dahai; Zheng, Song Guo

    2017-01-01

    Ischemic stroke therapy and prognosis outcomes largely depend on the time periods after symptom onset. This study aims to explore the difference of global gene expression profiles and impairment of biological functions between short-term and long-term after stroke onset. We compared three short-term (3 h, 5 h and 24 h) and a long-term (6-month) gene expression levels by a multi-platform microarray data integration method. RankProd was used to calculate the differentially expressed genes between stroke patients and controls. DAVID Bioinformatics Resources was utilized to determine affected biological functions. Consensus cluster and hierarchical cluster methods were employed to compare the gene expression patterns of the commonly biological functions among these four time course groups. The results showed that severe impairment of inflammation and immune related functions in 5 h and 24 h after symptom onset. However, these functions were less affected in the 3 h and the 6-month groups. In addition, several key genes (CCL20, THBS1, EREG, and IL6 et al.) were dramatically down-regulated in 5 h and 24 h groups, whereas these genes showed no change or even a slight contrary expression in 3 h or 6-month groups. This study has identified the large differences of altered immune and inflammation functions based on gene levels between short and long-term after stroke onset. The findings provide valuable insight into the clinical practice and prognosis evaluation of ischemic stroke. PMID:28337302

  16. Different impairment of immune and inflammation functions in short and long-term after ischemic stroke.

    PubMed

    Li, Wen-Xing; Qi, Fei; Liu, Jia-Qian; Li, Gong-Hua; Dai, Shao-Xing; Zhang, Tao; Cheng, Fei; Liu, Dahai; Zheng, Song Guo

    2017-01-01

    Ischemic stroke therapy and prognosis outcomes largely depend on the time periods after symptom onset. This study aims to explore the difference of global gene expression profiles and impairment of biological functions between short-term and long-term after stroke onset. We compared three short-term (3 h, 5 h and 24 h) and a long-term (6-month) gene expression levels by a multi-platform microarray data integration method. RankProd was used to calculate the differentially expressed genes between stroke patients and controls. DAVID Bioinformatics Resources was utilized to determine affected biological functions. Consensus cluster and hierarchical cluster methods were employed to compare the gene expression patterns of the commonly biological functions among these four time course groups. The results showed that severe impairment of inflammation and immune related functions in 5 h and 24 h after symptom onset. However, these functions were less affected in the 3 h and the 6-month groups. In addition, several key genes (CCL20, THBS1, EREG, and IL6 et al.) were dramatically down-regulated in 5 h and 24 h groups, whereas these genes showed no change or even a slight contrary expression in 3 h or 6-month groups. This study has identified the large differences of altered immune and inflammation functions based on gene levels between short and long-term after stroke onset. The findings provide valuable insight into the clinical practice and prognosis evaluation of ischemic stroke.

  17. Swimming exercise during pregnancy alleviates pregnancy-associated long-term memory impairment.

    PubMed

    Kim, Kijeong; Chung, Eunhee; Kim, Chang-Ju; Lee, Sukho

    2012-08-20

    Regular exercise has been shown to be beneficial to the brain functions, but little is known about the effects of exercise during pregnancy on the long-term memory function of the mothers. The objective of this study was to determine the effects of swimming during pregnancy on long-term memory function in rats on postpartum day 8. We examined the impact of swimming exercise during pregnancy on cell proliferation and apoptotic neuronal cell death in the hippocampus of peripartum rats. The rats were divided into three groups: the control group, the pregnant non-swimming group, and the pregnant swimming group. We found that pregnancy impaired the long-term memory while swimming during pregnancy alleviated the memory impairment. Pregnancy decreased cell proliferation in the dentate gyrus of the hippocampus, but swimming exercise during pregnancy reversed pregnancy-associated decreased cell proliferation back to control level. There was no difference in apoptotic neuronal cell death in the hippocampus among groups. Our results suggest that swimming during pregnancy alleviates pregnancy-associated decrease in memory function of mothers through an increase in cell proliferation in the hippocampus. Published by Elsevier Inc.

  18. Isoflurane impairs odour discrimination learning in rats: differential effects on short- and long-term memory

    PubMed Central

    Pearce, R. A.; Duscher, P.; Van Dyke, K.; Lee, M.; Andrei, A. C.; Perouansky, M.

    2012-01-01

    Background Anaesthetics suppress the formation of lasting memories at concentrations that do not suppress perception, but it is unclear which elements of the complex cascade leading from a conscious experience to a lasting memory trace are disrupted. Experiments in conscious humans suggest that subhypnotic concentrations of anaesthetics impair consolidation or maintenance rather than acquisition of a representation (long-term more than short-term memory). We sought to test whether these agents similarly impair learning in rats. Methods We used operant conditioning in rats to examine the effect of isoflurane on acquisition compared with long-term (24 h) memory of non-aversive olfactory memories using two different odour discrimination tasks. Rats learned the ‘valences’ of odour pairs presented either separately (task A) or simultaneously (task B), under control conditions and under isoflurane inhalation. In a separate set of experiments, we tested the ability of the animals to recall a learning set that had been acquired 24 h previously. Results Under 0.4% isoflurane inhalation, the average number of trials required to reach criterion performance (18 correct responses in 20 successive trials) increased from 21.9 to 43.5 (P<0.05) and 24.2 to 54.4 (P<0.05) for tasks A and B, respectively. Under 0.3% isoflurane inhalation, only task B was impaired (from 24.2 to 31.5 trials, P<0.05). Recall at 24 h was dose-dependently impaired or prevented by isoflurane for both tasks. Conclusions Isoflurane interfered with long-term memory of odour valence without preventing its acquisition. This paradigm may serve as a non-aversive animal model of conscious amnesia. PMID:22258200

  19. Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment.

    PubMed

    Chepkova, Aisa N; Sergeeva, Olga A; Haas, Helmut L

    2006-09-01

    Hyperammonemia, a major pathophysiological factor in hepatic encephalopathy, impairs long-term potentiation (LTP) of synaptic transmission, a cellular model of learning and memory, in the hippocampus. We have now studied the protective action of taurine on this paradigm by analyzing LTP characteristics in mouse hippocampal slices treated with ammonium chloride (1 mM) in the presence of taurine (1 mM), an ubiquitous osmolyte, antioxidant, and neuromodulator, as well as other substances with such properties. Ammonia-treated slices displayed a significant impairment of LTP maintenance. Taurine and the mitochondrial enhancer l-carnitine, but not the antioxidants (ascorbate, carnosine, and the novel compound GVS-111) or the osmolyte betaine prevented this impairment. The protective effect of taurine was preserved under the blockade of inhibitory GABA(A) and glycine receptors. It is suggested that taurine may rescue the mechanisms of hippocampal synaptic plasticity by improving mitochondrial function under hyperammonemic conditions.

  20. Loss of FMRP Impaired Hippocampal Long-Term Plasticity and Spatial Learning in Rats.

    PubMed

    Tian, Yonglu; Yang, Chaojuan; Shang, Shujiang; Cai, Yijun; Deng, Xiaofei; Zhang, Jian; Shao, Feng; Zhu, Desheng; Liu, Yunbo; Chen, Guiquan; Liang, Jing; Sun, Qiang; Qiu, Zilong; Zhang, Chen

    2017-01-01

    Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene that inactivate expression of the gene product, the fragile X mental retardation 1 protein (FMRP). In this study, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology to generate Fmr1 knockout (KO) rats by disruption of the fourth exon of the Fmr1 gene. Western blotting analysis confirmed that the FMRP was absent from the brains of the Fmr1 KO rats (Fmr1(exon4-KO) ). Electrophysiological analysis revealed that the theta-burst stimulation (TBS)-induced long-term potentiation (LTP) and the low-frequency stimulus (LFS)-induced long-term depression (LTD) were decreased in the hippocampal Schaffer collateral pathway of the Fmr1(exon4-KO) rats. Short-term plasticity, measured as the paired-pulse ratio, remained normal in the KO rats. The synaptic strength mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was also impaired. Consistent with previous reports, the Fmr1(exon4-KO) rats demonstrated an enhanced 3,5-dihydroxyphenylglycine (DHPG)-induced LTD in the present study, and this enhancement is insensitive to protein translation. In addition, the Fmr1(exon4-KO) rats showed deficits in the probe trial in the Morris water maze test. These results demonstrate that deletion of the Fmr1 gene in rats specifically impairs long-term synaptic plasticity and hippocampus-dependent learning in a manner resembling the key symptoms of FXS. Furthermore, the Fmr1(exon4-KO) rats displayed impaired social interaction and macroorchidism, the results consistent with those observed in patients with FXS. Thus, Fmr1(exon4-KO) rats constitute a novel rat model of FXS that complements existing mouse models.

  1. Similar autobiographical memory impairment in long-term secondary progressive multiple sclerosis and Alzheimer's disease.

    PubMed

    Müller, S; Saur, R; Greve, B; Melms, A; Hautzinger, M; Fallgatter, A J; Leyhe, T

    2013-02-01

    Memory disturbance is a common symptom of multiple sclerosis (MS), but little is known about autobiographical memory deficits in the long-term course of different MS subtypes. Inflammatory activity and demyelination is pronounced in relapsing-remitting multiple sclerosis (RRMS) whereas, similar to Alzheimer's disease, neurodegeneration affecting autobiographical memory-associated areas is seen in secondary progressive multiple sclerosis (SPMS). In light of distinct disease mechanisms, we evaluated autobiographical memory in different MS subtypes and hypothesized similarities between elderly patients with SPMS and Alzheimer's disease. We used the Autobiographical Memory Interview to assess episodic and semantic autobiographical memory in 112 education- and gender-matched participants, including healthy controls and patients with RRMS, SPMS, amnesic mild cognitive impairment (aMCI) and early Alzheimer's dementia (AD). Patients with SPMS, AD, and aMCI, but not with RRMS, exhibited a pattern of episodic autobiographical memory impairment that followed Ribot's Law; older memories were better preserved than more recent memories. In contrast to aMCI and AD, neither SPMS nor RRMS was associated with semantic autobiographical memory impairment. Our neuropsychological findings suggest that episodic autobiographical memory is affected in long-term patients with SPMS, possibly due to neurodegenerative processes in functional relevant brain regions.

  2. Altered neural network supporting declarative long-term memory in mild cognitive impairment.

    PubMed

    Poettrich, Katrin; Weiss, Peter H; Werner, Annett; Lux, Silke; Donix, Markus; Gerber, Johannes; von Kummer, Rüdiger; Fink, Gereon R; Holthoff, Vjera A

    2009-02-01

    Autobiographical episodic memory represents a subsystem of declarative long-term memory and largely depends on combining information from multiple sources. The purpose of this study was to assess neural correlates of declarative long-term memory in patients with amnestic mild cognitive impairment (MCI) and controls using fMRI and a task requiring autobiographical and semantic memory retrieval. Comparison of the network supporting episodic autobiographical and semantic memory irrespective of remoteness (recent and remote) revealed significant activations in right parietal cortex and precuneus bilaterally in the patients. Autobiographical episodic versus semantic memory retrieval in the controls led to significant bilateral activations of the parietal-temporal junction, left temporal pole, anterior cingulate, retrosplenial cortex and cerebellum. In contrast, MCI patients activated left supplementary motor area, left premotor and superior temporal cortex. In MCI patients compared to controls a dysfunction of the retrosplenial cortex during memory retrieval was revealed by a lack of differential activation in relation to recency of memories and memory type. Our data suggest that MCI leads to a loss of specificity in the neural network supporting declarative long-term memory.

  3. Caffeine and diphenyl diselenide improve long-term memory impaired in middle-aged rats.

    PubMed

    Leite, Marlon R; Marcondes Sari, Marcel Henrique; de Freitas, Mayara L; Oliveira, Lia P; Dalmolin, Laíza; Brandão, Ricardo; Zeni, Gilson

    2014-05-01

    The aim of the present study was to evaluate the effects of diphenyl diselenide (PhSe)2 supplemented diet (10ppm) associated to the administration of caffeine (15mg/kg; i.g.) for 30days on the novel object recognition memory in middle-aged rats. The present findings showed that (PhSe)2-supplemented diet enhanced short-term memory, but not long-term memory, of middle-aged rats in the novel object recognition task. The (PhSe)2 supplemented diet associated with caffeine administration improved long-term memory, but did not alter short-term memory, impaired in middle-aged rats. Daily caffeine administration to middle-aged rats had no effect on the memory tasks. Diet supplemented with (PhSe)2 plus caffeine administration increased the number of crossings and rearings reduced in middle-aged rats. Caffeine administration plus (PhSe)2 diets were effective in increasing the number of rearings and crossings, respectively, in middle-aged rats, [(3)H] glutamate uptake was reduced in hippocampal slices of rats from (PhSe)2 and caffeine plus (PhSe)2 groups. In addition, animals supplemented with (PhSe)2 showed an increase in the pCREB/CREB ratio whereas pAkt/Akt ratio was not modified. These results suggest that the effects of (PhSe)2 on the short-term memory may be related to its ability to decrease the uptake of glutamate, influencing the increase of CREB phosphorylation. (PhSe)2-supplemented diet associated to the administration of caffeine improved long-term memory impaired in middle-aged rats, an effect independent of CREB and Akt phosphorylation. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Long-term exposure to microgravity impairs vestibulo-cardiovascular reflex

    PubMed Central

    Morita, Hironobu; Abe, Chikara; Tanaka, Kunihiko

    2016-01-01

    The vestibular system is known to have an important role in controlling blood pressure upon posture transition (vestibulo-cardiovascular reflex, VCR). However, under a different gravitational environment, the sensitivity of the vestibular system may be altered. Thus, the VCR may become less sensitive after spaceflight because of orthostatic intolerance potentially induced by long-term exposure to microgravity. To test this hypothesis in humans, we investigated the ability of the VCR to maintain blood pressure upon head-up tilt before and after a 4–6 months stay on the International Space Station. To detect the functional state of the VCR, galvanic vestibular stimulation (GVS) was applied. As GVS transiently interrupts the vestibular-mediated pressor response, impaired VCR is detected when the head-up tilt-induced blood pressure response does not depend on GVS. During the first 20 s of head-up tilt, a transient blood pressure increase (11.9 ± 1.6 mmHg) was observed at pre-spaceflight but not at 1–4 days after return from spaceflight. The magnitude of VCR recovered to the pre-spaceflight levels within 2 months after return. These results indicate that long-term exposure to microgravity induces VCR impairment, which may be involved in a mechanism of spaceflight-induced orthostatic intolerance. PMID:27634181

  5. Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

    PubMed Central

    Rozas, Natalia S.; Redell, John B.; Pita-Almenar, Juan D.; Mckenna, James; Moore, Anthony N.; Gambello, Michael J.

    2015-01-01

    The mechanistic Target of Rapamycin Complex 1 (mTORC1), a key regulator of protein synthesis and cellular growth, is also required for long-term memory formation. Stimulation of mTORC1 signaling is known to be dependent on the availability of energy and growth factors, as well as the presence of amino acids. In vitro studies using serum- and amino acid-starved cells have reported that glutamine addition can either stimulate or repress mTORC1 activity, depending on the particular experimental system that was used. However, these experiments do not directly address the effect of glutamine on mTORC1 activity under physiological conditions in nondeprived cells in vivo. We present experimental results indicating that intrahippocampal administration of glutamine to rats reduces mTORC1 activity. Moreover, post-training administration of glutamine impairs long-term spatial memory formation, while coadministration of glutamine with leucine had no influence on memory. Intracellular recordings in hippocampal slices showed that glutamine did not alter either excitatory or inhibitory synaptic activity, suggesting that the observed memory impairments may not result from conversion of glutamine to either glutamate or GABA. Taken together, these findings indicate that glutamine can decrease mTORC1 activity in the brain and may have implications for treatments of neurological diseases associated with high mTORC1 signaling. PMID:25878136

  6. Long-term exposure to microgravity impairs vestibulo-cardiovascular reflex.

    PubMed

    Morita, Hironobu; Abe, Chikara; Tanaka, Kunihiko

    2016-09-16

    The vestibular system is known to have an important role in controlling blood pressure upon posture transition (vestibulo-cardiovascular reflex, VCR). However, under a different gravitational environment, the sensitivity of the vestibular system may be altered. Thus, the VCR may become less sensitive after spaceflight because of orthostatic intolerance potentially induced by long-term exposure to microgravity. To test this hypothesis in humans, we investigated the ability of the VCR to maintain blood pressure upon head-up tilt before and after a 4-6 months stay on the International Space Station. To detect the functional state of the VCR, galvanic vestibular stimulation (GVS) was applied. As GVS transiently interrupts the vestibular-mediated pressor response, impaired VCR is detected when the head-up tilt-induced blood pressure response does not depend on GVS. During the first 20 s of head-up tilt, a transient blood pressure increase (11.9 ± 1.6 mmHg) was observed at pre-spaceflight but not at 1-4 days after return from spaceflight. The magnitude of VCR recovered to the pre-spaceflight levels within 2 months after return. These results indicate that long-term exposure to microgravity induces VCR impairment, which may be involved in a mechanism of spaceflight-induced orthostatic intolerance.

  7. Long-Term Biological Monitoring of an Impaired Stream: Implications for Environmental Management [Special Issue

    SciTech Connect

    Adams, Marshall; Brandt, Craig C; Christensen, Sigurd W; Efroymson, Rebecca Ann; Greeley Jr, Mark Stephen; Ham, Kenneth; Kszos, Lynn A; Loar, James M; McCracken, Kitty; Morris, Gail Wright; Peterson, Mark J; Ryon, Michael G; Smith, John G; Southworth, George R; Stewart, Arthur J

    2011-01-01

    The long-term ecological recovery of an impaired stream in response to an industrial facility's pollution abatement actions and the implications of the biological monitoring effort to environmental management is the subject of this special issue of Environmental Management. This final article focuses on the synthesis of the biological monitoring program's components and methods, the efficacy of various biological monitoring techniques to environmental management, and the lessons learned from the program that might be applicable to the design and application of other programs. The focus of the 25-year program has been on East Fork Poplar Creek, an ecologically impaired stream in Oak Ridge, Tennessee with varied and complex stressors from a Department of Energy facility in its headwaters. Major components of the long-term program included testing and monitoring of invertebrate and fish toxicity, bioindicators of fish health, fish contaminant accumulation, and instream communities (including periphyton, benthic macroinvertebrate, and fish). Key parallel components of the program include water chemistry sampling and data management. Multiple lines of evidence suggested positive ecological responses during three major pollution abatement periods. Based on this case study and the related literature, effective environmental management of impaired streams starts with program design that is consistent across space and time, but also adaptable to changing conditions. The biological monitoring approaches used for the program provided a strong basis for assessments of recovery from remedial actions, and the likely causes of impairment. This case study provides a unique application of multidisciplinary and quantitative techniques to address multiple and complex regulatory and programmatic goals, environmental stressors, and remedial actions.

  8. Long-term Biological Monitoring of an Impaired Stream: Synthesis and Environmental Management Implications

    SciTech Connect

    Peterson, Mark J; Efroymson, Rebecca Ann; Adams, Marshall

    2011-01-01

    The long-term ecological recovery of an impaired stream in response to an industrial facility's pollution abatement actions and the implications of the biological monitoring effort to environmental management is the subject of this special issue of Environmental Management. This final article focuses on the synthesis of the biological monitoring program's components and methods, the efficacy of various biological monitoring techniques to environmental management, and the lessons learned from the program that might be applicable to the design and application of other programs. The focus of the 25-year program has been on East Fork Poplar Creek, an ecologically impaired stream in Oak Ridge, Tennessee with varied and complex stressors from a Department of Energy facility in its headwaters. Major components of the long-term program included testing and monitoring of invertebrate and fish toxicity, bioindicators of fish health, fish contaminant accumulation, and instream communities (including periphyton, benthic macroinvertebrate, and fish). Key parallel components of the program include water chemistry sampling and data management. Multiple lines of evidence suggested positive ecological responses during three major pollution abatement periods. Based on this case study and the related literature, effective environmental management of impaired streams starts with program design that is consistent across space and time, but also adaptable to changing conditions. The biological monitoring approaches used for the program provided a strong basis for assessments of recovery from remedial actions, and the likely causes of impairment. This case study provides a unique application of multidisciplinary and quantitative techniques to address multiple and complex regulatory and programmatic goals, environmental stressors, and remedial actions.

  9. Long-Term Biological Monitoring of an Impaired Stream: Synthesis and Environmental Management Implications

    NASA Astrophysics Data System (ADS)

    Peterson, Mark J.; Efroymson, Rebecca A.; Adams, S. Marshall

    2011-06-01

    The long-term ecological recovery of an impaired stream in response to an industrial facility's pollution abatement actions and the implications of the biological monitoring effort to environmental management is the subject of this special issue of Environmental Management. This final article focuses on the synthesis of the biological monitoring program's components and methods, the efficacy of various biological monitoring techniques to environmental management, and the lessons learned from the program that might be applicable to the design and application of other programs. The focus of the 25-year program has been on East Fork Poplar Creek, an ecologically impaired stream in Oak Ridge, Tennessee with varied and complex stressors from a Department of Energy facility in its headwaters. Major components of the long-term program included testing and monitoring of invertebrate and fish toxicity, bioindicators of fish health, fish contaminant accumulation, and instream communities (including periphyton, benthic macroinvertebrate, and fish). Key parallel components of the program include water chemistry sampling and data management. Multiple lines of evidence suggested positive ecological responses during three major pollution abatement periods. Based on this case study and the related literature, effective environmental management of impaired streams starts with program design that is consistent across space and time, but also adaptable to changing conditions. The biological monitoring approaches used for the program provided a strong basis for assessments of recovery from remedial actions, and the likely causes of impairment. This case study provides a unique application of multidisciplinary and quantitative techniques to address multiple and complex regulatory and programmatic goals, environmental stressors, and remedial actions.

  10. Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory

    PubMed Central

    Park, Alan J.; Tolentino, Rosa E.; Bruinenberg, Vibeke M.; Tudor, Jennifer C.; Lee, Yool; Hansen, Rolf T.; Guercio, Leonardo A.; Linton, Edward; Neves-Zaph, Susana R.; Meerlo, Peter; Baillie, George S.; Houslay, Miles D.

    2016-01-01

    Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. SIGNIFICANCE STATEMENT Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular

  11. Subtle cognitive impairments in patients with long-term cure of Cushing's disease.

    PubMed

    Tiemensma, Jitske; Kokshoorn, Nieke E; Biermasz, Nienke R; Keijser, Bart-Jan S A; Wassenaar, Moniek J E; Middelkoop, Huub A M; Pereira, Alberto M; Romijn, Johannes A

    2010-06-01

    Active Cushing's disease is associated with cognitive impairments. We hypothesized that previous hypercortisolism in patients with Cushing's disease results in irreversible impairments in cognitive functioning. Therefore, our aim was to assess cognitive functioning after long-term cure of Cushing's disease. Cognitive assessment consisted of 11 tests, which evaluated global cognitive functioning, memory, and executive functioning. We included 74 patients cured of Cushing's disease and 74 controls matched for age, gender, and education. Furthermore, we included 54 patients previously treated for nonfunctioning pituitary macroadenomas (NFMA) and 54 controls matched for age, gender, and education. Compared with NFMA patients, patients cured from Cushing's disease had lower scores on the Mini Mental State Examination (P = 0.001), and on the memory quotient of the Wechsler Memory Scale (P = 0.050). Furthermore, patients cured from Cushing's disease tended to recall fewer words on the imprinting (P = 0.013), immediate recall (P = 0.012), and delayed recall (P = 0.003) trials of the Verbal Learning Test of Rey. On the Rey Complex Figure Test, patients cured from Cushing's disease had lower scores on both trials (P = 0.002 and P = 0.007) compared with NFMA patients. Patients cured from Cushing's disease also made fewer correct substitutions on the Letter-Digit Substitution Test (P = 0.039) and came up with fewer correct patterns on the Figure Fluency Test (P = 0.003) compared with treated NFMA patients. Cognitive function, reflecting memory and executive functions, is impaired in patients despite long-term cure of Cushing's disease. These observations indicate irreversible effects of previous hypercortisolism on cognitive function and, thus, on the central nervous system. These observations may also be of relevance for patients treated with high-dose exogenous glucocorticoids.

  12. Chronic dietary chlorpyrifos causes long-term spatial memory impairment and thigmotaxic behavior.

    PubMed

    López-Granero, Caridad; Ruiz-Muñoz, Ana M; Nieto-Escámez, Francisco A; Colomina, María T; Aschner, Michael; Sánchez-Santed, Fernando

    2016-03-01

    Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months-of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioral disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2mg/kg of MK801 and 1 or 3mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Impaired Fear Memory Specificity Associated with Deficient Endocannabinoid-Dependent Long-Term Plasticity

    PubMed Central

    Lovelace, Jonathan W; Vieira, Philip A; Corches, Alex; Mackie, Ken; Korzus, Edward

    2014-01-01

    In addition to its central role in learning and memory, N-methyl D-aspartate receptor (NMDAR)-dependent signaling regulates central glutamatergic synapse maturation and has been implicated in schizophrenia. We have transiently induced NMDAR hypofunction in infant mice during postnatal days 7–11, followed by testing fear memory specificity and presynaptic plasticity in the prefrontal cortex (PFC) in adult mice. We show that transient NMDAR hypofunction during early brain development, coinciding with the maturation of cortical plasticity results in a loss of an endocannabinoid (eCB)-mediated form of long-term depression (eCB-LTD) at adult central glutamatergic synapses, while another form of presynaptic long-term depression mediated by the metabotropic glutamate receptor 2/3 (mGluR2/3-LTD) remains intact. Mice with this selective impairment of presynaptic plasticity also showed deficits in fear memory specificity. The observed deficit in cortical presynaptic plasticity may represent a neural maladaptation contributing to network instability and abnormal cognitive functioning. PMID:24457285

  14. Impaired fear memory specificity associated with deficient endocannabinoid-dependent long-term plasticity.

    PubMed

    Lovelace, Jonathan W; Vieira, Philip A; Corches, Alex; Mackie, Ken; Korzus, Edward

    2014-06-01

    In addition to its central role in learning and memory, N-methyl D-aspartate receptor (NMDAR)-dependent signaling regulates central glutamatergic synapse maturation and has been implicated in schizophrenia. We have transiently induced NMDAR hypofunction in infant mice during postnatal days 7-11, followed by testing fear memory specificity and presynaptic plasticity in the prefrontal cortex (PFC) in adult mice. We show that transient NMDAR hypofunction during early brain development, coinciding with the maturation of cortical plasticity results in a loss of an endocannabinoid (eCB)-mediated form of long-term depression (eCB-LTD) at adult central glutamatergic synapses, while another form of presynaptic long-term depression mediated by the metabotropic glutamate receptor 2/3 (mGluR2/3-LTD) remains intact. Mice with this selective impairment of presynaptic plasticity also showed deficits in fear memory specificity. The observed deficit in cortical presynaptic plasticity may represent a neural maladaptation contributing to network instability and abnormal cognitive functioning.

  15. Relationship between cognitive impairment and nutritional assessment on functional status in Calabrian long-term-care

    PubMed Central

    Malara, Alba; Sgrò, Giovanni; Caruso, Chiara; Ceravolo, Francesco; Curinga, Giuseppe; Renda, Grazia Francesca; Spadea, Fausto; Garo, Michele; Rispoli, Vincenzo

    2014-01-01

    Objective The interaction between dementia and nutritional state is very complex and not yet fully understood. The aim of the present study was to assess the interaction between cognitive impairment and nutritional state in a cohort of residential elderly in relationship with functional condition of patients and their load of assistance in long-term-care facilities of the National Association of Third Age Structures (ANASTE) Calabria. Methods One hundred seventy-four subjects (122 female and 52 male) were admitted to the long-term-care ANASTE Calabria study. All patients underwent multidimensional geriatric assessment. Nutritional state was assessed with the Mini Nutritional Assessment (MNA), whereas cognitive performance was evaluated by the Mini-Mental State Examination (MMSE). The functional state was assessed by Barthel Index (BI) and Activity Daily Living (ADL). The following nutritional biochemical parameters were also evaluated: albumin, cholesterol, iron, and hemoglobin. All patients were reassessed 180 days later. Results A severe cognitive impairment in MMSE performance was displayed in 49.7% patients, while 39.8% showed a moderate deficit; 6.9% had a slight deficit; and 3.4% evidenced no cognitive impairment. In MNA, 30% of patients exhibited an impairment of nutritional state; 56% were at risk of malnutrition; and 14% showed no nutritional problems. Malnutrition was present in 42% of patients with severe cognitive impairment, but only 4% of malnourished patients showed moderate cognitive deficit. The statistical analysis displayed a significant correlation between MNA and MMSE (P<0.001), as did MMSE correlated with Activity Daily Living (P<0.001) and BI (P<0.05). MNA correlated with BI (P<0.001) and albumin (P<0.001). The follow-up showed a strong correlation between cognitive deterioration and worsening of nutritional state (P<0.005) as well as with the functional state (P<0.05) and mortality (P<0.01). Conclusion The present study clearly shows that

  16. Impaired splenic function and tuftsin deficiency in patients with intestinal failure on long term intravenous nutrition

    PubMed Central

    Zoli, G; Corazza, G; Wood, S; Bartoli, R; Gasbarrini, G; Farthing, M

    1998-01-01

    Background—Reticuloendothelial system function is impaired in humans receiving lipid regimens. 
Aims—To evaluate the effects of long term administration of long chain triglyceride emulsions on reticuloendothelial system function. 
Methods—Splenic function and tuftsin activity were measured in 20 patients on intravenous nutrition for intestinal failure, 20 patients with Crohn's disease who were not receiving intravenous nutrition, and 50 healthy controls. 
Results—Pitted red cells counts in patients on intravenous nutrition (8.0%) were significantly higher (p<0.001) than in healthy controls (0.6%) and in patients with Crohn's disease (0.9%). No difference was found between healthy controls and patients with Crohn's disease. There was a correlation (r=0.50; p<0.03) between percentage of pitted red cells and duration of intravenous nutrition. Tuftsin activity was significantly reduced in the intravenous nutrition patient group (6%) compared with both disease controls (16.5%, p<0.01) and healthy volunteers (17.8%, p<0.001) . An inverse correlation between tuftsin activity and pitted red cell percentage was found in the patients on intravenous nutrition (rs =−0.44, p<0.05). No relation was found in the patients on intravenous nutrition between pitted red cell percentage or tuftsin activity and type of disease, percentage of ideal body weight, residual length of small intestine, or administration (quantity and frequency) of lipid emulsion. Eight patients on intravenous nutrition had serious infections within the previous 12months. 
Conclusions—Patients with a short bowel treated with long term intravenous nutrition have impaired splenic function, reduced tuftsin activity, and an increased risk of infection. 

 Keywords: splenic function; hyposplenism; tuftsin; home parenteral nutrition; short bowel syndrome PMID:9824601

  17. Migraine Mutations Impair Hippocampal Learning Despite Enhanced Long-Term Potentiation

    PubMed Central

    Dilekoz, Ergin; Houben, Thijs; Eikermann-Haerter, Katharina; Balkaya, Mustafa; Lenselink, A. Mariette; Whalen, Michael J.; Spijker, Sabine; Ferrari, Michel D.; van den Maagdenberg, Arn M.J.M.

    2015-01-01

    To explain cognitive and memory difficulties observed in some familial hemiplegic migraine (FHM) patients, we examined hippocampal neurotransmission and plasticity in knock-in mice expressing the FHM type 1 (FHM1) R192Q gain-of function mutation in the CACNA1A gene that encodes the α1A subunit of neuronal CaV2.1 channels. We determined stimulus intensity–response curves for anterior commissure-evoked hippocampal CA1 field potentials in strata pyramidale and radiatum and assessed neuroplasticity by inducing long-term potentiation (LTP) and long-term depression (LTD) in anesthetized mice in vivo. We also studied learning and memory using contextual fear-conditioning, Morris water maze, and novel object recognition tests. Hippocampal field potentials were significantly enhanced in R192Q mice compared with wild-type controls. Stimulus intensity–response curves were shifted to the left and displayed larger maxima in the mutants. LTP was augmented by twofold in R192Q mice, whereas LTD was unchanged compared with wild-type mice. R192Q mice showed significant spatial memory deficits in contextual fear-conditioning and Morris water maze tests compared with wild-type controls. Novel object recognition was not impaired in R192Q mice; however, mice carrying the more severe S218L CACNA1A mutation showed marked deficits in this test, suggesting a genotype–phenotype relationship. Thus, whereas FHM1 gain-of-function mutations enhance hippocampal excitatory transmission and LTP, learning and memory are paradoxically impaired, providing a possible explanation for cognitive changes detected in FHM. Data suggest that abnormally enhanced plasticity can be as detrimental to efficient learning as reduced plasticity and highlight how genetically enhanced neuronal excitability may impact cognitive function. PMID:25716839

  18. Early Exposure to Volatile Anesthetics Impairs Long-Term Associative Learning and Recognition Memory

    PubMed Central

    Lee, Bradley H.; Chan, John Thomas; Hazarika, Obhi; Vutskits, Laszlo; Sall, Jeffrey W.

    2014-01-01

    Background Anesthetic exposure early in life affects neural development and long-term cognitive function, but our understanding of the types of memory that are altered is incomplete. Specific cognitive tests in rodents that isolate different memory processes provide a useful approach for gaining insight into this issue. Methods Postnatal day 7 (P7) rats were exposed to either desflurane or isoflurane at 1 Minimum Alveolar Concentration for 4 h. Acute neuronal death was assessed 12 h later in the thalamus, CA1-3 regions of hippocampus, and dentate gyrus. In separate behavioral experiments, beginning at P48, subjects were evaluated in a series of object recognition tests relying on associative learning, as well as social recognition. Results Exposure to either anesthetic led to a significant increase in neuroapoptosis in each brain region. The extent of neuronal death did not differ between groups. Subjects were unaffected in simple tasks of novel object and object-location recognition. However, anesthetized animals from both groups were impaired in allocentric object-location memory and a more complex task requiring subjects to associate an object with its location and contextual setting. Isoflurane exposure led to additional impairment in object-context association and social memory. Conclusion Isoflurane and desflurane exposure during development result in deficits in tasks relying on associative learning and recognition memory. Isoflurane may potentially cause worse impairment than desflurane. PMID:25165850

  19. Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus

    PubMed Central

    Cooke, Jennifer D.; Cavender, Hannah M.; Lima, Hope K.; Grover, Lawrence M.

    2014-01-01

    Rationale Monoamine reuptake inhibitors can stimulate expression of brain-derived neurotrophic factor (BDNF) and alter long-term potentiation (LTP), a widely used model for the synaptic mechanisms that underlie memory formation. BDNF expression is up-regulated during LTP, and BDNF in turn positively modulates LTP. Previously, we found that treatment with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), but not citalopram, a selective serotonin reuptake inhibitor (SSRI) reduced LTP in hippocampal area CA1 without changing hippocampal BDNF protein expression. Objectives We tested the hypothesis that combined serotonin and norepinephrine reuptake inhibition is necessary for LTP impairment, and we reexamined the potential role of BNDF by testing for region-specific changes in areas CA1, CA3 and dentate gyrus. We also tested whether early events in the LTP signaling pathway were altered to impair LTP. Methods Animals were treated for 21 days with venlafaxine, imipramine, fluoxetine, or maprotiline. In vitro hippocampal slices were used for electrophysiological measurements. Protein expression was measured by enzyme-linked immunosorbent assay (ELISA) and western blotting. Results LTP was impaired only following treatment with combined serotonin and norepinephrine reuptake inhibitors (venlafaxine, imipramine) but not with selective serotonin (fluoxetine) or norepinephrine (maprotiline) reuptake inhibitors. BDNF protein expression was not altered by venlafaxine or imipramine treatment, nor were postsynaptic depolarization during LTP inducing stimulation or synaptic membrane NMDA receptor subunit expression affected. Conclusions LTP is impaired by chronic treatment with antidepressant that inhibit both serotonin and norepinephrine reuptake; this impairment results from changes that are downstream of postsynaptic depolarization and calcium-influx. PMID:24781518

  20. Minocycline Prevents the Impairment of Hippocampal Long-Term Potentiation in the Septic Mouse.

    PubMed

    Hoshino, Koji; Hayakawa, Mineji; Morimoto, Yuji

    2017-02-09

    Sepsis-associated encephalopathy is a major complication during sepsis, and an effective treatment remains unknown. Although minocycline (MINO) has neuroprotective effects and is an attractive candidate for treating sepsis-associated encephalopathy, the effect of MINO on synaptic plasticity during sepsis is still unclear. In the present study, we investigated the effects of MINO on long-term potentiation (LTP) in the hippocampus in a cecal ligation and puncture (CLP) mouse model. We divided mice into 4 groups; (1) sham + vehicle, (2) sham + MINO (60 mg/kg, i.p. for 3 consecutive days before slice preparation), (3) CLP + vehicle, and (4) CLP + MINO. We tested LTP in the CA1 region of the hippocampus, using slices taken 24 h after surgery. Because MINO is also anti-inflammatory, LTP was analyzed following 30 min of IL-1 receptor antagonist (IL-1ra) perfusion. The endotoxin level in the blood was increased at 24 h after CLP operations regardless of MINO administrations, and LTP in the CLP + vehicle group mice was severely impaired (P < 0.05). High doses of MINO prevented the LTP impairment during sepsis in the CLP + MINO group. Interleukin (IL) -1ra administration ameliorated LTP impairment only in the CLP + vehicle group (P < 0.05); it had no additional effects on LTP in the CLP + MINO group. In conclusion, we have provided the first evidence that MINO prevents impaired LTP related to sepsis-induced encephalopathy in the mouse hippocampus, and that mechanisms associated with IL-1 receptor activity may be involved.

  1. Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory.

    PubMed

    Havekes, Robbert; Park, Alan J; Tolentino, Rosa E; Bruinenberg, Vibeke M; Tudor, Jennifer C; Lee, Yool; Hansen, Rolf T; Guercio, Leonardo A; Linton, Edward; Neves-Zaph, Susana R; Meerlo, Peter; Baillie, George S; Houslay, Miles D; Abel, Ted

    2016-08-24

    Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular compartments. The

  2. IRS-2 Deficiency Impairs NMDA Receptor-Dependent Long-term Potentiation

    PubMed Central

    Martín, Eduardo D.; Sánchez-Perez, Ana; Trejo, José Luis; Martin-Aldana, Juan Antonio; Cano Jaimez, Marife; Pons, Sebastián; Acosta Umanzor, Carlos; Menes, Lorena; White, Morris F.

    2012-01-01

    The beneficial effects of insulin and insulin-like growth factor I on cognition have been documented in humans and animal models. Conversely, obesity, hyperinsulinemia, and diabetes increase the risk for neurodegenerative disorders including Alzheimer's disease (AD). However, the mechanisms by which insulin regulates synaptic plasticity are not well understood. Here, we report that complete disruption of insulin receptor substrate 2 (Irs2) in mice impairs long-term potentiation (LTP) of synaptic transmission in the hippocampus. Basal synaptic transmission and paired-pulse facilitation were similar between the 2 groups of mice. Induction of LTP by high-frequency conditioning tetanus did not activate postsynaptic N-methyl-D-aspartate (NMDA) receptors in hippocampus slices from Irs2−/− mice, although the expression of NR2A, NR2B, and PSD95 was equivalent to wild-type controls. Activation of Fyn, AKT, and MAPK in response to tetanus stimulation was defective in Irs2−/− mice. Interestingly, IRS2 was phosphorylated during induction of LTP in control mice, revealing a potential new component of the signaling machinery which modulates synaptic plasticity. Given that IRS2 expression is diminished in Type 2 diabetics as well as in AD patients, these data may reveal an explanation for the prevalence of cognitive decline in humans with metabolic disorders by providing a mechanistic link between insulin resistance and impaired synaptic transmission. PMID:21955917

  3. Long-term administration of large doses of paracetamol impairs the reproductive competence of male rats.

    PubMed

    Ratnasooriya, W D; Jayakody, J R

    2000-12-01

    To evaluate the antireproductive effect of paracetamol in male rats. Male rats were orally administered daily with 500 mg/kg or 1000 mg/kg of paracetamol for 30 consecutive days. Their sexual behaviour and fertility were evaluated using receptive females. At 2 h after treatment, sexual behaviour was not inhibited but on day 30 both doses of paracetamol caused marked impairment of libido (assessed by % mounting, % intromission and % ejaculation), sexual vigour (number of mounts and intromissions and copulatory efficiency) or sexual performance (intercopulatory interval). In mating experiments, the fertility (in terms of quantal pregnancy, fertility index, implantation index and number of implants) was significantly reduced. All these effects were reversible. The antireproductive effect was not due to a general toxicity but due to an increase in pre-implantation losses resulting from oligozoospermia, impairments of normal and hyper-activated sperm motility, and reduction in the fertilizing potential of spermatozoa. Long-term use of high doses of paracetamol may be detrimental to male reproductive competence.

  4. 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

  5. Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

    PubMed

    Fá, M; Puzzo, D; Piacentini, R; Staniszewski, A; Zhang, H; Baltrons, M A; Li Puma, D D; Chatterjee, I; Li, J; Saeed, F; Berman, H L; Ripoli, C; Gulisano, W; Gonzalez, J; Tian, H; Costa, J A; Lopez, P; Davidowitz, E; Yu, W H; Haroutunian, V; Brown, L M; Palmeri, A; Sigurdsson, E M; Duff, K E; Teich, A F; Honig, L S; Sierks, M; Moe, J G; D'Adamio, L; Grassi, C; Kanaan, N M; Fraser, P E; Arancio, O

    2016-01-20

    Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.

  6. Factors Contributing to Long-Term Severe Visual Impairment in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

    PubMed

    Jongkhajornpong, Passara; Lekhanont, Kaevalin; Siriyotha, Sukanya; Kanokrungsee, Silada; Chuckpaiwong, Varintorn

    2017-01-01

    Purpose. To study the correlation between demographics and clinical variables and long-term severe visual impairment in patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Methods. A retrospective chart review of SJS/TEN patients between 2004 and 2014 was conducted. Demographics, causative agents, ocular manifestations, and visual outcomes were collected. The data were analyzed using a multivariate logistic regression model. Results. Of the 89 patients including SJS (65, 73.03%), TEN (15, 16.85%), and SJS-TEN overlap (9, 10.11%), 55 were female. The mean age was 41.58 ± 19.17 years. The most common identified agents were medications. Among these groups, antibiotics were the most prevalent (47.19%). Three patients (3.7%) had unknown etiology. Antibiotics and nonpharmaceutical triggers were significantly associated with long-term severe visual impairment (odds ratio 4.32; P = 0.015 and 7.20; P = 0.037, resp.). There was a significant negative relationship between HIV infection and long-term severe visual impairment (P = 0.021). Among all chronic ocular complications, only corneal neovascularization significantly correlated with severe visual impairment (P = 0.001). Conclusions. SJS/TEN patients caused by nonpharmaceutical triggers or antibiotics have an increased risk of developing long-term severe visual impairment from corneal neovascularization. HIV infection might be a protective factor against long-term poor visual outcomes.

  7. Memantine rescues transient cognitive impairment caused by high-molecular-weight aβ oligomers but not the persistent impairment induced by low-molecular-weight oligomers.

    PubMed

    Figueiredo, Cláudia P; Clarke, Julia R; Ledo, José Henrique; Ribeiro, Felipe C; Costa, Carine V; Melo, Helen M; Mota-Sales, Axa P; Saraiva, Leonardo M; Klein, William L; Sebollela, Adriano; De Felice, Fernanda G; Ferreira, Sergio T

    2013-06-05

    Brain accumulation of soluble amyloid-β oligomers (AβOs) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-weight (LMW) and high-molecular-weight (HMW) Aβ oligomers differentially impact synapses and memory. A single intracerebroventricular injection of LMW AβOs (10 pmol) induced rapid and persistent cognitive impairment in mice. On the other hand, memory deficit induced by HMW AβOs (10 pmol) was found to be reversible. While memory impairment in LMW oligomer-injected mice was associated with decreased hippocampal synaptophysin and GluN2B immunoreactivities, synaptic pathology was not detected in the hippocampi of HMW oligomer-injected mice. On the other hand, HMW oligomers, but not LMW oligomers, induced oxidative stress in hippocampal neurons. Memantine rescued both neuronal oxidative stress and the transient memory impairment caused by HMW oligomers, but did not prevent the persistent cognitive deficit induced by LMW oligomers. Results establish that different Aβ oligomer assemblies act in an orchestrated manner, inducing different pathologies and leading to synapse dysfunction. Furthermore, results suggest a mechanistic explanation for the limited efficacy of memantine in preventing memory loss in AD.

  8. Early Impairment of Long-Term Depression in the Perirhinal Cortex of a Mouse Model of Alzheimer's Disease

    PubMed Central

    Tamagnini, Francesco; Burattini, Costanza; Casoli, Tiziana; Balietti, Marta; Fattoretti, Patrizia

    2012-01-01

    Abstract Visual recognition memory is early impaired in Alzheimer's disease. Long-term depression of synaptic transmission in the perirhinal cortex is critically involved in this form of memory. We found that synaptic transmission was impaired in perirhinal cortex slices obtained from 3-month-old Tg2576 mice, and that 3,000 pulses at 5 Hz induced long-term depression in perirhinal cortex slices from age-matched control mice, but not in those from Tg2576 mice. To our knowledge, these data provide the first evidence of synaptic transmission and long-term depression impairment in the perirhinal cortex in an animal model of Alzheimer's disease, and the earliest synaptic deficit in Tg2576 mice. PMID:22533438

  9. Long Term Caregiving: Helping Families of Persons with Mild Cognitive Impairment Cope

    PubMed Central

    Austrom, Mary Guerriero; Lu, Yvonne

    2010-01-01

    The purpose of the paper is to describe common psychological and caregiving issues that can cause stress in family members of persons with mild cognitive impairment (PwMCI) in order to assist family members in providing care and support to the PwMCI while also caring for themselves over long periods of time. Because PwMCI and their family members have time to prepare for the future should the PwMCI no longer be able to participate in their own care, it is important that clinicians offer support, education, and referrals for services and interventions when needed. The results of a review and synthesis of the caregiving literature found that much information exists from educational and intervention programs designed to help caregivers of Alzheimer disease however little empirical information is available for clinicians to assist PwMCI and their family members. This paper provides valuable and practical information for clinicians and other care providers to assist family members of PwMCI to cope with the uncertainty of the diagnosis, prepare for the future, and manage their stress over the long-term. PMID:19689239

  10. Acute stress does not impair long-term memory retrieval in older people.

    PubMed

    Pulopulos, Matias M; Almela, Mercedes; Hidalgo, Vanesa; Villada, Carolina; Puig-Perez, Sara; Salvador, Alicia

    2013-09-01

    Previous studies have shown that stress-induced cortisol increases impair memory retrieval in young people. This effect has not been studied in older people; however, some findings suggest that age-related changes in the brain can affect the relationships between acute stress, cortisol and memory in older people. Our aim was to investigate the effects of acute stress on long-term memory retrieval in healthy older people. To this end, 76 participants from 56 to 76 years old (38 men and 38 women) were exposed to an acute psychosocial stressor or a control task. After the stress/control task, the recall of pictures, words and stories learned the previous day was assessed. There were no differences in memory retrieval between the stress and control groups on any of the memory tasks. In addition, stress-induced cortisol response was not associated with memory retrieval. An age-related decrease in cortisol receptors and functional changes in the amygdala and hippocampus could underlie the differences observed between the results from this study and those found in studies performed with young people.

  11. Psychiatric drug-induced Chronic Brain Impairment (CBI): implications for long-term treatment with psychiatric medication.

    PubMed

    Breggin, Peter R

    2011-01-01

    Understanding the hazards associated with long-term exposure to psychiatric drugs is very important but rarely emphasized in the scientific literature and clinical practice. Drawing on the scientific literature and clinical experience, the author describes the syndrome of Chronic Brain Impairment (CBI) which can be caused by any trauma to the brain including Traumatic Brain Injury (TBI), electroconvulsive therapy (ECT), and long-term exposure to psychiatric medications. Knowledge of the syndrome should enable clinicians to more easily identify long-term adverse effects caused by psychiatric drugs while enabling researchers to approach the problem with a more comprehensive understanding of the common elements of brain injury as they are manifested after long-term exposure to psychiatric medications. Treatment options are also discussed.

  12. Subregion-Specific p300 Conditional Knock-Out Mice Exhibit Long-Term Memory Impairments

    ERIC Educational Resources Information Center

    Oliveira, Ana M. M.; Estevez, Marcel A.; Hawk, Joshua D.; Grimes, Shannon; Brindle, Paul K.; Abel, Ted

    2011-01-01

    Histone acetylation plays a critical role during long-term memory formation. Several studies have demonstrated that the histone acetyltransferase (HAT) CBP is required during long-term memory formation, but the involvement of other HAT proteins has not been extensively investigated. The HATs CBP and p300 have at least 400 described interacting…

  13. Subregion-Specific p300 Conditional Knock-Out Mice Exhibit Long-Term Memory Impairments

    ERIC Educational Resources Information Center

    Oliveira, Ana M. M.; Estevez, Marcel A.; Hawk, Joshua D.; Grimes, Shannon; Brindle, Paul K.; Abel, Ted

    2011-01-01

    Histone acetylation plays a critical role during long-term memory formation. Several studies have demonstrated that the histone acetyltransferase (HAT) CBP is required during long-term memory formation, but the involvement of other HAT proteins has not been extensively investigated. The HATs CBP and p300 have at least 400 described interacting…

  14. Cocaine withdrawal impairs metabotropic glutamate receptor-dependent long-term depression in the nucleus accumbens.

    PubMed

    Huang, Chiung-Chun; Yeh, Che-Ming; Wu, Mei-Ying; Chang, Alice Y W; Chan, Julie Y H; Chan, Samuel H H; Hsu, Kuei-Sen

    2011-03-16

    Neuroadaptation in the nucleus accumbens (NAc), a central component of the mesolimbic dopamine (DA) system, has been implicated in the development of cocaine-induced psychomotor sensitization and relapse to cocaine seeking. However, little is known about the cellular and synaptic mechanisms underlying such adaptation. Using a mouse model of behavioral sensitization, we show that animals withdrawn from repeated cocaine exposure have a selective deficit in the ability to elicit metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) in the shell of the NAc in response to bath application of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG). Experiments conducted in the presence of the selective mGluR1 antagonists 7-(hydroxyimino)cyclopropachromen-carboxylate ethyl ester and (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid, or the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine, demonstrated that the impaired DHPG-LTD is likely attributable to a loss of mGluR5 function. Quantitative real-time reverse transcriptase-PCR and Western blot analysis revealed significant downregulation of mGluR5, but not mGluR1, mRNA and protein levels in the NAc shell. The inhibitory effect of repeated cocaine exposure on DHPG-LTD was selectively prevented when cocaine was coadministered with the selective D(1)-like DA receptor antagonist (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Furthermore, the levels of brain-derived neurotrophic factor (BDNF) protein in the NAc shell increased progressively after cocaine withdrawal, and the impairment of DHPG-LTD in the NAc shell was not found in slices from BDNF-knock-out mice after cocaine withdrawal. These results suggest that withdrawal from repeated cocaine exposure may result in increased BDNF levels in the NAc shell, which leads to a selective downregulation of mGluR5 and thereby impairs the induction of mGluR-dependent LTD.

  15. Assessment of cognitive impairment in long-term oxygen therapy-dependent COPD patients.

    PubMed

    Karamanli, Harun; Ilik, Faik; Kayhan, Fatih; Pazarli, Ahmet Cemal

    2015-01-01

    A number of studies have shown that COPD, particularly in its later and more severe stages, is associated with various cognitive deficits. Thus, the primary goal of the present study was to elucidate the extent of cognitive impairment in patients with long-term oxygen therapy-dependent (LTOTD) COPD. In addition, this study aimed to determine the effectiveness of two cognitive screening tests, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), for COPD patients and the ability of oxygen therapy to mitigate COPD-related deficits in cognitive function. The present study enrolled 45 subjects: 24 nonuser and 21 regular-user LTOTD-COPD patients. All subjects had a similar grade of education, and there were no significant differences regarding age or sex. The MoCA (cutoff: <26 points) and MMSE (cutoff: ≤24 points) scores were compared between these two groups. The nonuser LTOTD-COPD group had a significantly lower MoCA score than that of the regular-user LTOTD-COPD group (19.38±2.99 vs 21.68±2.14, respectively) as well as a significantly lower MMSE score. Moreover, the absence of supplemental oxygen therapy increased the risk of cognitive impairment (MoCA, P=0.007 and MMSE, P=0.014), and the MoCA and MMSE scores significantly correlated with the number of emergency admissions and the number of hospitalizations in the last year. In the present study, the nonuser LTOTD-COPD group exhibited a significant decrease in cognitive status compared with the regular-user LTOTD-COPD group. This suggests that the assessment of cognitive function in nonuser LTOTD-COPD patients and the use of protective strategies, such as continuous supplemental oxygen treatment, should be considered during the management of COPD in this population. In addition, the MoCA score was superior to the MMSE score for the determination of cognitive impairment in the nonuser LTOTD-COPD patients.

  16. Cholecystokinin-octapeptide restored morphine-induced hippocampal long-term potentiation impairment in rats.

    PubMed

    Wen, Di; Zang, Guoqing; Sun, DongLei; Yu, Feng; Mei, Dong; Ma, Chunling; Cong, Bin

    2014-01-24

    Cholecystokinin-octapeptide (CCK-8), which is a typical brain-gut peptide, exerts a wide range of biological activities on the central nervous system. We have previously reported that CCK-8 significantly alleviated morphine-induced amnesia and reversed spine density decreases in the CA1 region of the hippocampus in morphine-treated animals. Here, we investigated the effects of CCK-8 on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of rat dentate gyrus (DG) in acute saline or morphine-treated rats. Population spikes (PS), which were evoked by stimulation of the LPP, were recorded in the DG region. Acute morphine (30mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and CCK-8 (1μg, i.c.v.) restored the amplitude of PS that was attenuated by morphine injection. Furthermore, microinjection of CCK-8 (0.1 and 1μg, i.c.v.) also significantly augmented hippocampal LTP in saline-treated (1ml/kg, s.c.) rats. Pre-treatment of the CCK2 receptor antagonist L-365,260 (10μg, i.c.v) reversed the effects of CCK-8, but the CCK1 receptor antagonist L-364,718 (10μg, i.c.v) did not. The present results demonstrate that CCK-8 attenuates the effect of morphine on hippocampal LTP through CCK2 receptors and suggest an ameliorative function of CCK-8 on morphine-induced memory impairment.

  17. Validity of Motor Impairment Scale in Long-Term Care Insurance System of Korea

    PubMed Central

    Kim, Yeo Hyung; Kwon, Chan Hyuk

    2013-01-01

    Objective To validate the Motor Impairment Scale (MIS) of the Korean long-term care insurance (LTCI) system by comparing with the service time offered for aiding activities of daily living (ADL) and the ADL score. Methods A total of 407 elderly subjects without dementia who had used LTCI services were included in this study. Spearman correlations and multivariate linear regression models were employed to determine the relationship of the upper and lower limb MIS (U-MIS and L-MIS, respectively) to the service time and ADL. Stratified analyses for the facility group (n=121) and the domiciliary group (n=286) were performed. Results There were significant differences in characteristics between facility group and domiciliary group. The MIS was significantly correlated with service time in facility group (Spearman p=0.41 for U-MIS, Spearman p=0.40 for L-MIS). After adjusting for age, sex, and cognition score, U-MIS was an independent predictor for service time in facility group (p=0.04). In domiciliary group, no significant correlation was found between the MIS and service time. The MIS correlated with all of the ADL items and total ADL score in both groups. After adjusting for other factors including age, sex, and cognitive score, U-MIS and L-MIS were independent variables for explaining the total ADL score in both groups. Conclusion The validity of the MIS as an evaluation tool in the physically-disabled elderly is higher in facility group than in domiciliary group. As an easy, objective, and simple method, MIS can be a useful tool in the LTCI system of Korea. PMID:23869339

  18. Impaired long-term potentiation induction in dentate gyrus of calretinin-deficient mice

    PubMed Central

    Schurmans, Stéphane; Schiffmann, Serge N.; Gurden, Hirac; Lemaire, Martine; Lipp, Hans-Peter; Schwam, Valérie; Pochet, Roland; Imperato, Assunta; Böhme, Georg Andrees; Parmentier, Marc

    1997-01-01

    Calretinin (Cr) is a Ca2+ binding protein present in various populations of neurons distributed in the central and peripheral nervous systems. We have generated Cr-deficient (Cr−/−) mice by gene targeting and have investigated the associated phenotype. Cr−/− mice were viable, and a large number of morphological, biochemical, and behavioral parameters were found unaffected. In the normal mouse hippocampus, Cr is expressed in a widely distributed subset of GABAergic interneurons and in hilar mossy cells of the dentate gyrus. Because both types of cells are part of local pathways innervating dentate granule cells and/or pyramidal neurons, we have explored in Cr−/− mice the synaptic transmission between the perforant pathway and granule cells and at the Schaffer commissural input to CA1 pyramidal neurons. Cr−/− mice showed no alteration in basal synaptic transmission, but long-term potentiation (LTP) was impaired in the dentate gyrus. Normal LTP could be restored in the presence of the GABAA receptor antagonist bicuculline, suggesting that in Cr−/− dentate gyrus an excess of γ-aminobutyric acid (GABA) release interferes with LTP induction. Synaptic transmission and LTP were normal in CA1 area, which contains only few Cr-positive GABAergic interneurons. Cr−/− mice performed normally in spatial memory task. These results suggest that expression of Cr contributes to the control of synaptic plasticity in mouse dentate gyrus by indirectly regulating the activity of GABAergic interneurons, and that Cr−/− mice represent a useful tool to understand the role of dentate LTP in learning and memory. PMID:9294225

  19. Aluminium chloride impairs long-term memory and downregulates cAMP-PKA-CREB signalling in rats.

    PubMed

    Zhang, Lifeng; Jin, Cuihong; Lu, Xiaobo; Yang, Jinghua; Wu, Shengwen; Liu, Qiufang; Chen, Rong; Bai, Chunyu; Zhang, Di; Zheng, Linlin; Du, Yanqiu; Cai, Yuan

    2014-09-02

    Epidemiological investigations have indicated that aluminium (Al) is an important environmental neurotoxicant that may be involved in the aetiology of the cognitive dysfunction associated with neurodegenerative diseases. Additionally, exposure to Al is known to cause neurobehavioural abnormalities in animals. Previous studies demonstrated that Al impaired early-phase long-term potentiation (E-LTP) in vivo and in vitro. Our previous research revealed that Al could impair long-term memory via the impairment of late-phase long-term potentiation (L-LTP) in vivo. However, the exact mechanism by which Al impairs long-term memory has been poorly studied thus far. This study was designed not only to observe the effects of subchronic Al treatment on long-term memory and hippocampal ultrastructure but also to explore a possible underlying mechanism (involving the cAMP-PKA-CREB signalling pathway) in the hippocampus of rats.. Pregnant Wistar rats were assigned to four groups. Neonatal rats were exposed to Al by parental lactation for 3 weeks and then fed with distilled water containing 0, 0.2%, 0.4% or 0.6% Al chloride (AlCl3) for 3 postnatal months. The levels of Al in the blood and hippocampus were quantified by atomic absorption spectrophotometry. The shuttle-box test was performed to detect long-term memory. The hippocampus was collected for ultrastructure observation, and the level of cAMP-PKA-CREB signalling was examined. The results showed that the Al concentrations in the blood and hippocampus of Al-treated rats were higher than those of the control rats. Al may impair the long-term memory of rats. Hippocampal cAMP, cPKA, pCREB, BDNF and c-jun expression decreased significantly, and the neuronal and synaptic ultrastructure exhibited pathological changes after Al treatment. These results indicated that Al may induce long-term memory damage in rats by inhibiting cAMP-PKA-CREB signalling and altering the synaptic and neuronal ultrastructure in the hippocampus. Copyright

  20. Failure of delayed nonsynaptic neuronal plasticity underlies age-associated long-term associative memory impairment

    PubMed Central

    2012-01-01

    Background Cognitive impairment associated with subtle changes in neuron and neuronal network function rather than widespread neuron death is a feature of the normal aging process in humans and animals. Despite its broad evolutionary conservation, the etiology of this aging process is not well understood. However, recent evidence suggests the existence of a link between oxidative stress in the form of progressive membrane lipid peroxidation, declining neuronal electrical excitability and functional decline of the normal aging brain. The current study applies a combination of behavioural and electrophysiological techniques and pharmacological interventions to explore this hypothesis in a gastropod model (Lymnaea stagnalis feeding system) that allows pinpointing the molecular and neurobiological foundations of age-associated long-term memory (LTM) failure at the level of individual identified neurons and synapses. Results Classical appetitive reward-conditioning induced robust LTM in mature animals in the first quartile of their lifespan but failed to do so in animals in the last quartile of their lifespan. LTM failure correlated with reduced electrical excitability of two identified serotonergic modulatory interneurons (CGCs) critical in chemosensory integration by the neural network controlling feeding behaviour. Moreover, while behavioural conditioning induced delayed-onset persistent depolarization of the CGCs known to underlie appetitive LTM formation in this model in the younger animals, it failed to do so in LTM-deficient senescent animals. Dietary supplementation of the lipophilic anti-oxidant α-tocopherol reversed the effect of age on CGCs electrophysiological characteristics but failed to restore appetitive LTM function. Treatment with the SSRI fluoxetine reversed both the neurophysiological and behavioural effects of age in senior animals. Conclusions The results identify the CGCs as cellular loci of age-associated appetitive learning and memory

  1. Subregion-specific p300 conditional knock-out mice exhibit long-term memory impairments.

    PubMed

    Oliveira, Ana M M; Estévez, Marcel A; Hawk, Joshua D; Grimes, Shannon; Brindle, Paul K; Abel, Ted

    2011-01-01

    Histone acetylation plays a critical role during long-term memory formation. Several studies have demonstrated that the histone acetyltransferase (HAT) CBP is required during long-term memory formation, but the involvement of other HAT proteins has not been extensively investigated. The HATs CBP and p300 have at least 400 described interacting proteins including transcription factors known to play a role in long-term memory formation. Thus, CBP and p300 constitute likely candidates for transcriptional coactivators in memory formation. In this study, we took a loss-of-function approach to evaluate the role of p300 in long-term memory formation. We used conditional knock-out mice in which the deletion of p300 is restricted to the postnatal phase and to subregions of the forebrain. We found that p300 is required for the formation of long-term recognition memory and long-term contextual fear memory in the CA1 area of the hippocampus and cortical areas.

  2. Impaired Heart Rate Response to Exercise in Diabetes and Its Long-term Significance.

    PubMed

    Sydó, Nóra; Sydó, Tibor; Merkely, Béla; Carta, Karina Gonzales; Murphy, Joseph G; Lopez-Jimenez, Francisco; Allison, Thomas G

    2016-02-01

    To investigate the effect of diabetes mellitus on exercise heart rate and the role of impaired heart rate in excess mortality in diabetes. Patients without cardiovascular disease who underwent exercise testing from September 1, 1993, through December 31, 2010, were included. Mortality was determined from Mayo Clinic records and the Minnesota Death Index. Multivariate linear regression was used to compare heart rate responses in patients with vs without diabetes. Cox regression was used to determine the effect of abnormal heart rate recovery and abnormal chronotropic index on survival. A total of 21,396 patients (65.4% men) with a mean ± SD age of 51±11 years, including 1200 patients with diabetes (5.4%), were included. Patients with diabetes had a higher resting heart rate (81±14 vs 77±13 beats/min), lower peak heart rate (154±20 vs 165±19 beats/min), heart rate reserve (73±19 vs 88±19 beats/min), chronotropic index (0.86±0.22 vs 0.99±0.20), and heart rate recovery (15±8 vs 19±9 beats/min) vs patients without diabetes. There were 1362 deaths (6.4%) during a mean ± SD follow-up of 11.9±4.9 years. Adjusting for age, sex, and heart rate-lowering drug use, a chronotropic index less than 0.8 contributed significantly to risk in patients with diabetes (hazard ratio [HR], 2.21; 95% CI, 1.62-3.00; P<.001) and patients without diabetes (HR, 1.94; 95% CI, 1.71-2.20; P<.001), as did abnormal heart rate recovery (patients with diabetes: HR, 2.21; 95% CI, 1.60-5.05; P<.001; patients without diabetes: HR, 1.75; 95% CI, 1.55-1.97). Patients with diabetes exhibit abnormal heart rate responses to exercise, which are independently predictive of reduced long-term survival in patients with diabetes as in patients without diabetes. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  3. Long-term clinical effect of Tangyiping Granules () on patients with impaired glucose tolerance.

    PubMed

    Huang, Yan-Qin; Yang, Qing-Feng; Wang, Hua; Xu, Yun-Sheng; Peng, Wei; Jiang, Yue-Hua

    2016-09-01

    To evaluate the long-term clinical effect of Tangyiping Granules (, TYP) on patients with impaired glucose tolerance (IGT) to achieve normal glucose tolerance (NGT) and hence preventing them from conversion to diabetes mellitus (DM). In total, 127 participants with IGT were randomly assigned to the control (63 cases, 3 lost to follow-up) and treatment groups (64 cases, 4 lost to follow-up) according to the random number table. The control group received lifestyle intervention alone, while the patients in the treatment group took orally 10 g of TYP twice daily in addition to lifestyle intervention for 12 weeks. The rates of patients achieving NGT or experiencing conversion to DM as main outcome measure were observed at 3, 12, and 24 months after TYP treatment. The secondary outcome measures included fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2hPG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS), 2-h insulin (2hINS), homeostatic model assessment of insulin resistance (HOMA-IR), blood lipid and patients' complains of Chinese medicine (CM) symptoms before and after treatment. A higher proportion of the treatment group achieved NGT compared with the control group after 3-, 12- and 24-month follow-up (75.00% vs. 43.33%, 58.33% vs. 35.00%, 46.67% vs. 26.67%, respectively, P<0.05). The IGT to DM conversion rate of the treatment group was significantly lower than that of the control group at the end of 24-month follow-up (16.67% vs. 31.67%, P<0.05). Before treatment, FPG, 2hPG, HbA1c, FINS, 2hINS, HOMA-IR, triglyceride (TG), total cholesterol, low- and high-density lipoprotein cholesterol levels had no statistical difference between the two groups (P>0.05). After treatment, the 2hPG, HbA1c, HOMA-IR, and TG levels of the treatment group decreased significantly compared with those of the control group (P<0.05). CM symptoms such as exhaustion, irritability, chest tightness and breathless, spontaneous sweating, constipation, and dark thick and

  4. The compensatory effect of regular exercise on long-term memory impairment in sleep deprived female rats.

    PubMed

    Salari, Maryam; Sheibani, Vahid; Saadati, Hakimeh; Pourrahimi, Alimohammad; khaksarihadad, Mohammad; Esmaeelpour, Khadijeh; Khodamoradi, Mehdi

    2015-10-01

    Previous studies have been shown that exercise can improve short-term spatial learning, memory and synaptic plasticity impairments in sleep deprived female rats. The aim of the present study was to investigate the effects of treadmill exercise on sleep deprivation (SD) induced impairment in hippocampal dependent long-term memory in female rats. Intact and ovariectomized female rats were used in the current study. Exercise protocol was 4 weeks treadmill running. Twenty four hour SD was induced by using multiple platform apparatus after learning phase. Spatial learning and long-term memory was examined by using the Morris Water Maze (MWM) test. Our results indicated that sleep deprivation impaired long term memory in the intact and ovariectomized female rats, regardless of reproductive status (p<0.05) and treadmill exercise compensated this impairment (p<0.05). In conclusion the results of the current study confirmed the negative effect of SD on cognitive functions and regular exercise seems to protect rats from these factors, however more investigations need to be done. Copyright © 2015. Published by Elsevier B.V.

  5. Remote Lower White Matter Integrity Increases the Risk of Long-Term Cognitive Impairment After Ischemic Stroke in Young Adults.

    PubMed

    Schaapsmeerders, Pauline; Tuladhar, Anil M; Arntz, Renate M; Franssen, Sieske; Maaijwee, Noortje A M; Rutten-Jacobs, Loes C A; Schoonderwaldt, Hennie C; Dorresteijn, Lucille D A; van Dijk, Ewoud J; Kessels, Roy P C; de Leeuw, Frank-Erik

    2016-10-01

    Poststroke cognitive impairment occurs frequently in young patients with ischemic stroke (18 through 50 years of age). Accumulating data suggest that stroke is associated with lower white matter integrity remote from the stroke impact area, which might explain why some patients have good long-term cognitive outcome and others do not. Given the life expectancy of decades in young patients, we therefore investigated remote white matter in relation to long-term cognitive function. We included all consecutive first-ever ischemic stroke patients, left/right hemisphere, without recurrent stroke or transient ischemic attack during follow-up, aged 18 through 50 years, admitted to our university medical center between 1980 and 2010. One hundred seventeen patients underwent magnetic resonance imaging scanning including a T1-weighted scan, a diffusion tensor imaging scan, and completed a neuropsychological assessment. Patients were compared with a matched stroke-free control group (age, sex, and education matched). Cognitive impairment was defined as >1.5 SD below the mean cognitive index score of controls and no cognitive impairment as ≤1 SD. Tract-Based Spatial Statistics was used to assess the white matter integrity (fractional anisotropy and mean diffusivity). About 11 years after ischemic stroke, lower remote white matter integrity was associated with a worse long-term cognitive performance. A lower remote white matter integrity, even in the contralesional hemisphere, was observed in cognitively impaired patients (n=25) compared with cognitively unimpaired patients (n=71). These findings indicate that although stroke has an acute onset, it might have long lasting effects on remote white matter integrity and thereby increases the risk of long-term cognitive impairment. © 2016 American Heart Association, Inc.

  6. Intrahippocampal Glutamine Administration Inhibits mTORC1 Signaling and Impairs Long-Term Memory

    ERIC Educational Resources Information Center

    Rozas, Natalia S.; Redell, John B.; Pita-Almenar, Juan D.; McKenna, James, III.; Moore, Anthony N.; Gambello, Michael J.; Dash, Pramod K.

    2015-01-01

    The mechanistic Target of Rapamycin Complex 1 (mTORC1), a key regulator of protein synthesis and cellular growth, is also required for long-term memory formation. Stimulation of mTORC1 signaling is known to be dependent on the availability of energy and growth factors, as well as the presence of amino acids. In vitro studies using serum- and amino…

  7. Intrahippocampal Glutamine Administration Inhibits mTORC1 Signaling and Impairs Long-Term Memory

    ERIC Educational Resources Information Center

    Rozas, Natalia S.; Redell, John B.; Pita-Almenar, Juan D.; McKenna, James, III.; Moore, Anthony N.; Gambello, Michael J.; Dash, Pramod K.

    2015-01-01

    The mechanistic Target of Rapamycin Complex 1 (mTORC1), a key regulator of protein synthesis and cellular growth, is also required for long-term memory formation. Stimulation of mTORC1 signaling is known to be dependent on the availability of energy and growth factors, as well as the presence of amino acids. In vitro studies using serum- and amino…

  8. Factors associated with eating performance for long-term care residents with moderate-to-severe cognitive impairment.

    PubMed

    Liu, Wen; Galik, Elizabeth; Boltz, Marie; Nahm, Eun-Shim; Lerner, Nancy; Resnick, Barbara

    2016-02-01

    The aim of this study was to examine the association of specific personal and environmental factors with eating performance among long-term care residents with moderate-to-severe cognitive impairment. Eating is the one of the most basic and easiest activities of daily living to perform. While multilevel factors can be associated with eating performance, the evidence among those with dementia was insufficient. A secondary analysis of baseline data collected between March and September in 2012 from 199 residents in eight long-term care facilities. Eating performance was conceptualized using the single self-care 'feeding' item in the Barthel Index and was scored based on four levels of dependence and assistance required. Binary logistic regression was used to examine the adjusted association of specific factors with eating performance. Almost one-third of the residents needed help with eating. After adjusting the type of facility, number of comorbidities, chair-sitting balance, agitation and depression, compromised eating performance was associated with severe cognitive impairment and low physical capability. This study supported the association of eating performance with cognitive impairment and physical capability among long-term care residents with moderate-to-severe cognitive impairment. Targeted interventions should be implemented to reduce the impact of cognitive decline on eating performance and promote physical capability to optimize eating performance. Future work need to use validated multiple-item measures for eating performance and test the association of personal and environmental factors with eating performance among a larger heterogeneous group of long-term care residents to enhance understanding of the factors. © 2015 John Wiley & Sons Ltd.

  9. Impairments of long-term depression induction and motor coordination precede Aβ accumulation in the cerebellum of APPswe/PS1dE9 double transgenic mice.

    PubMed

    Kuwabara, Yuki; Ishizeki, Masato; Watamura, Naoto; Toba, Junya; Yoshii, Aya; Inoue, Takafumi; Ohshima, Toshio

    2014-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder that represents the most common type of dementia among elderly people. Amyloid beta (Aβ) peptides in extracellular Aβ plaques, produced from the amyloid precursor protein (APP) via sequential processing by β- and γ-secretases, impair hippocampal synaptic plasticity, and cause cognitive dysfunction in AD patients. Here, we report that Aβ peptides also impair another form of synaptic plasticity; cerebellar long-term depression (LTD). In the cerebellum of commonly used AD mouse model, APPswe/PS1dE9 mice, Aβ plaques were detected from 8 months and profound accumulation of Aβ plaques was observed at 18 onths of age. Biochemical analysis revealed relatively high levels of APP protein and Aβ in the cerebellum of APPswe/PS1dE9 mice. At pre-Aβ accumulation stage, LTD induction, and motor coordination are disturbed. These results indicate that soluble Aβ oligomers disturb LTD induction and cerebellar function in AD mouse model. © 2014 International Society for Neurochemistry.

  10. Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors.

    PubMed

    Chung, Woosuk; Park, Saegeun; Hong, Jiso; Park, Sangil; Lee, Soomin; Heo, Junyoung; Kim, Daesoo; Ko, Youngkwon

    2015-10-01

    To examine whether neonatal exposure to sevoflurane induces autism-like behaviors in mice. There are continuing reports regarding the potential negative effects of anesthesia on the developing brain. Recently, several studies suggest that neurotoxicity caused by anesthesia may lead to neurodevelopmental impairments. However, unlike reports focusing on learning and memory, there are only a few animal studies focusing on neurodevelopmental disorders after general anesthesia. Therefore, we have focused on autism, a representative neurodevelopmental disorder. Neonatal mice (P6-7) were exposed to a titrated dose of sevoflurane for 6 h. Apoptosis was evaluated by assessing the expression level of cleaved (activated) caspase-3. Autism-like behaviors, general activity, anxiety level, and long-term memory were evaluated with multiple behavioral assays. Western blotting confirmed that neonatal exposure to sevoflurane increased the expression level of activated caspase-3, indicative of apoptosis. Mice exposed to sevoflurane also showed impaired long-term memory in fear tests. However, sevoflurane-exposed mice did not exhibit autism-like features in all of the following assays: social interaction (three-chamber test, caged social interaction), social communication (ultrasonic vocalization test), or repetitive behavior (self-grooming test, digging). There were also no differences in general activity (open field test, home cage activity) and anxiety (open field test, light-dark box) after sevoflurane exposure. Our results confirm previous studies that neonatal sevoflurane exposure causes neurodegeneration and long-term memory impairment in mice. However, sevoflurane did not induce autism-like features. Our study suggests that mice are more vulnerable to long-term memory deficits than autism-like behaviors after exposure to sevoflurane. © 2015 John Wiley & Sons Ltd.

  11. Rescue of impaired long-term facilitation at sensorimotor synapses of Aplysia following siRNA knockdown of CREB1.

    PubMed

    Zhou, Lian; Zhang, Yili; Liu, Rong-Yu; Smolen, Paul; Cleary, Leonard J; Byrne, John H

    2015-01-28

    Memory impairment is often associated with disrupted regulation of gene induction. For example, deficits in cAMP response element-binding protein (CREB) binding protein (CBP; an essential cofactor for activation of transcription by CREB) impair long-term synaptic plasticity and memory. Previously, we showed that small interfering RNA (siRNA)-induced knockdown of CBP in individual sensory neurons significantly reduced levels of CBP and impaired 5-HT-induced long-term facilitation (LTF) in sensorimotor cocultures from Aplysia. Moreover, computational simulations of the biochemical cascades underlying LTF successfully predicted training protocols that restored LTF following CBP knockdown. We examined whether simulations could also predict a training protocol that restores LTF impaired by siRNA-induced knockdown of the transcription factor CREB1. Simulations based on a previously described model predicted rescue protocols that were specific to CREB1 knockdown. Empirical studies demonstrated that one of these rescue protocols partially restored impaired LTF. In addition, the effectiveness of the rescue protocol was enhanced by pretreatment with rolipram, a selective cAMP phosphodiesterase inhibitor. These results provide further evidence that computational methods can help rescue disruptions in signaling cascades underlying memory formation. Moreover, the study demonstrates that the effectiveness of computationally designed training protocols can be enhanced with complementary pharmacological approaches.

  12. Rescue of Impaired Long-Term Facilitation at Sensorimotor Synapses of Aplysia following siRNA Knockdown of CREB1

    PubMed Central

    Zhou, Lian; Zhang, Yili; Liu, Rong-Yu; Smolen, Paul; Cleary, Leonard J.

    2015-01-01

    Memory impairment is often associated with disrupted regulation of gene induction. For example, deficits in cAMP response element-binding protein (CREB) binding protein (CBP; an essential cofactor for activation of transcription by CREB) impair long-term synaptic plasticity and memory. Previously, we showed that small interfering RNA (siRNA)-induced knockdown of CBP in individual sensory neurons significantly reduced levels of CBP and impaired 5-HT-induced long-term facilitation (LTF) in sensorimotor cocultures from Aplysia. Moreover, computational simulations of the biochemical cascades underlying LTF successfully predicted training protocols that restored LTF following CBP knockdown. We examined whether simulations could also predict a training protocol that restores LTF impaired by siRNA-induced knockdown of the transcription factor CREB1. Simulations based on a previously described model predicted rescue protocols that were specific to CREB1 knockdown. Empirical studies demonstrated that one of these rescue protocols partially restored impaired LTF. In addition, the effectiveness of the rescue protocol was enhanced by pretreatment with rolipram, a selective cAMP phosphodiesterase inhibitor. These results provide further evidence that computational methods can help rescue disruptions in signaling cascades underlying memory formation. Moreover, the study demonstrates that the effectiveness of computationally designed training protocols can be enhanced with complementary pharmacological approaches. PMID:25632137

  13. LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent

    PubMed Central

    Puzzo, Daniela; Piacentini, Roberto; Fá, Mauro; Gulisano, Walter; Li Puma, Domenica D; Staniszewski, Agnes; Zhang, Hong; Tropea, Maria Rosaria; Cocco, Sara; Palmeri, Agostino; Fraser, Paul; D'Adamio, Luciano; Grassi, Claudio; Arancio, Ottavio

    2017-01-01

    The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAβ and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oAβ, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oAβ and oTau requires expression of APP. Finally, the toxic effect of both extracellular oAβ and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oAβ- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of Aβ and/or Tau. DOI: http://dx.doi.org/10.7554/eLife.26991.001 PMID:28696204

  14. Nicotine blocks stress-induced impairment of spatial memory and long-term potentiation of the hippocampal CA1 region.

    PubMed

    Aleisa, Abdulaziz M; Alzoubi, Karem H; Gerges, Nashaat Z; Alkadhi, Karim A

    2006-08-01

    The effect of chronic nicotine treatment on chronic psychosocial stress-induced impairment of short-term memory and long-term potentiation (LTP) was determined. An "intruder" stress model was used to induce psychosocial stress for 4-6 wk, during which rats were injected with saline or nicotine (1 mg/kg s.c.) twice a day. The radial arm water maze memory task was used to test hippocampus-dependent spatial memory. Chronic psychosocial stress impaired short-term memory without affecting the learning phase or long-term memory. Concurrent chronic nicotine treatment prevented stress-induced short-term memory impairment. In normal rats chronic nicotine treatment had no effect on learning and memory. Extracellular recordings from the CA1 region of anaesthetized rats showed severe reduction of LTP magnitude in stressed rats, which was normalized in nicotine-treated stressed rats. Nicotine had no effect on LTP in control animals. These results showed that chronic nicotine treatment improved hippocampus-dependent spatial memory and LTP only when impaired by stress.

  15. 40 CFR 51.306 - Long-term strategy requirements for reasonably attributable visibility impairment.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... impairment of visibility in any mandatory Class I Federal area. (c) The plan must provide for periodic review... visibility impairment. The plan must provide for such periodic review and revision not less frequently than... for periodic progress reports set forth in § 51.308(g). Until the State revises its plan to meet this...

  16. 40 CFR 51.306 - Long-term strategy requirements for reasonably attributable visibility impairment.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... impairment of visibility in any mandatory Class I Federal area. (c) The plan must provide for periodic review... visibility impairment. The plan must provide for such periodic review and revision not less frequently than... for periodic progress reports set forth in § 51.308(g). Until the State revises its plan to meet this...

  17. A ketogenic diet does not impair rat behavior or long-term potentiation.

    PubMed

    Thio, Liu Lin; Rensing, Nicholas; Maloney, Susan; Wozniak, David F; Xiong, Chengjie; Yamada, Kelvin A

    2010-08-01

    The effect of the ketogenic diet on behavior and cognition is unclear. We addressed this issue in rats behaviorally and electrophysiologically.We fed postnatal day 21 rats a standard diet (SD), ketogenic diet (KD), or calorie-restricted diet (CR) for 2–3 weeks. CR controlled for the slower weight gain experienced by KD-fed rats. We assessed behavioral performance with a locomotor activity and a conditioned fear test. To evaluate possible parallel effects of diet on synaptic function, we examined paired-pulse modulation (PPM) and long-term potentiation (LTP) in the medial perforant path in vivo. KD-fed rats performed similarly to SD-fed rats on the behavioral tests and electrophysiologic assays. These data suggest that the KD does not alter behavioral performance or synaptic plasticity.

  18. Long-term social isolation in the adulthood results in CA1 shrinkage and cognitive impairment.

    PubMed

    Pereda-Pérez, Inmaculada; Popović, Natalija; Otalora, Beatriz Baño; Popović, Miroljub; Madrid, Juan Antonio; Rol, Maria Angeles; Venero, César

    2013-11-01

    Social isolation in adulthood is a psychosocial stressor that can result in endocrinological and behavioral alterations in different species. In rodents, controversial results have been obtained in fear conditioning after social isolation at adulthood, while neural substrates underlying these differences are largely unknown. Neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) are prominent modulators of synaptic plasticity underlying memory processes in many tasks, including fear conditioning. In this study, we used adult female Octodon degus to investigate the effects of long-term social isolation on contextual and cued fear conditioning, and the possible modulation of the synaptic levels of NCAM and PSA-NCAM in the hippocampus. After 6½ months of social isolation, adult female degus showed a normal auditory-cued fear memory, but a deficit in contextual fear memory, a hippocampal dependent task. Subsequently, we observed reduced hippocampal synaptic levels of PSA-NCAM in isolated compared to grouped-housed female degus. No significant differences were found between experimental groups in hippocampal levels of the three main isoforms of NCAM (NCAM180, NCAM140 and NCAM120). Interestingly, social isolation reduced the volume of the hippocampal CA1 subfield, without affecting the volume of the CA3 subregion or the total hippocampus. Moreover, attenuated body weight gain and reduced number of granulocytes were detected in isolated animals. Our findings indicate for the first time, that long-term social isolation of adult female animals induces a specific shrinkage of CA1 and a decrease in synaptic levels of PSA-NCAM in the hippocampus. These effects may be related to the deficit in contextual fear memory observed in isolated female degus.

  19. Hypertension impairs hippocampus-related adult neurogenesis, CA1 neuron dendritic arborization and long-term memory.

    PubMed

    Shih, Y-H; Tsai, S-F; Huang, S-H; Chiang, Y-T; Hughes, M W; Wu, S-Y; Lee, C-W; Yang, T-T; Kuo, Y-M

    2016-05-13

    Hypertension is associated with neurodegenerative diseases and cognitive impairment. Several studies using spontaneous hypertensive rats to study the effect of hypertension on memory performance and adult hippocampal neurogenesis have reached inconsistent conclusions. The contradictory findings may be related to the genetic variability of spontaneous hypertensive rats due to the conventional breeding practices. The objective of this study is to examine the effect of hypertension on hippocampal structure and function in isogenic mice. Hypertension was induced by the '2 kidneys, 1 clip' method (2K1C) which constricted one of the two renal arteries. The blood pressures of 2K1C mice were higher than the sham group on post-operation day 7 and remained high up to day 28. Mice with 2K1C-induced hypertension had impaired long-term, but not short-term, memory. Dendritic complexity of CA1 neurons and hippocampal neurogenesis were reduced by 2K1C-induced hypertension on post-operation day 28. Furthermore, 2K1C decreased the levels of hippocampal brain-derived neurotrophic factor, while blood vessel density and activation status of astrocytes and microglia were not affected. In conclusion, hypertension impairs hippocampus-associated long-term memory, dendritic arborization and neurogenesis, which may be caused by down-regulation of brain-derived neurotrophic factor signaling pathways.

  20. Hyperammonemia impairs NMDA receptor-dependent long-term potentiation in the CA1 of rat hippocampus in vitro.

    PubMed

    Muñoz, M D; Monfort, P; Gaztelu, J M; Felipo, V

    2000-04-01

    Hyperammonemia is considered the main factor responsible for the neurological and cognitive alterations found in hepatic encephalopathy and in patients with congenital deficiencies of the urea cycle enzymes. The underlying mechanisms remain unclear. Chronic moderate hyperammonemia reduces nitric oxide-induced activation of soluble guanylate cyclase and glutamate-induced formation of cGMP. NMDA receptor-associated transduction pathways, including activation of soluble guanylate cyclase, are involved in the induction of long-term potentiation (LTP), a phenomenon that is considered to be the molecular basis for some forms of memory and learning. Using an animal model we show that chronic hyperammonemia significantly reduces the degree of long-term potentiation induced in the CA1 of hippocampus slices (200% increase in control and 50% increase in slices of hyperammonemic animals). Also, addition of 1 mM ammonia impaired the maintenance of non-decremental LTP. The LTP impairment could be involved in the intellectual impairment present in chronic hepatocerebral disorders associated with hyperammonemia.

  1. Long-Term Habituation to Repeated Loud Noise Is Impaired by Relatively Short Interstressor Intervals in Rats

    PubMed Central

    Masini, Cher V.; Day, Heidi E. W.; Campeau, Serge

    2008-01-01

    The phenomenon of spaced (longer intertrial interval) compared with massed (shorter intertrial interval) training leading to better long-term habituation and associative learning is well documented. However, the effects of intertrial intervals on response habituation to repeated stress exposures have not been previously examined. The present experiments found that massed (six 30-min exposures of 95 dB white noise in 6 hr) and spaced (one 30-min exposure daily for 6 days) noise exposures led to similar habituation of plasma corticosterone and ACTH responses, heart rate, and core body temperature after the 6th exposure in male Sprague–Dawley rats. However, these habituated responses were not retained in the massed group on a similar noise re-exposure 48 hr later, compared with the spaced group. The habituated responses found in the massed group after the 6 noise exposures were not due to differential hearing threshold shifts, as examined with modifications of the acoustic startle reflex. These data indicate that relatively short interstressor intervals impair long-term stress adaptation. This series of studies supports the idea of distinct short- and long-term habituation processes to stress responsiveness. PMID:18298264

  2. Long-term habituation to repeated loud noise is impaired by relatively short interstressor intervals in rats.

    PubMed

    Masini, Cher V; Day, Heidi E W; Campeau, Serge

    2008-02-01

    The phenomenon of spaced (longer intertrial interval) compared with massed (shorter intertrial interval) training leading to better long-term habituation and associative learning is well documented. However, the effects of intertrial intervals on response habituation to repeated stress exposures have not been previously examined. The present experiments found that massed (six 30-min exposures of 95 dB white noise in 6 hr) and spaced (one 30-min exposure daily for 6 days) noise exposures led to similar habituation of plasma corticosterone and ACTH responses, heart rate, and core body temperature after the 6th exposure in male Sprague-Dawley rats. However, these habituated responses were not retained in the massed group on a similar noise re-exposure 48 hr later, compared with the spaced group. The habituated responses found in the massed group after the 6 noise exposures were not due to differential hearing threshold shifts, as examined with modifications of the acoustic startle reflex. These data indicate that relatively short interstressor intervals impair long-term stress adaptation. This series of studies supports the idea of distinct short- and long-term habituation processes to stress responsiveness.

  3. Depletion of Serotonin Selectively Impairs Short-Term Memory without Affecting Long-Term Memory in Odor Learning in the Terrestrial Slug "Limax Valentianus"

    ERIC Educational Resources Information Center

    Santa, Tomofumi; Kirino, Yutaka; Watanabe, Satoshi; Shirahata, Takaaki; Tsunoda, Makoto

    2006-01-01

    The terrestrial slug "Limax" is able to acquire short-term and long-term memories during aversive odor-taste associative learning. We investigated the effect of the selective serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) on memory. Behavioral studies indicated that 5,7-DHT impaired short-term memory but not long-term memory. HPLC…

  4. Depletion of Serotonin Selectively Impairs Short-Term Memory without Affecting Long-Term Memory in Odor Learning in the Terrestrial Slug "Limax Valentianus"

    ERIC Educational Resources Information Center

    Santa, Tomofumi; Kirino, Yutaka; Watanabe, Satoshi; Shirahata, Takaaki; Tsunoda, Makoto

    2006-01-01

    The terrestrial slug "Limax" is able to acquire short-term and long-term memories during aversive odor-taste associative learning. We investigated the effect of the selective serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) on memory. Behavioral studies indicated that 5,7-DHT impaired short-term memory but not long-term memory. HPLC…

  5. Stress Administered Prior to Encoding Impairs Neutral but Enhances Emotional Long-Term Episodic Memories

    ERIC Educational Resources Information Center

    Payne, Jessica D.; Jackson, Eric D.; Hoscheidt, Siobhan; Ryan, Lee; Jacobs, W. Jake; Nadel, Lynn

    2007-01-01

    Stressful events frequently comprise both neutral and emotionally arousing information, yet the impact of stress on emotional and neutral events is still not fully understood. The hippocampus and frontal cortex have dense concentrations of receptors for stress hormones, such as cortisol, which at high levels can impair performance on hippocampally…

  6. Sustained Impairments in Cutaneous Vasodilation and Sweating in Grafted Skin Following Long-Term Recovery

    PubMed Central

    Davis, Scott L.; Shibasaki, Manabu; Low, David A.; Cui, Jian; Keller, David M.; Wingo, Jonathan E.; Purdue, Gary F.; Hunt, John L.; Arnoldo, Brett D.; Kowalske, Karen J.; Crandall, Craig G.

    2009-01-01

    We previously identified impaired cutaneous vasodilation and sweating in grafted skin 5 to 9 months postsurgery. The aim of this investigation was to test the hypothesis that cutaneous vasodilation, but not sweating, is restored as the graft heals. Skin blood flow and sweat rate were assessed from grafted skin and adjacent noninjured skin in three groups of subjects: 5 to 9 months postsurgery (n = 13), 2 to 3 years postsurgery (n = 13), and 4 to 8 years postsurgery (n = 13) during three separate protocols: 1) whole-body heating and cooling, 2) local administration of vasoactive drugs, and 3) local heating and cooling. Cutaneous vasodilation and sweating during whole-body heating were significantly lower (P < .001) in grafted skin when compared with noninjured skin across all groups and demonstrated no improvements with recovery time postsurgery. Maximal endothelial-dependent (acetylcholine) and endothelial-independent (sodium nitroprusside) cutaneous vasodilation remained attenuated (P < .001) in grafted skin up to 4 to 8 years postsurgery, indicating postsynaptic impairments. In grafted skin, cutaneous vasoconstriction during whole-body and local cooling was preserved, whereas vasodilation to local heating was impaired, regardless of the duration postsurgery. Split-thickness skin grafts have impaired cutaneous vasodilation and sweating up to 4 to 8 years postsurgery, thereby limiting the capability of this skin’s contribution to thermoregulation during a heats stress. In contrast, grafted skin has preserved vasoconstrictor capacity. PMID:19506504

  7. Stress Administered Prior to Encoding Impairs Neutral but Enhances Emotional Long-Term Episodic Memories

    ERIC Educational Resources Information Center

    Payne, Jessica D.; Jackson, Eric D.; Hoscheidt, Siobhan; Ryan, Lee; Jacobs, W. Jake; Nadel, Lynn

    2007-01-01

    Stressful events frequently comprise both neutral and emotionally arousing information, yet the impact of stress on emotional and neutral events is still not fully understood. The hippocampus and frontal cortex have dense concentrations of receptors for stress hormones, such as cortisol, which at high levels can impair performance on hippocampally…

  8. Environmental Novelty Activates β2-Adrenergic Signaling to Prevent the Impairment of Hippocampal LTP by Aβ Oligomers

    PubMed Central

    Li, Shaomin; Jin, Ming; Zhang, Dainan; Yang, Ting; Koeglsperger, Thomas; Fu, Hongjun; Selkoe, Dennis J.

    2013-01-01

    Summary A central question about human brain aging is whether cognitive enrichment slows the development of Alzheimer changes. Here we show that prolonged exposure to an enriched environment (EE) facilitated signaling in the hippocampus of wild-type mice that promoted long-term potentiation. A key feature of the EE effect was activation of β2-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid β-protein (Aβ) isolated from AD cortex. Protection by EE occurred in both young and middle-aged wild-type mice. Exposure to novelty afforded greater protection than did aerobic exercise. Mice chronically fed a β-adrenergic agonist without EE were protected from hippocampal impairment by Aβ oligomers. Thus, EE enhances hippocampal synaptic plasticity by activating β-adrenoceptor signaling and mitigating synaptotoxicity of human Aβ oligomers. These mechanistic insights support using prolonged exposure to cognitive novelty and/or oral β-adrenergic agonists to lessen the effects of Aβ accumulation during aging. PMID:23473322

  9. Spatial memory and long-term object recognition are impaired by circadian arrhythmia and restored by the GABAAAntagonist pentylenetetrazole.

    PubMed

    Ruby, Norman F; Fernandez, Fabian; Garrett, Alex; Klima, Jessy; Zhang, Pei; Sapolsky, Robert; Heller, H Craig

    2013-01-01

    Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopus sungorus) [corrected] so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN), but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day) to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome) mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus.

  10. Repeated Neonatal Propofol Administration Induces Sex-Dependent Long-Term Impairments on Spatial and Recognition Memory in Rats

    PubMed Central

    Gonzales, Edson Luck T.; Yang, Sung Min; Choi, Chang Soon; Mabunga, Darine Froy N.; Kim, Hee Jin; Cheong, Jae Hoon; Ryu, Jong Hoon; Koo, Bon-Nyeo; Shin, Chan Young

    2015-01-01

    Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner. PMID:25995824

  11. Spatial Memory and Long-Term Object Recognition Are Impaired by Circadian Arrhythmia and Restored by the GABAAAntagonist Pentylenetetrazole

    PubMed Central

    Ruby, Norman F.; Fernandez, Fabian; Garrett, Alex; Klima, Jessy; Zhang, Pei; Sapolsky, Robert; Heller, H. Craig

    2013-01-01

    Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopussungorus) so that we could investigate the contribution of the circadian system to learning and memory in animals that are neurologically and genetically intact. Male and female adult hamsters were rendered arrhythmic by a disruptive phase shift protocol that eliminates cycling of clock genes within the suprachiasmatic nucleus (SCN), but preserves sleep architecture. These arrhythmic animals have deficits in spatial working memory and in long-term object recognition memory. In a T-maze, rhythmic control hamsters exhibited spontaneous alternation behavior late in the day and at night, but made random arm choices early in the day. By contrast, arrhythmic animals made only random arm choices at all time points. Control animals readily discriminated novel objects from familiar ones, whereas arrhythmic hamsters could not. Since the SCN is primarily a GABAergic nucleus, we hypothesized that an arrhythmic SCN could interfere with memory by increasing inhibition in hippocampal circuits. To evaluate this possibility, we administered the GABAA antagonist pentylenetetrazole (PTZ; 0.3 or 1.0 mg/kg/day) to arrhythmic hamsters for 10 days, which is a regimen previously shown to produce long-term improvements in hippocampal physiology and behavior in Ts65Dn (Down syndrome) mice. PTZ restored long-term object recognition and spatial working memory for at least 30 days after drug treatment without restoring circadian rhythms. PTZ did not augment memory in control (entrained) animals, but did increase their activity during the memory tests. Our findings support the hypothesis that circadian arrhythmia impairs declarative memory by increasing the relative influence of GABAergic inhibition in the hippocampus. PMID:24009680

  12. Long-term ovo-lacto vegetarian diet impairs vitamin B-12 status in pregnant women.

    PubMed

    Koebnick, Corinna; Hoffmann, Ingrid; Dagnelie, Pieter C; Heins, Ulrike A; Wickramasinghe, Sunitha N; Ratnayaka, Indrika D; Gruendel, Sindy; Lindemans, Jan; Leitzmann, Claus

    2004-12-01

    A well-planned vegetarian diet has been stated to be adequate during pregnancy. The aim of the present study was to compare serum vitamin B-12 and homocysteine concentrations in pregnant women (n = 109) consuming vegetarian and Western diets and to evaluate the adequacy of current dietary reference intakes of vitamin B-12 for these women. Pregnant women adhering to vegetarian diets for at least 3 y, with subgroups of ovo-lacto vegetarians (OLVs; n = 27), low-meat eaters (LME, n = 43), and women eating an average Western diet (control group, n = 39), were recruited. Dietary vitamin B-12 intake, serum vitamin B-12, and plasma total homocysteine (tHcy) concentrations were measured in wk 9-12, 20-22, and 36-38 of pregnancy. During pregnancy serum vitamin B-12 concentrations of ovo-lacto vegetarians (P < 0.001) and low-meat eaters (P = 0.050) were lower than those of the control group. We observed the combination of low serum vitamin B-12 concentrations and elevated plasma tHcy in 22% of ovo-lacto vegetarians, in 10% of low-meat eaters, and in 3% of controls (P = 0.003). In OLVs, serum vitamin B-12 predicted 60% of the plasma tHcy variation (P < 0.001), but in LMEs and controls only <10% (NS). Serum vitamin B-12 concentrations increased and plasma tHcy decreased sharply with increasing dietary intake of vitamin B-12 toward a cutoff point of 3 mug/d. Pregnant women consuming a long-term predominantly vegetarian diet have an increased risk of vitamin B-12 deficiency. Current recommended dietary intakes urgently need reevaluation.

  13. 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.

  14. Long-Term Heavy Ketamine Use is Associated with Spatial Memory Impairment and Altered Hippocampal Activation

    PubMed Central

    Morgan, Celia J. A.; Dodds, Chris M.; Furby, Hannah; Pepper, Fiona; Fam, Johnson; Freeman, Tom P.; Hughes, Emer; Doeller, Christian; King, John; Howes, Oliver; Stone, James M.

    2014-01-01

    Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 poly-drug controls, matched for IQ, age, years in education. We used fMRI utilizing an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus, and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users. PMID:25538631

  15. Long-term behavioral impairment following acute embryonic ethanol exposure in zebrafish.

    PubMed

    Bailey, J M; Oliveri, A N; Zhang, C; Frazier, J M; Mackinnon, S; Cole, G J; Levin, E D

    2015-01-01

    Developmental exposure to ethanol has long been known to cause persisting neurobehavioral impairment. However, the neural and behavioral mechanisms underlying these deficits and the importance of exposure timing are not well-characterized. Given the importance of timing and sequence in neurodevelopment it would be expected that alcohol intoxication at different developmental periods would result in distinct neurobehavioral consequences. Zebrafish embryos were exposed to ethanol (0%, 1%, 3%) at either 8-10 or 24-27 h post-fertilization (hpf) then reared to adolescence and evaluated on several behavioral endpoints. Habituation to a repeated environmental stimulus and overall sensorimotor function were assessed using a tap startle test; measurements of anxiety and exploration behavior were made following introduction to a novel tank; and spatial discrimination learning was assessed using aversive control in a three-chambered apparatus. Overt signs of dysmorphogenesis were also scored (i.e. craniofacial malformations, including eye diameter and midbrain-hindbrain boundary morphology). Ethanol treated fish were more active both at baseline and following a tap stimulus compared to the control fish and were hyperactive when placed in a novel tank. These effects were more prominent following exposure at 24-27 hpf than with the earlier exposure window, for both dose groups. Increases in physical malformation were only present in the 3% ethanol group; all malformed fish were excluded from behavioral testing. These results suggest specific domains of behavior are affected following ethanol exposure, with some but not all of the tests revealing significant impairment. The behavioral phenotypes following distinct exposure windows described here can be used to help link cellular and molecular mechanisms of developmental ethanol exposure to functional neurobehavioral effects. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice.

    PubMed

    Kennedy, Bruce C; Dimova, Jiva G; Dakoji, Srikanth; Yuan, Li-Lian; Gewirtz, Jonathan C; Tran, Phu V

    2016-07-01

    The mounting of appropriate emotional and neuroendocrine responses to environmental stressors critically depends on the hypothalamic-pituitary-adrenal (HPA) axis and associated limbic circuitry. Although its function is currently unknown, the highly evolutionarily conserved transmembrane protein 35 (TMEM35) is prominently expressed in HPA circuitry and limbic areas, including the hippocampus and amygdala. To investigate the possible involvement of this protein in neuroendocrine function, we generated tmem35 knockout (KO) mice to characterize the endocrine, behavioral, electrophysiological, and proteomic alterations caused by deletion of the tmem35 gene. While capable of mounting a normal corticosterone response to restraint stress, KO mice showed elevated basal corticosterone accompanied by increased anxiety-like behavior. The KO mice also displayed impairment of hippocampus-dependent fear and spatial memories. Given the intact memory acquisition but a deficit in memory retention in the KO mice, TMEM35 is likely required for long-term memory consolidation. This conclusion is further supported by a loss of long-term potentiation in the Schaffer collateral-CA1 pathway in the KO mice. To identify putative molecular pathways underlying alterations in plasticity, proteomic analysis of synaptosomal proteins revealed lower levels of postsynaptic molecules important for synaptic plasticity in the KO hippocampus, including PSD95 and N-methyl-d-aspartate receptors. Pathway analysis (Ingenuity Pathway Analysis) of differentially expressed synaptic proteins in tmem35 KO hippocampus implicated molecular networks associated with specific cellular and behavioral functions, including decreased long-term potentiation, and increased startle reactivity and locomotion. Collectively, these data suggest that TMEM35 is a novel factor required for normal activity of the HPA axis and limbic circuitry. Copyright © 2016 the American Physiological Society.

  17. Negative illness perceptions are associated with impaired quality of life in patients after long-term remission of Cushing's syndrome.

    PubMed

    Tiemensma, Jitske; Kaptein, Adrian A; Pereira, Alberto M; Smit, Johannes W A; Romijn, Johannes A; Biermasz, Nienke R

    2011-10-01

    Illness perceptions pertain to the pattern of beliefs patients develop about their illness. Illness perceptions are determinants of quality of life (QoL). Factors contributing to persisting impaired QoL after Cushing's syndrome (CS) remain largely unknown. Therefore, the objective of this study was to explore illness perceptions, as potentially modifiable psychological factors, in relation to QoL in patients with long-term remission of CS. Cross-sectional study. We included patients with long-term remission of CS (n=52). Illness perceptions were evaluated using the Illness Perception Questionnaire (IPQ)-Revised, and QoL was measured using the physical symptom checklist, EuroQoL-5D (EQ-5D), and the CushingQoL. Reference data were derived from recent studies and included patients with vestibular schwannoma (n=80), acute (n=35) or chronic (n=63) pain, and chronic obstructive pulmonary disease (COPD; n=171). Illness perceptions showed a strong correlation with QoL. Patients with CS scored distinctively more negative on the IPQ compared with patients with vestibular schwannoma and patients with acute pain, and also reported more illness-related complaints (all P<0.01). There were also some differences in illness perceptions between patients with CS and patients with chronic pain and patients with COPD, but there was no distinct pattern. Patients after long-term remission of CS report more negative illness perceptions compared with patients with other acute or chronic conditions. Further research is needed to assess whether QoL in CS can be improved by addressing these illness perceptions, for example, by a self-management intervention program.

  18. Neonatal sevoflurane anesthesia induces long-term memory impairment and decreases hippocampal PSD-95 expression without neuronal loss.

    PubMed

    Wang, S-Q; Fang, F; Xue, Z-G; Cang, J; Zhang, X-G

    2013-04-01

    Volatile anesthetics are widely used in the clinic, and sevoflurane is the most prevalent volatile anesthetic in pediatric anesthesia. Recent findings question the potential risks of volatile anesthetics on brain development. Evidence suggests that sevoflurane may cause neuronal deficiency. This study investigates the long-term effect of sevoflurane in the developing brain. We anesthetized 7 day-old rats for 4 h with 2.5% sevoflurane. A Morris water maze was used to evaluate hippocampal function 7 weeks after sevoflurane exposure. Nissl staining was performed to analyze neuronal loss. PSD-95 (postsynaptic density protein-95) expression in the hippocampus was measured using a western blot. The exposure to 2.5% sevoflurane caused long-term deficits in hippocampal function and decreased hippocampal PSD-95 expression without neuronal loss. This study demonstrates that P7 rats exposed for 4 h to 2.5% sevoflurane have significant spatial learning and memory impairment 7 weeks after anesthesia. In addition, PSD-95 expression in the hippocampus decreased at P56 without neuronal loss. These data suggest that sevoflurane causes neurotoxicity in the developing brain, which may be attributed to decreased PSD-95 in the hippocampus.

  19. Long-term intermittent feeding restores impaired GR signaling in the hippocampus of aged rat.

    PubMed

    Tesic, Vesna; Perovic, Milka; Lazic, Divna; Kojic, Snezana; Smiljanic, Kosara; Ruzdijic, Sabera; Rakic, Ljubisav; Kanazir, Selma

    2015-05-01

    Diminished glucocorticoid signaling is associated with an age-related decline in hippocampal functioning. In this study we demonstrate the effect of intermittent, every other day (EOD) feeding on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the hippocampus of middle-aged (18-month-old) and aged (24-month-old) Wistar rats. In aged ad libitum-fed rats, a decrease in the level of total GR and GR phosphorylated at Ser(232) (pGR) was detected. Conversely, aged rats subjected to EOD feeding, starting from 6 months of age, showed an increase in GR and pGR levels and a higher content of hippocampal corticosterone. Furthermore, prominent nuclear staining of pGR was observed in CA1 pyramidal and DG granule neurons of aged EOD-fed rats. These changes were accompanied by increased Sgk-1 and decreased GFAP transcription, pointing to upregulated transcriptional activity of GR. EOD feeding also induced an increase in the expression of the mineralocorticoid receptor. Our results reveal that intermittent feeding restores impaired GR signaling in the hippocampus of aged animals by inducing rather than by stabilizing GR signaling during aging.

  20. Long-term consumption of fish oil-enriched diet impairs serotonin hypophagia in rats.

    PubMed

    Watanabe, Regina L H; Andrade, Iracema S; Telles, Mônica M; Albuquerque, Kelse T; Nascimento, Cláudia M O; Oyama, Lila M; Casarini, Dulce E; Ribeiro, Eliane B

    2010-10-01

    Hypothalamic serotonin inhibits food intake and stimulates energy expenditure. High-fat feeding is obesogenic, but the role of polyunsaturated fats is not well understood. This study examined the influence of different high-PUFA diets on serotonin-induced hypophagia, hypothalamic serotonin turnover, and hypothalamic protein levels of serotonin transporter (ST), and SR-1B and SR-2C receptors. Male Wistar rats received for 9 weeks from weaning a diet high in either soy oil or fish oil or low fat (control diet). Throughout 9 weeks, daily intake of fat diets decreased such that energy intake was similar to that of the control diet. However, the fish group developed heavier retroperitoneal and epididymal fat depots. After 12 h of either 200 or 300 μg intracerebroventricular serotonin, food intake was significantly inhibited in control group (21-25%) and soy group (37-39%) but not in the fish group. Serotonin turnover was significantly lower in the fish group than in both the control group (-13%) and the soy group (-18%). SR-2C levels of fish group were lower than those of control group (50%, P = 0.02) and soy group (37%, P = 0.09). ST levels tended to decrease in the fish group in comparison to the control group (16%, P = 0.339) and the soy group (21%, P = 0.161). Thus, unlike the soy-oil diet, the fish-oil diet decreased hypothalamic serotonin turnover and SR-2C levels and abolished serotonin-induced hypophagia. Fish-diet rats were potentially hypophagic, suggesting that, at least up to this point in its course, the serotonergic impairment was either compensated by other factors or not of a sufficient extent to affect feeding. That fat pad weight increased in the absence of hyperphagia indicates that energy expenditure was affected by the serotonergic hypofunction.

  1. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

    PubMed Central

    2011-01-01

    Background The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD) patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Results Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I), and activated caspase-9, which is related to the apoptotic mitochondrial pathway. Conclusions This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers. PMID:21645391

  2. Methionine-enriched diet decreases hippocampal antioxidant defences and impairs spontaneous behaviour and long-term potentiation in rats.

    PubMed

    Viggiano, Alessandro; Viggiano, Emanuela; Monda, Marcellino; Ingrosso, Diego; Perna, Alessandra F; De Luca, Bruno

    2012-08-30

    Diets high in methionine lead to elevation of plasma homocysteine levels which are possibly linked to neurodegenerative diseases and oxidative stress. In the present study, we investigated the effects of methionine-enriched diet on antioxidant defences, on rat spontaneous behaviour and on the ability to sustain long-term potentiation in the dentate gyrus (DG). Sprague-Dawley rats were fed either a standard laboratory diet or a methionine enriched-diet (1% or 5% methionine in drinking water) for 8 weeks. After the 8 weeks, the animals were tested for spontaneous motor activity and habituation in an open field maze, for anxiety-like behaviour in an elevated plus maze and for the ability to sustain long-term potentiation (LTP) induced in the dentate gyrus under urethane anaesthesia. The brains were then removed and histochemically stained for superoxide dismutase (SOD) activity. Rats fed on 5% methionine significantly reduced total distance travelled during the open field test and exhibited no habituation with respect to the other two groups. Rats fed on 5% methionine also showed a significant increase of the anxiety level. Moreover, in this group, the ability to induce LTP in DG was impaired. SOD activity was significantly increased in the cerebral cortex of the rats fed on 1% and 5% methionine with respect to the control group. In conclusion, 5% methionine in drinking water led to evident impairment of locomotor skills and of synaptic plasticity. SOD activity in the cortex was increased in both the groups fed on 1% and 5% methionine, thus suggesting that metabolic adjustments, triggered by the methionine-enriched diet, are likely mediated by reactive oxygen species. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. The Effect of Long-Term Environmental Enrichment in Chronic Cerebral Hypoperfusion-Induced Memory Impairment in Rats.

    PubMed

    Park, Jong-Min; Seong, Ho-Hyun; Jin, Han-Byeol; Kim, Youn-Jung

    2017-05-01

    Vascular dementia (VaD) is the second most common cause of dementia. It occurs when the cerebral blood supply is reduced by disarrangement of the circulatory system. Environmental enrichment (EE) has been associated with cognitive improvement, motor function recovery, and anxiety relief with respect to various neurodegenerative diseases and emotional stress models. The purpose of this study was to determine whether long-term EE influenced cognitive impairment in a rat model of chronic hypoperfusion induced by permanent occlusion of bilateral common carotid arteries (BCCAo). The Y-maze and Morris water maze tests were performed to evaluate the rats' cognitive functions. Also, the protein expression of brain-derived neurotrophic factor (BDNF), phosphorylated cAMP-calcium response element binding protein (pCREB), and vascular endothelial growth factor (VEGF) were confirmed by Western blot. The microvessels and angiogenesis-associated proteins in the hippocampal region were investigated using immunohistochemistry. The VaD + EE group showed significantly better cognitive functions than the VaD group in both the Y-maze and MWM tests. In addition, the VaD + EE group showed significantly increased expression of BDNF, pCREB, and VEGF in the hippocampus compared to the VaD group. Rats in the VaD + EE group also had increased length of microvessels and VEGF expression in the hippocampus. These results suggest that long-term EE exerts neuroprotective effects against cognitive impairment induced by chronic cerebral hypoperfusion through the enhancement of BDNF, pCREB, and VEGF expression and indicate that EE may be a good nursing intervention in vascular dementia patients.

  4. Increased total number but impaired migratory activity and adhesion of endothelial progenitor cells in patients on long-term hemodialysis.

    PubMed

    Herbrig, Kay; Pistrosch, Frank; Oelschlaegel, Uta; Wichmann, Gunnar; Wagner, Andrea; Foerster, Sarah; Richter, Susanne; Gross, Peter; Passauer, Jens

    2004-11-01

    Endothelial progenitor cells (EPCs), derived from bone marrow, contribute to vessel repair and neovascularization. Because uremia is a state of endothelial dysfunction associated with high cardiovascular mortality, as well as a state of reduced hematopoiesis, we studied the number and function of EPCs in patients on long-term hemodialysis (HD) therapy. We counted the number of EPCs in 20 HD patients and 16 healthy volunteers. To assess EPC function, we measured migratory activity, adhesion to matrix proteins, and adhesion to endothelial cells. Furthermore, we measured blood levels of vascular endothelial growth factor (VEGF) and granulocyte-macrophage colony-stimulating factor, factors known to influence EPC kinetics. Circulating precursor cells (CD34+ , CD34+ /CD133+ , CD34+ /KDR+ cells) were counted by means of flow cytometric analysis. The number of EPCs in HD patients was significantly elevated compared with controls (459.7 +/- 92 versus 364.8 +/- 77.4 EPC/high-power field). However, migratory activity was markedly decreased in HD patients (47.5 +/- 27.7 versus 84.7 +/- 3.2 EPC/high-power field). EPCs of HD patients showed impaired adhesion to extracellular matrix and endothelial cells. VEGF blood levels in HD patients were 2-fold greater compared with controls. The number of circulating CD34+ and CD34+ /133+ cells was reduced in HD patients. There were no differences in total numbers of CD34+ /KDR+ cells. This study shows an elevated number, but pronounced functional impairment, of EPCs in patients on long-term HD therapy. The latter may result in limited endothelial repair, which, in turn, may contribute to endothelial dysfunction in this particular group of patients.

  5. Long-Term Cognitive Impairments and Pathological Alterations in a Mouse Model of Repetitive Mild Traumatic Brain Injury

    PubMed Central

    Luo, Jian; Nguyen, Andy; Villeda, Saul; Zhang, Hui; Ding, Zhaoqing; Lindsey, Derek; Bieri, Gregor; Castellano, Joseph M.; Beaupre, Gary S.; Wyss-Coray, Tony

    2014-01-01

    Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all traumatic brain injuries. The consequences of repetitive mTBI have become of particular concern for individuals engaged in certain sports or in military operations. Many mTBI patients suffer long-lasting neurobehavioral impairments. In order to expedite pre-clinical research and therapy development, there is a need for animal models that reflect the long-term cognitive and pathological features seen in patients. In the present study, we developed and characterized a mouse model of repetitive mTBI, induced onto the closed head over the left frontal hemisphere with an electromagnetic stereotaxic impact device. Using GFAP-luciferase bioluminescence reporter mice that provide a readout of astrocyte activation, we observed an increase in bioluminescence relative to the force delivered by the impactor after single impact and cumulative effects of repetitive mTBI. Using the injury parameters established in the reporter mice, we induced a repetitive mTBI in wild-type C57BL/6J mice and characterized the long-term outcome. Animals received repetitive mTBI showed a significant impairment in spatial learning and memory when tested at 2 and 6 months after injury. A robust astrogliosis and increased p-Tau immunoreactivity were observed upon post-mortem pathological examinations. These findings are consistent with the deficits and pathology associated with mTBI in humans and support the use of this model to evaluate potential therapeutic approaches. PMID:24550885

  6. 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.

  7. Selective cholinergic depletion in medial septum leads to impaired long term potentiation and glutamatergic synaptic currents in the hippocampus.

    PubMed

    Kanju, Patrick M; Parameshwaran, Kodeeswaran; Sims-Robinson, Catrina; Uthayathas, Subramaniam; Josephson, Eleanor M; Rajakumar, Nagalingam; Dhanasekaran, Muralikrishnan; Suppiramaniam, Vishnu

    2012-01-01

    Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning.

  8. Effects of selenium treatment on 6-n-propyl-2-thiouracil-induced impairment of long-term potentiation.

    PubMed

    Bitiktaş, Soner; Tan, Burak; Batakçı, Melek; Kavraal, Şehrazat; Dursun, Nurcan; Süer, Cem

    2016-08-01

    The goal of this study was to evaluate whether sodium selenite could afford protection against the effects of hypothyroidism on long-term potentiation (LTP), which is thought to be the cellular basis for learning and memory. Hypothyroidism was induced in young-adult rats by the administration of 6-n-propyl-2-thiouracil (PTU) in tap water for 21 days. Half of these hypothyroid and euthroid rats were given 10ppM selenium with their drinking water. Field potentials were recorded from the dentate gyrus in response to stimulation of the medial perforant pathway in vivo. PTU treatment resulted in a significant reduction in both free T3 and free T4 levels, whereas selenium administration to PTU-treated rats restored only the levels of free T3 to their control values. Thyroid hormone levels were not affected by selenium in euthyroid rats. PTU-treated rats exhibited an attenuation of population spike (PS) - LTP, but a comparable potentiation of excitatory postsynaptic potential (EPSP) was found among these rats. The administration of selenium to PTU-treated rats was partially able to attenuate impairment of LTP, but not of potentiation during the LTP induction protocol in hypothyroid rats. Interestingly, the hypothyroid rats that were supplemented with selenium had a lower EPSP potentiation during induction protocol than the control rats. The present study suggests a possible importance of T3 in Se-induced rescue of impaired PS-LTP in hypothyroidism.

  9. Benefits and Safety of Long-Term Fenofibrate Therapy in People With Type 2 Diabetes and Renal Impairment

    PubMed Central

    Ting, Ru-Dee; Keech, Anthony C.; Drury, Paul L.; Donoghoe, Mark W.; Hedley, John; Jenkins, Alicia J.; Davis, Timothy M.E.; Lehto, Seppo; Celermajer, David; Simes, R. John; Rajamani, Kushwin; Stanton, Kim

    2012-01-01

    OBJECTIVE Diabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) are at particular cardiovascular risk. Fenofibrate’s safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate’s effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (aged 50–75 years) with eGFR ≥30 mL/min/1.73 m2 were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30–59, 60–89, and ≥90 mL/min/1.73 m2). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine >400 μmol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat. RESULTS Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80–0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30–59 mL/min/1.73 m2: 0.68 [0.47–0.97], P = 0.035; eGFR ≥90 mL/min/1.73 m2: 0.85 [0.70–1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment. CONCLUSIONS Patients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate

  10. Preventive effect of theanine intake on stress-induced impairments of hippocamapal long-term potentiation and recognition memory.

    PubMed

    Tamano, Haruna; Fukura, Kotaro; Suzuki, Miki; Sakamoto, Kazuhiro; Yokogoshi, Hidehiko; Takeda, Atsushi

    2013-06-01

    Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. On the basis of the preventive effect of theanine intake after birth on mild stress-induced attenuation of hippocamapal CA1 long-term potentiation (LTP), the present study evaluated the effect of theanine intake after weaning on stress-induced impairments of LTP and recognition memory. Young rats were fed water containing 0.3% theanine for 3 weeks after weaning and subjected to water immersion stress for 30min, which was more severe than tail suspension stress for 30s used previously. Serum corticosterone levels were lower in theanine-administered rats than in the control rats even after exposure to stress. CA1 LTP induced by a 100-Hz tetanus for 1s was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an N-methyl-d-aspartate (NMDA) receptor antagonist, in hippocampal slices from the control rats and was attenuated by water immersion stress. In contrast, CA1 LTP was not significantly inhibited in the presence of APV in hippocampal slices from theanine-administered rats and was not attenuated by the stress. Furthermore, object recognition memory was impaired in the control rats, but not in theanine-administered rats. The present study indicates the preventive effect of theanine intake after weaning on stress-induced impairments of hippocampal LTP and recognition memory. It is likely that the modification of corticosterone secretion after theanine intake is involved in the preventive effect. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Long-term reading and spelling outcome in Italian adolescents with a history of specific language impairment.

    PubMed

    Brizzolara, Daniela; Gasperini, Filippo; Pfanner, Lucia; Cristofani, Paola; Casalini, Claudia; Chilosi, Anna M

    2011-09-01

    Specific language impairment (SLI) diagnosed in the pre-school years is frequently associated with reading and writing difficulties at school age. The nature of this relationship is unclear, despite the availability of a large number of studies, mostly on English speaking children. Phonological processing deficits have been considered the prominent cause of both difficulties. However recent findings in both children with SLI and in children with reading difficulties are not easily accommodated within a single dimensional model explaining the relationship between oral and written language deficits. Our study focuses on the long-term reading and spelling outcome in relation to preschool oral language skills in a group of Italian adolescents with a documented history of SLI. Sixteen Italian adolescents diagnosed as SLI at our Hospital in the pre-school years and 32 normal controls were submitted to an extensive assessment of oral and written language skills. At a group level SLI adolescents had weak oral and written language skills in almost all tests. Results show that reading difficulties have some features in common with those of Italian developmental dyslexics but also have distinct characteristics, since reading accuracy and written comprehension, usually relatively spared in Italian developmental dyslexics, were impaired in adolescents with SLI. Longitudinal analyses showed that expressive morpho-syntactic and lexical abilities at pre-school age were the oral language skills that best predicted reading and spelling outcomes in adolescents with SLI. However, also children with severe phonological impairment in the absence of other oral language deficits showed later literacy difficulties, although less severe and mainly limited to reading accuracy. Our study supports the notion that there is a complex relationship between oral and written language difficulties which may change at different developmental time points, not captured by a single deficit model, but

  12. Steroid-induced impairment of glucose tolerance: Prevalence among pediatric patients on long-term steroid use in Nigeria.

    PubMed

    Chikani, U N; Ibekwe, M U; Oguonu, T; Mungai, L; Bisi-Onyemaechi, A I; Ugege, O M; Ogbonna, I F; de Beaufort, Carine

    2017-03-06

    Glucocorticoid (referred to from here on as simply steroid) is used for effective treatment of various inflammatory disorders since its discovery in 1940s. However, these useful drugs cause important side effects, such as impairment of glucose tolerance. We sought to determine the prevalence of steroid-induced impairment of glucose tolerance in pediatric patients on long-term steroid use. A cross-sectional, descriptive and hospital-based study. Consenting subjects who met the inclusion criteria were screened with random glucometer measurements repeated twice. An average of both readings obtained from the initial measurement of their random blood glucose (RBG) and a repeat during the next clinic visit was taken as the RBG. Hundred patients were studied, 66 males/34 females. Subjects with nephrotic syndrome were 61 while 39 had asthma. Mean age of 10.13 years (range: 0.5-18 years); mean body mass index (BMI): 18.2 kg/m(2) (range: 6.6 to 26.30 kg/m(2) ). The subjects with nephrotic syndrome were on oral prednisolone while the asthmatics were on inhaled fluticasone, budesonide and oral methylprednisolone. Mean (range) duration of steroid use was 9.74 (0.5-72) months. Mean (range) RBG was 3.49 (3.3-7.5) mmol/L. None of the subjects showed abnormal RBG. However, the RBG was further categorized into low, moderate and high normal RBG. A positive correlation between longer duration of steroid use as well as high doses of both oral and inhaled steroids, and high normal RBG existed (P = .015). No statistically significant relationship existed between body mass index (BMI) percentile and RBG (P = .437). Low to moderate doses of oral and inhaled steroids should be used when indicated as they are associated with lesser risk of impairment of glucose tolerance in the pediatric population. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Behavioral cues to expand a pain model of the cognitively impaired elderly in long-term care

    PubMed Central

    Burfield, Allison H; Wan, Thomas TH; Sole, Mary Lou; Cooper, James W

    2012-01-01

    Background The purpose of this study was to determine the relationship between hypothesized pain behaviors in the elderly and a measurement model of pain derived from the Minimum Data Set-Resident Assessment Instrument (MDS-RAI) 2.0 items. Methods This work included a longitudinal cohort recruited from Medicare-certified longterm care facilities across the United States. MDS data were collected from 52,996 residents (mean age 83.7 years). Structural equation modeling was used to build a measurement model of pain to test correlations between indicators and the fit of the model by cognitive status. The model evaluates the theoretical constructs of pain to improve how pain is assessed and detected within cognitive levels. Results Using pain frequency and intensity as the only indicators of pain, the overall prevalence of pain was 31.2%; however, analysis by cognitive status showed that 47.7% of the intact group was in pain, while only 18.2% of the severely, 29.4% of the moderately, and 39.6% of the mildly cognitively impaired groups were experiencing pain. This finding supports previous research indicating that pain is potentially under-reported in severely cognitively impaired elderly nursing home residents. With adjustments to the measurement model, a revised format containing affective, behavioral, and inferred pain indicates a better fit of the data to include these domains, as a more complete measure of the pain construct. Conclusion Pain has a significant effect on quality of life and long-term health outcomes in nursing home residents. Patients most at risk are those with mild to severe cognitive decline, or those unable to report pain verbally. Nursing homes are under great scrutiny to maintain standards of care and provide uniform high-quality care outcomes. Existing data from federally required resident surveys can serve as a valuable tool to identify indicators of pain and trends in care. Great responsibility lies in ensuring pain is included and monitored

  14. Feasibility and acceptability of a delirium prevention program for cognitively impaired long term care residents: a participatory approach.

    PubMed

    Voyer, Philippe; McCusker, Jane; Cole, Martin G; Monette, Johanne; Champoux, Nathalie; Vu, Minh; Ciampi, Antonio; Sanche, Steven; Richard, Sylvie; de Raad, Manon

    2014-01-01

    In this participatory action research study, researchers conducted a total of 3 implementation cycles to evaluate the feasibility and acceptability of a new delirium prevention program (DPP) for cognitively impaired residents in long term care (LTC) settings. Researchers interviewed 95 health care staff to obtain feedback on their use of the DPP and then modified the DPP and tested the changes in the next implementation cycle. Our results indicated that the DPP was feasible and that health care staff would accept it under certain conditions. We found there were 4 keys to successful implementation of the DPP: support for the program from both the administration and the users; effective clinician leadership to ensure proper delivery of the DPP (format, content and values) and its appropriate adaptation to the LTC facility's internal culture and policies; a sense of ownership among the DPP users; and, last, practical hands-on training as well as theoretical training for staff. Copyright © 2014 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.

  15. Inhibition of mGluR1 and IP3Rs impairs long-term memory formation in young chicks.

    PubMed

    Baker, K D; Edwards, T M; Rickard, N S

    2008-07-01

    Calcium (Ca(2+)) is involved in a myriad of cellular functions in the brain including synaptic plasticity. However, the role of intracellular Ca(2+) stores in memory processing remains poorly defined. The current study explored a role for glutamate-dependent intracellular Ca(2+) release in memory processing via blockade of metabotropic glutamate receptor subtype 1 (mGluR1) and inositol (1,4,5)-trisphosphate receptors (IP(3)Rs). Using a single-trial discrimination avoidance task developed for the young chick, administration of the specific and potent mGluR1 antagonist JNJ16259685 (500nM, immediately post-training, ic), or the IP(3)R antagonist Xestospongin C (5microM, immediately post-training, ic), impaired retention from 90min post-training. These findings are consistent with mGluR1 activating IP(3)Rs to release intracellular Ca(2+) required for long-term memory formation and have been interpreted within an LTP2 model. The consequences of different patterns of retention loss following ryanodine receptor (RyR) and IP(3)R inhibition are discussed.

  16. Enhanced perisomatic inhibition and impaired long-term potentiation in the CA1 region of juvenile CHL1-deficient mice.

    PubMed

    Nikonenko, Alexander G; Sun, Mu; Lepsveridze, Eka; Apostolova, Ivayla; Petrova, Iveta; Irintchev, Andrey; Dityatev, Alexander; Schachner, Melitta

    2006-04-01

    The cell adhesion molecule, CHL1, like its close homologue L1, is important for normal brain development and function. In this study, we analysed the functional role of CHL1 in synaptic transmission in the CA1 region of the hippocampus using juvenile CHL1-deficient (CHL1-/-) and wild-type (CHL1+/+) mice. Inhibitory postsynaptic currents evoked in pyramidal cells by minimal stimulation of perisomatically projecting interneurons were increased in CHL1-/- mice compared with wild-type littermates. Also, long-term potentiation (LTP) at CA3-CA1 excitatory synapses was reduced under physiological conditions in CHL1-/- mice. This abnormality was abolished by application of a GABAA receptor antagonist, suggesting that enhanced inhibition is the cause of LTP impairment. Quantitative ultrastructural and immunohistochemical analyses revealed aberrations possibly related to the abnormally high inhibition observed in CHL1-/- mice. The length and linear density of active zones in symmetric synapses on pyramidal cell bodies, as well as number of perisomatic puncta containing inhibitory axonal markers were increased. Density and total number of parvalbumin-positive interneurons was also abnormally high. These observations and the finding that CA1 interneurons express CHL1 protein indicate that CHL1 is important for regulation of inhibitory synaptic transmission and interneuron populations in the postnatal brain. The observed enhancement of inhibitory transmission in CHL1-/- mice is in contrast to the previous finding of reduced inhibition in L1 deficient mice and indicates different functions of these two closely related molecules.

  17. Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor

    PubMed Central

    Savonenko, A.; Munoz, P.; Melnikova, T.; Wang, Q.; Liang, X.; Breyer, R. M.; Montine, T. J.; Kirkwood, A.; Andreasson, K.

    2009-01-01

    Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl D aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE2 EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer’s disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2 −/− mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2−/− mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE2 signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia. PMID:19416671

  18. p-Coumaric acid enhances long-term potentiation and recovers scopolamine-induced learning and memory impairments.

    PubMed

    Kim, Hyun-Bum; Lee, Seok; Hwang, Eun-Sang; Maeng, Sungho; Park, Ji-Ho

    2017-10-21

    Due to the improvement of medical level, life expectancy increased. But the increased incidence of cognitive disorders is an emerging social problem. Current drugs for dementia treatment can only delay the progress rather than cure. p-Coumaric acid is a phenylpropanoic acid derived from aromatic amino acids and known as a precursor for flavonoids such as resveratrol and naringenin. It was shown to reduce oxidative stress, inhibit genotoxicity and exert neuroprotection. Based on these findings, we evaluated whether p-coumaric acid can protect scopolamine induced learning and memory impairment by measuring LTP in organotypic hippocampal slice and cognitive behaviors in rats. p-Coumaric acid dose-dependently increased the total activity of fEPSP after high frequency stimulation and attenuated scopolamine-induced blockade of fEPSP in the hippocampal CA1 area. In addition, while scopolamine shortened the step-through latency in the passive avoidance test and prolonged the latency as well as reduced the latency in the target quadrant in the Morris water maze test, co-treatment of p-coumaric acid improved avoidance memory and long-term retention of spatial memory in behavioral tests. Since p-coumaric acid improved electrophysiological and cognitive functional deterioration by scopolamine, it may have regulatory effects on central cholinergic synapses and is expected to improve cognitive problems caused by abnormality of the cholinergic nervous system. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Impaired Global Right Ventricular Longitudinal Strain Predicts Long-Term Adverse Outcomes in Patients with Pulmonary Arterial Hypertension

    PubMed Central

    Park, Jae-Hyeong; Park, Margaret M.; Farha, Samar; Sharp, Jacqueline; Lundgrin, Erika; Comhair, Suzy; Tang, Wai Hong; Erzurum, Serpil C.

    2015-01-01

    Background New 2-dimensional strain echocardiography enables quantification of right ventricular (RV) mechanics by assessing global longitudinal strain of RV (GLSRV) in patients with pulmonary arterial hypertension (PAH). However, the prognostic significance of impaired GLSRV is unclear in these patients. Methods Comprehensive echocardiography was performed in 51 consecutive PAH patients without atrial fibrillation (40 females, 48 ± 14 years old) with long-term follow-up. GLSRV was measured with off-line with velocity vector imaging (VVI, Siemens Medical System, Mountain View, CA, USA). Results GLSRV showed significant correlation with RV fractional area change (r = -0.606, p < 0.001), tricuspid annular plane systolic excursion (r = -0.579, p < 0.001), and RV Tei index (r = 0.590, p < 0.001). It showed significant correlations with pulmonary vascular resistance (r = 0.469, p = 0.001) and B-natriuretic peptide concentration (r = 0.351, p = 0.012). During a clinical followup time (45 ± 15 months), 20 patients experienced one or more adverse events (12 death, 2 lung transplantation, and 15 heart failure hospitalization). After multivariate analysis, age [hazard ratio (HR) = 2.343, p = 0.040] and GLSRV (HR = 2.122, p = 0.040) were associated with adverse clinical events. Age (HR = 3.200, p = 0.016) and GLSRV (HR = 2.090, p = 0.042) were also significant predictors of death. Impaired GLSRV (≥ -15.5%) was associated with lower event-free survival (HR = 4.906, p = 0.001) and increased mortality (HR = 8.842, p = 0.005). Conclusion GLSRV by VVI showed significant correlations with conventional echocardiographic parameters indicating RV systolic function. Lower GLSRV (≥ -15.5%) was significantly associated with presence of adverse clinical events and deaths in PAH patients. PMID:26140151

  20. General Anesthesia Causes Long-term Impairment of Mitochondrial Morphogenesis and Synaptic Transmission in Developing Rat Brain

    PubMed Central

    Sanchez, Victoria; Feinstein, Shawn D.; Lunardi, Nadia; Joksovic, Pavle M.; Boscolo, Annalisa; Todorovic, Slobodan M.; Jevtovic-Todorovic, Vesna

    2011-01-01

    Background Clinically used general anesthetics, alone or in combination, are damaging to the developing mammalian brain. In addition to causing widespread apoptotic neurodegeneration in vulnerable brain regions, exposure to general anesthesia at the peak of synaptogenesis causes learning and memory deficiencies later in life. Our in-vivo rodent studies have suggested that activation of the intrinsic (mitochondria-dependent) apoptotic pathway is the earliest warning sign of neuronal damage, suggesting that a disturbance in mitochondrial integrity and function could be the earliest triggering events. Methods Since proper and timely mitochondrial morphogenesis is critical for brain development, we examined the long-term effects of a commonly used anesthesia combination (isoflurane, nitrous oxide, and midazolam) on the regional distribution, ultrastructural properties, and electron transport chain function of mitochondria, as well as synaptic neurotransmission, in the subiculum of rat pups. Results This anesthesia, administered at the peak of synaptogenesis, causes protracted injury to mitochondria, including significant enlargement of mitochondria (over 30%, p < 0.05), impairment of their structural integrity, about 28% increase in their complex IV activity (p < 0.05) and two-fold decrease in their regional distribution in presynaptic neuronal profiles (p < 0.05) where their presence is crucially important for the normal development and functioning of synapses. Consequently, we showed that impaired mitochondrial morphogenesis is accompanied by heightened autophagic activity, decrease in mitochondrial density (about 27%, p < 0.05) and long-lasting disturbances in inhibitory synaptic neurotransmission. The interrelation of these phenomena remains to be established. Conclusion Developing mitochondria are exquisitely vulnerable to general anesthesia and may be important early target of anesthesia-induced developmental neurodegeneration. PMID:21909020

  1. The impairment of true glomerular filtration rate in long-term cyclosporine-treated pediatric allograft recipients

    SciTech Connect

    McDiarmid, S.V.; Ettenger, R.B.; Hawkins, R.A.; Senguttvan, P.; Busuttil, R.W.; Vargas, J.; Berquist, W.E.; Ament, M.E.

    1990-01-01

    We performed indium-111-DTPA plasma clearance studies in 61 pediatric kidney and liver recipients treated with cyclosporine to compare true glomerular filtration rate with calculated GFR (cGFR). The mean true GFR of 61.9 +/- 36.6 ml/min/1.73 m2 indicated renal impairment. The mean cGFR of 85.2 +/- 22.4 ml/min/1.73 m2 was significantly higher (P less than 0.001), and overestimated GFR by 38%. cGFR alone did not accurately reflect the degree of renal dysfunction. A group of 48 pediatric orthotopic liver transplant recipients was studied in more detail: 73% of these patients had a true GFR less than 70 ml/min/1.73 m2, while 85% had a true GFR below 90 ml/min/1.73 m2, the lower limit for normal GFR in children. The mean true GFR for patients treated more than 24 months with CsA was lower (P = 0.02) than patients treated with CsA for 12 to 24 months. OLT patients with normal true GFR (greater than 90 ml/min/1.73 m2) had significantly lower plasma CsA levels, and 50% of patients with a true GFR less than or equal to 50 ml/min/1.73 m2 had hypertension. There was no effect on true GFR of age, liver function, azathioprine use, or peritransplant treatment with other nephrotoxic drugs. We conclude that true GFR is significantly impaired in long-term CsA-treated allograft pediatric recipients. Calculations of GFR underestimate the degree of renal dysfunction. As patients treated greater than 24 months had the lowest true GFRs, the fall in GFR may be progressive.

  2. Impairment of long-term potentiation induction is essential for the disruption of spatial memory after microwave exposure.

    PubMed

    Wang, Hui; Peng, Ruiyun; Zhou, Hongmei; Wang, Shuiming; Gao, Yabing; Wang, Lifeng; Yong, Zheng; Zuo, Hongyan; Zhao, Li; Dong, Ji; Xu, Xinping; Su, Zhentao

    2013-12-01

    To assess the impact of microwave exposure on learning and memory and to explore the underlying mechanisms. 100 Wistar rats were exposed to a 2.856 GHz pulsed microwave field at average power densities of 0 mW/cm(2), 5 mW/cm(2), 10 mW/cm(2) and 50 mW/cm(2) for 6 min. The spatial memory was assessed by the Morris Water Maze (MWM) task. An in vivo study was conducted soon after microwave exposure to evaluate the changes of population spike (PS) amplitudes of long-term potentiation (LTP) in the medial perforant path (MPP)-dentate gyrus (DG) pathway. The structure of the hippocampus was observed by the light microscopy and the transmission electron microscopy (TEM) at 7 d after microwave exposure. Our results showed that the rats exposed in 10 mW/cm(2) and 50 mW/cm(2) microwave displayed significant deficits in spatial learning and memory at 6 h, 1 d and 3 d after exposure. Decreased PS amplitudes were also found after 10 mW/cm(2) and 50 mW/cm(2) microwave exposure. In addition, varying degrees of degeneration of hippocampal neurons, decreased synaptic vesicles and blurred synaptic clefts were observed in the rats exposed in 10 mW/cm(2) and 50 mW/cm(2) microwave. Compared with the sham group, the rats exposed in 5 mW/cm(2) microwave showed no difference in the above experiments. This study suggested that impairment of LTP induction and the damages of hippocampal structure, especially changes of synapses, might contribute to cognitive impairment after microwave exposure.

  3. Long-term trends in visibility and impacts of aerosol composition on visibility impairment in Baoji, China

    NASA Astrophysics Data System (ADS)

    Xiao, S.; Wang, Q. Y.; Cao, J. J.; Huang, R.-J.; Chen, W. D.; Han, Y. M.; Xu, H. M.; Liu, S. X.; Zhou, Y. Q.; Wang, P.; Zhang, J. Q.; Zhan, C. L.

    2014-11-01

    Visibility impairment has become an important environmental issue receiving great attention from both the scientific community and the public. Long-term meteorological data from Baoji, China, were collected to investigate the trend in visibility change from 1980 to 2012. The 33-year average visual range is 12.0 km. The best 20% of the visibility observations in a calendar year shows a general decreasing trend from 1994 onwards, while the worst 20% exhibits a slight increasing trend from 1997 onwards. These results suggest the progressive degradation of air quality in Baoji in recent years. Intensive PM2.5 measurements were conducted from March 2012 to February 2013 to determine the causes of visibility impairment. An analysis based on IMPROVE equation reveals that PM2.5 organic matter (OM) contributes to 34.2% of the light extinction coefficient (bext) on an annual basis, followed by (NH4)2SO4 (30.0%), NH4NO3 (20.1%), elemental carbon (9.2%) and soil dust (6.5%). The largest contributor to bext for the Worst 20% group is (NH4)2SO4, and the contribution of NH4NO3 for the Worst 20% group increases by a factor of ~ 3 compared with the Best 20% group. Source apportionment using a positive matrix factorization receptor model indicates that secondary sulfate is the main source of PM2.5 (23.0%), followed by fugitive dust (20.5%), coal combustion (19.9%), secondary nitrate (15.5%), biomass burning (14.3%) and motor vehicle emissions (6.8%). These quantitative results could be useful for policy makers to take effective measures to control the haze pollution in Baoji. Further, the results also are likely to be relevant for other mid-sized cities in China.

  4. Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes

    PubMed Central

    Garcia-Alvarez, Gisela; Shetty, Mahesh S.; Lu, Bo; Yap, Kenrick An Fu; Oh-Hora, Masatsugu; Sajikumar, Sreedharan; Bichler, Zoë; Fivaz, Marc

    2015-01-01

    Recent findings point to a central role of the endoplasmic reticulum-resident STIM (Stromal Interaction Molecule) proteins in shaping the structure and function of excitatory synapses in the mammalian brain. The impact of the Stim genes on cognitive functions remains, however, poorly understood. To explore the function of the Stim genes in learning and memory, we generated three mouse strains with conditional deletion (cKO) of Stim1 and/or Stim2 in the forebrain. Stim1, Stim2, and double Stim1/Stim2 cKO mice show no obvious brain structural defects or locomotor impairment. Analysis of spatial reference memory in the Morris water maze revealed a mild learning delay in Stim1 cKO mice, while learning and memory in Stim2 cKO mice was indistinguishable from their control littermates. Deletion of both Stim genes in the forebrain resulted, however, in a pronounced impairment in spatial learning and memory reflecting a synergistic effect of the Stim genes on the underlying neural circuits. Notably, long-term potentiation (LTP) at CA3-CA1 hippocampal synapses was markedly enhanced in Stim1/Stim2 cKO mice and was associated with increased phosphorylation of the AMPA receptor subunit GluA1, the transcriptional regulator CREB and the L-type Voltage-dependent Ca2+ channel Cav1.2 on protein kinase A (PKA) sites. We conclude that STIM1 and STIM2 are key regulators of PKA signaling and synaptic plasticity in neural circuits encoding spatial memory. Our findings also reveal an inverse correlation between LTP and spatial learning/memory and suggest that abnormal enhancement of cAMP/PKA signaling and synaptic efficacy disrupts the formation of new memories. PMID:26236206

  5. Anisomycin injection in area CA3 of the hippocampus impairs both short-term and long-term memories of contextual fear.

    PubMed

    Remaud, Jessica; Ceccom, Johnatan; Carponcy, Julien; Dugué, Laura; Menchon, Gregory; Pech, Stéphane; Halley, Helene; Francés, Bernard; Dahan, Lionel

    2014-05-15

    Protein synthesis is involved in the consolidation of short-term memory into long-term memory. Previous electrophysiological data concerning LTP in CA3 suggest that protein synthesis in that region might also be necessary for short-term memory. We tested this hypothesis by locally injecting the protein synthesis inhibitor anisomycin in hippocampal area CA1 or CA3 immediately after contextual fear conditioning. As previously shown, injections in CA1 impaired long-term memory but spared short-term memory. Conversely, injections in CA3 impaired both long-term and short-term memories. We conclude that early steps of experience-induced plasticity occurring in CA3 and underlying short-term memory require protein synthesis. © 2014 Remaud et al.; Published by Cold Spring Harbor Laboratory Press.

  6. Soluble Prion Protein and Its N-terminal Fragment Prevent Impairment of Synaptic Plasticity by Aβ Oligomers: Implications for Novel Therapeutic Strategy in Alzheimer’s Disease

    PubMed Central

    Choi, Jin-Kyu; Ruffin, Vernon A.; Salameh, Ahlam I.; Nieznanski, Krzysztof; Costa, Alberto C.S.; Surewicz, Witold K.

    2016-01-01

    The pathogenic process in Alzheimer’s disease (AD) appears to be closely linked to the neurotoxic action of amyloid-β (Aβ) oligomers. Recent studies have shown that these oligomers bind with high affinity to the membrane-anchored cellular prion protein (PrPC). It has also been proposed that this binding might mediate some of the toxic effects of the oligomers. Here, we show that the soluble (membrane anchor-free) recombinant human prion protein (rPrP) and its N-terminal fragment N1 block Aβ oligomers-induced inhibition of long-term potentiation (LTP) in hippocampal slices, an important surrogate marker of cognitive deficit associated with AD. rPrP and N1 are also strikingly potent inhibitors of Aβ cytotoxicity in primary hippocampal neurons. Furthermore, experiments using hippocampal slices and neurons from wild-type and PrPC null mice (as well as rat neurons in which PrPC expression was greatly reduced by gene silencing) indicate that, in contrast to the impairment of synaptic plasticity by Aβ oligomers, the cytotoxic effects of these oligomers, and the inhibition of these effects by rPrP and N1, are independent of the presence of endogenous PrPC. This suggests fundamentally different mechanisms by which soluble rPrP and its fragments inhibit these two toxic responses to Aβ. Overall, these findings provide strong support to recent suggestions that PrP-based compounds may offer new avenues for pharmacological intervention in AD. PMID:26949218

  7. Long-Term Memory: A Review and Meta-Analysis of Studies of Declarative and Procedural Memory in Specific Language Impairment

    ERIC Educational Resources Information Center

    Lum, Jarrad A. G.; Conti-Ramsden, Gina

    2013-01-01

    This review examined the status of long-term memory systems in specific language impairment (SLI)--declarative memory and aspects of procedural memory in particular. Studies included in the review were identified following a systematic search of the literature and findings combined using meta-analysis. This review showed that individuals with SLI…

  8. Long-Term Memory: A Review and Meta-Analysis of Studies of Declarative and Procedural Memory in Specific Language Impairment

    ERIC Educational Resources Information Center

    Lum, Jarrad A. G.; Conti-Ramsden, Gina

    2013-01-01

    This review examined the status of long-term memory systems in specific language impairment (SLI)--declarative memory and aspects of procedural memory in particular. Studies included in the review were identified following a systematic search of the literature and findings combined using meta-analysis. This review showed that individuals with SLI…

  9. 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...

  10. Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice: a role for Toll-like receptor activation.

    PubMed

    Costello, Derek A; Lyons, Anthony; Denieffe, Stephanie; Browne, Tara C; Cox, F Fionnuala; Lynch, Marina A

    2011-10-07

    The membrane glycoprotein CD200 is expressed on several cell types, including neurons, whereas expression of its receptor, CD200R, is restricted principally to cells of the myeloid lineage, including microglia. The interaction between CD200 and CD200R maintains microglia and macrophages in a quiescent state; therefore, CD200-deficient mice express an inflammatory phenotype exhibiting increased macrophage or microglial activation in models of arthritis, encephalitis, and uveoretinitis. Here, we report that lipopolysaccharide (LPS) and Pam(3)CysSerLys(4) exerted more profound effects on release of the proinflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα), in glia prepared from CD200(-/-) mice compared with wild type mice. This effect is explained by the loss of CD200 on astrocytes, which modulates microglial activation. Expression of Toll-like receptors 4 and 2 (TLR4 and -2) was increased in glia prepared from CD200(-/-) mice, and the evidence indicates that microglial activation, assessed by the increased numbers of CD11b(+) cells that stained positively for both MHCII and CD40, was enhanced in CD200(-/-) mice compared with wild type mice. These neuroinflammatory changes were associated with impaired long term potentiation (LTP) in CA1 of hippocampal slices prepared from CD200(-/-) mice. One possible explanation for this is the increase in TNFα in hippocampal tissue prepared from CD200(-/-) mice because TNFα application inhibited LTP in CA1. Significantly, LPS and Pam(3)CysSerLys(4), at concentrations that did not affect LTP in wild type mice, inhibited LTP in slices prepared from CD200(-/-) mice, probably due to the accompanying increase in TLR2 and TLR4. Thus, the neuroinflammatory changes that result from CD200 deficiency have a negative impact on synaptic plasticity.

  11. Immune recovery in HIV-infected patients after Candida esophagitis is impaired despite long-term antiretroviral therapy

    PubMed Central

    Stuehler, Claudia; Bernardini, Claudia; Elzi, Luigia; Stoeckle, Marcel; Zimmerli, Stefan; Furrer, Hansjakob; Günthard, Huldrych F.; Leibundgut-Landmann, Salomé; Battegay, Manuel; Khanna, Nina

    2016-01-01

    Objective: Candida esophagitis belongs to the most common AIDS-defining diseases; however, a comprehensive immune pathogenic concept is lacking. Design: We investigated the immune status of 37 HIV-1-infected patients from the Swiss HIV cohort study at diagnosis of Candida esophagitis, 1 year before, 1 year later and after 2 years of suppressed HIV RNA. We compared these patients with three groups: 37 HIV-1-infected patients without Candida esophagitis but similar CD4+ cell counts as the patients at diagnosis (advanced HIV group), 15 HIV-1-infected patients with CD4+ cell counts higher than 500 cells/μl, CD4+ cell nadirs higher than 350 cells/μl and suppressed HIV RNA under combination antiretroviral therapy (cART) (early cART group) and 20 healthy individuals. Methods: We investigated phenotype, cytokine production and proliferative capacity of different immune cells by flow cytometry and enzyme-linked immunosorbent spot. Results: We found that patients with Candida esophagitis had nearly abolished CD4+ cell proliferation in response to Candida albicans, significantly increased percentages of dysfunctional CD4+ cells, significantly decreased cytotoxic natural killer cell counts and peripheral innate lymphoid cell counts and significantly reduced IFN-γ and IL-17 production compared with the early cART group and healthy individuals. Most of these defects remained for more than 2 years despite viral suppression. The advanced HIV group without opportunistic infection showed partly improved immune recovery. Conclusion: Our data indicate that Candida esophagitis in HIV-1-infected patients is caused by an accumulation of multiple, partly Candida-specific immunological defects. Long-term immune recovery is impaired, illustrating that specific immunological gaps persist despite cART. These data also support the rationale for early cART initiation to prevent irreversible immune defects. PMID:27149086

  12. Alzheimer's disease like pathology induced six weeks after aggregated amyloid-beta injection in rats: increased oxidative stress and impaired long-term memory with anxiety-like behavior.

    PubMed

    Sharma, Sheetal; Verma, Sonia; Kapoor, Monika; Saini, Avneet; Nehru, Bimla

    2016-09-01

    Amyloid-beta (Aβ) peptide deposition into insoluble plaques is a pathological hallmark of Alzheimer's disease (AD), but soluble oligomeric Aβ is considered to be more potent and has been hypothesized to directly impair learning and memory. Also, evidences from some clinical studies indicated that Aβ oligomer formation is the major cause for early AD onset. However, the biochemical mechanism involved in the oligomer-induced toxicity is not very well addressed. So, thise present study was undertaken to study the effects of single intracerebroventricular (icv) injection of protofibrillar Aβ 1-42 on the behavioral and biochemical profile in rats. Rats were divided into two groups (n = 8 per group): (1) sham control group and (2) Aβ 1-42 injected group. A single dose of protofibrillar Aβ 1-42 (5 ul) through icv injection was bilaterally administered into the dorsal hippocampus, while sham control animals were administered with 5 µl of vehicle. The results demonstrated that the protofibrillar Aβ significantly inhibited long-term memory retention and increased anxiety levels as shown by the behavioral studies. The amyloid deposits were present inside the brain even six weeks after injection as confirmed by thioflavin-T staining and the neurodegeneration induced by these deposits was confirmed by Nissl's staining in hippocampal and cortical regions. The amyloid aggregates induced reactive oxygen species (ROS) production, acetylcholinesterase activity, nitrite levels, lipid peroxidation, and inhibited antioxidant enzyme activity in hippocampus, cortex, and striatum regions of rat brain after six weeks. The present study indicated that protofibrillar Aβ 1-42 injection altered long term memory, induced anxiety-like behavior and also developed Alzheimer's disease like pathology in rats.

  13. Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory.

    PubMed

    Lana, D; Di Russo, J; Mello, T; Wenk, G L; Giovannini, M G

    2017-01-01

    The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the cholinergic input to trigger the formation of long term memories, similar to what we demonstrated in CA1 hippocampus. We performed in vivo behavioral experiments using the step down inhibitory avoidance test in adult Wistar rats to evaluate memory formation under different conditions. We examined the effects of rapamycin, an inhibitor of mTORC1 formation, scopolamine, a muscarinic receptor antagonist or mecamylamine, a nicotinic receptor antagonist, on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition was conducted 30min after i.c.v. injection of rapamycin. Recall testing was performed 1h, 4h or 24h after acquisition. We found that (1) mTOR and p70S6K activation in CA3 pyramidal neurons were involved in long term memory formation; (2) rapamycin significantly inhibited mTOR and of p70S6K activation at 4h, and long term memory impairment 24h after acquisition; (3) scopolamine impaired short but not long term memory, with an early increase of mTOR/p70S6K activation at 1h followed by stabilization at longer times; (4) mecamylamine and scopolamine co-administration impaired short term memory at 1h and 4h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1h and 4h; (5) mecamylamine and scopolamine treatment did not impair long term memory formation; (6) unexpectedly, rapamycin increased mTORC2 activation in microglial cells. Our results demonstrate that in CA3 pyramidal neurons the mTOR/p70S6K pathway is under the modulation of the cholinergic system and is involved in long-term memory encoding, and are consistent with the hypothesis that the CA3 region of the hippocampus is involved in memory mechanisms based on rapid, one-trial object-place learning and recall. Furthermore, our results are in accordance with previous reports that selective

  14. Amyloid beta oligomers induce impairment of neuronal insulin receptors.

    PubMed

    Zhao, Wei-Qin; De Felice, Fernanda G; Fernandez, Sara; Chen, Hui; Lambert, Mary P; Quon, Michael J; Krafft, Grant A; Klein, William L

    2008-01-01

    Recent studies have indicated an association between Alzheimer's disease (AD) and central nervous system (CNS) insulin resistance. However, the cellular mechanisms underlying the link between these two pathologies have not been elucidated. Here we show that signal transduction by neuronal insulin receptors (IR) is strikingly sensitive to disruption by soluble Abeta oligomers (also known as ADDLs). ADDLs are known to accumulate in AD brain and have recently been implicated as primary candidates for initiating deterioration of synapse function, composition, and structure. Using mature cultures of hippocampal neurons, a preferred model for studies of synaptic cell biology, we found that ADDLs caused a rapid and substantial loss of neuronal surface IRs specifically on dendrites bound by ADDLs. Removal of dendritic IRs was associated with increased receptor immunoreactivity in the cell body, indicating redistribution of the receptors. The neuronal response to insulin, measured by evoked IR tyrosine autophosphorylation, was greatly inhibited by ADDLs. Inhibition also was seen with added glutamate or potassium-induced depolarization. The effects on IR function were completely blocked by NMDA receptor antagonists, tetrodotoxin, and calcium chelator BAPTA-AM. Downstream from the IR, ADDLs induced a phosphorylation of Akt at serine473, a modification associated with neurodegenerative and insulin resistance diseases. These results identify novel factors that affect neuronal IR signaling and suggest that insulin resistance in AD brain is a response to ADDLs, which disrupt insulin signaling and may cause a brain-specific form of diabetes as part of an overall pathogenic impact on CNS synapses.

  15. Subcortical deafferentation impairs behavioral reinforcement of long-term potentiation in the dentate gyrus of freely moving rats.

    PubMed

    Almaguer-Melian, W; Rosillo, J C; Frey, J U; Bergado, J A

    2006-01-01

    Long-term potentiation is a form of neural functional plasticity which has been related with memory formation and recovery of function after brain injury. Previous studies have shown that a transient early-long-term potentiation can be prolonged by direct stimulation of distinct brain areas, or behavioral stimuli with a high motivational content. The basolateral amygdala and other subcortical structures, like the medial septum and the locus coeruleus, are involved in mediating the reinforcing effect. We have previously shown that the lesion of the fimbria-fornix--the main entrance of subcortical afferents to the hippocampus--abolishes the reinforcing basolateral amygdala-effects on long-term potentiation in the dentate gyrus in vivo. It remains to be investigated, however, if such subcortical afferents may also be important for behavioral reinforcement of long-term potentiation. Young-adult (8 weeks) Sprague-Dawley male rats were fimbria-fornix-transected under anesthesia, and electrodes were implanted at the dentate gyrus and the perforant path. One week after surgery the freely moving animals were studied. Fimbria-fornix-lesion reduced the ability of the animals to develop long-term potentiation when a short pulse duration was used for tetanization (0.1 ms per half-wave of a biphasic stimulus), whereas increasing the pulse duration to 0.2 ms per half-wave during tetanization resulted in a transient early-long-term potentiation lasting about 4 h in the lesioned animals, comparable to that obtained in non-lesioned or sham-operated control rats. In water-deprived (24 h) control animals, i.e. in non-lesioned and sham-operated rats, early-long-term potentiation could be behaviorally reinforced by drinking 15 min after tetanization. However, in fimbria-fornix-lesioned animals long-term potentiation-reinforcement by drinking was not detected. This result indicates that the effect of behavioral-motivational stimuli to reinforce long-term potentiation is mediated by

  16. Problems identified by dual sensory impaired older adults in long-term care when using a self-management program: A qualitative study

    PubMed Central

    Zuidema, Sytse; Vernooij-Dassen, Myrra; Dees, Marianne; Hermsen, Pieter; Kempen, Gertrudis; Graff, Maud

    2017-01-01

    Objective To gain insights into the problems of dual sensory impaired older adults in long-term care. Insights into these problems are essential for developing adequate policies which address the needs of the increasing population of dual sensory impaired older adults in long-term care. Methods A qualitative study was conducted in parallel with a cluster randomized controlled trial. Dual sensory impaired older adults in the intervention group (n = 47, age range 82–98) were invited by a familiar nurse to identify the problems they wanted to address. Data were taken from the semi-structured intervention diaries in which nurses noted the older adults’ verbal responses during a five-month intervention period in 17 long-term care homes across the Netherlands. The data were analyzed using descriptive statistics and qualitative content analysis based on the Grounded Theory. Findings The 47 dual sensory impaired older adults identified a total of 122 problems. Qualitative content analysis showed that the older adults encountered participation problems and problems controlling what happens in their personal environment. Three categories of participation problems emerged: (1) existential concerns of not belonging or not being able to connect with other people, (2) lack of access to communication, information and mobility, and (3) the desire to be actively involved in care delivery. Two categories of control-in-personal-space problems emerged: (1) lack of control of their own physical belongings, and (2) lack of control regarding the behavior of nurses providing daily care in their personal environment. Conclusions The invasive problems identified indicate that dual sensory impaired older adults experience great existential pressures on their lives. Long-term care providers need to develop and implement policies that identify and address these problems, and be aware of adverse consequences of usual care, in order to improve dual sensory impaired residents’ autonomy and

  17. Problems identified by dual sensory impaired older adults in long-term care when using a self-management program: A qualitative study.

    PubMed

    Roets-Merken, Lieve; Zuidema, Sytse; Vernooij-Dassen, Myrra; Dees, Marianne; Hermsen, Pieter; Kempen, Gertrudis; Graff, Maud

    2017-01-01

    To gain insights into the problems of dual sensory impaired older adults in long-term care. Insights into these problems are essential for developing adequate policies which address the needs of the increasing population of dual sensory impaired older adults in long-term care. A qualitative study was conducted in parallel with a cluster randomized controlled trial. Dual sensory impaired older adults in the intervention group (n = 47, age range 82-98) were invited by a familiar nurse to identify the problems they wanted to address. Data were taken from the semi-structured intervention diaries in which nurses noted the older adults' verbal responses during a five-month intervention period in 17 long-term care homes across the Netherlands. The data were analyzed using descriptive statistics and qualitative content analysis based on the Grounded Theory. The 47 dual sensory impaired older adults identified a total of 122 problems. Qualitative content analysis showed that the older adults encountered participation problems and problems controlling what happens in their personal environment. Three categories of participation problems emerged: (1) existential concerns of not belonging or not being able to connect with other people, (2) lack of access to communication, information and mobility, and (3) the desire to be actively involved in care delivery. Two categories of control-in-personal-space problems emerged: (1) lack of control of their own physical belongings, and (2) lack of control regarding the behavior of nurses providing daily care in their personal environment. The invasive problems identified indicate that dual sensory impaired older adults experience great existential pressures on their lives. Long-term care providers need to develop and implement policies that identify and address these problems, and be aware of adverse consequences of usual care, in order to improve dual sensory impaired residents' autonomy and quality of life.

  18. Oxygen-induced retinopathy induces short-term glial stress and long-term impairment of photoentrainment in mice.

    PubMed

    Mehdi, Madah Khawn-I-Muhammad; Sage-Ciocca, Dominique; Challet, Etienne; Malan, André; Hicks, David

    2014-04-01

    Retinopathy of prematurity is a serious potentially blinding disease of pre-term infants. There is extensive vascular remodeling and tissue stress, but data concerning alterations in retinal neurons and glia, and long-term functional sequelae are still incomplete. ROP was induced using the oxygen-induced retinopathy (OIR) mouse model. Postnatal day 7 (P7) 129SVE mice were exposed to hyperoxia (75 ± 0.5 % oxygen) for 5 days, and then returned to normoxia to induce OIR. Exposed animals were euthanized at 5 (P17-OIR) and 14 days (P26-OIR) after return to normal air, together with corresponding age-matched control mice (P17-C and P26-C respectively) raised only in room air. Their retinas were examined by immunohistochemistry using a battery of antibodies against key glial and neuronal proteins. A further group of OIR mice and controls were examined at 10 weeks of age for their ability to re-entrain to changing 12 h light/12 h dark cycles, assayed by wheel-running actimetry. In this protocol, animals were subjected to three successive conditions of 300 lux, 15 lux and 1 lux ambient light intensity coupled with 6 hours of jetlag. Animals were euthanized at 4 months of age and used in immunoblotting for rhodopsin. Compared to P17-C, immunohistochemical staining of P17-OIR sections showed up-regulation of stress-related and glutamate-regulatory proteins in astrocytes and Müller glial cells. In contrast, glial phenotypic expression in P26-OIR retinas largely resembled that in P26-C. There was no loss in total retinal ganglion cells (RGC) at either P17-OIR or P26-OIR compared to corresponding controls, whereas intrinsically photosensitive RGC showed significant decreases, with 375 ± 13/field in P26-OIR compared to 443 ± 30/field in P26-C (p < 0.05). Wheel actimetry performed on control and OIR-treated mice at 4 months demonstrated that animals raised in hyperoxic conditions had impaired photoentrainment at low illuminance of 1 lux, as well as significantly reduced

  19. Lidocaine Injections Targeting CA3 Hippocampus Impair Long-Term Spatial Memory and Prevent Learning-Induced Mossy Fiber Remodeling

    PubMed Central

    Holahan, Matthew R.; Routtenberg, Aryeh

    2010-01-01

    Learning a spatial location induces remodeling of the mossy fiber terminal field (MFTF) in the CA3 subfield of the dorsal hippocampus (Holahan et al., 2006; Ramirez-Amaya et al., 2001; Rekart et al., 2007a). These fibers appear to grow from the stratum lucidum (SL) into distal stratum oriens (dSO). Is this axonal growth dependent on ‘repeated and persistent’ neural activity in the CA3 region during training? To address this issue, we targeted local inactivation of the MFTF region in a post-training, consolidation paradigm. Male Wistar rats, bilaterally implanted with chronic indwelling cannulae aimed at the MFTF CA3 region, were trained on a hidden platform water maze task (10 trials per day for 5 days). Immediately after the 10th trial on each training day, rats were injected with lidocaine (4% w/V; 171 mM; n = 7) or phosphate-buffered saline (PBS; n = 7). Behavioral measures of latency, path length and thigmotaxis were recorded, as was directional heading. A retention test (probe trial) was given 7 days after the last training day and brains were subsequently processed for MFTF distribution (Timm’s stain) and cannula location. Lidocaine treatment was found to block the learning-associated structural remodeling of the MFTF that was reported previously and observed in the PBS-injected controls. During training, the lidocaine group showed elevated latencies and a misdirected heading to locate the platform on the first trial of each training day. On the 7-day retention probe trial, the lidocaine-injected group showed poor retention indicated by the absence of a search bias in the area where the platform had been located during training. These data suggest that reduction of neuronal activity in the CA3 region impairs long-term storage of spatial information. As this was associated with reduced MFTF structural remodeling, it provides initial anatomical and behavioral evidence for an activity – dependent, presynaptic growth model of memory. PMID:20865723

  20. Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

    PubMed Central

    Kittelberger, Kara A.; Piazza, Fabrizio; Tesco, Giuseppina; Reijmers, Leon G.

    2012-01-01

    Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss. PMID:22238679

  1. Preservation of long-term memory and synaptic plasticity despite short-term impairments in the Tc1 mouse model of Down syndrome.

    PubMed

    Morice, Elise; Andreae, Laura C; Cooke, Sam F; Vanes, Lesley; Fisher, Elizabeth M C; Tybulewicz, Victor L J; Bliss, Timothy V P

    2008-07-01

    Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O'Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a detailed analysis of cognitive function and synaptic plasticity in Tc1 mice. Here we show that Tc1 mice have impaired spatial working memory (WM) but spared long-term spatial reference memory (RM) in the Morris watermaze. Similarly, Tc1 mice are selectively impaired in short-term memory (STM) but have intact long-term memory (LTM) in the novel object recognition task. The pattern of impaired STM and normal LTM is paralleled by a corresponding phenotype in long-term potentiation (LTP). Freely-moving Tc1 mice exhibit reduced LTP 1 h after induction but normal maintenance over days in the dentate gyrus of the hippocampal formation. Biochemical analysis revealed a reduction in membrane surface expression of the AMPAR (alpha-amino-3-hydroxy-5-methyl-4-propionic acid receptor) subunit GluR1 in the hippocampus of Tc1 mice, suggesting a potential mechanism for the impairment in early LTP. Our observations also provide further evidence that STM and LTM for hippocampus-dependent tasks are subserved by parallel processing streams.

  2. Proteasome Inhibition Enhances the Induction and Impairs the Maintenance of Late-Phase Long-Term Potentiation

    ERIC Educational Resources Information Center

    Dong, Chenghai; Upadhya, Sudarshan C.; Ding, Lan; Smith, Thuy K.; Hegde, Ashok N.

    2008-01-01

    Protein degradation by the ubiquitin-proteasome pathway plays important roles in synaptic plasticity, but the molecular mechanisms by which proteolysis regulates synaptic strength are not well understood. We investigated the role of the proteasome in hippocampal late-phase long-term potentiation (L-LTP), a model for enduring synaptic plasticity.…

  3. Impairment and Abuse of Elderly by Staff in Long-Term Care in Michigan: Evidence from Structural Equation Modeling

    ERIC Educational Resources Information Center

    Conner, Tom; Prokhorov, Artem; Page, Connie; Fang, Yu; Xiao, Yimin; Post, Lori A.

    2011-01-01

    Elder abuse in long-term care has become a very important public health concern. Recent estimates of elder abuse prevalence are in the range of 2% to 10% (Lachs & Pillemer, 2004), and current changes in population structure indicate a potential for an upward trend in prevalence (Malley-Morrison, Nolido, & Chawla, 2006; Post et al., 2006).…

  4. Proteasome Inhibition Enhances the Induction and Impairs the Maintenance of Late-Phase Long-Term Potentiation

    ERIC Educational Resources Information Center

    Dong, Chenghai; Upadhya, Sudarshan C.; Ding, Lan; Smith, Thuy K.; Hegde, Ashok N.

    2008-01-01

    Protein degradation by the ubiquitin-proteasome pathway plays important roles in synaptic plasticity, but the molecular mechanisms by which proteolysis regulates synaptic strength are not well understood. We investigated the role of the proteasome in hippocampal late-phase long-term potentiation (L-LTP), a model for enduring synaptic plasticity.…

  5. Impairment and Abuse of Elderly by Staff in Long-Term Care in Michigan: Evidence from Structural Equation Modeling

    ERIC Educational Resources Information Center

    Conner, Tom; Prokhorov, Artem; Page, Connie; Fang, Yu; Xiao, Yimin; Post, Lori A.

    2011-01-01

    Elder abuse in long-term care has become a very important public health concern. Recent estimates of elder abuse prevalence are in the range of 2% to 10% (Lachs & Pillemer, 2004), and current changes in population structure indicate a potential for an upward trend in prevalence (Malley-Morrison, Nolido, & Chawla, 2006; Post et al., 2006).…

  6. DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function

    PubMed Central

    Plotegher, N.; Berti, G.; Ferrari, E.; Tessari, I.; Zanetti, M.; Lunelli, L.; Greggio, E.; Bisaglia, M.; Veronesi, M.; Girotto, S.; Dalla Serra, M.; Perego, C.; Casella, L.; Bubacco, L.

    2017-01-01

    Parkinson’s disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration. PMID:28084443

  7. DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function.

    PubMed

    Plotegher, N; Berti, G; Ferrari, E; Tessari, I; Zanetti, M; Lunelli, L; Greggio, E; Bisaglia, M; Veronesi, M; Girotto, S; Dalla Serra, M; Perego, C; Casella, L; Bubacco, L

    2017-01-13

    Parkinson's disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration.

  8. NAP prevents acute cerebral oxidative stress and protects against long-term brain injury and cognitive impairment in a model of neonatal hypoxia-ischemia.

    PubMed

    Greggio, Samuel; de Paula, Simone; de Oliveira, Iuri M; Trindade, Cristiano; Rosa, Renato M; Henriques, João A P; DaCosta, Jaderson C

    2011-10-01

    Hypoxia-ischemia (HI) is a common cause of neonatal brain damage with lifelong morbidities in which current therapies are limited. In this study, we investigated the effect of neuropeptide NAP (NAPVSIPQ) on early cerebral oxidative stress, long-term neurological function and brain injury after neonatal HI. Seven-day-old rat pups were subjected to an HI model by applying a unilateral carotid artery occlusion and systemic hypoxia. The animals were randomly assigned to groups receiving an intraperitoneal injection of NAP (3 μg/g) or vehicle immediately (0 h) and 24 h after HI. Brain DNA damage, lipid peroxidation and reduced glutathione (GSH) content were determined 24 h after the last NAP injection. Cognitive impairment was assessed on postnatal day 60 using the spatial version of the Morris water maze learning task. Next, the animals were euthanized to assess the cerebral hemispheric volume using the Cavalieri principle associated with the counting point method. We observed that NAP prevented the acute HI-induced DNA and lipid membrane damage and also recovered the GSH levels in the injured hemisphere of the HI rat pups. Further, NAP was able to prevent impairments in learning and long-term spatial memory and to significantly reduce brain damage up to 7 weeks following the neonatal HI injury. Our findings demonstrate that NAP confers potent neuroprotection from acute brain oxidative stress, long-term cognitive impairment and brain lesions induced by neonatal HI through, at least in part, the modulation of the glutathione-mediated antioxidant system.

  9. Maternal separation impairs long term-potentiation in CA1-CA3 synapses and hippocampal-dependent memory in old rats.

    PubMed

    Sousa, Vasco C; Vital, Joana; Costenla, Ana Rita; Batalha, Vânia L; Sebastião, Ana M; Ribeiro, Joaquim A; Lopes, Luísa V

    2014-07-01

    Exposure to chronic stress during the neonatal period is known to induce permanent long-term changes in the central nervous system and hipothalamic-pituitary-adrenal axis reactivity that are associated with increased levels of depression, anxiety, and cognitive impairments. In rodents, a validated model of early life stress is the maternal separation (MS) paradigm, which has been shown to have long-term consequences for the pups that span to adulthood. We hypothesized that the early life stress-associated effects could be exacerbated with aging, because it is often accompanied by cognitive decline. Using a MS model in which rat pups were separated from their mothers for 3 hours daily, during postnatal days 2-14, we evaluated the long-term functional consequences to aged animals (70-week-old), by measuring synaptic plasticity and cognitive performance. The baseline behavioral deficits of aged control rats were further exacerbated in MS animals, indicating that early-life stress induces sustained changes in anxiety-like behavior and hippocampal-dependent memory that are maintained much later in life. We then investigated whether these differences are linked to impaired function of hippocampal neurons by recording hippocampal long-term potentiation from Schaffer collaterals/CA1 synapses. The magnitude of the hippocampal long-term potentiation induced by high-frequency stimulation was significantly lower in aged MS animals than in age-matched controls. These results substantiate the hypothesis that the neuronal and endocrine alterations induced by early-life stress are long lasting, and are able to exacerbate the mild age-associated deficits. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Repeated mild lateral fluid percussion brain injury in the rat causes cumulative long-term behavioral impairments, neuroinflammation, and cortical loss in an animal model of repeated concussion.

    PubMed

    Shultz, Sandy R; Bao, Feng; Omana, Vanessa; Chiu, Charlotte; Brown, Arthur; Cain, Donald Peter

    2012-01-20

    There is growing evidence that repeated brain concussion can result in cumulative and long-term behavioral symptoms, neuropathological changes, and neurodegeneration. Little is known about the factors and mechanisms that contribute to these effects. The current study addresses the need to investigate and better understand the effects of repeated concussion through the development of an animal model. Male Long-Evans rats received 1, 3, or 5 mild lateral fluid percussion injuries or sham injuries spaced 5 days apart. After the final injury, rats received either a short (24 h) or long (8 weeks) post-injury recovery period, followed by a detailed behavioral analysis consisting of tests for rodent anxiety-like behavior, cognition, social behavior, sensorimotor function, and depression-like behavior. Brains were examined immunohistochemically to assess neuroinflammation and cortical damage. Rats given 1, 3, or 5 mild percussion injuries displayed significant short-term cognitive impairments. Rats given repeated mild percussion injuries displayed significantly worse short- and long-term cognitive impairments. Rats given 5 mild percussion injuries also displayed increased anxiety- and depression-like behaviors. Neuropathological analysis revealed short-term neuroinflammation in 3-injury rats, and both short- and long-term neuroinflammation in 5-injury rats. There was also evidence that repeated injuries induced short- and long-term cortical damage. These cumulative and long-term changes are consistent with findings in human patients suffering repeated brain concussion, provide support for the use of repeated mild lateral fluid percussion injuries to study repeated concussion in the rat, and suggest that neuroinflammation may be important for understanding the cumulative and chronic effects of repeated concussion.

  11. Sucrose and naltrexone prevent increased pain sensitivity and impaired long-term memory induced by repetitive neonatal noxious stimulation: Role of BDNF and β-endorphin.

    PubMed

    Nuseir, Khawla Q; Alzoubi, Karem H; Alhusban, Ahmed; Bawaane, Areej; Al-Azzani, Mohammed; Khabour, Omar F

    2017-10-01

    Pain in neonates is associated with short and long-term adverse outcomes. Data demonstrated that long-term consequences of untreated pain are linked to the plasticity of the neonate's brain. Sucrose is effective and safe for reducing painful procedures from single events. However, the mechanism of sucrose-induced analgesia is not fully understood. The role of the opioid system in this analgesia using the opioid receptor antagonist Naltrexone was investigated, plus the long-term effects on learning and memory formation during adulthood. Pain was induced in rat pups via needle pricks of the paws. Sucrose solution and/or naltrexone were administered before the pricks. All treatments started on day one of birth and continued for two weeks. At the end of 8weeks, behavioral studies were conducted to test spatial learning and memory using radial arm water maze (RAWM), and pain threshold via foot-withdrawal response to a hot plate. The hippocampus was dissected; levels of brain derived neurotrophic factor (BDNF) and endorphins were assessed using ELISA. Acute repetitive neonatal pain increased pain sensitivity later in life, while naltrexone with sucrose decreased pain sensitivity. Naltrexone and/or sucrose prevented neonatal pain induced impairment of long-term memory, while neonatal pain decreased levels of BDNF in the hippocampus; this decrease was averted by sucrose and naltrexone. Sucrose with naltrexone significantly increased β-endorphin levels in noxiously stimulated rats. In conclusion, naltrexone and sucrose can reverse increased pain sensitivity and impaired long-term memory induced by acute repetitive neonatal pain probably by normalizing BDNF expression and increasing β-endorphin levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. AMYLOID BETA OLIGOMERS IMPAIR FEAR CONDITIONED MEMORY IN A CALCINEURIN-DEPENDENT FASHION IN MICE

    PubMed Central

    Dineley, Kelly T.; Kayed, Rakez; Neugebauer, Volker; Fu, Yu; Zhang, Wenru; Reese, Lindsay C.; Taglialatela, Giulio

    2010-01-01

    Soluble oligomeric aggregates of the amyloid beta (Aβ) peptide are believed to be the most neurotoxic Aβ species affecting the brain in Alzheimer Disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underlined by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that Aβ oligomers are recruited at the synapse, oppose expression of long term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of Aβ-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in the pathological processes of AD. CaN is especially abundant in the CNS where it is involved in synaptic activity, LTP and memory function. Here, we describe how oligomeric Aβ treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of Aβ oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by Aβ oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disrupting effect induced by acute oligomeric Aβ treatment in mice. PMID:20544830

  13. Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice.

    PubMed

    Dineley, Kelly T; Kayed, Rakez; Neugebauer, Volker; Fu, Yu; Zhang, Wenru; Reese, Lindsay C; Taglialatela, Giulio

    2010-10-01

    Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice. (c) 2010 Wiley-Liss, Inc.

  14. Docosahexaenoic Acid Reduces Cerebral Damage and Ameliorates Long-Term Cognitive Impairments Caused by Neonatal Hypoxia-Ischemia in Rats.

    PubMed

    Arteaga, Olatz; Revuelta, M; Urigüen, L; Martínez-Millán, L; Hilario, E; Álvarez, A

    2016-10-29

    As the interest in the neuroprotective possibilities of docosahexaenoic acid (DHA) for brain injury has grown in the recent years, we aimed to investigate the long-term effects of this fatty acid in an experimental model of perinatal hypoxia-ischemia in rats. To this end, motor activity, aspects of learning, and memory function and anxiety, as well as corticofugal connections visualized by using tracer injections, were evaluated at adulthood. We found that in the hours immediately following the insult, DHA maintained mitochondrial inner membrane integrity and transmembrane potential, as well as the integrity of synaptic processes. Seven days later, morphological damage at the level of the middle hippocampus was reduced, since neurons and myelin were preserved and the astroglial reactive response and microglial activation were seen to be diminished. At adulthood, the behavioral tests revealed that treated animals presented better long-term working memory and less anxiety than non-treated hypoxic-ischemic animals, while no difference was found in the spontaneous locomotor activity. Interestingly, hypoxic-ischemic injury caused alterations in the anterograde corticofugal neuronal connections which were not so evident in rats treated with DHA. Thus, our results indicate that DHA treatment can lead to long-lasting neuroprotective effects in this experimental model of neonatal hypoxia-ischemic brain injury, not only by mitigating axonal changes but also by enhancing cognitive performance at adulthood.

  15. Evaluation of nurses’ changing perceptions when trained to implement a self-management programme for dual sensory impaired older adults in long-term care: a qualitative study

    PubMed Central

    Roets-Merken, Lieve M; Vernooij-Dassen, Myrra J F J; Zuidema, Sytse U; Dees, Marianne K; Hermsen, Pieter G J M; Kempen, Gertrudis I J M; Graff, Maud J L

    2016-01-01

    Objectives To gain insights into the process of nurses’ changing perceptions when trained to implement a self-management programme for dual sensory impaired older adults in long-term care, and into the factors that contributed to these changes in their perceptions. Design Qualitative study alongside a cluster randomised controlled trial. Setting 17 long-term care homes spread across the Netherlands. Participants 34 licensed practical nurses supporting 54 dual sensory impaired older adults. Intervention A 5-month training programme designed to enable nurses to support the self-management of dual sensory impaired older adults in long-term care. Primary outcomes Nurses’ perceptions on relevance and feasibility of the self-management programme collected from nurses’ semistructured coaching diaries over the 5-month training and intervention period, as well as from trainers’ reports. Results Nurses’ initial negative perceptions on relevance and feasibility of the intervention changed to positive as nurses better understood the concept of autonomy. Through interactions with older adults and by self-evaluations of the effect of their behaviour, nurses discovered that their usual care conflicted with client autonomy. From that moment, nurses felt encouraged to adapt their behaviour to the older adults’ autonomy needs. However, nurses’ initial unfamiliarity with conversation techniques required a longer exploration period than planned. Once client autonomy was understood, nurses recommended expanding the intervention as a generic approach to all their clients, whether dual sensory impaired or not. Conclusions Longitudinal data collection enabled exploration of nurses’ changes in perceptions when moving towards self-management support. The training programme stimulated nurses to go beyond ‘protocol thinking’, discovering client autonomy and exploring the need for their own behavioural adaptations. Educational programmes for practical nurses should offer

  16. EphrinA4 mimetic peptide targeted to EphA binding site impairs the formation of long-term fear memory in lateral amygdala

    PubMed Central

    Dines, M; Lamprecht, R

    2014-01-01

    Fear conditioning leads to long-term fear memory formation and is a model for studying fear-related psychopathologies conditions such as phobias and posttraumatic stress disorder. Long-term fear memory formation is believed to involve alterations of synaptic efficacy mediated by changes in synaptic transmission and morphology in lateral amygdala (LA). EphrinA4 and its cognate Eph receptors are intimately involved in regulating neuronal morphogenesis, synaptic transmission and plasticity. To assess possible roles of ephrinA4 in fear memory formation we designed and used a specific inhibitory ephrinA4 mimetic peptide (pep-ephrinA4) targeted to EphA binding site. We show that this peptide, composed of the ephrinA4 binding domain, interacts with EphA4 and inhibits ephrinA4-induced phosphorylation of EphA4. Microinjection of the pep-ephrinA4 into rat LA 30 min before training impaired long- but not short-term fear conditioning memory. Microinjection of a control peptide derived from a nonbinding E helix site of ephrinA4, that does not interact with EphA, had no effect on fear memory formation. Microinjection of pep-ephrinA4 into areas adjacent to the amygdala had no effect on fear memory. Acute systemic administration of pep-ephrinA4 1 h after training also impaired long-term fear conditioning memory formation. These results demonstrate that ephrinA4 binding sites in LA are essential for long-term fear memory formation. Moreover, our research shows that ephrinA4 binding sites may serve as a target for pharmacological treatment of fear and anxiety disorders. PMID:25268254

  17. EphrinA4 mimetic peptide targeted to EphA binding site impairs the formation of long-term fear memory in lateral amygdala.

    PubMed

    Dines, M; Lamprecht, R

    2014-09-30

    Fear conditioning leads to long-term fear memory formation and is a model for studying fear-related psychopathologies conditions such as phobias and posttraumatic stress disorder. Long-term fear memory formation is believed to involve alterations of synaptic efficacy mediated by changes in synaptic transmission and morphology in lateral amygdala (LA). EphrinA4 and its cognate Eph receptors are intimately involved in regulating neuronal morphogenesis, synaptic transmission and plasticity. To assess possible roles of ephrinA4 in fear memory formation we designed and used a specific inhibitory ephrinA4 mimetic peptide (pep-ephrinA4) targeted to EphA binding site. We show that this peptide, composed of the ephrinA4 binding domain, interacts with EphA4 and inhibits ephrinA4-induced phosphorylation of EphA4. Microinjection of the pep-ephrinA4 into rat LA 30 min before training impaired long- but not short-term fear conditioning memory. Microinjection of a control peptide derived from a nonbinding E helix site of ephrinA4, that does not interact with EphA, had no effect on fear memory formation. Microinjection of pep-ephrinA4 into areas adjacent to the amygdala had no effect on fear memory. Acute systemic administration of pep-ephrinA4 1 h after training also impaired long-term fear conditioning memory formation. These results demonstrate that ephrinA4 binding sites in LA are essential for long-term fear memory formation. Moreover, our research shows that ephrinA4 binding sites may serve as a target for pharmacological treatment of fear and anxiety disorders.

  18. Brief Embryonic Strychnine Exposure in Zebrafish Causes Long-Term Adult Behavioral Impairment with Indications of Embryonic Synaptic Changes

    PubMed Central

    Roy, Nicole M.; Arpie, Brianna; Lugo, Joseph; Linney, Elwood; Levin, Edward D.; Cerutti, Daniel

    2015-01-01

    Zebrafish provide a powerful model of the impacts of embryonic toxicant exposure on neural development that may result in long-term behavioral dysfunction. In this study, zebrafish embryos were treated with 1.5 mM strychnine for short embryonic time windows to induce transient changes in inhibitory neural signaling, and were subsequently raised in untreated water until adulthood. PCR analysis showed indications that strychnine exposure altered expression of some genes related to glycinergic, GABAergic and glutamatergic neuronal synapses during embryonic development. In adulthood, treated fish showed significant changes in swimming speed and tank diving behavior compared to controls. Taken together, these data show that a short embryonic exposure to a neurotoxicant can alter development of neural synapses and lead to changes in adult behavior. PMID:23022260

  19. Brief embryonic strychnine exposure in zebrafish causes long-term adult behavioral impairment with indications of embryonic synaptic changes.

    PubMed

    Roy, Nicole M; Arpie, Brianna; Lugo, Joseph; Linney, Elwood; Levin, Edward D; Cerutti, Daniel

    2012-01-01

    Zebrafish provide a powerful model of the impacts of embryonic toxicant exposure on neural development that may result in long-term behavioral dysfunction. In this study, zebrafish embryos were treated with 1.5mM strychnine for short embryonic time windows to induce transient changes in inhibitory neural signaling, and were subsequently raised in untreated water until adulthood. PCR analysis showed indications that strychnine exposure altered expression of some genes related to glycinergic, GABAergic and glutamatergic neuronal synapses during embryonic development. In adulthood, treated fish showed significant changes in swimming speed and tank diving behavior compared to controls. Taken together, these data show that a short embryonic exposure to a neurotoxicant can alter development of neural synapses and lead to changes in adult behavior. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. The Representational Consequences of Intentional Forgetting: Impairments to Both the Probability and Fidelity of Long-Term Memory

    PubMed Central

    2016-01-01

    We investigated whether intentional forgetting impacts only the likelihood of later retrieval from long-term memory or whether it also impacts the fidelity of those representations that are successfully retrieved. We accomplished this by combining an item-method directed forgetting task with a testing procedure and modeling approach inspired by the delayed-estimation paradigm used in the study of visual short-term memory (STM). Abstract or concrete colored images were each followed by a remember (R) or forget (F) instruction and sometimes by a visual probe requiring a speeded detection response (E1–E3). Memory was tested using an old–new (E1–E2) or remember-know-no (E3) recognition task followed by a continuous color judgment task (E2–E3); a final experiment included only the color judgment task (E4). Replicating the existing literature, more “old” or “remember” responses were made to R than F items and RTs to postinstruction visual probes were longer following F than R instructions. Color judgments were more accurate for successfully recognized or recollected R than F items (E2–E3); a mixture model confirmed a decrease to both the probability of retrieving the F items as well as the fidelity of the representation of those F items that were retrieved (E4). We conclude that intentional forgetting is an effortful process that not only reduces the likelihood of successfully encoding an item for later retrieval, but also produces an impoverished memory trace even when those items are retrieved; these findings draw a parallel between the control of memory representations within working and long-term memory. PMID:26709589

  1. Environmental enrichment improves age-related immune system impairment: long-term exposure since adulthood increases life span in mice.

    PubMed

    Arranz, Lorena; De Castro, Nuria M; Baeza, Isabel; Maté, Ianire; Viveros, Maria Paz; De la Fuente, Mónica

    2010-08-01

    Age-related changes in immunity have been shown to highly influence morbidity and mortality. The aim of the present work was to study the effects of environmental enrichment (EE) (8-16 weeks) on several functions and oxidative stress parameters of peritoneal leukocytes, previously described as health and longevity markers, in mice at different ages, namely adult (44 +/- 4 weeks), old (69 +/- 4 weeks), and very old (92 +/- 4 weeks). Mortality rates were monitored in control and enriched animals, and effects on survival of long-term exposure to EE until natural death were determined. The results showed that exposure to EE was efficient in improving the function (i.e., macrophage chemotaxis and phagocytosis, lymphocyte chemotaxis and proliferation, natural killer cell activity, interleukin-2 and tumor necrosis factor-alpha levels) and decreasing the oxidative-inflammatory stress (i.e., lowered oxidized glutathione content, xanthine oxidase activity, expression of Toll-like receptors 2 and 4 on CD4 and CD8 cells, and increased reduced glutathione and glutathione peroxidase and catalase activities) of immune cells. These positive effects of EE were especially remarkable in animals at older ages. Importantly, long-term exposure to EE from adult age and until natural death stands out as a useful strategy to extend longevity. Thus, the present work confirms the importance of maintaining active mental and/or physical activity aiming to improve quality of life in terms of immunity, and demonstrates that this active life must be initiated at early stages of the aging process and preserved until death to improve life span.

  2. 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)

  3. Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer’s disease

    PubMed Central

    Ferreira, Sergio T.; Lourenco, Mychael V.; Oliveira, Mauricio M.; De Felice, Fernanda G.

    2015-01-01

    Alzheimer’s disease (AD) is the most common form of dementia in the elderly, and affects millions of people worldwide. As the number of AD cases continues to increase in both developed and developing countries, finding therapies that effectively halt or reverse disease progression constitutes a major research and public health challenge. Since the identification of the amyloid-β peptide (Aβ) as the major component of the amyloid plaques that are characteristically found in AD brains, a major effort has aimed to determine whether and how Aβ leads to memory loss and cognitive impairment. A large body of evidence accumulated in the past 15 years supports a pivotal role of soluble Aβ oligomers (AβOs) in synapse failure and neuronal dysfunction in AD. Nonetheless, a number of basic questions, including the exact molecular composition of the synaptotoxic oligomers, the identity of the receptor(s) to which they bind, and the signaling pathways that ultimately lead to synapse failure, remain to be definitively answered. Here, we discuss recent advances that have illuminated our understanding of the chemical nature of the toxic species and the deleterious impact they have on synapses, and have culminated in the proposal of an Aβ oligomer hypothesis for Alzheimer’s pathogenesis. We also highlight outstanding questions and challenges in AD research that should be addressed to allow translation of research findings into effective AD therapies. PMID:26074767

  4. 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.

  5. NLRP3 inflammasome activation by mitochondrial reactive oxygen species plays a key role in long-term cognitive impairment induced by paraquat exposure.

    PubMed

    Chen, Liuji; Na, Ren; Boldt, Erin; Ran, Qitao

    2015-09-01

    Exposure to environmental toxins such as pesticides is implicated in increasing Alzheimer's disease risk. In this study, we investigated the long-term effects of paraquat exposure on cognition of Alzheimer's disease animal model APP/PS1 mice and wild-type (WT) mice. Our results showed that APP/PS1 mice had exacerbated cognition impairment and elevated Aβ levels at 5 months after paraquat exposure, and that WT mice had cognition impairment at 5 and 16 months after paraquat exposure. In addition, increased mitochondrial oxidative stress and augmented brain inflammation were observed in both paraquat-exposed APP/PS1 mice and WT mice. Interestingly, activation of NLRP3 inflammasome, which triggers inflammation in response to mitochondrial stress, was enhanced in paraquat-exposed mice. Moreover, transgenic mice overexpressing Prdx3, a key enzyme in detoxifying mitochondrial H2O2, had suppressed NLRP3 inflammasome activation, reduced brain inflammation, and attenuated cognition impairment after paraquat exposure. Together, our results indicate that NLRP3 inflammasome activation induced by mitochondrial reactive oxygen species plays a key role in mediating paraquat-induced long-term cognition decline by elevating brain inflammation.

  6. Impairment of catecholamine systems during induction of long-term potentiation at hippocampal CA1 synapses in HPC-1/syntaxin 1A knock-out mice.

    PubMed

    Mishima, Tatsuya; Fujiwara, Tomonori; Kofuji, Takefumi; Akagawa, Kimio

    2012-01-04

    The membrane protein HPC-1/syntaxin 1A is believed to play a key role in synaptic vesicle exocytosis, and it was recently suggested to be required for synaptic plasticity. Despite evidence for the function of HPC-1/syntaxin 1A in synaptic plasticity, the underlying cellular mechanism is unclear. We found that although fast synaptic transmission and long-term depression were unaffected, HPC-1/syntaxin 1A knock-out (STX1A(-/-)) mice showed impaired long-term potentiation (LTP) in response to theta-burst stimulation in CA1 hippocampal slices. The impairment in LTP was rescued by the application of forskolin, an adenylyl cyclase activator, or more robust stimulation, suggesting that cAMP/protein kinase A signaling was suppressed in these mice. In addition, catecholamine release from the hippocampus was significantly reduced in STX1A(-/-) mice. Because HPC-1/syntaxin 1A regulates exocytosis of dense-core synaptic vesicles, which contain neuromodulatory transmitters such as noradrenaline, dopamine and 5-HT, we examined the effect of neuromodulatory transmitters on LTP induction. Noradrenaline and dopamine enhanced LTP induction in STX1A(-/-) mice, whereas catecholamine depletion reduced LTP induction in wild-type mice. Theses results suggest that HPC-1/syntaxin 1A regulates catecholaminergic systems via exocytosis of dense-core synaptic vesicles, and that deletion of HPC-1/syntaxin 1A causes impairment of LTP induction.

  7. Reconsolidation of a long-term spatial memory is impaired by cycloheximide when reactivated with a contextual latent learning trial in male and female rats.

    PubMed

    Flint, R W; Valentine, S; Papandrea, D

    2007-09-21

    Reconsolidation of long-term memory has become a topic of great interest in recent years, and has the potential to provide important information regarding memory processes and the treatment of memory-related disorders. The present study examined the role of systemic protein synthesis inhibition in reconsolidation of a long-term spatial memory reactivated by a contextual latent learning trial in male and female rats. Using the Morris water maze, we demonstrate that: 1) a contextual latent reactivation treatment enhances memory, 2) systemic protein synthesis inhibition selectively impairs test performance when administered in conjunction with a memory reactivation treatment, and 3) that these effects are more pronounced in female rats. These findings indicate a role for protein synthesis in the reconsolidation of a contextually reactivated long-term spatial memory using the water maze, and a potential differential effect of sex in this apparatus. The role of the strength of the memory trace is discussed and the relevance of these findings to theories of reconsolidation and therapeutic treatment of post-traumatic stress disorder is discussed.

  8. Correlates of cognitive impairment in elderly residents of long term care institutions in the metropolitan area of Guadalajara, Mexico.

    PubMed

    Arias-Merino, E D; Orozco-Mares, I; Garabito-Esparza, L C; Fernandez-Cruz, L; Arias-Merino, M J; Celis de la Rosa, A; Cabrera-Pivaral, C; Gonzalez-P Rez, G J

    2003-01-01

    To determine the prevalence of cognitive impairment and to examine the correlation between demographic and social factors, the activities of daily living (ADL), and depression with cognitive function in elderly Mexicans living in nursing homes. Cross-sectional. Fourteen nursing homes in Guadalajara. Data were drawn from a random sample of 451 elderly, aged 60-104 years. The Spanish versions of MMSE (Folstein), ADL index (Barthel), and the Geriatric Depression Screening (GDS) (Yesavage); demographic factors were obtained. The prevalence of cognitive impairment was 52.3%, with a cut-off of 19/20 (Bohnstedt). Cognitive impairment was significantly related to gender, educational level, activity participation, pension, ADL, and depression. The results indicate a higher prevalence of cognitive impairment than in other Mexican studies. The data are consistent with previous findings that cognitive impairment in the elderly is more common among females, those with a low level of education, the lack of participation in social/leisure activities, ADL dependencies, and depression.

  9. ASK1 is involved in cognitive impairment caused by long-term high-fat diet feeding in mice

    PubMed Central

    Toyama, Kensuke; Koibuchi, Nobutaka; Hasegawa, Yu; Uekawa, Ken; Yasuda, Osamu; Sueta, Daisuke; Nakagawa, Takashi; Ma, Mingjie; Kusaka, Hiroaki; Lin, Bowen; Ogawa, Hisao; Ichijo, Hidenori; Kim-Mitsuyama, Shokei

    2015-01-01

    Although high-fat diet intake is known to cause obesity and diabetes, the effect of high-fat diet itself on cognitive function remains to be clarified. We have previously shown that apoptosis signal-regulating kinase 1 (ASK1) is responsible for cognitive impairment caused by chronic cerebral hypoperfusion. The present work, by using ASK1 deficient mice, was undertaken to explore the influence of chronic high-fat diet intake on cognitive function and the role of ASK1. Cognitive function in wild-type mice fed high-fat diet from 2 to 24 months of age was significantly impaired compared to those fed control diet, which was associated with the significant white matter lesions, reduction of hippocampal capillary density, and decrement of hippocampal neuronal cell. However, ASK1 deficiency abolished the development of cognitive impairment and cerebral injury caused by high-fat diet. Our results provided the evidence that high-fat diet itself causes cognitive impairment and ASK1 participates in such cognitive impairment. PMID:26044555

  10. Constitutive caspase activation and impaired death-inducing signaling complex formation in CD95-resistant, long-term activated, antigen-specific T cells.

    PubMed

    Strauss, Gudrun; Knape, Ingrid; Melzner, Ingo; Debatin, Klaus-Michael

    2003-08-01

    Elimination of T cells during an immune response is mediated by activation-induced cell death (AICD) and CD95-mediated apoptosis. Chronic graft-vs-host disease and T cell-mediated autoimmune diseases are caused by the persistence of activated T cells that escaped tolerance induction by deletion or silencing. To mimic the in vivo situation of long-term activated T cells, we generated an in vitro system using HLA-A1-specific T cells, weekly restimulated by Ag. While short-term activated T cells (two to five rounds of stimulation) were CD95 sensitive and susceptible to AICD, T cells stimulated more than eight times acquired constitutive CD95 resistance and exhibited reduced AICD. Phenotypically, these long-term activated T cells could be identified as effector/memory T cells. The expression of the proforms of the CD95 receptor initiator caspases, caspase-8 and -10, and the effector caspase-3 was strongly decreased in these cells, and only active caspase fragments were detected. In contrast to short-term activated T cells, constitutive CD95 receptor clustering was observed on the cell surface, and caspase-8 was bound to the CD95 receptor in the absence of receptor triggering. After further cross-linking of CD95, additional formation of the death-inducing signaling complex (DISC) was strongly impaired. Reduced DISC formation in long-term activated T cells was associated with the loss of PTEN expression and the increased phosphorylation of protein kinase B. Inhibitors of phosphoinositol 3-kinase restored CD95 sensitivity and DISC formation in long-term activated T cells. These data suggest that defective CD95 signaling in effector/memory T cells may contribute to the apoptosis resistance toward physiological stimuli in T cells mediating tissue destruction in vivo.

  11. Long-term nutrition education reduces several risk factors for type 2 diabetes mellitus in Brazilians with impaired glucose tolerance.

    PubMed

    Pimentel, Gustavo D; Portero-McLellan, Kátia C; Oliveira, Erick P; Spada, Ana P M; Oshiiwa, Marie; Zemdegs, Juliane C S; Barbalho, Sandra M

    2010-03-01

    The aim of this study was to evaluate the effects of a nutrition education program (NEP) on anthropometric, dietetic, and metabolic parameters in high-risk subjects for type 2 diabetes mellitus. Fifty-one participants, both sexes, were randomly assigned to either the control (58.8%) or the intervention (NEP) group. The intervention group received frequent individual and group nutritional counseling from a team of nutritionists. Participants were assessed at baseline (M0) and after 12 months (M1) for anthropometric, dietetic, and metabolic parameters. The hypothesis was that high-risk subjects for type 2 diabetes mellitus participating in NEP would show an improvement in these parameters. At M1, the intervention group showed a significant decline in body weight (-3.4%), body mass index (-5.7%), cholesterol intake (-49.5%), fasting glycemia (-14.0%), fasting insulin (-9.0%), postprandial glycemia (-21.0%), postprandial insulin (-71.0%), total serum cholesterol (-23.0%), and glycated hemoglobin (-24.0%). A decrease in energy intake (5%, P = .06) and low-density lipoprotein cholesterol (25%, P = .07) was observed in the interventional group, although it did not reach statistical significance. In contrast, the control group presented a significantly higher energy intake (19%, P = .04) and a nonsignificant increase in consumption of all macronutrients. The long-term NEP was found to improve anthropometric, dietary, and metabolic parameters in high-risk subjects for type 2 diabetes mellitus.

  12. Long-term exposure to decabrominated diphenyl ether impairs CD8 T-cell function in adult mice.

    PubMed

    Zeng, Weihong; Wang, Ying; Liu, Zhicui; Khanniche, Asma; Hu, Qingliang; Feng, Yan; Ye, Weiyi; Yang, Jianglong; Wang, Shujun; Zhou, Lin; Shen, Hao; Wang, Yan

    2014-07-01

    Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their effect on the immune system is not well understood. In this study, experimental adult mice were intragastrically administered 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) at doses of 8, 80 or 800 mg/kg of body weight (bw) at 2-day intervals. Our results showed that continuous exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes, decreased cytokine (IFN-γ, IL-2 and TNF-α) production and lower CD8 T-cell proliferation were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209 exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant Listeria monocytogenes expressing ovalbumin (rLm-OVA) and the OVA-specific CD8 T cells had reduced functionality. Taken together, our study demonstrates that continuous BDE-209 exposure causes adverse effects on the number and functionality of immune cells in adult mice.

  13. Repair of impaired pulmonary function is possible in very-long-term allogeneic stem cell transplantation survivors.

    PubMed

    Jain, Natasha A; Pophali, Priyanka A; Klotz, Jeffrey K; Ito, Sawa; Koklanaris, Eleftheria; Chawla, Kamna; Hourigan, Christopher S; Gormley, Nicole; Savani, Bipin N; Barrett, Austin John; Battiwalla, Minoo

    2014-02-01

    Both early- and late-onset noninfectious pulmonary injury are important contributors to the nonrelapse mortality seen after allogeneic stem cell transplantation (allo-SCT), particularly in subjects conditioned with high-dose total body irradiation (TBI). To characterize the kinetics of recovery from pulmonary injury in long-term survivors, we collected data on 138 subjects who survived > 3 years (median survival, 10.2 years) after predominantly TBI-based allo-SCT from their HLA-matched siblings. Baseline pulmonary function tests served as the reference for subsequent measurements at 3, 5, 10, and 15 years for each survivor. The only parameter showing a clinically and statistically significant decline post-transplant was adjusted diffusion capacity of lung for carbon monoxide (DLCO), which reached a nadir at 5 years but surprisingly normalized at the 10-year mark. Multivariable modeling identified chronic graft-versus-host disease (P < .02) and abnormal baseline-adjusted DLCO (P < .03) as the only significant factors associated with the decline in adjusted DLCO at 5 years but excluded smoking, conditioning intensity, baseline C-reactive protein level, TBI dose to the lungs, disease, and demographic variables. In conclusion, pulmonary injury as monitored by the adjusted DLCO continues to deteriorate in the first 5 years after allo-SCT but recovers at 10 years.

  14. Nonword Repetition Problems in Children with Specific Language Impairment: A Deficit in Accessing Long-Term Linguistic Representations?

    ERIC Educational Resources Information Center

    Leclercq, Anne-Lise; Maillart, Christelle; Majerus, Steve

    2013-01-01

    Children with specific language impairment (SLI) consistently show poor nonword repetition (NWR) performance. However, the reason for these difficulties remains a matter of intensive debate. Nonword repetition is a complex psycholinguistic task that heavily relies upon phonological segmentation and phonological knowledge, and even lexical…

  15. Repetitive Closed-Head Impact Model of Engineered Rotational Acceleration induces long-term cognitive impairments with persistent astrogliosis and microgliosis in mice.

    PubMed

    Chen, Huazhen; Desai, Abhishek; Kim, Hee-Yong

    2017-03-13

    Repeated mild traumatic brain injury (rmTBI) has been identified as a high-risk factor for dementia at a later stage by epidemiology. The animal models to replicate complex features of human rmTBI and/or to evaluate long-term effects on brain function have not been established. In this study, we used a novel Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) to investigate long-term neuropathological and cognitive functional consequences of rmTBI. Adult C57BL/6 male mice were subjected to CHIMERA for three consecutive days 24 h apart. Functional outcomes were assessed by the beam walk and Morris water maze tests. Neuropathology was evaluated by immunostaining of glial fibrillary acidic protein (GFAP), amyloid precursor protein (APP), and ionizing calcium-binding adaptor molecule-1 (Iba-1) and by qRT-PCR or western blotting of GFAP, Iba-1 and TNF-α. Repeated CHIMERA (rCHIMERA) resulted in motor deficits at 3 days and learning and memory impairments which were sustained up to 6-months post injury. GFAP and TNF-α gene expression was increased within a week while astrogliosis and microgliosis were induced starting from day 1 up to 6.5 months after rCHIMERA with upregulated GFAP and Iba-1 protein levels. rCHIMERA also induced APP protein deposition from day 1 to day 7, but diminished by 1 month. In conclusion, rCHIMERA produces long-lasting cognitive impairments with astrogliosis and microgliosis in mice, suggesting that rCHIMERA can be a useful animal model to study the long-term complications as well as cellular and molecular mechanisms of human rmTBI.

  16. Impaired recruitment of seizure-generated neurons into functional memory networks of the adult dentate gyrus following long-term amygdala kindling.

    PubMed

    Fournier, Neil M; Botterill, Justin J; Marks, Wendie N; Guskjolen, Axel J; Kalynchuk, Lisa E

    2013-06-01

    Epileptic seizures increase the birth of new neurons in the adult hippocampus. Although the consequences of aberrant neurogenesis on behavior are not fully understood, one hypothesis is that seizure-generated neurons might form faulty circuits that disrupt hippocampal functions, such as learning and memory. In the present study, we employed long-term amygdala kindling (i.e., rats receive 99-electrical stimulations) to examine the effect of repeated seizures on hippocampal neurogenesis and behavior. We labeled seizure-generated cells with the proliferation marker BrdU after 30-stimulations and continued kindling for an additional 4weeks to allow newborn neurons to mature under conditions of repeated seizures. After kindling was complete, rats were tested in a trace fear conditioning task and sacrificed 2h later to examine if 4-week old newborn cells were recruited into circuits involved in the retrieval of emotional memory. Compared to non-kindled controls, long-term kindled rats showed significant impairments in fear memory reflected in a decrease in conditioned freezing to both tone and contextual cues during testing. Moreover, long-term kindling also prevented the activation of 4-week old newborn cells in response to fear memory retrieval. These results indicate that the presence of seizure activity during cell maturation impedes the ability of new neurons to integrate properly into circuits important in memory formation. Together, our findings suggest that aberrant seizure-induced neurogenesis might contribute to the development of learning impairments in chronic epilepsy and raise the possibility that targeting the reduced activation of adult born neurons could represent a beneficial strategy to reverse cognitive deficits in some epileptic patients. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Major Impairments of Glutamatergic Transmission and Long-Term Synaptic Plasticity in the Hippocampus of Mice Lacking the Melanin-Concentrating Hormone Receptor-1

    PubMed Central

    Pachoud, Bastien; Adamantidis, Antoine; Ravassard, Pascal; Luppi, Pierre-Hervé; Grisar, Thierry; Lakaye, Bernard

    2010-01-01

    The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis, anxiety, and sleep regulation. Since the MCH receptor-1 (MCH-R1), the only functional receptor that mediates MCH functions in rodents, facilitates behavioral performance in hippocampus-dependent learning tasks, we investigated whether glutamatergic transmission in CA1 pyramidal cells could be modulated in mice lacking the MCH-R1 gene (MCH-R1−/−). We found that both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated transmissions were diminished in the mutant mice compared with their controls. This deficit was explained, at least in part, by a postsynaptic down-regulation of these receptors since the amplitude of miniature excitatory postsynaptic currents and the NMDA/AMPA ratio were decreased. Long-term synaptic potentiation (LTP) was also impaired in MCH-R1−/− mice. This was due to an altered induction, rather than an impaired, expression because repeating the induction stimulus restored LTP to a normal magnitude. In addition, long-term synaptic depression was strongly diminished in MCH-R1−/− mice. These results suggest that MCH exerts a facilitatory effect on CA1 glutamatergic synaptic transmission and long-term synaptic plasticity. Recently, it has been shown that MCH neurons fire exclusively during sleep and mainly during rapid eye movement sleep. Thus these findings provide a mechanism by which sleep might facilitate memory consolidation. PMID:20592115

  18. Effects of long-term feeding of chitosan on postprandial lipid responses and lipid metabolism in a high-sucrose-diet-impaired glucose-tolerant rat model.

    PubMed

    Liu, Shing-Hwa; He, Sih-Pin; Chiang, Meng-Tsan

    2012-05-02

    This study was designed to investigate the effects of long-term feeding of chitosan on postprandial lipid response and lipid metabolism in a high-sucrose (HS)-diet-impaired glucose-tolerant rat model. As the results, HS-diet-fed rats supplemented with 5 and 7% chitosan in diets for 9 weeks had lower postprandial plasma total cholesterol (TC) levels, but 7% chitosan in the diet had higher postprandial plasma triglyceride (TG) and TG-rich lipoprotein TG levels. Supplementation of chitosan significantly decreased the postprandial ratio of apolipoprotein B (apoB)48/apoB100 in TG-rich lipoprotein fractions of HS-diet-fed rats. Long-term supplementation of 5 and 7% chitosan in diets for 16 weeks had lower plasma TC, low-density lipoprotein cholesterol (LDL-C) + very low density lipoprotein cholesterol (VLDL-C), TC/high-density lipoprotein (HDL-C) ratio, leptin, and tumor necrosis factor-α (TNF-α) levels in HS-diet-fed rats. Moreover, it was noticed that the VLDL receptor (VLDLR) protein expression in skeletal muscles of HS-diet-fed rats was significantly decreased, which could be significantly reversed by supplementation of 5 and 7% chitosan. Rats supplemented with 7% chitosan in the diet significantly elevated the lipolysis rate and decreased the accumulation of TG in epididymal fat pads of HS-diet-fed rats. The plasma angiopoietin-like 4 (ANGPTL4) protein expression was not affected in HS-diet-fed rats, but it was significantly increased in 7% chitosan-supplemented HS-diet-fed rats. Taken together, these results indicate that supplementation of chitosan in the diet can improve the impairment of lipid metabolism in a HS-diet-fed rat model, but long-term high-dose chitosan feeding may enhance postprandial plasma TG and TG-rich lipoprotein TG levels in HS-diet-fed rats through an ANGPTL4-regulated pathway.

  19. Association of urinary incontinence with impaired functional status among older people living in a long-term care setting.

    PubMed

    Chiu, Aih-Fung; Huang, Mei-Huang; Hsu, Mei-Hsiu; Liu, Ju-Ling; Chiu, Jui-Fang

    2015-03-01

    To examine the association between functional status and urinary incontinence. A total of 27 participants with urinary incontinence and 50 participants without urinary incontinence were analyzed at a long-term care setting in Pingtung County, Taiwan, in 2011. The recruitment criteria were age older than 65 years, ability to communicate with the researcher, agreement to participate in the present study and potential ability to complete at least one measurement of functional status. Urinary incontinence was defined as urine leakage at least once a week during the past 4 weeks, whereas functional status was assessed by the body composition (body mass index and waist circumference), upper body strength (grasp test), lower body strength (30-s and 5-times chair stand test), upper body flexibility (back scratch test), lower body flexibility (chair sit-and-reach test) and agility/dynamic balance (8-ft up-and-go test). In univariate analyses, performances on the tests of 5-time chair stand, 30-s chair stand, 8-ft up-and-go, chair sit-and-reach, and grasp were significantly different between the participants with and without urinary incontinence (all P < 0.05). However, after multiple logistical regression adjusting sex, age and chronic illnesses, just two tests, 8-ft up-and-go and chair sit-and-reach, were independent predictors of urinary incontinence. Poor performance on the tests of 8-ft up-and-go and chair sit-and-reach were the predominated risk factors of urinary incontinence. Further studies regarding how to improve the functional status, especially focusing on the function of the lower body, might be required in order to enhance continence care. © 2014 Japan Geriatrics Society.

  20. 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

  1. Post-Weaning Protein Malnutrition in the Rat Produces Short and Long Term Metabolic Impairment, in Contrast to Earlier and Later Periods

    PubMed Central

    del Carmen Miñana-Solis, María; Escobar, Carolina

    2008-01-01

    Malnutrition during gestation and lactation modifies metabolic strategies and leads to metabolic disease in adult life. Studies in human populations suggest that malnutrition during infancy may also induce long term metabolic disorders. The present study investigated if post-weaning and a late period of development might be sensitive for long term metabolic impairment. Hereto male Wistar rats were malnourished with a low protein diet (6%), during gestation and lactation (MGL), from weaning to 55 days (MPW) or during adulthood from 90 to 120 days (MA). Control rats (C) were fed with a regular diet (23% protein). We determine plasma concentrations of insulin, glucagon, triacylglycerols (TAG), free fatty acids (FFA), and liver glycogen after a Glucose Tolerance Test (GTT). Independent of the age of onset, malnutrition induced low body weight. Early and post-weaning malnutrition produced impaired glucose tolerance and low values of TAG, also in MPW induced low values of insulin and glucagon. At 90 days, after balanced diet rehabilitation, the MGL group showed a similar glucose tolerance test as the controls but display low values of insulin, while the MPW group exhibited high levels of glucose and TAG, and low values of insulin, glucagon, FFA and hepatic glycogen. At 180 days, after balanced rehabilitation only MPW rats showed metabolic alterations. Malnutrition during adult life (MA) did not produce metabolic disturbances. Surprisingly the results uncover the post-weaning stage as a vulnerable period to malnutrition that induces long lasting metabolic alterations and deficiency in pancreatic function. PMID:19043606

  2. 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 ...

  3. Levothyroxine rescues the lead-induced hypothyroidism and impairment of long-term potentiation in hippocampal CA1 region of the developmental rats

    SciTech Connect

    Wu Chuanyun; Liu Bing; Wang Huili; Ruan Diyun

    2011-10-15

    Lead (Pb) exposure during development has been associated with impaired long-term potentiation (LTP). Hypothyroidism happening upon subjects with occupational exposure to Pb is suggestive of an adverse effect of Pb on thyroid homeostasis, leading to the hypothesis that Pb exposure may alter thyroid hormone homeostasis. Hippocampus is one of the targets of Pb exposure, and is sensitive to and dependent on thyroid hormones, leading us to explore whether levothyroxine (L-T{sub 4}) administration could alter the thyroid disequilibrium and impairment of LTP in rat hippocampus caused by Pb exposure. Our results show that Pb exposure caused a decrease in triiodothyronine (T{sub 3}) and tetraiodothyronine (T{sub 4}) levels accompanied by a dramatic decrease of TSH and application of L-T{sub 4} restored these changes to about control levels. Hippocampal and blood Pb concentration were significantly reduced following L-T{sub 4} treatment. L-T{sub 4} treatment rescued the impairment of LTP induced by the Pb exposure. These results suggest that Pb exposure may lead to thyroid dysfunction and induce hypothyroidism and provide a direct electrophysiological proof that L-T{sub 4} relieves chronic Pb exposure-induced impairment of synaptic plasticity. - Highlights: > Lead may interfere with thyroid hormone homeostasis and induce hypothyroidism. > Levothyroxine decreases the hippocampal and blood Pb concentration. > Levothyroxine amends the T{sub 3}, T{sub 4} and TSH levels in blood. > Levothyroxine rescues the impaired LTP in CA1.

  4. 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

  5. Cognitive sequelae of methanol poisoning involve executive dysfunction and memory impairment in cross-sectional and long-term perspective.

    PubMed

    Bezdicek, O; Michalec, J; Vaneckova, M; Klempir, J; Liskova, I; Seidl, Z; Janikova, B; Miovsky, M; Hubacek, J; Diblik, P; Kuthan, P; Pilin, A; Kurcova, I; Fenclova, Z; Petrik, V; Navratil, T; Pelclova, D; Zakharov, S; Ruzicka, E

    2017-03-01

    Methanol poisoning leads to lesions in the basal ganglia and subcortical white matter, as well as to demyelination and atrophy of the optic nerve. However, information regarding cognitive deficits in a large methanol sample is lacking. The principal aim of the present study was to identify the cognitive sequelae of methanol poisoning and their morphological correlates. A sample of 50 patients (METH; age 48 ± 13 years), 3-8 months after methanol poisoning, and 57 control subjects (CS; age 49 ± 13 years) were administered a neuropsychological battery. Forty-six patients were followed in 2 years' perspective. Patients additionally underwent 1.5T magnetic resonance imaging (MRI). Three biochemical and toxicological metabolic markers and a questionnaire regarding alcohol abuse facilitated the classification of 24 patients with methanol poisoning without alcohol abuse (METHna) and 22 patients with methanol poisoning and alcohol abuse (METHa). All groups were compared to a control group of similar size, and matched for age, education, premorbid intelligence level, global cognitive performance, and level of depressive symptoms. Using hierarchical multiple regression we found significant differences between METH and CS, especially in executive and memory domains. METHa showed a similar pattern of cognitive impairment with generally more severe executive dysfunction. Moreover, all METH patients with extensive involvement on brain MRI (lesions in ≥2 anatomical regions) had a more severe cognitive impairment. From a longitudinal perspective, we did not find any changes in their cognitive functioning after 2 years' follow-up. Our findings suggest that methanol poisoning is associated with executive dysfunction and explicit memory impairment, supposedly due to basal ganglia dysfunction and disruption of frontostriatal circuitry proportional to the number of brain lesions, and that these changes are persistent after 2 years' follow-up.

  6. Long-Term Air Pollution and Traffic Noise Exposures and Mild Cognitive Impairment in Older Adults: A Cross-Sectional Analysis of the Heinz Nixdorf Recall Study

    PubMed Central

    Tzivian, Lilian; Dlugaj, Martha; Winkler, Angela; Weinmayr, Gudrun; Hennig, Frauke; Fuks, Kateryna B.; Vossoughi, Mohammad; Schikowski, Tamara; Weimar, Christian; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Hoffmann, Barbara

    2016-01-01

    Background: Mild cognitive impairment (MCI) describes the intermediate state between normal cognitive aging and dementia. Adverse effects of air pollution (AP) on cognitive functions have been proposed, but investigations of simultaneous exposure to noise are scarce. Objectives: We analyzed the cross-sectional associations of long-term exposure to AP and traffic noise with overall MCI and amnestic (aMCI) and nonamnestic (naMCI) MCI. Methods: At the second examination of the population-based Heinz Nixdorf Recall study, cognitive assessment was completed in 4,086 participants who were 50–80 years old. Of these, 592 participants were diagnosed as having MCI (aMCI, n = 309; naMCI, n = 283) according to previously published criteria using five neuropsychological subtests. We assessed long-term residential concentrations for size-fractioned particulate matter (PM) and nitrogen oxides with land use regression, and for traffic noise [weighted 24-hr (LDEN) and night-time (LNIGHT) means]. Logistic regression models adjusted for individual risk factors were calculated to estimate the association of environmental exposures with MCI in single- and two-exposure models. Results: Most air pollutants and traffic noise were associated with overall MCI and aMCI. For example, an interquartile range increase in PM2.5 and a 10 A-weighted decibel [dB(A)] increase in LDEN were associated with overall MCI as follows [odds ratio (95% confidence interval)]: 1.16 (1.05, 1.27) and 1.40 (1.03, 1.91), respectively, and with aMCI as follows: 1.22 (1.08, 1.38) and 1.53 (1.05, 2.24), respectively. In two-exposure models, AP and noise associations were attenuated [e.g., for aMCI, PM2.5 1.13 (0.98, 1.30) and LDEN 1.46 (1.11, 1.92)]. Conclusions: Long-term exposures to air pollution and traffic noise were positively associated with MCI, mainly with the amnestic subtype. Citation: Tzivian L, Dlugaj M, Winkler A, Weinmayr G, Hennig F, Fuks KB, Vossoughi M, Schikowski T, Weimar C, Erbel R, Jöckel KH

  7. Long-Term Air Pollution and Traffic Noise Exposures and Mild Cognitive Impairment in Older Adults: A Cross-Sectional Analysis of the Heinz Nixdorf Recall Study.

    PubMed

    Tzivian, Lilian; Dlugaj, Martha; Winkler, Angela; Weinmayr, Gudrun; Hennig, Frauke; Fuks, Kateryna B; Vossoughi, Mohammad; Schikowski, Tamara; Weimar, Christian; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Hoffmann, Barbara

    2016-09-01

    Mild cognitive impairment (MCI) describes the intermediate state between normal cognitive aging and dementia. Adverse effects of air pollution (AP) on cognitive functions have been proposed, but investigations of simultaneous exposure to noise are scarce. We analyzed the cross-sectional associations of long-term exposure to AP and traffic noise with overall MCI and amnestic (aMCI) and nonamnestic (naMCI) MCI. At the second examination of the population-based Heinz Nixdorf Recall study, cognitive assessment was completed in 4,086 participants who were 50-80 years old. Of these, 592 participants were diagnosed as having MCI (aMCI, n = 309; naMCI, n = 283) according to previously published criteria using five neuropsychological subtests. We assessed long-term residential concentrations for size-fractioned particulate matter (PM) and nitrogen oxides with land use regression, and for traffic noise [weighted 24-hr (LDEN) and night-time (LNIGHT) means]. Logistic regression models adjusted for individual risk factors were calculated to estimate the association of environmental exposures with MCI in single- and two-exposure models. Most air pollutants and traffic noise were associated with overall MCI and aMCI. For example, an interquartile range increase in PM2.5 and a 10 A-weighted decibel [dB(A)] increase in LDEN were associated with overall MCI as follows [odds ratio (95% confidence interval)]: 1.16 (1.05, 1.27) and 1.40 (1.03, 1.91), respectively, and with aMCI as follows: 1.22 (1.08, 1.38) and 1.53 (1.05, 2.24), respectively. In two-exposure models, AP and noise associations were attenuated [e.g., for aMCI, PM2.5 1.13 (0.98, 1.30) and LDEN 1.46 (1.11, 1.92)]. Long-term exposures to air pollution and traffic noise were positively associated with MCI, mainly with the amnestic subtype. Tzivian L, Dlugaj M, Winkler A, Weinmayr G, Hennig F, Fuks KB, Vossoughi M, Schikowski T, Weimar C, Erbel R, Jöckel KH, Moebus S, Hoffmann B, on behalf of the Heinz Nixdorf Recall study

  8. 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

  9. 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.

  10. Chronic brain hypoperfusion causes early glial activation and neuronal death, and subsequent long-term memory impairment.

    PubMed

    Cechetti, Fernanda; Pagnussat, Aline S; Worm, Paulo V; Elsner, Viviane Rostirolla; Ben, Juliana; da Costa, Marcelo Siveira; Mestriner, Régis; Weis, Simone Nardin; Netto, Carlos Alexandre

    2012-01-04

    Reduction of cerebral blood flow is an important risk factor for dementia states and other brain dysfunctions. In present study, the effects of permanent occlusion of common carotid arteries (2VO), a well established experimental model of brain ischemia, on memory function were investigated, as assessed by reference and working spatial memory protocols and the object recognition task; cell damage to the hippocampus, as measured through changes in immunoreactivity for GFAP and the neuronal marker NeuN was also studied. The working hypothesis is that metabolic impairment following hypoperfusion will affect neuron and glial function and result in functional damage. Adult male Wistar rats were submitted to the modified 2VO method, with the right common carotid artery being occluded first and the left one week later, and tested seven days, three and six months after the ischemic event. A significant cognitive deficit was found in both reference and working spatial memory, as well as in the object recognition task, three and six months after surgery. Neuronal death and reactive astrogliosis were already present at 7 days and continued for up to 3 months after the occlusion; interestingly, there was no significant reduction in hippocampal volume. Present data suggests that cognitive impairment caused by brain hypoperfusion is long - lasting and persists beyond the time point of recovery from glial activation and neuronal loss. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. The Impact of Renal Impairment on Long-Term Safety and Effectiveness of Drug-Eluting Stents

    PubMed Central

    Stefanini, Giulio G.; Taniwaki, Masanori; Kalesan, Bindu; Räber, Lorenz; Stortecky, Stefan; Pilgrim, Thomas; Onuma, Yoshinobu; Silber, Sigmund; Serruys, Patrick W.; Meier, Bernhard; Jüni, Peter; Windecker, Stephan

    2014-01-01

    Background Renal impairment (RI) is associated with impaired prognosis in patients with coronary artery disease. Clinical and angiographic outcomes of patients undergoing percutaneous coronary intervention (PCI) with the use of drug-eluting stents (DES) in this patient population are not well established. Methods We pooled individual data for 5,011 patients from 3 trials with the exclusive and unrestricted use of DES (SIRTAX - N = 1,012, LEADERS - N = 1,707, RESOLUTE AC - N = 2,292). Angiographic follow-up was available for 1,544 lesions. Outcomes through 2 years were stratified according to glomerular filtration rate (normal renal function: GFR≥90 ml/min; mild RI: 90impaired among patients with moderate/severe RI. PMID:25184244

  12. Long-term ambient air pollution and lung function impairment in Chinese children from a high air pollution range area: The Seven Northeastern Cities (SNEC) study

    NASA Astrophysics Data System (ADS)

    Zeng, Xiao-Wen; Vivian, Elaina; Mohammed, Kahee A.; Jakhar, Shailja; Vaughn, Michael; Huang, Jin; Zelicoff, Alan; Xaverius, Pamela; Bai, Zhipeng; Lin, Shao; Hao, Yuan-Tao; Paul, Gunther; Morawska, Lidia; Wang, Si-Quan; Qian, Zhengmin; Dong, Guang-Hui

    2016-08-01

    Epidemiological studies have reported inconsistent and inconclusive associations between long-term exposure to ambient air pollution and lung function in children from Europe and America, where air pollution levels were typically low. The aim of the present study is to examine the relationship between air pollutants and lung function in children selected from heavily industrialized and polluted cities in northeastern China. During 2012, 6740 boys and girls aged 7-14 years were recruited in 24 districts of seven northeastern cities. Portable electronic spirometers were used to measure lung function. Four-year average concentrations of particulate matter with an aerodynamic diameter ≤10 μm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) were measured at monitoring stations in the 24 districts. Two-staged regression models were used in the data analysis, controlling for covariates. Overall, for all subjects, the increased odds of lung function impairment associated with exposure to air pollutants, ranged from 5% (adjusted odds ratio [aOR] = 1.05; 95% confidence interval [CI] = 1.01, 1.10) for FVC < 85% predicted per 46.3 μg/m3 for O3 to 81% (aOR = 1.81; 95%CI = 1.44, 2.28) for FEV1 < 85% predicted per 30.6 μg/m3 for PM10. The linear regression models consistently showed a negative relationship between all air pollutants and lung function measures across subjects. There were significant interaction terms indicating gender differences for lung function impairment and pulmonary function from exposure to some pollutants (P < 0.10). In conclusion, long term exposure to high concentrations of ambient air pollution is associated with decreased pulmonary function and lung function impairment, and females appear to be more susceptible than males.

  13. Optimizing Eating Performance for Long-Term Care Residents With Dementia: Testing the Impact of Function-Focused Care for Cognitively Impaired.

    PubMed

    Liu, Wen; Galik, Elizabeth; Nahm, Eun-Shim; Boltz, Marie; Resnick, Barbara

    2015-12-01

    The objective of this study was to evaluate the impact of a well-developed theory-based function-focused care for cognitively impaired (FFC-CI) intervention on eating performance among long-term care (LTC) residents with moderate-to-severe cognitive impairment. A secondary analysis of longitudinal data from 2 cluster-randomized controlled trials that originally tested the impact of FFC-CI on all function and physical activities. Participants were 199 residents with moderate-to-severe cognitive impairment from 4 nursing homes and 4 assisted living facilities. Data at baseline, and 3 and 6 months were used. Resident outcome data used in this analysis included eating performance conceptualized using the single self-care "feeding" item in the Barthel Index, cognitive function by Mini-Mental State Examination, sitting balance conceptualized using the single "chair sit-sitting balance" item in the Tinetti Gait and Balance scale, physical capability by Physical Capability Scale, depression by Cornell Scale for Depression in Dementia, and agitation by Cohen-Mansfield Agitation Inventory (short form). At baseline, almost one-third (32.2%) of the 199 residents needed help with eating. There was no significant change with regard to eating performance over time in both groups, and no significant treatment by time difference between groups in eating performance (P = .195). Current findings support a need to revise the FFC-CI to better address eating performance. Future work may benefit from a stronger focus on eating performance rather than the more commonly addressed functional tasks, such as bathing, dressing, and ambulation. In addition, the inclusion of a more heterogeneous group of LTC residents with regard to eating performance is needed to test the impact of the revised approach on eating performance. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

  14. Etomidate Impairs Long-Term Potentiation In Vitro by Targeting α5-Subunit Containing GABAA Receptors on Nonpyramidal Cells

    PubMed Central

    Rodgers, F. Clifford; Zarnowska, Ewa D.; Laha, Kurt T.; Engin, Elif; Zeller, Anja; Keist, Ruth; Rudolph, Uwe

    2015-01-01

    Previous experiments using genetic and pharmacological manipulations have provided strong evidence that etomidate impairs synaptic plasticity and memory by modulating α5-subunit containing GABAA receptors (α5-GABAARs). Because α5-GABAARs mediate tonic inhibition (TI) in hippocampal CA1 pyramidal cells and etomidate enhances TI, etomidate enhancement of TI in pyramidal cells has been proposed as the underlying mechanism (Martin et al., 2009). Here we tested this hypothesis by selectively removing α5-GABAARs from pyramidal neurons (CA1–pyr–α5–KO) and comparing the ability of etomidate to enhance TI and block LTP in fl–α5 (WT), global–α5–KO (gl–α5–KO), and CA1–pyr–α5–KO mice. Etomidate suppressed LTP in slices from WT and CA1–pyr–α5–KO but not gl–α5–KO mice. There was a trend toward reduced TI in both gl–α5–KO and CA1–pyr–α5–KO mice, but etomidate enhanced TI to similar levels in all genotypes. The dissociation between effects of etomidate on TI and LTP in gl–α5–KO mice indicates that increased TI in pyramidal neurons is not the mechanism by which etomidate impairs LTP and memory. Rather, the ability of etomidate to block LTP in WT and CA1–pyr–α5–KO mice, but not in gl–α5–KO mice, points toward α5-GABAARs on nonpyramidal cells as the essential effectors controlling plasticity in this in vitro model of learning and memory. PMID:26134653

  15. Unilateral lesion of dorsal hippocampus in adult rats impairs contralateral long-term potentiation in vivo and spatial memory in the early postoperative phase.

    PubMed

    Li, Hongjie; Wu, Xiaoyan; Bai, Yanrui; Huang, Yan; He, Wenting; Dong, Zhifang

    2012-05-01

    It is well documented that bilateral hippocampal lesions or unilateral hippocampal lesion at birth causes impairment of contralateral LTP and long-term memory. However, effects of unilateral hippocampal lesion in adults on contralateral in vivo LTP and memory are not clear. We here examined the influence of unilateral electrolytic dorsal hippocampal lesion in adult rats on contralateral LTP in vivo and spatial memory during different postoperative phases. We found that acute unilateral hippocampal lesion had no effect on contralateral LTP. However, contralateral LTP was impaired at 1 week after lesion, and was restored to the control level at postoperative week 4. Similarly, spatial memory was also impaired at postoperative week 1, and was restored at postoperative week 4. In addition, the rats at postoperative week 1 showed stronger spatial exploratory behavior in a novel open-field environment. The sham operation had no effects on contralateral LTP, spatial memory and exploration at either postoperative week 1 or week 4. These results suggest that unilateral dorsal hippocampal lesion in adult rats causes transient contralateral LTP impairment and spatial memory deficit. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Mice deficient for striatal Vesicular Acetylcholine Transporter (VAChT) display impaired short-term but normal long-term object recognition memory.

    PubMed

    Palmer, Daniel; Creighton, Samantha; Prado, Vania F; Prado, Marco A M; Choleris, Elena; Winters, Boyer D

    2016-09-15

    Substantial evidence implicates Acetylcholine (ACh) in the acquisition of object memories. While most research has focused on the role of the cholinergic basal forebrain and its cortical targets, there are additional cholinergic networks that may contribute to object recognition. The striatum contains an independent cholinergic network comprised of interneurons. In the current study, we investigated the role of this cholinergic signalling in object recognition using mice deficient for Vesicular Acetylcholine Transporter (VAChT) within interneurons of the striatum. We tested whether these striatal VAChT(D2-Cre-flox/flox) mice would display normal short-term (5 or 15min retention delay) and long-term (3h retention delay) object recognition memory. In a home cage object recognition task, male and female VAChT(D2-Cre-flox/flox) mice were impaired selectively with a 15min retention delay. When tested on an object location task, VAChT(D2-Cre-flox/flox) mice displayed intact spatial memory. Finally, when object recognition was tested in a Y-shaped apparatus, designed to minimize the influence of spatial and contextual cues, only females displayed impaired recognition with a 5min retention delay, but when males were challenged with a 15min retention delay, they were also impaired; neither males nor females were impaired with the 3h delay. The pattern of results suggests that striatal cholinergic transmission plays a role in the short-term memory for object features, but not spatial location.

  17. Immunization with DAT fragments is associated with long-term striatal impairment, hyperactivity and reduced cognitive flexibility in mice

    PubMed Central

    2012-01-01

    Background Possible interactions between nervous and immune systems in neuro-psychiatric disorders remain elusive. Levels of brain dopamine transporter (DAT) have been implicated in several impulse-control disorders, like attention deficit / hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Here, we assessed the interplay between DAT auto-immunity and behavioural / neurochemical phenotype. Methods Male CD-1 mice were immunized with DAT peptide fragments (DAT-i), or vehicle alone (VEH), to generate elevated circulating levels of DAT auto-antibodies (aAbs). Using an operant delay-of-reward task (20 min daily sessions; timeout 25 sec), mice had a choice between either an immediate small amount of food (SS), or a larger amount of food after a delay (LL), which increased progressively across sessions (from 0 to 150 sec). Results DAT-i mice exhibited spontaneous hyperactivity (2 h-longer wake-up peak; a wake-up attempt during rest). Two sub-populations differing in behavioural flexibility were identified in the VEH control group: they showed either a clear-cut decision to select LL or clear-cut shifting towards SS, as expected. Compared to VEH controls, choice-behaviour profile of DAT-i mice was markedly disturbed, together with long-lasting alterations of the striatal monoamines. Enhanced levels of DA metabolite HVA in DAT-i mice came along with slower acquisition of basal preferences and with impaired shifting; elevation also in DOPAC levels was associated with incapacity to change a rigid selection strategy. This scarce flexibility of performance is indicative of a poor adaptation to task contingencies. Conclusions Hyperactivity and reduced cognitive flexibility are patterns of behaviour consistent with enduring functional impairment of striatal regions. It is yet unclear how anti-DAT antibodies could enter or otherwise affect these brain areas, and which alterations in DAT activity exactly occurred after immunization. Present neuro

  18. Ketamine alters cortical integration of GABAergic interneurons and induces long-term sex-dependent impairments in transgenic Gad67-GFP mice

    PubMed Central

    Aligny, C; Roux, C; Dourmap, N; Ramdani, Y; Do-Rego, J-C; Jégou, S; Leroux, P; Leroux-Nicollet, I; Marret, S; Gonzalez, B J

    2014-01-01

    Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, widely used as an anesthetic in neonatal pediatrics, is also an illicit drug named Super K or KitKat consumed by teens and young adults. In the immature brain, despite several studies indicating that NMDA antagonists are neuroprotective against excitotoxic injuries, there is more and more evidence indicating that these molecules exert a deleterious effect by suppressing a trophic function of glutamate. In the present study, we show using Gad67-GFP mice that prenatal exposure to ketamine during a time-window in which GABAergic precursors are migrating results in (i) strong apoptotic death in the ganglionic eminences and along the migratory routes of GABAergic interneurons; (ii) long-term deficits in interneuron density, dendrite numbers and spine morphology; (iii) a sex-dependent deregulation of γ-aminobutyric acid (GABA) levels and GABA transporter expression; (iv) sex-dependent changes in the response to glutamate-induced calcium mobilization; and (v) the long-term sex-dependent behavioral impairment of locomotor activity. In conclusion, using a preclinical approach, the present study shows that ketamine exposure during cortical maturation durably affects the integration of GABAergic interneurons by reducing their survival and differentiation. The resulting molecular, morphological and functional modifications are associated with sex-specific behavioral deficits in adults. In light of the present data, it appears that in humans, ketamine could be deleterious for the development of the brain of preterm neonates and fetuses of addicted pregnant women. PMID:24991763

  19. Long-term impairment of Streptococcus pneumoniae lung clearance is observed after initial infection with influenza A virus but not human metapneumovirus in mice.

    PubMed

    Ludewick, Herbert P; Aerts, Laetitia; Hamelin, Marie-Eve; Boivin, Guy

    2011-07-01

    Human metapneumovirus (hMPV) is a paramyxovirus responsible for respiratory tract infections in humans. Our objective was to investigate whether hMPV could predispose to long-term bacterial susceptibility, such as previously observed with influenza viruses. BALB/c mice were infected with hMPV or influenza A and, 14 days following viral infection, challenged with Streptococcus pneumoniae. Only mice previously infected with influenza A demonstrated an 8% weight loss of their body weight 72 h following S. pneumoniae infection, which correlated with an enhanced lung bacterial replication of >7 log(10) compared with pneumococcus infection alone. This enhanced bacterial replication was not related to altered macrophage or neutrophil recruitment or deficient production of critical cytokines. However, bacterial challenge induced the production of gamma interferon in bronchoalveolar lavages of influenza-infected mice, but not in those of hMPV-infected animals. In conclusion, hMPV does not cause long-term impairment of pneumococcus lung clearance, in contrast to influenza A virus.

  20. Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs from Long-term Belatacept-Treated Kidney Transplant Patients.

    PubMed

    Alvarez Salazar, Evelyn Katy; Cortés-Hernández, Arimelek; Alemán-Muench, Germán Rodrigo; Alberú, Josefina; Rodríguez-Aguilera, Jesús R; Recillas-Targa, Félix; Chagoya de Sánchez, Victoria; Cuevas, Eric; Mancilla-Urrea, Eduardo; Pérez García, María; Mondragón-Ramírez, Guillermo; Vilatobá, Mario; Bostock, Ian; Hernández-Méndez, Erick; De Rungs, David; García-Zepeda, Eduardo A; Soldevila, Gloria

    2017-01-01

    Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we analyzed the phenotype, function, and the epigenetic status of the Treg-specific demethylated region (TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients under BLT or Cyclosporine A treatment. We found a significant reduction in the proportion of CD4(+)CD25(hi)CD127(lo/-)FOXP3(+) T cells in all patients compared to healthy individual (controls). Interestingly, only BLT-treated patients displayed an enrichment of the CD45RA(+) "naïve" Tregs, while the expression of Helios, a marker used to identify stable FOXP3(+) thymic Tregs remained unaffected. Functional analysis demonstrated that Tregs from transplanted patients displayed a significant reduction in their suppressive capacity compared to Tregs from controls, which is associated with decreased levels of FOXP3 and CD25. Analysis of the methylation status of the FOXP3 gene showed that BLT treatment results in methylation of CpG islands within the TSDR, which could be associated with the impaired Treg suppression function. Our data indicate that analysis of circulating Tregs cannot be used as a marker for assessing tolerance toward the allograft in long-term kidney transplant patients. Trial registration number IM103008.

  1. Impaired immunity in harbour seals (Phoca vitulina) exposed to bioaccumulated environmental contaminants: review of a long-term feeding study.

    PubMed Central

    de Swart, R L; Ross, P S; Vos, J G; Osterhaus, A D

    1996-01-01

    Mass mortalities among seals and dolphins inhabiting contaminated marine regions have led to speculation about a possible involvement of immunosuppression associated with environmental pollution. To evaluate whether contaminants at ambient environmental levels can affect immune function of seals, we carried out an immunotoxicological study under semifield conditions. Two groups of 11 harbour seals (Phoca vitulina) originating from a relatively uncontaminated area were fed herring from either the highly polluted Baltic Sea or the relatively uncontaminated Atlantic Ocean. Changes in immune function were monitored over a 2 1/2-year period. The seals that were fed contaminated Baltic herring developed significantly higher body burdens of potentially immunotoxic organochlorines and displayed impaired immune responses as demonstrated by suppression of natural killer cell activity and specific T-cell responses. During a 2-week fasting experiment performed at the end of the feeding study, mobilization of organochlorines from the blubber did not lead to a strong increase of contaminant levels in the blood, and no enhancement of the existing immunosuppression was observed. These results demonstrate that chronic exposure to environmental contaminants accumulated through the food chain affects immune function in harbour seals, whereas short-term fasting periods, which are normal for seals, do not seem to pose an additional risk. The seals of this study were not exposed perinatally to high levels of environmental chemicals, and body burdens of organochlorines measured near the end of the study were lower than those generally observed in free-ranging seals inhabiting many contaminated regions. Therefore, it may be expected that environmental contaminants adversely affect immune function of free-ranging seals inhabiting contaminated regions at least as seriously as observed in these studies. PMID:8880005

  2. Reversible short-term and delayed long-term cognitive impairment induced by chronic mild cerebral hypoperfusion in rats.

    PubMed

    Thong-asa, Khwanjai; Chompoopong, Supin; Tantisira, Mayuree H; Tilokskulchai, Kanokwan

    2013-08-01

    Chronic cerebral hypoperfusion induced by aging in combination with vascular disorder potentially contributes to the development of vascular dementia. This study aimed to investigate the age-related changes in spatial performances in chronic mild cerebral hypoperfusion induced by permanent right common carotid artery occlusion (rCCAO) in rats. Four-month-old male Sprague-Dawley rats (n = 20) were randomly assigned into sham and rCCAO groups. Spatial performances of young adult rats (age 4-8 months) were evaluated repeatedly by the radial arm water maze at 6 days, and 1, 2 and 4 months after surgery. The spatial performance was re-assessed by the Morris water maze when the rats were 18 months old. The present results revealed that the rCCAO rats developed progressive deficit in spatial learning and memory, starting from day 6 and significant deficit was found at 2 months after rCCAO (p < 0.05). However, the spatial performance of the rCCAO rats was recovered at 4 months after surgery. Testing of the cognitive flexibility of the aged rCCAO rats (18 months old), indicated that the learning flexibility of the aged rCCAO rats was significantly impaired. This deficit was found in parallel with pronounced white matter damage in the corpus callosum and internal capsule and significant cell death in the dorsal hippocampus. Our results suggested that vascular risk insult in young adult rats resulted in spatial learning deficit which could be completely compensated later on. However, such previous vascular risk could be exacerbated by advancing age and subsequently lead to a deficit in cognitive flexibility with white matter damage and significant neuronal death in the dorsal hippocampus.

  3. Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization.

    PubMed

    Pavesi, Eloisa; Heldt, Scott A; Fletcher, Max L

    2013-08-16

    Experience-induced changes associated with odor learning are mediated by a number of signaling molecules, including nitric oxide (NO), which is predominantly synthesized by neuronal nitric oxide synthase (nNOS) in the brain. In the current study, we investigated the role of nNOS in the acquisition and retention of conditioned olfactory fear. Mice lacking nNOS received six training trials, each consisting of an odor-CS co-terminating with a foot shock-US. Mice showed reduced freezing responses to the trained odor 24 h and 7 d after training, compared to wild-type mice. Pretraining systemic injections of the NO donor, molsidomine, rescued fear retention in nNOS knockout mice. In wild-type mice, pretraining systemic injections of L-NAME, a nonspecific nNOS blocker, disrupted odor-CS fear retention in a dose-dependent manner. To evaluate whether NO signaling is involved in generalization of fear memories, nNOS knockout mice and wild-type mice receiving L-NAME were trained to one odor and tested with a series of similar odors. In both cases, we found increased generalization, as measured by increased freezing to similar, unpaired odors. Despite the impairment in fear memory retention and generalization, neither mice receiving injections of L-NAME nor nNOS knockout mice showed any deficits in either novel odor investigation time or odor habituation, suggesting intact olfactory perception and short-term memory olfactory learning. These results support a necessary role for neuronal NO signaling in the normal expression and generalization of olfactory conditioned fear.

  4. Associations of Newborn Brain Magnetic Resonance Imaging with Long-Term Neurodevelopmental Impairments in Very Preterm Children.

    PubMed

    Anderson, Peter J; Treyvaud, Karli; Neil, Jeffrey J; Cheong, Jeanie L Y; Hunt, Rodney W; Thompson, Deanne K; Lee, Katherine J; Doyle, Lex W; Inder, Terrie E

    2017-08-01

    To determine the relationship between brain abnormalities on newborn magnetic resonance imaging (MRI) and neurodevelopmental impairment at 7 years of age in very preterm children. A total of 223 very preterm infants (<30 weeks of gestation or <1250 g) born at Melbourne's Royal Women's Hospital had a brain MRI scan at term equivalent age. Scans were scored using a standardized system that assessed structural abnormality of cerebral white matter, cortical gray matter, deep gray matter, and cerebellum. Children were assessed at 7 years on measures of general intelligence, motor functioning, academic achievement, and behavior. One hundred eighty-six very preterm children (83%) had both an MRI at term equivalent age and a 7-year follow-up assessment. Higher global brain, cerebral white matter, and deep gray matter abnormality scores were related to poorer intelligence quotient (IQ) (Ps < .01), spelling (Ps < .05), math computation (Ps < .01), and motor function (Ps < .001). Higher cerebellum abnormality scores were related to poorer IQ (P = .001), math computation (P = .018), and motor outcomes (P = .001). Perinatal, neonatal, and social confounders had little effect on the relationships between the MRI abnormality scores and outcomes. Moderate-severe global abnormality on newborn MRI was associated with a reduction in IQ (-6.9 points), math computation (-7.1 points), and motor (-1.9 points) scores independent of the other potential confounders. Structured evaluation of brain MRI at term equivalent is predictive of outcome at 7 years of age, independent of clinical and social factors. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment.

    PubMed

    Gallant, Michel; Aspiotis, Renee; Day, Stephen; Dias, Rebecca; Dubé, Daniel; Dubé, Laurence; Friesen, Richard W; Girard, Mario; Guay, Daniel; Hamel, Pierre; Huang, Zheng; Lacombe, Patrick; Laliberté, Sebastien; Lévesque, Jean-François; Liu, Susana; Macdonald, Dwight; Mancini, Joseph; Nicholson, Donald W; Styhler, Angela; Townson, Karen; Waters, Kerry; Young, Robert N; Girard, Yves

    2010-11-15

    The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis. Copyright © 2010 Elsevier Ltd. All rights reserved.

  6. (G2019S) LRRK2 causes early-phase dysfunction of SNpc dopaminergic neurons and impairment of corticostriatal long-term depression in the PD transgenic mouse.

    PubMed

    Chou, Jun-Shiao; Chen, Chu-Yu; Chen, Ying-Ling; Weng, Yi-Hsin; Yeh, Tu-Hsueh; Lu, Chin-Song; Chang, Ya-Ming; Wang, Hung-Li

    2014-08-01

    Twelve- to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive neuronal death of substantia nigra pars compacta (SNpc) dopaminergic cells. In the present study, we hypothesized that prior to a late-phase death of SNpc dopaminergic neurons, (G2019S) LRRK2 also causes an early-phase neuronal dysfunction of SNpc dopaminergic cells in the (G2019S) LRRK2 mouse. Eight to nine-month-old (G2019S) LRRK2 transgenic mice exhibited the symptom of hypoactivity in the absence of the degeneration of SNpc dopaminergic neurons or nigrostriatal dopaminergic terminals. Whole-cell current-clamp recordings of SNpc dopaminergic cells in brain slices demonstrated a significant decrease in spontaneous firing frequency of SNpc dopaminergic neurons of 8-month-old (G2019S) LRRK2 mice. Carbon fiber electrode amperometry recording using striatal slices showed that (G2019S) LRRK2 transgenic mice at the age of 8 to 9months display an impaired evoked dopamine release in the dorsolateral striatum. Normal nigrostriatal dopaminergic transmission is required for the induction of long-term synaptic plasticity expressed at corticostriatal glutamatergic synapses of striatal medium spiny neurons. Whole-cell voltage-clamp recordings showed that in contrast to medium spiny neurons of 8 to 9-month-old wild-type mice, high-frequency stimulation of corticostriatal afferents failed to induce long-term depression (LTD) of corticostriatal EPSCs in medium spiny neurons of (G2019S) LRRK2 mice at the same age. Our study provides the evidence that mutant (G2019S) LRRK2 causes early-phase dysfunctions of SNpc dopaminergic neurons, including a decrease in spontaneous firing rate and a reduction in evoked dopamine release, and impairment of corticostriatal LTD in the (G2019S) LRRK2 transgenic mouse.

  7. Reversal of Impaired Hippocampal Long-term Potentiation and Contextual Fear Memory Deficits in Angelman Syndrome Model Mice by ErbB Inhibitors

    PubMed Central

    Kaphzan, Hanoch; Hernandez, Pepe; Jung, Joo In; Cowansage, Kiriana K.; Deinhardt, Katrin; Chao, Moses V.; Abel, Ted; Klann, Eric

    2012-01-01

    Background Angelman syndrome (AS) is a human neuropsychiatric disorder associated with autism, mental retardation, motor abnormalities, and epilepsy. In most cases, AS is caused by the deletion of the maternal copy of UBE3A gene, which encodes the enzyme ubiquitin ligase E3A, also termed E6-AP. A mouse model of AS has been generated and these mice exhibit many of the observed neurological alterations in humans. Because of clinical and neuroanatomical similarities between AS and schizophrenia, we examined AS model mice for alterations in the neuregulin-ErbB4 pathway, which has been implicated in the pathophysiology of schizophrenia. We focused our studies on the hippocampus, one of the major brain loci impaired in AS mice. Methods We determined the expression of NRG1 and ErbB4 receptors in AS mice and wild-type littermates (ages 10-16 weeks), and studied the effects of ErbB inhibition on long-term potentiation (LTP) in hippocampal area CA1 and on hippocampus-dependent contextual fear memory. Results We observed enhanced neuregulin-ErbB4 signaling in the hippocampus of AS model mice and found that ErbB inhibitors could reverse deficits in LTP, a cellular substrate for learning and memory. In addition, we found that an ErbB inhibitor enhanced long-term contextual fear memory in AS model mice. Conclusions Our findings suggest that neuregulin-ErbB4 signaling is involved in synaptic plasticity and memory impairments in AS model mice, suggesting that ErbB inhibitors have therapeutic potential for the treatment of AS. PMID:22381732

  8. Long-term cognitive impairments and attentional deficits in patients with Cushing's disease and cortisol-producing adrenal adenoma in remission.

    PubMed

    Ragnarsson, Oskar; Berglund, Peter; Eder, Derek N; Johannsson, Gudmundur

    2012-09-01

    Cognitive function is impaired in patients with active Cushing's syndrome (CS). The aim was to study cognitive function in patients with CS in long-term remission. We conducted a cross-sectional, case-controlled, single center study. Fifty-five patients previously treated for Cushing's disease (n = 43) and cortisol-producing adrenal adenoma (n = 12) and 55 controls matched for age, gender, and educational level participated in the study. Working memory, attention, information-processing speed, verbal fluency, and reading speed were studied using standardized neuropsychological testing and alerting, orienting, and executive control using the Attentional Network Test. Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue and affective disorder. Median (interquartile range) duration of remission was 13 (5-19) yr and the mean ± SD age at follow-up was 54 ± 14 yr. Compared to controls, patients had a higher score on the fatigue impact scale, indicating greater burdens of fatigue, and a higher score on the comprehensive psychopathological rating scale subscales for depression and anxiety. In a multivariate analysis, attention, spatial orienting, alerting, working memory, verbal fluency, and reading speed were all diminished in comparison to controls, independent of scores for affective disorder and fatigue. No overall difference in outcome was seen between patients in long-term remission for Cushing's disease and cortisol-producing adrenal adenoma. Patients with CS in remission have impaired cognitive function that cannot be explained by the coexistence of affective disorder or chronic fatigue. The pattern of cognitive and attentional deficits suggests a more global involvement of the brain function than has previously been suggested.

  9. Rapid and reversible impairments of short- and long-term social recognition memory are caused by acute isolation of adult rats via distinct mechanisms.

    PubMed

    Shahar-Gold, Hadar; Gur, Rotem; Wagner, Shlomo

    2013-01-01

    Mammalian social organizations require the ability to recognize and remember individual conspecifics. This social recognition memory (SRM) can be examined in rodents using their innate tendency to investigate novel conspecifics more persistently than familiar ones. Here we used the SRM paradigm to examine the influence of housing conditions on the social memory of adult rats. We found that acute social isolation caused within few days a significant impairment in acquisition of short-term SRM of male and female rats. Moreover, SRM consolidation into long-term memory was blocked following only one day of social isolation. Both impairments were reversible, but with different time courses. Furthermore, only the impairment in SRM consolidation was reversed by systemic administration of arginine-vasopressin (AVP). In contrast to SRM, object recognition memory was not affected by social isolation. We conclude that acute social isolation rapidly induces reversible changes in the brain neuronal and molecular mechanisms underlying SRM, which hamper its acquisition and completely block its consolidation. These changes occur via distinct, AVP sensitive and insensitive mechanisms. Thus, acute social isolation of rats swiftly causes changes in their brain and interferes with their normal social behavior.

  10. 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

  11. Oxidative Impairment of Hippocampal Long-term Potentiation Involves Activation of Protein Phosphatase 2A and Is Prevented by Ketone Bodies

    PubMed Central

    Maalouf, Marwan; Rho, Jong M.

    2008-01-01

    Previous studies have shown that ketone bodies (KB) exert antioxidant effects in experimental models of neurological disease. In the present study, we explored the effects of the KB acetoacetate (ACA) and β-hydroxybutyrate (BHB) on impairment of hippocampal long-term potentiation (LTP) in rats by hydrogen peroxide (H2O2) using electrophysiological, fluorescence imaging and enzyme assay techniques. We found that: (1) a combination of ACA and BHB (1 mM each) prevented impairment of LTP by H2O2 (200 μM); (2) KB significantly lowered intracellular levels of reactive oxygen species (ROS) — measured with the fluorescent indicator carboxy-H2DCFDA — in CA1 pyramidal neurons exposed to H2O2; (3) the effect of KB on LTP was replicated by the protein phosphatase 2A (PP2A) inhibitor fostriecin; (4) KB prevented impairment of LTP by the PP2A activator C6 ceramide; (5) fostriecin did not prevent the increase in ROS levels in CA1 pyramidal neurons exposed to H2O2, and C6 ceramide did not increase ROS levels; (6) PP2A activity was enhanced by both H2O2and rotenone – a mitochondrial complex I inhibitor that increases endogenous superoxide production; and (7) KB inhibited PP2A activity in protein extracts from brain tissue treated with either H2O2 or ceramide. We propose that oxidative impairment of hippocampal LTP is associated with PP2A activation, and that KB prevent this impairment in part by inducing PP2A inhibition through an antioxidant mechanism. PMID:18646208

  12. Association of Nondisease-Specific Problems with Mortality, Long-Term Care, and Functional Impairment among Older Adults Who Require Skilled Nursing Care after Dialysis Initiation.

    PubMed

    Bowling, C Barrett; Plantinga, Laura; Hall, Rasheeda K; Mirk, Anna; Zhang, Rebecca; Kutner, Nancy

    2016-12-07

    The majority of older adults who initiate dialysis do so during a hospitalization, and these patients may require post-acute skilled nursing facility (SNF) care. For these patients, a focus on nondisease-specific problems, including cognitive impairment, depressive symptoms, exhaustion, falls, impaired mobility, and polypharmacy, may be more relevant to outcomes than the traditional disease-oriented approach. However, the association of the burden of nondisease-specific problems with mortality, transition to long-term care (LTC), and functional impairment among older adults receiving SNF care after dialysis initiation has not been studied. We identified 40,615 Medicare beneficiaries ≥65 years old who received SNF care after dialysis initiation between 2000 and 2006 by linking renal disease registry data with the Minimum Data Set. Nondisease-specific problems were ascertained from the Minimum Data Set. We defined LTC as ≥100 SNF days and functional impairment as dependence in all four essential activities of daily living at SNF discharge. Associations of the number of nondisease-specific problems (≤1, 2, 3, and 4-6) with 6-month mortality, LTC, and functional impairment were examined. Overall, 39.2% of patients who received SNF care after dialysis initiation died within 6 months. Compared with those with ≤1 nondisease-specific problems, multivariable adjusted hazard ratios (95% confidence interval) for mortality were 1.26 (1.19 to 1.32), 1.40 (1.33 to 1.48), and 1.66 (1.57 to 1.76) for 2, 3, and 4-6 nondisease-specific problems, respectively. Among those who survived, 37.1% required LTC; of those remaining who did not require LTC, 74.7% had functional impairment. A higher likelihood of transition to LTC (among those who survived 6 months) and functional impairment (among those who survived and did not require LTC) was seen with a higher number of problems. Identifying nondisease-specific problems may help patients and families anticipate LTC needs and

  13. Effect of low frequency electrical stimulation on seizure-induced short- and long-term impairments in learning and memory in rats.

    PubMed

    Esmaeilpour, Khadijeh; Sheibani, Vahid; Shabani, Mohammad; Mirnajafi-Zadeh, Javad

    2017-01-01

    Kindled seizures can impair learning and memory. In the present study the effect of low-frequency electrical stimulation (LFS) on kindled seizure-induced impairment in spatial learning and memory was investigated and followed up to one month. Animals were kindled by electrical stimulation of hippocampal CA1 area in a semi-rapid manner (12 stimulations per day). One group of animals received four trials of LFS at 30s, 6h, 24h, and 30h following the last kindling stimulation. Each LFS trial was consisted of 4 packages at 5min intervals. Each package contained 200 monophasic square wave pulses of 0.1ms duration at 1Hz. The Open field, Morris water maze, and novel object recognition tests were done 48h, 1week, 2weeks, and one month after the last kindling stimulation respectively. Kindled animals showed a significant impairment in learning and memory compared to control rats. LFS decreased the kindling-induced learning and memory impairments at 24h and one week following its application, but not at 2week or 1month after kindling. In the group of animals that received the same 4 trials of LFS again one week following the last kindling stimulation, the improving effect of LFS was observed even after one month. Obtained results showed that application of LFS in fully kindled animals has a long-term improving effect on spatial learning and memory. This effect can remain for a long duration (one month in this study) by increasing the number of applied LFS. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. 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

  15. Single fluoxetine treatment before but not after stress prevents stress-induced hippocampal long-term depression and spatial memory retrieval impairment in rats.

    PubMed

    Han, Huili; Dai, Chunfang; Dong, Zhifang

    2015-07-28

    A growing body of evidence has shown that chronic treatment with fluoxetine, a widely prescribed medication for treatment of depression, can affect synaptic plasticity in the adult central nervous system. However, it is not well understood whether acute fluoxetine influences synaptic plasticity, especially on hippocampal CA1 long-term depression (LTD), and if so, whether it subsequently impacts hippocampal-dependent spatial memory. Here, we reported that LTD facilitated by elevated-platform stress in hippocampal slices was completely prevented by fluoxetine administration (10 mg/kg, i.p.) 30 min before stress. The LTD was not, however, significantly inhibited by fluoxetine administration immediately after stress. Similarly, fluoxetine incubation (10 μM) during electrophysiological recordings also displayed no influence on the stress-facilitated LTD. In addition, behavioral results showed that a single fluoxetine treatment 30 min before but not after acute stress fully reversed the impairment of spatial memory retrieval in the Morris water maze paradigm. Taken together, these results suggest that acute fluoxetine treatment only before, but not after stress, can prevent hippocampal CA1 LTD and spatial memory retrieval impairment caused by behavioral stress in adult animals.

  16. Maternal sleep deprivation at different stages of pregnancy impairs the emotional and cognitive functions, and suppresses hippocampal long-term potentiation in the offspring rats.

    PubMed

    Peng, Yan; Wang, Wei; Tan, Tao; He, Wenting; Dong, Zhifang; Wang, Yu Tian; Han, Huili

    2016-02-15

    Sleep deprivation during pregnancy is a serious public health problem as it can affect the health of pregnant women and newborns. However, it is not well studied whether sleep deprivation at different stages of pregnancy has similar effects on emotional and cognitive functions of the offspring, and if so, the potential cellular mechanisms also remain poorly understood. In the present study, the pregnant rats were subjected to sleep deprivation for 6 h per day by gentle handling during the first (gestational days 1-7), second (gestational days 8-14) and third trimester (gestational days 15-21) of pregnancy, respectively. The emotional and cognitive functions as well as hippocampal long-term potentiation (LTP) were tested in the offspring rats (postnatal days 42-56). The offspring displayed impaired hippocampal-dependent spatial learning and memory, and increased depressive- and anxiety-like behaviors. Quantification of BrdU-positive cells revealed that adult hippocampal neurogenesis was significantly reduced compared to control. Electrophysiological recording showed that maternal sleep deprivation impaired hippocampal CA1 LTP and reduced basal synaptic transmission, as reflected by a decrease in the frequency and amplitude of miniature excitatory postsynaptic current in the hippocampal CA1 pyramidal neurons. Taken together, these results suggest that maternal sleep deprivation at different stages of pregnancy disrupts the emotional and cognitive functions of the offspring that might be attributable to the suppression of hippocampal LTP and basal synaptic transmission.

  17. Protracted withdrawal from alcohol and drugs of abuse impairs long-term potentiation of intrinsic excitability in the juxtacapsular bed nucleus of the stria terminalis

    PubMed Central

    Francesconi, Walter; Berton, Fulvia; Repunte-Canonigo, Vez; Hagihara, Kazuki; Thurbon, David; Lekic, Dusan; Specio, Sheila E.; Greenwell, Thomas N.; Chen, Scott A.; Rice, Kenner C.; Richardson, Heather N.; O’Dell, Laura E.; Zorrilla, Eric P.; Morales, Marisela; Koob, George F.; Sanna, Pietro Paolo

    2010-01-01

    The juxtacapsular BNST (jcBNST) is activated in response to basolateral amygdala (BLA) inputs through the stria terminalis and projects back to the anterior BLA and to the central nucleus of the amygdala (CeA). Here we show a form of long-term potentiation of the intrinsic excitability (LTP-IE) of jcBNST neurons in response to high-frequency stimulation (HFS) of the stria terminalis. This LTP-IE, which was characterized by a decrease in the firing threshold and increased temporal fidelity of firing, was impaired during protracted withdrawal from self-administration of alcohol, cocaine, and heroin. Such impairment was graded and was more pronounced in rats that self-administered amounts of the drugs sufficient to maintain dependence. Dysregulation of the CRF system has been implicated in manifestation of protracted withdrawal from dependent drug use. Administration of the selective corticotropin-releasing factor receptor 1 (CRF1) antagonist R121919, but not of the CRF2 antagonist astressin2-B (A2-B), normalized jcBNST LTP-IE in animals with a history of alcohol dependence; repeated, but not acute, administration of CRF itself produced a decreased jcBNST LTP-IE. Thus, changes in the integration properties of jcBNST neurons mediated by chronic activation of the CRF system may contribute to the persistent emotional dysregulation associated with protracted withdrawal. PMID:19403807

  18. 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.

  19. Early Beneficial Effect of Matrix Metalloproteinase Inhibition on BBB Permeability as Measured by MRI Countered by Impaired Long-Term Recovery After Stroke in Rat Brain

    PubMed Central

    Sood, Rohit; Taheri, Saeid; Candelario-Jalil, Eduardo; Estrada, Eduardo Y.; Rosenberg, Gary A.

    2008-01-01

    Proteolytic disruption of the extracellular matrix with opening of the blood-brain barrier (BBB) due to MMPs occurs in reperfusion injury after stroke. MMP inhibition blocks the early disruption of the BBB, but the long-term consequences of short-term MMP inhibition are not known. Recently, a method to quantify BBB permeability by graphical methods was described that provides a way to study both early disruption of the BBB and long-term effects on recovery in the same animal. We used a broad-spectrum MMP inhibitor, BB1101, to determine both the usefulness of the MRI method for treatment studies and the long-term effects on recovery. MRI studies were performed in control (N=6) and drug treated (N=8) groups on a dedicated 4.7T MRI scanner. Adult WKY rats had a 2 hr MCAO and an MRI study after 3 hrs of reperfusion, which consisted of T2 and diffusion-weighted technique. Additionally, a rapid T1 mapping protocol was also implemented to acquire one pre-Gd-DTPA baseline data set followed by post injection data sets at 3 min intervals for 45 min. The same animal was imaged again at 48 hrs for lesion size estimation. Data was post processed pixel-wise to generate ADC and permeability coefficient maps. Treatment with BB-1101 significantly reduced BBB permeability at 3 hrs, but failed to reduce lesion size at 48 hrs. Behavioral studies showed impairment in recovery in treated rats. MRI allowed for the monitoring of multiple parameters in the same animal. Our studies showed that BB-1101 was an excellent inhibitor of the BBB damage. However, results show that BB-1101 may be responsible for significant deterioration in neurological status of treated animals. While these preliminary results suggest that BB-1101 is useful in reducing early BBB leakage due to reperfusion injury in stroke, further studies will be needed to determine whether the later detrimental effects can be eliminated by shorter time course of drug delivery. PMID:17700631

  20. Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs from Long-term Belatacept-Treated Kidney Transplant Patients

    PubMed Central

    Alvarez Salazar, Evelyn Katy; Cortés-Hernández, Arimelek; Alemán-Muench, Germán Rodrigo; Alberú, Josefina; Rodríguez-Aguilera, Jesús R.; Recillas-Targa, Félix; Chagoya de Sánchez, Victoria; Cuevas, Eric; Mancilla-Urrea, Eduardo; Pérez García, María; Mondragón-Ramírez, Guillermo; Vilatobá, Mario; Bostock, Ian; Hernández-Méndez, Erick; De Rungs, David; García-Zepeda, Eduardo A.; Soldevila, Gloria

    2017-01-01

    Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we analyzed the phenotype, function, and the epigenetic status of the Treg-specific demethylated region (TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients under BLT or Cyclosporine A treatment. We found a significant reduction in the proportion of CD4+CD25hiCD127lo/−FOXP3+ T cells in all patients compared to healthy individual (controls). Interestingly, only BLT-treated patients displayed an enrichment of the CD45RA+ “naïve” Tregs, while the expression of Helios, a marker used to identify stable FOXP3+ thymic Tregs remained unaffected. Functional analysis demonstrated that Tregs from transplanted patients displayed a significant reduction in their suppressive capacity compared to Tregs from controls, which is associated with decreased levels of FOXP3 and CD25. Analysis of the methylation status of the FOXP3 gene showed that BLT treatment results in methylation of CpG islands within the TSDR, which could be associated with the impaired Treg suppression function. Our data indicate that analysis of circulating Tregs cannot be used as a marker for assessing tolerance toward the allograft in long-term kidney transplant patients. Trial registration number IM103008. PMID:28316600

  1. Cocaine Withdrawal Impairs mGluR5-Dependent Long-Term Depression in Nucleus Accumbens Shell Neurons of Both Direct and Indirect Pathways.

    PubMed

    Huang, Chiung-Chun; Liang, Ying-Ching; Lee, Cheng-Che; Hsu, Kuei-Sen

    2015-12-01

    We previously reported that animals withdrawn from repeated cocaine exposure exhibited a selective deficit in the ability to elicit metabotropic glutamate receptor 5 (mGluR5)-dependent long-term depression (LTD) in the nucleus accumbens (NAc) shell. To determine whether such impairment occurs in the NAc in a cell-type-specific manner, we used bacterial artificial chromosome (BAC) transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of gene regulatory elements for the dopamine D1 receptor (Drd1) or dopamine D2 receptor (Drd2) to identify distinct subpopulations of medium spiny neurons (MSNs). We found that bath application of group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) reliably induced LTD in both NAc shell and core MSNs of wild-type, hemizygous Drd1-eGFP, and Drd2-eGFP mice. Confirming our previous results, cocaine withdrawal selectively impaired DHPG-LTD in NAc shell Drd1-expressing direct and Drd2-expressing indirect pathway MSNs. We also found that the expression of DHPG-LTD in NAc MSNs was not affected by the Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 1-naphthyl acetyl spermine. Furthermore, systemic administration of mGluR5-negative allosteric modulator fenobam before the daily injection of cocaine preserved mGluR5 function and significantly reduced the expression of cocaine-induced behavioral sensitization. These results reveal that withdrawal from repeated cocaine exposure may result in the impairment of NAc mGluR5-LTD in a subregion- but not cell-type-specific manner and suggests that pharmacological antagonism of mGluR5 may represent a potential strategy for reducing cocaine-induced addictive behaviors.

  2. Long-term, but not short-term high-fat diet induces fiber composition changes and impaired contractile force in mouse fast-twitch skeletal muscle.

    PubMed

    Eshima, Hiroaki; Tamura, Yoshifumi; Kakehi, Saori; Kurebayashi, Nagomi; Murayama, Takashi; Nakamura, Kyoko; Kakigi, Ryo; Okada, Takao; Sakurai, Takashi; Kawamori, Ryuzo; Watada, Hirotaka

    2017-04-01

    In this study, we investigated the effects of a short-term and long-term high-fat diet (HFD) on morphological and functional features of fast-twitch skeletal muscle. Male C57BL/6J mice were fed a HFD (60% fat) for 4 weeks (4-week HFD) or 12 weeks (12-week HFD). Subsequently, the fast-twitch extensor digitorum longus muscle was isolated, and the composition of muscle fiber type, expression levels of proteins involved in muscle contraction, and force production on electrical stimulation were analyzed. The 12-week HFD, but not the 4-week HFD, resulted in a decreased muscle tetanic force on 100 Hz stimulation compared with control (5.1 ± 1.4 N/g in the 12-week HFD vs. 7.5 ± 1.7 N/g in the control group; P < 0.05), whereas muscle weight and cross-sectional area were not altered after both HFD protocols. Morphological analysis indicated that the percentage of type IIx myosin heavy chain fibers, mitochondrial oxidative enzyme activity, and intramyocellular lipid levels increased in the 12-week HFD group, but not in the 4-week HFD group, compared with controls (P < 0.05). No changes in the expression levels of calcium handling-related proteins and myofibrillar proteins (myosin heavy chain and actin) were detected in the HFD models, whereas fast-troponin T-protein expression was decreased in the 12-week HFD group, but not in the 4-week HFD group (P < 0.05). These findings indicate that a long-term HFD, but not a short-term HFD, impairs contractile force in fast-twitch muscle fibers. Given that skeletal muscle strength largely depends on muscle fiber type, the impaired muscle contractile force by a HFD might result from morphological changes of fiber type composition. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  3. The relationship between NMDA receptors and microwave-induced learning and memory impairment: a long-term observation on Wistar rats.

    PubMed

    Wang, Hui; Peng, Ruiyun; Zhao, Li; Wang, Shuiming; Gao, Yabing; Wang, Lifeng; Zuo, Hongyan; Dong, Ji; Xu, Xinping; Zhou, Hongmei; Su, Zhentao

    2015-03-01

    Abstract Purpose: To investigate whether high power microwave could cause continuous disorders to learning and memory in Wistar rats and to explore the underlying mechanisms. Eighty Wistar rats were exposed to a 2.856 GHz pulsed microwave source at a power density of 0 mW/cm(2) and 50 mW/cm(2) microwave for 6 min. The spatial memory ability, the structure of the hippocampus, contents of amino acids neurotransmitters in hippocampus and the expression of N-methyl-D-aspartic acid receptors (NMDAR) subunit 1, 2A and 2B (NR1, NR2A and NR2B) were detected at 1, 3, 6, 9, 12 and 18 months after microwave exposure. Our results showed that the microwave-exposed rats showed consistent deficiencies in spatial learning and memory. The level of amino acid neurotransmitters also decreased after microwave radiation. The ratio of glutamate (Glu) and gammaaminobutyric acid (GABA) significantly decreased at 6 months. Besides, the hippocampus showed varying degrees of degeneration of neurons, increased postsynaptic density and blurred synaptic clefts in the exposure group. The NR1 and NR2B expression showed a significant decrease, especially the NR2B expression. This study indicated that the content of amino acids neurotransmitters, the expression of NMDAR subunits and the variation of hippocampal structure might contribute to the long-term cognitive impairment after microwave exposure.

  4. Methylglyoxal (MG) and cerebro-renal interaction: does long-term orally administered MG cause cognitive impairment in normal Sprague-Dawley rats?

    PubMed

    Watanabe, Kimio; Okada, Kana; Fukabori, Ryoji; Hayashi, Yoshimitsu; Asahi, Koichi; Terawaki, Hiroyuki; Kobayashi, Kazuto; Watanabe, Tsuyoshi; Nakayama, Masaaki

    2014-01-07

    Methylglyoxal (MG), one of the uremic toxins, is a highly reactive alpha-dicarbonyl compound. Recent clinical studies have demonstrated the close associations of cognitive impairment (CI) with plasma MG levels and presence of kidney dysfunction. Therefore, the present study aims to examine whether MG is a direct causative substance for CI development. Eight-week-old male Sprague-Dawley (SD) rats were divided into two groups: control (n = 9) and MG group (n = 10; 0.5% MG in drinking water), and fed a normal diet for 12 months. Cognitive function was evaluated by two behavioral tests (object exploration test and radial-arm maze test) in early (4-6 months of age) and late phase (7-12 months of age). Serum MG was significantly elevated in the MG group (495.8 ± 38.1 vs. 244.8 ± 28.2 nM; p < 0.001) at the end of study. The groups did not differ in cognitive function during the course of study. No time-course differences were found in oxidative stress markers between the two groups, while, antioxidants such as glutathione peroxidase and superoxide dismutase activities were significantly increased in the MG group compared to the control. Long-term MG administration to rats with normal kidney function did not cause CI. A counter-balanced activation of the systemic anti-oxidant system may offset the toxicity of MG in this model. Pathogenetic significance of MG for CI requires further investigation.

  5. 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.

  6. Impaired Long-term Potentiation and Enhanced Neuronal Excitability in the Amygdala of CaV1.3 Knockout Mice

    PubMed Central

    McKinney, Brandon C.; Sze, Wilson; Lee, Benjamin; Murphy, Geoffrey G.

    2009-01-01

    Previously, we demonstrated that mice in which the gene for the L-type voltage-gated calcium channel CaV1.3 is deleted (CaV1.3 knockout mice) exhibit an impaired ability to consolidate contextually-conditioned fear. Given that this form of Pavlovian fear conditioning is critically dependent on the basolateral complex of the amygdala (BLA), we were interested in the mechanisms by which CaV1.3 contributes to BLA neurophysiology. In the present study, we used in vitro amygdala slices prepared from CaV1.3 knockout mice and wild-type littermates to explore the role of CaV1.3 in long-term potentiation (LTP) and intrinsic neuronal excitability in the BLA. We found that LTP in the lateral nucleus (LA) of the BLA, induced by high-frequency stimulation of the external capsule, was significantly reduced in CaV1.3 knockout mice. Additionally, we found that BLA principal neurons from CaV1.3 knockout mice were hyperexcitable, exhibiting significant increases in firing rates and decreased interspike intervals in response to prolonged somatic depolarization. This aberrant increase in neuronal excitability appears to be at least in part due to a concomitant reduction in the slow component of the post-burst afterhyperpolarization. Together, these results demonstrate altered neuronal function in the BLA of CaV1.3 knockout mice which may account for the impaired ability of these mice to consolidate contextually-conditioned fear. PMID:19595780

  7. Long-Term Effect of Exercise Therapy and Patient Education on Impairments and Activity Limitations in People With Hip Osteoarthritis: Secondary Outcome Analysis of a Randomized Clinical Trial.

    PubMed

    Svege, Ida; Fernandes, Linda; Nordsletten, Lars; Holm, Inger; Risberg, May Arna

    2016-06-01

    The effect of exercise on specific impairments and activity limitations in people with hip osteoarthritis (OA) is limited. The study objective was to evaluate the long-term effect of exercise therapy and patient education on range of motion (ROM), muscle strength, physical fitness, walking capacity, and pain during walking in people with hip OA. This was a secondary outcome analysis of a randomized clinical trial. The setting was a university hospital. One hundred nine people with clinically and radiographically evident hip OA were randomly allocated to receive both exercise therapy and patient education (exercise group) or patient education only (control group). All participants attended a patient education program consisting of 3 group meetings led by 2 physical therapists. Two other physical therapists were responsible for providing the exercise therapy program, consisting of 2 or 3 weekly sessions of strengthening, functional, and stretching exercises over 12 weeks. Both interventions were conducted at a sports medicine clinic. Outcome measures included ROM, isokinetic muscle strength, predicted maximal oxygen consumption determined with the Astrand bicycle ergometer test, and distance and pain during the Six-Minute Walk Test (6MWT). Follow-up assessments were conducted 4, 10, and 29 months after enrollment by 5 physical therapists who were unaware of group allocations. No significant group differences were found for ROM, muscle strength, predicted maximal oxygen consumption, or distance during the 6MWT over the follow-up period, but the exercise group had less pain during the 6MWT than the control group at 10 months (mean difference=-8.5 mm; 95% confidence interval=-16.1, -0.9) and 29 months (mean difference=-9.3 mm; 95% confidence interval=-18.1, -0.6). Limitations of the study were reduced statistical power and 53% rate of adherence to the exercise therapy program. The previously described effect of exercise on self-reported function was not reflected by

  8. Long-Term Feeding of Chitosan Ameliorates Glucose and Lipid Metabolism in a High-Fructose-Diet-Impaired Rat Model of Glucose Tolerance.

    PubMed

    Liu, Shing-Hwa; Cai, Fang-Ying; Chiang, Meng-Tsan

    2015-12-10

    This study was designed to investigate the effects of long-term feeding of chitosan on plasma glucose and lipids in rats fed a high-fructose (HF) diet (63.1%). Male Sprague-Dawley rats aged seven weeks were used as experimental animals. Rats were divided into three groups: (1) normal group (normal); (2) HF group; (3) chitosan + HF group (HF + C). The rats were fed the experimental diets and drinking water ad libitum for 21 weeks. The results showed that chitosan (average molecular weight was about 3.8 × 10⁵ Dalton and degree of deacetylation was about 89.8%) significantly decreased body weight, paraepididymal fat mass, and retroperitoneal fat mass weight, but elevated the lipolysis rate in retroperitoneal fats of HF diet-fed rats. Supplementation of chitosan causes a decrease in plasma insulin, tumor necrosis factor (TNF)-α, Interleukin (IL)-6, and leptin, and an increase in plasma adiponectin. The HF diet increased hepatic lipids. However, intake of chitosan reduced the accumulation of hepatic lipids, including total cholesterol (TC) and triglyceride (TG) contents. In addition, chitosan elevated the excretion of fecal lipids in HF diet-fed rats. Furthermore, chitosan significantly decreased plasma TC, low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), the TC/high-density lipoprotein cholesterol (HDL-C) ratio, and increased the HDL-C/(LDL-C + VLDL-C) ratio, but elevated the plasma TG and free fatty acids concentrations in HF diet-fed rats. Plasma angiopoietin-like 4 (ANGPTL4) protein expression was not affected by the HF diet, but it was significantly increased in chitosan-supplemented, HF-diet-fed rats. The high-fructose diet induced an increase in plasma glucose and impaired glucose tolerance, but chitosan supplementation decreased plasma glucose and improved impairment of glucose tolerance and insulin tolerance. Taken together, these results indicate that supplementation with chitosan can improve the impairment of

  9. Benzodiazepine long-term administration is associated with impaired attention/working memory in schizophrenia: results from the national multicentre FACE-SZ data set.

    PubMed

    Fond, Guillaume; Berna, F; Boyer, L; Godin, O; Brunel, L; Andrianarisoa, M; Aouizerate, B; Capdevielle, D; Chereau, I; Danion, J M; Dubertret, C; Dubreucq, J; Faget, C; Gabayet, F; Le Gloahec, T; Llorca, P M; Mallet, J; Misdrahi, D; Rey, R; Richieri, R; Passerieux, C; Portalier, C; Roux, P; Vehier, A; Yazbek, H; Schürhoff, F; Bulzacka, E

    2017-03-27

    The effect of benzodiazepine long-term administration (BLTA) in cognitive functioning of subjects with schizophrenia (SZ) has been partially explored to date. The objective was to assess BLTA-associated cognitive impairment with a comprehensive cognitive battery in a non-selected multicentric/national community-dwelling sample of stabilized SZ subjects. 407 community-dwelling stabilized SZ subjects were consecutively included in the FondaMental Academic Centers of Expertise for Schizophrenia Cohort (FACE-SZ). Patients taking daily benzodiazepine were defined as BLTA+ as all patients examined by the Expert Center were clinically stabilized and under stable dose of treatment for at least 3 months. Each patient has been administered a 1-day long comprehensive cognitive battery (including The National Adult Reading Test, the Wechsler Adult Intelligence Scale, the Trail Making Test, the California Verbal Learning Test, the Doors test, and The Continuous Performance Test-Identical Pairs). In the multivariate analyses, results showed that BLTA was associated with impaired attention/working memory (OR 0.60, 95% confidence interval 0.42-0.86; p = 0.005) independently of socio-demographic variables and illness characteristics. Verbal and performance current IQ-[respectively, OR 0.98, 95% CI (0.96;0.99), p = 0.016 and 0.98, 95% CI(0.97;0.99), p = 0.034] but not premorbid IQ-(p > 0.05) have been associated with BLTA in a multivariate model including the same confounding variables. BLTA is associated with impaired attention/working memory in schizophrenia. The BLTA benefit/risk ratio should be regularly reevaluated. Alternative pharmacological and non-pharmacological strategies for comorbid anxiety disorders and sleep disorders should be preferred when possible. It seems reasonable to withdraw BLTA before the start of cognitive remediation therapy, as soon as possible, to improve the effectiveness of this therapy. Limits: the delay between the last benzodiazepine

  10. 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. ...

  11. Long-Term Treatment of Clonidine, Atenolol, Amlodipine and Dihydrochlorothiazide, but Not Enalapril, Impairs the Sexual Function in Male Spontaneously Hypertensive Rats

    PubMed Central

    Lin, Li-Li; Wang, Dong; Wang, Wei; Cheng, Yan-Qiong; Su, Ding-Feng; Liu, Ai-Jun

    2015-01-01

    This study was designed to investigate the impact of representative antihypertensive drugs of 5 classes on the sexual function in male spontaneously hypertensive rats (SHR) at doses that achieved similar blood pressure (BP) reduction. The experiment was performed in 6 groups of male SHR. The dose are 20 μg/kg/day for clonidine, 3 mg/kg/day for enalapril, 20 mg/kg/day for atenolol, 2 mg/kg/day for amlodipine, and 10 mg/kg/day for dihydrochlorothiazide. SHR were treated for 3 months, and then the penile erection and sexual behavior were detected. After BP recording, SHR were killed to evaluate the organ-damage, weight of accessory sex organs and levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone in serum. Five drugs had the similar efficacy on BP reduction. All drugs except of enalapril, significantly prolonged the mount latency, and decreased the mount frequency (P<0.05). Clonidine also reduced the conception rate (45% vs. 80% in control group, P<0.05). Amlodipine and dihydrochlorothiazide significantly increased the testosterone level (0.79±0.30, 0.80±0.34 vs. 0.49±0.20 in control group, unit: ng/dl, P<0.05). Enalapril, atenolol and amlodipine also significantly decreased the BP variability (systolic, 8.2±2.5, 7.6±1.8, 8.9±2.0 vs. 12.2±3.8 in control group, unit: mm Hg). All these drugs significantly decreased the organ-damage (P<0.05). In conclusion, long-term treatment with 5 common antihypertensive drugs possessed obvious organ protection in SHR. Clonidine, atenolol, amlodipine and dihydrochlorothiazide, but not enalapril, impair sexual function. PMID:25615941

  12. The RAS/PI3K Pathway is Involved in the Impairment of Long-term Potentiation Induced by Acute Aluminum Treatment in Rats.

    PubMed

    Song, Jing; Liu, Ying; Zhang, Hui Fang; Niu, Qiao

    2016-11-01

    To explore the role of RAS/PI3K pathway in the impairment of long-term potentiation (LTP) induced by acute aluminum (Al) treatment in rats in vivo. First, different dosages of aluminum-maltolate complex [Al(mal)3] were given to rats via acute intracerebroventricular (i.c.v.) injection. Following Al exposure, the RAS activity of rat hippocampus were detected by ELISA assay after the hippocampal LTP recording by field potentiation technique in vivo. Second, the antagonism on the aluminum-induced suppression of hippocampal LTP was observed after the treatment of the RAS activator epidermal growth factor (EGF). Finally, the antagonism on the downstream molecules (PKB activity and the phosphorylation of GluR1 S831 and S845) were tested by ELISA and West-blot assays at the same time. With the increasing aluminum dosage, a gradually decreasing in RAS activity of the rat hippocampus was produced after a gradually suppressing on LTP. The aluminum-induced early suppression of hippocampal LTP was antagonized by the RAS activator epidermal growth factor (EGF). And the EGF treatment produced changes similar to those observed for LTP between the groups on PKB activity as well as the phosphorylation of GluR1 S831 and S845. The RAS→PI3K/PKB→GluR1 S831 and S845 signal transduction pathway may be involved in the inhibition of hippocampal LTP by aluminum exposure in rats. However, the mechanisms underlying this observation need further investigation. Copyright © 2016 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  13. A novel β-sheet breaker, RS-0406, reverses amyloid β-induced cytotoxicity and impairment of long-term potentiation in vitro

    PubMed Central

    Nakagami, Yasuhiro; Nishimura, Satoko; Murasugi, Takako; Kaneko, Isao; Meguro, Masaki; Marumoto, Shinji; Kogen, Hiroshi; Koyama, Kazuo; Oda, Tomiichiro

    2002-01-01

    Fibril formation of amyloid β peptide (Aβ) is considered to be responsible for the pathology of Alzheimer's disease (AD). The Aβ fibril is formed by a protein misfolding process in which intermolecular β-sheet interactions become stabilized abnormally. Thus, to develop potential anti-AD drugs, we screened an in-house library to find compounds which have a profile as a β-sheet breaker. We searched for a β-sheet breaker profile in an in-house library of approximately 113,000 compounds. From among the screening hits, we focused on N,N′-bis(3-hydroxyphenyl)pyridazine-3,6-diamine (named RS-0406), which had been newly synthesized in our laboratory. This compound (10–100 μg ml−1) was found to be capable of significantly inhibiting 25 μM Aβ1–42 fibrillogenesis and, furthermore, disassembling preformed Aβ1–42 fibrils in vitro. We then investigated the effect of RS-0406 on 111 nM Aβ1–42-induced cytotoxicity in primary hippocampal neurons, and found that 0.3–3 μg ml−1 RS-0406 ameliorates the cytotoxicity. Moreover, 3 μg ml−1 RS-0406 reversed 1 μM Aβ1–42-induced impairment of long-term potentiation in hippocampal slices. In this study, we have succeeded in identifying RS-0406 which has potential to inhibit Aβ1–42 fibrillogenesis, and to protect neurons against Aβ1–42-induced biological toxicity in vitro. These results suggest that RS-0406 or one of the derivatives could become a therapeutic agent for AD patients. PMID:12381681

  14. Non-word repetition in children with specific language impairment: a deficit in phonological working memory or in long-term verbal knowledge?

    PubMed

    Casalini, Claudia; Brizzolara, Daniela; Chilosi, Anna; Cipriani, Paola; Marcolini, Stefania; Pecini, Chiara; Roncoli, Silvia; Burani, Cristina

    2007-08-01

    In this study we investigated the effects of long-term memory (LTM) verbal knowledge on short-term memory (STM) verbal recall in a sample of Italian children affected by different subtypes of specific language impairment (SLI). The aim of the study was to evaluate if phonological working memory (PWM) abilities of SLI children can be supported by LTM linguistic representations and if PWM performances can be differently affected in the various subtypes of SLI. We tested a sample of 54 children affected by Mixed Receptive-Expressive (RE), Expressive (Ex) and Phonological (Ph) SLI (DSM-IV - American Psychiatric Association, 1994) by means of a repetition task of words (W) and non-words (NW) differing in morphemic structure [morphological non-words (MNW), consisting of combinations of roots and affixes - and simple non-words - with no morphological constituency]. We evaluated the effects of lexical and morpho-lexical LTM representations on STM recall by comparing the repetition accuracy across the three types of stimuli. Results indicated that although SLI children, as a group, showed lower repetition scores than controls, their performance was affected similarly to controls by the type of stimulus and the experimental manipulation of the non-words (better repetition of W than MNW and NW, and of MNW than NW), confirming the recourse to LTM verbal representations to support STM recall. The influence of LTM verbal knowledge on STM recall in SLI improved with age and did not differ among the three types of SLI. However, the three types of SLI differed in the accuracy of their repetition performances (PMW abilities), with the Phonological group showing the best scores. The implications for SLI theory and practice are discussed.

  15. 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

  16. Prefrontal blood flow and oxygenation measured by NIRS during long-term memory tasks are impaired by acute hyperglycemia (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Harris, R. Luke; Bell, Lindsay; Reimer, Andrea; Pettersen, Jacqueline A.; Siakaluk, Paul; Duffels, Brian

    2017-02-01

    Our goal was to use 2-channel frequency domain near-infrared spectroscopy (NIRS) to investigate the hemodynamic and metabolic mechanisms underlying hyperglycemia-associated long-term memory impairment. We hypothesized that prefrontal cortex (PFC) oxygen saturation (%Sat) and perfusion (tHb, i.e. total hemoglobin) would decrease due to hyperglycemia during learning, and then increase during recall. During learning, participants' blood glucose was manipulated with beverages containing either 47.4 mg saccharine control (CON, n = 10), or 50 g dextrose + 23.7 mg saccharine (GLC, n = 10). In the Symbol-Digit Modalities Test (SMDT) participants matched nine symbols to corresponding digits (1-9 inclusive), completing 105 learning and 15 testing trials on day 1 and 15 testing trials on day 2. From learning to recall, CON SMDT performance was unchanged, but GLC SMDT performance was decreased 11% (P = 0.0173). There were significant interactions (2-way ANOVA) between the CON-GLC treatment effects and the learning-recall effects for both PFC perfusion and oxygen saturation. Specifically, comparing learning to recall, CON exhibited no tHb differences but for GLC there was a large tHb decrease during learning with a partial recovery toward CON values during recall (P = 0.0012); and, comparing learning to recall, CON exhibited a large %Sat decrease but GLC exhibited a large %Sat increase (P = 0.021). We speculate that, during learning, after overnight fasting (CON) the PFC demands more hemodynamic and metabolic resources and "works" harder, but with readily available sugar (GLC) the PFC exhibits decreased "effort."

  17. Significant long-term, but not short-term, hippocampal-dependent memory impairment in adult rats exposed to alcohol in early postnatal life.

    PubMed

    Goodfellow, Molly J; Lindquist, Derick H

    2014-09-01

    In rodents, ethanol exposure in early postnatal life is known to induce structural and functional impairments throughout the brain, including the hippocampus. Herein, rat pups were administered one of three ethanol doses over postnatal days (PD) 4-9, a period of brain development comparable to the third trimester of human pregnancy. As adults, control and ethanol rats were trained and tested in a variant of hippocampal-dependent one-trial context fear conditioning. In Experiment 1, subjects were placed into a novel context and presented with an immediate footshock (i.e., within ∼8 sec). When re-exposed to the same context 24 hr later low levels of conditioned freezing were observed. Context pre-exposure 24 hr prior to the immediate shock reversed the deficit in sham-intubated and unintubated control rats, enhancing freezing behavior during the context retention test. Even with context pre-exposure, however, significant dose-dependent reductions in contextual freezing were seen in ethanol rats. In Experiment 2, the interval between context pre-exposure and the immediate shock was shortened to 2 hr, in addition to the standard 24 hr. Ethanol rats trained with the 2 hr, but not 24 hr, interval displayed retention test freezing levels roughly equal to controls. Results suggest the ethanol rats can encode a short-term context memory and associate it with the aversive footshock 2 hr later. In the 24 hr ethanol rats the short-term context memory is poorly transferred or consolidated into long-term memory, we propose, impeding the memory's subsequent retrieval and association with shock. © 2014 Wiley Periodicals, Inc.

  18. 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

  19. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial.

    PubMed

    Keech, Anthony; Colquhoun, David; Best, James; Kirby, Adrienne; Simes, R John; Hunt, David; Hague, Wendy; Beller, Elaine; Arulchelvam, Manjula; Baker, Jennifer; Tonkin, Andrew

    2003-10-01

    Diabetes, a major health problem worldwide, increases the risk of cardiovascular disease and its associated mortality: The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that cholesterol-lowering treatment with pravastatin reduced mortality and coronary heart disease (CHD) events in 9014 patients aged 31-75 years with CHD and total cholesterol 4.0-7.0 mmol/l. We measured the effects of pravastatin therapy, 40 mg/day over 6.0 years, on the risk of CHD death or nonfatal myocardial infarction and other cardiovascular outcomes in 1,077 LIPID patients with diabetes and 940 patients with impaired fasting glucose (IFG). In patients allocated to placebo, the risk of a major CHD event was 61% higher in patients with diabetes and 23% higher in the IFG group than in patients with normal fasting glucose, and the risk of any cardiovascular event was 37% higher in the diabetic group and 19% higher in the IFG group. Pravastatin therapy reduced the risk of a major CHD event overall from 15.9 to 12.3% (relative risk reduction [RRR] 24%, P < 0.001) and from 23.4 to 19.6% in the diabetic group (19%, P = 0.11); in the diabetic group, the reduction was not significantly different from the reductions in the other groups. Pravastatin reduced the risk of any cardiovascular event from 52.7 to 45.2% (21%, P < 0.008) in patients with diabetes and from 45.7 to 37.1% (26%, P = 0.003) in the IFG group. Pravastatin reduced the risk of stroke from 9.9 to 6.3% in the diabetic group (RRR 39%, CI 7-61%, P = 0.02) and from 5.4 to 3.4% in the IFG group (RRR 42%, CI -9 to 69%, P = 0.09). Pravastatin did not reduce the incidence of diabetes. Over 6 years, pravastatin therapy prevented one major CHD event (CHD death or nonfatal myocardial infarction) in 23 patients with IFG and 18 patients with diabetes. A meta-analysis of other major trials confirmed the high absolute risks of diabetes and IFG and the absolute benefits of statin therapy in these patients. Cholesterol

  20. The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory.

    PubMed

    Hornick, A; Lieb, A; Vo, N P; Rollinger, J M; Stuppner, H; Prast, H

    2011-12-01

    In a previous study the simple, naturally derived coumarin scopoletin (SCT) was identified as an inhibitor of acetylcholinesterase (AChE), using a pharmacophore-based virtual screening approach. In this study the potential of SCT as procholinergic and cognition-enhancing therapeutic was investigated in a more detailed way, using different experimental approaches like measuring newly synthesized acetylcholine (ACh) in synaptosomes, long-term potentiation (LTP) experiments in hippocampal slices, and behavior studies. SCT enhanced the K+-stimulated release of ACh from rat frontal cortex synaptosomes, showing a bell-shaped dose effect curve (E(max): 4 μM). This effect was blocked by the nicotinic ACh receptor (nAChR) antagonists mecamylamine (MEC) and dihydro-β-erythroidine (DHE). The nAChR agonist (and AChE inhibitor) galantamine induced a similar increase in ACh release (E(max): 1 μM). SCT potentiated LTP in hippocampal slices of rat brain. The high-frequency stimulation (HFS)-induced, N-methyl-D-aspartate (NMDA) receptor dependent LTP of field excitatory postsynaptic potentials at CA3-CA1 synapses was greatly enhanced by pre-HFS application of SCT (4 μM for 4 min). This effect was mimicked by nicotine (2 μM) and abolished by MEC, suggesting an effect on nAChRs. SCT did not restore the total inhibition of LTP by NMDA receptor antagonist D, L-2-amino-5-phosphonopentanoic acid (AP-5). SCT (2 μg, i.c.v.) increased T-maze alternation and ameliorated novel object recognition of mice with scopolamine-induced cholinergic deficit. It also reduced age-associated deficits in object memory of 15-18-month-old mice (2 mg/kg sc). Our findings suggest that SCT possesses memory-improving properties, which are based on its direct nAChR agonistic activity. Therefore, SCT might be able to rescue impaired cholinergic functions by enhancing nAChR-mediated release of neurotransmitters and promoting neural plasticity in hippocampus. Copyright © 2011 IBRO. Published by Elsevier Ltd

  1. The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory

    PubMed Central

    Hornick, A.; Lieb, A.; Vo, N.P.; Rollinger, J.M.; Stuppner, H.; Prast, H.

    2011-01-01

    In a previous study the simple, naturally derived coumarin scopoletin (SCT) was identified as an inhibitor of acetylcholinesterase (AChE), using a pharmacophore-based virtual screening approach. In this study the potential of SCT as procholinergic and cognition-enhancing therapeutic was investigated in a more detailed way, using different experimental approaches like measuring newly synthesized acetylcholine (ACh) in synaptosomes, long-term potentiation (LTP) experiments in hippocampal slices, and behavior studies. SCT enhanced the K+-stimulated release of ACh from rat frontal cortex synaptosomes, showing a bell-shaped dose effect curve (Emax: 4 μM). This effect was blocked by the nicotinic ACh receptor (nAChR) antagonists mecamylamine (MEC) and dihydro-β-erythroidine (DHE). The nAChR agonist (and AChE inhibitor) galantamine induced a similar increase in ACh release (Emax: 1 μM). SCT potentiated LTP in hippocampal slices of rat brain. The high-frequency stimulation (HFS)-induced, N-methyl-D-aspartate (NMDA) receptor dependent LTP of field excitatory postsynaptic potentials at CA3-CA1 synapses was greatly enhanced by pre-HFS application of SCT (4 μM for 4 min). This effect was mimicked by nicotine (2 μM) and abolished by MEC, suggesting an effect on nAChRs. SCT did not restore the total inhibition of LTP by NMDA receptor antagonist d, l-2-amino-5-phosphonopentanoic acid (AP-5). SCT (2 μg, i.c.v.) increased T-maze alternation and ameliorated novel object recognition of mice with scopolamine-induced cholinergic deficit. It also reduced age-associated deficits in object memory of 15–18-month-old mice (2 mg/kg sc). Our findings suggest that SCT possesses memory-improving properties, which are based on its direct nAChR agonistic activity. Therefore, SCT might be able to rescue impaired cholinergic functions by enhancing nAChR-mediated release of neurotransmitters and promoting neural plasticity in hippocampus. PMID:21945033

  2. Anisomycin Injection in Area CA3 of the Hippocampus Impairs Both Short-Term and Long-Term Memories of Contextual Fear

    ERIC Educational Resources Information Center

    Remaud, Jessica; Ceccom, Johnatan; Carponcy, Julien; Dugué, Laura; Menchon, Gregory; Pech, Stéphane; Halley, Helene; Francés, Bernard; Dahan, Lionel

    2014-01-01

    Protein synthesis is involved in the consolidation of short-term memory into long-term memory. Previous electrophysiological data concerning LTP in CA3 suggest that protein synthesis in that region might also be necessary for short-term memory. We tested this hypothesis by locally injecting the protein synthesis inhibitor anisomycin in hippocampal…

  3. Anisomycin Injection in Area CA3 of the Hippocampus Impairs Both Short-Term and Long-Term Memories of Contextual Fear

    ERIC Educational Resources Information Center

    Remaud, Jessica; Ceccom, Johnatan; Carponcy, Julien; Dugué, Laura; Menchon, Gregory; Pech, Stéphane; Halley, Helene; Francés, Bernard; Dahan, Lionel

    2014-01-01

    Protein synthesis is involved in the consolidation of short-term memory into long-term memory. Previous electrophysiological data concerning LTP in CA3 suggest that protein synthesis in that region might also be necessary for short-term memory. We tested this hypothesis by locally injecting the protein synthesis inhibitor anisomycin in hippocampal…

  4. Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: results from the TULIP study.

    PubMed

    Schmid, Vera; Wagner, Robert; Sailer, Corinna; Fritsche, Louise; Kantartzis, Konstantinos; Peter, Andreas; Heni, Martin; Häring, Hans-Ulrich; Stefan, Norbert; Fritsche, Andreas

    2017-08-24

    Lifestyle intervention is effective to prevent type 2 diabetes. However, a considerable long-term non-response occurs to a standard lifestyle intervention. We investigated which risk phenotypes at baseline and their changes during the lifestyle intervention predict long-term glycaemic non-response to the intervention. Of 300 participants at high risk for type 2 diabetes who participated in a 24 month lifestyle intervention with diet modification and increased physical activity, 190 participants could be re-examined after 8.7 ± 1.6 years. All individuals underwent a five-point 75 g OGTT and measurements of body fat compartments and liver fat content with MRI and spectroscopy at baseline, 9 and 24 months during the lifestyle intervention, and at long-term follow-up. Fasting proinsulin to insulin conversion (PI/I ratio) and insulin sensitivity and secretion were calculated from the OGTT. Non-response to lifestyle intervention was defined as no decrease in glycaemia, i.e. no decrease in AUC for glucose at 0-120 min during OGTT (AUCglucose0-120 min). Before the lifestyle intervention, 56% of participants had normal glucose regulation and 44% individuals had impaired fasting glucose and/or impaired glucose tolerance. At long-term follow-up, 11% had developed diabetes. Multivariable regression analysis with adjustment for age, sex, BMI and change in BMI during the lifestyle intervention revealed that baseline insulin secretion and insulin sensitivity, as well as change in insulin sensitivity during the lifestyle intervention, predicted long-term glycaemic control after 9 years. In addition, increased hepatic lipid content as well as impaired fasting proinsulin conversion at baseline were newly detected phenotypes that independently predicted long-term glycaemic control. Increased hepatic lipid content and impaired proinsulin conversion are new predictors, independent of change in body weight, for non-response to lifestyle intervention in addition to the

  5. [Interventions based on exercise and physical environment for preventing falls in cognitively impaired older people living in long-term care facilities: A systematic review and meta-analysis].

    PubMed

    González-Román, Loreto; Bagur-Calafat, Caritat; Urrútia-Cuchí, Gerard; Garrido-Pedrosa, Jèssica

    2016-01-01

    This systematic review aims to report the effectiveness of interventions based on exercise and/or physical environment for reducing falls in cognitively impaired older adults living in long-term care facilities. In July 2014, a literature search was conducted using main databases and specialised sources. Randomised controlled trials assessing the effectiveness of fall prevention interventions, which used exercise or physical environment among elderly people with cognitive impairment living in long-term care facilities, were selected. Two independent reviewers checked the eligibility of the studies, and evaluated their methodological quality. If it was adequate, data were gathered. Fourteen studies with 3,539 participants using exercise and/or physical environment by a single or combined approach were included. The data gathered from studies that used both interventions showed a significant reduction in fall rate. Further research is needed to demonstrate the effectiveness of those interventions for preventing falls in the elderly with cognitive impairment living in long-term care establishments. Copyright © 2015 SEGG. Published by Elsevier Espana. All rights reserved.

  6. Enhanced long-term and impaired short-term spatial memory in GluA1 AMPA receptor subunit knockout mice: evidence for a dual-process memory model.

    PubMed

    Sanderson, David J; Good, Mark A; Skelton, Kathryn; Sprengel, Rolf; Seeburg, Peter H; Rawlins, J Nicholas P; Bannerman, David M

    2009-06-01

    The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of GluA1-dependent synaptic plasticity for short-term memory of recently visited places, but not for the ability to form long-term associations between a particular spatial location and an outcome. This hypothesis is in concordance with the theory that short-term and long-term memory depend on dissociable psychological processes. In this study we tested GluA1-/- mice on both short-term and long-term spatial memory using a simple novelty preference task. Mice were given a series of repeated exposures to a particular spatial location (the arm of a Y-maze) before their preference for a novel spatial location (the unvisited arm of the maze) over the familiar spatial location was assessed. GluA1-/- mice were impaired if the interval between the trials was short (1 min), but showed enhanced spatial memory if the interval between the trials was long (24 h). This enhancement was caused by the interval between the exposure trials rather than the interval prior to the test, thus demonstrating enhanced learning and not simply enhanced performance or expression of memory. This seemingly paradoxical enhancement of hippocampus-dependent spatial learning may be caused by GluA1 gene deletion reducing the detrimental effects of short-term memory on subsequent long-term learning. Thus, these results support a dual-process model of memory in which short-term and long-term memory are separate and sometimes competitive processes.

  7. Improvement of glucose metabolism in patients with impaired glucose tolerance or diabetes by long-term administration of a palatinose-based liquid formula as a part of breakfast.

    PubMed

    Sakuma, Masae; Arai, Hidekazu; Mizuno, Akira; Fukaya, Makiko; Matsuura, Motoi; Sasaki, Hajime; Yamanaka-Okumura, Hisami; Yamamoto, Hironori; Taketani, Yutaka; Doi, Toshio; Takeda, Eiji

    2009-09-01

    A palatinose-based liquid formula (palatinose-formula), suppresses postprandial plasma glucose and insulin levels in healthy men. The objective of this study was to investigate the effects of long-term palatinose-formula ingestion on glucose metabolism in patients with impaired glucose tolerance (IGT) or type 2 diabetes. Two patients with IGT and 7 patients with type 2 diabetes participated in the palatinose-formula and dextrin-based liquid formula (dextrin-formula) loading test and long-term palatinose-formula administration study. After a 3-month control period, palatinose-formula (1046 kJ) was ingested daily by patients as a part of breakfast for 5 months. In the loading test, palatinose-formula suppressed postprandial plasma glucose and insulin levels and areas under the curve compared with those after dextrin-formula ingestion. In the long-term study, glycated hemoglobin levels (after 3 months and 5 months of treatment) and serum 8-hydroxydeoxyguanosine levels (after 5 months of treatment) were markedly decreased comparing with those at baseline. Intake of 1046 kJ palatinose-formula as a part of breakfast over a long-term period may be effective for improvement of glucose metabolism in patients with IGT or type 2 diabetes.

  8. The clearance of oral high-risk human papillomavirus infection is impaired by long-term persistence of cervical human papillomavirus infection.

    PubMed

    Louvanto, K; Rautava, J; Syrjänen, K; Grénman, S; Syrjänen, S

    2014-11-01

    Persistence of high-risk (HR-) human papillomavirus (HPV) infection of the uterine cervix increases the risk of cervical cancer. Oral HPV infections are among potential covariates of long-term genotype-specific persistent cervical HR-HPV infections. It is not known whether this persistence reflects inability of the host to reject HPV infections in general. A case-control setting was designed to estimate the covariates of long-term persistent cervical HR-HPV infections using multivariate generalized estimating equation (GEE) models. HPV was detected with PCR using GP05+/GP06+-primers and genotyped for 24 HPVs with a Multimetrix-kit. The cases (n=43) included women who had genotype-specific persistent cervical HR-HPV infection for at least 24 months (24M+) and controls were women who tested repeatedly HPV-negative in their cervical samples (n=52). These women represent a sub-cohort of the Finnish Family HPV Study. The cases differed significantly from the HPV-negative controls in several aspects: they were younger, had a longer mean time to incident oral HPV infection (40.7 versus 23.6 months), longer duration of oral HPV persistence (38.4 versus 14.1 months), and longer time to clearance of their oral HPV infection (50.0 versus 28.2 months). In multivariate GEE analysis, the second pregnancy during the follow up was the only independent predictor with significant protective effect against 24M+ persistent cervical HR-HPV infections, OR of 0.15 (95% CI 0.07-0.34). To conclude, long-term persistent cervical HR-HPV infections are associated with a prolonged clearance of oral HR-HPV infections while new pregnancy protects against persistent cervical HR-HPV infections. © 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.

  9. Traumatic injury to the immature frontal lobe: a new murine model of long-term motor impairment in the absence of psychosocial or cognitive deficits.

    PubMed

    Chen, Chien-Yi; Noble-Haeusslein, Linda J; Ferriero, Donna; Semple, Bridgette D

    2013-01-01

    Traumatic brain injury in children commonly involves the frontal lobes and is associated with distinct structural and behavioral changes. Despite the clinical significance of injuries localized to this region during brain development, the mechanisms underlying secondary damage and long-term recovery are poorly understood. Here, we have characterized the first model of unilateral focal traumatic injury to the developing frontal lobe. Male C57Bl/6J mice at postnatal day (p)21, an age approximating a toddler-aged child, received a controlled cortical impact or sham surgery to the left frontal lobe and were euthanized 1 or 7 days later. A necrotic cavity and local inflammatory response were largely confined to the unilateral frontal lobe, dorsal corpus callosum and striatum anterior to the bregma. While cell death and accumulated β-amyloid precursor protein were characteristic features of the pericontusional motor cortex, corpus callosum, cingulum and dorsal striatum, underlying structures including the hippocampus showed no overt pathology. To determine the long-term functional consequences of injury at p21, two additional cohorts were subjected to a battery of behavioral tests in adolescence (p35-45) or adulthood (p70-80). In both cohorts, brain-injured mice showed normal levels of anxiety, sociability, spatial learning and memory. The signature phenotypic features were deficits in motor function and motor learning, coincident with a reduction in ipsilateral cortical brain volumes. Together, these findings demonstrate classic morphological features of a focal traumatic injury, including early cell death and axonal injury, and long-term volumetric loss of cortical volumes. The presence of deficits in sensorimotor function and coordination in the absence of abnormal findings related to anxiety, sociability and memory likely reflects several variables, including the unique location of the injury and the emergence of favorable compensatory mechanisms during subsequent

  10. Traumatic injury to the immature frontal lobe: A new murine model of long-term motor impairment in the absence of psychosocial or cognitive deficits

    PubMed Central

    Chen, Chien-Yi; Noble-Haeusslein, Linda J; Ferriero, Donna; Semple, Bridgette D

    2014-01-01

    Traumatic brain injury in children commonly involves the frontal lobes, and is associated with distinct structural and behavioral changes. Despite the clinical significance of injuries localized to this region during brain development, the mechanisms underlying secondary damage and long-term recovery are poorly understood. Here we have characterized the first model of unilateral focal traumatic injury to the developing frontal lobe. Male C57Bl/6J mice at postnatal day (p) 21, an age approximating a toddler-aged child, received a controlled cortical impact or sham surgery to the left frontal lobe and were euthanized 1 and 7 d later. A necrotic cavity and local inflammatory response were largely confined to the unilateral frontal lobe, dorsal corpus callosum and striatum anterior to Bregma. While cell death and accumulated beta-amyloid precursor protein were characteristic features of the peri-contusional motor cortex, corpus callosum, cingulum and dorsal striatum, underlying structures including the hippocampus showed no overt pathology. To determine the long-term functional consequences of injury at p21, two additional cohorts were subjected to a battery of behavioral tests in adolescence (p35-45) or adulthood (p70-80). In both cohorts, brain-injured mice showed normal levels of anxiety, sociability, spatial learning and memory. The signature phenotypic features were deficits in motor function and motor learning, coincident with a reduction in ipsilateral cortical brain volumes. Together, these findings demonstrate classic morphological features of a focal traumatic injury, including early cell death and axonal injury, and long-term volumetric loss of cortical volumes. The presence of deficits in sensorimotor function and coordination in the absence of abnormal findings related to anxiety, sociability and memory, likely reflect several variables including the unique location of the injury and the emergence of favorable compensatory mechanisms during subsequent

  11. Short-Term and Working Memory Impairments in Early-Implanted, Long-Term Cochlear Implant Users Are Independent of Audibility and Speech Production

    PubMed Central

    AuBuchon, Angela M.; Pisoni, David B.; Kronenberger, William G.

    2015-01-01

    OBJECTIVES Determine if early-implanted, long-term cochlear implant (CI) users display delays in verbal short-term and working memory capacity when processes related to audibility and speech production are eliminated. DESIGN Twenty-three long-term CI users and 23 normal-hearing controls each completed forward and backward digit span tasks under testing conditions which differed in presentation modality (auditory or visual) and response output (spoken recall or manual pointing). RESULTS Normal-hearing controls reproduced more lists of digits than the CI users, even when the test items were presented visually and the responses were made manually via touchscreen response. CONCLUSIONS Short-term and working memory delays observed in CI users are not due to greater demands from peripheral sensory processes such as audibility or from overt speech-motor planning and response output organization. Instead, CI users are less efficient at encoding and maintaining phonological representations in verbal short-term memory utilizing phonological and linguistic strategies during memory tasks. PMID:26496666

  12. Short-Term and Working Memory Impairments in Early-Implanted, Long-Term Cochlear Implant Users Are Independent of Audibility and Speech Production.

    PubMed

    AuBuchon, Angela M; Pisoni, David B; Kronenberger, William G

    2015-01-01

    To determine whether early-implanted, long-term cochlear implant (CI) users display delays in verbal short-term and working memory capacity when processes related to audibility and speech production are eliminated. Twenty-three long-term CI users and 23 normal-hearing controls each completed forward and backward digit span tasks under testing conditions that differed in presentation modality (auditory or visual) and response output (spoken recall or manual pointing). Normal-hearing controls reproduced more lists of digits than the CI users, even when the test items were presented visually and the responses were made manually via touchscreen response. Short-term and working memory delays observed in CI users are not due to greater demands from peripheral sensory processes such as audibility or from overt speech-motor planning and response output organization. Instead, CI users are less efficient at encoding and maintaining phonological representations in verbal short-term memory using phonological and linguistic strategies during memory tasks.

  13. Long-term but not short-term plasticity at mossy fiber synapses is impaired in neural cell adhesion molecule-deficient mice

    PubMed Central

    Cremer, Harold; Chazal, Geneviève; Carleton, Alan; Goridis, Christo; Vincent, Jean-Didier; Lledo, Pierre-Marie

    1998-01-01

    Cell adhesion molecules (CAMs) are known to be involved in a variety of developmental processes that play key roles in the establishment of synaptic connectivity during embryonic development, but recent evidence implicates the same molecules in synaptic plasticity of the adult. In the present study, we have used neural CAM (NCAM)-deficient mice, which have learning and behavioral deficits, to evaluate NCAM function in the hippocampal mossy fiber system. Morphological studies demonstrated that fasciculation and laminar growth of mossy fibers were strongly affected, leading to innervation of CA3 pyramidal cells at ectopic sites, whereas individual mossy fiber boutons appeared normal. Electrophysiological recordings performed in hippocampal slice preparations revealed that both basal synaptic transmission and two forms of short-term plasticity, i.e., paired-pulse facilitation and frequency facilitation, were normal in mice lacking all forms of NCAM. However, long-term potentiation of glutamatergic excitatory synapses after brief trains of repetitive stimulation was abolished. Taken together, these results strongly suggest that in the hippocampal mossy fiber system, NCAM is essential both for correct axonal growth and synaptogenesis and for long-term changes in synaptic strength. PMID:9789073

  14. Lithium and memantine improve spatial memory impairment and neuroinflammation induced by β-amyloid 1-42 oligomers in rats.

    PubMed

    Budni, J; Feijó, D P; Batista-Silva, H; Garcez, M L; Mina, F; Belletini-Santos, T; Krasilchik, L R; Luz, A P; Schiavo, G L; Quevedo, J

    2017-05-01

    Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The main hallmarks of this disease include progressive cognitive dysfunction and an accumulation of soluble oligomers of β-amyloid (Aβ) 1-42 peptide. In this research, we show the effects of lithium and memantine on spatial memory and neuroinflammation in an Aβ1-42 oligomers-induced animal model of dementia in rats. Aβ 1-42 oligomers were administered intrahippocampally to male wistar rats to induce dementia. Oral treatments with memantine (5mg/kg), lithium (5mg/kg), or both drugs in combination were performed over a period of 17days. 14days after the administration of the Aβ1-42 oligomers, the radial arm-maze task was performed. At the end of the test period, the animals were euthanized, and the frontal cortex and hippocampus were removed for use in our analysis. Our results showed that alone treatments with lithium or memantine ameliorate the spatial memory damage caused by Aβ1-42. The animals that received combined doses of lithium and memantine showed better cognitive performance in their latency time and total errors to find food when compared to the results from alone treatments. Moreover, in our study, lithium and/or memantine were able to reverse the decreases observed in the levels of interleukin (IL)-4 that were induced by Aβ1-42 in the frontal cortex. In the hippocampus, only memantine and the association of memantine and lithium were able to reverse this effect. Alone doses of lithium and memantine or the association of lithium and memantine caused reductions in the levels of IL-1β in the frontal cortex and hippocampus, and decreased the levels of TNF-α in the hippocampus. Taken together, these data suggest that lithium and memantine might be a potential therapy against cognitive impairment and neuroinflammation induced by Aβ1-42, and their association may be a promising alternative to be investigated in the treatment of AD-like dementia. Copyright © 2017 Elsevier

  15. PERSISTENT IMPAIRMENTS IN SHORT-TERM BUT ENHANCED LONG-TERM SYNAPTIC PLASTICITY IN HIPPOCAMPAL AREA CA1 FOLLOWING DEVELOPMENTAL HYPOTHYROIDISM.

    EPA Science Inventory

    Thyroid hormones (TH) are critical for nervous system development. Deficiency of TH during development impair performance on tasks of learning and memory that rely upon the hippocampus, but the mechanism underlying this impairment is not well understood. The present study was ...

  16. PERSISTENT IMPAIRMENTS IN SHORT-TERM BUT ENHANCED LONG-TERM SYNAPTIC PLASTICITY IN HIPPOCAMPAL AREA CA1 FOLLOWING DEVELOPMENTAL HYPOTHYROIDISM.

    EPA Science Inventory

    Thyroid hormones (TH) are critical for nervous system development. Deficiency of TH during development impair performance on tasks of learning and memory that rely upon the hippocampus, but the mechanism underlying this impairment is not well understood. The present study was ...

  17. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity.

    PubMed

    Izzo, Nicholas J; Xu, Jinbin; Zeng, Chenbo; Kirk, Molly J; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Cruchaga, Carlos; Goate, Alison; Cahill, Michael A; Arancio, Ottavio; Mach, Robert H; Craven, Rolf; Head, Elizabeth; LeVine, Harry; Spires-Jones, Tara L; Catalano, Susan M

    2014-01-01

    Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of

  18. Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

    PubMed Central

    Izzo, Nicholas J.; Xu, Jinbin; Zeng, Chenbo; Kirk, Molly J.; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Cruchaga, Carlos; Goate, Alison; Cahill, Michael A.; Arancio, Ottavio; Mach, Robert H.; Craven, Rolf; Head, Elizabeth; LeVine, Harry; Spires-Jones, Tara L.; Catalano, Susan M.

    2014-01-01

    Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of

  19. Rapid-rate transcranial magnetic stimulation of animal auditory cortex impairs short-term but not long-term memory formation.

    PubMed

    Wang, Hong; Wang, Xu; Wetzel, Wolfram; Scheich, Henning

    2006-04-01

    Bilateral rapid-rate transcranial magnetic stimulation (rTMS) of gerbil auditory cortex with a miniature coil device was used to study short-term and long-term effects on discrimination learning of frequency-modulated tones. We found previously that directional discrimination of frequency modulation (rising vs. falling) relies on auditory cortex processing and that formation of its memory depends on local protein synthesis. Here we show that, during training over 5 days, certain rTMS regimes contingent on training had differential effects on the time course of learning. When rTMS was applied several times per day, i.e. four blocks of 5 min rTMS each followed 5 min later by a 3-min training block and 15-min intervals between these blocks (experiment A), animals reached a high discrimination performance more slowly over 5 days than did controls. When rTMS preceded only the first two of four training blocks (experiment B), or when prolonged rTMS (20 min) preceded only the first block, or when blocks of experiment A had longer intervals (experiments C and D), no significant day-to-day effects were found. However, in experiment A, and to some extent in experiment B, rTMS reduced the within-session discrimination performance. Nevertheless the animals learned, as demonstrated by a higher performance the next day. Thus, our results indicate that rTMS treatments accumulate over a day but not strongly over successive days. We suggest that rTMS of sensory cortex, as used in our study, affects short-term memory but not long-term memory formation.

  20. Resistance of Dynamin-related Protein 1 Oligomers to Disassembly Impairs Mitophagy, Resulting in Myocardial Inflammation and Heart Failure.

    PubMed

    Cahill, Thomas J; Leo, Vincenzo; Kelly, Matthew; Stockenhuber, Alexander; Kennedy, Nolan W; Bao, Leyuan; Cereghetti, Grazia; Harper, Andrew R; Czibik, Gabor; Lao, Chunyan; Bellahcene, Mohamed; Steeples, Violetta; Ghaffari, Safar; Yavari, Arash; Mayer, Alice; Poulton, Joanna; Ferguson, David J P; Scorrano, Luca; Hettiarachchi, Nishani T; Peers, Chris; Boyle, John; Hill, R Blake; Simmons, Alison; Watkins, Hugh; Dear, T Neil; Ashrafian, Houman

    2015-10-23

    We have reported previously that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy. The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and to define the cellular sequelae leading to heart failure in the Python monogenic dilated cardiomyopathy model. We found that the C452F mutation increased Drp1 GTPase activity. The mutation also conferred resistance to oligomer disassembly by guanine nucleotides and high ionic strength solutions. In a mouse embryonic fibroblast model, Drp1 C452F cells exhibited abnormal mitochondrial morphology and defective mitophagy. Mitochondria in C452F mouse embryonic fibroblasts were depolarized and had reduced calcium uptake with impaired ATP production by oxidative phosphorylation. In the Python heart, we found a corresponding progressive decline in oxidative phosphorylation with age and activation of sterile inflammation. As a corollary, enhancing autophagy by exposure to a prolonged low-protein diet improved cardiac function in Python mice. In conclusion, failure of Drp1 disassembly impairs mitophagy, leading to a downstream cascade of mitochondrial depolarization, aberrant calcium handling, impaired ATP synthesis, and activation of sterile myocardial inflammation, resulting in heart failure.

  1. Temporary renal ischemia during nephron sparing surgery is associated with short-term but not long-term impairment in renal function.

    PubMed

    Yossepowitch, Ofer; Eggener, Scott E; Serio, Angel; Huang, William C; Snyder, Mark E; Vickers, Andrew J; Russo, Paul

    2006-10-01

    The emergence of laparoscopic nephron sparing surgery has rekindled interest in the impact of warm renal ischemia on renal function. To provide data with which warm renal ischemia can be compared we analyzed short-term and long-term changes in the glomerular filtration rate after temporary cold renal ischemia. In patients undergoing open nephron sparing surgery the estimated glomerular filtration rate was assessed preoperatively, early in the postoperative hospital stay, and 1 and 12 months after surgery using the abbreviated Modification of Diet in Renal Disease Study equation. We separately analyzed 70 patients with a solitary kidney and 592 with 2 functioning kidneys. The end point was the percent change from the baseline glomerular filtration rate. A linear regression model was used to test the association between the glomerular filtration rate change, and ischemia time, patient age, tumor size, estimated blood loss and intraoperative fluid administration. Median cold ischemia time was 31 minutes in patients with a solitary kidney and 35 minutes in those with 2 kidneys. Compared to patients with 2 kidneys those with a solitary kidney had a significantly lower preoperative estimated glomerular filtration rate (p < 0.001), which decreased a median of 30% during the early postoperative period, and 15% and 32% 1 and 12 months after surgery, respectively. In patients with 2 kidneys the corresponding glomerular filtration rate decreases were 16%, 13% and 14%, respectively. On multivariate analyses in each group cold ischemia duration and intraoperative blood loss were significantly associated with early glomerular filtration rate changes. However, 12 months after surgery age was the only independent predictor of a glomerular filtration rate decrease in patients with 2 kidneys. Cold renal ischemia during nephron sparing surgery is a significant determinant of the short-term postoperative glomerular filtration rate. Longer clamping time is particularly detrimental in

  2. Caffeine treatment prevents rapid eye movement sleep deprivation-induced impairment of late-phase long-term potentiation in the dentate gyrus.

    PubMed

    Alhaider, Ibrahim A; Alkadhi, Karim A

    2015-11-01

    The CA1 and dentate gyrus (DG) are physically and functionally closely related areas of the hippocampus, but they differ in various respects, including their reactions to different insults. The purpose of this study was to determine the protective effects of chronic caffeine treatment on late-phase long-term potentiation (L-LTP) and its signalling cascade in the DG area of the hippocampus of rapid eye movement sleep-deprived rats. Rats were chronically treated with caffeine (300 mg/L drinking water) for 4 weeks, after which they were sleep-deprived for 24 h. L-LTP was induced in in anaesthetized rats, and extracellular field potentials from the DG area were recorded in vivo. The levels of L-LTP-related signalling proteins were assessed by western blot analysis. Sleep deprivation markedly reduced L-LTP magnitude, and basal levels of total cAMP response element-binding protein (CREB), phosphorylated CREB (P-CREB), and calcium/calmodulin kinase IV (CaMKIV). Chronic caffeine treatment prevented the reductions in the basal levels of P-CREB, total CREB and CaMKIV in sleep-deprived rats. Furthermore, caffeine prevented post-L-LTP sleep deprivation-induced downregulation of P-CREB and brain-derived neurotrophic factor in the DG. The current findings show that caffeine treatment prevents acute sleep deprivation-induced deficits in brain function.

  3. Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness

    PubMed Central

    Zakirova, Zuchra; Tweed, Miles; Crynen, Gogce; Reed, Jon; Abdullah, Laila; Nissanka, Nadee; Mullan, Myles; Mullan, Michael J.; Mathura, Venkatarajan; Crawford, Fiona; Ait-Ghezala, Ghania

    2015-01-01

    Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans. PMID:25785457

  4. Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in beagle dogs.

    PubMed

    Milgram, Norton W; Head, Elizabeth; Zicker, Steven C; Ikeda-Douglas, Candace; Murphey, Heather; Muggenberg, Bruce A; Siwak, Christina T; Tapp, P Dwight; Lowry, Stephen R; Cotman, Carl W

    2004-05-01

    The effects of long-term treatment with both antioxidants and a program of behavioral enrichment were studied as part of a longitudinal investigation of cognitive aging in beagle dogs. Baseline performance on a battery of cognitive tests was used to assign 48 aged dogs (9-12 years) into four cognitively equivalent groups, of 12 animals per group: Group CC (control food-control environment), group CE (control food-enriched environment); Group AC (antioxidant fortified food-control environment); Group AE (fortified food-enriched environment). We also tested a group of young dogs fed the control food and a second group fed the fortified food. Both groups of young dogs received a program of behavioral enrichment. To evaluate the effects of the interventions on cognition after 1 year, the dogs were tested on a size discrimination learning task and subsequently on a size discrimination reversal learning task. Both tasks showed age-sensitivity, with old dogs performing more poorly than young dogs. Both tasks were also improved by both the fortified food and the behavioral enrichment. However, in both instances the treatment effects largely reflected improved performance in the combined treatment group. These results suggest that the effectiveness of antioxidants in attenuating age-dependent cognitive decline is dependent on behavioral and environmental experience.

  5. Posttraining activation of CB1 cannabinoid receptors in the CA1 region of the dorsal hippocampus impairs object recognition long-term memory.

    PubMed

    Clarke, Julia R; Rossato, Janine I; Monteiro, Siomara; Bevilaqua, Lia R M; Izquierdo, Iván; Cammarota, Martín

    2008-09-01

    Evidence indicates that brain endocannabinoids are involved in memory processing. However, the participation of CB1 and CB2 cannabinoid receptors in recognition memory has not been yet conclusively determined. Therefore, we evaluated the effect of the posttraining activation of hippocampal cannabinoid receptors on the consolidation of object recognition memory. Rats with infusion cannulae stereotaxically aimed to the CA1 region of the dorsal hippocampus were trained in an object recognition learning task involving exposure to two different stimulus objects. Memory retention was assessed at different times after training. In the test sessions, one of the objects presented during training was replaced by a novel one. When infused in the CA1 region immediately after training, the non-selective cannabinoid receptor agonist WIN-55,212-2 and the endocannabinoid membrane transporter inhibitor VDM-11 blocked long-term memory retention in a dose-dependent manner without affecting short-term memory, exploratory behavior, anxiety state or the functionality of the hippocampus. The amnesic effect of WIN-55,212-2 and VDM-11 was not due to state-dependency and was completely reversed by co-infusion of the CB1 receptor antagonist AM-251 and mimicked by the CB1 receptor agonist ACEA but not by the CB2 receptor agonists JWH-015 and palmitoylethanolamide. Our data indicate that activation of hippocampal CB1 receptors early after training hampers consolidation of object recognition memory.

  6. Chronic cocaine administration induces long-term impairment in the drive to obtain natural reinforcers in high- but not low-demanding tasks.

    PubMed

    Barnea-Ygael, Noam; Gal, Ram; Zangen, Abraham

    2016-03-01

    Repeated drug exposure induces short- and long-term neuroadaptations in brain reward circuitries that are normally involved in the regulation of motivation. Hence, repeated drug exposure has been suggested to also affect the drive to acquire natural reinforcers. Here, we tested how chronic exposure of rats to cocaine, as well as a subsequent withdrawal period, affects acquisition of natural reinforcers in high- and low-demanding tasks (HD and LD tasks, respectively). We chronically administered cocaine (i.p., 15 mg/kg once daily, or saline in control) for 30 days, followed by a 30-day withdrawal period. We tested the effect of this treatment on the acquisition of two natural appetitive reinforcers, namely self-administering a 10% sucrose solution and mounting a receptive female, under LD and HD conditions. During the cocaine exposure period, behavioral testing took place 18 hours after cocaine injection, namely after the acute pharmacologic effect of the drug dissipated. We show that chronic i.p. cocaine exposure decreased procurement of both reinforcers in HD but not in LD tasks. The effect was observed throughout the administration period with partial recovery after withdrawal. Taken together, we present empirical evidence that chronic exposure to a constant dose of cocaine is sufficient to reduce natural reinforcement, and that this decrease can outlast drug exposure. Importantly, such effects are observed only when high demands are opposing the consumption of the natural reinforcer. © 2014 Society for the Study of Addiction.

  7. Gulf War agent exposure causes impairment of long-term memory formation and neuropathological changes in a mouse model of Gulf War Illness.

    PubMed

    Zakirova, Zuchra; Tweed, Miles; Crynen, Gogce; Reed, Jon; Abdullah, Laila; Nissanka, Nadee; Mullan, Myles; Mullan, Michael J; Mathura, Venkatarajan; Crawford, Fiona; Ait-Ghezala, Ghania

    2015-01-01

    Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans.

  8. 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.

  9. Deleting Both PHLPP1 and CANP1 Rescues Impairments in Long-Term Potentiation and Learning in Both Single Knockout Mice

    ERIC Educational Resources Information Center

    Liu, Yan; Sun, Jiandong; Wang, Yubin; Lopez, Dulce; Tran, Jennifer; Bi, Xiaoning; Baudry, Michel

    2016-01-01

    Calpain-1 (CANP1) has been shown to play a critical role in synaptic plasticity and learning and memory, as its deletion in mice results in impairment in theta-burst stimulation (TBS)-induced LTP and various forms of learning and memory. Likewise, PHLPP1 (aka SCOP) has also been found to participate in learning and memory, as PHLPP1 overexpression…

  10. Effects of an Exercise Program on Mentally Impaired Older Adults--Alzheimer's and Dementia Residents in a Long-Term Care Facility.

    ERIC Educational Resources Information Center

    Frizzell, Linda Bane

    This study attempted to define the current bases for physical exercise and activity for healthy older adults and to use those data as a basis for developing physical exercises and activities for older adults with mental impairments. An 8-week exercise program was developed and evaluated to determine its effect on satisfaction and quality of life…

  11. Deleting Both PHLPP1 and CANP1 Rescues Impairments in Long-Term Potentiation and Learning in Both Single Knockout Mice

    ERIC Educational Resources Information Center

    Liu, Yan; Sun, Jiandong; Wang, Yubin; Lopez, Dulce; Tran, Jennifer; Bi, Xiaoning; Baudry, Michel

    2016-01-01

    Calpain-1 (CANP1) has been shown to play a critical role in synaptic plasticity and learning and memory, as its deletion in mice results in impairment in theta-burst stimulation (TBS)-induced LTP and various forms of learning and memory. Likewise, PHLPP1 (aka SCOP) has also been found to participate in learning and memory, as PHLPP1 overexpression…

  12. Long-term exposures to di-n-butyl phthalate inhibit body growth and impair gonad development in juvenile Murray rainbowfish (Melanotaenia fluviatilis).

    PubMed

    Bhatia, Harpreet; Kumar, Anupama; Chapman, John C; McLaughlin, Mike J

    2015-07-01

    The aim of the present study was to evaluate whether long-term exposures to environmentally relevant concentrations of di-n-butyl phthalate (DnBP) disrupt the reproduction-based endpoints in juvenile Murray rainbowfish (Melanotaenia fluviatilis). Fish were exposed to 5, 15 or 50 µg l(-1) DnBP for 30, 60 and 90 days each, and the effects on survival, body growth, whole-body concentrations of sex steroid hormones and gonadal development were investigated. The lowest observed effective concentration to affect the condition factor after 90 days was 5 µg l(-1). Complete feminization of the gonad was noted in fish exposed to 5 µg l(-1) for 90 days and to 15 and 50 µg l(-1) of DnBP for 30 or 60 days. After 90 days of exposure to DnBP, the ovaries were regressed and immature as opposed to the control fish which were in early-vitellogenic stage. Testes, present only in fish exposed to 5 µg l(-1) of DnBP for 30 or 60 days, were immature in comparison to the control fish that contained testes in the mid-spermatogenic phase. The E2/11-KT ratio was significantly higher only after exposures to 5 µg l(-1) DnBP for 90 days and 50 µg l(-1) DnBP for 30 days. Our data suggest that exposures to 5 µg l(-1) DnBP for 30 days did not have profound effects on body growth and gonadal differentiation of fish. However, 30 days of exposure to 15 µg l(-1) could interfere with the gonad development and to 50 µg l(-1) could compromise the hormonal profile of juvenile fish.

  13. Simple kcal/kg formula is comparable to prediction equations for estimating resting energy expenditure in older cognitively impaired long term care residents.

    PubMed

    Silver, H J; Wall, R; Hollingsworth, E; Pruitt, A; Shotwell, M; Simmons, S

    2013-01-01

    Assessment of energy needs is a critical step in developing the nutrition care plan, especially for individuals unable to modulate their own energy intakes. The purpose of this study was to assess precision and accuracy of commonly used prediction equations in comparison to measured resting energy expenditure in a sample of "oldest old" adults residing in long term care (LTC). Resting energy expenditure (mREE) was measured by indirect calorimetry in 45 residents aged 86.1 ± 7.3 years, and compared to frequently used prediction equations (pREE): Mifflin St.Jeor, Harris Benedict, World Health Organization and Owen. Precision and accuracy were determined by concordance correlation coefficients and number of individuals within ± 10% of mREE. Bland Altman plots with linear dependence trends were constructed to visualize agreement. To complete analyses, the common 25 kcal/kg formula was assessed and alternative formulas were determined for best fit by regressing adjusted mREE on body weight. mREE averaged 976.2 ± 190.3 kcal/day for females and 1260.0 ± 275.9 kcal/d for males. The strength of the relationships between pREE and mREE were only moderate (r = 0.41 - 0.72). In examining linear trends in the Bland Altman plots, significant systematic deviation from mREE was detected for all pREE. Two kcal/kg formulas were generated: 20.6 kcal/kg for females and 22.7 kcal/kg for males, which were not significantly different. None of the prediction equations adequately estimated energy needs in this sample of the "oldest old." A simple formula using 21-23 kcal/kg may be a more practical and reliable method to determine energy needs in the LTC setting.

  14. Long-term inhibition of Rho-kinase restores the LTP impaired in chronic forebrain ischemia rats by regulating GABAA and GABAB receptors.

    PubMed

    Huang, L; Zhao, L B; Yu, Z Y; He, X J; Ma, L P; Li, N; Guo, L J; Feng, W Y

    2014-09-26

    We previously demonstrated that inactivation of Rho-kinase by hydroxyfasudil could impact N-methyl-d-aspartate (NMDA) excitatory interneurons in the hippocampus and attenuate the spatial learning and memory dysfunction of rats caused by chronic forebrain hypoperfusion ischemia. Complementary interactions between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA form the molecular basis of synaptic plasticity and cognitive performance. However, whether the GABAergic inhibitory interneurons are involved in the mechanisms underlying these processes remains unclear. Here, we further examined the role of GABAergic interneurons in the neuroprotective effect of the Rho-kinase inhibitor. Chronic forebrain ischemia was induced in Wistar rats by bilateral common carotid artery occlusion (BCAO). The general synaptic transmission and long-term potentiation (LTP) of hippocampal CA3 neurons were evaluated at 30 days after sham surgery or BCAO. Real-time PCR and Western blot analyses were conducted to determine the effect of the Rho-kinase inhibitor hydroxyfasudil on GABAergic inhibitory interneuron expression and function after ischemia. Hydroxyfasudil showed no significant effect on general synaptic transmission, but it could abolish the inhibition of LTP induced by chronic forebrain ischemia. Moreover, the mRNA and protein levels of GABAA and GABAB in three brain regions after ischemia were markedly decreased, and hydroxyfasudil could up-regulate all mRNA and protein expression levels in these areas except for GABAA mRNA in the cerebral cortex and striatum. Using phosphorylation antibodies against specific sites on the GABAA and GABAB receptors, we further demonstrated that hydroxyfasudil could inhibit GABAergic interneuron phosphorylation triggered by the theta burst stimulation. In summary, our results indicated that the inactivation of Rho-kinase could enhance GABAA and GABAB expressions by different mechanisms to guarantee the induction of

  15. Developmental exposure to a commercial PCB mixture (Aroclor 1254) produces a persistent impairment in long-term potentiation in the rat dentate gyrus in vivo.

    PubMed

    Gilbert, M E; Crofton, K M

    1999-12-11

    Developmental exposure to polycholorinated biphenyls (PCBs) has been associated with cognitive deficits in humans and laboratory animals. The present study sought to examine synaptic plasticity in the hippocampus, a brain region critical for some types of memory function, in animals exposed to PCBs early in development. Pregnant Long-Evans rats were administered either corn oil (control) or 6 mg/kg/day of a commercial PCB mixture, Aroclor 1254 (A1254) by gavage from gestational day (GD) 6 until pups were weaned on postnatal day (PND) 21. In adult male offspring (3-6 months of age), field potentials evoked by perforant path stimulation were recorded in the dentate gyrus under urethane anesthesia. Input/output (I/O) functions were assessed by averaging the response evoked in the dentate gyrus to stimulus pulses delivered to the perforant path in an ascending intensity series. Long-term potentiation (LTP) was induced by delivering a series of brief high frequency (400 Hz) train bursts to the perforant path at a moderate stimulus intensity and I/O functions were reassessed 1 h later. No differences in baseline synaptic population spike (PS) and minor effects on excitatory postsynaptic potential (EPSP) slope amplitudes were discerned between the groups prior to train delivery. Post-train I/O functions, however, revealed a 50% decrement in the magnitude of LTP in PCB-exposed animals. These data are the first to demonstrate persistent decrements in hippocampal synaptic plasticity in the intact animal following developmental exposure to PCBs. Disruption of early brain ontogeny due to developmental PCB exposure may underlie perturbations in the neurological substrates that support synaptic plasticity and contribute to deficits in LTP and learning that persist into adulthood.

  16. Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

    PubMed Central

    Goodman, Andrew D; Bethoux, Francois; Brown, Theodore R; Schapiro, Randall T; Cohen, Ron; Marinucci, Lawrence N; Henney, Herbert R

    2015-01-01

    Background: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). Objectives: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). Methods: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. Results: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. Conclusions: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders. PMID:25583832

  17. Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials.

    PubMed

    Goodman, Andrew D; Bethoux, Francois; Brown, Theodore R; Schapiro, Randall T; Cohen, Ron; Marinucci, Lawrence N; Henney, Herbert R; Blight, Andrew R

    2015-09-01

    In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders. © The Author(s), 2015.

  18. Acetyl-L-carnitine normalizes the impaired long-term potentiation and spine density in a rat model of global ischemia.

    PubMed

    Kocsis, K; Knapp, L; Gellért, L; Oláh, G; Kis, Zs; Takakuwa, H; Iwamori, N; Ono, E; Toldi, J; Farkas, T

    2014-06-06

    As a consequence of an ischemic episode, energy production is disturbed, leading to neuronal cell death. Despite intensive research, the quest for promising neuroprotective drugs has largely failed, not only because of ineffectiveness, but also because of serious side-effects and dosing difficulties. Acetyl-l-carnitine (ALC) is an essential nutrient which plays a key role in energy metabolism by transporting fatty acids into mitochondria for β-oxidation. It is an endogenous compound and can be used at high dose without toxicity in research into ischemia. Its neuroprotective properties have been reported in many studies, but its potential action on long-term potentiation (LTP) and dendritic spine density has not been described to date. The aim of the present study was an evaluation of the possible protective effect of ALC after ischemic insults inflicted on hippocampal synaptic plasticity in a 2-vessel occlusion (2VO) model in rats. For electrophysiological measurements, LTP was tested on hippocampal slices. The Golgi-Cox staining technique was used to determine spine density. 2VO resulted in a decreased, unstable LTP and a significant loss of dendritic spines. ALC administered after 2VO was not protective, but as pretreatment prior to 2VO it restored LTP nearly to the control level. This finding paralleled the histological analysis: ALC pretreatment resulted in the reappearance of dendritic spines on the CA1 pyramidal cells. Our data demonstrate that ALC administration can restore hippocampal function and spine density. ALC probably acts by enhancing the aerobic metabolic pathway, which is inhibited during and following ischemic attacks.

  19. A decision aid regarding long-term tube feeding targeting substitute decision makers for cognitively impaired older persons in Japan: A small-scale before-and-after study

    PubMed Central

    2014-01-01

    Background In Japan, there is no decision-making guide regarding long-term tube feeding that specifically targets individuals making decisions on behalf of cognitively impaired older persons (substitute decision makers). The objective of this study was to describe the development and evaluation of such a decision aid. Methods In this before-and-after study, participants comprised substitute decision makers for 13 cognitively impaired inpatients aged 65 years and older who were being considered for placement of a percutaneous endoscopic gastrostomy tube in acute care hospitals and mixed-care hospitals in Japan. Questionnaires were used to compare substitute decision makers’ knowledge, decisional conflict, and predisposition regarding feeding tube placement before and after exposure to a decision aid. The acceptability of the decision aid was also assessed. Paired t-tests were used to compare participants’ knowledge and decisional conflict scores before and after using the decision aid. Results Substitute decision makers showed significantly increased knowledge (P < .001) and decreased decisional conflict (P < .01) regarding long-term tube feeding after using the decision aid. All substitute decision makers found the decision aid helpful and acceptable. Conclusions The decision aid facilitated the decision-making process of substitute decision makers by decreasing decisional conflict and increasing knowledge. PMID:24495735

  20. Long-Term Post-Stroke Changes Include Myelin Loss, Specific Deficits in Sensory and Motor Behaviors and Complex Cognitive Impairment Detected Using Active Place Avoidance

    PubMed Central

    Li, Jie; Ooi, Evelyn; Bloom, Jonathan; Poon, Carrie; Lax, Daniel; Rosenbaum, Daniel M.; Barone, Frank C.

    2013-01-01

    Persistent neurobehavioral deficits and brain changes need validation for brain restoration. Two hours middle cerebral artery occlusion (tMCAO) or sham surgery was performed in male Sprague-Dawley rats. Neurobehavioral and cognitive deficits were measured over 10 weeks included: (1) sensory, motor, beam balance, reflex/abnormal responses, hindlimb placement, forepaw foot fault and cylinder placement tests, and (2) complex active place avoidance learning (APA) and simple passive avoidance retention (PA). Electroretinogram (ERG), hemispheric loss (infarction), hippocampus CA1 neuronal loss and myelin (Luxol Fast Blue) staining in several fiber tracts were also measured. In comparison to Sham surgery, tMCAO surgery produced significant deficits in all behavioral tests except reflex/abnormal responses. Acute, short lived deficits following tMCAO were observed for forelimb foot fault and forelimb cylinder placement. Persistent, sustained deficits for the whole 10 weeks were exhibited for motor (p<0.001), sensory (p<0.001), beam balance performance (p<0.01) and hindlimb placement behavior (p<0.01). tMCAO produced much greater and prolonged cognitive deficits in APA learning (maximum on last trial of 604±83% change, p<0.05) but only a small, comparative effect on PA retention. Hemispheric loss/atrophy was measured 10 weeks after tMCAO and cross-validated by two methods (e.g., almost identical % ischemic hemispheric loss of 33.4±3.5% for H&E and of 34.2±3.5% for TTC staining). No visual dysfunction by ERG and no hippocampus neuronal loss were detected after tMCAO. Fiber tract damage measured by Luxol Fast Blue myelin staining intensity was significant (p<0.01) in the external capsule and striatum but not in corpus callosum and anterior commissure. In summary, persistent neurobehavioral deficits were validated as important endpoints for stroke restorative research in the future. Fiber myelin loss appears to contribute to these long term behavioral dysfunctions and can be

  1. Long-term post-stroke changes include myelin loss, specific deficits in sensory and motor behaviors and complex cognitive impairment detected using active place avoidance.

    PubMed

    Zhou, Jin; Zhuang, Jian; Li, Jie; Ooi, Evelyn; Bloom, Jonathan; Poon, Carrie; Lax, Daniel; Rosenbaum, Daniel M; Barone, Frank C

    2013-01-01

    Persistent neurobehavioral deficits and brain changes need validation for brain restoration. Two hours middle cerebral artery occlusion (tMCAO) or sham surgery was performed in male Sprague-Dawley rats. Neurobehavioral and cognitive deficits were measured over 10 weeks included: (1) sensory, motor, beam balance, reflex/abnormal responses, hindlimb placement, forepaw foot fault and cylinder placement tests, and (2) complex active place avoidance learning (APA) and simple passive avoidance retention (PA). Electroretinogram (ERG), hemispheric loss (infarction), hippocampus CA1 neuronal loss and myelin (Luxol Fast Blue) staining in several fiber tracts were also measured. In comparison to Sham surgery, tMCAO surgery produced significant deficits in all behavioral tests except reflex/abnormal responses. Acute, short lived deficits following tMCAO were observed for forelimb foot fault and forelimb cylinder placement. Persistent, sustained deficits for the whole 10 weeks were exhibited for motor (p<0.001), sensory (p<0.001), beam balance performance (p<0.01) and hindlimb placement behavior (p<0.01). tMCAO produced much greater and prolonged cognitive deficits in APA learning (maximum on last trial of 604±83% change, p<0.05) but only a small, comparative effect on PA retention. Hemispheric loss/atrophy was measured 10 weeks after tMCAO and cross-validated by two methods (e.g., almost identical % ischemic hemispheric loss of 33.4±3.5% for H&E and of 34.2±3.5% for TTC staining). No visual dysfunction by ERG and no hippocampus neuronal loss were detected after tMCAO. Fiber tract damage measured by Luxol Fast Blue myelin staining intensity was significant (p<0.01) in the external capsule and striatum but not in corpus callosum and anterior commissure. In summary, persistent neurobehavioral deficits were validated as important endpoints for stroke restorative research in the future. Fiber myelin loss appears to contribute to these long term behavioral dysfunctions and can be

  2. Cytotoxicity and proliferative capacity impairment induced on human brain cell cultures after short- and long-term exposure to magnetite nanoparticles.

    PubMed

    Coccini, Teresa; Caloni, Francesca; Ramírez Cando, Lenin Javier; De Simone, Uliana

    2017-03-01

    Since magnetic iron oxide nanoparticles (IONP) as magnetite (Fe3 O4 NPs) have potential applications in life sciences, industrial fields and biomedical care, the risks for occupational, general population and patients rises correspondingly. Excessive IONP accumulation in central nervous system (CNS) cells can lead to a disruption of normal iron metabolism/homeostasis, which is a characteristic hallmark resembling that of several neurodegenerative disorders. Fe3 O4 NPs- versus Fe3 O4 bulk-induced toxic effects have been assessed in two human CNS cells namely astrocytes (D384) and neurons (SH-SY5Y) after short-term exposure (4-24-48 h) to 1-100 μg ml(-1) , and long-term exposure to lower concentrations. Short-term Fe3 O4 NPs induced significant concentration- and time-dependent alterations of mitochondrial function in D384 (25-75% cell viability decrease): effects started at 25 μg ml(-1) after 4 h, and 1 μg ml(-1) after 48 h. SH-SY5Y were less susceptible: cytotoxicity occurred after 48  h only with 35-45% mortality (10-100 μg ml(-1) ). Accordingly, a more marked intracellular iron accumulation was observed in astrocytes than neurons. Membrane integrity was unaltered in both CNS cell types. Lowering Fe3 O4 NP concentrations (0.05-10 μg ml(-1) ) and prolonging the exposure time (up to 10 days), D384 toxicity was again observed (colony number decrease at ≥0.05 μg ml(-1) , morphology alterations and colony size reduction at ≥0.5 μg ml(-1) ). Effects on SH-SY5Y appeared at the highest concentration only. Fe3 O4 bulk was always remarkably toxic toward both cells. In summary, human cultured astrocytes were susceptible to both Fe3 O4 NP and bulk forms following short-term and extended exposure to low concentrations, while neurons were more resistant to NPs. Cellular iron overload may trigger adverse responses by releasing iron ions (particularly in astrocytes) thus compromising the normal functions of CNS. Copyright © 2016

  3. Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons.

    PubMed

    Cerpa, Waldo; Farías, Ginny G; Godoy, Juan A; Fuenzalida, Marco; Bonansco, Christian; Inestrosa, Nibaldo C

    2010-01-18

    Soluble amyloid-beta (Abeta;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Abeta oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation. We report here that the Wnt signaling activation prevents the synaptic damage triggered by Abeta oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components. These results indicate that post-synaptic damage induced by Abeta oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation.

  4. Wnt-5a occludes Aβ oligomer-induced depression of glutamatergic transmission in hippocampal neurons

    PubMed Central

    2010-01-01

    Background Soluble amyloid-β (Aβ;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation. Results We report here that the Wnt signaling activation prevents the synaptic damage triggered by Aβ oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Aβ oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Aβ oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Aβ oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Aβ oligomers inversely modulate postsynaptic components. Conclusion These results indicate that post-synaptic damage induced by Aβ oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation. PMID:20205789

  5. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control

    PubMed Central

    Kohan, Donald E; Fioretto, Paola; Tang, Weihua; List, James F

    2014-01-01

    In patients with diabetes, glycemic improvement by sodium-glucose cotransporter-2 inhibition depends on the kidney's ability to filter glucose. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces hyperglycemia in patients with diabetes and normal or mildly impaired renal function. In this randomized, double-blind, placebo-controlled study we assessed daily treatment with dapagliflozin in 252 patients with inadequately controlled type 2 diabetes and moderate renal impairment. The primary endpoint, the mean change in HbA1c, was not statistically different from placebo after 24 weeks (−0.41% and −0.44% for 5- and 10-mg doses, respectively, and −0.32% for placebo). The mean weight change from baseline was −1.54 and −1.89 kg for the 5- and 10-mg doses, respectively, and +0.21 kg for placebo. The mean systolic and diastolic blood pressure decreased in the dapagliflozin groups compared to placebo. Through 104 weeks, 13 patients receiving dapagliflozin and no patients receiving placebo experienced bone fracture. At 1 week, the mean serum creatinine increased with dapagliflozin 5 mg (+0.13 mg/dl) and 10 mg (+0.18 mg/dl) and did not change further after 104 weeks. Mean serum electrolytes did not change in any group, and there were fewer episodes of hyperkalemia with dapagliflozin than placebo. Thus, in patients with moderate renal impairment, dapagliflozin did not improve glycemic control, but reduced weight and blood pressure. PMID:24067431

  6. Cognitive impairment among World Trade Center responders: Long-term implications of re-experiencing the 9/11 terrorist attacks.

    PubMed

    Clouston, Sean A P; Kotov, Roman; Pietrzak, Robert H; Luft, Benjamin J; Gonzalez, Adam; Richards, Marcus; Ruggero, Camilo J; Spiro, Avron; Bromet, Evelyn J

    2016-01-01

    During the World Trade Center (WTC) attacks, responders who helped in search, rescue, and recovery endured multiple traumatic and toxic exposures. One-fifth subsequently developed post-traumatic stress disorder (PTSD). PTSD has been linked to dementia in veterans. This study examined the association between WTC-related PTSD and cognitive impairment (CI) in WTC responders. A one-third sample of responders (N = 818) reporting for annual monitoring visits were screened for cognitive impairment and dementia using the Montreal Cognitive Assessment from January 2014-April 2015. Concurrent diagnoses of PTSD and major depressive disorder (MDD), as well as serial PTSD and depressive symptom inventories, collected since 2002, were examined in relation to current CI. Approximately 12.8% and 1.2% of responders in this sample respectively had scores indicative of CI and possible dementia. Current PTSD and MDD were associated with CI. Longitudinal results revealed that re-experiencing symptoms were consistently associated with CI (aRR = 2.88, 95% confidence interval = 1.35-6.22), whereas longitudinal increases in other PTSD and depressive symptoms in the years before screening were evident only among those with CI. Analyses replicated results from Veterans studies and further highlighted the importance of re-experiencing symptoms, a major component of PTSD that was consistently predictive of CI 14 years later. Clinicians should monitor CI when treating individuals with chronic PTSD.

  7. Renal impairment has no clinically relevant effect on the long-term exposure of linagliptin in patients with type 2 diabetes.

    PubMed

    Friedrich, Christian; Emser, Angela; Woerle, Hans-Juergen; Graefe-Mody, Ulrike

    2013-01-01

    Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily nonrenal route of excretion. Consequently, renal impairment should not substantially affect drug exposure. This analysis was undertaken to compare steady-state trough concentrations of linagliptin among patients with type-2 diabetes receiving linagliptin 5 mg in phase 3 studies. Data were pooled from 3 randomized studies from the global phase 3 program of linagliptin (5 mg daily in each) in patients with type-2 diabetes. These studies were selected for their inclusion of pharmacokinetic data. Linagliptin plasma concentrations were available for 969 patients who were determined by estimated glomerular filtration rate to have normal renal function (n = 438), mild renal impairment (RI) (n = 429), moderate RI (n = 44), or severe RI (n = 58). In patients with normal renal function, the geometric mean linagliptin trough concentration (coefficient of variation) was 5.93 nmol/L (56.3%); in patients with mild, moderate, or severe RI, geometric mean concentrations were 6.07 nmol/L (62.9%), 7.34 nmol/L (58.6%), and 8.13 nmol/L (49.8%), respectively. In patients with type-2 diabetes, RI had a minor effect on linagliptin exposure. Therefore, neither dose-adjustment nor drug-related monitoring of estimated glomerular filtration rate is necessary for patients with RI.

  8. Reproduction impairment and endocrine disruption in female zebrafish after long-term exposure to MC-LR: A life cycle assessment.

    PubMed

    Hou, Jie; Li, Li; Wu, Ning; Su, Yujing; Lin, Wang; Li, Guangyu; Gu, Zemao

    2016-01-01

    Microcystin-LR (MC-LR) has been found to cause reproductive and developmental impairments as well as to disrupt sex hormone homeostasis of fish during acute and sub-chronic toxic experiments. However, fish in natural environments are continuously exposed to MC-LR throughout their entire life cycle as opposed to short-term exposure. Here, we tested the hypothesis that the mechanism by which MC-LR harms female fish reproduction and development within natural water bodies is through interference of the reproductive endocrine system. In the present study, zebrafish hatchlings (5 d post-fertilization) were exposed to 0, 0.3, 3 and 30 μg/L MC-LR for 90 d until reaching sexual maturity. Female zebrafish were selected, and the changes in growth and developmental indicators, ovarian ultrastructure as well as the levels of gonadal steroid hormones and vitellogenin (VTG) were examined along with the transcription of related genes in the hypothalamic-pituitary-gonadal-liver axis (HPGL-axis). The results showed for the first time, a life cycle exposure to MC-LR caused growth inhibition, decreased ovary weight and ovarian ultra-pathological lesions. Decreased ovarian testosterone levels indicated that MC-LR disrupted sex steroid hormone balance. Significantly up-regulated transcription of brain FSHβ and LHβ along with ovarian ERα, FSHR and LHR suggested positive feedback regulation in the HPGL-axis was induced as a compensatory mechanism for MC-LR damage. It was also noted that ovarian VTG content and hepatic ERα and VTG1 expression were all down-regulated, which might be responsible for reduced vitellus storage noted in our histological observations. Our findings indicate that a life cycle exposure to MC-LR impairs the development and reproduction of female zebrafish by disrupting the transcription of related HPGL-axis genes, suggesting that MC-LR has potential adverse effects on fish reproduction and thus population dynamics in MCs-contaminated aquatic environment

  9. Mice lacking the PSD-95–interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning

    PubMed Central

    Park, Hanwool; Yang, Jinhee; Kim, Ryunhee; Li, Yan; Lee, Yeunkum; Lee, Chungwoo; Park, Jongil; Lee, Dongmin; Kim, Hyun; Kim, Eunjoon

    2015-01-01

    Protein ubiquitination has a significant influence on diverse aspects of neuronal development and function. Dorfin, also known as Rnf19a, is a RING finger E3 ubiquitin ligase implicated in amyotrophic lateral sclerosis and Parkinson’s disease, but its in vivo functions have not been explored. We report here that Dorfin is a novel binding partner of the excitatory postsynaptic scaffolding protein PSD-95. Dorfin-mutant (Dorfin−/−) mice show reduced adult neurogenesis and enhanced long-term potentiation in the hippocampal dentate gyrus, but normal long-term potentiation in the CA1 region. Behaviorally, Dorfin−/− mice show impaired contextual fear conditioning, but normal levels of cued fear conditioning, fear extinction, spatial learning and memory, object recognition memory, spatial working memory, and pattern separation. Using a proteomic approach, we also identify a number of proteins whose ubiquitination levels are decreased in the Dorfin−/− brain. These results suggest that Dorfin may regulate adult neurogenesis, synaptic plasticity, and contextual fear memory. PMID:26553645

  10. Older Adults with Mild Cognitive Impairments Show Less Driving Errors after a Multiple Sessions Simulator Training Program but Do Not Exhibit Long Term Retention

    PubMed Central

    Teasdale, Normand; Simoneau, Martin; Hudon, Lisa; Germain Robitaille, Mathieu; Moszkowicz, Thierry; Laurendeau, Denis; Bherer, Louis; Duchesne, Simon; Hudon, Carol

    2016-01-01

    The driving performance of individuals with mild cognitive impairment (MCI) is suboptimal when compared to healthy older adults. It is expected that the driving will worsen with the progression of the cognitive decline and thus, whether or not these individuals should continue to drive is a matter of debate. The aim of the study was to provide support to the claim that individuals with MCI can benefit from a training program and improve their overall driving performance in a driving simulator. Fifteen older drivers with MCI participated in five training sessions in a simulator (over a 21-day period) and in a 6-month recall session. During training, they received automated auditory feedback on their performance when an error was noted about various maneuvers known to be suboptimal in MCI individuals (for instance, weaving, omitting to indicate a lane change, to verify a blind spot, or to engage in a visual search before crossing an intersection). The number of errors was compiled for eight different maneuvers for all sessions. For the initial five sessions, a gradual and significant decrease in the number of errors was observed, indicating learning and safer driving. The level of performance, however, was not maintained at the 6-month recall session. Nevertheless, the initial learning observed opens up possibilities to undertake more regular interventions to maintain driving skills and safe driving in MCI individuals. PMID:28082883

  11. WRP/srGAP3 Facilitates the Initiation of Spine Development by an Inverse F-BAR Domain, and Its Loss Impairs Long-Term Memory

    PubMed Central

    Carlson, Benjamin R.; Lloyd, Krissey E.; Kruszewski, Allison; Kim, Il-Hwan; Rodriguiz, Ramona M.; Heindel, Clifford; Faytell, Marika; Dudek, Serena M.; Wetsel, William C.; Soderling, Scott H.

    2012-01-01

    The WAVE-associated Rac GAP, WRP, is thought to regulate key aspects of synapse development and function and may be linked to mental retardation in humans. WRP contains a newly described inverse F-BAR (IF-BAR) domain of unknown function. Our studies show that this domain senses/facilitates outward protrusions analogous to filopodia and that the molecular basis for this is likely explained by a convex lipid-binding surface on the WRP IF-BAR domain. In dendrites the IF-BAR domain of WRP forms a bud on the shaft from which precursors to spines emerge. Loss of WRP in vivo and in vitro results in reduced density of spines. In vivo this is primarily a loss of mushroom-shaped spines. Developmentally, WRP function is critical at the onset of spinogenesis, when dendritic filopodia are prevalent. Finally, because WRP is implicated in mental retardation, behaviors of WRP heterozygous and null mice have been evaluated. Results from these studies confirm that loss of WRP is linked to impaired learning and memory. PMID:21325512

  12. WRP/srGAP3 facilitates the initiation of spine development by an inverse F-BAR domain, and its loss impairs long-term memory.

    PubMed

    Carlson, Benjamin R; Lloyd, Krissey E; Kruszewski, Allison; Kim, Il-Hwan; Rodriguiz, Ramona M; Heindel, Clifford; Faytell, Marika; Dudek, Serena M; Wetsel, William C; Soderling, Scott H

    2011-02-16

    The WAVE-associated Rac GAP, WRP, is thought to regulate key aspects of synapse development and function and may be linked to mental retardation in humans. WRP contains a newly described inverse F-BAR (IF-BAR) domain of unknown function. Our studies show that this domain senses/facilitates outward protrusions analogous to filopodia and that the molecular basis for this is likely explained by a convex lipid-binding surface on the WRP IF-BAR domain. In dendrites the IF-BAR domain of WRP forms a bud on the shaft from which precursors to spines emerge. Loss of WRP in vivo and in vitro results in reduced density of spines. In vivo this is primarily a loss of mushroom-shaped spines. Developmentally, WRP function is critical at the onset of spinogenesis, when dendritic filopodia are prevalent. Finally, because WRP is implicated in mental retardation, behaviors of WRP heterozygous and null mice have been evaluated. Results from these studies confirm that loss of WRP is linked to impaired learning and memory.

  13. Older Adults with Mild Cognitive Impairments Show Less Driving Errors after a Multiple Sessions Simulator Training Program but Do Not Exhibit Long Term Retention.

    PubMed

    Teasdale, Normand; Simoneau, Martin; Hudon, Lisa; Germain Robitaille, Mathieu; Moszkowicz, Thierry; Laurendeau, Denis; Bherer, Louis; Duchesne, Simon; Hudon, Carol

    2016-01-01

    The driving performance of individuals with mild cognitive impairment (MCI) is suboptimal when compared to healthy older adults. It is expected that the driving will worsen with the progression of the cognitive decline and thus, whether or not these individuals should continue to drive is a matter of debate. The aim of the study was to provide support to the claim that individuals with MCI can benefit from a training program and improve their overall driving performance in a driving simulator. Fifteen older drivers with MCI participated in five training sessions in a simulator (over a 21-day period) and in a 6-month recall session. During training, they received automated auditory feedback on their performance when an error was noted about various maneuvers known to be suboptimal in MCI individuals (for instance, weaving, omitting to indicate a lane change, to verify a blind spot, or to engage in a visual search before crossing an intersection). The number of errors was compiled for eight different maneuvers for all sessions. For the initial five sessions, a gradual and significant decrease in the number of errors was observed, indicating learning and safer driving. The level of performance, however, was not maintained at the 6-month recall session. Nevertheless, the initial learning observed opens up possibilities to undertake more regular interventions to maintain driving skills and safe driving in MCI individuals.

  14. Long-term administration of PACAP receptor antagonist, PACAP(6-27), impairs glucose tolerance and insulin sensitivity in obese diabetic ob/ob mice.

    PubMed

    Green, Brian D; Irwin, Nigel; Cassidy, Roslyn S; Gault, Victor A; Flatt, Peter R

    2006-09-01

    Pituitary adenylate cyclase-activating peptide (PACAP) is a ubiquitous peptide of the glucagon superfamily that is involved in glucose homeostasis and regulation of insulin secretion. This study employed the PACAP receptor antagonist, PACAP(6-27) to evaluate the role of endogenous PACAP in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob mice. Acute in vivo antagonistic potency of PACAP(6-27) was confirmed in ob/ob mice by blockade of the insulin-releasing action but not hyperglycaemia. In longer-term studies, ob/ob mice were given once daily injections of PACAP(6-27) or vehicle for 14 days. Feeding activity, body weight, basal plasma glucose and plasma insulin concentrations were not significantly affected by chronic PACAP(6-27) treatment. However, PACAP(6-27) treatment impaired glucose tolerance, insulin sensitivity and the glycaemic response to feeding. Plasma glucagon and lipids were unchanged. These observations indicate a role of endogenous PACAP for normal glucose homeostasis, but indicate a minor involvement in the regulation of insulin secretion in ob/ob mice.

  15. Long-term effects of leisure time physical activity on risk of insulin resistance and impaired glucose tolerance, allowing for body weight history, in Danish men.

    PubMed

    Berentzen, T; Petersen, L; Pedersen, O; Black, E; Astrup, A; Sørensen, T I A

    2007-01-01

    To determine if the level of leisure time physical activity (LTPA) in young adulthood in obese and non-obese men reduces the risk of insulin resistance (IR) and impaired glucose tolerance (IGT) in middle age, and if such an effect is explained by the current level of LTPA, or by the body mass index (BMI) history preceding and subsequent to the assessment of LTPA. Longitudinal study of groups of obese and randomly selected non-obese men identified at around age 19, and re-examined at mean ages of 32, 44 and 51. BMI was measured at all four examinations. LTPA was assessed by self-administrated questionnaires at the last three examinations. IR and the presence of IGT was determined by an oral glucose tolerance test at the last examination. LTPA in young adulthood reduced the risk of IR and IGT in middle age throughout the range of BMI. Adjustment for the BMI history preceding and subsequent to the assessment of LTPA attenuated the association with IR and IGT, but active men remained at low risk of IR and IGT. Adjustment for subsequent and current levels of LTPA, smoking habits, alcohol intake, educational level and family history of diabetes had no notable influence on the results. LTPA appears to reduce the risk of IR and IGT, an effect which is not explained by the current level of physical activity, and only partially explained by the BMI history preceding and subsequent to the assessment of LTPA.

  16. 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.

  17. 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.

  18. 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

  19. Intermittent hypoxia during recovery from neonatal hyperoxic lung injury causes long-term impairment of alveolar development: A new rat model of BPD.

    PubMed

    Mankouski, Anastasiya; Kantores, Crystal; Wong, Mathew J; Ivanovska, Julijana; Jain, Amish; Benner, Eric J; Mason, Stanley N; Tanswell, A Keith; Auten, Richard L; Jankov, Robert P

    2017-02-01

    Bronchopulmonary dysplasia (BPD) is a chronic lung injury characterized by impaired alveologenesis that may persist into adulthood. Rat models of BPD using varying degrees of hyperoxia to produce injury either cause early mortality or spontaneously recover following removal of the inciting stimulus, thus limiting clinical relevance. We sought to refine an established rat model induced by exposure to 60% O2 from birth by following hyperoxia with intermittent hypoxia (IH). Rats exposed from birth to air or 60% O2 until day 14 were recovered in air with or without IH (FIO2 = 0.10 for 10 min every 6 h) until day 28 Animals exposed to 60% O2 and recovered in air had no evidence of abnormal lung morphology on day 28 or at 10-12 wk. In contrast, 60% O2-exposed animals recovered in IH had persistently increased mean chord length, more dysmorphic septal crests, and fewer peripheral arteries. Recovery in IH also increased pulmonary vascular resistance, Fulton index, and arterial wall thickness. IH-mediated abnormalities in lung structure (but not pulmonary hypertension) persisted when reexamined at 10-12 wk, accompanied by increased pulmonary vascular reactivity and decreased exercise tolerance. Increased mean chord length secondary to IH was prevented by treatment with a peroxynitrite decomposition catalyst [5,10,15,20-Tetrakis(4-sulfonatophenyl)-21H,23H-porphyrin iron (III) chloride, 30 mg/kg/day, days 14-28], an effect accompanied by fewer inflammatory cells. We conclude that IH during recovery from hyperoxia-induced injury prevents recovery of alveologenesis and leads to changes in lung and pulmonary vascular function lasting into adulthood, thus more closely mimicking contemporary BPD.

  20. Effects of secreted oligomers of amyloid β-protein on hippocampal synaptic plasticity: a potent role for trimers

    PubMed Central

    Townsend, Matthew; Shankar, Ganesh M; Mehta, Tapan; Walsh, Dominic M; Selkoe, Dennis J

    2006-01-01

    The accumulation of amyloid β-protein (Aβ) in brain regions serving memory and cognition is a central pathogenic feature of Alzheimer's disease (AD). We have shown that small soluble oligomers of human Aβ that are naturally secreted by cultured cells inhibit hippocampal long-term potentiation (LTP) in vitro and in vivo and transiently impair the recall of a complex learned behaviour in rats. These results support the hypothesis that diffusible oligomers of Aβ initiate a synaptic dysfunction that may be an early event in AD. We now report detailed electrophysiological analyses that define conditions under which acute application of soluble Aβ inhibits hippocampal synaptic plasticity in wild-type mice. To ascertain which Aβ assemblies contribute to the impairment of LTP, we fractionated oligomers by size-exclusion chromatography and found that Aβ trimers fully inhibit LTP, whereas dimers and tetramers have an intermediate potency. Natural Aβ oligomers are sensitive to heat denaturation, primarily inhibit the induction phase of LTP, and cause a sustained impairment of LTP even after extensive washout. We observed no effects of Aβ oligomers on presynaptic vesicle release. LTP in juvenile mice is resistant to the effects of Aβ oligomers, as is brain-derived-neurotrophic-factor-induced LTP in adult hippocampus. We conclude that specific assemblies, particularly timers, of naturally secreted Aβ oligomers are potent and selective inhibitors of certain forms of hippocampal LTP. PMID:16469784

  1. Long-term schisandrin B treatment mitigates age-related impairments in mitochondrial antioxidant status and functional ability in various tissues, and improves the survival of aging C57BL/6J mice.

    PubMed

    Ko, Kam Ming; Chen, Na; Leung, Hoi Yan; Leong, Eriol P K; Poon, Michel K T; Chiu, Po Yee

    2008-01-01

    Mitochondrial decay is a major cause of aging, leading to the subsequent death of aerobic organisms including humans. In the present study, we examined the effects of supplementation with schisandrin B (Sch B, a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis), administered at 0.012% (w/w) of diet, starting from the age of 36 weeks, on age-dependent changes in mouse mitochondrial antioxidant status and functional ability in various tissues (brain, heart, liver, and kidney) up to the age of 120 weeks. We also monitored survival of male and female C57BL/6J mice. Aging caused progressive impairment in mitochondrial antioxidant status in various tissues, as evidenced by decreases in reduced glutathione and alpha-tocopherol levels, and Mn-superoxide dismutase activity. Impairments in mitochondrial antioxidant status were invariably associated with increases in mitochondria-driven reactive oxygen species (ROS) production in tissue homogenates, as well as decreased mitochondrial ATP-generation capacities (ATP-GCs), in all tested tissues. Diet supplementation with Sch B ameliorated impairment in mitochondrial antioxidant status during aging. The effects were more pronounced in younger than in older mice, when compared to age-matched non-supplemented controls. Sch B supplementation also suppressed mitochondria-driven ROS production and enhanced mitochondrial ATP-GC in various tissues during aging. The beneficial effects of Sch B supplementation on mitochondrial antioxidant status and functional ability were paralleled by survival improvement in aging male mice, when compared with controls. Sch B supplementation also improved the survival in female mice. In conclusion, long-term Sch B supplementation mitigated age-dependent impairments in mitochondrial antioxidant capacity and functional ability, thereby retarding the aging process in mice, particularly during early aging.

  2. 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

  3. 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

  4. The amyloid-beta25-35 injection into the CA1 region of the neonatal rat hippocampus impairs the long-term memory because of an increase of nitric oxide.

    PubMed

    Díaz, Alfonso; De Jesús, Luis; Mendieta, Liliana; Calvillo, Minerva; Espinosa, Blanca; Zenteno, Edgar; Guevara, Jorge; Limón, Ilhuicamina Daniel

    2010-01-04

    Alzheimer's disease (AD) is characterized by the amyloid-beta (Abeta) aggregation but it is unclear when this process begins. Previously, we showed that amyloid-beta(25-35) (Abeta(25-35)) increases the nitric oxide (NO) pathways and causes neurodegenerative effects in rats. The excessive increase of NO during brain development can promote a persistent oxidative stress, but the role of the Abeta(25-35) in the neonatal age and its effects over the long term is unclear. Our aim was to evaluate if the Abeta(25-35) injection on postnatal day 7 causes loss in spatial memory by NO pathways in adult rats. Our results showed that neonatal-Abeta(25-35) injection into the hippocampus (Hp) causes significant impairments in the spatial memory after 90 days. The NO levels were found increased and argynophilic in the Hp. Other evidence of neuronal damage was an increase of the immunoreactivity for 3-nitrotyrosine (3-NT) and the glial-fibrilar acid protein (GFAP) in the Hp of the Abeta(25-35) group. In contrast, these effects were blocked by the administration of L-NAME (inhibitor of nitric oxide synthase) before the injection of Abeta(25-35). The L-NAME plus Abeta(25-35) group showed a better performance in the spatial memory compared to the Abeta(25-35) group. In addition in this group we found a decrease of NO, 3-NT and neurodegeneration in the Hp compared to the Abeta(25-35) group. This finding is a novel result about the role of Abeta(25-35) during the neonatal stage that enhances the NO production, which appears to impair the spatial memory in adult rats.

  5. 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

  6. 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.

  7. 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

  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. A randomized, double-blind, placebo-controlled study on long-term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the long-term ASP1941 safety evaluation in patients with type 2 diabetes with renal impairment (LANTERN) study.

    PubMed

    Kashiwagi, A; Takahashi, H; Ishikawa, H; Yoshida, S; Kazuta, K; Utsuno, A; Ueyama, E

    2015-02-01

    To assess the effects of renal impairment (RI) on the efficacy and safety of ipragliflozin in patients with type 2 diabetes mellitus (T2DM). A cohort of Japanese patients with T2DM and mild to moderate RI and poor glycaemic control, despite diet/exercise therapy alone or diet/exercise therapy in combination with an oral hypoglycaemic agent (an α-glucosidase inhibitor, a sulfonylurea, or pioglitazone), were randomized in a double-blind manner to 50 mg ipragliflozin or placebo once daily for 24 weeks. The patients continued open-label ipragliflozin for a 28-week extension period (total treatment duration: 52 weeks). Ipragliflozin significantly decreased glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels and body weight from baseline to week 24 (last observation carried forward) compared with placebo in all patients with RI. The decreases in HbA1c and FPG levels were statistically significant in patients with mild RI, but not in patients with moderate RI. Ipragliflozin significantly reduced body weight in both RI groups. The improvements in glycaemic control were maintained in the 28-week extension period. Ipragliflozin was associated with no clinically significant safety concerns, and its safety profiles were not influenced by the severity of RI. Ipragliflozin significantly improved glycaemic control and body weight in patients with T2DM with mild RI, but did not improve glycaemic control in patients with moderate RI. Ipragliflozin is a valid treatment option for patients with mild RI but not those with moderate RI. © 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  10. Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice.

    PubMed

    MacPherson, Kathryn P; Sompol, Pradoldej; Kannarkat, George T; Chang, Jianjun; Sniffen, Lindsey; Wildner, Mary E; Norris, Christopher M; Tansey, Malú G

    2017-06-01

    Clinical and animal model studies have implicated inflammation and peripheral immune cell responses in the pathophysiology of Alzheimer's disease (AD). Peripheral immune cells including T cells circulate in the cerebrospinal fluid (CSF) of healthy adults and are found in the brains of AD patients and AD rodent models. Blocking entry of peripheral macrophages into the CNS was reported to increase amyloid burden in an AD mouse model. To assess inflammation in the 5xFAD (Tg) mouse model, we first quantified central and immune cell profiles in the deep cervical lymph nodes and spleen. In the brains of Tg mice, activated (MHCII(+), CD45(high), and Ly6C(high)) myeloid-derived CD11b(+) immune cells are decreased while CD3(+) T cells are increased as a function of age relative to non-Tg mice. These immunological changes along with evidence of increased mRNA levels for several cytokines suggest that immune regulation and trafficking patterns are altered in Tg mice. Levels of soluble Tumor Necrosis Factor (sTNF) modulate blood-brain barrier (BBB) permeability and are increased in CSF and brain parenchyma post-mortem in AD subjects and Tg mice. We report here that in vivo peripheral administration of XPro1595, a novel biologic that sequesters sTNF into inactive heterotrimers, reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4(+) T cells. In addition, XPro1595 treatment in vivo rescued impaired long-term potentiation (LTP) measured in brain slices in association with decreased Aβ plaques in the subiculum. Selective targeting of sTNF may modulate brain immune cell infiltration, and prevent or delay neuronal dysfunction in AD.

  11. Influenza in long-term care facilities: preventable, detectable, treatable.

    PubMed

    Mossad, Sherif B

    2009-09-01

    Influenza in long-term care facilities is an ever more challenging problem. Vaccination of residents and health care workers is the most important preventive measure. Although vaccine efficacy has been questioned, the preponderance of data favors vaccination. Antiviral resistance complicates postexposure chemoprophylaxis and treatment. Factors that limit the choice of antiviral agents in this patient population include limited vaccine supplies and impaired dexterity and confusion in long-term care residents.

  12. Wnt signaling is required for long-term memory formation

    PubMed Central

    Tan, Ying; Yu, Dinghui; Busto, Germain U.; Wilson, Curtis; Davis, Ronald L.

    2013-01-01

    SUMMARY Wnt signaling regulates synaptic plasticity and neurogenesis in the adult nervous system, suggesting a potential role in behavioral processes. Here, we probed the requirement for Wnt signaling during olfactory memory formation in Drosophila using an inducible RNA interference approach. Interfering with β-catenin expression in the adult mushroom body neurons specifically impaired long-term memory without altering short-term memory. The impairment was reversible, rescued with expression of a wild-type β-catenin transgene, and correlated with a disruption of a cellular long-term memory trace. Inhibition of wingless, a Wnt ligand, and arrow, a Wnt co-receptor, also impaired long-term memory. Wingless expression in wild type flies was transiently elevated in the brain after long-term memory conditioning. Thus, inhibiting three key components of the Wnt signaling pathway in the adult mushroom bodies impairs long-term memory, collectively indicating that this pathway mechanistically underlies this specific form of memory. PMID:24035392

  13. β-Amyloid (Aβ) Oligomers Impair Brain-derived Neurotrophic Factor Retrograde Trafficking by Down-regulating Ubiquitin C-terminal Hydrolase, UCH-L1*

    PubMed Central

    Poon, Wayne W.; Carlos, Anthony J.; Aguilar, Brittany L.; Berchtold, Nicole C.; Kawano, Crystal K.; Zograbyan, Vahe; Yaopruke, Tim; Shelanski, Michael; Cotman, Carl W.

    2013-01-01

    We previously found that BDNF-dependent retrograde trafficking is impaired in AD transgenic mouse neurons. Utilizing a novel microfluidic culture chamber, we demonstrate that Aβ oligomers compromise BDNF-mediated retrograde transport by impairing endosomal vesicle velocities, resulting in impaired downstream signaling driven by BDNF/TrkB, including ERK5 activation, and CREB-dependent gene regulation. Our data suggest that a key mechanism mediating the deficit involves ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that functions to regulate cellular ubiquitin. Aβ-induced deficits in BDNF trafficking and signaling are mimicked by LDN (an inhibitor of UCH-L1) and can be reversed by increasing cellular UCH-L1 levels, demonstrated here using a transducible TAT-UCH-L1 strategy. Finally, our data reveal that UCH-L1 mRNA levels are decreased in the hippocampi of AD brains. Taken together, our data implicate that UCH-L1 is important for regulating neurotrophin receptor sorting to signaling endosomes and supporting retrograde transport. Further, our results support the idea that in AD, Aβ may down-regulate UCH-L1 in the AD brain, which in turn impairs BDNF/TrkB-mediated retrograde signaling, compromising synaptic plasticity and neuronal survival. PMID:23599427

  14. β-Amyloid (Aβ) oligomers impair brain-derived neurotrophic factor retrograde trafficking by down-regulating ubiquitin C-terminal hydrolase, UCH-L1.

    PubMed

    Poon, Wayne W; Carlos, Anthony J; Aguilar, Brittany L; Berchtold, Nicole C; Kawano, Crystal K; Zograbyan, Vahe; Yaopruke, Tim; Shelanski, Michael; Cotman, Carl W

    2013-06-07

    We previously found that BDNF-dependent retrograde trafficking is impaired in AD transgenic mouse neurons. Utilizing a novel microfluidic culture chamber, we demonstrate that Aβ oligomers compromise BDNF-mediated retrograde transport by impairing endosomal vesicle velocities, resulting in impaired downstream signaling driven by BDNF/TrkB, including ERK5 activation, and CREB-dependent gene regulation. Our data suggest that a key mechanism mediating the deficit involves ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that functions to regulate cellular ubiquitin. Aβ-induced deficits in BDNF trafficking and signaling are mimicked by LDN (an inhibitor of UCH-L1) and can be reversed by increasing cellular UCH-L1 levels, demonstrated here using a transducible TAT-UCH-L1 strategy. Finally, our data reveal that UCH-L1 mRNA levels are decreased in the hippocampi of AD brains. Taken together, our data implicate that UCH-L1 is important for regulating neurotrophin receptor sorting to signaling endosomes and supporting retrograde transport. Further, our results support the idea that in AD, Aβ may down-regulate UCH-L1 in the AD brain, which in turn impairs BDNF/TrkB-mediated retrograde signaling, compromising synaptic plasticity and neuronal survival.

  15. Soluble amyloid beta oligomers block the learning-induced increase in hippocampal sharp wave-ripple rate and impair spatial memory formation.

    PubMed

    Nicole, Olivier; Hadzibegovic, Senka; Gajda, Judyta; Bontempi, Bruno; Bem, Tiaza; Meyrand, Pierre

    2016-03-07

    Post-learning hippocampal sharp wave-ripples (SWRs) generated during slow wave sleep are thought to play a crucial role in memory formation. While in Alzheimer's disease, abnormal hippocampal oscillations have been reported, the functional contribution of SWRs to the typically observed spatial memory impairments remains unclear. These impairments have been related to degenerative synaptic changes produced by soluble amyloid beta oligomers (Aβos) which, surprisingly, seem to spare the SWR dynamics during routine behavior. To unravel a potential effect of Aβos on SWRs in cognitively-challenged animals, we submitted vehicle- and Aβo-injected mice to spatial recognition memory testing. While capable of forming short-term recognition memory, Aβ mice exhibited faster forgetting, suggesting successful encoding but an inability to adequately stabilize and/or retrieve previously acquired information. Without prior cognitive requirements, similar properties of SWRs were observed in both groups. In contrast, when cognitively challenged, the post-encoding and -recognition peaks in SWR occurrence observed in controls were abolished in Aβ mice, indicating impaired hippocampal processing of spatial information. These results point to a crucial involvement of SWRs in spatial memory formation and identify the Aβ-induced impairment in SWRs dynamics as a disruptive mechanism responsible for the spatial memory deficits associated with Alzheimer's disease.

  16. Soluble amyloid beta oligomers block the learning-induced increase in hippocampal sharp wave-ripple rate and impair spatial memory formation

    PubMed Central

    Nicole, Olivier; Hadzibegovic, Senka; Gajda, Judyta; Bontempi, Bruno; Bem, Tiaza; Meyrand, Pierre

    2016-01-01

    Post-learning hippocampal sharp wave-ripples (SWRs) generated during slow wave sleep are thought to play a crucial role in memory formation. While in Alzheimer’s disease, abnormal hippocampal oscillations have been reported, the functional contribution of SWRs to the typically observed spatial memory impairments remains unclear. These impairments have been related to degenerative synaptic changes produced by soluble amyloid beta oligomers (Aβos) which, surprisingly, seem to spare the SWR dynamics during routine behavior. To unravel a potential effect of Aβos on SWRs in cognitively-challenged animals, we submitted vehicle- and Aβo-injected mice to spatial recognition memory testing. While capable of forming short-term recognition memory, Aβ mice exhibited faster forgetting, suggesting successful encoding but an inability to adequately stabilize and/or retrieve previously acquired information. Without prior cognitive requirements, similar properties of SWRs were observed in both groups. In contrast, when cognitively challenged, the post-encoding and -recognition peaks in SWR occurrence observed in controls were abolished in Aβ mice, indicating impaired hippocampal processing of spatial information. These results point to a crucial involvement of SWRs in spatial memory formation and identify the Aβ-induced impairment in SWRs dynamics as a disruptive mechanism responsible for the spatial memory deficits associated with Alzheimer’s disease. PMID:26947247

  17. 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

  18. 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.

  19. Alzheimer Amyloid-β Oligomer Bound to Post-Synaptic Prion Protein Activates Fyn to Impair Neurons

    PubMed Central

    Um, Ji Won; Nygaard, Haakon B.; Heiss, Jacqueline K.; Kostylev, Mikhail A.; Stagi, Massimiliano; Vortmeyer, Alexander; Wisniewski, Thomas; Gunther, Erik C.; Strittmatter, Stephen M.

    2012-01-01

    SUMMARY Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer’s disease (AD) pathophysiology. Cellular Prion Protein (PrPC) selectively binds oligomeric Aβ and can mediate AD-related phenotypes. Here, we examined the specificity, distribution and signaling from Aβ/PrP complexes, seeking to explain how they might alter the function of NMDA receptors in neurons. PrPC is enriched in post-synaptic densities, and Aβ/PrPC interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from human AD brain interact with PrPC to activate Fyn. Aβ engagement of PrPC/Fyn signaling yields phosphorylation of the NR2B subunit of NMDA-receptors, which is coupled to an initial increase and then loss of surface NMDA-receptors. Aβ-induced LDH release and dendritic spine loss require both PrPC and Fyn, and human familial AD transgene-induced convulsive seizures do not occur in mice lacking PrPC. These results delineate an Aβ oligomer signal transduction pathway requiring PrPC and Fyn to alter synaptic function with relevance to AD. PMID:22820466

  20. Long-term Outcomes of Childhood Onset Nephrotic Syndrome

    PubMed Central

    Hjorten, Rebecca; Anwar, Zohra; Reidy, Kimberly Jean

    2016-01-01

    There are limited studies on long-term outcomes of childhood onset nephrotic syndrome (NS). A majority of children with NS have steroid-sensitive nephrotic syndrome (SSNS). Steroid-resistant nephrotic syndrome (SRNS) is associated with a high risk of developing end-stage renal disease. Biomarkers and analysis of genetic mutations may provide new information for prognosis in SRNS. Frequently relapsing and steroid-dependent NS is associated with long-term complications, including dyslipidemia, cataracts, osteoporosis and fractures, obesity, impaired growth, and infertility. Long-term complications of SSNS are likely to be under-recognized. There remain many gaps in our knowledge of long-term outcomes of childhood NS, and further study is indicated. PMID:27252935

  1. Long-term Outcomes of Childhood Onset Nephrotic Syndrome.

    PubMed

    Hjorten, Rebecca; Anwar, Zohra; Reidy, Kimberly Jean

    2016-01-01

    There are limited studies on long-term outcomes of childhood onset nephrotic syndrome (NS). A majority of children with NS have steroid-sensitive nephrotic syndrome (SSNS). Steroid-resistant nephrotic syndrome (SRNS) is associated with a high risk of developing end-stage renal disease. Biomarkers and analysis of genetic mutations may provide new information for prognosis in SRNS. Frequently relapsing and steroid-dependent NS is associated with long-term complications, including dyslipidemia, cataracts, osteoporosis and fractures, obesity, impaired growth, and infertility. Long-term complications of SSNS are likely to be under-recognized. There remain many gaps in our knowledge of long-term outcomes of childhood NS, and further study is indicated.

  2. Amyloid β oligomer-induced ERK1/2-dependent serine 636/639 phosphorylation of insulin receptor substrate-1 impairs insulin signaling and glycogen storage in human astrocytes.

    PubMed

    Zhang, Qinghua; Guo, Shougang; Zhang, Xiao; Tang, Shi; Wang, Lu; Han, Xiaojuan; Shao, Wen; Cong, Lin; Du, Yifeng

    2015-04-25

    This study is to investigate the effect of amyloid β1-42 oligomers on insulin signaling in astrocytes. Synthetic Aβ1-42 oligomers were prepared and the oligomeric form of Aβ1-42 was verified by an electron microscope. Normal human astrocytes were cultured in Dulbecco's Modified Eagle Medium. Western blotting was employed to measure the amount of lysate proteins. Immunofluorescence was performed to detect the distribution of phosphorylated insulin receptor substrate-1 and expression of P-GSK3β in astrocytes under confocal microscopy and fluorescent microscopy, respectively. Periodic Acid-Schiff staining was used to detect glycogen, the content of which was measured using glycogen assay. Our data showed that Aβ1-42 oligomers inhibited insulin-induced serine phosphorylation of Akt at 473 and GSK3β at serine 9, as well as glycogen storage. However, the levels of phosphorylated GSK3β at tyrosine 216 were significantly increased in the presence of Aβ1-42 oligomers. In addition, the levels of phosphorylated ERK1/2 and insulin receptor substrate-1 at serine 636/639 were significantly increased in response to treatment with Aβ1-42 oligomers. Of note, the responses and inhibitory effects of Aβ1-42 oligomers on insulin signaling were partially reversed by ERK1/2 upstream inhibitor PD98059. Our results demonstrated that Aβ1-42 oligomers impaired insulin signaling and suppressed insulin-induced glycogen storage in human astrocytes, probably due to ERK1/2-dependent serine phosphorylation of insulin receptor substrate-1 at 636/639 induced by Aβ1-42 oligomers. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. 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. ...

  4. Structure-dependent effects of amyloid-β on long-term memory in Lymnaea stagnalis.

    PubMed

    Ford, Lenzie; Crossley, Michael; Vadukul, Devkee M; Kemenes, György; Serpell, Louise C

    2017-05-01

    Amyloid-β (Aβ) peptides are implicated in the causation of memory loss, neuronal impairment, and neurodegeneration in Alzheimer's disease. Our recent work revealed that Aβ 1-42 and Aβ 25-35 inhibit long-term memory (LTM) recall in Lymnaea stagnalis (pond snail) in the absence of cell death. Here, we report the characterization of the active species prepared under different conditions, describe which Aβ species is present in brain tissue during the behavioral recall time point and relate the sequence and structure of the oligomeric species to the resulting neuronal properties and effect on LTM. Our results suggest that oligomers are the key toxic Aβ1-42 structures, which likely affect LTM through synaptic plasticity pathways, and that Aβ 1-42 and Aβ 25-35 cannot be used as interchangeable peptides. © 2017 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

  5. Aβ42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-β42 species and protects synaptic structure and function

    NASA Astrophysics Data System (ADS)

    Barucker, Christian; Bittner, Heiko J.; Chang, Philip K.-Y.; Cameron, Scott; Hancock, Mark A.; Liebsch, Filip; Hossain, Shireen; Harmeier, Anja; Shaw, Hunter; Charron, François M.; Gensler, Manuel; Dembny, Paul; Zhuang, Wei; Schmitz, Dietmar; Rabe, Jürgen P.; Rao, Yong; Lurz, Rudi; Hildebrand, Peter W.; McKinney, R. Anne; Multhaup, Gerhard

    2015-10-01

    The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets a relatively well-defined population of low-n Aβ42 oligomers, rather than simply inhibiting the aggregation of Aβ monomers into oligomers. Our data show that AIP diminishes the loss of Aβ42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Aβ42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically “trapping” low-n oligomers provides a novel strategy for toxic Aβ42-oligomer recognition and removal.

  6. Aβ42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-β42 species and protects synaptic structure and function.

    PubMed

    Barucker, Christian; Bittner, Heiko J; Chang, Philip K-Y; Cameron, Scott; Hancock, Mark A; Liebsch, Filip; Hossain, Shireen; Harmeier, Anja; Shaw, Hunter; Charron, François M; Gensler, Manuel; Dembny, Paul; Zhuang, Wei; Schmitz, Dietmar; Rabe, Jürgen P; Rao, Yong; Lurz, Rudi; Hildebrand, Peter W; McKinney, R Anne; Multhaup, Gerhard

    2015-10-29

    The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets a relatively well-defined population of low-n Aβ42 oligomers, rather than simply inhibiting the aggregation of Aβ monomers into oligomers. Our data show that AIP diminishes the loss of Aβ42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Aβ42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically "trapping" low-n oligomers provides a novel strategy for toxic Aβ42-oligomer recognition and removal.

  7. Aβ42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-β42 species and protects synaptic structure and function

    PubMed Central

    Barucker, Christian; Bittner, Heiko J.; Chang, Philip K.-Y.; Cameron, Scott; Hancock, Mark A.; Liebsch, Filip; Hossain, Shireen; Harmeier, Anja; Shaw, Hunter; Charron, François M.; Gensler, Manuel; Dembny, Paul; Zhuang, Wei; Schmitz, Dietmar; Rabe, Jürgen P.; Rao, Yong; Lurz, Rudi; Hildebrand, Peter W.; McKinney, R. Anne; Multhaup, Gerhard

    2015-01-01

    The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets a relatively well-defined population of low-n Aβ42 oligomers, rather than simply inhibiting the aggregation of Aβ monomers into oligomers. Our data show that AIP diminishes the loss of Aβ42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Aβ42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically “trapping” low-n oligomers provides a novel strategy for toxic Aβ42-oligomer recognition and removal. PMID:26510576

  8. 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.

  9. 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.

  10. 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.

  11. 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…

  12. 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 ...

  13. 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.

  14. The antineoplastic drug flavopiridol reverses memory impairment induced by Amyloid-ß1-42 oligomers in mice.

    PubMed

    Leggio, Gian Marco; Catania, Maria Vincenza; Puzzo, Daniela; Spatuzza, Michela; Pellitteri, Rosalia; Gulisano, Walter; Torrisi, Sebastiano Alfio; Giurdanella, Giovanni; Piazza, Cateno; Impellizzeri, Agata Rita; Gozzo, Lucia; Navarria, Andrea; Bucolo, Claudio; Nicoletti, Ferdinando; Palmeri, Agostino; Salomone, Salvatore; Copani, Agata; Caraci, Filippo; Drago, Filippo

    2016-04-01

    The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer's disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of Aß1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of Aβ-injected mice, paralleling memory deficits. Starting from three days after Aβ injection, flavopiridol (0.5, 1 and 3mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1mg/kg) was able to rescue the loss of memory induced by Aβ1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.

  15. 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.

  16. [Renal side effects of long-term lithium therapy].

    PubMed

    Ibbeken, C; Becker, J U; Baumgärtel, M W

    2012-01-01

    Lithium is widely used in the treatment of bipolar disorders. Long-term administration of lithium often leads to side effects concerning the subjects: nephrology, endocrinology and surgery. This review emphasizes nephrotoxicity.Lithium treatment may disturb responsiveness to antidiuretic hormone (ADH), causing a nephrogenic diabetes insipidus. Furthermore long-term lithium therapy may trigger hyperparathyreoidism with hypercalcemia and chronic interstitial nephritis with development of microcysts. Long-term patients have an increased risk to develop impaired renal function. Lithium-induced endstage renal disease is rare. Termination of lithium treatment may decrease the risk of progression.To ensure security of lithium treatment regular controls of urine osmolarity, lithium-, creatinine- , thyroid stimulating hormone- and calcium-levels are essential. Patients with decreased renal function should be referred to a specialist early.

  17. [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.

  18. 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

  19. 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.

  20. Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models.

    PubMed

    Kostylev, Mikhail A; Kaufman, Adam C; Nygaard, Haakon B; Patel, Pujan; Haas, Laura T; Gunther, Erik C; Vortmeyer, Alexander; Strittmatter, Stephen M

    2015-07-10

    Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrP(C))-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrP(C)-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrP(C) expression in mice with relatively low PrP(C)-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP(C)-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD.

  1. Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models*

    PubMed Central

    Kostylev, Mikhail A.; Kaufman, Adam C.; Nygaard, Haakon B.; Patel, Pujan; Haas, Laura T.; Gunther, Erik C.; Vortmeyer, Alexander; Strittmatter, Stephen M.

    2015-01-01

    Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrPC)-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrPC-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrPC expression in mice with relatively low PrPC-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrPC-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD. PMID:26018073

  2. 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…

  3. 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…

  4. 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…

  5. 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.

  6. 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

  7. The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to β-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment.

    PubMed

    Ostapchenko, Valeriy G; Chen, Megan; Guzman, Monica S; Xie, Yu-Feng; Lavine, Natalie; Fan, Jue; Beraldo, Flavio H; Martyn, Amanda C; Belrose, Jillian C; Mori, Yasuo; MacDonald, John F; Prado, Vania F; Prado, Marco A M; Jackson, Michael F

    2015-11-11

    In Alzheimer's disease, accumulation of soluble oligomers of β-amyloid peptide is known to be highly toxic, causing disturbances in synaptic activity and neuronal death. Multiple studies relate these effects to increased oxidative stress and aberrant activity of calcium-permeable cation channels leading to calcium imbalance. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca(2+)-permeable nonselective cation channel activated by oxidative stress, has been implicated in neurodegenerative diseases, and more recently in amyloid-induced toxicity. Here we show that the function of TRPM2 is augmented by treatment of cultured neurons with β-amyloid oligomers. Aged APP/PS1 Alzheimer's mouse model showed increased levels of endoplasmic reticulum stress markers, protein disulfide isomerase and phosphorylated eukaryotic initiation factor 2α, as well as decreased levels of the presynaptic marker synaptophysin. Elimination of TRPM2 in APP/PS1 mice corrected these abnormal responses without affecting plaque burden. These effects of TRPM2 seem to be selective for β-amyloid toxicity, as ER stress responses to thapsigargin or tunicamycin in TRPM2(-/-) neurons was identical to that of wild-type neurons. Moreover, reduced microglial activation was observed in TRPM2(-/-)/APP/PS1 hippocampus compared with APP/PS1 mice. In addition, age-dependent spatial memory deficits in APP/PS1 mice were reversed in TRPM2(-/-)/APP/PS1 mice. These results reveal the importance of TRPM2 for β-amyloid neuronal toxicity, suggesting that TRPM2 activity could be potentially targeted to improve outcomes in Alzheimer's disease. Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress sensing calcium-permeable channel that is thought to contribute to calcium dysregulation associated with neurodegenerative diseases, including Alzheimer's disease. Here we show that oligomeric β-amyloid, the toxic peptide in Alzheimer's disease, facilitates TRPM2 channel activation. In mice

  8. Short and Long-Term Outcomes for Extremely Preterm Infants

    PubMed Central

    Patel, Ravi Mangal

    2016-01-01

    Prematurity is the leading cause of infant mortality worldwide. In developed countries, extremely preterm infants contribute disproportionately to both neonatal and infant mortality. Survival of this high-risk population has incrementally improved in recent years. Despite these improvements, approximately 1 in 4 extremely preterm infants dies during the birth hospitalization. Among those who survive, respiratory and other morbidities are common, although their effect on quality of life is variable. In addition, long-term neurodevelopmental impairment is a large concern for patients, clinicians and families. However, the interplay of multiple factors contribute to neurodevelopmental impairment, with measures that change over time and outcomes that can be difficult to define and predict. Understanding outcomes of extremely preterm infants can help better counsel families regarding antenatal and postnatal care and guide strategies to improve survival without morbidity. This review summarizes recent evidence to provide an overview into the short- and long-term outcomes for extremely preterm infants. PMID:26799967

  9. 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.

  10. Post-Training Intrahippocampal Inhibition of Class I Histone Deacetylases Enhances Long-Term Object-Location Memory

    ERIC Educational Resources Information Center

    Hawk, Joshua D.; Florian, Cedrick; Abel, Ted

    2011-01-01

    Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance…

  11. Post-Training Intrahippocampal Inhibition of Class I Histone Deacetylases Enhances Long-Term Object-Location Memory

    ERIC Educational Resources Information Center

    Hawk, Joshua D.; Florian, Cedrick; Abel, Ted

    2011-01-01

    Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance…

  12. Long-term neurotoxic effects of dimethylamine borane intoxication.

    PubMed

    Liu, Chi-Hung; Wang, Hsuan-Min; Lin, Kun-Ju; Kuo, Hung-Chou; Weng, Yi-Hsin; Shih, Tung-Sheng; Huang, Chin-Chang

    2012-08-15

    To investigate the long-term neurotoxic effects in a patient with acute dimethylamine borane (DMAB) intoxication. A 38-year-old man, working in a semiconductor factory, with acute DMAB intoxication presented with confusion, and drowsiness, followed by cognitive impairments and motor-predominant axonal polyneuropathy. We performed serial neurobehavioral assessments and functional neuroimaging studies, including brain (99m)Tc-TRODAT single photon emission computed tomography (SPECT) and brain positron emission tomography (PET) scan to monitor the long-term central nervous system (CNS) effects of DMAB intoxication. Neurobehavioral tests revealed a persistent impairment in episodic memory of visual retention semantic category retrieval and working memory of digit span (backward). Brain (99m)Tc-TRODAT SPECT scan showed a lower radioactivity uptake in the left striatum and F-18 FDG PET scan revealed a relatively decreased cerebral metabolism at the anterior cingulate gyrus and both frontal regions. Follow-up neurobehavioral tests showed that the cognitive improvements were mainly documented in intelligence, attention function, conceptual shift, perceptual motor speed, verbal learning and working memory but were limited in visual memory and executive functions. Patients with acute DMAB intoxication may have a long-lasting CNS toxicity on the cognitive dysfunction, parkinsonism, and an impaired metabolic activity of the brain. Clinical improvements may sustain during the long-term follow-up period. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin

    PubMed Central

    Chang, Lan; Cui, Wei; Yang, Yong; Xu, Shujun; Zhou, Wenhua; Fu, Hongjun; Hu, Shengquan; Mak, Shinghung; Hu, Juwei; Wang, Qin; Pui-Yan Ma, Victor; Chung-lit Choi, Tony; Dik-lung Ma, Edmond; Tao, Liang; Pang, Yuanping; Rowan, Michael J.; Anwyl, Roger; Han, Yifan; Wang, Qinwen

    2015-01-01

    β-amyloid (Aβ) oligomers have been closely implicated in the pathogenesis of Alzheimer’s disease (AD). We found, for the first time, that bis(heptyl)-cognitin, a novel dimeric acetylcholinesterase (AChE) inhibitor derived from tacrine, prevented Aβ oligomers-induced inhibition of long-term potentiation (LTP) at concentrations that did not interfere with normal LTP. Bis(heptyl)-cognitin also prevented Aβ oligomers-induced synaptotoxicity in primary hippocampal neurons. In contrast, tacrine and donepezil, typical AChE inhibitors, could not prevent synaptic impairments in these models, indicating that the modification of Aβ oligomers toxicity by bis(heptyl)-cognitin might be attributed to a mechanism other than AChE inhibition. Studies by using dot blotting, immunoblotting, circular dichroism spectroscopy, and transmission electron microscopy have shown that bis(heptyl)-cognitin altered Aβ assembly via directly inhibiting Aβ oligomers formation and reducing the amount of preformed Aβ oligomers. Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of Aβ, which confers stabilizing powers and assembly alteration effects on Aβ. Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of Aβ oligomers in mice. These results clearly demonstrated how dimeric agents prevent Aβ oligomers-induced synaptic and memory impairments, and offered a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD. PMID:26194093

  14. 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, ...

  15. 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)

  16. 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 ...

  17. 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.

  18. Enhanced Long-Term and Impaired Short-Term Spatial Memory in GluA1 AMPA Receptor Subunit Knockout Mice: Evidence for a Dual-Process Memory Model

    ERIC Educational Resources Information Center

    Sanderson, David J.; Good, Mark A.; Skelton, Kathryn; Sprengel, Rolf; Seeburg, Peter H.; Rawlins, J. Nicholas P.; Bannerman, David M.

    2009-01-01

    The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of…

  19. Enhanced Long-Term and Impaired Short-Term Spatial Memory in GluA1 AMPA Receptor Subunit Knockout Mice: Evidence for a Dual-Process Memory Model

    ERIC Educational Resources Information Center

    Sanderson, David J.; Good, Mark A.; Skelton, Kathryn; Sprengel, Rolf; Seeburg, Peter H.; Rawlins, J. Nicholas P.; Bannerman, David M.

    2009-01-01

    The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of…

  20. 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.

  1. 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

  2. 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.

  3. Long-term follow-up of congenital diaphragmatic hernia.

    PubMed

    Hollinger, Laura E; Harting, Matthew T; Lally, Kevin P

    2017-06-01

    Increased survival of patients with congenital diaphragmatic hernia has created a unique cohort of children, adolescent, and adult survivors with complex medical and surgical needs. Disease-specific morbidities offer the opportunity for multiple disciplines to unite together to provide long-term comprehensive follow-up, as well as an opportunity for research regarding late outcomes. These children can exhibit impaired pulmonary function, altered neurodevelopmental outcomes, nutritional insufficiency, musculoskeletal changes, and specialized surgical needs that benefit from regular monitoring and intervention, particularly in patients with increased disease severity. Below we aim to characterize the specific challenges that these survivors face as well as present an algorithm for a multidisciplinary long-term follow-up program. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Chronic traumatic encephalopathy and other long-term sequelae.

    PubMed

    Jordan, Barry D

    2014-12-01

    Growing public health concern exists over the incidence of chronic traumatic brain injury (TBI) in athletes participating in contact sports. Chronic TBI represents a spectrum of disorders associated with long-term consequences of single or repetitive TBI and includes chronic traumatic encephalopathy (CTE), chronic postconcussion syndrome, and chronic neurocognitive impairment. Neurologists should be familiar with the different types of chronic TBI and their diagnostic criteria. CTE is the most severe chronic TBI and represents the neurologic consequences of repetitive mild TBI. It is particularly noted among boxers and football players. CTE presents with behavioral, cognitive, and motor symptoms, and can only be definitively diagnosed postmortem. Chronic postconcussion syndrome is defined as postconcussion symptoms that last longer than 1 year and do not appear to resolve; it may develop after a single concussive event. Chronic neurocognitive impairment is an all-encompassing clinical term denoting long-term neurologic sequelae secondary to sports-related trauma and can present either within the postconcussion syndrome or years after a symptom-free interval. This article discusses the diagnostic evaluation of chronic TBI, including clinical history, neurologic examination, neuropsychological testing, neuroimaging, and laboratory testing, as well as the distinctions between CTE, chronic postconcussion syndrome, and chronic neurocognitive impairment. Neurologic impairment among athletes exposed to repetitive brain injury appears to be a real phenomenon. Because CTE has no established treatment, prevention is of paramount importance for athletes participating in contact sports.

  5. Pulmonary complications after long term amiodarone treatment.

    PubMed Central

    Roca, J; Heras, M; Rodriguez-Roisin, R; Magriñà, J; Xaubet, A; Sanz, G

    1992-01-01

    BACKGROUND: Amiodarone hydrochloride is an antiarrhythmic agent useful in arrhythmias refractory to standard therapy. Although interstitial pneumonitis is known to be its most serious side effect, several aspects of amiodarone lung toxicity are still controversial. METHODS: Pulmonary side effects were examined in a sample of 61 symptomless patients (mean (SD) age 55 (7) years) who had had long term treatment with amiodarone (daily maintenance dose 400 mg), selected from 482 men attending the University of Barcelona myocardial infarction project. To allow for the confounding effects of coronary artery disease and tobacco history on lung function, 46 patients who had taken amiodarone for more than one year were matched with a control group from the same population. Subjects underwent measurement of lung volumes, arterial blood gas analysis and an incremental bicycle exercise test. RESULTS: Most lung function values were close to predicted values, though there was a small increase in resting alveolar-arterial oxygen tension difference (A-aDO2) at rest (4.8 (1.4) kPa in both groups). There were no differences in the results of forced spirometry or static lung volumes between the two groups, or in the fall in A-aDO2 from rest to exercise. There was a small difference between the amiodarone and the control group in transfer factor for carbon monoxide corrected for lung volume (KCO 1.67 (0.3) and 1.83 (0.3) mmol min-1 kPa-1 l-1 respectively) and in exercise capacity (140 (25) and 120 (30)w). Only three patients showed lung function impairment consistent with pneumonitis. No relation between lung function measures and cumulative doses of amiodarone or desethylamiodarone was found. CONCLUSIONS: The prevalence of clinically evident pulmonary side effects was 4.9%, which is lower than that reported in studies in which higher daily maintenance doses of amiodarone were given. The slightly lower KCO values and lower work load achieved by the patients taking amiodarone suggest a

  6. 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

  7. 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.

  8. 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

  9. 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

  10. [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.

  11. 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

  12. Long-Term Dietary Supplementation with Selenium-Enriched Yeast Improves Cognitive Impairment, Reverses Synaptic Deficits, and Mitigates Tau Pathology in a Triple Transgenic Mouse Model of Alzheimer's Disease.

    PubMed

    Zhang, Zhong-Hao; Wen, Lei; Wu, Qiu-Yan; Chen, Chen; Zheng, Rui; Liu, Qiong; Ni, Jia-Zuan; Song, Guo-Li

    2017-06-21

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multiple histopathological changes in the brain and by impairments in memory and cognitive function. Currently, there is no effective treatment that can halt or reverse the progression of this disease. Here, we explored the effects of 3 months of treatment with selenium-enriched yeast (Se-yeast), which is commonly used as a source of organic selenium (Se) for nutrition, on cognitive dysfunction and neuropathology in the triple transgenic mouse model of AD (3×Tg-AD mice). As the results revealed that Se-yeast significantly improved the spatial learning and memory retention of 3×Tg-AD mice, promoted neuronal activity, attenuated the activation of astrocytes and microglia, mitigated synaptic deficits, and reduced the levels of total tau and phosphorylated tau though inhibiting the activity of GSK-3β, dietary supplementation with Se-yeast exerted multiple beneficial effects on the prevention or treatment of AD. These findings provide evidence of a potentially viable compound for AD treatment.

  13. 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…

  14. 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…

  15. 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…

  16. 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…

  17. 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.

  18. 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…

  19. 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...

  20. 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…

  1. 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…

  2. 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…

  3. 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...

  4. 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,…

  5. 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.

  6. 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...

  7. 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)

  8. 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.

  9. 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.

  10. 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.

  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 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,…

  13. 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…

  14. 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.

  15. 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…

  16. 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…

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. Outcomes of long-term audiological rehabilitation in charge syndrome.

    PubMed

    Trevisi, P; Ciorba, A; Aimoni, C; Bovo, R; Martini, A

    2016-06-01

    The aim of this paper is to assess the long-term audiological features and outcomes of hearing rehabilitation in a large group of individuals with CHARGE Syndrome. The study has been conducted retrospectively, on a paediatric patient database, at the Audiology Department of the University Hospitals of Ferrara and Padua. The study sample included 31 children presenting with different degrees of hearing impairment associated with CHARGE syndrome. Hearing was assessed using auditory brainstem responses (ABRs) and/or electrocochleography, or conditioned audiometry (visual reinforcement audiometry [VRA] or play audiometry). Auditory-perceptual outcomes in terms of communication skills and expressive language were also recorded. The effects of hearing rehabilitation (with hearing aids or cochlear implants) in this group of children and language outcomes after rehabilitation were monitored during long-term follow-up. The outcomes of rehabilitation measures differed in relation to the heterogeneous and often severe disabilities associated with CHARGE syndrome, e.g. developmental delay, intellectual delay, visual impairment, thin 8(th) nerve with retrocochlear auditory dysfunction (as described in cases of auditory neuropathy/dyssynchrony). Oral expressive language was severely impaired in most cases, even after lengthy follow-up, suggesting the need for alternative augmentative communication modes. The early identification of sensorineural hearing loss, and carefully planned rehabilitation treatments, can be of some benefit in children with CHARGE syndrome.

  2. Role of skeletal muscle-fibre type in regulation of glucose metabolism in middle-aged subjects with impaired glucose tolerance during a long-term exercise and dietary intervention.

    PubMed

    Venojärvi, M; Puhke, R; Hämäläinen, H; Marniemi, J; Rastas, M; Rusko, H; Nuutila, P; Hänninen, O; Aunola, S

    2005-11-01

    The aim of this study was to investigate the role of skeletal muscle fibre type in the regulation of glucose metabolism in middle-aged obese subjects with impaired glucose tolerance (IGT) during a 2-year exercise and dietary intervention. Muscle biopsies (musculus vastus lateralis) were taken from 22 subjects belonging to the intervention group of the Finnish Diabetes Prevention Study [1]. According to their myosin heavy chain (MHC) profile at the baseline, the subjects were divided into two groups: IGT(slow) (n=10) with a high proportion of MHC I isoforms and IGT(fast) (n=12) with a high proportion of MHC II isoforms in the vastus lateralis muscle. The intervention consisted of dietary counselling, strength and power training and/or aerobic exercise. The amount of exercise was the same in both groups; the exercise frequency was 5.1+/-2.7 h/week in the IGT(slow) and 5.1+/-2.8 h/week in the IGT(fast) group. Fasting glucose (p<0.05), 2-h glucose (p<0.05), fasting insulin (p<0.05), haemoglobin A1c (HbA(1c)) (p<0.01) and insulin resistance (p<0.05) [homeostasis model assessment for insulin resistance (HOMA-IR)] decreased in the IGT(fast) group, whereas only the 2-h glucose and HbA(1c) concentrations decreased in the IGT(slow) group. The amount of the glycogen synthase kinase-3-alphabeta (GSK-3-alphabeta) decreased in the IGT(fast) group (p<0.05). Exercise training increased the lactate dehydrogenase (LDH) (p<0.01), LDH-1 (p<0.05) and citrate synthase (CS) (p<0.05) activities in the vastus lateralis muscle in the IGT(slow) group, but only the CS activity (p<0.05) in the IGT(fast) group. The glucose metabolism improved both in the IGT(slow) and IGT(fast) group during the 2-year exercise and dietary intervention. The change was more prominent in the IGT(fast) group than in the IGT(slow) group, associated with the decrease of the GSK-alphabeta protein expression in skeletal muscle. The exercise training improved both glycolytic and oxidative capacity in the vastus

  3. Long-term memory deficits in temporal lobe epilepsy.

    PubMed

    Tramoni-Negre, E; Lambert, I; Bartolomei, F; Felician, O

    Memory complaints and deficits are common in patients with epilepsy, especially temporal lobe epilepsy (TLE), where memory-related brain structures are directly involved in the epileptic process. In recent years, substantial progress has been made in delineating memory impairment in TLE, challenging the traditional neuropsychological approach of the disorder. In particular, several lines of evidence have suggested that, beyond the apparent deficit demonstrable by standardized neuropsychological evaluations, TLE may also negatively interact with long-term memory, producing considerable loss of information of the patient's autobiographical history and an inability to maintain newly acquired information over a period of time. These observations have led to the development of innovative assessment techniques, and prompted a new domain of investigation focused on the relationships between interictal epileptiform activities and the integrity of anatomo-functional systems. The present paper reviews the available evidence for long-term memory deficits in TLE with respect to remote and very long-term memory, and discusses their putative pathophysiological mechanisms and the developing potential strategies to improve memory functioning. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Predicting long-term sickness absence from sleep and fatigue.

    PubMed

    Akerstedt, Torbjorn; Kecklund, Goran; Alfredsson, Lars; Selen, Jan

    2007-12-01

    Disturbed or shortened sleep is prospectively related to disease. One might also expect that sickness absence would be another consequence but very little data seem to exist. The present study used 8300 individuals in a national sample to obtain information on reports of disturbed sleep and fatigue one [corrected] year and merged this with data on long-term sickness absence two [corrected] years later. A logistic regression analysis was applied to the data with adjustments for demographic and work environment variables. The results showed that individuals without registered sickness absence at the start had a higher probability of entering a period of long-term (>/=90 days, odds ratio [OR] = 1.24 with 95% Confidence Interval [CI] = 1.09[corrected]-2.18[corrected]) sickness absence two [corrected] years later if they reported disturbed sleep at the start. The value [corrected] for fatigue was OR = 1.69[corrected] (CI = 1.23[corrected]-2.33[corrected]). When fatigue or disturbed sleep was separately excluded the OR increased to OR = 1.90[corrected] and OR = 1.86[corrected], respectively. Intermediate sickness absence (14-89 days) showed similar but slightly weaker results. The results indicate that disturbed sleep and fatigue are predictors of long-term absence and it is suggested that impaired sleep may be part of a chain of causation, considering its effects on fatigue.

  5. 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

  6. Phenylethynyl terminated imide oligomers

    NASA Technical Reports Server (NTRS)

    Hergenrother, Paul M. (Inventor); Bryant, Robert G. (Inventor); Jensen, Brian J. (Inventor); Havens, Stephen J. (Inventor)

    1995-01-01

    Four phenylethynyl amine compounds - 3 and 4-aminophenoxy-4'-phenylethynylbenzophenone, and 3 and 4-amino-4'-phenylethynylbenzophenone - were readily prepared and were used to endcap imide oligomers. Phenylethynyl-terminated amide acid oligomers and phenylethynyl-terminated imide oligomers with various molecular weights and compositions were prepared and characterized. These oligomers were cured at 300 to 400 C to provide crosslinked polyimides with excellent solvent resistance, high strength and modulus, and good high temperature properties. Adhesive panels, composites, films, and moldings from these phenylethynyl terminated imide oligomers gave excellent mechanical performance.

  7. Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis.

    PubMed

    Barker, Melinda J; Greenwood, Kenneth M; Jackson, Martin; Crowe, Simon F

    2004-04-01

    Despite the widespread prescribing of benzodiazepines, uncertainty still surrounds the potential for cognitive impairment following their long-term use. Furthermore, the degree of recovery that may take place after withdrawal or the level of residual impairment, if any, that is maintained in long-term benzodiazepine users is also unclear. The current paper employed meta-analytic techniques to address two questions: (1) Does the cognitive function of long-term benzodiazepine users improve following withdrawal? (2) Are previous long-term benzodiazepine users still impaired at follow-up compared to controls or normative data? Results of the meta-analyses indicated that long-term benzodiazepine users do show recovery of function in many areas after withdrawal. However, there remains a significant impairment in most areas of cognition in comparison to controls or normative data. The findings of this study highlight the problems associated with long-term benzodiazepine therapy and suggest that previous benzodiazepine users would be likely to experience the benefit of improved cognitive functioning after withdrawal. However, the reviewed data did not support full restitution of function, at least in the first 6 months following cessation and suggest that there may be some permanent deficits or deficits that take longer than 6 months to completely recover.

  8. 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.

  9. 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.

  10. 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.

  11. [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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Evaluation of Long-Term Migration Testing from Can Coatings into Food Simulants: Polyester Coatings.

    PubMed

    Paseiro-Cerrato, Rafael; Noonan, Gregory O; Begley, Timothy H

    2016-03-23

    FDA guidance for food contact substances recommends that for food packaging intended for use at sterilized, high temperature processed, or retorted conditions, a migration test with a retort step at 121 °C for 2 h followed by a 10 day migration test at 40 °C should be performed. These conditions are in intended to simulate processing and long-term storage. However, can coatings may be in contact with food for years, and there are very few data evaluating if this short-term testing accurately simulates migration over extended time periods. A long-term migration test at 40 °C with retorted and non-retorted polyester cans using several food simulants (water, 3% acetic acid, 10% ethanol, 50% ethanol, and isooctane) was conducted to verify whether traditional migration testing protocols accurately predict migration from food contact materials used for extended time periods. Time points were from 1 day to 515 days. HPLC-MS/MS was used to analyze polyester monomers, and oligomer migration was monitored using HPLC-DAD/CAD and HPLC-MS. Concentrations of monomers and oligomers increased during the migration experiments, especially in ethanol food simulants. The data suggest that current FDA migration protocols may need to be modified to address changes in migrants as a result of long-term storage conditions.

  3. Working Memory, Long-Term Memory, and Medial Temporal Lobe Function

    ERIC Educational Resources Information Center

    Jeneson, Annette; Squire, Larry R.

    2012-01-01

    Early studies of memory-impaired patients with medial temporal lobe (MTL) damage led to the view that the hippocampus and related MTL structures are involved in the formation of long-term memory and that immediate memory and working memory are independent of these structures. This traditional idea has recently been revisited. Impaired performance…

  4. Working Memory, Long-Term Memory, and Medial Temporal Lobe Function

    ERIC Educational Resources Information Center

    Jeneson, Annette; Squire, Larry R.

    2012-01-01

    Early studies of memory-impaired patients with medial temporal lobe (MTL) damage led to the view that the hippocampus and related MTL structures are involved in the formation of long-term memory and that immediate memory and working memory are independent of these structures. This traditional idea has recently been revisited. Impaired performance…

  5. Long-term disability due to guinea worm disease.

    PubMed

    Hours, M; Cairncross, S

    1994-01-01

    The village-based surveillance system for guinea worm disease (dracunculiasis), which has been established in all endemic villages in Ghana, was used to carry out a retrospective study of long-term disability due to the disease. A sample of 195 cases was interviewed and examined, 12-18 months after emergence of the worm. Currently continuing pain when walking or working, attributable by its location and date of onset to the episode of dracunculiasis, was reported by 55 persons (28.2%). Some difficulty in performing at least one of 6 everyday physical activities, attributable after careful interview to the episode, was reported by 66 respondents (34.0%), of whom 10 (5.1%) were unable to carry out one of the activities. In one case, the disease had caused impairment of movement of the joints of the right thumb. The prevalence of serious permanent physical impairment among the cases in the study was thus 0.5%.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Perinatal alcohol exposure in rat induces long-term depression of respiration after episodic hypoxia.

    PubMed

    Kervern, Myriam; Dubois, Christophe; Naassila, Mickael; Daoust, Martine; Pierrefiche, Olivier

    2009-04-01

    Little is known about the effects of alcohol exposure during pregnancy, which is responsible for fetal alcohol syndrome and the respiratory network functions, especially respiratory network plasticity (e.g., long-term facilitation) elicited after repeated short-lasting hypoxic episodes. The mechanism of induction of respiratory long-term facilitation involves 5-HT(2A/2C) receptors, which also participate in the response to hypoxia. Because fetal alcohol exposure is known to reduce serotonin centrally, and synaptic plasticity in the hippocampus, we hypothesized that alcohol exposure during gestation might impair respiratory long-term facilitation after hypoxic episodes. To analyze the effects of prenatal and postnatal alcohol exposure on respiratory long-term facilitation in 5- to 7-day-old rats. Respiratory frequency and amplitude were measured in vivo and in an in vitro rhythmic medullary slice before and after three hypoxia episodes or three applications of a 5-HT(2A/2C) receptor agonist in vitro. 5-HT(2A/2C) receptor mRNA was measured from the slice. Alcohol exposure impaired respiratory long-term facilitation and induced long-term depression of respiration in both in vivo and in vitro models. Alcohol altered 5-HT(2A/2C) mRNA expression, although 5-HT(2A/2C) agonist efficacy was not altered in increasing rhythmic activity in slices. However, a higher concentration of 5-HT(2A/2C) agonist was necessary to induce transient facilitation in slices from ethanol-exposed animals, suggesting disturbances in induction and maintenance mechanisms of respiratory long-term facilitation. Respiratory facilitation after repeated hypoxia was converted to long-term depression in rats treated with alcohol in utero. Alcohol exposure during pregnancy may therefore induce long-term maladaptive behavior of the respiratory system in neonates.

  17. 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.

  18. 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

  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. Long-term outcome of abusive head trauma.

    PubMed

    Chevignard, Mathilde P; Lind, Katia

    2014-12-01

    Abusive head trauma is a severe inflicted traumatic brain injury, occurring under the age of 2 years, defined by an acute brain injury (mostly subdural or subarachnoidal haemorrhage), where no history or no compatible history with the clinical presentation is given. The mortality rate is estimated at 20-25% and outcome is extremely poor. High rates of impairments are reported in a number of domains, such as delayed psychomotor development; motor deficits (spastic hemiplegia or quadriplegia in 15-64%); epilepsy, often intractable (11-32%); microcephaly with corticosubcortical atrophy (61-100%); visual impairment (18-48%); language disorders (37-64%), and cognitive, behavioral and sleep disorders, including intellectual deficits, agitation, aggression, tantrums, attention deficits, memory, inhibition or initiation deficits (23-59%). Those combined deficits have obvious consequences on academic achievement, with high rates of special education in the long term. Factors associated with worse outcome include demographic factors (lower parental socioeconomic status), initial severe presentation (e.g., presence of a coma, seizures, extent of retinal hemorrhages, presence of an associated cranial fracture, extent of brain lesions, cerebral oedema and atrophy). Given the high risk of severe outcome, long-term comprehensive follow-up should be systematically performed to monitor development, detect any problem and implement timely adequate rehabilitation interventions, special education and/or support when necessary. Interventions should focus on children as well as families, providing help in dealing with the child's impairment and support with psychosocial issues. Unfortunately, follow-up of children with abusive head trauma has repeatedly been reported to be challenging, with very high attrition rates.

  12. Adults with VATER association: long-term prognosis.

    PubMed

    Wheeler, Patricia G; Weaver, David D

    2005-10-15

    VATER "association" is a common condition, with the diagnosis typically based on a characteristic constellation of congenital anomalies. Reported long-term follow-up information on VATER association is limited, thus making it difficult to prognosticate the future of infants and children with this condition. Further, there are few data on how often the initial diagnosis of VATER association is correct. Some information has been published on growth deficiency and mental retardation, but these data are minimal [Bull et al., 1985; Mapstone et al., 1986; Weaver et al., 1986] and for the most part look at children under the age of 10 years. We have undertaken a long-term follow-up of individuals with VATER association originally reported by Weaver et al. [1986] or diagnosed with VATER association by his associates and him after 1986. Out of the 50 patients, we were able to contact 20 individuals or families. Two of the 20 individuals had died: 1 at 3 days with cardiac failure due to a truncus arteriosus, and 1 at 4 years of unspecified cause. Two were unwilling to participate. Of the rest, we interviewed and examined seven persons, and interviewed another nine by telephone. Of the 16, 5 had some degree of cognitive impairment. These individuals were more likely to have congenital anomalies outside of the typical scope of VATER association, such as prune belly sequence or findings of CHARGE association. Of the nine individuals with a history of imperforate anus, five had partial or complete incontinence as adults leading to difficulties in maintaining employment. Height was at the 5th centile or less in 6 of 16 patients. Three of four patients who were trying to have children, had infertility. In two women, the infertility was thought to be related to congenital anomalies of the genitourinary system and multiple pelvic operations. We also present the long-term medical and neurologic problems in these individuals.

  13. 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

  14. Surgical treatment of bronchiectasis: early and long-term results.

    PubMed

    Giovannetti, Riccardo; Alifano, Marco; Stefani, Alessandro; Legras, Antoine; Grigoroiu, Madalina; Collet, Jean-Yves; Magdelenat, Pierre; Regnard, Jean-François

    2008-08-01

    Management of bronchiectasis remains controversial and information on long-term results of surgical treatment is poor. Clinical records of 45 patients, who underwent surgery for bronchiectasis in an 8-year period, were retrospectively reviewed. Bronchiectasis focus was isolated in 24 cases, associated with a limited homolateral or controlateral focus in 9 and 11, respectively; two patients had bilateral evident foci. Bronchiectasis was responsible for lobe destruction in 23 cases. All patients had symptoms: haemoptysis (n=7), recurrent pneumonia (n=7), persistent bronchorrea with recurrent infection (n=15), hemoptysis and recurrent infection (n=16). A total of 23 lobectomies, 11 lobectomies+segmentectomies, 2 bi-lobectomies, 9 segmentectomies and 1 pneumonectomy were carried out. There were no perioperative deaths; complications occurred in 5 patients (postoperative pneumonia in 2, prolonged air-leak, residual air-space and bronchial infection 1 each). Symptoms disappeared in 32 patients, 10 patients experienced a significant improvement. Exercise tolerance remained stable or improved in 33 and 2 cases, respectively, a slight impairment was observed in 9. Out of 32 evaluable patients 11 had an unchanged FEV(1), 15 had a limited FEV(1) lowering (<15%), and 9 had a more important functional loss. Surgical treatment of bronchiectasis obtains satisfactory long-term results, with acceptable morbidity rates.

  15. Simulated long-term driving performance before and after uvulopalatopharyngoplasty.

    PubMed

    Haraldsson, P O; Carenfelt, C; Persson, H E; Sachs, C; Törnros, J

    1991-01-01

    To investigate whether automobile drivers with the clinical features of sleep apnea syndrome (SAS) perform worse than controls in a simulated long-term test drive, and to see if their driving improves after uvulopalatopharyngoplasty (UPPP), 15 male drivers with SAS, suffering from sleep spells whilst driving, and 10 matched controls without a history of SAS or hypersomnia at the wheel were tested in an advanced driving simulator. Brake reaction time, lateral position deviation and off-road episodes were measured during a 90-min rural drive at twilight conditions. The clinical evaluation was made by a questionnaire scoring symptoms of snoring, sleep disturbances and diurnal sleepiness before and after surgery. Before UPPP the patient group showed impaired performance in all three effect measures compared to controls. UPPP resulted in improved reaction time performance (average mean improvement: 0.5 s, average 90th percentile improvement 0.8 s). Furthermore, 12 of the 15 patients reported a marked improvement regarding sleepiness whilst driving. For these clinically successful cases the number of off-road episodes decreased substantially. We conclude that most patients improve their long-term driving performance as a result of UPPP.

  16. Physical long-term side-effects in young adult cancer survivors: germ cell tumors model.

    PubMed

    Kourie, Hampig Raphael; Klastersky, Jean A

    2017-07-01

    After the important advances in the treatment of germ cell tumors (GCTs) leading to high cure rates, physical long-term side-effects represent an important cause of death in these young adult survivors. Highlighting these physical long-term side-effects, their monitoring and their prevention modalities is necessary for a better management of these cancer survivors. Impaired fertility, increased risk of developing a second cancer, cardiac, pulmonary, renal and neural toxicity, hearing and vision impairment are the major physical side-effects in young adult cancer survivors. Long-term cardiac toxicity, next to second malignancies, represents life-threatening conditions in testicular cancer survivors. The long-term nephrotoxity in testicular GCTs survivors is most frequently associated to the treatment either in those treated with cisplatin-based chemotherapy, mainly Bleomycine, Etoposide, Cisplatin, or those receiving infradiaphragmatic radiation therapy, whereas pulmonary toxicity is mainly attributed to bleomycin related toxicities. There are no clear and comprehensive data concerning the monitoring and prevention of long-term side-effects in testicular cancer survivors. Physical activity and interventions in modifiable cardiovascular risk factors and lifestyles may reduce the incidence of long-term side-effects in these cancer survivors.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. [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.

  8. [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.