A cross-sectional survey on French psychiatrists' knowledge and perceptions of dissociative identity disorder.

OBJECTIVE: The aim of this study was to determine French psychiatrists' level of general knowledge about dissociative identity disorder and to evaluate their perceptions of this condition. METHODS: In this study, French psychiatrists were invited by e-mail to answer an online survey. The questionnaire asked about their general knowledge and perceptions of dissociative identity disorder. RESULTS: We received 924 answers including 582 complete questionnaires. The survey revealed that almost two-thirds (60.8%) of psychiatrists working in France had never received any training on dissociative disorders and 62% had never managed patients suffering from dissociative identity disorder. Only 19.5% of them claimed to believe unreservedly in the existence of the diagnosis of dissociative identity disorder. The psychiatrists' confidence in diagnosing or treating dissociative identity disorder was low (mean confidence in diagnosis: 3.32 out of 10 (SD 1.89), mean confidence in treatment: 3.1 out of 10 (SD 1.68)). Fifty percent believed that dissociative identity disorder is an entity created by cinema, medias or social networks. Seventy-seven point seven percent thought that confusion with borderline personality disorder is possible, and 41.3% with schizophrenia. CONCLUSION: In France, there is a lack of training and knowledge about dissociative identity disorder, as well as persistent skepticism about the validity of the diagnosis. Specific training seems essential for a better understanding of dissociative identity disorder.

Identification of a virulent phage infecting species of Nitrosomonas.

In the first and limiting step of nitrification, ammonia (NH3) is oxidised to nitrite (NO2-) by the action of some prokaryotes, including bacteria of the Nitrosomonas genus. A potential approach to nitrification inhibition would be through the application of phages, but until now this method has been unexplored and no virulent phages that infect nitrifying bacteria have been described. In this study, we report the isolation of the first phage infecting some Nitrosomonas species. This polyvalent virulent phage (named ΦNF-1) infected Nitrosomonas europaea, Nitrosomonas communis, and Nitrosomonas nitrosa. Phage ΦNF-1 has the morphology of the Podoviridae family, a dsDNA genome of 41,596 bp and a 45.1 % GC content, with 50 predicted open reading frames. Phage ΦNF-1 was found to inhibit bacterial growth and reduce NH4+ consumption in the phage-treated cultures. The application of phages as biocontrol agents could be a useful strategy for nitrification inhibition without the restrictions associated with chemical inhibitors.

Diacutaneous Fibrolysis Intervention in Patients with Mild to Moderate Carpal Tunnel Syndrome May Avoid Severe Cases in Elderly: A Randomized Controlled Trial.

BACKGROUND: Carpal Tunnel Syndrome (CTS) mainly affects adults of working age. The prevalence of severe cases is higher in elderly patients (>65 years old). Clinical guidelines recommend conservative treatment as the best option in the initial stages of CTS to avoid severe cases. Diacutaneous Fibrolysis (DF) has demonstrated to improve nerve conduction studies and mechanosensitivity. The main purpose was to quantify changes in the cross-sectional area (CSA) of the median nerve, transversal carpal ligament (TCL) thickness, numbness intensity, and the subjective assessment of clinical change after DF treatment in patients with CTS. METHODS: a double-blind, randomized, placebo-controlled trial was designed. A number of 44 patients (60 wrists) with CTS were randomized to the DF group or the sham group. CSA and TCL thickness variables were registered by ultrasound. Clinical variables were assessed by the visual analogue scale and GROC scale. SPSS version 24.0 for MAC was used for statistical analysis. The group by time interaction between groups was analyzed using two-way repeated measures analysis of variance. RESULTS: The DF group reduced CSA with a mean of 0.45 mm2 (IC 95% 0.05 to 0.86) and TCL thickness with a mean reduction of 0.4 mm (IC 95% 0.6 to 2.1) compared to the sham group (p < 0.01, p < 0,03, respectively). Additionally, the DF group decreased the numbness intensity with a mean reduction of 3.47 (IC 95% 2.50 to 4.44, p < 0.01) and showed a statistically significant improvement on the GROC scale (p < 0.01). CONCLUSIONS: DF treatment may significantly reduce CSA and TCL thickness, numbness intensity, and improved clinical perspective. DF applied in patients with mild to moderate CTS may prevent the progression of the disease as they age.

Effects of Diacutaneous Fibrolysis on Mechanosensitivity, Disability, and Nerve Conduction Studies in Mild to Moderate Carpal Tunnel Syndrome: Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: People diagnosed with carpal tunnel syndrome (CTS) have fibrosis between the soft, connective, and neural tissues that could worsen the compression of the median nerve. The diacutaneous fibrolysis (DF) technique may release tissue adhesions and increase the mobility of connective tissues. The purpose of this study was to compare the outcomes of DF in people with mild to moderate CTS on mechanosensitivity, disability, and nerve conduction studies. METHODS: This was a secondary analysis of a double-blinded, randomized, placebo-controlled trial. Patients were recruited between April and September 2016 from the Department of Neurophysiology at the Hospital Miguel Servet, Zaragoza, Spain. Thirty-nine people (52 wrists) diagnosed with mild to moderate CTS were included. Participants were randomly assigned to either the DF group (n = 26) or the sham group (n = 26). Both groups received 5 therapy sessions, 2 sessions per week. Mechanosensitivity with the Upper Limb Neurodynamic Test 1, symptom severity and functional status with the Boston Carpal Tunnel Questionnaire, and median nerve sensory conduction velocity with nerve conduction studies were the outcomes measured. Assessments were recorded at baseline and after the intervention. RESULTS: The DF group showed significant improvements in the following: mechanosensitivity, with 28.46 degrees of elbow extension range of motion (95% CI = 19.2-37.7); an increase of 1.0 point (95% CI = 0.7-1.4) for the Boston Carpal Tunnel Questionnaire symptom severity and functional status score; and sensory conduction velocity of median nerve, which improved to 5.8 m/s (95% CI = 2.5-9.2). CONCLUSION: Participants with mild to moderate CTS experienced improvements in symptom severity, functional status, mechanosensitivity, and nerve conduction studies after 5 sessions of DF. IMPACT: This study provides evidence of an approach based on soft and connective tissues around the median nerve in patients with CTS.

RNAi-Based GluN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neurons (MSNs) in the striatum. A key early pathogenic mechanism is dysregulated synaptic transmission due to enhanced surface expression of juvenile NMDA-type glutamate receptors containing GluN3A subunits, which trigger the aberrant pruning of synapses formed by cortical afferents onto MSNs. Here, we tested the therapeutic potential of silencing GluN3A expression in YAC128 mice, a well-established HD model. Recombinant adeno-associated viruses encoding a short-hairpin RNA against GluN3A (rAAV-shGluN3A) were generated, and the ability of different serotypes to transduce MSNs was compared. A single injection of rAAV9-shGluN3A into the striatum of 1-month-old mice drove potent (>90%) and long-lasting reductions of GluN3A expression in MSNs, prevented dendritic spine loss and improved motor performance in YAC128 mice. Later delivery, when spine pathology is already apparent, was also effective. Our data provide proof-of-concept for GluN3A silencing as a beneficial strategy to prevent or reverse corticostriatal disconnectivity and motor impairment in HD and support the use of RNAi-based or small-molecule approaches for harnessing this therapeutic potential.

The effect of nitrification inhibitors on NH3 and N2O emissions in highly N fertilized irrigated Mediterranean cropping systems.

There is an increasing concern about the negative impacts associated to the release of reactive nitrogen (N) from highly fertilized agro-ecosystems. Ammonia (NH3) and nitrous oxide (N2O) are harmful N pollutants that may contribute both directly and indirectly to global warming. Surface applied manure, urea and ammonium (NH4+) based fertilizers are important anthropogenic sources of these emissions. Nitrification inhibitors (NIs) have been proposed as a useful technological approach to reduce N2O emission although they can lead to large NH3 losses due to increasing NH4+ pool in soils. In this context, a field experiment was carried out in a maize field with aiming to simultaneously quantify NH3 volatilization and N2O emission, assessing the effect of two NIs 3,4­dimethilpyrazol phosphate (DMPP) and 3,4­dimethylpyrazole succinic acid (DMPSA). The first treatment was pig slurry (PS) before seeding (50 kg N ha-1) and calcium ammonium nitrate (CAN) at top-dressing (150 kg N ha-1), and the second was DMPP diluted in PS (PS + DMPP) (50 kg N ha-1) and CAN + DMPSA (150 kg N ha-1) also before seeding and at top-dressing, respectively. Ammonia emissions were quantified by a micrometeorological method during 20 days after fertilization and N2O emissions were assessed using manual static chambers during all crop period. The treatment with NIs was effective in reducing c. 30% cumulative N2O losses. However, considering only direct N2O emissions after second fertilization event, a significant reduction was not observed using CAN+DMPSA, probably because high WFPS of soil, driven by irrigation, favored denitrification. Cumulative NH3 losses were not significantly affected by NIs. Indeed, NH3 volatilization accounted 14% and 10% of N applied in PS + DMPP and PS plots, respectively and c. 2% of total N applied in CAN+DMPSA and CAN plots. Since important NH3 losses still exist even although abating strategies are implemented, structural and political initiatives are needed to face this issue.

Increased Levels of Rictor Prevent Mutant Huntingtin-Induced Neuronal Degeneration.

Rictor associates with mTOR to form the mTORC2 complex, which activity regulates neuronal function and survival. Neurodegenerative diseases are characterized by the presence of neuronal dysfunction and cell death in specific brain regions such as for example Huntington's disease (HD), which is characterized by the loss of striatal projection neurons leading to motor dysfunction. Although HD is caused by the expression of mutant huntingtin, cell death occurs gradually suggesting that neurons have the capability to activate compensatory mechanisms to deal with neuronal dysfunction and later cell death. Here, we analyzed whether mTORC2 activity could be altered by the presence of mutant huntingtin. We observed that Rictor levels are specifically increased in the striatum of HD mouse models and in the putamen of HD patients. Rictor-mTOR interaction and the phosphorylation levels of Akt, one of the targets of the mTORC2 complex, were increased in the striatum of the R6/1 mouse model of HD suggesting increased mTORC2 signaling. Interestingly, acute downregulation of Rictor in striatal cells in vitro reduced mTORC2 activity, as shown by reduced levels of phospho-Akt, and increased mutant huntingtin-induced cell death. Accordingly, overexpression of Rictor increased mTORC2 activity counteracting cell death. Furthermore, normalization of endogenous Rictor levels in the striatum of R6/1 mouse worsened motor symptoms suggesting an induction of neuronal dysfunction. In conclusion, our results suggest that increased Rictor striatal levels could counteract neuronal dysfunction induced by mutant huntingtin.

Reliability of measurement of the carpal tunnel and median nerve in asymptomatic subjects with ultrasound.

BACKGROUND: Morphology of the carpal tunnel changes with varying wrist postures and compressive forces applied to the wrist. These changes may affect the morphology and pressure on the median nerve and could be used as part of the treatment of the carpal tunnel syndrome patients. Reliability of the ultrasonographic measurements of the median nerve has been widely studied. However, there is a lack of investigation regarding reliability of ultrasonographic measurements of the carpal tunnel. OBJECTIVE: The purpose of this study was to assess intra-tester and inter-tester reliability of measurement of dimensions of the carpal tunnel and median nerve with ultrasound in asymptomatic volunteers. DESIGN: A cross-sectional methodological study. METHODS: Aspects measured were mediolateral and anteroposterior diameters, flattening ratio, circularity, perimeter and cross-section area of the carpal tunnel and median nerve. RESULTS: Intra-tester reliability was excellent for the carpal tunnel (ICCs from 0.91 to 0.97) and for the median nerve (ICCs from 0.79 to 0.94) measurements. The flattening ratio of the median nerve showed good agreement (ICC = 0.68). Inter-tester reliability was excellent for the carpal tunnel measurements (ICCs from 0.76 to 0.95) and, for the cross sectional area, the perimeter and mediolateral diameter of the median nerve, the ICC values were 0.89, 0.84 and 0.81, respectively. CONCLUSION: In the context of this study, ultrasound was a reliable instrument for measuring carpal tunnel and median nerve dimensions in asymptomatic subjects. LEVEL OF EVIDENCE: 1b.

No tillage and liming reduce greenhouse gas emissions from poorly drained agricultural soils in Mediterranean regions.

No tillage (NT) has been associated to increased N2O emission from poorly drained agricultural soils. This is the case for soils with a low permeable Bt horizon, which generates a perched water layer after water addition (via rainfall or irrigation) over a long period of time. Moreover, these soils often have problems of acidity and require liming application to sustain crop productivity; changes in soil pH have large implications for the production and consumption of soil greenhouse gas (GHG) emissions. Here, we assessed in a split-plot design the individual and interactive effects of tillage practices (conventional tillage (CT) vs. NT) and liming (Ca-amendment vs. not-amendment) on N2O and CH4 emissions from poorly drained acidic soils, over a field experiment with a rainfed triticale crop. Soil mineral N concentrations, pH, temperature, moisture, water soluble organic carbon, GHG fluxes and denitrification capacity were measured during the experiment. Tillage increased N2O emissions by 68% compared to NT and generally led to higher CH4 emissions; both effects were due to the higher soil moisture content under CT plots. Under CT, liming reduced N2O emissions by 61% whereas no effect was observed under NT. Under both CT and NT, CH4 oxidation was enhanced after liming application due to decreased Al(3+) toxicity. Based on our results, NT should be promoted as a means to improve soil physical properties and concurrently reduce N2O and CH4 emissions. Raising the soil pH via liming has positive effects on crop yield; here we show that it may also serve to mitigate CH4 emissions and, under CT, abate N2O emissions.

GluN3A promotes NMDA spiking by enhancing synaptic transmission in Huntington's disease models.

Age-inappropriate expression of juvenile NMDA receptors (NMDARs) containing GluN3A subunits has been linked to synapse loss and death of spiny projection neurons of the striatum (SPNs) in Huntington's disease (HD). Here we show that suppressing GluN3A expression prevents a multivariate synaptic transmission phenotype that precedes morphological signs at early prodromal stages. We start by confirming that afferent fiber stimulation elicits larger synaptic responses mediated by both AMPA receptors and NMDARs in SPNs in the YAC128 mouse model of HD. We then show that the enhancement mediated by both is fully prevented by suppressing GluN3A expression. Strong fiber-stimulation unexpectedly elicited robust NMDAR-mediated electrogenic events (termed "upstates" or "NMDA spikes"), and the effective threshold for induction was more than 2-fold lower in YAC128 SPNs because of the enhanced synaptic transmission. The threshold could be restored to control levels by suppressing GluN3A expression or by applying the weak NMDAR blocker memantine. However, the threshold was not affected by preventing glutamate spillover from synaptic clefts. Instead, long-lasting NMDAR responses interpreted previously as activation of extrasynaptic receptors by spilled-over glutamate were caused by NMDA spikes occurring in voltage clamp mode as escape potentials. Together, the results implicate GluN3A reactivation in a broad spectrum of early-stage synaptic transmission deficits in YAC128 mice; question the current concept that NMDAR mislocalization is the pathological trigger in HD; and introduce NMDA spikes as a new candidate mechanism for coupling NMDARs to neurodegeneration.

N2O and CH4 emissions from a fallow-wheat rotation with low N input in conservation and conventional tillage under a Mediterranean agroecosystem.

Conservation agriculture that includes no tillage (NT) or minimum tillage (MT) and crop rotation is an effective practice to increase soil organic matter in Mediterranean semiarid agrosystems. But the impact of these agricultural practices on greenhouse gases (GHGs), such as nitrous oxide (N2O) and methane (CH4), is variable depending mainly on soil structure and short/long-term tillage. The main objective of this study was to assess the long-term effect of three tillage systems (NT, MT and conventional tillage (CT)) and land-covers (fallow/wheat) on the emissions of N2O and CH4 in a low N input agricultural system during one year. This was achieved by measuring crop yields, soil mineral N and dissolved organic C contents, and fluxes of N2O and CH4. Total cumulative N2O emissions were not significantly different (P>0.05) among the tillage systems or between fallow and wheat. The only difference was produced in spring, when N2O emissions were significantly higher (P<0.05) in fallow than in wheat subplots, and NT reduced N2O emissions (P<0.05) compared with MT and CT. Taking into account the water filled pore space (WFPS), both nitrification and denitrification could have occurred during the experimental period. Denitrification capacity in March was similar in all tillage systems, in spite of the higher DOC content maintained in the topsoil of NT. This could be due to the similar denitrifier densities, targeted by nirK copy numbers at that time. Cumulative CH4 fluxes resulted in small net uptake for all treatments, and no significant differences were found among tillage systems or between fallow and wheat land-covers. These results suggest that under a coarse-textured soil in low N agricultural systems, the impact of tillage on GHG is very low and that the fallow cycle within a crop rotation is not a useful strategy to reduce GHG emissions.

Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models.

Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. Yet, it remains unclear how the HTT mutation affects NMDAR function, and direct evidence for a causative role is missing. Here we show that mutant HTT redirects an intracellular store of juvenile NMDARs containing GluN3A subunits to the surface of striatal neurons by sequestering and disrupting the subcellular localization of the endocytic adaptor PACSIN1, which is specific for GluN3A. Overexpressing GluN3A in wild-type mouse striatum mimicked the synapse loss observed in Huntington's disease mouse models, whereas genetic deletion of GluN3A prevented synapse degeneration, ameliorated motor and cognitive decline and reduced striatal atrophy and neuronal loss in the YAC128 Huntington's disease mouse model. Furthermore, GluN3A deletion corrected the abnormally enhanced NMDAR currents, which have been linked to cell death in Huntington's disease and other neurodegenerative conditions. Our findings reveal an early pathogenic role of GluN3A dysregulation in Huntington's disease and suggest that therapies targeting GluN3A or pathogenic HTT-PACSIN1 interactions might prevent or delay disease progression.

Tyrosine phosphorylation regulates the endocytosis and surface expression of GluN3A-containing NMDA receptors.

Selective control of receptor trafficking provides a mechanism for remodeling the receptor composition of excitatory synapses, and thus supports synaptic transmission, plasticity, and development. GluN3A (formerly NR3A) is a nonconventional member of the NMDA receptor (NMDAR) subunit family, which endows NMDAR channels with low calcium permeability and reduced magnesium sensitivity compared with NMDARs comprising only GluN1 and GluN2 subunits. Because of these special properties, GluN3A subunits act as a molecular brake to limit the plasticity and maturation of excitatory synapses, pointing toward GluN3A removal as a critical step in the development of neuronal circuitry. However, the molecular signals mediating GluN3A endocytic removal remain unclear. Here we define a novel endocytic motif (YWL), which is located within the cytoplasmic C-terminal tail of GluN3A and mediates its binding to the clathrin adaptor AP2. Alanine mutations within the GluN3A endocytic motif inhibited clathrin-dependent internalization and led to accumulation of GluN3A-containing NMDARs at the cell surface, whereas mimicking phosphorylation of the tyrosine residue promoted internalization and reduced cell-surface expression as shown by immunocytochemical and electrophysiological approaches in recombinant systems and rat neurons in primary culture. We further demonstrate that the tyrosine residue is phosphorylated by Src family kinases, and that Src-activation limits surface GluN3A expression in neurons. Together, our results identify a new molecular signal for GluN3A internalization that couples the functional surface expression of GluN3A-containing receptors to the phosphorylation state of GluN3A subunits, and provides a molecular framework for the regulation of NMDAR subunit composition with implications for synaptic plasticity and neurodevelopment.

Demandas assistenciais frente à gestação e o nascimento de bebês com malformação / Forward claims assistance pregnancy and birth of baby malformation

Objetivo: descrever as demandas assistenciais do binômio mãe/filho na presença de malformação durante o período gravídico-puerperal. Métodos: pesquisa qualitativa, descritivo-exploratória, desenvolvida junto a nove mães de bebês nascidos entre novembro de 2008 à fevereiro de 2009, no município de Maringá-PR. Os dados foram coletados em maio de 2009, por meio de entrevista semiestruturada e submetidos a análise de conteúdo. Resultados: durante a gestação, a assistência baseou-se em consultas de pré-natal, encaminhamentos e orientações. No período de hospitalização, o atendimento para algumas foi essencial, para outras houve falhas. No puerpério, identificou-se que não receberam visita de profissionais de saúde, apenas foram convidadas a ir à Unidade Básica de Saúde (UBS) realizar a vacinação e acompanhamento do bebê. Considerações finais: Este estudo permitiu compreender que o binômio e família enfrentam grandes dificuldades durante todo o ciclo gravídico-puerperal, sendo necessário que a equipe de saúde busque alternativas para minimizá-las, a fim de prestar um atendimento diferenciado e humanizado.

Objective: to describe on the health care demands both mother / child in the presence of malformations during pregnancy and childbirth. Methods: qualitative research, and exploratory posology described, developed with nine mothers of infants born between November 2008 to February 2009, in Maringá -PR. Data were collected in May 2009, through semi-structured interviews and submitted to content analysis. Results: during pregnancy assistance was based on prenatal care, referrals and advice. During hospitalization care was essential for some, for others it has failed. In the puerperium identified that were not visited by health professionals were only asked to go to the Basic Health Unit (BHU) to carry out vaccination and monitoring of the baby. Conclusion: this study allowed us to understand that the binomial and family are struggling throughout the pregnancy and childbirth, being necessary for the health care team seeks alternatives to minimize them in order to provide a differentiated service and humanized.

Objetivo: describir las demandas asistenciales del binomio madre/hijo en presencia de malformaciones durante el embarazo y el parto. Métodos: la investigación cualitativa, descriptiva y exploratoria, esarrollada con nueve madres de bebés nacidos entre noviembre de 2008 hasta febrero de 2009 en Maringá-PR. Los datos fueron recogidos en mayo de 2009, a través de entrevistas semi-estructuradas y sometido a análisis de contenido. Resultados: durante el embarazo la asistencia se basa en la atención prenatal, encaminamientos y orientaciones. Durante la hospitalización fue esencial para algunos, para otros, ha fracasado. En el puerperio fue identificado que no recibirán visitas de los profesionales de la salud, sólo fueron invitados para ir en la Unidad de atención primaria de salud (UBS) para llevar a cabo la vacunación y la vigilancia del bebé. Conclusión: este estudio ha permitido comprender que el binomio y la familia enfrentan grandes dificultades durante todo el embarazo y el parto, siendo necesario para el equipo de atención de la salud busca alternativas para reducir al mínimo a fin de ofrecer un servicio diferenciadoy humanizada.

The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation.

Excitotoxicity due to excessive activation of glutamate receptors is a primary mediator of cell death in acute and chronic neurological disorders, and NMDA-type glutamate receptors (NMDARs) are thought to be involved. NMDARs assemble from heteromeric combinations of GluN1, GluN2 and GluN3 subunits, yielding a variety of receptor subtypes that differ in biophysical properties, signaling, and synaptic targeting. Inclusion of inhibitory GluN3 subunits reduces Ca2+ influx via NMDAR channels and alters their synaptic targeting, thus modifying the two hallmarks of NMDARs that are critical for their roles on neuronal death and survival. Here we evaluated the neuroprotective potential of GluN3A subunits by analyzing the susceptibility to striatal excitotoxic damage of transgenic mice overexpressing GluN3A. We found that mild GluN3A overexpression protected susceptible striatal neurons from lesions induced by the neurotoxin 3-nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II/succinate dehydrogenase. GluN3A-mediated neuroprotection was dose-dependent, and correlated with the levels of transgenic GluN3A expressed by two different mice strains. Neuroprotection was associated with a potent reduction of the activation of calpain, a Ca2+-dependent protease, which was measured as a decrease in 3-NP-induced fodrin and STEP cleavage in GluN3A transgenic mice relative to controls. We further show that transgenic GluN3A subunits incorporate into extrasynaptic compartments in mouse striatum, suggesting that reductions of toxic calpain activation might be linked to inhibition by GluN3A of pathological extrasynaptic NMDAR activity.

Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease.

Alzheimer's disease (AD) and ageing are associated with impaired learning and memory, and recent findings point toward modulating chromatin remodeling through histone acetylation as a promising therapeutic strategy. Here we report that systemic administration of the HDAC inhibitor 4-phenylbutyrate (PBA) reinstated fear learning in the Tg2576 mouse model of AD. Tg2576 mice develop age-dependent amyloid pathology and cognitive decline that closely mimics disease progression in humans. Memory reinstatement by PBA was observed independently of the disease stage: both in 6-month-old Tg2576 mice, at the onset of the first symptoms, but also in aged, 12- to 16-month-old mice, when amyloid plaque deposition and major synaptic loss has occurred. Reversal of learning deficits was associated to a PBA-induced clearance of intraneuronal Aß accumulation, which was accompanied by mitigation of endoplasmic reticulum (ER) stress, and to restoration of dendritic spine densities of hippocampal CA1 pyramidal neurons to control levels. Furthermore, the expression of plasticity-related proteins such as the NMDA receptor subunit NR2B and the synaptic scaffold SAP102 was significantly increased by PBA. Our data suggest that the beneficial effects of PBA in memory are mediated both via its chemical chaperone-like activity and via the transcriptional activation of a cluster of proteins required for the induction of synaptic plasticity and structural remodeling.

Structure and fertilizer properties of byproducts formed in the synthesis of EDDHA.

The synthesis of commercial EDDHA produces o,o-EDDHA as the main reaction product, together with a mixture of regioisomers (o,p-EDDHA and p,p-EDDHA) and other unknown byproducts also able to complex Fe3+. These compounds have been obtained by direct synthesis, and their structures have been determined by ESI-MS analysis as oligomeric EDDHA-like products, formed by polysubstitution in the phenolic rings. Short-term experiments show that the iron complexes of samples enriched in these oligomeric byproducts have adequate stability in solution, but a significant amount of them is lost after interaction with soils and soil materials. Mildly chlorotic cucumber plants are able to reduce iron better from o,p-EDDHA/Fe3+ than from the iron complexes of the oligomeric byproducts. In hydroponics, the chlorotic soybean susceptible plants have a lower potential for Fe absorption from these byproducts than from o,o-EDDHA/Fe3+ and from o,p-EDDHA/Fe3+. In the studied conditions, the iron chelates of EDDHA byproducts do not have the long-lasting effect shown by o,o-EDDHA/Fe3+ and present a less efficient fast-action effect than the o,p-EDDHA/Fe3+.

Amyloid beta-peptide1-42 alters tight junction protein distribution and expression in brain microvessel endothelial cells.

Alzheimer's disease is characterised by neuronal loss, numerous intraneuronal deposits of neurofibrillary tangles, senile plaques, and cerebrovascular amyloid deposits. The major component of senile plaques and cerebrovascular deposits is the 39-43 amino acid beta-amyloid peptide (Abeta). The effects of Abeta on cerebral endothelium and thus the blood-brain barrier remain unclear. Utilising endothelial cells isolated from rat cerebral cortex microvessels, we have examined effects of Abeta peptides on tight junction protein behaviour. The transmembrane tight junction proteins occludin, claudin-1 and claudin-5, as well as the cytoplasmic accessory proteins ZO-1 and ZO-2 displayed a continuous distribution at cell boundaries. Endothelial cells exposed to Abeta1-42 (20 microM) for 3 days showed a disrupted plasma membrane pattern of claudin-5 and ZO-2 with relocation to the cytoplasm. These effects were not seen with Abeta25-35 or Abeta1-40[Gln22] (Dutch type). Abeta1-42 treatment altered also protein expression: occludin was lower at 1st day, claudin-1 increased at all times, and ZO-2 increased after 1 day and then decreased. These data suggest that Abeta1-42 effects on tight junction protein complexes may alter blood-brain barrier integrity and contribute to the neuropathological sequelae of Alzheimer's disease.

Reduced expression of the TrkB receptor in Huntington's disease mouse models and in human brain.

Deficits of neurotrophic support caused by reduced levels of brain-derived neurotrophic factor (BDNF) have been implicated in the selective vulnerability of striatal neurones in Huntington's disease (HD). Therapeutic strategies based on BDNF administration have been proposed to slow or prevent the disease progression. However, the effectiveness of BDNF may depend on the proper expression of its receptor TrkB. In this study, we analysed the expression of TrkB in several HD models and in postmortem HD brains. We found a specific reduction of TrkB receptors in transgenic exon-1 and full-length knock-in HD mouse models and also in the motor cortex and caudate nucleus of HD brains. Our findings also demonstrated that continuous expression of mutant huntingtin is required to down-regulate TrkB levels. This was shown by findings in an inducible HD mouse model showing rescue of TrkB by turning off mutant huntingtin expression. Interestingly, the length of the polyglutamine tract in huntingtin appears to modulate the reduction of TrkB. Finally, to analyse the effect of BDNF in TrkB we compared TrkB expression in mutant huntingtin R6/1 and double mutant (R6/1 : BDNF+/-) mice. Similar TrkB expression was found in both transgenic mice suggesting that reduced TrkB is not a direct consequence of decreased BDNF. Therefore, taken together our findings identify TrkB as an additional component that potentially might contribute to the altered neurotrophic support in HD.

Chromatographic determination of Fe chelated by ethylenediamine-N-(o-hydroxyphenylacetic)-N'-(p-hydroxyphenylacetic) acid in commercial EDDHA/Fe3+ fertilizers.

EDDHA/Fe3+ chelates are the most common fertilizers used to solve Fe chlorosis in established crops. Commercial products contain two regioisomers, ethylenediamine-N,N'-bis(o-hydroxyphenylacetic) acid (o,o-EDDHA)/Fe3+ and ethylenediamine-N-(o-hydroxyphenylacetic)-N'-(p-hydroxyphenylacetic) acid (o,p-EDDHA)/Fe3+. Although several chromatographic methods exist for the determination of Fe3+ chelated by the o,o-EDDHA isomer, no method has been described for the quantification of Fe3+ chelated by o,p-EDDHA. In this work, factors that affect the behavior of o,p-EDDHA/Fe3+ in ion pair chromatography are reviewed: pH, ion pair reagent, and organic modifier. The best chromatographic performance was obtained with an aqueous mobile phase at pH 6.0 containing 35% acetonitrile and 5 mM tetrabutylammonium hydroxide under isocratic elution conditions. This method was applied to the quantification of commercial samples.