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Combination of multiple neurodegenerative proteinopathies is frequent in the elderly. We report the case of an octogenarian who attempted suicide and deceased after hospital admission. Anatomical mapping was performed in several cortical and subcortical brain regions using antibodies against phospho-tau, 4R tau, 3R tau, phospho-TDP-43, ubiquitin, α-synuclein, Aβ and p62. Unexpectedly, histopathologic examination showed prominent subpial, subependymal, grey and white matter, and perivascular aging-related tau astrogliopathy (ARTAG) affecting cortical and subcortical brain regions. This pathology was associated with intermediate Alzheimer’s disease neuropathologic change, cerebral amyloid angiopathy, Lewy-body-type and astroglial synuclein proteinopathy and a multiple system TDP-43 proteinopathy involving also the astroglia. This unusual case of extensive and widespread ARTAG with a complex multiproteinopathy may represent an independent disease entity in the elderly with tau astrogliopathy as the leading force.
Recognize astroglial protein deposits in neurodegeneration
ABSTRACT IMPACT: Melanoma leptomeningeal disease (LMD) is a devastating subtype of central nervous system (CNS) metastatic disease that is associated with limited treatment options and an extremely poor prognosis, thus requiring the development of preclinical models of LMD for therapeutic development. OBJECTIVES/GOALS:
1. Develop an immunocompetent murine model of melanoma LMD with tumors bearing genetic mutations commonly found in patients, specifically BRAF(V600E)/PTEN-/-
2. Assess the safety of intrathecal (IT) immunotherapy, specifically anti-PD1 antibody (aPD1)
3. Evaluate the therapeutic efficacy of IT aPD1 checkpoint blockade in murine melanoma LMD METHODS/STUDY POPULATION: To develop BRAF(V600E)/PTEN-/- LMD models, we acquired BP, D4M, and D4M-UV2 (irradiated) murine melanoma cell lines and luciferase-tagged them. 1.5x10^4 cells were suspended in 10 uL serum-free media and injected into the cisterna magna of female C57BL/6 mice. Brain and spinal cord were harvested for histologic assessment once mice were moribund. To assess safety of IT aPD1, we injected IT control IgG or IT aPD1 (13 ug, 26 ug, 39 ug) and monitored weights or harvested at days 7 or 14 for IHC staining of inflammation markers. To evaluate therapeutic efficacy of IT aPD1, BP cells were directly injected as above. After 3 days, mice underwent imaging to confirm tumor uptake and randomization to receive 13 ug IT control IgG or aPD1 once + 200 ug systemic (Sys) control IgG or aPD1 (days 0, 3, and 5), and then monitored for survival. RESULTS/ANTICIPATED RESULTS: For LMD development, all mice survived cisternal injection of BP, D4M, and D4M-UV2 cells and median survival was 17, 19, and 30 days, respectively. Presence of leptomeningeal deposits was confirmed for all tumor-bearing mice by IHC for MART1. For safety of IT aPD1, all mice survived the procedure and no mice displayed morbidity or >10% weight loss over 14 days of observation. IHC assessment of brain and spinal cord samples from mice treated with 13 ug aPD1 revealed focal ischemia related to injection site and no other signs of neurological damage or inflammation. IT aPD1 treatment of mice with BP leptomeningeal tumors demonstrated no significant survival advantage, although both IT aPD1 +/- Sys aPD1 had mice live up to days 29 and 26, respectively, compared to both IT control IgG +/- Sys aPD1, for which all mice died by day 22. DISCUSSION/SIGNIFICANCE OF FINDINGS: We demonstrate that cisternal injection of murine BRAF(V600E)/PTEN-/- melanoma cell lines yield LMD with reproducible survival and that treatment with IT aPD1 in this model is feasible and safe. Together these findings establish a new model to facilitate the development of more effective immunotherapy strategies for melanoma patients with LMD.
In Argentina, the mosquito Aedes aegypti (L.) (Diptera: Culicidae) is distributed from subtropical to temperate climates. Here, we hypothesized that the expansion of Ae. aegypti into colder regions is favoured by high-phenotypic plasticity and an adaptive inhibition of egg hatching at low temperatures. Thus, we investigated the hatching response of eggs of three populations: one from a subtropical region (Resistencia) and two from temperate regions (Buenos Aires City and San Bernardo) of Argentina. Eggs collected in the field were raised in three experimental colonies. F1 eggs were acclimated for 7 days prior to immersion at 7.6 or 22°C (control eggs). Five immersion temperatures were tested: 7.6, 10.3, 11.8, 14.1 and 16°C (range of mean winter temperatures of the three localities). A second immersion at 22°C was performed 2 weeks later to assess the inhibition to hatch under favourable conditions. After the first immersion, we compared the proportions of hatched eggs and dead larvae among treatment levels, whereas after the second immersion we compared the hatching response among the three populations. The factors that most influenced the egg hatching response were the geographical origin of the populations and the immersion temperature, but not the acclimation temperature. The proportions of hatching and larval mortality at low temperatures were higher for Resistencia than for Buenos Aires and San Bernardo, whereas the hatching response at ambient temperature was lower for San Bernardo than for Buenos Aires and Resistencia. The results support the hypothesis that populations from colder regions show an adaptive inhibition of egg hatching.
Pilot randomized double-blind-controlled trial of repetitive paired associative stimulation (rPAS), a paradigm that combines transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) with peripheral median nerve stimulation.
To study the impact of rPAS on DLPFC plasticity and working memory performance in Alzheimer’s disease (AD).
Thirty-two patients with AD (females = 16), mean (SD) age = 76.4 (6.3) years were randomized 1:1 to receive a 2-week (5 days/week) course of active or control rPAS. DLPFC plasticity was assessed using single session PAS combined with electroencephalography (EEG) at baseline and on days 1, 7, and 14 post-rPAS. Working memory and theta–gamma coupling were assessed at the same time points using the N-back task and EEG.
There were no significant differences between the active and control rPAS groups on DLPFC plasticity or working memory performance after the rPAS intervention. There were significant main effects of time on DLPFC plasticity, working memory, and theta–gamma coupling, only for the active rPAS group. Further, on post hoc within-group analyses done to generate hypotheses for future research, as compared to baseline, only the rPAS group improved on post-rPAS day 1 on all three indices. Finally, there was a positive correlation between working memory performance and theta–gamma coupling.
This study did not show a beneficial effect of rPAS for DLPFC plasticity or working memory in AD. However, post hoc analyses showed promising results favoring rPAS and supporting further research on this topic. (Clinicaltrials.gov-NCT01847586)
This research communication addresses the hypothesis that, during the summer in the subtropics, natural tree shade helps to improve milk functional characteristics such as stability and acidity. Sixteen Holstein lactating cows were enrolled. The study consisted of three periods (pre-stress, heat stress and post-stress) based on allocating grazing cows into two treatments (with and without access to shade during the Heat Stress period). Overall THI during the trial was (mean ± se) 76.0 ± 3.4. Access to shade prevented the heat stress-related decrease in milk stability both in the ethanol and in the coagulation time test, as well as maintained milk acidity within an acceptable range (14 to 18°D).
Neurotoxic effects of alcohol consumption are well-known. There is plenty of literature on frontal lobe impairment on the behavioral and structural brain imaging level. However, only few functional imaging studies investigated altered neural patterns and even less abstinence-related neural recovery. Here, we investigated if frontal lobe activity tends to normalize in patients that remain successfully abstinent.
In a cross-sectional design three patient groups (acute withdrawal, detoxified, abstinent) and healthy controls (each n = 20) performed a phonological and semantical verbal fluency task (VFT) while brain activity was measured with near-infrared spectroscopy (NIRS).
First, for the phonological condition patients in the acute withdrawal phase and also detoxified patients showed less fluency-related frontal lobe activation compared to controls despite equal performance. Second, significant linear trend effects from withdrawal patients over detoxified and abstinent patients up to healthy controls indicated more normal activation patterns in the abstinent group that did not differ from the controls. In the detoxified group brain activation increased with time since detoxification.
Our results support the assumption of an increase in frontal brain activity from alcohol dependency over abstinence up to normal functioning. Longitudinal studies are needed to further elucidate recovery processes in alcohol dependency.
This paper reviews and presents data of practical impact for those administering electroconvulsive therapy (ECT). In the first section, physical and physiological aspects of the stimulus as well as methods of stimulation are discussed. The second section deals with indications for ECT, efficacy and treatment modalities such as seizure duration, treatment frequency and total number of ECT applications. The last section is devoted to side effects, risks, comedication and comorbidity.
The aim of this analysis is to describe medication adherence, and treatment persistence, in adults with attention deficit/hyperactivity disorder (ADHD) treated for 24 weeks with extended release methylphenidate (MPH-ER). Additionally, patient-, disorder- and treatment-related factors associated with adherence and persistence will be identified.
Post-hoc analysis of the active treatment group of a placebo-controlled, randomised, 24 week trial with MPH-ER with univariate description and multiple logistic regression models and Hosmer and Lemeshow tests.
In the sample of 241 adults with ADHD (mean age of 35.2 ± 10.1 years), 9.4% of the patients were non-adherent, taking less than 80% of the dispensed medication. Factors associated with non-adherence included age < 25 years, education level lower than secondary education, lacking family history of ADHD, lower ADHD baseline severity and lower self- and observer-rated medication efficacy. Lacking family history of ADHD, lower education level and lower self-rated medication efficacy, predicted non-adherence with a prediction accuracy of 16%. Seventeen percent of the patients discontinued early with most discontinuing within the first five weeks of the MPH-ER titration phase. Mean persistence in the discontinuing group was 63.4 ± 49.4 days. Factors associated with discontinuation included male gender, lower education level, lacking family history of ADHD and lower self- and observer-rated medication efficacy. Treatment non-response, male gender and lower education level predicted treatment discontinuation with a prediction accuracy of 22.7%.
Male adults without relatives with ADHD, with lower educational level and lower self- and observer-rated medication efficacy, who are newly treated with MPH-ER, are at increased risk of non-adherence and treatment discontinuation. Patients are at increased risk of treatment discontinuation during the medication titration phase.
False-positive drug screenings have been reported for several drugs and can affect the therapeutic relationship.
We wanted to find out, which medication can cause false-positive phencyclidine drug screenings.
We systematically looked at all psychiatric inpatients with phencyclidine positive urine drug screenings using a kinetic interaction of microparticles in a solution (KIMS) based system treated in our psychiatric department between 2008 and 2013.
39 of 40 positive phencyclidine urine drug screenings could plausibly be explained as false-positives by psychopharmacologic medication. The most frequent common medication in our case series was chlorprothixene, which has not been reported as a cause for any false-positive drug screenings so far. We also found trimipramine as a medication in three cases, being structurally similar to imipramine, which has been reported before to potentially cause cross-reactivity. Other false-positive results could be explained by venlafaxine, lamotrigine, imipramine and tramadol, which have been reported to have the capacity for cross-reactivity. Chlorprothixene and venlafaxine accounted for almost 75 % of the positive screenings.
Confirmation by a second method like gas chromatography/mass spectrometry should follow positive drug screenings for phencyclidine.
Previous research revealed substantial relations between the experience of childhood adversities and the development of borderline personality disorders (BPD) in adulthood. However, research about antecedents of adolescent BPD is still in its beginnings. Moreover, there is an ongoing controversy regarding transgenerational effects of childhood adversities and potential mediators.
We aim to investigate transgenerational effects of parental childhood experiences on the development of adolescent BPD within the next generation. Hereby, we are focusing on the investigation of differential effects of maternal and paternal experiences of childhood adversities on adolescent BPD and on underlying mechanisms.
We consecutively recruited 91 female inpatients (Mage = 15.6 years) from the Department of Child and Adolescent Psychiatry, University Hospital Heidelberg, as well as 87 mothers and 59 fathers. Childhood adversities were assessed for parents and adolescents with the German Childhood Experiences of Care and Abuse Questionnaire, adolescent BPD by means of structured clinical interviews (SKID II).
Our results are in favor of a transgenerational effect of parental childhood adversities on the development of adolescent BPD. This effect turned out to be stronger for paternal than for maternal childhood adversities. Moreover, paternal childhood adversities revealed to be related to experiences of childhood adversities within the next generation.
Our results underline the importance of taking the family environment into consideration when developing prevention and treatment programs for adolescent BPD.
The study examined the developmental trajectories of deliberate self-harm behavior (e.g. of non-suicidal self-injury, suicidality and substance use) in a community sample of 514 adolescents from 14.5 to 16.5 years of age. Data were taken from the German sample of the Saving and Empowering Young Lives in Europe study (SEYLE; Wasserman et al., 2010) and its consecutive follow-up assessments. Using general growth mixture modeling, distinctive classes for each self-harm behavior were identified. The high risk non-suicidal self-injury class as well as the high risk suicidality class demonstrated high initial values with a gradual decrease over adolescence. The substance use high risk class had a low initial value and presented acceleration with time. The high overlap between the three high-risk classes supports the notion that certain personality traits such as affective dysregulation or impulsivity may underlie these three behaviors. Compared to the low or moderate risk classes, individuals belonging to high risk classes revealed significantly higher scores in the SCID-II questionnaire for DSM-IV borderline personality disorder.
Non-suicidal self-injury (NSSI) is an increasing phenomenon among adolescents. So far, comparable data on prevalence and psychosocial correlates are still rare due to different definitions, study samples, and measures.
To investigate the prevalence and associated psychosocial factors of occasional and repetitive non-suicidal self-injury (NSSI) and its relationship to suicide attempts in a representative adolescent samples from eleven European countries.
Cross sectional assessment of adolescents was performed within the European Union funded project, Saving and Empowering Young Lives in Europe (SEYLE), which was conducted in eleven European countries. The representative sample comprised 12,068 adolescents (F/M: 6,717/5,351; mean age: 14.9±0.89) recruited from randomly selected schools. Frequency of NSSI was assessed by a modified version of the Deliberate Self-Harm Inventory (DSHI) and the Paykel Suicide Scale. Additionally, a broad range of demographic, social and psychological factors was assessed.
Overall lifetime prevalence of NSSI was 27.6%; 19.7% reported occasional NSSI and 7.8% repetitive NSSI. Lifetime prevalence ranged from 17.1% to 38.6% across countries. Suicidality, anxiety and depression had the highest odds ratios for both occasional and repetitive NSSI.
Results suggest high lifetime prevalence of NSSI in European adolescents, with significant country differences. A strong association of NSSI with both psychopathology and risk-behaviours, including family-related neglect and peer-related rejection/victimization could be found. These results, combined with the observed gender and country differences, support the need for a multidimensional approach to better understand the development of NSSI and facilitate culturally adapted prevention/intervention.
Cognitive processes are impaired in Schizophrenia (SKZ). The nature of such impairment escapes definition.
Identification of a genetic profile at risk of cognitive impairment.
Identifying a molecular pathways enriched for mutations associated with cognitive impairment.
Seven hundred and sixty-five individuals from the CATIE, M = 556, mean age = 40.93 ± 11.03 were included. Verbal memory was outcome. R and Plink served for the analyses. Inflation factor was controlled by lambda values. Input for the pathway analysis were SNPs associated with outcome (P < 0.05) genomewide.
Gender (male, P = 2.34e–05;t = –4.26) and years of education (P = 1.57e–03;t = 6.502) were associated with verbal memory. Inflammation and oxidation were associated with outcome (Table 1, adj_P < 0.01).
Being male and poorly educated were associated with poorer verbal memory. Inflammation and the arachidonic acid pathway were enriched in mutations associated with poorer verbal memory. This finding is in line with previous reports [1,2,3].
Arrhythmia is a potentially fatal side effect of antipsychotics. A biologic predictive tool to prevent it is missing.
Identification of a genetic profile at risk for antipsychotic induced arrhythmia.
Identifying a molecular pathway enriched for antipsychotic induced QT-modifications.
Seven hundred and sixty-five SKZ individuals, M = 556, age = 40.93 ± 11.03 were included. QT-variation was a phase-specific created variable. A nested mixed regression served in R for clinical and molecular pathway analyses. Plink served for genetic analyses. Quality checking was standard, inflation factor was controlled by lambda values.
Quetiapine and Perphenazine were associated with QT variation (P = 0.002; Estimate = 5.79 and P = 5.67e-06; Estimate = 8.96 respectively). No other significant association was detected. No inflation was detected. Axon guidance and Collagen biosynthesis (Table 1) were associated with QT variation at a conservative (adjusted) P value < 0.01.
Two molecular pathways were identified as possibly involved in QT modifications during antispsychotic treatment in SKZ patients. Previous evidence supports a role of the same pathways in cardiac disorders [1,2]. Interaction of specific SNPs with the drugs will be focus of further research.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
We have analyzed Chandra/High Energy Transmission Grating spectra of the X-ray emission line gas in the Seyfert galaxy NGC 4151. The zeroth-order spectral images show extended H- and He-like O and Ne, up to a distance r ˜ 200 pc from the nucleus. Using the 1st-order spectra, we measure an average line velocity ˜230 km s–1, suggesting significant outflow of X-ray gas. We generated Cloudy photoionization models to fit the 1st-order spectra; the fit required three distinct emission-line components. To estimate the total mass of ionized gas (M) and the mass outflow rates, we applied the model parameters to fit the zeroth-order emission-line profiles of Ne IX and Ne X. We determined an M ≍ 5.4 × 105Mʘ. Assuming the same kinematic profile as that for the [O III] gas, derived from our analysis of Hubble Space Telescope/Space Telescope Imaging Spectrograph spectra, the peak X-ray mass outflow rate is approximately 1.8 Mʘ yr–1, at r ˜ 150 pc. The total mass and mass outflow rates are similar to those determined using [O III], implying that the X-ray gas is a major outflow component. However, unlike the optical outflows, the X-ray emitting mass outflow rate does not drop off at r > 100pc, which suggests that it may have a greater impact on the host galaxy.
We present spatially resolved kinematics of ionized gas in the narrow-line region (NLR) and extended narrow-line region (ENLR) in a sample of nearby active galaxies. Utilizing long-slit spectroscopy from Apache Point Observatory (APO)13s ARC 3.5 m Telescope and Hubble Space Telescope (HST) we analyzed the strong λ5007 Å [O III] emission line profiles and mapped the radial velocity distribution of gas at increasing radii from the center. We identified the extents of Active Galactic Nuclei (AGN) driven outflows in our sample and determined the distances at which the observed gas kinematics is being dominated by the rotation of the host galaxy. We also measured the effectiveness of radiative driving of the ionized gas using mass distribution profiles calculated with two-dimensional modeling of surface brightness profiles in our targets. Finally, we compared our kinematic results of the outflow sizes with the maximum distances at which the gas is being radiatively driven to investigate whether these outflows are capable of disrupting or evacuating the star-forming gas at these distances.
We used Space Telescope Imaging Spectrograph (STIS) long slit medium-resolution G430M and G750M spectra to analyze the extended [O III] λ5007 emission in a sample of twelve QSO2s from Reyes et al. (2008). The purpose of the study was to determine the properties of the mass outflows and their role in AGN feedback. We measured fluxes and velocities as functions of deprojected radial distances. Using photoionization models and ionizing luminosities derived from [O III], we were able to estimate the densities for the emission-line gas. From these results, we derived masses, mass outflow rates, kinetic energies and kinetic luminosity rates as a function of radial distance for each of the targets. Masses are several times 103 - 107 solar masses, which are comparable to values determined from a recent photoionization study of Mrk 34 (Revalski). Additionally, we are studying the possible role of X-ray winds in these QSO2s.