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Cooperative interactions are widespread in the animal kingdom. Their occurrence can be explained by mutually non-exclusive benefits increasing an individual's (1) indirect fitness by cooperating with kin, and (2) direct fitness by mutually or reciprocally cooperating with others. Many cooperative behaviors require well-developed neuroendocrine mechanisms regulating their quantity and quality. Fishes offer great opportunities to increase our insight into ultimate and proximate questions of cooperation. Their social systems range from solitary- and pair-living to lose fission–fusion groups and highly complex societies. Cooperative interactions are an essential part of the behavioural repertoire of most fish species, occurring in a variety of social situations like predator inspection, foraging, mating, or brood care. Such interactions take place among related and unrelated individuals and even between members of different species. This fascinating diversity allows investigating all crucial factors mediating cooperation, e.g., by studying behavioural interactions within and between species, by applying comparative approaches between taxonomic groups and by using state-of-the-art genetic and neuroendocrine technologies to resolve the underlying mechanisms. This chapter provides an overview of the mechanisms and functions of cooperative behaviour in fishes, with the overall aim to illuminate the evolution of cooperative behaviour in general.
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
To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study.
Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed.
Community-based multi-centered study based in Toronto across 5 academic sites.
Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls.
We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores.
A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD.
This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.
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.
Barriers to research participation by racial and ethnic minority group members are multi-factorial, stem from historical social injustices and occur at participant, research team, and research process levels. The informed consent procedure is a key component of the research process and represents an opportunity to address these barriers. This manuscript describes the development of the Strengthening Translational Research in Diverse Enrollment (STRIDE) intervention, which aims to improve research participation by individuals from underrepresented groups.
We used a community-engaged approach to develop an integrated, culturally, and literacy-sensitive, multi-component intervention that addresses barriers to research participation during the informed consent process. This approach involved having Community Investigators participate in intervention development activities and using community engagement studios and other methods to get feedback from community members on intervention components.
The STRIDE intervention has three components: a simulation-based training program directed toward clinical study research assistants that emphasizes cultural competency and communication skills for assisting in the informed consent process, an electronic consent (eConsent) framework designed to improve health-related research material comprehension and relevance, and a “storytelling” intervention in which prior research participants from diverse backgrounds share their experiences delivered via video vignettes during the consent process.
The community engaged development approach resulted in a multi-component intervention that addresses known barriers to research participation and can be integrated into the consent process of research studies. Results of an ongoing study will determine its effectiveness at increasing diversity among research participants.
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)
OBJECTIVES/GOALS: Peri-implantitis is the inflammation of peri-implant mucosa and subsequent loss of supporting bone. Its treatment is only <40% successful mainly due to persistent bacterial infection. The goal of this project is to increase success rates by developing a robust antibiofilm multi-biomolecular membrane that can be placed around implant surfaces. METHODS/STUDY POPULATION: A collagen membrane was soaked in the antimicrobial peptide GL13K solution overnight to form an interpenetrating fibrillary network. The nanostructure of the membrane was imaged with scanning electron microscope (SEM). The hydrophobicity of the membrane was analyzed by water contact angle (WCA) measurements. The biodegradability was tested in a 0.01 mg/mL Type I collagenase solution for up to 5 weeks. The antimicrobial activity of the membrane was assessed with Gram-positive oral bacteria Streptococcus gordonii. The cytotoxicity was evaluated by culturing human gingival fibroblasts (HGF), and the osteogenesis was assessed using preosteoblasts MC3T3. Pure collagen membrane was used as the control. Statistical significance (p<0.05) was determined by one-way ANOVA with Tukey’s HSD test. RESULTS/ANTICIPATED RESULTS: The antimicrobial peptide GL13K self-assembled to short fibrils (< 1 µm long), which entangled with the larger collagen fibers (around 200 nm in diameter). The collagen fibers presented characteristic periodic banding structures, which provided biomimetic cues for cell behavior as extracellular matrix. The interpenetrated GL13K fibrils turned the highly hydrophilic collagen membrane to a hydrophobic membrane (WCA = 135 °) and significantly reduced the rate of degradation by collagenases. The developed membrane was efficient in preventing the attachment of S. gordonii. A large portion of the attached bacteria was killed on the surface of the membrane. The incorporation of GL13K did not affect the cytocompatibility of the membrane for HGF. DISCUSSION/SIGNIFICANCE OF IMPACT: We developed an antibiofilm membrane with interpenetrating collagen and antimicrobial peptide fibrils. The strong antimicrobial activity and low cytotoxicity support its further translational evaluation as scaffolds for increasing success rate in treating peri-implantitis.
Current treatment approaches for depression center on various forms of psychosocial therapy and the use of antidepressant drugs. The response rates for both of these approaches are similar, with mostly reduction, but not complete remission, of symptoms. Poor adherence to recommended treatment is an issue complicating the management of depression and prevention of recurrent episodes. This study evaluated the efficacy of a novel form of receptive music therapy which can be easily adminstered to out patients.
Enrolled subjects (n=203, average age 49.6 ± 13.1 years, 28.1% male) were randomized into four arms: Music Therapy 1 (MT1), Music Therapy 2 (MT2), Placebo (nature sounds) and waiting-list Control. Subjects listened for 30 minutes, twice daily. Multivariate linear regression models assessed depressive symptom changes over five weeks, based on a composite scale (COMP) and the Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS-D) alone.
On average, a significant, positive change in COMP was observed for MT1 (β=1.44, p=0.030), but not for MT2 (β=1.14, p=0.059) or Placebo (β=0.57, p=0.397). After 15 weeks, study participation was associated with a mean HAM-D score reduction of 60% for 89,1% of the compliant probands.
Newly composed receptive music therapy, as explored in this study, is associated with reduced depressive symptoms and high treatment compliance, and may therefore potentially represent an effective depression treatment alternative or adjunctive therapy to pharmacological and psychosocial approaches.
When comparing the efficay of antipsychotics in clinical studies it would be of high practical relevance to know which doses of the respective drugs would result in equivalent blocking of dopamine-D2-receptors. This study aimed to find clinically applicable dose equivalents for haloperidol, risperidone and olanzapine.
As the occurrence of EPS correlates closely with a blockade of about 80% or more of dopamin-D2-receptors the proportion of patients developing EPS in relation to various doses of either Haloperidol (n=5252), risperidone (n=5017) or olanzapine (n =5029) was calculated. This retrospective, observational study included 20.252 inpatients from 20 hospitals with a diagnosis of schizophrenia and related disorders (ICD10 F20-25). The prescription of anticholinergic medication was utilized as surrogate parameter for the occurrence of EPS. OR, RR and NNH under different doses of AP were calculated and data entered into a probit model to predict the risk of EPS over a continuous dose range. For filtering the data ToscanaJ (FBA) was used.
1.) Same doses of risperidone and haloperidol induced the same proportion of EPS, reflected in a constant dose ratio of both drugs of ∼ 1:1 over the whole dose range.
2.) Over the whole dose range there was no linear relation between olanzapine on one hand and haloperidol and risperidone on the other hand.
3.) The results were corroborated by the probit analysis.
Previous clinical trials comparing olanzapine, risperidone and haloperidol found higher risks of EPS for Haloperidol. We propose a new model to calculate dose equivalents.
The majority of women in drug treatment facilities are of childbearing age. According to a SAMHSA Report, four percent of women aged between 15 and 44, are pregnant while entering treatment systems. These women represent a challenging patient population, that is in need of a comprehensive model of care, consisting of psychiatrists, psychologists, social workers, nurses and OBGYNs. Exposure to illegal substances during pregnancy may have consequences on the course of pregnancy and neonatal outcome. The fact that almost all patients showing up are also nicotine-dependent, should be taken into account, as neonatal withdrawal symptoms can be worsened. Furthermore, substance dependent women often find themselves in a situation of psychosocial instability. Prevalence of co-morbid somatic (e.g. hepatitis C, malnutrition) and psychiatric disorders (PTSD, depression)is high. As these pregnancies are rated as “high-risk”, prenatal checks should be undergone frequently. Recommended treatment for opioid-dependent, pregnant women is maintenance therapy with opioids. Post-delivery, 55 – 94% of infants exposed to substances in utero, may develop a neonatal abstinence syndrome (NAS). Incidence, time of onset and severity of NAS are associated with type of substances used. A standardized procedure of assessment and monitoring of NAS, as well as pharmacological and non-pharmacological treatment of these neonates is highly needed. By the means of a multi-professional treatment approach, the length of hospital stay may be shortened dramatically. In regard to a better future outcome, special aftercare (medical care plus psychosocial support) for mothers and infants should be provided, as well as further research.
Increasing research interest is focussing also on Quality of Life (QoL) in substance dependent individuals. QoL-assessments have been acknowledged as promising measurements in order to evaluate drug treatment programs.
A prospective, randomized, double-blind, double-dummy, cross-over study design was used in order to compare methadone and slow-release morphine maintenance on patients´ QoL. Sixty-four participants were randomized between two treatment groups receiving either slow-release morphine capsules for 7 weeks followed by methadone oral solution for another 7 weeks (group A), or vice versa (group B). At baseline, week 7 and week 14 QoL status was evaluated using the German version of the Lancashire Quality of Life Profile.
A significant time effect with respect to the domains: general state of health (0.018), mental health (p=0.001), general well-being (p<0.001), leisure time at home (p=0.032) and leisure time out of home (p=0.008). Our findings did not show any statistically significant differences between between the two treatment groups in any Quality of Life scores at week 7 and 14. At the end of study phase (week 14) group A showed significant increases in the domains general well-being (0.010), leisure time at home (p=0.014). Significant improvements for group B were assessed with regard to general well-being (p=0.003), mental health (p=0.003) and general state of health (p=0.017).
The development of treatment programs should focus also on the patients´ subjective perspective. According to our findings agonistic opioid maintenance treatment yields not only to treatment response but also to improvements in patients quality of life.
The effect of treatment (28 days) with zopiclone, triazolam, flunitrazepam and placebo on sleep quality and daytime well-being was proven in a randomised, double-blind, parallel group, multicentre study in private practice. Results of an exploratory statistic of treatment efficacy in a subgroup of 1,291 patients suffering from insomnia are presented. Patients met the following criteria: insomnia lasting at least four weeks and the presence of at least two of the following: 1) sleep latency ≥ 45 minutes, 2) total sleep time ≤ 6 hours, and 3) nocturnal awakening ≥3 times. Treatment efficacy was assessed according to the following factors: either a shortening of sleep latency by at least 15 minutes, or prolongation of total sleep time by at least 20%, or reduction of the number of nocturnal awakenings to three or less and a refreshed feeling in the morning as well as no impairment in daytime well-being due to tiredness or anxiety. The total response rate was markedly higher with zopiclone (42.3%; p = 0.0003) than with placebo (29.0%). Triazolam (36.6%; p = 0.0905) and flunitrazepam (33.1%; p = 0.3401) were also more effective than the placebo, but they both tended to have a lower response rate than with zopiclone (p = 0.1199 and 0.0151, respectively). Total response was found to be essentially a reflection of the response of the socially important parameter of daytime well-being. These results suggest that zopiclone is more effective in the treatment of insomnia than either triazolam or flunitrazepam. Since the response of daytime well-being to therapy was generally poor, this parameter embodies the next main therapeutic challenge in the treatment of patients with insomnia.
Depression is a prevalent, often chronic and disabling disease. Current psychosocial and antidepressant treatments result in similar response rates with mostly symptom reduction, but not complete remission. Poor treatment adherence complicates depression management and prevention of recurrent episodes. Therefore, new therapies must be developed urgently, that alone or combined with present treatments, can significantly improve therapy outcomes.
Depression is potentially associated with decreased heart rate variability (HRV). Based on our previous studies' results which demonstrated HRV increase following auditory stimulation, we developed two interventions based on specifically for depression treatment composed and arranged music and tested the efficacy in a waiting list and placebo controlled double-blind study with depressed outpatients.
Depression status was assessed at the beginning of T1 and T2 using the Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale (HADS-D) and by a composite (COMP) scale based on HAM-D, BDI and HADS-D z-scores. Changes in depressive symptoms between T1 and T2 (5 week period) were assessed based on COMP and on HAM-D, BDI and HADS-D scores alone. Compared to the control arm, a significant, positive effect in COMP was observed for MT1 at T2. Both MT1 and MT2 were associated with significant positive effects (HAM-D and HADS-D scores). MT2 resulted in positive effects on BDI scores. No significant change in any depression score was detected in the placebo arm. Treatment continuation was associated with an effect increase (mean HAM-D score reduction of 60%) after 10 to 15 weeks of treatment.
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.
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.