Circulating delta‐like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus‐based immunosuppression

Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta‐like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR‐based, calcineurin inhibitor‐free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers— SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.     

Direct and indirect costs of refractory epilepsy in a tertiary epilepsy center in Germany

PURPOSE: There are only few studies on the costs of epilepsy in Germany. Therefore, we performed a pilot study to estimate the direct and indirect costs of refractory epilepsy in a German epilepsy center. METHODS: A "prevalence-based," cross-sectional convenience sample of adults with active epilepsy attending the outpatient clinic of our tertiary epilepsy center was evaluated. Seizure-free patients and patients presenting with their first seizure were excluded. Direct and indirect costs were prospectively recorded over a three-month period using questionnaires and a patient diary. Cost driving factors were identified. RESULTS: One hundred one patients were included (40.7+/-15.2 years; disease duration: 18.1+/-15.3 years; 6 patients had focal epilepsy with simple partial seizures only, 28 with complex partial seizures, 43 with secondarily generalized tonic-clonic seizures; 20 had idiopathic generalized epilepsy with generalized tonic-clonic seizures). The total costs of epilepsy per patient were in average euro 2610+/-4200 over the three-month period. Direct cost contributed 39% to the total costs. Costs of anticonvulsant medication were the main contributor to the direct costs while indirect costs were caused mainly by losses due to early retirement. Cost driving factors included higher seizure frequency, longer disease duration, ictal falls, and situationally inappropriate complex behavior during or after the seizure. CONCLUSIONS: Indirect costs were higher than direct costs in adult patients with active epilepsy attending a German epilepsy center. Medication contributed the most to the direct costs and early retirement was the main factor for the indirect costs. The costs of poorly controlled epilepsy in this German study were above average of the European costs of epilepsy.     

Initial rewarding effects of cocaine and amphetamine assessed in a day using the single‐exposure place preference protocol

In rodents, only a single dose of cocaine or amphetamine is required to cause a marked increase in extracellular dopamine, induce hyperlocomotion and cause persistent plasticity changes within dopaminergic neurons of the ventral tegmental area (VTA). The initial drug experience is suggested to predict vulnerability of developing addiction, but only few studies have assessed the perception of reward accompanying this initial exposure. We recently presented an approach to assess the initial rewarding effects of cocaine in mice with a single‐exposure place preference (sePP) protocol, avoiding repeated drug injections. Here, we demonstrate a condensed version of the sePP, allowing assessment of initial subjective reward‐perception within a day. By using this protocol, we demonstrate that a single exposure to both cocaine and amphetamine is sufficient to induce place preference. Furthermore, we use chemogenetics ( Designer Receptors Exclusively Activated by Designer Drugs [DREADD]) to show that both inhibitory and stimulatory modulation of VTA DA signalling disrupts cocaine‐induced place preference in the condensed sePP. Our findings support the presence of initial reward‐perception of both cocaine and amphetamine, and the formation of drug‐context association. In addition, our data support that VTA DA signalling prior to drug exposure affects either reward‐perception or the time during which associations are formed, thereby preventing induction of cocaine‐induced place preference in the sePP. The easy and timesaving sePP protocol should form a critical basis for further deciphering the complex mechanisms underlying the progression from the initial drug experience to escalating drug intake and addiction.     

Reduction of the HIV-1 reservoir in resting CD4+ T-lymphocytes by high dosage intravenous immunoglobulin treatment: a proof-of-concept study

Background  

The latency of HIV-1 in resting CD4⁺ T-lymphocytes constitutes a major obstacle for the eradication of virus in patients on antiretroviral therapy (ART). As yet, no approach to reduce this viral reservoir has proven effective.     

Psychometric properties of the apathy evaluation scale in patients with Parkinson's disease

Parkinson's disease (PD) frequently entails non‐motor symptoms, worsening the course of the disease. Apathy is one of the core neuropsychiatric symptoms that has been investigated in recent years; research is however hampered by the limited availability of well‐evaluated apathy scales for these patients. We evaluated the psychometric properties of the Apathy Evaluation Scale (AES) in a sample of PD patients. Psychometric properties, convergent and discriminant validity and sensitivity/specificity were evaluated in patients with (n = 582) or without dementia/depression (n = 339). Internal consistency was high in the entire sample as well as in patients without dementia/depression. Correlations were moderate for convergent validity (UPDRS I item 4: motivation). While apathy could be differentiated from cognitive decline, it was related to depression (Geriatric Depression Scale, GDS‐15). The overall classification accuracy based on the UPDRS I item 4 was comparable for AES and GDS scores. The AES exhibits good psychometric properties in PD patients with and without dementia and/or depression. Commonly used screenings on the presence of apathy had low detection rates compared to the AES and reflected both apathetic and depressive symptoms. Psychometric evaluation of available instruments will support further research on the clinical relevance of apathy for disease progression and treatment approaches in PD patients.     

Regulation of oligodendrocyte precursor maintenance by chondroitin sulphate glycosaminoglycans

Chondroitin sulfate proteoglycans (CSPGs) have been proven to inhibit morphological maturation of oligodendrocytes as well as their myelination capabilities. Yet, it remained unclear, whether CSPGs and/or their respective chondroitin sulfate glycosaminoglycan (CS‐GAG) side chains also regulate the oligodendrocyte lineage progression. Here, we initially show that CS‐GAGs detected by the monoclonal antibody 473HD are expressed by primary rat NG2‐positive oligodendrocyte precursor cells (OPCs) and O4‐positive immature oligodendrocytes. CS‐GAGs become down‐regulated with ongoing oligodendrocyte differentiation. Enzymatic removal of the CS‐GAG chains by the bacterial enzyme Chondroitinase ABC (ChABC) promoted spontaneous differentiation of proliferating rat OPCs toward O4‐positive immature oligodendrocytes. Upon forced differentiation, the enzymatic removal of the CS‐GAGs accelerated oligodendrocyte differentiation toward both MBP‐positive and membrane forming oligodendrocytes. These processes were attenuated on enriched CSPG fractions, mainly consisting of Phosphacan/RPTPβ/ζ and to less extent of Brevican and NG2. To qualify CS‐GAGs as universal regulators of oligodendrocyte biology, we finally tested the effect of CS‐GAG removal on OPCs from different sources such as mouse cortical oligospheres, mouse spinal cord neurospheres, and most importantly human‐induced pluripotent stem cell‐derived radial glia‐like neural precursor cells. For all culture systems used, we observed a similar inhibitory effect of CS‐GAGs on oligodendrocyte differentiation. In conclusion, this study clearly suggests an important fundamental principle for complex CS‐GAGs to regulate the oligodendrocyte lineage progression. Moreover, the use of ChABC in order to promote oligodendrocyte differentiation toward myelin gene expressing cells might be an applicable therapeutic option to enhance white matter repair. GLIA 2016;64:270–286