Intrinsic up-regulation of 2-AG favors an area specific neuronal survival in different in vitro models of neuronal damage

BACKGROUND: The endocannabinoid 2-arachidonoyl glycerol (2-AG) acts as a retrograde messenger and modulates synaptic signaling e. g. in the hippocampus. 2-AG also exerts neuroprotective effects under pathological situations. To better understand the mechanism beyond physiological signaling we used Organotypic Entorhino-Hippocampal Slice Cultures (OHSC) and investigated the temporal regulation of 2-AG in different cell subsets during excitotoxic lesion and dendritic lesion of long range projections in the enthorhinal cortex (EC), dentate gyrus (DG) and the cornu ammonis region 1 (CA1). RESULTS: 2-AG levels were elevated 24 h after excitotoxic lesion in CA1 and DG (but not EC) and 24 h after perforant pathway transection (PPT) in the DG only. After PPT diacylglycerol lipase alpha (DAGL) protein, the synthesizing enzyme of 2-AG was decreased when Dagl mRNA expression and 2-AG levels were enhanced. In contrast to DAGL, the 2-AG hydrolyzing enzyme monoacylglycerol lipase (MAGL) showed no alterations in total protein and mRNA expression after PPT in OHSC. MAGL immunoreaction underwent a redistribution after PPT and excitotoxic lesion since MAGL IR disappeared in astrocytes of lesioned OHSC. DAGL and MAGL immunoreactions were not detectable in microglia at all investigated time points. Thus, induction of the neuroprotective endocannabinoid 2-AG might be generally accomplished by down-regulation of MAGL in astrocytes after neuronal lesions. CONCLUSION: Increase in 2-AG levels during secondary neuronal damage reflects a general neuroprotective mechanism since it occurred independently in both different lesion models. This intrinsic up-regulation of 2-AG is synergistically controlled by DAGL and MAGL in neurons and astrocytes and thus represents a protective system for neurons that is involved in dendritic reorganisation

An energy-economic analysis of real-world hybrid building energy systems

A coordinated operation of decentralised micro-scale hybrid energy systems within a locally managed network such as a district or neighbourhood will play a significant role in the sector-coupled energy grid of the future. A quantitative analysis of the effects of the primary energy factors, energy conversion efficiencies, load profiles, and control strategies on their energy-economic balance can aid in identifying important trends concerning their deployment within such a network. In this contribution, an analysis of the operational data from five energy laboratories in the trinational Upper-Rhine region is evaluated and a comparison to a conventional reference system is presented. Ten exemplary data-sets representing typical operation conditions for the laboratories in different seasons and the latest information on their national energy strategies are used to evaluate the primary energy consumption, CO2 emissions, and demand-related costs. Various conclusions on the ecologic and economic feasibility of hybrid building energy systems are drawn to provide a toe-hold to the engineering community in their planning and development

Individualized web-based exercise for the treatment of depression : randomized controlled trial

Background: Due to the high prevalence of depressive disorders, it is mandatory to develop therapeutic strategies that provide universal access and require limited financial and human resources. Web-based therapeutic approaches fulfill these conditions. Objective: The objective of our study was to assess the feasibility, acceptability, and efficacy of a supervised, individualized 8-week Web-based exercise intervention conducted for patients with moderate to severe depression. Methods: We recruited 20 patients with unipolar depression and randomly assigned them into 2 groups (intervention, exercise program group, n=14, and control, treatment-as-usual group, n=6). At baseline, depressive symptoms were rated via the Quick Inventory of Depressive Symptomatology (QIDS) by patients themselves (QIDS–self-report, QIDS-SR) and by a blinded psychiatrist (QIDS–clinician rating, QIDS-C). In addition, performance diagnostics (lactate analysis, spiroergometry during a treadmill walking test) were conducted. Quality of life was assessed via the Short Form-36 questionnaire (SF-36) and self-efficacy via the General Self Efficacy scale (GSE). In addition, habitual physical activity (HPA) was determined via the Baecke questionnaire. Participants of the intervention group received exercise schedules once weekly with endurance and strength training instructions. Rating of depressive symptoms was repeated after 6-12 days and 8 weeks; performance diagnostics and the completion of all the questionnaires were repeated after 8 weeks only. Results: The severity of depression subsided significantly in the intervention group after 8 weeks (median change in QIDS-SR: −5; interquartile range, IQR: −2 to −10), although it was already evident within the first 6-12 days (median change in QIDS-SR: −6; IQR: −2 to −8). During the intervention, participants undertook a median of 75 (IQR: 63 to 98) minutes of endurance training per week or 84% (16 [IQR: 9 to 19] of 19 [IQR: 15 to 21]) recommended endurance units in total. In addition, 9 (IQR: 4 to 12) of 10 (IQR: 8 to 13) recommended strength training exercise units were conducted during the 8 weeks. Performance diagnostics revealed a substantial increase in the maximum output in Watt for the intervention group after 8 weeks. Moreover, the intervention showed a favorable effect on SF-36 items “emotional well-being” and “social functioning” as well as on GSE and HPA scores. Conclusions: Our individualized Web based exercise intervention for moderate to severe depression was highly accepted by the patients and led to a significant and clinically relevant improvement of depressive symptoms

Hubungan Tingkat Pengetahuan Ibu, Dukungan Keluarga dan Peran Tenaga Kesehatan terhadap Pemberian Inisiasi Menyusu Dini di Puskesmas Banjar Serasan Kecamatan Pontianak Timur Tahun 2013

Latar belakang: Inisiasi menyusu dini (IMD) adalah proses bayi menyususendiri segera setelah lahir dimana bayi dibiarkan mencari puting susuibunya sendiri selama 1 jam pertama kelahirannya. Puskesmas BanjarSerasan merupakan puskesmas dengan angka pemberian IMD terendahdi Kota Pontianak dengan angka pemberian IMD hanya sebesar 17,94%.Beberapa faktor yang dicurigai mempengaruhi pemberian IMD adalahpengetahuan ibu, dukungan keluarga dan peran tenaga kesehatan.Tujuan: Mengetahui hubungan antara pengetahuan ibu, dukungankeluarga dan peran tenaga kesehatan dengan pemberian IMD.Metodologi: Penelitian analitik dengan pendekatan cross sectional.Penelitian ini dilakukan selama bulan Oktober sampai Desember 2013.Subjek penelitian adalah ibu post partum yang terdata di PuskesmasBanjar Serasan yang memenuhi kriteria sampel. Total sampel sebanyak48 responden. Pengumpulan data menggunakan kuesioner dan diambildengan metode purposive sampling. Analisis data dengan teknik chisquare. Hasil: Sebanyak 75% responden dengan umur20 - 35 tahun, 50% responden dengan pendidikan menengah, 75%responden dengan multipara, 60,42% responden memiliki pengetahuanbaik, 56,25% responden dengan dukungan keluarga baik, 50% respondendengan peran tenaga kesehatan baik dan 64,5% responden memberikanIMD. Terdapat hubungan bermakna antara peran tenaga kesehatandengan pemberian IMD (p=0,007). Tidak terdapat hubungan bermaknaantara umur (p=0,056), tingkat pendidikan (p=0,547) dan paritas (p=0,732)dengan pengetahuan responden. Tidak terdapat hubungan bermaknaantara pengetahuan responden (p=0,867) dan dukungan keluarga(p=0,342) dengan pemberian IMD. Kesimpulan: Peran tenaga kesehatanmemiliki hubungan bermakna dengan pemberian IMD. Pengetahuan ibudan dukungan keluarga tidak memiliki hubungan bermakna denganpemberian IMD. Kata kunci: IMD, pengetahuan ibu, dukungan keluarga, peran tenagakesehatan.1. Program Studi Pendidikan Dokter, Fakultas Kedokteran UniversitasTanjungpura, Pontianak, Kalimantan Barat. 2. Departermen Kesehatan Masyarakat, Fakultas Kedokteran UniversitasTanjungpura, Pontianak, Kalimantan Barat. 3. Departemen Histologi, Fakultas Kedokteran Universitas Tanjungpura,Pontianak, Kalimantan Barat

Radiological and pathological findings of a metastatic composite paraganglioma with neuroblastoma in a man: a case report

INTRODUCTION: Composite tumors of the adrenal medulla or paraganglia are extremely rare and present a diagnostic dilemma. These tumors consist of a neuroendocrine component mixed with a neural component.We describe the imaging characteristics together with the corresponding pathological findings of a composite tumor. Apart from any component-specific imaging findings, the hallmark of this entity is the presence of histologically distinguishable components. CASE PRESENTATION: A 61-year-old Caucasian man was referred to our hospital due to a suspect lesion found on chest computed tomography carried out for unclear thoracic pain. An abdominal computed tomography scan and ultrasound examination detected a retroperitoneal tumor comprising two different tumor components. Twenty-four-hour urine revealed high levels of normetanephrine, characteristic of a neuroendocrine tumor. An octreoscan prior to surgical procedures revealed multiple osseous and intra-hepatic metastases. The final histopathological workup revealed a composite paraganglioma with neuroblastoma. Our patient died ten months after the initial diagnosis from tumor-associated complications. CONCLUSIONS: Composite paragangliomas with neuroblastoma are rare tumors of the retroperitoneum. Such tumors should be considered in the differential diagnosis of retroperitoneal masses

Evaluation of a Novel Thiol–Norbornene-Functionalized Gelatin Hydrogel for Bioprinting of Mesenchymal Stem Cells

Introduction: Three-dimensional bioprinting can be considered as an advancement of the classical tissue engineering concept. For bioprinting, cells have to be dispersed in hydrogels. Recently, a novel semi-synthetic thiolene hydrogel system based on norbornene-functionalized gelatin (GelNB) and thiolated gelatin (GelS) was described that resulted in the photoclick hydrogel GelNB/GelS. In this study, we evaluated the printability and biocompatibility of this hydrogel system towards adipose-tissue-derived mesenchymal stem cells (ASCs). Methods: GelNB/GelS was synthesized with three different crosslinking densities (low, medium and high), resulting in different mechanical properties with moduli of elasticity between 206 Pa and 1383 Pa. These hydrogels were tested for their biocompatibility towards ASCs in terms of their viability, proliferation and differentiation. The extrusion-based bioprinting of ASCs in GelNB/GelS-high was performed to manufacture three-dimensional cubic constructs. Results: All three hydrogels supported the viability, proliferation and chondrogenic differentiation of ASCs to a similar extent. The adipogenic differentiation of ASCs was better supported by the softer hydrogel (GelNB/GelS-low), whereas the osteogenic differentiation was more pronounced in the harder hydrogel (GelNB/GelS-high), indicating that the differentiation fate of ASCs can be influenced via the adaption of the mechanical properties of the GelNB/GelS system. After the ex vivo chondrogenic differentiation and subcutaneous implantation of the bioprinted construct into immunocompromised mice, the production of negatively charged sulfated proteoglycans could be observed with only minimal inflammatory signs in the implanted material. Conclusions: Our results indicate that the GelNB/GelS hydrogels are very well suited for the bioprinting of ASCs and may represent attractive hydrogels for subsequent in vivo tissue engineering applications

Discrete States of a Protein Interaction Network Govern Interphase and Mitotic Microtubule Dynamics

The cytoplasm of eukaryotic cells is thought to adopt discrete “states” corresponding to different steady states of protein networks that govern changes in subcellular organization. For example, in Xenopus eggs, the interphase to mitosis transition is induced solely by activation of cyclin-dependent kinase 1 (CDK1) that phosphorylates many proteins leading to a reorganization of the nucleus and assembly of the mitotic spindle. Among these changes, the large array of stable microtubules that exists in interphase is replaced by short, highly dynamic microtubules in metaphase. Using a new visual immunoprecipitation assay that quantifies pairwise protein interactions in a non-perturbing manner in Xenopus egg extracts, we reveal the existence of a network of interactions between a series of microtubule-associated proteins (MAPs). In interphase, tubulin interacts with XMAP215, which is itself interacting with XKCM1, which connects to APC, EB1, and CLIP170. In mitosis, tubulin interacts with XMAP215, which is connected to EB1. We show that in interphase, microtubules are stable because the catastrophe-promoting activity of XKCM1 is inhibited by its interactions with the other MAPs. In mitosis, microtubules are short and dynamic because XKCM1 is free and has a strong destabilizing activity. In this case, the interaction of XMAP215 with EB1 is required to counteract the strong activity of XKCM1. This provides the beginning of a biochemical description of the notion of “cytoplasmic states” regarding the microtubule system

Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity

Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease