The Role of Hippocampus in the Pathophysiology of Depression

Hippocampus, as a part of the limbic cortex, has a variety of functions ranging from mating behavior to memory besides its role in the regulation of emotions. The hippocampus has reciprocal interactions of with other brain regions which act in the pathophysiology of major depressive disorder (MDD). Moreover, since the hippocampus is a scene for the neurogenesis, which can be seen as a response to antidepressant treatment, the hippocampus became a focus of attention in neuroimaging studies of MDD. It has been shown that brain derived neurotrophic factor (BDNF), that is responsible from the neurogenesis, is associated with the response to the antidepressants and antidepressant drugs are ineffective if neurogenesis is hindered.Hippocampal atrophy is expected with the decrease of neurogenesis as a result of the lower BDNF levels with the deleterious effects of glucocorticoids in depression. Recurrent and severe depression seems to cause such a volume reduction though first episode MDD subjects do not differ from healthy individuals in respect to their hippocampal volumes (HCVs) measured by magnetic resonance imaging methods. One may argue regarding these findings that the atrophy in the hippocampus may be observed in the long term and the decrease in BDNF levels may predispose the volume reduction. Although it has been postulated that smaller HCV as a result of genetic and environmental factors and prior to the illness, may cause a vulnerability to MDD, sufficient evidence has not been accumulated yet and the view that HCV loss develops as depression progresses is widely accepted. Findings that serum BDNF (sBDNF) is lower in MDD patients though HCVs of patients do not differ from healthy individuals and the positive correlation of sBDNF with HCV seen only in the patient group support this view. It can be assumed that depressed patients have sensitivity for the fluctuations in BDNF levels. Follow-up studies which consider effects of hipotalamo-pituiter-adrenal axis dysregulation and monoamine systems are needed to further elucidate the role of BDNF in the pathogenesis of MDD. Results of these studies may lead the way for the treatment of resistant or recurrent depressive disorder

The Steady Spin Down Rate of 4U 1907+09

Using X-ray data from the Rossi X-Ray Timing Explorer (RXTE), we report the pulse timing results of the accretion powered high mass X-ray binary (HMXRB) pulsar 4U 1907+09 covering a time span of almost two years. We measured three new pulse periods in addition to the previously measured four pulse periods. We are able to connect pulse arrival times in phase for more than a year. The source has been spinning down almost at a constant rate with a spin down rate of \dot \nu = (-3.54 \pm 0.02) \times 10^{-14} Hz s ^{-1} for more than 15 years. Residuals of pulse arrival times yield a very low level of random walk noise strengths \sim 2 \times 10^{-20} rad ^{2} sec ^{-3} on a time scale of 383 days, which is four decades lower than that of the HMXRB pulsar Vela X-1. The noise strength is only a factor of 5 greater than that of the low mass X-ray binary pulsar (LMXRB) 4U 1626-67. The low level of the timing noise and the very stable spin down rate of 4U 1907+09 makes this source unique among the HMXRBs, providing another example, in addition to 4U 1626-67, of long term quiet spin down from an accreting source. These examples show that the extended quiet spin down episodes observed in the anomalous X-ray pulsars (AXPs) pulsars 1RXS J170849.0-400910 and 1E 2259+586 do not necessarly imply that these sources are not accreting pulsars.Comment: Submitted to MNRA

Rationale and design for the randomized placebo-controlled double-blind trial studying the effect of single antiplatelet therapy (clopidogrel) versus dual antiplatelet therapy (clopidogrel/acetylsalicylic acid) on the occurrence of atherothrombotic events following lower extremity peripheral transluminal angioplasty (CLEAR-PATH)

Rationale: Antiplatelet therapy (APT) is the standard of care after endovascular revascularization (EVR) in patients with peripheral artery disease (PAD). APT aims to prevent both major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Nonetheless, the rates of MACE and MALE after EVR remain high. In coronary artery and cerebrovascular disease, dual APT (DAPT)compared to acetylsalicylic acid alone has been proven to reduce MACE without increasing the risk of major bleeding when applied for a restricted number of weeks. However, within the PAD population, insufficient data are available to understand the potential attributable effect of DAPT over single APT (SAPT). Therefore, prospective randomized studies in targeted study populations are warranted. Trial design: CLEAR-PATH is a Dutch multicenter, double-blind, placebo-controlled, randomized trial comparing SAPT (clopidogrel 75 mg plus placebo) with DAPT (clopidogrel 75 mg plus acetylsalicylic acid 80 mg) in patients with PAD undergoing EVR. CLEAR-PATH includes a time-to-event analysis with a follow-up of one year. The primary composite efficacy endpoint consists of all-cause mortality, nonfatal stroke, nonfatal myocardial infarction, severe limb ischemia, (indication for) re-intervention due to any symptomatic restenosis, re-occlusion, or due to acute limb ischemia, and major amputation. The primary safety endpoint contains major bleeding following the Thrombolysis in Myocardial Infarction classification. The enrolment started in August 2022. In total 450 primary efficacy outcome events are required which expectedly amounts to 1696 subjects. Recruitment will take approximately 36 months. Conclusion: CLEAR-PATH will assess the efficacy and safety of DAPT compared to SAPT following EVR in PAD patients. Trial registration number: : NL80009.041.21

The Energy Application Domain Extension for CityGML: enhancing interoperability for urban energy simulations

The road towards achievement of the climate protection goals requires, among the rest, a thorough rethinking of the energy planning tools (and policies) at all levels, from local to global. Nevertheless, it is in the cities where the largest part of energy is produced and consumed, and therefore it makes sense to focus the attention particularly on the cities as they yield great potentials in terms of energy consumption reduction and efficiency increase. As a direct consequence, a comprehensive knowledge of the demand and supply of energy resources, including their spatial distribution within urban areas, is therefore of utmost importance. Precise, integrated knowledge about 3D urban space, i.e. all urban (above and underground) features, infrastructures, their functional and semantic characteristics, and their mutual dependencies and interrelations play a relevant role for advanced simulation and analyses. As a matter of fact, what in the last years has proven to be an emerging and effective approach is the adoption of standard-based, integrated semantic 3D virtual city models, which represent an information hub for most of the abovementioned needs. In particular, being based on open standards (e.g. on the CityGML standard by the Open Geospatial Consortium), virtual city models firstly reduce the effort in terms of data preparation and provision. Secondly, they offer clear data structures, ontologies and semantics to facilitate data exchange between different domains and applications. However, a standardised and omni-comprehensive urban data model covering also the energy domain is still missing at the time of writing (January 2018). Even CityGML falls partially short when it comes to the definition of specific entities and attributes for energy-related applications. Nevertheless, and starting from the current version of CityGML (i.e. 2.0), this article describes the conception and the definition of an Energy Application Domain Extension (ADE) for CityGML. The Energy ADE is meant to offer a unique and standard-based data model to fill, on one hand, the above-mentioned gap, and, on the other hand, to allow for both detailed single-building energy simulation (based on sophisticated models for building physics and occupant behaviour) and city-wide, bottom-up energy assessments, with particular focus on the buildings sector. The overall goal is to tackle the existing data interoperability issues when dealing with energy-related applications at urban scale. The article presents the rationale behind the Energy ADE, it describes its main characteristics, the relation to other standards, and provides some examples of current applications and case studies already adopting it

Neurocysticercosis: An Overview of Pathology and Pathogenesis

Neurocysticercosis (NCC), a subtle parasite infection of the central nervous system, is a powerful example of the complex interaction between human behavior, zoonotic transmission, and neurological illness development. Given the disease’s worldwide prevalence and potentially fatal neurological consequences, research into NCC is critical for advancing knowledge, creating effective diagnostic tools and treatment options, and adopting preventative measures to lessen the disease’s impact. Cysticerci causes an immunological response in the CNS, resulting in inflammation and immune cell recruitment. The existence of intraventricular cysts, cysts in the cerebral aqueduct or fourth ventricle, and the degree of inflammation and scarring induced by the infection are all risk factors for the development of hydrocephalus. This book chapter provides an in-depth exploration of the pathology and pathogenesis of NCC, discussing the life cycle of the Taenia solium parasite, its invasion of the central nervous system, and the formation of cysticerci, as well as the diagnostic challenges and imaging findings, clinical manifestations, and potential neurological complications associated with NCC, serving as a valuable resource for medical professionals, researchers, and policymakers

The Dutch chronic lower limb-threatening ischemia registry (THRILLER): A study protocol for popliteal and infrapopliteal endovascular interventions

INTRODUCTION: Chronic limb-threatening ischemia (CLTI) is the end stage of peripheral arterial disease (PAD) and is associated with high amputation rates, mortality and disease-related health care costs. In infrapopliteal arterial disease (IPAD), endovascular revascularization should be considered for the majority of anatomical and clinical subgroups of CLTI. However, a gap of high-quality evidence exists in this field. The aim of the Dutch Chronic Lower Limb-Threatening Ischemia Registry (THRILLER) is to collect real world data on popliteal and infrapopliteal endovascular interventions. METHODS: THRILLER is a clinician-driven, prospective, multicenter, observational registry including all consecutive patients that undergo a popliteal or infrapopliteal endovascular intervention in seven Dutch hospitals. We estimate that THRILLER will include 400-500 interventions annually. Standardized follow-up visits with wound monitoring, toe pressure measurement and duplex ultrasonography will be scheduled at 6-8 weeks and 12 months after the intervention. The independent primary endpoints are primary patency, limb salvage and amputation free survival. Patients must give informed consent before participation and will be included according to predefined reporting standards. A data log of patients who meet the inclusion criteria but are not included in the registry will be maintained. We intend to conduct the first interim analysis two years after the start of inclusion. The results will be published in a scientific journal. DISCUSSION: Despite innovations in medical therapy and revascularization techniques, patients with CLTI undergoing endovascular revascularization still have a moderate prognosis. Previous prospective cohort studies were hampered by small sample sizes or heterogeneous reporting. Randomized controlled trials (RCTs) have high costs, potential conflicts of interest and give a limited reflection of daily practice. THRILLER aims to provide the largest prospective well phenotyped up-to-date dataset on treatment outcomes in CLTI patients to answer multiple underexplored research questions regarding diagnostics, medication, patient selection, treatment strategies and post intervention follow-up

A multicenter randomized clinical trial investigating the cost-effectiveness of treatment strategies with or without antibiotics for uncomplicated acute diverticulitis (DIABOLO trial)

Background. Conservative treatment of uncomplicated or mild diverticulitis usually includes antibiotic therapy. It is, however, uncertain whether patients with acute diverticulitis indeed benefit from antibiotics. In most guidelines issued by professional organizations antibiotics are considered mandatory in the treatment of mild diverticulitis. This advice lacks evidence and is merely based on experts' opinion. Adverse effects of the use of antibiotics are well known, including allergic reactions, development of bacterial resistance to antibiotics and other side-effects. Methods. A randomized multicenter pragmatic clinical trial comparin

GPCR-Gα protein precoupling: Interaction between Ste2p, a yeast GPCR, and Gpa1p, its Gα protein, is formed before ligand binding via the Ste2p C-terminal domain and the Gpa1p N-terminal domain

G protein coupled receptors bind ligands that initiate intracellular signaling cascades via heterotrimeric G proteins. In this study, involvement of the N-terminal residues of yeast G-alpha (Gpa1p) with the C-terminal residues of a full-length or C-terminally truncated Ste2p were investigated using bioluminescence resonance energy transfer (BRET), a non-radiative energy transfer phenomenon where protein-protein interactions can be quantified between a donor bioluminescent molecule and a suitable acceptor fluorophore. Constitutive and position-dependent BRET signal was observed in the absence of agonist (α-factor). Upon the activation of the receptors with α-factor, no significant change in BRET signal was observed. The location of Ste2p–Gpa1p heterodimer was investigated using confocal fluorescence microscopy and bimolecular fluorescence complementation (BiFC) assay, a technique where two non-fluorescent fragments of a fluorescent protein reassemble in vivo to restore fluorescence property thereby directly reporting a protein-protein interaction. BiFC experiments resulted in a dimerization signal intracellularly during biosynthesis on the endoplasmic reticulum (ER) and on the plasma membrane (PM). The constitutive BRET and BiFC signals observed on ER between Ste2p and Gpa1p in their quiescent and activated states are indicative of pre-coupling between these two proteins. This study is the first to show that the extreme N-terminus of yeast G protein alpha subunit is in close proximity to its receptor. The data suggests a pre-coupled heterodimer prior to receptor activation. The images presented in this study are the first direct in vivo evidence showing the localization of receptor - G protein heterodimers during biosynthesis and before reaching the plasma membrane