Reversal of Status Dystonicus after Relocation of Pallidal Electrodes in DYT6 Generalized Dystonia

Background: DYT6 dystonia can have an unpredictable clinical course and the result of deep brain stimulation (DBS) of the internal part of the globus pallidus (GPi) is known to be less robust than in other forms of autosomal dominant dystonia. Patients who had previous stereotactic surgery with insufficient clinical benefit form a particular challenge with very limited other treatment options available. Case Report: A pediatric DYT6 patient unexpectedly deteriorated to status dystonicus 1 year after GPi DBS implantation with good initial clinical response. After repositioning the DBS electrodes the status dystonicus resolved. Discussion: This case study demonstrates that medication-resistant status dystonicus in DYT6 dystonia can be reversed by relocation of pallidal electrodes. This case highlights that repositioning of DBS electrodes may be considered in patients with status dystonicus, especially when the electrode position is not optimal, even after an initial clinical response to DBS

Authenticity, self and Santa: an existential perspective of the tourist experience.

This study investigates existential authenticity, which focuses on how the tourist object helps (re-)discover one’s own true self, at Santa Claus Office, Rovaniemi (Finland). It aims at providing a better understanding of existential authenticity in the context of tourism, consumer behavior and hospitality managemen

1,2,3-Triazoles as inhibitors of indoleamine 2,3-dioxygenase 2 (IDO2).

Indoleamine 2,3-dioxygenase 2 (IDO2) is a potential therapeutic target for the treatment of diseases that involve immune escape such as cancer. In contrast to IDO1, only a very limited number of inhibitors have been described for IDO2 due to inherent difficulties in expressing and purifying a functionally active, soluble form of the enzyme. Starting from our previously discovered highly efficient 4-aryl-1,2,3-triazole IDO1 inhibitor scaffold, we used computational structure-based methods to design inhibitors of IDO2 which we then tested in cellular assays. Our approach yielded low molecular weight inhibitors of IDO2, the most active displaying an IC50 value of 51μM for mIDO2, and twofold selectivity over hIDO1. These compounds could be useful as molecular probes to investigate the biological role of IDO2, and could inspire the design of new IDO2 inhibitors

Deep brain stimulation in patients on chronic antiplatelet or anticoagulation treatment

Background!#!In the aging society, many patients with movement disorders, pain syndromes, or psychiatric disorders who are candidates for deep brain stimulation (DBS) surgery suffer also from cardiovascular co-morbidities that require chronic antiplatelet or anticoagulation treatment. Because of a presumed increased risk of intracranial hemorrhage during or after surgery and limited knowledge about perioperative management, chronic antiplatelet or anticoagulation treatment often has been considered a relative contraindication for DBS. Here, we evaluate whether or not there is an increased risk for intracranial hemorrhage or thromboembolic complications in patients on chronic treatment (paused for surgery or bridged with subcutaneous heparin) as compared to those without.!##!Methods!#!Out of a series of 465 patients undergoing functional stereotactic neurosurgery, 34 patients were identified who were on chronic treatment before and after receiving DBS. In patients with antiplatelet treatment, medication was stopped in the perioperative period. In patients with vitamin K antagonists or novel oral anticoagulants (NOACs), heparin was used for bridging. All patients had postoperative stereotactic CT scans, and were followed up for 1 year after surgery.!##!Results!#!In patients on chronic antiplatelet or anticoagulation treatment, intracranial hemorrhage occurred in 2/34 (5.9%) DBS surgeries, whereas the rate of intracranial hemorrhage was 15/431 (3.5%) in those without, which was statistically not significant. Implantable pulse generator pocket hematomas were seen in 2/34 (5.9%) surgeries in patients on chronic treatment and in 4/426 (0.9%) without. There were only 2 instances of thromboembolic complications which both occurred in patients without chronic treatment. There were no hemorrhagic complications during follow-up for 1 year.!##!Conclusions!#!DBS surgery in patients on chronic antiplatelet or anticoagulation treatment is feasible. Also, there was no increased risk of hemorrhage in the first year of follow-up after DBS surgery. Appropriate patient selection and standardized perioperative management are necessary to reduce the risk of intracranial hemorrhage and thromboembolic complications

Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds

Reversal of Status Dystonicus after Relocation of Pallidal Electrodes in DYT6 Generalized Dystonia

Background: DYT6 dystonia can have an unpredictable clinical course and the result of deep brain stimulation (DBS) of the internal part of the globus pallidus (GPi) is known to be less robust than in other forms of autosomal dominant dystonia. Patients who had previous stereotactic surgery with insufficient clinical benefit form a particular challenge with very limited other treatment options available. Case Report: A pediatric DYT6 patient unexpectedly deteriorated to status dystonicus 1 year after GPi DBS implantation with good initial clinical response. After repositioning the DBS electrodes the status dystonicus resolved. Discussion: This case study demonstrates that medication-resistant status dystonicus in DYT6 dystonia can be reversed by relocation of pallidal electrodes. This case highlights that repositioning of DBS electrodes may be considered in patients with status dystonicus, especially when the electrode position is not optimal, even after an initial clinical response to DBS

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article