G-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through autocrine/paracrine mediators

G-protein-coupled receptors (GPCRs), especially chemokine receptors, play a central role in the regulation of T cell migration. Various GPCRs are upregulated in activated CD4 T cells, including P2Y10, a putative lysophospholipid receptor that is officially still considered an orphan GPCR, i.e., a receptor with unknown endogenous ligand. Here we show that in mice lacking P2Y10 in the CD4 T cell compartment, the severity of experimental autoimmune encephalomyelitis and cutaneous contact hypersensitivity is reduced. P2Y10-deficient CD4 T cells show normal activation, proliferation and differentiation, but reduced chemokine-induced migration, polarization, and RhoA activation upon in vitro stimulation. Mechanistically, CD4 T cells release the putative P2Y10 ligands lysophosphatidylserine and ATP upon chemokine exposure, and these mediators induce P2Y10-dependent RhoA activation in an autocrine/paracrine fashion. ATP degradation impairs RhoA activation and migration in control CD4 T cells, but not in P2Y10-deficient CD4 T cells. Importantly, the P2Y10 pathway appears to be conserved in human T cells. Taken together, P2Y10 mediates RhoA activation in CD4 T cells in response to auto-/paracrine-acting mediators such as LysoPS and ATP, thereby facilitating chemokine-induced migration and, consecutively, T cell-mediated diseases. P2Y10 is a G-protein-coupled receptor that is expressed in CD4 T cells. Here authors show that its ligands, lysophosphatidylserine and ATP, are induced in T cells upon chemokine stimulation and regulate RhoA activation and migration through an autocrine/paracrine loop

Entwicklung eines Lehrprojekts zur interprofessionellen Zusammenarbeit von Medizin- und Pharmaziestudierenden zur Verbesserung der Arzneimitteltherapiesicherheit bei Polypharmazie (PILLE)

Aim: Interprofessional collaboration is particularly relevant to patient safety in outpatient care with polypharmacy. The educational project "PILLE" is meant to give medical and pharmacy students an understanding of the roles and competencies needed for cooperation in the provision of healthcare and to enable interprofessional learning.Method: The curriculum is aimed at pharmacy and medical students and was developed in six steps according to the Kern cycle. It is comprised of an interprofessional seminar, a joint practical training in a simulated pharmacy, and a tandem job shadowing at a primary care practice.The project was implemented in three stages due to the pandemic: The interprofessional online seminar based on the ICAP model and the digital inverted classroom was held in the 2020 winter semester; the interprofessional practical training was added in the 2021 summer semester; and the interprofessional tandem job shadowing at a primary care practice in the 2021 winter semester.Attitudes toward interprofessional learning, among other things, was measured in the evaluation using the SPICE-2D questionnaire (Student Perceptions of Physician-Pharmacist Interprofessional Clinical Education).Results: In the first three semesters, a total of 105 students (46 pharmacy, 59 medicine) participated in the project, of which 78 participated in the evaluation (74% response rate). The students stated, in particular, that they had learned about the competencies and roles of the other profession and desired additional and more specific preparatory materials for the course sessions. The SPICE-2D questionnaire showed high values for both groups of students already in the pre-survey and these increased further as a result of the project.Conclusion: Joint case-based learning could be implemented under the conditions imposed by the pandemic. Online teaching is a low-threshold means to enable interprofessional exchange.Zielsetzung: In der ambulanten Versorgung von Patient*innen mit Polypharmazie ist interprofessionelle Zusammenarbeit für die Patientensicherheit besonders relevant. Das Lernprojekt PILLE soll Rollenverständnis und Kompetenzen für eine kooperative Versorgung an Pharmazie- und Medizinstudierende vermitteln und interprofessionelles Lernen ermöglichen.Methodik: Das Curriculum wurde nach dem Kern-Zyklus in sechs Schritten entwickelt und umfasst ein interprofessionelles Seminar, eine gemeinsame Fallbearbeitung in einer Simulationsapotheke und eine Hospitation in einer Hausarztpraxis für Pharmazie- und Medizinstudierende. Pandemiebedingt wurde das Lernprojekt in drei Stufen implementiert: im Wintersemester 2020 das Online-Seminar basierend auf dem ICAP-Modell und dem Konzept des digitalen inverted classroom, im Sommersemester 2021 ergänzend das interprofessionelle Praktikum und im Wintersemester 2021 die Hospitation in einer Hausarztpraxis. In der Evaluation wurde u.a. die Einstellung zu interprofessionellem Lernen mit dem SPICE-2D Fragebogen (Student Perceptions of Physician-Pharmacist Interprofessional Clinical Education) erhoben.Ergebnisse: In den ersten drei Semestern nahmen insgesamt 105 Studierende (46 Pharmazie, 59 Medizin) am Lernprojekt teil, davon beteiligten sich 78 an der Evaluation (74% Rücklauf). Die Studierenden geben an, besonders zu Kompetenzen und Rolle der anderen Berufsgruppe gelernt zu haben und wünschen sich weitere gezielte Vorbereitungsmaterialien für den Unterricht. Der SPICE-2D Fragebogen zeigt bereits vorab hohe Werte bei beiden Studierendengruppen, die sich durch das Lernprojekt weiter erhöhten.Schlussfolgerung: Gemeinsames fallbasiertes Lernen war unter Pandemiebedingungen umsetzbar. Online-Lehre bietet eine niedrigschwellige Möglichkeit, interprofessionellen Austausch zu ermöglichen

Benzodiazepines in the Management of Seizures and Status Epilepticus: A Review of Routes of Delivery, Pharmacokinetics, Efficacy, and Tolerability.

Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and SE is a constant challenge for healthcare professionals, in both the pre-hospital and the in-hospital settings. Benzodiazepines (BZDs) are the first-line treatment for SE worldwide due to their efficacy, tolerability, and rapid onset of action. Although all BZDs act as allosteric modulators at the inhibitory gamma-aminobutyric acid (GABA) <sub>A</sub> receptor, the individual agents have different efficacy profiles and pharmacokinetic and pharmacodynamic properties, some of which differ significantly. The conventional BZDs clonazepam, diazepam, lorazepam and midazolam differ mainly in their durations of action and available routes of administration. In addition to the common intravenous, intramuscular and rectal administrations that have long been established in the acute treatment of SE, other administration routes for BZDs-such as intranasal administration-have been developed in recent years, with some preparations already commercially available. Most recently, the intrapulmonary administration of BZDs via an inhaler has been investigated. This narrative review provides an overview of the current knowledge on the efficacy and tolerability of different BZDs, with a focus on different routes of administration and therapeutic specificities for different patient groups, and offers an outlook on potential future drug developments for the treatment of prolonged seizures and SE