Partizipation von Studierenden mit neurokognitiven Beeinträchtigungen am Beispiel von ADHS und spezifischen Lernstörungen

Zusammenfassung: Das Hauptziel des vorliegenden Beitrags ist eine kritische Reflexion der Situation von Studierenden mit neurokognitiven Beeinträchtigungen in Hinblick auf deren Partizipation im universitären Setting. Nach einer kurzen Erläuterung der aktuellen universitätsrechtlichen Rahmenbedingungen in Deutschland, Österreich und der Schweiz werden (i) am Beispiel von Aufmerksamkeitsstörungen und spezifischen Lernstörungen charakteristische Schwierigkeiten von betroffenen Studierenden beim Studium anhand von Fallvignetten dargestellt und (ii) Ziele in Hinblick auf eine gelingende Partizipation und Chancengleichheit für Studierende mit Beeinträchtigungen skizziert. Anhand eines tentativen Rahmenmodells zur Förderung der Partizipation diskutieren wir die Notwendigkeit differenzierter universitätsinterner und -externer struktureller Rahmenbedingungen, die zusätzlich zu den bereits bestehenden – aber nicht ausreichenden – universitätsinternen Maßnahmen wie dem Nachteilsausgleich implementiert werden sollten. Participation of University Students with Neurocognitive Deficiencies: Evidence from ADHD and Specific Learning Disorders Abstract: This paper critically reflects on the current situation of students with neurocognitive deficiencies regarding their participation in the academic setting. After providing a brief summary of the relevant judicial frameworks implemented at universities in Germany, Austria, and Switzerland, we (1) present single-case histories to delineate characteristic difficulties encountered by students with attention and/or specific learning disorders; and (2) formulate a desirable target state regarding successful participation and equal opportunities for students with neurocognitive deficiencies. We suggest a tentative model targeted at fostering students’ participation and discuss the necessity to provide effective basic parameters at different levels both within and outside the academic setting which go beyond the currently offered disadvantage compensation

Effect of Conformational Diversity on the Bioactivity of µ-Conotoxin PIIIA Disulfide Isomers

Cyclic µ-conotoxin PIIIA, a potent blocker of skeletal muscle voltage-gated sodium channel NaV1.4, is a 22mer peptide stabilized by three disulfide bonds. Combining electrophysiological measurements with molecular docking and dynamic simulations based on NMR solution structures, we investigated the 15 possible 3-disulfide-bonded isomers of µ-PIIIA to relate their blocking activity at NaV1.4 to their disulfide connectivity. In addition, three µ-PIIIA mutants derived from the native disulfide isomer, in which one of the disulfide bonds was omitted (C4-16, C5-C21, C11-C22), were generated using a targeted protecting group strategy and tested using the aforementioned methods. The 3-disulfide-bonded isomers had a range of different conformational stabilities, with highly unstructured, flexible conformations with low or no channel-blocking activity, while more constrained molecules preserved 30% to 50% of the native isomer’s activity. This emphasizes the importance and direct link between correct fold and function. The elimination of one disulfide bond resulted in a significant loss of blocking activity at NaV1.4, highlighting the importance of the 3-disulfide-bonded architecture for µ-PIIIA. µ-PIIIA bioactivity is governed by a subtle interplay between an optimally folded structure resulting from a specific disulfide connectivity and the electrostatic potential of the conformational ensemble

Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

Background The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K). Methods Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate. Results Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002). Conclusion In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making

Partizipation von Studierenden mit neurokognitiven Beeinträchtigungen am Beispiel von ADHS und spezifischen Lernstörungen

<jats:p> Zusammenfassung: Das Hauptziel des vorliegenden Beitrags ist eine kritische Reflexion der Situation von Studierenden mit neurokognitiven Beeinträchtigungen in Hinblick auf deren Partizipation im universitären Setting. Nach einer kurzen Erläuterung der aktuellen universitätsrechtlichen Rahmenbedingungen in Deutschland, Österreich und der Schweiz werden (i) am Beispiel von Aufmerksamkeitsstörungen und spezifischen Lernstörungen charakteristische Schwierigkeiten von betroffenen Studierenden beim Studium anhand von Fallvignetten dargestellt und (ii) Ziele in Hinblick auf eine gelingende Partizipation und Chancengleichheit für Studierende mit Beeinträchtigungen skizziert. Anhand eines tentativen Rahmenmodells zur Förderung der Partizipation diskutieren wir die Notwendigkeit differenzierter universitätsinterner und -externer struktureller Rahmenbedingungen, die zusätzlich zu den bereits bestehenden – aber nicht ausreichenden – universitätsinternen Maßnahmen wie dem Nachteilsausgleich implementiert werden sollten. </jats:p&gt

OR2AT4 and OR1A2 counterregulate molecular pathophysiological processes of steroid-resistant inflammatory lung diseases in human alveolar macrophages

$\bf Background:$ Therapeutic options for steroid-resistant non-type 2 inflammation in obstructive lung diseases are lacking. Alveolar macrophages are central in the progression of these diseases by releasing proinflammatory cytokines, making them promising targets for new therapeutic approaches. Extra nasal expressed olfactory receptors (ORs) mediate various cellular processes, but clinical data are lacking. This work investigates whether ORs in human primary alveolar macrophages could impact pathophysiological processes and could be considered as therapeutic targets. $\bf Methods:$ Human primary alveolar macrophages were isolated from bronchoalveolar lavages of 50 patients with pulmonary diseases. The expression of ORs was validated using RT-PCR, immunocytochemical staining, and Western blot. Changes in intracellular calcium levels were analyzed in real-time by calcium imaging. A luminescent assay was used to measure the cAMP concentration after OR stimulation. Cytokine secretion was measured in cell supernatants 24 h after stimulation by ELISA. Phagocytic ability was measured by the uptake of fluorescent-labeled beads by flow cytometry. $\bf Results:$ We demonstrated the expression of functional OR2AT4 and OR1A2 on mRNA and protein levels. Both ORs were primarily located in the plasma membrane. Stimulation with Sandalore, the ligand of OR2AT4, and Citronellal, the ligand of OR1A2, triggered a transient increase of intracellular calcium and cAMP. In the case of Sandalore, this calcium increase was based on a cAMP-dependent signaling pathway. Stimulation of alveolar macrophages with Sandalore and Citronellal reduced phagocytic capacity and release of proinflammatory cytokines. $\bf Conclusion:$ These are the first indications for utilizing olfactory receptors as therapeutic target molecules in treating steroid-resistant lung diseases with non-type 2 inflammation

ADHD in context: Young adults’ reports of the impact of occupational environment on the manifestation of ADHD

Does changing context play a role in the decline in ADHD symptoms in adulthood? Insufficient research has explored the functioning of adults with ADHD. As adults, individuals with ADHD have significantly more latitude to control aspects of their day-to-day environments. Do the new contexts young adults find themselves in alter their experience of ADHD? Are there particular occupational or educational contexts in which young adults report functioning better than others? To examine this issue, we conducted semi-structured interviews at four North American sites in 2010-11 with 125 young adults, originally diagnosed with ADHD as children, regarding their work and post-secondary educational environments. Many subjects describe their symptoms as context-dependent. In some contexts, participants report feeling better able to focus; in others, their symptoms—such as high energy levels—become strengths rather than liabilities. Modal descriptions included tasks that were stressful and challenging, novel and required multitasking, busy and fast-paced, physically demanding or hands-on, and/or intrinsically interesting. Consistent with a developmental psychopathology framework, ADHD is experienced as arising from an interaction between our subjects and their environments. These findings demonstrate the need to account for the role of context in our understanding of ADHD as a psychiatric disorder, especially as it manifests in young adulthood

Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations

Background: Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed. - Methods: We retrospectively analyzed a large multi-center cohort of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM. - Results: AML patients with EM presented with significantly higher counts of white blood cells (p < 0.0001), peripheral blood blasts (p < 0.0001), bone marrow blasts (p = 0.019), and LDH (p < 0.0001). Regarding molecular genetics, EM AML was associated with mutations of NPM1 (OR: 1.66, p < 0.001), FLT3-ITD (OR: 1.72, p < 0.001) and PTPN11 (OR: 2.46, p < 0.001). With regard to clinical outcomes, EM AML patients were less likely to achieve complete remissions (OR: 0.62, p = 0.004), and had a higher early death rate (OR: 2.23, p = 0.003). Multivariable analysis revealed EM as an independent risk factor for reduced overall survival (hazard ratio [HR]: 1.43, p < 0.001), however, for patients who received allogeneic hematopoietic cell transplantation (HCT) survival did not differ. For patients bearing EM AML, multivariable analysis unveiled mutated TP53 and IKZF1 as independent risk factors for reduced event-free (HR: 4.45, p < 0.001, and HR: 2.05, p = 0.044, respectively) and overall survival (HR: 2.48, p = 0.026, and HR: 2.63, p = 0.008, respectively). - Conclusion: Our analysis represents one of the largest cohorts of EM AML and establishes key molecular markers linked to EM, providing new evidence that EM is associated with adverse risk in AML and may warrant allogeneic HCT in eligible patients with EM