RepoMed (Medizinische Hochschule Hannover)
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Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients
No full textThe antisense oligonucleotide nusinersen was the first drug treatment available for all types of 5q-spinal muscular atrophy (SMA). The dosing regime has been derived from pivotal clinical trials in infants and children. The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been conducted. In the present study, we systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach. We found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration. Symptoms and functions affected were mainly general strength and arm and leg muscle function next to endurance and independence in daily routine. Lack of walking ability and higher body mass index were characteristic phenotypic features in patients with consistent wearing-off effects. We assume that specific SMA phenotypes might benefit from higher dosing, shorter treatment intervals, change of treatment administration or a combination of all. Efforts towards treatment optimization may result in higher efficacy in distinct phenotypes
Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients.
Get PDFApproval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy
Evaluation of perfusion changes using a 2D Parametric Parenchymal Blood Flow technique with automated vessel suppression following partial spleen embolization in patients with hypersplenism and portal hypertension.
Get PDFAbstract To evaluate the feasibility and potential value of 2D Parametric Parenchymal Blood Flow (2D-PPBF) for the assessment of perfusion changes following partial spleen embolization (PSE) in a retrospective observational study design.Overall, 12 PSE procedures in 12 patients were included in this study. The outcome of the study was the platelet response (PR), calculated as the percentage increase of platelet count (PLT), following PSE. To quantify perfusion changes using 2D-PPBF, the acquired digital subtraction angiography series were post-processed. A reference region-of-interest (ROI) was placed in the afferent splenic artery and a target ROI was positioned on the embolization territory of the spleen on digital subtraction angiography series pre- and post-embolization. The ratios of the target ROIs to the reference ROIs were calculated for the Wash-In-Rate (WIR), the Time-To-Peak (TTP) and the Area-Under-the-Curve (AUC). Comparisons between pre- and post-embolization data were made using Wilcoxon signed-rank test and Spearman's rank correlation coefficient (r). Afterwards, the study population was divided by the median of the TTP before PSE to analyze its value for the prediction of PR following PSE.Following PSE, PLT increased significantly from 43,000 ± 21,405 platelets/μL to 128,500 ± 66,083 platelets/μL with a PR of 255 ± 243% (P = .003). In the embolized splenic territory, the pre-/post-embolization 2D-PPBF parameter changed significantly: WIRpre-PSE 1.23 ± 2.42/WIRpost-PSE 0.09 ± 0.07; -64 ± 46% (p = 0.04), TTPpre-PSE 4.41 ± 0.99/TTPpost-PSE 5.67 ± 1.52 (P = .041); +34 ± 47% and AUCpost-PSE 0.81 ± 0.85/AUCpost-PSE 0.14 ± 0.08; -71 ± 18% (P = .002). A significant correlation of a 2D-PPBF parameter with the PLT was found for TTPpre-PSE/PLTpre-PSE r = -0.66 (P = .01). Subgroup analysis showed a significantly increased PR for the group with TTPpre-PSE >4.44 compared to the group with TTPpre-PSE ≤4.44 (404 ± 267% versus 107 ± 76%; P = .04).2D-PPBF is an objective approach to analyze the perfusion reduction of embolized splenic tissue. TTP derived from 2D-PPBF has the potential to predict the extent of PR during PSE
Unraveling a Force-Generating Allosteric Pathway of Actomyosin Communication Associated with ADP and Pi Release.
Get PDFThe actomyosin system generates mechanical work with the execution of the power stroke, an ATP-driven, two-step rotational swing of the myosin-neck that occurs post ATP hydrolysis during the transition from weakly to strongly actin-bound myosin states concomitant with Pi release and prior to ADP dissociation. The activating role of actin on product release and force generation is well documented; however, the communication paths associated with weak-to-strong transitions are poorly characterized. With the aid of mutant analyses based on kinetic investigations and simulations, we identified the W-helix as an important hub coupling the structural changes of switch elements during ATP hydrolysis to temporally controlled interactions with actin that are passed to the central transducer and converter. Disturbing the W-helix/transducer pathway increased actin-activated ATP turnover and reduced motor performance as a consequence of prolonged duration of the strongly actin-attached states. Actin-triggered Pi release was accelerated, while ADP release considerably decelerated, both limiting maximum ATPase, thus transforming myosin-2 into a high-duty-ratio motor. This kinetic signature of the mutant allowed us to define the fractional occupancies of intermediate states during the ATPase cycle providing evidence that myosin populates a cleft-closure state of strong actin interaction during the weak-to-strong transition with bound hydrolysis products before accomplishing the power stroke
Diffuse midline gliomas, H3 K27M-mutant are associated with less peritumoral edema and contrast enhancement in comparison to glioblastomas, H3 K27M-wildtype of midline structures
No full textDie vollkommen anonymisierten Daten beinhalten die Resultate eine Analyse von MRT Bildern von Patienten mit genetisch definierten infratentoriell lokalisierten Glioblastomen bzw. diffusen Mittelliniengliomen. Die zentrale Fragestellung der Studie ist es zu prüfen, ob man anhand der MRT Signatur beide Entitäten voneinander unterscheiden kann
Assessing the relationship between neural health measures and speech performance with simultaneous electric stimulation in cochlear implant listeners.
No full textObjectives The relationship between electrode-nerve interface (ENI) estimates and inter-subject differences in speech performance with sequential and simultaneous channel stimulation in adult cochlear implant listeners were explored. We investigated the hypothesis that individuals with good ENIs would perform better with simultaneous compared to sequential channel stimulation speech processing strategies than those estimated to have poor ENIs. Methods Fourteen postlingually deaf implanted cochlear implant users participated in the study. Speech understanding was assessed with a sentence test at signal-to-noise ratios that resulted in 50% performance for each user with the baseline strategy F120 Sequential. Two simultaneous stimulation strategies with either two (Paired) or three sets of virtual channels (Triplet) were tested at the same signal-to-noise ratio. ENI measures were estimated through: (I) voltage spread with electrical field imaging, (II) behavioral detection thresholds with focused stimulation, and (III) slope (IPG slope effect) and 50%-point differences (dB offset effect) of amplitude growth functions from electrically evoked compound action potentials with two interphase gaps. Results A significant effect of strategy on speech understanding performance was found, with Triplets showing a trend towards worse speech understanding performance than sequential stimulation. Focused thresholds correlated positively with the difference required to reach most comfortable level (MCL) between Sequential and Triplet strategies, an indirect measure of channel interaction. A significant offset effect (difference in dB between 50%-point for higher eCAP growth function slopes with two IPGs) was observed. No significant correlation was observed between the slopes for the two IPGs tested. None of the measures used in this study correlated with the differences in speech understanding scores between strategies. Conclusions The ENI measure based on behavioral focused thresholds could explain some of the difference in MCLs, but none of the ENI measures could explain the decrease in speech understanding with increasing pairs of simultaneously stimulated electrodes in processing strategies
Hepatorenale Tyrosinämie: Einfluss einer vereinfachten Diät auf metabolische Kontrolle und klinisches Outcome
No full textEarly Detection and Prevention of Schizophrenic Psychosis: a review
No full textPsychotic disorders often run a chronic course and are associated with a considerable emotional and social impact for patients and their relatives. Therefore, early recognition, combined with the possibility of preventive intervention, is urgently warranted since the duration of untreated psychosis (DUP) significantly determines the further course of the disease. In addition to established diagnostic tools, neurobiological factors in the development of schizophrenic psychoses are increasingly being investigated. It is shown that numerous molecular alterations already exist before the clinical onset of the disease. As schizophrenic psychoses are not elicited by a single mutation in the deoxyribonucleic acid (DNA) sequence, epigenetics likely constitute the missing link between environmental influences and disease development and could potentially serve as a biomarker. The results from transcriptomic and proteomic studies point to a dysregulated immune system, likely evoked by epigenetic alterations. Despite the increasing knowledge of the neurobiological mechanisms involved in the development of psychotic disorders, further research efforts with large population-based study designs are needed to identify suitable biomarkers. In conclusion, a combination of blood examinations, functional imaging techniques, electroencephalography (EEG) investigations and polygenic risk scores should be considered as the basis for predicting how subjects will transition into manifest psychosis
Multimodal Assessment and Characterization of Sicca Syndrome.
No full textBackground: Sicca syndrome represents a heterogeneous group of conditions, such as Sjögren syndrome, causing xerophthalmiaand xerostomia. This study characterizes in depth patients with Sicca syndrome and evaluates salivary gland ultrasound (SGUS). Methods: Principal component analysis and hierarchical clustering of clinical parameters, such as ESSPRI, ESSDAI and laboratory data, were performed on all referrals for assessment of Sicca symptoms between October 2018 and March 2021. SGUS and labial gland biopsies were compared across groups. Results: A total of 583 patients were assessed. Objective dryness was confirmed in 73% of the patients. Cluster analysis identified 3 groups with post-hoc analysis confirming distinct phenotypes: Somatic Group (283/583; 49%) with more frequent symptoms but limited objective dryness; Dry Without Autoimmune Features (DAFneg, 206/584; 35%), and Dry With Autoimmune Features (DAFpos, 94/584;16%). DAFpos patients had highest autoantibody titers (anti-SSA(Ro) 240 vs. 3.6 vs. 3.8; p < 0.001), most extra-glandular manifestations (p < 0.001), and highest median SGUS Score (DAFpos: 8 [IQR 4-10] vs. SG: 2 [1-4] vs. DAFneg 4 [2-5]; p < 0.001). No tangible correlation with primary Sjögren syndrome criteria was observed. Discussion: SGUS score correlated with a subset of patients with Sjögren syndrome, identified in the DAFpos cluster. This study highlights heterogeneity within sicca and, indeed, Sjögren syndrome, highlighting the need for further studies
