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Effects of combined vibration ergometry and botulinum toxin on gait improvement in asymmetric lower limb spasticity: a pilot study
Get PDFOBJECTIVE: Botulinum neurotoxin type A (BoNT/A) injections and the new vibration ergometry training (VET) are studied for their combined effect on improving functional mobility in patients with asymmetric lower limb spasticity. METHOD: Gait was analyzed using the Infotronic® system, which measures ground reaction forces and foot contact patterns by means of special force-sensitive shoes strapped over feet or street shoes. Gait was measured several times, depending on the protocol patients underwent. Seven patients with asymmetric lower limb spasticity were analyzed according to the control protocol (CG-group): after a baseline walk of 20 m (NV-W1) patients received their routine BoNT/A injection and had to walk the same distance a second time (NV-W2). Approximately 3-5 weeks later, they had to walk a third time (NV-W3). A further seven patients (VG-group) were analyzed according to the vibration protocol: after a baseline walk (V-W1), patients underwent a first vibration training (VET1), walked a second time (V-W2), received their routine BoNT/A injection, and walked a third time (V-W3). About four weeks later, they had to walk again (V-W4), received another vibration training (VET3), and walked a fifth time (V-W5). At least six months after the analysis according to the vibration protocol, these patients were also analyzed according to the control protocol. Eleven gait parameters were compared between the CG- and VG-group, and within the VG-group. RESULT: Patients in the VG-group experienced a significant improvement in gait four weeks after BoNT/A injection, unlike the patients in the CG-group. VG-patients also showed improved gait after two VET sessions. However, there was no further functional improvement of gait when BoNT/A injections and VET sessions were combined. CONCLUSIONS: BoNT/A injections enhance functional mobility in patients with mild asymmetric leg spasticity. VET also induces an immediate gait improvement and offers a further treatment approach for leg spasticity. Whether combining BoNT treatment and vibration training offers superior outcomes compared to either treatment alone requires further investigation
Effects of altered gravity on adrenergic-mediated cAMP signalling in intact cells
Get PDFSpaceflight-induced cardiac atrophy and rhythm disorders are linked to dysregulation of the adrenergic-cAMP-PKA pathway. Gravity-dependent alterations in adrenergic signaling, particularly cAMP dynamics, remain poorly understood. Using fluorescence biosensors, we studied intact cells under simulated microgravity and hypergravity. We observed shifts in the EC50 of cAMP production: leftward under hypergravity and rightward in microgravity, with faster cAMP accumulation kinetics in hypergravity. Cytoskeletal remodelling, hypothesized to be a determinant of such chances, was negligible, suggesting alternative mechanisms. These findings highlight significant gravity-induced offsets in the pharmacology of a prototypical GPCR, with implications not only for adrenergic signalling but also for other pathways of pharmacological interest, potentially informing countermeasures for astronaut health and pharmacology in altered gravity settings
The mechanotransduction protein STOML3 is required for proprioceptor plasticity following peripheral nerve regeneration
Get PDFNerve regeneration is associated with the plasticity of sensory neurons such that even muscle afferents directed to the skin form mechanosensitive receptive fields appropriate for the new target. STOML3 is an essential mechanotransduction component in many cutaneous mechanoreceptors. Here, we asked whether STOML3 is required for functional and anatomical plasticity following peripheral nerve regeneration. We used a cross-anastomosis model adapted to the mouse, in which the medial gastrocnemius nerve was redirected to innervate hairy skin previously occupied by the sural nerve. We recorded from muscle afferents innervating the skin and found that in wild-type mice their receptive properties were largely identical to normal skin mechanoreceptors. However, in mice lacking STOML3, muscle afferents largely failed to form functional mechanosensitive receptive fields, despite making anatomically appropriate endings in the skin. Our tracing experiments demonstrated that muscle afferents from both wild-type and stoml3 mutant mice display remarkable anatomical plasticity, forming new somatotopically appropriate synaptic terminals in the region of the dorsal horn representing the sural nerve territory. The dramatic reduction in stimulus-evoked activity from the cross-anastomosed gastrocnemius nerve in stoml3 mutant mice did not prevent central anatomical plasticity. Our results have identified a molecular factor required for functional plasticity following peripheral nerve injury
ImmuneLENS characterizes systemic immune dysregulation in aging and cancer
Get PDFRecognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells
Smoking status and vascular risk factors as predictors of disability in AQP4-NMOSD and MOGAD
Get PDFBACKGROUND: Smoking and vascular risk factors (VRFs) are reported to have adverse effects in multiple sclerosis but data are limited in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). This study aimed to measure their impact on disability. METHODS: Smoking status was defined as never, past or current smokers and VRF comprised of ⩾1: hypertension, dyslipidemia, high body mass index or diabetes. Logistic regression models were fitted to predict their influence on recovery from attack and attack. RESULTS: A total of 442 patients were included. Current MOGAD smokers had a higher risk of disability from onset attack and first ON attack than never smokers (odds ratio (OR) 2.9, 95% confidence interval (CI) 1.3-6.9; OR 3.3, 95% CI 1.4-7.8). VRF in MOGAD was not predictive of disability. Current AQP4-NMOSD smokers and VRFs had a higher risk of residual disability from onset attacks (OR 7.5, 95% CI 2.1-27.7; OR 1.9, 95% CI 1.0-3.4). VRF was associated with higher risk of visual disability (OR 2.6, 95% CI 1.08-6.46) while smoking status was not. CONCLUSIONS: Current smoking status detrimentally influenced onset attack recovery in AQP4-NMOSD and MOGAD patients, including visual recovery in MOGAD. Non-smoking VRFs influenced clinical and visual outcomes in AQP4-NMOSD
Circulating amyloid beta 1-40 peptide as an associate of renal function decline
Get PDFBACKGROUND: Recent evidence suggests that Alzheimer's amyloid-beta (1-40) (Αβ1-40), an emerging biomarker of cardiovascular disease, may be involved in the heart-brain-renal axis. We aimed to comprehensively explore the association between circulating Aβ1-40 levels and renal function and its clinical relevance. METHODS: Consecutively recruited subjects in the Athens Angiometabolic Registry with measured Aβ1-40 plasma levels (n = 811) were analysed. Αβ1-40 was measured by enzyme-linked immunosorbent assay and glomerular filtration rate (GFR) was calculated using the abbreviated four-variable Modification of Diet in Renal Disease (MDRD) formula. All-cause mortality was the main clinical endpoint across a median follow-up of 47 months. RESULTS: Cross-sectionally, a bidirectional association between Αβ1-40 [adjusted odds ratio (adjOR) = 3.67 for highest tertile of Αβ1-40 and chronic kidney disease (CKD) stage ≥3, p < .001] and CKD stage ≥3 (adjOR = 3.52 for association with highest Aβ1-40 tertile, p < .001) was observed. Longitudinally, increased Αβ1-40 at baseline was associated with decline in renal function at follow-up (adjOR for CKD stage ≥3 = 2.26, p = .033). Similarly, longitudinal changes in Aβ1-40 were inversely associated with changes in GFR (OR = .77 per 1 SD increase in Aβ1-40, p = .006). Aβ1-40 was associated with all-cause mortality, independently of traditional risk factors (hazard ratio = 1.20 per 1 SD increase in Aβ1-40, p = .016). An indirect effect of GFR on the association between Aβ1-40 and mortality (p < .05) with an estimated indirect-to-total effect ratio of .334, but not of Αβ1-40 on GFR with mortality, was observed. CONCLUSIONS: In a population with a wide range of GFR, we found a bidirectional association between Αβ1-40 levels and renal function. The association of Αβ1-40 with all-cause mortality was partly mediated by lower GFR
A proteogenomic view of synchronous endometrioid endometrial and ovarian cancer
No full textPURPOSE: Increasing genomics-based evidence suggests that synchronous endometrial and ovarian cancer (SEOC) represents clonally related primary and metastatic tumors. A systematic analysis of the global protein landscape of SEOCs, heretofore lacking, could reveal functional and disease-specific consequences of known genetic alterations, the directionality of metastasis, and accurate histologic markers to distinguish SEOCs from single-site tumors. EXPERIMENTAL DESIGN: We performed a systematic proteogenomic analysis of 29 patients diagnosed with SEOC at three international gynecologic oncology treatment centers (Chicago, Vancouver, and Tübingen). For direct comparison with single-site tumors, we included 9 patients with single-site endometrioid ovarian and 26 patients with single-site endometrioid endometrial cancer (EEC). For all 64 patients, we performed sequencing of a 275-gene cancer panel combined with compartment-resolved mass spectrometry–based proteomics of consecutive tissue sections to compare global (6,000+ proteins), tumor, and stromal proteomes. RESULTS: DNA-based panel sequencing confirmed that most SEOCs are clonally related. Global proteome profiling uncovered pronounced differences between SEOCs and single tumors and underscored the importance of the stromal proteome in defining and identifying SEOCs. We identified molecularly unique SEOC stromal proteomes, which were globally more related to single endometrial cancers. We finally derived a proteomic predictor distinguishing SEOCs from single-site ovarian and uterine tumors. CONCLUSIONS: The integrated proteogenomic data show that SEOCs are distinguishable from endometrioid endometrial or endometrioid ovarian cancer. Based on their proteogenomic similarity to EECs, we conclude that most SEOCs represent primary EECs that have metastasized to the ovary
From womb to world: the interplay between maternal immune activation, neuroglia, and neurodevelopment
No full textThis chapter introduces and discusses maternal immune activation (MIA) as a contributing factor in increasing the risk of neurodevelopmental disorders, particularly in relation to its interactions with neuroglia.
Here we first provide an overview of the neuroglia—astroglia, oligodendroglia, microglia, and radial glial cells—and their important role during early brain development and in adulthood. We then present and discuss MIA, followed by a critical overview of inflammatory molecules and temporal stages associated to maternal inflammation during pregnancy. We provide an overview of animal and human models used to mimic and study MIA. Furthermore, we review the possible interaction between MIA and neuroglia, focusing on the current advances in both modeling and therapeutics. Additionally, we discuss and provide preliminary and interesting insights into the most recent pandemic, COVID-19, and how the infection may be associated to MIA and increased risk for neurodevelopmental disorders. Finally, we provide a critical overview of challenges and future opportunities to study how MIA may contribute to higher risk of developing neurodevelopmental disorders
Maternal platelet-derived factors induce trophoblastic LAIR2 expression to promote trophoblast invasion and inhibit platelet activation at the fetal-maternal interface
Get PDFBACKGROUND: During human placentation, extravillous trophoblasts (EVTs) arising from cell column trophoblasts (CCTs) invade the highly differentiated uterine mucosa, called decidua, where they erode blood vessels and replace vascular endothelial cells. Maternal platelets have been detected in intercellular gaps of CCTs, but their physiological role remains unclear. OBJECTIVES: This study aimed to elucidate the impact of platelet-derived factors on trophoblasts that are exposed to maternal platelets through erosion of decidual blood vessels. METHODS: Trophoblast cell line ACH-3P spheroids were incubated either with platelet-derived factors or isolated platelets obtained from pregnant women and then subjected to RNA sequencing followed by validation using quantitative polymerase chain reaction, ELISA, and in situ padlock hybridization. Among the deregulated genes, leukocyte associated immunoglobulin-like receptor 2 (LAIR2) expression was confirmed in first trimester placenta and primary trophoblast organoids. The functional role of LAIR2 in trophoblast invasion and platelet activation was studied. RESULTS: Platelet-derived factors altered the transcriptional profile of ACH-3P spheroids, including deregulation of genes linked to embryonic development. Among them, LAIR2 was exclusively detected in CCTs and invaded EVTs of first trimester decidua. Histology showed extravasated maternal erythrocytes within interstitial gaps of highly invaded decidua samples, coinciding with LAIR2-positive EVTs. LAIR2 inhibited type 1 collagen-induced platelet activation and enhanced invasiveness of trophoblasts. CONCLUSION: This study suggests that maternal platelet-derived factors affect the transcriptional profile of trophoblasts, including upregulation of LAIR2, which may be involved in fine-tuning the coagulation of maternal blood leaking from eroded decidual blood vessels and could increase the invasiveness of EVTs into the decidua through an autocrine mechanism
Content-based image retrieval assists radiologists in diagnosing eye and orbital mass lesions in MRI
Get PDFDiagnosing eye and orbit pathologies through radiological imaging presents considerable challenges due to their low prevalence, the extensive range of possible conditions, and their variable presentations, necessitating substantial domain-specific expertise. This study evaluates whether a ML-based content-based image retrieval (CBIR) tool, combined with a curated database of orbital MRI cases with verified diagnoses, can enhance diagnostic accuracy and reduce reading time for radiologists diagnosing eye and orbital pathologies. It explores whether this tool alone, or in combination with status quo reference tools (e.g. Radiopaedia.org, StatDx) provides these benefits. In a multi-reader, multi-case study involving 36 radiologists and 48 retrospective orbital MRI cases, participants diagnosed eight cases: four using status quo reference tools and four with the addition of the CBIR tool. Analysis using linear mixed-effects models revealed significant improvements in diagnostic accuracy when using the CBIR tool alone (55.88% vs. 70.59%, p = 0.03, odds ratio = 2.07) and an even greater improvement when used alongside status quo tools (55.88% vs. 83.33%, p = 0.02, odds ratio = 3.65). Reading time decreased when using the CBIR tool alone (334 s vs. 236 s, p < 0.001) but increased when used in conjunction with status quo tools (334 s vs. 396 s, p < 0.001). These findings indicate that CBIR tools can significantly enhance diagnostic accuracy for eye and orbit diagnostics, though their impact on reading time varies