👤 Buşra G Tosun

Peripheral nerve injuries often lead to significant functional impairment. While autografts remain the gold standard for repairing critical-sized nerve defects, donor site morbidity and limited graft availability have prompted the exploration of alternative strategies. Although studies investigating nerve regeneration using nerve conduits and biological agents are present in the literature, research investigating the effect of neurotrophic factors enriched secretome with biocompatible 3D conduits combination is insufficient. The aim of this study is to evaluate the regenerative potential of 3D biodegradable chitosan-PCL nerve conduit combined with BDNF-enriched secretome in peripheral nerve defects. In this study, biodegradable three-dimensional (3D) nerve conduits composed of polycaprolactone (PCL) and chitosan (75:25 wt/wt) were fabricated and used to bridge 10 mm sciatic nerve defects in rats. The conduits were evaluated alone or in combination with the secretome derived from Wharton's Jelly mesenchymal stem cells (WJ-MSC), either in the native form or enriched with brain-derived neurotrophic factor (BDNF). Thirty-two adult male Wistar Albino rats (mean weight 300-400 g) were randomized into four groups: Autograft (Group 1), conduit only (Group 2), conduit and WJ-MSC derived secretome (Group 3), and conduit combined with BDNF-enriched WJ-MSC derived secretome (Group 4). Functional recovery was assessed using the sciatic functional index (SFI), electromyography (EMG), and gastrocnemius muscle wet weight. Morphological and histological evaluations were performed at 12 weeks postoperatively. At the end of 12 weeks, Group 4 (-49.48 ± 2.82) exhibited significantly improved SFI values compared to Group 2 (-66.62 ± 5.31) and Group 3 (-60.60 ± 5.34) (p < 0.05). Electromyographic analysis revealed higher compound muscle action potential amplitutes in Group 4 (19.72 ± 3.62 mV) than Group 2 and Group 3 (p < 0.05), with values compared to the autograft group. Gasrtrocnemius muscle wet weight ratios were also significantly higher in Group 4 (69.09% ± 9.88%) than in Groups 2 and 3. Histological analyses showed enhanced axonal regeneration, reduced inflammation, and better myelination in Group 4. Scanning electron microscopy confirmed the conduit structural integrity and stability over the 12-week period. The combination of a 3D biodegradable chitosan-PCL conduit with BDNF-enriched WJ-MSC-derived secretome significantly enhanced peripheral nerve regeneration in a rat model. This strategy shows strong potential as an alternative to autografts for treating critical-sized nerve defects. Show less

New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA. Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA. APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD. Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses. Show less

17β-Hydroxysteroid dehydrogenase 3 deficiency (17β-HSDD) and 5α-reductase type 2 deficiency (5α-RD) are rare 46,XY differences of sex development (DSD). This study aims to enlarge the limited knowledge on long-term gonadal function and gonadal pathology in these conditions. Retrospective multicentre cohort study. Data on phenotype, laboratory results, and hormone treatment were collected from patients aged ≥16 years at time of data collection with genetically confirmed 17β-HSDD and 5α-RD from 10 centres via the I-DSD Registry. If gonadectomy or gonadal biopsy had been performed, pathology reports and/or gonadal tissue or images were collected. All 16 patients with 17β-HSDD were raised female; 1 (6%) changed to male gender at age 14. Three females were treated with gonadotrophin-releasing hormone agonists (GnRHa) to prevent virilisation. Thirteen underwent gonadectomy at median age 8 (range 0-17). None had germ cell (pre)malignancies. Of 14 patients with 5α-RD, 10 (71%) were raised female. Five changed gender at age 7-23, of whom 4 to male gender. One was treated with GnRHa. Six underwent gonadectomy at median age 10 (range 0-31). None had germ cell (pre)malignancies. With gonads in situ, puberty spontaneously progressed. Three were treated with dihydrotestosterone. A significant percentage of individuals with 17β-HSDD and 5α-RD changed gender, and some were treated with GnRHa to prevent virilisation before making a definitive decision about gonadectomy. When left in situ, spontaneous puberty occurs and germ cell (pre)malignancies seem uncommon at least until early adulthood. Together, these data support delaying a decision about gonadectomy until late adolescence in these conditions. Show less