The Linkou Chang Gung Memorial Hospital (CGMH; Chinese: 林口長庚紀念醫院; pinyin: Lín Kǒu Cháng Gēng Jì Niàn Yī Yuàn) also known as Chang Gung Memorial Hospital or "Chang Gung Hospital", is a hospital located in Guishan District, Taoyuan City, Taiwan. It is part of the Chang Gung Medical Foundation hospital network. The Linkou Chang Gung Memorial Hospital offers nearly 4,000 beds and is among the largest hospitals in bed capacity.
Heterozygous (G603R) LRP10 mutation causes autosomal dominant Parkinson's disease (PD). Heterozygous Lrp10G603R/+ mice were prepared to unravel pathomechanisms underlying (G603R) Lrp10-induced death of substantia nigra (SN) dopaminergic neurons. Lrp10G603R/+ mouse exhibited PD movement deficits, neurodegeneration of SN dopaminergic cells and existence of SN phospho-α-synuclein-containing aggregates. Lrp10 was expressed in mouse SN dopaminergic neurons, and WT LRP10 exerted neuroprotection function on dopaminergic cells by repressing α-synuclein gene transcription and downregulating α-synuclein mRNA. (G603R) LRP10 failed to negatively regulate α-synuclein mRNA of dopaminergic neurons, and heterozygous (G603R) Lrp10 mutation elevated protein and mRNA of pathological α-synuclein or α-synuclein oligomers in SN dopaminergic cells of Lrp10G603R/+ mouse. Macroautophagy activator rapamycin reversed (G603R) Lrp10-induced increment of α-synuclein, death of SN dopaminergic cells and PD locomotor disability in Lrp10G603R/+ mouse. (G603R) Lrp10 upregulation of α-synuclein increased ER α-synuclein and activated ER stress and UPR, resulting in excitation of ER stress pro-apoptotic pathway in SN of Lrp10G603R/+ mouse. Upregulated α-synuclein within SN dopaminergic cells increased mitochondrial α-synuclein and induced mitochondrial detriment and oxidative insult in SN of Lrp10G603R/+ mouse. (G603R) Lrp10-evoked overexpression of Puma, Noxa or Bim and mitochondrial abnormality excited mitochondrial apoptotic process in SN of Lrp10G603R/+ mouse. Elevated α-synuclein oligomers excited NLRP3 inflammasome and microglia in SN of Lrp10G603R/+ mouse, leading to incremented IL-1β-, IL-18- or TNF-α-triggered MKK4-JNK-c-Jun/ATF-2 degeneration and RIPK1-RIPK3-MLKL necroptotic pathways. Our data propose that heterozygous loss-of-function (G603R) mutation of LRP10 debilitates WT LRP10-mediated downregulation of α-synuclein mRNA, leading to elevated α-synuclein-evoked neurodegeneration of SN dopaminergic cells and autosomal dominant PD.
Heterozygous missense mutations of TAU cause frontotemporal dementia with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). FTDP-17T neurodegeneration of hippocampal and substantia nigra dopaminergic cells causes dementia and parkinsonism motor deficits. FTDP-17T cellular model of mutant TAU-expressing differentiated dopaminergic or hippocampal neurons was utilized to test hypothesis that FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs located in different domains of TAU cause neurodegeneration with the same pathomechanism. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs caused degeneration of dopaminergic or hippocampal neurons via mutation-induced gain-of-neurotoxicity. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations promoted Ser202/Ser396/Ser404 phosphorylations of TAU and formation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers in dopaminergic or hippocampal neurons. GSK-3β inhibitor AR-A014418 completely blocked (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity by preventing (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations-augmented Ser202/Ser396/Ser404 phosphorylations and genesis of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers. Phospho-(R5H), phospho-(N279K), phospho-(K298E), phospho-(P301S), phospho-(K317M) or phospho-(G389R) TAUSer202/Ser396/Ser404 oligomers were found in ER of dopaminergic or hippocampal neurons and activated ER stress, UPR and ER stress apoptotic signaling. Overexpression of mitochondrial phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers caused mitochondrial malfunction via depolarizing mitochondrial membrane potential and oxidative damage by increasing ROS. Phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers-evoked upregulation of Noxa, Bim or Puma and mitochondrial defect and oxidative stress excited mitochondrial pro-apoptotic pathway. Our results suggest that shared pathomechanism underlying FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity is mutation-augmented GSK-3β-mediated Ser202/Ser396/Ser404 phosphorylations and generation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers, which cause neurodegeneration by stimulating ER stress and mitochondrial pro-apoptotic cascades.
The large volume of abdominal computed tomography (CT) scans1,2 coupled with the shortage of radiologists3-6 have intensified the need for automated medical image analysis tools. Previous state-of-the-art approaches for automated analysis leverage vision-language models (VLMs) that jointly model images and radiology reports7-12. However, current medical VLMs are generally limited to 2D images and short reports. Here to overcome these shortcomings for abdominal CT interpretation, we introduce Merlin, a 3D VLM that learns from volumetric CT scans, electronic health record data and radiology reports. This approach is enabled by a multistage pretraining framework that does not require additional manual annotations. We trained Merlin using a high-quality clinical dataset of paired CT scans (>6 million images from 15,331 CT scans), diagnosis codes (>1.8 million codes) and radiology reports (>6 million tokens). We comprehensively evaluated Merlin on 6 task types and 752 individual tasks that covered diagnostic, prognostic and quality-related tasks. The non-adapted (off-the-shelf) tasks included zero-shot classification of findings (30 findings), phenotype classification (692 phenotypes) and zero-shot cross-modal retrieval (image-to-findings and image-to-impression). The model-adapted tasks included 5-year chronic disease prediction (6 diseases), radiology report generation and 3D semantic segmentation (20 organs). We validated Merlin at scale, with internal testing on 5,137 CT scans and external testing on 44,098 CT scans from 3 independent sites and 2 public datasets. The results demonstrated high generalization across institutions and anatomies. Merlin outperformed 2D VLMs, CT foundation models and off-the-shelf radiology models. We also computed scaling laws and conducted ablation studies to identify optimal training strategies. We release our trained models, code and dataset for 25,494 pairs of abdominal CT scans and radiology reports. Our results demonstrate how Merlin may assist in the interpretation of abdominal CT scans and mitigate the burden on radiologists while simultaneously adding value for future biomarker discovery and disease risk stratification.
BACKGROUND:The incidence of diabetic atherosclerosis (DMA) is increasing worldwide, but its pathogenesis remains incompletely understood. In addition to cardiovascular complications, bladder dysfunction is one of the common comorbidities associated with DMA but is often refractory to current treatments. AIM:To investigate the therapeutic effect of human amniotic fluid stem cell-derived extracellular vesicles (hAFSC-EVs) on the recovery of bladder dysfunction in DMA rats. METHODS:Eighty rats were divided into normal control, streptozotocin-induced diabetic rats, diabetic rats subjected to arterial balloon endothelial injury of common iliac artery (DMA), and DMA rats treated with hAFSC-EVs (DMA + hAFSC-EVs). At 4 weeks and 12 weeks after DMA induction, levels of blood glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, homeostasis model assessment (HOMA)-insulin resistance, and HOMA-β were measured. Cystometry, common iliac artery wall thickness, and bladder tumor necrosis factor (TNF)-α, interleukin (IL)-6, transforming growth factor (TGF)-β1, Smad3, connective tissue growth factor (CTGF) and fibronectin were also evaluated. RESULTS:Bladder weight and blood glucose, triglyceride, HOMA-insulin resistance, common iliac artery intima thickness, voided volume, intercontraction interval, bladder capacity, and mRNA expression of TNF-α, IL-6, TGF-β1, Smad3, CTGF and fibronectin were significantly increased at 4 weeks and 12 weeks after induction, while the HOMA-β level decreased at 4 weeks and 12 weeks, and the high-density lipoprotein cholesterol level decreased at 12 weeks. hAFSC-EVs treatment in DMA rats significantly reduced bladder weight and blood glucose, thickness of common iliac arterial intima, voided volume, intercontraction interval and bladder capacity at 4 weeks. The mRNA expression of TNF-α, TGF-β1, and CTGF in DMA rats treated with hAFSC-EVs were significantly decreased at 4 weeks, while the mRNA expressions of IL-6 and Smad3 were significantly decreased 12 weeks. CONCLUSION:hAFSC-EVs treatment can help restore DMA-induced bladder dysfunction, which is associated with lowered blood glucose levels, reduced arterial wall thickness, and decreased TNF-α, IL-6, TGF-β1, Smad3, and CTGF expression.
