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Purpose: Osteoarthritis of the knee is commonly associated with malalignment of the lower limb. Recent classifications, as the Coronal Plane Alignment of the Knee (CPAK) and Functional Phenotype classification, describe the bony knee morphology in addition to the overall limb alignment. Data on distribution of these classifications is not sufficient in large populations. The aim of this study was to analyse the preoperative knee morphology with regard to the aforementioned classifications in long leg radiographs prior to total knee arthroplasty surgery using Artificial Intelligence., Methods: The cohort comprised 8739 preoperative long leg radiographs of 7456 patients of all total knee arthroplasty surgeries between 2009 and 2021 from our institutional database. The automated measurements were performed with the validated Artificial Intelligence software LAMA (ImageBiopsy Lab, Vienna) and included standardized axes and angles [hip-knee-ankle angle (HKA), mechanical lateral distal femur angle (mLDFA), mechanical medial proximal tibia angle (mMPTA), mechanical axis deviation (MAD), anatomic mechanic axis deviation (AMA) and joint line convergence angle (JLCA)]. CPAK and functional phenotype classifications were performed and all measurements were analysed for gender, age, and body mass index (BMI) within these subgroups., Results: Varus alignment was more common in men (m: 2008, 68.5%; f: 2953, 50.8%) while neutral (m: 578, 19.7%; f: 1357, 23.4%) and valgus (m: 345, 11.8%; f: 1498, 25.8%) alignment was more common in women. The most common morphotypes according to CPAK classification were CPAK Type I (2454; 28.1%), Type II (2383; 27.3%), and Type III (1830; 20.9%). An apex proximal joint line (CPAK Type VII, VIII and IX) was only found in 1.3% of all cases (n = 121). In men, CPAK Type I (1136; 38.8%) and CPAK Type II (799; 27.3%) were the most common types and women were spread more equally between CPAK Type I (1318; 22.7%), Type II (1584; 27.3%) and Type III (1494; 25.7%) (p < 0.001). The most common combination of femur and tibia types was NEU mLDFA 0°,NEU mMPTA 0° (m: 514, 17.5%; f: 1004, 17.3%), but men showed femoral varus more often. Patients with a higher BMI showed a significantly lower age at surgery (R 2  = 0.09, p < 0.001). There were significant differences between men and women for all radiographic parameters (p < 0.001)., Conclusion: Distribution in knee morphology with gender-specific differences highlights the wide range in osteoarthritic knees, characterized by CPAK and phenotype classification and may influence future surgical planning., Level of Evidence: Level III., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Niemann-Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here, we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions of Npc1 -/- mice and evaluated specific effects of treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography (HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses showed disrupted S1P metabolism in Npc1 -/- mice in all brain regions, together with distinct changes in S1pr3 /S1PR3 and S1pr5 /S1PR5 expression. Brains of Npc1 -/- mice showed only weak treatment effects. However, side effects of the treatment were observed in Npc1 +/+ mice. The S1P/S1PR axis seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects make examination of further treatment strategies indispensable.

In this study, we demonstrate that, among all five CBX Polycomb proteins, only CBX7 possesses the ability to control self-renewal of human hematopoietic stem and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in increased multi-lineage long-term engraftment and myelopoiesis. Gene expression and chromatin analyses revealed perturbations in genes involved in differentiation, DNA and chromatin maintenance, and cell cycle control. CBX7 is upregulated in acute myeloid leukemia (AML), and its genetic or pharmacological repression in AML cells inhibited proliferation and induced differentiation. Mass spectrometry analysis revealed several non-histone protein interactions between CBX7 and the H3K9 methyltransferases SETDB1, EHMT1, and EHMT2. These CBX7-binding proteins possess a trimethylated lysine peptide motif highly similar to the canonical CBX7 target H3K27me3. Depletion of SETDB1 in AML cells phenocopied repression of CBX7. We identify CBX7 as an important regulator of self-renewal and uncover non-canonical crosstalk between distinct pathways, revealing therapeutic opportunities for leukemia., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)