Models of <i>KPTN</i>-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.</p

Post-Franco Theatre

In the multiple realms and layers that comprise the contemporary Spanish theatrical landscape, “crisis” would seem to be the word that most often lingers in the air, as though it were a common mantra, ready to roll off the tongue of so many theatre professionals with such enormous ease, and even enthusiasm, that one is prompted to wonder whether it might indeed be a miracle that the contemporary technological revolution – coupled with perpetual quandaries concerning public and private funding for the arts – had not by now brought an end to the evolution of the oldest of live arts, or, at the very least, an end to drama as we know it

The medial open-wegde osteotomy generates progressive intrameniscal integrity changes in the lateral knee compartment: a prospective MR-assessment after valgic osteotomy in the varus gonarthritic knee

Bick F, Iffland Y, Zimmermann E, Welsch F, Hoffmann R, Stein T. The medial open-wegde osteotomy generates progressive intrameniscal integrity changes in the lateral knee compartment: a prospective MR-assessment after valgic osteotomy in the varus gonarthritic knee. KNEE SURGERY SPORTS TRAUMATOLOGY ARTHROSCOPY. 2019;27(4):1339-1346.PurposeMeniscal changes in the lateral knee compartment after medial-opening high tibial osteotomy (HTO) with valgic overcorrection have not been investigated clinically with magnetic resonance imaging (MRI). The hypothesis of this study was that HTO with valgic overcorrection affects the lateral compartment due to the change in the bearing axis and the shift in the pressure load from the medial to the lateral compartment. This should lead to an accelerated degeneration of the lateral compartment.MethodsTwenty-four patients (mean age, 45.77.6years) were prospectively and longitudinally monitored with MRI after medial-opening high tibial osteotomy. The degeneration of the meniscus was assessed at the anterior horn, pars intermedia, and posterior horn using the Stoller classification. The morphological changes were also assessed at the anterior horn, pars intermedia, and posterior horn using the relative vertical and transverse diameters of the examined part of the meniscus, according to the ratio maximal meniscal diameter/maximal tibial width. These parameters were analyzed preoperatively and at follow-up (mean 5.31.5years after surgery).Results During the follow-up period, there were no significant morphological changes in either the anterior horn, pars intermedia, or posterior horn. Nor were there any correlations between the morphological parameters, bodyweight, and the follow-up period. Despite these findings, an MRI evaluation showed progressive degeneration in every part of the meniscus according to the Stoller classification, and this was significant at the anterior horn (p<0.01), pars intermedia (p=0.021), and posterior horn (p<0.01).Conclusion High tibial osteotomy did not lead to morphological changes in the external meniscus over a follow-up period of 5.3 +/- 1.5years. However, progressive degeneration of the meniscus was observed in the imaging data. Further research is required to confirm the observed degeneration and to evaluate the consequences of the observed degeneration