Geranylgeranyl pyrophosphate is crucial for neuronal survival but has no special role in Purkinje cell degeneration in Niemann Pick type C1 disease.

Niemann Pick type C (NPC1) is a rare fatal hereditary cholesterol storage disease associated with a massive Purkinje cells loss. The mechanisms leading to neurodegeneration are still poorly understood. Different laboratories pointed to hypersensitivity to cytotoxic effects of statins (HMG-CoA reductase inhibitors) in NPC1 and suggested an underlying lack of geranylgeranyl pyrophosphate (GGPP). GGPP is a non-sterol isoprenoid essential for cell survival and differentiation. We measured GGPP levels in cerebella of a NPC1 mouse model and of wild-type littermates and found a physiological increase of GGPP levels between post-natal days 21 and 49 in wild-type mice but not in NPC mice. This further supports the hypothesis that Purkinje cell loss may be due to an extremely low level of GGPP. The progressive Purkinje cell loss in NPC starts between p21 and p49. To test the hypothesis, we used long-term organotypic slice cultures of NPC1 mice that display the natural history of NPC1 disease in vitro and tested if chronic administration of GGPP might prevent Purkinje cell loss. We did not see a beneficial effect. This suggests, in contrast to the expectations, that the relative lack of GGPP may not significantly contribute to mechanisms of Purkinje cell loss in NPC1.

The natural history of cerebellar degeneration of Niemann-Pick C mice monitored in vitro.

AIMS: Niemann-Pick type C (NPC) disease is a fatal hereditary lysosomal lipid storage disease caused by mutations in NPC1 or NPC2. It is still unknown how this disorder evokes clinical signs. Typically, patients develop severe cerebellar ataxia due to progressive Purkinje cell loss. Hitherto, in vitro studies did not allow monitoring the natural process of NPC-associated Purkinje cell degeneration. Aim of this study was to evaluate whether organotypic slice cultures are usable to monitor the natural process of NPC-associated Purkinje-cell degeneration. METHODS: We used organotypic cerebellar slice cultures of a well-established NPC mouse model to display the natural history of cerebellar degeneration in vitro and cultivated them for a prolonged time period of 6 weeks for the first time. Moreover we tested several therapeutic candidates and evaluated their effect on Purkinje-cell survival. RESULTS: Our approach proves that it is possible to monitor and to prevent NPC-related Purkinje cell death reliably in vitro. This is beneficial because in vivo Purkinje cell loss directly translates into clinical signs. Thus, therapeutically interesting compounds can be tested in vitro, not only to correct biochemical abnormalities, but also to show the likelihood of a compound to prevent ataxia. As to be expected from the results of previous animal experiments, 2-hydroxypropyl-ß-cyclodextrin rescued Purkinje cells. We also discovered that 3-methyladenine preserved Purkinje cell numbers by adjusting the autophagic flux in NPC slices. CONCLUSION: We provide evidence that cerebellar slice cultures are a powerful in vitro tool to study NPC-associated Purkinje cell death in an organotypic setting.

The 'Hip Vacuum Sign'-a new radiographic phenomenon in femoro-acetabular impingement.

Femoro-acetabular impingement (FAI) is a frequent cause for groin pain in young and active patients. We discovered a so far undescribed radiographic phenomenon only visible in frog-leg lateral radiographs. The aim of this study was to describe this new radiological sign, to determine its prevalence in a symptomatic population and to investigate the correlation to a potential underlying pathology. We retrospectively reviewed all patients, who had been sent to our clinic between 2010 and 2012 for hip complaints. We excluded patients older than 50 years and patients with advanced osteoarthritis. Two independent investigators blinded to clinical data independently examined all images for the presence, location and dimension of a vacuum phenomenon and a potential underlying hip pathology. We included 242 patients. 137 of them showed clinical and radiological signs of FAI. A hip vacuum phenomenon was identified in 20 of 242 patients (8%). Interestingly, all these patients showed distinct signs of femoro-acetabular impingement. In reference to this, the prevalence of the "Hip Vacuum Sign" was 15% (20/137) in symptomatic patients with FAI. There was no correlation with age or gender. We identified a new radiological sign, the "Hip Vacuum Sign", in 15% of symptomatic patients with FAI. It was only visible in frog-leg lateral radiographs. We suggest that it represents a subluxation of the femoral head due to a lever mechanism between the femoral neck and the acetabular rim and is, therefore, a hint for a relevant femoro-acetabular impingement mechanism.