Reducing the lipase LIPE in mutant α-synuclein mice improves Parkinson-like deficits and reveals sex differences in fatty acid metabolism.

Impaired lipid metabolism is a risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) ratio toward aggregation prone monomers. A resultant increase in phospho-serine 129+ αS monomers associating with excess mono- and polyunsaturated fatty acids contributes to the αS aggregation. We previously reported that decreasing the release of monounsaturated fatty acids (MUFAs) by reducing or inhibiting the hormone sensitive lipase (LIPE) reversed pathologic αS phosphorylation and improved soluble αS homeostasis in cultured αS triplication PD neurons and reduced DAergic neurodegeneration in a C.elegans αS model. However, assessing LIPE as a potential therapeutic target for progressive PD motor phenotypes has not been investigated. 3K αS mice, representing a biochemical and neuropathological amplification of the E46K fPD-causing mutation, have decreased αS T:M ratios, lipidic aggregates, and a L-DOPA responsive PD-like motor syndrome. Here, we reduced LIPE by crossings of 3K mice with LIPE null mice, which attenuated motor deficits in male LIPE+/- knockdown (LKD)-3K mice. Heterozygous LIPE reduction was associated with an improved αS T:M ratio, and dopaminergic neurotransmitter levels and fiber densities. In female 3K-LKD mice, an increase in pS129+ and larger lipid droplets (LDs) likely decreased the benefits seen in males. Reducing LIPE decreased MUFA release from neutral lipid storage, thereby reducing MUFA in phospholipid membranes with which αS interacts. Our study highlights fatty acid turnover as a therapeutic target for Lewy body diseases and support LIPE as a promising target in males. LIPE regulation represents a novel approach to mitigate PD and DLB risk and treat disease.

Does tranexamic acid reliably reduce blood loss in proximal femur fracture surgery?

PURPOSE: The aim of our study was to investigate the use of tranexamic acid in patients with proximal femoral fractures and compare the total blood loss, transfusion rates, complications, and the application method. METHODS: A retrospective single center cohort study (level I trauma center) with 1479 patients treated operatively for a proximal femoral fracture between January 2016 and June 2020 was performed. 1 g of tranexamic acid was applied (systemic, topic or combined application). Patient data, surgical procedure, complications, and mortality were assessed. Hemoglobin levels, blood loss and transfusion rates for patients with and without tranexamic acid and the application methods were compared. RESULTS: 667 femoral neck fractures, 701 pertrochanteric and 109 subtrochanteric fractures were included. Mean age was 80.8 years. 274 patients received tranexamic acid. At admission average hemoglobin was 12.2 g/l. Hemoglobin drop postoperatively was less after tranexamic acid (9.72 vs. 9.35 g/dl). Transfusion rates were lowered significantly by 17.1% after tranexamic acid. Blood loss was reduced for all patients after tranexamic acid independent of fracture morphology. The combination of 1 g i.v. and 1 g topical-applied tranexamic acid seems to be more effective. Complication rates did not differ. CONCLUSION: Tranexamic acid is effective in reducing blood loss and transfusion rates, without increasing the risk of thromboembolic events after proximal femoral fractures. For open reduction and nailing and arthroplasty in fracture setting combined topical and single i.v. application seems most effective and closed reduction with nailing can be treated by single dose i.v. application of 1 g tranexamic acid.

[Three-point buttressing with internal fixator for minimally invasive stabilization of the anterior pelvic ring : Operative technique and first clinical results]. / Die Dreipunktabstützung mittels Fixateur interne zur minimalinvasiven Stabilisierung des vorderen Beckenrings : Operative Technik und erste klinische Ergebnisse.

BACKGROUND: The changing age distribution in society inevitably leads to a percentage increase in osteoporotic and fatigue fractures as well as the absolute number of insufficiency fractures of the pelvic ring. Due to pain these fractures lead to a loss of mobility and autonomy. To prevent these consequences surgical treatment is increasingly being performed. OBJECTIVE: This article presents a new configuration of an internal fixator on the anterior pelvic ring, the principle of which correlates to a three-point buttressing. METHODS: In addition to a description of the configuration of the internal fixator on the anterior pelvic ring and the surgical technique, the article presents the results after the first 23 applications. RESULTS: The first results after application of the new internal fixator on the pelvic ring show a low risk, sufficient and minimally invasive stabilization with an encouraging clinical and radiological outcome. CONCLUSION: Missing long-term results, also taking into account a higher number of patients, as well as the biomechanical examination of the presented fixator configuration still have to be evaluated.

Impaired olfactory bulb neurogenesis depends on the presence of human wild-type alpha-synuclein.

Synucleinopathies including Parkinson's disease (PD) are characterized by the accumulation of alpha-synuclein (α-syn) within neural cell bodies and their processes. Transgenic mice overexpressing human wild-type or mutant forms of α-syn under the control of different promoters were developed to analyse the underlying neuropathology of PD. One of the earliest clinical symptoms associated with PD is olfactory impairment. The generation of new neurons persists up to adulthood in mammals, in particular the olfactory bulb (OB). In order to assess this process in relation to α-syn accumulation, we used mice overexpressing human wild-type α-syn under the regulatable control (tet-off) of the calcium/calmodulin-dependent protein kinase IIα-promoter (CaMKII). We observed a decrease in OB neurogenesis in transgenic animals compared to controls using 5-bromo-2'-deoxyuridine (BrdU) to label newly generated cells (neuron-specific nuclear protein; NeuN). After cessation of transgene expression we detected an increase in newly generated cells both in granular (GCL) and glomerular (GLOM) layers of the OB. This led to a rescue of newly generated neurons (BrdU(+)/NeuN(+)) within the GLOM with a distinct specificity for the dopaminergic subpopulation. In contrast, we did not detect a cell-specific rescue of neuronal cells in the GCL suggesting diverse effects of alpha-synucleinopathy in both interneuronal layers of the OB. Colabelling of BrdU with glial markers showed that a differentiation into neither astroglia nor microglia attributed to the observed phenotype in the GCL. In particular, BrdU(+) particles located within microglial cells were predominantly associated close to the membrane therefore the resembling phagocytosed nuclear fragments of BrdU(+) cells. Thus, our study further contributes insights into α-syn accumulation as a causative player in the impairment of adult neurogenesis and emphasizes its diverse role in cell renewal of distinct OB cell layers.

Genetic causes of Parkinson's disease: extending the pathway.

The functional characterization of identified disease genes in monogenic forms of Parkinson's disease (PD) allows first insights into molecular pathways leading to neurodegeneration and dysfunction of the nigrostriatal system. There is increasing evidence that disturbance of the ubiquitin proteasome pathway is one important feature of this process underscoring the relevance of protein misfolding and accumulation in the neurodegenerative process of PD. Other genes are involved in mitochondrial homeostasis and still others link newly identified signalling pathways to the established paradigm of oxidative stress in PD. Additional factors are posttranslational modifications of key proteins such as phosphorylation. Also, molecular data support the role of altered iron metabolism in PD. Here we describe known genes and novel genetic susceptibility factors and define their role in neurodegeneration.

[Stabilisation of unstable trochanteric femoral fractures. Dynamic hip screw (DHS) with trochanteric stabilisation plate vs. proximal femur nail (PFN)]. / Stabilisierung von instabilen trochantären Mehrfragmentfrakturen. Vergleich zwischen PFN und DHS mit Trochanterabstützplatte.

The dynamic hip screw (DHS) with trochanteric stabilisation plate (TSP) as the extramedullary power transmission system and the proximal femur nail (PFN) as the means of intramedullary stabilisation are both standard in the treatment of unstable trochanteric femoral fractures in the case of old people. A total of 129 patients (average age: 81,5 years) with 31 A2.2 and A2.3 as well as per-/subtrochanteric femoral fractures were treated by means of osteosynthesis with DHS and TSP (n=64) or with PFN (n=65),and the results plotted in a retro-/prospective study. At low complication rates, the radiological operation results are equally good. 6 revisions were necessary in the case of the DHS with TSP and 4 in the case of PFN. A significantly shorter operation time (44.3 vs. 57.3 min) and a considerably shorter in-patient stay (18.6 vs. 21.3 days) were common with PFN. The application of full-weightbearing immediately after the operation was possible for 97% of the PFN patients and 88% of the DHS patients. In a follow-up 6 months after the operation, the PFN patients displayed a significantly lower pain intensity in the operated leg at the same score for ambulation and the same subjective degree of satisfaction. Unstable pertrochanteric and per-/subtrochanteric femoral comminuted fractures can be treated just as well with PFN as with DHS and TSP. Our study results,however, lead us to recommend treatment with PFN.