Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease

Axonal degeneration determines the clinical outcome of multiple sclerosis and is thought to result from exposure of denuded axons to immune-mediated damage. Therefore, myelin is widely considered to be a protective structure for axons in multiple sclerosis. Myelinated axons also depend on oligodendrocytes, which provide metabolic and structural support to the axonal compartment. Given that axonal pathology in multiple sclerosis is already visible at early disease stages, before overt demyelination, we reasoned that autoimmune inflammation may disrupt oligodendroglial support mechanisms and hence primarily affect axons insulated by myelin. Here, we studied axonal pathology as a function of myelination in human multiple sclerosis and mouse models of autoimmune encephalomyelitis with genetically altered myelination. We demonstrate that myelin ensheathment itself becomes detrimental for axonal survival and increases the risk of axons degenerating in an autoimmune environment. This challenges the view of myelin as a solely protective structure and suggests that axonal dependence on oligodendroglial support can become fatal when myelin is under inflammatory attack

A comparison between Asians and Caucasians in the dimensions of the femoral isthmus based on a 3D-CT analysis of 1189 adult femurs

Introduction!#!For successful intramedullary implant placement at the femur, such as nailing in unstable proximal femur fractures, the use of an implant that at least reaches or exceeds the femoral isthmus and yields sufficient thickness is recommended. A number of complications after intramedullary femoral nailing have been reported, particularly in Asians. To understand the anatomical features of the proximal femur and their ethnic differences, we aimed to accurately calculate the femoral isthmus dimensions and proximal distance of Asians and Caucasians.!##!Methods!#!In total, 1189 Asian and Caucasian segmented 3D CT data sets of femurs were analyzed. The individual femoral isthmus diameter was precisely computed to investigate whether gender, femur length, age, ethnicity or body mass index have an influence on isthmus diameters.!##!Results!#!The mean isthmus diameter of all femurs was 10.71 ± 2.2 mm. A significantly larger diameter was found in Asians when compared to Caucasians (p < 0.001). Age was a strong predictor of the isthmus diameter variability in females (p < 0.001, adjusted r!##!Conclusions!#!In absolute values, the proximal isthmus distance did not show much variation but is more proximal in Asians. The detailed data presented may be helpful in the development of future implant designs. The length and thickness of future standard implants may be considered based on the findings

Extended approach to the lateral tibial plateau with central meniscal subluxation in fracture repair: feasibility and first clinical and radiographic results

Purpose!#!Anatomic reduction in tibial plateau fractures remains to be demanding. For further visualisation of and approach to the joint surface an extended lateral approach using a lateral femoral epicondyle osteotomy and subluxation of the lateral meniscus was recently described. First clinical and radiographic mid-term results of this technique are presented in this feasibility study.!##!Method!#!Ten complex tibial plateau fractures treated with extended lateral approach and lateral meniscal subluxation were prospectively analysed. Clinical and radiographic results were objectified according to the Rasmussen scores.!##!Results!#!After a median follow-up of 8.6 (IQR 4.3) months good to excellent clinical and radiographic results were noted. The clinical Rasmussen Score showed a median of 25 (IQR 2.8) and radiographic a median of 17 (IQR 2.0) points.!##!Conclusion!#!Good to excellent clinical and radiological scores were obtained after using an extended lateral approach with lateral femoral epicondyle osteotomy and central meniscus subluxation. No approach specific complications could be observed

An All-Arthroscopic Technique for Complex Posterolateral Corner Reconstruction

Injuries to the posterolateral corner (PLC) often result in lateral, rotational, and dorsal instability, which need appropriate and differentiated treatment. Besides posterior cruciate ligament reconstruction for posterior instability, the technique according to LaPrade et al. efficiently stabilizes posterolateral rotational and lateral instability as described in Fanelli type B or C injuries. This technique has been exclusively used as an open procedure. In this article, we present an all-arthroscopic technique for the posterolateral stabilization procedure. To achieve this, 5 different arthroscopic portals are needed. The PLC is visualized by a trans-septal approach. Directly posterior to the popliteal tendon, arthroscopic preparation is started and the medial part of the fibular head is exposed. Two anatomic drill channels are placed in the lateral femoral condyle, with one tibial channel in the distal third of the sulcus popliteus and one channel in the fibular head. The popliteal tendon, popliteofibular ligament, and lateral collateral ligament are reconstructed with autologous hamstring tendons. The advantages of an all-arthroscopic anatomic PLC reconstruction are the protection of the soft tissues and the precise anatomic tunnel placement under direct visualization. The described procedure is a safe and anatomic method for posterolateral stabilization

The influence of bone quality on radiological outcome in 50 consecutive acetabular fractures treated with a pre-contoured anatomic suprapectineal plate

Purpose!#!To investigate the range of indications of an anatomical-preshaped three-dimensional suprapectineal plate and to assess the impact of the bone mass density on radiologic outcomes in different types of acetabular fractures.!##!Patients and methods!#!A consecutive case series of 50 acetabular fractures (patient age 69 ± 23 years) treated with suprapectineal anatomic plates were analyzed in a retrospective study. The analysis included: Mechanism of injury, fracture pattern, surgical approach, need for additional total hip arthroplasty, intra- or postoperative complications, as well as bone mass density and radiological outcome on postoperative computed tomography.!##!Results!#!Most frequently, anterior column fracture patterns with and without hemitransverse components as well as associated two column fractures were encountered. The anterior intrapelvic approach (AIP) was used in 98% (49/50) of the cases as primary approach with additional utilization of the first window of the ilioinguinal approach in 13/50 cases (26%). Determination of bone density revealed impaired bone quality in 70% (31/44). Postoperative steps and gaps were significantly greater in this subgroup (p < 0.05). Fracture reduction quality for postoperative steps revealed anatomic results in 92% if the bone quality was normal and in 46% if impaired (p < 0.05). In seven cases (14%), the plate was utilized in combination with acute primary arthroplasty.!##!Conclusion!#!A preshaped suprapectineal plate provides good radiological outcomes in a variety of indications in a predominantly geriatric cohort. Impaired bone quality has a significantly higher risk of poor reduction results. In cases with extensive joint destruction, the combination with total hip arthroplasty was a valuable option

Natural history of meningiomas: a serial volumetric analysis of 240 tumors.

OBJECTIVE The management of asymptomatic intracranial meningiomas is controversial. Through the assessment of growth predictors, the authors aimed to create the basis for practicable clinical pathways for the management of these tumors. METHODS The authors volumetrically analyzed meningiomas radiologically diagnosed at their institution between 2003 and 2015. The primary endpoint was growth of tumor volume. The authors used significant variables from the multivariable regression model to construct a decision tree based on the exhaustive Chi-Square Automatic Interaction Detection (CHAID) algorithm. RESULTS Of 240 meningiomas, 159 (66.3%) demonstrated growth during a mean observation period of 46.9 months. On multivariable logistic regression analysis, older age (OR 0.979 [95% CI 0.958-1.000], p = 0.048) and presence of calcification (OR 0.442 [95% CI 0.224-0.872], p = 0.019) had a negative predictive value for tumor growth, while T2-signal iso-/hyperintensity (OR 4.415 [95% CI 2.056-9.479], p < 0.001) had a positive predictive value. A decision tree model yielded three growth risk groups based on T2 signal intensity and presence of calcifications. The median tumor volume doubling time (Td) was 185.7 months in the low-risk, 100.1 months in the intermediate-risk, and 51.7 months in the high-risk group (p < 0.001). Whereas 0% of meningiomas in the low- and intermediate-risk groups had a Td of ≤ 12 months, the percentage was 8.9% in the high-risk group (p = 0.021). CONCLUSIONS Most meningiomas demonstrated growth during follow-up. The absence of calcifications and iso-/hyperintensity on T2-weighted imaging offer a practical way of stratifying meningiomas as low, intermediate, or high risk. Small tumors in the low- or intermediate-risk categories can be monitored with longer follow-up intervals

Conservative versus operative treatment of FFP II fractures in a geriatric cohort: a prospective randomized pilot trial

Abstract A clear recommendation regarding treatment strategy of fragility fractures of the pelvic ring is missing. The most typical fracture pattern is a lateral compression type injury with non-displaced fractures of the anterior pubic rami and a unilateral os sacrum fracture (FFP II). We hypothesized that operative treatment would be superior to conservative treatment. From October 2017 to April 2020, a randomized prospective non-blinded trial with n = 39 patients was carried out. Two arms with 17 operative versus 22 conservative cases were created. Inclusion criteria were a posterior pelvic ring fracture FFP type II, age over 60 years and acute fracture (< 3 weeks). Barthel index, pain level (VAS), quality of life (EQ-5D-3L), and Tinetti–Gait Test were determined on admission, at discharge, and after 3, 6, 12 and 24 months. Median follow-up was 12.9 months. The Barthel index (= 0.325), VAS (p = 0.711), quality of life (p = 0.824), and Tinetti–Gait Test (p = 0.913) showed no significant differences between the two groups after 12 months. Two patients switched from the conservative to the operative arm due to persistent immobilization and pain. The one-year mortality rate showed no significant difference (p = 0.175). Our hypothesis that surgical treatment is superior was refuted. No significant benefit was shown in terms of quality of life, mortality and pain levels. The results suggest a more differentiated treatment approach in the future, with initial conservative treatment preferred. A larger multi-center trial is required to confirm these findings. Trial registration: The study was retrospectively registered with the German Clinical Trials Registry (DRKS00013703) on 10/12/2018

Histone Deacetylases 1 and 2 Regulate Microglia Function during Development, Homeostasis, and Neurodegeneration in a Context-Dependent Manner

Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival. In contrast, Hdac1 and Hdac2 were not required for adult microglia survival during homeostasis. In a mouse model of Alzheimer's disease, deletion of Hdac1 and Hdac2 in microglia, but not in neuroectodermal cells, resulted in a decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a role for epigenetic factors that differentially affect microglia development, homeostasis, and disease that could potentially be utilized therapeutically

Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease.

As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFAs). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation

Etiology, Risk Factors, and Diagnosis of Back Pain in Children and Adolescents: Evidence- and Consensus-Based Interdisciplinary Recommendations

Using a structured approach and expert consensus, we developed an evidence-based guideline on the diagnosis of back pain and the treatment of non-specific back pain in children and adolescents. The first part comprises etiology, risk factors, and diagnosis. The second part, published in the same issue, includes treatment and prevention. A comprehensive and systematic literature search was conducted to identify relevant guidelines and studies. Based on the findings of this literature search, recommendations on risk factors and diagnosis were formulated and voted on by experts in a structured consensus-building process. Notable red flags for specific back pain and evidence-based risk factors for non-specific back pain in children and adolescents were identified. Only three evidence-based recommendations could be formulated for causes, red flags, and risk factors for back pain, while two recommendations are based on expert consensus. Regarding diagnostics, eight expert consensus recommendations and one evidence-based recommendation could be provided. Despite the importance of adequate diagnosis for the treatment of back pain in children and adolescents, results of this work confirm the deficit in research investment in this area