BoneMaster (BM) is a thin electrochemically applied hydroxyapatite (HA) implant coating marketed with expectations of improved osseointegration properties but less polyethylene (PE) wear. We compared the midterm cup migration and PE wear of cementless porous-coated hemispherical cups with and without BM.

The tripartite partition defect (PAR) polarity complex, which includes the proteins PAR3, atypical protein kinase C (aPKC), and PAR6, is a major regulator of cellular polarity. It is highly conserved and expressed in various tissues. Its largest component, PAR3, controls protein-protein interactions of the PAR complex with a variety of interaction partners, and PAR3 self-association is critical for the formation of filament-like structures. However, little is known about the structure of the PAR complex. Here, we purified non-filamentous PAR3 and the aPKC-PAR6 complex and characterized them by single-particle electron microscopy (EM). We expressed and purified an oligomerization-deficient form of PAR3, PAR3V13D,D70K, and the active aPKC-PAR6 dimer. For PAR3, engineering at two positions is sufficient to form stable single particles with a maximum dimension of 20 nm. aPKC-PAR6 forms a complex with a maximum dimension of 13.5 nm that contains single copies of aPKC. Thus, the data present a basis for further high-resolution studies of PAR proteins and PAR complex formation.

Cytosine arabinoside (AraC) is one of the main therapeutic treatments for several types of cancer, including acute myeloid leukaemia. However, after a high-dose AraC chemotherapy regime, patients develop severe neurotoxicity and cell death in the central nervous system leading to cerebellar ataxia, dysarthria, nystagmus, somnolence and drowsiness. AraC induces apoptosis in dividing cells. However, the mechanism by which it leads to neurite degeneration and cell death in mature neurons remains unclear. We hypothesise that the upregulation of the death receptor p75NTR is responsible for AraC-mediated neurodegeneration and cell death in leukaemia patients undergoing AraC treatment. To determine the role of AraC-p75NTR signalling in the cell death of mature neurons, we used mature cerebellar granule neurons' primary cultures from p75NTR knockout and p75NTRCys259 mice. Evaluation of neurite degeneration, cell death and p75NTR signalling was done by immunohistochemistry and immunoblotting. To assess the interaction between AraC and p75NTR, we performed cellular thermal shift and AraTM assays as well as Homo-FRET anisotropy imaging. We show that AraC induces neurite degeneration and programmed cell death of mature cerebellar granule neurons in a p75NTR-dependent manner. Mechanistically, Proline 252 and Cysteine 256 residues facilitate AraC interaction with the transmembrane domain of p75NTR resulting in uncoupling of p75NTR from the NFκB survival pathway. This, in turn, exacerbates the activation of the cell death/JNK pathway by recruitment of TRAF6 to p75NTR. Our findings identify p75NTR as a novel molecular target to develop treatments for counteract AraC-mediated cell death of mature neurons.

Preclinical studies reveal that the multimodal antidepressant vortioxetine enhances long-term potentiation and dendritic branching compared to a selective serotonin reuptake inhibitor (SSRI). In the present study, we investigated vortioxetine׳s effects on spines and dendritic morphology in rat hippocampus at two time points compared to the SSRI, fluoxetine. Rats were dosed for 1 and 4 weeks with vortioxetine and fluoxetine at doses relevant for antidepressant activity. Dendritic morphology of pyramidal neurons (i.e., dendritic length, dendritic branch, spine number and density, and Sholl analysis) was examined in Golgi-stained sections from hippocampal CA1. After 1 week of treatment, vortioxetine significantly increased spine number (apical and basal dendrites), spine density (only basal), dendritic length (only apical), and dendritic branch number (apical and basal), whereas fluoxetine had no effect. After 4 weeks of treatment, vortioxetine significantly increased all measures of dendritic spine morphology as did fluoxetine except for spine density of basal dendrites. The number of intersections in the apical and basal dendrites was also significantly increased for both treatments after 4 weeks compared to control. In addition, 4 weeks of vortioxetine treatment, but not fluoxetine, promoted a decrease in spine neck length. In conclusion, 1-week vortioxetine treatment induced changes in spine number and density and dendritic morphology, whereas an equivalent dose of fluoxetine had no effects. Decreased spine neck length following 4-week vortioxetine treatment suggests a transition to mature spine morphology. This implies that vortioxetine׳s effects on spine and dendritic morphology are mediated by mechanisms that go beyond serotonin reuptake inhibition.

Ischemic preconditioning (IPC) has been shown to protect the liver against ischemia-reperfusion (I/R) injuries. However, ischemic post-conditioning has received little attention. The aim of the present study was to quantify and compare the hepato-protective properties of IPC and IPO, for the first time, using unbiased design-based stereological methods.

We are currently investigating microglial activation and neuronal precursor cell (NPC) proliferation after transient middle cerebral artery occlusion (tMCAo) in rats. This study aimed: (1) to investigate differences in hippocampal NPC proliferation in outbred male spontaneously hypertensive rats (SHRs) and Sprague-Dawley rats (SDs) one week after tMCAo; (2) to present the practical use of the optical fractionator and 2D nucleator in stereological brain tissue analyses; and (3) to report our experiences with an intraluminal tMCAo model where the occluding filament is advanced 22 mm beyond the carotid bifurcation and the common carotid artery is clamped during tMCAo.

Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1beta is primarily neurotoxic in ischemic stroke, TNF-alpha may have neurotoxic and/or neuroprotective effects. We investigated whether IL-1beta and TNF-alpha are synthesized by overlapping or segregated populations of cells after ischemic stroke in mice.

The effect of postoperative intra-articular bolus injections after total hip arthroplasty (THA) remains unclear. We tested the hypothesis that intra-articular bolus injections administered every 6 hours after surgery during the first 24 hours would significantly improve analgesia after THA.

The neurovascular plasticity of hippocampus is an important theory underlying major depression. Ketamine as a novel glutamatergic antidepressant drug can induce a rapid antidepressant effect within hours. In a mechanistic proof of this concept, we examined whether ketamine leads to an increase in synaptogenesis and vascularization within 24 hours after a single injection in a genetic rat model of depression.

Symptomatic hip dysplasia is primarily treated surgically with periacetabular osteotomy (PAO). It is unclear whether changes in quality of life (QoL) and changes in hip function follow the same pattern of improvement as pain following PAO. The aim of the study is to investigate whether changes in pain were associated with changes in QoL and hip function 2 years after PAO. Furthermore, to examine patient satisfaction 2 years after PAO. This is a follow-up study with data from Aarhus University Hospital Denmark. Pain was measured using the Visual Analogue Scale, QoL with Short-Form 36 and hip function with Hip disability and Osteoarthritis Outcome Score both preoperatively and 2 years after PAO in 321 patients. Multiple linear regressions were applied. Significant mean improvements in pain, QoL and hip function were found (P < 0.05). Significant associations between changes in pain and changes in physically related QoL and changes in hip function, respectively were found (P < 0.05). A non-significant association between changes in pain and changes in mentally- related QoL was found (P = 0.13). The majority of patients (84%) reported satisfaction with the result of PAO and would undergo PAO again if they had known the results in advance. The study had a loss to follow-up of 26%. Decreased pain was significantly associated with increased physically related QoL and improved hip function 2 years after PAO. A non-significant association between decreased pain and increased mentally related QoL was found. Patients were in general satisfied with treatment and results 2 years after PAO.

The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective overexpression resulted in decreased insulin signaling presumably mediated through alterations of the integrin β1 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondrial function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.

Background and purpose - Knowledge of physical activity profiles among patients with hip dysplasia is lacking. We investigated whether patients with hip dysplasia change physical activity profile from before to 1 year after periacetabular osteotomy. Furthermore, we investigated associations between change in accelerometer-based physical activity and change in self-reported participation in preferred physical activities (PA). Patients and methods - Physical activity was objectively measured at very low to high intensity levels with accelerometer-based sensors. Subjectively, PA was recorded with Copenhagen Hip and Groin Outcome Score (HAGOS) in 77 patients. Associations between the 2 were analyzed with simple linear regression analyses. Results - Changes in accelerometer-based physical activity ranged from -2.2 to 4.0% points at all intensity levels from baseline to 1-year follow-up. These changes represent very small effect sizes (-0.16 to 0.14). In contrast, self-reported PA showed a statistically and clinically relevant increase of 22 (CI 14-29) HAGOS PA points 1 year post-surgery. Associations between change in accelerometer-based physical activity and change in self-reported PA were, however, not statistically significant and correspond to a percentage change in physical activity of only -0.87% to 0.65% for a change of 10 HAGOS PA points. Interpretation - Patients with hip dysplasia do not seem to change physical activity profile 1 year post-surgery if measured with objective accelerometer-based sensors. This is interesting as self-reported PA indicates that patients' ability to participate in physical activity increases, suggesting that this increased self-reported participatory capacity is not manifested as increased objectively measured physical activity.

Data on outcome in patients with acetabular retroversion (AR) treated with reverse periacetabular osteotomy (reverse PAO) are sparse. The aim of the study was to investigate changes in pain and hip function among patients with AR 2 years after reverse PAO and to examine whether changes in pain were associated with changes in hip function. In addition, to evaluate patient satisfaction and changes in quality of life (QoL). We present a prospective follow-up study with patient-reported outcome data from Aarhus University Hospital in Denmark. Pain at rest and during activity was measured with a Visual Analogue Scale (VAS), hip function with the Hip disability and Osteoarthritis Outcome Score (HOOS) and QoL with the Short-Form 36, pre-operatively and 2 years after reverse PAO in 74 patients. Changes were analysed using paired t-test and multiple linear regressions. Significant and clinically relevant mean improvements in pain and hip function were found. The numbers of responders achieving a minimal clinically important difference varied from 51 to 73%. Positive significant association between changes in pain and changes in hip function were found. Significant mean improvement in QoL was found. The study had a loss to follow-up of 23%. Two years after reverse PAO, patients diagnosed with AR showed significant and clinically relevant mean improvements in pain and hip function. Decreased pain was significantly associated with improved hip function. The majority of patients were satisfied with the result of surgery and QoL was similar to the Danish background population.

Background and purpose - Telemedicine could allow patients to be discharged more quickly after surgery and contribute to improve fast-track procedures without compromising quality, patient safety, functionality, anxiety, or other patient-perceived parameters. We investigated whether using telemedicine support (TMS) would permit hospital discharge after 1 day without loss of self-assessed quality of life, loss of functionality, increased anxiety, increased rates of re-admission, or increased rates of complications after hip replacement. Patients and methods - We performed a randomized controlled trial involving 72 Danish patients in 1 region who were referred for elective fast-track total hip replacement between August 2009 and March 2011 (654 were screened for eligibility). Half of the patients received a telemedicine solution connected to their TV. The patients were followed until 1 year after surgery. Results - Length of stay was reduced from 2.1 days (95% CI: 2.0-2.3) to 1.1 day (CI: 0.9-1.4; p < 0.001) with the TMS intervention. Health-related quality of life increased in both groups, but there were no statistically significant differences between groups. There were also no statistically significant differences between groups regarding timed up-and-go test and Oxford hip score at 3-month follow-up. At 12-month follow-up, the rates of complications and re-admissions were similar between the groups, but the number of postoperative hospital contacts was lower in the TMS group. Interpretation - Length of postoperative stay was shortened in patients with the TMS solution, without compromising patient-perceived or clinical parameters in patients undergoing elective fast-track surgery. These results indicate that telemedicine can be of value in fast-track treatment of patients undergoing total hip replacement.

Many studies suggest that the hippocampus is involved in the pathophysiology of psychiatric disorders, especially major depressive disorder (MDD) and schizophrenia. Especially, in vivo imaging studies indicate that the volume of hippocampus may be reduced in both disorders. Moreover, suicide may have a unique neurobiology. The aim of the present study is to investigate if depression, schizophrenia or suicide is associated with reduced postmortem volume of the hippocampal formation and/or changes in the numbers of neurons and/or glial cells in the different subregions of the hippocampus. We studied postmortem brain samples from 10 subjects with schizophrenia, 8 subjects with major depression, 11 suicide subjects with a history of depressive disorder, and 10 control subjects with no history of psychiatric or neurological diseases. The total volume and numbers of neurons and glial cells were estimated for the main hippocampal subregions using design-unbiased stereological techniques. We found the total volume and total numbers of neurons and glial cells similarly reduced by approximately 20% to 35% in depression and schizophrenia subjects relative to control subjects across all hippocampal regions. In suicide subjects, we only found increased neuron number in CA2/3 subregion. The volume and number of cells are reduced in depression and schizophrenia subjects relative to control subjects across all hippocampal regions. Our findings imply that the hippocampus may be a common site of pathophysiology in depression and schizophrenia. Community living suicide subjects seem to differ in hippocampal neurobiology compared to hospitalized subjects dying with MDD without suicide.

Protection of the brain from viral infections involves the type I IFN (IFN-I) system, defects in which render humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels lead to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we showed that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, whereas lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices or mice treated with a caspase inhibitor exhibited lower viral load and an improved infection outcome. Collectively, we identify an activation-induced apoptosis program in brain immune cells that downmodulates local immune responses.

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleinopathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2/Nrf2) is recognized as 'the master regulator of cellular anti-oxidant response', both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on the serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, expressing the mutant human A53T aSyn), which manifests widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

Electroconvulsive therapy is a fast-acting and efficient treatment of depression used in the clinic. The underlying mechanism of its therapeutic effect is still unclear. However, recovery of synaptic connections and synaptic remodeling is thought to play a critical role for the clinical efficacy obtained from a rapid antidepressant response. Here, we investigated the relationship between synaptic changes and concomitant nonneuronal changes in microvasculature and mitochondria and its relationship to brain-derived neurotrophic factor level changes after repeated electroconvulsive seizures, an animal model of electroconvulsive therapy.

Developmental dysplasia of the hip (DDH) is a common condition involving instability of the hip with multifactorial etiology. Early diagnosis and treatment are critical as undetected DDH is an important cause of long-term hip complications. Better diagnostics may be achieved through genetic methods, especially for patients with positive family history. Several candidate genes have been reported but the exact molecular etiology of the disease is yet unknown. In the present study, we performed whole exome sequencing of DDH patients from 28 families with at least two affected first-degree relatives. Four genes previously not associated with DDH (METTL21B, DIS3L2, PPP6R2, and TM4SF19) were identified with the same variants shared among affected family members, in more than two families. Among known association genes, we found damaging variants in DACH1, MYH10, NOTCH2, TBX4, EVC2, OTOG, and SHC3. Mutational burden analysis across the families identified 322 candidate genes, and enriched pathways include the extracellular matrix, cytoskeleton, ion-binding, and detection of mechanical stimulus. Taken altogether, our data suggest a polygenic mode of inheritance for DDH, and we propose that an impaired transduction of the mechanical stimulus is involved in the etiopathological mechanism. Our findings refine our current understanding of candidate causal genes in DDH, and provide a foundation for downstream functional studies.

The primary aim was to identify muscle-tendon-related pain in 100 patients with hip dysplasia. The secondary aim was to test whether muscle-tendon-related pain is associated with self-reported hip disability and muscle strength in patient with hip dysplasia. One hundred patients (17 men) with a mean age of 29 years (SD 9) were included. Clinical entity approach was carried out to identify muscle-tendon-related pain. Associations between muscle-tendon-related pain and self-reported hip disability and muscle strength were tested with multiple regression analysis, including adjustments for age and gender. Self-reported hip disability was recorded with the Copenhagen Hip and Groin Outcome Score (HAGOS), and muscle strength was assessed with a handheld dynamometer. Iliopsoas- and abductor-related pain were most prevalent with prevalences of 56% (CI 46; 66) and 42% (CI 32; 52), respectively. Adductor-, hamstrings- and rectus abdominis-related pain were less common. There was a significant inverse linear association between muscle-tendon-related pain and self-reported hip disability ranging from -3.35 to - 7.51 HAGOS points in the adjusted analysis (P < 0.05). Besides the association between muscle-tendon-related pain and hip extension a significant inverse linear association between muscle-tendon-related pain and muscle strength was found ranging from -0.11 to - 0.12 Nm/kg in the adjusted analysis (P < 0.05). Muscle-tendon-related pain exists in about half of patients with hip dysplasia with a high prevalence of muscle-tendon-related pain in the iliopsoas and the hip abductors and affects patients' self-reported hip disability and muscle strength negatively.