Transgenic expression of the HERV-W envelope protein leads to polarized glial cell populations and a neurodegenerative environment.

The human endogenous retrovirus type W (HERV-W) has been identified and repeatedly confirmed as human-specific pathogenic entity affecting many cell types in multiple sclerosis (MS). Our recent contributions revealed the encoded envelope (ENV) protein to disturb myelin repair by interfering with oligodendroglial precursor differentiation and by polarizing microglial cells toward an axon-damage phenotype. Indirect proof of ENV's antiregenerative and degenerative activities has been gathered recently in clinical trials using a neutralizing anti-ENV therapeutic antibody. Yet direct proof of its mode of action can only be presented here based on transgenic ENV expression in mice. Upon demyelination, we observed myelin repair deficits, neurotoxic microglia and astroglia, and increased axon degeneration. Experimental autoimmune encephalomyelitis activity progressed faster in mutant mice equally accompanied by activated glial cells. This study therefore provides direct evidence on HERV-W ENV's contribution to the overall negative impact of this activated viral entity in MS.

Translational value of choroid plexus imaging for tracking neuroinflammation in mice and humans.

Neuroinflammation is a pathophysiological hallmark of multiple sclerosis and has a close mechanistic link to neurodegeneration. Although this link is potentially targetable, robust translatable models to reliably quantify and track neuroinflammation in both mice and humans are lacking. The choroid plexus (ChP) plays a pivotal role in regulating the trafficking of immune cells from the brain parenchyma into the cerebrospinal fluid (CSF) and has recently attracted attention as a key structure in the initiation of inflammatory brain responses. In a translational framework, we here address the integrity and multidimensional characteristics of the ChP under inflammatory conditions and question whether ChP volumes could act as an interspecies marker of neuroinflammation that closely interrelates with functional impairment. Therefore, we explore ChP characteristics in neuroinflammation in patients with multiple sclerosis and in two experimental mouse models, cuprizone diet-related demyelination and experimental autoimmune encephalomyelitis. We demonstrate that ChP enlargement-reconstructed from MRI-is highly associated with acute disease activity, both in the studied mouse models and in humans. A close dependency of ChP integrity and molecular signatures of neuroinflammation is shown in the performed transcriptomic analyses. Moreover, pharmacological modulation of the blood-CSF barrier with natalizumab prevents an increase of the ChP volume. ChP enlargement is strongly linked to emerging functional impairment as depicted in the mouse models and in multiple sclerosis patients. Our findings identify ChP characteristics as robust and translatable hallmarks of acute and ongoing neuroinflammatory activity in mice and humans that could serve as a promising interspecies marker for translational and reverse-translational approaches.

Single-Dose Intraprocedural Steroid Administration Does Not Impact Early Atrial Fibrillation Recurrence.

PURPOSE: To evaluate the effect of single-dose intravenous dexamethasone on atrial fibrillation (AF) recurrence following radiofrequency catheter ablation. METHODS: A cohort of 84 adult patients (> 18 years) underwent catheter ablation at Mayo Clinic Rochester from January to March 2019. Only first-time ablation patients were included, with all re-do ablations excluded to minimize heterogeneity. Administration of intraoperative dexamethasone 4 mg or 8 mg was determined by chart review from the procedure. At our institution, intraoperative intravenous steroids are administered for postoperative nausea and vomiting (PONV) prophylaxis at the discretion of the anesthesiologist. AF recurrence was determined by ECG or cardiac monitoring within 3 months or between 3 and 12 months post-ablation with an in-person follow-up visit. RESULTS: A total of 31 (36.9%) patients received intravenous dexamethasone compared to 54 (63.1%) who did not (approximating a 2:1 comparison group). The incidence of documented AF or atrial flutter, lasting greater than 30 s, within the first 3 months post-ablation was 29.0% in the dexamethasone group versus 24.5% in the non-dexamethasone group (p value 0.80). AF or atrial flutter recurrence at 3-12 months post-ablation was 3.2% in the dexamethasone group compared to 9.4% in the non-dexamethasone group (p value 0.41). CONCLUSION: These data suggest that intraoperative intravenous dexamethasone administered during AF ablation for postoperative nausea and vomiting prophylaxis may not have a significant effect on AF recurrence rates.

Operative treatment of periprosthetic fractures of the proximal femur with a contralateral, upside-down LISS plate in elderly patients.

BACKGROUND: Increasing expectancy of life and levels of activity in the growing geriatric population lead to a rising number of prosthetic implants of the hip and consequently the incidence of periprosthetic fractures of the femur increase. The fracture pattern and the possible instability of the stem are a challenge to the orthopaedic surgeon. Treatment options are complete replacement of the implant or a solitary osteosynthesis. The goal of this study was to analyse the feasibility of the operative intervention using a contralateral reversed anatomic distal femoral LISS® locking plate and the radiological and functional outcome in a geriatric cohort. METHODS: We included all patients older than 75 years of age with a Vancouver type B fracture, which have been treated by osteosynthesis using a LISS® (contralateral reversed) plate in our institution in an interdisciplinary ortho-geriatric setting between 7/2013 and 12/2021. Perioperative morbidities, clinical and radiological outcome during follow-up were retrospectively analysed. RESULTS: During the observed time period, 83 patients (mean age: 88 years (range: 76-103), male/female: 26/57) were treated. Most fractures were Vancouver type B2 (n = 45, 54%) followed by B1 (n = 20, 24%) and B3 (n = 18, 22%). The most prevalent postoperative surgical complication was anaemia (n = 73, 88%) followed by infections (n = 12, 14%, urinary infections, pneumonia) and cardiovascular decompensation (n = 8, 10%). Clinical and radiological follow up 6-8 weeks postoperative was possible for 59 patients (70%). The majority of them did not describe pain (n = 50, 85%) and had a good or excellent radiological outcome. Three cases needed revision surgery due to infection and another three due to non-union, loosening of the stem or an additional fracture. 1-year mortality was 30%. CONCLUSION: We are convinced that the reversed contralateral LISS-plate is an easy-to-use implant with a small complication rate but a very successful and high healing rate in a geriatric, polymorbid cohort.

Human skin biofilm model: translational impact on swabbing and debridement.

OBJECTIVE: Wound biofilms are one of the greatest challenges in the therapy of hard-to-heal (chronic) wounds, as potent antimicrobial substances fail to eradicate bacteria within short incubation periods. Preclinical investigations using novel model systems that closely mimic the human wound environment and wound biofilm are required to identify new and effective therapeutic options. This study aims to identify bacterial colonisation patterns that are relevant for diagnosis and therapy. METHOD: In this study, a recently established human plasma biofilm model (hpBIOM) was incorporated into a wound within human dermal resectates after abdominoplasty. The interaction of the biofilm-forming bacteria meticillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa with the skin cells was investigated. Possible effects on wound healing processes in correlation with the persistence of the biofilm in the wound environment were analysed in patients with leg ulcers of different aetiologies and biofilm burden. RESULTS: Using haematoxylin and eosin staining, species-dependent infiltration modes of the bacteria into the wound tissue were determined for the pathogens MRSA and Pseudomonas aeruginosa. The spreading behaviour correlated with clinical observations of the spatial distributions of the bacteria. In particular, the clinically prominent Pseudomonas aeruginosa-specific distension of the wound margin was identified as epidermolysis due to persistent infiltration. CONCLUSION: The hpBIOM applied in this study represents a potential tool for preclinical analyses dealing with approval processes for new antimicrobial applications. In terms of clinical practice, a microbiological swabbing technique including the wound margin should be routinely applied to prevent wound exacerbation.

Interventions to optimise nutrition in older people in hospitals and long-term care: Umbrella review.

BACKGROUND: Inpatients have a high need for protein-energy intake because of increased physical stress metabolism due to illnesses. Protein-energy undernutrition in older patients increases the risk of complications such as falls, pressure ulcers and even death. An overview of effective interventions addressing this complex issue of malnutrition in older people is missing. AIMS: To give an overview of effective interventions to optimise nutrition in older people in hospitals and long-term care. DESIGN: An umbrella review, according to the Joanna Briggs Institute and PRISMA statement, was conducted in April 2020. METHODS: A systematic search of publications from 2010 until 2020 was conducted in CINAHL, PubMed and Cochrane Database. Included were studies reporting nutrition interventions that involved nurses or the interprofessional team in optimising older hospitalised people's nutrition. Excluded were studies investigating the effects of parenteral nutrition, certain food supplements or tube feeding and research from intensive, community or palliative care. Components of interventions were classified according to the intervention Nutrition management: Patients' assistance, patients' instruction, foodservice, environment for meals and nutrient-dense snacks. FINDINGS: Included were 13 reviews from 19 countries of the continents Asia, Australia, Europe and North America from hospitals and long-term care settings. An interprofessional food promoting culture, including staff training as part of a multi-component measure, has shown to be a successful element in implementing activities of Nutrition Management. CONCLUSION: Several studies synthesised that optimising nutrition in older people in hospitals and long-term care is achievable. Interventions were effective if-on a meta-level-staff training was addressed as part of a multi-component measure to reach an interprofessional food promoting culture. IMPLICATIONS FOR PRACTICE: Interventions to optimise older people's nutrition have to consider an interprofessional food promoting culture, including staff training about the importance of nutrition, patients' assistance and an appropriate environment for meals.

[Risk of malnutrition in elderly patients in acute hospitals - implications for nursing practice]. / Gefahr einer Mangelernährung älterer Patient_innen im Akutspital.

Risk of malnutrition in elderly patients in acute hospitals - implications for nursing practice Abstract. Background: The risk of malnutrition is increased in advanced age and acute illness, and its assessment and needs-based support are part of the responsibility of nursing. Research question / objective: The following research question aims to analyse the nutritional status and possible correlations with nursing diagnoses and other patient characteristics from persons who are 80 years old and older: Which patterns in the sense of clusters can be identified concerning calorie and protein requirements and other patient characteristics? METHODS: Explorative cross-sectional study with cluster analysis based on food intake protocols and nursing documentation. Patients from surgery, internal medicine and university acute geriatric care wards were included in this non-probability sample. RESULTS: Four groups were formed out of the data from 135 patients (protein requirement coverage): Well-nourished (116 %), sufficiently-nourished (77 %), insufficiently-nourished (59 %) and poorly-nourished (40 %). A significant correlation between calorie and protein requirement coverage and treatment area has been shown. CONCLUSIONS: The degree of coverage of protein- and energy requirement is related to the treatment area and consequently to its team culture and treatment concept. Based on the characteristics of the well-nourished, a positive effect of interprofessional cooperation and systematic recording of the risk of malnutrition, as implemented in the treatment area of acute geriatric care, might be concluded.

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.

Elevated Prosthetic Valve Gradients: What to Consider When Determining an Etiology.

DOPPLER echocardiography is a useful noninvasive tool for the assessment of cardiac hemodynamics. However, it is subject to limitations that can have important clinical implications, especially in the setting of valve prosthesis. Elevation in mean transvalvular gradient is a finding that has a variety of etiologies. One such etiology is the pressure-recovery (PR) phenomenon, a consequence of stream convergence and energy conversion across a narrowing, which is an artifact of Doppler echocardiographic calculations of valvular flow. The elevated gradient measured with Doppler echocardiography as a result of PR is not present on cardiac catheterization and does not represent true problematic valve hemodynamics. PR should be suspected with an elevated gradient on Doppler echocardiography with normal leaflet motion, especially in the setting of a small proximal aorta. Understanding and awareness of PR are important because PR can lead to overestimation of disease severity in the clinical setting.

Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity.

T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is associated with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metabolism in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network analysis revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, especially estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metabolism, which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.

Richard Lewontin and the "complications of linkage".

During the 1960s and 1970s population geneticists pushed beyond models of single genes to grapple with the effect on evolution of multiple genes associated by linkage. The resulting models of multiple interacting loci suggested that blocks of genes, maybe even entire chromosomes or the genome itself, should be treated as a unit. In this context, Richard Lewontin wrote his famous 1974 book The Genetic Basis of Evolutionary Change, which concludes with an argument for considering the entire genome as the unit of selection as a result of linkage. Why did Lewontin and others devote so much intellectual energy to the "complications of linkage" in the 1960s and 1970s? We argue that this attention to linkage should be understood in the context of research on chromosomal inversions and co-adapted gene complexes that occupied mid-century evolutionary genetics. For Lewontin, the complications of linkage were an extension of this chromosomal focus expressed in the new language of models for linkage disequilibrium.

Comparison of different optomotor response readouts for visual testing in experimental autoimmune encephalomyelitis-optic neuritis.

Optomotor response is increasingly used in preclinical research for evaluating the visual function in rodents. However, the most suitable measuring protocol for specific scientific questions is not always established. We aimed to determine the optimal parameters for visual function analysis in experimental autoimmune encephalomyelitis optic neuritis (EAEON), an animal model for multiple sclerosis. Contrast sensitivity as well as spatial frequency both had a low variance and a good test-retest reliability. Also, both parameters were able to differentiate between the EAEON and the control group. Correlations with the retinal degeneration, assessed by optical coherence tomography, the infiltration of immune cells, and the clinical disability score revealed that spatial frequency was superior to contrast sensitivity analysis. We therefore conclude that spatial frequency testing is better suited as visual acuity assessment in C57Bl/6 J EAEON mice. Furthermore, contrast sensitivity measurements are more time consuming, possibly leading to more stress for the animals.

A Tale of Two Valves: Bioprosthetic Aortic Valve Obstruction in Systemic Lupus Erythematosus and Antiphospholipid Antibody Syndrome.

Patients with systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APLAS) are at risk for cardiac manifestations, specifically valvular heart disease requiring valve replacement. Bioprosthetic valve endocarditis is an important cause of valve failure, and it is important to keep a wide differential, especially in patients with preexisting SLE and APLAS. In this E-challenge, 2 cases of bioprosthetic aortic valve endocarditis are presented; 1 case describes infective bacterial endocarditis on an aortic prosthesis and the second describes a patient with SLE and APLAS who developed bioprosthetic valve obstruction secondary to vegetations, consistent with nonbacterial endocarditis and thrombus. Etiologies for bioprosthetic valve obstruction and evaluation by echocardiography are explored. The comparison between these 2 cases specifically highlights the importance of keeping a wide differential in endocarditis, prosthetic valve vegetations, and bioprosthetic valve obstruction.

Repeated exposure of epithelial cells to apoptotic cells induces the specific selection of an adaptive phenotype: Implications for tumorigenesis.

The consequences of apoptosis extend beyond the mere death of the cell. We have shown that receptor-mediated recognition of apoptotic target cells by viable kidney proximal tubular epithelial cells (PTECs) inhibits PTEC proliferation, growth, and survival. Here, we tested the hypothesis that continual exposure to apoptotic targets can induce a phenotypic change in responding PTECs, as in other instances of natural selection. In particular, we demonstrate that repeated exposure to apoptotic targets leads to emergence of a PTEC line (denoted BU.MPTSEL) resistant to apoptotic target-induced death. Resistance is exquisitely specific. Not only are BU.MPTSEL responders fully resistant to apoptotic target-induced death (∼85% survival versus <10% survival of nonselected cells) but do so while retaining sensitivity to all other target-induced responses, including inhibition of proliferation and growth. Moreover, the resistance of BU.MPTSEL responders is specific to target-induced apoptosis, as apoptosis in response to other suicidal stimuli occurs normally. Comparison of the signaling events induced by apoptotic target exposure in selected versus nonselected responders indicated that the acquired resistance of BU.MPTSEL cells lies in a regulatory step affecting the generation of the pro-apoptotic protein, truncated BH3 interacting-domain death agonist (tBID), most likely at the level of BID cleavage by caspase-8. This specific adaptation has especial relevance for cancer, in which the prominence and persistence of cell death entail magnification of the post-mortem effects of apoptotic cells. Just as cancer cells acquire specific resistance to chemotherapeutic agents, we propose that cancer cells may also adapt to their ongoing exposure to apoptotic targets.

Assessing the anterior visual pathway in optic neuritis: recent experimental and clinical aspects.

PURPOSE OF REVIEW: Multiple sclerosis (MS) and related autoimmune disorders of the central nervous system such as neuromyelitis optica spectrum disorders (NMOSD) are characterized by chronic disability resulting from autoimmune neuroinflammation, with demyelination, astrocyte damage, impaired axonal transmission and neuroaxonal loss. Novel therapeutics stopping or reversing the progression of disability are still urgently warranted. This review addresses research on optic neuritis in preclinical experimental models and their translation to clinical trials. RECENT FINDINGS: Optic neuritis can be used as paradigm for an MS relapse which can serve to evaluate the efficacy of novel therapeutics in clinical trials with a reasonable duration and cohort size. The advantage is the linear structure of the visual pathway allowing the assessment of visual function and retinal structure as highly sensitive outcome parameters. Experimental autoimmune encephalomyelitis is an inducible, inflammatory and demyelinating central nervous system disease extensively used as animal model of MS. Optic neuritis is part of the clinicopathological manifestations in a number of experimental autoimmune encephalomyelitis models. These have gained increasing interest for studies evaluating neuroprotective and/or remyelinating substances as longitudinal, visual and retinal readouts have become available. SUMMARY: Translation of preclinical experiments, evaluating neuroprotective or remyelinating therapeutics to clinical studies is challenging. In-vivo readouts like optical coherence tomography, offers the possibility to transfer experimental study designs to clinical optic neuritis trials.

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.

BACKGROUND: Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings. METHODS: Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG35-55) or with bovine myelin basic protein (MBP), in TCR2D2 mice immunized with MOG35-55, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP139-151). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment. RESULTS: Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG35-55 EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG35-55-immunized TCR2D2 mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy. CONCLUSIONS: Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG35-55 in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.

Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis.

Multiple sclerosis is characterised by inflammatory neurodegeneration, with axonal injury and neuronal cell death occurring in parallel to demyelination. Regarding the molecular mechanisms responsible for demyelination and axonopathy, energy failure, aberrant expression of ion channels and excitotoxicity have been suggested to lead to Ca2+ overload and subsequent activation of calcium-dependent damage pathways. Thus, the inhibition of Ca2+ influx by pharmacological modulation of Ca2+ channels may represent a novel neuroprotective strategy in the treatment of secondary axonopathy. We therefore investigated the effects of the L-type voltage-gated calcium channel blocker nimodipine in two different models of mouse experimental autoimmune encephalomyelitis (EAE), an established experimental paradigm for multiple sclerosis. We show that preventive application of nimodipine (10 mg/kg per day) starting on the day of induction had ameliorating effects on EAE in SJL/J mice immunised with encephalitic myelin peptide PLP139-151 , specifically in late-stage disease. Furthermore, supporting these data, administration of nimodipine to MOG35-55 -immunised C57BL/6 mice starting at the peak of pre-established disease, also led to a significant decrease in disease score, indicating a protective effect on secondary CNS damage. Histological analysis confirmed that nimodipine attenuated demyelination, axonal loss and pathological axonal ß-amyloid precursor protein accumulation in the cerebellum and spinal cord in the chronic phase of disease. Of note, we observed no effects of nimodipine on the peripheral immune response in EAE mice with regard to distribution, antigen-specific proliferation or activation patterns of lymphocytes. Taken together, our data suggest a CNS-specific effect of L-type voltage-gated calcium channel blockade to inflammation-induced neurodegeneration.

Early alpha-lipoic acid therapy protects from degeneration of the inner retinal layers and vision loss in an experimental autoimmune encephalomyelitis-optic neuritis model.

BACKGROUND: In multiple sclerosis (MS), neurodegeneration is the main reason for chronic disability. Alpha-lipoic acid (LA) is a naturally occurring antioxidant which has recently been demonstrated to reduce the rate of brain atrophy in progressive MS. However, it remains uncertain if it is also beneficial in the early, more inflammatory-driven phases. As clinical studies are costly and time consuming, optic neuritis (ON) is often used for investigating neuroprotective or regenerative therapeutics. We aimed to investigate the prospect for success of a clinical ON trial using an experimental autoimmune encephalomyelitis-optic neuritis (EAE-ON) model with visual system readouts adaptable to a clinical ON trial. METHODS: Using an in vitro cell culture model for endogenous oxidative stress, we compared the neuroprotective capacity of racemic LA with the R/S-enantiomers and its reduced form. In vivo, we analyzed retinal neurodegeneration using optical coherence tomography (OCT) and the visual function by optokinetic response (OKR) in MOG35-55-induced EAE-ON in C57BL/6J mice. Ganglion cell counts, inflammation, and demyelination were assessed by immunohistological staining of retinae and optic nerves. RESULTS: All forms of LA provided equal neuroprotective capacities in vitro. In EAE-ON, prophylactic LA therapy attenuated the clinical EAE score and prevented the thinning of the inner retinal layer while therapeutic treatment was not protective on visual outcomes. CONCLUSIONS: A prophylactic LA treatment is necessary to protect from visual loss and retinal thinning in EAE-ON, suggesting that a clinical ON trial starting therapy after the onset of symptoms may not be successful.

Perioperative Fractures in Cementless Total Hip Arthroplasty Using the Direct Anterior Minimally Invasive Approach: Reduced Risk With Short Stems.

BACKGROUND: The direct minimally invasive anterior approach (DMIAA) and the use of uncemented stems demonstrated an increase in intraoperative fractures in recent literature. Whether the different design of the stems additionally influences the incidence of perioperative local complications, was the goal of this study. METHODS: From January 2008 until June 2010, all patients undergoing primary cementless total hip arthroplasty, using a DMIAA, were consecutively included. The choice of the implant was defined by the day of operation. Age, gender, body mass index, type of prosthesis, and the practical experience of the performing surgeon were retrospectively analyzed. Of main interest were intraoperative fractures, postoperative hematoma, and wound healing. RESULTS: Six hundred forty consecutive patients (64 years [18-94], 339 female, 53%, body mass index 26) have been included. A Quadra-H stem (Medacta) was used in 457 patients (71%). In 183 (29%) patients, a short stem designed for the DMIAA (130 Fitmore, Zimmer and 53 AMIStem, Medacta) was used. We counted 34 (5.3%) intraoperative fractures (16 at the greater trochanter, 18 proximal shaft fractures), 20 (4%) hematomas, and 8 (2%) wound healing problems. The standard length stem showed more local complications (11.8% vs 4.4%) (P = .014, odds ratio 1.63, confidence interval 1.1-2.4) and significantly more (6.8% vs 1.6%) intraoperative fractures (P = .027, odds ratio 1.98, confidence interval 1.1-3.6). CONCLUSION: The standard length stem showed more perioperative complications, especially periprosthetic fractures. It seems that these implants not only put more stress to proximal osseous structures, but there might also be more traction and irritation to the soft tissue while preparing, resulting in more hematomas and wound healing problems.

Absence of system xc- on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System xc- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. METHODS: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system xc-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT-/-) mice and irradiated mice reconstituted in xCT-/- bone marrow (BM), to their proper wild type (xCT+/+) controls. RESULTS: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT+/+ mice, xCT-/- mice were equally susceptible to EAE, whereas mice transplanted with xCT-/- BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. CONCLUSIONS: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system xc- on immune cells invading the CNS participates to EAE. Since a total loss of system xc- had no net beneficial effects, these results have important implications for targeting system xc- for treatment of MS.