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Erdheim-Chester disease (ECD) is a rare non-Langerhans’ cell histiocytosis. Mild but permanent juxta-articular bone pain in mainly knees and ankles is the most frequent associated symptom. Despite the pathognomonic radiographic findings, most cases are still diagnosed by the pathologist. The lesions consist of lipid-storing CD 68 +/ CD 1a – non- Langerhans’ cell histiocytes, most frequently localized in bone but also involving multiple organ systems in the body. We present a case report in which the diagnosis of ECD was established with 99mTc MDP bone SPECT/CT.

Cultured beef is a method where stem cells from skeletal muscle of cows are cultured in vitro to gain edible muscle tissue. For large-scale production of cultured beef, the culture technique needs to become more efficient than today's 2-dimensional (2D) standard technique that was used to make the first cultured hamburger. Options for efficient large-scale production of stem cells are to culture cells on microcarriers, either in suspension or in a packed bed bioreactor, or to culture aggregated cells in suspension. We discuss the pros and cons of these systems as well as the possibilities to use the systems for tissue culture. Either of the production systems needs to be optimized to achieve an efficient production of cultured beef. It is anticipated that the optimization of large-scale cell culture as performed for other stem cells can be translated into successful protocols for bovine satellite cells resulting in resource and cost efficient cultured beef.

Introduction: Long COVID is defined as the continuation of symptoms, unexplainable by alternative diagnosis, longer than four weeks after SARS-CoV-2 infection. These symptoms might hinder daily activities and overall well-being, ultimately impacting quality of life (QoL). Several studies have reported fatigue as the most common symptom, followed by dyspnoea, headache and myalgia. Although it is assumed that long COVID affects 10-20% of SARS-CoV-2 infected individuals, recently numbers up to 60% were described for patients with cancer. This study uncovers the impact of the COVID-19 pandemic on QoL of patients with cancer and how long COVID manifests in this cohort., Methods: A group of 96 patients with cancer was followed from March 2022 till March 2023. Online questionnaires assessing symptoms associated with long COVID, anxiety and depression (HADS), quality of life (EORTC-QLQ-C30) and cognitive functioning (CFQ) were sent every three months during this period. Furthermore, a semi-structured focus group was organised for qualitative data collection., Results: Overall, these patients reported a negative impact of the enforced COVID-19 restrictions on the emotional and psychological wellbeing. Forty nine patients with cancer (51.0%) were infected with SARS-CoV-2 over the course of the study, of which 39 (79.6%) reported long COVID symptoms. The most commonly reported symptoms were myalgia (46.2%), fatigue (38.5%) and disturbed sleep (35.9%) and it was observed that male sex is associated with poor long COVID outcomes., Conclusion: While patients with cancer experience similar long COVID symptoms as healthy controls, the prevalence is remarkably higher possibly due to their compromised immune system and weakened physiological reserve., (© 2024. The Author(s).)

Background: Currently, nanoliposomal irinotecan (nal-IRI) + 5-fluorouracil/folinic acid (5-FU/LV) is the only approved second-line treatment for patients suffering from metastatic pancreatic ductal adenocarcinoma (mPDAC). However, also other chemotherapeutic regimens are used in this setting and due to the lack of clear real-world data on the efficacy of the different regimens, there is no consensus on the optimal treatment sequence for mPDAC patients., Objectives: To provide information on the safe and efficacious use of nal-IRI + 5-FU/LV in clinical practice in Belgium, which is needed for healthcare professionals to estimate the risk-benefit ratio of the intervention., Methods: Medical data of adult patients with mPDAC who were treated with nal-IRI + 5-FU/LV in one of the participating Belgian hospitals were retrospectively collected. Kaplan-Meier analysis was performed to obtain survival curves to estimate the median overall survival (OS) and progression-free survival (PFS). All other results were presented descriptively., Results: A total of 56 patients [median age at diagnosis: 69 years (range 43 years), 57.1% male] were included. Patients received a median of 5 (range 49 cycles) nal-IRI + 5-FU/LV cycles, extended over 10 weeks (range 130.8 weeks). The median start dose for nal-IRI was 70 mg/m² (range 49.24 mg/m²) and chemotherapy dose reduction and delay occurred in, respectively, 42.8% and 37.5% of the patients. The median OS was 6.8 months (95% CI: 5.6-8.4 months) with a 6-month survival rate of 57.4% and a 1-year survival rate of 27.8% in the overall study population. The median OS for patients treated with nal-IRI as second-line therapy or as later-line treatment was, respectively, 6.8 months (95% CI: 5.9-7.0 months) and 5.6 months (95% CI: 4.2- no upper limit ). In the overall study population, a median PFS of 3.1 months (95% CI: 2.4-4.6 months) and a disease control rate of 48.3%, comprising 30.4% stable disease, 16.1% partial and 1.8% complete response, was observed. The median PFS for patients treated with nal-IRI as second-line therapy was 3.9 months (95% CI: 2.8-4.8 months) while this was 2.4 months (95% CI: 1.9-9.1 months) for those that received nal-IRI in a later-line treatment. In terms of safety, gastrointestinal problems occurred most (64.3% of the patients) and from all reported treatment emergent adverse events, 39.2% were grade 3 or 4., Conclusion: Nal-IRI + 5-FU/LV is a valuable, effective, and safe sequential treatment option following gemcitabine-based therapy in patients with mPDAC., Trial Details: Retrospective study on the efficacy and tolerability of liposomal irinotecan (NALIRI); ClinicalTrials.gov Identifier: NCT0509506 (https://clinicaltrials.gov/ct2/show/NCT05095064?term=naliri&draw=2&rank=2)., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Purpose: Patients with cancer display reduced humoral responses after double-dose COVID-19 vaccination, whereas their cellular response is more comparable with that in healthy individuals. Recent studies demonstrated that a third vaccination dose boosts these immune responses, both in healthy people and patients with cancer. Because of the availability of many different COVID-19 vaccines, many people have been boosted with a different vaccine from the one used for double-dose vaccination. Data on such alternative vaccination schedules are scarce. This prospective study compares a third dose of BNT162b2 after double-dose BNT162b2 (homologous) versus ChAdOx1 (heterologous) vaccination in patients with cancer., Experimental Design: A total of 442 subjects (315 patients and 127 healthy) received a third dose of BNT162b2 (230 homologous vs. 212 heterologous). Vaccine-induced adverse events (AE) were captured up to 7 days after vaccination. Humoral immunity was assessed by SARS-CoV-2 anti-S1 IgG antibody levels and SARS-CoV-2 50% neutralization titers (NT50) against Wuhan and BA.1 Omicron strains. Cellular immunity was examined by analyzing CD4+ and CD8+ T-cell responses against SARS-CoV-2-specific S1 and S2 peptides., Results: Local AEs were more common after heterologous boosting. SARS-CoV-2 anti-S1 IgG antibody levels did not differ significantly between homologous and heterologous boosted subjects [GMT 1,755.90 BAU/mL (95% CI, 1,276.95-2,414.48) vs. 1,495.82 BAU/mL (95% CI, 1,131.48-1,977.46)]. However, homologous-boosted subjects show significantly higher NT50 values against BA.1 Omicron. Subjects receiving heterologous boosting demonstrated increased spike-specific CD8+ T cells, including higher IFNγ and TNFα levels., Conclusions: In patients with cancer who received double-dose ChAdOx1, a third heterologous dose of BNT162b2 was able to close the gap in antibody response., (©2022 American Association for Cancer Research.)

Background: Patients with cancer, especially hematological cancer, are at increased risk for breakthrough COVID-19 infection. So far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed., Methods: We employed machine learning approaches to identify a biomarker signature based on blood cytokines, chemokines, and immune- and non-immune-related growth factors linked to vaccine immunogenicity in 199 cancer patients receiving the BNT162b2 vaccine., Results: C-reactive protein (general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) correctly classified patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments., Conclusion: We propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at persistent high risk of COVID-19 despite vaccination with BNT162b2. Our data also suggest that such a signature may reflect the inherent immunological constitution of some cancer patients who are refractive to immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Konnova, De Winter, Gupta, Verbruggen, Hotterbeekx, Berkell, Teuwen, Vanhoutte, Peeters, Raats, Massen, De Keersmaecker, Debie, Huizing, Pannus, Neven, Ariën, Martens, Bulcke, Roelant, Desombere, Anguille, Berneman, Goossens, Goossens, Malhotra-Kumar, Tacconelli, Vandamme, Peeters, van Dam and Kumar-Singh.)

The cystine/glutamate antiporter system x c - has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT -/- ) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT -/- mice led to the hypothesis that system x c - deletion would negatively affect life- and healthspan. Still, till now the role of system x c - in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT -/- mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT +/+ mice, was attenuated in xCT -/- mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT -/- mice. Targeting system x c - is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging., (© 2022. The Author(s).)

The astrocytic cystine/glutamate antiporter system x c - (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson's disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT -/- ) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT +/+ ) littermates. Contrary to adult mice, aged xCT -/- mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT +/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT -/- mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT -/- mice when compared to age-matched xCT +/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT -/- mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system x c - in mechanisms of dopaminergic cell loss and its interaction with aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bentea, De Pauw, Verbruggen, Winfrey, Deneyer, Moore, Albertini, Sato, Van Eeckhaut, Meshul and Massie.)

Background: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear., Patients and Methods: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster., Results: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200 IU/ml) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission., Conclusion: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections., Competing Interests: Disclosure MP declares to have an advisory role within Remedus. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

The astrocytic cystine/glutamate antiporter system x c - represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system x c - , xCT (xCT -/- mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT -/- mice. A proteomic and kinomic screen of the striatum of xCT -/- mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT -/- mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system x c - plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior., (© 2020. The Author(s).)

Despite ample evidence for the therapeutic potential of inhibition of the cystine/glutamate antiporter system x c - in neurological disorders and in cancer, none of the proposed inhibitors is selective. In this context, a lot of research has been performed using the EMA- and FDA-approved drug sulfasalazine (SAS). Even though this molecule is already on the market for decades as an anti-inflammatory drug, serious side effects due to its use have been reported. Whereas for the treatment of the main indications, SAS needs to be cleaved in the intestine into the anti-inflammatory compound mesalazine, it needs to reach the systemic circulation in its intact form to allow inhibition of system x c - . The higher plasma levels of intact SAS (or its metabolites) might induce adverse effects, independent of its action on system x c - . Some of these effects have however been attributed to system x c - inhibition, calling into question the safety of targeting system x c - . In this study we chronically treated system x c - - deficient mice and their wildtype littermates with two different doses of SAS (160 mg/kg twice daily or 320 mg/kg once daily, i.p.) and studied some of the adverse effects that were previously reported. SAS had a negative impact on the survival rate, the body weight, the thermoregulation and/or stress reaction of mice of both genotypes, and thus independent of its inhibitory action on system x c - . While SAS decreased the total distance travelled in the open-field test the first time the mice encountered the test, it did not influence this parameter on the long-term and it did not induce other behavioral changes such as anxiety- or depressive-like behavior. Finally, no major histological abnormalities were observed in the spinal cord. To conclude, we were unable to identify any undesirable system x c - -dependent effect of chronic administration of SAS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Verbruggen, Sprimont, Bentea, Janssen, Gharib, Deneyer, De Pauw, Lara, Sato, Nicaise and Massie.)

Proper glutamatergic neurotransmission requires a balance between glutamate release and removal. The removal is mainly catalyzed by the glutamate transporters EAAT1-3, while the glutamate-cystine exchanger (system x c - with specific subunit xCT) represents one of the release mechanisms. Previous studies of the spinal cord have focused on the cellular distribution of EAAT1-3 with special reference to the dorsal horn, but have not provided quantitative data and have not systematically compared multiple segments. Here we have studied the distribution of EAAT1-3 and xCT in sections of multiple spinal cord segments using knockout tissue as negative controls. EAAT2 and EAAT3 were evenly expressed in all gray matter areas at all segmental levels, albeit with slightly higher levels in laminae 1-4 (dorsal horn). Somewhat higher levels of EAAT2 were also seen in lamina 9 (ventral horn), while EAAT3 was also detected in the lateral spinal nucleus. EAAT1 was concentrated in laminae 1-3, lamina 10, the intermediolateral nucleus and the sacral parasympathetic nucleus, while xCT was concentrated in laminae 1-3, lamina 10 and the leptomeninges. The levels of these four transporters were low in white matter, which represents 42% of the spinal cord volume. Quantitative immunoblotting revealed that the average level of EAAT1 in the whole spinal cord was 0.6 ± 0.1% of that in the cerebellum, while the levels of EAAT2, EAAT3 and xCT were, respectively, 41.6 ± 12%, 39.8 ± 7.6%, and 30.8 ± 4.3% of the levels in the hippocampus (mean values ± SEM). Conclusions: Because the hippocampal tissue content of EAAT2 protein is two orders of magnitude higher than the content of the EAAT3, it follows that most of the gray matter in the spinal cord depends almost exclusively on EAAT2 for glutamate removal, while the lamina involved in the processing of autonomic and nociceptive information rely on a complex system of transporters., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Overt hepatic encephalopathy (OHE) negatively impacts the prognosis of liver transplant candidates. However, it is not taken into account in most prioritizing organ allocation systems. We aimed to assess the impact of OHE on waitlist mortality in 3 cohorts of cirrhotic patients awaiting liver transplantation, with differences in the composition of patient population, transplantation policy, and transplantation rates. These cohorts were derived from two centers in the Netherlands (reference and validation cohort, n = 246 and n = 205, respectively) and one in Spain (validation cohort, n = 253). Competing-risk regression analysis was applied to assess the association of OHE with 1-year waitlist mortality. OHE was found to be associated with mortality, independently of MELD score, other cirrhosis-related complications and hepatocellular carcinoma (HCC; sHR = 4.19, 95% CI = 1.9-9.5, P = 0.001). The addition of extra MELD points for OHE counteracted its negative impact on survival. These findings were confirmed in the Dutch validation cohort, whereas in the Spanish cohort, containing a significantly greater proportion of HCC and with higher transplantation rates, OHE was not associated with mortality. In conclusion, OHE is an independent risk factor for 1-year waitlist mortality and might be a prioritization rule for organ allocation. However, its impact seems to be attenuated in settings with significantly higher transplantation rates., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In Parkinson's disease, striatal dopamine depletion leads to plastic changes at excitatory corticostriatal and thalamostriatal synapses. The functional consequences of these responses on the expression of behavioral deficits are incompletely understood. In addition, most of the information on striatal synaptic plasticity has been obtained in models with severe striatal dopamine depletion, and less is known regarding changes during early stages of striatal denervation. Using a partial model of nigral cell loss based on intranigral injection of the proteasome inhibitor lactacystin, we demonstrate ultrastructural changes at corticostriatal synapses with a 15% increase in the length and 30% increase in the area of the postsynaptic densities at corticostriatal synapses 1 week following toxin administration. This increase was positively correlated with the performance of lactacystin-lesioned mice on the rotarod task, such that mice with a greater increase in the size of the postsynaptic density performed better on the rotarod task. We therefore propose that lengthening of the postsynaptic density at corticostriatal synapses acts as a compensatory mechanism to maintain motor function under conditions of partial dopamine depletion. The ultrastructure of thalamostriatal synapses remained unchanged following lactacystin administration. Our findings provide novel insights into the mechanisms of synaptic plasticity and behavioral compensation following partial loss of substantia nigra pars compacta neurons, such as those occurring during the early stages of Parkinson's disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Zonisamide (ZNS), an anticonvulsant drug exhibiting symptomatic effects in Parkinson's disease (PD), was recently reported to exert neuroprotection in rodent models. One of the proposed neuroprotective mechanisms involves increased protein expression of xCT, the specific subunit of the cystine/glutamate antiporter system x c - , inducing glutathione (GSH) synthesis. Here, we investigated the outcome of ZNS treatment in a mouse model of PD based on intranigral proteasome inhibition, and whether the observed effects would be mediated by system x c - . The proteasome inhibitor lactacystin (LAC) was administered intranigrally to male C57BL/6J mice receiving repeated intraperitoneal injections of either ZNS 30mgkg -1 or vehicle. Drug administration was initiated three days prior to stereotaxic LAC injection and was maintained until six days post-surgery. One week after lesion, mice were behaviorally assessed and investigated in terms of nigrostriatal neurodegeneration and molecular changes at the level of the basal ganglia, including expression levels of xCT. ZNS reduced the loss of nigral dopaminergic neurons following LAC injection and the degree of sensorimotor impairment. ZNS failed, however, to modulate xCT expression in basal ganglia of lesioned mice. In a separate set of experiments, the impact of ZNS treatment on system x c - was investigated in control conditions in vivo as well as in vitro. Similarly, ZNS did not influence xCT or glutathione levels in naive male C57BL/6J mice, nor did it alter system x c - activity or glutathione content in vitro. Taken together, these results demonstrate that ZNS treatment provides neuroprotection and behavioral improvement in a PD mouse model based on proteasome inhibition via system x c - independent mechanisms., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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 x c - 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 x c - , 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 x c - on immune cells invading the CNS participates to EAE. Since a total loss of system x c - had no net beneficial effects, these results have important implications for targeting system x c - for treatment of MS.

The pathological hallmarks of Parkinson's disease are the progressive loss of nigral dopaminergic neurons and the formation of intracellular inclusion bodies, termed Lewy bodies, in surviving neurons. Accumulation of proteins in large insoluble cytoplasmic aggregates has been proposed to result, partly, from a failure in the function of intracellular protein degradation pathways. Evidence in support for such a hypothesis emerged in the beginning of the years 2000 with studies demonstrating structural and functional deficits in the ubiquitin-proteasome pathway in post-mortem nigral tissue of patients with Parkinson's disease. These fundamental findings have inspired the development of a new generation of animal models based on the use of proteasome inhibitors to disturb protein homeostasis and trigger nigral dopaminergic neurodegeneration. In this review, we provide an updated overview of the current approaches in employing proteasome inhibitors to model Parkinson's disease, with particular emphasis on rodent studies. In addition, the mechanisms underlying proteasome inhibition-induced cell death and the validity criteria (construct, face and predictive validity) of the model will be critically discussed. Due to its distinct, but highly relevant mechanism of inducing neuronal death, the proteasome inhibition model represents a useful addition to the repertoire of toxin-based models of Parkinson's disease that might provide novel clues to unravel the complex pathogenesis of this disorder.

Erdheim-Chester disease (ECD) is a rare non-Langerhans' cell histiocytosis. Mild but permanent juxta-articular bone pain in mainly knees and ankles is the most frequent associated symptom. Despite the pathognomonic radiographic findings, most cases are still diagnosed by the pathologist.The lesions consist of lipid-storing CD 68 +/CD 1a--non-Langerhans' cell histiocytes, most frequently localized in bone but also involving multiple organ systems in the body. We present a case report in which the diagnosis of ECD was established with 99mTc MDP bone SPECT/CT.

Paget's disease of bone (PDB) is, after osteoporosis, the second most common metabolic bone disorder in the elderly Caucasian population. Mutations in the sequestosome 1 gene (SQSTM1) are responsible for the etiology of PDB in a subset of patients, but the disease pathogenesis in the remaining PDB patients is still unknown. Therefore association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed in order to find the susceptibility polymorphisms. In this paper, we sought to determine whether polymorphisms in 3 functional candidate genes play a role in the development of sporadic PDB: TNFSF11 (receptor activator of nuclear factor κB ligand, RANKL), VCP (valosin-containing protein) and IL-6 (interleukin 6). Analyzing 9 tag SNPs and 2 multi-marker tests (MMTs) in TNFSF11, 3 tag SNPs and 1 MMT in VCP and 8 tag SNPs in IL-6 in a population of 196 Belgian patients with sporadic PDB and 212 Belgian control individuals revealed that one VCP SNP (rs565070) turned out to be associated with PDB in this Belgian study population (p=5.5×10(-3)). None of the tag SNPs or MMTs selected for TNFSF11 or IL-6 was associated with PDB. Still, replication of our findings in the VCP gene in other populations is important to confirm our results. However, when combining data of VCP with those from other susceptible gene regions from previous association studies (i.e. TNFRSF11A, CSF1, OPTN and TM7SF4), independent effect of each gene region was found and the cumulative population attributable risk is 72.7%., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Paget's disease of bone (PDB) is one of the most frequent metabolic bone disorders (1-5%), next to osteoporosis, affecting individuals above age 55. Sequestosome1 mutations explain a part of the PDB patients, but still the disease pathogenesis in the remaining PDB patients is largely unknown. Therefore, association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed to find the genetic risk variants. Previously such studies indicated a role of the OPG and RANK gene. The latter was recently confirmed in a genome-wide association study (GWAS) which also indicated the involvement of chromosomal regions harbouring the CSF1 and OPTN gene. In this study, we sought to replicate these findings in a Belgian and a Dutch population. Similar significant results were obtained for the single nucleotide polymorphisms and the haplotypes. The most significant results are found in the CSF1 gene region, followed by the OPTN and TNFRSF11A gene region (p values ranging from 1.3 × 10(-4) to 3.8 × 10(-8), OR = 1.523-1.858). We next obtained significant association with a polymorphism from the chromosomal region around the TM7SF4 gene (p = 2.7 × 10(-3), OR = 1.427), encoding DC-STAMP which did not reach genome-wide significance in the GWAS, but based on its function in osteoclasts it can be considered a strong candidate gene. After meta-analysis with the GWAS data, p values ranged between 2.6 × 10(-4) and 8.8 × 10(-32). The calculated cumulative population attributable risk of these four loci turned out to be about 67% in our two populations, indicating that most of the genetic risk for PDB is coming from genetic variants close to these four genes.

RANK (receptor activator of nuclear factor-κB), encoded by TNFRSF11A, is a key protein in osteoclastogenesis. TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (ie, familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset PDB) and an osteoclast-poor form of osteopetrosis. However, no TNFRSF11A mutations have been found in classic PDB, neither in familial nor in isolated cases. To investigate the possible relationship between TNFRSF11A polymorphisms and sporadic PDB, we conducted an association study including 32 single-nucleotide polymorphisms (SNPs) in 196 Belgian sporadic PDB patients and 212 control individuals. Thirteen SNPs and 3 multimarker tests (MMTs) turned out to have a p value of between .036 and 3.17 × 10(-4) , with the major effect coming from females. Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction (p < .002). Replication studies were performed for 2 nonsynonymous SNPs (rs35211496 and rs1805034) in a Dutch and a British cohort. Interestingly, both SNPs resulted in p values ranging from .013 to 8.38 × 10(-5) in both populations. Meta-analysis over three populations resulted in p = .002 for rs35211496 and p = 1.27 × 10(-8) for rs1805034, again mainly coming from the female subgroups. In an attempt to identify the underlying causative SNP, we performed functional studies for the coding SNPs as well as resequencing efforts of a 31-kb region harboring a risk haplotype within the Belgian females. However, neither approach resulted in significant evidence for the causality of any of the tested genetic variants. Therefore, further studies are needed to identify the real cause of the increased risk to develop PDB shown to be present within TNFRSF11A., (Copyright © 2010 American Society for Bone and Mineral Research.)

Unlabelled: We studied the role of TNFRSF11B polymorphisms on the risk to develop Paget's disease of bone in a Belgian study population. We observed no association in men, but a highly significant association was found in women, and this was confirmed in a population from the United Kingdom., Introduction: Juvenile Paget's disease has been shown to be caused by mutations in TNFRSF11B encoding osteoprotegerin. Although mutations in this gene have never been found in patients with typical Paget's disease of bone (PDB), there are indications that polymorphisms in TNFRSF11B might contribute to the risk of developing PDB., Materials and Methods: We recruited a population of 131 Belgian patients with sporadic PDB and 171 Belgian controls. By means of the HapMap, we selected 17 SNPs that, in combination with four multimarker tests, contain most information on common genetic variation in TNFRSF11B. To replicate the findings observed in the Belgian study population, genotyping data of SNPs generated in a UK population were reanalyzed., Results: In our Belgian study population, associations were found for two SNPs (rs11573871, rs1485286) and for one multimarker test involving rs1032129. When subsequently analyzing men and women separately, these associations turned out to be driven by women (56 cases, 78 controls). In addition, three other tagSNPs turned out to be associated in women only. These were rs2073617 (C950T), rs6415470, and rs11573869. Reanalysis of genotyping data from a UK study population indicated that the associations found for C950T and C1181G were also exclusively driven by women (146 cases, 216 controls). Meta-analysis provided evidence for risk increasing effects of the T allele of C950T and the G allele of C1181G in the female population (p = 0.002 and 0.003, respectively). The haplotypes formed by the SNPs associated in the Belgian population were also distributed differentially between female cases and controls., Conclusions: We showed for the first time that SNPs influencing the risk to develop PDB could be sex-specific. Further research is necessary to identify the causative variants in TNFRSF11B and to elucidate the molecular pathogenic mechanism.

Background: Anti-extractable nuclear antigen antibodies (ENA) are markers of connective tissue diseases (CTDs)., Methods: We compared FIDIS reagents in the multiplex fluorescent microsphere immunodetection system to INNO-LIA and immunodiffusion for 174 antinuclear antibody-positive patients, 102 with well-defined CTDs and 72 disease controls., Results: No significant differences were found in sensitivity or specificity between FIDIS and immunodiffusion, or between FIDIS and INNO-LIA for all anti-ENA in all CTD patients; nor were any differences found for individual anti-ENAs within distinct CTDs. The FIDIS sensitivity was 41% (anti-SSA) and 17% (anti-SSB) in lupus erythematosus (LE) or primary Sjögren's syndrome; 5% (anti-ribosome and anti-Sm) in LE; 17% (anti-RNP) in LE or mixed CTD; 21% (anti-Scl70) in systemic sclerosis; and 61% (anti-centromere) in limited systemic sclerosis. The specificity reached 88%-100%. Receiver operating characteristic curve areas did not differ between FIDIS and INNO-LIA. Agreement ranged from 91% (anti-SSB) to 99% (anti-Jo1) between FIDIS and INNO-LIA, and from 95% (anti-Scl70) to 100% (anti-Sm) between FIDIS and immunodiffusion. Samples scored positive with all techniques in 83% (anti-centromere), 70% (anti-RNP), 67% (anti-Jo1), 60% (anti-SSA), 40% (anti-SSB), 33% (anti-ribosome), 25% (anti-Sm) and 13% (anti-Scl70) of cases., Conclusions: The diagnostic performance of FIDIS anti-ENA reagents is comparable to immunodiffusion and INNO-LIA.

Although there is strong evidence supporting the short-term efficacy and safety of anti-tumour necrosis factor-alpha agents, few studies have examined the long-term effects. We evaluated 511 patients with long-standing refractory rheumatoid arthritis treated with intravenous infusions of infliximab 3 mg/kg at weeks 0, 2, 6, and 14 and every 8 weeks thereafter for 4 years. Among the initial 511 patients included in the study, 479 could be evaluated; of these, 295 (61.6%) were still receiving infliximab treatment at year 4 of follow-up. The most common reasons for treatment discontinuation were lack of efficacy (65 patients, 13.6%), safety (81 patients, 16.9%), and elective change (38 patients, 7.9%). Analysis of disease activity scores (DAS28 [disease activity score based on the 28-joint count]) over time showed that, after the initial rapid improvement during the first 6 to 22 weeks of therapy, a further decrease in disease activity of 0.2 units in the DAS28 score per year was observed. DAS28 scores, measured at week 14 or 22, were found to predict subsequent discontinuation due to lack of efficacy. In conclusion, long-term maintenance therapy with infliximab 3 mg/kg is effective in producing further reductions in disease activity. Disease activity measured by the DAS28 at week 14 or 22 of infliximab therapy was the best predictor of long-term attrition.

Camurati-Engelmann disease (CED) is a rare autosomal dominant type of bone dysplasia. This review is based on the unpublished and detailed clinical, radiological, and molecular findings in 14 CED families, comprising 41 patients, combined with data from 10 other previously reported CED families. For all 100 cases, molecular evidence for CED was available, as a mutation was detected in TGFB1, the gene encoding transforming growth factor (TGF) beta1. Pain in the extremities was the most common clinical symptom, present in 68% of the patients. A waddling gait (48%), easy fatigability (44%), and muscle weakness (39%) were other important features. Radiological symptoms were not fully penetrant, with 94% of the patients showing the typical long bone involvement. A large percentage of the patients also showed involvement of the skull (54%) and pelvis (63%). The review provides an overview of possible treatments, diagnostic guidelines, and considerations for prenatal testing. The detailed description of such a large set of CED patients will be of value in establishing the correct diagnosis, genetic counselling, and treatment.

The aim of this study was to compare the socioeconomic consequences of early and late rheumatoid arthritis in Belgium and to assess the patient out-of-pocket contributions. This multicentre longitudinal study in Belgium evaluated patients with rheumatoid arthritis. Early disease was defined as diagnosis since less than 1 year. At baseline sociodemographic and disease characteristics were assessed and during the following year patients recorded all healthcare- and non-healthcare-related direct costs and out-of-pocket contributions. The study included 48 patients with early and 85 patients with late rheumatoid arthritis. Mean disease duration was 0.5 vs 12.5 years in patients with early and late rheumatoid arthritis, respectively. The disease activity score (DAS28) was comparable between both groups (4.1 vs 4.5, p = 0.14), but physical function (Health Assessment Questionnaire, HAQ) was more impaired in patients with long-standing disease (1.0 vs 1.7, p < 0.001). Work disability had increased from 2% in patients with early to 18% in patients with late disease. The annual societal direct costs per patient were 3055 Euros (median: 1518 Euros) opposed to 9946 Euros (median: 4017 Euros) for early and late rheumatoid arthritis, respectively. The higher direct cost for patients with long-standing disease was seen for all categories, but especially for physiotherapy and need for devices and adaptations. Patients with early as well as late disease contribute out of pocket about one-third to the direct healthcare costs. Within each group, HAQ was a strong determinant of costs. In Belgium, patients with long-standing rheumatoid arthritis are nine times more likely to be work disabled than patients with less than 1 year disease duration and have a threefold increase in costs. Differences in healthcare consumption between patients could be mainly explained by differences in physical function (HAQ).