[Show abstract][Hide abstract] ABSTRACT: A remarkable pathological difference between grey matter lesions (GML) and white matter lesions (WML) in Multiple Sclerosis (MS) patients is the paucity of infiltrating leukocytes in GML. To better understand these pathological differences, we hypothesize that the chemokine monocyte chemotactic protein-1 (MCP-1 or CCL2), of importance for leukocyte migration, and its receptor CCR2 are more abundantly expressed in WML than in GML of MS patients. To this end, we analyzed CCL2 and CCR2 expression in the hippocampus, comprising WML and GML, of post-mortem MS patients, and of control subjects.CCL2 and CCR2 mRNA were significantly increased in demyelinated MS hippocampus. Semi-quantification of CCL2 and CCR2 immunoreactivity showed that CCL2 is present in astrocytes only in active WML. CCR2 is upregulated in monocytes/macrophages or amoeboid microglia in active WML, and in ramified microglia in active GML, although to a lesser extent. As a follow-up, we observed a significantly increased CCL2 production by WM-, but not GM-derived astrocytes upon stimulation with bz-ATP in vitro. Finally, upon CCL2 stimulation, GM-derived microglia significantly increased their proliferation rate.We conclude that within hippocampal lesions, CCL2 expression is mainly restricted to WML, whereas the receptor CCR2 is upregulated in both WML and GML. The relative absence of CCL2 in GML may explain the lack of infiltrating immune cells in this type of lesions. We propose that the divergent expression of CCL2 and CCR2 in WML and GML explains or contributes to the differences in WML and GML formation in MS.
[Show abstract][Hide abstract] ABSTRACT: Activated microglia and macrophages play a key role in driving demyelination during multiple sclerosis (MS), but the factors responsible for their activation remain poorly understood. Here, we present evidence for a dual-trigger role of IFN-γ and alpha B-crystallin (HSPB5) in this context. In MS-affected brain tissue, accumulation of the molecular chaperone HSPB5 by stressed oligodendrocytes is a frequent event. We have shown before that this triggers a TLR2-mediated protective response in surrounding microglia, the molecular signature of which is widespread in normal-appearing brain tissue during MS. Here, we show that IFN-γ, which can be released by infiltrated T cells, changes the protective response of microglia and macrophages to HSPB5 into a robust pro-inflammatory classical response. Exposure of cultured microglia and macrophages to IFN-γ abrogated subsequent IL-10 induction by HSPB5, and strongly promoted HSPB5-triggered release of TNF-α, IL-6, IL-12, IL-1β and reactive oxygen and nitrogen species. In addition, high levels of CXCL9, CXCL10, CXL11, several guanylate-binding proteins and the ubiquitin-like protein FAT10 were induced by combined activation with IFN-γ and HSPB5. As immunohistochemical markers for microglia and macrophages exposed to both IFN-γ and HSPB5, these latter factors were found to be selectively expressed in inflammatory infiltrates in areas of demyelination during MS. In contrast, they were absent from activated microglia in normal-appearing brain tissue. Together, our data suggest that inflammatory demyelination during MS is selectively associated with IFN-γ-induced re-programming of an otherwise protective response of microglia and macrophages to the endogenous TLR2 agonist HSPB5.
[Show abstract][Hide abstract] ABSTRACT: Our patient was diagnosed with unilateral familial retinoblastoma at the age of thirteen days. Nineteen months later magnetic resonance (MR) images of the brain showed a suspicious cystic pineal gland. On a follow-up MR scan after another nine months this lesion was diagnosed as pineoblastoma. The tumor was resected and subsequently high-dose chemotherapy was given, concluded with autologous stem cell reinfusion. The patient was doing well at the last visit (35 months since resection). This case emphasizes that if there is any suspicious finding concerning the pineal gland on brain MR images in retinoblastoma patients, follow-up scans are highly recommended.
[Show abstract][Hide abstract] ABSTRACT: To ensure efficient energy supply to the high demanding brain, nutrients are transported into brain cells via specific glucose (GLUT) and monocarboxylate transporters (MCT). Mitochondrial dysfunction and altered glucose metabolism are thought to play an important role in the progression of neurodegenerative diseases, including multiple sclerosis (MS). Here, we investigated the cellular localization of key GLUT and MCT proteins in human brain tissue of non-neurological controls and MS patients. We show that in control brain tissue GLUT and MCT proteins were abundantly expressed in a variety of central nervous system cells, particularly in microglia and endothelial cells. In active MS lesions, GLUTs and MCTs were highly expressed in infiltrating leukocytes and reactive astrocytes. Astrocytes manifest increased MCT1 staining and maintain GLUT expression in inactive lesions, whereas demyelinated axons exhibit significantly reduced GLUT3 and MCT2 immunoreactivity in inactive lesions. Finally, we demonstrated that the co-transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), an important protein involved in energy metabolism, is highly expressed in reactive astrocytes in active MS lesions. Overexpression of PGC-1α in astrocyte-like cells resulted in increased production of several GLUT and MCT proteins. In conclusion, we provide for the first time a comprehensive overview of key nutrient transporters in white matter brain samples. Moreover, our data demonstrate an altered expression of these nutrient transporters in MS brain tissue, including a marked reduction of axonal GLUT3 and MCT2 expression in chronic lesions, which may impede efficient nutrient supply to the hypoxic demyelinated axons thereby contributing to the ongoing neurodegeneration in MS. GLIA 2014.
[Show abstract][Hide abstract] ABSTRACT: Lymphomatoid granulomatosis (LG) is a B-cell type lymphoproliferative disease. It mainly affects the lungs but may have extrapulmonary manifestations, especially in the central nervous system. The purpose of this study was to review the pediatric cases in the literature and add 2 new cases to the existing literature. A review of the literature was performed on children (0 to 18 years of age at diagnosis) with pathologically proven LG. We found 47 case reports, which, together with 2 new cases, were systematically analyzed. The median age was 12 years. The main symptoms were general, pulmonary, and neurological. Approximately one third of the patients were immunocompromised. High mortality rate was observed. Pediatric LG is a rare disease, which appears to be more frequently seen in immunocompromised patients, especially patients with leukemia. The disease has a high mortality rate; therefore, aggressive therapy according to a high-grade B-cell lymphoma protocol is justified.
Journal of Pediatric Hematology/Oncology 01/2014; · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system (CNS), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is well-known in Alzheimer's and Parkinson's disease, it is also observed in neurotropic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis, amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is also implicated in neurodegenerative diseases contributing to tissue damage, but also playing important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that maybe human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigating the personal, economic and social impact of these diseases. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.
[Show abstract][Hide abstract] ABSTRACT: Objective
Differentiation of oligodendroglial precursor cells is crucial for central nervous system remyelination and is influenced by both extrinsic and intrinsic factors. Recent studies showed that human endogenous retrovirus type W (HERV-W) contributes significantly to brain damage. In particular, its envelope protein ENV can mediate injury to specific cell types of the brain and immune system. Here, we investigated whether ENV protein affects oligodendroglial differentiation. Methods
Immunostaining and gene expression analyses were performed to establish the expression and regulation of the known ENV receptor, Toll-like receptor 4 (TLR4), on oligodendroglial precursor cells in human brain tissue and in culture. Cultured primary oligodendroglial precursor cells were stimulated with ENV protein to determine the effects of this ligand/receptor interaction. ResultsWe demonstrated that the ENV protein is present in close proximity to TLR4-expressing oligodendroglial precursor cells adjacent to multiple sclerosis lesions. Human and rat oligodendroglial precursor cells expressed TLR4, and the ENV-mediated activation of TLR4 led to the induction of proinflammatory cytokines and inducible nitric oxide synthase as well as the formation of nitrotyrosine groups and a subsequent reduction in myelin protein expression. InterpretationOur findings suggest that ENV-mediated induction of nitrosative stress via activation of TLR4 results in an overall reduction of the oligodendroglial differentiation capacity, thereby contributing to remyelination failure. Therefore, pharmacological or antibody-mediated inhibition of ENV may prevent the blockade of myelin repair in the diseased or injured central nervous system. Ann Neurol 2013;74:721–732
Annals of Neurology 11/2013; 74(5). · 11.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autoimmunity to neuronal proteins occurs in several neurological syndromes, where cellular and humoral responses are directed to surface as well as intracellular antigens. Similar to myelin autoimmunity, pathogenic immune response to neuroaxonal components such as neurofilaments may contribute to neurodegeneration in multiple sclerosis.
We studied the immune response to the axonal protein neurofilament light (NF-L) in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis. To examine the association between T cells and axonal damage, pathology studies were performed on NF-L immunized mice. The interaction of T cells and axons was analyzed by confocal microscopy of central nervous system tissues and T-cell and antibody responses to immunodominant epitopes identified in ABH (H2-Ag7) and SJL/J (H2-As) mice. These epitopes, algorithm-predicted peptides and encephalitogenic motifs within NF-L were screened for encephalitogenicity.
Confocal microscopy revealed both CD4+ and CD8+ T cells alongside damaged axons in the lesions of NF-L immunized mice. CD4+ T cells dominated the areas of axonal injury in the dorsal column of spastic mice in which the expression of granzyme B and perforin was detected. Identified NF-L epitopes induced mild neurological signs similar to the observed with the NF-L protein, yet distinct from those characteristic of neurological disease induced with myelin oligodendrocyte glycoprotein.
Our data suggest that CD4+ T cells are associated with spasticity, axonal damage and neurodegeneration in NF-L immunized mice. In addition, defined T-cell epitopes in the NF-L protein might be involved in the pathogenesis of the disease.
Journal of Neuroinflammation 09/2013; 10(1):118. · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Microglial nodules are frequently observed in the normal-appearing white matter of multiple sclerosis (MS) patients. Previously, we have shown that these clusters, which we call "preactive MS lesions," are closely associated with stressed oligodendrocytes and myelin sheaths that contain markedly elevated levels of the small stress protein alpha-B-crystallin (HspB5). Here, we show that microglia in these lesions express the recently identified receptors for HspB5, that is, CD14, Toll-like receptor family 1 and 2 (TLR1 and TLR2), and several molecular markers of the microglial response to HspB5. These markers were identified by genome-wide transcript profiling of 12 primary human microglial cultures at 2 time points after exposure to HspB5. These data indicate that HspB5 activates production by microglia of an array of chemokines, immune-regulatory mediators, and a striking number of antiviral genes that are generally inducible by type I interferons. Together, our data suggest that preactive MS lesions are at least in part driven by HspB5 derived from stressed oligodendrocytes and may reflect a local attempt to restore tissue homeostasis.
Journal of neuropathology and experimental neurology. 09/2013;
[Show abstract][Hide abstract] ABSTRACT: Early events in multiple sclerosis (MS) lesion formation are loss of blood-brain barrier (BBB) integrity, immune cell trafficking into the central nervous system, and demyelination. To date, the molecular mechanisms underlying these pathogenic events are poorly understood. Heparin-binding epidermal growth factor (HB-EGF) is a trophic factor that is induced by inflammatory stimuli and has previously been shown to interact with tetraspanins (TSPs), a family of transmembrane proteins that are involved in cellular migration and adhesion. Given the known roles of TSPs and HB-EGF, we hypothesized that HB-EGF and TSPs may play a role in the processes that underlie MS lesion formation. We examined the expression of HB-EGF and the TSPs CD9 and CD81 in MS brain and found that HB-EGF was highly induced in reactive astrocytes in active lesions. TSPs were constitutively expressed throughout normal appearing white matter and control white matter. In contrast, CD9 was reduced in demyelinated lesions and increased on blood vessels in lesion areas. In vitro studies revealed that expression of HB-EGF and TSPs is regulated during inflammation. Importantly, blocking either HB-EGF or CD9 significantly reduced the migration of monocytes across brain endothelial cell monolayers. Moreover, blocking CD9 strongly enhanced the barrier function of the BBB in vitro. Together, we demonstrate that these molecules are likely implicated in processes that are highly relevant for MS lesion formation, and therefore, HB-EGF and TSPs are promising therapeutic targets. GLIA 2013.
[Show abstract][Hide abstract] ABSTRACT: Communication between the immune system and the central nervous system (CNS) is exemplified by cross-talk between glia and neurons shown to be essential for maintaining homeostasis. While microglia are actively modulated by neurons in the healthy brain, little is known about the cross-talk between oligodendrocytes and microglia. Oligodendrocytes, the myelin forming cells in the CNS, are essential for the propagation of action potentials along axons, and additionally serve to support neurons by producing neurotrophic factors. In demyelinating diseases such as multiple sclerosis, oligodendrocytes are thought to be the victims. Here, we review evidence that oligodendrocytes also have strong immune functions, express a wide variety of innate immune receptors, and produce and respond to chemokines and cytokines that modulate immune responses in the CNS. We also review evidence that during stress events in the brain, oligodendrocytes can trigger a cascade of protective and regenerative responses, in addition to responses that elicit progressive neurodegeneration. Knowledge of the cross-talk between microglia and oligodendrocytes may continue to uncover novel pathways of immune regulation in the brain that could be further exploited to control neuroinflammation and degeneration. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Objectives: The objective of this randomised, cross-over study was to compare a new single-dose dry powder inhaler (Elpenhaler (EH)), with a widely used, multi-dose dry powder inhaler (Diskus (DK)) on critical errors, patient preference, and satisfaction with the inhalers. Methods: First, patients read the instructions of one device, followed by a first inhalation attempt. Inhalation errors were assessed and if mistakes were made, correct inhaler use was demonstrated. Then patients had to demonstrate again and mistakes were registered. This was repeated up to four times. After completing the first device, the same procedure was started with the second inhaler. Primary outcome was the percentage of patients making at least one critical error after reading the insert. Secondary outcomes were inhaler preference and satisfaction with the inhalers. Results: After reading the insert, 19 of 113 patients (17%) made at least one critical error with DK and 40 (35%) with EH (p = 0.001); 73% preferred the DK and 27% the EH (p < 0.001). The mean overall satisfaction score (1 = very satisfied; 5 = very dissatisfied) for DK was 1.59 and for EH 2.48 (p < 0.001). Conclusion: With DK fewer errors were made, more patients preferred DK over EH and patients were more satisfied with DK. This may enable DK to improve treatment outcomes more than EH.
Expert Opinion on Drug Delivery 07/2013; · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) frequently coexists with other diseases. Whereas COPD action plans are currently part of usual care, they are less suitable and potentially unsafe for use in the presence of comorbidities. This study evaluates whether an innovative treatment approach directed towards COPD and frequently existing comorbidities can reduce COPD exacerbation days. We hypothesise that this approach, which combines self-initiated action plans and nurse support, will accelerate proper treatment actions and lead to better control of deteriorating symptoms. METHODS: In this multicenter randomised controlled trial we aim to include 300 patients with COPD (GOLD II-IV), and with at least one comorbidity (cardiovascular disease, diabetes, anxiety and/or depression). Patients will be recruited from hospitals in the Netherlands (n=150) and Australia (n=150) and will be assigned to an intervention or control group. All patients will learn to complete daily symptom diaries for 12-months. Intervention group patients will participate in self-management training sessions to learn the use of individualised action plans for COPD and comorbidities, linked to the diary. The primary outcome is the number of COPD exacerbation days. Secondary outcomes include hospitalisations, quality of life, self-efficacy, adherence, patient's satisfaction and confidence, health care use and cost data. ANALYSES: Intention-to-treat analyses (random effect negative binomial regression and random effect mixed models) and cost-effectiveness analyses will be performed. DISCUSSION: Prudence should be employed before extrapolating the use of COPD specific action plans in patients with comorbidities. This study evaluates the efficacy of tailored action plans for both COPD and common comorbidities.
[Show abstract][Hide abstract] ABSTRACT: Objective: To assess preference, satisfaction and critical errors with a novel, breath-actuated, multi-dose dry powder inhaler (DPI; Genuair®/Pressair™), versus a widely used, single-dose DPI (HandiHaler®) in patients with moderate-to-severe chronic obstructive pulmonary disease. Methods: In this randomised, open-label, multicentre, cross-over study, patients (aged ≥ 40 years) inhaled placebo once daily through both inhalers for 2 weeks in addition to current medication. The primary end point was percentage of patients who preferred Genuair to HandiHaler. Overall patient satisfaction (5-point scale: 1 = very dissatisfied; 5 = very satisfied), critical errors and willingness to continue using each inhaler (0 = not willing; 100 = definitely willing) were assessed. Results: Of 130 patients randomised, 105 were included in the intent-to-treat population (71.4% male; mean age 65.7 years). After 2 weeks, significantly more patients preferred Genuair than HandiHaler (79.1 vs 20.9%; p < 0.0001). Overall satisfaction scores (4.6 vs 3.8; p < 0.0001) and willingness to continue use scores (84.0 vs 62.5; p < 0.0001) were significantly higher with Genuair versus HandiHaler. Significantly fewer patients made ≥ 1 critical error with Genuair only compared with HandiHaler only (2.9 vs 19.0%; p < 0.0001). Conclusion: After 2 weeks' practice, patients preferred and were more willing to continue using Genuair than HandiHaler. Genuair was associated with higher patient satisfaction and fewer critical errors than HandiHaler.
Expert Opinion on Drug Delivery 06/2013; · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Macrophages play a dual role in multiple sclerosis (MS) pathology. They can exert neuroprotective and growth promoting effects but also contribute to tissue damage by production of inflammatory mediators. The effector function of macrophages is determined by the way they are activated. Stimulation of monocyte-derived macrophages in vitro with interferon-gamma and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages. METHODS: For this study, the expression of a panel of typical M1 and M2 markers on human monocyte derived M1 and M2 macrophages was analyzed using flow cytometry. This revealed that CD40 and mannose receptor (MR) were the most distinctive markers for human M1 and M2 macrophages, respectively. Using a panel of M1 and M2 markers we next examined the activation status of macrophages/microglia in MS lesions, normal appearing white matter and healthy control samples. RESULTS: Our data show that M1 markers, including CD40, CD86, CD64 and CD32 were abundantly expressed by microglia in normal appearing white matter and by activated microglia and macrophages throughout active demyelinating MS lesions. M2 markers, such as MR and CD163 were expressed by myelin-laden macrophages in active lesions and perivascular macrophages. Double staining with anti-CD40 and anti-MR revealed that approximately 70% of the CD40-positive macrophages in MS lesions also expressed MR, indicating that the majority of infiltrating macrophages and activated microglial cells display an intermediate activation status. CONCLUSIONS: Our findings show that, although macrophages in active MS lesions predominantly display M1 characteristics, a major subset of macrophages have an intermediate activation status.
Journal of Neuroinflammation 03/2013; 10(1):35. · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Microglial nodules in the normal-appearing white matter have been suggested as the earliest stage(s) of multiple sclerosis (MS) lesion formation. Such nodules are characterized by an absence of leukocyte infiltration, astrogliosis or demyelination, and may develop into active demyelinating MS lesions. Although the etiology of MS is still not known, inflammation and autoimmunity are considered to be the central components of this disease. Previous studies provide evidence that Wallerian degeneration, occurring as a consequence of structural damage in MS lesions, might be responsible for observed pathological abnormalities in connected normal-appearing white matter. As innate immune cells, microglia/macrophages are the first to react to even minor pathological changes in the CNS. Biopsy tissue from 27 MS patients and autopsy and biopsy tissue from 22 normal and pathological controls were analyzed to determine the incidence of microglial nodules. We assessed MS periplaque white matter tissue from early disease stages to determine whether microglial nodules are associated with altered axons. With immunohistochemical methods, the spatial relation of the two phenomena was visualized using HLA-DR antibody for MHC II expression by activated microglia/macrophages and by applying antibodies against damaged axons, i.e., SMI32 (non-phosphorylated neurofilaments) and amyloid precursor protein as well as neuropeptide Y receptor Y1, which marks axons undergoing Wallerian degeneration. Our data demonstrate that the occurrence of microglial nodules is not specific to MS and is associated with degenerating as well as damaged axons in early MS. In addition, we show that early MS microglial nodules exhibit both pro- and antiinflammatory phenotypes.
[Show abstract][Hide abstract] ABSTRACT: Multiple Sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system (CNS) gray and white matter. Although the cause of MS is unknown, it is widely appreciated that innate and adaptive immune processes contribute to its pathogenesis. These include microglia/macrophage activation, pro-inflammatory T-cell (Th1) responses and humoral responses. Additionally, there is evidence indicating that MS has a neurodegenerative component since neuronal and axonal loss occurs even in the absence of overt inflammation. These aspects also form the rationale for clinical management of the disease. However, the currently available therapies to control the disease are only partially effective at best indicating that more effective therapeutic solutions are urgently needed.
It is appreciated that in the immune-driven and neurodegenerative processes MS-specific deregulation of gene expressions and resulting protein dysfunction are thought to play a central role. These deviations in gene expression patterns contribute to the inflammatory response in the CNS, and to neuronal or axonal loss. Epigenetic mechanisms control transcription of most, if not all genes, in nucleated cells including cells of the CNS and in haematopoietic cells. MS-specific alterations in epigenetic regulation of gene expression may therefore lie at the heart of the deregulation of gene expression in MS. As such, epigenetic mechanisms most likely play an important role in disease pathogenesis.
In this review we discuss a role for MS-specific deregulation of epigenetic features that control gene expression in the CNS and in the periphery. Furthermore, we discuss the application of small molecule inhibitors that target the epigenetic machinery to ameliorate disease in experimental animal models, indicating that such approaches may be applicable to MS patients.
Multiple Sclerosis and Related Disorders. 01/2013;
[Show abstract][Hide abstract] ABSTRACT: Bartter syndrome encompasses a variety of inheritable renal tubular transport disorders characterized by hypokalemia and hypochloremic metabolic alkalosis. Bartter syndrome Type III is caused by genetic alterations in the chloride channel kidney B (CLCNKB) gene and often presents in the first 2 years of life, known as classic Bartter syndrome. However, in rare cases Bartter syndrome Type III has an antenatal presentation with polyhydramnios, premature delivery and severe dehydration in the first weeks of life. Associations between congenital anomalies of the kidney and urinary tract and Bartter syndrome are extremely rare. This case report presents a girl with Bartter syndrome Type III due to a homozygous CLCNKB mutation and bilateral congenital anomalies of the kidney and urinary tract. In addition, we describe the antenatal presentation as well as its perinatal management.