Treatment of progressive multiple sclerosis with high-dose all-trans retinoic acid - no clear evidence of positive disease modifying effects.

BACKGROUND: All-trans retinoic acid (ATRA) is an acid derivative of vitamin A which is discussed as a promising candidate to ameliorate the disease course of multiple sclerosis (MS) by immunomodulation or even by promoting regeneration in progressive MS. Here we report a patient who significantly improved for MS related disability following administration of chemotherapy including ATRA for mitoxantrone-related acute promyelocytic leukemia and assess the effect of high-dose ATRA in three additional patients with progressive MS. METHODS: Patients with progressive MS who had failed previous therapies were treated with high-dose ATRA. Patients underwent clinical and routine laboratory monitoring. Additionally, PBMCs were analyzed by flow cytometry for lymphocyte subsets. RESULTS: ATRA was well tolerated and no pathological laboratory abnormalities were observed. After initial mild (not statistically significant) improvement of EDSS and mean MSFC z-score, ongoing disease progression was observed. One patient subacutely experienced severe cognitive and motor worsening. Cerebral MRI revealed persistent gadolinium-enhancing lesions. Flow cytometric alterations of peripheral blood naïve, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasmablasts and natural killer (NK) cells did not reach statistical significance. CONCLUSIONS: Stand-alone therapy with ATRA did not ameliorate progressive MS in our limited cohort and we did not observe consistent alterations of T and B cell subsets. Intriguingly, application of ATRA may have caused marked disease exacerbation in one patient.

Resource Theory of Coherence Based on Positive-Operator-Valued Measures.

Quantum coherence is a fundamental feature of quantum mechanics and an underlying requirement for most quantum information tasks. In the resource theory of coherence, incoherent states are diagonal with respect to a fixed orthonormal basis; i.e., they can be seen as arising from a von Neumann measurement. Here, we introduce and study a generalization to a resource theory of coherence defined with respect to the most general quantum measurements, i.e., to arbitrary positive-operator-valued measures (POVMs). We establish POVM-based coherence measures and POVM-incoherent operations that coincide for the case of von Neumann measurements with their counterparts in standard coherence theory. We provide a semidefinite program that allows us to characterize interconversion properties of resource states and exemplify our framework by means of the qubit trine POVM, for which we also show analytical results.

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients.

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In 50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients presented after one year of age. Six patients died prior to data collection. Long-term neurological complications were common. Half of the patients had a normal cognitive development while the remainder showed psychomotor deficits. We identified seven novel HMGCL mutations. In agreement with previous reports, no clear genotype-phenotype correlation could be found. This is the largest cohort of HMGCLD patients reported so far, demonstrating that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important.

[Emergency Doctor Training for Psychiatric Emergencies: Evaluation of an Interactive Training Program]. / Notarztschulung über psychiatrische Notfälle: Evaluation eines interaktiven Fortbildungsprogramms.

Aim Emergency physicians are often confronted with psychiatric emergencies, but are not well trained for it and often feel unable to cope sufficiently with them. The aim of this investigation was to examine whether multisensoric training may improve learning effects in the training of emergency physicians with regard to psychiatric emergencies. Method Participation in a multi-modal, multi-media training program with video case histories and subsequent evaluation by questionnaire. Results 66 emergency physicians assessed their learning effects. 75 % or 73 % rated it as "rather high" or "very high". In particular, in comparison with classical training/self-study 89 % assessed the effects in learning as "rather high" or "very high" . Conclusion This training receives a high level of acceptance. Using videos, learning content may be provided more practice-related. Thus, emergency physicians are able to develop a greater understanding of psychiatric emergencies.

Sex-specific variation in signaling pathways and gene expression patterns in human leukocytes in response to endotoxin and exercise.

BACKGROUND: While exercise effects on the immune system have received increasing attention in recent years, it remains unclear to what extent gender and fluctuations in sex hormones during menstrual cycle influence immunological responses to exercise. METHODS: We investigated mRNA changes induced through exhaustive exercise (half-marathon; pre-exercise and post-exercise [30 min, 3 h, 24 h] on whole blood cultures ± lipopolysaccharide [LPS] [1 h]) with a specific focus on sex differences (men vs women in luteal phase) as an extension of our previous study. RESULTS: Inflammation related signaling pathways, TLRs, cytosolic DNA sensing and RIG-I like receptors were differentially activated between sexes in LPS-stimulated cultures. Genes differentially regulated between sexes included TNIP-1, TNIP-3, IL-6, HIVEP1, CXCL3, CCR3, IL-8, and CD69, revealing a bias towards less anti-inflammatory gene regulation in women compared to men. In addition, several genes relevant to brain function (KMO, DDIT4, VEGFA, IGF1R, IGF2R, and FGD4) showed differential activation between sexes. Some of these genes (e.g., KMO in women, DDIT4 in both sexes) potentially constitute neuroprotective mechanisms. CONCLUSIONS: These data reveal that the exercise-induced change in gene expression might be gender and menstrual cycle phase dependent.

Morphologic and Clinical Outcome of Intracranial Aneurysms after Treatment Using Flow Diverter Devices: Mid-Term Follow-Up.

Flow diverters (FDs) are designed for the endovascular treatment of complex intracranial aneurysm configurations. From February 2009 to March 2013 28 patients (22 females, 6 males) were treated with FD; mean age was 57 years. Data, including aneurysm features, clinical presentation, history of previous bleeding, treatment, and follow-up results, are presented. Early postinterventional neurological deficits (transient: n = 3/enduring: n = 1) appeared in 4/28 patients (14%), and early improvement of neurological symptoms was observed in 7 patients with previous restriction of cranial nerve function. The overall occlusion rate was 20/26 (77%; 59% after 3 months). 77% achieved best results according to O'Kelly-Marotta score grade D with no contrast material filling (70% of those after 3 months). In 4/6 patients who did not achieve grade D, proximal and/or distal stent overlapping ≥5 mm was not guaranteed sufficiently. During follow-up we did not detect any aneurysm recurrence or haemorrhage. In-stent stenosis emerged as the most frequent complication (4/27; 15%) followed by 2 cases of vascular obliteration (AICA/VA). In conclusion endovascular reconstruction using a FD represents a modern and effective treatment in those aneurysms that are not suitable for conventional interventional or surgical treatment. The appearance of severe complications was rare.

Low frequencies of central memory CD4 T cells in progressive multifocal leukoencephalopathy.

OBJECTIVES: To assess alterations in the composition of peripheral immune cells in acute progressive multifocal leukoencephalopathy (PML). METHODS: Fresh blood samples from 5 patients with acute PML and 10 healthy controls were analyzed by flow cytometry for naive, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasma blasts, and natural killer (NK) cells. The frequency of central memory CD4 T cells was determined longitudinally during the course of PML in 2 patients. RESULTS: The frequencies of naive, central memory and effector memory CD8 T cells, B cells, plasma cells, and NK cells were not altered in patients with PML. In contrast, the frequencies of naive CD4 T cells (p = 0.04) and central memory CD4 T cells (p < 0.00001) were reduced and the frequencies of effector memory CD4 T cells were increased (p = 0.01). Longitudinal analysis showed that this pattern was preserved in a patient with fatal PML outcome and restored in one patient who recovered from PML. CONCLUSIONS: These data indicate that PML is associated with reduced frequencies of peripheral central memory helper T cells but not with alterations in the frequencies of cytotoxic T cell populations, B lymphocytes, plasma cells, or NK cells.

The role of the ubiquitin-editing enzyme A20 in diseases of the central nervous system and other pathological processes.

In recent years, the ubiquitin-editing enzyme A20 has been shown to control a large set of molecular pathways involved in the regulation of protective as well as self-directed immune responses. Here, we assess the current and putative roles of A20 in inflammatory, vascular and degenerative diseases of the central nervous system and explore future directions of research.

Case report of a patient with progressive multifocal leukoencephalopathy under treatment with dimethyl fumarate.

BACKGROUND: Progressive multifocal leukoencephalopathy is a severe demyelinating disease caused by the polyoma JC virus in patients with reduced immunocompetence. A few cases of progressive multifocal leukoencephalopathy have been reported in patients treated with fumaric acid esters. CASE PRESENTATION: A 53-year-old Caucasian woman reported to our clinic with a first focal epileptic seizure and mild cognitive impairment. Since 1.5 years, she was treated with fumaderm for her psoriasis. During that time, her lymphocyte counts ranged between 450 and 700/µl. Cerebral magnet resonance imaging showed multifocal subcortical T2 hyperintense lesions with partial gadolinium enhancement. She did not have antibodies against human immunodeficiency virus 1 and 2 and cerebrospinal fluid-polymerase chain reaction for viral infections including a sensitive JC-virus polymerase chain reaction were negative. The diagnosis of progressive multifocal leukoencephalopathy was established by histological analysis and detection of JC-virus desoxyribonucleic acid in brain biopsy specimens. Dimethyl fumarate was stopped and Mirtazapin and Mefloquin were initiated. Neurological examination and imaging remained stable. CONCLUSIONS: Progressive multifocal leukoencephalopathy can occur in patients with lymphocyte counts between 450 and 700/µl, produce only faint symptoms and is not excluded by negative JC-virus-polymerase chain reaction in cerebrospinal fluid. The incidence of progressive multifocal leukoencephalopathy may thus be underestimated and a more careful surveillance of patients would be necessary.

Analysis of periinterventional complications of intracranial angioplasty and stenting: a single center experience.

BACKGROUND AND PURPOSE: Treatment of symptomatic intracranial atherosclerotic disease by angioplasty and stenting (PTAS) is limited by a high rate of periinterventional strokes. We performed a detailed analysis of these strokes at our center in order to identify strategies to reduce the risk of periinterventional complications. METHODS: Case records and imaging data of 80 patients with a symptomatic 70-99% stenosis of a major intracranial artery treated with PTAS between July 2007 and December 2013 were reviewed. All patients had a sufficient response to aspirin and clopidogrel. Periinterventional strokes were categorized as either ischemic (perforator territory, distal embolic or delayed stent thrombosis) or hemorrhagic (intraparenchymal, subarachnoid). RESULTS: Periinterventional complications occurred in 6/80 (7.5%) patients, consisting of 2 ischemic strokes (2.5%, both perforator territory), 3 hemorrhagic strokes (3.8%, 2 intraparenchymal due to reperfusion injury, 1 subarachnoid due to vessel rupture) and one death (1.3%) unrelated to stroke. All strokes occurred within 24h after PTAS. CONCLUSION: Our retrospective data analysis suggests that the risk of periinterventional stroke after PTAS of symptomatic intracranial atherosclerotic disease might be reduced by sufficient antiplatelet therapy and optimized management of patients with high risk for reperfusion injury or perforator strokes, including selection of a stenting device adapted to individual vessel morphology.

Dendritic cells and anergic type I NKT cells play a crucial role in sulfatide-mediated immune regulation in experimental autoimmune encephalomyelitis.

CD1d-restricted NKT cells can be divided into two groups: type I NKT cells use a semi-invariant TCR, whereas type II express a relatively diverse set of TCRs. A major subset of type II NKT cells recognizes myelin-derived sulfatides and is selectively enriched in the CNS tissue during experimental autoimmune encephalomyelitis (EAE). We have shown that activation of sulfatide-reactive type II NKT cells by sulfatide prevents induction of EAE. In this article, we have addressed the mechanism of regulation, as well as whether a single immunodominant form of synthetic sulfatide can treat ongoing chronic and relapsing EAE in SJL/J mice. We have shown that the activation of sulfatide-reactive type II NKT cells leads to a significant reduction in the frequency and effector function of myelin proteolipid proteins 139-151/I-A(s)-tetramer(+) cells in lymphoid and CNS tissues. In addition, type I NKT cells and dendritic cells (DCs) in the periphery, as well as CNS-resident microglia, are inactivated after sulfatide administration, and mice deficient in type I NKT cells are not protected from disease. Moreover, tolerized DCs from sulfatide-treated animals can adoptively transfer protection into naive mice. Treatment of SJL/J mice with a synthetic cis-tetracosenoyl sulfatide, but not α-galactosylceramide, reverses ongoing chronic and relapsing EAE. Our data highlight a novel immune-regulatory pathway involving NKT subset interactions leading to inactivation of type I NKT cells, DCs, and microglial cells in suppression of autoimmunity. Because CD1 molecules are nonpolymorphic, the sulfatide-mediated immune-regulatory pathway can be targeted for development of non-HLA-dependent therapeutic approaches to T cell-mediated autoimmune diseases.

Diffusion restriction of the optic nerve in patients with acute visual deficit.

PURPOSE: Diffusion magnetic resonance imaging (MRI) is commonly used in acute stroke, but not considered diagnostic in ischemic optic neuropathy. This study evaluates the presence of diffusion restriction in patients with acute visual loss by analyzing diffusion-weighted images (DWI). MATERIALS AND METHODS: A retrospective study of all patients who clinically presented with acute visual loss and who underwent MRI with DWI between January 2011 and May 2012 were evaluated. Patients with suspected brainstem ischemia were used as a control group. Two neuroradiologists evaluated the DWI for the presence of diffusion restriction within the optic nerve. RESULTS: In all, 34 patients with acute visual deficit and 32 controls were evaluated. In all five cases of acute optic ischemia, diffusion restriction with reduced apparent diffusion coefficient was present. In 2/25 patients with clinically defined optic neuritis, a diffusion restriction was present. No diffusion restriction was seen in the control cases or in cases with other causes for an acute visual deficit. CONCLUSION: DWI can identify ischemic lesions of the optic nerve. As in acute multiple sclerosis lesions, optic neuritis can also present in rare circumstances with diffusion restriction and can therefore not be ruled out solely by DWI MRI.

Suppression of experimental autoimmune encephalomyelitis by interleukin-10 transduced neural stem/progenitor cells.

Neural stem/progenitor cells (NSPCs) have the ability to migrate into the central nervous system (CNS) to replace damaged cells. In inflammatory CNS disease, cytokine transduced neural stem cells may be used as vehicles to specifically reduce inflammation and promote cell replacement. In this study, we used NSPCs overexpressing IL-10, an immunomodulatory cytokine, in an animal model for CNS inflammation and multiple sclerosis (MS). Intravenous injection of IL-10 transduced neural stem/progenitor cells (NSPC(IL-10)) suppressed myelin oligodendrocyte glycoprotein aa 35-55 (MOG35-55)- induced experimental autoimmune encephalomyelitis (EAE) and, following intravenous injection, NSPC(IL-10) migrated to peripheral lymphoid organs and into the CNS. NSPC(IL-10 )suppressed antigen-specific proliferation and proinflammatory cytokine production of lymph node cells obtained from MOG35-55 peptide immunized mice. In this model, IL-10 producing NSPCs act via a peripheral immunosuppressive effect to attenuate EAE.

CD62L(high) Treg cells with superior immunosuppressive properties accumulate within the CNS during remissions of EAE.

The role of regulatory T cell populations within the CNS in the regulation of CNS-autoimmunity is controversial. We show that during recovery from relapsing remitting experimental autoimmune encephalomyelitis, regulatory T cells accumulate within the CNS that express high levels of CD62L. These CD62L(high) Treg cells express increased amounts of CTLA-4, ICOS and TGF-ß and are more potent than CD62L(low) Treg cells in suppressing proliferation and inducing apoptosis in effector T cells. CD62L(high) Treg cells thus represent a population of Treg cells that display superior immunosuppressive properties and accumulate in the CNS during recovery from CNS-autoimmunity.

Recurrent myelitis after allogeneic stem cell transplantation. Report of two cases.

BACKGROUND: Allogeneic and autologous haematopoietic stem cell transplantation are established treatment options for haematological malignancies and may possibly be employed to treat a range of genetic and autoimmune diseases. CASE PRESENTATION: We report two patients who developed an acute myelitis within their thoracic spinal cord after allogeneic stem cell transplantation. Myelitis in these patients was not related to graft versus host disease or immune reconstitution and was responsive to intravenous methylprednisolone and cyclophosphamide. CONCLUSIONS: Myelitis is a possibly disabling consequence of haematopoietic stem cell transplantation.

Differential modulation of CNS-specific effector and regulatory T cells during tolerance induction by recombinant invariant chains in vivo.

Inflammation within the Central Nervous System (CNS) is largely controlled by the balance between CNS-specific effector and regulatory T lymphocytes. To suppress CNS-inflammation in an antigen-specific manner, CNS-specific effector and regulatory T cells thus have to be differentially regulated. We employed recombinant peptide/MHC class II tetramers to assess CNS-specific effector and regulatory T cells during the specific suppression of myelin proteolipid protein aa139-151 (PLP139-151)-induced experimental autoimmune encephalomyelitis (EAE) by intravenous injection of recombinant invariant chains (Ii) in which the CLIP region has been replaced by the PLP139-151 epitope (Ii-PLP139-151). Injection of Ii-PLP139-151 induced apoptosis in CNS-specific effector T cells. In contrast, the proportion of specific regulatory T cells was increased and these cells expressed larger amounts of molecules that mediate regulatory T cell function including transforming growth factor beta and the inducible costimulator (ICOS). Consequently, regulatory T cells from Ii-treated mice were more potent than regulatory T cells from control-treated animals in suppressing effector T cell proliferation. These data demonstrate that effector T cells and regulatory T cells directed against the same CNS-antigen can be differentially regulated in vivo to suppress CNS-autoimmunity. Recombinant Ii induce apoptosis in CNS-specific effector T cells and provoke qualitative changes in specific regulatory T cells that enhance their immunosuppressive properties.

Dendritic cell-regulatory T-cell interactions control self-directed immunity.

In addition to their immunostimulatory capacity, dendritic cells (DCs) play a crucial role in central and peripheral tolerance mechanisms. In the absence of an infection, immature DCs constantly take up, process and present self-antigens to specific T cells, which leads to the induction of T-cell anergy or deletion. In recent years, several additional mechanisms have been identified by which DCs constantly downregulate immune responses to maintain immunological tolerance. Among these are the complex interactions between several DC subtypes and different types of regulatory T cells. In this review, we summarize recent key findings and concepts in this field.

Suppression of verbal hallucinations and changes in regional cerebral blood flow after intravenous lidocaine: a case report.

Simple and complex auditory phantom-perceptions such as tinnitus and musical hallucinations occur predominantly in elderly subjects and are often associated with hearing impairment. Isolated verbal hallucinations without other psychotic features are rare. It has been shown that an intravenous (i.v.) injection of lidocaine can transiently suppress tinnitus. Here we present the case of a 74 year old left-handed women with severely distressing, continuous verbal auditory hallucinations without other psychotic features. I.v. injections of 100 mg lidocaine but not saline resulted in substantial transient suppressions of the hallucinations for several hours. Using [(15)O]H(2)O positron-emission tomography (PET) decreased regional cerebral blood flow associated with reduced perception of voices was found in the right angular and supramarginal gyrus, right inferior frontal gyrus, orbitofronal cortex and in major parts of the cingulate cortex. These data suggest to further investigate the clinical relevance of i.v. lidocaine in patients with therapy-resistant verbal hallucinations, support the notion of common pathophysiological mechanisms in different forms of auditory phantom-perception and demonstrate the feasibility of a new strategy for imaging studies on auditory hallucinations.

Induction of autoimmunity by expansion of autoreactive CD4+CD62Llow cells in vivo.

The prerequisites of peripheral activation of self-specific CD4(+) T cells that determine the development of autoimmunity are incompletely understood. SJL mice immunized with myelin proteolipid protein (PLP) 139-151 developed experimental autoimmune encephalomyelitis (EAE) when pertussis toxin (PT) was injected at the time of immunization but not when injected 6 days later, indicating that PT-induced alterations of the peripheral immune response lead to the development of autoimmunity. Further analysis using IA(s)/PLP(139-151) tetramers revealed that PT did not change effector T cell activation or regulatory T cell numbers but enhanced IFN-gamma production by self-specific CD4(+) T cells. In addition, PT promoted the generation of CD4(+)CD62L(low) effector T cells in vivo. Upon adoptive transfer, these cells were more potent than CD4(+)CD62L(high) cells in inducing autoimmunity in recipient mice. The generation of this population was paralleled by higher expression of the costimulatory molecules CD80, CD86, and B7-DC, but not B7-RP, PD-1, and B7-H1 on CD11c(+)CD4(+) dendritic cells whereas CD11c(+)CD8alpha(+) dendritic cells were not altered. Collectively, these data demonstrate the induction of autoimmunity by specific in vivo expansion of CD4(+)CD62L(low) cells and indicate that CD4(+)CD62L(low) effector T cells and CD11c(+)CD4(+) dendritic cells may be attractive targets for immune interventions to treat autoimmune diseases.