Publications by authors named "Ingrid Wagner"

24 Publications

  • Page 1 of 1

Formation and immunomodulatory function of meningeal B-cell aggregates in progressive CNS autoimmunity.

Brain 2021 Mar 9. Epub 2021 Mar 9.

Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, 81675 Munich, Germany.

Meningeal B lymphocyte aggregates have been described in autopsy material of patients with chronic Multiple Sclerosis. The presence of meningeal B cell aggregates has been correlated with worse disease. However, the functional role of these meningeal B cell aggregates is not understood. Here, we use a mouse model of Multiple Sclerosis, the spontaneous opticospinal encephalomyelitis model, which is built on the double transgenic expression of myelin oligodendrocyte glycoprotein-specific T cell- and B cell-receptors, to show that the formation of meningeal B cell aggregates is dependent on the expression of α4 integrins by antigen-specific T cells. T cell-conditional genetic ablation of α4 integrins in opticospinal encephalomyelitis mice impaired the formation of meningeal B cell aggregates, and surprisingly, led to a higher disease incidence as compared to opticospinal encephalomyelitis mice with α4 integrin-sufficient T cells. B cell-conditional ablation of α4 integrins in opticospinal encephalomyelitis mice resulted in the entire abrogation of the formation of meningeal B cell aggregates, and opticospinal encephalomyelitis mice with α4 integrin-deficient B cells suffered from a higher disease burden than regular opticospinal encephalomyelitis mice. While anti-CD20 antibody-mediated systemic depletion of B cells in opticospinal encephalomyelitis mice after onset of disease failed to efficiently decrease meningeal B cell aggregates without significantly modulating disease progression, treatment with anti-CD19 chimeric antigen receptor-T cells eliminated meningeal B cell aggregates and exacerbated clinical disease in opticospinal encephalomyelitis mice. Since about 20 percent of B cells in organised meningeal B cell aggregates produced either IL-10 or IL-35, we propose that meningeal B cell aggregates might also have an immunoregulatory function as to the immunopathology in adjacent spinal cord white matter. The immunoregulatory function of meningeal B cell aggregates needs to be considered when designing highly efficient therapies directed against meningeal B cell aggregates for clinical application in Multiple Sclerosis.
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http://dx.doi.org/10.1093/brain/awab093DOI Listing
March 2021

Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation.

J Exp Med 2021 May;218(5)

Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk-associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications.
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http://dx.doi.org/10.1084/jem.20201290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938362PMC
May 2021

Persistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling.

Nat Commun 2021 02 12;12(1):1009. Epub 2021 Feb 12.

Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.

Self-reactive CD8 T cells are important mediators of progressive tissue damage in autoimmune diseases, but the molecular program underlying these cells' functional adaptation is unclear. Here we characterize the transcriptional and epigenetic landscape of self-reactive CD8 T cells in a mouse model of protracted central nervous system (CNS) autoimmunity and compare it to populations of CNS-resident memory CD8 T cells emerging from acute viral infection. We find that autoimmune CD8 T cells persisting at sites of self-antigen exhibit characteristic transcriptional regulation together with distinct epigenetic remodeling. This self-reactive CD8 T cell fate depends on the transcriptional regulation by the DNA-binding HMG-box protein TOX which remodels more than 400 genomic regions including loci such as Tcf7, which is central to stemness of CD8 T cells. Continuous exposure to CNS self-antigen sustains TOX levels in self-reactive CD8 T cells, whereas genetic ablation of TOX in CD8 T cells results in shortened persistence of self-reactive CD8 T cells in the inflamed CNS. Our study establishes and characterizes the genetic differentiation program enabling chronic T cell-driven immunopathology in CNS autoimmunity.
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http://dx.doi.org/10.1038/s41467-021-21109-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881115PMC
February 2021

Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation.

Nat Neurosci 2021 03 25;24(3):355-367. Epub 2021 Jan 25.

Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany.

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. In the present study, we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient, loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy.
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http://dx.doi.org/10.1038/s41593-020-00780-7DOI Listing
March 2021

Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity.

Nat Neurosci 2019 10 9;22(10):1731-1742. Epub 2019 Sep 9.

Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.

Mitochondria vary in morphology and function in different tissues; however, little is known about their molecular diversity among cell types. Here we engineered MitoTag mice, which express a Cre recombinase-dependent green fluorescent protein targeted to the outer mitochondrial membrane, and developed an isolation approach to profile tagged mitochondria from defined cell types. We determined the mitochondrial proteome of the three major cerebellar cell types (Purkinje cells, granule cells and astrocytes) and identified hundreds of mitochondrial proteins that are differentially regulated. Thus, we provide markers of cell-type-specific mitochondria for the healthy and diseased mouse and human central nervous systems, including in amyotrophic lateral sclerosis and Alzheimer's disease. Based on proteomic predictions, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neuronal mitochondria. We also characterize cell-type differences in mitochondrial calcium buffering via the mitochondrial calcium uniporter (Mcu) and identify regulator of microtubule dynamics protein 3 (Rmdn3) as a determinant of endoplasmic reticulum-mitochondria proximity in Purkinje cells. Our approach enables exploring mitochondrial diversity in many in vivo contexts.
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http://dx.doi.org/10.1038/s41593-019-0479-zDOI Listing
October 2019

Brain-resident memory T cells generated early in life predispose to autoimmune disease in mice.

Sci Transl Med 2019 06;11(498)

Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.

Epidemiological studies associate viral infections during childhood with the risk of developing autoimmune disease during adulthood. However, the mechanistic link between these events remains elusive. We report that transient viral infection of the brain in early life, but not at a later age, precipitates brain autoimmune disease elicited by adoptive transfer of myelin-specific CD4 T cells at sites of previous infection in adult mice. Early-life infection of mouse brains imprinted a chronic inflammatory signature that consisted of brain-resident memory T cells expressing the chemokine (C-C motif) ligand 5 (CCL5). Blockade of CCL5 signaling via C-C chemokine receptor type 5 prevented the formation of brain lesions in a mouse model of autoimmune disease. In mouse and human brain, CCL5 T were located predominantly to sites of microglial activation. This study uncovers how transient brain viral infections in a critical window in life might leave persisting chemotactic cues and create a long-lived permissive environment for autoimmunity.
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http://dx.doi.org/10.1126/scitranslmed.aav5519DOI Listing
June 2019

Neurons under T Cell Attack Coordinate Phagocyte-Mediated Synaptic Stripping.

Cell 2018 10 30;175(2):458-471.e19. Epub 2018 Aug 30.

Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland. Electronic address:

Inflammatory disorders of the CNS are frequently accompanied by synaptic loss, which is thought to involve phagocytic microglia and complement components. However, the mechanisms accounting for aberrant synaptic connectivity in the context of CD8 T cell-driven neuronal damage are poorly understood. Here, we profiled the neuronal translatome in a murine model of encephalitis caused by CD8 T cells targeting antigenic neurons. Neuronal STAT1 signaling and downstream CCL2 expression were essential for apposition of phagocytes, ensuing synaptic loss and neurological disease. Analogous observations were made in the brains of Rasmussen's encephalitis patients. In this devastating CD8 T cell-driven autoimmune disease, neuronal STAT1 phosphorylation and CCL2 expression co-clustered with infiltrating CD8 T cells as well as phagocytes. Taken together, our findings uncover an active role of neurons in coordinating phagocyte-mediated synaptic loss and highlight neuronal STAT1 and CCL2 as critical steps in this process that are amenable to pharmacological interventions.
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http://dx.doi.org/10.1016/j.cell.2018.07.049DOI Listing
October 2018

Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8 T Cells.

Immunity 2018 05;48(5):937-950.e8

Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland. Electronic address:

Infections are thought to trigger CD8 cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue-destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection. TOX repressed the activity of several transcription factors (including Id2, TCF-1, and Notch) that are known to drive CTL differentiation. TOX also reduced immune checkpoint sensitivity by restraining the expression of the inhibitory checkpoint receptor CD244 on the surface of CTLs, leading to increased CTL-mediated damage in the CNS. Our results identify TOX as a transcriptional regulator of tissue-destructive CTLs in autoimmunity, offering a potential mechanistic link to microbial triggers.
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http://dx.doi.org/10.1016/j.immuni.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040915PMC
May 2018

A retrospective analysis of biochemical and haematological parameters in patients with eating disorders.

J Eat Disord 2017 2;5:32. Epub 2017 Oct 2.

Eating Disorders Service, Royal Brisbane and Women's Hospital, Brisbane, QLD Australia.

Background: The objective of the study was to determine whether levels of biochemical and haematological parameters in patients with eating disorders (EDs) varied from the general population. Whilst dietary restrictions can lead to nutritional deficiencies, specific abnormalities may be relevant to the diagnosis, pathogenesis and treatment of EDs.

Methods: With ethics approval and informed consent, a retrospective chart audit was conducted of 113 patients with EDs at a general practice in Brisbane, Australia. This was analysed first as a total group (TG) and then in 4 ED subgroups: Anorexia nervosa (AN), Bulimia nervosa (BN), ED Not Otherwise Specified (EDNOS), and AN/BN. Eighteen parameters were assessed at or near first presentation: cholesterol, folate, vitamin B12, magnesium, manganese, zinc, calcium, potassium, urate, sodium, albumin, phosphate, ferritin, vitamin D, white cell count, neutrophils, red cell count and platelets. Results were analysed using IBM SPSS 21 and Microsoft Excel 2013 by two-tailed, one-sample t-tests (TG and 4 subgroups) and chi-square tests (TG only) and compared to the population mean standards. Results for the TG and each subgroup individually were then compared with the known reference interval (RI).

Results: For the total sample, t-tests showed significant differences for all parameters ( < 0.05) except cholesterol. Most parameters gave results below population levels, but folate, phosphate, albumin, calcium and vitamin B12 were above. More patients than expected were below the RI for most parameters in the TG and subgroups.

Conclusions: At diagnosis, in patients with EDs, there are often significant differences in multiple haematological and biochemical parameters. Early identification of these abnormalities may provide additional avenues of ED treatment through supplementation and dietary guidance, and may be used to reinforce negative impacts on health caused by the ED to the patient, their family and their treatment team (general practitioner, dietitian and mental health professionals). Study data would support routine measurement of a full blood count and electrolytes, phosphate, magnesium, liver function tests, ferritin, vitamin B12, red cell folate, vitamin D, manganese and zinc for all patients at first presentation with an ED.
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http://dx.doi.org/10.1186/s40337-017-0158-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623971PMC
October 2017

Brain-resident memory T cells represent an autonomous cytotoxic barrier to viral infection.

J Exp Med 2016 07 4;213(8):1571-87. Epub 2016 Jul 4.

Departement de Pathologie et Immunologie, Centre Medical Universitaire, University of Geneva, 1211 Geneva, Switzerland Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland

Tissue-resident memory T cells (TRM) persist at sites of prior infection and have been shown to enhance pathogen clearance by recruiting circulating immune cells and providing bystander activation. Here, we characterize the functioning of brain-resident memory T cells (bTRM) in an animal model of viral infection. bTRM were subject to spontaneous homeostatic proliferation and were largely refractory to systemic immune cell depletion. After viral reinfection in mice, bTRM rapidly acquired cytotoxic effector function and prevented fatal brain infection, even in the absence of circulating CD8(+) memory T cells. Presentation of cognate antigen on MHC-I was essential for bTRM-mediated protective immunity, which involved perforin- and IFN-γ-dependent effector mechanisms. These findings identify bTRM as an organ-autonomous defense system serving as a paradigm for TRM functioning as a self-sufficient first line of adaptive immunity.
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http://dx.doi.org/10.1084/jem.20151916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986533PMC
July 2016

Victoria's Child FIRST and IFS differential response system: progress and issues.

Child Abuse Negl 2015 Jan 2;39:41-9. Epub 2014 Sep 2.

School of Public Health and Social Work, Queensland University of Technology, Victoria Park Road, Kelvin Grove, Queensland 4059, Australia.

Differential response has long been utilized by statutory child protection systems in Australia. This article describes the advent and history of Victoria's differential response system, with a particular focus on the Child FIRST and IFS programme. This program entails a partnership arrangement between the Department of Human Services child protection services and community-based, not-for-profit agencies to provide a diverse range of early intervention and prevention services. The findings of a recent external service system evaluation, a judicial inquiry, and the large-scale Child and Family Services Outcomes Survey of parents/carers perspectives of their service experiences are used to critically examine the effectiveness of this differential response approach. Service-user perspectives of the health and wellbeing of children and families are identified, as well as the recognized implementation issues posing significant challenges for the goal of an integrated partnership system. The need for ongoing reform agendas is highlighted along with the policy, program and structural tensions that exist in differential response systems, which are reliant upon partnerships and shared responsibilities for protecting children and assisting vulnerable families. Suggestions are made for utilizing robust research and evaluation that gives voice to service users and promotes their rights and interests.
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http://dx.doi.org/10.1016/j.chiabu.2014.08.003DOI Listing
January 2015

Intraventricular fibrinolysis does not increase perihemorrhagic edema after intracerebral hemorrhage.

Stroke 2013 Feb 10;44(2):362-6. Epub 2013 Jan 10.

Department of Neurology, University of Erlangen-Nure, Schwabachanlage 6, 91054 Erlangen, Germany.

Background And Purpose: Additional intraventricular hemorrhage leads to higher mortality and worse functional outcome after intracerebral hemorrhage (ICH). Intraventricular fibrinolysis (IVF) with recombinant tissue plasminogen activator (rtPA) is an emerging treatment strategy for such patients. However, experimental studies suggest that rtPA may exert proedematous effects and lead to increased perihemorrhagic edema (PHE) after ICH. We aimed to compare the course of PHE after ICH between patients who received IVF with rtPA and controls matched for ICH volume.

Methods: Patients were identified retrospectively from our institutional ICH database. Sixty-four patients with ICH and intraventricular hemorrhage who were treated with IVF were compared with 64 controls, who did not receive IVF, matched for ICH volume. The course of PHE was assessed on computed tomography scans (day 1, days 2 and 3, days 4-6, 7-9, and 10-12) using a threshold-based semiautomatic volumetric algorithm. Relative PHE was calculated as a ratio of PHE volume and initial ICH volume.

Results: The matching algorithm resulted in similar mean ICH volumes in both groups (20.01 ± 17.5 mL, IVF vs 20.08 ± 17.1 mL, control). Intraventricular hemorrhage volume was larger in the IVF group (26.8 ± 19.2 mL vs 9.2 ± 13.4 mL). The mean total rtPA dose used for IVF was 8 ± 6 mg. PHE increased over time in both groups until day 12. At all investigated time points, there was no significant difference in relative PHE between the IVF group and controls (F=0.39; P=0.844).

Conclusions: IVF with rtPA did not lead to a relevant increase in PHE after ICH. rtPA doses used in the current study seem to be safe regarding PHE.
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http://dx.doi.org/10.1161/STROKEAHA.112.673228DOI Listing
February 2013

Mild prolonged hypothermia for large intracerebral hemorrhage.

Neurocrit Care 2013 Apr;18(2):178-83

Department of Neurology, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.

Background: Perihemorrhagic edema (PHE) develops after intracerebral hemorrhage (ICH). It can worsen the clinical situation by its additional mass effect. Therapeutic hypothermia (TH) might be an effective method to control PHE, but has not been sufficiently studied in ICH patients.

Methods: We report data on n = 25 consecutive patients with large supratentorial ICH (volume > 25 ml) who were treated by mild TH of 35 °C for 8-10 days. Body temperature was controlled by endovascular cooling catheters. We followed the clinical course during hospital stay and measured volumes of ICH and PHE in regularly performed serial cranial computed tomography. Outcome was assessed after 3 and 12 months. These data were compared to a historical group of n = 25 patients with large ICH.

Results: While PHE continuously increased in the historical control group up to day 10, PHE volumes in the hypothermia group remained stable. There was a significant difference from day 3 after symptom onset. Shivering (36 %) and pneumonia (96 %) were the most frequent complications during TH. Mortality rate was 8.3 % in TH versus 16.7 % in the control group after 3 months and 28 versus 44 % after 1 year.

Conclusions: These data support the promising results of our first case series on TH in large ICH. TH prevents the development of PHE and its complications. Side effects of TH appeared often, but could be treated sufficiently. Therefore, TH might represent a new therapy for PHE after large ICH, but has to be further tested in randomized trials.
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http://dx.doi.org/10.1007/s12028-012-9762-5DOI Listing
April 2013

Natural course of perihemorrhagic edema after intracerebral hemorrhage.

Stroke 2011 Sep 7;42(9):2625-9. Epub 2011 Jul 7.

Department of Neurology, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.

Background And Purpose: There is only limited knowledge on the time course of perihemorrhagic edema (PHE) after intracerebral hemorrhage (ICH). We aimed to investigate the chronological PHE course and its relation to in-hospital mortality in a large retrospective ICH cohort.

Methods: Patients with supratentorial ICH treated at our institution between 2006 and 2009, who had received at least 3 CT scans in the course of conservative treatment, were included in the present analysis. PHE at Days 1, 2, 3, 4 to 6, 7 to 11, 12 to 16, 17 to 21, and >22 was assessed using a threshold based semiautomatic volumetric algorithm. A chart review was performed to achieve data on duration of stay, ventilation, treatment with external ventricular drains, and in-hospital mortality.

Results: Two hundred nineteen patients aged 69.9±10.5 years with deep (n=103) or lobar (n=116) ICH were included in the study. Mean ICH volume was 35.7±31.5 mL. Mean absolute PHE volume significantly increased from initially 32.6±29.9 mL to 63.7±46.7 mL at Days 7 to 11. No significant changes were observed at later time points. ICH volume was strongly correlated with absolute PHE volume (ρ=0.8, P<0.001) and inversely correlated with relative PHE (ρ=-0.4 to -0.5, P<0.001). Increase in absolute PHE between Days 1 and 3 was significantly predictive for in-hospital mortality (P=0.014, ExpB=1.04).

Conclusions: PHE develops early after ICH and doubles within the first 7 to 11 days after the initial bleeding event. This additional mass effect may contribute to secondary clinical deterioration and mortality, especially in larger ICH. Because of its inverse correlation with ICH volume, relative PHE may not be suitable for analyses considering the clinical impact of PHE.
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http://dx.doi.org/10.1161/STROKEAHA.111.618611DOI Listing
September 2011

Dose effect of intraventricular fibrinolysis in ventricular hemorrhage.

Stroke 2011 Jul 5;42(7):2061-4. Epub 2011 May 5.

Department of Neurology, University of Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.

Background And Purpose: The aim of the current study was to investigate the dose-dependent efficacy of intraventricular fibrinolysis (IVF) in patients with severe intraventricular hemorrhage (IVH).

Methods: Patients with intracerebral hemorrhage, severe IVH, and obstructive hydrocephalus with the need for external ventricular drainage were treated with IVF through external ventricular drainage. The time course of IVH resolution and the safety profile were compared between patients treated with high-dose IVF (4 mg alteplase every 12 hours, maximum 20 mg; n=32) and low-dose IVF (1 mg alteplase every 8 hours, maximum 12 mg; n=22). CT scans on Days 1 to 4, 7 ± 1 and 10 ± 1 after admission, were analyzed volumetrically. Outcome was assessed after 3 months.

Results: The overall effect of IVF dosage was not significantly different between the 2 groups (F=1.3, P=0.25). The course of IVH volume in the third and fourth ventricles was similar with high- and low-dose IVF. High-dose IVF resulted in lower total IVH volumes on Days 7 (4.4 ± 4.2 mL versus 8.8 ± 8.1 mL; P=0.01) and 10 (1.4 ± 2.8 mL versus 4.9 ± 65.8 mL; P=0.005). Total clot half-life was 78 ± 43 hours in the low-dose and 56 ± 25 hours in the high-dose group (P=0.02). One asymptomatic ventricular bleeding, 2 cases of ventriculitis, and 1 death due to pulmonary embolism occurred in the high-dose group. There was no difference in outcome at 3 months.

Conclusions: Low-dose IVF (3 mg alteplase/day) has a similar effect on IVH clearance from the third and fourth ventricles and a similar safety profile when compared with high-dose IVF (8 mg alteplase/day).
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http://dx.doi.org/10.1161/STROKEAHA.110.608190DOI Listing
July 2011

Prognostic significance of third ventricle blood volume in intracerebral haemorrhage with severe ventricular involvement.

J Neurol Neurosurg Psychiatry 2011 Nov 21;82(11):1260-3. Epub 2011 Apr 21.

Department of Neurology, University of Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.

Background And Purpose: Intraventricular haemorrhage (IVH) is an independent predictor of poor outcome in spontaneous intracerebral haemorrhage (ICH). Larger IVH volume and increasing number of affected ventricles have been associated with worse prognosis, however, little is known about the prognostic value of blood volume in the different parts of the ventricular system. Therefore, the correlation of IVH volume in the third, fourth and lateral ventricles with outcome in patients with ICH and severe IVH, treated with intraventricular fibrinolysis (IVF), was investigated.

Methods: Patients with ICH <40 ml, severe IVH and acute hydrocephalus were treated with IVF. The course of IVH volume for each ventricle was measured by CT based volumetry. Outcome at 90 days was assessed by a telephone follow-up survey and correlated with initial IVH volume.

Results: 50 patients aged 62.5±10.3 years with spontaneous ICH (12.5±10.8 ml) and severe IVH (33.5±25 ml) were included. Clearance of the third and fourth ventricle from blood occurred after 3±1.9 days. Initial IVH volume in the third ventricle (3.8±3.3 ml) was predictive for poor outcome (OR 2.6 per ml, p=0.02). Correlation between larger IVH volume in the fourth ventricle and poor outcome showed a trend towards significance (p=0.07). Total IVH volume and lateral ventricle IVH volume were not correlated with outcome.

Conclusion: Despite rapid clot removal, initial IVH volume in the third ventricle was a strong and independent negative predictor. This is possibly explained by irreversible damage of brainstem structures by the initial mass effect of IVH.
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http://dx.doi.org/10.1136/jnnp.2010.234542DOI Listing
November 2011

Effects of continuous hypertonic saline infusion on perihemorrhagic edema evolution.

Stroke 2011 Jun 21;42(6):1540-5. Epub 2011 Apr 21.

Neurology Department, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany.

Background And Purpose: Mass effect of hematoma and the associated perihematomal edema are commonly responsible for neurological deterioration after intracerebral hemorrhage. Efficacy of surgical and medical therapy is limited. We studied the effect of early continuous hypertonic saline infusion on development of perihematomal edema after severe spontaneous supratentorial hemorrhage.

Methods: Patients with spontaneous lobar and basal ganglia/thalamic bleeding >30 mL (n=26) were treated with early (<72 hours) continuous hypertonic saline infusion (3%) to achieve sodium of 145 to 155 mmol/L and osmolality of 310 to 320 mOsmol/kg. Evolution of absolute edema volume and relative edema volume (ratio absolute edema volume/initial hematoma volume) was assessed on repeated cranial CT and compared to historical patients (n=64) identified on database with hematoma >30 mL.

Results: In the treatment group, absolute edema volume was significant smaller between day 8 and day 14 (P(absolute edema volume)= 0.04) and relative edema volume was significant smaller between day 2 and day 14 (P(relative edema volume)=0.02). Intracranial pressure crisis (>20 mm Hg for >20 minutes or new anisocoria) occurred less frequently in the treatment group (12 versus 56; P=0.048). In-hospital mortality was 3 (11.5%) in the hypertonic saline group and 16 (25%) in the control group (P=0.078). Side effects theoretically associated with hypertonic saline including cardiac arrhythmia and acute heart and renal failure occurred in both groups to a similar extent.

Conclusions: Early and continuous infusion of hypertonic saline in patients with severe spontaneous intracerebral hemorrhage was feasible and safe. The beneficial effect of this treatment regimen on edema evolution and outcome has to be demonstrated in a controlled trial.
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http://dx.doi.org/10.1161/STROKEAHA.110.609479DOI Listing
June 2011

Semi-automatic volumetric assessment of perihemorrhagic edema with computed tomography.

Eur J Neurol 2011 Nov 4;18(11):1323-8. Epub 2011 Apr 4.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background And Purpose: Magnetic resonance imaging (MRI) shows perihemorrhagic edema (PHE) after intracerebral hemorrhage (ICH) with high contrast, but the procedure is often difficult or not available for clinical use. The aim of the present study was to establish and validate an observer independent method for quantification of PHE on computed tomography (CT) by comparing with simultaneously performed MRI.

Methods: Patients with spontaneous supratentorial ICH were included. Twenty-two patients received coregistered MRI and CT on day 1, and 27 patients on day 5 after admission. Volumes for PHE and ICH were measured (i) manually on CT, (ii) manually on MRI (fluid-attenuated inversion recovery sequence), and (iii) threshold based on CT. To identify optimal threshold values (Hounsfield units) for best correlation of CT with MRI, upper and lower thresholds were adjusted gradually until the PHE volume on CT best fitted the PHE volume on MRI. The established threshold range was prospectively validated in another 15 patients.

Results: A threshold range 5-33 Hounsfield units (HU) resulted in best correlation both on days 1 and 5. Using these thresholds in the validation group, PHE volumes on CT and MRI were highly comparable (31 ± 26 ml vs. 30 ± 27 ml) with good correlation (R(2) = 0.96, P < 0.01) and high inter- (0.96) and intraobserver (0.96) reliability. Manually traced PHE on CT was significantly larger (37.3 ± 37 ml vs. 30 ± 27 ml, P < 0.01) with worse inter- (0.89) and intraobserver (0.90) reliability.

Conclusions: Threshold-based CT volumetry of PHE with a threshold range 5-33 HU is a reliable and observer independent method for quantification of PHE after spontaneous ICH.
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http://dx.doi.org/10.1111/j.1468-1331.2011.03395.xDOI Listing
November 2011

Early recognition of lumbar overdrainage by lumboventricular pressure gradient.

Neurosurgery 2011 May;68(5):1187-91; discussion 1191

Department of Neurology, University of Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.

Background: Lumbar drainage (LD) represents a promising treatment strategy for prevention of vasospasm after aneurysmal subarachnoid hemorrhage (SAH).

Objective: To report on transient herniation caused by lumbar overdrainage in 3 patients with severe SAH who were treated with early LD within an ongoing feasibility study.

Methods: Patients with first-time aneurysmal SAH received LD within 72 hours of symptom onset, after aneurysm clipping or coiling. LD, with a target drainage amount of 5 to 10 mL, was continued for 6 to 9 days. External ventricular drainage (EVD) was begun on admission when hydrocephalus was present. With both catheters in place, intracranial pressure (ICP) and lumbar pressure (LP) were monitored simultaneously.

Results: Three of 22 patients developed a progressive lumboventricular pressure gradient, likely due to cerebrospinal fluid (CSF) overdrainage. Two patients showed signs of herniation. Clamping of LD resulted in complete reversal of symptoms in those patients. The lumboventricular pressure gradient began to evolve at least 12 hours before clinical symptoms developed, and gradually disappeared in all 3 patients after LD clamping.

Conclusion: Lumbar overdrainage should be avoided in severe SAH, and lumboventricular pressure measurement may be a useful monitoring tool. Herniation due to lumbar overdrainage is a feared complication that can be avoided by following a strict LD management protocol.
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http://dx.doi.org/10.1227/NEU.0b013e31820c0274DOI Listing
May 2011

TAK1 downregulation reduces IL-1beta induced expression of MMP13, MMP1 and TNF-alpha.

Biomed Pharmacother 2006 Feb 27;60(2):55-61. Epub 2005 Dec 27.

Institut für Klinische Chemie, University of Cologne, Germany.

The paper provides evidence that transforming growth factor-beta activated kinase 1 (TAK1, MEKK7), a downstream mediator of IL-1beta signal transduction, plays an important role in the regulation of catabolic events and inflammatory processes in the context of degenerative joint diseases. We investigated the expression of TAK1 in human articular chondrocytes and in the murine growth plate by cDNA array, quantitative RT-PCR and immunohistochemistry, respectively. The human chondrosarcoma cell line SW1353 was stimulated with the proinflammatory cytokine IL-1beta. The subsequent expression of proteolytic enzymes and proinflammatory cytokines was quantified. TAK1 specific siRNA was used to study the influence of TAK1 downregulation on the expression of MMP-13, MMP1 and TNF-alpha. As a result we demonstrated the expression of TAK1 in normal and osteoarthritic human articular cartilage. Expression of TAK1 in the hypertrophic zone of the growth plate gave us a first evidence for a catabolic function of TAK1 concerning cartilage metabolism. By gene suppression with RNAi technology we could show that TAK1 downregulation leads to a 60-70% reduced release of TNF-alpha, a 40-50% reduced release of MMP13, and a 20-30% reduction of MMP1 release. As TNF-alpha is a main player in inflammatory processes, and MMP13 is one of the major proteases involved in cartilage degradation, our results suggests that TAK1 has an important regulatory role in the context of degenerative joint diseases and thus is an attractive drug target in attempts to reduce inflammation and suppress structural changes in OA induced by IL-1beta.
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http://dx.doi.org/10.1016/j.biopha.2005.08.007DOI Listing
February 2006

Models and patterns of service in child and youth consultation-liaison services.

Australas Psychiatry 2005 Sep;13(3):273-8

Principal Social Worker, Child and Youth Mental Health Service, Royal Children's Hospital and Health Service District, Spring Hill, Qld, Australia.

Objective: The aim was to examine referral pathways to child and youth consultation-liaison (C-L) services to identify patterns associated with demographic characteristics of patients, referral sources, the presenting problem and models of service.

Method: A case record review with a cross-sectional design. Data were extracted from the records of all patients referred to the C-L service for a 3 month period.

Results: Adolescents were more likely to access mental health services through informal liaison services. Medical specialty areas that were inclusive of nursing and allied health, in both the request for service and initial response to the request, had higher frequencies of referral. There was no difference between the disciplines of medicine and social work in the frequency of referrals. However, medicine, social work and nursing differed in the number of staff who initiated the request for consultation, and the types of problems that were presented as reasons for referral.

Conclusions: Inclusive multidisciplinary models may facilitate the development of service relationships in paediatric hospital settings, due to the stability of staffing arrangements. The wider participation of allied health and nursing staff within paediatric hospitals may extend opportunities for the identification of mental health problems and enhance timely management of referrals.
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http://dx.doi.org/10.1080/j.1440-1665.2005.02201.xDOI Listing
September 2005

Redevelopment of a consultation-liaison service at a tertiary paediatric hospital.

Australas Psychiatry 2005 Jun;13(2):169-72

Bardon Specialist Group, Bardon, Qld, Australia.

Objective: This paper aims to describe the way a multidisciplinary team set out to redevelop a consultation-liaison (C-L) service at a tertiary paediatric hospital.

Method: The activities and processes in which the team members engaged were documented within a continuous quality improvement cycle. These activities included literature review, analysis of referral patterns, consultation with extant services, survey of referral sources and consultation with other tertiary paediatric services.

Results: The outcomes of these initiatives were integrated into a re-formulated multidisciplinary team model dedicated to providing C-L services to the paediatric hospital. Significant challenges identified in the initial process were ongoing issues with caseload management and clarification of boundary demarcations.

Conclusion: There has been a gradual acceptance of the new C-L service by medical staff. The structure has resulted in a focused and coordinated C-L team that has contributed to innovations in the C-L process within the hospital.
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http://dx.doi.org/10.1080/j.1440-1665.2005.02182.xDOI Listing
June 2005

Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors.

FASEB J 2003 Jun 22;17(9):1186-8. Epub 2003 Apr 22.

Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany.

Hypoxia-inducible transcription factors (HIF) mediate complex adaptations to reduced oxygen supply, including neoangiogenesis. Regulation of HIF occurs mainly through oxygen-dependent destruction of its alpha subunit. In the presence of oxygen, two HIFalpha prolyl residues undergo enzymatic hydroxylation, which is required for its proteasomal degradation. We therefore tested whether pharmacological activation of HIFalpha by hydroxylase inhibitors may provide a novel therapeutic strategy for the treatment of ischemic diseases. Three distinct prolyl 4-hydroxylase inhibitors-l-mimosine (L-Mim), ethyl 3,4-dihydroxybenzoate (3,4-DHB), and 6-chlor-3-hydroxychinolin-2-carbonic acid-N-carboxymethylamid (S956711)-demonstrated similar effects to hypoxia (0.5% O2) by inducing HIFalpha protein in human and rodent cells. L-Mim, S956711, and, less effectively, 3,4-DHB also induced HIF target genes in cultured cells, including glucose transporter 1 and vascular endothelial growth factor, as well as HIF-dependent reporter gene expression. Systemic administration of L-Mim and S956711 in rats led to HIFalpha induction in the kidney. In a sponge model for angiogenesis, repeated local injection of the inhibitors strongly increased invasion of highly vascularized tissue into the sponge centers. In conclusion, structurally distinct inhibitors of prolyl hydroxylation are capable of inducing HIFalpha and HIF target genes in vitro and in vivo and induce adaptive responses to hypoxia, including angiogenesis.
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http://dx.doi.org/10.1096/fj.02-1062fjeDOI Listing
June 2003