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Search Results: 1 - 10 of 143 matches for " Raimund Helbok "
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IgG-index predicts neurological morbidity in patients with infectious central nervous system diseases
Peter Lackner, Elif Guengoer, Ronny Beer, Gregor Broessner, Raimund Helbok, Florian Deisenhammer, Erich Schmutzhard, Bettina Pfausler
BMC Infectious Diseases , 2010, DOI: 10.1186/1471-2334-10-202
Abstract: White blood cell count, CSF/serum glucose ratio, protein, CSF/serum albumin quotient and Immunoglobulin indices for IgG, IgA and IgM were analyzed in 90 patients with bacterial meningitis, 117 patients with viral meningoencephalitis and 36 patients with leptomeningeal metastases in a total of 480 CSF samples.In the initial spinal tap, the IgG-index was the only independent predictor for unfavorable outcome (GOS < 5) in patients with infectious CNS diseases but not in patients with leptomeningeal metastases. The sensitivity and specificity of an IgG-index of 0.75 and higher for predicting unfavorable outcome was 40.9% and 80.8% in bacterial meningitis and 40% and 94.8% in viral meningoencephalitis, respectively. No significant associations between CSF parameters and outcome could be observed in follow-up CSF samples.The present study suggests that in infectious CNS diseases an elevated IgG-Index might be an additional marker for the early identification of patients at risk for neurological morbidity.The clinical course of infectious and neoplastic disorders of the central nervous system is sometimes difficult to predict. While the diagnosis of bacterial meningitis, viral meningitis/meningoencephalitis and leptomeningeal metastases (LM) mainly relies on the analysis of cerebrospinal fluid (CSF), only limited data on the prognostic value of CSF parameters exist [1]. Yet, initial risk assessment of individual patients is of paramount importance in order to choose the appropriate level of further surveillance (i.e. general ward versus critical care unit) [2]. Of course, clinical presentation is one of the most important issues in this respect [3]. This has been shown by different authors and complex scores have been developed in order to raise the predictive accuracy of clinical signs and symptoms [2,4-7]. In addition, other studies have tried to assess the role of imaging techniques such as computed tomography or transcranial Doppler sonography [8,9]. Despite these impr
Scanning electron microscopy of the neuropathology of murine cerebral malaria
Peter Lackner, Ronny Beer, Raimund Helbok, Gregor Broessner, Klaus Engelhardt, Christian Brenneis, Erich Schmutzhard, Kristian Pfaller
Malaria Journal , 2006, DOI: 10.1186/1475-2875-5-116
Abstract: C57BL/6J mice were infected with Plasmodium berghei ANKA blood stages. When typical symptoms of CM developed perfused brains were processed for SEM or light microscopy, respectively.Ultrastructural hallmarks were disruption of vessel walls, parenchymal haemorrhage, leukocyte sequestration to the endothelium, and diapedesis of macrophages and lymphocytes into the Virchow-Robin space. Villous appearance of observed lymphocytes were indicative of activated state. Cerebral oedema was evidenced by enlargement of perivascular spaces.The results of the present study corroborate the current understanding of CM pathophysiology, further support the prominent role of the local immune system in the neuropathology of CM and might expose new perspectives for further interventional studies.Cerebral malaria (CM) is a major cause of mortality and morbidity in severe Plasmodium falciparum malaria. Frequently seen neurological dysfunctions are delirium, convulsions, coma and eventual death if the disease is not controlled. Post mortem analyses of brains of CM patients show adherence of parasitized red blood cells (pRBC) and inflammatory cells to the microvasculature of the brain, parenchymal microhaemorrhages and oedema. The pathophysiological mechanisms of CM are still discussed controversially. However, most researchers agree that two main factors contribute to the development of CM. On the one hand sequestration of blood cells (i.e. pRBC, leukocytes and thrombocytes) on activated endothelia causes obstruction of microvascular flow leading to local hypoxia [1,2]. On the other hand, excessively elevated cytokines in serum lead to activation of brain resident microglial cells which trigger local inflammatory processes [3-5]. Most of the knowledge about the pathophysiological mechanisms originates from studies in animal models (i.e. rodents) since the early stages of the disease are neuropathologically not addressable in humans. Hence the histopathology of murine CM has been studied in
Complement factors C1q, C3 and C5 in brain and serum of mice with cerebral malaria
Peter Lackner, Christian Hametner, Ronny Beer, Christoph Burger, Gregor Broessner, Raimund Helbok, Cornelia Speth, Erich Schmutzhard
Malaria Journal , 2008, DOI: 10.1186/1475-2875-7-207
Abstract: C57BL/6J mice were infected with Plasmodium berghei ANKA blood stages. The clinical severity of the disease was assessed by a battery of 40 standardized tests for evaluating neurological functions in mice. Brain homogenates and sera of mice with CM, infected animals without CM and non-infected control animals were analyzed for C1q, C3 and C5 up-regulation by Western blotting.Densitometric analysis of Western blots of brain homogenates yielded statistically significant differences in the levels of C1q and C5 in the analyzed groups. Correlation analysis showed a statistically significant association of C1q and C5 levels with the clinical severity of the disease. More severely affected animals showed higher levels of C1q and C5. No differences in complement levels were observed between frontal and caudal parts of the brain. Densitometric analysis of Western blot of sera yielded statistically lower levels of C1q in infected animals without CM compared to animals of the control group.The current study provides direct evidence for up-regulation of complement factors C1q and C5 in the brains of animals with CM. Local complement up-regulation is a possible mechanism for brain damage in experimental cerebral malaria.Cerebral malaria (CM) is a major cause of morbidity and mortality of Plasmodium falciparum malaria. It presents as a diffuse encephalopathy with alteration of consciousness, ranging from drowsiness to deep coma and is frequently accompanied by seizures [1]. Mortality is high and neurological sequelae are observed in approximately 10% of the survivors [2]. The pathophysiological mechanisms of CM are not yet fully understood. Most researchers agree that the immune response of the host is a critical factor in the pathogenesis of CM. Different aspects have been studied and in particular pro-inflammatory cytokines and activated T-lymphocytes have been shown to be related to the development of CM [3,4]. One potent stimulator of inflammation is the complement system. It
Differential Regulation of Matrix-Metalloproteinases and Their Tissue Inhibitors in Patients with Aneurysmal Subarachnoid Hemorrhage
Marlene Fischer, Anelia Dietmann, Ronny Beer, Gregor Broessner, Raimund Helbok, Bettina Pfausler, Erich Schmutzhard, Peter Lackner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059952
Abstract: Background Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in vascular remodeling, (neuro)inflammation, blood-brain barrier breakdown and neuronal apoptosis. Proinflammatory mechanisms are suggested to play an important role during early brain injury and cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This study aimed to analyze MMP-3, MMP-9, TIMP-1 and TIMP-3 in patients with SAH and their respective association with cerebral vasospasm (CVS). Methods Blood samples were collected in 20 SAH patients on days 1 to 7, 9, 11, 13 and 15 and 20 healthy age and gender matched volunteers. Serum MMPs and TIMPs were analyzed using enzyme-linked immunosorbent assay. Doppler sonographic CVS was defined as a mean blood flow velocity above 120 cm/sec in the middle cerebral artery. When discharged from hospital and at 6 month follow-up neurological outcome was evaluated using the Glasgow Outcome Score and the modified Rankin Scale. Results MMP-9 was higher in SAH patients compared to healthy controls (p<0.001). Patients with CVS (n = 11) had elevated MMP-9 serum levels compared to patients without CVS (n = 9, p<0.05). Higher MMP-9 was observed in the presence of cerebral ischemia associated with cerebral vasospasm (p<0.05). TIMP-1 was increased in patients with SAH on day 4 (p<0.05). There was an imbalance of the MMP-9/TIMP-1 ratio in favor of MMP-9 in SAH patients, in particular those with CVS (p<0.001). MMP-3 and TIMP-3 were significantly lower in SAH patients throughout day 4 and day 7, respectively (p<0.05). We did not find an association between MMP-, TIMP levels and neurological outcome after 6 months. Conclusions MMP-3 and -9 are differentially regulated in SAH patients with both enzymes showing peak levels correlating with the development of CVS. The inhibitors TIMP-1 and -3 were low during the acute phase after SAH and increased later on which might suggest a preponderance of pro-inflammatory mechanisms.
Nogo-A Expression in the Brain of Mice with Cerebral Malaria
Peter Lackner,Ronny Beer,Gregor Broessner,Raimund Helbok,Karolin Dallago,Michael W. Hess,Kristian Pfaller,Christine Bandtlow,Erich Schmutzhard
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025728
Abstract: Cerebral malaria (CM) is associated with a high rate of transient or persistent neurological sequelae. Nogo-A, a protein that is highly expressed in the endoplasmic reticulum (ER) of the mammalian central nervous system (CNS), is involved in neuronal regeneration and synaptic plasticity in the injured CNS. The current study investigates the role of Nogo-A in the course of experimental CM. C57BL/6J mice were infected with Plasmodium berghei ANKA blood stages. Brain homogenates of mice with different clinical severity levels of CM, infected animals without CM and control animals were analyzed for Nogo-A up-regulation by Western blotting and immunohistochemistry. Brain regions with Nogo-A upregulation were evaluated by transmission electron microscopy. Densitometric analysis of Western blots yielded a statistically significant upregulation of Nogo-A in mice showing moderate to severe CM. The number of neurons and oligodendrocytes positive for Nogo-A did not differ significantly between the studied groups. However, mice with severe CM showed a significantly higher number of cells with intense Nogo-A staining in the brain stem. In this region ultrastructural alterations of the ER were regularly observed. Nogo-A is upregulated during the early course of experimental CM. In the brain stem of severely affected animals increased Nogo-A expression and ultrastructural changes of the ER were observed. These data indicate a role of Nogo-A in neuronal stress response during experimental CM.
Angiopoietin-1 is associated with cerebral vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage
Marlene Fischer, Gregor Broessner, Anelia Dietmann, Ronny Beer, Raimund Helbok, Bettina Pfausler, Andreas Chemelli, Erich Schmutzhard, Peter Lackner
BMC Neurology , 2011, DOI: 10.1186/1471-2377-11-59
Abstract: 20 patients with subarachnoid hemorrhage (SAH) and 20 healthy controls (HC) were included in this prospective study. Blood samples were collected from days 1 to 7 and every other day thereafter. Ang-1 and Ang-2 were measured in serum samples using commercially available enzyme-linked immunosorbent assay. Transcranial Doppler sonography was performed to monitor the occurrence of cerebral vasospasm.SAH patients showed a significant drop of Ang-1 levels on day 2 and 3 post SAH compared to baseline and HC. Patients, who developed Doppler sonographic CVS, showed significantly lower levels of Ang-1 with a sustained decrease in contrast to patients without Doppler sonographic CVS, whose Ang-1 levels recovered in the later course of the disease. In patients developing cerebral ischemia attributable to vasospasm significantly lower Ang-1 levels have already been observed on the day of admission. Differences of Ang-2 between SAH patients and HC or patients with and without Doppler sonographic CVS were not statistically significant.Ang-1, but not Ang-2, is significantly altered in patients suffering from SAH and especially in those experiencing CVS and cerebral ischemia. The loss of vascular integrity, regulated by Ang-1, might be in part responsible for the development of cerebral vasospasm and subsequent cerebral ischemia.Subarachnoid hemorrhage (SAH) accounts for 2-5% of all new strokes and is still associated with high morbidity and mortality [1,2]. In about 85% of all patients, non-traumatic SAH is caused by the rupture of an intracranial aneurysm [3]. Cerebral vasospasm (CVS) is one of the most important complications of SAH and may be associated with delayed cerebral ischemia (DCI) frequently resulting in poor functional outcome and death [4-6]. Various mechanisms are discussed to be involved in the pathophysiology of CVS. Apart from smooth muscle contraction and an increase of spasmogens such as oxyhemoglobin or bilirubin oxidation products an imbalance of endothelium-
Glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study
Peter Lackner, Andrea Part, Christoph Burger, Anelia Dietmann, Gregor Broessner, Raimund Helbok, Markus Reindl, Erich Schmutzhard, Ronny Beer
Malaria Journal , 2009, DOI: 10.1186/1475-2875-8-36
Abstract: GA treatment led to a statistically significant lower risk for developing CM (57.7% versus 84.6%) in treated animals. The drug had no effect on the course of parasitaemia. The mechanism of action seems to be an immunomodulatory effect since lower IFN-gamma levels were observed in treated animals in the early course of the disease (day 4 post-infection) which also led to a lower number of brain sequestered leukocytes in treated animals. No direct neuro-protective effect such as an inhibition of apoptosis or reduction of micro-bleedings in the brain was found.These findings support the important role of the host immune response in the pathophysiology of murine CM and might lead to the development of new adjunctive treatment strategies.A major cause of morbidity and mortality of Plasmodium falciparum malaria is cerebral malaria (CM). It presents as a diffuse encephalopathy with alteration of consciousness, ranging from drowsiness to deep coma and is frequently accompanied by seizures [1]. Mortality is high and neurological sequelae are observed in approximately 10% of the survivors [2]. The pathophysiological mechanisms of CM are yet not fully understood. Most researchers agree that the immune response of the host is a critical factor in the pathogenesis of CM. Different aspects have been studied and in particular pro-inflammatory cytokines and activated T-lymphocytes have been shown to be related to the development of CM [3-5]. Importantly, recent studies suggest a critical role of interferon-responsive mechanisms in murine and human CM [6,7]. Therefore, immunomodulatory drugs have been considered as potential adjunctive treatment regimens for severe malaria. Despite beneficial effects in the mouse model [8,9], corticosteroids have been shown to be ineffective or even deleterious in human CM [10,11]. Similar findings were observed with TNF-alpha antagonists. While TNF-alpha blockage reduces the rate of CM in mice, the data from human trials are far from clear [12-14].
Opposed circulating plasma levels of endothelin-1 and C-type natriuretic peptide in children with Plasmodium falciparum malaria
Anelia Dietmann, Peter Lackner, Raimund Helbok, Katharina Spora, Saadou Issifou, Bertrand Lell, Markus Reindl, Peter G Kremsner, Erich Schmutzhard
Malaria Journal , 2008, DOI: 10.1186/1475-2875-7-253
Abstract: Plasma levels of ET-1 and N-terminal fragments of CNP (NT-proCNP) were studied on admission and after 24 hours of treatment, using enzyme-linked-immunosorbent-assay (ELISA) technique, in Gabonese children with severe falciparum malaria (SM, n = 50), with uncomplicated malaria (UM, n = 39) and healthy controls (HC, n = 25).Compared to HC, malaria patients had significantly higher plasma levels of ET-1 and significantly lower levels of NT-proCNP (p < 0.001 and p < 0.024 respectively). Plasma levels of NT-proCNP were additionally decreased in SM patients compared to HC (p = 0.034), whereas UM was not significantly different to HC. In the SM group we found a trend towards lower ET-1 levels compared to UM (p = 0.085).In the present study, an imbalance between the vasoconstricitve and vasorelaxant endothelium-derived substances ET-1 and CNP in the plasma of children with falciparum malaria is demonstrated, presumably in favor of vasoconstrictive and pro-inflammatory effects. These results may indicate involvement of ET-1 and CNP in malaria pathogenesis. Furthermore, results of lower ET-1 and CNP levels in SM may reflect endothelial cell damage.Malaria, beside HIV and tuberculosis, is still a major cause of death in developing countries, accounting for 300 – 500 million clinical cases and more than one million deaths per year [1]. Plasmodium falciparum may lead to severe malaria (SM), a complex clinical syndrome with yet incompletely understood pathomechanisms.It has been shown that the endothelium is critically involved in the development of severe malaria [2-4]. The endothelial response to injury in acute inflammation can be divided into two phases: an initial rapid endothelial cell activation with recruitment of neutrophils, changes in levels of nitric oxide (NO), endothelin-1 (ET-1) and C-type natriuretic peptide (CNP) amongst others, and a slower response that depends on new gene expression and fundamental changes in cell surface characteristics [5]. Endothelins are r
Effects of the neurological wake-up test on clinical examination, intracranial pressure, brain metabolism and brain tissue oxygenation in severely brain-injured patients
Raimund Helbok, Pedro Kurtz, Michael J Schmidt, Morgan R Stuart, Luis Fernandez, Sander E Connolly, Kiwon Lee, Erich Schmutzhard, Stephan A Mayer, Jan Claassen, Neeraj Badjatia
Critical Care , 2012, DOI: 10.1186/cc11880
Abstract: This prospective observational study was performed in a neuroscience intensive care unit in a tertiary-care academic center. Twenty consecutive severely brain-injured patients with multimodal neuromonitoring were analyzed for levels of brain lactate, pyruvate and glucose, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygen tension (PbtO2) during IS trials.Of the 82 trial days, 54 IS-trials were performed as interruption of sedation and analgesics were not considered safe on 28 days (34%). An increase in the FOUR Score (Full Outline of UnResponsiveness score) was observed in 50% of IS-trials by a median of three (two to four) points. Detection of a new neurologic deficit occurred in one trial (2%), and in one-third of IS-trials the trial had to be stopped due to an ICP-crisis (> 20 mmHg), agitation or systemic desaturation. In IS-trials that had to be aborted, a significant increase in ICP and decrease in PbtO2 (P < 0.05), including 67% with critical values of PbtO2 < 20 mmHg, a tendency to brain metabolic distress (P < 0.07) was observed.Interruption of sedation revealed new relevant clinical information in only one trial and a large number of trials could not be performed or had to be stopped due to safety issues. Weighing pros and cons of IS-trials in patients with acute brain injury seems important as related side effects may overcome the clinical benefit.Titrating sedatives and analgesics to achieve the right balance between deep sedation and wakefulness and to ameliorate patients' comfort in the intensive care unit (ICU) is an integral part of critical care [1]. Over-sedation can lead to prolonged duration of mechanical ventilation and ICU stay and increase the incidence of secondary complications, including nosocomial infections and delirium.Daily interruption of sedation trials (IS-trials) have been implemented in many surgical and medical ICUs after randomized controlled trials demonstrated that IS decreased the duration of
High dose Erythropoietin increases Brain Tissue Oxygen Tension in Severe Vasospasm after Subarachnoid Hemorrhage
Raimund Helbok, Ehab Shaker, Ronny Beer, Andreas Chemelli, Martin Sojer, Florian Sohm, Gregor Broessner, Peter Lackner, Monika Beck, Alexandra Zangerle, Bettina Pfausler, Claudius Thome, Erich Schmutzhard
BMC Neurology , 2012, DOI: 10.1186/1471-2377-12-32
Abstract: Seven consecutive poor grade SAH patients with multimodal neuromonitoring (MM) received systemic EPO therapy (30.000?IU per day for 3 consecutive days) for severe cerebral vasospasm. Cerebral perfusion pressure (CPP), mean arterial blood pressure (MAP), intracranial pressure (ICP), PbtO2 and brain metabolic changes were analyzed during the next 24 hours after each dose given. Statistical analysis was performed with a mixed effects model.A total of 22 interventions were analyzed. Median age was 47?years (32–68) and 86?% were female. Three patients (38?%) developed DCI. MAP decreased 2 hours after intervention (P?<?0.04) without significantly affecting CPP and ICP. PbtO2 significantly increased over time (P?<?0.05) to a maximum of 7?±?4?mmHg increase 16 hours after infusion. Brain metabolic parameters did not change over time.EPO increases PbtO2 in poor grade SAH patients with severe cerebral vasospasm. The effect on outcome needs further investigation.
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