Biomedical subjects

M Spranger

Publications and source records attributed to M Spranger.

At least 19 recordsLinked to original sources

PubMed2003

SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6.

An expanded polyglutamine domain in the TATA-binding protein (TBP) has been described in patients with spinocerebellar ataxia type 17 (SCA17) characterized by cerebellar ataxia associated with dementia. TBP is a general transcription initiation factor that regulates the expression of most eukaryotic genes transcribed by RNA polymerase II. SCA17, as an autosomal dominantly inherited progressive neurodegenerative disorder, is caused by heterozygous expansion of a CAG repeat coding for glutamine. Alleles with 27 to a maximum of 44 glutamine residues were found as the normal range, whereas expansions above 45 repeat units were considered pathological. Here, we present a patient with a very severe phenotype with a late onset but rapidly progressing ataxia associated with dementia and homozygous 47 glutamine residues caused by an apparent partial isodisomy 6. This extraordinary case has important implications for the insights of TBP and SCA17. The expanded polyglutamine domain in both TBP copies is not correlated with embryonic death indicating that the normal function of the protein is not disrupted by this kind of mutation but may account for the dementia seen in this patient.

Adult↗

PubMed2000

Adenosine-induced expression of interleukin-6 in astrocytes through protein kinase A and NF-IL-6.

In various neurologic diseases, astrocytes express interleukin-6 (IL-6), which is an endogenous pyrogen, a neuroprotective factor, and a regulator of the blood-brain barrier. The expression of IL-6 in astrocytes is stimulated by extracellular adenosine through A(2B) receptors. To investigate the signaling cascade that induces IL-6 gene transcription further, we transfected primary mouse astrocytes with a reporter gene construct, in which luciferase expression is directed by the human IL-6 promoter. Expression of PKI, an inhibitor of protein kinase A (PKA), interfered with IL-6 transcription indicating that PKA mediates the effect of adenosine. The CAAT box of the IL-6 promoter is necessary for the stimulation by adenosine as a mutation in this element reduced the stimulation by adenosine. Indeed, the cAMP agonist forskolin increased the binding of the transcription factors NF-IL-6 and C/EBPdelta to the CAAT box of the IL-6 promoter in nuclear extracts of astrocytes. Inhibition of the de novo synthesis of NF-IL-6 by cycloheximide or an antisense oligonucleotide reduced the enhancement of NF-IL-6 binding to the CAAT box and inhibited stimulation of IL-6 transcription by forskolin. In addition, overexpression of NF-IL-6 induced IL-6 transcription. This suggests that adenosine induces the de novo synthesis of NF-IL-6 through activation of PKA and thereby stimulates transcription of IL-6 in astrocytes.

Adenosine↗

PubMed1999

Expression of cell death-associated phospho-c-Jun and p53-activated gene 608 in hippocampal CA1 neurons following global ischemia.

Persistent activation of c-Jun N-terminal kinases (JNKs) and phosphorylation of c-Jun has been shown in various cell death paradigms. Inhibition of the JNK signal transduction pathway prevented neuronal cell death both in vitro and in vivo. In the present study, nuclear phospho-c-Jun immunoreactivity became apparent selectively in vulnerable hippocampal CA1 neurons at 24 h after transient global cerebral ischemia. A high constitutive expression of phospho-JNK1 was detected by immunoblot analysis of hippocampal extracts. Expression of JNK interacting protein-1 (JIP-1), which facilitates JNK signaling, remained unchanged in post-ischemic hippocampal neurons. By contrast, p53-activated gene 608 (PAG608), which promotes cell death in vitro, was strongly induced in post-ischemic CA1 neurons. Our data suggest that transcription factors p53 and phospho-c-Jun may contribute to programmed CA1 cell death following ischemia.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Brain-derived neurotrophic factor prevents neuronal death and glial activation after global ischemia in the rat.

The expression of brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B are both increased after global ischemia. Therefore, a protective action of BDNF against the delayed degeneration of vulnerable neurons has been suggested. We have investigated the neuroprotective action of BDNF in global ischemia induced by a four-vessel occlusion in the rat. Following reperfusion, 0.06 microg/hr BDNF was continuously administered intracerebroventricularly with an osmotic minipump. Rats were sacrificed up to 7 days after ischemia and neuronal degeneration was identified by terminal transferase and biotin-dUTP nick end labeling (TUNEL) staining. Additionally, the glial reaction was investigated immunohistochemically and by measuring the activation of immunological nitric oxide synthase protein expression. Postischemic intracerebroventricular infusion of BDNF prevented neuronal death in the vulnerable CA1 region of the hippocampus. Additionally, astroglial activation and macrophage infiltration, which were observed in association with neuronal death, were inhibited by BDNF. This was paralleled by an inhibition of inducible nitric oxide synthase (iNOS) expression in the hippocampus. Thus, the observed neuroprotective effects of continuous BDNF administration after reperfusion suggest a therapeutic potential for BDNF in cerebral ischemia.

Animals↗

PubMed1999

Brain-derived neurotrophic factor improves long-term potentiation and cognitive functions after transient forebrain ischemia in the rat.

We investigated the effect of brain-derived neurotrophic factor (BDNF) on hippocampal long-term potentiation (LTP) and cognitive functions after global cerebral ischemia in the rat. After four-vessel occlusion, BDNF was administered via an osmotic minipump continuously over 14 days intracerebroventricularly. Electrophysiological experiments were performed 14 days after cerebral ischemia. Test stimuli and tetanization were delivered to the Schaffer collaterals of the hippocampus and field excitatory postsynaptic potentials (fEPSP) were recorded in the CA1 region. Cognitive impairment was analyzed repeatedly with a passive avoidance test, a hole-board test, and with an activity center on the same animal. In sham-operated animals, LTP was consistantly induced after delivering a tetanus (increase of initial slope of fEPSP to 173 +/- 12% of baseline; n = 6). After transient forebrain ischemia LTP could not be induced (117 +/- 4% of baseline; n = 7). In ischemic animals treated with BDNF, LTP could be induced (168 +/- 28% of baseline; n = 8). Transient forebrain ischemia resulted in a significant decrease in spatial discrimination performance but not of associative memory. The ratios for working memory (WM) and reference memory (RM) 15 days after ischemia were lower in the ischemic rats (n = 10) than in the sham-operated control animals (n = 10; WM: 22 +/- 6 vs 72 +/- 7; RM: 30 +/- 7 vs 72 +/- 5). Postischemic intracerebroventricular BDNF infusion increased both WM (63 +/- 4; n = 10) and RM (58 +/- 5; n = 10). The spontaneous locomotor activity did not differ significantly in the three groups. These data indicate a protective effect of BDNF for synaptic transmission and cognitive functions after transient forebrain ischemia.

Animals↗

PubMed1999

[Disease picture of myotonic muscular dystrophy in patients with large CTG triplet expansion].

Myotonic dystrophy is an autosomal dominant multisystem disorder involving muscle, brain, heart, eyes, and endocrine organs. The underlying mutation is an expanding trinucleotide CTG repeat in the 3'prime untranslated region of a serine-threonine kinase gene on chromosome 19q. A statistical correlation exists between the CTG copy number and the severity of the disease. Infants with severe congenital myotonic dystrophy have been shown to have on average a greater amplification of the CTG repeat than is seen in the non-congenital myotonic dystrophy population. However, not all patients with many CTG copies develop congenital myotonic dystrophy. We present 13 patients with more than 1500 CTG trinucleotide repeats and show their variable clinical course.

Adolescent↗

PubMed1999

[Moderate hypothermia for the treatment of malignant middle cerebral artery infarct].

Moderate hypothermia was induced in 30 patients with malignant middle cerebral artery (MCA) territory infarction. Patients were kept at 33 degrees C body-core temperature for 48 to 72 h, and ICP, CPP, and brain temperature were monitored. Outcome at 4 weeks and at 3 months after the stroke as well as side effects of moderate hypothermia were analysed. Mortality of malignant MCA infarction could be reduced from 80% in historical controls, to 43% (13/30) under hypothermia. During hypothermia elevated ICP values could be significantly reduced. Herniation due to a secondary rise of ICP after rewarming was the cause of death in all 13 patients. The most frequent complication of moderate hypothermia was pneumonia in 12 of the 30 patients (40%). Other severe side effects of hypothermia could not be detected. Moderate hypothermia may improve clinical outcome in patients with malignant MCA infarction.

Adolescent↗

PubMed1999

Inhibition of caspases prevents cell death of hippocampal CA1 neurons, but not impairment of hippocampal long-term potentiation following global ischemia.

An essential role for caspases in programmed neuronal cell death has been demonstrated in various in vitro studies, and synthetic caspase inhibitors have recently been shown to prevent neuronal cell loss in animal models of focal cerebral ischemia and traumatic brain injury, respectively. The therapeutic utility of caspase inhibitors, however, will depend on preservation of both structural and functional integrity of neurons under stressful conditions. The present study demonstrates that expression and proteolytic activity of caspase-3 is up-regulated in the rat hippocampus after transient forebrain ischemia. Continuous i.c.v. infusion of the caspase inhibitor N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone significantly attenuated caspase-3-like enzymatic activity, and blocked delayed cell loss of hippocampal CA1 neurons after ischemia. Administration of N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone, however, did not prevent impairment of induction of long-term potentiation in post-ischemic CA1 cells, suggesting that caspase inhibition alone does not preserve neuronal functional plasticity.

Animals↗

PubMed1999

Bradykinin induces interleukin-6 expression in astrocytes through activation of nuclear factor-kappaB.

Bradykinin, a mediator of inflammation, is produced in the brain during trauma and stroke. It is thought to open the blood-brain barrier, although the mechanism is unclear. We have investigated, therefore, the effect of bradykinin on the expression of interleukin-6 (IL-6), a putative modulator of the blood-brain barrier, in astrocytes. IL-6 gene transcription was evaluated by transient transfection of the human IL-6 promoter linked to the luciferase gene. In murine astrocytes, bradykinin stimulated IL-6 secretion and gene transcription. The effect of bradykinin was blocked by KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinases, and by bisindolylmaleimide I, an inhibitor of protein kinase C, suggesting the involvement of these protein kinases. Mutations in the multiple response element and the binding site for nuclear factor-kappaB (NF-kappaB), but not in other known elements of the IL-6 promoter, interfered with induction of IL-6 transcription. The involvement of NF-kappaB was supported further by the finding that overexpression of nmIkappaB alpha, a stable inhibitor of NF-kappaB, inhibited the induction of IL-6 by bradykinin. Bradykinin activated NF-kappaB in primary astrocytes as shown by increased DNA binding of NF-kappaB. These data demonstrate that bradykinin stimulates IL-6 expression through activation of NF-kappaB, which may explain several inflammatory effects of bradykinin.

Animals↗

PubMed1999

Familial hemiplegic migraine with cerebellar ataxia and paroxysmal psychosis.

Familial hemiplegic migraine is a rare autosomal dominant disorder associated with stereotypic neurologic aura phenomena including hemiparesis. So far two chromosomal loci have been identified. Families linked to the chromosome 19 locus display missense mutations within the CACNL1A4 gene. Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks. Based on the clinical and haplotype evidence indicating linkage to chromosome 19 in this family, we hypothesize that a dysfunction of the mutated calcium channel may be involved not only in the development of hemiplegic migraine but also in the acute psychotic episodes observed in these patients.

Adolescent↗

PubMed1999

Neurochemical monitoring of fatal middle cerebral artery infarction.

BACKGROUND: Microdialysis is a method for neurochemical monitoring that has been applied more frequently over the past few years in patients suffering from subarachnoid hemorrhage, acute brain injury, and stroke. It is used to study the course of extracellular molecules of low molecular weight, such as excitatory amino acids or metabolic end products. CASE DESCRIPTION: We report the case of a 43-year-old patient suffering from left hemispheric stroke with a space-occupying postischemic edema leading to a considerable mass effect on the contralateral side. For treatment of severe edema, hypothermia was initiated. The microdialysis and intracranial pressure probe were placed into the noninfarcted hemisphere. A massive increase in levels of glutamate, glycerine, and the lactate-pyruvate ratio was measured 24 hours before intracranial pressure elevation was observed and brain death occurred. CONCLUSIONS: Monitoring excitatory amino acids, glycerine as a membrane component, and lactate-pyruvate ratio as an energy marker by microdialysis is a useful tool to increase our understanding of biochemical events in secondary brain damage. For future prevention of secondary ischemia in patients with massive stroke, close neurochemical monitoring might be valuable to improve therapy, particularly in the critically ill.

Adult↗

PubMed1999

Thrombolysis in acute ischemic stroke: controlled trials and clinical experience.

Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) is approved in the United States for treatment of acute ischemic stroke. Approval was granted after a large, randomized, placebo-controlled study by the National Institute of Neurological Disorders and Stroke (NINDS) showed a significant improvement in 3-month outcomes with rtPA despite a significant risk for symptomatic hemorrhage. Two other trials, the first and second European Cooperative Acute Stroke Study (ECASS I and II), have shown comparable results, but neither was statistically positive for the predefined primary end point. An analysis of the risk/benefit profile of rtPA therapy based on the results of these three trials indicates that the treatment is effective and, when administered within 3 hours of symptom onset at a dose of 0.9 mg/kg, the benefits by far outweigh the risks for eligible patients. Even with the 6-hour time window of the two ECASS trials, a combined analysis of the three studies shows the number of disabled or dead patients to be significantly reduced. Preliminary data collected on the use of rtPA outside of clinical trials in the United States and Europe suggest that, when rtPA is used according to the trial protocol, the risks and benefits are similar to those observed in clinical trials. However, even within the United States, rtPA is underutilized. The most substantial treatment barrier is the narrow time window, which may be expanded if long-term experience shows that this is possible. Most stroke patients arrive at the hospital too late to be eligible for screening and treatment. Education of the public and physicians may help to overcome this difficulty.

Acute Disease↗

PubMed1998

Heparin inhibits induction of nitric oxide synthase by cytokines in rat brain microvascular endothelial cells.

The inflammatory reaction following ischemic brain injury involves bioactive mediators released mainly from leukocytes. The aim of this in vitro-study was to evaluate possible modulatory actions of heparin on nitric oxide synthesis induced by proinflammatory cytokines. Rat microvascular brain endothelial cells were isolated from adult rat brains and treated with interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta) with or without heparin. The expression of inducible nitric oxide synthase (iNOS) mRNA and the iNOS protein activity was analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Griess reagent, respectively. Heparin in a dose-dependent manner attenuated the increase in iNOS expression and NO release after cytokine activation. Thus, in addition to its anticoagulatory effect, heparin may also be effective in the prevention of inflammatory reaction after cerebral ischemia.

Animals↗

PubMed1998

Manganese augments nitric oxide synthesis in murine astrocytes: a new pathogenetic mechanism in manganism?

Since manganese (Mn2+) is known to be sequestered in glial cells, we investigated possible neurotoxic mechanisms involving astrocytes in vitro. Low concentrations of Mn2+ were toxic only in astrocyte-neuronal cocultures but not in pure astrocyte or neuronal cultures. As a possible mediator of manganese-derived neurotoxicity, we measured the production of nitric oxide in astrocytes. Manganese, but not other transition metals, dose dependently increased iNOS mRNA and protein levels and the release of nitric oxide in activated astrocytes. This effect was specific for astrocytes, since we observed no stimulation in microglial cells. The observations suggest that besides the known inhibition of mitochondrial function the neurotoxic effect of manganese in low concentrations might be mediated by the increased production of nitric oxide in astrocytes.

Animals↗

PubMed1998

["Paradoxical" herniation after decompressive trephining].

The intracranial space is divided into two large compartments by the tentorium. The hydrostatic pressure of spinal fluid is responsible for buoyancy of the brain within these compartments. In patients with craniectomy this equilibrium is exposed to atmospheric pressure. We report on four cases of reversible herniation after either bilateral or unilateral decompressive craniectomy performed for increased intracranial pressure (ICP) and failure of conservative ICP treatment. All four patients had survived a severe neurological disease (encephalitis, subdural haematoma, stroke) which required craniectomy to control raised ICP. All were successfully weaned from the ventilator and awake and CT scans showed no space-occupying lesion anymore. The patients showed a typical "sunken pattern" at the trepanation site. All patients developed clinical signs of transtentorial herniation (i.e. unilateral dilated pupils, deteriorated alertness, and extensor posturing) shortly after either diagnostic or presumed therapeutic lumbar puncture. One patient developed herniation a second time while in the typical 30 degrees upright position. After craniectomy, transtentorial herniation is possible even in the absence of increased ICP. It is related to a negative gradient between atmospheric and intracranial pressure, which is enhanced by changes in the CSF compartment following lumbar puncture. Lumbar puncture should be avoided if possible and, when necessary, only be performed in the head-down position. Acute therapy in these cases is quite simple; it requires flat or even head-down positioning and early cranioplasty.

Adult↗

PubMed1998

Acute ischaemic stroke: revascularizing therapy. Stroke Council of the American Heart Association.

The principal goals of thrombolytic therapy for stroke are early restitution of cerebral blood flow, reduction of ischaemia, and attenuation of neurological disability through lysis of an occluding thrombus and consequent rapid restoration of circulation in the affected territory. Therapy should be initiated as soon as possible, at least within 4-6 h of stroke onset, to prevent major infarction and to salvage the hypoperfused but potentially viable zone adjacent to the central ischaemic area known as the ischaemic penumbra. This survey focuses on the safety and efficacy of thrombolytic therapy in acute ischaemic stroke in clinical trials. The results of two successful major randomized studies using tissue plasminogen activator (t-PA) were recently published. Intravenous thrombolysis seemed to be effective in improving functional and neurological outcome in a clearly defined subgroup of patients meeting the inclusion criteria of the studies. However, the identification of those patients proved to be difficult and depended on expertise in recognizing the early infarction signs on initial computed tomography. Since treating ineligible patients is associated with an unacceptable risk of intracranial bleeding complications and death, intravenous thrombolysis should only be performed at selected centres in selected patients.

Cerebral Revascularization↗

PubMed1998

Reoxygenation increases the release of reactive oxygen intermediates in murine microglia.

Respiratory burst activity of murine microglial cells was investigated in vitro under normoxic and hypoxic conditions with a chemoluminometric assay. Hypoxia for 24 hours reduced the release of extracellular reactive oxygen intermediates (ROIs), whereas reoxygenation increased the chemoluminescence more than sevenfold. Blockade of potassium channels inhibited the increase of oxidative burst after reoxygenation, indicating that potassium ions, which were increased in the supernatant of hypoxic microglial cells, were involved in this activation process. Also, blockade of voltage-gated calcium channels with nifedipine attenuated the increased release of ROIs. With fura-2 analysis, it was shown that the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by potassium ions was mediated by calcium influx via voltage-gated calcium channels. Thus, influx of calcium ions through voltage-gated channels activates the NADPH oxidase in microglial cells during reoxygenation. By the increased production of ROIs, microglial cells may add to the reperfusion injury after ischemia in vivo.

Animals↗

PubMed1998

Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction.

BACKGROUND AND PURPOSE: Animal research and clinical studies in head trauma patients suggest that moderate hypothermia may improve outcome by attenuating the deleterious metabolic processes in neuronal injury. Clinical studies on moderate hypothermia in the treatment of acute ischemic stroke patients are still lacking. METHODS: Moderate hypothermia was induced in 25 patients with severe ischemic stroke in the middle cerebral artery (MCA) territory for therapy of postischemic brain edema. Hypothermia was induced within 14+/-7 hours after stroke onset and achieved by external cooling with cooling blankets, cold infusions, and cold washing. Patients were kept at 33 degreesC body-core temperature for 48 to 72 hours, and intracranial pressure (ICP), cerebral perfusion pressure, and brain temperature were monitored continuously. Outcome at 4 weeks and 3 months after the stroke was analyzed with the Scandinavian Stroke Scale (SSS) and Barthel index. The side effects of induced moderate hypothermia were analyzed. RESULTS: Fourteen patients survived the hemispheric stroke (56%). Neurological outcome according to the SSS score was 29 (range, 25 to 37) 4 weeks after stroke and 38 (range 28 to 48) 3 months after stroke. During hypothermia, elevated ICP values could be significantly reduced. Herniation caused by a secondary rise in ICP after rewarming was the cause of death in all remaining patients. The most frequent complication of moderate hypothermia was pneumonia in 10 of the 25 patients (40%). Other severe side effects of hypothermia could not be detected. CONCLUSIONS: Moderate hypothermia in the treatment of severe cerebral ischemia is not associated with severe side effects. Moderate hypothermia can help to control critically elevated ICP values in severe space-occupying edema after MCA stroke and may improve clinical outcome in these patients.

Adult↗