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Biomedical subjects

M Holzer

Publications and source records attributed to M Holzer.

At least 55 records · Page 3Linked to original sources
PubMed1999

Time course of serum neuron-specific enolase. A predictor of neurological outcome in patients resuscitated from cardiac arrest.

BACKGROUND AND PURPOSE: The prediction of neurological outcome in comatose cardiac arrest survivors has enormous ethical and socioeconomic implications. The purpose of the present study was to investigate the prognostic relevance of the time course of serum neuron-specific enolase (NSE) as a biochemical marker of hypoxic brain damage. METHODS: Serial analysis of serum NSE levels was performed in 56 patients resuscitated from witnessed, nontraumatic, normothermic, in- or out-of-hospital cardiac arrest. The neurological outcome was evaluated with the use of the cerebral performance category (CPC) within 6 months after restoration of spontaneous circulation (ROSC). The Mann-Whitney U test was used to compare patients with good (CPC 1 to 2) and bad (CPC 3 to 4) neurological outcome. The diagnostic performance at different time points after ROSC was described in terms of areas under receiver operating characteristic curves according to standard methods. RESULTS: Patients with a bad neurological outcome (CPC 3 to 4) had significantly higher NSE levels than those with a good neurological outcome at 12 (P=0.004), 24 (P=0.04), 48 (P<0.001), and 72 hours (P<0.001) after ROSC. The maximum NSE level measured within 72 hours after ROSC was also significantly higher in patients with a bad neurological outcome (P<0.001). The NSE value at 72 hours after ROSC was the best predictor of neurological outcome (area under the curve=0.92+/-0.04). In addition, we also found a significant difference in the time course of NSE concentrations during the first 3 days after ROSC. CONCLUSIONS: Serum NSE levels are valuable adjunctive parameters for assessing neurological outcome after cardiac arrest.

Adolescent↗
PubMed1998

Cumulative epinephrine dose during cardiopulmonary resuscitation and neurologic outcome.

BACKGROUND: Epinephrine is the drug of choice in advanced cardiac life support, but it can have deleterious side effects after restoration of spontaneous circulation. OBJECTIVE: To investigate the association between the cumulative epinephrine dose used in advanced cardiac life support and neurologic outcome after cardiac arrest. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENTS: Adults admitted to the emergency department with witnessed, nontraumatic, normothermic ventricular fibrillation cardiac arrest and unsuccessful initial defibrillation. MEASUREMENTS: Functional neurologic outcome was regularly assessed by cerebral performance category (CPC) within 6 months after cardiac arrest. A CPC of 1 or 2 was defined as favorable recovery. RESULTS: Among 178 enrolled patients, the median cumulative epinephrine dose administered was 4 mg (range, 0 to 50 mg). In 151 patients (84%), spontaneous circulation was restored; 63 of these 151 patients (42%) had favorable neurologic recovery. Patients with an unfavorable CPC received a significantly higher cumulative dose of epinephrine than did patients with a favorable CPC (4 mg compared with 1 mg; P < 0.001). This finding persisted after stratification by duration of resuscitation. After possible cofounders were controlled for, the cumulative epinephrine dose remained an independent predictor of unfavorable neurologic outcome. CONCLUSIONS: The results indicate that an increasing cumulative dose of epinephrine administered during resuscitation is independently associated with unfavorable neurologic outcome after ventricular fibrillation cardiac arrest.

Adrenergic Agonists↗
PubMed1998

Aberrancies in signal transduction and cell cycle related events in Alzheimer's disease.

Neurodegeneration in Alzheimer's disease (AD) is associated with the appearance of dystrophic neuronal growth profiles that most likely reflects an aberrant attempt of neuronal repair. This process of neuronal reorganisation, which eventually goes awry and becomes a disease itself, might be initiated physiologically as a response to neuronal injuries. Minor neuronal damage due to a variety of life events or genetic pertubations that are usually compensated in the normal adult brain by adaptation and repair might thus be amplified and accumulated, thereby resulting in a progressive neurodegeneration. The present paper summarizes recent evidence supporting the hypothesis that a primary impairment of intracellular signal transduction that is mediated by a hierarchy of phosphorylation signals and associated with a aborted attempt of neurons to re-enter the cell-cycle is a key element in the pathomechanism of AD. These changes might result in malfunction of neuronal adaptation and repair and eventually lead to neuronal death. During the process of aging as well as in chronic neurodegenerative disorders such as Alzheimer's disease (AD), the continuous but rather slow action of pathogenetic factors might give room for the activation of compensatory mechanisms, serving to regain a neuronal population much of its synaptic connectivity in the presence of cell loss. An upregulation in the capacity to synthesize and store neurotransmitters (Lapchak et al., 1991), an increased expression of trophic factors (Hellweg et al., 1990; Arendt et al., 1995a,b), as well as regenerative sprouting (Fritschy and Grzanna, 1992), synaptic enlargement (Scheff et al., 1990; Lippa et al., 1992), and neosynaptogenesis (Ramirez and Ulfhake, 1992) have been described among other processes.

Adult↗
PubMed1998

Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer's disease.

Neurodegeneration and cell death in Alzheimer's disease might be associated with aberrant proliferative mechanisms and activation of cell-cycle related events. We reported previously on the elevated expression of the cyclin dependent kinase inhibitor p16INK4a in Alzheimer's disease closely associated with neurofibrillary degeneration. In the present study, we demonstrate that other members of the INK4-family of cyclin dependent kinase inhibitors such as p15INK4b, p18INK4c and p19INK4d that bind directly to cdk4/6 or to complexes of cdk4/6 with D-type cyclins are all elevated. In contrast, no indication of altered expression of the cyclin dependent kinase inhibitors p21Cip1 and p27Kip1 were observed. Inhibitors of the INK4-family were strongly expressed in tangle-bearing neurones and neuritic components of plaques. A much lower expression was also seen in astrocytes. These findings add further evidence to the suggestion that a dysfunction of cell cycle regulation is of critical importance in the pathomechanism of Alzheimer's disease.

Aged↗
PubMed1998

The influence of chronic prearrest health conditions on mortality and functional neurological recovery in cardiac arrest survivors.

PURPOSE: To study the impact of chronic prearrest health conditions on mortality and neurological recovery in patients after witnessed cardiac arrest and primary successful resuscitation. PATIENTS AND METHODS: The study was set in the community of Vienna, Austria. Data concerning cardiopulmonary resuscitation of adult patients who survived a witnessed cardiac arrest were collected according to an internationally recommended protocol (Utstein-Style). Chronic prearrest health conditions and New York Heart Association (NYHA) functional classes were evaluated. All patients were followed up for 6 months after the event or death. Adverse outcome was defined as death or severe neurological impairment. A forward stepwise logistic regression model was applied to assess the impact of pre-arrest morbidity on unfavorable outcome, expressed as odds ratio (OR) with 95% confidence intervals (CI). RESULTS: Of 411 patients, 269 (66%) had one or more of the following pre-arrest diseases: coronary heart disease (45%), hypertension (26%), congestive heart failure (20%), diabetes mellitus (14%), chronic pulmonary disease (6%), and cerebrovascular disease (5%). In 22% a NYHA class of III or IV was present before cardiac arrest. At 6-month follow-up, 161 (40%) of the patients were alive with favorable neurological recovery; overall mortality was 57% (n = 233). Increasing NYHA classes (OR 1.4 per NYHA class increase; CI 1.1 to 1.7) and increasing age were independent predictors of adverse outcome (OR 1.03 per 10-year increase; CI 1.01 to 1.05), as were durations of cardiac arrest (OR 1.10 per 5-minute increase; CI 1.07 to 1.12) and the presence of ventricular fibrillation or tachycardia (OR 0.3; CI 0.2 to 0.5). The remaining health conditions, as listed above, were not independently associated with outcome. CONCLUSIONS: A large proportion of patients with cardiac arrest had chronic diseases before the event. The presence of impaired functional performance in patients with structural heart disease increased unfavorable outcome within 6 months in primary cardiac arrest survivors. However, the impact of chronic prearrest conditions on outcome seems to be very small, and should not influence decisions whether to withhold or withdraw therapy.

Aged↗
PubMed1998

Percutaneous cardiopulmonary bypass for therapy resistant cardiac arrest from digoxin overdose.

A 79-year 65 kg male called the ambulance service 4 h after ingestion of 100 tablets of digoxin 0.1 mg complaining of nausea and vomiting. The ECG showed an idioventricular escape rhythm with a heart rate of 30/min. After 0.5 mg atropine, heart rate increased to 80/min. Soon after admission to the emergency department, the patient developed electromechanical dissociation. Due to persistent cardiac arrest, percutaneous cardiopulmonary bypass was started, and the ECG rhythm changed to ventricular fibrillation. Several attempts to terminate ventricular fibrillation by electrical defibrillation failed. Fifty-eight minutes after cardiac arrest, antidigoxin-Fab was administered and 1 h 25 min after cardiac arrest, ventricular fibrillation was terminated by the tenth electrical defibrillation attempt. Initially, the patient's overall status improved over the next 2 days, but then he developed a severe adult respiratory distress syndrome and died of unresponsive septic shock 12 days after ingestion of digoxin. This case demonstrates that percutaneous cardiopulmonary bypass may provide support in patients with cardiac arrest due to massive digoxin overdose. This temporary support can maintain adequate tissue perfusion during the time required for drug neutralization in order to achieve successful defibrillation. Percutaneous cardiopulmonary bypass should be considered in patients with severe, but temporary cardiac dysfunction due to a life-threatening drug overdose.

Aged↗
PubMed1998

Reversible in vivo phosphorylation of tau induced by okadaic acid and by unspecific brain lesion in rat.

Alzheimer's disease (AD) is histopathologically characterised by the formation of neurofibrillary tangles (NFTs) that are largely composed of hyperphosphorylated tau protein (PHF-tau), and senile plaques which contain aggregates of the Abeta peptide. Formation of PHF-tau and amyloidogenic processing of the amyloid precursor protein (APP) might be related to a disturbance in the balance between protein phosphorylation and dephosphorylation. In the present study, the effects of injections into the cerebral cortex of either okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A, or saline were investigated. Both kinds of injections induced a reversible phosphorylation of tau, albeit to a different extent. The secretion of soluble APP was reduced after OA but not affected after injection of saline. It is concluded that phosphorylation of tau, similar though not identical to those seen in AD can be induced in vivo by inhibition of protein dephosphorylation as well as by unspecific lesion of cortical neurones. It might, therefore, be suggested that phosphorylation processes involved in PHF-formation in AD similarly reflect a neuronal response to injury.

Animals↗
PubMed1997

Blot analyses and immunocytochemistry of neural antigens with digoxigenylated primary and secondary antibodies.

While the digoxigenin-anti-digoxigenin (DIG) method is currently the preferred tool for non-radioactive in situ hybridization this study extends its application field to Western blotting of proteins and summarizes advantageous properties of digoxigenylated antibodies in immunocytochemistry. An established protocol for the preparation of digoxigenylated primary antibodies is complemented by dot blot analyses confirming the high sensitivity of hapten-anti-hapten techniques based on primary digoxigenylated antibodies. The comparative Western blot analysis of calcium-binding proteins in nervous tissue is used as an example to show the highly specific detection of relevant antigens with unmodified primary antibodies, digoxigenylated secondary antibodies and anti-digoxigenin-peroxidase conjugates. The application of the DIG technology seems to be especially indicated in tissues containing high amounts of endogenous biotin-bearing proteins which might induce false-positive staining in conventional streptavidin/biotin techniques. Finally, the previously shown suitability of digoxigenylated antibodies for different immunocytochemical procedures is completed here by examples for sensitive single immunoperoxidase staining of neural markers in rat brain and for carbocyanine double immunofluorescence labelling of senile plaques in old rhesus monkeys.

Animals↗
PubMed1996

Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer's disease.

Recent evidence indicates that an impairment of neuronal adaptive and reparative processes might be a key feature of the pathomechanism of Alzheimer's disease. Aberrations in the reparative neuronal response are likely to result from alterations of intracellular signal transduction cascades. As a consequence of abnormal intracellular signalling, the activation of those molecular events might be triggered in neurones which, in dividing cells, would lead to cellular transformation. In the present study, changes in the expression of the cyclin-dependent kinase inhibitor p16, a regulator of the orderly progression through the cell cycle, were investigated by immunocytochemical methods in the temporal cortex of patients with Alzheimer's disease. Both neurofibrillary tangles and neuritic components of plaques showed strong p16 immunoreactivity. These findings support the hypothesis that an aborted attempt of terminally differentiated neurones to re-enter the cell cycle might be a critical event in the pathology of Alzheimer's disease.

Aged↗
PubMed1996

Distribution of isoforms of the microtubule-associated protein tau in grey and white matter areas of human brain: a two-dimensional gelelectrophoretic analysis.

The microtubule-associated protein tau in human brain consists of six molecular isoforms derived from a single gene by alternative mRNA-splicing and further modified by posttranslational processing. In the present study, the distribution of tau isoforms in grey and white matter of human temporal cortex was investigated by two-dimensional gelelectrophoresis. More than 80 isoforms were detected. The pattern of isoforms obtained after treatment with alkaline phosphatase was still more complex than those of recombinant tau, indicating that posttranslational modifications other than phosphorylation contribute to the molecular heterogeneity of tau. The tau isoform D according to Goedert containing four tubulin-binding regions shown to promote tubulin polymerisation most efficiently was present in higher amounts in white as compared to grey matter. The pattern of isoform distribution was not significantly altered in Alzheimer's disease. It is concluded that molecular isoforms that differ in their tubulin-binding characteristics are differentially distributed in subcellular neuronal compartments and/or neuronal types.

Alzheimer Disease↗
PubMed1996

An aqueous endpoint assay of snake venom phospholipase A2.

Phospholipase A2 (PLA2), an enzyme found in most snake venoms, catalyzes the hydrolysis of phospholipids in biological membranes, and some have presynaptic neurotoxic activity. A synthetic substrate, 4-nitro-3-(octanoyloxy)benzoic acid, was synthesized and purified on a silica gel column using a published method. This substrate was used to develop an endpoint assay which is rapid and requires a minimum of equipment. This aqueous assay system allowed enzyme activity to be examined without the use of radioactive substrates or organic solvents, minimizing waste disposal concerns. Whole venoms, partially purified enzyme isolated from Crotalus mitchelli pyrrhus venom, tissue extracts and commercial preparations were employed as sources of PLA2. Results show that this method is a convenient and specific assay for PLA2 from several sources and is particularly suited for assaying large numbers of fractions generated during purification procedures.

Animals↗
PubMed1995

Induction of p21ras in Alzheimer pathology.

Changes in the expression of the small G-protein p21ras, a critical regulator of cell proliferation and differentiation, were investigated by immunohistochemical methods in the temporal cortex of patients with Alzheimer's disease. In both normal brain and in Alzheimer's disease, the H-ras, K-ras and N-ras gene products were equally detected in almost all neurones and occasionally also in glial cells. In Alzheimer's disease an increased expression of p21ras was observed within neuritic plaques as well as in neurones and glial cells closely associated with plaques. Neurones containing tangle-bearing material also showed a high level of expression. It is suggested that activation of p21ras dependent signalling pathways are involved in the processes of neurodegeneration and/or aberrant repair in Alzheimer's disease.

Aged↗
PubMed1995

Digoxigenylated primary antibodies for sensitive dual-peroxidase labelling of neural markers.

This study extends the application of the digoxigenin-anti-digoxigenin (DIG) technique to immunocytochemistry by using digoxigenin-tagged primary antibodies. Certain features of this technique when applied to non-radioactive in situ hybridization, such as the absence of endogeneous digoxigenin immunoreactivity in animal tissues, seem to be advantageous also for its application to immunocytochemistry. Thus, the present work is focused on dual-peroxidase staining experiments based on digoxigenylated antibodies directed against glial fibrillary acidic protein, parvalbumin, and calbindin, in a straightforward combination with conventional cytochemical methods. The protocols include the concomitant detection of two antigens, for which only primary antibodies from one animal species are available, with differently haptenized antibodies (e.g., biotinylated anti-calbindin and digoxigenylated anti-parvalbumin). The versatility of the DIG technique is exemplified by the combination of lectin and immunocytochemical procedures for the detection of astrocytes and microglia, and the simultaneous visualization of perineuronal nets and parvalbumin-containing neurons in the rat brain.

Animals↗
PubMed1995

Increased expression and subcellular translocation of the mitogen activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer's disease.

The sequential activation of the mitogen-activated protein kinase kinase and its substrate, the mitogen-activated protein kinase is involved in a cascade of protein kinases which link a number of cell surface signals to intracellular changes in enzyme activity and gene expression. In vitro, mitogen-activated protein kinase is able to phosphorylate the microtubule-associated protein tau at Ser-Pro and Thr-Pro sites, thereby generating abnormally hyperphosphorylated tau species that are similar to paired helical filament-tau found in Alzheimer's disease. In the present study, we analysed the levels of immunoreactive mitogen-activated protein kinase kinase and mitogen-activated protein kinase in the temporal cortex (area 22) of patients with Alzheimer's disease by means of enzyme-linked immuno-sorbent assays and compared these changes with the content of abnormally phosphorylated paired helical filament-tau. The levels of immunochemically detected mitogen-activated protein kinase kinase and mitogen-activated protein kinase were both increased in Alzheimer's disease by between 35 and 40% compared with age-matched controls. Elevation of mitogen-activated protein kinase kinase was most pronounced during early stages of Alzheimer's disease and was inversely related to the tissue content of abnormally phosphorylated paired helical filament-tau. Pronounced immunoreactivity of mitogen-activated protein kinase kinase and mitogen-activated protein kinase was present in both tangle bearing neurons and unaffected neurons of the temporal cortex. Immunoreactive neurons were most often localized in the direct vicinity of neuritic plaques. In Alzheimer's disease, the subcellular distribution of mitogen-activated protein kinase kinase and mitogen-activated protein kinase showed a striking translocation from the cytoplasmic to the nuclear compartment. It is suggested that the activation of the mitogen-activated protein kinase cascade which appears to be an early feature of Alzheimer's disease might be critically involved in self-stimulating processes of neurodegeneration and aberrant repair under these conditions.

Aged↗
PubMed1995

Paired helical filament-like phosphorylation of tau, deposition of beta/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A.

Alzheimer's disease is histopathologically characterized by neurofibrillary tangles, formed by the abnormally high phosphorylated tau protein, and senile plaques which largely consist of the beta/A4-amyloid peptide. Metabolism of the amyloid precursor protein and its processing into beta/A4-amyloid is regulated by protein phosphorylation. Thus, an imbalance between protein phosphorylation and dephosphorylation might be crucial for the development of the molecular hallmarks of Alzheimer's disease. We report here that chronic infusion into rat brain ventricles of okadaic acid, a specific inhibitor of the serine/threonine protein phosphatases 1 and 2A, results in a severe memory impairment, accompanied by a paired helical filament-like phosphorylation of tau protein and the formation of beta/A4-amyloid containing plaque-like structures in gray and white matter areas.

Amyloid beta-Peptides↗