Biomedical subjects
Publications and source records attributed to M Holzer.
Protected mercaptoalkylpyrimidinones: synthesis and test for immunostimulating activity 3-Hydroxyalkyl-pyrimidine 1 reacts with phosphoroxychloride and thioglycolic acid or thiourea to yield pyrimidin-3-ylalkylthioacetic acids 3 or pyrimidin-3-ylalkylthiouroniumsalts 5 respectively. Some of the pyrimidines 3 and 5 showed immunomodulatory activity.
Filamentous tau protein deposits are a pathological hallmark of a group of neurodegenerative disorders (tauopathies). Tau protein in these aggregates is highly phosphorylated at different phosphorylation sites. Although tau filaments can be formed by heparin-induced aggregation of unphosphorylated recombinant tau, it is not known how tau phosphorylation modulates aggregation behaviour. Analysis of the effect of tau phosphorylation at defined single or multiple sites is hampered by the low specificity of protein kinases and the highly dynamic turnover of phosphorylation in vivo. To overcome this problem we employed site-directed mutagenesis to convert serine and threonine to aspartic acid or glutamic acid, which introduce a negative charge and conformational change that mimic phosphorylation. We tested 14 different mutated tau proteins for their propensity for self-aggregation and formation of tau filaments. Tau aggregation was monitored with thioflavin S fluorescence in the presence of different inducers such as heparin, Al3+, Fe2+ and Fe3+. We found that mutations in the N-terminal portion up to amino acid 208 mainly suppress tau aggregation, whereas mutations in the C-terminal region mainly lead to an enhanced aggregation. Mutations in the middle portion of tau showed a mixed picture of suppression and enhancement of aggregation. A single amino acid change Ser422Glu has aggregation-favouring properties with all four inducers.
The effects of various compounds on the aerobic stability of silages were evaluated. It has been observed that inoculation of whole-crop maize with homofermentative lactic acid bacteria leads to silages which have low stability against aerobic deterioration, while inoculation with heterofermentative lactic acid bacteria, such as Lactobacillus brevis or Lactobacillus buchneri, increases stability. Acetic acid has been proven to be the sole substance responsible for the increased aerobic stability, and this acid acts as an inhibitor of spoilage organisms. Therefore, stability increases exponentially with acetic acid concentration. Only butyric acid has a similar effect. Other compounds, like lactic acid, 1,2-propanediol, and 1-propanol, have been shown to have no effect, while fructose and mannitol reduce stability.
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OBJECTIVE: the aim of the study is to investigate the effect of thrombolytic therapy on neurological outcome in patients after cardiac arrest due to acute myocardial infarction. Laboratory investigations have demonstrated that thrombolytic therapy after cardiopulmonary resuscitation improves neurological function. METHODS: from July 1991 to June 1996, patients with witnessed ventricular fibrillation cardiac arrest due to acute MI and successful restoration of spontaneous circulation admitted to the emergency department were analyzed retrospectively. A logistic regression model was used to assess the association between thrombolytic therapy and neurological outcome [best cerebral performance category (CPC) within 6 months after cardiac arrest]. RESULTS: all 157 patients [median age 57 years (IQR 50-69)] were analyzed. Thrombolytic therapy was applied in 42 patients (27%). With thrombolytic therapy good functional neurological recovery (CPC 1 or 2) was achieved more frequently (69 vs. 50%, P=0.03). After controlling for age, prehospital dosage of epinephrine, and the duration of cardiac arrest we found a non significant trend towards good neurological recovery when thrombolytic therapy was given (OR 1.9, 95% CI 0.8-4.6). CONCLUSION: thrombolytic therapy after cardiac arrest due to acute myocardial infarction is associated with improved neurological outcome.
Cell-cycle dysregulation might be critically involved in the process of neurodegeneration in Alzheimer's disease (AD). We now provide evidence for a dysfunction of the cell division cycle as a more general cellular phenomenon of the disease. Peripheral blood lymphocytes, stimulated with mitogenic compounds, were less able to express CD69, an early proliferation marker, in AD patients than in age-matched controls. Expression levels of CD69 of both T-cells and B-cells correlated inversely with the Mini-mental Scale. The results suggest that a systemic failure of cellular proliferation control might be of critical importance for the pathomechanism of AD.
The nitric oxide-synthesizing enzyme nitric oxide synthase (NOS) is present in the mammalian brain in three different isoforms, two constitutive enzymes (i.e., neuronal, nNOS, and endothelial eNOS) and one inducible enzyme (iNOS). All three isoforms are aberrantly expressed in Alzheimer's disease giving rise to elevated levels of nitric oxide apparently involved in the pathogenesis of this disease by various different mechanisms including oxidative stress and activation of intracellular signalling mechanisms. It still is a matter of debate, however, whether the abnormal expression of NOS isoforms has some primary importance in the pathogenetic chain and might thus be a potential therapeutic target or only reflects a secondary effect that occurs at more advanced stages of the disease process. To tackle this question, we analysed the expression of both eNOS and iNOS in patients with sporadic AD, in transgenic mice expressing human amyloid precursor protein (APP) with the Swedish double mutation under control of the Thy1 promotor (APP23 mice), and after electrolytic cortical lesion in rat, an experimental paradigm associated with elevated expression of APP. In all three conditions, an astrocytosis was induced accompanied by a strong increase of both iNOS and eNOS. Both NOS isoforms were frequently though not always colocalized. Thus, based on the expression pattern of NOS isoforms three types of astrocytes, expressing only one of the two isoforms or both together could be distinguished. In both AD and transgenic mice eNOS-expressing astrocytes exceeded iNOS-expressing astrocytes in number. Astrocytes with elevated levels of iNOS or eNOS were constantly seen in direct association with Abeta-deposits in AD and transgenic mice and were found in the vicinity of the lesion site in the rat cortex. The results of the present study show that expression of both iNOS and eNOS is increased in activated astrocytes under experimental conditions associated with elevated expression of APP (electrolytic brain lesion) or Abeta-deposition (APP23 transgenic mice). Therefore, it is suggested that altered expression of these NOS isoforms being part of AD pathology is secondary to the amyloid pathology and might not be primarily involved in the pathogenetic chain though it might contribute to the maintenance, self-perpetuation and progression of the neurodegenerative process.
BACKGROUND: Moderate elevation of brain temperature, when present during or after ischemia, may markedly worsen the resulting injury. OBJECTIVE: To evaluate the impact of body temperature on neurologic outcome after successful cardiopulmonary resuscitation. METHODS: In patients who experienced a witnessed cardiac arrest of presumed cardiac cause, the temperature was recorded on admission to the emergency department and after 2, 4, 6, 12, 18, 24, 36, and 48 hours. The lowest temperature within 4 hours and the highest temperature during the first 48 hours after restoration of spontaneous circulation were recorded and correlated to the best-achieved cerebral performance categories' score within 6 months. RESULTS: Over 43 months, of 698 patients, 151 were included. The median age was 60 years (interquartile range, 53-69 years); the estimated median no-flow duration was 5 minutes (interquartile range, 0-10 minutes), and the estimated median low-flow duration was 14.5 minutes (interquartile range, 3-25 minutes). Forty-two patients (28%) underwent bystander-administered basic life support. Within 6 months, 74 patients (49%) had a favorable functional neurologic recovery, and a total of 86 patients (57%) survived until 6 months after the event. The temperature on admission showed no statistically significant difference (P =.39). Patients with a favorable neurologic recovery showed a higher lowest temperature within 4 hours (35.8 degrees C [35.0 degrees C-36.1 degrees C] vs 35.2 degrees C [34.5 degrees C-35.7 degrees C]; P =.002) and a lower highest temperature during the first 48 hours after restoration of spontaneous circulation (37.7 degrees C [36.9 degrees C-38.6 degrees C] vs 38.3 degrees C [37.8 degrees C-38.9 degrees C]; P<.001) (data are given as the median [interquartile range]). For each degree Celsius higher than 37 degrees C, the risk of an unfavorable neurologic recovery increases, with an odds ratio of 2.26 (95% confidence interval, 1.24-4.12). CONCLUSION: Hyperthermia is a potential factor for an unfavorable functional neurologic recovery after successful cardiopulmonary resuscitation.
OBJECTIVE: To assess the validity of early sensory evoked potential (SEP) recording for reliable outcome prediction in comatose cardiac arrest survivors within 48 h after restoration of spontaneous circulation (ROSC). DESIGN AND SETTING: Prospective cohort study in a medical intensive care unit of a university hospital. PATIENTS: Twenty-five comatose, mechanically ventilated patients following cardiopulmonary resuscitation MEASUREMENTS AND RESULTS: Median nerve short- and long-latency SEP were recorded 4, 12, 24, and 48 h after ROSC. Cortical N20 peak latency and cervicomedullary conduction time decreased (improved) significantly between 4, 12, and 24 h after resuscitation in 22 of the enrolled patients. There was no further change in short-latency SEP at 48 h. The cortical N70 peak was initially detectable in seven patients. The number of patients with increased N70 peak increased to 11 at 12 h and 14 at 24 h; there was no further change at 48 h. Specificity of the N70 peak latency (critical cutoff 130 ms) increased from 0.43 at 4 h to 1.0 at 24 h after ROSC. Sensitivity decreased from 1.0 at 4 h to 0.83 at 24 h after ROSC. CONCLUSION: Within 24 h after ROSC there was a significant improvement in SEP. Therefore we recommend allowing a period of at least 24 h after cardiopulmonary resuscitation for obtaining a reliable prognosis based on SEP.
OBJECTIVE: To evaluate the effects of basic life support, time to first defibrillation and emergency medical service arrival time on neurologic outcome and expenses for hospital care in patients after cardiac arrest. SETTING: Large urban emergency medical services system and emergency department in a 2000-bed university hospital. DESIGN: Outcome and cost benefit analysis of patients admitted to the hospital after witnessed, out-of-hospital, ventricular fibrillation cardiac arrest from October 1, 1991, until December 31, 1997. PATIENTS: Out of 1054 patients with out-of-hospital cardiac arrest, 276 were eligible. MEASUREMENTS AND RESULTS: The effects of basic and advanced life support measures on neurologic outcome and hospital expenses were evaluated. In contrast to intubation (odds ratio 1.08; 95% CI: 0.51-2.31; p=0.84), basic life support (odds ratio 0.44; 95% CI: 0.24-0.77; p=0.004) and time to first defibrillation (odds ratio 1.08; 95% CI: 1.03-1.13; p=0.001) were significantly correlated with good neurologic outcome. Among the patients who did not receive basic life support, the average cost per patient with good neurologic outcome significantly increased with the delay of the first defibrillation (p<0.001). CONCLUSIONS: In contrast to intubation, bystander basic life support and time to first defibrillation were significantly associated with good neurologic outcome and resulted in fewer expenses spent on in-hospital efforts.
OBJECTIVE: The components of the 'chain of survival' remain the strongest pathway to save more people from out-of-hospital cardiac arrest. The 'Utstein Style' terminology has been applied to this study to evaluate survival in patients cared for by Emergency Medical Technicians--Defibrillation (EMT-D) and physicians in a rural alpine area. METHODS: Over a 6-year period in a descriptive observational study with prospective data collection special efforts were made to identify weaknesses in the 'links' of our emergency cardiac care system considering the special geographical and legal aspects. Data from all emergency calls dispatched by the ambulance centre for patients with cardiac arrest were collected and are presented as a median and interquartile range. RESULTS: We recorded 368 cardiac arrests and in 338 patients resuscitation was attempted. Ventricular fibrillation (VF) was observed in 118 patients (35%), of whom 13 (4%) were defibrillated by EMT-Ds and 105 (31%) by physicians. Response times were 1 (0,2) min to call, 8 (6-11) min to arrival of first tier and 16 (10-26) min to defibrillation. Restoration of spontaneous circulation was achieved in 54 (46%) VF-patients. In EMT-D vs. physician treated VF-patients 1 year survival was 1 (8%) versus 20 (19%). CONCLUSION: With the exception of publications on avalanche victims and mountaineers, there are no reports of patients with out-of-hospital cardiac arrest in alpine areas. Response intervals and survival rate are not as poor as might be expected and are similar to metropolitan areas.
Alterations in the phosphorylation state of the microtubule-associated protein tau have been associated with the pathogenesis of neurofibrillary degeneration as well as with a neuroprotective action against apoptotic cell death. Mitogen-activated protein kinases (MAPK) phosphorylate tau protein in vitro but the pathophysiological significance of this tau phosphorylation and its effects on neuronal viability is far from clear. Moreover, an in vivo model of activation of MAPK, a key candidate for in vivo tau phosphorylation, is still lacking. The aim of the present study and the accompanying paper was to establish an animal model of stimulated MAPK and to analyse the consequences on tau phosphorylation and the neuronal cytoskeleton. We took advantage of transgenic mice with neurone-specific expression of activated ras protein (p21H-ras(Val12)). The expression of the transgene in these animals is forced to a subset of neurones by the use of the synapsin I promoter. Activity of B-raf was elevated by 37%, while activity of MAPK (ERK1/ERK2) was increased by 25% associated with a subcellular redistribution from the cytoplasmic to the nuclear compartment. Kinases downstream of MAPK such as p90rsk and glycogen synthase kinase 3beta were only marginally affected. Activity of p70S6 kinase was unaltered. The present model might be useful to study the effects of activation of the MAPK cascade on tau phosphorylation and its cell biological sequelae.
In the present study, we analysed changes in the expression, subcellular distribution and phosphorylation state of the microtubule-associated protein tau and other cytoskeletal proteins after neurone-specific activation of the mitogen-activated protein kinase (MAPK) in the CNS in vivo. We used transgenic mice with a neurone-specific expression of activated ras protein (p21H-ras(Val12), synapsin I promoter) that is associated with an augmented activity of the MAPK. Chronic activation of MAPK cascade influenced tau protein phosphorylation, localisation and dendritic morphology. While the amount of tau protein was elevated by 9%, phospho-epitopes detected by the monoclonal antibodies AT270, 12E8 and SMI34 were increased by about 21%, 40% and 59% respectively. Steady-state levels of tau mRNA were not affected. Thus, the increase in tau protein was most likely due to stabilisation of tau protein by augmented phosphorylation. While in wild-type animals tau protein was preferentially localised in axons, a prominent immunoreactivity was found in the somatodendritic compartment of transgenic mice. This subcellular translocation typically seen in pyramidal neurones was associated with an increase in the dendritic calibre by about 30% and is paralleled by an increase in tubulin of 19%. We were unable to obtain any morphological indication of neurodegenerative processes in these animals. We suggest that the moderate increase in tau protein and phosphorylation may be part of the neuroprotective mechanism. However, further studies on aged transgenic mice will be necessary to establish potential effects on neuronal viability.
UNLABELLED: Important adverse effects of bystander cardiopulmonary resuscitation (CPR) are well known. We describe the number of nonmedical professional CPR-related complications in patients surviving cardiac arrest, as assessed by chest radiograph. Within 2 yr, all consecutive patients admitted to the department of emergency medicine at a university hospital who had a witnessed, nontraumatic, normothermic cardiac arrest were studied. Radiologically evaluated adverse effects were compared with Mann-Whitney U-tests between patients who received bystander basic life support (Bystander group) and patients who did not receive bystander basic life support before advanced life support was started (ALS group). For assessment of bystander CPR-associated complications, chest radiographs were used. Of 224 patients, 173 were eligible. The median age was 58 yr (interquartile range, 51-71 yr), and 126 patients (73%) were men. The incidence of adverse effects associated with assisted-ventilation maneuvers and external chest compressions did not differ significantly between groups (severe gastric insufflation, 17% vs 18% between the Bystander group [n = 59] and the ALS group [n = 96], respectively; suspicion of aspiration, 22% vs 17%, respectively; soft tissue emphysema, 2% vs 1%, respectively; and serial rib fractures, 8% vs 8%, respectively). CPR administered by nonmedical personnel did not increase the number of life support-related adverse effects in patients surviving cardiac arrest as assessed by means of chest radiograph on admission. IMPLICATIONS: Complications related to cardiopulmonary bypass (CPR) are not increased when CPR is administered by nonmedical personnel, as assessed by chest radiograph. These data may be valuable in motivating lay people to perform basic life support.
This review discusses the mechanisms of neurologic damage during and after global cerebral ischemia caused by cardiac arrest. The different pathways of membrane destruction by radicals, free fatty acids, excitatory amino acids (neurotransmitters), calcium, glucose metabolism, and oxygen availability and demand in relation to metabolic rate are briefly discussed. The main focus of this review paper, however, lies in therapeutic (resuscitative) hypothermia after cardiac arrest. Two pioneering studies of the 1950s and four recent publications (in part preliminary results of ongoing studies) in humans are discussed in detail. The conclusions are as follows: (1) hypothermia holds promise as the only specific brain therapy after cardiac arrest so far; (2) hyperthermia is not tolerable after successful resuscitation; and (3) if the ongoing European multicenter trial of hypothermia after cardiac arrest finds a significant benefit to mild hypothermia, withholding hypothermia may be ethically hard to defend.
The stability of silages after opening the silo depends strongly on the products formed by the microorganism flora present during the conservation process. A silage additive developed at IFA-Tulln showed best results on different crops. In the starting phase of silage fermentation, acetic acid was formed by the heterofermentative lactic acid bacteria L. brevis from sugars. In the later stages, L. buchneri converts also lactic acid into acetic acid. Several trials involving different formulations of starters with varying amounts of single homo- and heterofermentative lactic acid bacteria were tested in laboratory and clump silos. Finally, an optimum composition of lactic acid bacteria, which reliably increases aerobic stability of silages and still guaranties highest quality, was evaluated.
OBJECTIVE: To evaluate the safety of edrophonium chloride in the course of the Tensilon test by measurement of hemodynamic and ECG parameters and the observation of adverse events. METHODS: 25 patients with known or suspected myasthenia gravis were included in an open, prospective study concerning the performance of the Tensilon test. Blood pressure, heart rate, continuous ECG and adverse events were recorded 10 minutes following intravenous application of Tensilon. RESULTS: Blood pressure and heart rate did not change significantly during the observation period. One patient on beta-blockers developed a grade I AV block. Self-limiting adverse events of short duration were observed in 11 patients. Serious adverse events such as syncope or hemodynamic deterioration did not occur. CONCLUSION: The Tensilon test appears to be a safe procedure. A detailed clinical cardiac history, the history of medication and twelve lead ECG recordings should be documented in all patients undergoing the Tensilon test. Patients with a history of dysrhythmia receiving digitalis, beta-blocking agents or Ca antagonist therapy should be managed with special care, as Tensilon enhances vagal effects.