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Biomedical subjects

M Neumann

Publications and source records attributed to M Neumann.

At least 37 records · Page 2Linked to original sources
PubMed2000

[Your help is needed! Autopsy brings new knowledge regarding Alzheimer dementia].

Diagnosis upon autopsy of patients suffering from Alzheimer's disease (AD) and other dementing disorders is required to confirm or reject the clinical diagnosis. Autopsy studies are crucial to validate diagnostic criteria as well as to gain new insights in AD epidemiology, genetics, pathophysiology and therapy. The current decrease of autopsy rates leads to a lack of research which is essential to improve diagnosis and therapy of AD. Only the cooperation between physicians in memory-clinics, general practitioners and neuropathologists can prevent this unfortunate development. Brain-Net, the German brain bank, is a unique approach to provide organisational support for such a concerted action.

Aged↗
PubMed2000

Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha -synuclein in human and transgenic mouse brain.

Mutations in the alpha-synuclein (alphaSYN) gene are associated with rare cases of familial Parkinson's disease, and alphaSYN is a major component of Lewy bodies and Lewy neurites. Here we have investigated the localization of wild-type and mutant [A30P]alphaSYN as well as betaSYN at the cellular and subcellular level. Our direct comparative study demonstrates extensive synaptic colocalization of alphaSYN and betaSYN in human and mouse brain. In a sucrose gradient equilibrium centrifugation assay, a portion of betaSYN floated into lower density fractions, which also contained the synaptic vesicle marker synaptophysin. Likewise, wild-type and [A30P]alphaSYN were found in floating fractions. Subcellular fractionation of mouse brain revealed that both alphaSYN and betaSYN were present in synaptosomes. In contrast to synaptophysin, betaSYN and alphaSYN were recovered from the soluble fraction upon lysis of the synaptosomes. Synaptic colocalization of alphaSYN and betaSYN was directly visualized by confocal microscopy of double-stained human brain sections. The Parkinson's disease-associated human mutant [A30P]alphaSYN was found to colocalize with betaSYN and synaptophysin in synapses of transgenic mouse brain. However, in addition to their normal presynaptic localization, transgenic wild-type and [A30P]alphaSYN abnormally accumulated in neuronal cell bodies and neurites throughout the brain. Thus, mutant [A30P]alphaSYN does not fail to be transported to synapses, but its transgenic overexpression apparently leads to abnormal cellular accumulations.

Amino Acid Sequence↗
PubMed2000

Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

OBJECTIVES: Decreased levels of Abeta1-42 are found in CSF of patients with AD. Because early stages of Creutzfeldt-Jakob disease (CJD) and AD share several clinical features, we investigated Abeta1-42 levels in CSF of these groups, inferring that this might give additional help in differentiating patients with CJD from AD patients. METHODS: We investigated 27 patients with CJD, 14 patients with AD, 19 patients with other dementias, and 20 nondemented controls (NDC) for Abeta1-42 in CSF. Twenty-four of the 27 CJD patients were neuropathologically verified. All the neuropathologically verified patients presented with a type 1 prion protein pattern. CJD patients were all homozygous for methionine at codon 129. Except in five CJD patients, no beta-amyloid plaques were seen. Additionally, APOE status was determined in patients with CJD. RESULTS: Levels of Abeta1-42 in CSF were decreased in patients with AD as well as in CJD. Levels of Abeta1-42 in CSF of patients with CJD and AD were significantly different from the other dementia and NDC groups. There was no substantial difference between the CJD and AD groups (p = 0.66). Decreased levels of Abeta1-42 did not correlate with the APOE epsilon4 load in patients with CJD. CONCLUSION: Low levels of Abeta1-42 in CSF do not exclude a diagnosis of CJD. Decreased levels of Abeta1-42 in CSF can occur without beta-amyloid plaque formation in the brain. However, the underlying mechanism of this phenomenon must be elucidated.

Adult↗
PubMed2000

Capillary array scanner for time-resolved detection and identification of fluorescently labelled DNA fragments.

The first capillary array scanner for time-resolved fluorescence detection in parallel capillary electrophoresis based on semiconductor technology is described. The system consists essentially of a confocal fluorescence microscope and a x,y-microscope scanning stage. Fluorescence of the labelled probe molecules was excited using a short-pulse diode laser emitting at 640 nm with a repetition rate of 50 MHz. Using a single filter system the fluorescence decays of different labels were detected by an avalanche photodiode in combination with a PC plug-in card for time-correlated single-photon counting (TCSPC). The time-resolved fluorescence signals were analyzed and identified by a maximum likelihood estimator (MLE). The x,y-microscope scanning stage allows for discontinuous, bidirectional scanning of up to 16 capillaries in an array, resulting in longer fluorescence collection times per capillary compared to scanners working in a continuous mode. Synchronization of the alignment and measurement process were developed to allow for data acquisition without overhead. Detection limits in the subzeptomol range for different dye molecules separated in parallel capillaries have been achieved. In addition, we report on parallel time-resolved detection and separation of more than 400 bases of single base extension DNA fragments in capillary array electrophoresis. Using only semiconductor technology the presented technique represents a low-cost alternative for high throughput DNA sequencing in parallel capillaries.

DNA↗
PubMed2000

[The effect of inhalable dust particles (PN10) on lung function and respiratory symptoms of school children in Lower Austria].

The effect of PM10 (particulate matter less than 10 microns in diameter) on respiratory symptoms and lung function was evaluated in 881 children (aged 8 to 11 years) in 8 communities in Lower Austria. In each community, air pollution data (PM10, SO2, NO2, O3) were collected. The examination of each child included a questionnaire (spring 1996), and two lung function tests (autumn 1995, spring 1996). Statistically significant relationships were observed between PM10 levels (annual mean, 15.8-26.9 micrograms/m3) and parameters of lung function (adjusted for sex, height, atopy, passive smoking, altitude, temperature). A 10 micrograms/m3 increase in the last two weeks' mean PM10 in spring 1996 was associated with a 0.05% decrease in FVC, a 0.05% decrease in FEV1, a 0.15% decrease in MEF50, and a 0.13% decrease in MEF75-25. Furthermore, a 10 micrograms/m3 increase in last year's mean PM10 was associated with a 0.07% decrease in FVC. No association between the prevalence of respiratory symptoms and the last year's mean PM10-exposure was found. Our study demonstrates a small effect of low-level particulate air pollution on lung function of healthy school children.

Age Factors↗
PubMed2000

17beta-estradiol prevents programmed cell death in cardiac myocytes.

The cardioprotective effects of estrogens are clearly established. However, the underlying mechanisms are poorly understood. Because programmed cell death (apoptosis) probably contributes to the loss of cardiac myocytes in heart failure and because estrogens prevent apoptosis in breast cancer cells, we investigated whether the loss of cardiac myocytes by programmed cell death could be prevented by physiological doses of 17beta-estradiol. Apoptosis of cultured cardiac myocytes was induced by staurosporine. 17beta-estradiol (10 nM) had an antiapoptotic effect as determined by morphological analysis, vital staining using the Hoechst dye 33342 and terminal transferase dUTP nick-end labeling (TUNEL). As a potential mechanism for the antiapoptotic effect of 17beta-estradiol we found a reduced activity of the ICE-like protease caspase-3 in hormone-treated myocytes. Furthermore, inhibition of apoptosis by estradiol was associated with a reduced activity of NF-kappaB transcription factors, particularly p65/RelA and p50. To our knowledge, these data provide the first indication that 17beta-estradiol in physiological concentrations inhibits apoptosis in cardiac myocytes. The antiapoptotic effect of estrogens might contribute to the known cardioprotective effect of estrogens and provides a starting point for the development of future treatment options.

Animals↗
PubMed2000

Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to exert potent cytotoxic activity against many tumor cell lines but not against normal cells. It has been hypothesized that this difference in TRAIL sensitivity between normal and transformed cells might be due to the expression of the non-death-inducing TRAIL receptors (TRAIL-R) TRAIL-R3 and TRAIL-R4, presumably by competition for limited amounts of TRAIL. To assess the regulation of resistance versus sensitivity to TRAIL in primary as well as transformed keratinocytes, we examined TRAIL sensitivity, TRAIL receptor expression, and intracellular signaling events induced by TRAIL. Although TRAIL induced apoptosis in primary as well as transformed keratinocytes, a marked difference in sensitivity could be observed with primary keratinocytes (PK) being 5-fold less sensitive to TRAIL than transformed keratinocytes (TK). Yet both cell types exhibited similar TRAIL receptor surface expression, suggesting that expression of TRAIL-R3 and TRAIL-R4 may not be the main regulator of sensitivity to TRAIL. Biochemical analysis of the signaling events induced by TRAIL revealed that PK could be sensitized for TRAIL and, similarly, for TRAIL-R1- and TRAIL-R2-specific apoptosis by pretreatment of the cells with cycloheximide (CHX). This sensitization concomitantly resulted in processing of caspase-8, which did not occur in TRAIL-resistant PK. These data indicate that an early block of TRAIL-induced apoptosis was present in PK compared with TK or PK treated with CHX. Interestingly, cellular FLICE inhibitory protein (cFLIP) levels, high in PK and low in TK and several other squamous cell carcinoma cell lines, decreased rapidly after treatment of PK with CHX, correlating with the increase in TRAIL sensitivity and caspase-8 processing. Furthermore, ectopic expression of cFLIP long (cFLIP(L)) in TK by transfection with a cFLIP(L) expression vector resulted in resistance to TRAIL-mediated apoptosis of these cells. Thus, our results demonstrate that TRAIL sensitivity in PK is primarily regulated at the intracellular level rather than at the receptor level.

Apoptosis↗
PubMed2000

Differential expression of Rel/NF-kappaB and octamer factors is a hallmark of the generation and maturation of dendritic cells.

A key feature of maturation of dendritic cells is the down-regulation of antigen-processing and up-regulation of immunostimulatory capacities. To study the differential expression of transcription factors in this process, we investigated the nuclear translocation and DNA binding of Rel/NF-kappaB and octamer factors during in vitro generation and maturation of dendritic cells compared with macrophage development. RelB was the only factor strongly up-regulated during the generation of both immature dendritic cells and macrophages. Cytokine-induced maturation of dendritic cells resulted in an increase in nuclear RelB, p50, p52, and especially c-Rel, whereas cytokine-treated macrophages responded poorly. This up-regulation of NF-kappaB factors did not correlate with lower levels of cytosolic NF-kappaB inhibitors, the IkappaBs. One IkappaB, Bcl-3, was strongly expressed only in mature dendritic cells. Furthermore, generation and maturation of dendritic cells led to a continuous down-regulation of the octamer factor Oct-2, whereas monocytes and macrophages displayed high Oct-2 levels. A similar pattern of maturation-induced changes in transcription factor levels was found in cultured murine epidermal Langerhans cells, suggesting a general physiological significance of these findings. Finally, this pattern of differential activation of Rel and octamer factors appears to be suitable in determining the maturation stage of dendritic cells generated by treatment with different cytokine combinations in vitro. (Blood. 2000;95:277-285)

Animals↗
PubMed2000

[Neuropathological diagnosis of neurodegenerative and dementia diseases].

Neurodegenerative and dementing disorders such as Parkinson disease and Alzheimer disease are among the most common diseases of advanced age. Despite progress in the clinical diagnosis of neurodegenerative disorders, definite diagnosis for most of these disorders is still possible only by neuropathological examination of the brain. The neuropathological diagnosis and classification of neurodegenerative disorders has made clear advances in recent years, particularly due to the results of genetic and biochemical studies, resulting in the development of new disease-specific antibodies. Internationally recognized consensus criteria for most neurodegenerative disorders allow a definite and standardized diagnosis to be made. To obtain further knowledge about the etiopathogenesis, particularly with regard to new therapeutic strategies, studies with clinically and neuropathologically well-documented cases are needed. The project "Brain-Net" has therefore been established with the aim of setting up a German Brain and Tissue Bank for Diseases of the Central Nervous System. The project is funded by the Federal Ministry of Education and Research.

Alzheimer Disease↗
PubMed2000

Alpha-synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies.

We studied a 27-year-old woman who died after a 6-year history of progressive dementia, dystonia, ataxia, apraxia, spasticity, choreoathetosis, visual and auditory hallucinations, and optic atrophy. Magnetic resonance imaging showed decreased intensity in the globus pallidus, substantia nigra, and dentate nuclei in T2-weighted images, supporting the clinical diagnosis of neurodegeneration with brain iron accumulation type 1 (NBIA-1; formerly known as Hallervorden-Spatz syndrome). At autopsy the brain showed mild frontotemporal atrophy and discoloration of the globus pallidus and the substantia nigra pars reticularis. Histologically, features typical of NBIA-1 were found including widespread axonal spheroids and large deposits of iron pigment in the discolored regions. Additionally, excessive numbers of Lewy bodies (LBs) were found throughout all examined brain stem and cortical regions. LBs of both types, as well as Lewy neurites in this case of NBIA-1, were strongly labeled by antibodies against alpha-synuclein. These findings give further evidence that accumulation of alpha-synuclein is generally associated with LB formation, i.e., in Parkinson's disease, dementia with Lewy bodies and NBIA-1. The case presented here is particularly notable for its high number of LBs in all areas of the cerebral cortex.

Adult↗
PubMed2000

Characterization of Wue-1, a novel monoclonal antibody that stimulates the growth of plasmacytoma cell lines.

A new monoclonal antibody, Wue-1, which specifically recognizes normal and malignant plasma cells, is characterized. Biochemical studies showed that monoclonal antibodies (mAbs) recognize a protein of 94 kDa. Using triple-staining flow cytometry and double-labeling immunohistochemical techniques, two populations of plasma cells, i.e. lymphoplasmocytoid plasma cells located in the germinal center of lymphoid organs and reticular plasma cells at the paracortex or medullary cords of secondary lymphoid tissues, were distinguished. Wue-1 is expressed when B-cell markers become lost and secretory activity with plasma cell morphology appears. Cell surface markers were identified on normal plasma cells and compared with their malignant counterpart in vivo. Terminal plasma-cellular differentiation of malignant low- and high-grade B-cell lymphoma and anaplastic plasmacytoma, otherwise difficult to identify with conventional B-cell markers on tissue sections or fluorescence-activated cell sorter analyses, were detectable by Wue-1. In cell culture, Wue-1 enhanced the proliferation of myeloma cell lines but not normal plasma cells in a dose-dependent manner. Since Wue-1-induced proliferation was increased by interleukin (IL)-6, Wue-1 recognizes a so far unidentified antigen with functional properties. Therefore, Wue-1 represents a useful new tool for therapy and for the in vivo and in vitro studying of B-cell lymphomas and the mechanisms of B-cell differentiation.

Animals↗
PubMed2000

Intensity dependence of auditory evoked cortical potentials in migraine families.

Intensity dependence of auditory evoked cortical potentials is abnormal in migraine. This study investigated intensity dependence in migraine and healthy families using group comparisons and analysis of individual differences. Migraineurs were characterized by a steeper amplitude/stimulus function slope and more pronounced difference between the amplitudes of N1-P2 on the more and the less intensive tones than healthy age matched subjects. Apart from migraine, the age of the participants was an important predictive variable of intensity dependence. Analysis of individual differences revealed low sensitivity and moderate specificity of intensity dependence for migraine. Familial prevalence of intensity dependence among first-degree relatives in migraine families was equal to that in healthy families. These findings support the assumption that high-intensity dependence reflects a functional CNS trait which is more pronounced and prevalent in migraine, but may also be found in healthy individuals and in other neuropsychiatric disorders. Increased intensity dependence is only one of several factors contributing to the risk for this form of headache.

Acoustic Stimulation↗
PubMed2000

Ictal generalized rhythmic alpha activity during non-convulsive status epilepticus.

We investigated the repetitive manifestation of non-convulsive status epilepticus with an uncommon ictal electroencephalographic pattern observed in two patients suffering from epilepsy (aged 29 and 55 years). The patients had suffered from epilepsy since the age of 1 and 40 years, respectively. Interictal and ictal neurological, neuropsychological and electroencephalographic investigations were carried out. Non-convulsive status started and ended abruptly, clinically as well as electroencephalographically. The ictal electroencephalographic pattern was a monomorphic alpha activity with a generalized bilateral distribution. Altered responsiveness, sometimes eyelid myoclonia (in one patient) and amnesia were the most characteristic clinical findings during non-convulsive status. Intellectual development was delayed in the patient with early onset of epilepsy. However, this was not the case in the other patient, who developed memory impairment during the course of the disease. In both patients, lamotrigine added to valproate reduced the frequency of status epileptici significantly. Obviously, these patients suffer(ed) from a type of generalized non-convulsive status epilepticus with an uncommon electroencephalographic pattern.

Adult↗
PubMed2000

The Erlangen Endo-Trainer: life-like simulation for diagnostic and interventional endoscopic retrograde cholangiography.

The Erlanger Endo-Trainer offers a large spectrum of training possibilities in endoscopic techniques using life-like biological specimens. We organised the first pilot study of interventions at the papilla and the bile duct under x-ray control. Specially prepared upper visceral porcine organ packages including the esophagus, stomach, duodenum, liver, gallbladder and bile ducts were implanted into the Endo-Trainer. Furthermore, small stones were introduced into the bile duct. The test study was carried out by a senior endoscopist assisted by his endoscopy nurse. The following steps could therefore be carried out as a structured team-training scheme: Introduction of the side-viewing endoscope and passage into the duodenum; identification and adjustment at the papilla; cannulation of the papilla; selective bile duct imaging with contrast application under x-ray vision; placement of a guidewire; papillotomy; stone extraction and finally placement of a plastic stent. The special value of this type of simulation is the fact that endoscopic techniques can be trained in the usual manner with real tissue-feeling using regular commercial instruments. Although there is general consent that individual practice on the patient cannot be completely replaced by simulator training, a suitable and realistic simulation model can be of great value, for initial steps prior to "real" patient contact as well as for refining techniques and tactics.

Animals↗
PubMed2000

Acute severe isovolemic anemia impairs cognitive function and memory in humans.

BACKGROUND: Erythrocytes are transfused to prevent or treat inadequate oxygen delivery resulting from insufficient hemoglobin concentration. Previous studies failed to find evidence of inadequate systemic oxygen delivery at a hemoglobin concentration of 5 g/dl. However, in those studies, sensitive, specific measures of critical organ function were not used. This study tested the hypothesis that acute severe decreases of hemoglobin concentration alters human cognitive function. METHODS: Nine healthy volunteers, age 29 +/- 5 yr (mean +/- SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and after acute isovolemic reduction of their hemoglobin to 7, 6, and 5 g/dl and again after transfusion of their autologous erythrocytes to return their hemoglobin concentration to 7 g/dl. To control for duration of the experiment, each volunteer also completed the same tests on a separate day, without alteration of hemoglobin, at times of the day approximately equivalent to those on the experimental day. RESULTS: No test showed any change in reaction time or error rate at hemoglobin concentration of 7 g/dl compared with the data at the baseline hemoglobin concentration of 14 g/dl. Reaction time, but not error rate, for horizontal addition and digit-symbol substitution test (DSST) increased at hemoglobin 6 g/dl (mean horizontal addition, 19%; 95% confidence interval [CI], 4-34%; mean DSST, 10%; 95% CI, 4-17%) and further at 5 g/dl (mean horizontal addition, 43%; 95% CI, 6-79%; mean DSST, 18%; 95% CI, 4-31%). Immediate and delayed memory was degraded at hemoglobin 5 g/dl but not at 6 g/dl. Return of hemoglobin to 7 g/dl returned all tests to baseline, except for the DSST, which significantly improved, and returned to baseline the following morning after transfusion of all autologous erythrocytes. CONCLUSION: Acute reduction of hemoglobin concentration to 7 g/dl does not produce detectable changes in human cognitive function. Further reduction of hemoglobin level to 6 and 5 g/dl produces subtle, reversible increases in reaction time and impaired immediate and delayed memory. These are the first prospective data to demonstrate subtle degraded human function with acute anemia of hemoglobin concentrations of 6 and 5 g/dl. This reversibility of these decrements with erythrocyte transfusion suggests that our model can be used to test the efficacy of erythrocytes, oxygen therapeutics, or other treatments for acute anemia.

Adult↗
PubMed2000

Spectromicroscopy of boron in human glioblastomas following administration of Na2B12H11SH.

Boron neutron capture therapy (BNCT) is an experimental, binary treatment for brain cancer which requires as the first step that tumor tissue is targeted with a boron-10 containing compound. Subsequent exposure to a thermal neutron flux results in destructive, short range nuclear reaction within 10 microm of the boron compound. The success of the therapy requires than the BNCT agents be well localized in tumor, rather than healthy tissue. The MEPHISTO spectromicroscope, which performs microchemical analysis by x-ray absorption near edge structure (XANES) spectroscopy from microscopic areas, has been used to study the distribution of trace quantities of boron in human brain cancer tissues surgically removed from patients first administered with the compound Na2B12H11SH (BSH). The interpretation of XANES spectra is complicated by interference from physiologically present sulfur and phosphorus, which contribute structure in the same energy range as boron. We addressed this problem with the present extensive set of spectra from S, B, and P in relevant compounds. We demonstrate that a linear combination of sulfate, phosphate and BSH XANES can be used to reproduce the spectra acquired on boron-treated human brain tumor tissues. We analyzed human glioblastoma tissue from two patients administered and one not administered with BSH. As well as weak signals attributed to BSH, x-ray absorption spectra acquired from tissue samples detected boron in a reduced chemical state with respect to boron in BSH. This chemical state was characterized by a sharp absorption peak at 188.3 eV. Complementary studies on BSH reference samples were not able to reproduce this chemical state of boron, indicating that it is not an artifact produced during sample preparation or x-ray exposure. These data demonstrate that the chemical state of BSH may be altered by in vivo metabolism.

Borohydrides↗
PubMed2000

Physiology and pathophysiology of alpha-synuclein. Cell culture and transgenic animal models based on a Parkinson's disease-associated protein.

The 15-20 kDa synuclein (SYN) phosphoproteins are abundantly expressed in nervous tissue. Members of the family include alpha- and beta-SYN, and the more distantly related gamma-SYN and synoretin. SYN genes have been identified in Torpedo, canary, and several mammalian species, indicating an evolutionary conserved role. Expression of alpha-SYN was found to be modulated in situations of neuronal remodeling, namely, songbird learning and after target ablation of dopaminergic striatonigral neurons in the rat. The presynaptic localization of alpha-SYN is further supportive of a direct physiological role in neuronal plasticity. The extensive synaptic co-localization of alpha- and beta-SYN might indicate functional redundancy of these highly homologous synucleins. However, alpha-SYN was the only family member identified in Lewy bodies and cytoplasmic inclusions characteristic for multiple system atrophy. Moreover, alpha-SYN was genetically linked to familial Parkinson's disease. The two Parkinson's disease-associated mutations accelerated the intrinsic aggregation property of alpha-SYN in vitro. Post-translational modifications, such as phosphorylation and proteolysis, and/or interaction with other proteins, might regulate alpha-SYN fibril formation in vivo. Cytoskeletal elements and signal transduction intermediates have been recently identified as binding partners for alpha-SYN. Preliminary data available from transgenic mice suggest that (over)expressed human alpha-SYN proteins are less efficiently cleared from the neuronal cytosol. Thus, Parkinson's disease-associated mutations might perturb axonal transport, leading to somal accumulation of alpha-SYN and eventually Lewy body formation.

Amino Acid Sequence↗