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Biomedical subjects

S Poser

Publications and source records attributed to S Poser.

At least 37 records · Page 2Linked to original sources
PubMed2002

The macrophage activity marker sCD14 is increased in patients with multiple sclerosis and upregulated by interferon beta-1b.

The soluble form of the CD14 molecule (sCD14), a macrophage activity marker, was measured in the plasma of 17 patients with primary progressive multiple sclerosis (PPMS) and 20 patients with relapsing remitting MS (RRMS). In patients with PPMS, sCD14 levels were determined before and after treatment with interferon beta (IFNB). In both PPMS and in RRMS, sCD14 levels were significantly elevated compared to healthy controls. In patients with PPMS, sCD14 levels increased significantly during the first 3 months of IFNB therapy, then slightly decreased, but still remained elevated compared with levels before therapy. Therefore, the elevated sCD14 levels may be a marker in evaluating biological response to IFNB therapy.

Adult↗
PubMed2001

Analysis of interleukin-4 receptor alpha chain variants in multiple sclerosis.

A recent candidate gene study employing microsatellite markers suggested a possible linkage of multiple sclerosis (MS) with the interleukin-4 receptor (IL4R) gene. Consequently, we investigated the association of different IL4R variants with MS in 341 German MS patients and 305 healthy controls. Analysis of the first 100 MS patients for six IL4R variants showed an increased frequency of the R551 variant in MS patients versus healthy controls and carriage of the same IL4R variant was weakly associated with myelin oligodendrocyte glycoprotein (MOG) autoantibody production. However, further analysis of all 341 MS patients did not confirm the finding that this IL4R variant represents a general genetic risk factor for MS but revealed an increased frequency of the R551 variant in MS patients with primary progressive MS (PPMS, n=48) as compared to patients with relapsing remitting MS or secondary progressive MS (RR/SPMS n=284; P=0.005 for genotype differences) and to 305 healthy controls (P=0.001 for genotype differences). This association was statistically independent of the presence of the well-known MS susceptibility allele HLA-DRB1*15. After correction for multiple comparisons only the genotype differences between PPMS patients and healthy controls remained statistically significant. These results indicate, that the IL4R variant R551 may influence the genetic predisposition for PPMS but does not represent a general genetic risk factor for MS.

Adult↗
PubMed2001

Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons.

Activation of the extracellular signal-regulated kinase 1 (ERK1) and ERK2 by neurotrophins, neuronal activity, or cAMP has been strongly implicated in differentiation, survival, and adaptive responses of neurons during development and in the adult brain. Recently, a new member of the mitogen-activated protein (MAP) kinase family, ERK5, was discovered. Like ERK1 and ERK2, ERK5 is expressed in neurons, and ERK5 stimulation by epidermal growth factor is blocked by the MAP kinase/ERK kinase 1 (MEK1) inhibitors PD98059 and U0126. This suggests the interesting possibility that some of the functions attributed to ERK1/2 may be mediated by ERK5. However, the regulatory properties of ERK5 in primary cultured neurons have not been reported. Here we examined the regulation of ERK5 signaling in primary cultured cortical neurons. Our data demonstrate that, similar to ERK1/2, ERK5 is activated by neurotrophins including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4. BDNF stimulation of ERK5 required the activity of MEK5. Surprisingly, ERK5 was not stimulated by cAMP or neuronal activity induced by glutamate or membrane depolarization. In contrast to ERK1/2, ERK5 strongly activated the transcriptional activity of myocyte enhancer factor 2C (MEF2C) in pheochromocytoma 12 (PC12) cells and was required for neurotrophin stimulation of MEF2C transcription in both PC12 cells and cortical neurons. Furthermore, ERK1/2, but not ERK5, induced transcription from Elk1 and the cAMP/ Ca(2+) response element in PC12 cells. Our data suggest that mechanisms for regulation of ERK5 and downstream transcriptional pathways regulated by ERK5 are distinct from those of ERK1/2 in neurons. Furthermore, ERK5 is the first MAP kinase identified whose activity is stimulated by neurotrophins but not by neuronal activity.

Animals↗
PubMed2001

Unaltered apoptotic behaviour of mononuclear cells from patients with sporadic Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) belongs to the group of transmissible spongiform encephalopathies. It is suspected that a pathologically altered form of the prion protein (PrPSc) is the decisive trigger of the disease. Data from animal experiments suggest an involvement of the lymphatic system in the intracorporal transport of PrPSc. However, it has not so far been possible to detect PrPSc on mononuclear cells (MNCs) either in the sporadic form of CJD or in the new variant of CJD (vCJD). In order to determine a possible alteration of MNCs in CJD, we investigated the natural and induced apoptotic behaviour of these cells. MNCs from 19 patients with sporadic CJD and from 20 patients with other neurological disorders were used. The cells were analysed by fluorescence cytometry with and without apoptosis induction by xanthine oxidase and hypoxanthine. The apoptosis rate was quantified using the stain 7-amino-actinomycin D (7-AAD). In the morphological investigation of the cells before apoptosis induction, there were no significant differences between the groups with regard to cell size and granularity of the MNCs. After apoptosis induction, the typical significant decrease in cell size and increase in granularity of the cells occurred in both groups. Significant differences between the patient populations were not found. For the first time, our investigation has demonstrated that a functional impairment of MNCs with regard to their apoptotic behaviour does not occur in sporadic CJD. It remains open to question whether this mechanism plays an important role in forms of transmissible encephalopathy other than sporadic CJD, especially after oral transmission.

Adult↗
PubMed2001

Polymorphisms within the prion-like protein gene (Prnd) and their implications in human prion diseases, Alzheimer's disease and other neurological disorders.

Only 10% of human transmissible spongiform encephalopathies (TSEs) are associated with mutations of the Prnp region encoding the prion protein (PrP). Recently, the murine PrP-like protein doppel (Dpl) was described and was shown to be overexpressed in certain strains of PrP knockout mice and to cause neurological diseases such as ataxia and Purkinje cell loss. To answer the question of whether there are any polymorphisms within the PrP-like protein gene (Prnd) that might cause or be involved in the development of TSEs, we investigated the complete open reading frame of the human Prnd gene from 58 patients who had died of genetic or sporadic Creutzfeldt-Jakob disease (CJD), Alzheimer's disease or other neurological disorders and from 111 controls. We found five new polymorphisms and one frame shift mutation. One silent polymorphism, which does not lead to an altered amino acid sequence, was also observed. Statistical analysis revealed a significant difference in the distribution of the Prnd genotype at codon 174 between sporadic CJD patients and healthy controls.

Alzheimer Disease↗
PubMed2001

Role of Ca2+-stimulated adenylyl cyclases in LTP and memory formation.

Studies with invertebrates and vertebrates have strongly implicated the CREB/CRE transcriptional pathway in long-term memory (LTM) and transcriptionally-dependent L-LTP. It is hypothesized that LTM and L-LTP are both dependent upon a Ca2+ signal generated through activation of NMDA receptors. This review discusses evidence that Ca2+ signals generated through activation of NMDA receptors coactivate the Erk/MAP kinase and cAMP signal transduction pathways. It is hypothesized that activation of these two regulatory pathways increases the transcription of a family of genes through the CREB/CRE transcriptional pathway. Gene disruption studies have shown that Ca2+ activated adenylyl cyclases play a critical role in generating the cAMP signal required for LTM and L-LTP. Although cAMP may be required for several events in this complex signal transduction cascade, one of the major roles of cAMP may be to support nuclear translocation of Erk/MAP kinase in hippocampal neurons.

Activating Transcription Factor 2↗
PubMed2001

Immunochemical determination of cellular prion protein in plasma from healthy subjects and patients with sporadic CJD or other neurologic diseases.

BACKGROUND: Creutzfeldt-Jakob disease is thought to be caused by conversion of cellular prion protein (PrP) from its soluble form (PrP(sen)) to a pathologic form (PrP(res)). The occurrence of a new variant of CJD has increased the demand for a rapid assay capable of detecting a theoretical risk of transmission of the disease by blood or plasma. STUDY DESIGN AND METHODS: A quantitative sandwich ELISA for routine screening was developed for analysis of PrP levels in plasma. The time-resolved dissociation-enhanced fluorescence technology allowed a detection limit in plasma samples of approximately 50 pg/mL. Levels of PrP(sen) were tested in plasma from 31 patients with CJD, from 11 patients with other neurodegenerative diseases, and from a control group of 200 healthy subjects. RESULTS: The assay recognized both PrP(sen) and pathologic PrP(res), but did not differentiate between the two isoforms. PrP(sen) levels were higher in plasma from both patient groups than in plasma from the control group: 27 of the 31 (87%) CJD patients and all patients with other neurodegenerative diseases had higher levels than the highest concentration found in the control group. No correlation was found between age and PrP level. No signal could be detected in the CJD samples after protease K digestion, indicating that all detected PrP was protease-sensitive and therefore not pathologic. CONCLUSION: These data suggest that soluble PrP(sen) in plasma samples might be useful as a surrogate marker for a broad spectrum of neurologic diseases as well as for CJD.

Adolescent↗
PubMed2001

C-reactive protein and IL-6: new marker proteins for the diagnosis of CJD in plasma?

BACKGROUND: CJD is usually diagnosed by clinical and neuropathological findings. A number of proteins regarded as markers for neuronal damage in plasma or serum have recently been described. Markers typical for tissue damage, although not usually associated with CJD, are another possibility. An evaluation of the relative usefulness of markers of neuronal and tissue damage in identifying CJD could be beneficial. STUDY DESIGN AND METHODS: Plasma samples were collected from 46 patients with sporadic CJD and from a control group of 42 healthy subjects. The samples were analyzed with tests that were specific for C-reactive protein (CRP), IL-6, neuron-specific enolase (NSE), S-100 proteins, and cellular prion protein (PrP(c)). The results were compared, and a cutoff level for each test used was defined as the 90th percentile from the control group. RESULTS: The assay specific for NSE identified only 13 percent of the sporadic CJD patients as positive. The identification rate of the other markers was significantly higher: S-100, 76.1 percent; PrP(c), 76.1 percent; CRP, 78.3 percent; and IL-6, 73.3 percent. Only three of the samples were positive in all five tests. CONCLUSION: The markers for tissue damage, CRP and IL-6, are as useful as the previously described markers for neuronal damage in the diagnosis of CJD in plasma. All the markers tested are, however, of only limited value in the diagnosis of CJD in plasma. A combination of all surrogate markers improves the specificity but still provides no definitive diagnosis of the disease.

Biomarkers↗
PubMed2001

Patients with Alzheimer's disease and dementia with Lewy bodies mistaken for Creutzfeldt-Jakob disease.

OBJECTIVES: To describe the clinical presentation of patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) who were suspected of having Creutzfeldt-Jakob disease (CJD) and to investigate whether current clinical diagnostic criteria cover these atypical forms of AD and DLB. METHODS: Brains from necropsy were examined for the diagnosis of CJD at the German reference centre for spongiform encephalopathies. Symptoms and signs in patients with suspected CJD in whom necropsy showed AD (n=19) or DLB (n=12) were analysed. Their data were compared with a group of patients with CJD (n=25) to determine overlapping and discriminating clinical features. All patients were classified according to clinical diagnostic criteria for CJD, AD, and DLB. RESULTS: Demented patients were suspected of having CJD if disease was rapidly progressing and/or focal neurological signs appeared and/or an EEG showed sharp wave complexes. Myoclonus and limb rigidity were the most common neurological signs in all three dementias. DLB was not suspected in any patient, although patients with DLB showed parkinsonism (58%) and fluctuations (58%). Periodic sharp wave complexes (PSWCs) in EEG typical of CJD were found in five patients with AD and one patient with DLB. 14-3-3 Protein in CSF was detected in 20 patients with CJD, in two patients with AD, but not in any patient with DLB. Although most patients with DLB or AD met the clinical criteria for their respective diagnosis (74% and 90%), they also fulfilled criteria for CJD (42% and 58%). CONCLUSIONS: In patients with rapidly progressive dementia and focal neurological signs, CJD should be the first line diagnosis. Facing the triad dementia, myoclonus, and rigidity, AD should be considered if the disease course is longer and DLB is the differential diagnosis if parkinsonism or fluctuations are present. Findings on EEG or CSF typical of CJD do not exclude AD or DLB.

Alzheimer Disease↗
PubMed2000

Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease.

OBJECTIVE: To improve diagnostic criteria for sporadic Creutzfeldt-Jakob disease (CJD). METHODS: Pooled data on initial and final diagnostic classification of suspected CJD patients were accumulated, including results of investigations derived from a coordinated multinational study of CJD. Prospective analysis for a comparison of clinical and neuropathologic diagnoses and evaluation of the sensitivity and specificity of EEG and 14-3-3 CSF immunoassay were conducted. RESULTS: Data on 1,003 patients with suspected CJD were collected using a standard questionnaire. After follow-up was carried out, complete clinical data and neuropathologic diagnoses were available in 805 cases. In these patients, the sensitivity of the detection of periodic sharp wave complexes in the EEG was 66%, with a specificity of 74%. The detection of 14-3-3 proteins in the CSF correlated with the clinical diagnosis in 94% (sensitivity). The specificity (84%) was higher than that of EEG. A combination of both investigations further increased the sensitivity but decreased the specificity. CONCLUSIONS: Incorporation of CSF 14-3-3 analysis in the diagnostic criteria for CJD significantly increases the sensitivity of case definition. Amended diagnostic criteria for CJD are proposed.

14-3-3 Proteins↗
PubMed2000

SRF-dependent gene expression is required for PI3-kinase-regulated cell proliferation.

Recent evidence indicates that phosphatidylinositol 3-kinase (PI3K) is a central regulator of mitosis, apoptosis and oncogenesis. Nevertheless, the mechanisms by which PI3K regulates proliferation are not well characterized. Mitogens stimulate entry into the cell cycle by inducing the expression of immediate early genes (IEGs) that in turn trigger the expression of G(1) cyclins. Here we describe a novel PI3K- regulated transcriptional cascade that is critical for mitogen regulation of the IEG, c-fos. We show that PI3K activates gene expression by transactivating SRF-dependent transcription independently of the previously described Rho and ETS TCF pathways. PI3K-stimulated cell cycle progression requires transactivation of SRF and expression of dominant- negative PI3K blocks mitogen-stimulated cell cycle progression. Furthermore, dominant-interfering SRF mutants attenuate mitogen-stimulated cell cycle progression, but are without effect on MEK-stimulated cell cycle entry. Moreover, expression of constitutively active SRF is sufficient for cell cycle entry. Thus, we delineate a novel SRF-dependent mitogenic cascade that is critical for PI3K- and growth factor-mediated cell cycle progression.

3T3 Cells↗
PubMed2000

Ultrasensitive detection of pathological prion protein aggregates by dual-color scanning for intensely fluorescent targets.

A definite diagnosis of prion diseases such as Creutzfeldt-Jakob disease (CJD) relies on the detection of pathological prion protein (PrP(Sc)). However, no test for PrP(Sc) in cerebrospinal fluid (CSF) has been available thus far. Based on a setup for confocal dual-color fluorescence correlation spectroscopy, a technique suitable for single molecule detection, we developed a highly sensitive detection method for PrP(Sc). Pathological prion protein aggregates were labeled by specific antibody probes tagged with fluorescent dyes, resulting in intensely fluorescent targets, which were measured by dual-color fluorescence intensity distribution analysis in a confocal scanning setup. In a diagnostic model system, PrP(Sc) aggregates were detected down to a concentration of 2 pM PrP(Sc), corresponding to an aggregate concentration of approximately 2 fM, which was more than one order of magnitude more sensitive than Western blot analysis. A PrP(Sc)-specific signal could also be detected in a number of CSF samples from patients with CJD but not in control samples, providing the basis for a rapid and specific test for CJD and other prion diseases. Furthermore, this method could be adapted to the sensitive detection of other disease-associated amyloid aggregates such as in Alzheimer's disease.

Animals↗
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

Magnetic resonance imaging in the clinical diagnosis of Creutzfeldt-Jakob disease.

OBJECTIVE: To evaluate the diagnostic usefulness of magnetic resonance imaging (MRI) in the clinical diagnosis of Creutzfeldt-Jakob disease (CJD). BACKGROUND: Creutzfeldt-Jakob disease is a rare neurodegenerative disease that belongs to the group of human spongiform encephalopathies and usually affects elderly people. It is clinically characterized by rapidly progressive dementia and development of neurological symptoms, such as myoclonus or ataxia. Until now, neuroradiologic investigations have only played a minor role in establishing the clinical diagnosis of CJD, and they are often performed to exclude differential diagnoses. SETTING: A university hospital, base of the German National Creutzfeldt-Jakob Disease Surveillance Study. METHODS AND PATIENTS: In this study, MRIs from suspected cases of CJD were examined by one investigator blinded to the diagnosis. Patients were classified according to the established clinical and neuropathological criteria. RESULTS: Bilateral symmetric, high signal intensities on T2-weighted MRIs were present in the basal ganglia of 109 (67%) of 162 patients with CJD. In the control group, which consisted of non-CJD dementia patients, these abnormalities on T2-weighted MRIs were found in 4 (7%) of 58 patients. This corresponds to a high specificity in the differential diagnosis of CJD. CONCLUSION: These results indicate that MRI is a useful and valuable tool with reasonable sensitivity (67%) and high specificity (93%) and should be considered as an additional cornerstone in the clinical diagnosis of CJD.

Adult↗
PubMed2000

Clinical and differential diagnosis of Creutzfeldt-Jakob disease.

Until recently, the clinical diagnosis of CJD relied mainly on three criteria. These include patient history (rapidly progressive dementia), neurological findings (ataxia, pyramidal/extrapyramidal signs, myoclonus, akinetic mutism) and typical electroencephalographic (EEG) findings. These criteria are fulfilled in typical cases. The occurrence or increase of certain proteins in cerebrospinal fluid (CSF; 14-3-3, neuron-specific enolase) now provide important adjuncts in recognizing variant forms. Although these proteins can be detected in other neurological diseases accompanied with substantial brain damage such as encephalitis, they are also characterized by their high sensitivity and specificity with regard to other dementing processes (Alzheimer and vascular dementia). The increase in the number of positive cases during the last years in Germany reflects an improved case ascertainment rather than the appearance of the variant CJD (vCJD). Although several recent cases with a long duration of the disease were actually recognized, they did not reveal the typical florid plaques at autopsy. They were revealed as a rare variant of sporadic CJD, which is characterized by homocygosity for valine at codon 129 and PrP(Sc) type 1. This variant is positive for the 14-3-3 protein in CSF. Further subtypes described by Parchi et al. can also be characterized by a certain pattern of clinical symptomatology, EEG- and 14-3-3-findings. In addition, differential diagnosis revealed some treatable dementias among the most common diseases (Alzheimer and vascular dementia) such as herpes encephalitis, multiple sclerosis and Hashimoto encephalitis, particularly in the younger age group.

Cerebrospinal Fluid↗