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Biomedical subjects

E Schuller

Publications and source records attributed to E Schuller.

At least 19 recordsLinked to original sources
PubMed2001

Brain t-complex polypeptide 1 (TCP- 1) related to its natural substrate beta1 tubulin is decreased in Alzheimer's disease.

The t-complex polypeptide 1 is a selective molecular chaperone in tubulin biogenesis, by that nascent tubulin subunits are bound to t-complex polypeptide 1 and released in assembly competent forms. In neurodegenerative diseases with Alzheimer pathology cytoskeletal proteins are deficient and aggregated. Therefore we examined t-complex polypeptide 1 as represented by the zeta subunit and its specific substrate beta 1 tubulin represented by a truncated product in six brain regions of nine patients with Alzheimer's disease, nine patients with Down syndrome and nine controls. We used 2 dimensional electrophoresis with in-gel-digestion and matrix-assisted laser desorption/ ionization- mass spectrometry for the separation and identification of human brain t-complex polypeptide 1 and beta 1 tubulin. When t-complex polypeptide I was related to its natural and specific substrate beta 1 tubulin, the ratio was significantly decreased in the temporal, frontal, parietal cortex and in thalamus of patients with Alzheimer's disease. In Down syndrome the t-complex polypeptide 1/beta 1 tubulin ratio was significantly increased in frontal and parietal cortex suggesting a different mechanism for aggregation of microfilament proteins e.g. beta 1 tubulin. Relatively decreased molecular chaperoning of beta 1 tubulin by t-complex polypeptide 1 may lead to misfolded tubulin aggregating and accumulating in plaques and tangles, a hallmark of Alzheimer's disease. Our contribution provides first clues for a mechanism of microtubular accumulation in Alzheimer's disease and challenges further studies on different chaperones and chaperonins in the brain of patients with neurodegenerative diseases.

Alzheimer Disease↗
PubMed2001

Prolonged second response to cisplatin, etoposide, and ifosfamide in a child with a recurrent brainstem glioblastoma.

The prognosis for patients with malignant brainstem tumors is poor. The authors report on a 6-year-old girl with a biopsy proven pontine glioblastoma, who, after initial chemo-radiotherapy and tumor progression, experienced a prolonged second response to a salvage therapy consisting of cisplatin, etoposide, and ifosfamide. The patient recovered from her life-threatening condition with almost complete resolution of all neurologic deficits paralleled by a dramatic shrinkage of the tumor documented by magnetic resonance imaging.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Differences in protein level between neonatal and adult brain.

Age is a physiological condition that affects protein expression. We investigated differences in protein level between newborn and adult brains. Brain tissue extracts from male and female adult and neonatal rats were analyzed by two-dimensional gel electrophoresis. Gel comparison revealed the presence of many differences, of qualitative and quantitative nature, between a neonatal and adult brain. The most significant age-related difference concerned alpha-fetoprotein, which was detected in the brain of neonatal rats only. The levels of 22 proteins, including dihydropyrimidinase-related proteins 1,3, and 4 and 14-3-3 proteins, were higher in the neonatal brain, whereas the levels of 28 proteins, including dihydropyrimidinase-related protein 2, dynamin-1 and many enzymes were higher in the adult brain. We did not detect a consistent sex-related difference in the brain proteins. An inconsistency was observed in the location of the spot representing glial fibrillary acidic protein in the male brain.

Aging↗
PubMed2000

[Immunosuppressive macrolides and their use in dermatology].

The immunosuppressive macrolides are a novel class of antiinflammatory substances, which could supplant glucocorticosteroids for the topical treatment of some chronic inflammatory skin diseases. Cyclosporine A (CyA), well known from transplantation medicine for years, is licensed in Germany for oral treatment of psoriasis and atopic dermatitis but is not suitable for topical therapy. Tacrolimus (FK506) penetrates the inflamed epidermis and is regarded as the key immunosuppressive macrolide. Clinical trials have demonstrated the efficacy of FK506 ointment for atopic dermatitis, many case reports have been published regarding other inflammatory skin diseases. The ascomycin derivative ASM 981 has many of the properties of FK506 but less data is available at present. Sirolimus (Rapamycin) is structurally related to FK506 but has other biological effects since its molecular actions involve different biochemical pathways. A review of the biochemical and cellular properties, mode of action, therapeutic efficacy and unwanted side effects, as well as data from clinical trials and status of licensing, is given for the respective drugs.

Administration, Topical↗
PubMed2000

The genetic background modifies the effects of the obesity mutation, 'fatty', on apolipoprotein gene regulation in rat liver.

BACKGROUND: Obesity is associated with disorders of plasma lipid transport in many, but not in all obese subjects. The effects of obesity on the regulation of genes involved in plasma lipid transport may depend on specific mutations causing or contributing to obesity and/or on interactions of a specific obesity mutation with the genetic background. The 'fatty' (Glu269Pro) leptin receptor mutation causes severe obesity associated with hypertriglyceridaemia and altered hepatic apolipoprotein gene regulation in Zucker fatty rats. OBJECTIVE: To determine whether the effects of the obesity mutation 'fatty' on apolipoprotein gene regulation in rat liver depend on the genetic background. METHODS: We studied hepatic apolipoprotein (apo) A-IV, A-I, and C-III gene expression in obese rats carrying the 'fatty' mutation on the background of the Zucker or Wistar strain. RESULTS: Basal apoA-IV gene expression was increased in fatty rats of both strains, whereas apoA-I and apoC-III gene expression differed between Wistar and Zucker fatty rats: apoA-I gene transcription was reduced to half and apoC-III mRNA was increased two-fold in Wistar fatty, but not in Zucker fatty rats vs lean controls. A fish oil diet suppressed apoA-IV, but not apoA-I gene transcription in Wistar fatty rats, whereas in Zucker fatty rats apoA-IV transcription was unaffected, but apoA-I transcription was suppressed. CONCLUSIONS: Interactions of the 'fatty' leptin receptor mutation with the genetic background significantly affect the basal and diet-induced regulation of the apoA-IV, C-III and A-I genes in rat liver. The genetic background may therefore be a major determinant of the consequences of a specific obesity mutation for plasma lipid transport.

Animals↗
PubMed2000

Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic forms of atopic dermatitis.

UNLABELLED: Atopic dermatitis (AD) is a clinically characteristic, chronic inflammatory skin disease of unknown origin. IgE-mediated uptake and antigen focusing of environmental allergens by dendritic cells (DCs) is assumed to be a central immunopathogenetic event. A so-called intrinsic type of AD (IAD) has been delineated from the more common extrinsic AD (EAD) by normal serum IgE levels, negative RAST tests and negative immediate-type skin reactions towards environmental allergens. The recently characterized human autoantigen Hom S 1 has been proposed to play a part in the pathogenesis of IAD. OBJECTIVES: To compare clinical and laboratory data between patients with IAD and EAD, and to investigate potential differences in the inflammatory micromilieu of the epidermal compartment in IAD and EAD lesions. METHODS: Epidermal DC phenotyping, a recently validated technique based on the three-colour flow cytometric analysis of Langerhans cells and the so-called inflammatory dendritic epidermal cells from epidermal single-cell suspensions, was performed on samples from 69 patients with AD (seven with IAD and 62 with EAD) and 94 controls. RESULTS: Patients with EAD tended to have an earlier onset of disease but similar disease duration and family history of atopic diseases. Quantitative analysis of CD36 expression on DCs as a marker of inflammation, as well as the percentage of inflammatory dendritic epidermal cells in the CD1a+ epidermal DC pool, indicated a comparable disease activity in IAD and EAD. EAD was characterized by a significantly higher FcepsilonRI expression on the CD1a+ epidermal DCs than IAD. Using the FcepsilonRI/FcgammaRII expression ratio as a disease marker for AD, values for IAD fell below the diagnostic cut-off level of 1.5 for this ratio. CONCLUSIONS: While IAD is clinically similar to EAD, the inflammatory microenvironment in this condition seems different from classical EAD and can be distinguished by phenotyping of epidermal DCs.

Adolescent↗
PubMed1999

Rat brain proteins: two-dimensional protein database and variations in the expression level.

A two-dimensional database of rat brain proteins was constructed. Brain samples from newborn animals were analyzed by two-dimensional electrophoresis and the proteins were identified by matrix-assisted laser desorption/ionization mass spectrometry. The database comprises 210 different proteins, the majority of which are structural components, heat shock proteins and enzymes with various catalytic activities. Several minor differences in the expression level were detected, mainly of quantitative nature, which most likely represent allelic differences. The map may be useful in studies of neurological disorders in animal models of human diseases.

Animals↗
PubMed1999

Downregulation of the transcription factor scleraxis in brain of patients with Down syndrome.

Performing gene hunting in fetal Down Syndrome (DS) brain, we found a downregulated sequence with 100% homology to the basic-helix-loop-helix transcription factor (TF) scleraxis (Scl). It was the aim of the study to evaluate Scl-mRNA steady state levels in adult DS brain with Alzheimer's disease (AD) neuropathological changes, brain of patients with AD, and controls in order to find out whether Scl-downregulation is linked to DS per se or simply to neurodegeneration, common to both disorders. Determination of Scl-mRNA steady state levels was carried out by a blotting method in frontal, parietal, temporal, occipital lobe and cerebellum. We found significantly decreased Scl-transcripts in brain of DS and AD, both, when normalized versus the house-keeping gene beta actin or total RNA. We demonstrate the significant decrease of Scl-mRNA steady state levels in the pathogenesis of DS and AD suggesting a tentative role for this transcription factor in the development of the neurodegenerative processes known to occur in both disorders. More specifically, the biological meaning of the downregulation of Scl may be the involvement in the pathogenesis of impaired neuronal plasticity and wiring observed in DS and AD, phenomena regulated by the concerted action of the many transcription factors expressed in human brain.

Adult↗
PubMed1999

Genes involved in the pathophysiology of perinatal asphyxia.

Mechanisms in the pathogenesis of perinatal asphyxia (PA) at the gene level are only beginning to be elucidated, although gene hunting using differential display has revealed differences in gene expression between hypoxic and normoxic cells in vitro. As no information on gene expression was available from in vivo studies, we decided to use a non-invasive and clinically relevant animal model of PA for mRNA hunting applying the subtractive hybridization method. mRNAs from normoxic rat brain and brain of rat pups with 20 min of asphyxia were isolated and compared by this technique. The resulting subtracted mRNAs were converted to cDNA, sequenced and identified by gene bank data. A series of transcripts representing transcription factors, transporters, metabolic factors, were found to be up- or downregulated providing insight into mechanisms of PA, and on the other hand, genes with unknown functions could be given a preliminary role i.e. in PA. Results obtained with this powerful tool are now challenging quantitative determination of these genes and gene products at the protein and activity level to confirm their role in PA.

Animals↗
PubMed1999

Relation of plasma leptin to lipoproteins in overweight children undergoing weight reduction.

BACKGROUND: In obese children, plasma leptin is elevated and correlates with the body mass index (BMI). In obese adults, plasma leptin decreases during weight reduction. Since the leptin system changes dynamically in puberty, we asked whether weight reduction in obese adolescents has similar consequences for plasma leptin as in overweight adults. In plasma, a portion of leptin is bound to several as yet uncharacterised proteins. We therefore studied the possible association of leptin with plasma lipoproteins. SUBJECTS AND METHODS: We measured plasma leptin, lipoprotein cholesterol and apolipoproteins (apo) A-I and B in 34 obese children (age 12.5+/-1.9 y, relative BMI 165.0+/-28.1%) before and after three weeks of weight reduction in a dietary camp. Lipoprotein binding of endogenous and exogenously radiolabelled leptin was studied by preparative ultracentrifugation. RESULTS: Plasma leptin was higher in obese children than in normal weight controls and fell from 16.5+/-9.8 ng/ml to 10.0+/-8.6 ng/ml after weight reduction (P < 0.001). In multivariate regression, relative BMI and apoA-I were significant predictors of baseline leptin and accounted for 38% (P = 0.003) and 15% (P = 0.006) of the variance of baseline leptin concentrations in obese children. Only the difference in plasma high-density lipoprotein (HDL)-cholesterol independently predicted the change of plasma leptin that was associated with weight reduction, explaining 29% of the variance of leptin changes (P = 0.0032). A substantial portion of both endogenous and exogenously labelled leptin was recovered with HDL isolated by ultracentrifugation. CONCLUSIONS: We conclude that plasma leptin decreases in overweight children undergoing short term weight reduction. In obese children, plasma apoA-I and HDL-cholesterol are independent predictors of leptin concentrations during weight loss, respectively. In addition, HDLs transport a variable portion of leptin in the circulation.

Adult↗
PubMed1998

Apolipoprotein E and multiple sclerosis: a biochemical and genetic investigation.

Apolipoprotein E (apo E) is postulated to be a major lipid carrier protein in the brain involved in brain development and repair. Multiple sclerosis (MS) is a major demyelinating disease characterized by destruction of myelin and marked alteration of myelin cholesterol and lipid metabolism. We have determined serum and cerebrospinal fluid (CSF) apo E concentrations using an original time-resolved immunofluorometric assay and calculated intrathecal apo E concentration. Apo E concentrations were determined in 13 control subjects and 129 neurological patients: 34 definite MS patients, 25 with Guillain-Barré syndrome (GBS), 32 with amyotrophic lateral sclerosis (ALS) and 38 with other neurological diseases. Seven clinical parameters (sex, age, age at MS onset, duration of the disease, course, clinical status and disability score) were considered in MS patients. Significant (P < 0.01) decrease in CSF apo E was observed in MS, linked to a decrease in intrathecal apo E. The decreased CSF apo E concentration in MS patients occur independent of the apo E genotype. Apo E is considered as a neurotrophic factor in the brain. Any decrease in intrathecal apo E synthesis would thus contribute to progression of neurological diseases, such as MS.

Adult↗
PubMed1997

Evidence against increased oxidative DNA-damage in Down syndrome.

In Down syndrome (DS), oxidative DNA-damage may play a role in the pathogenesis of characteristic mental retardation and precocious dementia of Alzheimer type. We measured the oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (8-OHdG), in nuclear DNA (nDNA) isolated from four different regions of cerebral cortex and cerebellum in 10 adult DS and 10 Alzheimer's disease (AD) patients compared to normal controls. Levels of 8-OHdG in post-mortem brain tissue were investigated by means of high-performance liquid chromatography with electrochemical detection. There was no significant increase in DS and AD compared to controls in any of the brain regions. Highest amounts of 8-OHdG were in temporal cortex in DS (180.0 +/- 9.6 nmol/g wet weight tissue), AD (172.4 +/- 14.6 nmol/g wet weight tissue) and controls (183.4 +/- 12.7 nmol/g). We conclude that the results provide evidence against an increased reactive oxygen species (ROS) induced damage to nDNA in DS and AD.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Evidence against increased glycoxidation in patients with Alzheimer's disease.

Neuropathological findings of Alzheimer's disease (AD) are intracellular (neurofibrillary tangles) and extracellular (senile plaques) filamentous protein aggregates. Non-enzymatic glycation has been proposed as a primary factor in this pathogenesis, leading to increased insolubility of tau protein and beta-amyloid. The aim of our study was to test the hypothesis that increased glycoxidation, i.e. increased levels of oxidized products from non-enzymatic glycation could be found in brains of patients with AD and of aged Down syndrome (DS) subjects with abundant AD-like neuropathological lesions. Frontal cortex specimens were assayed for pentosidine (Pent) and N-epsilon-carboxymethyl-lysine (CML) by reversed phase high performance liquid chromatographical methods. Pent and CML levels in AD (n = 10; Pent, 35.5 +/- 4.84 mumol/g wet-weight tissue; CML, 135.2 +/- 5.0 mumol/g wet-weight tissue) were comparable to DS (n = 9; Pent, 36.4 +/- 3.21; CML, 133.5 +/- 4.7) and controls (n = 10; Pent, 35.2 +/- 3.55; CML, 136.9 +/- 3.3). We conclude that the results are not compatible with the concept of increased glycoxidation in AD compared to normal aging.

Aged↗
PubMed1997

Photopolymerization of Acrylate Films under an Imposed Spatial Irradiation: Thermodynamics of Relief Self-Development

UV irradiation through a lined mask of acrylate-based self-developing materials leads to the formation of a relief in the irradiated areas. Investigation of the effect of various properties, through a known two-layer model, showed the paramount importance of surface state on relief height. Both relief height and inhibition time of the growing kinetics are shown to be directly dependent on two surface properties: surface free energy and viscosity of the condensed state of the gaseous atmosphere adjoining the film.

Journal Article↗
PubMed1997

Molecular heterogeneity of classical and Duarte galactosemia: mutation analysis by denaturing gradient gel electrophoresis.

Classical galactosemia is caused by one common missense mutation (Q188R) and by several rare mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. The most common variant of GALT, the Duarte variant, occurs as two types, Duarte-1 (D-1) and Duarte-2 (D-2), both of which carry the sequence change N314D. D-1 increases, whereas D-2 decreases GALT activity. To study the molecular genetics of classical and Duarte galactosemia, we analyzed the GALT mutations in 30 families with classical galactosemia, in 10 families with the D-2 variant and in 3 individuals carrying the D-1 allele by denaturing gradient gel electrophoresis (DGGE). DGGE detected 59 of the 60 classical galactosemia alleles. Q188R accounted for 60%, K285N accounted for 28% of these alleles. Eight novel candidate galactosemia mutations were found. On all D-2 alleles N314D occurred in cis with two intronic sequence changes, on the D-1 alleles in cis with a neutral mutation in exon 7. We conclude that the mutations causing galactosemia are highly heterogeneous and that K285N is a second common galactosemia mutation in our population.

Adult↗
PubMed1997

Multiple sclerosis and intrathecal IgA synthesis.

A clinically definite diagnosis of multiple sclerosis was done in a 61 year-old woman who displayed severe cerebellar and pyramidal tract involvement. Symptoms developed 5 years before with unsteadiness of gait and difficulties in walking. Diagnosis was supported by evoked potentials studies and magnetic resonance imaging. However, the cerebrospinal fluid (CSF) analysis was very unusual. CSF albumin and IgG concentrations were normal, as well as the IgG index. In contrast, the IgA level and the IgA index were markedly increased and the local synthesis of IgA was estimated at 31.36 mg/l. Reduction by dithiotreitol did not change the IgA level. On affinity immunoblots, oligoclonal IgA bands were not detected but oligoclonal IgG bands were present. The strong local production of IgA in this patient seems to be therefore polyclonal.

Dithioerythritol↗