Biomedical subjects

S Schmidt

Publications and source records attributed to S Schmidt.

At least 109 records · Page 6Linked to original sources

PubMed2002

Impaired up-regulation of CD70 and CD86 in naive (CD27-) B cells from patients with common variable immunodeficiency (CVID).

CVID is characterized by reduced serum levels of all switched immunoglobulin isotypes (IgG, IgA, IgE) predisposing patients to recurrent infections of their respiratory and gastrointestinal tract. Correspondingly, most CVID patients exhibit a severely decreased proportion of class switched memory B cells (CD19+CD27+IgD-IgM-IgG+ or IgA+) in their peripheral blood (CVID type I). We previously identified a subgroup of CVID patients showing a significantly reduced expression of CD86 and CD137 following activation in vitro of PBMC or purified B cells (CD19+) with anti-IgM plus IL-2. Here we extend our previous studies by asking whether highly purified, cell-sorted naive B cells show already an expression defect of B cell surface molecules relevant in activation (CD39, CD69), differentiation (CD24, CD27, CD38) or T-B interaction (CD25, CD70, CD86). We stimulated cell-sorted, naive B cells (CD19+CD27-IgM+IgDhighIgG-IgA-) from 10 CVID patients and 10 healthy controls for 4 days with anti-IgM plus IL-2 in the absence or presence of autologous CD4+ T cells and measured the expression of the referred surface molecules. Based on reduced or normal numbers of switched memory B cells the CVID patients had previously been classified into eight type I patients and two type II patients, respectively. Interestingly, only the molecules CD25, CD70 and CD86, all relevant in cognate T-B interaction, showed a significantly lower expression in naive B cells from CVID patients compared to controls. While coculture with autologous CD4+ T cells normalized the CD25 expression, CD70 and CD86 expression remained subnormal, notably in the eight CVID patients of type I. These findings strongly suggest an intrinsic signalling or expression defect for CD70/CD86 at the level of naive B cells in type I CVID patients.

Adult↗

PubMed2002

Synthesis and anti-HIV activity of [d4U]-[trovirdine analogue] and [d4T]-[trovirdine analogue] heterodimers as inhibitors of HIV-1 reverse transcriptase.

A series of eleven heterodimers containing both a nucleoside analogue (d4U, d4T) and a non-nucleoside type inhibitor (Trovirdine analogue) were synthesized and evaluated for their ability to inhibit HIV replication. Unfortunately, the (N-3)d4U-Trovirdine conjugates (9a-e) and (N-3)d4T-Trovirdine conjugates (10a-f) were found to be inactive suggesting that the two individual inhibitor compounds do not bind simultaneously in their respective sites.

Anti-HIV Agents↗

PubMed2002

Genetic basis for clinical expression in multiple sclerosis.

Multiple sclerosis is a clinically heterogeneous demyelinating disease and an important cause of acquired neurological disability. An underlying complex genetic susceptibility plays an important role in multiple sclerosis aetiology; however, the role of genetic factors in determining clinical features of multiple sclerosis is unknown. We studied 184 stringently ascertained Caucasian multiple sclerosis families with multiple affected cases. A detailed evaluation of patient histories identified clinical variables including age of onset, initial clinical manifestations and disease severity. The concordance within families for continuous and categorical clinical variables was investigated using an intraclass correlation or Cohen's kappa coefficient, respectively. Genetic analyses included model-dependent, model-independent and association methodology. Linear and logistic regression models were used to evaluate the effect of human leucocyte antigen (HLA)-DR2 (DRB1*1501, DQB1*0602) on clinical outcome, taking account of correlation within families. Significant concordance for early clinical manifestations within families was observed for individuals with exclusive optic neuritis and/or spinal cord involvement as first and second multiple sclerosis attacks (P < 10(-6)). Linkage (LOD = 3.80, theta = 0.20) and association (P = 0.0002) to HLA-DR were present in the dataset; however, linkage was restricted to families in which the DR2 haplotype was present in at least one nuclear member. No evidence for linkage to HLA-DR in DR2-negative families was observed. When families were stratified by concordance of early clinical manifestations, a significant DR2 association was present in all subgroups. Concordance for early manifestations of multiple sclerosis was present in this familial dataset, but was not associated with HLA-DR2. The association of DR2 in families with different clinical presentations suggests that a common basis exists for susceptibility in multiple sclerosis. However, non-HLA genes or other epigenetic factors must modulate disease expression. Locus heterogeneity at the HLA region suggests a distinct immunopathogenesis in DR2 negative patients.

Adolescent↗

PubMed2002

Immunomodulatory effects of glatiramer acetate on superantigen- and mitogen-induced T-cell stimulation in vitro.

Glatiramer acetate (GA) interferes with antigen recognition and modulates cytokine secretion of T cells in an antigen-specific manner. Here we analysed the capacity of GA to modulate proliferative responses and cytokine secretion of peripheral blood mononuclear cells (PBMCs) in response to antigen-independent stimuli, i.e., phytohaemagglutinin (PHA) and staphylococcal enterotoxin B (SEB) stimulation in five healthy volunteers. A significant reduction of proliferative responses, as well as interferon-gamma (IFNalpha) and tumour necrosis factor-alpha (TNFalpha) secretion, was observed at concentrations of 200 microg/ml suggesting that GA may also exert immunomodulatory effects on mitogen- and superantigen-induced T-cell stimulation in vitro. However, since systemic GA concentrations of this magnitude are highly unlikely to occur in vivo the immunomodulatory effects observed here are not likely to contribute to the therapeutic mechanisms of action under physiological conditions.

Adult↗

PubMed2002

[Optimization of radiotherapy planning for non-small cell lung cancer (NSCLC) using 18FDG-PET].

AIM: In recent years, FDG-PET examinations have become more important for problems in oncology, especially in staging of bronchogenic carcinoma. In the retrospective study presented here, the influence of PET on the planning of radiotherapy for patients with non-small-cell lung cancer (NSCLC) was investigated. METHODS: The study involved 39 patients with NSCLC who had been examined by PET for staging. They received radiotherapy on the basis of the anterior/posterior portals including the primary tumour and the mediastinum planned according to CT- and bronchoscopic findings. The results of the PET examination were not considered in initial radiotherapy planning. The portals were retrospectively redefined on the basis of FDG uptake considering the size and localization of the primary tumour; and FDG activities outside the mediastinal part of the portals. RESULTS: In 15 out of 39 patients, the CT/PET-planned portals differed from the CT-planned ones. In most causes (n = 12) the CT/PET field was smaller than the CT field. The median geometric field size of the portals was 179 cm2, after redefinition using PET 166 cm2. In 20 patients with disturbed ventilation caused by the tumour (atelectasis, dystelectosis), a correction of the portal was suggested significantly more frequently than in the other patients (p = 0.03). CONCLUSIONS: Our results demonstrate the synergism of topographical (CT) and metabolic (FDG-PET) information, which could be helpful in planning radiotherapy of bronchial carcinoma, especially for patients with disturbed ventilation.

Carcinoma, Non-Small-Cell Lung↗

PubMed2002

Influence of pregnancy and breast-feeding on quantitative ultrasonometry of bone in postmenopausal women.

OBJECTIVE: Reproductive factors such as parity and breast-feeding may be associated with low bone mass and osteoporotic fractures in later years. In this study, os calcis quantitative ultrasonometry was used to elucidate the relationship between parity, lactation and bone mass in postmenopausal women. DESIGN: This was a comparison study using subsequent matched pairs analysis as well as multiple linear regression analysis. The study was carried out at five centers in Germany. The study included 2,080 postmenopausal women (age (mean +/- SD) 58.8 +/- 8.2 years), who were attending for routine check-up and in whom diseases and drug treatments known to affect bone metabolism had been excluded. METHODS AND OUTCOME MEASURES: Women underwent quantitative ultrasonometry (QUS) measurement at the heel. Values of the ultrasonometry variables -speed of sound, broadband ultrasound attenuation and stiffness index -were calculated and compared for nulliparous and parous women and for women who had and had not breast-fed. Because of some significant intergroup differences, and to determine any effect of the number of live births and the duration of breast-feeding on ultrasonometry results, second analyses were undertaken using equally sized samples, matched for possible confounding variables such as age and body mass index (matched pairs). In these analyses, nulliparous women were compared with parous women, grouped according to number of live births, and women who had never breast-fed were compared with women who had breast-fed, grouped according to duration of breast-feeding. Furthermore, a multiple linear regression analysis was performed to examine the combined effects of reproductive factors on QUS variables. RESULTS: No statistically significant associations were found between ultrasonometry variables and parity or breast-feeding, even after controlling for confounding variables in matched-pairs analysis or in a multiple linear regression analysis.

Adult↗

PubMed2001

Simultaneous measurement of biopolymer-mediated Mac-1 up-regulation and adherence of neutrophils: a novel flow cytometric approach for predicting initial inflammatory interaction with foreign materials.

Implantation of any medical device normally causes an inflammatory cell interaction with the foreign material. In vitro cell activation of human neutrophils (Mac-1 upregulation) has been taken as one measure to assess the attributable risk of inflammation due to biopolymers before their clinical application. Mac-1 expression has generally been measured by flow cytometric assays, whereas quantification of neutrophil adhesion to the biopolymer surfaces has been performed by separate and time-consuming assays, e.g. microscopically by differential cell counting. However, due to an increasing number of surface-modified novel biopolymers entering clinical usage, effective testing of their inflammatory potential is now mandatory. To facilitate these analyses, we have developed a novel flow cytometric assay permitting simultaneous measurement of biopolymer-mediated neutrophil activation and adhesion. The biopolymers were used as beads (diameter 25+/-10 microm), and were demonstrated to be non-phagocytosable and non-fluorescent before being co-incubated with whole human blood (range of ratio granulocytes/beads from 5:1 to 1:1). Besides flow cytometric measurement of Mac-1 up-regulated neutrophils as fluorescing events, a fluorescence of the bead population indicates the adherence of activated neutrophils to the biopolymer surface.After establishing this assay, we evaluated it by comparing six different biopolymers. We observed high levels of Mac-1 expression (>70% of positive control) accompanied by increased adhesiveness (>60% of neutrophils) for polyurethane (PUR), polymethylmetacrylate (PMMA), and poly-DL-lactide (PDLLA) beads. Low Mac-1 expression levels (<10%) accompanied by a low percentage of adhering neutrophils (<10%) were observed for polyethylene (PE), polyisoprene (PI), and silicone (SI) beads.

Biocompatible Materials↗

PubMed2001

Characterization of nano-dimensional thin-film elastic moduli using magnetoelastic sensors.

Application of magnetoelastic thick-film sensors to the measurement of thin-film elastic moduli is described in this study. An analytical model is derived, that relates the resonant frequency of a magnetoelastic sensor to the elasticity and density of an applied thin-film. Limits of the model are analyzed, and related to experimental measurements using thin-films of silver and aluminum. For 500 nm thick-films, the measured Young's modulus of elasticity for Al and Ag is found to be within 1.6% of standard data. Using commercially available magnetoelastic sensors, the elasticity of coatings, approximately 30 nm thick, can readily be measured.

Aluminum↗

PubMed2001

The protein phosphatase 2A B'-regulatory subunit par1p is implicated in regulation of the S. pombe septation initiation network.

In order to identify regulators of the Schizosaccharomyces pombe septation initiation network (SIN), which signals the onset of cell division, we have isolated extragenic suppressors of mutations in the GTPase spg1p, which is a central element in this pathway. One of these encodes the protein phosphatase 2A (PP2A) B'-regulatory subunit par1p. Loss of par1p function rescues mutants in cdc11, cdc7, and spg1, but no other SIN mutants. Our data suggest that PP2A-par1p acts as a negative regulator of SIN signalling.

Cell Division↗

PubMed2001

Dioxygenative cleavage of C-methylated hydroquinones and 2,6-dichlorohydroquinone by Pseudomonas sp. HH35.

The dioxygenolytic catabolism of five C-methylated hydroquinones and 2,6-dichlorohydroquinone in Pseudomonas sp. strain HH35 was elucidated. This organism, which is known to catabolise 2,6-dimethylhydroquinone by 1,2-cleavage, accumulated metabolites from 2-methyl-, 2,3-dimethyl-, 2,5-dimethyl-, 2,3,5-trimethyl- and 2,3,5,6-tetramethylhydroquinone which we isolated and characterised by mass spectrometry and (1)H NMR and UV spectroscopy. The identification of these metabolites defined the impact of methyl groups present in the hydroquinone and showed how each substitution pattern determined the site of the initial enzymic attack. With the exception of the 2,3,5,6-tetramethylhydroquinone, all C-methylated hydroquinones were catabolised by an initial dioxygenolytic cleavage occurring adjacent (1,2- or 3,4-cleavage) to a hydroxy group. In addition, our results indicated that the 2,6-dichlorohydroquinone is catabolised in a similar way by this strain.

Hydroquinones↗

PubMed2001

The gene for a new brain specific RhoA exchange factor maps to the highly unstable chromosomal region 1p36.2-1p36.3.

Guanine nucleotide exchange factors from the Dbl family are proto-oncogenic proteins that activate small GTPases of the Rho family. Here we report the characterization of GEF720, a novel Dbl-like protein related to p115Rho-GEF. GEF720 activated RhoA both in our recently developed Yeast Exchange Assay and in biochemical in vitro exchange assays. GEF720 induced RhoA dependent assembly of actin stress fibers in REF52 fibroblastic cells. In NIH3T3 cells this Dbl-like protein elicited formation of transformation foci with a morphology similar to RhoA-V14 induced foci. In the PC12 neuron-like cell line, expression of GEF720, whose mRNA is brain specific, inhibited NGF-induced neurite outgrowth. Finally, GEF720 gene is located on human chromosome 1 on band 1p36, between Tumor Protein 73 and Tumor Necrosis Factor Receptor 12, two genes rearranged in many neuroblastoma cell lines. Together, these results show that this new Dbl related protein, GEF720, is an exchange factor that can directly activate RhoA in vivo and is potentially involved in the control of neuronal cell differentiation. GEF720 is also a new candidate gene involved in the progression of neuroblastoma and developmental abnormalities associated with rearrangements in the 1p36 chromosomal region.

3T3 Cells↗

PubMed2001

S. pombe cdc11p, together with sid4p, provides an anchor for septation initiation network proteins on the spindle pole body.

BACKGROUND: The signal for the onset of septum formation in the fission yeast Schizosaccharomyces pombe is transduced by the septation initiation network (SIN). Many of the components of the SIN are located on the spindle pole body during mitosis, from where it is presumed that the signal for septum formation is delivered. Cdc11 mutants are defective in SIN signaling, but the role of cdc11 in the pathway has remained enigmatic. RESULTS: We have cloned the cdc11 gene by a combination of chromosome walking and transfection of cosmids into a cdc11 mutant. Cdc11p most closely resembles Saccharomyces cerevisiae Nud1p and is essential for septum formation. Cdc11p is a phosphoprotein, which becomes hyperphosphorylated during anaphase. It localizes to the spindle pole body at all stages of the cell cycle, in a sid4p-dependent manner, and cdc11p is required for the localization of all the known SIN components, except sid4p, to the SPB. Cdc11p and sid4p can be coimmunoprecipitated from cell extracts. Finally, like its S. cerevisiae ortholog Nud1p, cdc11p is involved in the proper organization of astral microtubules during mitosis. CONCLUSIONS: We propose that cdc11p acts as a bridge between sid4p and the other SIN proteins, mediating their association with the spindle pole body.

Cell Cycle↗

PubMed2001

The two mitochondrial heat shock proteins 70, Ssc1 and Ssq1, compete for the cochaperone Mge1.

Two members of the heat shock protein 70 kDa (Hsp70) family, Ssc1 and Ssq1, perform important functions in the mitochondrial matrix. The essential Ssc1 is an abundant ATP-binding protein required for both import and folding of mitochondrial proteins. The function of Ssc1 is supported by an interaction with the preprotein translocase subunit Tim44, the cochaperone Mdj1, and the nucleotide exchange factor Mge1. In contrast, only limited information is available on Ssq1. So far, a basic characterization of Ssq1 has demonstrated its involvement in the maintenance of mitochondrial DNA, the maturation of the yeast frataxin (Yfh1) after import, and assembly of the mitochondrial Fe/S cluster. Here, we analyzed the biochemical properties and the interaction partners of Ssq1 in detail. Ssq1 showed typical chaperone properties by binding to unfolded substrate proteins in an ATP-regulated manner. Ssq1 was able to form a specific complex with the nucleotide exchange factor Mge1. In particular, complex formation in organello was enhanced significantly when Ssc1 was inactivated selectively. However, even under these conditions, no interaction of Ssq1 with the two other mitochondrial Hsp70-cochaperones, Tim44 and Mdj1, was observed. The Ssq1-Mge1 interaction showed a lower overall stability but the same characteristic nucleotide-dependence as the Ssc1-Mge1 interaction. A quantitative analysis of the interaction properties indicated a competition of Ssq1 with Ssc1 for binding to Mge1. Perturbation of Mge1 function or amounts resulted in direct effects on Ssq1 activity in intact mitochondria. We conclude that mitochondria represent the unique case where two Hsp70s compete for the interaction with one nucleotide exchange factor.

Adenosine Triphosphate↗

PubMed2001

Proton magnetic resonance spectroscopy and transcranial magnetic stimulation for the detection of upper motor neuron degeneration in ALS patients.

Transcranial magnetic stimulation (TMS) was compared to proton magnetic resonance spectroscopy (1H-MRS) for the detection of upper motor neuron loss or dysfunction in 49 ALS patients classified according to the El Escorial criteria. Abnormal NAA/Cho ratios were detected in 53% of ALS patients. Abnormal TMS results (i.e. cortical inexcitability or prolonged CMCT's) were obtained in 63% of ALS patients. If one or both methods were considered for diagnosis of upper motor neuron degeneration/dysfunction, the percentage of abnormal findings was 77%, whilst in 39% of all patients both methods produced abnormal results. Compared to TMS, 1H-MRS detected more patients with upper motor neuron involvement in the suspected El Escorial subgroup (42% versus 25%), whereas TMS detected more patients with upper motor neuron involvement in the possible (81% versus 50%), probable (71% versus 57%) and definite El Escorial subgroup (71% versus 64%). We conclude that the combined use of 1H-MRS and TMS increases diagnostic accuracy for the detection of upper motor neuron involvement in ALS patients.

Adult↗

PubMed2001

Passive immunization with Neisseria meningitidis PorA specific immune sera reduces nasopharyngeal colonization of group B meningococcus in an infant rat nasal challenge model.

To examine the protective efficacy of specific immune sera generated by meningococcal vaccine candidates against nasopharyngeal colonization, we developed an infant rat nasal colonization model for group B meningococcus. In this model, Sprague-Dawley infant rats were challenged intranasally in with host adapted, piliated Neisseria meningitidis group B strains H355 or H44/76 administered concurrently with iron dextran. Colonization was assessed by quantitative culture of nasal homogenates and expressed as log(10) colony forming units (c.f.u.) per nose. Three to five log(10) c.f.u. of N. meningitidis were routinely recovered from the nasal tissue up to 4 days post-challenge. Passive immunization (i.p.) of the infant rats with either PorA or whole cell antisera 24 h prior to homologous challenge resulted in a significant reduction of N. meningitidis colonization in the nasal tissues of these animals. These results demonstrate that this model can be utilized to evaluate the role of antibody to prevent the initial nasopharyngeal colonization by group B meningococcus.

Administration, Intranasal↗

PubMed2001

Serum autoantibody responses to myelin oligodendrocyte glycoprotein and myelin basic protein in X-linked adrenoleukodystrophy and multiple sclerosis.

We analyzed the sera of 51 patients with various phenotypes of X-linked adrenoleukodystrophy (X-ALD), 20 patients with multiple sclerosis (MS) and 22 healthy volunteers for the presence of autoantibodies specific for the recombinant extracellular immunoglobulin-like domain of human myelin oligodendrocyte glycoprotein (rhMOG(Igd)) and myelin basic protein (MBP). Anti-rhMOG(Igd) autoantibodies were significantly more frequent in X-ALD and MS patients as opposed to healthy individuals (p<0.05). Anti-MBP autoantibodies were present in about one-fourth of X-ALD and MS patients but in less than 10% of healthy individuals. Anti-rhMOG(Igd) autoantibody responses were not accompanied by increased T cell reactivity against rhMOG(Igd). These findings may have important implications for the understanding of humoral anti-myelin immunoreactivity in demyelinating diseases of the central nervous system such as X-ALD and MS.

Adolescent↗

PubMed2001

Temperature dependence of the Kondo resonance and its satellites in CeCu2Si2.

We present high-resolution photoemission spectroscopy studies on the Kondo resonance of the strongly correlated Ce system CeCu2Si2. By exploiting the thermal broadening of the Fermi edge we analyze position, spectral weight, and temperature dependence of the low-energy 4f spectral features, whose major weight lies above the Fermi level E(F). We also present theoretical predictions based on the single-impurity Anderson model using an extended noncrossing approximation, including all spin-orbit and crystal field splittings of the 4f states. The excellent agreement between theory and experiment provides strong evidence that the spectral properties of CeCu2Si2 can be described by single-impurity Kondo physics down to T approximately 5 K.

Journal Article↗

PubMed2001

Phased chest and abdominal compression-decompression versus conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest.

BACKGROUND: Several methods have been developed to improve the efficacy of mechanical resuscitation, because organ perfusion achieved with conventional manual resuscitation is often insufficient. In animal studies, phased chest and abdominal compression-decompression resuscitation by use of the Lifestick device has resulted in a better outcome compared with that of conventional resuscitation. In end-of-life patients, an increased coronary perfusion pressure was achieved. The aim of the present study was to determine the feasibility, safety, and efficacy of the Lifestick compared with conventional resuscitation in patients with sudden nontraumatic out-of-hospital cardiac arrest. METHODS AND RESULTS: The crews of 4 mobile intensive care units, staffed by an emergency physician and a paramedic, were trained to use the device. Fifty patients were randomized by sealed envelopes to either Lifestick (n=24) or conventional (n=26) resuscitation. No differences were found regarding demographic and logistical conditions between the groups. Nineteen of the patients (73%) with conventional resuscitation had ventricular fibrillation, 13 of whom survived to hospital admission (no survivals with other arrhythmias) and 7 were discharged. In contrast, in the Lifestick-CPR group, only 9 patients had ventricular fibrillation (38%; P=<0.02; OR, 2.5; 95% CI, 0.6 to 10.6). Four of these 9 patients and 5 of 15 patients with other arrhythmias survived to hospital admission, but none survived to hospital discharge. Autopsy in a subgroup of patients who died at the scene revealed less injuries with Lifestick than with conventional resuscitation. CONCLUSION: Lifestick resuscitation is feasible and safe and may be advantageous in patients with asystole or pulseless electric activity.

Abdomen↗