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S Thiel

Publications and source records attributed to S Thiel.

At least 19 recordsLinked to original sources
PubMed2006

The mannan-binding lectin pathway and lung disease in cystic fibrosis--disfunction of mannan-binding lectin-associated serine protease 2 (MASP-2) may be a major modifier.

The lectin pathway of complement activation is initiated by mannan-binding lectin (MBL) or the ficolins through the common MBL-associated serine protease-2 (MASP-2). Deficiency of MBL has been associated with poorer outcome in cystic fibrosis (CF). We investigated the MBL pathway further by analysis of the MASP-2 deficiency mutation (D105G) as well as MBL-2 genotypes. Concentrations and genotypes of MASP-2 and MBL in 109 CF patients were correlated to lung function and chronic infections. We describe the first CF patient homozygous for the mutation, a girl with extremely severe lung disease with no other precipitating factors. We suspect total MASP-2 dysfunction to be a major modifier of CF lung disease. However, heterozygosity for the D105G mutation of MASP-2 had no correlation to MBL pathway function or poor lung function. Lung function was higher in the MBL deficiency determining genotypes (XA/YO+YO/YO) than in the other genotypes.

Adolescent↗
PubMed2006

MBL2 polymorphism and risk of severe infections in multiple myeloma patients receiving high-dose melphalan and autologous stem cell transplantation.

Severe infections related to treatment are common in patients with multiple myeloma (MM). Genetic polymorphisms of the immune system may influence the risk of infections. Mannan-binding lectin (MBL) is part of the innate immune system, and individuals homozygous for wild-type MBL encoding gene (MBL2) have a well-functioning MBL pathway of complement activation, in contrast to individuals carrying one or two variant alleles. We evaluated 113 courses of high-dose melphalan and autologous stem cell transplantation (ASCT) in patients with MM. Patients homozygous for wild-type MBL2 had a significantly reduced risk of septicaemia during the ASCT procedure compared with patients carrying variant MBL2: Odds Ratio (OR) 0.19 (95% CI: 0.04-0.77), (P=0.02) in multivariate analysis. The risk of Common Toxicity Criteria grade 3-4 infections in general was not affected by wild-type MBL2: OR 1.20 (95% CI: 0.52-2.78), (P=0.67). The findings indicate that MBL to some extent protects against the most severe infections during ASCT.

Adult↗
PubMed2006

Tunable quasi-two-dimensional electron gases in oxide heterostructures.

We report on a large electric-field response of quasi-two-dimensional electron gases generated at interfaces in epitaxial heterostructures grown from insulating oxides. These device structures are characterized by doping layers that are spatially separated from high-mobility quasi-two-dimensional electron gases and therefore present an oxide analog to semiconducting high-electron mobility transistors. By applying a gate voltage, the conductivity of the electron gases can be modulated through a quantum phase transition from an insulating to a metallic state.

Journal Article↗
PubMed2006

Subtleties in ADF imaging and spatially resolved EELS: A case study of low-angle twist boundaries in SrTiO3.

A screw dislocation network at the low-angle SrTiO3/Nb:SrTiO3 twist grain boundary has been analyzed by annular dark field (ADF) imaging and spatially resolved electron energy loss spectroscopy (EELS) in a scanning transmission electron microscope (STEM). The cores of one set of dislocations running parallel to the beam direction appear dark in the ADF STEM images. EELS on the dislocation core reveals a reduced Sr/Ti ratio compared to the bulk suggesting Sr-deficient cores. The second set of dislocations, orthogonal to the latter, is imaged by its strain field using low-angle annular dark field (LAADF) imaging. Multislice image simulations suggest channeling of the electron probe on the atomic columns for small tilts, theta < 1 degree, where the Sr columns act as beam guides. Only for larger tilts is the channeling effect strongly reduced and the fringe contrast approaches the value predicted by a purely incoherent imaging model. Ti-L(2,3) EELS across the dislocation core shows an asymmetry between the EELS and the ADF signal which cannot be explained by the geometry or beam broadening. This asymmetry might be explained by an effective nonlocal potential representing inelastic scattering in EELS.

Journal Article↗
PubMed2006

[Vocal efficiency parameters in children and adolescents: effect of physical development and singing activity].

The influence of physical development and singing activity on vocal efficiency in children and adolescents is well known from clinical experience. There is, however, no comparative study between singing and non-singing children which also considers the influence of age and gender. Therefore, standard values for evaluation in clinical practice are missing. We examined the following parameters in 164 healthy children and adolescents (90 boys, 74 girls; 11-16 years), 86 without singing activity (group A) and 78 members of children's and youth choirs (group B): frequency and dynamic range of voice and its borders with a voice range profile, mean fundamental frequency (normal and loud phonation), maximum voice intensity, and maximum duration of intonation. The statistical analysis was performed using three-way ANOVA. We found significantly higher ranges of frequency and intensity in singing children and adolescents (p<0.0001). The borders of the dynamic range and the upper border of the frequency range were significantly higher in group B (p<0.0001). The boys in group B used a higher mean fundamental frequency during loud phonation. There were no significant differences between groups in maximum voice intensity (p=0.051) but a tendency towards higher values in singing children. As an unexpected result, we found significantly higher values in maximum duration of intonation in group A (p<0.0001) independent of age and gender, which seems to be related to the methods used. Regular training of the singing voice results in positive effects on several voice parameters in children as well as adolescents. Our results can be used for estimating standard values in professional clinical and educational care of young singing voices and non-singing children. For this purpose, voice range profile is particularly suitable.

Adolescent↗
PubMed2006

Clinical manifestations of mannan-binding lectin deficiency.

Mannan-binding lectin (MBL) is a plasma protein of the innate immune system with the ability to initiate antimicrobial and inflammatory actions. MBL deficiency is common. More than 10% of the general population may, depending on definition, be classified as MBL deficient, underlining the redundancy of the immune system. Ongoing research attempt to illuminate at which conditions MBL deficiency may lead to disease. With examples, this review illustrates the diversity of results obtained so far.

Animals↗
PubMed2006

Elevated levels of mannan-binding lectin [corrected] (MBL) and eosinophilia in patients of bronchial asthma with allergic rhinitis and allergic bronchopulmonary aspergillosis associate with a novel intronic polymorphism in MBL.

Mannan-binding lectin (MBL), an important component of innate immunity, binds to a range of foreign antigens and initiates the lectin complement pathway. Earlier studies have reported high plasma MBL levels in allergic patients in comparison to healthy controls. In view of varied plasma MBL levels being determined by genetic polymorphisms in its collagen region, we investigated the association of single nucleotide polymorphisms (SNPs) in the collagen region of human MBL with respiratory allergic diseases. The study groups comprised patients of bronchial asthma with allergic rhinitis (n = 49) and allergic bronchopulmonary aspergillosis (APBA) (n = 11) and unrelated age-matched healthy controls of Indian origin (n = 84). A novel intronic SNP, G1011A of MBL, showed a significant association with both the patient groups in comparison to the controls (P < 0.01). Patients homozygous for the 1011A allele showed significantly higher plasma MBL levels and activity than those homozygous for the 1011G allele (P < 0.05). The 1011A allele also showed a significant correlation with high peripheral blood eosinophilia (P < 0.05) and low forced expiratory volume in 1 s (FEV(1)) (P < 0.05) of the patients. We conclude that the 1011A allele of MBL may contribute to elevated plasma MBL levels and activity and to increased severity of the disease markers in patients of bronchial asthma with allergic rhinitis and ABPA.

Adolescent↗
PubMed2006

Influence of major surgery on the mannan-binding lectin pathway of innate immunity.

The mannan-binding lectin (MBL) pathway of complement activation is important in host defence against pathogens and possibly against cancer. We investigated the effect of major surgery on two central components of the MBL pathway; MBL and the MBL-associated serine protease MASP-2, and for comparison also measured the interleukin (IL)-6 and C-reactive protein (CRP) levels. Serial blood samples were obtained from patients belonging to two different cohorts. Cohort 1 comprised 60 patients undergoing open or laparoscopic colectomy for benign disease (n = 12) or colon cancer (n = 48). Cohort 2 comprised 27 patients undergoing elective, open surgery for colorectal cancer, and was included in order to cover blood sampling between days 2 and 6. As expected, the surgical stress induced a marked acute phase response, as evidenced by a large increase in IL-6 (18-fold) and CRP (13-fold) levels with maximum at 12 h and 2 days, respectively. However, in both cohorts the levels of MBL and MBL-associated serine protease 2 (MASP-2) were largely unaffected, except for a minor but significant increase around day 8 in cohort 1. The preoperative levels of IL-6 and CRP were correlated significantly in both cohorts (r = 0.71, P < 0.0001 and r = 0.65, P = 0.005, respectively). Preoperative MASP-2 correlated with preoperative CRP (r = 0.59, P = 0.001) and IL-6 (r = 0.55, P = 0.02) in cohort 2 only. In contrast to the marked effects on the levels of IL-6 and CRP, the surgery influenced only marginally the two proteins of the MBL pathway.

Acute-Phase Proteins↗
PubMed2006

Hormonal regulation of mannan-binding lectin synthesis in hepatocytes.

Activation of the complement system via the plasma protein mannan-binding lectin (MBL) provides a first line of defence against infections. The plasma level of MBL is, in part, determined genetically, but may also be influenced by different hormones in vivo. Here we study the hormonal regulation of MBL synthesis from the human hepatocyte cell line HuH-7. Cells were exposed to medium with growth hormone (GH), hydrocortisone, insulin-like growth factor (IGF)-1, insulin, interleukin (IL)-6 or thyroid hormones (T3 or T4). After 3 days the concentration of MBL in the culture supernatants was determined and the amount of mRNA for MBL was measured, relative to mRNA for beta2 microglobulin. GH, IL-6, T3 and T4 significantly increased MBL synthesis in a dose-dependent manner, while hydrocortisone, insulin and IGF-1 had no effect. T3 caused a fourfold increase at 1 nM of T3 (P < 0.001) and at 100 nM of T3 the production was increased more than eightfold. The effect of T4 was less potent, reaching an eightfold increase at 1 microM of T4 (P < 0.001). GH augmented the production of MBL threefold at a concentration of 100 ng/ml (P = 0.018) with no further effect up to 10 microg/ml, whereas IL-6 caused only a very weak increase in MBL production. MBL mRNA levels were stable during the first 24 h of T3 stimulation but increased significantly between 24 and 48 h. The results suggest that MBL synthesis in humans may be increased by thyroid hormone and GH, whereas it does not exhibit a classical IL-6-dependent response.

C-Reactive Protein↗
PubMed2005

Role of collectins in innate immunity against aspergillosis.

The protective role of lung surfactant proteins SP-A, SP-D and MBL in the host defense against both allergic and invasive aspergillosis was identified and established by a series of in vitro and in vivo studies. Therapeutic administration of SP-D and MBL proteins in a murine model of pulmonary invasive aspergillosis rescued mice from death. In mice mimicking human allergic bronchopulmonary aspergillosis, SP-A and SP-D suppressed IgE levels, eosinophilia, pulmonary cellular infiltration and cause a marked shift from a pathogenic Th2 to a protective Th1 cytokine profile. SP-A and SP-D knock-out mice studies made significant contributions in understanding the mechanisms by which SP-A and SP-D modulate the host defense response in patients suffering from pulmonary allergies and infections. The results suggested that individuals with any structural or functional defects in these innate immune molecules due to genetic variations might be susceptible to aspergillosis. SNPs in SP-A2 and MBL genes showed significant associations with patients of allergic bronchopulmonary aspergillosis in an Indian population. The patients carrying either one or both of GCT and AGG alleles of SP-A2 and patients with A allele at position 1011 of MBL had markedly higher eosinophilia, total IgE antibodies and lower FEV1 (the clinical markers of ABPA). Our results show that collectins play an important role in Aspergillus mediated allergies and infections.

Animals↗
PubMed2005

Deficiency of the mannan-binding lectin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship.

In cystic fibrosis (CF) prognosis concerning lung damage development is highly variable and difficult to predict. Mannan-binding lectin (MBL) deficiency has been reported to be associated with poor outcome in CF lung disease. MBL is a recognition molecule of the MBL pathway of the complement system and is encoded by a gene characterized by a high degree of polymorphism. Some genotypes result in low serum concentrations of MBL. MBL-associated serine protease 2 (MASP-2) is another protein belonging to the MBL pathway. A mutation resulting in low levels of MASP-2 in serum has been described recently. In the present study, 112 CF patients aged 4-54 years were investigated for MBL and MASP-2 genotypes, serum levels of MBL and MASP-2 and the MBL pathway function in serum. No correlation to reduced lung function or need for lung transplantation was seen, either for MBL deficiency, MASP-2 gene mutation or reduced MBL pathway function. However, in the 27 patients colonized with Staphylococcus aureus, MBL-deficient genotypes were associated with decreased lung function. As expected, MBL pathway function in serum was reduced both in MBL-deficient patients and in patients carrying a mutant MASP-2 allele. An unexpected finding was that CF patients had higher serum levels of MBL than healthy controls when corrected for MBL genotype. In conclusion, MBL pathway function was affected both by MBL and by MASP-2 genotypes. However, MBL or MASP-2 levels in serum did not affect the clinical outcome in the cohort of CF patients studied.

Adolescent↗
PubMed2005

Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury.

Organ damage as a consequence of ischaemia and reperfusion (I/R) is a major clinical problem in an acute renal failure and transplantation. Ligands on surfaces of endothelial cells that are exposed due to the ischaemia may be recognized by pattern recognition molecules such as mannan-binding lectin (MBL), inducing complement activation. We examined the contribution of the MBL complement pathway in a bilateral renal I/R model (45 min of ischaemia followed by 24 h of reperfusion), using transgenic mice deficient in MBL-A and MBL-C [MBL double knockout (MBL DKO)] and in wildtype (WT) mice. Kidney damages, which were evaluated by levels of blood urea nitrogen (BUN) and creatinine, showed that MBL DKO mice were significantly protected compared with WT mice. MBL DKO mice, reconstituted with recombinant human MBL, showed a dose-dependent severity of kidney injury increasing to a comparable level to WT mice. Acute tubular necrosis was evident in WT mice but not in MBL DKO mice after I/R, confirming renal damages in WT mice. MBL ligands in kidneys were observed to be present after I/R but not in sham-operated mice. C3a (desArg) levels in MBL DKO mice were decreased after I/R compared with that in WT mice, indicating less complement activation that was correlated with less C3 deposition in the kidneys of MBL DKO mice. Our data implicate a role of MBL in I/R-induced kidney injury.

Acute Kidney Injury↗
PubMed2005

M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement.

Ficolins play a role in the innate immune defence as pathogen-associated molecular pattern recognition molecules. Three ficolins are found in humans: H-ficolin, L-ficolin and M-ficolin. L-ficolin and H-ficolin circulate in blood in complexes with mannan-binding lectin-associated serine proteases (MASPs) and are capable of activating the complement system. L-ficolin shows affinity for acetylated compounds and binds to various capsulated strains of bacteria. H-ficolin has been shown to bind Aerococcus viridans. Less is known about M-ficolin, but it is thought to be present only on monocytes. We have synthesized recombinant M-ficolin and find that it, in a manner similar to L-ficolin, is able to bind to acetylated compounds and to associate with recombinant MASP-2. Upon binding to M-ficolin ligands, the associated MASP-2 zymogen is activated and cleaves C4, thus triggering the complement system. We developed a monoclonal rat anti-human-M/L-ficolin antibody and verified by flow cytometric analysis the presence of ficolin on the surface of peripheral blood monocytes.

Acetylation↗
PubMed2004

Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy.

AIMS/HYPOTHESIS: Diabetic nephropathy is associated with insulin resistance, and low-grade inflammation and activation of the complement system may contribute to this cascade. Mannan-binding lectin (MBL) activates the complement system, and elevated MBL concentrations have been observed in normoalbuminuric type 1 diabetic patients. The aim of this study was to assess whether MBL is associated with diabetic nephropathy in type 1 diabetes, and whether there is an association between MBL and low-grade inflammatory markers or insulin resistance. METHODS: A total of 191 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based upon their AER. Patients with normal AER (n=67) did not take antihypertensive medication, while patients with microalbuminuria (n=62) or macroalbuminuria (n=62) were all treated with an ACE inhibitor. As a measure of insulin sensitivity we used estimated glucose disposal rate. MBL was measured by an immunofluorometric assay, C-reactive protein by a radioimmunoassay and IL-6 by high-sensitivity enzyme immunoassay. RESULTS: Patients with normal AER (median [interquartile range]: 1,154 microg/l [180-2,202 microg/l]) had lower levels of MBL than patients with microalbuminuria (1,713 microg/l [724-2,760 microg/l]; p=0.029) or macroalbuminuria (1,648 microg/l [568-3,394 microg/l]; p=0.019). There was a significant correlation between MBL and estimated glucose disposal rate, but not between MBL and C-reactive protein or IL-6 levels in univariate analysis. However, in a multiple regression analysis, HbA1c was the single variable independently associated with MBL (beta+/-SEM: 0.26+/-0.08; p=0.003). CONCLUSIONS/INTERPRETATION: MBL concentrations are increased in type 1 diabetic patients with diabetic nephropathy. MBL was not associated with low-grade inflammatory markers.

Adult↗
PubMed2004

Increased activity of the mannan-binding lectin complement activation pathway in patients with colorectal cancer.

BACKGROUND: Postoperative bacterial infectious complications are frequent in patients with colorectal cancer (CRC), with subsequent increased recurrence rates and poor prognosis. Deficiency of the mannan-binding lectin (MBL) complement activation pathway may cause increased risk of infection in certain patient groups. It is hypothesized that a deficient MBL pathway might be more frequent among patients with CRC than in healthy individuals. The MBL pathway was therefore evaluated in serum obtained preoperatively from 193 patients with primary CRC and in serum from 150 healthy volunteers. METHODS: Serum MBL concentrations and MBL/MASP activity were determined using immunofluorometric assays. The levels are presented as the median, inter-quartile range and range. RESULTS: Serum MBL levels were significantly (P < 0.0002) increased in patients with colorectal cancer (1384 (400-2188) ng/mL) (median, inter-quartile range) compared with levels in healthy blood donors (924 (230-1476) ng/mL). Similarly, the MBL/MASP activity was significantly (P < 0.0002) increased in patients (584 (202-914) mU/mL) compared with in blood donors (319 (0-684) mU/mL). This was independent of age, gender, tumour location in the colon or rectum, and disease stages according to Dukes' classification. No statistical difference (P=0.20) in frequency of MBL deficiency was found between the patients (20%) and the donors (27%). CONCLUSIONS: Overall, the MBL complement activation pathway is significantly increased in patients with colorectal cancer compared with healthy persons. However, similar frequencies of MBL pathway deficiency are observed in patients and healthy persons.

Adult↗
PubMed2004

Mannan-binding lectin modulates the response to HSV-2 infection.

Viruses have developed numerous strategies to escape recognition by the immune system. However, some viruses such as herpes simplex virus-2 (HSV-2) are recognized by initiators of the complement system, e.g. mannan-binding lectin (MBL). To study the effects of MBL deficiency during viral infection we have chosen a model of generalized HSV-2 infection. We infected MBL-A and MBL-C double knock-out mice (DKO) with HSV-2 via the intraperitoneal (i.p.) route. DKO mice cleared HSV-2 from the liver less efficiently than the comparable wild-type animals. The impairment to effectively neutralize HSV-2 correlated with compromised liver function as measured by increased plasma levels of alanine-amino transferase. No differences in the viral burden were found in other organs such as spleen or brain. Thus, MBL-mediated protection was limited to the effects of preservation of liver homeostasis. Reconstitution with recombinant human MBL before and during the HSV-2 infection dramatically lowered the viral titres in the liver. Taken together, the data show that MBL modulates the response to HSV-2 in mice by affecting neutralization of the virus. To analyse if MBL plays a role in establishment and progression of human HSV-2 infection we analysed MBL levels in the serum samples from asymptomatic (virus-exposed people who have never displayed symptoms of HSV-2 infection) and symptomatic HSV-2 patients (people with recurrent HSV-2 infections). We found that the frequency of the MBL deficiency (<100 ng/ml) was higher in the symptomatic group and significantly different from that in the asymptomatic group (P = 0.0369). This suggests that lack of MBL-mediated complement activation increases susceptibility to viral infection.

Adult↗
PubMed2003

Murine serine proteases MASP-1 and MASP-3, components of the lectin pathway activation complex of complement, are encoded by a single structural gene.

Activation of the lectin pathway of complement is initiated by the binding to microbial carbohydrate structures of a multimolecular fluid-phase complex composed of a carbohydrate recognition subcomponent that associates with three specific serine proteases and an enzymatically inert protein of 19 kDa. The first carbohydrate recognition subcomponent of the lectin pathway identified was mannan-binding lectin (MBL), hence the serine proteases were named MBL-associated serine proteases (MASPs) and numbered according to the sequence of their discovery. Here we describe the primary structures of the two distinct serine proteases MASP-1 and MASP-3 in the rat (and of MASP-3 in the mouse), show their association with plasma MBL complexes, and demonstrate that in rat and mouse, as in man, MASP-1 and MASP-3 are encoded by a single structural gene. For both species, we present the genomic region and regulatory elements responsible for the processing of either MASP-1 or MASP-3 mRNA by alternative splicing/alternative polyadenylation. Furthermore, we demonstrate the evolutionary conservation of MASP-3 mRNA in cDNA transcripts from guinea pig, rabbit, pufferfish, and cow.

Alternative Splicing↗