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Biomedical subjects

E Schmidt

Publications and source records attributed to E Schmidt.

At least 19 recordsLinked to original sources
PubMed2007

Rituximab in autoimmune bullous diseases: mixed responses and adverse effects.

BACKGROUND: Intolerably high doses of systemic corticosteroids and additional immunosuppressants may be required to control disease activity in autoimmune bullous skin diseases. New therapeutic options are needed for such patients. OBJECTIVES: To determine the efficacy and adverse effects of adjuvant rituximab. METHODS: Seven patients with refractory autoimmune blistering diseases (pemphigus vulgaris, PV, n = 4; bullous pemphigoid, BP, n = 2; mucous membrane pemphigoid, MMP, n = 1) were treated four times with rituximab at an individual dose of 375 mg m(-2) at weekly intervals. RESULTS: All lesions cleared in three patients (two PV, one BP), while they were reduced by more than 50% in three others (two PV, one BP). The concomitant immunosuppressive medication was reduced in five patients (four PV, one BP). The patient with MMP developed bilateral blindness while nasopharyngeal lesions resolved. Three patients (two BP, one PV) experienced severe adverse events including fatal pneumonia. CONCLUSIONS: Adjuvant B-cell depletion by rituximab is effective in otherwise therapy-resistant bullous autoimmune disorders but may be associated with substantial adverse effects including fatal outcomes.

Adolescent↗
PubMed2006

Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption.

BACKGROUND: Pemphigus vulgaris is a life-threatening autoimmune blistering skin disease, usually treated with high-dose corticosteroids in combination with other immunosuppressants. However, this regimen may prove inadequate in severe cases and can cause dangerous side-effects. We have recently reported protein A immunoadsorption (PAIA) to be an effective adjuvant treatment for induction of remission in severe pemphigus. However, in a significant number of cases, the disease rapidly recurred once PAIA and immunosuppressive medication were tapered. AIMS: The aim of the present study was to develop a PAIA-based therapeutic regimen that would result in a more prolonged remission of pemphigus. METHODS: Nine patients with pemphigus vulgaris were treated with a modified protocol characterized by a combination of PAIA with a higher initial dose of systemic methylprednisolone (2 mg/kg). In addition, azathioprine or mycophenolate mofetil was administered as a steroid-sparing agent. RESULTS: In all nine patients treated with this regimen, we observed a sharp decline of circulating autoantibody levels and dramatic improvement of cutaneous and mucosal lesions within 4 weeks of therapy. The patients remained free of clinical disease for up to 26 months after PAIA treatment was discontinued. CONCLUSION: The improved treatment protocol appears to combine highly effective induction of clinical remission in severe or treatment-resistant pemphigus with a prolonged subsequent symptom-free interval.

Aged↗
PubMed2006

Electrogenic ammonium transport by renal Rhbg.

The recently cloned, non-erythrocyte Rh glycoproteins (Rhbg and Rhcg) are expressed in the intercalated cells of the renal collecting duct. The apical Rhcg and the basolateral Rhbg are likely involved in NH3 and/or NH4+ transport, yet the characteristics of this transport are not yet certain. In this study we investigated the mechanism of NH4+ transport by Rhbg and Rhcg expressed in Xenopus oocytes. We used a two-electrode voltage-clamp and ion-selective microelectrodes to measure NH4+-induced currents (I(NH4)) and changes in pHi, respectively. In oocytes expressing Rhcg, exposure to bath [NH4+] of 2.5-20 mM induced inward currents that were slightly more than those in H2O-injected (control) oocytes. I-V plots in the presence of NH4+ showed a small increase in slope conductance only at positive potentials. On the other hand, in oocytes expressing Rhbg, 5 mM NH4+ induced an inward I(NH4) of -79 nA, decreased pHi (DeltapHi) by 0.13 at a rate (dpHi/dt) of -2 7 x 10(-4) pH/s and depolarized the cell by 45 mV. These changes were significantly more than those in control oocytes. I-V plots in the presence of NH4+ showed substantial increase in conductance. Amiloride (1 mM) inhibited I(NH4), DeltapHi and dpHi/dt in oocytes expressing Rhbg but not in control oocytes. Raising bath [NH4+] in increments from 1 to 20 mM elicited a faster dpHi/dt, a larger decrease in pHi and a larger depolarization. Net NH4+ flux by Rhbg (estimated from dpHi/dt) was proportional to [NH4+] gradient and followed saturation kinetics with an apparent Km of 2.3 mM. Methyl ammonium (5 mM) induced a current of -63 nA in Rhbg oocytes but did not cause any change in control oocytes. These data indicate that: 1) Rhbg transport of NH4+ is electrogenic. 2) Methyl ammonium is transported by Rhbg. 3) NH4+ transport by Rhbg is saturated at high concentrations with Michaelis-Menten kinetics.

Amiloride↗
PubMed2006

Effect of Flt3 ligand gene transfer in experimental pancreatic cancer.

BACKGROUND: Fms-like tyrosine kinase 3 receptor (Flt3) is an important receptor expressed on the cell membrane of immature antigen-presenting cells. The binding of Flt3 to its ligand (FL) activates the proliferation of dendritic cells (DCs). This mechanism is currently being evaluated in the therapy of malignant tumors. The aim of the present study was to study the effect of FL gene transfer on the immune response and tumor growth in experimental pancreatic cancer. MATERIALS AND METHODS: The rat FL was sequenced and cloned from total mRNA extract of the spleen. Transfection efficiency of subcutaneously growing rat duct-like pancreatic cancer (DSL6A) with DOTAP-/cholesterol-based liposomes was tested using a pcDNA3.1-lacZ construct. Flt3 ligand production of in vitro transfected tumor cells and in vivo transfected tumors was measured by enzyme-linked immunosorbent assay. Tumor induction was achieved in Lewis rats by a subcutaneous inoculation of syngeneic pancreatic tumor cells (DSL6A). The animals were allocated into three groups: control, mock treatment, and treatment with FL plasmid. The plasmid was injected intratumorally three times per week for 2 weeks. The total observation time was 6 weeks. RESULTS: The tumor volume was significantly lower in the FL-transfected group during the first 3 weeks. The number of responders was significantly higher in the FL group compared with control and mock treatment. The number of CD80+ DCs in the spleen was significantly higher after FL gene transfer. The responders showed a significantly higher number of splenic natural killer (NK) cells. There were no differences of infiltrating lymphocytes, proliferation, and tumor blood vessels between the groups. CONCLUSION: Intratumoral gene transfer of FL in rats activated proliferation of DCs and NK cells, which causes a moderate reduction of tumor growth. This improvement of local tumor control during the first weeks could be explained by an improved antigen presentation.

Adenocarcinoma↗
PubMed2006

[Measurement of peripapillary nerve fiber layer thickness at different distances from the optic nerve head with OCT].

PURPOSE: The aim of this study was to assess which distance to the optic nerve head is most favorable for circular measurements of retinal nerve fiber layer thickness (RNFLT) with OCT to detect differences between glaucoma and normal subjects. METHODS: A total of 98 eyes of 67 subjects (normal subjects and POAG patients) were examined by Stratus OCT (Zeiss, Model 3000, Software Version 2.0). Images were scanned in the "proportional circle" mode and analyzed with the "RNFL thickness analysis" protocol. For statistical analysis the Friedman test and the Mann-Whitney U test with Bonferroni correction were used. RESULTS: For 23 normal and 19 eyes of POAG patients a complete set of scans could be analyzed by the OCT software. RNFLT was statistically significantly different in scan diameters in both groups (P=0.000). Differences between the groups were statistically significant for the 1.0-fold (P=0.003), for the 1.4-fold (P=0.01), and for the 1.8-fold (P=0.002) disc diameter. CONCLUSION: Circular scans with a 1-fold and with a 1.8-fold disc diameter seem to be able to differentiate best between glaucoma and normal subjects.

Adolescent↗
PubMed2006

[Comparative measurements of central corneal thickness with two ultrasound pachymeters].

BACKGROUND: The aim of this study was to compare two different ultrasound pachymeters based on measurements of central corneal thickness (CCT). METHODS: CCT of 1,070 eyes of 535 patients (glaucoma and glaucoma suspects) was determined using the ultrasound pachymeter IOPac (Heidelberg Engineering, Germany) and SP-3000 (Tomey Corporation, Japan). With the IOPac 8 measurements are averaged by the instrument and with the SP-3000 200 measurements, respectively. For statistical purposes intraclass correlation coefficients (ICC) and Bland-Altman analysis were calculated. RESULTS: The mean CCT was 561.3+/-35.6 microm (IOPac) and 561.8+/-35.6 microm (SP-3000). The mean difference between both pachymeters was 0+/-8 microm. ICC was 0.9746 (95% confidence interval: 0.9714-0.9774). CONCLUSIONS: The use of the two instruments tested has no influence on the determination of CCT. The measured CCT of glaucoma patients or suspects were slightly above the CCT of normals of other studies.

Adolescent↗
PubMed2006

Rituximab in refractory autoimmune bullous diseases.

Treatment of autoimmune blistering diseases consists of systemic glucocorticosteroids usually in combination with additional immunosuppressants such as azathioprine and mycophenolate mofetil or immunomodulators such as dapsone, antibiotics, intravenous immunoglobulins, and immunoadsorption. In some patients, these treatment regimens are not sufficient to control disease activity and/or lead to intolerable adverse events. Rituximab, originally developed for the treatment of non-Hodgkin's lymphoma, is an anti-CD20 humanized monoclonal antibody leading to transitory B-cell depletion. For this indication, rituximab is widely employed, and severe side-effects rarely observed. Subsequently, the B-cell-depleting effect of rituximab has been exploited successfully in various autoimmune disorders, including autoimmune blistering diseases. Here, we review the effect of rituximab in such diseases. To date, application of rituximab has been reported in 26 treatment-resistant patients with the vulgaris, foliaceus, and paraneoplastic variants of pemphigus as well as in bullous pemphigoid and epidermolysis bullosa acquisita. All but a single patient showed clinical improvement with reduction of lesion formation. In about a third, a clinical remission requiring further immunsuppressive medication was achieved, and in about a quarter, complete remission was induced. In addition, the mode of action and adverse events of rituximab as well as adjuvant immunosuppressive treatments, and the effect on levels of circulating autoantibodies in these patients are discussed.

Antibodies, Monoclonal↗
PubMed2005

Reactome: a knowledgebase of biological pathways.

Reactome, located at http://www.reactome.org is a curated, peer-reviewed resource of human biological processes. Given the genetic makeup of an organism, the complete set of possible reactions constitutes its reactome. The basic unit of the Reactome database is a reaction; reactions are then grouped into causal chains to form pathways. The Reactome data model allows us to represent many diverse processes in the human system, including the pathways of intermediary metabolism, regulatory pathways, and signal transduction, and high-level processes, such as the cell cycle. Reactome provides a qualitative framework, on which quantitative data can be superimposed. Tools have been developed to facilitate custom data entry and annotation by expert biologists, and to allow visualization and exploration of the finished dataset as an interactive process map. Although our primary curational domain is pathways from Homo sapiens, we regularly create electronic projections of human pathways onto other organisms via putative orthologs, thus making Reactome relevant to model organism research communities. The database is publicly available under open source terms, which allows both its content and its software infrastructure to be freely used and redistributed.

Animals↗
PubMed2005

Concept of "true ICP" in monitoring and prognostication in head trauma.

OBJECTIVE: To propose a new coefficient, which contains information about both the absolute ICP and the position of the 'working point' on the pressure-volume curve. METHOD: ICP was monitored continuously in 187 sedated and ventilated patients. The RAP coefficient was calculated as the running (3 minutes) correlation coefficient between slow changes in pulse amplitude and mean ICP. RAP has value 0 on the flat part of the Pressure-Volume Curve and +1 on the ascending exponential part. Then RAP decreases to zero or becomes negative when ICP increases further and affects cerebrovascular pressure-reactivity (which flattens the pressure-volume curve). Variable tICP = ICP* (1 - RAP) has been called 'trueICP'. It magnifies the critical values of ICP when cerebrovascular reactivity is exhausted and dampens those states where absolute ICP is elevated but vascular reactivity is not affected. RESULTS: Both Mean ICP and RAP were independently correlated with outcome (ANOVA:ICP-GOS: F = 22; p < 0.00001, RAP-GOS: F = 9; p < 0.001). 'TrueICP' had stronger association with outcome: F = 28; p < 0.000001. Mortality in those patients having 'trueICP' above the threshold of 19 mm Hg was above 80%, while the mortality in those having cICP below 19 mm Hg was only 20% (F = 80; p < 10(-8)). 'TrueICP' was also suitable for continuous monitoring: sustained rise in tICP above 19 mm Hg was strongly associated with fatal complications. CONCLUSION: The proposed variable is a powerful predictor of fatal outcome following head injury. It is sensitive to both the rising absolute ICP and the critical loss of cerebrovascular regulation.

Adolescent↗
PubMed2005

Reconstructed epidermis versus human and animal skin in skin absorption studies.

European chemical policy in general and the REACH initiative in particular will increase the number of chemical substances submitted to toxicological evaluation by several orders of magnitude compared to the current status. To limit animal exposure the resulting enormous increase in testing, however, asks for validated in vitro test systems. While the OECD favours in vitro testing for cutaneous absorption using viable human and animal skin (Guideline 428) the availability of viable human skin is already limited today. We present a comparison of various in vitro techniques suitable for routine skin absorption studies including commercially available reconstructed human epidermis which may be a reliable alternative to excised human and animal skin. In order to develop a protocol for the subsequent transfer to partner laboratories the experimental set-up was analysed stepwise using the OECD reference compounds caffeine and testosterone. Franz cell type, the donor and receptor media for hydrophilic/lipophilic substances, albumin and tensid addition, and storage conditions of the excised skins were systematically varied. A protocol has been developed which now allows to proceed to the pre-validation process.

Administration, Topical↗
PubMed2004

Intracranial hypertension: what additional information can be derived from ICP waveform after head injury?

OBJECTIVE: Although intracranial hypertension is one of the important prognostic factors after head injury, increased intracranial pressure (ICP) may also be observed in patients with favourable outcome. We have studied whether the value of ICP monitoring can be augmented by indices describing cerebrovascular pressure-reactivity and pressure-volume compensatory reserve derived from ICP and arterial blood pressure (ABP) waveforms. METHOD: 96 patients with intracranial hypertension were studied retrospectively: 57 with fatal outcome and 39 with favourable outcome. ABP and ICP waveforms were recorded. Indices of cerebrovascular reactivity (PRx) and cerebrospinal compensatory reserve (RAP) were calculated as moving correlation coefficients between slow waves of ABP and ICP, and between slow waves of ICP pulse amplitude and mean ICP, respectively. The magnitude of 'slow waves' was derived using ICP low-pass spectral filtration. RESULTS: The most significant difference was found in the magnitude of slow waves that was persistently higher in patients with a favourable outcome (p<0.00004). In patients who died ICP was significantly higher (p<0.0001) and cerebrovascular pressure-reactivity (described by PRx) was compromised (p<0.024). In the same patients, pressure-volume compensatory reserve showed a gradual deterioration over time with a sudden drop of RAP when ICP started to rise, suggesting an overlapping disruption of the vasomotor response. CONCLUSION: Indices derived from ICP waveform analysis can be helpful for the interpretation of progressive intracranial hypertension in patients after brain trauma.

Adolescent↗
PubMed2004

Evidence of downregulation of matrix extracellular phosphoglycoprotein during terminal differentiation in human osteoblasts.

Matrix extracellular phosphoglycoprotein (MEPE) is an extracellular matrix protein that was first detected in tumor-induced osteomalacia (TIO). Investigations in mice revealed that MEPE is expressed in bone and teeth in a maturation-dependent manner, reaching its maximum during mineralization. However, from knockout experiments, although it has become clear that MEPE might function as a mineralization inhibitor, the exact mechanism of action is still unclear. Even less is known about the regulation of MEPE in men. Therefore, we have studied the time- and maturation-dependent expression of MEPE in two human osteoblast culture systems, the osteosarcoma cell line HOS 58 and primary trabecular osteoblasts. Cells were cultured for up to 29 days, and the influence of beta-glycerophosphate (bGP), ascorbate, transforming growth factor beta (TGF-beta), BMP-2, and dexamethasone was studied. HOS 58 cells showed no significant effect on MEPE gene expression up to 5.0 mM, but a significant inhibition was revealed at 10 and 20 mM, when osteocalcin (OC) expression was maximal. Under the same conditions, primary human osteoblasts showed no effect on MEPE gene expression. However, when cultured in the presence of 5 mM beta-glycerophosphate, ascorbate, and dexamethasone for 29 days, which are similar conditions to those described by Owen in his differentiation model in rat osteoblasts, a progressive inhibition of MEPE gene expression to 20% of the maximum was observed. Increasing osteocalcin expression indicated advancing differentiation. In conclusion, in contrast to the results in mice, when MEPE was maximally expressed during mineralization, in the human system, this factor seems to be maximally active in the proliferation and early matrix maturation phase. It was, however, strongly suppressed, associated with the mineralization phase.

Adult↗
PubMed2004

Comparative analysis of extracellular matrix proteins in chronic pancreatitis: differences between pancreatic head and tail.

OBJECTIVES: In patients with chronic pancreatitis (cP) with an inflammatory mass in the pancreatic head, the degree of fibrosis in the pancreatic head compared with the tail should be determined and differences in the expression pattern of collagen types I, III, and IV; laminin; vitronectin; and fibronectin should be evaluated. METHODS: From 12 patients with alcohol-induced and idiopathic cP who underwent surgery due to local complications, 24 corresponding cP tissue samples from the pancreatic head and the resection margin were obtained. The degree of fibrosis was calculated using a computer-assisted method (Adobe Photo Shop). The expression pattern of extracellular matrix proteins (ECMPs) was investigated by immunostaining using the streptavidin-peroxidase technique. RESULTS: In each case, the degree of fibrosis was higher in the pancreatic head than in the resection margin. For alcohol-induced cP, the median degree of fibrosis in the head was 64% versus 47% in the resection margin, and for idiopathic cP, it was 40% versus 32%. Staining intensity of collagen type IV and laminin in the head was higher than in the resection surface. In degenerative tissue, collagen types I, III, and IV and laminin were moderately expressed, fibronectin was weakly expressed, and vitronectin was not expressed, with no differences between the head and resection margin. Basement membranes in the head and the resection margin predominantly consisted of collagen types I, III, and IV and laminin. In ductal epithelia, collagen type IV staining in the head was stronger than in the resection margin. CONCLUSIONS: In cP with an inflammatory mass in the head, the degree of fibrosis in the pancreatic head is higher than in the resection margin. Differences in the expression pattern of ECMPs could be detected for collagen type IV and laminin. These results underline the hypothesis of the pancreatic head being the pacemaker of cP in which collagen type IV and laminin may play an important role.

Adult↗
PubMed2004

Elevated expression and release of tissue-type, but not urokinase-type, plasminogen activator after binding of autoantibodies to bullous pemphigoid antigen 180 in cultured human keratinocytes.

In bullous pemphigoid (BP), the binding of BP180-specific antibodies to their hemidesmosomal target antigen is not sufficient for blister formation, but must be accompanied by the release of proteases. Using plasminogen activator (PA) knock-out mice, the PA system has previously been shown to be a prerequisite for blister formation in experimental murine BP. Here, we found elevated levels of plasmin and tPA, but not of uPA, in blister fluid from BP patients (n = 7) compared to blisters from patients with toxic epidermal necrolysis (n = 4) and suction blisters in healthy controls (n = 7). Subsequently, we addressed the question whether keratinocytes release PA in response to the binding of anti-BP180 antibodies. Treatment of cultured normal human keratinocytes with BP IgG, but not with control IgG, led to both increased protein and mRNA levels of tPA, but not of uPA, as determined by ELISA and RT-PCR, respectively. The specificity of this finding was confirmed using BP180-deficient keratinocytes from a patient with generalized atrophic benign epidermolysis bullosa, where no tPA release was observed after stimulation with BP IgG. Our results show the elevated expression and release of tPA from normal human keratinocytes upon stimulation with antibodies to human BP180. Keratinocytes, by secreting tPA, may thus play an active role in blister formation of BP.

Autoantibodies↗