Biomedical subjects

A Kern

Publications and source records attributed to A Kern.

At least 19 recordsLinked to original sources

PubMed2004

Fast spike pattern detection using the correlation integral.

Conventional approaches to detect patterns in neuronal firing are template based. As the pattern length increases, the number of trial patterns to be tested leads to strongly divergent computational costs. To remedy this problem, we propose a different statistical approach, based on the correlation integral. Applications of our method to model and neuronal data demonstrate its reliability, even in the presence of noise. Additionally, our investigation provides interesting insights into the nature of correlation-integral anomalies.

Action Potentials↗

PubMed2004

Essential auditory contrast-sharpening is preneuronal.

Contrast-sharpening is a fundamental feature of mammalian sensory perception. Whereas visual contrast-sharpening has been fully understood in terms of the retinal neuronal wiring [DeVries, S. H. & Baylor, D. A. (1993) Cell 72, Suppl., 139-149], a corresponding explanation of auditory contrast-sharpening is still lacking. Here, we show that the essentials of auditory contrast-sharpening can be explained by using cochlear biophysics. This finding indicates that the phenomenon is basically of preneuronal origin.

Acoustic Stimulation↗

PubMed2004

Limit cycles, noise, and chaos in hearing.

Based on insight obtained from a newly developed cochlea model, we argue that noise-driven limit cycles are the basic ingredient in the mammalian cochlea hearing process. For insect audition, we provide evidence in favor of the persistence of this principle. We emphasize the role of bifurcations for the emergence of broad-range sound perception, both in the frequency and amplitude domain, and indicate that this crucially depends on the correct coupling between limit cycles. We review the limit-cycle coupling universality, and outline how it can be used to encode information. Cortical noise is the microscopic basis for this encoding, whereas chaos emerges as the macroscopic expression of computation being done in the network. Large neuron firing variability is one possible consequence of the proposed mechanism that may apply to both vertebrate and insect hearing.

Animals↗

PubMed2003

Essential Role of Couplings between Hearing Nonlinearities.

Hopf-type nonlinearities have been recently found to be the basic mechanism of the mammalian cochlear response. Physiology requires that these nonlinearities be coupled. By suitably implementing a biomorphic coupling scheme of cochlear nonlinearities, we obtain a simple cochlea model that faithfully reproduces measured basilar membrane response, validating the utility of the Hopf amplifier concept. Our results demonstrate that the correct coupling between nonlinearities is as important as the nonlinearities themselves.

Animals↗

PubMed2003

Identification of a heparin-binding motif on adeno-associated virus type 2 capsids.

Infection of cells with adeno-associated virus (AAV) type 2 (AAV-2) is mediated by binding to heparan sulfate proteoglycan and can be competed by heparin. Mutational analysis of AAV-2 capsid proteins showed that a group of basic amino acids (arginines 484, 487, 585, and 588 and lysine 532) contribute to heparin and HeLa cell binding. These amino acids are positioned in three clusters at the threefold spike region of the AAV-2 capsid. According to the recently resolved atomic structure for AAV-2, arginines 484 and 487 and lysine 532 on one site and arginines 585 and 588 on the other site belong to different capsid protein subunits. These data suggest that the formation of the heparin-binding motifs depends on the correct assembly of VP trimers or even of capsids. In contrast, arginine 475, which also strongly reduces heparin binding as well as viral infectivity upon mutation to alanine, is located inside the capsid structure at the border of adjacent VP subunits and most likely influences heparin binding indirectly by disturbing correct subunit assembly. Computer simulation of heparin docking to the AAV-2 capsid suggests that heparin associates with the three basic clusters along a channel-like cavity flanked by the basic amino acids. With few exceptions, mutant infectivities correlated with their heparin- and cell-binding properties. The tissue distribution in mice of recombinant AAV-2 mutated in R484 and R585 indicated markedly reduced infection of the liver, compared to infection with wild-type recombinant AAV, but continued infection of the heart. These results suggest that although heparin binding influences the infectivity of AAV-2, it seems not to be necessary.

Amino Acid Motifs↗

PubMed2002

Association of p53 mutations, microvessel density and neoangiogenesis in pairs of colorectal cancers and corresponding liver metastases.

p53 suppressor gene mutations are a well known step which occurs in the late stages of the complex tumourigenesis of colorectal cancer. A deregulation of p53 protein function may be associated with increased neovascularization and aggressive tumour growth. In vitro studies have shown that these genetic alterations cause a loss of wild-type p53-induced anti-angiogenetic control and could possibly induce expression of the neoangiogenic vascular endothelial growth factor (VEGF). Therefore, this in vivo study was performed to assess p53 mutations, i.e. hot spots in exons 4-9, in primary colorectal cancers and in corresponding liver metastases in order to test whether there is an association between p53 mutated tumours with increased microvessel density (MVD) and VEGF overexpression. Twenty-two tissue samples taken from primary colorectal cancers and the corresponding liver metastases were immediately snap-frozen in liquid nitrogen and fixed in formaldehyde. After DNA extraction exons 4-9 were amplified and directly sequenced. Cryostat sections were stained immunohistochemically using antibodies against VEGF, CD34, and p53 protein. A modified semiquantitative Weidner score and interactive computerized image analysis was used to assess MVD. Overexpression of immunohistochemically detected p53 protein was found in 7 of the 11 primary tumours and liver metastases (64%). Sequencing showed 3 out of 11 primary tumours (27%) and 5 out of 11 liver metastases (46%) to have p53 point or frameshift mutations; these samples tested immunohistochemically positive for p53 protein. Two p53 mutations in samples of liver metastases were not detectable in the corresponding primaries. We detected one frameshift mutation in exon 4 that has not yet been described in the literature. Tumour samples with p53 mutations and increased VEGF immunoreactivity were associated with higher MVD (p<0.01 and p<0.05, respectively). However, there was no association detected immunohistochemically between p53 and MVD as well as p53 mutations and VEGF overexpression. Our data demonstrate specific genetic alterations in the coding regions of p53 suppressor gene in both primary colorectal cancers and corresponding liver metastases, these alterations are associated with an increase in MVD, but not in VEGF overexpression. In addition, a novel frameshift mutation in both colorectal cancer and metastasis is described.

Antigens, CD34↗

PubMed2001

Induction of sTNF-R1 and sTNF-R2 by interferon beta-1b in correlation with clinical and MRI activity.

OBJECTIVES: To investigate the influence of interferon (IFN) beta-1b on the serum levels of sTNF-R1, sTNF-R2 and TNF-beta in patients with multiple sclerosis (MS) in correlation with clinical and MRI activity. MATERIALS AND METHODS: Serum samples were obtained every 3 months from 24 patients treated with 8 x 10(6) U of IFN beta-lb every other day (treatment group) and from 21 patients without any immunomodulatory therapy (control group) over a 15-month observation period. The cytokine levels were measured by ELISA. Cranial MRI was performed every 6 months to determine the burden of disease of every patient. RESULTS: In the treatment group we found an obvious increase of sTNFR1 and sTNF-R2 (P < 0.001) and relatively stable serum levels of TNFbeta with no statistical significance (P = 0.56). In the control group, sTNF-R1 showed a significant decrease (P < 0.001) during the same observation period of 15 months. During the 15-month observation period, the MRI-responders group had significant larger mean AUC (area under the concentration-time curve) values of sTNF-R1 (P = 0.04) and sTNF-R2 (P = 0.01) when compared to the group of MRInonresponders. CONCLUSION: The present data suggest that IFN beta-1b induces the expression and shedding of TNF-R1 and TNF-R2. The magnitude of an increase of sTNF-Rs may be a marker for the effectiveness of treatment with IFN beta-1b.

Adjuvants, Immunologic↗

PubMed2001

Modification of fibroblast gamma-interferon responses by extracellular matrix.

Fibroblasts from scaffold-based three-dimensional human cultures have been demonstrated to colonize ulcer wound beds and persist for at least 6 mo without rejection. This study examines the expression in these cultures of molecules associated with activation of the immune system in acute rejection. Studies in monolayer cultures showed that fibroblasts expressed CD40 at about 10% of the surface density seen in umbilical vein endothelial cells, whereas HLA-DR was undetectable. In these cultures, both molecules were induced by gamma-interferon. In scaffold-based three-dimensional cultures, however, a majority of the fibroblasts showed little induction of CD40 and HLA-DR in response to gamma-interferon, although HLA class I expression was increased. Fibroblasts re- isolated from the three-dimensional cultures and cultured in monolayers recovered HLA-DR induction in response to gamma-interferon. Fibroblasts cultured in an alternative three-dimensional system using collagen gels showed CD40 and HLA-DR induction by gamma-interferon in the same manner as monolayer cultures. Comparison of phosphorylation of signal transducer and activator of transcription 1 on tyrosine-701 showed it to be similar in monolayer and three-dimensional culture, and phospho-signal transducer and activator of transcription 1 moved into the nucleus. Induction of the class II transcription activator was greatly reduced, however. We propose that interaction of fibroblasts with the fibroblast-derived extracellular matrix is an important modulator of gamma-interferon responsiveness and that this interaction may play a role in the low immunogenicity of allogeneic fibroblasts grown on scaffolds.

Antigens, CD↗

PubMed2001

[Hydro-MRI in inflammatory bowel diseases: a comparison with colonoscopy and histology].

PURPOSE: To compare hydro-MRI with colonoscopy and biopsy specimen regarding the assessment of inflammatory activity and the differentiation of inflammatory bowel diseases. MATERIAL AND METHODS: After an oral bowel opacification using 1000 ml of a 2.5% mannitol solution and a rectal bowel opacification using 250-500 ml of a 0.9% saline solution, axial and coronal breath-hold sequences +/- Gd-DTPA (HASTE-["half-Fourier acquisition single-shot turbo spin echo"] and dynamic FLASH-["fast low angle shot"]) were acquired in 27 patients with inflammatory bowel disease. The enhancement of the bowel wall as well as morphological MRI findings were correlated with colonoscopy and biopsy specimens. By means of the MRI findings, Crohn's disease (CD) and ulcerative colitis (UC) should be differentiated. RESULTS: In CD, a significant correlation between the contrast enhancement of the inflamed bowel wall (delta SI) and the endoscopic/histopathologic indices could be established (r = 0.52; p = 0.02 and r = 0.72; p = 0.001). In UC, no correlations between delta SI and the endoscopic/histopathologic indices could be found. The correct diagnosis of CD and UC by MRI findings was possible in 22/27 patients (81%). CONCLUSION: Hydro-MRI with dynamic studies is suitable for the assessment of disease activity in CD, but unreliable in UC. Hydro-MRI provides useful information for the differentiation of CD and UC.

Adolescent↗

PubMed2001

[Hydro-MRI for abdominal diagnostics in children].

PURPOSE: A clinical evaluation of hydro-MRI as an alternative method to barium studies in children with abdominal pain of unknown origin is presented. PATIENTS AND METHODS: 20 children with abdominal pain of unknown origin aged from 9 - 16 years were examined after oral bowel opacification using 1000 ml of 2.5 % mannitol solution with a 1.0 T MRI system. The investigation was done in 2 planes (coronal and axial) under breath-hold conditions. Imaging procedures included various sequences (T2W HASTE + FS, contrast-enhanced T1W FLASH FS). Suspicious findings in bowel segments and extra-intestinal changes were assessed. RESULTS: In 21/24 examinations the small bowel was completely visualized, in 15/24 cases colon segments were identified. An accurate assessment of the terminal ileum was not possible in 3/24 procedures. Breathing artefacts occurred in 3/24 examinations. Signs of Crohn's disease were found in 4 examinations, inflammatory changes of the ileum were detected in 3 cases. Inflammation of the colon was demonstrated in 2 children. Furthermore, pathological findings included constipation in one child and inflammation of the ileo-colic and mesenterial lymph nodes were found in another child. Extra-intestinal changes in 3 children were caused by ovarian cysts, and in one case by pleural effusion. In 4 examinations we detected ascites in the absence of other pathological findings. In 5 children there was no pathological correlation in the bowel or extra-intestinal region for the complaints. The children tolerated the hydro-MRI very well. There were no side effects using oral mannitol. CONCLUSION: Hydro-MRI is a valuable non-invasive method in the diagnosis of abdominal pain of unknown origin. In children it should be the method of choice because it further offers the advantage of the absence of ionizing radiation. Patient compliance is a prerequisite for this new examination. In our experience this requirement was met in children older than 9 years. Further studies should prove the necessity of conventional radiology following negative hydro-MRI.

Abdominal Pain↗

PubMed2000

Expression and characterization of the N- and C-terminal ATP-binding domains of MRP1.

The His(6)-tagged N- and C-terminal nucleotide binding (ATP Binding Cassette, ABC) domains of the human multidrug resistance associated protein, MRP1, were expressed in bacteria in fusion to the bacterial maltose binding protein and a two-step affinity purification was utilized. Binding of a fluorescent ATP-analogue occurred with micromolar dissociation constants, MgATP was able to inhibit the ATP-analogue binding with 70 and 200 micromolar apparent inhibition constants, while AMP was nearly ineffective. Both MRP1 nucleotide binding domains showed ATPase activities (V(max) values between 5-10 nmoles/mg protein/min), which is fifty to hundred times lower than that of parent transporter. The K(M) value of the ATP hydrolysis by the nucleotide binding domains were 1.5 mM and 1.8 mM, which is similar to the K(M) value of the native or the purified and reconstituted transporter, N-ethylmaleinimide and A1F(4) inhibited the ATPase activity of both nucleotide binding domains.

Adenosine Triphosphatases↗

PubMed2000

Pharmacokinetics of ropivacaine during extradural anesthesia for total hip replacement.

STUDY OBJECTIVE: To determine plasma concentrations of ropivacaine during epidural anesthesia with ropivacaine 10 mg/mL in patients undergoing elective total hip replacement. DESIGN: Phase III prospective study. SETTING: Orthopedic surgical unit of the University Hospital in Kiel, Germany PATIENTS: 11 ASA physical status I, II, and III patients undergoing elective total hip replacement after premedication with a benzodiazepine. INTERVENTIONS: Peripheral venous plasma samples were collected prior to and 10, 15, 20, 30, 45, 60, 90, and 120 minutes following the epidural dose. MEASUREMENTS AND MAIN RESULTS: After solid phase extraction, plasma concentrations of ropivacaine were measured by high-performance liquid chromatography (HPLC). Free unbound concentrations were determined after ultracentrifugation. In 9 of 11 patients excellent epidural anesthesia was achieved with an initial dose of 144 +/- 13 mg (120 to 150 mg) of ropivacaine corresponding to a dose of 1.9 +/- 0.4 mg/kg body weight. We suspected inadvertent intravascular catheter malposition in one case. Peak plasma concentrations occurred after 20 minutes (10 to 30 min) with a mean of 1.38 +/- 0.42 micrograms/mL (range 0.95 to 2.26 micrograms/mL). Maximum unbound free plasma concentrations of ropivacaine were 0.05 +/- 0.03 microgram/mL (range 0.02 to 0.13 microgram/mL). CONCLUSION: Ropivacaine 10 mg/mL proved to be suitable for epidural anesthesia for total hip replacement. The plasma concentrations after 120 to 200 mg of its epidural application were not associated with signs of local anesthetic toxicity in patients pretreated with benzodiazepines, even in one case of suspected inadvertent intravascular application.

Adult↗

PubMed2000

Soluble and cell surface ICAM-3 in blood and cerebrospinal fluid of patients with multiple sclerosis: influence of methylprednisolone treatment and relevance as markers for disease activity.

OBJECTIVE: The expression of intercellular adhesion molecule-3 (ICAM-3), a member of the Ig supergene family, is restricted to immune competent cells. Expression of soluble and cell surface ICAM-3 (s- and c-ICAM-3) is preferentially seen in the state of low activation of the immune system. We studied the relevance of the expression levels of s- and c-ICAM-3 in cerebrospinal fluid (CSF) and blood as markers for disease activity as well as the influence of high-dose methylprednisolone (MP) treatment upon the expression of s- and c-ICAM-3 in blood of patients with multiple sclerosis (MS). MATERIALS AND METHODS: A total of 33 patients (relapses n = 25, remission n = 8) with relapsing-remitting MS were included into the study. CSF and blood were acquired from all of them. Of the patients 24 were treated with high-dose MP. In those, blood was additionally collected at the 10th day of the therapy and after 3 months. Expression of c-ICAM-3 was determined by two colour FACS analysis, whereas the concentration levels of s-ICAM-3 were measured by ELISA. RESULTS: In CSF we detected a significant decrease of the expression levels of c-ICAM-3 on CD3+ T cells in 25 patients suffering from an acute relapse in contrast to 8 patients with remission (P= 0.04). In comparison to the levels before treatment and after 3 months, at the 10th day of MP treatment we obtained highly significant changes of the expression values of c-ICAM-3 both on CD3+ T cells (P = 0.0004; P= 0.005) and CD14+ monocytes/macrophages (P =0.0006; P=0.008) on the 10th day of high-dose MP treatment from 24 MS patients. CONCLUSION: The increase of ICAM-3 levels might indicate the anti-inflammatory effect of the MP treatment. It could be interesting to search for similar effects investigating the new immune modulatoring therapy forms of MS.

Acute Disease↗

PubMed2000

Three-dimensional transcranial colour-coded duplex sonography of the transverse sinus.

The case of a patient with partial superior sagittal sinus and partial right sided transverse sinus thrombosis, and posterior fossa venous collaterals is presented. We report on the use of venous transcranial colour-coded duplex sonography (TCCS), combined with a new three-dimensional transcranial duplex data acquisition system, which allows free hand scanning of the region of interest. TCCS with three-dimensional image reconstruction allowed a more precise spatial localization of venous flow signals in the posterior fossa and facilitated the understanding of the haemodynamics of the venous collateral network.

Adult↗

PubMed2000

[Assessment of inflammatory activity in Crohn disease with hydro-MRI].

PURPOSE: To assess the value of hydro-MRI in the assessment of the activity of Crohn's disease. MATERIALS AND METHODS: After an oral bowel opacification using 1000 ml of a 2.5% mannitol solution, axial and coronal breath-hold sequences (T2W HASTE +/- FS, contrast-enhanced T1W FLASH FS) were acquired in 63 patients with Crohn's disease at 1.0 T. The enhancement of the bowel wall was correlated with other MRI findings, with the Crohn's disease activity index (CDAI), and the C-reactive protein (CRP). RESULTS: In Crohn's disease, contrast enhancement of the affected bowel wall is markedly increased in comparison with the normal bowel wall (+80 +/- 23% vs. +43 +/- 11%; p = 8 x 10(-11)). Positive correlations could be established between the increase of bowel wall enhancement and other MRI findings. Between the increase of bowel wall enhancement and the CDAI a poor correlation was found (r = 0.25; p = 0.046). There was no statistical correlation between the increase of bowel wall enhancement and the CRP (r = 0.09; p = 0.24). CONCLUSION: Hydro-MRI allows an assessment of the activity of Crohn's disease.

Adolescent↗

PubMed2000

Hydro-MRI in Crohn's disease: appraisal of disease activity.

RATIONALE AND OBJECTIVES: To appraise the value of hydro-MRI in the assessment of activity in Crohn's disease. METHODS: After bowel opacification with 1000 mL of an orally administered 2.5% mannitol solution was achieved, axial and coronal breath-hold sequences (T2-weighted half-Fourier acquisition single-shot turbo spin-echo sequences with or without fat saturation, dynamic T1-weighted fast low-angle shot sequences, and contrast-enhanced T1-weighted fast low-angle shot with fat saturation sequences) were acquired in 82 patients with proved Crohn's disease at 1.0 T. Enhancement of the bowel wall was correlated with other MRI findings, with the Crohn's disease activity index (CDAI), and with levels of C-reactive protein (CRP). RESULTS: In Crohn's disease, contrast enhancement of the affected bowel wall was markedly increased in comparison with the normal bowel wall (+80% +/- 22% versus +43% +/- 12%; P = 3 x 10(-15)). Positive correlations could be established between the increase in bowel wall enhancement and many other MRI findings. Between the increase in bowel wall enhancement and the CDAI, only a poor correlation was found (r = 0.25, P = 0.02). There was no statistical correlation between the increase in bowel wall enhancement and CRP. CONCLUSIONS: Hydro-MRI seems to be superior to the CDAI and CRP for the registration of Crohn's disease activity. In particular, differentiation between an active and an inactive (scarred) stenosis, which is crucial for the choice of therapeutic procedures, seems to be more reliable by the interpretation of several morphological and functional parameters on hydro-MRI than by the use of CDAI and CRP.

Adult↗

PubMed2000

Ergogenic aids.

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Dietary Supplements↗

PubMed1999

Titration of AAV-2 particles via a novel capsid ELISA: packaging of genomes can limit production of recombinant AAV-2.

We demonstrate the rapid and reliable quantification of physical AAV-2 (adeno-associated virus type 2) particles via a novel ELISA based on a monoclonal antibody which selectively recognizes assembled AAV-2 capsids. Titration of a variety of recombinant AAV-2 (rAAV) preparations revealed that at least 80+percent of all particles were empty, compared with a maximum of 50percent in wild-type AAV-2 stocks, indicating that the recombinant genomes were less efficiently encapsidated. This finding was confirmed upon titration of CsCl gradient fractions from recombinant and wild-type AAV-2 stocks. ELISA-based measurement of capsid numbers revealed a large number of physical particles with low densities corresponding to empty capsids in the recombinant, but not in the wild-type AAV-2 preparations. Moreover, additional expression of VP proteins during rAAV production was found to result in an excessive capsid formation, whilst yielding only minor increases in DNA-containing or transducing rAAV particles. We conclude that encapsidation of viral genomes rather than capsid assembly can be limiting for rAAV production, provided that a critical level of VP expression is maintained. The feasibility of quantifying AAV-2 capsid numbers via the ELISA allows determination of physical to DNA-containing or infectious particle ratios. These are important parameters which should help to optimize and standardize the production and application of recombinant AAV-2.

Antibodies, Monoclonal↗