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Biomedical subjects

K Muller

Publications and source records attributed to K Muller.

At least 19 recordsLinked to original sources
PubMed2003

A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32.

Developmental dyslexia is a distinct learning disability with unexpected difficulty in learning to read despite adequate intelligence, education, and environment, and normal senses. The genetic aetiology of dyslexia is heterogeneous and loci on chromosomes 2, 3, 6, 15, and 18 have been repeatedly linked to it. We have conducted a genome scan with 376 markers in 11 families with 38 dyslexic subjects ascertained in Finland. Linkage of dyslexia to the vicinity of DYX3 on 2p was confirmed with a non-parametric linkage (NPL) score of 2.55 and a lod score of 3.01 for a dominant model, and a novel locus on 7q32 close to the SPCH1 locus was suggested with an NPL score of 2.77. The SPCH1 locus has previously been linked with a severe speech and language disorder and autism, and a mutation in exon 14 of the FOXP2 gene on 7q32 has been identified in one large pedigree. Because the language disorder associated with the SPCH1 locus has some overlap with the language deficits observed in dyslexia, we sequenced the coding region of FOXP2 as a candidate gene for our observed linkage in six dyslexic subjects. No mutations were identified. We conclude that DYX3 appears to be important for dyslexia susceptibility in many Finnish families, and a suggested linkage of dyslexia to chromosome 7q32 will need verification in other data sets.

Chromosome Mapping↗
PubMed2001

Symbolic description of intracerebral vessels segmented from magnetic resonance angiograms and evaluation by comparison with X-ray angiograms.

We describe and evaluate methods that create detailed vessel trees by linking vessels that have been segmented from magnetic resonance angiograms (MRA). The tree-definition process can automatically exclude erroneous vessel segmentations. The parent-child connectivity information provided by our vessel trees is important to both surgical planning and to guidance of endovascular procedures. We evaluated the branch connection accuracy of our 3D vessel trees by asking two neuroradiologists to evaluate 140 parent-child connections comprising seven vascular trees against 17 digital subtraction angiography (DSA) views. Each reviewer rated each connection as (1) Correct, (2) Incorrect, (3) Partially correct (a minor error without clinical significance), or (4) Indeterminate. Analysis was summarized for each evaluator by calculating 95% confidence intervals for both the proportion completely correct and the proportion clinically acceptable (completely or partially correct). In order to protect the overall Type I error rate, alpha-splitting was done using a top down strategy. We additionally evaluated segmentation completeness by examining each slice in 11 MRA datasets in order to determine unlabeled vessels identifiable in cross-section following segmentation. Results indicate that only one vascular parent-child connection was judged incorrect by both reviewers. MRA segmentations appeared complete within MRA resolution limits. We conclude that our methods permit creation of detailed vascular trees from segmented 3D image data. We review the literature and compare other approaches to our own. We provide examples of clinically useful visualizations enabled by our methodology and taken from a visualization program now in clinical use.

Angiography, Digital Subtraction↗
PubMed2000

Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial.

OBJECTIVE: To determine whether treatment with creatine can improve exercise intolerance in myophosphorylase deficiency (McArdle disease). DESIGN: Double-blind, placebo-controlled crossover study with oral creatine monohydrate supplementation. PATIENTS: Nine patients with biochemically and genetically proven McArdle disease were treated. INTERVENTION: Five days of daily high-dose creatine intake (150 mg/kg body weight) were followed by daily low-dose creatine intake (60 mg/kg). Each treatment phase with creatine or placebo lasted 5 weeks. MAIN OUTCOME MEASURES: The effect of treatment was estimated at the end of each treatment phase by recording clinical scores, ergometer exercise test results, phosphorus 31 nuclear magnetic resonance spectroscopy, and surface electromyography. RESULTS: Of 9 patients, 5 reported improvement of muscle complaints with creatine. Force-time integrals (P =.03) and depletion of phosphocreatine (P =.04) increased significantly during ischemic exercise with creatine. Phosphocreatine depletion also increased significantly during aerobic exercise (P =.006). The decrease of median frequency in surface electromyograms during contraction was significantly larger (P =.03) with creatine. CONCLUSION: This is the first controlled study indicating that creatine supplementation improves skeletal muscle function in McArdle disease.

Administration, Oral↗
PubMed1999

Speed performance and long-term functional and vocational outcome in a group of young patients with moderate or severe traumatic brain injury.

We studied specific aspects of speed performance in neuropsychological tests and functional and vocational long-term outcome among moderate or severe traumatic brain injury (TBI) patients admitted to a rehabilitation programme. A group of 140 patients with mild, moderate or severe TBI was followed up for a minimum of 5 years in a rehabilitation programme. Severity of TBI was estimated using the Glasgow Coma Scale (GCS) scores on emergency hospital admission. The patients, grouped by age at injury into the categories: 7 or younger, 8-16 and 17 years of age or older, were tested five or more years post-injury with comprehensive neuropsychological tests, including a speed performance test with the Stroop material, the Purdue Pegboard (PB) test and simple visual and auditive reaction times. The outcome variables were functional outcome, as measured by the Glasgow Outcome Scale (GOS) score, and capacity for employment at the end of follow-up, i.e. on average 12 years post-injury. The patients with mild TBI were excluded from further analysis of outcome. The study was carried out at the Kauniala outpatient neurological clinic. In the Stroop test, patients with a GOS score of 3 and patients who were incapable of employment were slower (P = 0.0046 and P = 0.0015, respectively) than those with a GOS score of 1 or 2 and those capable of independent or subsidized employment, respectively. The PB test also differentiated significantly between the patients with a GOS score of 3 and those with a GOS score of 1 or 2 at the end of follow-up (P = 0.0413), and predicted incapacity for employment (P = 0.032), those with worse outcome being slower. Simple reaction times did not differ significantly between the GOS scores at the end of follow-up, and neither did they predict capacity or incapacity for employment. Our data suggest that the Stroop and PB tests can help estimate functional outcome, as measured by the GOS, among patients with initially moderate or severe TBI and who were referred to a rehabilitation programme. The same tests could also be useful in predicting long-term vocational outcome.

Adolescent↗
PubMed1999

High-energy-phosphates measured by 31P-MRS during LBNP in exercising human leg muscle.

Subatmospheric pressure applied to the human body from the iliac crest caudally (Lower Body Negative Pressure, LBNP) has been known to cause various central and peripheral cardiovascular reactions. We investigated the effects of such a LBNP maneuver on energy metabolism of human skeletal leg muscle. We tested the hypothesis whether an altered fluid distribution induced by LBNP may cause any effect on aerobic and/or anaerobic energy metabolism and cellular pH-regulation during isometric contraction monitored by 31P-MRS.

Energy Metabolism↗
PubMed1998

The hypothalamo-pituitary-adrenal axis of athymic Swiss nude mice. The implications of T lymphocytes in the ACTH release from immune cells.

Because of the well-known role of the thymus in the regulation of immune function, we investigated whether the lack of thymus may affect hypothalamo-pituitary-adrenal (HPA) axis activity. Eight-week-old female Swiss nude (athymic) and BALB/c (normal) mice were used to study (a) the "in vivo" response of the HPA axis to various stresses and stimuli acting at either hypothalamic, pituitary, or adrenal levels and (b) the "in vitro" response of pituitary and adrenal cells to CRH and ACTH stimulation, respectively. The results indicate that (1) basal plasma ACTH levels were significantly (p < 0.05) higher in Swiss nude than in BALB/c mice, whereas basal corticosterone (B) levels were similar in both strains of mice; (2) the stress-induced release of ACTH and B in plasma was significantly (p < 0.05) lower in Swiss nude than in BALB/c mice, regardless of the stimulus applied; (3) the "in vitro" pituitary response to CRH and the adrenal response to ACTH were significantly (p < 0.05) lower in Swiss nude than in BALB/c mice; and (4) whereas hypothalamic CRH and pituitary ACTH contents were similar in both strains, adrenal B content was significantly (p < 0.05) lower in athymic mice. Immune reconstitution of the athymic nude mice by injecting splenocytes obtained from syngeneic heterozygous (i.e., immunologically fully competent) donors produced a significant increase in the B adrenal content of the nude mice. Among the splenocytes, CD4+ T-lymphocytes play a particularly important role in the release of ACTH from cells of the immune system. In conclusion, our results indicate that athymic nude mice have a blunted HPA axis response to various stresses and stimuli; this defect seems to reside at both the pituitary and adrenal levels. Immune reconstitution of the nude mice leads to a normalization of the adrenal B content.

Adrenal Glands↗
PubMed1998

A possible role for soluble IL-6 receptor in the pathogenesis of systemic onset juvenile chronic arthritis.

Investigation of the agonist and two antagonists to interleukin 6 (IL-6) and their possible role in the pathogenesis of different sub-groups of juvenile chronic arthritis (JCA). Sera of 54 patients and 10 age-matched controls were tested: 20 with pauci-articular JCA, 12 with polyarticular JCA, and 22 systemic JCA. Interleukin 6, soluble interleukin 6 receptor (agonist), soluble gp130 and autoantibodies to IL-6 (antagonist to IL-6) were measured, as well as C-reactive protein as an indicator of disease activity. In addition, during fever two systemic JCA patients were analysed longitudinally for these parameters. There was a significant increase in soluble IL-6 receptor (sIL-6R) concentrations. No difference in the levels of soluble gp130 and autoantibodies to IL-6 in the systemic JCA group was found. In two patients the fever curves corresponded to the IL-6 levels measured. sIL-6R serum concentrations also showed a tendency to follow the fever. The authors have shown that in systemic JCA, the levels of sIL-6R, agonist of IL-6, were increased significantly compared to the other groups, while levels of antagonists to IL-6 were not changed in the face of increased levels of IL-6 in systemic JCA. These results suggest an imbalance of IL-6 homeostasis.

Arthritis, Juvenile↗
PubMed1998

Contrast limited adaptive histogram equalization image processing to improve the detection of simulated spiculations in dense mammograms.

The purpose of this project was to determine whether Contrast Limited Adaptive Histogram Equalization (CLAHE) improves detection of simulated spiculations in dense mammograms. Lines simulating the appearance of spiculations, a common marker of malignancy when visualized with masses, were embedded in dense mammograms digitized at 50 micron pixels, 12 bits deep. Film images with no CLAHE applied were compared to film images with nine different combinations of clip levels and region sizes applied. A simulated spiculation was embedded in a background of dense breast tissue, with the orientation of the spiculation varied. The key variables involved in each trial included the orientation of the spiculation, contrast level of the spiculation and the CLAHE settings applied to the image. Combining the 10 CLAHE conditions, 4 contrast levels and 4 orientations gave 160 combinations. The trials were constructed by pairing 160 combinations of key variables with 40 backgrounds. Twenty student observers were asked to detect the orientation of the spiculation in the image. There was a statistically significant improvement in detection performance for spiculations with CLAHE over unenhanced images when the region size was set at 32 with a clip level of 2, and when the region size was set at 32 with a clip level of 4. The selected CLAHE settings should be tested in the clinic with digital mammograms to determine whether detection of spiculations associated with masses detected at mammography can be improved.

Female↗
PubMed1998

Formoterol and isoproterenol induce c-fos gene expression in osteoblast-like cells by activating beta2-adrenergic receptors.

Formoterol, a beta2-adrenergic agonist has been shown in ovariectomized rat models to have anabolic effects on bone. However, those studies did not determine whether the effect of formoterol was by a direct action on bone cells themselves or indirectly via anabolic action on muscle. To address the question of whether formoterol could directly affect osteoblast function we investigated the expression patterns of beta3-adrenergic receptors (betaARs) in human osteoblast-like cells and functional coupling to gene expression. Northern blot analysis showed that betaAR subtypes are expressed at different levels in the osteoblast-like cell lines TE-85, SaOS-2, MG-63, and OHS-4. beta1AR expression was found in SaOS-2, OHS-4, and TE-85, but not MG-63 cells. beta2ARs are expressed at higher levels in MG-63 cells than in TE-85 and SaOS-2 cells, but were not detected in OHS-4 cells. PCR analysis paralleled the northern blot analysis except that beta3AR expression was found in one of three human primary osteoblast cDNAs tested. beta3AR expression was not found in any of the osteoblast-like cell lines. The nonspecific betaAR agonist, isoproterenol, and the beta2AR-specific agonist, formoterol, induced c-fos gene expression in cultured SaOS-2 cells in an immediate early fashion. This effect was inhibited by the beta2AR-specific antagonist, ICI 118551, but not by the beta1AR-specific antagonist, CGP 20712, indicating that induction of c-fos gene expression is specifically mediated by beta2ARs. c-fos gene expression was induced by both isoproterenol and formoterol via increases in cAMP, which in turn activated the cAMP/PKA pathway; the PKA inhibitor, H89, inhibited c-fos gene expression. Thus, betaARs are expressed in osteoblast-like cells and are coupled to c-fos gene expression via the beta2AR, increases in cAMP levels and activation of a PKA-dependent pathway.

Adrenergic beta-Agonists↗
PubMed1997

Laser Rapid Prototyping of Photonic Band-Gap Microstructures

Three-dimensional periodic microstructures of aluminum oxide, which are important for creating photonic band-gap structures (PBGs), were fabricated by laser rapid prototyping by means of laser-induced direct-write deposition from the gas phase. The structures consisted of layers of parallel rods forming a face-centered tetragonal lattice with lattice constants of 66 and 133 micrometers. These structures showed transmission minima centered around 4 terahertz (75 micrometers) and 2 terahertz (150 micrometers), respectively. PBGs will allow precise control of the optical properties of materials, including lasers without threshold.

Journal Article↗
PubMed1997

Does intensity windowing improve the detection of simulated calcifications in dense mammograms?

This study attempts to determine whether intensity windowing (IW) improves detection of simulated calcifications in dense mammograms. Clusters of five simulated calcifications were embedded in dense mammograms digitized at 50-microns pixels, 12 bits deep. Film images with no windowing applied were compared with film images with nine different window widths and levels applied. A simulated cluster was embedded in a realistic background of dense breast tissue, with the position of the cluster varied. The key variables involved in each trial included the position of the cluster, contrast level of the cluster, and the IW settings applied to the image. Combining the ten IW conditions, four contrast levels and four quadrant positions gave 160 combinations. The trials were constructed by pairing 160 combinations of key variables with 160 backgrounds. The entire experiment consisted of 800 trials. Twenty student observers were asked to detect the quadrant of the image in which the mass was located. There was a statistically significant improvement in detection performance for clusters of calcifications when the window width was set at 1024 with a level of 3328, and when the window width was set at 1024 with a level of 3456. The selected IW settings should be tested in the clinic with digital mammograms to determine whether calcification detection performance can be improved.

Breast Neoplasms↗
PubMed1997

The effect of intensity windowing on the detection of simulated masses embedded in dense portions of digitized mammograms in a laboratory setting.

The purpose of this study was to determine whether intensity windowing (IW) improves detection of simulated masses in dense mammograms. Simulated masses were embedded in dense mammograms digitized at 50 microns/pixel, 12 bits deep. Images were printed with no windowing applied and with nine window width and level combinations applied. A simulated mass was embedded in a realistic background of dense breast tissue, with the position of the mass (against the background) varied. The key variables involved in each trial included the position of the mass, the contrast levels and the IW setting applied to the image. Combining the 10 image processing conditions, 4 contrast levels, and 4 quadrant positions gave 160 combinations. The trials were constructed by pairing 160 combinations of key variables with 160 backgrounds. The entire experiment consisted of 800 trials. Twenty observers were asked to detect the quadrant of the image into which the mass was located. There was a statistically significant improvement in detection performance for masses when the window width was set at 1024 with a level of 3328. IW should be tested in the clinic to determine whether mass detection performance in real mammograms is improved.

Analysis of Variance↗
PubMed1993

A formal curriculum in breast imaging for radiology residents.

RATIONAL AND OBJECTIVES: Training in breast imaging is highly variable among radiology programs. The authors have developed a standardized breast imaging curriculum for radiology residents. METHODS: This curriculum has been implemented within the residency program at the University of North Carolina at Chapel Hill. It includes nine standardized components: 1) the clinical activities of the service; 2) the study of breast imaging teaching file films and contribution of new cases; 3) selected readings; 4) formal discussion with faculty on the readings; 5) review of this material using an interactive computer program; 6) formal conferences; 7) technical and quality control activities; 8) research activities; and 9) an evaluation. The participating residents have been surveyed regarding their opinions of their educational experience. RESULTS AND CONCLUSION: The standardized curriculum has been well received by the participating residents. Conclusions about the educational efficacy of such a curriculum cannot be made until more residents have used it.

Computer-Assisted Instruction↗
PubMed1991

Restoration of daunomycin retention in multidrug-resistant P388 cells by submicromolar concentrations of SDZ PSC 833, a nonimmunosuppressive cyclosporin derivative.

Overexpression of P-glycoprotein may cause increased efflux of a variety of anticancer drugs (ACD) leading to multidrug resistance (MDR) of tumor cells. Two sublines of murine monocytic leukemia P388 cells were used, one parental (Par-P388) and one multidrug resistant (MDR-P388). In cell growth inhibition assays in vitro, the Par-P388 cells showed a normal sensitivity to daunomycin (DAU) while the MDR-P388 cells were 200-fold resistant. In cellular fluorescence assays, DAU retention in MDR-P388 cells reached only 5% of the level achieved in Par-P388 cells. This cell line pair was used to compare the nonimmunosuppressive cyclosporin analog PSC 833 with several resistance-modifying agents (RMAs) for their in vitro chemosensitizing activity and for their restoration of DAU retention. PSC 833 sensitized the MDR-P388 cells 60- and 140-fold when used at 0.1 and 0.3 micrograms/ml (0.08 and 0.25 microM), respectively, a complete restoration of sensitivity being obtained at 1.0 micrograms/ml PSC 833. Similarly as little as 0.1 micrograms/ml (0.08 microM) PSC 833 was sufficient to restore intracellular DAU retention to 60% of the level found in Par-P388 cells, a 3-fold higher concentration restoring virtually the whole DAU retention. For both these activities, PSC 833 was at least one order of magnitude more active than CsA, which was itself an order of magnitude stronger than verapamil, another RMA already used in clinic. Since PSC 833 had no effect on the PAR-P388 cells, neither on chemosensitization nor on drug retention, it is assumed that it acts on the P-glycoprotein, which is highly expressed on the membrane of the MDR-P388 cells, by inhibiting the function of the P-glycoprotein pump and thus restoring a normal ACD-sensitivity of the MDR-P388 cells.

Amiodarone↗