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Biomedical subjects

M Nielsen

Publications and source records attributed to M Nielsen.

At least 37 records · Page 2Linked to original sources
PubMed2001

Non-rigid registration by geometry-constrained diffusion.

Assume that only partial knowledge about a non-rigid registration is given: certain points, curves or surfaces in one 3D image are known to map to certain points, curves or surfaces in another 3D image. In trying to identify the non-rigid displacement field, we face a generalized aperture problem since along the curves and surfaces, point correspondences are not given. We will advocate the viewpoint that the aperture and the 3D interpolation problem may be solved simultaneously by finding the simplest displacement field. This is obtained by a geometry-constrained diffusion, which in a precise sense yields the simplest displacement field. The point registration obtained may be used for segmentation, growth modeling, shape analysis or kinematic interpolation. The algorithm applies to geometrical objects of any dimensionality. We may thus keep any number of fiducial points, curves and/or surfaces fixed while finding the simplest registration. Examples of inferred point correspondences in a synthetic example and a longitudinal growth study of the human mandible are given.

Algorithms↗
PubMed2001

Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells.

Interleukin-2 (IL-2) is a growth factor which upon binding to high-affinity receptors (IL-2Ralphabetagamma) triggers mitogenesis in T cells. IL-2Ralpha expression is restricted to T cells which have recently encountered antigen, and in healthy individuals the majority (>95%) of peripheral T cells are IL-2Ralpha negative. An aberrant expression of IL-2Ralpha has recently been described in cutaneous T-cell lymphoma (CTCL). Here, we study the regulation of IL-2Ralpha expression and STATs in a tumor cell line obtained from peripheral blood from a patient with Sezary syndrome (SS), a leukemic variant of CTCL. We show that (1) STAT3 (a transcription factor known to regulate IL-2Ralpha transcription) is constitutively tyrosine-phosphorylated in SS tumor cells, but not in non-malignant T cells; (2) STAT3 binds constitutively to a STAT-binding sequence in the promotor of the IL-2Ralpha gene; (3) the Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel; and (4) tyrphostine AG490 inhibits IL-2 driven mitogenesis and triggers apoptosis in SS tumor cells. In conclusion, we provide the first example of a constitutive STAT3 activation in SS tumor cells. Moreover, our findings suggest that STAT3 activation might play an important role in the constitutive IL-2Ralpha expression, survival, and growth of malignant SS cells.

Antineoplastic Agents↗
PubMed2001

Insecticide-treated bed nets reduce plasma antibody levels and limit the repertoire of antibodies to Plasmodium falciparum variant surface antigens.

The use of insecticide-treated bed nets (ITN) has been documented to reduce malaria morbidity and mortality in areas with endemic malaria, but concerns have been raised that ITN usage could affect the acquisition of malaria immunity. Several lines of evidence have indicated that antibodies against variant surface antigens (VSA) are important in the development of naturally acquired immunity to Plasmodium falciparum malaria and may thus be good indicators of immune status. We have compared the levels of VSA antibodies in plasma from children who have used ITN for 4 years to levels in plasma from children from a nearby village not using ITN. A total of 97 plasma samples were analyzed using 13 different P. falciparum isolates. We found that the children using ITN had significantly lower VSA antibody levels and recognized a smaller proportion of the VSA expressed by the tested parasite isolates than children not using ITN.

Antibodies, Protozoan↗
PubMed2001

Somatic cell exchange occurs between mouse fetal gonads and mesonephroi during in vitro culture.

Mesonephric cell contribution to the developing mouse gonad has previously been shown to be male-specific in in vitro culture models. This study shows that somatic cell exchange occurs between fetal mouse mesonephroi and gonads during in vitro culture of assembled tissues. Assembling gonads with cell marker-carrying mesonephroi and vice versa identified cell exchange. Two different cell markers were used. One of the markers was the thymidine analogue bromodeoxyuridine (BrdU), which was added to the culture medium during an initial culture period before in vitro culture of assembled tissues in medium without BrdU. The other was bacterial beta-galactosidase, which is expressed ubiquitously in tissues from the transgenic mouse strain ROSA26. The tissues were taken from either 10.5- or 11.5-day-old mouse fetuses, and the assembled tissues were cultured for 36-60 h. Both cell markers demonstrated the occurrence of a cell exchange in both directions between the mesonephros and the gonad. The cell contribution was found to be minor and independent of the initial age of the tissue and hours in culture. Further, mesonephric cell contribution was not male-specific. Cell exchange between the two tissues may be due to growth between the assembled tissues rather than active signal-regulated migration. It is suggested that in vitro culture models may not be applicable for investigating mesonephric cell contribution to the developing mouse gonad.

Animals↗
PubMed2001

Interferon-alpha induces transient suppressors of cytokine signalling expression in human T cells.

The suppressors of cytokine signalling (SOCS) proteins comprise a newly identified family of negative feedback regulators of cytokine signalling. SOCS expression is differentially induced upon cytokine stimulation in different cell types. Here we show that interferon-alpha (IFNalpha) is a potent inducer of SOCS expression in human T cells, as high expression of CIS, SOCS-1, SOCS-2, and SOCS-3 was detectable after IFNalpha stimulation. After 4 h of stimulation, CIS, SOCS-1, and SOCS-3 expression had returned to baseline levels, whereas SOCS-2 expression had not declined. In contrast, after IL-2 induction neither CIS, SOCS-1, nor SOCS-2 expression levels declined after 6 h. In conclusion, we provide the first evidence that IFNalpha induces SOCS expression in human T cells. Moreover, we show that IFNalpha and IL-2 induce distinct patterns of expression kinetics, suggesting that dynamic changes in cytokine sensitivity might be mediated via induction of SOCS expression with different kinetics in T cells.

CD4-Positive T-Lymphocytes↗
PubMed2001

Oligonucleotide fishing for STAT6: cross-talk between IL-4 and chemokines.

Signal transducer and activator of transcription 6 (STAT6) is essential for the biological activities of interleukin-4 (IL-4) and the development of allergic responses in mice. Here we report on a sensitive and specific assay for STAT6 activation in response to IL-4. We took advantage of double-stranded oligonucleotide probes containing a STAT6-binding gene-sequence from the promotor of the immunoglobulin heavy chain germline epsilon transcript to study the IL-4-induced DNA binding of STAT6. Using these probes, we show that repeated adjacent STAT6-binding sites result in enhanced STAT6-DNA binding. Moreover, the distance between the binding sites is critical for STAT-DNA binding, i.e. STAT6 binding is decreased at distances above 20 nucleotides between neighbouring binding sites. Using this assay to study cross-talk between IL-4 and chemokines, we provide evidence that MIP-1beta and MIG inhibit IL-4-induced STAT6 activation, whereas other chemokines and cytokines do not. In conclusion, our data show that oligonucleotide fishing is a supplementary tool for studying cytokine cross-talk at a genomic level.

Animals↗
PubMed2001

Honokiol and magnolol selectively interact with GABAA receptor subtypes in vitro.

Honokiol and magnolol have been identified as modulators of the GABAA receptors in vitro. Our previous study suggested a possible selectivity of honokiol and magnolol on GABAA receptor subtypes. This possibility was examined in the current study by 3H-muscimol and 3H-flunitrazepam binding assays on various rat brain membrane preparations and human recombinant GABA(A) receptor subunit combinations expressed by the Sf-9/baculovirus system. Generally, honokiol and magnolol have a similar enhancing effect on (3)H-muscimol binding to various membrane preparations in nonsaturation binding assays. Honokiol and magnolol preferentially increased (3)H-muscimol binding to hippocampus compared to cortex and cerebellum (with a maximum enhancement of 400% of control). As for subunit combinations, honokiol and magnolol have a more potent enhancing effect on alpha2 subunit containing combinations (with a maximum enhancement of 400-450% of control). This action was independent of the gamma subunit. In saturation binding assays, magnolol affected either the number of binding sites (ca. 4-fold on alpha2 containing combinations) or the binding affinity (on alpha1 containing combinations) of (3)H-muscimol binding to various GABAA receptor subunit combinations. In contrast, honokiol increased only binding sites on alpha2beta3gamma2s and alpha2beta3 combinations, but both the number of binding sites and the binding affinity on alpha1beta2gamma2S and alpha(1)beta2 combinations. These results indicate that honokiol and magnolol have some selectivity on different GABAA receptor subtypes. The property of interacting with GABAA receptors and their selectivity could be responsible for the reported in vivo effects of these two compounds.

Animals↗
PubMed2000

Low-temperature structure of indium quantum chains on silicon

The array of quasi-one-dimensional indium chains in the Si(111)- (4x1)-In surface reconstruction exhibits a phase transition to a low-temperature (8x2) phase. It has been suggested that this phase transition is related to a charge density wave (CDW) formation. The x-ray diffraction results presented here demonstrate that at 20 K the CDW has not yet condensed into a superstructure even though good transverse coupling was established. This indicates that CDW formation cannot be the driving force for the phase transition. Furthermore we elucidate the subtle highly anisotropic interchain correlations and reveal the detailed atomic structure of the low-temperature (8x2) phase.

Journal Article↗
PubMed2000

Prediction of protein secondary structure at 80% accuracy.

Secondary structure prediction involving up to 800 neural network predictions has been developed, by use of novel methods such as output expansion and a unique balloting procedure. An overall performance of 77.2%-80.2% (77.9%-80.6% mean per-chain) for three-state (helix, strand, coil) prediction was obtained when evaluated on a commonly used set of 126 protein chains. The method uses profiles made by position-specific scoring matrices as input, while at the output level it predicts on three consecutive residues simultaneously. The predictions arise from tenfold, cross validated training and testing of 1032 protein sequences, using a scheme with primary structure neural networks followed by structure filtering neural networks. With respect to blind prediction, this work is preliminary and awaits evaluation by CASP4.

Neural Networks, Computer↗
PubMed2000

Ischemic tolerance affects the adenylation state of GluR2 mRNA.

To analyse GluR2 regulations in the rat hippocampal CA1 region following global and tolerance-inducing ischemia in situ hybridization (ISH) and quantitative PCR (Q-PCR) was applied. In addition, cDNA was synthesised from two different primer combinations in order to elucidate possible differences in the adenylation state of GluR2 mRNA. Following global ischemia, ISH and Q-PCR both showed reductions to half of control levels of GluR2 mRNA in consent with previously published results. Following tolerance induction, ISH showed no changes, whereas PCR analysis showed up-regulation to 228% of control value for the general cDNA synthesis, and no change for the specific cDNA synthesis. This indicates that tolerance-inducing ischemia does not increase the amount of GluR2 mRNA; instead polyadenylation of the existing GluR2 mRNA pool takes place.

Animals↗
PubMed2000

Resveratrol reverses tumor-promoter-induced inhibition of gap-junctional intercellular communication.

The naturally occurring stilbene/alexin trans-resveratrol (trans-3,5, 4'-trihydroxystilbene) is a promising agent for the prevention of cancer. We investigated the effect of resveratrol on gap-junctional intercellular communication (GJIC) in WB-F344 rat liver epithelial cells because inhibition of GJIC is an important mechanism of tumor promotion. Seventeen to 50 microM resveratrol increased GJIC significantly by a factor of 1.3 compared with solvent vehicle controls, when the WB-F344 cells were exposed to resveratrol for 6 h. Most tumor promoters, including the phorbol ester TPA and the insecticide DDT, block GJIC. Resveratrol at 17-50 microM also significantly prevented down-regulation of GJIC by TPA and DDT, by a factor of 2.7 and 1.8, respectively. This recovery of GJIC from TPA inhibition was partly correlated with hindered hyperphosphorylation of Cx43. In conclusion, resveratrol was found to enhance GJIC and counteract the effects of tumor promoters on GJIC, and this is likely a mechanism that contributes to the antipromotional and anticarcinogenic properties of resveratrol.

Animals↗
PubMed2000

What and when: parallel and convergent processing in motor control.

Successful motor behavior requires making appropriate response (response selection) at the right time (timing adjustment). Earlier psychological studies have suggested that the response selection and timing adjustment processes are performed serially in separate stages. We tested this hypothesis using functional magnetic resonance imaging. The subjects performed a choice reaction time task in four conditions: two (on-line response selection required or not) by two (on-line timing adjustment required or not). We found that the neural correlates for the two processes were indeed separate: the anterior medial premotor cortex (presupplementary motor area) was selectively active in response selection, whereas the cerebellar posterior lobe was selectively active in timing adjustment. However, the functional separation was only partial in that the lateral premotor cortex and the intraparietal sulcus were active equally for response selection and timing adjustment. The lateral premotor cortex was most active when both processes were required, suggesting that it integrates the information on response selection and the information on timing adjustment; alternatively, it might contribute to the allocation of attentional resources during dual information processing. The intraparietal sulcus was equally active when either response selection or timing adjustment was required, suggesting that it modifies, rather than integrates, these processes. Furthermore, our results suggest that these activations related to response selection and timing adjustment were distinct from sensory or motor processes.

Adult↗
PubMed2000

Acquired generalized lipoatrophy (AGL): highly selective MR lipid imaging and localized (1)H-MRS.

Frequency-selective chemical shift magnetic resonance (MR) imaging was applied on the calf musculature and the abdomen of a patient with acquired generalized lipoatrophy (AGL; Lawrence syndrome), a very rare syndrome affecting selectively several types of adipose tissue accompanied by alterations in glucose and energy metabolism. In addition, (1)H-MRS was used for assessment of intra- (IMCL) and extramyocellular lipid stores (EMCL) in the skeletal musculature of the calf. Results from the AGL patient were compared with an age-matched group of five healthy volunteers. Fat-selective imaging of the calf revealed a total lack of subcutaneous adipose tissue. No EMCL signal was found in the spectra from the soleus muscle of the AGL patient. IMCL signals were present in the spectra but were clearly lower than in the controls (14% of normal value in the soleus muscle). In abdominal images, subcutaneous fat signal was not detectable, as in the calf, but nearly normal conditions were shown for visceral adipose tissue between abdominal organs. Fat-selective images showed the liver with high signal intensity, indicating hepatic steatosis combined with hepatosplenomegaly. Modern chemical shift-selective MR imaging and localized spectroscopy allow a noninvasive and quantitative assessment of tissue composition in patients with disorders of carbohydrate and lipid metabolism.

Adipose Tissue↗
PubMed2000

Interleukin 15 is a growth factor for human thymocytes with preferential effect on CD8(+)cells.

The effects of IL-15, as compared to IL-2, on growth of human thymocytes has been evaluated. Expression of comparable amounts of receptor chains was found on IL-2 and IL-15 cultured thymocytes, as well as comparable receptor signalling. However, IL-15 was superior to IL-2 in promoting CD8(+)thymocyte growth, whereas CD4(+)cells proliferated to a higher extent in IL-2 cultures. CD4(+)8(+)and CD4(-)8(-)thymocytes expanded equally well in both culture types.

CD8-Positive T-Lymphocytes↗
PubMed2000

The PPARgamma2 polymorphism pro12Ala is associated with better insulin sensitivity in the offspring of type 2 diabetic patients.

Recently, a highly prevalent polymorphism of the PPARgamma2-receptor (Pro12Ala) was described and found to be associated with reduced transcriptional activity. Both human and animal studies suggested that this polymorphism may be associated with increased insulin sensitivity. However, an effect independent of other factors known to influence insulin sensitivity has yet to be demonstrated. Therefore, we compared insulin sensitivity using the hyperinsulinemic-euglycemic clamp technique in 37 subjects heterozygous for the PPARgamma2-Pro12Ala mutation and 37 control subjects negative for the PPARgamma2-Pro12Ala. The control group was selected from 190 subjects by pair-matching for sex, BMI, fat distribution and body composition. In the group heterozygous for the polymorphism steady-state plasma insulin during the clamp was significantly lower (63.3 microU/ml +/- 2.8) than in the control group (74.9 microU/ml +/- 4.0, p = 0.02). While MCR of glucose was similar in the PPARgamma2-Pro12Ala group (8.1 ml/kg x min x 100 +/- 0.5) and the control group (7.6 ml/kg x min x 100 +/- 3.0, p = 0.7), the insulin sensitivity index was significantly higher in the PPARgamma2-Pro12Ala group (12.5 mg/kg x min x microU/ml +/- 0.9 vs. 9.7 mg/kg x min x microU/ml +/- 0.8, p = 0.039). In addition, an arbitrary lipolysis index (decrease in FFA divided by increase in insulin) was also found to be marginally higher in the PPARgamma2-Pro12Ala group (8.0 +/- 0.9) compared to the control group (6.1 +/- 0.7, p = 0.097). In conclusion, these data suggest that the PPARgamma2-Pro12Ala mutation is associated with better insulin sensitivity of glucose disposal and possibly, also of antilipolysis.

Adult↗
PubMed2000

2-Oxo-2H-Pyrimido[2,1-b]benzothiazoles inhibit brain benzodiazepine receptor binding in vitro.

2-Oxo-2H-pyrimido[2,1-b]benzothiazole derivatives were found to inhibit the in vitro binding of (3)H-Ro 15-1788 ((3)H-flumazenil) to rat cortical benzodiazepine receptors with IC(50) values in the range of 0.7-13 micromol/l. The most potent compound, 2-oxo-4-phenyl-2H-pyrimido[2,1-b]- benzothiazole showed a similar potency to inhibit (3)H-Ro 15-1788 binding to membrane preparations of rat brain cortex, cerebellum and hippocampus as well as to various subunit combinations of recombinant human gamma-aminobutyric acid(A)/benzodiazepine receptors. Scatchard plot analysis showed that 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole is a competitive inhibitor of (3)H-Ro 15-1788 binding to rat brain cortical membrane preparations.

Animals↗
PubMed2000

Suppression of systemic, intramuscular, and subcutaneous adipose tissue lipolysis by insulin in humans.

In addition to sc and visceral fat deposits, muscle has been shown to contain relevant amounts of lipids whose breakdown is subject to hormonal regulation. The aim of the present study was to determine insulin dose-response characteristics of systemic, sc adipose tissue and muscle lipolysis in humans. We used a combination of isotopic (primed continuous infusion of [d5]glycerol) and microdialysis techniques (catheters placed in the anterior tibial muscle and sc abdominal adipose tissue) during a three-step hyperinsulinemic-euglycemic clamp (insulin infusion, 0.1, 0.25, 1.0 mU/kg x min) in 13 lean, healthy volunteers. The glycerol rate of appearance was used as the index for systemic lipolysis; interstitial glycerol concentrations were used as the index for muscle and sc adipose tissue lipolysis. The insulin concentrations resulting in a half-maximal suppression (EC50) of systemic lipolysis, adipose tissue, and muscle lipolysis were 51, 68, and 44 pmol/L, respectively (between one another, P < 0.001). For each compartment there were significant correlations between the EC50 and the insulin sensitivity index for glucose disposal (r > 0.67; P < 0.05). However, lipolysis (as percent of baseline) was similar during the first two insulin infusion steps, but was significantly lower in adipose (22+/-2%) than in muscle (53+/-4%; P < 0.001) during step 3. Although we have no direct measurement of interstitial insulin concentrations, we conclude that based on the EC50 values, muscle is more sensitive with respect to the net effect of circulating insulin (transendothelial transport plus intracellular action) on lipolysis than sc adipose tissue in terms of exerting its full suppression within the physiological insulin range. This could be important in muscle for switching from preferential utilization of free fatty acids to glucose in the postprandial state. Inadequate suppression of im lipolysis resulting in excessive local availability of free fatty acids may represent a novel mechanism contributing to the pathogenesis of impaired glucose disposal, i.e. insulin resistance, in muscle.

Adipose Tissue↗