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Search Results: 1 - 10 of 1258 matches for " Ulla Feldt-Rasmussen "
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Can bone loss be reversed by antithyroid drug therapy in premenopausal women with Graves' disease?
Tina Z Belsing, Charlotte Tofteng, Bente L Langdahl, Peder Charles, Ulla Feldt-Rasmussen
Nutrition & Metabolism , 2010, DOI: 10.1186/1743-7075-7-72
Abstract: Prospective examination of the influence of thyroid hormones and/or thyroid autoantibodies on BMD in premenopause.We have examined 32 premenopausal women with untreated active Graves' disease from time of diagnosis, during 18 months of antithyroid drug therapy (ATD) and additionally 18 months after discontinuing ATD. Variables of thyroid metabolism, calcium homeostasis and body composition were measured every 3 months. BMD of lumbar spine and femoral neck were measured at baseline, 18 ± 3 and 36 ± 3 months. Data were compared to base line, a sex- and age matched control group and a group of patients with Hashimoto's thyroiditis treated with non-suppressive doses of levothyroxine.The study showed significantly (p < 0.002) lower BMD in the thyrotoxic state compared to the control group with subsequent significant improvement during 18 ± 3 months of ATD compared to baseline (p < 0.001). However, during the following 18 months after stopping ATD femoral neck BMD decreased again unrelated to age (more than 0.4% per year, p < 0,002). The wellestablished effect of thyrotoxicosis on calcium homeostasis was confirmed. The positive predictor for best BMD was TSH receptor antibodies (TRAb) while free T4 correlated negatively in the thyrotoxic female Graves' patients (p < 0.02 and p < 0.003). In healthy controls and patients with treated Graves' disease both TSH and T4 correlated negatively to the bone mass (BMC) (p < 0.003).The results indicated a clinically relevant impact of thyroid function on bone modulation also in premenopausal women with Graves' disease, and further indicated the possibility for a direct action of TRAb on bones.Thyroid hormones are known to stimulate bone turnover [1], and previous studies have shown decreased bone mineral density (BMD) [2] and increased risk of osteoporotic fractures [3-5] in patients with thyrotoxicosis [6]. However, many studies have been composed of a mixture of patients with different diagnoses (Graves' disease, toxic multinodular
Fabry Disease and Early Stroke
U. Feldt-Rasmussen
Stroke Research and Treatment , 2011, DOI: 10.4061/2011/615218
Abstract: Fabry disease, an X-linked lysosomal storage disorder, results from deficient activity of the enzyme α-galactosidase A. Affected males with the classic phoenotype have acroparaesthesias, hypohidrosis, and corneal opacities in childhood and develop renal failure, cardiac hypertrophy or strokes in the third to fifth decade of life. Some female heterozygotes are asymptomatic, some as severely affected as males. The natural history of Fabry patients includes transitory cerebral ischaemia and strokes, even in very young persons of both genders. The mechanism is partly due to vascular endothelial accumulation of GL-3. White matter lesions on MRI occur. Both males and females can be safely treated with enzyme replacement; and thus screening for Fabry disease of young stroke populations should be considered. There are, however, no hard data of treatment effect on mortality and morbidity. The analyses of results from ongoing studirs will add to the decision on whether or not to screen young stroke patients for Fabry disease. Finally, stroke prophylactic therapy should be used liberally in patients of both genders with verified Fabry disease. This includes primary prevention such as lifestyle counseling, targeting blood pressure, managing atrial fibrillation, diabetes mellitus, hyperlipidaemia, and ASA. 1. Introduction Fabry disease is a rare X-linked inborn error of glycosphingolipid metabolism resulting from reduced production of lysosomal (α-galactosidase A (α-Gal A)) [1]. The enzymatic deficiency leads to lysosomal accumulation of glycosphingolipids, primarily globotriaosylceramide (GL-3), particularly in vascular endothelial cells throughout the body. Affected males and symptomatic heterozygous females with the classical phenotype have manifestations in childhood or adolescence including angiokeratoma, acroparesthesia, gastrointestinal manifestations, and corneal opacities. With advancing age, the progressive vascular involvement results in renal insufficiency, cardiac disease, and strokes [1]. Patients with Fabry disease have a shortened life expectancy due to the development of a specific vasculopathy. Male patients typically develop renal impairment in their third or fourth decade of life, as well as cardiac hypertrophy and conduction abnormalities. Life expectancy is reduced with a median life expectancy between 50 and 57 years for the male population [2–4]. In females, the disease is more variable, with less involvement of the kidneys, but life span is shortened as well [2, 3, 5]. In female patients, cardiac disease and cerebral white matter lesions
Do Thyroid Disrupting Chemicals Influence Foetal Development during Pregnancy?
Marie-Louise Hartoft-Nielsen,Malene Boas,Sofie Bliddal,?ase Krogh Rasmussen,Katharina Main,Ulla Feldt-Rasmussen
Journal of Thyroid Research , 2011, DOI: 10.4061/2011/342189
Abstract: Maternal euthyroidism during pregnancy is crucial for normal development and, in particular, neurodevelopment of the foetus. Up to 3.5 percent of pregnant women suffer from hypothyroidism. Industrial use of various chemicals—endocrine disrupting chemicals (EDCs)—has been shown to cause almost constant exposure of humans with possible harmful influence on health and hormone regulation. EDCs may affect thyroid hormone homeostasis by different mechanisms, and though the effect of each chemical seems scarce, the added effects may cause inappropriate consequences on, for example, foetal neurodevelopment. This paper focuses on thyroid hormone influence on foetal development in relation to the chemicals suspected of thyroid disrupting properties with possible interactions with maternal thyroid homeostasis. Knowledge of the effects is expected to impact the general debate on the use of these chemicals. However, more studies are needed to elucidate the issue, since human studies are scarce. 1. Introduction Maintaining maternal euthyroidism during pregnancy is important for growth and development, in particular neurodevelopment of the foetus. Even subtle changes in thyroid function of the pregnant woman can cause detrimental effects for the foetus [1–5]. In the first trimester, the foetus relies solely on the thyroid hormones thyroxine (T4) and tri-iodothyronine (T3) and iodine from the mother. Later in pregnancy and during lactation, maternal thyroid hormones still contribute significantly to foetal thyroid homeostasis [6–8]. Worldwide, both overt and subclinical hypothyroidism are frequent among fertile women [9–14]. Prior maternal thyroid diseases as well as iodine and selenium deficiencies are known risk factors for hypothyroidism. Abundant industrial and household use of various chemicals—called endocrine disrupting chemicals (EDCs)—expose humans with potential harmful influences on health and hormone regulation. As recently reviewed, several of these EDCs have been found to have thyroid disrupting properties as well [15–17]. Probably each chemical has limited thyroid disruptive effects at environmental exposure doses. However, the combined influence of several chemicals through different pathways of thyroid hormone synthesis and action may have significant impact on both maternal and foetal thyroid function [18, 19] and, thus, a potential to compromise foetal development and maturation. This paper will focus on the influence of thyroid hormones on foetal development in relation to the chemicals suspected to have thyroid disrupting properties. Knowledge on
Challenges in Interpretation of Thyroid Function Tests in Pregnant Women with Autoimmune Thyroid Disease
Ulla Feldt-Rasmussen,Anne-Sofie Bliddal Mortensen,?se Krogh Rasmussen,Malene Boas,Linda Hilsted,Katharina Main
Journal of Thyroid Research , 2011, DOI: 10.4061/2011/598712
Abstract: Physiological changes during gestation are important to be aware of in measurement and interpretation of thyroid function tests in women with autoimmune thyroid diseases. Thyroid autoimmune activity is decreasing in pregnancy. Measurement of serum TSH is the first-line screening variable for thyroid dysfunction also in pregnancy. However, using serum TSH for control of treatment of maternal thyroid autoimmunity infers a risk for compromised foetal development. Peripheral thyroid hormone values are highly different among laboratories, and there is a need for laboratory-specific gestational age-related reference ranges. Equally important, the intraindividual variability of the thyroid hormone measurements is much narrower than the interindividual variation (reflecting the reference interval). The best laboratory assessment of thyroid function is a free thyroid hormone estimate combined with TSH. Measurement of antithyroperoxidase and/or TSH receptor antibodies adds to the differential diagnosis of autoimmune and nonautoimmune thyroid diseases. 1. Introduction Diagnosing maternal thyroid dysfunction during all stages of pregnancy is very important for the outcome for both mother and foetus [1, 2]. Women with hypothyroidism treated insufficiently with levothyroxine (high serum concentration of thyrotropin (TSH) or serum free thyroxine (T4) in the low normal range) deliver babies with significantly lower IQ and/or other inhibited neuropsychological development [3, 4]. Such offspring outcome has even been demonstrated in women with a serum concentration of T4 in the low normal range during pregnancy [5]. Prevalence of autoimmune thyroid disease (AITD) is high in women of reproductive age, whether or not they are pregnant [6]. AITD not only affects fertility [6], but may also lead to a decreased thyroid reserve with decreased availability of thyroxine. This is particularly important in the first half of pregnancy, in which the foetal development depends on the delivery of thyroxine from the mother [7, 8]. Although autoimmune thyrotoxicosis, Graves’ disease, is rare in pregnant women, transfer of TSH receptor antibodies, which can be either stimulating or blocking, may give rise to foetal and neonatal thyrotoxicosis or hypothyroidism, respectively [9, 10]. As a natural consequence of the importance of thyroid hormones for foetal brain development much focus has been given to diagnosing both overt and subclinical (or mild) thyroid dysfunction as early as possible in pregnant women, recently resulting in international consensus guidelines [10]. Although the
Rationale and design of the participant, investigator, observer, and data-analyst-blinded randomized AGENDA trial on associations between gene-polymorphisms, endophenotypes for depression and antidepressive intervention: the effect of escitalopram versus placebo on the combined dexamethasone-corticotrophine releasing hormone test and other potential endophenotypes in healthy first-degree relatives of persons with depression
Ulla Knorr, Maj Vinberg, Marianne Klose, Ulla Feldt-Rasmussen, Linda Hilsted, Anders Gade, Eva Haastrup, Olaf Paulson, J?rn Wetterslev, Christian Gluud, Ulrik Gether, Lars Kessing
Trials , 2009, DOI: 10.1186/1745-6215-10-66
Abstract: The AGENDA trial is designed as a participant, investigator, observer, and data-analyst-blinded randomized trial. Participants are 80 healthy first-degree relatives of patients with depression. Participants are randomized to escitalopram 10 mg per day versus placebo for four weeks. Randomization is stratified by gender and age. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test at entry before intervention to after four weeks of intervention. With the inclusion of 80 participants, a 60% power is obtained to detect a clinically relevant difference in the primary outcome between the intervention and the placebo group. Secondary outcome measures are changes from baseline to four weeks in scores of: 1) cognition and 2) neuroticism. Tertiary outcomes measures are changes from baseline to four weeks in scores of: 1) depression and anxiety symptoms; 2) subjective evaluations of depressive symptoms, perceived stress, quality of life, aggression, sleep, and pain; and 3) salivary cortisol at eight different timepoints during an ordinary day. Assessments are undertaken by assessors blinded to the randomization group.Local Ethics Committee: H-KF 307413Danish Medicines Agency: 2612-3162.EudraCT: 2006-001750-28.Danish Data Agency: 2006-41-6737.ClinicalTrials.gov: NCT 00386841Robins and Guze described five phases in the development of a valid classification of psychiatric illness: clinical description, laboratory studies, delimitation from other disorders, follow-up studies and family studies [1]. Later, response to treatment was added as a sixth phase [2]. Recently, the endophenotype concept has emerged as a strategic tool in neuropsychiatric research [3].Endophenotypes are quantifiable components in the "genes-to-behaviours" pathways distinct from psychiatric symptoms [3]. In parallel with the classification of psychiatric diseases, endophenotypes are validated by specificity, state independence, heritability,
Mannose 6-Phosphate Receptor and Sortilin Mediated Endocytosis of α-Galactosidase A in Kidney Endothelial Cells
Thaneas Prabakaran, Rikke Nielsen, Simon C. Satchell, Peter W. Mathieson, Ulla Feldt-Rasmussen, S?ren S. S?rensen, Erik I. Christensen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039975
Abstract: Prominent vasculopathy in Fabry disease patients is caused by excessive intracellular accumulation of globotriaosylceramide (GL-3) throughout the vascular endothelial cells causing progressive cerebrovascular, cardiac and renal impairments. The vascular lesions lead to myocardial ischemia, atherogenesis, stroke, aneurysm, thrombosis, and nephropathy. Hence, injury to the endothelial cells in the kidney is a key mechanism in human glomerular disease and endothelial cell repair is an important therapeutic target. We investigated the mechanism of uptake of α-galactosidase A (α-Gal A) in renal endothelial cells, in order to clarify if the recombinant enzyme is targeted to the lysosomes via the universal mannose 6-phosphate receptor (M6PR) and possibly other receptors. Immunohistochemical localization of infused recombinant α-Gal A in a renal biopsy from a classic Fabry disease patient showed that recombinant protein localize in the endothelial cells of the kidney. Affinity purification studies using α-Gal A resins identified M6PR and sortilin as α-Gal A receptors in cultured glomerular endothelial cells. Immunohistochemical analyses of normal human kidney with anti-sortilin and anti-M6PR showed that sortilin and M6PR were expressed in the endothelium of smaller and larger vessels. Uptake studies in cultured glomerular endothelial cells of α-Gal A labeled with fluorescence and 125I showed by inhibition with RAP and M6P that sortilin and M6PR mediated uptake of α-Gal A. Biacore studies revealed that α-Gal A binds to human M6PR with very high affinity, but M6PR also binds to sortilin in a way that prevents α-Gal A binding to sortilin. Taken together, our data provide evidence that sortilin is a new α-Gal A receptor expressed in renal endothelial cells and that this receptor together with the M6PR is able to internalize circulating α-Gal A during enzyme replacement therapy in patients with Fabry disease.
Escitalopram and Neuroendocrine Response in Healthy First-Degree Relatives to Depressed Patients – A Randomized Placebo-Controlled Trial
Ulla Knorr, Maj Vinberg, Allan Hansen, Marianne Klose, Ulla Feldt-Rasmussen, Linda Hilsted, J?rgen Hasselstr?m, Ulrik Gether, Per Winkel, Christian Gluud, J?rn Wetterslev, Lars Vedel Kessing
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021224
Abstract: Introduction The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether long-term intervention with SSRI versus placebo affects the cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD). Methods Eighty healthy first-degree relatives to patients with MDD were randomized to escitalopram 10 mg versus matching placebo daily for four weeks. The primary outcome measure was the intervention difference in the change of the total area under the curve (CorAUCtotal) for plasma cortisol in the DEX-CRH test at entry to after four weeks of intervention. Results Change in CorAUCtotal showed no statistically significant difference between the escitalopram and the placebo group, p = 0.47. There were large intra- and inter-individual differences in the results of the DEX-CRH test. There was statistically significant negative correlation between the plasma escitalopram concentration and change in CorAUCtotal, rho = ?0.41, p = 0.01. Post-hoc analyses showed a statistically significant interaction between age and intervention group and change in log CorAUCtotal. Conclusion The present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis in healthy first-degree relatives to patients with MDD. Increasing levels of escitalopram tended to decrease the HPA-response in the DEX-CRH test and this effect increased with age. Trial Registration ClinicalTrials.gov [NCT00386841
Plasma neutrophil gelatinase associated lipocalin (NGAL) is associated with kidney function in uraemic patients before and after kidney transplantation
Nils E Magnusson, Mads Hornum, Kaj J?rgensen, Jesper Hansen, Claus Bistrup, Bo Feldt-Rasmussen, Allan Flyvbjerg
BMC Nephrology , 2012, DOI: 10.1186/1471-2369-13-8
Abstract: NGAL was measured using a validated in-house Time-Resolved Immuno-flourometric assay (TRIFMA). Repeated measurements differed by < 10% and mean values were used for statistical analyses. Spearman rank order correlation analysis and the Kruskal-Wallis non-parametric test were used to evaluate the association of NGAL concentrations with clinical parameters.Plasma NGAL levels before transplantation in the Tx and uraemic groups were significantly higher than in the healthy controls (1,251 μg/L, 1,478 μg/L vs. 163 μg/L, p < 0.0001). In the Tx group NGAL concentrations were associated with serum creatinine (R = 0.51, p < 0.0001), duration of end-stage renal failure (R = 0.41, p = 0.002) and leukocyte count (R = 0.29, p < 0.026). At 3 and 12 months plasma NGAL concentrations declined to 223 μg/L and 243 μg/L, respectively and were associated with homocysteine (R = 0.39, p = 0.0051 and R = 0.47, p = 0.0007).Plasma NGAL is a novel marker of kidney function, which correlates to duration of end-stage renal failure (ESRD) and serum creatinine in uraemic patients awaiting kidney transplantation. Plasma NGAL is associated with homocysteine in transplanted patients. The prognostic value of these findings requires further studies.Neutrophil gelatinase associated lipocalin (NGAL) also known as Lipocalin 2 or Lcn2 is a 25 kDa protein identified originally as a protein associated with matrix metalloproteinase 9 (MMP-9) of human neutrophils [1]. Lipocalins are extracellular proteins which share a common tertiary structure that forms a barrel-like hydrophobic ligand binding site [2]. When bound to MMP-9, NGAL protects it from proteolytic degradation sustaining the proteolytic activity of MMP-9. No specific receptor for NGAL has yet been identified. However, the endocytosis low density lipoprotein receptor Megalin has been shown to bind NGAL with high affinity suggesting that NGAL is taken up by host cells [3]. NGAL has been suggested as a bacteriostatic agent indicating involvement of N
Receptor-Mediated Endocytosis of α-Galactosidase A in Human Podocytes in Fabry Disease
Thaneas Prabakaran, Rikke Nielsen, Jakob V. Larsen, S?ren S. S?rensen, Ulla Feldt- Rasmussen, Moin A. Saleem, Claus M. Petersen, Pierre J. Verroust, Erik I. Christensen
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025065
Abstract: Injury to the glomerular podocyte is a key mechanism in human glomerular disease and podocyte repair is an important therapeutic target. In Fabry disease, podocyte injury is caused by the intracellular accumulation of globotriaosylceramide. This study identifies in the human podocyte three endocytic receptors, mannose 6-phosphate/insulin-like growth II receptor, megalin, and sortilin and demonstrates their drug delivery capabilities for enzyme replacement therapy. Sortilin, a novel α-galactosidase A binding protein, reveals a predominant intracellular expression but also surface expression in the podocyte. The present study provides the rationale for the renal effect of treatment with α-galactosidase A and identifies potential pathways for future non-carbohydrate based drug delivery to the kidney podocyte and other potential affected organs.
The protein map of Synechococcus sp. PCC 7942 - the first overlook
Olga A. Koksharova,Johan Klint,Ulla Rasmussen
Quantitative Biology , 2005,
Abstract: The unicellular cyanobacterium Synechococcus PCC 7942 has been used as a model organism for studies of prokaryotic circadian rhythms, carbon-concentrating mechanisms, response to a variety of nutrient and environmental stresses, and cell division. This paper presents the results of the first proteomic exploratory study of Synechococcus PCC 7942. The proteome was analyzed using two-dimensional gel electrophoresis followed by MALDI-TOF mass spectroscopy, and database searching. Of 140 analyzed protein spots, 110 were successfully identified as 62 different proteins, many of which occurred as multiple spots on the gel. The identified proteins were organized into 18 different functional categories reflecting the major metabolic and cellular processes occurring in the cyanobacterial cells in the exponential growth phase. Among the identified proteins, 14 previously unknown or considered to be hypothetical are here shown to be true gene products in Synechococcus sp. PCC 7942, and may be helpful for annotation of the newly sequenced genome.
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