Biomedical subjects

U Eriksson

Publications and source records attributed to U Eriksson.

At least 19 recordsLinked to original sources

PubMed2006

Hep27, a member of the short-chain dehydrogenase/reductase family, is an NADPH-dependent dicarbonyl reductase expressed in vascular endothelial tissue.

Human Hep27 was originally isolated from growth-arrested HepG2 cells and identified as a member of the superfamily of short-chain dehydrogenases/reductases (SDR). Its substrate specificity has not been determined, but a cross-species comparison suggests that it occurs in widely divergent species, such as human, Cenorhabditis elegans, Drosophila and Arabidopsis thaliana. In this study, Hep27 was expressed as a His(6) fusion protein, and subjected to a substrate screen, using a compound library of SDR substrates, comprising steroids, retinoids, sugars and carbonyl compounds. Whereas no steroid dehydrogenase or retinoid activity was detected, it was found that Hep27 catalyzed the NADPH-dependent reduction of dicarbonyl compounds, like 3,4-hexanedione and 1-phenyl-1,2-propanedione with similar turnover numbers as DCXR (a mitochondrial dicarbonyl reductase/xylulose reductase). In contrast, Hep27 does not convert sugar substrates like xylulose or threose. Based on its substrate specificity and expression in endothelial tissues, it is suggested that Hep27 functions as a dicarbonyl reductase in enzymatic inactivation of reactive carbonyls, involved in covalent modification of cellular components.

Alcohol Dehydrogenase↗

PubMed2005

[Amiodarone-induced thyrotoxicosis: a diagnostic and therapeutic challenge].

Amiodaron is a widely used antiarrhytmic drug in a number of cardiac conditions. The most common side effects affect the thyroid gland (14-18% of treated patients) resulting in hypothyroidism or hyperthyroidism. We describe a complex case of amiodaron-induced thyrotoxicosis (AIT) and discuss the pathogenesis of the different subtypes (AIT I, II and mixed forms) and the diagnostic and therapeutic challenges in such patients.

Amiodarone↗

PubMed2005

[Asymptomatic myocarditis after infection of the upper respiratory tract].

HISTORY AND CLINICAL FINDINGS: A 20-year-old patient was hospitalized with persistent high fever after tonsillitis and swelling of the talocalcanean joint. INVESTIGATIONS: The ECG showed a partial right bundle branch block pattern and pathological T inversions on the left precordial leads. Cardiac Troponin I levels were slightly elevated and echocardiography revealed a dyscinetic area at the right ventricular apex. The anti-streptolysin titer was elevated. DIAGNOSIS: Post-streptococcal rheumatic myocarditis. THERAPY AND FOLLOW-UP: Antibiotic therapy for 2 weeks. The patient showed subjective full recovery after 6 weeks. The anti-streptolysin titer further increases. Nuclear spin tomography of the heart reveal postinflammatory alterations at the apex of the right ventricle. CONCLUSION: Rheumatoid fever is a rare diagnosis in developed countries. This case, however, illustrates that the true prevalence of rheumatoid carditis might be underestimated in the presence of only minimal heart-and joint-specific symptoms.

Adult↗

PubMed2005

[Septic shock: diagnosis and management].

Sepsis is the most important reason for death among intensive care patients. This review will cover the actual definition of septic shock, and the difficulties regarding the diagnosis of sepsis. The principles of management of sepsis, the recently established principles as early goal directed therapy, low dose steroid substitution, insulin therapy, and the activated protein C are discussed.

Adrenal Cortex Hormones↗

PubMed2004

Physiological roles of angiotensin-converting enzyme 2.

Angiotensin-converting enzyme 2 (ACE2) is a recently discovered homologue of the key enzyme of the renin-angiotensin system, the angiotensin-converting enzyme. The ACE2 enzyme is mainly expressed in cardiac blood vessels and tubular epithelia of the kidneys. Together with ACE2's unique metallocarboxypeptidase activity, the restricted tissue distribution suggests a distinctive physiological function in blood pressure, blood flow and fluid regulation. The ace2 gene was mapped to quantitative trait loci affecting susceptibility to hypertension in rats. Furthermore, ACE2 appears to be a negative regulator of ACE in the heart. ACE2 messenger RNA and protein levels are substantially regulated in the kidney of diabetic and pregnant rats. The mechanism of ACE2 function and its physiologic significance are not yet fully understood; however, as ACE2 differs in its specificity and physiological role from ACE, this opens a new potential venue for drug discovery aimed at cardiovascular disease, hypertension and diabetic complications.

Angiotensin-Converting Enzyme 2↗

PubMed2003

Adverse cardiac events in ICU patients with presumptive antidepressant overdose.

BACKGROUND: Antidepressants account for most poison-related admissions to intensive care units. In selected patients with confirmed cyclic antidepressant intoxication a QRS interval <0.1 s in the ECG limb leads during the first six hours excludes adverse cardiac events. However, the incidence of cardiac events and the value of ECG criteria have never been assessed prospectively on patients with presumed antidepressant overdose. AIM: To assess ingested drugs, adverse cardiac events, and ECG findings in ICU patients with a presumptive diagnosis of antidepressant overdose. METHODS: 103 consecutive patients with a presumptive diagnosis of antidepressant overdose were enrolled and prospectively followed. Outcome criteria were arrhythmias, mortality, and duration of the ICU stay. RESULTS: Mixed intoxication was identified in 66 (64%) patients. Tricyclic antidepressants were found in 88 (85%), and serotonin-reuptake inhibitors in 25 (24%) patients. Mean APACHE II score was 9.5 (SD +/- 6.0). Arrhythmias affected 15 (15%) and cardiopulmonary resuscitation was performed on 4 (4%) patients. Three patients (3%) died in the ICU. Median duration of the ICU stay was 1 day (12 hours to 6 days). Adverse cardiac events affected patients with normal and prolonged QRS interval at study entry. CONCLUSIONS: Mixed intoxication is present in most ICU patients with suspected antidepressant overdose. There is a considerable risk for adverse cardiac events, even in the presence of normal ECG recordings within the first six hours after hospital admission.

Adolescent↗

PubMed2002

[Henoch-Schoenlein syndrome in an 80-year-old patient].

HISTORY AND CLINICAL FINDINGS: An 80-year old female patient, hospitalised with pneumonia and myocardial infarction, suddenly developed fever, dyspnoea, malaise, arthralgia and crampy abdominal pain. On the following day, she developed a petechial rash and on the 6 (th) day, macroscopic haematuria. On physical examination, the patient presented with a temperature of 40 degrees C, tachypnoea, tachycardia, and on auscultation coarse crepitations at the left lower base. The abdomen was tender upon deep palpation but bowel sounds were normal. Initially the petechial rash was located at the trunk, later progressing towards the extremities. INVESTIGATIONS: Chest X-ray and laboratory tests were consistent with left lower lobe pneumonia. The clinical picture was not consistent with any haematological causes, coagulopathy or any medication the patient was taking. Rheumatological blood tests (involving ANA, ANCA, rheumatoid factors) were basically negative. A skin biopsy revealed microvessel necrosis and IgA deposits, verifying Henoch-Schoenlein Purpura. An immune electrophoresis revealed a selective IgG-deficiency, which may explain the cause for the patient's recurrent pneumonias. COURSE: The patient recovered well under antibiotic treatment and skin lesions healed without sequelae. CONCLUSION: We present an unusual case of Henoch Schoenlein purpura associated with strictly petechial rash in an 80 year old female.

Aged↗

PubMed2001

[Anthrax--the Swedish perspective].

The recent occurrence in the USA of deliberate release of virulent Bacillus anthracis in letters sent to three media corporations and to the American senate has led to a great anxiety in Sweden and elsewhere in Europe. Numerous letters have been suspected to contain B. anthracis spores and several have contained powder of different types. In none of the tested letters collected by the Swedish police have we been able to detect anthrax bacilli. Powder containing letters have been tested with either bacterial isolation and/or B. anthracis specific PCR. Anthrax is a disease found naturally in herbivores and is occasionally spread to humans. It is caused by the gram-positive rod B. anthracis that was discovered by Robert Koch in 1876. Beginning in the 1930s many states have developed B. anthracis for use as a weapon. A few releases of the bacteria have been reported before October 2001. B. anthracis causes three forms of disease, cutaneous, pulmonary and gastro-intestinal. The pulmonary form is the most dangerous and may lead to death merely one to two days after onset of severe symptoms. This is due to the rapid growth and release of several potent toxins that engage the immune system and promote tissue destruction. B. anthracis infection can be treated with several antibiotics, among which quinolones and tetracyclins have been recommended. Diagnosis can readily be achieved by microscopy, bacterial isolation and PCR at the Swedish Institute for Infectious Disease Control and the Swedish Defence Research Agency. Antibiotics relevant for treatment of B. anthracis infections are already stockpilled in our country. Further actions to strengthen our capability to deal with bioterrorism are ongoing.

Anthrax↗

PubMed2001

Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: induction by IL-12 and protection by IFN-gamma.

IL-12 and IFN-gamma positively regulate each other and type 1 inflammatory responses, which are believed to cause tissue damage in autoimmune diseases. We investigated the role of the IL-12/IFN-gamma (Th1) axis in the development of autoimmune myocarditis. IL-12p40-deficient mice on a susceptible background resisted myocarditis. In the absence of IL-12, autospecific CD4(+) T cells proliferated poorly and showed increased Th2 cytokine responses. However, IFN-gamma-deficient mice developed fatal autoimmune disease, and blockade of IL-4R signaling did not confer susceptibility to myocarditis in IL-12p40-deficient mice, demonstrating that IL-12 triggers autoimmunity by a mechanism independent of the effector cytokines IFN-gamma and IL-4. In conclusion, our results suggest that the IL-12/IFN-gamma axis is a double-edged sword for the development of autoimmune myocarditis. Although IL-12 mediates disease by induction/expansion of Th1-type cells, IFN-gamma production from these cells limits disease progression.

Amino Acid Sequence↗

PubMed2001

Biochemical defects in 11-cis-retinol dehydrogenase mutants associated with fundus albipunctatus.

Mutations in the gene encoding 11-cis-retinol dehydrogenase (RDH5; EC ) are associated with fundus albipunctatus, an autosomal recessive eye disease characterized by stationary night blindness and accumulation of white spots in the retina. In addition, some mutated alleles are associated with development of cone dystrophy, especially in elderly patients. The numbers of identified RDH5 mutations linked to fundus albipunctatus have increased considerably during recent years. In this work, we have characterized the biochemical and cell biological properties of 11 mutants of RDH5 to understand the molecular pathology of the disease. All RDH5 mutants showed decreased protein stability and subcellular mislocalization and, in most cases, loss of enzymatic activity in vitro and in vivo. Surprisingly, mutant A294P displays significant enzymatic activity. Cross-linking studies and molecular modeling showed that RDH5 is dimeric, and co-expression analyses of wild-type and mutated alleles showed that the mutated enzymes, in a trans-dominant-negative manner, influenced the in vivo enzymatic properties of functional variants of the enzyme, particularly the A294P mutant. Thus, under certain conditions, nonfunctional alleles act in a dominant-negative way on functional but relatively unstable mutated alleles. However, in heterozygous individuals carrying one wild-type allele, the disease is recessive, probably due to the stability of the wild-type enzyme.

Alcohol Oxidoreductases↗

PubMed2001

Increased retinoid signaling in vascular smooth muscle cells by proinflammatory cytokines.

Retinoids have been shown to modulate inflammation and the immune response in many cell types including macrophages, endothelial cells, and vascular smooth muscle cells. However, present knowledge of whether inflammatory mediators modulate vitamin A status in these cells is limited. To identify the role of inflammation on retinoid metabolism in vascular smooth muscle cells, the cells were exposed to a combination of proinflammatory cytokines: interleukin-1beta, interferon-gamma, and lipopolysaccharides. Without stimulation with proinflammatory cytokines, vascular smooth muscle cells expressed retinol dehydrogenases-2 and 5 mRNA detected by RT-PCR. Stimulation with the combination of cytokines induced a substantial increase of retinol dehydrogenase-5 mRNA. This was associated with increased production of ligands for retinoic acid receptors, when assayed in a retinoic acid receptor-dependent luciferase reporter system. Our results demonstrate that inflammatory mediators activate the retinoid metabolic pathway in vascular smooth muscle cells, which potentially may modulate the inflammatory response in the vascular wall.

Alcohol Oxidoreductases↗

PubMed2001

Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect.

BACKGROUND: Vascular endothelial growth factors (VEGFs) and their receptors are essential regulators of vasculogenesis and angiogenesis in both embryos and adults. One of the factors with a still unknown physiological function is VEGF-B, which is expressed in many tissues, including the heart. METHODS AND RESULTS: Mice carrying a targeted deletion in the VEGF-B gene were developed. In VEGF-B(-/-) animals, no gross abnormalities were observed in organs that normally show high expression of VEGF-B, such as the heart, muscle, and kidney. Analysis of heart function by ECG showed that adult VEGF-B(-/-) mice have an atrial conduction abnormality characterized by a prolonged PQ interval. VEGF- or basic fibroblast growth factor-induced corneal angiogenesis was similar in normal and VEGF-B(-/-) mice. CONCLUSIONS: VEGF-B seems to be required for normal heart function in adult animals but is not required for proper development of the cardiovascular system either during development or for angiogenesis in adults.

Animals↗

PubMed2001

Chromosomal location, exon structure, and vascular expression patterns of the human PDGFC and PDGFD genes.

BACKGROUND: Platelet-derived growth factor (PDGF), which is a major mitogen for vascular smooth muscle cells and has been implicated in the pathogenesis of arteriosclerosis, is composed of dimers of PDGF-A and PDGF-B polypeptide chains, encoded by different genes. Here, we have analyzed the chromosomal localization, structure, and expression of 2 newly identified human genes of the PDGF family, called PDGFC and PDGFD. METHODS AND RESULTS: We used fluorescence in situ hybridization to locate PDGFC and PDGFD in chromosomes 4q32 and 11q22.3 to 23.2, respectively. Exon structures of PDGFC and PDGFD were determined by sequencing from genomic DNA clones. The coding region of PDGFC consists of 6 and PDGFD of 7 exons, of which the last 2 encode the C-terminal PDGF cystine knot growth factor homology domain. An N-terminal CUB domain is encoded by exons 2 and 3 of both genes, and a region of proteolytic cleavage involved in releasing and activating the growth factor domain is located in exon 4 in PDGFC and exon 5 in PDGFD. PDGF-C was expressed predominantly in smooth muscle cells and PDGF-D in fibroblastic adventitial cells, and both genes were active in cultured endothelial cells and in a variety of tumor cell lines. Both PDGF-C and PDGF-D also stimulated human coronary artery smooth muscle cells. CONCLUSIONS: PDGFC and PDGFD have similar genomic structures, which resemble those of the PDGFA and PDGFB genes. Their expression in the arterial wall and cultured vascular cells suggests that they can transduce proliferation/migration signals to pericytes and smooth muscle cells.

Amino Acid Motifs↗

PubMed2001

Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis.

The association of pericytes (PCs) to newly formed blood vessels has been suggested to regulate endothelial cell (EC) proliferation, survival, migration, differentiation, and vascular branching. Here, we addressed these issues using PDGF-B-- and PDGF receptor-beta (PDGFR-beta)--deficient mice as in vivo models of brain angiogenesis in the absence of PCs. Quantitative morphological analysis showed that these mutants have normal microvessel density, length, and number of branch points. However, absence of PCs correlates with endothelial hyperplasia, increased capillary diameter, abnormal EC shape and ultrastructure, changed cellular distribution of certain junctional proteins, and morphological signs of increased transendothelial permeability. Brain endothelial hyperplasia was observed already at embryonic day (E) 11.5 and persisted throughout development. From E 13.5, vascular endothelial growth factor-A (VEGF-A) and other genes responsive to metabolic stress became upregulated, suggesting that the abnormal microvessel architecture has systemic metabolic consequences. VEGF-A upregulation correlated temporally with the occurrence of vascular abnormalities in the placenta and dilation of the heart. Thus, although PC deficiency appears to have direct effects on EC number before E 13.5, the subsequent increased VEGF-A levels may further abrogate microvessel architecture, promote vascular permeability, and contribute to formation of the edematous phenotype observed in late gestation PDGF-B and PDGFR-beta knock out embryos.

Animals↗

PubMed2001

Biosynthesis of 9-cis-retinoic acid in vivo. The roles of different retinol dehydrogenases and a structure-activity analysis of microsomal retinol dehydrogenases.

Retinoic acid is generated by a two-step mechanism. First, retinol is converted into retinal by a retinol dehydrogenase, and, subsequently, retinoic acid is formed by a retinal dehydrogenase. In vitro, several enzymes are suggested to act in this metabolic pathway. However, little is known regarding their capacity to contribute to retinoic acid biosynthesis in vivo. We have developed a versatile cell reporter system to analyze the role of several of these enzymes in 9-cis-retinoic acid biosynthesis in vivo. Using a Gal4-retinoid X receptor fusion protein-based luciferase reporter assay, the formation of 9-cis-retinoic acid from 9-cis-retinol was measured in cells transfected with expression plasmids encoding different combinations of retinol and retinal dehydrogenases. The results suggested that efficient formation of 9-cis-retinoic acid required co-expression of retinol and retinal dehydrogenases. Interestingly, the cytosolic alcohol dehydrogenase 4 failed to efficiently catalyze 9-cis-retinol oxidation. A structure-activity analysis showed that mutants of two retinol dehydrogenases, devoid of the carboxyl-terminal cytoplasmic tails, displayed greatly reduced enzymatic activities in vivo, but were active in vitro. The cytoplasmic tails mediate efficient endoplasmic reticulum localization of the enzymes, suggesting that the unique milieu in the endoplasmic reticulum compartment is necessary for in vivo activity of microsomal retinol dehydrogenases.

Alcohol Dehydrogenase↗

PubMed2001

Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial.

OBJECTIVE: To test the hypothesis that amphotericin B deoxycholate is less toxic when given by continuous infusion than by conventional rapid infusion. DESIGN: Randomised, controlled, non-blinded, single centre study. SETTING: University hospital providing tertiary clinical care. PATIENTS: 80 mostly neutropenic patients with refractory fever and suspected or proved invasive fungal infections. INTERVENTION: Patients were randomised to receive 0.97 mg/kg amphotericin B by continuous infusion over 24 hours or 0.95 mg/kg by rapid infusion over four hours. MAIN OUTCOME MEASURES: Patients were evaluated for side effects related to infusion, nephrotoxicity, and mortality up to three months after treatment. Analysis was on an intention to treat basis. RESULTS: Patients in the continuous infusion group had fewer side effects and significantly reduced nephrotoxicity than those in the rapid infusion group. Overall mortality was higher during treatment and after three months' follow up in the rapid infusion than in the continuous infusion group. CONCLUSION: Continuous infusions of amphotericin B reduce nephrotoxicity and side effects related to infusion without increasing mortality.

Adolescent↗

PubMed2001

The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.

UNLABELLED: Suboptimal gastrointestinal absorption is a problem for many direct thrombin inhibitors. The studies presented herein describe the new oral direct thrombin inhibitor H 376/95, a prodrug with two protecting residues added to the direct thrombin inhibitor melagatran. Absorption properties in vitro: H 376/95 is uncharged at intestinal pH while melagatran is charged. H 376/95 is 170 times more lipophilic (octanol water partition coefficient) than melagatran. As a result, the permeability coefficient across cultured epithelial Caco-2 cells is 80 times higher for H 376/95 than for melagtran. Pharmacokinetic studies in healthy volunteers: H 376/95 is converted to melagatran in man. Oral bioavailability, measured as melagatran in plasma, is about 20% after oral administration of H 376/95, which is 2.7-5.5 times higher than after oral administration of melagatran. The variability in the area under the drug plasma concentration vs. time curve (AUC) is much smaller with oral H 376/95 (coefficient of variation 20%) than with oral melagatran (coefficient of variation 38%). Pharmacodynamic properties: H 376/95 is inactive towards human alpha-thrombin compared with melagatran [inhibition constant (K(i)) ratio, 185 times], a potential advantage for patients with silent gastrointestinal bleeding. In an experimental thrombosis model in the rat, oral H 376/95 was more effective than the subcutaneous low molecular weight heparin dalteparin in preventing thrombosis. CONCLUSION: By the use of the prodrug principle, H 376/95 endows the direct thrombin inhibitor melagatran with pharmacokinetic properties required for oral administration without compromising the promising pharmacodynamic properties of melagatran.

Administration, Oral↗

PubMed2001

Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice: enhanced disease severity by impaired inducible nitric oxide synthase induction.

BACKGROUND: Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS: We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS: Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.

Adjuvants, Immunologic↗