Ethical dilemmas in Swedish neonatal intensive care.
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Abnormalities, Multiple↗
Biomedical subjects
M Eriksson
Publications and source records attributed to M Eriksson.
Functional expression of Cre recombinase in sub-regions of mouse CNS and retina.
We describe a strategy for generating CNS and retina sub-region-specific mutations using the Cre/loxP system. Transgenic mice expressing Cre recombinase under the control of the c-kit promoter were established. Functional Cre expression was predominantly found to be restricted to the CA1, CA2 and CA3 regions of the hippocampus, the anterior region of the dentate gyrus, and to the ganglion cell layer of the retina.
Animals↗
Independent regulation of the myotonic dystrophy 1 locus genes postnatally and during adult skeletal muscle regeneration.
Myotonic dystrophy is caused by a CTG(n) expansion in the 3'-untranslated region of a serine/threonine protein kinase gene (DMPK), which is flanked by two other genes, DMWD and SIX5. One hypothesis to explain the wide-ranging effects of this expansion is that, as the mutation expands, it alters the expression of one or more of these genes. The effects may vary in different tissues and developmental stages, but it has been difficult to develop these hypotheses as the normal postnatal developmental expression patterns of these genes have not been adequately investigated. We have developed accurate transcript quantification based on fluorescent real-time reverse transcription-polymerase chain reaction (TaqMan) to develop gene expression profiles during postnatal development in C57Bl/10 mice. Our results show extensive independent postnatal regulation of the myotonic dystrophy-locus genes in selected tissues and demonstrate which are the most highly expressed of the genes in each tissue. All three genes at the locus are expressed in the adult lens, questioning a previous model of cataractogenesis mediated solely by effects on Six5 expression. Additionally, using an in vivo model, we have shown that Dmpk levels decrease during the early stages of muscle regeneration. Our data provide a framework for investigation of tissue-specific pathological mechanisms in this disorder.
Animals↗
The Crd1 gene encodes a putative di-iron enzyme required for photosystem I accumulation in copper deficiency and hypoxia in Chlamydomonas reinhardtii.
Chlamydomonas reinhardtii adapts to copper deficiency by degrading apoplastocyanin and inducing Cyc6 and Cpx1 encoding cytochrome c(6) and coproporphyrinogen oxidase, respectively. To identify other components in this pathway, colonies resulting from insertional mutagenesis were screened for copper- conditional phenotypes. Twelve crd (copper response defect) strains were identified. In copper-deficient conditions, the crd strains fail to accumulate photosystem I and light-harvesting complex I, and they contain reduced amounts of light-harvesting complex II. Cyc6, Cpx1 expression and plastocyanin accumulation remain copper responsive. The crd phenotype is rescued by a similar amount of copper as is required for repression of Cyc6 and Cpx1 and for maintenance of plastocyanin at its usual stoichiometry, suggesting that the affected gene is a target of the same signal transduction pathway. The crd strains represent alleles at a single locus, CRD1, which encodes a 47 kDa, hydrophilic protein with a consensus carboxylate-bridged di-iron binding site. Crd1 homologs are present in the genomes of photosynthetic organisms. In Chlamydomonas, Crd1 expression is activated in copper- or oxygen-deficient cells, and Crd1 function is required for adaptation to these conditions.
Amino Acid Sequence↗
[Respiratory syncytial virus infections are the most common cause of hospitalization among children. Prophylaxis of high-risk individuals is red but the local epidemiology should be decisive].
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Antibodies, Monoclonal↗
Coordinate copper- and oxygen-responsive Cyc6 and Cpx1 expression in Chlamydomonas is mediated by the same element.
Chlamydomonas reinhardtii activates the transcription of the Cyc6 and the Cpx1 genes (encoding cytochrome c(6) and coprogen oxidase) in response to copper deficiency. Mutational analysis of promoter regions of the Cyc6 and Cpx1 genes revealed a four nucleotide sequence, GTAC, which was absolutely essential for copper responsiveness. The Cyc6 promoter contains two copper response elements, each with a functionally important GTAC sequence, whereas the Cpx1 promoter contains only one. This may contribute to the stronger and more tightly regulated expression of the Cyc6 gene. Mutation or deletion of sequences flanking the GTACs implicates additional nucleotides contributing to copper-responsive expression, but none are absolutely essential. Metal ion selectivity of Cpx1 expression is identical to that described previously for Cyc6 and is restricted to the copper deficiency-induced Cpx1 transcript. The Cyc6 and Cpx1 genes are also induced by oxygen deficiency. Reporter gene constructs indicate that the induction occurs at the level of transcription and requires the same GTAC sequence that is critical for copper responsiveness. We suggest that components of the copper-responsive signal transduction pathway are used for some of the changes in gene expression in hypoxic cells.
Animals↗
Expression of Ly49A on T cells alters the threshold for T cell responses.
In this study we investigated the balance between activating and inhibitory signals during T cell activation. We have used transgenic mice in which CD8+ T cells expressed an inhibitory receptor, Ly49A, and a specific activating alphabeta TCR. This TCR recognizes an lymphocytic choriomeningitis virus peptide in combination with H-2Db. We observed a quantitative influence on cellular responses that depended upon the activating signals received through the TCR and the inhibitory signals received through Ly49A. By varying the peptide concentration given to stimulating cells or target cells, we could adjust the amount of ligand available to trigger the TCR. At low doses of peptide, Ly49A-expressing T cells were unresponsive on target cells that expressed H-2Dd, but responded against target cells without H-2Dd. However, this inhibition could be overcome by increasing the peptide concentration or by addition of anti-Ly49A F(ab')2 fragments. Thus, rather than behaving as simple "off" switches, our data indicate that Ly49 receptors modulate T cell signaling so that higher amounts of activating signals are required for effector-cell responses.
Animals↗
The basic helix-loop-helix transcription factor E2-2 is involved in T lymphocyte development.
E2A, HEB and E2-2 genes encode a group of basic helix-loop-helix (bHLH) transcription factors that are structurally and functionally similar. Deletion of the genes encoding either of these proteins leads to early lethality and a block in B lymphocyte development. Evidence for a function in T lymphocyte development has, however, only been reported for E2A and HEB. To further elucidate the role of E2-2 at developmental stages that have proven difficult to study due to the early lethality phenotype of mice defective in E2-2, we generated and analyzed mice conditionally mutated in the E2-2 gene. These mice are mosaic with respect to E2-2 expression, consisting of cells with either one functional and one null mutated E2-2 allele or two null mutated alleles. Using this experimental model, we find that cells with a homozygous null mutated E2-2 gene are under-represented in B lymphocyte as well as T lymphocyte cell lineages as compared to other hematopoietic or non-hematopoietic cell lineages. Our data suggests that E2-2 deficiency leads to a partial block in both B and T lymphocyte development. The block in T cell development appears to occur at an early stage in differentiation, since skewing in the mosaicism is observed already in CD4+8+ double-positive thymocytes.
Alleles↗
Biological degradation of selected hydrocarbons in an old PAH/creosote contaminated soil from a gas work site.
An old PAH/creosote contaminated soil (total approximately 300 microg PAH/g soil) from a former gas work site in Stockholm, Sweden, has been treated at 20 degrees C with the addition of various nutrients and inoculated with bacteria (isolated from the soil) to enhance the degradation of selected hydrocarbons. Microcosm studies showed that the soil consisted of two contaminant fractions: one available, easily degraded fraction and a strongly sorbed, recalcitrant one. The bioavailable fraction, monitored by headspace solid phase microextraction, contained aromatics with up to three rings, and these were degraded within 20 days down to non-detectable levels (ng PAH/g soil) by both the indigenous bacteria and the externally inoculated samples. The nutrient additives were: a minimal medium (Bushnell-Haas), nitrate, nitrite, potting soil (Anglamark, Sweden), sterile water and aeration with Bushnell-Haas medium. After 30 days treatment most of the sorbed fractions were still present in the soil. Stirring or mechanical mixing of the soil slurries had the greatest effect on degradation, indicating that the substances were too strongly sorbed for the microorganisms. When stirring the choice of nutrient seemed less important. For the non-stirred samples the addition of nitrate with the bacterial inoculum showed the best degradation, compared to the other non-stirred samples. At the end of the experiments, accumulations of metabolites/degradation products, such as 9H-fluorenone, 4-hydroxy-9H-fluorenone, 9,10-phenanthrenedione and 4H-cyclopenta[def]phenanthrenone were detected. The metabolite 4-hydroxy-9H-fluorenone increased by several orders of magnitude during the biological treatments. Microbial activity in the soil was measured by oxygen consumption and carbon dioxide production.
Biodegradation, Environmental↗
Is there an association between alcohol intake or smoking and small bowel adenocarcinoma? Results from a European multi-center case-control study.
OBJECTIVE: To discover whether tobacco smoking and intake of different types of alcoholic drinks are associated with small bowel adenocarcinoma (SBA). METHODS: A population-based European multi-center case-control study was conducted from 1995 to 1997. RESULTS: After a histological review using uniform diagnostic criteria, 47 (33%) of the 142 identified cases of SBA were excluded due to reclassification as either tumors of the papilla of Vater (n = 22), stromal tumors, or metastases; 95 cases were accepted for study. In all, 70 cases of SBA together with 2070 controls matched by age, sex, and region were interviewed. A high intake (more than 24 g alcohol per day) of beer or spirits was associated with SBA, an odds ratio (OR) of 3.5 and 95% confidence intervals (CI) of 1.5-8.0 and 3.4 (95% CI 1.3-9.2), respectively). There was no association with wine intake or total alcohol intake. Tobacco smoking was probably unrelated to SBA. CONCLUSIONS: A high intake of beer or spirits seems to be a risk factor for SBA. Since this association was not seen for wine drinkers, protective components of wine may counterbalance a carcinogenic effect of alcohol on the small bowel. Alternatively, the result may be confounded by other factors, e.g. dietary factors.
Adenocarcinoma↗
Wheezing following lower respiratory tract infections with respiratory syncytial virus and influenza A in infancy.
We examined the incidence of subsequent wheezing in 292 children, hospitalized for influenza A or respiratory syncytial virus (RSV) lower respiratory tract infection, during two consecutive seasons (November-December, 1993 and March-April, 1995). Questionnaires concerning episodes of wheezing and known risk factors for wheezy bronchitis were mailed to parents 1 year after hospitalization. Sixty per cent of parents reported two or more episodes of wheezing following either influenza A or RSV. Hospitalization as a result of wheezing was necessary in 15% of the patients. The severity of the primary infection, as indicated by the need for treatment in the intensive care unit (ICU), was correlated with later wheezing. No additional significant risk factors predicting later wheezing could be identified.
Asthma↗
Lipid peroxidation induced by an early inflammatory response in endotoxaemia.
BACKGROUND: Endotoxaemic challenge promptly causes lipid peroxidation. Porcine endotoxaemia can be used to replicate severe human septic shock. This model was used to evaluate non-enzymatic [8-Iso-prostaglandin F2alpha (8-Iso-PGF2alpha)] and enzymatic [15-keto-13,14-dihydro-prostaglandin F2alpha (15-K-DH-PGF2alpha)] lipid peroxidation, respectively, in relation to survival. The aim of this study was to correlate, if possible, pathophysiologic events during endotoxaemia to the levels of these arachidonic acid metabolites. METHODS: Nineteen pigs were anaesthetised, monitored (circulatory and respiratory variables in relation to lipid peroxidation) and given a continuous 6 h E. coli endotoxin (10 microg x kg(-1) x h(-1)) infusion. All animals were mechanically ventilated at constant tidal volumes and the inspired oxygen fraction was kept constant during the experimental period. RESULTS: This endotoxin infusion caused expressed derangements in all pigs and death in 9 of them. The levels of 8-Iso-PGF2alpha, indicating oxidative injury, were different in time course, magnitude and fashion between survivors and non-survivors. The levels of 15-K-DH-PGF2alpha, indicating inflammatory response, showed a similar pattern. At 1 h the CO2 partial pressure in arterial blood was significantly higher in non-surviving pigs and correlated (r: 0.7; P<0.05) to the levels of 15-K-DH-PGF2alpha. Prostaglandin F2alpha is mainly metabolised in the lung. The lung weights were significantly (P<0.05) higher in non-surviving than in surviving animals. Both free radical and cyclooxygenase catalysed oxidative modification occurs during endotoxaemia. CONCLUSION: Increased metabolism and inflammation, as evaluated by 15-K-DH-PGF2alpha, in the group of non-survivors may mediate the increase in arterial CO2. Thus, increased lipid peroxidation seems to be associated with endotoxaemic organ dysfunction and increased mortality.
Animals↗
Effects of melagatran, an inhibitor of thrombin, on fibrin deposits, haemodynamics, and platelet count in endotoxaemic pigs.
BACKGROUND: Thrombin plays a pivotal role in the development of septic shock. Porcine endotoxaemia can replicate this condition. We wanted to evaluate whether melagatran, a novel inhibitor of thrombin, would counteract some of the endotoxin-induced changes in this model. METHODS: Fifteen pigs were anaesthetised, monitored (circulatory and respiratory variables) and subjected to an infusion of E. coli endotoxin at 10 microg x kg(-1) x h(-1). Six pigs were given melagatran during the first 3 h of the 6-h endotoxaemic period. Nine controls were given the corresponding volume of saline instead of melagatran. Specimens from the liver and the left lung were taken for light microscopy post mortem. RESULTS: The endotoxin-induced increase in pulmonary capillary wedge pressure and drop in platelet count were significantly less pronounced in the melagatran-treated pigs. Deposits of pulmonary fibrin were significantly reduced in the melagatran group, without improving oxygenation. Light microscopy revealed no hepatic fibrin in the pigs treated with melagatran in contrast to the endotoxaemic controls. Hepatic neutrophil accumulation was reduced in the melagatran group as compared to controls. Hepatocellular degeneration and plasma levels of tumour necrosis factor alpha (TNF alpha) and bilirubin were of the same magnitude in both groups. CONCLUSION: Melagatran reduced pulmonary capillary wedge pressure, a retrograde reflection of the left ventricular end-diastolic filling pressure, and also pulmonary stasis in pigs subjected to endotoxaemic challenge. Pulmonary and hepatic fibrin depositions were reduced, but PaO2 levels or liver function markers were not affected by melagatran during the early phase of endotoxaemia. Obstruction of the intrahepatic bile ducts, by fibrin depositions, is not responsible for reduced excretion of conjugated bilirubin during endotoxaemia. The beneficial effects of melagatran during endotoxaemia were not due to any reduction of plasma TNF alpha.
Animals↗
LDL-apheresis in patients with nephrotic syndrome: effects on serum albumin and urinary albumin excretion.
BACKGROUND: Hyperlipidemia is a common feature of the nephrotic syndrome (NS). From retrospective studies, it has been suggested that aggressive lipid-lowering with low-density lipoprotein apheresis (LDL-A) may not only improve dyslipidemia but also decrease urinary albumin excretion and increase serum levels of albumin in patients with focal segmental sclerosis. METHODS: Seven patients (6 males) aged 44 +/-7 years (SEM) with NS (duration 29+/-11 months) of diverse etiologies were investigated in a prospective study. A fixed protocol of LDL-A was designed for treatment twice-a-week for 3 weeks and then once a week for 7 weeks. The effects of LDL-A on lipid parameters (cholesterol, triglycerides, HDL, Lp(a), apo A-I, apo B) and renal parameters (iohexol clearance, serum albumin and 24-h urinary albumin excretion) were evaluated. RESULTS: Following treatment by LDL-A a remission in the severity of the NS was observed in two patients whereas a clear improvement was observed in four of the patients. A small, but significant (P<0.05), increase in serum albumin levels from 20+/-2 to 24+/-2 g L(-1) was noted after LDL-A. As expected, serum lipid parameters improved during LDL-A, and significant decreases in serum cholesterol, apo B and plasma Lp(a) were observed at different time-points of LDL-A. Conversely, no significant changes in either triglyceride, HDL or apo A-I levels were observed during LDL-A. CONCLUSIONS: The present uncontrolled prospective study shows that LDL-A causes a rapid 30-40% decrease in serum cholesterol and plasma Lp(a) levels in patients with NS. The present prospective study also suggests that short-term LDL-A treatment may increase serum albumin levels in nephrotic patients.
Adult↗
Vitamin E in relation to lipid peroxidation in experimental septic shock.
Lipid peroxidation and antioxidant balance in the body is a crucial factor in the pathophysiology of various diseases. This study investigates the circulatory alpha-tocopherol levels and its relationship with 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a non-enzymatic and, 15-keto-13,14-dihydro-PGF2alpha (15-K-DH-PGF2alpha), a cyclooxygenase catalysed oxidation product of arachidonic acid in experimental septic shock in pigs. A steady decrease in alpha-tocopherol levels in plasma was observed in both survivor and non-survivor animals. A simultaneous increase of oxidative injury indicator, plasma 8-iso-PGF2alpha was seen in both groups but with a different fashion. 8-Iso-PGF2alpha levels increased steadily in the animals that died during the experiment. An early and rapid increase of plasma 15-K-DH-PGF2alpha, an inflammatory response indicator, was also observed in all animals. There was a significant difference in the kinetics of decrement of alpha-tocopherol levels and a concomitant increase in 15-K-DH-PGF2alpha levels among the non-survivors. Thus, a successive disappearance of circulatory vitamin E in conjunction with the surge of plasma isoprostanes and prostaglandins impairs the oxidant-antioxidant balance in favour of the former and may possibly have an effect on the survivality during experimental porcine septicaemia.
Animals↗
Budesonide delivered by dosimetric jet nebulization to preterm very low birthweight infants at high risk for development of chronic lung disease.
UNLABELLED: We investigated the effect of an aerosolized corticosteroid (budesonide) on the oxygen requirement of infants at high risk for developing chronic lung disease (CLD) in a randomized, double-blind study. The study objective was to attain a 30% decrease in FiO2 levels in the budesonide treatment group after 14 d of therapy. Thirty very low birthweight (VLBW) infants (median (range)) gestational age 26 wk (23-29) and birthweight 805 g (525-1227) were randomized. Inclusion criteria were mechanical ventilation on day 6 of life, or if extubated on nasal continuous positive airway pressure with FiO2 > or = 0.3. The budesonide (Pulmicort) dose was 500 microg bid, or placebo. The aerosol was delivered with a dosimetric jet nebulizer, with variable inspiratory time and breath sensitivity. Inhalations were started on day 7 of life. Twenty-seven patients completed the study. A significant lowering of the FiO2 levels at 21 d of life was not detected. Infants who received budesonide were more often extubated during the study period (7/8 vs 2/9) and had a greater relative change from baseline in their oxygenation index (budesonide decreased 26% vs placebo increased 60%). Subsequent use of intravenous dexamethasone or inhaled budesonide in the treatment group was significantly less. All patients required O2 supplementation on day 28 of life. At 36 wk postconceptual age, 61% of infants in the budesonide group needed supplemental O2 as opposed to 79% in the placebo group. No side effects on growth or adrenal function were observed. CONCLUSION: We conclude that inhaled budesonide aerosol via dosimetric jet nebulizer started on day 7 of life for infants at high risk for developing CLD decreases the need for mechanical ventilation similar to intravenous dexamethasone, but without significant side effects.
Aerosols↗
Children of mothers abusing amphetamine: head circumference during infancy and psychosocial development until 14 years of age.
OBJECTIVE: To study the relationship between head circumference (HC) at birth (HO) and at 1 y of age (HI) and later outcome variables in children exposed to amphetamine during fetal life through maternal drug abuse. METHOD: Prospective longitudinal study of 65 children born to women abusing amphetamine. Potential bivariate and partial correlations between HC and outcome variables at 4, 8 and 14 y of age were studied. In multivariate analyses on outcome variables, HC, maternal and perinatal factors were used as predictors. Analyses were performed for all children and separately for boys and girls. RESULTS: Head circumference at birth and 1 y of age were significant predictors for the level of achievement in Swedish language at 14 y. Head circumference at birth was a significant predictor for grades in mathematics in boys. Combined assessment of psychomotor development and psychosocial adjustment at 4 and 8 y correlated with HI in girls. CONCLUSION: Head circumference at birth and at 1 y of age correlated with school achievement at 14 y. HI also correlated with adjustment at 4 and 8 y in girls. A difference in vulnerability between girls and boys is important and should be considered in longitudinal studies of risk cohorts.
Adolescent↗
Reliability and content validity of a new instrument for assessment of communicative skills and language abilities in young Swedish children.
The Swedish Early Communicative Development Inventories (SECDI)--w&g (words and gestures; 8-16 months) and w&s (words and sentences; 16-28 months)--is a new instrument to assess communicative and language abilities in Swedish speaking children. Test-retest reliability and content validity of SECDI were examined. The results show that the SECDI covers common words in Swedish children's vocabulary and that its grammar scale (w&s) incorporates items that develop early among many children. Test-retest was analysed over 2 or 3 months, first for 57 and then for 60 children. Test-retest reliability scores are as follows: SECDI--w&g = between 0.70 and 0.90 in most age ranges; and SECDI--w&s = close to or above 0.90 on most measures.
Child Development↗