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Biomedical subjects

T W Hansen

Publications and source records attributed to T W Hansen.

At least 55 records · Page 3Linked to original sources
PubMed1997

Acute management of extreme neonatal jaundice--the potential benefits of intensified phototherapy and interruption of enterohepatic bilirubin circulation.

Increasing numbers of neonates are being admitted to hospital because of extreme jaundice. Phototherapy should be very effective in such infants, because the efficacy of phototherapy is proportional to the concentration of bilirubin in the skin. Here, I report on four infants who were admitted for indirect serum bilirubin levels of >500 micromol/l (>>30 mg/dl). In one of them, unrecognized Rhesus immunization was the main cause of hyperbilirubinemia, while in the other three increased enterohepatic circulation of bilirubin was thought to be an important contributory factor. In all four infants phototherapy (11-14 microW/cm2/nm) with whole body exposure plus ad lib feeding with milk were initiated immediately upon admission to the nursery. After 2h serum bilirubin values were reduced by 170-185 micromol/l (10-11 mg/dl) in the first three infants, while in the fourth infant a reduction of 195 micromol/l (11.3 mg/dl) was seen in the 5 h interval between the first and second bilirubin measurement. This experience suggests that in some infants with extreme jaundice, intensified phototherapy plus feeding with milk may be very effective in reducing serum bilirubin levels. Even if an exchange transfusion is performed, using this strategy in the waiting period may be beneficial, as both the rapid reduction in serum bilirubin levels as well as the conversion of significant amounts of bilirubin into water-soluble isomers may reduce the risk of neurotoxicity.

Bilirubin↗
PubMed1997

Modulation of the effect of bilirubin on protein phosphorylation by lysine-containing peptides.

Protein phosphorylation is an important mechanism for regulation of cell processes. Bilirubin inhibits phosphorylation of several peptides/proteins by a number of different kinases, and this may contribute to the toxic effects of bilirubin on cells, particularly neurons. Bilirubin binds to lysine residues on both albumin and ligandin. The ATP-binding subdomain II on protein kinases contains an invariant lysine, which might hypothetically be involved in mediation or modulation of bilirubin-inhibition of protein phosphorylation. We have studied the ability of lysine-containing peptides to modulate the effects of bilirubin, using phosphorylation of a phospholemman peptide catalyzed by protein kinase A as a model system. Addition of bilirubin (50 microM) decreased the activity of the catalytic subunit of protein kinase A by 75%. A synthetic lysine-containing decapeptide which mimicked part of subdomain II on the protein kinase family was partially able to prevent the bilirubin effects. Similar effects were not observed with two other decapeptides in which lysine had been replaced by arginine or alanine. Polylysine (100 microM) completely prevented the inhibitory effect of 50 microM bilirubin, whereas polyglutamate and polyarginine did not have this effect. Poly-D-lysine and poly-L-lysine appeared to be equivalent in their ability to prevent the bilirubin effect. These data support the notion that binding of bilirubin to lysine may play a role in the mediation and/or modulation of bilirubin neurotoxicity.

Amino Acid Sequence↗
PubMed1997

Effective reduction of infarct volume by gap junction blockade in a rodent model of stroke.

Several lines of evidence indicate that the extent of ischemic injury is not defined immediately after arterial occlusion, but that infarction expands over time. Episodes of spreading depression have been linked to this secondary increase in infarct volume. Tissue bordering the infarction fails to repolarize following spreading depression and is incorporated into the lesion. The result is that ischemic infarctions expand stepwise after each episode of spreading depression. Another line of evidence has demonstrated that gap junction blockers effectively inhibit spreading depression. These observations suggest that traffic of potentially harmful cytosolic messengers between ischemic cells and surrounding nonischemic cells might cause amplification of injury in focal stroke. It is therefore conceivable that minimizing gap junction permeability might reduce final infarct volume. To test this hypothesis, the authors pretreated rats with the gap junction blocker, octanol, before occluding the middle cerebral artery and compared the sizes of the ischemic lesions to those in rats that received the vehicle, dimethyl sulfoxide, prior to arterial occlusion. Histopathological analysis was performed 24 hours later. The 12 octanol-treated animals showed a significantly decreased mean infarction volume (80 +/- 16 mm3) compared with the nine control rats (148 +/- 9 mm3). In a separate set of experiments, the frequency of experimentally induced waves of spreading depression was evaluated after octanol treatment. Octanol pretreatment resulted in complete inhibition in two of nine animals, transient inhibition in five, and no inhibition in two. The results indicate that gap junction inhibitors, when not limited by toxicity, have significant therapeutic potential in the treatment of acute stroke.

Animals↗
PubMed1996

[Treatment of incterus in newborn infants. Norwegian guidelines in international perspective].

Jaundice is common in neonates and often requires diagnostic and therapeutic intervention. Recently a case has been made for less aggressive intervention when jaundice occurs in healthy term infants. This issue is also being discussed by Norwegian pediatricians. The present paper compares the most commonly used guidelines in Norwegian pediatrics with the results of a recent international survey of therapeutic practices in cases of neonatal jaundice. The survey documented wide variation in the approach to this common problem. Norwegian intervention limits for premature/SGA infants are generally at or above the 90th centile for the international sample, and must be said to be fairly unaggressive. The Norwegian intervention limits for term infants are generally between the median and the 75th centile. Thus they are on the less aggressive side of the international sample. Though it is likely that many term infants can tolerate quite high serum bilirubin levels without significant risk of brain damage, arguments for further elevation of the intervention limits are problematic as long as we do not have the tools to identify individuals, possibly very few, with lower tolerance.

Humans↗
PubMed1996

Neuropsychological and linguistic follow-up studies of children with galactosaemia from an unscreened population.

Many galactosaemics appear to have neuropsychological and/or linguistic problems in spite of dietary treatment. Because the neonatal screening program in Norway does not include galactosaemia, we have re-examined Norwegian galactosaemics. Of 16 known patients, 8 patients participated in the study. They had been diagnosed between 2 and 11 weeks of age, and were between 9 months and 19 years old at the time of this study. All had very low or 0 activity of galactose-1-phosphate uridyl transferase. As part of the study all were examined neurologically, and had an age-appropriate developmental/IQ test, an ABR and an EEG, and a comprehensive psycholinguistic evaluation. The three youngest patients had normal developmental/IQ tests, while the five older patients had IQ scores in or below low range of normal. The majority had delayed language development and three patients were classified as having verbal dyspraxia. ABR and EEG showed mild pathology in the oldest patient only. Galactosaemia appears to be associated with significant risks of developmental and language delays in this unscreened population.

Adolescent↗
PubMed1996

Hemolytic anemia does not increase entry into, nor alter rate of clearance of bilirubin from rat brain.

The risk of bilirubin encephalopathy is believed to be increased in hemolytic relative to nonhemolytic jaundice. Young SPRD rats were injected with either acetylphenylhydrazine (APHZ, n = 22) 75 mg/kg or an equivalent volume of the solvent (control, n = 22) intraperitoneally for 3 successive days. One the 4th day, hyperbilirubinemia was induced by a 5-min intravenous infusion of 50 mg/kg bilirubin. After sacrifice (at 10 or 60 min) the brain vessels were flushed in situ with ice-cold saline. Serum bilirubin was 600 +/- 108 mumol/l (mean +/- SD) at 10 min, and 295 +/- 98 mumol/l at 60 min. Hematocrit was significantly reduced in the APHZ rats versus controls (26 +/- 3 vs. 41 +/- 3, p < 0.0001). The concentration of bilirubin in brain was determined by acid chloroform extraction and diazotization. The brain bilirubin values were 5.5 +/- 1.5 versus 5.4 +/- 2.1 mmol/g at 10 min (APHZ vs. control), and 1.3 +/- 0.6 versus 0.8 +/- 0.7 nmol/g at 60 min. The half-life of bilirubin in brain was calculated with an exponential fitting program. The half-life of bilirubin in brain for the two groups was 24.3 +/- 21.9 versus 18.5 +/- 28.3 min. There were no significant differences between the groups in either of these measures. We conclude that in young rats, hemolytic anemia does not increase the acute entry of bilirubin into brain, nor does it affect the clearance of bilirubin from brain.

Anemia, Hemolytic↗
PubMed1996

Bilirubin-oxidizing activity in rat brain.

Bilirubin may be cleared from the brain by transport across the blood-brain barrier and by a 'sink effect' into the cerebrospinal fluid. However, there is also evidence to suggest that bilirubin may be metabolized in the brain by a process of oxidation. The purpose of this study was to confirm the existence of bilirubin metabolism in the brain and to examine the possible contribution of such an activity to the bilirubin staining pattern characteristic of kernicterus. Mitochondrial membrane fractions were prepared in 0.32 M sucrose from whole rat brains as well as brain regions. The change in optical density of a bilirubin solution at 440 nm was measured over time following addition of the mitochondrial suspension. Our results confirmed the existence of a bilirubin-metabolizing activity in brain mitochondrial membranes. This activity could be removed by heating the mitochondrial suspension and had a definable temperature and pH maxima. The rate of oxidation of bilirubin ranged from 109 to 164 pmol/min/mg protein. There were significant differences between rat brain regions in the ability to oxidize bilirubin. However, these differences could not explain the kernicterus staining phenomenon, because the highest activities were found in brain regions which are more heavily stained in kernicterus. We conclude that bilirubin is metabolized by brain mitochondrial membranes at a rate that would appear to represent a biologically meaningful contribution to bilirubin clearance from the brain. In the present model, differences in such an activity between brain regions do not appear to be compatible with a kernicteric staining pattern.

Animals↗
PubMed1996

Therapeutic approaches to neonatal jaundice: an international survey.

Jaundice is one of the most common clinical phenomena in the neonatal period and a frequent indication for treatment with phototherapy, exchange transfusion, or drugs. The present study documents the variability in approaches to the treatment of this condition. A mail questionnaire was sent to neonatal units worldwide. One hundred and eight answers (49% response rate) were received from Europe (n = 72), North America (n = 28), Africa (n = 7), and Asia (n = 1). The neonatal intensive care units represented by the respondents had 31 +/- 18 beds [mean +/- SD], and 638 +/- 519 admissions per year. All units offered phototherapy, 106/108 performed exchange transfusion, while 44/108 used some form of drug therapy. There was considerable variability among the units in their approaches to the jaundiced neonate. This applied to all aspects of care, including type of phototherapy lights used, practical implementation of phototherapy, use of fluid supplementation, and use of prophylactic phototherapy. The majority used written protocols for investigation and treatment of neonatal jaundice and would let their decision on whether to treat be influenced by the infant's clinical state. There was great variability between units in the level of serum bilirubin that would trigger therapy. This applied across weight groups and to phototherapy as well as exchange transfusion. The significant heterogeneity in our approach to the treatment of jaundiced neonates suggests that our understanding of the biology of neonatal jaundice is inadequate and that further research will be necessary in order to provide a more solid biological foundation for therapy.

Exchange Transfusion, Whole Blood↗
PubMed1996

Bilirubin entry into and clearance from rat brain during hypercarbia and hyperosmolality.

Brain bilirubin concentrations are increased by hyperosmolality and hypercarbia, but the mechanism is not known. The same applies to the mechanism for preferential localization of bilirubin to basal ganglia. Young Sprague-Dawley rats were used. Groups were: control (n = 15), hypercarbia (n = 16, pH approximately 6.95), and hyperosmolality (n = 13, serum osmolality approximately 390 mosm/L). Hyperbilirubinemia was induced by a 5-min infusion of 50 mg/kg bilirubin, containing approximately 20 microCi [3H]bilirubin. Rats were killed at 15-min intervals up to 60 min, and the brains were flushed in situ, dissected into seven regions, weighed, and dissolved. Brain bilirubin was determined by scintillation counting. The half-life of bilirubin in brain was calculated by exponential fitting, which also allowed an estimation of brain bilirubin at the end of the bilirubin bolus. The kinetics of bilirubin clearance from brain were first order. The half-life of bilirubin in brain was significantly prolonged in hyperosmolality (38.2 +/- 28.8 min [mean +/- SD]) compared with control (16.1 +/- 7.7 min) and hypercarbia (12.6 +/- 8.6 min) (F = 12.6, p < 0.0001 after log transformation) results. The estimated acute entry of bilirubin into brain was significantly increased in hypercarbia (13.9 +/- 7.4 nmol/g) compared with control (5.6 +/- 2.1 nmol/g) and hyperosmolality (6.5 +/- 2.1 nmol/g) (F = 19.2, p < 0.0001 after log transformation) results. There were no significant differences between brain regions in acute entry or clearance of bilirubin. The kinetics of increased brain bilirubin differ between hypercarbia (increased acute entry) and hyperosmolality (delayed clearance). Preferential localization of bilirubin to basal ganglia is not produced under, and may not be explained by, the conditions investigated.

Animals↗
PubMed1996

Bilirubin has widespread inhibitory effects on protein phosphorylation.

The neurotoxic effects of bilirubin may involve modulation of neuronal protein phosphorylation systems. Using in vitro phosphorylation assays and a variety of protein substrates and purified protein kinases, we have studied the mechanism of bilirubin-induced inhibition of protein phosphorylation. Bilirubin was found to inhibit cAMP-dependent, cGMP-dependent, Ca(2+)- calmodulin-dependent, and Ca(2+)-phospholipid-dependent protein kinases, irrespective of substrate properties. Fifty percent inhibition occurred at bilirubin concentrations varying from 20 to 125 microM. Kinetic analysis, using the isolated catalytic subunit of cAMP-dependent kinase and a synthetic peptide substrate derived from the protein phospholemman, indicated that bilirubin (50 microM) decreased the apparent Vmax of the reaction, irrespective of whether ATP or peptide levels were varied, without significantly altering the apparent K(m) value. Thus our results indicate that bilirubin can inhibit catalytic domain(s) of protein kinases by apparent noncompetitive mechanism(s), presumably by interacting with noncatalytic domains on the enzyme. Given the key role of protein phosphorylation in cellular regulation, the widespread inhibitory effect of bilirubin on protein kinases may contribute to bilirubin neurotoxicity.

Bilirubin↗
PubMed1995

[Nitrogen oxide in the treatment of oxygenation failure in neonates].

Oxygenation problems are common in very sick infants, and involve a high risk of mortality or residual morbidity. We describe two infants with severe oxygenation difficulties. In one baby these were caused by meconium aspiration, while in the second, premature (1,500 g birth weight) infant Escherichia coli septicemia had precipitated persistent pulmonary hypertension. Inhaled nitric oxide led to immediate improvement in oxygenation, and the one infant was weaned off mechanical ventilatory support after four days, the other after ten days. There were no discernible side effects in either baby. Nitric oxide treatment should be considered for infants with life-threatening oxygenation problems who do not respond adequately to conventional management.

Extracorporeal Membrane Oxygenation↗
PubMed1995

[Ethical considerations in neonatal medicine].

Ethical dilemmas are a daily occurrence in neonatal intensive care units. Some of these questions relate to life-and-death issues such as whom to treat or not to treat, if and when to discontinue life support, and organ donation. However, other issues are just as important in daily practice. These include the choice of a framework for ethical discussions, the question of who participates in the discussions, the parents' right to participation and information, the process and timing of decision-making, the ethics of clinical research in subjects unable to consent, respect and communication between health professionals, and the limits of confidentiality. In most of these dilemmas there is no quick and easy route to the one and only true answer. Neonatal health care workers are frequently confronted with ethical dilemmas, and are forced to reflect ethically. In this process, it is essential to be able to listen attentively to others, health workers as well as lay persons, and to integrate their opinions into one's own reflections. These two factors together must form the basis for daily clinical work and for ethical decisions.

Ethics, Medical↗
PubMed1995

[Persistent pulmonary hypertension in a newborn infant treated with extracorporeal membrane oxygenation].

Extracorporeal membrane oxygenation is a recent addition to our therapeutic arsenal in infants with life-threatening respiratory failure. We have treated a neonate with persistent pulmonary hypertension secondary to meconium aspiration with veno-arterial extracorporeal membrane oxygenation. Both conventional, pressure-controlled ventilation and high-frequency jet ventilation having failed, extracorporeal membrane oxygenation was life-saving for this infant. A clotting episode in the extracorporeal membrane oxygenation circuit resulted in focal as well as global ischemic changes in the brain. In spite of this complication the child was found to be normal upon neurodevelopmental evaluation at one year of age. Extracorporeal membrane oxygenation is a high-technology therapy which should probably be centralized to only one to two units in Norway. It may be life-saving for selected patients who do not respond to other forms of therapy, but the risk of sequelae is not insignificant.

Critical Illness↗
PubMed1995

[Instruction in neonatal resuscitation. A survey among Norwegian pediatricians].

Neonatal resuscitation requires a combination of theoretical knowledge and practical, hands-on skill. By means of a mailed questionnaire we surveyed the training programmes in paediatric departments in Norway. Most departments provide some kind of instruction for new staff members, but several had no structured programmes for maintaining the skills of existing staff. Many departments are too small to provide adequate clinical material for necessary instruction and maintenance of skills. Thus, other kinds of teaching materials should be used. Several departments continue to use recently expired patients for such training, although the Council for Medical Ethics, under the Norwegian Medical Association, has pronounced this practice unethical. We join others who suggest that the Council's position should be reevaluated.

Clinical Competence↗
PubMed1995

Acute entry of bilirubin into rat brain regions.

In kernicterus bilirubin appears at higher concentrations in the basal ganglia, the cerebellum, and the medulla. The mechanism for this distribution is unknown, but might involve differences in bilirubin entry among brain regions. We infused [3H]bilirubin (30 mg/kg over 5 min) intravenously into young Sprague-Dawley rats (n = 21, weight 144 +/- 10 g, mean +/- SD). Blood was sampled from the tail, and groups of rats were killed at 15, 30, 45, 60, and 75 min by intravenous pentobarbital. After in situ flushing of the brain vasculature, the brain was dissected into seven regions, each of which was weighed, dissolved in Soluene-350, and subsequently scintillation counted. Blood samples were analyzed for bilirubin (including specific activity), albumin, and blood gases. Brain bilirubin concentrations in each of the regions were calculated by comparing the radioactivity in that region with the specific activity of bilirubin. Using a curve-fitting program (EXPOFIT), the concentrations of bilirubin in each brain region at 5 min (i.e. the end of bilirubin infusion) could be estimated, and were as follows (nmol/g +/- SD): cortex 6.4 +/- 4.4; hippocampus 6.2 +/- 3.3; striatum 6.3 +/- 4.5; midbrain 7.3 +/- 4.4; hypothalamus 6.3 +/- 4.6; cerebellum 6.7 +/- 4.1, and medulla 7.0 +/- 4.0. There were no significant differences in the bilirubin concentrations between brain regions (F6,140 0.205). The mechanism for preferential localization of bilirubin to the basal ganglia probably does not involve the acute entry of bilirubin into brain.

Animals↗
PubMed1995

Rates of bilirubin clearance from rat brain regions.

The mechanism for the preferential distribution of bilirubin to basal ganglia ('kernicterus') is unknown. We hypothesized that differences in bilirubin clearance rates between brain regions might explain this phenomenon. Bilirubin [30 mg/kg over 5 min, with 370-740 kBq (10-20 mu Ci) tritiated bilirubin] was infused into a peripheral vein in unanesthetized, young Sprague-Dawley rats (n=36, weight 149 +/- 15 g, mean +/- SD). After blood sampling, groups of rats were killed at 15, 30, 45, 60, 75, 180, and 360 min with an intravenous injection of pentobarbital. Brain vasculature was flushed in situ and brains dissected into seven regions, which were weighed, dissolved and scintillation counted. Blood was analyzed for bilirubin, albumin, and blood gases. Brain bilirubin concentrations were calculated after determining the specific activity of bilirubin in serum at the time of sacrifice. Bilirubin half-lives in serum and brain regions were (in minutes, mean +/- SD): serum 24.6 +/- 17.2, whole brain 18.5 +/- 21.5, cortex 17.6 +/- 19.3, hippocampus 19.0 +/- 21.5, striatum 17.1 +/- 18.5, midbrain 16.3 +/- 18.6, hypothalamus 17.4 +/- 21.0, cerebellum 21.6 +/- 33.8, medulla 20.0 +/- 24.1. There were no significant differences in bilirubin half-lives between regions. The half-life of bilirubin in brain reported here is appreciably shorter than the 1.7 h previously found in rats with opened blood-brain barriers, but appears compatible with data on auditory brainstem response reversibility following exchange transfusion in jaundiced infants. We conclude that bilirubin disappeares rapidly from brains with intact blood-brain carriers.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗