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Biomedical subjects

T W Hansen

Publications and source records attributed to T W Hansen.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Early discharge from maternity and neonatal care units--limitations and perspectives].

Early discharge from maternity units has become more frequent over the last decade. The driving forces have been historical, ideological, logistic, and financial. Often early discharge has been implemented without adequate changes in follow-up practices, resulting in increased readmission rates to hospitals. Many infants recalled for metabolic screening have not showed up, with the attending risk of mental retardation. The question of length of maternity stays has not been adequately studied. Established practice should therefore be changed cautiously. Mechanisms for quality control must be in place to ensure early detection of unanticipated problems. Early discharge from neonatal intensive care units is happening in several countries, either due to lack of equipment or bed space, or to reduce the cost of care. In wealthier countries technology-dependent infants are increasingly being cared for at home. These practices have also not been well studied, and probably should be. Of particular interest is the question of parents' ability to cope with the challenges of caring for these infants.

Adult↗
PubMed1999

Oxidation of bilirubin in the brain-further characterization of a potentially protective mechanism.

Bilirubin is a well-known neurotoxin and presents a particular problem in newborn infants. This is partly due to the high incidence of unconjugated hyperbilirubinemia in that age group, but may also be due to increased vulnerability to bilirubin toxicity. The brain may be able to protect itself against bilirubin toxicity through a process of oxidation. The responsible enzyme is localized on the inner mitochondrial membrane and appears to be more active in glia than in neurons and to increase in activity with postnatal maturation. Here we have investigated the possibility that the responsible enzyme might be a cytochrome oxidase, malate dehydrogenase, or monoamine oxidase, all enzymes located on the inner mitochondrial membrane. Mitochondria were obtained from rat brains through homogenization and differential centrifugation in sucrose medium. The ability of mitochondrial membranes to oxidize bilirubin was measured by following the change in optical density at 440 nm of a bilirubin solution to which a membrane suspension had been added. The activity was not changed by in vitro inhibitors of malate dehydrogenase or monoamine oxidase, but was moderately inhibited by ketoconazole and clotrimazole, both known inhibitors of hepatic cytochrome P450 oxidases. Activity was inhibited by depletion of cytochrome c in the mitochondria and reconstituted by reintroducing cytochrome c into the reaction mixture. The reaction was not modified by the addition of a free radical quencher, but was inhibited by removal of oxygen from the reaction mixture. The activity was significantly inhibited by cyanide. Activity was retained in a 100,000-g pellet and was not influenced by the addition of NAD, NADP, NADH, NADPH, GSH, or GSSH to this pellet. We conclude that the bilirubin-oxidizing activity in brain mitochondrial membranes is cytochrome c dependent, but does not appear to be unequivocally identifiable as a cytochrome P450 oxidase.

Animals↗
PubMed1999

Bilirubin inhibits Ca2+-dependent release of norepinephrine from permeabilized nerve terminals.

Although the well-known neurotoxic agent bilirubin can induce alterations in neuronal signaling, direct effects on neurotransmitter release have been difficult to demonstrate. In the present study we have used permeabilized nerve terminals (synaptosomes) from rat brain prelabeled with [3H]norepinephrine to examine the effects of bilirubin on transmitter release. Rat cerebrocortical synaptosomes were permeabilized with streptolysin-O (2 U/ml) in the absence or presence of bilirubin (10 microM-320 microM) and Ca2+ (100 microM), and the amount of radiolabeled transmitter released during 5 min to the medium was analysed. Low levels of bilirubin decreased Ca2+-evoked release in a dose-dependent manner, with half-maximal effect at approx 25 microM bilirubin. Higher levels of bilirubin (100-320 microM) increased [3H]norepinephrine efflux in the absence of Ca2+, suggesting that high bilirubin levels induced leakage of transmitter from vesicles. The nontoxic precursor biliverdin had no effect on Ca2+-dependent exocytosis. Our data indicate that bilirubin directly inhibits both exocytotic release and vesicular storage of brain catecholamines.

Animals↗
PubMed1999

Intensified phototherapy using daylight fluorescent lamps.

Jaundice is a common reason for therapeutic intervention in newborn infants and phototherapy is effective treatment if enough light energy is delivered to a skin surface area of sufficient size. Narrow spectrum blue light is superior to white light, but in developing countries fluorescent blue lamps often have to be imported and are much more expensive than white lamps. We developed a phototherapy unit in which seven daylight fluorescent tubes are placed immediately under the floor of a transparent plexiglass crib. The efficacy of this unit, delivering approximately 19 microW/cm2/nm, was compared with that of two conventional phototherapy units using overhead lamps placed 35 cm above the infants. One unit used daylight fluorescent tubes and delivered approximately 4 microW/cm2/nm, the other unit used special blue fluorescent tubes and delivered approximately 22 microW/cm2/nm. Fifty-one infants were included in the analyses, all of them breastfed on demand. Serum bilirubin levels were determined spectrophotometrically at 0, 12 and 24 h. The decrement in serum bilirubin concentrations was significantly greater in infants undergoing phototherapy with the new device or with special blue lamps compared to conventional overhead daylight lamps (p < 0.001 both at 12 and at 24 h). We conclude that highly efficient phototherapy may be delivered with daylight fluorescent lamps placed in very close proximity to the patient. Thus, lack of access to expensive imported special blue lamps does not preclude delivery of effective phototherapy in developing countries.

Circadian Rhythm↗
PubMed1998

Astrocytic gap junctions remain open during ischemic conditions.

Gap junctions are highly conductive channels that allow the direct transfer of intracellular messengers such as Ca2+ and inositol triphosphate (IP3) between interconnected cells. In brain, astrocytes are coupled extensively by gap junctions. We found here that gap junctions among astrocytes in acutely prepared brain slices as well as in culture remained open during ischemic conditions. Uncoupling first occurred after the terminal loss of plasma membrane integrity. Gap junctions therefore may link ischemic astrocytes in an evolving infarct with the surroundings. The free exchange of intracellular messengers between dying and potentially viable astrocytes might contribute to secondary expansion of ischemic lesions.

Animals↗
PubMed1998

[Neonatal hemochromatosis].

Neonatal haemochromatosis is a disorder which affects foetuses and newborns. It is characterized by hepatocellular insufficiency, often appearing on the first day of life in the form of coagulopathy, hypoalbuminemia, hypoglycemia and jaundice. While spontaneous recovery has been reported, most of these infants die, and the diagnosis was previously often made during autopsy. With the help of MRI and salivary gland biopsies, plus increasing awareness of this disorder, the diagnosis is now often made quite early, and successful liver transplantations have been reported. Recently, there have also been encouraging preliminary reports of successful intervention with antioxidant and chelation pharmacotherapy, using a combination of selenium, vitamin E, N-acetylcysteine, deferoxamine, and prostaglandin E. We describe two patients with neonatal haemochromatosis who were both treated with this new "cocktail", one of whom died at five days of age, while the other survived, but needed a liver transplant at 2 1/2 months of age. The pathology of this condition is characterized by hepatic cirrhosis with giant cell transformation, and by siderosis of extrahepatic tissues. The prognosis is poor, and our experience with antioxidant treatment has been disappointing. Liver transplantation is a therapeutic option, but its use is limited by the scarcity of donor organs and the small size of many of the patients.

Antioxidants↗
PubMed1998

Gap-junction-mediated propagation and amplification of cell injury.

Gap junctions are conductive channels that connect the interiors of coupled cells. We determined whether gap junctions propagate transcellular signals during metabolic stress and whether such signaling exacerbates cell injury. Although overexpression of the human proto-oncogene bcl2 in C6 glioma cells normally increased their resistance to injury, the relative resistance of bcl2+ cells to calcium overload, oxidative stress and metabolic inhibition was compromised when they formed gap junctions with more vulnerable cells. The likelihood of death was in direct proportion to the number and density of gap junctions with their less resistant neighbors. Thus, dying glia killed neighboring cells that would otherwise have escaped injury. This process of glial 'fratricide' may provide a basis for the secondary propagation of brain injury in cerebral ischemia.

Animals↗
PubMed1998

Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies.

BACKGROUND: Neonatal hemochromatosis (NH), also known as perinatal hemochromatosis or neonatal iron storage disease, is a disorder in fetuses and newborn infants. A retrospective study was conducted to report management of patients with NH. METHODS: Retrospective analysis was conducted by chart review and by review of histologic material from patients with NH. RESULTS: Neonatal hemochromatosis was diagnosed in 14 patients between 1985 and 1995. All were considered for orthotopic liver transplantation (OLTX). From 1993 onward, all patients were treated with an antioxidant-chelation "cocktail," consisting of deferoxamine, vitamin E, N-acetylcysteine, selenium, and prostaglandin-E1. Of 6 patients with NH diagnosed before 1993, 4 underwent OLTX; only 1 is still alive. Of 8 patients with NH diagnosed after 1993 and treated with the cocktail, 7 expired before OLTX. One stabilized on therapy, but having never recovered full synthetic liver function, underwent OLTX and is now alive and well. CONCLUSION: Neonatal hemochromatosis carries a grim prognosis; however, successful OLTX is curative. The use of an antioxidant-chelation cocktail did not improve outcome in the patients studied. Earlier (perinatal) diagnosis may be required for optimal results. Further study of other interventions, including antenatal diagnosis and earlier institution or modification of cocktail therapy appears warranted.

Acetylcysteine↗
PubMed1998

Effect of phenobarbital on bilirubin metabolism in rat brain.

Bilirubin is metabolized by brain mitochondrial membranes. This activity increases with postnatal age, is higher in glia than in neurons, and is subject to genetic variability. The rates of oxidation are such that this mechanism probably contributes meaningfully to clearance of bilirubin from brain. Phenobarbital is a well-known inducer of bilirubin-metabolizing enzymes in the liver. Previous incomplete data had suggested that phenobarbital treatment might also affect bilirubin metabolism in brain. We studied the clearance of bilirubin from brain (branch 1) as well as the oxidation of bilirubin by brain mitochondrial membranes (branch 2) following pretreatment of young adult SPRD rats with phenobarbital 75 mg/kg i.p. daily for 7 days; controls received solvent only. On day 8, rats in branch 1 (n = 8 in both phenobarbital-treated and control groups) were anesthetized and 50 mg/kg bilirubin was infused i.v. over 5 min. Rats were sacrificed after 60 min and brain bilirubin determined by acid chloroform extraction. In branch 2 (n = 7 in both groups) rats were sacrificed with i.p. pentobarbital, brains were homogenized in 0.32 M sucrose and mitochondria separated out by differential centrifugation. The mitochondrial membrane suspension was added to a 10-mumol/1 bilirubin solution, and the rate of bilirubin oxidation was measured at 440 nm. As expected following phenobarbital treatment, serum bilirubin was slightly lower in phenobarbital-treated vs. control rats [126 +/- 32 vs. 140 +/- 21 mumol/1 (mean +/- SD); p = 0.3]. Brain bilirubin values were also lower in the phenobarbital-treated rats (0.44 +/- 0.06 vs. 0.52 +/- 0.08 nmol/g, p = 0.044). As the lower brain bilirubin values in phenobarbital-treated rats could be due entirely to lower serum bilirubin values, we compared the brain:serum bilirubin ratios in the two groups. These were not different (0.0063 +/- 0.0016 vs. 0.0064 +/- 0011). The rate of bilirubin oxidation was significantly lower in phenobarbital-treated vs. control rats (256 +/- 10 vs. 286 +/- 26 pmol/min/mg protein, p = 0.023). We conclude that phenobarbital inhibits bilirubin metabolism in brain. However, albeit statistically significant, the difference is small and may not be biologically meaningful. Thus, pretreatment with phenobarbital had no effect on overall brain bilirubin clearance rate. We speculate that phenobarbital treatment may be neither helpful nor harmful relative to the neurotoxic effects of bilirubin in infants with already established jaundice.

Animals↗
PubMed1998

Effects of endotoxemia and sepsis on bilirubin oxidation by rat brain mitochondrial membranes.

Sepsis is believed to increase the risk of bilirubin brain toxicity, but the mechanism is not known. Adult male Sprague-Dawley rats were injected intraperitoneally with either 20 mg/kg Escherichia coli lipopolysaccharide, approximately 5 x 10(9)/kg CFU Listeria monocytogenes or vehicle 48 h prior to sacrifice. Rats were killed with an intraperitoneal injection of pentobarbital. Mitochondrial membrane fractions were produced by homogenization of the brains and differential centrifugation in 0.32 M sucrose. The mitochondrial pellet was resuspended in distilled water and sonicated to rupture the mitochondria. The protein concentration of the suspension was standardized to 2.5 mg/ml. Bilirubin oxidation was assayed in a pH 8.2, 0.1 M barbital buffer containing 10 microM bilirubin, 5 mM EDTA, and 500 U/ml catalase. Optical density was measured at 440 nm before and after a 60-min incubation at 37.5 degrees C. There were no differences between the control, endotoxemic, and septic groups as far as the ability of brain mitochondrial membranes to oxidize bilirubin (bilirubin oxidation rate: 289 +/- 11 vs. 295 +/- 9 vs. 296 +/- 12 pmol/min/mg protein, mean +/- SD). We conclude that endotoxemia or sepsis do not change the ability of brain mitochondrial membranes to oxidize bilirubin. If sepsis truly increases the risk of bilirubin encephalopathy in neonatal jaundice, this is likely to involve other mechanisms.

Animals↗
PubMed1998

Bilirubin inhibits transport of neurotransmitters in synaptic vesicles.

Uptake of neurotransmitters into synaptic vesicles occurs through specific transport proteins which are driven by an ATPase-generated electrochemical force consisting of a proton gradient and a membrane potential. In this study we examined the effects of bilirubin, a well known neurotoxic agent, on the vesicle uptake both of [3H]dopamine (which is driven mostly by the proton gradient) and [3H]glutamate (which is driven mostly by the membrane potential), and compared these to the vesicular proton gradient, which was estimated by analyzing the uptake of [14C]methylamine. Bilirubin inhibited the uptake of both dopamine and glutamate (p < 0.01), with an identical dose-response curve for both transmitters. Inhibition was detected readily at 75 microM. The effects of bilirubin were dependent on the concentration of vesicles in the assay, suggesting that the concentration of bilirubin in the membranes and not the water phase was important. Bilirubin also decreased uptake-dependent efflux of dopamine from the vesicles. In contrast, bilirubin had no effect on the vesicular proton gradient, as measured by methylamine uptake. Our results show that bilirubin has essentially identical inhibitory effects on the uptake of both a monoamine transmitter and an amino acid transmitter into synaptic vesicles, but does not influence the vesicular H+-ATPase or proton translocation. Our data suggest an inhibitory interaction between bilirubin and several transport proteins in synaptic vesicle membranes.

Animals↗
PubMed1998

Brain bilirubin content is increased in P-glycoprotein-deficient transgenic null mutant mice.

P-glycoprotein (P-gp), encoded by the mdr1a gene, is an ATP-dependent plasma membrane protein that is expressed in abundance on the blood-brain barrier (BBB). P-gp limits the CNS influx and retention of a variety of lipophilic compounds. We hypothesized that brain bilirubin content after an i.v. bilirubin infusion would be increased in P-gp-deficient mdr1a null mutant transgenic mice (mdr1a(-/-)) compared with controls. Eighteen mdr1a(-/-) null mutant and 18 P-gp-sufficient wild type mice (+/+) were anesthetized and 50 mg/kg bilirubin infused through the tail vein. Brain bilirubin content (mean +/- SEM) 10 min after infusion was significantly higher in mdr1a(-/-) (18.1 +/- 2.4 nmol/g) compared with (+/+) mice (10.4 +/- 1.0 nmol/g). Brain bilirubin content declined 60 min after infusion but remained higher in mdr1a(-/-) (10.3 +/- 1.4 nmol/g) compared with (+/+) mice (5.3 +/- 0.9 nmol/g). Brain bilirubin clearance did not differ between groups (t 1/2 approximately 55 min). We conclude that P-gp-deficient mdr1a(-/-) mice have significantly higher brain bilirubin content compared with controls after an i.v. bilirubin load. These data suggest that 1) bilirubin is a substrate for P-gp and 2) the increased brain bilirubin content in mdr1a(-/-) mice is due to enhanced brain bilirubin influx. We speculate that BBB P-gp provides a protective effect against bilirubin neurotoxicity by reducing brain bilirubin influx.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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 following arterial occlusion; rather that infarction expands over time. Episodes of spreading depression have been linked to this secondary increase in infarct volume. Tissue bordering the infarct fails to repolarize following spreading depression and is incorporated into the infarction. The result is that ischemic infarcts expand stepwise following each episode of spreading depression. Another line of evidence has demonstrated that gap junction blockers effectively inhibit spreading depression. These observations suggest that the efflux of potentially harmful cytosolic messengers from ischemic cells into 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 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 following octanol treatment. Octanol pretreatment resulted in complete inhibition in two of nine animals, transient inhibition in five of nine, and no inhibition in two of nine. The results indicate that gap junction inhibitors, when not limited by toxicity, have significant therapeutic potential in the treatment of acute stroke.

Journal Article↗
PubMed1997

[Cytomegalovirus infection in neonates. Diagnosis and therapeutic experiences].

Approximately 0.5-1% of all newborns are born infected with cytomegalovirus (CMV), but of these only one out of ten show symptoms at birth, most often with hepatosplenomegaly, thrombocytopenia, and/or brain affection. Of the remaining nine, one may later develop sequelae with hearing loss and/or mental retardation. CMV infection may also be acquired perinatally or in the newborn period, and may cause pneumonia and/or sepsis, possibly also gastrointestinal symptoms like blood in the stool, and poor weight-gain. We have diagnosed CMV infection in ten neonates and infants, and describe these patients in terms of symptoms, diagnosis and treatment. Ganciclovir is being tested in clinical trials as a treatment for congenital CMV infection, and was given to two of our patients with apparently good results.

Antiviral Agents↗
PubMed1997

Oxidation of bilirubin by brain mitochondrial membranes--dependence on cell type and postnatal age.

Bilirubin is oxidized by brain mitochondrial membranes at a rate which may contribute significantly to clearance of bilirubin from the brain. Neurons appear to be more sensitive to bilirubin toxicity than glial cells. Clinical experience has suggested that sensitivity to bilirubin neurotoxicity may be greater in the neonate than later in life. We hypothesized that the ability to oxidize bilirubin would be lower in mitochondrial membranes from a pure neuronal compared to a mixed glial/neuronal source, and lower in immature than more mature brains. Mitochondria of synaptosomal and nonsynaptosomal origin were obtained from young rat brains by differential centrifugation in sucrose gradients. Synaptosomes were lysed by hypoosmotic treatment, and mitochondria were ruptured by sonication. The change in optical density of a bilirubin solution at 440 nm was measured over time following addition of the membrane suspension. The rate of bilirubin oxidation was significantly higher in nonsynaptic than in synaptic mitochondrial membranes [99.1 +/- 42.3 (mean +/- SD) vs 69.9 +/- 30.9 pmol/ min/mg protein, t = 4.835, P = 0.0003]. "Crude" mitochondrial membranes were obtained by differential centrifugation in sucrose from the forebrains of rats of 7, 14, and 21 days postnatal age as well as adults, and from rabbits of 1 and 7 days postnatal age as well as adults. In both species the rates of bilirubin oxidation increased significantly with postnatal age (rats: F = 55.3, P < 0.0001; rabbits: F = 101, P < 0.0001). Mitochondrial membranes from a pure neuronal source oxidize bilirubin at a significantly lower rate than membranes from a mixed glial/neuronal source. This suggests that neurons may be less able to detoxify bilirubin locally and thus might contribute to the apparent higher sensitivity to bilirubin toxicity in these cells vs glia. Similarly, the lower bilirubin-oxidizing ability of mitochondrial membranes from immature brains seems compatible with the clinical impression of increased vulnerability to bilirubin neurotoxicity in the newborn.

Aging↗
PubMed1997

Oxidation of bilirubin by rat brain mitochondrial membranes-genetic variability.

Bilirubin is oxidized by brain mitochondrial membranes at a rate which may contribute significantly to clearance of bilirubin from brain. Different strains of congenitally jaundiced rats (Gunn rats) vary widely as far as the mortality rate of the homozygous (jaundiced) pups. Because the ability to oxidize bilirubin in brain may protect against toxicity, we hypothesized that the ability to oxidize bilirubin would be lower in Gunn rat strains (ACI/N-j) with a high mortality rate in the homozygous pups. Mitochondria were obtained from young rat brains by differential centrifugation in sucrose gradients. The mitochondria were ruptured by sonication. The change in optical density of a bilirubin solution at 440 nm was measured over time following addition of the membrane suspension. The rate of bilirubin oxidation was significantly lower in rats of the RHA/N-j strain both at 7-8 days of age and in adults, compared to rats of the ACI/N-j and the Sprague-Dawley strains at the same age points. Differences in mortality rates between the RHA/N-j and the ACI/N-j strains of Gunn rats could not be explained on the basis of differences in the ability of brain mitochondrial membranes to oxidize bilirubin, as these activities were lower in the RHA/N-j rats, which also have lower mortality rates, but higher in the ACI/N-j rats, which have remarkably high mortality rates. This study also confirmed previous findings relative to age maturation of the enzyme activity.

Animals↗
PubMed1997

Respiratory syncytial virus pneumonia ventilated with high-frequency oscillatory ventilation.

Four infants below 6 months of age with proven respiratory syncytial virus infection in need of assisted mechanical ventilation were successfully treated by high-frequency oscillatory ventilation. One of the four infants fulfilled the criteria for extracorporeal membrane oxygenation before the start of oscillation, and one on the second day on high-frequency oscillatory ventilation. However, extracorporeal membrane oxygenation was not needed in any of the infants. All survived, and three appeared to be without any pulmonary sequelae.

Disease-Free Survival↗