Studies of bilirubin toxicity at the synaptosome and cellular levels.
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Dopamine↗
Biomedical subjects
D Schiff
Publications and source records attributed to D Schiff.
Neonatal jaundice and bilirubin encephalopathy: a clinical and experimental reappraisal.
Hyperbilirubinemia and bilirubin encephalopathy are well-known occurrences in the neonatal period. The fact that bilirubin might be toxic to neural cells stems from the neurological picture that has emerged and the associated hyperbilirubinemia. Studies of the relationship between hyperbilirubinemia in healthy full-term infants and the long-term consequences showed little or no effect of bilirubin. Nevertheless, bilirubin is still considered toxic to premature infants and infants with hemolysis. In addition, in spite of a fairly detailed understanding of the chemistry of bilirubin and the biochemistry of bilirubin metabolism, the primary target of its toxic effect is still not known. The difficulties in analyzing the results are due to the variation in experimental designs, the use of different animal models and cell systems and the use of unstable bilirubin solutions. We review some of the problems related to clinical and experimental studies of bilirubin toxicity.
Animals↗
The Koch pouch: radiographic evaluation of the orthotopic and cutaneous forms.
The Koch pouch is a continent ileal reservoir. It has several advantages over the standard ileal conduit. The pouch can be attached to the skin (cutaneous type) or the male urethra (orthotopic type). Both variations have special imaging considerations. The suggested imaging protocol is based upon experience with 47 patients (22 with orthotopic and 25 with cutaneous pouches). The normal appearance of the new and mature pouch and its complications and their management are presented.
Adolescent↗
Bilirubin-neural cell interaction: characterization of initial cell surface binding leading to toxicity in the neuroblastoma cell line N-115.
The toxicity of bilirubin to the nervous system might be due to its effect on several key enzyme reactions occurring in the intracellular compartment as suggested by in vitro studies. The question of how bilirubin, a molecule with poor solubility in water and organic solvents, interacts with the plasma membrane and reaches intracellular targets is unclear. In an attempt to get some insight into this problem, we have measured the uptake of bilirubin from bilirubin-albumin solutions by the murine neuroblastoma cell line N-115. At a constant total concentration of bilirubin, the initial rate, as well as the extent of uptake, increases with increasing bilirubin to albumin molar ratio (B/A). The binding is reversible, at least partially, as indicated by the ability of albumin to extract cell-bound bilirubin. The cellular uptake of bilirubin was found to depend also on the concentration of bilirubin, on temperature and on pH. The results are not consistent with either a carrier-mediated transport or passive diffusion across the plasma membrane. The data, however, seem to fit a multistep binding of bilirubin to the plasma membrane proposed for the interaction of bilirubin with synaptosomal plasma membrane vesicles, erythrocyte ghosts and lipid vesicles. These studies, thus, reveal the complexity of the binding interaction at the level of the plasma membrane and leave open the question of transport across the membrane.
Albumins↗
Monochorionic diamniotic minimally conjoined twins: a case report.
We present the second case of monochorionic diamniotic (MC/DA) conjoined twins. There was minimal conjunction, which was predominantly extrafetal and confined to the periumbilical ventral region. The omphalopagus twins, attached to a single forked umbilical cord, were connected by a shared umbilical hernia containing the ileum of twin B. The only visceral conjunction, located just within the belly of twin A, was midileal with the 2 separate ileums converging toward a short segment of shared muscularis propria and of side-to-side fistulization. Gastrointestinal and musculoskeletal anomalies were present in both twins with severe amyoplasia and arthrogryposis multiplex in twin A. Possible mechanisms underlying this unusual form of MZ twinning are discussed.
Abnormalities, Multiple↗
Effects of lesions of the nucleus of the optic tract on optokinetic nystagmus and after-nystagmus in the monkey.
1. The nucleus of the optic tract (NOT) and the dorsal terminal nucleus (DTN) of the accessory optic system were lesioned electrolytically or with kainic acid in rhesus monkeys. When lesions involved NOT and DTN, peak velocities of optokinetic nystagmus (OKN) with slow phases toward the side of the lesion were reduced, and optokinetic after-nystagmus (OKAN) was reduced or abolished. The jump in slow phase eye velocity at the onset of OKN was smaller in most animals, but was not lost. Initially, there was spontaneous nystagmus with contralateral slow phases. OKN and OKAN with contralateral slow phases were unaffected. 2. Damage to adjacent regions had no effect on OKN or OKAN with two exceptions: 1. A vascular lesion in the MRF, medial to NOT and adjacent to the central gray matter, caused a transient loss of the initial jump in OKN. The slow rise in slow phase velocity was prolonged, but the gain of OKAN was unaffected. There was no effect after a kainic acid lesion in this region in another animal. 2. Lesions of the fiber tract in the pulvinar that inputs to the brachium of the superior colliculus caused a transient reduction in the buildup and peak velocity of OKN and OKAN. 3. In terms of a previous model (Cohen et al. 1977; Waespe et al. 1983), the findings suggest that the indirect pathway that activates the velocity storage integrator in the vestibular system to produce the slow rise in ipsilateral OKN and OKAN, lies in NOT and DTN. Activity for the rapid rise in OKN, carried in the direct pathway, is probably transmitted to the pontine nuclei and flocculus via an anatomically separate fiber pathway that lies in the MRF. A fiber tract in the pulvinar that inputs to the brachium of the superior colliculus appears to carry activity related to retinal slip from the visual cortex to NOT and DTN.
Animals↗
Contribution of the nucleus of the optic tract to optokinetic nystagmus and optokinetic afternystagmus in the monkey: clinical implications.
1. The role of the pretectal NOT and the DTN in producing horizontal OKN and OKAN were studied using electrical stimulation and lesions. Positive stimulation sites lay in NOT, DTN, and in a fiber bundle in the pulvinar that is presumably a cortical input to NOT. 2. When the region of NOT was electrically stimulated in darkness, horizontal nystagmus was evoked with ipsilateral slow phases. Eye velocity rose slowly to a steady-state level and was followed by afternystagmus at the end of stimulation. The time constant of rise of stimulus-induced nystagmus was similar to the slow rise of slow-phase eye velocity during OKN. The saturation velocity of the induced nystagmus and the falling time constant of the stimulus afternystagmus were the same as those of OKAN. This suggests that electrical stimulation of NOT and DTN had elicited the slow component of OKN, i.e., that component produced by the velocity storage mechanism in the vestibular system. 3. Consistent with this postulate, activity induced by NOT stimulation could enhance, prolong, or block the slow component of OKN and OKAN depending on whether slow phases were to the same or opposite side. Stimulus-induced activity also interacted with vestibular nystagmus as would OKN and OKAN. 4. Unilateral lesions of NOT and DTN caused a loss of OKAN and the slow rise in OKN to the ipsilateral side. Steady-state velocities of OKN were reduced. The initial jump of OKN slow-phase velocity was the same or somewhat less after lesions but was not lost. 5. Partial lesions of a fiber bundle in the lateral pulvinar caused a transient change in OKN and OKAN, consistent with the idea that it carries activity for the slow component from the cortex to NOT. A lesion of the MRF, just rostral to the superior colliculus, caused a transient loss of the rapid component of OKN. This region appears to carry activity responsible for the initial jump in slow-phase velocity at the onset of stimulation. 6. We conclude that: (a) NOT and probably DTN lie in the indirect pathway that produces the slow component of horizontal OKN and OKAN to the ipsilateral side in the rhesus monkey. This pathway activates the velocity storage mechanism in the vestibular nuclei. (b) At the level of NOT, the pathway responsible for the slow component of OKN and OKAN is anatomically distinct from the pathway responsible for rapid changes in eye velocity at the onset of OKN.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
[Use of objective structured clinical examinations in the pre-graduation evaluation of medical students in pediatrics].
The present article deals, firstly with the analysis of the classic evaluation procedures for assessing the pregraduate medical students employed in our University, and their negative influence upon the results obtained in the studying procedures as well as in the degree of acquaintance. A new model, previously assayed in other universities and named objective structured clinical examination, which combines the assessing of the theoretical and practical knowledge, is proposed. Its peculiarities are explained, as well as its advantages and disadvantages; we also suggest the way of starting its application considering the features of the educational system ruling our University.
Clinical Competence↗
Bilirubin toxicity in a neuroblastoma cell line N-115: I. Effects on Na+K+ ATPase, [3H]-thymidine uptake, L-[35S]-methionine incorporation, and mitochondrial function.
Though bilirubin is reported to affect a variety of cellular functions, the primary target of its toxic effect is still not known. A major problem in understanding this is the wide variation in results reported by different groups. This is probably due to the differences in stability of bilirubin solutions arising from large differences in bilirubin:albumin molar ratios used in experiments. Hence in studying the toxic effects of bilirubin in tissue culture systems, it is important to be certain that the bilirubin is maintained in solution throughout the time of the exposure to bilirubin. Spectrophotometric measurements have shown that bilirubin is stable in Dulbecco's modified Eagle medium solution at bilirubin:albumin molar ratios up to 3. Under these defined conditions, bilirubin was found to affect Na+K+ ATPase, [3H]-thymidine uptake, L-[35S]methionine incorporation into protein and mitochondrial function at bilirubin concentrations up to 125 microM and bilirubin:albumin molar ratio of 1.5. Toxic effects on all parameters measured were evident at bilirubin:albumin molar ratio of 1.5 after a minimum of 2 h of exposure. No effect was evident at a bilirubin:albumin molar ratio below 1. Although it is not possible to identify with certainty the primary target, the effect on mitochondrial function appeared earlier and was more profound than that seen with the other assessed functions.
Albumins↗
Bilirubin toxicity in a neuroblastoma cell line N-115: II. Delayed effects and recovery.
Clinical studies have suggested that the early stages of bilirubin encephalopathy are reversible. These phenomena are investigated at the cellular level using the neuroblastoma cell line N-115 as a model system. To determine whether the cell line N-115 can recover from bilirubin toxicity, and whether the cellular function remains intact after a short period of bilirubin exposure during which time no toxic effects are manifest, the cells are exposed to bilirubin at varying concentrations and varying bilirubin:albumin ratios for 1 and 2 h. The bilirubin is then washed out, and the cells are reincubated in fresh media with appropriate amounts of albumin. Mitochondrial function, [3H]thymidine uptake and L-[35S]methionine uptake are assessed at 2, 8, and 24 h of reincubation after the bilirubin washout. After the short-term exposure, the cells begin to demonstrate evidence of toxicity in all parameters measured 8-24 h after the bilirubin washout. After the 2-h exposure to bilirubin, the cells demonstrate significant toxicity within 2 h of the bilirubin washout. The degree of toxicity seems to depend on the bilirubin:albumin ratio and bilirubin concentration. In general, after bilirubin exposure of 1 h or longer, the N-115 cells develop evidence of toxicity which is progressive and irreversible.
Albumins↗
Dilepton production at finite temperature: Perturbative treatment at order alpha s.
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Journal Article↗
Nystagmus induced by stimulation of the nucleus of the optic tract in the monkey.
1. The nucleus of the optic tract (NOT) was electrically stimulated in alert rhesus monkeys. In darkness stimulation evoked horizontal nystagmus with ipsilateral slow phases, followed by after-nystagmus in the same direction. The rising time course of the slow phase velocity was similar to the slow rise in optokinetic nystagmus (OKN) and to the charge time of optokinetic after-nystagmus (OKAN). The maximum velocity of the steady state nystagmus was approximately the same as that of OKAN, and the falling time course of the after-nystagmus paralleled OKAN. 2. Increases in frequency and duration of stimulation caused the rising and falling time constants of the nystagmus and after-nystagmus to become shorter. Changes in the falling time constant of the after-nystagmus were similar to changes in the time constant of OKAN produced by increases in the velocity or duration of optokinetic stimulation. 3. Stimulus-induced nystagmus was combined with OKN, OKAN and per- and post-rotatory nystagmus. The slow component of OKN as well as OKAN could be prolonged or blocked by stimulation, leaving the rapid component of OKN unaffected. Activity induced by electrical stimulation could also sum with activity arising in the semicircular canals to reduce or abolish post-rotatory nystagmus. 4. Positive stimulus sites for inducing nystagmus were located in the posterolateral pretectum. This included portions of NOT that lie in and around the brachium of the superior colliculus and adjacent regions of the dorsal terminal nucleus (DTN). 5. The data indicate that NOT stimulation had elicited the component of OKN which is responsible for the slow rise in slow phase velocity and for OKAN. The functional implication is that NOT, and possibly DTN, are major sources of visual information related to retinal slip in the animal's yaw plane for semicircular canal-related neurons in the vestibular nuclei. Analyzed in terms of a model of OKN and OKAN (Cohen et al. 1977; Waespe et al. 1983), the indirect pathway, which excites the velocity storage mechanism in the vestibular system to produce the slow component of OKN and OKAN, lies in NOT in the monkey, as it probably also does in cat, rat and rabbit. Pathways carrying activity for the rapid rise in slow phase velocity during OKN or for ocular pursuit appear to lie outside NOT.
Animals↗
Bilirubin diffusion through lipid membranes.
The possibility that bilirubin can diffuse through lipid bilayers is investigated with liposomes prepared from dipalmitoylphosphatidylcholine (DPPC), egg phosphatidylcholine (egg PC) with 22 mole percent cholesterol, and a lipid extract preparation from N115 neuroblastoma cells. Liposomes were prepared with internalized bilirubin and bovine or human serum albumin, and bilirubin efflux into an exogenous solution of human serum albumin was measured. Efflux from DPPC liposomes was significantly higher above the phase transition temperature than below it. This change was dependent on the lipid undergoing a phase transition and could not be accounted for by 6 K change in temperature. Maximum bilirubin efflux from egg PC-cholesterol liposomes was found to depend on the relative internal and external albumin pools, suggesting an equilibrium distribution of bilirubin between them. These observations demonstrate that bilirubin can diffuse freely through these lipid membranes.
Bilirubin↗
Quantitative analysis of cerebral asymmetries. Fronto-occipital correlation, sexual dimorphism and association with handedness.
To investigate the biological and functional significance of cerebral asymmetries, we measured lateral differences of the frontal and occipital poles on computed tomographic scans of 66 adult outpatients with no diagnosed abnormalities. In addition to confirming the greater average sizes of the right frontal and left occipital poles, we found a significant linear correlation relating anterior and posterior difference measures. Men showed greater degrees of frontal and occipital asymmetries than women; reversals of the typical asymmetries were more common among women. Reduction or reversal of the usual left occipital predominance in the presence of typical right frontal predominance was associated with non-right-handedness. These findings clarify and extend prior qualitative observations and relate to the possible role of testosterone in modulation of cortical asymmetries. Reduced structural asymmetries among women and non-right-handers may provide an anatomical basis for clinical and laboratory findings of lessened functional lateralization in these groups.
Adult↗
Bilirubin toxicity in neural cell lines N115 and NBR10A.
The toxicity of bilirubin was investigated in 2 neural cell lines NBR10A and N115 using a quantitative dye assay 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium biomide (MTT) as a measure of cell viability and [3H]thymidine incorporation as a measure of DNA synthesis. Short exposures (up to 2 h) to bilirubin, even up to a bilirubin-albumin molar ratio of 1.5, yielded no evidence of toxicity using these assays. At longer exposure times (24 h) a decrease in cell viability and [3H]thymidine incorporation was detected at a molar ratio of 0.8 when the bilirubin concentration was 0.1 mM or higher, whereas lower bilirubin levels at this molar ratio showed no deleterious effect. The effect of bilirubin is more pronounced at a molar ratio of 1.5 with longer incubation periods. The MTT assay showed the N115 cells appeared to be more resistant to bilirubin cytotoxicity than NBR10A cells, a finding which was not obtained from [3H]thymidine incorporation studies. This discrepancy can be explained by the fact that we are measuring two different variables; the MTT assay estimates the number of viable cells at the end of the experiment by measuring mitochondrial function whereas the [3H]thymidine assay measures the rate of DNA synthesis during the last 2 h of the experiment. The concentration effect of bilirubin is evident from the [3H]-thymidine studies in that at a molar ratio of 1.5 and bilirubin concentration of 0.075 mM or higher, there is both cell kill (decrease in DNA) and inhibition of [3H]thymidine incorporation (decrease in specific activity).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Multiple-dose kinetics of digoxin in neonates.
Multiple-dose kinetics of digoxin were studied over a 7-day period in five neonates receiving intravenous digoxin therapy (one initial digitalizing dose followed by single daily doses). Their weights ranged from 1.04 to 2.68 kg (means = 1.61 kg), gestational ages from 28 to 39 weeks (means = 31.8 weeks), and postnatal ages from 2 to 19 days (means = 8.0 days). The 24-hour serum digoxin levels and urinary creatinine and digoxin excretion after the 1st and 7th doses on days 1 and 7 were employed to derive the kinetic parameters. Values of each following parameter (mean +/- SD) were obtained on days 1 and 7, respectively: (1) creatinine clearance (ml/min/1.73 m2) 12 +/- 6, 13 +/- 8; (2) renal digoxin clearance (ml/min/1.73 m2) 13 +/- 8, 15 +/- 10; (3) total body digoxin clearance (ml/min/1.73 m2) 35 +/- 14, 39 +/- 24; (4) volume of distribution (L/kg) 7.2 +/- 1.0, 6.9 +/- 1.1; and (5) half-life (hours) 48 +/- 19, 49 +/- 27. No consistent changes of the above kinetic parameters from days 1 to 7 were observed in these five neonates (P greater than 0.05, paired student's t-test).
Birth Weight↗
Total body digoxin clearance and steady-state concentrations in low birth weight infants.
Serial serum digoxin concentrations were measured over a 10-day period in 15 low birth weight infants requiring digoxin therapy. The calculated total body digoxin clearance (TBDC) was found to be highly dependent on gestational age and body weight, with dose-normalized, steady-state digoxin concentrations inversely related to the same factors. Because of the decreased TBDC in low birth weight infants, our data support the recent recommendations in the literature to reduce maintenance doses of digoxin in these infants. Our study has further demonstrated that the reduction should be proportional to both gestational age and body weight.
Birth Weight↗
Pharmacokinetics of digoxin in low-birth-weight infants.
Digoxin pharmacokinetics were studied in 13 low-birth-weight infants requiring digoxin therapy. Their weights ranged from 820 to 2,710 g (mean = 1,440 g) and gestational ages ranged from 26 to 38 weeks (mean = 30.9 weeks). The distribution and elimination of digoxin can be described by an open two-compartment model. Poor correlation between volume of distribution Vd beta 95.7 +/- 1.0 liters/kg) and gestational age (GA) or weight (Wt) was observed. Digoxin half-life (47 +/- 21 h) was inversely related to GA and Wt (r = 0.69 and 0.66, respectively), but total body digoxin clearance (29.8 +/- 14.7 ml/min/1.73 m2) was found to be highly dependent on these two variables (r = 0.87 and 0.88, respectively). According to the results of this study and our previous investigation, digitalizing and maintenance dosages of digoxin were recommended.
Digoxin↗