Biomedical subjects

Steven M Shapiro

Publications and source records attributed to Steven M Shapiro.

10 recordsLinked to original sources

PubMed2006

Biliverdin-induced brainstem auditory evoked potential abnormalities in the jaundiced Gunn rat.

Brainstem auditory evoked potential (BAEP) abnormalities occur in jaundiced Gunn rats given sulfadimethoxine to displace bilirubin bound to serum albumin, releasing it into the tissues. One problem with the model is that after displacement, plasma bilirubin levels drop and do not correlate with neurological dysfunction. In this report, we administered biliverdin, the immediate precursor of bilirubin, in 15- to 17-day-old Gunn rat pups to create an improved model of bilirubin-induced neurological dysfunction. Total plasma bilirubin (TB) levels were measured with a Leica bilirubinometer. Biliverdin (40 mg/kg) or phosphate-buffered saline (PBS) was administered either once and BAEPs recorded 8 h later or twice, 12 h apart, and BAEPs recorded 24 h after the initial injection. A single biliverdin injection produced a significantly decreased amplitude of BAEP wave III, 1.21+/-0.25 vs. 0.49+/-0.27 microV (control vs. biliverdin). The two-injection paradigm resulted in a significantly elevated TB (9.9+/-1.2 vs. 14.9+/-3.1 mg/dl; control vs. biliverdin), significant increases in I-II (1.15+/-0.08 vs. 1.42+/-0.09 ms) and I-III (2.17+/-0.08 vs. 2.5+/-0.13 ms) interwave intervals and a decrease in the amplitude of wave III (1.36+/-0.30 vs. 0.38+/-0.26 microV). Additionally, there were significant correlations between TB and the amplitude of wave III (r2=0.74) and TB and the I-III interwave interval (r2=0.51). In summary, biliverdin administration in jaundiced Gunn rat pups produces BAEP abnormalities consistent with those observed in the sulfadimethoxine model and human newborn hyperbilirubinemia and resulted in increased plasma bilirubin levels that correlate with the degree of neurological dysfunction.

Animals↗

PubMed2006

Hyperbilirubinemia and kernicterus.

This article describes new findings concerning the basic science of bilirubin neurotoxicity, new considerations of the definition of clinical kernicterus, and new and useful tools to diagnose kernicterus in older children, and discusses treatments for kernicterus beyond the newborn period and why proper diagnosis is important.

Bilirubin↗

PubMed2006

Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns.

PURPOSE: We sought to evaluate the sensitivity and specificity of total serum bilirubin concentration (TSB) and free (unbound) bilirubin concentration (Bf) as predictors of risk for bilirubin toxicity and kernicterus and to examine consistency between these findings and proposed mechanisms of bilirubin transport and brain uptake. METHODS: A review of literature was undertaken to define basic principles of bilirubin transport and brain uptake leading to neurotoxicity. We then reviewed experimental and clinical evidence that relate TSB or Bf to risk for bilirubin toxicity and kernicterus. RESULTS: There are insufficient published data to precisely define sensitivity and specificity of either TSB or Bf in determining risk for acute bilirubin neurotoxicity or chronic sequelae (kernicterus). However, available laboratory and clinical evidence indicate that Bf is better than TSB in discriminating risk for bilirubin toxicity in patients with severe hyperbilirubinemia. These findings are consistent with basic pharmacokinetic principles involved in bilirubin transport and tissue uptake. CONCLUSIONS: Experimental and clinical data strongly suggest that measurement of Bf in newborns with hyperbilirubinemia will improve risk assessment for neurotoxicity, which emphasizes the need for additional clinical evaluation relating Bf and TSB to acute bilirubin toxicity and long-term outcome. We speculate that establishing risk thresholds for neurotoxicity by using newer methods for measuring Bf in minimally diluted serum samples will improve the sensitivity and specificity of serum indicators for treating hyperbilirubinemia, thus reducing unnecessary aggressive intervention and associated cost and morbidity.

Bilirubin↗

PubMed2005

Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND).

Kernicterus, currently used to describe both the neuropathology of bilirubin-induced brain injury and its associated clinical findings, is a complex syndrome. The neurobiology of kernicterus, including the determinants and mechanisms of neuronal injury, is discussed along with traditional and evolving definitions ranging from classical kernicterus with athetoid cerebral palsy, impaired upward gaze and deafness, to isolated conditions, for example, auditory neuropathy or dys-synchrony (AN/AD), and subtle bilirubin-induced neurological dysfunction (BIND). The clinical expression of BIND varies with location, severity, and time of assessment, influenced by the amount, duration and developmental age of exposure to excessive free bilirubin. Although total serum bilirubin (TSB) is important, kernicterus cannot be defined based solely on TSB. For study purposes kernicterus may be defined in term and near-term infants with TSB > or = 20 mg/dl using abnormal muscle tone on examination, auditory testing diagnostic of AN/AD, and magnetic resonance imaging showing bilateral lesions of globus pallidus+/-subthalamic nucleus.

Age Factors↗

PubMed2005

The jaundiced gunn rat model of auditory neuropathy/dyssynchrony.

OBJECTIVE: High levels of bilirubin are neurotoxic and may result in deafness or auditory neuropathy/auditory dyssynchrony (AN/AD). The jaundiced (jj) Gunn rat animal model of kernicterus has electrophysiologic and neuroanatomic abnormalities of brainstem auditory nuclei with normal cochlear microphonic recordings. We examined morphologic changes in the cochlea, spiral ganglion, and auditory nerve and relate these findings to current understanding of AN/AD. METHODS: At 15 days of age, jj and nonjaundiced (Nj) littermates were injected with sulfadimethoxine (sulfa) and killed 3 days later by transcardial perfusion. Sections were cut through decalcified temporal bones, cochlear nerves, and auditory brainstem and processed for light and electron microscopy and immunohistochemical localization of calbindin-D and parvalbumin. RESULTS: Spiral ganglion neurons were severely degenerated with a paucity of myelinated axons in jj animals. Electron microscopy of the intramodilar auditory nerve revealed a lack of large caliber axons in jj-sulfa versus Nj-sulfa controls. Large diameter degenerating axons were characterized by an electron-dense atrophied axis cylinder resembling an axonopathy. CONCLUSIONS: Our findings of abnormal spiral ganglion cells and selective loss of large, myelinated auditory nerve fibers with no abnormalities in cochlear hair cells, support the sulfa-treated jj Gunn rat as a model for bilirubin induced AN/AD. The paucity of large caliber neurons undermines temporal coding of auditory information and neural synchrony and demonstrates that in addition to brainstem auditory nuclei, spiral ganglion neurons are selectively vulnerable to bilirubin toxicity.

Animals↗

PubMed2004

Kernicterus in sick and preterm infants (1999-2002): a need for an effective preventive approach.

Kernicterus in sick and preterm infants is a rarity. Universal availability of phototherapy and concerted clinical efforts to identify, effectively manage and establish clinical guidelines have been instrumental in preventing kernicterus in US intensive care nurseries. However, in sick and preterm infants the absence of precise data on prevalence of bilirubin induced neurologic injury, the lack of proven predictive indices and the absence of evidence-based studies that clearly demonstrate the actual risk of kernicterus. These leave questions regarding the basis for clinical strategies and recommendations for the management of neonatal jaundice in this select population. This article reviews 6 preterm infants selected from the Pilot Kernicterus Registry who had recovered from life-threatening neonatal illnesses, briefly discusses current indices used to ascertain risk, and offers an initial bilirubin level based identification of infants while future directions and studies are conducted to supplement our presently incomplete knowledge for safer clinical practice.

Bilirubin↗

PubMed2003

Bilirubin toxicity in the developing nervous system.

Bilirubin toxicity remains a significant problem despite recent advances in the care of jaundiced (hyperbilirubinemic) neonates. A recent surge in reported cases of classical kernicterus, due in part to earlier hospital discharge and relaxation of treatment criteria for hyperbilirubinemia, and new reports of hyperbilirubinemia-induced auditory dysfunction using evoked potential based infant testing and hearing screening, underscore the need to better understand how hyperbilirubinemia causes brain damage in some infants, especially because the damage is preventable. Recent progress in understanding bilirubin binding and neurotoxicity resulting from unbound or "free" unconjugated bilirubin, how bilirubin affects the central nervous system in vivo and in vitro, and the use of new clinical tools in neonates, for example magnetic resonance imaging revealing bilateral lesions in globus pallidus and subthalamus, and abnormal brainstem auditory evoked potentials with normal inner ear function, may lead to improved detection and prevention of neurologic dysfunction and damage from bilirubin. Finally, the concern is raised that partial or isolated neurologic sequelae, for example auditory neuropathy and other central auditory processing disorders, may result from excessive amount and duration of exposure to free, unconjugated bilirubin at different stages of neurodevelopment.

Animals↗

PubMed2002

Changes in calcium-binding protein expression in the auditory brainstem nuclei of the jaundiced Gunn rat.

Sensorineural hearing loss and auditory dysfunction are major sequelae of neonatal hyperbilirubinemia. The sites and cellular effects of bilirubin toxicity in the auditory brainstem pathway are not easily detected. Since altered intracellular calcium homeostasis may play a role in neuronal cell death, we hypothesized that the expression of calcium-binding proteins may be altered in the classic animal model of bilirubin neurotoxicity. The expression of the calcium-binding proteins, calbindin-D28k and parvalbumin, in the brainstem auditory pathway of homozygous recessive jaundiced (jj) Gunn rats was examined by light and electron microscopic immunohistochemistry at 18 days postnatally and compared to the findings obtained from age-matched non-jaundiced heterozygous (Nj) littermate control rats. Immunoreactive staining for both calbindin and parvalbumin was reduced in the cochlear nuclei and the superior olivary complex in jj rats. The extent of the reduction in immunoreactivity was related to the severity of the clinical symptoms. By contrast, immunoreactive staining in other brainstem areas (e.g., dorsal and ventral nuclei of the lateral lemniscus, inferior colliculus), thalamic (medial geniculate body) auditory areas, and neighboring non-auditory structures was similar in jaundiced and control rats. Calbindin-immunoreactive staining in the superior paraolivary and medial superior olivary nuclei in Nj rats was associated with myelinated axons, whereas parvalbumin-immunoreactive staining was localized postsynaptically in neuronal somata and dendrites. Immunoreactive staining for the calcium-binding proteins calbindin and parvalbumin in lower brainstem auditory nuclei shows abnormalities in areas susceptible to the effects of hyperbilirubinemia and provides a sensitive new way to assess bilirubin toxicity in the auditory system.

Animals↗

PubMed2002

Immunohistochemical localization of calcium-binding proteins in the brainstem vestibular nuclei of the jaundiced Gunn rat.

Vestibular gaze and postural abnormalities are major sequelae of neonatal hyperbilirubinemia. The sites and cellular effects of bilirubin toxicity in the brainstem vestibular pathway are not easily detected. Since altered intracellular calcium homeostasis may play a role in neuronal cell death, we hypothesized that altered expression of calcium-binding proteins may occur in brainstem vestibular nuclei of the classic animal model of bilirubin neurotoxicity. The expression of the calcium-binding proteins calbindin-D28k and parvalbumin in the brainstem vestibular pathways and cerebellum of homozygous recessive jaundiced (jj) Gunn rats was examined by light microscopy and immunohistochemistry at 18 days postnatally and compared to the findings obtained from age-matched non-jaundiced heterozygous (Nj) littermate controls. Jaundiced animals exhibited decreased parvalbumin immunoreactivity specifically in synaptic inputs to superior, medial, and inferior vestibular nuclei, and to oculomotor and trochlear nuclei, whereas the neurons retained their normal immunoreactivity. Jaundiced animals also demonstrated a decrease in calbindin expression in the lateral vestibular nuclei and a paucity of calbindin-immunoreactive synaptic endings on the somata of Deiters' neurons. The involved regions are related to the control of the vestibulo-ocular and vestibulospinal reflexes. Decreased expression of calcium-binding proteins in brainstem vestibular neurons may relate to the vestibulo-ocular and vestibulospinal dysfunction seen with clinical kernicterus, and may provide a sensitive new way to assess bilirubin toxicity in the vestibular system.

Animals↗

PubMed2002

Somatosensory and brainstem auditory evoked potentials in the Gunn rat model of acute bilirubin neurotoxicity.

Brainstem auditory evoked potentials (BAEPs) are a sensitive indicator of bilirubin neurotoxicity. Somatosensory evoked potentials (SEPs) have been proposed as another measure of toxicity, though the lemniscal pathways that generate the SEP are not involved in kernicterus. In 16 to 17-d-old jaundiced (jj) Gunn rats, serial BAEPs and SEPs were obtained up to 8 h after acute bilirubin toxicity. jjs were injected with 150 mg/kg sulfadimethoxine to displace bilirubin into brain tissue (n = 8); littermate controls were jjs given saline (n = 4) and nonjaundiced given sulfadimethoxine or saline (n = 7). After anesthesia, BAEP and SEP recordings were obtained at baseline and serially after injection. SEPs to median nerve stimulation were recorded from surface electrodes over the brachial plexus (Erb's) and contralateral parietal cortex, and subtracted to obtain central conduction time (CCT). There were no statistically significant different baseline values between groups. Baseline BAEP I, I-II, and I-III were 1.22 +/- 0.13, 1.11 +/- 0.12, and 2.10 +/- 0.15 ms, and SEP Erb's and CCT were 1.48 +/- 0.20 and 5.59 +/- 0.50 ms, respectively (n = 19). At 6.8 +/- 1.5 h after injection BAEP I, I-II, and I-III increased 0.10 +/- 0.08, 0.18 +/- 0.17, and 0.56 +/- 0.33 ms over baseline, respectively (p = 0.005, 0.01, and 0.001, respectively, paired, 1-tailed t-tests), in experimental but not control groups. SEP Erb's decreased slightly, -0.06 +/- 0.04 ms in experimental and -0.08 +/- 0.08 ms in control groups, while CCT did not change significantly. BAEPs were completely abolished in two jjs with no SEP changes. When injection of sulfonamide induced significant peripheral and central BAEP abnormalities in jaundiced rats, no SEP abnormalities occurred. SEPs assess proprioception but not other somatosensory function or sensory integration. The results demonstrate the selectivity of acute bilirubin toxicity for the auditory nervous system.

Animals↗