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Background: Kernicterus spectrum disorder (KSD) resulting from neonatal hyperbilirubinemia remains a common cause of cerebral palsy worldwide. This 12-month prospective cohort study followed neonates with hyperbilirubinemia to determine which clinical measures best predict KSD., Methods: The study enrolled neonates ≥35 weeks gestation with total serum bilirubin (TSB) ≥ 20 mg/dl admitted to Aminu Kano Hospital, Nigeria. Clinical measures included brain MRI, TSB, modified bilirubin-induced neurologic dysfunction (BIND-M), Barry-Albright Dystonia scale (BAD), auditory brainstem response (ABR), and the modified KSD toolkit. MRI signal alteration of the globus pallidus was scored using the Hyperbilirubinemia Imaging Rating Tool (HIRT)., Results: Of 25 neonates enrolled, 13/25 completed 12-month follow-up and six developed KSD. Neonatal BIND-M ≥ 3 was 100% sensitive and 83% specific for KSD. Neonatal ABR was 83% specific and sensitive for KSD. Neonatal HIRT score of 2 was 67% sensitive and 75% specific for KSD; this increased to 100% specificity and sensitivity at 12 months. BAD ≥ 2 was 100% specific for KSD at 3-12 months, with 50-100% sensitivity., Conclusions: Neonatal MRIs do not reliably predict KSD. BIND-M is an excellent screening tool for KSD, while the BAD or HIRT score at 3 or 12 months can confirm KSD, allowing for early diagnosis and intervention., Impact: The first prospective study of children with acute bilirubin encephalopathy evaluating brain MRI findings over the first year of life. Neonatal MRI is not a reliable predictor of kernicterus spectrum disorders (KSD). Brain MRI at 3 or 12 months can confirm KSD. The modified BIND scale obtained at admission for neonatal hyperbilirubinemia is a valuable screening tool to assess risk for developing KSD. The Barry Albright Dystonia scale and brain MRI can be used to establish a diagnosis of KSD in at-risk infants as early as 3 months., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Competing Interests: Declaration of Competing Interest The authors have no potential, perceived, or real conflicts of interest to disclose.

Background: Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels., Objective: To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34-36 weeks gestational age in infants born ≤ 750 g or < 27 weeks' gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered., Methods: Pilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤ 750 g or < 27 weeks' gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34-36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22-26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis., Discussion: Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing., Trial Registration: Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983 Protocol version: Version 3.2 (10/5/2022)., (© 2023. The Author(s).)

Inhaled treprostinil is an approved therapy for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease in the United States. Studies have confirmed the robust benefits and safety of nebulized inhaled treprostinil, but it requires a time investment for nebulizer preparation, maintenance, and treatment. A small, portable treprostinil dry powder inhaler has been developed for the treatment of PAH. The primary objective of this study was to evaluate the safety and tolerability of treprostinil inhalation powder (TreT) in patients currently treated with treprostinil inhalation solution. Fifty-one patients on a stable dose of treprostinil inhalation solution enrolled and transitioned to TreT at a corresponding dose. Six-minute walk distance (6MWD), device preference and satisfaction (Preference Questionnaire for Inhaled Treprostinil Devices [PQ-ITD]), PAH Symptoms and Impact (PAH-SYMPACT®) questionnaire, and systemic exposure and pharmacokinetics for up to 5 h were assessed at baseline for treprostinil inhalation solution and at Week 3 for TreT. Adverse events (AEs) were consistent with studies of inhaled treprostinil in patients with PAH, and there were no study drug-related serious AEs. Statistically significant improvements occurred in 6MWD, PQ-ITD, and PAH-SYMPACT. Forty-nine patients completed the 3-week treatment phase and all elected to participate in an optional extension phase. These results demonstrate that, in patients with PAH, transition from treprostinil inhalation solution to TreT is safe, well-tolerated, and accompanied by statistically significant improvements in key clinical assessments and patient-reported outcomes with comparable systemic exposure between the two formulations at evaluated doses (trial registration: clinicaltrials.gov identifier: NCT03950739)., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.A.B. has received funding from Janssen, Bayer, and Actelion for research and honoraria from United Therapeutics Corporation, Bayer, Janssen, AstraZeneca, Intuitive, and Boehringer Ingelheim for lectures, presentations, or speakers' bureau. C.D.B. has no conflict of interest. C.D. is an employee of United Therapeutics Corporation. S.V.D. has no conflict of interest. M.S.E. reports ongoing industry‐sponsored research with Acceleron, Merck, and United Therapeutics Corporation. K.A.E. has received fees from United Therapeutics Corporation for serving on a speakers' bureau and advisory boards; from J&J Actelion for serving on advisory boards; and from Acceleron for consulting services; and institutional research funding from UT and J&J Actelion. M.R.F. has no conflict of interest. S.J. has received research funding from United Therapeutics Corporation and Bellerophon Therapeutics and honoraria from Actelion and Bayer for speakers programs. J.M. has received speaker fees from United Therapeutics Corporation. M.M. is an employee of United Therapeutics Corporation. J.M.J. has no conflict of interest. H.I.P. has received honoraria from Acceleron, United Therapeutics Corporation, and Actelion‐Janssen for serving on advisory boards. G.V.R. has no conflict of interest. R.R.J. has received fees from United Therapeutics Corporation, Bayer, and J&J Actelion for consulting, serving on a speakers' bureau, and research funding. S.S. has served as a consultant for United Therapeutics Corporation, Acceleron, Actelion, and Bayer Pharmaceuticals; as an advisor and speaker for United Therapeutics Corporation, Actelion, and Bayer; and as clinical trial site PI for United Therapeutics Corporation, Actelion, Merck, Liquidia Technologies, Altavant Sciences, and Gossamer Bio; and has received research grant support from ACCP CHEST and United Therapeutics Corporation. T.G.S. has served as an advisor for Bayer Pharmaceuticals and Liquidia Technologies and as clinical trial site PI for United Therapeutics Corporation, Actelion/J &J, Liquidia Technologies, Bayer Pharmaceuticals, and Regeneron Pharmaceuticals. S.M.S. has no conflict of interest. P.S. is an employee of United Therapeutics Corporation. L.A.S. has received consulting fees from Gossamer Bio and has served as clinical trial site PI for United Therapeutics Corporation, Gossamer Bio, INSMED, Actelion, Liquidia, Merck, and Altavant Sciences., (© 2022 United Therapeutics Corporation. United Therapeutics Corporation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Kernicterus Spectrum Disorders (KSDs) result from hyperbilirubinemia-induced brain injury. We developed a Toolkit (KSD-TK) to predict the likelihood of KSDs. This study aims to validate the KSD-TK by comparing it to clinical diagnoses made by the Kernicterus Clinic in the Division of Neurology., Methods: Through retrospective chart review, we completed a KSD-TK for 37 patients evaluated between 2011 and 2019 using highest bilirubin, newborn risk factors, neonatal exam, follow-up exam, auditory testing, tooth enamel, and MRI brain results. KSD-TK results were compared to the clinical diagnoses given by a kernicterus expert (SS)., Results: Of 37 patients, 29 were clinically diagnosed with kernicterus, including 14/14 with KSD-TK scored as "definite", 14/15 "probable", and 1/2 with "possible" kernicterus. None of 6 patients with KSD-TK "not kernicterus" were clinically diagnosed with kernicterus. Combining KSD-TK "definite" and "probable", the KSD-TK has 96.6% sensitivity and 87.5% specificity. Each KSD-TK component had high sensitivity, but only three had specificity ≥0.75: auditory neuropathy spectrum disorder, abnormal movements and/or tone on follow-up exam, and abnormal globus pallidus and/or subthalamic nucleus on MRI., Conclusion: The KSD-TK is a promising screening tool for patients at risk for kernicterus., Impact: This study provides validation of a Kernicterus Spectrum Disorders (KSDs) Toolkit. The toolkit provides screening criteria for predicting KSD diagnosis. Scores of definite or probable have high sensitivity and specificity for KSDs. Abnormal auditory processing, exam, and MRI were most specific for KSDs., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Kernicterus is a permanent condition caused by brain damage from bilirubin toxicity. Dystonia is one of the most debilitating symptoms of kernicterus and results from damage to the globus pallidus (GP). One potential therapeutic strategy to treat dystonia in kernicterus is to replace lost GP neurons and restore basal ganglia circuits through stem cell transplantation. Toward this end, we differentiated human embryonic stem cells (hESCs) into medial ganglion eminence (MGE; the embryological origin of most of the GP neurons)-like neural precursor cells (NPCs). We determined neurochemical phenotype in cell culture and after transplanting into the GP of jaundiced Gunn rats. We also determined grafted cell survival as well as migration, distribution, and morphology after transplantation. As in the GP, most cultured MGE-like NPCs expressed γ-aminobutyric acid (GABA), with some co-expressing markers for parvalbumin (PV) and others expressing markers for pro-enkephalin (PENK). MGE-like NPCs survived in brains at least 7 weeks after transplantation, with most aggregating near the injection site. Grafted cells expressed GABA and PV or PENK as in the normal GP. Although survival was low and the maturity of grafted cells varied, many cells produced neurite outgrowth. While promising, our results suggest the need to further optimize the differentiation protocol for MGE-like NPC for potential use in treating dystonia in kernicterus.

DNA and RNA have been measured with many techniques but often with relatively long analysis times. In this study, we utilize fast-scan cyclic voltammetry (FSCV) for the subsecond codetection of adenine, guanine, and cytosine, first as free nucleosides, and then within custom synthesized oligos, plasmid DNA, and RNA from the nematode Caenorhabditis elegans . Previous studies have shown the detection of adenosine and guanosine with FSCV with high spatiotemporal resolution, while we have extended the assay to include cytidine and adenine, guanine, and cytosine in RNA and single- and double-stranded DNA (ssDNA and dSDNA). We find that FSCV testing has a higher sensitivity and yields higher peak oxidative currents when detecting shorter oligonucleotides and ssDNA samples at equivalent nucleobase concentrations. This is consistent with an electrostatic repulsion from negatively charged oxide groups on the surface of the carbon fiber microelectrode (CFME), the negative holding potential, and the negatively charged phosphate backbone. Moreover, as opposed to dsDNA, ssDNA nucleobases are not hydrogen-bonded to one another and thus are free to adsorb onto the surface of the carbon electrode. We also demonstrate that the simultaneous determination of nucleobases is not masked even in biologically complex serum samples. This is the first report demonstrating that FSCV, when used with CFMEs, is able to codetect nucleobases when polymerized into DNA or RNA and could potentially pave the way for future uses in clinical, diagnostic, or research applications., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Previously in Part I of this two-part review, we discussed the current and recent advances in the understanding of the molecular biology and neuropathology of bilirubin neurotoxicity (BNTx). Here in Part II, we summarize current treatment options available to treat the severely jaundiced infants to prevent significant brain damage and improve clinical outcomes. In addition, we review potential novel therapies that are in various stages of research and development. We will emphasize treatments for both prevention and treatment of both acute bilirubin encephalopathy (ABE) and kernicterus spectrum disorders (KSDs), highlighting the treatment of the most disabling neurological sequelae of children with mild-to-severe KSDs whose "rare disease" status often means they are overlooked by the clinical research community at large. As with other secondary dystonias, treatment of the dystonic motor symptoms in kernicterus is the greatest clinical challenge.

The development of regenerative therapies for central nervous system diseases can likely benefit from an understanding of the peripheral nervous system repair process, particularly in identifying potential gene pathways involved in human nerve repair. This study employed RNA sequencing (RNA-seq) technology to analyze the whole transcriptome profile of the human peripheral nerve in response to an injury. The distal sural nerve was exposed, completely transected, and a 1 to 2 cm section of nerve fascicles was collected for RNA-seq from six participants with Parkinson's disease, ranging in age between 53 and 70 yr. Two weeks after the initial injury, another section of the nerve fascicles of the distal and pre-degenerated stump of the nerve was dissected and processed for RNA-seq studies. An initial analysis between the pre-lesion status and the postinjury gene expression revealed 3,641 genes that were significantly differentially expressed. In addition, the results support a clear transdifferentiation process that occurred by the end of the 2-wk postinjury. Gene ontology (GO) and hierarchical clustering were used to identify the major signaling pathways affected by the injury. In contrast to previous nonclinical studies, important changes were observed in molecular pathways related to antiapoptotic signaling, neurotrophic factor processes, cell motility, and immune cell chemotactic signaling. The results of our current study provide new insights regarding the essential interactions of different molecular pathways that drive neuronal repair and axonal regeneration in humans.

Despite the availability of successful prevention strategies to prevent excessive hyperbilirubinemia, the neurological sequelae of bilirubin neurotoxicity (BNTx) still occur throughout the world. Kernicterus, encephalopathy due to BNTx, is now understood to be a spectrum of severity and phenotypes known as kernicterus spectrum disorder (KSD). A better understanding of the selective neuropathology and molecular biology of BNTx and using consistent clinical definitions of KSDs as outcome measure can lead to more accurately predicting the risk and causes of BNTx and KSDs. In Part I of our two-part review, we will summarize current and recent advances in the understanding of the selective neuropathology and molecular biology of the disease. Herein we emphasize the role of unbound, free unconjugated bilirubin as well as genetic contributions to the susceptibility BNTx and the development of KSDs. In Part II, we focus on current and possible novel methods to prevent BNTx and ABE and treat ABE and KSDs.

Background: The DelIVery for Pulmonary Arterial Hypertension clinical trial was a multi-center, prospective, single arm, Investigational Device Exemption study utilizing a fully implantable, programmable intravascular delivery system consisting of a pump and a catheter for intravenous treprostinil. The study met its primary endpoint and demonstrated that the intravascular delivery system significantly reduced catheter related complications at 22,000 subject-days of follow-up compared with a predefined objective performance criterion. Here we summarize the results obtained during a 6.4-year follow-up period., Methods: Throughout study follow-up, participants had clinic visits and medication refills at least every 12 weeks (dependent on the subjects' dose). All adverse events and intravascular delivery system complications were evaluated and recorded., Results: Sixty pulmonary arterial hypertension subjects were followed post device implantation for approximately 282 patient-years (range 87 days to 6.4 years). Of the 60 subjects, 14 died (1 related to intravascular delivery system pump failure), 2 withdrew after lung transplants, and 2 withdrew due to pump pocket infection. No catheter-related bloodstream infections, catheter thrombosis or occlusions, or catheter kinks occurred through 282 patient-years. Two participants had adverse events of abdominal pain, rash, due to subcutaneous treprostinil "leaks" after one catheter puncture and one catheter laceration during pump refill and replacement, respectively. Eight pump failure events occurred: seven pump motor stalls and one early replacement (faulty battery)., Conclusion: Delivery of treprostinil with an intravascular delivery system is a safe alternative to an external delivery system, while providing enhanced life experiences. To preserve the risk-benefit ratio, treatment at specialized pulmonary arterial hypertension centers is recommended until training is disseminated at other sites., (© The Author(s) 2019.)

Neonatal hyperbilirubinemia targets specific brain regions and can lead to kernicterus. One of the most debilitating symptoms of kernicterus is dystonia, which results from bilirubin toxicity to the globus pallidus (GP). Stem cell transplantation into the GP to replace lost neurons and restore basal ganglia circuits function is a potential therapeutic strategy to treat dystonia in kernicterus. In this study we transplanted human medial ganglionic eminence (MGE)-like neural progenitor cells (NPCs) that we differentiated into a primarily gamma-aminobutyric acid (GABA)ergic phenotype, into the GP of non-immunosuppressed jaundiced (jj) and non-jaundiced (Nj) rats. We assessed the survival and development of graft cells at three time-points post-transplantation. While grafted MGE-like NPCs survived and generated abundant fibers in both jj and Nj brains, NPC survival was greater in the jj brain. These results were consistent with our previous finding that excitatory spinal interneuron-like NPCs exhibited a higher survival rate in the jj brain than in the Nj brain. Our findings further support our hypothesis that slightly elevated bilirubin levels in the jj brain served as an antioxidant and immunosuppressant to protect the transplanted cells. We also identified graft fibers growing toward brain regions that receive projections from the GP, as well as host fibers extending toward the graft. These promising findings suggest that MGE-like NPCs may have the capacity to restore the circuits connecting GP and other nuclei.

High levels of bilirubin in infants can cause kernicterus, which includes basal ganglia damage and dystonia. Stem cell transplantation may be an effective treatment for this disease. In this study, we transplanted human neural progenitor cells differentiated toward propriospinal interneurons into the striatum of 20-day-old spontaneously jaundiced (jj) Gunn rats and nonjaundiced (Nj) littermates. Using immunohistochemical methods, we found that grafted cells survived and grew fibers in jj and Nj brains 3 weeks after transplantation. Grafted cells had a higher survival rate in jj than in Nj brains, suggesting that slightly elevated bilirubin may protect graft survival due to its antioxidative and immunosuppressive effects. Despite their survival, only a small portion of grafted neurons expressed GAD-6 or ChAT, which mark GABAergic and cholinergic neurons, respectively, and are the cells that we are attempting to replace in kernicterus. Thus, NPCs containing large populations of GABAergic and cholinergic neurons should be used for further study in this field.

Background: Despite its lengthy history, the study of jaundice, hyperbilirubinemia and kernicterus suffers from a lack of clarity and consistency in the key terms used to describe both the clinical and pathophysiological nature of these conditions. For example, the term Bilirubin-induced Neurological Dysfunction (BIND) has been used to refer to all neurological sequelae caused by exposure to high levels of bilirubin, to only mild neurological sequelae, or to scoring systems that quantitate the progressive stages of Acute Bilirubin Encephalopathy (ABE)., Objective: We seek to clarify and simplify terminology by introducing, defining, and proposing new terms and diagnostic criteria for kernicterus., Methods: We propose a systematic nomenclature based on pathophysiological and clinical criteria, presenting a logical argument for each term. Acknowledging observations that kernicterus is symptomatically broad and diverse, we propose the use of the overarching term Kernicterus Spectrum Disorders (KSDs) to encompass all the neurological sequelae of bilirubin neurotoxicity including Acute Bilirubin Neurotoxicity (ABE). We further suggest subclassification of KSDs based on the principal disabling features of kernicterus (motor, auditory). Finally, we suggest the term subtle KSD to designate a child with a history of significant bilirubin neurotoxicity with mild or subtle developmental delays., Results and Conclusion: We conclude with a brief description of the limited treatments currently available for KSD, thereby underscoring the importance of further research. We believe that adopting a systematic nomenclature for the spectrum of clinical consequences of hyperbilirubinemia will help unify the field and promote more effective research in both prevention and treatment of KSDs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Kernicterus is a common cause of death and morbidity in many Low- Middle-income Countries (LMICs) and still occurs in affluent nations. In either case, the immediate cause is delayed treatment of severe hyperbilirubinemia. In the West, a provider driven "systems approach" has been widely adopted to identify babies at risk prior to discharge from birthing centers with follow up monitoring based on the serum bilirubin level at time of discharge. The situation is more complicated in regions of the world where kernicterus is endemic, especially in LMICs where Glucose-6-phosphate Dehydrogenase Deficiency (G6PDd) is common and the system of jaundice management is often fragmented., Objective: To examine reasons for errors in jaundice management leading to kernicterus and the potential beneficial role of enlisting more parental participation in management decisions., Method: We searched world literature related to pitfalls in jaundice management including deficiencies in providers' and parents' knowledge and behavior. Perspectives from mothers of children with kernicterus supplemented the literature review., Result: System failures contributing to kernicterus in affluent countries include a lack of follow up planning, bad advice by providers, and a delay in care seeking by parents. In many LMICs, the majority of births occur at home with unskilled attendants. Traditional practices potentiate hemolysis in G6PDd babies. The danger of severe jaundice is frequently underestimated both by parents and care providers, and cultural and economic barriers as well as ineffective therapies delay care seeking. The failure to provide parents information about identifying severe jaundice and knowledge about the risks and treatment of hyperbilirubinemia has contributed to delayed treatment in both affluent and low-middle-income countries. A recent non-randomized clinical trial, supports teaching all parents skills to monitor jaundice, signs of early neurotoxicity, the importance of breast feeding, avoidance of ineffective or dangerous practices, and when/where to seek help., Conclusion: Empowering parents allow them to participate more fully in care decisions and to confront obstacles to care when provider services fail., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Right heart thrombus in transit (RHTT) is a rare, severe form of venous thromboembolism that carries a high mortality rate. The optimal treatment for RHTT has not been well established. Thrombolysis is a therapeutic modality for RHTT but carries the risk of bleeding complications including intracranial hemorrhage. Low-dose thrombolysis has been shown to be effective in treating submassive pulmonary emboli without an increased risk in bleeding complications, but it has not been studied in patients with RHTT. Here, we discuss the case of a 74-year-old male with lung cancer and recent craniotomy with metastasectomy 30 days prior to admission presenting with RHTT and bilateral pulmonary emboli (PE). He was treated successfully with low-dose thrombolysis, despite his relative contraindication to thrombolytics. To our knowledge, this is the first reported case of low-dose alteplase (tissue plasminogen activator [tPA]) used to treat an in-transit PE in the setting of recent craniotomy with metastasectomy., (© The Author(s) 2016.)

Unconjugated bilirubin (UCB) is known to be one of the most potent endogenous antioxidant substances. While hyperbilirubinemia has long been recognized as an ominous sign of liver dysfunction, recent data strongly indicate that mildly elevated bilirubin (BLB) levels can be protective against an array of diseases associated with increased oxidative stress. These clinical observations are supported by new discoveries relating to the role of BLB in immunosuppression and inhibition of protein phosphorylation, resulting in the modulation of intracellular signaling pathways in vascular biology and cancer, among others. Collectively, the evidence suggests that targeting BLB metabolism could be considered a potential therapeutic approach to ameliorate a variety of conditions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Genetic-based susceptibility to bilirubin neurotoxicity and chronic bilirubin encephalopathy (kernicterus) is still poorly understood. Neonatal jaundice affects 60-80% of newborns, and considerable effort goes into preventing this relatively benign condition from escalating into the development of kernicterus making the incidence of this potentially devastating condition very rare in more developed countries. The current understanding of the genetic background of kernicterus is largely comprised of mutations related to alterations of bilirubin production, elimination, or both. Less is known about mutations that may predispose or protect against CNS bilirubin neurotoxicity. The lack of a monogenetic source for this risk of bilirubin neurotoxicity suggests that disease progression is dependent upon an overall decrease in the functionality of one or more essential genetically controlled metabolic pathways. In other words, a "load" is placed on key pathways in the form of multiple genetic variants that combine to create a vulnerable phenotype. The idea of epistatic interactions creating a pathway genetic load (PGL) that affects the response to a specific insult has been previously reported as a PGL score. We hypothesize that the PGL score can be used to investigate whether increased susceptibility to bilirubin-induced CNS damage in neonates is due to a mutational load being placed on key genetic pathways important to the central nervous system's response to bilirubin neurotoxicity. We propose a modification of the PGL score method that replaces the use of a canonical pathway with custom gene lists organized into three tiers with descending levels of evidence combined with the utilization of single nucleotide polymorphism (SNP) causality prediction methods. The PGL score has the potential to explain the genetic background of complex bilirubin induced neurological disorders (BIND) such as kernicterus and could be the key to understanding ranges of outcome severity in complex diseases. We anticipate that this method could be useful for improving the care of jaundiced newborns through its use as an at-risk screen. Importantly, this method would also be useful in uncovering basic knowledge about this and other polygenetic diseases whose genetic source is difficult to discern through traditional means such as a genome-wide association study.

Background: The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion., Methods: A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature., Results: Patients (n = 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4 weeks received an implant device and were followed up for 12.1 ± 4.4 months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5% upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days (P < .0001). Plasma treprostinil levels at 1 week postimplantation were highly correlated with baseline levels (r = 0.91; P < .0001). The delivery system management time as reported by the patients was 2.5 ± 1.7 hours per week preimplantation, and this time decreased to 0.6 ± 0.8 hour per week at 6 months' postimplantation (P < .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6 months. There were no catheter-related bloodstream infections or catheter occlusions., Conclusions: The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction., Trial Registry: ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Severe neonatal hyperbilirubinemia, defined as total serum bilirubin (TSB) ≥20 mg/dl, is associated with a higher risk of permanent neurological sequelae and death. Jaundice can and should be promptly diagnosed and treated. Reliable methods for TSB assay are not always readily available, particularly in low- and middle-income countries, making the true incidence of severe neonatal jaundice (NNJ) difficult to estimate. To gather a more comprehensive picture, a symposium addressing NNJ worldwide was organized during the 2015 Don Ostrow Trieste Yellow Retreat. Data collected by several researchers in different regions of the world were presented and differences/similarities discussed. This report points out the need for: (1) a coordinated worldwide effort to define the burden and the causes of severe NNJ and its consequences; (2) aggressive educational programs for families and health personnel to facilitate timely care-seeking, and (3) accurate diagnostics and effective phototherapy., (© 2016 S. Karger AG, Basel.)

Background: Neonatal jaundice resulting from elevated unconjugated bilirubin occurs in 60-80% of newborn infants. Although mild jaundice is generally considered harmless, little is known about its long-term consequences. Recent studies have linked mild bilirubin-induced neurological dysfunction (BIND) with a range of neurological syndromes, including attention-deficit hyperactivity disorder. The goal of this study was to measure BIND across the lifespan in the Gunn rat model of BIND., Methods: Using a sensitive force plate actometer, we measured locomotor activity and gait in jaundiced (jj) Gunn rats versus their nonjaundiced (Nj) littermates. Data were analyzed for young adult (3-4 mo), early middle-aged (9-10 mo), and late middle-aged (17-20 mo) male rats., Results: jj rats exhibited lower body weights at all ages and a hyperactivity that resolved at 17-20 mo of age. Increased propulsive force and gait velocity accompanied hyperactivity during locomotor bouts at 9-10 mo in jj rats. Stride length did not differ between the two groups at this age. Hyperactivity normalized, and gait deficits, including decreased stride length, propulsive force, and gait velocity, emerged in the 17-20-mo-old jj rats., Conclusion: These results demonstrate that, in aging, hyperactivity decreases with the onset of gait deficits in the Gunn rat model of BIND.

Background: Free bilirubin (Bf), the unbound fraction of unconjugated bilirubin (UCB), can induce neurotoxicity, including impairment of the auditory system, which can be assessed by brainstem auditory evoked potentials (BAEPs). We hypothesized that albumin might reduce the risk of neurotoxicity by decreasing Bf and its translocation into the brain., Aim: To determine the effects of albumin on BAEPs and brain bilirubin content in two Gunn rat pup models of acute hyperbilirubinemia., Methods: We used Gunn rat pups, which have a deficiency of the bilirubin-conjugating enzyme UGT1A1. We induced haemolysis by injection of phenylhydrazine (phz) into 14-days old pups. Subsequently, pups were treated with either i.p. human serum albumin (HSA; 2.5 g/kg; n = 8) or saline (control, n = 8). We induced acute neurotoxicity by injecting 16-days old pups with sulphadimethoxine (sulpha) and treated them with either HSA (n = 9) or saline (control, n = 10). To assess bilirubin neurotoxicity, we used the validated BAEP method and compared relevant parameters; i.e. peak latency values and interwave interval (IWI) between peak I and peak II, a marker of acute neurotoxicity., Results: Phz and sulpha significantly increased IWI I-II by 26% and 29% (P < 0.05) in the haemolysis and the displacement model, respectively. Albumin completely prevented the increase of IWI I-II in either model. The beneficial effect of albumin in the displacement-model by means of normal BAEPs was in line with less bilirubin in the brain (NS). Interestingly, in the haemolysis model the accumulation of total bilirubin in the brain was unaltered, and BAEPs still appeared normal. This might advocate for a role of brain Bf which was calculated and showed that albumin treatment non-significantly reduces Bf concentrations in brain, compared with saline treatment., Conclusions: Albumin treatment is neuroprotective in acute hyperbilirubinemia in Gunn rat pups. Our present results underline the importance of functional diagnostic test of neurotoxicity above biochemical concentrations., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We present an unusual case of hyperbilirubinemia with rapid early progression leading to bilirubin encephalopathy in a term neonate. Despite early recognition and intervention, the total serum bilirubin reached a maximum level of 39 mg/dL at 32 hours of life. Prior to an emergent exchange transfusion, the patient's diagnostic evaluation was significant for Coombs-negative microangiopathic hemolytic anemia and thrombocytopenia. Further testing revealed a deficiency of ADAMTS13 protein, or von Willebrand factor-cleaving protease, a finding diagnostic of congenital thrombotic thrombocytopenic purpura, or Upshaw-Schulman syndrome. This rare disease is often misdiagnosed, especially in the newborn period.

Background: Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor., Methods: A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score., Results: Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of &lt; 1 mg or discontinued because of adverse events (4 m)., Conclusions: The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies., Trial Registry: ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Background: Obstructive sleep apnea (OSA) is prevalent in adults with epilepsy, especially refractory, but limited data exist in children with epilepsy., Aims: We conducted a prospective pilot study in children with epilepsy to identify the prevalence of OSA and its relationship to the use of antiepileptic drugs (AEDs) and epilepsy types., Methods: We used Michigan Pediatric Sleep Questionnaire (PSQ) in children with epilepsy. Patients were classified by seizures frequency as mild (0-1 seizure/month) or severe, refractory epilepsy (> 1 seizures/month). We used PSQ ≥ 0.33 as a cutoff point to assess the risk of OSA., Results: Of 84 children, 52 were classified as mild and 32 as severe. Prevalence of OSA was significantly higher in the severe (43.8%) vs the mild group (30.7%, P < 0.05). Children on >1 AED had significantly higher prevalence of OSA (45.8%) than children on ≤1 AED (30.6%, P < 0.05). There was no significant correlation between the prevalence of OSA and seizure types., Conclusions:   OSA is more prevalent in refractory epilepsy and in children who are on multiple AEDs. While further studies are needed to confirm these findings and to assess the consequences of OSA, we believe it is important to screen the children with epilepsy for OSA., (© 2011 John Wiley & Sons A/S.)

Classical rate-based pathway models are invaluable for conceptualizing direct/indirect basal ganglia pathways, but cannot account for many aspects of normal and abnormal motor control. To better understand the contribution of patterned basal ganglia signaling to normal and pathological motor control, we simultaneously recorded multi-neuronal and EMG activity in normal and dystonic rats. We used the jaundiced Gunn rat model of kernicterus as our experimental model of dystonia. Stainless steel head fixtures were implanted on the skulls and EMG wires were inserted into antagonistic hip muscles in nine dystonic and nine control rats. Under awake, head-restrained conditions, neuronal activity was collected from up to three microelectrodes inserted in the principal motor regions of the globus pallidus (GP), subthalamic nucleus, and entopeduncular nucleus (EP). In normal animals, most neurons discharged in regular or irregular patterns, without appreciable bursting. In contrast, in dystonic animals, neurons discharged in slow bursty or irregular, less bursty patterns. In normal rats, a subset of neurons showed brief discharge bursts coinciding with individual agonist or antagonist EMG bursts. In contrast, in dystonics, movement related discharges were characterized by more prolonged bursts which persist over multiple dystonic co-contraction epics. The pattern of movement related decreases in discharge activity however did not differ in dystonics compared to controls. In severely dystonic rats, exclusively, simultaneously recorded units often showed abnormally synchronized movement related pauses in GP and bursts in EP. In conclusion, our findings support that slow, abnormally patterned neuronal signaling is a fundamental pathophysiological feature of intrinsic basal ganglia nuclei in dystonia. Moreover, from our findings, we suggest that excessive movement related silencing of neuronal signaling in GP profoundly disinhibits EP and in turn contributes to sustained, unfocused dystonic muscle contractions.

Classical and subtypes of kernicterus associated with bilirubin toxicity can be differentiated in part with physiological auditory measures that include auditory-evoked potentials and measures of cochlear integrity. The combination of these auditory measures suggests that bilirubin exposure results in auditory system damage initially at the level of the brainstem, progressing to the level of the VIII cranial nerve and then to greater neural centers. There is no evidence of neural damage at the level of the cochlea. Auditory neural damage from bilirubin toxicity ranges from neural timing deficits, including neural firing delays and dyssynchrony, to neural response reduction and even elimination of auditory neural responses. This condition is comprehensively described as auditory neuropathy spectrum disorder. Independent measures of cochlear function and auditory neural function up to the level of the brainstem can effectively diagnose auditory neural damage resulting from bilirubin neurotoxicity. Intervention, including cochlear implants can be effective., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A novel technique for neuronal recordings in awake head-restrained animals is presented. Our setup allows (1) daily repeat microelectrode studies in rats without use of anesthesia, (2) excellent stabilization of head using an eight point fixation, (3) painless head-restraint of the animal, (4) accurate stereotaxic localization during multiple sessions of recording, (5) to considerably reduced surgical time, (6) quick repositioning during chronic recording sessions and (7) high quality stabilized neuronal recordings during periods of rest and active movements., (Published by Elsevier B.V.)

Excessive hyperbilirubinemia in human neonates can cause permanent dysfunction of the auditory system, as assessed with brainstem auditory evoked potentials (BAEPs). Jaundiced Gunn rat pups (jjs) exhibit similar BAEP abnormalities as hyperbilirubinemic neonates. Sulfadimethoxine (sulfa) administration to jjs, which displaces bilirubin from serum albumin into tissues including brain, exacerbates acute toxicity. Minocycline administered prior to sulfa in jjs protects against BAEP abnormalities. This study evaluates the neuroprotective capabilities of minocycline HCl (50 mg/kg) administered 30 or 120 min after sulfa (200 mg/kg) in 16 days old jjs. BAEPs are recorded at 6 or 24 h post-sulfa. Abnormal BAEP waves exhibit increased latency and decreased amplitude. The sulfa/saline treated jjs exhibited a significantly increased interwave interval between waves I and II (I-II IWI) and significantly decreased amplitudes of waves II and III compared to the saline/saline jjs. The minocycline 30 min post-sulfa (sulfa/mino+30) group was not significantly different from the saline/saline control group, indicating neuroprotection. The minocycline 120 min post-sulfa (sulfa/mino+120) group had a significantly decreased amplitude of wave III at both 6 and 24h. These studies indicate that minocycline has a graded neuroprotective effect when administered after acute bilirubin neurotoxicity., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Chronic bilirubin encephalopathy (kernicterus) can be diagnosed using semi-objective criteria based on history, physical and neurological examination and laboratory findings including auditory brainstem responses and magnetic resonance imaging. Classical kernicterus is a well-described clinical tetrad of (i) abnormal motor control, movements and muscle tone, (ii) an auditory processing disturbance with or without hearing loss, (iii) oculomotor impairments, especially impairment of upward vertical gaze, and (iv) dysplasia of the enamel of deciduous teeth. Subtle kernicterus or bilirubin-induced neurologic dysfunction (BIND) refers to individuals with subtle neurodevelopmental disabilities without classical findings of kernicterus that, after careful evaluation and consideration, appear to be due to bilirubin neurotoxicity. Kernicterus can be further classified as auditory predominant or motor predominant and characterized based on the severity of clinical sequelae. Proposed research definitions for kernicterus diagnosis in infants from 3 to 18 months are reviewed, as are treatments of auditory and motor deficits and other complications of bilirubin encephalopathy., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Spontaneously jaundiced Gunn rats exposed to sulfadimethoxine develop bilirubin encephalopathy (kernicterus) with hearing loss and dystonia, closely resembling the human syndrome. We recently characterized the electromyographic activity in this animal model supporting our clinical impression of dystonia. The objective of this study was to develop a simple, non-invasive method to quantify the motor deficits in dystonic rodents. On postnatal day 16, Gunn rats were treated with 100mg/kg of sulfadimethoxine or saline. On postnatal day 31, the ventral view of the animals was videotaped while the animals walked inside a Plexiglas chamber. Individual video frames were reviewed and specific gait parameters including hindlimb spread, step length ratio variability, stance/swing ratio and walking speed were compared between dystonic and non-dystonic jaundiced and non-jaundiced littermates. Data analysis demonstrated statistically significant increases in hindlimb spread and step length ratio variability and decreases in walking speed in dystonic animals as compared to controls. This study demonstrates a valuable technique to objectively characterize dystonia in Gunn rats, which could have wide use for other experimental movement disorders as well.

Background: Effective doctor-patient communication has been linked to numerous benefits for both patient and physician. The purpose of this study was to evaluate the effectiveness of the University of Toronto's Therapeutic Communication Program (TCom) at improving first-year medical students' communication skills., Methods: Data were collected during the 1996/97, 1997/98, 1998/99 and 1999/00 academic years. The study used a repeated measures design with a waiting list control group: students were randomly assigned to groups starting the educational intervention in either September (N = 38) or February (N = 41), with the latter being used as a control for the former. Communication skills were assessed at the pre- and post-intervention times and at the end of the academic year from the perspectives of student, standardized patient and external rater., Results: Only the external rater, using an instrument designed to assess the students' empathy based on their written responses, showed a time x group interaction effect (p = 0.039), thereby partially supporting the hypothesis that TCom improved the students' communication skills. Students rated themselves less positively after participation in the program (p = 0.038), suggesting that self-evaluation was an ineffective measure of actual performance or that the program helped them learn to more accurately assess their abilities., Conclusion: The lack of strong findings may be partly due to the study's small sample sizes. Further research at other medical or professional schools could assess the effectiveness of similar courses on students' communication skills and on other capacities that were not measured in this study, such as their understanding of and comfort with patients, their management of the doctor-patient relationship, and their ability to give and receive feedback.

To identify antecedent clinical and health services events in infants (>/=35 weeks gestational age (GA)) who were discharged as healthy from their place of birth and subsequently sustained kernicterus. We conducted a root-cause analysis of a convenience sample of 125 infants >/=35 weeks GA cared for in US healthcare facilities (including off-shore US military bases). These cases were voluntarily reported to the Pilot USA Kernicterus Registry (1992 to 2004) and met the eligibility criteria of acute bilirubin encephalopathy (ABE) and/or post-icteric sequelae. Multiple providers at multiple sites managed this cohort of infants for their newborn jaundice and progressive hyperbilirubinemia. Clinical signs of ABE, verbalized by parents, were often inadequately elicited or recorded and often not recognized as an emergency. Clinical signs of ABE were reported in 7 of 125 infants with a subsequent diagnosis of kernicterus who were not re-evaluated or treated for hyperbilirubinemia, although jaundice was noted at outpatient visits. The remaining infants (n=118) had total serum bilirubin (TSB) levels >20 mg per 100 ml (342 micromol l(-1); range: 20.7 to 59.9 mg per 100 ml). No specific TSB threshold coincided with onset of ABE. Of infants <37 weeks GA with kernicterus, 34.9% were LGA (large for gestational age) as compared with 24.7% of term infants (>37 weeks GA). Although >90% mothers initiated breast-feeding, assessment of milk transfer and lactation support was suboptimal in most. Mortality was 4% (5 of 125) in infants readmitted at age 0.2 mg per 100 ml per hour), contributing factors, alone or in combination, included undiagnosed hemolytic disease, excessive bilirubin production related to extra-vascular hemolysis and delayed bilirubin elimination (including increased enterohepatic circulation, diagnosed and undiagnosed genetic disorders) in the context of known late prematurity (<37 weeks), glucose 6-phosphate-dehydrogenase deficiency, infection and dehydration. Readmission was at age 35 mg per 100 ml had post-icteric sequelae (n=73). There was a narrow margin of safety between birthing hospital discharge or home birth and readmission to a tertiary neonatal/pediatric facility. Progression of hyperbilirubinemia to hazardous levels and onset of neurological signs were often not identified as infant's care and medical supervision transitioned during the first week after birth. The major underlying root cause for kernicterus was systems failure of services by multiple providers at multiple sites and inability to identify the at-risk infant and manage severe hyperbilirubinemia in a timely manner.

Elastic neutron-scattering, inelastic x-ray scattering, specific-heat, and pressure-dependent electrical transport measurements have been made on single crystals of AuZn and Au0.52Zn0.48. Elastic neutron scattering detects new commensurate Bragg peaks (modulation) appearing at Q =(1.33,0.67,0) at temperatures corresponding to each sample's transition temperature (TM = 64 and 45 K, respectively). Although the new Bragg peaks appear in a discontinuous manner in the Au0.52Zn0.48 sample, they appear in a continuous manner in AuZn. Surprising us, the temperature dependence of the AuZn Bragg peak intensity and the specific-heat jump near TM are in favorable accord with a continuous transition. A fit to the pressure dependence of TM suggests the presence of a critical end point in the AuZn phase diagram located at TM* = 2.7 K and p* = 3.1 GPa.

Neonatal hyperbilirubinemia can cause bilirubin encephalopathy (kernicterus). Spontaneously jaundiced (jj) Gunn rats treated with sulfonamide (sulfa) to displace bilirubin from serum albumin, develop bilirubin encephalopathy and abnormal brainstem auditory evoked potentials (BAEPs) comparable with human newborns. We hypothesized phenylhydrazine (PHZ)-induced hemolysis would significantly elevate total plasma bilirubin (TB) in jj Gunn rat pups and produce BAEP abnormalities similar to those observed after sulfa. PHZ 0, 25, 50, or 75 mg/kg was administered intraperitonealy to 15-d-old jjs. An initial TB was recorded in each animal, and a second recorded 1-4 d postinjection to generate a dose-response curve. After PHZ 75 mg/kg, TB peaked at about 30 mg/dL at 48-72 h. A second group of jjs injected with PHZ (0, 25, 50, or 75 mg/kg) and nonjaundiced controls given PHZ 75 mg/kg had HCT and TB at baseline, and HCT, TB, and BAEPs recorded at 48 h. BAEP wave II and III amplitudes decreased, and I-II and I-III interwave intervals increased indicating abnormal central (brainstem) auditory function. PHZ-induced hemolysis in jaundiced Gunn rat pups produces sufficiently elevated TB levels to produce bilirubin encephalopathy. This new model may be a more clinically relevant experimental model of kernicterus- and bilirubin-induced neurologic disorders.

The momentum and temperature dependence of the lifetimes of acoustic phonons in the elemental superconductors lead and niobium were determined by resonant spin-echo spectroscopy with neutrons. In both elements, the superconducting energy gap extracted from these measurements was found to converge with sharp anomalies originating from Fermi-surface nesting (Kohn anomalies) at low temperatures. The results indicate electron many-body correlations beyond the standard theoretical framework for conventional superconductivity. A possible mechanism is the interplay between superconductivity and spin- or charge-density-wave fluctuations, which may induce dynamical nesting of the Fermi surface.

Background: Bilirubin encephalopathy or kernicterus is a potentially serious complication of neonatal hyperbilirubinemia. The mechanism of bilirubin-induced neurotoxicity is not known. Many neurological insults are mediated through NMDA receptor activation., Objective: We assessed the effect of the NMDA channel antagonist, MK-801 on bilirubin neurotoxicity in vivo and in vitro., Methods: Bilirubin toxicity in vitro was assessed using trypan blue staining. Sulfadimethoxine injected (i.p.) jaundiced Gunn rat pups exhibit many neurological sequelae observed in human hyperbilirubinemia. Brainstem auditory-evoked potentials (BAEPs), a noninvasive sensitive tool to assess auditory dysfunction due to bilirubin neurotoxicity, were used to assess neuroprotection with MK-801 (i.p.) in vivo., Results: In primary cultures of hippocampal neurons, 20 min exposure to 64:32 microM bilirubin:human serum albumin reduced the cell viability by approximately 50% ten hours later. MK-801 treatment did not protect the cells. MK-801 pretreatment doses ranging from 0.1-4.0 mg/kg did not protect against BAEP abnormalities in Gunn rat pups 6 h after sulfadimethoxine injection., Conclusion: Our findings suggest that bilirubin neurotoxicity is not mediated through NMDA receptor activation., ((c) 2007 S. Karger AG, Basel.)

Background: Extreme hyperbilirubinemia is treated with double volume exchange transfusion, which may take hours to commence. A neuroprotective agent that could be administered immediately might be clinically useful. Minocycline, an anti-inflammatory and anti-apoptotic semisynthetic tetracycline, prevents hyperbilirubinemia-induced cerebellar hypoplasia in Gunn rats. Acute brainstem auditory evoked potential (BAEP) abnormalities occur after giving sulfadimethoxine to 16-day-old jaundiced Gunn rats to displace bilirubin into tissue including brain., Objective: To assess whether minocycline is neuroprotective in this model of acute bilirubin encephalopathy., Methods: We recorded BAEPs at baseline and 6 h after injecting sulfadimethoxine. Minocycline 0.5 mg/kg (n = 4), 5 mg/kg (n = 9), 50 mg/kg (n = 9) or 500 mg/kg (n = 3, all died) was administered 15 min before sulfadimethoxine (0 h). Controls received saline followed by either sulfadimethoxine (n = 13) or saline (n = 7)., Results: At 6 h total plasma bilirubin decreased from 10.84 +/- 0.88 mg/dl (mean +/- SD) to 0.70 +/- 0.35 mg/dl (p <10(-9)) in all sulfadimethoxine-injected groups. At 6 h, there was complete protection against decreased amplitudes of BAEP waves II and III and increased I-II and I-III interwave intervals (brainstem conduction times corresponding to I-III and I-V in humans) with 50 mg/kg minocycline, and partial protection with lower doses., Conclusions: Minocycline 50 mg/kg 15 min prior to an intervention that normally produces acute bilirubin neurotoxicity is neuroprotective in jaundiced Gunn rat pups. Further studies are needed to investigate the temporal course and mechanism of neuroprotection. Minocycline, administered immediately, may be clinically useful in treating extreme neonatal hyperbilirubinemia and preventing kernicterus. We believe our model provides an efficient in vivo model to screen and evaluate new agents that are neuroprotective against bilirubin toxicity and kernicterus., ((c) 2007 S. Karger AG, Basel.)

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.

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.

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.

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.

SrTiO3 thin films were used as a model system to study the effects of strain and epitaxial constraint on structural phase transitions of perovskite films. The basic phenomena revealed will apply to a variety of important structural transitions including the ferroelectric transition. Highly strained SrTiO3 films were grown on different substrates, providing both compressive and tensile strain. The measured strain-temperature phase diagram is qualitatively consistent with theory; however, the increase in the phase transition temperature is much larger than predicted. Because of the epitaxial strain and substrate clamping, the SrTiO3 lattice is tetragonal at all temperatures. The phase transitions involve only changes in internal symmetry. The low temperature phase under tensile strain has a unique structure with orthorhombic Cmcm space group but a tetragonal lattice, an interesting consequence of epitaxial constraint.

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.

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.