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Article ; Online: Surgical Resection of Focal Cortical Dysplasia in a Neonate with Novel TSC1 Mutation Leading to Resolution of Refractory Seizures: Case Report.

Garavatti, Emily / Yamamoto, Erin / Collins, Kelly / Selden, Nathan / Bushlin, Ittai

2023 Volume 10, Page(s) 2329048X231219223

Abstract: We describe a neonate presenting on first day of life with refractory seizures secondary to a single, large area of focal cortical dysplasia (FCD) who underwent surgical resection at age 3 weeks leading to resolution of seizure activity and dramatic ... ...

Abstract	We describe a neonate presenting on first day of life with refractory seizures secondary to a single, large area of focal cortical dysplasia (FCD) who underwent surgical resection at age 3 weeks leading to resolution of seizure activity and dramatic improvement in developmental trajectory. Surgical intervention for epilepsy is infrequently offered for neonates, often reserved only for those with catastrophic presentations. This case demonstrates that surgical intervention can be safe and efficacious in neonates for pharmaco-resistant seizures associated with a focal lesion. Rapid whole exome sequencing in this case yielded a germline novel de novo TSC1 mutation, leading to a genetic diagnosis of tuberous sclerosis complex (TSC). Our patient demonstrates an atypical neonatal presentation of TSC. Limited data is available for those with isolated FCD in TSC; this is the first reported case in a neonate.
Language	English
Publishing date	2023-12-11
Publishing country	United States
Document type	Case Reports
ZDB-ID	2785453-X
ISSN	2329-048X ; 2329-048X
ISSN (online)	2329-048X
ISSN	2329-048X
DOI	10.1177/2329048X231219223
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Article ; Online: Clinical Reasoning: A 6-week-old infant with migrating focal seizures.

Bushlin, Ittai / Smith, Lacey / Peters, Jurriaan M / El Achkar, Christelle Moufawad

Neurology

2020 Volume 94, Issue 4, Page(s) 178–183

MeSH term(s)	Anticonvulsants/therapeutic use ; Humans ; Infant ; Male ; Nerve Tissue Proteins/genetics ; Polymorphism, Single Nucleotide ; Potassium Channels, Sodium-Activated/genetics ; Quinidine/therapeutic use ; Seizures/drug therapy ; Seizures/genetics
Chemical Substances	Anticonvulsants ; KCNT1 protein, human ; Nerve Tissue Proteins ; Potassium Channels, Sodium-Activated ; Quinidine (ITX08688JL)
Language	English
Publishing date	2020-01-13
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000008842
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Article ; Online: Consensus clinical management guideline for beta-propeller protein-associated neurodegeneration.

Wilson, Jenny L / Gregory, Allison / Kurian, Manju A / Bushlin, Ittai / Mochel, Fanny / Emrick, Lisa / Adang, Laura / Hogarth, Penelope / Hayflick, Susan J

Developmental medicine and child neurology

2021 Volume 63, Issue 12, Page(s) 1402–1409

Abstract: This review provides recommendations for the evaluation and management of individuals with beta-propeller protein-associated neurodegeneration (BPAN). BPAN is one of several neurodegenerative disorders with brain iron accumulation along with pantothenate ...

Abstract	This review provides recommendations for the evaluation and management of individuals with beta-propeller protein-associated neurodegeneration (BPAN). BPAN is one of several neurodegenerative disorders with brain iron accumulation along with pantothenate kinase-associated neurodegeneration, PLA2G6-associated neurodegeneration, mitochondrial membrane protein-associated neurodegeneration, fatty acid hydroxylase-associated neurodegeneration, and COASY protein-associated neurodegeneration. BPAN typically presents with global developmental delay and epilepsy in childhood, which is followed by the onset of dystonia and parkinsonism in mid-adolescence or adulthood. BPAN is an X-linked dominant disorder caused by pathogenic variants in WDR45, resulting in a broad clinical phenotype and imaging spectrum. This review, informed by an evaluation of the literature and expert opinion, discusses the clinical phenotype and progression of the disease, imaging findings, epilepsy features, and genetics, and proposes an approach to the initial evaluation and management of disease manifestations across the life span in individuals with BPAN. What this paper adds The complex epilepsy profile of beta-propeller protein-associated neurodegeneration (BPAN) often resolves in adolescence. The treatment for an individual with BPAN is supportive, with attention to sleep disorders, complex epilepsy, and behavioral problems. Individuals with BPAN have shifting needs throughout their life span requiring multidisciplinary care.
MeSH term(s)	Brain/metabolism ; Brain/pathology ; Disease Management ; Humans ; Iron/metabolism ; Neurodegenerative Diseases/diagnosis ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology
Chemical Substances	Iron (E1UOL152H7)
Language	English
Publishing date	2021-08-04
Publishing country	England
Document type	Journal Article ; Practice Guideline ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80369-8
ISSN	1469-8749 ; 0012-1622
ISSN (online)	1469-8749
ISSN	0012-1622
DOI	10.1111/dmcn.14980
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Article ; Online: Cannabis use and measurement of cannabinoids in plasma and breast milk of breastfeeding mothers.

Moss, Michael J / Bushlin, Ittai / Kazmierczak, Steven / Koop, Dennis / Hendrickson, Robert G / Zuckerman, Katharine E / Grigsby, Tamara M

Pediatric research

2021 Volume 90, Issue 4, Page(s) 861–868

Abstract: Background: Information on cannabinoids in breast milk and maternal cannabis use is limited. We quantified cannabinoids in plasma and breast milk of breastfeeding mothers and assessed cannabis use patterns.: Methods: This is a prospective study at a ... ...

Abstract	Background: Information on cannabinoids in breast milk and maternal cannabis use is limited. We quantified cannabinoids in plasma and breast milk of breastfeeding mothers and assessed cannabis use patterns. Methods: This is a prospective study at a university hospital in a state with legal medical and recreational cannabis. Breast milk and plasma samples along with survey data were collected from volunteers using cannabis in the last 48 h at 2 weeks and 2 months postpartum. Results: Twenty subjects were enrolled. Median age (IQR) was 27 (24-34) years. Median (IQR) instances of cannabis use in the last 7 days were visit 1: 17 (6-29) and visit 2: 23 (15-45). Median (IQR) tetrahydrocannabinol (THC) concentrations were: plasma 3.7 ng/ml (0.8-56.8) and breast milk 27.5 ng/ml (0.8-190.5). Median (IQR) cannabidiol (CBD) concentrations were: plasma 0.6 ng/ml (0.5-6.4) and breast milk 1.2 ng/ml (0.5-17.0). Median (IQR) THC M/P: 7.0 (1.8-34.6) and CBD M/P: 2.6. Median breast milk THC concentration increased from visit 1 to visit 2 by 30.2 ng/ml (95% CI 3.05-69.3 ng/ml). Conclusions: THC and CBD accumulate in breast milk. Breastfeeding mothers used cannabis frequently and increased use in the early postpartum period. Research on the effects of infant exposure to cannabinoids in breast milk is urgently needed. Impact: Cannabis use is increasing in the general population and many nursing mothers use cannabis. THC has been previously detected in breast milk but little is known on how it concentrates relative to plasma. Data on cannabinoids other than THC, reasons for cannabis use, and patterns of use in breastfeeding women are also limited. We detected THC and CBD in breast milk. Both concentrate in breast milk relative to plasma. We showed that breastfeeding mothers increased cannabis use in the weeks after childbirth. Further research is needed to evaluate infant exposure to cannabinoids via breast milk and effects on infant health.
MeSH term(s)	Adult ; Breast Feeding ; Cannabinoids/analysis ; Cannabinoids/blood ; Cannabis ; Female ; Humans ; Infant, Newborn ; Milk, Human/chemistry ; Mothers ; Prospective Studies
Chemical Substances	Cannabinoids
Language	English
Publishing date	2021-01-19
Publishing country	United States
Document type	Journal Article ; Observational Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	4411-8
ISSN	1530-0447 ; 0031-3998
ISSN (online)	1530-0447
ISSN	0031-3998
DOI	10.1038/s41390-020-01332-2
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Article ; Online: Magnetic resonance imaging-guided laser-induced thermal therapy for functional hemispherotomy in a child with refractory epilepsy and multiple medical comorbidities.

Chua, Melissa M J / Bushlin, Ittai / Stredny, Coral M / Madsen, Joseph R / Patel, Archana A / Stone, Scellig

Journal of neurosurgery. Pediatrics

2020 Volume 27, Issue 1, Page(s) 30–35

Abstract: Magnetic resonance imaging-guided laser-induced thermal therapy (MRgLITT) is a minimally invasive surgical approach increasingly employed for precise targeted ablation of epileptogenic brain foci. Recent reports have described corpus callosotomy using ... ...

Abstract	Magnetic resonance imaging-guided laser-induced thermal therapy (MRgLITT) is a minimally invasive surgical approach increasingly employed for precise targeted ablation of epileptogenic brain foci. Recent reports have described corpus callosotomy using MRgLITT, though its application in more extensive functional disconnections has not been documented. Here, the authors detail its use in achieving a palliative hemispherotomy in a 5-year-old with medically refractory hemiclonic seizures following a hemispheric infarction, highlighting a novel use of this surgical technique. In this particular case, open craniotomy was deemed high risk given the multiple medical comorbidities including congenital cardiac disease and end-stage renal failure. MRgLITT was considered an alternative approach with a lower risk for periprocedural hemodynamic perturbations. The patient tolerated the procedure well, attaining an Engel class IB outcome at 16 months' follow-up. This suggests that MRgLITT may be an alternative approach to an open hemispherectomy, particularly in cases in which multiple comorbidities pose significant risks and preclude an open procedure.
MeSH term(s)	Child, Preschool ; Drug Resistant Epilepsy/complications ; Drug Resistant Epilepsy/diagnostic imaging ; Drug Resistant Epilepsy/therapy ; Female ; Follow-Up Studies ; Hemispherectomy/methods ; Humans ; Laser Therapy/methods ; Magnetic Resonance Imaging/methods ; Renal Insufficiency/complications ; Renal Insufficiency/diagnostic imaging ; Renal Insufficiency/therapy ; Sepsis/complications ; Sepsis/diagnostic imaging ; Sepsis/therapy ; Treatment Outcome
Language	English
Publishing date	2020-10-23
Publishing country	United States
Document type	Case Reports
ZDB-ID	2403985-8
ISSN	1933-0715 ; 1933-0707
ISSN (online)	1933-0715
ISSN	1933-0707
DOI	10.3171/2020.6.PEDS20455
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Article: Antibodies to probe endogenous G protein-coupled receptor heteromer expression, regulation, and function.

Gomes, Ivone / Gupta, Achla / Bushlin, Ittai / Devi, Lakshmi A

Frontiers in pharmacology

2014 Volume 5, Page(s) 268

Abstract: Over the last decade an increasing number of studies have focused on the ability of G protein-coupled receptors to form heteromers and explored how receptor heteromerization modulates the binding, signaling and trafficking properties of individual ... ...

Abstract	Over the last decade an increasing number of studies have focused on the ability of G protein-coupled receptors to form heteromers and explored how receptor heteromerization modulates the binding, signaling and trafficking properties of individual receptors. Most of these studies were carried out in heterologous cells expressing epitope tagged receptors. Very little information is available about the in vivo physiological role of G protein-coupled receptor heteromers due to a lack of tools to detect their presence in endogenous tissue. Recent advances such as the generation of mouse models expressing fluorescently labeled receptors, of TAT based peptides that can disrupt a given heteromer pair, or of heteromer-selective antibodies that recognize the heteromer in endogenous tissue have begun to elucidate the physiological and pathological roles of receptor heteromers. In this review we have focused on heteromer-selective antibodies and describe how a subtractive immunization strategy can be successfully used to generate antibodies that selectively recognize a desired heteromer pair. We also describe the uses of these antibodies to detect the presence of heteromers, to study their properties in endogenous tissues, and to monitor changes in heteromer levels under pathological conditions. Together, these findings suggest that G protein-coupled receptor heteromers represent unique targets for the development of drugs with reduced side-effects.
Language	English
Publishing date	2014-12-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2014.00268
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Article ; Online: Cannabinoid-opioid interactions during neuropathic pain and analgesia.

Bushlin, Ittai / Rozenfeld, Raphael / Devi, Lakshmi A

Current opinion in pharmacology

2009 Volume 10, Issue 1, Page(s) 80–86

Abstract: Opiates and exogenous cannabinoids, both potent analgesics used for the treatment of patients with neuropathic pain, bind to and activate class A G-protein-coupled receptors (GPCRs). Several lines of evidence have recently suggested that opioid and ... ...

Abstract	Opiates and exogenous cannabinoids, both potent analgesics used for the treatment of patients with neuropathic pain, bind to and activate class A G-protein-coupled receptors (GPCRs). Several lines of evidence have recently suggested that opioid and cannabinoid receptors can functionally interact in the central nervous system (CNS). These interactions may be direct, such as through receptor heteromerization, or indirect, such as through signaling cross-talk that includes agonist-mediated release and/or synthesis of endogenous ligands that can activate downstream receptors. Interactions between opioid and cannabinoid receptors may mediate many of the behavioral phenomena associated with the use of these drugs, including the production of acute antinociception and the development of tolerance and cross-tolerance to the antinociceptive effects of opioid and cannabinoid-specific ligands. This review summarizes behavioral, anatomical, and molecular data characterizing these interactions during the development of neuropathic pain and during antinociceptive treatment with these drugs alone or in combination. These studies are critical for understanding how the receptor systems involved in pain relief are altered during acute or chronic pain, and for designing better antinociceptive drug therapies, such as the combined use of opioid and cannabinoid receptor agonists or selective activation of receptor heteromers, that directly target the altered neurophysiology of patients experiencing pain.
MeSH term(s)	Analgesics, Opioid/pharmacology ; Animals ; Cannabinoid Receptor Agonists ; Cannabinoids/pharmacology ; Central Nervous System/drug effects ; Central Nervous System/metabolism ; Drug Delivery Systems ; Drug Therapy, Combination ; Drug Tolerance ; Humans ; Neuralgia/drug therapy ; Neuralgia/physiopathology ; Pain/drug therapy ; Pain/physiopathology ; Receptors, Cannabinoid/metabolism ; Receptors, Opioid/agonists ; Receptors, Opioid/metabolism
Chemical Substances	Analgesics, Opioid ; Cannabinoid Receptor Agonists ; Cannabinoids ; Receptors, Cannabinoid ; Receptors, Opioid
Language	English
Publishing date	2009-10-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2009.09.009
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Article ; Online: Dimerization with cannabinoid receptors allosterically modulates delta opioid receptor activity during neuropathic pain.

Bushlin, Ittai / Gupta, Achla / Stockton, Steven D / Miller, Lydia K / Devi, Lakshmi A

PloS one

2012 Volume 7, Issue 12, Page(s) e49789

Abstract: The diversity of receptor signaling is increased by receptor heteromerization leading to dynamic regulation of receptor function. While a number of studies have demonstrated that family A G-protein-coupled receptors are capable of forming heteromers in ... ...

Abstract	The diversity of receptor signaling is increased by receptor heteromerization leading to dynamic regulation of receptor function. While a number of studies have demonstrated that family A G-protein-coupled receptors are capable of forming heteromers in vitro, the role of these heteromers in normal physiology and disease has been poorly explored. In this study, direct interactions between CB(1) cannabinoid and delta opioid receptors in the brain were examined. Additionally, regulation of heteromer levels and signaling in a rodent model of neuropathic pain was explored. First we examined changes in the expression, function and interaction of these receptors in the cerebral cortex of rats with a peripheral nerve lesion that resulted in neuropathic pain. We found that, following the peripheral nerve lesion, the expression of both cannabinoid type 1 receptor (CB(1)R) and the delta opioid receptor (DOR) are increased in select brain regions. Concomitantly, an increase in CB(1)R activity and decrease in DOR activity was observed. We hypothesize that this decrease in DOR activity could be due to heteromeric interactions between these two receptors. Using a CB(1)R-DOR heteromer-specific antibody, we found increased levels of CB(1)R-DOR heteromer protein in the cortex of neuropathic animals. We subsequently examined the functionality of these heteromers by testing whether low, non-signaling doses of CB(1)R ligands influenced DOR signaling in the cortex. We found that, in cortical membranes from animals that experienced neuropathic pain, non-signaling doses of CB(1)R ligands significantly enhanced DOR activity. Moreover, this activity is selectively blocked by a heteromer-specific antibody. Together, these results demonstrate an important role for CB(1)R-DOR heteromers in altered cortical function of DOR during neuropathic pain. Moreover, they suggest the possibility that a novel heteromer-directed therapeutic strategy for enhancing DOR activity, could potentially be employed to reduce anxiety associated with chronic pain.
MeSH term(s)	Allosteric Site ; Animals ; Cerebral Cortex/pathology ; Chronic Pain ; Dimerization ; Enzyme-Linked Immunosorbent Assay/methods ; Guanosine 5'-O-(3-Thiotriphosphate)/metabolism ; Hyperalgesia ; Immunohistochemistry/methods ; Ligands ; Male ; Neuralgia ; Protein Binding ; Rats ; Rats, Sprague-Dawley ; Receptors, Cannabinoid/chemistry ; Receptors, Cannabinoid/genetics ; Receptors, Opioid, delta/chemistry ; Receptors, Opioid, delta/metabolism ; Signal Transduction ; Time Factors
Chemical Substances	Ligands ; Receptors, Cannabinoid ; Receptors, Opioid, delta ; Guanosine 5'-O-(3-Thiotriphosphate) (37589-80-3)
Language	English
Publishing date	2012-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0049789
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Article: Partially overlapping distribution of epsin1 and HIP1 at the synapse: analysis by immunoelectron microscopy.

Yao, Pamela J / Bushlin, Ittai / Petralia, Ronald S

The Journal of comparative neurology

2006 Volume 494, Issue 2, Page(s) 368–379

Abstract: Synapses of neurons use clathrin-mediated endocytic pathways for recycling of synaptic vesicles and trafficking of neurotransmitter receptors. Epsin 1 and huntingtin-interacting protein 1 (HIP1) are endocytic accessory proteins. Both proteins interact ... ...

Abstract	Synapses of neurons use clathrin-mediated endocytic pathways for recycling of synaptic vesicles and trafficking of neurotransmitter receptors. Epsin 1 and huntingtin-interacting protein 1 (HIP1) are endocytic accessory proteins. Both proteins interact with clathrin and the AP2 adaptor complex and also bind to the phosphoinositide-containing plasma membrane via an epsin/AP180 N-terminal homology (ENTH/ANTH) domain. Epsin1 and HIP1 are found in neurons; however, their precise roles in synapses remain largely unknown. Using immunogold electron microscopy, we examine and compare the synaptic distribution of epsin1 and HIP1 in rat CA1 hippocampal synapse. We find that epsin1 is located across both sides of the synapse, whereas HIP1 displays a preference for the postsynaptic compartment. Within the synaptic compartments, espin1 is distributed similarly throughout, whereas postsynaptic HIP1 is concentrated near the plasma membrane. Our results suggest a dual role for epsin1 and HIP1 in the synapse: as broadly required factors for promoting clathrin assembly and as adaptors for specific endocytic pathways.
MeSH term(s)	Adaptor Proteins, Vesicular Transport ; Animals ; Clathrin/metabolism ; DNA-Binding Proteins/analysis ; Endocytosis/physiology ; Hippocampus/cytology ; Humans ; Immunohistochemistry ; Neurons/chemistry ; Neurons/ultrastructure ; Rats ; Synapses/chemistry ; Synapses/ultrastructure ; Vesicular Transport Proteins/analysis
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Clathrin ; DNA-Binding Proteins ; HIP1 protein, human ; Vesicular Transport Proteins ; epsin
Language	English
Publishing date	2006-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	3086-7
ISSN	1096-9861 ; 0021-9967 ; 0092-7317
ISSN (online)	1096-9861
ISSN	0021-9967 ; 0092-7317
DOI	10.1002/cne.20810
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Article ; Online: Role of antibodies in developing drugs that target G-protein-coupled receptor dimers.

Hipser, Chris / Bushlin, Ittai / Gupta, Achla / Gomes, Ivone / Devi, Lakshmi A

The Mount Sinai journal of medicine, New York

2011 Volume 77, Issue 4, Page(s) 374–380

Abstract: G-protein-coupled receptors are important molecular targets in drug discovery. These receptors play a pivotal role in physiological signaling pathways and are targeted by nearly 50% of currently available drugs. Mounting evidence suggests that G-protein- ... ...

Abstract	G-protein-coupled receptors are important molecular targets in drug discovery. These receptors play a pivotal role in physiological signaling pathways and are targeted by nearly 50% of currently available drugs. Mounting evidence suggests that G-protein-coupled receptors form dimers, and various studies have shown that dimerization is necessary for receptor maturation, signaling, and trafficking. However, the physiological implications of dimerization in vivo have not been well explored because detection of GPCR dimers in endogenous systems has been a challenging task. One exciting new approach to this challenge is the generation of antibodies against specific G-protein-coupled receptor dimers. Such antibodies could be used as tools for characterization of heteromer-specific function; as reagents for their purification, tissue localization, and regulation in vivo; and as probes for mapping their functional domains. In addition, such antibodies could serve as alternative ligands for G-protein-coupled receptor heteromers. Thus, heteromer-specific antibodies represent novel tools for the exploration and manipulation of G-protein-coupled receptor-dimer pharmacology.
MeSH term(s)	Antibodies/drug effects ; Antibodies/immunology ; Drug Design ; Humans ; Ligands ; Protein Binding ; Protein Multimerization/drug effects ; Protein Multimerization/immunology ; Protein Subunits/drug effects ; Protein Transport ; Receptors, G-Protein-Coupled/drug effects ; Receptors, G-Protein-Coupled/immunology ; Signal Transduction
Chemical Substances	Antibodies ; Ligands ; Protein Subunits ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2011-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	130499-9
ISSN	1931-7581 ; 0027-2507
ISSN (online)	1931-7581
ISSN	0027-2507
DOI	10.1002/msj.20199
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