Louella B. Amos

Metabotropic glutamate receptors (mGluR5) activate transient receptor potential canonical channels to improve the regularity of the respiratory rhythm generated by the pre-Bötzinger complex in mice.

Metabotropic glutamate receptors (mGluRs) are hypothesized to play a key role in generating the central respiratory rhythm and other rhythmic activities driven by central pattern generators (e.g. locomotion). However, the functional role of mGluRs in rhythmic respiratory activity and many motor patterns is very poorly understood. Here, we used mouse respiratory brain‐slice preparations containing the pre‐Bötzinger complex (pre‐BötC) to identify the role of group I mGluRs (mGluR1 and mGluR5) in respiratory rhythm generation. We found that activation of mGluR1/5 is not required for the pre‐BötC to generate a respiratory rhythm. However, our data suggest that mGluR1 and mGluR5 differentially modulate the respiratory rhythm. Blocking endogenous mGluR5 activity with 2‐Methyl‐6‐(phenylethynyl)pyridine (MPEP) decreases the inspiratory burst duration, burst area and frequency, whereas it increases the irregularity of the fictive eupneic inspiratory rhythm generated by the pre‐BötC. In contrast, blocking mGluR1 reduces the frequency. Moreover, the mGluR1/5 agonist 3,5‐dihydroxyphenylglycine increases the frequency and decreases the irregularity of the respiratory rhythm. Based on previous studies, we hypothesized that mGluR signaling decreases the irregularity of the respiratory rhythm by activating transient receptor potential canonical (TRPC) channels, which carry a non‐specific cation current (ICAN). Indeed, 3,5‐dihydroxyphenylglycine (DHPG) application reduces cycle‐by‐cycle variability and subsequent application of the TRPC channel blocker 1‐[2‐(4‐methoxyphenyl)‐2‐[3‐(4‐methoxyphenyl)propoxy]ethyl]imidazole (SKF‐96365) hydrochloride reverses this effect. Our data suggest that mGluR5 activation of ICAN‐carrying TRPC channels plays an important role in governing the cycle‐by‐cycle variability of the respiratory rhythm. These data suggest that modulation of TRPC channels may correct irregular respiratory rhythms in some central neuronal diseases.

Identification and characterization of a novel ABCA3 mutation

Mutations in the gene coding for ATP-binding cassette protein A3 (ABCA3) are recognized as a genetic cause of lung disease of varying severity. Characterization of a number of mutant ABCA3 proteins has demonstrated that the mutations generally affect intracellular localization or the ability of the protein to hydrolyze ATP. A novel heterozygous mutation that results in the substitution of cysteine for arginine at amino acid 295 in ABCA3 was identified in a premature infant with chronic respiratory insufficiency and abnormal lamellar bodies. Sequencing of DNA performed in study participants demonstrated that this was a mutation and not a common variant. Plasmid vectors containing ABCA3 with the identified novel mutation tagged with green fluorescent protein on the carboxy terminus were generated. The effect of the mutation on protein function was characterized by examining the glycosylation state of the mutant protein in transiently transfected HEK293 cells and by examining ATP hydrolysis activity of the mutant protein with a vanadate-induced nucleotide trapping assay in stably transfected HEK293 cells. The ABCA3 protein containing the R295C mutation undergoes normal glycosylation and intracellular localization but has dramatically reduced ATP hydrolysis activity (12% of wild type). The identification of one copy of this novel mutation in a premature infant with chronic respiratory insufficiency suggests that ABCA3 haploinsufficiency together with lung prematurity may result in more severe, or more prolonged, respiratory failure.

Treatment of Pediatric Restless Legs Syndrome

Objective. The primary aim was to determine if iron supplementation effectively treats children with restless legs syndrome (RLS), the time to improvement or resolution of symptoms, and patient characteristics (family history of RLS, secondary sleep disorders, medical diagnoses, and/or mental health diagnoses) that may affect outcome. Methods. This was a retrospective chart review of children between 5 and 18 years old who were diagnosed with RLS at the pediatric sleep disorders clinic at Children’s Hospital of Wisconsin in Milwaukee, Wisconsin. Documented RLS treatment approaches included supplemental iron, nonpharmacologic interventions, melatonin, gabapentin, clonidine, and dopamine agonists (pramipexole and ropinirole). Results. Ninety-seven children were diagnosed with RLS; 60.8% of children were between 5 and 11 years old. Most children (65%) received iron either as monotherapy or in combination with other treatments. Approximately 80% of the children who received iron and had follow-up had improvement or resolution of their symptoms. The median baseline ferritin level was 22.7 ng/mL, and 71% of children had a ferritin level less than 30 ng/mL. The median time to improvement or resolution of symptoms was 3.8 months. Conclusions. Supplemental iron as monotherapy or in combination with other treatments is effective in treating pediatric RLS. A prospective study could help determine if the initial ferritin level and degree of change in the ferritin level impact response to iron treatment. It is also important to study the long-term outcomes in these patients.

Chiari I malformation presenting as chronic cough

We present a 9‐month‐old infant with persistent cough refractory to conventional asthma therapy. An extensive evaluation eventually revealed a Chiari I malformation with syringohydromyelia. His cough resolved one month after surgical decompression, suggesting that brainstem compression from the Chiari malformation directly caused his symptoms. Pediatr Pulmonol. 2008; 43:1040–1042.

Severe central sleep apnea in a child with leukemia on chronic methadone therapy

We describe a child with acute myeloid leukemia (AML) who developed severe central sleep apnea (CSA) on methadone therapy for chronic pain management. His chemotherapy‐related cerebral atrophy and renal insufficiency with impaired methadone clearance may have also contributed to the severity of his sleep‐disordered breathing. Maintenance methadone treatment is not a common pediatric practice; therefore, the adverse effects of methadone therapy, including CSA, are rarely reported in children. Pediatr Pulmonol. 2013; 48:85–87.

Metabotropic glutamate receptors (mGluR5) activate TRPC channels to improve the regularity of the respiratory rhythm generated by the pre-Bötzinger Complex in mice

Metabotropic glutamate receptors (mGluRs) are hypothesized to play a key role in generating the central respiratory rhythm and other rhythmic activities driven by central pattern generators (e.g. locomotion). However, the functional role of mGluRs in rhythmic respiratory activity and many motor patterns is very poorly understood. Here, we used mouse respiratory brain‐slice preparations containing the pre‐Bötzinger complex (pre‐BötC) to identify the role of group I mGluRs (mGluR1 and mGluR5) in respiratory rhythm generation. We found that activation of mGluR1/5 is not required for the pre‐BötC to generate a respiratory rhythm. However, our data suggest that mGluR1 and mGluR5 differentially modulate the respiratory rhythm. Blocking endogenous mGluR5 activity with 2‐Methyl‐6‐(phenylethynyl)pyridine (MPEP) decreases the inspiratory burst duration, burst area and frequency, whereas it increases the irregularity of the fictive eupneic inspiratory rhythm generated by the pre‐BötC. In contrast, blocking mGluR1 reduces the frequency. Moreover, the mGluR1/5 agonist 3,5‐dihydroxyphenylglycine increases the frequency and decreases the irregularity of the respiratory rhythm. Based on previous studies, we hypothesized that mGluR signaling decreases the irregularity of the respiratory rhythm by activating transient receptor potential canonical (TRPC) channels, which carry a non‐specific cation current (ICAN). Indeed, 3,5‐dihydroxyphenylglycine (DHPG) application reduces cycle‐by‐cycle variability and subsequent application of the TRPC channel blocker 1‐[2‐(4‐methoxyphenyl)‐2‐[3‐(4‐methoxyphenyl)propoxy]ethyl]imidazole (SKF‐96365) hydrochloride reverses this effect. Our data suggest that mGluR5 activation of ICAN‐carrying TRPC channels plays an important role in governing the cycle‐by‐cycle variability of the respiratory rhythm. These data suggest that modulation of TRPC channels may correct irregular respiratory rhythms in some central neuronal diseases.

Neonatal esophageal trachealization and esophagocarinoplasty in the treatment of flow-limited Floyd II tracheal agenesis

From the Divisions of Pediatric Surgery, Pediatric Otolaryngology, Pediatric Pulmonary and Sleep Medicine, and Pediatric Cardiothoracic Surgery, Medical College of Wisconsin; the Clinical and Translational Sciences Institute of Southeast Wisconsin; Children’s Research Institute, Milwaukee; and the Department of Surgery, Marshfield Clinic, Marshfield, Wis. Disclosures: Authors have nothing to disclose with regard to commercial support. Received for publication Dec 11, 2016; accepted for publication Jan 6, 2017. Address for reprints: John C. Densmore, MD, Division of Pediatric Surgery, Medical College of Wisconsin, 9000 W Wisconsin Ave, Suite C320, Milwaukee, WI 53226 (E-mail: jdensmore@chw.org). J Thorac Cardiovasc Surg 2017;153:e121-5 0022-5223/

Nocturnal Choking, as an Isolated Manifestation of Epilepsy

36.00 Copyright 2017 by The American Association for Thoracic Surgery http://dx.doi.org/10.1016/j.jtcvs.2017.01.029 Floyd II tracheal agenesis with fistula (arrow) and after esophagocarinoplasty (right).

Metabotropic glutamate receptors (mGluR5) activate transient receptor potential canonical channels to improve the regularity of the respiratory rhythm generated by the pre-Bötzinger complex in mice: mGluR5 enhances respiratory rhythm regularity via TRPC channels

Nocturnal paroxysmal events can be easily misdiagnosed. Nighttime gasping is most often associated with obstructive sleep apnea (OSA); however, sudden awakenings with a choking sensation are also features of nocturnal epilepsy. Moreover, there may be an absence of epileptiform activity on a scalp electroencephalography (EEG) interictally and ictally, which creates a diagnostic dilemma.

BAG3 myofibrillar myopathy presenting with cardiomyopathy

Metabotropic glutamate receptors (mGluRs) are hypothesized to play a key role in generating the central respiratory rhythm and other rhythmic activities driven by central pattern generators (e.g. locomotion). However, the functional role of mGluRs in rhythmic respiratory activity and many motor patterns is very poorly understood. Here, we used mouse respiratory brain‐slice preparations containing the pre‐Bötzinger complex (pre‐BötC) to identify the role of group I mGluRs (mGluR1 and mGluR5) in respiratory rhythm generation. We found that activation of mGluR1/5 is not required for the pre‐BötC to generate a respiratory rhythm. However, our data suggest that mGluR1 and mGluR5 differentially modulate the respiratory rhythm. Blocking endogenous mGluR5 activity with 2‐Methyl‐6‐(phenylethynyl)pyridine (MPEP) decreases the inspiratory burst duration, burst area and frequency, whereas it increases the irregularity of the fictive eupneic inspiratory rhythm generated by the pre‐BötC. In contrast, blocking mGluR1 reduces the frequency. Moreover, the mGluR1/5 agonist 3,5‐dihydroxyphenylglycine increases the frequency and decreases the irregularity of the respiratory rhythm. Based on previous studies, we hypothesized that mGluR signaling decreases the irregularity of the respiratory rhythm by activating transient receptor potential canonical (TRPC) channels, which carry a non‐specific cation current (ICAN). Indeed, 3,5‐dihydroxyphenylglycine (DHPG) application reduces cycle‐by‐cycle variability and subsequent application of the TRPC channel blocker 1‐[2‐(4‐methoxyphenyl)‐2‐[3‐(4‐methoxyphenyl)propoxy]ethyl]imidazole (SKF‐96365) hydrochloride reverses this effect. Our data suggest that mGluR5 activation of ICAN‐carrying TRPC channels plays an important role in governing the cycle‐by‐cycle variability of the respiratory rhythm. These data suggest that modulation of TRPC channels may correct irregular respiratory rhythms in some central neuronal diseases.