Gabrielle C. Geddes

Physiological characterization of stolon regression in a colonial hydroid.

SUMMARY As with many colonial animals, hydractiniid hydroids display a range of morphological variation. Sheet-like forms exhibit feeding polyps close together with short connecting stolons, whereas runner-like forms have more distant polyps and longer connecting stolons. These morphological patterns are thought to derive from rates of stolon growth and polyp formation. Here, stolon regression is identified and characterized as a potential process underlying this variation. Typically, regression can be observed in a few stolons of a normally growing colony. For detailed studies, many stolons of a colony can be induced to regress by pharmacological manipulations of reactive oxygen species (e.g. hydrogen peroxide) or reactive nitrogen species (e.g. nitric oxide). The regression process begins with a cessation of gastrovascular flow to the distal part of the stolon. High levels of endogenous H2O2 and NO then accumulate in the regressing stolon. Remarkably, exogenous treatments with either H2O2 or an NO donor equivalently trigger endogenous formation of both H2O2 and NO. Cell death during regression is suggested by both morphological features, detected by transmission electron microscopy, and DNA fragmentation, detected by TUNEL. Stolon regression may occur when colonies detect environmental signals that favor continued growth in the same location rather than outward growth.

Pediatric Neck Masses

1. Gabrielle Geddes, MD* 2. Mark M. Butterly, MD*,† 3. Sonali Mehta Patel, MD*,† 4. Silvio Marra, MD* 1. *Advocate Hope Children’s Hospital, Oak Lawn, IL. 2. †Rosalind Franklin University of Medicine and Science, North Chicago, IL. * CRP: : C-reactive protein CT: : computed tomography ESR: : erythrocyte sedimentation rate FNA: : fine needle aspiration MRI: : magnetic resonance imaging A variety of lesions, some malignant, can manifest as masses in the neck, presenting real diagnostic challenges. Clinicians must understand the embryologic development of the head and neck and be familiar with the most recent diagnostic techniques. After completing this article, readers should be able to: 1. Know the differential diagnosis of the pediatric neck mass. 2. Understand how to conduct an evaluation of the pediatric neck mass. The broad differential diagnosis of pediatric neck masses typically fits into two main categories: congenital and acquired. Appreciation of the head and neck formation can simplify and greatly assist in identification of the underlying condition. We first review the embryonic formation as it relates to head and neck pathology, followed by key points of history and physical examination. The differential diagnostic possibilities are separated into categories of congenital and acquired neck masses. Finally, diagnostic clues and evaluation options are discussed. The head and neck are derived from the branchial apparatus, an anatomically distinct structure that undergoes a complex formative process involving generation and resorption. Appreciating some aspects of the degeneration process helps explain the relationship between anatomic structures as well as the actual formation process. By the fourth week of gestation, the individual branchial arches initially become visible. Each arch has its own group of uniquely designated tissue types. For simplification, arch structures will be referred to as a numbered arch without differentiation of clefts, pouches, or other structures. The six paired branchial arches forming the branchial apparatus have ectodermal, mesodermal, and endodermal components, each with its own unique designations and components as listed in Table 1. Branchial arches are numbered …

Multicellular Redox Regulation in an Early-Evolving Animal Treated with Glutathione

Redox signaling has emerged as a unifying theme in many seemingly disparate disciplines. Such signaling has been widely studied in bacteria and eukaryotic organelles and is often mediated by reactive oxygen species (ROS). In this context, reduced glutathione (GSH) acts as an important intracellular antioxidant, diminishing ROS and potentially affecting redox signaling. Complementing this cell‐level perspective, colonial hydroids can be a useful model for understanding organism‐level redox signaling. These simple, early‐evolving animals consist of feeding polyps connected by tubelike stolons. Colonies treated exogenously with GSH or reduced glutathione ethyl ester (GEE) were expected to show a morphological change to sheetlike growth typical of low levels of ROS. Contrary to expectations, diminished stolon branching and polyp initiation was observed. Such runnerlike growth is associated with higher levels of ROS, and surprisingly, such higher levels were found in GSH‐ and GEE‐treated colonies. Further investigations show that GSH triggered a feeding response in hydroid polyps, increasing oxygen uptake but at the same time relaxing mitochondrion‐rich contractile regions at the base of polyps. Diminished gastrovascular flow and increased emissions of mitochondrial ROS also correlated with the observed runnerlike growth. In contrast to cell‐level, “bottom‐up” views of redox signaling, here the phenotype may arise from a “top‐down” interaction of mitochondrion‐rich regions and organism‐level physiology. Such multicellular redox regulation may commonly occur in other animals as well.

The spectrum of manifestations in desmoplakin gene (DSP) spectrin repeat 6 domain mutations: Immunophenotyping and response to ustekinumab

Background The immune abnormalities underlying the ichthyoses are poorly understood. Objective To determine the immunophenotype of an ichthyosis resulting from mutations in the spectrin repeat 6 (SR6) domain of desmoplakin gene (DSP) and target therapy on the basis of molecular pathogenesis. Methods Immunophenotyping was performed by using the blood and skin of a girl with SR6 region DSP mutations causing erythroderma/ichthyosis and cardiomyopathy. Results On the basis of the discovery of T helper 1 and T helper 17/interleukin 23 skewing in the skin and T helper 17/interleukin 22 skewing in blood, ustekinumab therapy was initiated. Ustekinumab was also administered to a boy with an SR6 region DSP mutation and ichthyosis without cardiomyopathy. Both children responded despite previous poor responses to immunosuppressants and retinoids. Limitations Small number of patients and immunophenotyping in only 1 patient. Conclusion An understanding of the molecular basis of inflammation in rare cutaneous disorders can lead to targeted therapy, which promises to be more beneficial than broad immunosuppressants.

Bacteremia in Patients with Heterotaxy: A Review and Implications for Management.

Heterotaxy (HTX) is a laterality defect resulting in abnormal arrangement of the thoracic and abdominal organs across the right-left axis, and is associated with multiple anatomic and physiologic disruptions. HTX often occurs in association with complex congenital heart disease. Splenic abnormalities are also common and convey an increased risk of bacteremia (bacteremia) with a high associated mortality. We performed a systematic review of the literature studying the risk of infection in HTX patients and strategies that can be utilized to prevent such infections. Studies were identified for inclusion using PubMed, EMBASE, and OVID, as well as hand search of references from previously identified papers. Published studies specifically investigating bacteremia in HTX were identified and included as long as they were in English. Data were extracted by two separate authors independently with review of any findings that differed between the two authors. There were 42 documented cases of bacteremia in 32 patients. Approximately, 79% of these had absence of a spleen. The average age of bacteremia was 17 months. HTX patients are at high risk for bacteremia leading to mortality, regardless of anatomic splenic type. We propose strategies for the evaluation of splenic function in HTX patients, and review management practices to reduce the impact of infection risk in the HTX population.

Tricuspid atresia and pulmonary atresia in a child with Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome is a well-characterized condition causing distinctive physical characteristics, intellectual disability, and multiple congenital malformations. Cardiac abnormalities are found in a third of individuals with this condition and usually consist of isolated septal defects or patent ductus arteriosus, although more complex congenital lesions have been described. We present the first reported case of tricuspid atresia and pulmonary atresia with hypoplasia of the right ventricle in the setting of Rubenstein-Taybi syndrome.

Ciliopathy variant burden and developmental delay in children with hypoplastic left heart syndrome.

Purpose:To test the hypothesis that patients with hypoplastic left heart syndrome (HLHS) and developmental delay will have a higher average summative C-score in ciliopathy genes than patients with HLHS without developmental delay.Methods:Ciliopathy gene variant burden was determined utilizing a summative C-score for 14 ciliopathy genes in children with HLHS (n = 24). Mean summative C-scores were compared between children with and without developmental delay. Genome-wide randomizing gene sets were evaluated as a scoring control.Results:Children with developmental delay had a mean summative C-score of 4.05 in ciliopathy genes as compared to a mean summative C-score of 2.02 for children without developmental delay. This difference in means was higher than 99.1% (empirical P value <0.01) of 2 million random lists of 14 genes.Conclusion:Genetically complex disorders such as ciliopathies can be assessed to determine phenotypic risk with summative C-score in appropriately chosen gene sets. If these results are replicated in subsequent cohorts, a diagnostic gene panel could identify risk for developmental delay and other ciliopathy-related comorbidities in infants with congenital heart disease.Genet Med advance online publication 27 October 2016

Concomitant 11p15.4‐p15.5 duplication and terminal 22q13.33 deletion in a patient with features of Beckwith–Wiedemann syndrome

Concomitant 11p15.4-p15.5 Duplication and Terminal 22q13.33 Deletion in a Patient with Features of Beckwith–Wiedemann Syndrome Jess F. Peterson,* David P. Bick, Gabrielle C. Geddes, Julie McCarrier, John W. Grignon Jr, Brett Chirempes, Ulrich Broeckel, Fatima Abidi, Richard C. Rogers, Luigi Boccuto, Barbara DuPont, and Peter vanTuinen Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin Wisconsin Diagnostic Laboratories, Milwaukee, Wisconsin Department of Pediatrics, Section of Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin Advanced Genomics Laboratory, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Department of Pediatrics, Section of Genomic Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin Greenwood Genetic Center, Greenwood, South Carolina

A novel FOXF1 mutation associated with alveolar capillary dysplasia and coexisting colobomas and hemihyperplasia

Alveolar capillary dysplasia (ACD) is a rare and lethal cause of hypoxic respiratory failure in the neonate. Here we describe a term neonate with ACD that was found with a previously unreported p.Arg86Pro mutation in the FOXF1 (Forkhead Box-F1) gene and coexisting congenital anomalies, including colobomas of the iris and hemihyperplasia. This unique clinical presentation may indicate a novel, yet unconfirmed disease association for mutations in the FOXF1 gene. Rapid mutation analysis in FOXF1 may provide noninvasive early confirmation of ACD in neonates with respiratory failure and can aid in clinical decision making.

Pompe disease treatment with twice a week high dose alglucoside alfa in a patient with severe dilated cardiomyopathy

There is limited information regarding ideal dosage of alglucoside alfa in patients with Infantile Onset Pompe Disease (IOPD). The U.S. Food and Drug Administration approved alglucoside alfa at dosing of 20 mg/kg every other week, but there are small studies and case reports suggesting that dosing higher than this leads to improved ventilator free survival and development without adverse events. We review the clinical course and short term clinical outcomes one year following late diagnosis of IOPD in a 3 month old who presented severely affected and was treated with 40 mg/kg twice a week for 21 infusions until six months of age then transitioned to 40 mg/kg/week. The patient responded well to 40 mg/kg twice a week treatment without adverse reactions and significant clinical improvement.