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Marta Cristaldi¹, Rodolfo Mauceri¹, Laura Tomasello², Giuseppe Pizzolanti², Giovanni Zito⁵, Riccardo Alessandro^3,4, Carla Giordano^2*, Giuseppina Campisi¹

¹Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy

²Biomedical Department of Internal and Specialist Medicine (DIBIMIS), Laboratory of Regenerative Medicine, Section of Endocrinology, Diabetology and Metabolism, University of Palermo, Palermo, Italy

³Department of Biopathology and Medical Biotechnology, Section of Biology and Genetics, University of Palermo, Palermo, Italy

⁴Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Palermo, Italy

⁵Advanced Technologies Network (ATeN) Center, University of Palermo, Palermo, Italy

In the last three decades, the constantly increasing need for therapies, efficiently preventing and/or treating human diseases, has raised the interest in Regenerative Medicine (RM). RM is based on employing mesenchymal stem cells (MSCs), that showed to have great proliferation, self-renewal and multi-lineage differentiation potential, in vitro as well as in vivo. The opportunity of an accessible, painless and low-cost reservoir of MSCs constitutes the first important step of a successful regenerative therapy to include in the current clinical practice. Oral cavity has recently demonstrated to contain different MSCs niches: dental pulp from permanent and deciduous teeth, periodontal ligament, dental follicle, apical papilla and mucosa. MSCs from dental pulp of deciduous teeth, naturally lost in pediatric age, and the oral mucosa have shown to be easily harvested and to have a promising regenerative potential. Thus, the aim of the paper is to review the potentialities of human exfoliated deciduous teeth stem cells (SHEDs) and oral mucosa stem cells (OMSCs) in RM, with the purpose of their use as accessible source of MSCs for the future of pediatric patient.

Michelle Flippin

University of Rhode Island

Fousseyni Traore^1*, Belco Maiga¹, Konimba Diabaté², Yacaria Coulibaly³, Hawa Diall¹, Pierre Togo¹, Oumar Coulibaly¹, Issa Amadou³, Karamoko Sacko¹, Abdoul Karim Doumbia¹, Abdoul Aziz Diakite¹, Bakary Kamaté⁴, Fatoumata Dicko-Traoré¹, Mariam Sylla¹, Boubacar Togo¹

¹Gabriel Toure hospital, department of pediatrics, Bamako-Mali

²National hospital of Mali, Radiation therapy service, Bamako-Mali

³Gabriel Toure hospital, pediatric surgery service, Bamako-Mali

⁴Hospital of Point G, department of histopathology, Bamako-Mali

Purpose: Congenital mesoblastic nephroma (CMN) is a mesenchymal renal tumor of the newborn and young infant. This tumor is generally non-aggressive and amenable to surgical removal. Few studies are available in Africa about the treatment of CMN. The aim of this retrospective study was to evaluate the treatment of CMN in the pediatric oncology unit of teaching hospital Gabriel Toure in Bamako-Mali.

Patients and method: The study was performed retrospectively from 01 January 2005 to 31 December 2016 (duration 11 years), in the pediatric-oncology unit of Gabriel Touré Teaching Hospital. Were included, patients with histologically proven CMN. The uretero-nephrectomy was indicated for all included patients. Patients with significant tumor volume at abdominal CT-scan and those with no staging at surgery with imprecise histologic stage, received neoadjuvant and adjuvant chemotherapy, respectively.

Result:From 2005/01/01 to 2016/12/31 eight cases of CMN were included in the study. CMN accounted for 3% of renal tumors. The median age of patient was 4.5 months (1 month-6 months) with a sex ratio of 0.33 (M = 2, F = 6). Abdominal mass was the most common physical sign (n = 7; 87%). The CT scan was performed in five patients (62%). There was no difference in laterality (right kidney, n = 4, left kidney, n = 4).

Three patients received neoadjuvant chemotherapy (37%). Seventy-two percent of patients received initial nephro-ureterectomy. The histology confirmed CMN in all patients (n = 8, 100%). All patients had the classic histological form (n = 8; 100%). Stage 1 (n = 4; 50%), stage 2 (n = 2; 25%), unspecified (n = 2; 25%). Two patients received adjuvant chemotherapy (25%). Overall survival was 100% with a median follow-up of 8 years (6 -10 years).

Conclusion: Multidisciplinary collaboration is the key of therapeutic success of CMN.

Madison Nation, MD¹, Megyn Beyer, DO², Margaret Ellis, DO, MSPH³, Nicholas M. Potisek, MD^4*

¹Pediatric Residency

^4*Department of Pediatrics, Wake Forest Baptist Medical Center Winston-Salem, NC

Kyle N. Kaneko^1*, Miki Wong^1,3, Michael J. Corley^1,2, Ryan W.Y. Lee^1,2,3

¹Shriners Hospitals for Children®—Honolulu, Department of Research, Honolulu, HI, USA

²John A. Burns School of Medicine, University of Hawaii School of Medicine, Honolulu, HI, USA

³Milestones Center for Pediatric Neurodevelopment, Honolulu, HI, USA

Down syndrome is a common genetic intellectual disability seen in humans. Currently, therapeutic interventions are inadequate in improving the quality of life for individuals with Down syndrome that have cognitive and behavioral impairments. Nutrition therapies for Down syndrome have focused on addressing obesity but not intellectual disability and cognitive decline. The ketogenic diet is a very low carbohydrate, moderate protein, and high fat diet used to treat childhood and adult epilepsy, however, there is growing interest in its potential to improve cognition and behavior. There is evidence suggesting that the ketogenic diet may be effective in treating comorbidities associated with Down syndrome such as early onset of Alzheimer’s disease and dementia. This review aims to discuss the ketogenic diet and the potential benefits that the diet may provide in neurodevelopmental and neurodegenerative diseases. We propose that the ketogenic diet may be a therapeutic option for cognitive decline in Down syndrome and warrants investigation.

Danielle E. Arnold¹ and Jennifer Heimall^1*

¹Division of Allergy & Immunology, Children’s Hospital of Philadelphia, United States

Severe combined immunodeficiency (SCID) is a group of the most severe of primary immunodeficiencies and is typically fatal in the first year of life without hematopoietic cell transplantation (HCT). Improved transplantation techniques and supportive care measures have resulted in improved survival following HCT. Furthermore, patients are being diagnosed earlier since the widespread implementation of SCID newborn screening in the United States and moving on to transplantation before 3.5 months of age. As such, most SCID patients are now expected to live well into adulthood following successful HCT. Many centers are using conditioning with alkylating agents, including busulfan and melphalan, pre-transplantation to achieve full T and B cell immune reconstitution; however, significant concerns remain regarding the attendant risks of using chemotherapeutic agents in early infancy. Several long-term follow-up studies have demonstrated high rates of non-immunologic late effects depending on the conditioning regimen employed and SCID genotype. The full risk of conditioning in this patient population remains incompletely characterized, and further research on post-HCT outcomes is needed. It is imperative that all providers caring for SCID survivors both in childhood and adulthood be aware of the risk of late effects. Guidelines for long-term follow-up were recently published, and the recommendations are briefly summarized here.

Pinting Chen MS^1*, Anthony Khong MS², Gary Ledley MD³, Vicki Mahan MD⁴

^1,2Drexel University College of Medicine

³Hahnemann University Hospital, Drexel University College of Medicine

⁴St. Christopher’s Hospital for Children and Drexel University College of Medicine

Anomalous left coronary artery to pulmonary artery (ALCAPA) is a congenital heart defect in which the left coronary artery (LCA) originates from the pulmonary trunk instead of from the aorta. This disease occurs in 1 in 300,000 births and, if untreated, 90% of these neonates die within the first year. Individuals who live beyond this tend to be asymptomatic and either experience sudden death at an average age of 35 or present with cardiac abnormalities, including myocardial ischemia, arrhythmia, or mitral regurgitation. There are various surgical interventions used to treat ALCAPA, and the establishment of a two coronary artery system is the preferred treatment of choice. We report a case of a five-year-old presenting with supraventricular tachycardia since birth who, upon diagnosis of ALCAPA by angiography, was treated by surgical ligation. Thirty years later, he returned to a cardiologist with symptoms of congestive heart failure. The initial presentation of this patient is unusual because the manifestation of ALCAPA usually occurs within the first few months of birth and because ligation is no longer the preferred method of intervention. We discuss this unique case, suggest possible associations between ALCAPA and arrhythmias, review the various surgical methods used to treat ALCAPA, and evaluate the long-term outcome of ligation.

Xian Wu^1,2, Raymond Swetenburg², Forrest Goodfellow^1,2, Steven L. Stice^{1,2 *}

¹Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, United States

²Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, United States

Developmental neurotoxicity is any toxic effect on the developing nervous system interfering with normal nervous system structure or function before or after birth and can be associated with neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation and cerebral palsy. Currently, developmental neurotoxicity testing relies heavily on neurobehavioral and neuropathological studies in rodent models; however, an existing backlog of chemicals lack appropriate neurotoxicity information due to the low throughput nature and subsequent high cost of in vivo animal testing. Alternative models have been developed to replace rodent models (including non-mammalian models, brain slice culture, and primary and transformed cell models) though limitations to increasing throughput and reproducibility remain. In this review, we focus on the use of human pluripotent stem cells as a cell source for in vitro chemical screening. Pluripotent stem cell-based assays are derived from a virtually unlimited and uniform cell source making studies highly reproducible and relatively low cost compared to rodent models. Moreover, directed differentiation to distinct neural lineages, including neurons and astrocytes, provides isogenic, precise and tunable cell mixtures to mimic in vivo brain composition for high throughput screening. Thus, human pluripotent stem cell-derived neural models are poised to vastly increase throughput and decrease costs for developmental neurotoxicity screening.

Roberto Crepaz

Pediatric Cardiology and Congenital Heart Disease in the Adult Dept. of Cardiology Regional Hospital S. Maurizio Bolzano, Italy

Issaka Yougbaré^1-3, Darko Zdravic^1-4, Heyu Ni^1-6*

^1*Toronto Platelet Immunobiology Group

²Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON Canada

³Canadian Blood Services Centre for Innovation, Toronto, ON K1G 4J5, Canada

⁴Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada

⁵Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada

⁶Department of Medicine, University of Toronto, Toronto, ON M5S 1A8

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease. Maternal alloimmune responses against fetal platelet antigens in FNAIT may lead to clinical complications including bleeding disorders, intrauterine growth restriction (IUGR) and in severe cases fetal death (miscarriage). It has been long suspected that thrombocytopenia may be the reason for bleeding disorders in FNAIT, recent studies from us and other groups, however, suggested that the anti-angiogenic effects of anti-platelet antibodies may play a key role in bleeding, particularly in intracranial hemorrhages. Our earlier studies using murine models also suggested that some anti-platelet antibodies can activate platelets and initiate thrombotic events in the placenta, which may contribute to miscarriage. Most recently, we found that maternal anti-β3 integrin antibodies can target fetal allogenic trophoblasts, form immune complexes, and generate binding sites for natural killer (NK) cell Fcγ receptors. Uterine NK cell activation through NKp46 and perforin release caused trophoblast apoptosis, impaired spiral artery remodeling, and ultimately lead to IUGR and/or fetal death. We found that NK cell-mediated placental pathologies are preventable by anti-NK antibody treatments, which may have translational importance. This mini-review mainly discussed the latest discoveries regarding activated uterine NK cells-mediated miscarriage. Future research on placental inflammation and remodeling should open new avenues for interventions in FNAIT-mediated pregnancy failures.

^1*Megan E. Gray, ²Sheela V Shenoi, ³Rebecca Dillingham

^1*Division of Infectious Diseases and International Health. University of Virginia, Charlottesville, VA

²Assistant Professor of Medicine. Yale University, New Haven, CT

³Director of the Center for Global Health, Associate Professor of Medicine. Division of Infectious Diseases and International Health. University of Virginia, Charlottesville, VA

Ana Rita Soares^1*, Gonçalo Inocêncio², Céu Rodrigues², Elisa Proença³, Gabriela Soares¹, Ana Maria Fortuna¹, Céu Mota³

¹Medical Genetics Department, Centro de Genética Médica Doutor Jacinto Magalhães, Porto, Portugal

²Obstetrics/Gynecology Department, Centro Materno-Infantil do Norte, Porto, Portugal

³Neonatology Department, Centro Materno-Infantil do Norte, Porto, Portugal

Cornelia de Lange Syndrome is a rare disease characterized by prenatal and postnatal growth restriction, mild to severe intellectual disability, characteristic facial dysmorphisms, and other anomalies. The diagnosis is based on clinical criteria or on detection of a pathological variant in one of the five disease causing genes - NIPBL, RAD21, SMC3, HDAC8 or SMC1A. The prognosis may depend on the precocity of malformations’ treatment, early institution of therapies and careful follow-up of possible complications. We present a case of Cornelia de Lange Syndrome whose clinical diagnosis was made during perinatal period due to a suspicious prenatal history followed by characteristic dysmorphisms and anomalies. The molecular confirmation was only possible after two years, revealing a pathogenic variant in SMC1A gene, located at X chromosome, which occurred as de novo event. The clinical suspicion during perinatal period made it possible to start an earlier multidisciplinary follow-up and to offer a better management for the child and a proper genetic counseling for the parents.

Victoria Bell¹, Jorge Ferrao² and Tito Fernandes^3*

¹Faculty of Pharmacy, Coimbra University, Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal

²The Vice-Chancellor’s Office, Universidade Pedagógica, Rua João Carlos Raposo Beirão 135, Maputo, Moçambique

³Associação para o Desenvolvimento das Ciências Veterinárias (ACIVET), Faculty of Veterinary Medicine, Lisbon University, 1300-477 Lisboa, Portugal

The authors try to synthesise their communication elsewhere on general fermented foods giving an emphasis to its use in children. Most nutritional guidelines in the world, including in Asian countries where fermented foods are widely used, do not mention fermented foods and beverages besides yoghurt as a dairy product. Children get their gut microbioma from the stage of birth and milking and the intestinal flora remains most the same throughout their life. Fermented foods and mushroom biomass may modulate the probiotic profile of gut flora.

Tatsuo Tomita¹*

¹Departments of Integrative Bioscience and Pathology, Oregon Health and Science University 611 SW Campus Drive, Portland, Oregon 97239-3097, USA

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β-cells after asymptomatic period over years. Insulitis activates antigen presenting cells, which trigger activating DC4+ helper-T cells, releasing cytokines. Cytokines activate CD8+ cytotoxic –T cells and lead to β-cell destruction. Apoptosis pathway consists of extrinsic and intrinsic pathway. Extrinsic pathway includes Fas pathway to CD4+-CD8+ interaction whereas intrinsic pathway includes mitochondria-driven pathway at balance between anti-apoptotic Bcl-2 and Bcl-xL and pro-apoptotic proteins. Activated cleaved caspase-3 (ACC) is the converging point between extrinsic and intrinsic pathway. ACC may be used as a marker for β-cell apoptosis: inT1DM islets weakly insulin-positive β-cells are present with increased ACC positive β-cells whereas β-cell absent islets, which exclusively consist of α-cells and PP-cells with decreased ACC-cells, represent the end-stage of regenerating β-cells. Weakly insulin-positive β-cells could be rejuvenated to supply endogenous insulin. Apoptosis takes place only when pro-apoptotic protein exceeds anti-apoptotic proteins. Since concordance rate of T1D in the identical twins is about 50%, environmental factors are involved in development of T1D, opening a door to means to prevent autoimmune β-cell destruction for therapeutic application by transfecting β-cells with Casp3^-/- genes or pan-caspase inhibitor therapy. Prudent glucose control prevents ongoing hyperglycemia-induced β-cell apoptosis.

Chaowapong Jarasvaraparn¹, David A. Gremse^2*

¹Department of Pediatrics, University of South Alabama, Mobile, Alabama 36604, USA

²Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of South Alabama, Mobile, Alabama 36604, USA

Autoimmune hepatitis (AIH) is a chronic liver disease that may be associated with extrahepatic autoimmune disorders. Evans syndrome (ES) is an autoimmune disorder that is characterized by a combination of immune thrombocytopenia and autoimmune hemolytic anemia. Association of autoimmune hepatitis with Evans syndrome is rare, especially in children. We reported a 3-year-old-female with pre-existing Evans syndrome who developed AIH type 1^1_. This commentary reviews this case along with other reported cases of AIH and ES.

Ulrich Desselberger

Compared to classical ‘forward’ genetics in which the changed phenotype of an organism is correlated with mutations in the genome, the availability of complete nucleotide sequences of many microbes and animals now allows the rational engineering of mutations in individual genes and identification of the correlated change in phenotype of the reconstituted organism (‘reverse genetics’). Reverse genetics enables precise assignment of phenotypic changes to genomic mutations. The goal to ‘rescue’ infectious rotavirus from a mutated genome has eluded success for a long time, and only recently a plasmid only-based, helper virus-free reverse genetics system for species A rotaviruses has been developed. Based on background information on rotavirus structure, classification, replication and genetic research, the new procedure is reviewed in detail, and its versatility and significance for future basic and translational research are discussed.

Consuelo Romero- Sánchez^1,2*

Elsia A. Obus¹, Natalie H. Brito², Lauren Sanlorenzo², Corinna Rea², Laura Engelhardt², Kimberly G. Noble^1*

This study examines how the addition of a modest addendum to the well-established pediatric primary care program, Reach Out and Read (ROR), is associated with increased clinician adherence to ROR and caregiver home literacy behavior. This study took place in four ambulatory care clinics at a large urban medical center. All clinics received standard ROR training. Two of the four clinics received additional ROR training and bookmarks with age-specific advice about reading aloud with children. Following the intervention, medical providers reported no behavioral differences, however caregivers in the intervention group reported: more frequent trips to the library, receiving more books from their pediatrician, and receiving more advice on how to read with their child than caregivers in from the comparison clinics. Thus the addition of a modest training and bookmark intervention to the ROR program was associated with caregiver report of both increased clinician adherence to ROR and increased caregiver literacy behavior. The bookmark intervention may be an inexpensive way to improve the effects of the ROR program.

Deena L. Gibbons^1* and Paul Fleming²