Vol 2-1 Case Report

X-linked Cornelia de Lange Syndrome - Remembering a dysmorphology case in Neonatology

Ana Rita Soares1*, 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.

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Vol 2-1 Mini Review

Fermented Food Guidelines for Children

Victoria Bell1, Jorge Ferrão2 and Tito Fernandes3*

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.

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Vol 2-1 Mini Review

Pre-exposure Prophylaxis as HIV Prevention in High Risk Adolescents

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

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Vol 2-1 Mini Review

Fetal and neonatal alloimmune thrombocytopenia: Novel mechanisms of miscarriage learned from placental pathology in animal models

Issaka Yougbaré1-3, Darko Zdravic1-4, Heyu Ni1-6*

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.

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Vol 2-1 Mini Review

Abnormalities of aortic arch shape after successful repair of aortic coarctation and systemic arterial hypertension

Roberto Crepaz

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

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Vol 2-1 Mini Review

Modeling human pregnancy-associated developmental neurotoxicity in vitro using pluripotent stem cell-derived neurons and astrocytes

Xian Wu1,2, Raymond Swetenburg2, Forrest Goodfellow1,2, Steven L. Stice1,2 *

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.

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Vol 2-1 Mini Review

Apoptosis of pancreatic ?-cells in type 1 diabetes: The role of Caspase-3 in ?-cell apoptosis

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: in T1D 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.

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