Prenatal treatment path for angelman syndrome and other neurodevelopmental disorders

Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or deletion of the maternally inherited UBE3A allele. These pathogenic mutations lead to loss of maternal UBE3A expression in neurons. Antisense oligonucleotides and gene therapies are in development, which activate the intact but epigenetically silenced paternal UBE3A allele. Preclinical studies indicate that treating during the prenatal period could greatly reduce the severity of symptoms or prevent AS from developing. Genetic tests can detect the chromosome 15q11-q13 deletion that is the most common cause of AS. New, highly sensitive noninvasive prenatal tests that take advantage of single-cell genome sequencing technologies are expected to enter the clinic in the coming years and make early genetic diagnosis of AS more common. Efforts are needed to identify fetuses and newborns with maternal 15q11-q13 deletions and to phenotype these babies relative to neurotypical controls. Clinical and parent observations suggest AS symptoms are detectable in infants, including reports of problems with feeding and motor function. Quantitative phenotypes in the 0- to 1-year age range will permit a more rapid assessment of efficacy when future treatments are administered prenatally or shortly after birth. Although prenatal therapies are currently not available for AS, prenatal testing combined with prenatal treatment has the potential to revolutionize how clinicians detect and treat babies before they are symptomatic. This pioneering prenatal treatment path for AS will lay the foundation for treating other syndromic neurodevelopmental disorders. Autism Res 2020, 13: 11–17. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay summary: Prenatal treatment could benefit expectant parents whose babies test positive for the chromosome microdeletion that causes Angelman syndrome (AS). Prenatal treatment is predicted to have better outcomes than treating after symptoms develop and may even prevent AS altogether. This approach could generally be applied to the treatment of other syndromic neurodevelopmental disorders

Normoglycemic ketonemia as biochemical presentation in ketotic glycogen storage disease

Background: According to the textbooks, the ketotic glycogen storage disease (GSD) types 0, III, VI, IX, and XI are associated with fasting ketotic hypoglycemia and considered milder as gluconeogenesis is intact. Methods: A retrospective cohort study of biochemical profiles from supervised clinical fasting studies is performed in ketotic GSD patients in our metabolic center. For data analysis, hypoglycemia was defined as plasma glucose concentration <2.6 mmol/L. Total KB was defined as the sum of blood acetoacetate and β-hydroxybutyrate concentrations. If the product of glucose and KB concentrations was greater than 10, a ketolysis defect was suspected. Results: Data could be collected from 13 fasting studies in 12 patients with GSD III (n = 4), GSD VI (n = 3), and GSD IX (n = 5). Six patients remained normoglycemic with median glucose concentration of 3.9 mmol/L (range, 2.8–4.6 mmol/L) and median total KB concentration of 1.9 mmol/L (range, 0.6–5.1 mmol/L). The normoglycemic patients included type VI (3 out of 3) and type IX (3 out of 5) patients. All type III patients developed ketotic hypoglycemia. Interestingly, in five patients (one GSD III, one GSD VI, and three GSD IX), the biochemical profile suggested a ketolysis defect. Conclusion: Normoglycemic ketonemia is a common biochemical presentation in patients with GSD types VI and IX, and ketonemia can precede hypoglycemia in all studied GSD types. Therefore, GSD VI and GSD IX should be added to the differential diagnosis of ketotic normoglycemia, and KB concentrations should be routinely measured in ketotic GSD patients

E-cadherin in canine mast cell tumors: Decreased expression and altered subcellular localization in Grade 3 tumors

Mast cell tumors (MCTs) are the most frequent round cell tumors in dogs and comprise approximately 21% of all canine cutaneous tumors. MCTs are highly invasive and metastatic corresponding to the histological grade. E-cadherin is an adhesion molecule expressed in epithelial cells and although it is an epithelial cellular marker, studies have shown expression of E-cadherin in canine round cell tumors. To better characterize the expression pattern of E-cadherin in several different histological grades of MCTs in dogs, the expression and localization of the adhesion molecule was investigated using immunohistochemistry. For this purpose, 18 cutaneous MCTs were classified into three histological grades, 1, 2 or 3. Clinical history and follow-up data were available for all of the dogs. Cytoplasmic and nuclear expressions of E-cadherin in all three types of tumors were verified by immunostaining using two different antibodies. There was decreased E-cadherin expression in the more aggressive MCTs (Grade 3), suggesting an association between E-cadherin and tumor aggressiveness. Additionally, the loss of E-cadherin expression in either the cytoplasm or nucleus in more aggressive and undifferentiated tumor types confirmed the importance of cellular adhesion in tumor behavior. (C) 2012 Published by Elsevier Ltd.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2009/12827-1]; [2010/08523-4

Towards progressive regulatory approaches for agricultural applications of animal biotechnology.

Traditional breeding techniques, applied incrementally over thousands of years, have yielded huge benefits in the characteristics of agricultural animals. This is a result of significant, measurable changes to the genomes of those animal species and breeds. Genome editing techniques may now be applied to achieve targeted DNA sequence alterations, with the potential to affect traits of interest to production of agricultural animals in just one generation. New opportunities arise to improve characteristics difficult to achieve or not amenable to traditional breeding, including disease resistance, and traits that can improve animal welfare, reduce environmental impact, or mitigate impacts of climate change. Countries and supranational institutions are in the process of defining regulatory approaches for genome edited animals and can benefit from sharing approaches and experiences to institute progressive policies in which regulatory oversight is scaled to the particular level of risk involved. To facilitate information sharing and discussion on animal biotechnology, an international community of researchers, developers, breeders, regulators, and communicators recently held a series of seven virtual workshop sessions on applications of biotechnology for animal agriculture, food and environmental safety assessment, regulatory approaches, and market and consumer acceptance. In this report, we summarize the topics presented in the workshop sessions, as well as discussions coming out of the breakout sessions. This is framed within the context of past and recent scientific and regulatory developments. This is a pivotal moment for determination of regulatory approaches and establishment of trust across the innovation through-chain, from researchers, developers, regulators, breeders, farmers through to consumers

Prescribing indicators at primary health care centers within the WHO African region: a systematic analysis (1995-2015)

Abstract Background Rational medicine use is essential to optimize quality of healthcare delivery and resource utilization. We aim to conduct a systematic review of changes in prescribing patterns in the WHO African region and comparison with WHO indicators in two time periods 1995–2005 and 2006–2015. Methods Systematic searches were conducted in PubMed, Scopus, Web of science, Africa-Wide Nipad, Africa Journals Online (AJOL), Google scholar and International Network for Rational Use of Drugs (INRUD) Bibliography databases to identify primary studies reporting prescribing indicators at primary healthcare centres (PHCs) in Africa. This was supplemented by a manual search of retrieved references. We assessed the quality of studies using a 14-point scoring system modified from the Downs and Black checklist with inclusions of recommendations in the WHO guidelines. Results Forty-three studies conducted in 11 African countries were included in the overall analysis. These studies presented prescribing indicators based on a total 141,323 patient encounters across 572 primary care facilities. The results of prescribing indicators were determined as follows; average number of medicines prescribed per patient encounter = 3.1 (IQR 2.3–4.8), percentage of medicines prescribed by generic name =68.0 % (IQR 55.4–80.3), Percentage of encounters with antibiotic prescribed =46.8 % (IQR 33.7–62.8), percentage of encounters with injection prescribed =25.0 % (IQR 18.7–39.5) and the percentage of medicines prescribed from essential medicines list =88.0 % (IQR 76.3–94.1). Prescribing indicators were generally worse in private compared with public facilities. Analysis of prescribing across two time points 1995–2005 and 2006–2015 showed no consistent trends. Conclusions Prescribing indicators for the African region deviate significantly from the WHO reference targets. Increased collaborative efforts are urgently needed to improve medicine prescribing practices in Africa with the aim of enhancing the optimal utilization of scarce resources and averting negative health consequences

Regulamentação da edição genômica em plantas no Brasil e no mundo.

Aborda de forma detalhada as questões regulatórias que envolvem a edição genômica em diferentes no Brasil e em outros países do mundo