History of International Aid

The following interactive discussion questions are based on a fictional animated storyline developed from Chapter 2 of the third edition of An Introduction to Global Health by Michael Seear and Obidimma Ezezika. The storyline and questions are intended to provide students with the opportunity to understand trends that shaped the modern aid industry, the origins of foreign aid institutions and organizations, and the history that led to current large-scale foreign aid initiatives. There are questions for each of the five modules of the storyline as well as general reflection questions at the end. To answer the questions associated with the storyline, students will be required to explore external resources linked with the questions and integrate the acquired information with that available in the storyline. In some instances, students may also need to conduct independent research to learn more about a concept or topic to answer the questions adequately. Before watching the video, students are encouraged to read Chapter 2 of An Introduction to Global Health, 3rd edition

An Introduction to the Sustainable Developmental Goals through the lens of Dewroze

The following interactive discussion questions are based on a fictional animated storyline by Chapter 1 of the third edition of An Introduction to Global Health. The animated storyline and questions are intended to provide students with the opportunity to understand global health, the Sustainable Development Goals (SDGs), and barriers related to the social determinants of health, in the context of a developing country. Students will be introduced to the fictional village of Dewroze where they will learn how poverty shapes vulnerabilities that lead to health inequities. In this village, students will meet Ada, Ada’s father, Ada’s mother who is pregnant, Zaineb, and some of the health challenges they face

An Introduction to the Sustainable Developmental Goals through the lens of Dewroze

The following interactive discussion questions are based on a fictional animated storyline by Chapter 1 of the third edition of An Introduction to Global Health. The animated storyline and questions are intended to provide students with the opportunity to understand global health, the Sustainable Development Goals (SDGs), and barriers related to the social determinants of health, in the context of a developing country. Students will be introduced to the fictional village of Dewroze where they will learn how poverty shapes vulnerabilities that lead to health inequities. In this village, students will meet Ada, Ada’s father, Ada’s mother who is pregnant, Zaineb, and some of the health challenges they face. There are questions for each of the five modules of the storyline as well as general reflection questions at the end. To answer the questions associated with the animated storyline, students will be required to explore external resources linked in the questions and integrate the acquired information with that available in the storyline. In some instances, students may also need to conduct independent research to learn more about a concept or topic to answer the questions adequately. Before watching the video, students are encouraged to read Chapter 1 of An Introduction to Global Health, 3rd edition

Mutation analysis in South American patients with Mucopolysaccharidosis type I

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder due to the deficiency of-L-iduronidase (IDUA). Severely affected patients show coarse faces, hepatosplenomegaly and mental retardation. Mild cases have facial features, joint stiffness, short stature but no CNS involvement. The gene encoding IDUA was cloned in 1990 and more than 55 disease-causing mutations have been described so far. Mutation frequency varies worldwide but W402X is the most frequent mutation found in European patients. A group of 56 MPS I patients, 25 from Argentina and 31 from Brazil, were genotyped. By analyzing ten recurrent mutations we were able to define 76% of the Argentinean alleles and 60% of the genotypes. For the Brazilian group, 62% of the alleles and 45% of the genotypes were assigned by the analysis of these same ten mutations. Sequencing of Brazilian patients led to the discovery of 13 new mutations and 4 new ones were found in Argentineans. The two most frequent mutations in both populations were W402X and P533R. The number of alleles bearing private mutations in Argentinean patients was 3 out of 50 and among the Brazilians, 16 out of 58. Such genetic heterogeneity is a concern when analyzing patients from miscigenated populations, such as South American countries.Asociación de Antropología Biológica de la República Argentin

Neuraminidase 1 Is a Negative Regulator of Lysosomal Exocytosis

SummaryLysosomal exocytosis is a Ca2+-regulated mechanism that involves proteins responsible for cytoskeletal attachment and fusion of lysosomes with the plasma membrane. However, whether luminal lysosomal enzymes contribute to this process remains unknown. Here we show that neuraminidase NEU1 negatively regulates lysosomal exocytosis in hematopoietic cells by processing the sialic acids on the lysosomal membrane protein LAMP-1. In macrophages from NEU1-deficient mice, a model of the disease sialidosis, and in patients' fibroblasts, oversialylated LAMP-1 enhances lysosomal exocytosis. Silencing of LAMP-1 reverts this phenotype by interfering with the docking of lysosomes at the plasma membrane. In neu1−/− mice the excessive exocytosis of serine proteases in the bone niche leads to inactivation of extracellular serpins, premature degradation of VCAM-1, and loss of bone marrow retention. Our findings uncover an unexpected mechanism influencing lysosomal exocytosis and argue that exacerbations of this process form the basis for certain genetic diseases

Characterization of glycan substrates accumulating in GM1 Gangliosidosis

Introduction: GM1 gangliosidosis is a rare autosomal recessive genetic disorder caused by the disruption of the GLB1 gene that encodes β-galactosidase, a lysosomal hydrolase that removes β-linked galactose from the non-reducing end of glycans. Deficiency of this catabolic enzyme leads to the lysosomal accumulation of GM1 and its asialo derivative GA1 in β-galactosidase deficient patients and animal models. In addition to GM1 and GA1, there are other glycoconjugates that contain β-linked galactose whose metabolites are substrates for β-galactosidase. For example, a number of N-linked glycan structures that have galactose at their non-reducing end have been shown to accumulate in GM1 gangliosidosis patient tissues and biological fluids. Objective: In this study, we attempt to fully characterize the broad array of GLB1 substrates that require GLB1 for their lysosomal turnover. Results: Using tandem mass spectrometry and glycan reductive isotope labeling with data-dependent mass spectrometry, we have confirmed the accumulation of glycolipids (GM1 and GA1) and N-linked glycans with terminal beta-linked galactose. We have also discovered a novel set of core 1 and 2 O-linked glycan metabolites, many of which are part of structurally-related isobaric series that accumulate in disease. In the brain of GLB1 null mice, the levels of these glycan metabolites increased along with those of both GM1 and GA1 as a function of age. In addition to brain tissue, we found elevated levels of both N-linked and O-linked glycan metabolites in a number of peripheral tissues and in urine. Both brain and urine samples from human GM1 gangliosidosis patients exhibited large increases in steady state levels for the same glycan metabolites, demonstrating their correlation with this disease in humans as well. Conclusions: Our studies illustrate that GLB1 deficiency is not purely a ganglioside accumulation disorder, but instead a broad oligosaccharidosis that include representatives of many β-linked galactose containing glycans and glycoconjugates including glycolipids, N-linked glycans, and various O-linked glycans. Accounting for all β-galactosidase substrates that accumulate when this enzyme is deficient increases our understanding of this severe disorder by identifying metabolites that may drive certain aspects of the disease and may also serve as informative disease biomarkers to fully evaluate the efficacy of future therapies

Mutation analysis in South American patients with Mucopolysaccharidosis type I

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder due to the deficiency of-L-iduronidase (IDUA). Severely affected patients show coarse faces, hepatosplenomegaly and mental retardation. Mild cases have facial features, joint stiffness, short stature but no CNS involvement. The gene encoding IDUA was cloned in 1990 and more than 55 disease-causing mutations have been described so far. Mutation frequency varies worldwide but W402X is the most frequent mutation found in European patients. A group of 56 MPS I patients, 25 from Argentina and 31 from Brazil, were genotyped. By analyzing ten recurrent mutations we were able to define 76% of the Argentinean alleles and 60% of the genotypes. For the Brazilian group, 62% of the alleles and 45% of the genotypes were assigned by the analysis of these same ten mutations. Sequencing of Brazilian patients led to the discovery of 13 new mutations and 4 new ones were found in Argentineans. The two most frequent mutations in both populations were W402X and P533R. The number of alleles bearing private mutations in Argentinean patients was 3 out of 50 and among the Brazilians, 16 out of 58. Such genetic heterogeneity is a concern when analyzing patients from miscigenated populations, such as South American countries.Asociación de Antropología Biológica de la República Argentin

Partial Restoration of Mutant Enzyme Homeostasis in Three Distinct Lysosomal Storage Disease Cell Lines by Altering Calcium Homeostasis

A lysosomal storage disease (LSD) results from deficient lysosomal enzyme activity, thus the substrate of the mutant enzyme accumulates in the lysosome, leading to pathology. In many but not all LSDs, the clinically most important mutations compromise the cellular folding of the enzyme, subjecting it to endoplasmic reticulum–associated degradation instead of proper folding and lysosomal trafficking. A small molecule that restores partial mutant enzyme folding, trafficking, and activity would be highly desirable, particularly if one molecule could ameliorate multiple distinct LSDs by virtue of its mechanism of action. Inhibition of L-type Ca2+ channels, using either diltiazem or verapamil—both US Food and Drug Administration–approved hypertension drugs—partially restores N370S and L444P glucocerebrosidase homeostasis in Gaucher patient–derived fibroblasts; the latter mutation is associated with refractory neuropathic disease. Diltiazem structure-activity studies suggest that it is its Ca2+ channel blocker activity that enhances the capacity of the endoplasmic reticulum to fold misfolding-prone proteins, likely by modest up-regulation of a subset of molecular chaperones, including BiP and Hsp40. Importantly, diltiazem and verapamil also partially restore mutant enzyme homeostasis in two other distinct LSDs involving enzymes essential for glycoprotein and heparan sulfate degradation, namely α-mannosidosis and type IIIA mucopolysaccharidosis, respectively. Manipulation of calcium homeostasis may represent a general strategy to restore protein homeostasis in multiple LSDs. However, further efforts are required to demonstrate clinical utility and safety

Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype

Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetyl-α-D-glucosaminidase (NAGLU). Information on the natural course of MPS IIIB is scarce but much needed in view of emerging therapies. To improve knowledge on the natural course, data on all 52 MPS IIIB patients ever identified by enzymatic studies in the Netherlands were gathered. Clinical data on 44 patients could be retrieved. Only a small number (n = 9; 21%) presented with a classical MPS III phenotype; all other patients showed a much more attenuated course of the disease characterized by a significantly slower regression of intellectual and motor abilities. The majority of patients lived well into adulthood. First signs of the disease, usually mild developmental delay, were observed at a median age of 4 years. Subsequently, patients showed a slowing and eventually a stagnation of development. Patients with the attenuated phenotype had a stable intellectual disability for many years. Molecular analysis was performed in 24 index patients. The missense changes p.R643C, p.S612G, p.E634K, and p.L497V were exclusively found in patients with the attenuated phenotype. MPS IIIB comprises a remarkably wide spectrum of disease severity, and an unselected cohort including all Dutch patients showed a large proportion (79%) with an attenuated phenotype. MPS IIIB must be considered in patients with a developmental delay, even in the absence of a progressive decline in intellectual abilities. A key feature, necessitating metabolic studies, is the coexistence of behavioral problems