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Frontotemporal Dementias in Latin America: History, Epidemiology, Genetics, and Clinical Research
(2021)
Jorge J. Llibre-Guerra
;
BEHRENS PELLEGRINO, MARIA ISABEL
;
Mirna Lie Hosogi
;
Lucia Montero
;
Teresa Torralva
<jats:p><jats:bold>Introduction:</jats:bold> The historical development, frequency, and impact of frontotemporal dementia (FTD) are less clear in Latin America than in high-income countries. Although there is a growing number of dementia studies in Latin America, little is known collectively about FTD prevalence studies by country, clinical heterogeneity, risk factors, and genetics in Latin American countries.</jats:p><jats:p><jats:bold>Methods:</jats:bold> A systematic review was completed, aimed at identifying the frequency, clinical heterogeneity, and genetics studies of FTD in Latin American populations. The search strategies used a combination of standardized terms for FTD and related disorders. In addition, at least one author per Latin American country summarized the available literature. Collaborative or regional studies were reviewed during consensus meetings.</jats:p><jats:p><jats:bold>Results:</jats:bold> The first FTD reports published in Latin America were mostly case reports. The last two decades marked a substantial increase in the number of FTD research in Latin American countries. Brazil (165), Argentina (84), Colombia (26), and Chile (23) are the countries with the larger numbers of FTD published studies. Most of the research has focused on clinical and neuropsychological features (<jats:italic>n</jats:italic> = 247), including the local adaptation of neuropsychological and behavioral assessment batteries. However, there are little to no large studies on prevalence (<jats:italic>n</jats:italic> = 4), biomarkers (<jats:italic>n</jats:italic> = 9), or neuropathology (<jats:italic>n</jats:italic> = 3) of FTD.</jats:p><jats:p><jats:bold>Conclusions:</jats:bold> Future FTD studies will be required in Latin America, albeit with a greater emphasis on clinical diagnosis, genetics, biomarkers, and neuropathological studies. Regional and country-level efforts should seek better estimations of the prevalence, incidence, and economic impact of FTD syndromes.</jats:p>
Scopus© Citations 10 1
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Genomic analysis of the diversity, antimicrobial resistance and virulence potential of clinical Campylobacter jejuni and Campylobacter coli strains from Chile
(2021)
Veronica Bravo
;
Assaf Katz
;
PORTE TORRE, LORENA ISABEL
;
WEITZEL, THOMAS
;
Carmen Varela
<jats:p><jats:italic>Campylobacter jejuni</jats:italic> and <jats:italic>Campylobacter coli</jats:italic> are the leading cause of human gastroenteritis in the industrialized world and an emerging threat in developing countries. The incidence of campylobacteriosis in South America is greatly underestimated, mostly due to the lack of adequate diagnostic methods. Accordingly, there is limited genomic and epidemiological data from this region. In the present study, we performed a genome-wide analysis of the genetic diversity, virulence, and antimicrobial resistance of the largest collection of clinical <jats:italic>C</jats:italic>. <jats:italic>jejuni</jats:italic> and <jats:italic>C</jats:italic>. <jats:italic>coli</jats:italic> strains from Chile available to date (n = 81), collected in 2017–2019 in Santiago, Chile. This culture collection accounts for more than one third of the available genome sequences from South American clinical strains. cgMLST analysis identified high genetic diversity as well as 13 novel STs and alleles in both <jats:italic>C</jats:italic>. <jats:italic>jejuni</jats:italic> and <jats:italic>C</jats:italic>. <jats:italic>coli</jats:italic>. Pangenome and virulome analyses showed a differential distribution of virulence factors, including both plasmid and chromosomally encoded T6SSs and T4SSs. Resistome analysis predicted widespread resistance to fluoroquinolones, but low rates of erythromycin resistance. This study provides valuable genomic and epidemiological data and highlights the need for further genomic epidemiology studies in Chile and other South American countries to better understand molecular epidemiology and antimicrobial resistance of this emerging intestinal pathogen.</jats:p>
Scopus© Citations 23 4
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Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats
(2021)
Andrea Tapia-Bustos
;
Carolyne Lespay-Rebolledo
;
Valentina Vío
;
Ronald Pérez-Lobos
;
Emmanuel Casanova-Ortiz
<jats:p>The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 μL of vehicle (10% plasma) or 5 × 104 MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter.</jats:p>
Scopus© Citations 7 2
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Major Histocompatibility Complex Class I-Related Chain A (MICA) Allelic Variants Associate With Susceptibility and Prognosis of Gastric Cancer
(2021)
Karen Toledo-Stuardo
;
Carolina H. Ribeiro
;
Andrea Canals
;
Marcela Morales
;
Valentina Gárate
<jats:p>Gastric cancer (GC) is the fifth most prevalent type of cancer worldwide. Gastric tumor cells express MICA protein, a ligand to NKG2D receptor that triggers natural killer (NK) cells effector functions for early tumor elimination. <jats:italic>MICA</jats:italic> gene is highly polymorphic, thus originating alleles that encode protein variants with a controversial role in cancer. The main goal of this work was to study <jats:italic>MICA</jats:italic> gene polymorphisms and their relationship with the susceptibility and prognosis of GC. Fifty patients with GC and 50 healthy volunteers were included in this study. MICA alleles were identified using Sanger sequencing methods. The analysis of <jats:italic>MICA</jats:italic> gene sequence revealed 13 MICA sequences and 5 MICA-short tandem repeats (STR) alleles in the studied cohorts We identified MICA<jats:sup>*</jats:sup>002 (<jats:sup>*</jats:sup>A9) as the most frequent allele in both, patients and controls, followed by MICA<jats:sup>*</jats:sup>008 allele (<jats:sup>*</jats:sup>A5.1). MICA<jats:sup>*</jats:sup>009/049 allele was significantly associated with increased risk of GC (OR: 5.11 [95% CI: 1.39–18.74], <jats:italic>p</jats:italic> = 0.014). The analysis of MICA-STR alleles revealed a higher frequency of MICA<jats:sup>*</jats:sup>A5 in healthy individuals than GC patients (OR = 0.34 [95% CI: 0.12–0.98], <jats:italic>p</jats:italic> = 0.046). Survival analysis after gastrectomy showed that patients with MICA<jats:sup>*</jats:sup>002/002 or MICA<jats:sup>*</jats:sup>002/004 alleles had significantly higher survival rates than those patients bearing MICA<jats:sup>*</jats:sup>002/008 (<jats:italic>p</jats:italic> = 0.014) or MICA<jats:sup>*</jats:sup>002/009 (MICA<jats:sup>*</jats:sup>002/049) alleles (<jats:italic>p</jats:italic> = 0.040). The presence of threonine in the position MICA-181 (MICA<jats:sup>*</jats:sup>009/049 allele) was more frequent in GC patients than controls (<jats:italic>p</jats:italic> = 0.023). Molecular analysis of MICA-181 showed that the presence of threonine provides greater mobility to the protein than arginine in the same position (MICA<jats:sup>*</jats:sup>004), which could explain, at least in part, some immune evasion mechanisms developed by the tumor. In conclusion, our findings suggest that the study of MICA alleles is crucial to search for new therapeutic approaches and may be useful for the evaluation of risk and prognosis of GC and personalized therapy.</jats:p>
Scopus© Citations 12 1
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Atovaquone/Proguanil Resistance in an Imported Malaria Case in Chile
(2021)
Stella M. Chenet
;
Alan Oyarce
;
Jorge Fernandez
;
Rafael Tapia-Limonchi
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WEITZEL, THOMAS
<jats:title>ABSTRACT</jats:title><jats:p>In November 2018, we diagnosed a cluster of falciparum malaria cases in three Chilean travelers returning from Nigeria. Two patients were treated with sequential intravenous artesunate plus oral atovaquone/proguanil (AP) and one with oral AP. The third patient, a 23-year-old man, presented with fever on day 29 after oral AP treatment and was diagnosed with recrudescent falciparum malaria. The patient was then treated with oral mefloquine, followed by clinical recovery and resolution of parasitemia. Analysis of day 0 and follow-up blood samples, collected on days 9, 29, 34, 64, and 83, revealed that parasitemia had initially decreased but then increased on day 29. Sequencing confirmed Tyr268Cys mutation in the <jats:italic>cytochrome b</jats:italic> gene, associated with atovaquone resistance, in isolates collected on days 29 and 34 and <jats:italic>P. falciparum dihydrofolate reductase</jats:italic> mutation Asn51Ile, associated with proguanil resistance in all successfully sequenced samples. Molecular characterization of imported malaria contributes to clinical management in non-endemic countries, helps ascertain the appropriateness of antimalarial treatment policies, and contributes to the reporting of drug resistance patterns from endemic regions.</jats:p>
4Scopus© Citations 5
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Systematic Review: Genetic, Neuroimaging, and Fluids Biomarkers for Frontotemporal Dementia Across Latin America Countries
(2021)
Claudia Duran-Aniotz
;
Paulina Orellana
;
Tomas Leon Rodriguez
;
Victoria Cabello
;
Fernando Henriquez
<jats:p>Frontotemporal dementia (FTD) includes a group of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders, affecting the fronto-insular-temporal regions of the brain. Clinically, FTD is characterized by progressive deficits in behavior, executive function, and language and its diagnosis relies mainly on the clinical expertise of the physician/consensus group and the use of neuropsychological tests and/or structural/functional neuroimaging, depending on local availability. The modest correlation between clinical findings and FTD neuropathology makes the diagnosis difficult using clinical criteria and often leads to underdiagnosis or misdiagnosis, primarily due to lack of recognition or awareness of FTD as a disease and symptom overlap with psychiatric disorders. Despite advances in understanding the underlying neuropathology of FTD, accurate and sensitive diagnosis for this disease is still lacking. One of the major challenges is to improve diagnosis in FTD patients as early as possible. In this context, biomarkers have emerged as useful methods to provide and/or complement clinical diagnosis for this complex syndrome, although more evidence is needed to incorporate most of them into clinical practice. However, most biomarker studies have been performed using North American or European populations, with little representation of the Latin American and the Caribbean (LAC) region. In the LAC region, there are additional challenges, particularly the lack of awareness and knowledge about FTD, even in specialists. Also, LAC genetic heritage and cultures are complex, and both likely influence clinical presentations and may modify baseline biomarker levels. Even more, due to diagnostic delay, the clinical presentation might be further complicated by both neurological and psychiatric comorbidity, such as vascular brain damage, substance abuse, mood disorders, among others. This systematic review provides a brief update and an overview of the current knowledge on genetic, neuroimaging, and fluid biomarkers for FTD in LAC countries. Our review highlights the need for extensive research on biomarkers in FTD in LAC to contribute to a more comprehensive understanding of the disease and its associated biomarkers. Dementia research is certainly reduced in the LAC region, highlighting an urgent need for harmonized, innovative, and cross-regional studies with a global perspective across multiple areas of dementia knowledge.</jats:p>
1 2Scopus© Citations 23
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Multisite Detection of Tn
<i>1549</i>
-Mediated
<i>vanB</i>
Vancomycin Resistance in Multidrug-Resistant Enterococcus faecalis ST6 in Texas and Florida
(2023)
Shelby R. Simar
;
Truc T. Tran
;
Kirsten B. Rydell
;
Diana Panesso
;
German A. Contreras
<jats:p> In the United States, <jats:italic>vanB</jats:italic> -mediated resistance in enterococci is rare. We characterized three sequence type (ST) 6, vancomycin-resistant <jats:named-content content-type="genus-species">Enterococcus faecalis</jats:named-content> isolates causing bacteremia in unique patients in spatiotemporally distinct settings. </jats:p>
7 1Scopus© Citations 3
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Genetics of spontaneous cervical and coronary artery dissections
(2023)
Isabel Rada
;
CALDERON GIADROSIC, JUAN FRANCISCO
;
Gonzalo Martínez
;
MUÑOZ VENTURELLI, PAULA ANDREA
<jats:sec><jats:title>Objectives</jats:title><jats:p>Spontaneous cervical artery dissections (SCeAD) and coronary artery dissections (SCoAD) are major causes of neurovascular and cardiovascular morbidity in young adults. Although multiple aspects of their etiology are still unknown, most consensuses are focused on the presence of constitutional genetic aspects and environmental triggers. Since recent evidence of genetic contribution points to a possible overlap between these conditions, we aimed to describe current information on SCeAD and SCoAD genetics and their potential shared pathological aspects.</jats:p></jats:sec><jats:sec><jats:title>Materials and methods</jats:title><jats:p>A narrative review is presented. Publications in English and Spanish were queried using database search. The articles were evaluated by one team member in terms of inclusion criteria. After collecting, the articles were categorized based on scientific content.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Given that patients with SCeAD and SCoAD rarely present connective tissue disorders, other genetic loci are probably responsible for the increased susceptibility in some individuals. The common variant rs9349379 at <jats:italic>PHACTR1</jats:italic> gene is associated with predisposition to pathologies of the arterial wall, likely mediated by variations in Endothelin-1 (ET-1) levels. The risk of arterial dissection may be increased for those who carry the rs9349379(A) allele, associated with lower expression levels of ET-1; however, the local effect of this vasomotor imbalance remains unclear. Sex differences seen in SCeAD and SCoAD support a role for sex hormones that could modulate risk, tilting the delicate balance and forcing vasodilator actions to prevail over vasoconstriction due to a reduction in ET-1 expression.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>New evidence points to a common gene variation that could explain dissection in both the cervical and coronary vasculatures. To further confirm the risk conferred by the rs9349379 variant, genome wide association studies are warranted, hopefully in larger and ethnically diverse populations.</jats:p></jats:sec>
14Scopus© Citations 4
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Eco-epidemiology of rodent-associated trombiculid mites and infection with Orientia spp. in Southern Chile
(2023)
María Carolina Silva de la Fuente
;
Caricia Pérez
;
Constanza Martínez-Valdebenito
;
Pérez Ball, Ruth
;
VIAL COX, MARIA CECILIA
<jats:sec id="sec001"> <jats:title>Background</jats:title> <jats:p>Scrub typhus is a potentially severe infection caused by bacteria of the genus <jats:italic>Orientia</jats:italic>, endemic in Asia-Pacific and recently discovered in southern Chile. The presented study aimed to determine the prevalence and species richness of rodent-associated trombiculid mites and their infection with <jats:italic>Orientia</jats:italic> spp. in different areas of two regions in southern Chile.</jats:p> </jats:sec> <jats:sec id="sec002"> <jats:title>Methodology/Principal findings</jats:title> <jats:p>During summer 2020, trombiculid mites were collected from rodents captured in three areas in southern Chile known to be endemic for scrub typhus (Cochamó and Chiloé Island in the Los Lagos Region and Tortel in the Aysén Region). A total of 132 rodents belonging to five species were captured using Sherman-like traps; 89.4% were infested with trombiculids. Mite specimens were morphologically identified and subsequently tested by <jats:italic>Orientia</jats:italic>-specific qPCR. Six mite species were identified. Among chigger-infested rodents, 33.9% carried <jats:italic>Orientia</jats:italic>-positive mites; this rate was higher in Tortel (63.8%) than in Cochamó (45.0%) and Chiloé Island (2.0%). The analysis of individual mites (n = 901) revealed that 31.2% of <jats:italic>Herpetacarus antarctica</jats:italic> samples (n = 202) were positive for <jats:italic>Orientia</jats:italic> DNA; the prevalence was 7.0% in <jats:italic>Paratrombicula neuquenensis</jats:italic> (n = 213), 6.9% in <jats:italic>Herpetacarus eloisae</jats:italic> (n = 144), 3.6% in <jats:italic>Argentinacarus expansus</jats:italic> (n = 55), and 0% in <jats:italic>Paratrombicula goffi</jats:italic> (n = 110) and <jats:italic>Quadraseta chiloensis</jats:italic> (n = 177). The southernmost site (Tortel) showed the highest rates of trombiculid infestation, trombiculid load, and <jats:italic>Orientia</jats:italic> infection in the captured rodents.</jats:p> </jats:sec> <jats:sec id="sec003"> <jats:title>Conclusions/Significance</jats:title> <jats:p>Our study provides new insights into the trombiculid fauna and prevalence of <jats:italic>Orientia</jats:italic> in mites collected from wild rodents in southern Chile. <jats:italic>Orientia</jats:italic> DNA was detected in four of the six mite species. Rates of infestation, mite loads, and <jats:italic>Orientia</jats:italic> prevalences differed geographically and were highest in the Aysén Region. Our data improve our knowledge on possible vectors of scrub typhus and their distribution in Chile.</jats:p> </jats:sec>
1Scopus© Citations 9 2
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Delineation of functionally essential protein regions for 242 neurodevelopmental genes
(2022)
Sumaiya Iqbal
;
Tobias Brünger
;
PEREZ PALMA, EDUARDO ESTEBAN
;
Marie Macnee
;
Andreas Brunklaus
<jats:title>Abstract</jats:title> <jats:p>Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘variants of uncertain significance’. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants.</jats:p> <jats:p>We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including &gt;360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients.</jats:p> <jats:p>In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.</jats:p>
1Scopus© Citations 6 1

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