Background: Global brain health initiatives call for improving methods for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD) in underrepresented populations. However, ...diagnostic procedures in upper-middle-income countries (UMICs) and lower-middle income countries (LMICs), such as Latin American countries (LAC), face multiple challenges. These include the heterogeneity in diagnostic methods, lack of clinical harmonisation, and limited access to biomarkers. Methods: This cross-sectional observational study aimed to identify the best combination of predictors to discriminate between AD and FTD using demographic, clinical and cognitive data among 1794 participants 904 diagnosed with AD, 282 diagnosed with FTD, and 606 healthy controls (HCs) collected in 11 clinical centres across five LAC (ReDLat cohort). Findings: A fully automated computational approach included classical statistical methods, support vector machine procedures, and machine learning techniques (random forest and sequential feature selection procedures). Results demonstrated an accurate classification of patients with AD and FTD and HCs. A machine learning model produced the best values to differentiate AD from FTD patients with an accuracy = 0.91. The top features included social cognition, neuropsychiatric symptoms, executive functioning performance, and cognitive screening; with secondary contributions from age, educational attainment, and sex. Interpretation: Results demonstrate that data-driven techniques applied in archival clinical datasets could enhance diagnostic procedures in regions with limited resources. These results also suggest specific fine-grained cognitive and behavioural measures may aid in the diagnosis of AD and FTD in LAC. Moreover, our results highlight an opportunity for harmonisation of clinical tools for dementia diagnosis in the region. Funding: This work was supported by the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat), funded by NIA/NIH (R01AG057234), Alzheimer's Association (SG-20-725707-ReDLat), Rainwater Foundation, Takeda (CW2680521), Global Brain Health Institute; as well as CONICET; FONCYT-PICT (2017-1818, 2017-1820); PIIECC, Facultad de Humanidades, Usach; Sistema General de Regalías de Colombia (BPIN2018000100059), Universidad del Valle (CI 5316); ANID/FONDECYT Regular (1210195, 1210176, 1210176); ANID/FONDAP (15150012); ANID/PIA/ANILLOS ACT210096; and Alzheimer's Association GBHI ALZ UK-22-865742.
The tryptophan metabolite, quinolinic acid (QUIN), and the mitochondrial toxin 3-nitropropionic acid (3-NP) are two important tools for toxicological research commonly used in neurotoxic models of ...excitotoxicity, oxidative stress, energy depletion, and neuronal cell death in mammals. However, their toxic properties have yet to be explored in the nematode
Caenorhabditis elegans
(
C. elegans
) for the establishment of novel, simpler, complementary, alternative, and predictive neurotoxic model of mammalian neurotoxicity. In this work, the effects of QUIN (1–100 mM) and 3-NP (1–10 mM) were evaluated on various physiological parameters (survival, locomotion, and longevity) in a wild-type (WT) strand of
C. elegans
(N2). Their effects were also tested in the VC1772 strain (knock out for the antioxidant SKN-1 pathway) and the VP596 strain (worms with a reporter gene for glutathione S-transferase (GST) transcription) in order to establish the role of the SKN-1 pathway in the mode of action of QUIN and 3-NP. In N2, the higher doses of both toxins decreased survival, though only QUIN altered motor activity. Both toxins also reduced longevity in the VC1772 strain (as compared to N2 strain) and augmented GST transcription in the VP596 strain at the highest doses. The changes induced by both toxins require high doses, and therefore appear moderate when compared with other toxic agents. Nevertheless, the alterations produced by QUIN and 3-NP in
C. elegans
are relevant to mammalian neurotoxicity as they provide novel mechanistic approaches to the assessment of neurotoxic events comprising oxidative stress and excitotoxicity, in the nematode model.
INTRODUCTION
Mass spectrometry (MS) is a potentially useful tool for the study of the hemostasic system and its imbalances that lead to bleeding and thrombotic disorders. By harnessing the high ...throughput and broad scope of MS, vast data may be available to investigators and clinicians to help predict or manage hemostatic events. Although utilizing MS to evaluate coagulation proteins appears promising, amino acid (AA) substitutions resulting from genetic variation may yield a spectrum of mass-to-charge ratios (m/z) that can impede accurate protein identification. The goals of this study were to describe 1) the proteins present in a blood sample that might be involved in or otherwise affect coagulation, 2) the realm of variations that might occur with a single nucleotide substitution (SNS) in the reference coding sequences of these proteins, and 3) the variation of peptide fragments of these proteins when only one of the nucleotides is a variant.
METHODS
We obtained protein lists from the NCBI BioSystems database for the terms: Blood Clotting Cascade, Complement Cascade, Formation of Fibrin Clot, Hemostasis, Platelet Activation, Platelet Aggregation Plug Formation, Platelet Degranulation, Platelet Homeostasis, and Thrombin Signaling (e.g., http://www.ncbi.nlm.nih.gov/biosystems/198840). We linked the Symbol (gene) to the CCDS ID (consensus coding sequence, http://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi ). For each nucleotide, we enumerated the effect of a SNS relative to the other three nucleotides. We then generated every peptide of length 5-20, determined the change in mass based on the average, as opposed to the monoisotopic, mass of the substituted AA, and assessed whether the peptide was unique among those in the system. Finally, we determined whether possible N-linked glycosylation sites were preserved, destroyed, or created by SNS. We considered a putative site N^PS|T, that is N in position 1, not P in position 2, and either a S or T in position 3.
RESULTS
The proteins in the biosystems that were also in the CCDS database comprised 517 distinct Symbols and 951 distinct CCDS ID’s, comprising 2,180,352 codons. The duplicate Symbols include transcript variants, for instance, the Symbol F8 linked to CCDS ID’s 35457.1 and 44026.1, thereby diminishing the uniqueness of the peptides (transcript variants share some, if not most, of the reading frames). All of the codons were susceptible to an AA substitution; at least one variant nucleotide substation in position 1 or 2 of the codon always resulted in an AA substitution. SNS caused premature termination signals (stop codons) in 240,100 of these codons. Table 1 details the variations. A map of the N-glycosylation sites is available for each protein, although this may not affect MS directly. Of the 83,510 potential N-Linked Glycosylation sites, a SNS disrupted the putative AA sequence in 53,067 (64%). A SNS created a novel potential N-Linked Glycosylation site at 52,787 loci.
Table 1Wild-type OnlyWild-type and VariantsPeptide LengthPeptidesDistinct PeptidesPeptidesDistinct PeptidesRelative Change in Mass5722,174292,48524,470,5672,464,8730.05225010717,564350,57047,911,53520,982,6410.02596815712,954355,44671,052,56231,777,1530.01727320708,344357,17793,893,42342,465,3770.012939
CONCLUSIONS
Variant peptides due to a single SNS per peptide greatly outnumber wild-type peptides. The ability to identify a protein based on uniqueness of one of its peptides increases as the peptide size increases, but AA variations in those peptides that arise from one SNS will require 1) increased mass resolution and 2) both a search algorithm and database that accounts for the possible variations. Patients with hemostatic or thrombotic disorders may be more likely to have a variant, and these results highlight the need to know the genetic sequence associated with proteins being analyzes by MS if this technology is to be adopted for research and clinical purposes. The inclusion of currently identified SNPs and the effect of INDELs that preserve the reading frame is ongoing.
No relevant conflicts of interest to declare.
Base de datos de abejas ibéricas Bartomeus, Ignasi; Lanuza, Jose B.; Wood, Thomas J. ...
Ecosistemas revista científica y técnica de ecología y medio ambiente,
10/2022
Journal Article
Recenzirano
Odprti dostop
Las abejas son un grupo extremadamente diverso con más de 1000 especies descritas en la península ibérica. Además, son excelentes polinizadores y aportan numerosos servicios ecosistémicos ...fundamentales para la mayoría de ecosistemas terrestres. Debido a los diversos cambios ambientales inducidos por el ser humano, existen evidencias del declive de algunas de sus poblaciones para ciertas especies. Sin embargo, conocemos muy poco del estado de conservación de la mayoría de especies y de muchas de ellas ignoramos cuál es su distribución en la península ibérica. En este trabajo presentamos un esfuerzo colaborativo para crear una base de datos de ocurrencias de abejas que abarca la península ibérica e islas Baleares que permitirá resolver cuestiones como la distribución de las diferentes especies, preferencia de hábitat, fenología o tendencias históricas. En su versión actual, esta base de datos contiene un total de 87 684 registros de 923 especies recolectados entre 1830 y 2022, de los cuales un 87% presentan información georreferenciada. Para cada registro se incluye información relativa a la localidad de muestreo (89%), identificador y colector de la especie (64%), fecha de captura (54%) y planta donde se recolectó (20%). Creemos que esta base de datos es el punto de partida para conocer y conservar mejor la biodiversidad de abejas en la península ibérica e Islas Baleares. Se puede acceder a estos datos a través del siguiente enlace permanente: https://doi.org/10.5281/zenodo.6354502
The difficulty in diagnosis and the spectrum of clinical manifestations that can determine the choice of treatment for primary antiphospholipid syndrome (APS) has fostered the development of ...recommendations by the Spanish Society of Rheumatology (SER), based on the best possible evidence. These recommendations can serve as a reference for rheumatologists and other specialists involved in the management of APS.
A panel of four rheumatologists, a gynaecologist and a haematologist with expertise in APS was created, previously selected by the SER through an open call or based on professional merits. The stages of the work were: identification of the key areas for drafting the document, analysis and synthesis of the scientific evidence (using the Scottish Intercollegiate Guidelines Network SIGN levels of evidence) and formulation of recommendations based on this evidence and formal assessment or reasoned judgement techniques (consensus techniques).
46 recommendations were drawn up, addressing five main areas: diagnosis and evaluation, measurement of primary thromboprophylaxis, treatment for APS or secondary thromboprophylaxis, treatment for obstetric APS and special situations. These recommendations also include the role of novel oral anticoagulants, the problem of recurrences or the key risk factors identified in these subjects. This document reflects the first 21, referring to the areas of: diagnosis, evaluation and treatment of primary APS. The document provides a table of recommendations and treatment algorithms.
An update of the SER recommendations on APS is presented. This document corresponds to part I, related to diagnosis, evaluation and treatment. These recommendations are considered tools for decision-making for clinicians, taking into consideration both the decision of the physician experienced in APS and the patient. A part II has also been prepared, which addresses aspects related to obstetric SAF and special situations.
La dificultad para el diagnóstico y la variedad de manifestaciones clínicas que pueden determinar la elección del tratamiento del síndrome antifosfolípido (SAF) primario ha impulsado a la Sociedad Española de Reumatología (SER) en la elaboración de recomendaciones basadas en la mejor evidencia posible. Estas recomendaciones pueden servir de referencia para reumatólogos y otros profesionales implicados en el manejo de pacientes con SAF.
Se creó un panel formado por cuatro reumatólogos, una ginecóloga y una hematóloga, expertos en SAF, previamente seleccionados mediante una convocatoria abierta o por méritos profesionales. Las fases del trabajo fueron: identificación de las áreas claves para la elaboración del documento, análisis y síntesis de la evidencia científica (utilizando los niveles de evidencia del Scottish Intercollegiate Guidelines Network SIGN) y formulación de recomendaciones a partir de esta evidencia y de técnicas de «evaluación formal» o «juicio razonado».
Se han elaborado 46 recomendaciones que abordan cinco áreas principales: diagnóstico y evaluación, medidas de tromboprofilaxis primaria, tratamiento del SAF primario o tromboprofilaxis secundaria, tratamiento del SAF obstétrico y situaciones especiales. Se incluye también el papel de los nuevos anticoagulantes orales, el problema de las recurrencias o los principales factores de riesgo identificados en estos individuos. En este documento se reflejan las 21 primeras recomendaciones, referidas a las áreas de diagnóstico, evaluación y tratamiento del SAF primario. El documento contiene una tabla de recomendaciones y algoritmos de tratamiento.
Se presentan las recomendaciones de la SER sobre SAF primario. Este documento corresponde a la parte I, relacionada con el diagnóstico, la evaluación y el tratamiento. Estas recomendaciones se consideran herramientas en la toma de decisiones para los clínicos, teniendo en consideración tanto la decisión del médico experto en SAF como la opinión compartida con el paciente. Se ha elaborado también una parte II, que aborda aspectos relacionados con el SAF obstétrico y situaciones especiales.
Dementia is becoming increasingly prevalent in Latin America, contrasting with stable or declining rates in North America and Europe. This scenario places unprecedented clinical, social, and economic ...burden upon patients, families, and health systems. The challenges prove particularly pressing for conditions with highly specific diagnostic and management demands, such as frontotemporal dementia. Here we introduce a research and networking initiative designed to tackle these ensuing hurdles, the Multi-partner consortium to expand dementia research in Latin America (ReDLat). First, we present ReDLat's regional research framework, aimed at identifying the unique genetic, social, and economic factors driving the presentation of frontotemporal dementia and Alzheimer's disease in Latin America relative to the US. We describe ongoing ReDLat studies in various fields and ongoing research extensions. Then, we introduce actions coordinated by ReDLat and the Latin America and Caribbean Consortium on Dementia (LAC-CD) to develop culturally appropriate diagnostic tools, regional visibility and capacity building, diplomatic coordination in local priority areas, and a knowledge-to-action framework toward a regional action plan. Together, these research and networking initiatives will help to establish strong cross-national bonds, support the implementation of regional dementia plans, enhance health systems' infrastructure, and increase translational research collaborations across the continent.
To assess the value of the second trimester mean pulsatility index of the uterine arteries (MPI-UtA) to predict adverse perinatal outcome (APO) in women with systemic lupus erythematosus (SLE) and/or ...antiphospholipid syndrome (APS).
Pregnancies with either an SLE diagnosis or with primary APS controlled at our Hospital during a 10 years period were included. MPI-UtA was performed between 19-23 weeks' gestation. The MPI-UtA was defined as abnormal when it was >95
th
centile. APO was defined as the presence of: preeclampsia (PE), small for gestational age (SGA) newborn, preterm delivery, placental abruption and fetal or neonatal death.
There were 39 ongoing pregnancies, 16 of them with SLE and 23 with primary APS. Nine patients had no previous pregnancy (23%). Globally, 35 live births were recorded, being the mean gestational age at delivery 38.1 ± 2.1 weeks and the mean birth weight 2835 ± 492 g. Abnormal MPI-UtA was found in 6 (15%) pregnancies, all of them (100%) had an APO: there were 4 fetal deaths and 2 further severe PE with live newborn. Normal MPI-UtA was shown in the remaining 33 (84.6%); of them, 6 (18%) had an APO: one late PE with a premature newborn, another one severe preterm baby and 4 SGA term newborns. No cases of perinatal death occurred in this group. Therefore, accuracy of MPI-UtA evaluation for APO was: sensitivity 50%, specificity 100%, PPV 100% and NPV 82%, respectively (p < .001).
Abnormal second-trimester uterine artery Doppler evaluation is highly predictive for adverse perinatal outcome in pregnancies affected by SLE or APS.
Objective
Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the ...extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained.
Methods
A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty‐four clinical and serologic variables were used for clustering.
Results
Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement.
Conclusion
Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis.
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