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Brain : a Journal of Neurology Sep 2023Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid...
Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.
Topics: Child; Humans; Young Adult; Anoctamin-1; Chloride Channels; Moyamoya Disease; Neoplasm Proteins
PubMed: 37253099
DOI: 10.1093/brain/awad172 -
Annals of Emergency Medicine Oct 2023We examined the diagnostic performance of a recalibrated History, Electrocardiogram, Age, Risk factors, Troponin (HEART), and Thrombolysis in Myocardial Infarction...
STUDY OBJECTIVE
We examined the diagnostic performance of a recalibrated History, Electrocardiogram, Age, Risk factors, Troponin (HEART), and Thrombolysis in Myocardial Infarction (TIMI) score in patients with suspected acute cardiac syndrome (ACS). Recalibration of troponin thresholds was performed, including shifting from the 99th percentile to the limit of detection (LOD) or to the limit of quantification (LOQ) We compared the discharge potential and safety of the recalibrated composite scores using a single presentation high-sensitivity cardiac troponin (hs-cTn) T to the conventional scores and with a LOD/LOQ troponin strategy alone.
METHODS
We undertook a 2-center prospective cohort study in the United Kingdom (UK) (2018) (Clinicaltrials.gov NCT03619733) to specifically assess recalibrated risk scores (shifting the troponin subset scoring from 99th percentile to LOD [UK]) and combined the results of this with secondary analyses of 2 prospective cohort studies in the UK (2011) and the United States (2018, using LOQ rather than LOD). The primary outcome was major adverse cardiovascular events (MACE), defined as adjudicated type 1 myocardial infarction (MI), urgent coronary revascularization, and all-cause death, at 30 days. We evaluated the original scores using hs-cTn below the 99th percentile and recalibrated scores using hs-cTn <LOD/LOQ and compared these composite scores with a single hs-cTnT less than LOD/LOQ combined with a nonischemic ECG. For each discharge strategy, an assessment of clinical effectiveness was also made, defined as the proportion of patients eligible for discharge from the emergency department without the need for further inpatient testing.
RESULTS
We studied 3,752 patients (3,003 in the UK and 749 in the United States). Median age was 58 years, and 48% were female. At 30 days, 330/3,752 (8.8%) experienced MACE. The sensitivities of the original HEART less or equal to 3 and recalibrated HEART less or equal to 3 scores for rule-out were 96.1% (95% confidence interval [CI], 93.4 to 97.9) and 98.6% (95% CI, 96.5 to 99.5) respectively; the original TIMI less or equal to 1 and recalibrated TIMI less or equal to 1 scores' sensitivities were 79.7% (95% CI, 74.9 to 83.9) and 96.1% (95% CI, 93.4 to 97.9) respectively; and nonischemic ECG with hs-cTn T below the 99th percentile and hs-cTn T less than LOD/LOQ was 79.7% (95%CI, 0.749 to 0.839) and 99.1% (95% CI, 0.974 to 0.998), respectively. Recalibrated HEART less or equal to 3 was projected to discharge 14% more patients than hs-cTn T less than LOD/LOQ. The improved sensitivity of rule-out for recalibrated HEART less than or equal to 3 came at the cost of reduced specificity (50.8% versus 53.8% for recalibrated HEART and conventional HEART respectively).
CONCLUSION
This study indicates that recalibrated HEART score of less or equal to 3 is a feasible and safe early discharge strategy using a single presentation hs-cTnT. This finding should be further tested using competitor hs-cTn assays in independent prospective cohorts before implementation.
Topics: Humans; Female; Middle Aged; Male; Troponin T; Prospective Studies; Troponin; Myocardial Infarction; Acute Coronary Syndrome; Biomarkers; Emergency Service, Hospital
PubMed: 37306637
DOI: 10.1016/j.annemergmed.2023.04.024 -
Brain Sciences Feb 2022(1) Background: Odor identification (OI) dysfunction is a potential predictor of developing dementia in late life depression (LLD). However, it is not clear whether...
(1) Background: Odor identification (OI) dysfunction is a potential predictor of developing dementia in late life depression (LLD). However, it is not clear whether patients with early onset depression (EOD) and late onset depression (LOD) may exhibit different OI dysfunctions. The aim of this study was to compare OI between EOD patients and LOD patients and its relationship with cognitive function. (2) Methods: A total of 179 patients with LLD and 189 normal controls were recruited. Participants underwent clinical assessment, olfactory testing, and comprehensive neuropsychological assessment. The OI scores of EOD patients and LOD patients were compared, and correlation analyses and mediation analyses were used to explore the relationship between OI and cognition. (3) Result: LOD patients exhibited lower OI scores than EOD patients and normal controls (NCs). Additionally, the LOD patients exhibited a higher percentage of OI dysfunction than the EOD patients. Moreover, OI scores were associated with global cognition, memory, language, and visuospatial ability in the EOD group ( < 0.05) but were not associated with any cognitive score in the LOD patients ( > 0.05). Finally, the scores of the Auditory Verbal Learning Test Immediate recall and Boston Naming Test exhibited a partially mediating effect on the difference in OI scores between the EOD and LOD patients. (4) Conclusions: LOD patients exhibited worse OI than EOD patients, and their difference in OI was mediated by their memory and language function.
PubMed: 35204039
DOI: 10.3390/brainsci12020276 -
American Journal of Human Genetics Jun 2020Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the...
Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5' UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Asian People; Chromosomes, Human, Pair 19; DNA Methylation; Female; Humans; Lod Score; Male; Muscle, Skeletal; Muscular Dystrophies; Pedigree; RNA-Seq; Trinucleotide Repeat Expansion; Tumor Suppressor Protein p53; Young Adult
PubMed: 32413282
DOI: 10.1016/j.ajhg.2020.04.011 -
Journal of Alzheimer's Disease : JAD 2021There is a lack of research investigating whether there are differences in the domains of awareness according to the age at onset of dementia.
BACKGROUND
There is a lack of research investigating whether there are differences in the domains of awareness according to the age at onset of dementia.
OBJECTIVE
This study is designed to investigate differences in awareness of cognitive functioning and health condition, functional activity impairments, emotional state, and social functioning and relationships among people with young onset (YOD) and late onset dementia (LOD); and examine associations between awareness and its domains with cognition, functionality, neuropsychiatric symptoms, social and emotional functioning, and quality of life (QoL) in both groups.
METHODS
A group of 136 people with dementia and their respective caregivers (YOD = 50 and LOD = 86) were consecutively selected. We assessed awareness of disease, dementia severity, cognition, functionality, neuropsychiatric symptoms, social and emotional functioning, and QoL.
RESULTS
People with YOD had more neuropsychiatric symptoms than people with LOD. People with YOD were more aware of disease (total score), of their cognitive functioning and health condition and of their functional activity impairments, even if this group was more severely cognitive impaired and had a worse level of functionality than LOD group. Multivariate linear regressions showed that functionality has a wide relationship to awareness for people with YOD. While neuropsychiatric symptoms and QoL has a greater relation to awareness for people with LOD.
CONCLUSION
Different clinical variables are associated to different domains in YOD and LOD groups, reinforcing the heterogeneity of awareness in dementia.
Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Awareness; Caregivers; Cognition; Cross-Sectional Studies; Dementia; Emotions; Female; Humans; Male; Middle Aged; Quality of Life; Severity of Illness Index; Social Interaction
PubMed: 33749654
DOI: 10.3233/JAD-201603 -
BMC Chemistry Aug 2023This study aims to develop an effective and sensitive HPLC (High Performance Liquid Chromatography) method to determine the nitrate concentration in fruits and...
This study aims to develop an effective and sensitive HPLC (High Performance Liquid Chromatography) method to determine the nitrate concentration in fruits and vegetables (F & V) using a C column (ZORBAX Eclipse XDB-C, 80Å, 250 × 4.6 mm, 5 μm (Agilent Technologies)) maintained at 40 C, a mobile phase made up of methanol and buffer (pentane sulfonic acid sodium salt solution), and a Photo Diode Array Detector (PDA) at 225 nm. The developed method is validated in terms of selectivity, linearity, accuracy, precision, suitability, the limit of detection (LOD), and the limit of quantification (LOQ) according to the European Union Decision 2002/657/EC. The result revealed that a ratio of 30: 70 of the organic modifier methanol and buffer with pH 2.8 shows the highest efficiency. The calibration curve shows linearity with a correlation coefficient (r) of 0.9985. The LOD and LOQ were found to be 2.26 mg/kg and 7.46 mg/kg. The recovery was in the range of 98.96-100.21%. Moreover, the greenness assessment scores of different approaches (eco-scale score of 76, AGREE score of 0.71, and few red shades in GAPI portray) were at a very excellent level. Thus, our developed method is fully validated and can determine the nitrate content in F & V.
PubMed: 37620944
DOI: 10.1186/s13065-023-01008-y -
European Journal of Human Genetics :... Nov 2019Sphingolipidoses are monogenic lipid storage diseases caused by variants in enzymes of lipid synthesis and metabolism. We describe an autosomal recessive complex...
Sphingolipidoses are monogenic lipid storage diseases caused by variants in enzymes of lipid synthesis and metabolism. We describe an autosomal recessive complex neurological disorder affecting consanguineous kindred. All four affected individuals, born at term following normal pregnancies, had mild to severe intellectual disability, spastic quadriplegia, scoliosis and epilepsy in most, with no dysmorphic features. Brain MRI findings were suggestive of leukodystrophy, with abnormal hyperintense signal in the periventricular perioccipital region and thinning of the body of corpus callosum. Notably, all affected individuals were asymptomatic at early infancy and developed normally until the age of 8-18 months, when deterioration ensued. Homozygosity mapping identified a single 8.7 Mb disease-associated locus on chromosome 1q41-1q42.13 between rs1511695 and rs537250 (two-point LOD score 2.1). Whole exome sequencing, validated through Sanger sequencing, identified within this locus a single disease-associated homozygous variant in DEGS1, encoding C4-dihydroceramide desaturase, an enzyme of the ceramide synthesis pathway. The missense variant, segregating within the family as expected for recessive heredity, affects an evolutionary-conserved amino acid of all isoforms of DEGS1 (c.656A>G, c.764A>G; p.(N219S), p.(N255S)) and was not found in a homozygous state in ExAC and gnomAD databases or in 300 ethnically matched individuals. Lipidomcs analysis of whole blood of affected individuals demonstrated augmented levels of dihydroceramides, dihydrosphingosine, dihydrosphingosine-1-phosphate and dihydrosphingomyelins with reduced levels of ceramide, sphingosine, sphingosine-1-phosphate and monohexosylceramides, as expected in malfunction of C4-dihydroceramide desaturase. Thus, we describe a sphingolipidosis causing a severe regressive neurological disease.
Topics: Adolescent; Adult; Brain; Ceramides; Cerebrosides; Child; Child, Preschool; Fatty Acid Desaturases; Female; Genetic Predisposition to Disease; Genetic Variation; Homozygote; Humans; Infant; Intellectual Disability; Lysophospholipids; Male; Mutation, Missense; Nervous System Diseases; Pedigree; Phenotype; Sequence Analysis, DNA; Sphingosine; Exome Sequencing; Young Adult
PubMed: 31186544
DOI: 10.1038/s41431-019-0444-z -
G3 (Bethesda, Md.) Apr 2021Quantitative trait loci (QTL) hotspots (genomic locations enriched in QTL) are a common and notable feature when collecting many QTL for various traits in many areas of...
Quantitative trait loci (QTL) hotspots (genomic locations enriched in QTL) are a common and notable feature when collecting many QTL for various traits in many areas of biological studies. The QTL hotspots are important and attractive since they are highly informative and may harbor genes for the quantitative traits. So far, the current statistical methods for QTL hotspot detection use either the individual-level data from the genetical genomics experiments or the summarized data from public QTL databases to proceed with the detection analysis. These methods may suffer from the problems of ignoring the correlation structure among traits, neglecting the magnitude of LOD scores for the QTL, or paying a very high computational cost, which often lead to the detection of excessive spurious hotspots, failure to discover biologically interesting hotspots composed of a small-to-moderate number of QTL with strong LOD scores, and computational intractability, respectively, during the detection process. In this article, we describe a statistical framework that can handle both types of data as well as address all the problems at a time for QTL hotspot detection. Our statistical framework directly operates on the QTL matrix and hence has a very cheap computational cost and is deployed to take advantage of the QTL mapping results for assisting the detection analysis. Two special devices, trait grouping and top γn,α profile, are introduced into the framework. The trait grouping attempts to group the traits controlled by closely linked or pleiotropic QTL together into the same trait groups and randomly allocates these QTL together across the genomic positions separately by trait group to account for the correlation structure among traits, so as to have the ability to obtain much stricter thresholds and dismiss spurious hotspots. The top γn,α profile is designed to outline the LOD-score pattern of QTL in a hotspot across the different hotspot architectures, so that it can serve to identify and characterize the types of QTL hotspots with varying sizes and LOD-score distributions. Real examples, numerical analysis, and simulation study are performed to validate our statistical framework, investigate the detection properties, and also compare with the current methods in QTL hotspot detection. The results demonstrate that the proposed statistical framework can effectively accommodate the correlation structure among traits, identify the types of hotspots, and still keep the notable features of easy implementation and fast computation for practical QTL hotspot detection.
Topics: Chromosome Mapping; Computer Simulation; Lod Score; Phenotype; Quantitative Trait Loci
PubMed: 33638985
DOI: 10.1093/g3journal/jkab056 -
Journal of Acute Medicine Jun 2018The European Society of Cardiology (ESC) guidelines recommend the use of high-sensitivity cardiac troponin (hs-cTn) 0-hour/1-hour algorithms in patients presenting with... (Review)
Review
The European Society of Cardiology (ESC) guidelines recommend the use of high-sensitivity cardiac troponin (hs-cTn) 0-hour/1-hour algorithms in patients presenting with suspected non ST elevation myocardial infarction (NSTEMI) as Class I, Level B. This algorithm stratified patients into three group including, rule-out, observe, and rule-in. The introduction of a time axis consisting of a relatively short time, 0-hour/1-hour, is worth mentioning in this algorithm. The specificity and negative predictive value to rule-out of myocardial infarction (MI) was more than 95%, respectively. In prospective Asian study consist of around 400 patients with suspected NSTEMI, "elective" catheter intervention was performed on 13 patients in both rule-out and observe group. None of them had MI, or needed an urgent coronary angiography (CAG) within 30 days. Although there was two patients on whom CAG and percutaneous coronary intervention (PCI) were performed less than 7 hours after presenting to the emergency department (ED), they were classified as moderate risk according to the Framingham Risk Score. The diagnostic performance for patients with suspected NSTEMI to combine the novel risk score with the algorithm would be much improved. The development of excellent assays was also key to establish the algorithm. The hs-cTn assay has limits of detection (LoD) approximately 10-fold lower than those of conventional assays, and their 99th percentiles are analytically very precise. After the emergence of the hs-cTn assays, rises in the cases of NSTEMI were accompanied by a reciprocal reduction in the percentage of patients diagnosed with unstable angina (UA). This excellent algorithm has a possibility to reduce ED crowding and unnecessary CAG.
PubMed: 32995203
DOI: 10.6705/j.jacme.201806_8(2).0002