Response to letter to editor regarding Seizure-precipitating factors in dogs with idiopathic epilepsy

Non peer reviewe

Seizure-precipitating factors in dogs with idiopathic epilepsy

Background: Stress, sleep deprivation, and infectious diseases are important seizure-precipitating factors in human epilepsy patients. However, these factors have not been thoroughly studied in epileptic dogs. Objective: Seizure-precipitating factors are common in dogs with idiopathic epilepsy and the occurrence of these factors associate with the dogs' signalment, personality, and epilepsy-related factors. Animals: Fifty dogs with diagnosed idiopathic epilepsy from the hospital populations of University Veterinary Teaching Hospital of University of Helsinki and Referral Animal Hospital Aisti. Methods: In a retrospective cross-sectional observational study, owners were interviewed about their dogs' possible seizure-precipitating factors according to a predefined questionnaire. The dogs were identified and selected by searching the medical records of the participating animal hospitals. Results: The prevalence of seizure-precipitating factors in the study population was 74% (37/50). The most frequently reported factors included stress-related situations, sleep deprivation, weather, and hormonal factors. In dogs with focal onset seizures, the number of precipitating factors was 1.9 (95% CI 1.1-3.4) times higher compared to dogs with generalized seizures. Conclusions and Clinical Importance: Seizure-precipitating factors are common in dogs with idiopathic epilepsy, and the nature of these factors is consistent with those of human patients. Aside from antiepileptic medication, acknowledging and avoiding seizure-precipitating factors could help veterinarians achieve better treatment outcomes.Peer reviewe

0134 : Using cardiomyocytes differentiated from urine-derived hiPSCs to recapitulate electrophysiological characteristics of LQT2 syndrome

RationaleHuman genetically inherited cardiac diseases have mainly been studied in heterologous systems or animal models, independently of the patients’ genetic background. Because sources for human cardiomyocytes are extremely limited, the use of urine samples to derive cardiomyocytes would be a non-invasive method to identify cardiac dysfunctions that lead to pathologies within the patients’ specific genetic background.ObjectiveCardiomyocytes differentiated from urine-derived pluripotent stem cells (UhiPS-CMs) were obtained from a patient with long QT syndrome and a mutation in hERG KCNH2 gene (p. A561P), and were characterized.Methods and ResultsCells obtained from urine samples from the A561P patient and his asymptomatic mother carrying no hERG mutation were reprogrammed using the episomal-based method. UhiPS cells were then differentiated into cardiomyocytes using a modified matrix sandwich method. UhiPS-CMs showed proper expression of ventricular cytoskeletal proteins and ion channels. They were electrically functional, with nodal-, atrial- and ventricular-like action potentials (APs) recorded using both high-throughput CellOptiq and patch-clamp techniques. Application of ajmaline, 4-aminopyridine, nifedipine, chromanol 293B or E-4031 to the UhiPS-CMs confirmed that INa, Ito, ICa, IKs and IKr currents, respectively, contributed to the APs. Comparing hERG expression from the patient's UhiPS-CMs to the mother's UhiPS-CMs showed that the mutation led to a trafficking defect that resulted in a reduced IKr current. This phenotype led to APs prolongation that sometimes resulted in arrhythmias (early afterdepolarizations).ConclusionUrine-derived pluripotent stem cells from patients carrying ion channels mutations can be used as novel models to differentiate functional cardiomyocytes that recapitulate cardiac arrhythmia phenotypes

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Persistent fontanelles in Chihuahuas. Part II : Association with craniocervical junction abnormalities, syringomyelia, and ventricular volume

Background Persistent fontanelles (PFs) are, in Chihuahuas, almost ubiquitous. Furthermore, Chihuahuas are predisposed to other craniomorphological abnormalities, including syringomyelia (SM), ventriculomegaly, and craniocervical junction (CCJ) overcrowding resulting in neural tissue deviation. It is, however, undetermined if PFs are more common in dogs with these structural abnormalities, and their etiology is unknown. Hypothesis/Objectives Persistent fontanelles are more numerous and larger in Chihuahuas with low body weight, older age, SM, dilated fourth ventricle, ventriculomegaly, and CCJ overcrowding. Animals Fifty client-owned Chihuahuas. Methods Cross-sectional study evaluating the association of both the number of cranial sutures affected by PFs (NAS) and total fontanelle area (TFA), based on computed tomography with SM, fourth ventricle dilatation, lateral ventricle volume, and extent of neural tissue compression at the CCJ based on magnetic resonance images. Results The NASs was higher and TFA larger in dogs with low body weight (NAS: P = .007; 95% confidence interval [CI] = 0.384-0.861; TFA: P = .002; 95% CI = -1.91 to -0.478), larger lateral ventricles (NAS: P Conclusions and Clinical Importance Persistent fontanelles are associated with small size, SM, ventriculomegaly, and CCJ overcrowding.Peer reviewe

Persistent fontanelles in Chihuahuas. Part I. Distribution and clinical relevance

Background The Chihuahua dog breed is known for frequent occurrence of a bregmatic fontanelle on the dorsal skull. A common conception is that this skull defect is a clinically irrelevant finding. No studies, however, describe its prevalence or whether it is accompanied by other persistent fontanelles (PFs). Although Chihuahuas are predisposed to Chiari-like malformation (CM) and syringomyelia (SM), it is unknown whether PFs occur more commonly in dogs with clinical signs that are caused by CM or SM. Hypothesis/Objectives To describe the number and location of PFs at cranial sutures (CSs) and to compare the occurrence of these PFs in dogs with and without CM/SM-related clinical signs. We hypothesized that PFs also occur commonly at lateral and caudal cranial surfaces, affect a higher number of CSs, and are larger in dogs with CM/SM-related clinical signs. Animals Fifty client-owned Chihuahuas with or without CM/SM-related clinical signs. Results Of the 50 dogs evaluated, 46 (92%) had either 1 or several PFs. The mean +/- SD number of PFs was 2.8 +/- 3.0 (range, 0-13). A total of 138 PFs occupied 118 CSs with 57 (48%) located dorsally, 44 (37%) caudally, and 17 (14%) laterally. The number of CSs affected by PFs was significantly higher (P Conclusions and Clinical Importance Persistent fontanelles are very common in this group of Chihuahuas and appear at dorsal, lateral, and caudal cranial surfaces. They are more numerous and larger in Chihuahuas with CM/SM-related clinical signs.Peer reviewe

Identifying Optimal Precursors for Geopolymer Composite Mix Design for Different Regional Settings: A Multi-Objective Optimization Study

Global objectives to mitigate climate change in the construction industry have led to increasing geopolymer development as an alternative to carbon-intensive cement. Geopolymers can have similar mechanical properties and a lower carbon footprint. However, geopolymer production is not as homogeneous as cement because it is produced by synthesizing alkali solutions with different aluminosilicate precursors. This study assessed the feasibility of using conventional (fly ash, blast furnace slag, and metakaolin) and alternative precursors (steel slag, mine tailings, glass waste, sewage sludge ashes, and municipal solid waste incineration bottom ashes (MSWI BA)) in geopolymer mixes for different European regions (Belgium and Finland) from a sustainability perspective, using environmental, economic, and resource availability indicators as the criteria. A multi-objective optimization technique was applied to identify optimal precursors for geopolymer mixes using two scenarios: (1) considering both conventional and alternative precursors; (2) only considering alternative precursors. The results from the first scenario show that one of the most optimal precursor combinations for the geopolymer mix is 50% fly ash, 25% MSWI BA, and 25% sewage sludge ash for Belgium. For Finland, it is 19% fly ash, 27% mine tailings, and 45% MSWI BA. For the second scenario, one of the most optimal precursor combinations for Belgium is 87% MSWI BA and 13% steel slag. For Finland, it is 25% mine tailings and 75% MSWI BA. Subsequently, linear regression analysis was applied to predict the compressive strength of the identified optimal mixes, and the results for Belgium and Finland were between 31–55 MPa and 31–50 MPa for the first scenario and between 50–59 MPa and 50–55 Mpa for the second scenario, respectively.ISSN:2313-432

Toward Personalized Medicine: Using Cardiomyocytes Differentiated From Urine-Derived Pluripotent Stem Cells to Recapitulate Electrophysiological Characteristics of Type 2 Long QT Syndrome

International audienceBackground-—Human genetically inherited cardiac diseases have been studied mainly in heterologous systems or animal models, independent of patients' genetic backgrounds. Because sources of human cardiomyocytes (CMs) are extremely limited, the use of urine samples to generate induced pluripotent stem cell–derived CMs would be a noninvasive method to identify cardiac dysfunctions that lead to pathologies within patients' specific genetic backgrounds. The objective was to validate the use of CMs differentiated from urine-derived human induced pluripotent stem (UhiPS) cells as a new cellular model for studying patients' specific arrhythmia mechanisms. Methods and Results-—Cells obtained from urine samples of a patient with long QT syndrome who harbored the HERG A561P gene mutation and his asymptomatic noncarrier mother were reprogrammed using the episomal-based method. UhiPS cells were then differentiated into CMs using the matrix sandwich method. UhiPS-CMs showed proper expression of atrial and ventricular myofilament proteins and ion channels. They were electrically functional, with nodal-, atrial-and ventricular-like action potentials recorded using high-throughput optical and patch-clamp techniques. Comparison of HERG expression from the patient's UhiPS-CMs to the mother's UhiPS-CMs showed that the mutation led to a trafficking defect that resulted in reduced delayed rectifier

Recycling mica and carbonate-rich mine tailings in alkali-activated composites:a synergy with metakaolin

Abstract The main objective of this paper was to investigate the alkali activation of mine tailings (MT) after mechanochemical activation and the effect of metakaolin (MK) addition. Finnish mica-rich tailings from a phosphate mine were studied as precursors for alkali-activated materials (AAM) with a potential application as a substitute for ordinary Portland cement (OPC). The principal physical properties (water absorption, apparent porosity and unconfined compressive strength) were measured for samples containing 30% to 70% tailings. Zeolite phases such as natrolite and cancrinite were observed and the formation of C-(N)-A-S-H¹ and N-A-S-H gels was identified by XRD, DRIFT, FESEM-EDS and NMR technologies. A life cycle assessment (LCA) was conducted on specimens in comparison to OPC. This work indicated that phosphate MT can be recycled through alkali activation with lower CO₂ emission compared to all-metakaolin geopolymers and that the binder phase formed at the most promising tailings contents (60– 70%) was C-(N)-A-S-H gel