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Journal of Clinical Sleep Medicine :... Jul 2024Sleep disturbances are common in neurodevelopmental disorders (NDDs), affecting patients and caregivers' quality of life. -associated syndrome, a rare NDD, is marked by...
STUDY OBJECTIVES
Sleep disturbances are common in neurodevelopmental disorders (NDDs), affecting patients and caregivers' quality of life. -associated syndrome, a rare NDD, is marked by intellectual disability, developmental delay, epilepsy, and sleep issues. However, research on sleep quality in these individuals is limited. This study aimed to evaluate genetic variants, epilepsy, and sleep patterns in -associated syndrome patients and their caregivers.
METHODS
An online survey was applied to 11 caregivers of individuals diagnosed with SYNGAP1-associated syndrome. Specific clinical inquiries were included, addressing childbirth, previous surgeries, and medication use. Inquiries about epilepsy included type of epilepsy, type and frequency of seizures, anti-seizure medications, and complementary non-pharmacological treatments. Children's Sleep Habits Questionnaire (CSHQ) was applied to assess the patients' sleep profile. Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality of caregivers.
RESULTS
Genetic analysis showed heterozygous mutations in , often leading to loss of function. Epilepsy was present in 82% of participants, with 77.8% having drug-resistant seizures. Using the Children's Sleep Habits Questionnaire (CSHQ), 81.8% of patients exhibited poor sleep habits, including bedtime resistance, anxiety, night awakenings, parasomnias, and daytime sleepiness. Caregivers also reported poor sleep quality according to the Pittsburgh Sleep Quality Index (PSQI).
CONCLUSIONS
This study highlights the high prevalence of epilepsy and sleep problems in -associated syndrome, impacting both patients and caregivers. Further research is crucial to understand the syndrome's effects on sleep disturbances, emphasizing the need for targeted interventions to improve sleep quality in individuals with rare genetic syndromes and their caregivers.
PubMed: 38958060
DOI: 10.5664/jcsm.11246 -
Development (Cambridge, England) Jul 2024Transcription initiates at the core promoter, which contains distinct core promoter elements. Here, we highlight the complexity of transcriptional regulation by...
Transcription initiates at the core promoter, which contains distinct core promoter elements. Here, we highlight the complexity of transcriptional regulation by outlining the effect of core promoter-dependent regulation on embryonic development and the proper function of an organism. We demonstrate in vivo the importance of the downstream core promoter element (DPE) in complex heart formation in Drosophila. Pioneering a novel approach utilizing both CRISPR and nascent transcriptomics, we show the effects of mutating a single core promoter element within the natural context. Specifically, we targeted the downstream core promoter element (DPE) of the endogenous tin gene, encoding the Tinman transcription factor, a homologue of human NKX2-5 associated with congenital heart diseases. The 7bp substitution mutation results in massive perturbation of the Tinman regulatory network orchestrating dorsal musculature, manifested as physiological and anatomical changes in the cardiac system, impaired specific activity features and significantly compromised viability of adult flies. Thus, a single motif can have a critical impact on embryogenesis and, in the case of DPE, functional heart formation.
PubMed: 38958007
DOI: 10.1242/dev.202355 -
Physiological Research Jul 2024Chemogenetics is a newly developed set of tools that allow for selective manipulation of cell activity. They consist of a receptor mutated irresponsive to endogenous...
Chemogenetics is a newly developed set of tools that allow for selective manipulation of cell activity. They consist of a receptor mutated irresponsive to endogenous ligands and a synthetic ligand that does not interact with the wild-type receptors. Many different types of these receptors and their respective ligands for inhibiting or excitating neuronal subpopulations were designed in the past few decades. It has been mainly the G-protein coupled receptors (GPCRs) selectively responding to clozapine-N-oxide (CNO), namely Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), that have been employed in research. Chemogenetics offers great possibilities since the activity of the receptors is reversible, inducible on demand by the ligand, and non-invasive. Also, specific groups or types of neurons can be selectively manipulated thanks to the delivery by viral vectors. The effect of the chemogenetic receptors on neurons lasts longer, and even chronic activation can be achieved. That can be useful for behavioral testing. The great advantage of chemogenetic tools is especially apparent in research on brain diseases since they can manipulate whole neuronal circuits and connections between different brain areas. Many psychiatric or other brain diseases revolve around the dysfunction of specific brain networks. Therefore, chemogenetics presents a powerful tool for investigating the underlying mechanisms causing the disease and revealing the link between the circuit dysfunction and the behavioral or cognitive symptoms observed in patients. It could also contribute to the development of more effective treatments.
PubMed: 38957949
DOI: No ID Found -
Cureus Apr 2024Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it...
Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it presents distinctive clinical and neuroradiological features. Diagnosing it is challenging yet crucial for appropriate management. We describe a 21-month-old boy with clinical and neuroradiological manifestations of the diagnosis, including characteristic signs such as an eight-configured midbrain and hypoplasia of the brainstem and cerebellar structures. Genetic evaluation confirmed homozygous missense mutations in the AMPD2 gene. This case highlights the pathognomonic neuroradiological features of pontocerebellar hypoplasia type 9 that point toward diagnosis.
PubMed: 38957830
DOI: 10.7759/cureus.58522 -
Cureus Apr 2024Background Due to the emergence of new COVID-19 mutations and an increase in re-infection rates, it has become an important priority for the medical community to...
Background Due to the emergence of new COVID-19 mutations and an increase in re-infection rates, it has become an important priority for the medical community to identify the factors affecting the short- and long-term survival of patients. This study aimed to determine the risk factors of short- and long-term survival in patients with COVID-19 based on mixture and non-mixture cure models. Methodology In this study, the data of 880 patients with COVID-19 confirmed with polymerase chain reaction in Fereydunshahr city (Isfahan, Iran) from February 20, 2020, to December 21, 2021, were gathered, and the vital status of these patients was followed for at least one year. Due to the high rate of censoring, mixture and non-mixture cure models were applied to estimate the survival. Akaike information criterion values were used to evaluate the fit of the models. Results In this study, the mean age of the patients was 48.9 ± 21.23 years, and the estimated survival rates on the first day, the fourth day, the first week, the first month, and at one year were 0.997, 0.982, 0.973, 0.936, and 0.928, respectively. Among the parametric models, the log-logistic mixed cure model with the logit link, which showed the lowest Akaike information criterion value, demonstrated the best fit. The variables of age and prescribed medication type were significant predictors of long-term survival, while occupation was influential in the short-term survival of patients. Conclusions According to the results of this study, it can be concluded that elderly patients should observe health protocols more strictly and consider receiving booster vaccine doses. The log-logistic cure model with a logit link can be used for survival analysis in COVID-19 patients, a fraction of whom have long-term survival.
PubMed: 38957820
DOI: 10.7759/cureus.58550 -
Frontiers in Genetics 2024Long QT syndrome (LQTS) is an autosomal dominant inherited cardiac condition characterized by a QT interval prolongation and risk of sudden death. There are 17 subtypes...
INTRODUCTION
Long QT syndrome (LQTS) is an autosomal dominant inherited cardiac condition characterized by a QT interval prolongation and risk of sudden death. There are 17 subtypes of this syndrome associated with genetic variants in 11 genes. The second most common is type 2, caused by a mutation in the gene, which is part of the potassium channel and influences the final repolarization of the ventricular action potential. This case report presents an Ecuadorian teen with congenital Long QT Syndrome type 2 (OMIM ID: 613688), from a family without cardiac diseases or sudden cardiac death backgrounds.
CASE PRESENTATION
A 14-year-old girl with syncope, normal echocardiogram, and an irregular electrocardiogram was diagnosed with LQTS. Moreover, by performing Next-Generation Sequencing, a pathogenic variant in the gene p.(Ala614Val) (ClinVar ID: VCV000029777.14) associated with LQTS type 2, and two variants of uncertain significance in the p.(Arg1654GlyfsTer23) (rs779447911), and p. (Arg34653Cys) (ClinVar ID: VCV001475968.4) genes were identified. Furthermore, ancestry analysis showed a mainly Native American proportion.
CONCLUSION
Based on the genomic results, the patient was identified to have a high-risk profile, and an implantable cardioverter defibrillator was selected as the best treatment option, highlighting the importance of including both the clinical and genomics aspects for an integral diagnosis.
PubMed: 38957812
DOI: 10.3389/fgene.2024.1395012 -
Oxygen (Basel, Switzerland) Jun 2024Uterine fibroids are the most common tumors in females affecting up to 70% of women world-wide, yet targeted therapeutic options are limited. Oxidative stress has...
Uterine fibroids are the most common tumors in females affecting up to 70% of women world-wide, yet targeted therapeutic options are limited. Oxidative stress has recently surfaced as a key driver of fibroid pathogenesis and provides insights into hypoxia-induced cell transformation, extracellular matrix pathophysiology, hypoxic cell signaling cascades, and uterine biology. Hypoxia drives fibroid tumorigenesis through (1) promoting myometrial stem cell proliferation, (2) causing DNA damage propelling transformation of stem cells to tumor initiating cells, and (3) driving excess extracellular matrix (ECM) production. Common fibroid-associated DNA mutations include MED12 mutations, HMGA2 overexpression, and Fumarate hydratase loss of function. Evidence suggests an interaction between hypoxia signaling and these mutations. Fibroid development and growth are promoted by hypoxia-triggered cell signaling via various pathways including HIF-1, TGFβ, and Wnt/β-catenin. Fibroid-associated hypoxia persists due to antioxidant imbalance, ECM accumulation, and growth beyond adequate vascular supply. Current clinically available fibroid treatments do not take advantage of hypoxia-targeting therapies. Growing pre-clinical and clinical studies identify ROS inhibitors, anti-HIF-1 agents, Wnt/β-catenin inhibition, and TGFβ cascade inhibitors as agents that may reduce fibroid development and growth through targeting hypoxia.
PubMed: 38957794
DOI: 10.3390/oxygen4020013 -
Clinical Nephrology. Case Studies 2024We investigated the pathogenesis of a perihilar variant of focal segmental glomerulosclerosis detected by kidney biopsy in a 16-year-old male. The disease was refractory...
Renal and cardiac biopsy findings in an adolescent patient with the 3243A>G mitochondrial DNA mutation: Favorable renal prognosis post renal transplantation from the mother.
We investigated the pathogenesis of a perihilar variant of focal segmental glomerulosclerosis detected by kidney biopsy in a 16-year-old male. The disease was refractory to steroid therapy, and at the second kidney biopsy, abnormal mitochondrial proliferation was newly observed in the podocytes. The patient also developed late-onset hearing loss and had a family history of diabetes, and genetic testing confirmed the mitochondrial DNA mutation 3243A>G (48%). Eight months after hemodialysis was started, encephalopathy occurred presumably due to rapid dehydration. After changing dialysis into continuous ambulatory peritoneal dialysis, encephalopathy was resolved, but the patient developed myocardial hypertrophy, probably because of the myocardial overreaction to congestion. A myocardial biopsy showed mitochondrial proliferation in the myocardium. After renal transplantation from his mother with a heteroplasmy of 4%, the cardiomyopathy improved, and the renal function has remained stable for 4 years. We speculated that the abnormal mitochondrial morphology in the kidney and heart may be characteristic of mitochondrial genetic disease, and renal transplantation from the mother with a low heteroplasmy was considered desirable for mitochondrial nephropathy with poor prognosis.
PubMed: 38957708
DOI: 10.5414/CNCS111422 -
Open Forum Infectious Diseases Jul 2024Direct whole genome sequencing (WGS) of () can be used as a tool to study drug resistance, mixed infections, and within-host diversity. However, WGS is challenging to...
BACKGROUND
Direct whole genome sequencing (WGS) of () can be used as a tool to study drug resistance, mixed infections, and within-host diversity. However, WGS is challenging to obtain from clinical samples due to low number of bacilli against a high background.
METHODS
We prospectively collected 34 samples (sputum, n = 17; bronchoalveolar lavage, n = 13; and pus, n = 4) from patients with active tuberculosis (TB). Prior to DNA extraction, we used a ligand-mediated magnetic bead method to enrich from clinical samples and performed WGS on Illumina platform.
RESULTS
was definitively identified based on WGS from 88.2% (30/34) of the samples, of which 35.3% (12/34) were smear negative. The overall median genome coverage was 15.2% (interquartile range [IQR], 7.7%-28.2%). There was a positive correlation between load of bacilli on smears and genome coverage ( < .001). We detected 58 genes listed in the World Health Organization mutation catalogue in each positive sample (median coverage, 85% [IQR, 61%-94%]), enabling the identification of mutations missed by routine diagnostics. Mutations causing resistance to rifampicin, isoniazid, streptomycin, and ethambutol were detected in 5 of 34 (14.7%) samples, including the S441A mutation that confers resistance to rifampicin, which is not covered by Xpert MTB/RIF.
CONCLUSIONS
We demonstrate the feasibility of magnetic bead-based enrichment for culture-free WGS of from clinical specimens, including smear-negative samples. This approach can also be integrated with low-cost sequencing workflows such as targeted sequencing for rapid detection of and drug resistance.
PubMed: 38957687
DOI: 10.1093/ofid/ofae320 -
Ghana Medical Journal Sep 2023The study sought to determine clinical characteristics and histologic subtypes of a cohort of lung cancer patients in a tertiary facility.
OBJECTIVE
The study sought to determine clinical characteristics and histologic subtypes of a cohort of lung cancer patients in a tertiary facility.
DESIGN
Retrospective review of the medical records of histology-confirmed lung cancer cases at the respiratory clinic over a 3-year period.
SETTING
Respiratory Clinic, Korle-Bu Teaching Hospital, Accra, Ghana.
PARTICIPANTS
All adult patients with histologically diagnosed lung cancer were enrolled.
MAIN OUTCOME MEASURES
Lung cancer histological types.
RESULTS
The proportion of lung cancer cases was 12.4%. The majority were women (57.8%) and the mean age at diagnosis was 55.8±16.0 years. The patients were predominantly non-smokers (61%). Common symptoms were chronic cough and chest pain. More than two-thirds of the cases presented in clinical stages III and IV with the predominant histological subtype being adenocarcinoma in smokers and non-smokers. Genetic testing for epidermal growth factor receptor (EGFR) and Anaplastic Lymphoma kinase (ALK) mutations were largely absent.
CONCLUSIONS
The majority of lung cancer patients presented late with advanced disease. Adenocarcinoma was the predominant histological subtype in a predominantly non-smoking population, with an increased prevalence among women less than 60 years. This should encourage testing for genetic mutations to improve patient survival.
FUNDING
None declared.
Topics: Humans; Lung Neoplasms; Female; Middle Aged; Male; Retrospective Studies; Tertiary Care Centers; Aged; Adult; Ghana; Smoking; Adenocarcinoma; Neoplasm Staging; Cough; ErbB Receptors; Aged, 80 and over; Chest Pain
PubMed: 38957673
DOI: 10.4314/gmj.v57i3.2