Search Results (93)

Individuals with CHARGE syndrome often experience motor delays impacting their balance, flexibility, and hand–eye coordination. Due to the medical complications associated with CHARGE syndrome, 40% of children will not develop functional communication skills and many more will have difficulty with speech and oral communication. Family caregivers play a critical role in the care of children and youths with disabilities, especially CHARGE syndrome. However, there is minimal research on the parental experiences of children and youth with CHARGE syndrome. The purpose of this study was to understand the family caregiver experiences and needs of parents of children and youth with CHARGE syndrome and related disabilities. Six family caregivers of children and youth living with CHARGE syndrome in the United States were interviewed to understand their current quality of life, factors influencing their quality of life, and the coping strategies they use. The interviews were transcribed verbatim and then analyzed using qualitative content analysis. The themes generated from the qualitative analyses of interviews showed that family caregivers experienced significant challenges in their quality of life and faced barriers as they navigated a complex system of care. However, family caregivers described robust approaches such as social support for coping with some of the stresses. Full article

Spirulina (Arthrospira platensis) is a microalga widely used as a dietary supplement in sports nutrition and in treating metabolic diseases such as diabetes, obesity and metabolic syndrome. Spirulina’s cell structure limits digestibility and reduces the availability of bioactive compounds. The extraction processes, coupled with encapsulation, can enhance the bioavailability of nutritional and antioxidant compounds, protecting them from degradation, preserving their functional activity, and supporting controlled release. The physicochemical properties of liposomes (Lps), bilosomes (Bls), and gelatin-enriched bilosomes (G-Bls) with incorporated Spirulina extracts were investigated. The delivery systems exhibited small particle size (101.8 ± 0.5 to 129.7 ± 1.2 nm), homogeneous distribution (polydispersity index (PDI) 0.17 ± 6.67 to 0.33 ± 9.06), negative surface charges (−31.9 ± 5.2 to 31.1 ± 6.4 mV), and high entrapment efficiency (>80%). G-Bls demonstrated effective retention of the extract, with a low release rate at pH 1.2 (41.8% ± 6.1) and controlled release at pH 7.0 (52.5% ± 3.0). Biocompatibility studies on Caco-2 cells showed that G-Bls maintained high cell viability at 200 μg·mL⁻¹ (87.89% ± 10.35) and significantly mitigated H₂O₂-induced oxidative stress at 20 and 200 μg·mL⁻¹, increasing cell viability by 23.47% and 19.28%. G-Bls are a promising delivery system for enhancing the stability, bioavailability, and protective effects of Spirulina extracts, supporting their potential application in dietary supplements aimed at promoting sports performance and recovery, mitigating exercise-induced oxidative stress, and managing metabolic disorders. Full article

Background: This pilot investigation aimed to evaluate the efficacy of Global Intensive Feeding Therapy (GIFT) on feeding and swallowing abilities in children with CHARGE Syndrome (CS). GIFT is a novel rehabilitation program designed to leverage the principles of neuroplasticity, intensity, individualized treatment, and ecological validity. The program comprises 15 sessions conducted over one week, with sessions delivered three times per day. Methods: GIFT was preliminarily implemented in a cohort of seven children diagnosed with CS. To assess the risk of dysphagia, the Pediatric Screening–Priority Evaluation Dysphagia (PS-PED) was administered. The effectiveness of the intervention was evaluated using three instruments: the Karaduman Chewing Performance Scale (KCPS) for chewing performance, the American Speech-Language-Hearing Association National Outcome Measurement System (ASHA NOMS) for overall feeding abilities, and the Feeding Assessment Scale (FAS) to capture parents’ perceptions. Data were collected at baseline (T0), immediately post-intervention (T1), and at a six-month follow-up (T2). The Wilcoxon signed-rank test was employed for statistical analysis, and effect sizes for specific outcomes were determined using Kendall’s W. Results: The findings indicated that children with CS were at a high risk of dysphagia as measured by the PS-PED at baseline. Statistically significant improvements in chewing performance were observed at the six-month follow-up (p < 0.05). Feeding abilities, as measured by the ASHA NOMS, showed significant enhancement immediately post-intervention (p = 0.02) and at the follow-up (p = 0.03). Similarly, parents reported significant improvements in their children’s feeding abilities at both post-intervention and follow-up assessments (p = 0.02), further corroborating the clinical benefits of the intervention. Conclusions: These preliminary results suggest that GIFT may be an effective rehabilitation program for addressing feeding and swallowing disorders in children with CS. Further studies with larger sample sizes and controlled designs are warranted to substantiate these findings and refine the intervention protocol. Full article

Background/Objectives: Heterozygous variants in the heterogeneous nuclear ribonucleoprotein C gene (HNRNPC) have recently been reported to cause intellectual developmental disorder-74 (MRD74), a neurodevelopmental disorder with no recurrent diagnostic handles. Affected individuals show variable, non-specific, and subtle dysmorphic features. The degree of developmental delay (DD)/intellectual disability (ID) is also wide, ranging from mild to severe. The mutational spectrum is relatively broad with exon deletions and splice site and frameshift variants distributed along the entire length of the gene leading to HNRNPC loss of function. Only two missense changes located within the RNA-binding motif (RBM) and adjacent linker region of the more abundant isoform (Arg64Trp and Arg99Gln) have been described. Notably, the Arg99Gln amino acid substitution was reported in a subject presenting with a more complex and unique clinical phenotype characterized by distinctive facial features, DD/ID, cochlear aplasia, and bilateral colobomatous microphthalmia, suggesting the possible occurrence of phenotypic heterogeneity. Results: Here, we report the second individual carrying the Arg99Gln change in HNRNPC and having clinical features with a significant overlap with the peculiar phenotype of the previously described subject, supporting the occurrence of a genotype–phenotype correlation. Conclusions: Due to the concomitant occurrence of ocular and cochlear involvement as recognizable diagnostic handles, we propose that the HNRNPC^Arg99Gln-related phenotype should be considered as a potential differential diagnosis in subjects with ID and major signs of CHARGE syndrome not fulfilling the minimum criteria for a clinical diagnosis. Full article

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly arrhythmogenic syndrome triggered by stress, primarily linked to gain-of-function point mutations in the cardiac ryanodine receptor (RyR2). Flecainide, as an effective therapy for CPVT, is a known blocker of the surface-membrane Na⁺ channel, also affecting the intracellular RyR2 channel. The therapeutic relevance of the flecainide-RyR2 interaction remains controversial, as flecainide blocks only the RyR2 current flowing in the opposite direction to the physiological Ca²⁺ release from the sarcoplasmic reticulum (SR). However, it has been proposed that charge-compensating countercurrent from the cytosol to SR lumen plays a critical role, and its reduction may indeed suppress excessive diastolic SR Ca²⁺ release through RyR2 channels in CPVT. Monitoring single-channel properties, we examined whether flecainide can target intracellular pathways for charge-balancing currents carried by RyR2 and SR Cl⁻ channels under cell-like conditions. Particularly, the Tris⁺ countercurrent flowed through the RyR2 channel simultaneously with a dominant reverse Ca²⁺/Ba²⁺ current. We demonstrate that flecainide blocked the RyR2-mediated countercurrent without affecting channel activity. In contrast, the SR Cl⁻ channel was completely resistant to flecainide. Based on these findings, it is reasonable to propose that the primary intracellular target of flecainide in vivo is the RyR2-mediated countercurrent. Full article

The FDA approved rufinamide, chemically 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, a triazole-based scaffold, as an anticonvulsant drug in 2008. It is mainly used to treat seizures associated with Lennox–Gastaut Syndrome (LGS). The exact mechanism of rufinamide is unknown, but some literature reported that rufinamide works by regulating the brain’s sodium channel activity, which aids in maintaining the stability of neuronal membranes and averting the overabundance of electrical activity. In the view of computational chemistry, the amide group, fluorine atom, and triazole ring are the specific parts of this skeleton and play an important role in action with the receptor. This study explored computerized simulations of quantum chemistry techniques to investigate the chemical structure and electrical properties of rufinamide. An optimizing structure started the quantum calculation through the B3LYP 6311-G (++, d, p) basis set, explored along with investigating the maximal quantity of electronic charge transfer (N_max), chemical hardness (η), electrostatic potential, chemical potential (µ), and electrophilicity (ω). The Natural Bond Orbital (NBO) analysis-based observation reveals that the molecule’s chemically active regions have hyperconjugated electron interactions within the molecule, which contributes to the molecule’s stability. This study explores the role of the amide group and difluoro-substituted phenyl group in chemical structure and in binding property with the receptor of the Ca²⁺–and voltage-activated K⁺ channel. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn²⁺) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2′, suggesting interference with SARS-CoV-2’s spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies. Full article

Background: With the growing trends in recreational marijuana use, our study aims at analyzing the association between acute coronary syndromes (ACS) and ventricular fibrillation (Vfib) and cannabis use disorder in young adults (18–45). Methods: Young adult hospitalizations (18–45 years) with documented ACS/ventricular fibrillation and documented cannabis use were identified from the National Inpatient Sample (2019). Primary outcomes included prevalence and odds of ACS/ventricular fibrillation with cannabis use disorder. Patient factors that held significant association with adverse cardiovascular events in young cannabis users were studied. Propensity scoring and neighbor matching were used to compare resource utilization and in-hospital outcomes in the study population. Results: Among young patients (18–45) admitted for ACS, documented cannabis use disorder (CUD) had a statistically significant association with an odds ratio of 2.29 (2.48–3.04) after adjusting for age, sex, race, household income, smoking, cocaine use, uncontrolled hypertension, diabetes and hyperlipidemia. Documented CUD had a significant association with ventricular fibrillation in the population with an odds ratio of 2.29 (1.51–3.49) after adjusting for the above-mentioned factors. Among admissions with documented CUD, patient factors that held significant association with admitting diagnosis of ACS/Vfib were: black race (OR: 1.73), uncontrolled hypertension (OR: 4.08) and diabetes (OR: 2.45). Propensity-matched cohorts with documented CUD and ACS had significantly higher mean length of hospital stay 3.28 (2.98–3.53) days when compared to the cohort without documented CUD, 2.69 (2.32–2.82) days. The mean of total hospital charges was higher in the cohort with documented CUD at $92,390.64 (92,240.31–92,445.76) compared to $90,886.44 (89,932.21–91,042.56) in the cohort without cannabis use disorder. Conclusions: Documented diagnosis of cannabis use disorder had statistically significant association with admission diagnosis of ACS/Vfib even after accounting for confounders. A documented race as black and co-existing diagnosis of uncontrolled hypertension and diabetes had a significant association with admission diagnosis of ACS in the population with documented cannabis use disorder. Propensity-matched cohorts with cannabis use disorder with the main admitting diagnosis of ACS/Vfib were associated with a higher mean length of hospital stay and a higher mean of total charges compared to the matched cohorts without documented cannabis use disorder. Full article

Over the last decade there has been increasing interest in the links between the consumption of ultra-processed foods and various neuropsychiatric disorders, aggression, and antisocial behavior. Neurolaw is an interdisciplinary field that seeks to translate the rapid and voluminous advances in brain science into legal decisions and policy. An enhanced understanding of biophysiological mechanisms by which ultra-processed foods influence brain and behavior allows for a historical reexamination of one of forensic neuropsychiatry’s most famous cases—The People v. White and its associated ‘Twinkie Defense’. Here in this Viewpoint article, we pair original court transcripts with emergent research in neurolaw, including nutritional neuroscience, microbiome sciences (legalome), pre-clinical mechanistic research, and clinical intervention trials. Advances in neuroscience, and related fields such as the microbiome, are challenging basic assumptions in the criminal justice system, including notions of universal free will. Recent dismissals of criminal charges related to auto-brewery syndrome demonstrate that courts are open to advances at the intersection of neuromicrobiology and nutritional neuroscience, including those that relate to criminal intent and diminished capacity. As such, it is our contention that experts in the neurosciences will play an increasing role in shaping research that underpins 21st-century courtroom discourse, policy, and decision-making. Full article

Congenital heart disease (CHD) is the most commonly detected congenital anomaly and affects up to 1% of all live-born neonates. Current guidelines support the use of chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) as diagnostic approaches to identify genetic causes. The aim of our study was to evaluate the diagnostic yield of CMA and NGS in a cohort of neonates with both isolated and syndromic CHD. The present study included 188 infants under 28 days of age with abnormal echocardiography findings hospitalized at the Department of Neonatology, UMC Ljubljana, between January 2014 and December 2023. Phenotypic data were obtained for each infant via retrospective medical chart review. We established the genetic diagnosis of 22 distinct syndromes in 17% (32/188) of neonates. The most frequent genetic diagnoses in diagnosed cases were 22q11.2 microdeletion and CHARGE syndromes, followed by Noonan syndrome and Williams syndrome. In addition, we detected variants of uncertain significance in 4.8% (9/188) of neonates. Timely genetic diagnosis is important for the detection of syndrome-related comorbidities, prognosis, reproductive genetic risks and, when appropriate, genetic testing of other family members. Full article

The COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), began in 2019. One of the strategies for pandemic control was mass vaccination. In Brazil, the recombinant COVID-19 vaccine (RCV) was produced on a large scale and offered at no charge to the population. The specifications for quality control analyses of RCV included identity and infectivity determination. To validate the results, a reference material (RM) must be analyzed in parallel with the sample vaccine. This research aimed to establish the RM for use in the identity and infectivity assay for RCV. The candidate RM was analyzed using homogeneity and stability studies. The RM was considered homogeneous for identity (cycle threshold (Ct) ≤ 25.19) and infectivity (average $\stackrel{-}{\mathrm{x}}$ was 9.25 log₁₀ infectious units/mL). The RM was considered adequately stable for identity during the total period in all studies, being stable at −70, 5, and 22.5 °C for 380, 313, and 14 days, respectively (Ct ≤ 21.81). For infectivity, the RM was stable at −70, 5, and 22.5 °C for 380, 97, and three days, respectively. Since the property identity and infectivity values of the RM were established, the new RM could be used in quality control analysis. Full article

Sarcopenia is an age-related syndrome characterized by the loss of skeletal muscle mass and function. Community screening, commonly used in early diagnosis, usually lacks features such as real-time monitoring, low cost, and convenience. This study introduces a promising approach to sarcopenia screening by dynamic plantar pressure monitoring. We propose a wearable flexible-printed piezoelectric sensing array incorporating barium titanate thin films. Utilizing a flexible printer, we fabricate the array with enhanced compressive strength and measurement range. Signal conversion circuits convert charge signals of the sensors into voltage signals, which are transmitted to a mobile phone via Bluetooth after processing. Through cyclic loading, we obtain the average voltage sensitivity (4.844 mV/kPa) of the sensing array. During a 6 m walk, the dynamic plantar pressure features of 51 recruited participants are extracted, including peak pressures for both sarcopenic and control participants before and after weight calibration. Statistical analysis discerns feature significance between groups, and five machine learning models are employed to screen for sarcopenia with the collected features. The results show that the features of dynamic plantar pressure have great potential in early screening of sarcopenia, and the Support Vector Machine model after feature selection achieves a high accuracy of 93.65%. By combining wearable sensors with machine learning techniques, this study aims to provide more convenient and effective sarcopenia screening methods for the elderly. Full article

The synapse is a piece of information transfer machinery replacing the electrical conduction of nerve impulses at the end of the neuron. Like many biological mechanisms, its functioning is heavily affected by time constraints. The solution selected by evolution is based on chemical communication that, in theory, cannot compete with the speed of nerve conduction. Nevertheless, biochemical and biophysical compensation mechanisms mitigate this intrinsic weakness: (i) through the high concentrations of neurotransmitters inside the synaptic vesicles; (ii) through the concentration of neurotransmitter receptors in lipid rafts, which are signaling platforms; indeed, the presence of raft lipids, such as gangliosides and cholesterol, allows a fine tuning of synaptic receptors by these lipids; (iii) through the negative electrical charges of the gangliosides, which generate an attractive (for cationic neurotransmitters, such as serotonin) or repulsive (for anionic neurotransmitters, such as glutamate) electric field. This electric field controls the flow of glutamate in the tripartite synapse involving pre- and post-synaptic neurons and the astrocyte. Changes in the expression of brain gangliosides can disrupt the functioning of the glutamatergic synapse, causing fatal diseases, such as Rett syndrome. In this review, we propose an in-depth analysis of the role of gangliosides in the glutamatergic synapse, highlighting the primordial and generally overlooked role played by the electric field of synaptic gangliosides. Full article

The transmembrane protein β-amyloid precursor protein (APP) is central to the pathophysiology of Alzheimer’s disease (AD). The β-amyloid hypothesis posits that aberrant processing of APP forms neurotoxic β-amyloid aggregates, which lead to the cognitive impairments observed in AD. Although numerous additional factors contribute to AD, there is a need to better understand the synaptic function of APP. We have found that Drosophila APP-like (APPL) has both shared and non-shared roles at the synapse with Kismet (Kis), a chromatin helicase binding domain (CHD) protein. Kis is the homolog of CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively. Loss of function mutations in kis and animals expressing human APP and BACE in their central nervous system show reductions in the glutamate receptor subunit, GluRIIC, the GTPase Rab11, and the bone morphogenetic protein (BMP), pMad, at the Drosophila larval neuromuscular junction (NMJ). Similarly, processes like endocytosis, larval locomotion, and neurotransmission are deficient in these animals. Our pharmacological and epistasis experiments indicate that there is a functional relationship between Kis and APPL, but Kis does not regulate appl expression at the larval NMJ. Instead, Kis likely influences the synaptic localization of APPL, possibly by promoting rab11 transcription. These data identify a potential mechanistic connection between chromatin remodeling proteins and aberrant synaptic function in AD. Full article

Background: Neurodevelopmental disorders (NDDs) are a group of diseases that severely affect the physical and mental health of children. The PPP2R5D gene encodes B56δ, the regulatory subunit of protein phosphatase 2A (PP2A). NDDs related to the PPP2R5D gene have recently been defined as Houge–Janssens syndrome 1. Methods: Clinical/whole exome sequencing was performed on approximately 3000 patients with NDDs from 2017 to 2023. In vitro experiments were performed to assess the impairment of variants to protein expression and the assembly of PP2A holoenzyme. The genetic information and phenotypes of the reported patients, as well as patients in this study, were summarized, and the genotype–phenotype relationship was analyzed. The probability of pathogenic missense variants in PPP2R5D was predicted using AlphaMissense (AM), and the relationship between certain phenotype and 3D protein structural features were analyzed. Results: Thirteen new patients carrying twelve PPP2R5D gene variants were detected, including five novel missense variants and one novel frameshift variant. In vitro experiments revealed that the frameshift variant p.H463Mfs*3 resulted in a ~50 kDa truncated protein with lower expression level. Except for E420K and T536R, other missense variants impaired holoenzyme assembly. Furthermore, we found that pathogenic/likely pathogenic (P/LP) variants that have been reported so far were all missense variants and clustered in three conserved regions, and the likelihood of P/LP mutations located in these conserved regions was extremely high. In addition, the macrocephaly phenotype was related to negatively charged residues involved in substrate recruitment. Conclusions: We reported thirteen new patients with PPP2R5D gene variants and expanded the PPP2R5D variant spectrum. We confirmed the pathogenicity of novel variants through in vitro experiments. Our findings in genotype–phenotype relationship provide inspiration for genetic counseling and interpretation of variants. We also provide directions for further research on the mechanism of macrocephaly phenotype. Full article