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Frontiers in Pharmacology 2024Valproic acid (VPA) stands as one of the most frequently prescribed medications in children with newly diagnosed epilepsy. Despite its infrequent adverse effects within...
Valproic acid (VPA) stands as one of the most frequently prescribed medications in children with newly diagnosed epilepsy. Despite its infrequent adverse effects within therapeutic range, prolonged VPA usage may result in metabolic disturbances including insulin resistance and dyslipidemia. These metabolic dysregulations in childhood are notably linked to heightened cardiovascular risk in adulthood. Therefore, identification and effective management of dyslipidemia in children hold paramount significance. In this retrospective cohort study, we explored the potential associations between physiological factors, medication situation, biochemical parameters before the first dose of VPA (baseline) and VPA-induced dyslipidemia (VID) in pediatric patients. Binary logistic regression was utilized to construct a predictive model for blood lipid disorders, aiming to identify independent pre-treatment risk factors. Additionally, The Receiver Operating Characteristic (ROC) curve was used to evaluate the performance of the model. Through binary logistic regression analysis, we identified for the first time that direct bilirubin (DBIL) (odds ratios (OR) = 0.511, = 0.01), duration of medication (OR = 0.357, = 0.009), serum albumin (ALB) (OR = 0.913, = 0.043), BMI (OR = 1.140, = 0.045), and aspartate aminotransferase (AST) (OR = 1.038, = 0.026) at baseline were independent risk factors for VID in pediatric patients with epilepsy. Notably, the predictive ability of DBIL (AUC = 0.690, < 0.0001) surpassed that of other individual factors. Furthermore, when combined into a predictive model, incorporating all five risk factors, the predictive capacity significantly increased (AUC = 0.777, < 0.0001), enabling the forecast of 77.7% of dyslipidemia events. DBIL emerges as the most potent predictor, and in conjunction with the other four factors, can effectively forecast VID in pediatric patients with epilepsy. This insight can guide the formulation of individualized strategies for the clinical administration of VPA in children.
PubMed: 38628642
DOI: 10.3389/fphar.2024.1349043 -
JAMA Network Open Apr 2024Sydenham chorea is the most common acquired chorea of childhood worldwide; however, treatment is limited by a lack of high-quality evidence. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Sydenham chorea is the most common acquired chorea of childhood worldwide; however, treatment is limited by a lack of high-quality evidence.
OBJECTIVES
To evaluate historical changes in the clinical characteristics of Sydenham chorea and identify clinical and treatment factors at disease onset associated with chorea duration, relapsing disease course, and functional outcome.
DATA SOURCES
The systematic search for this meta-analysis was conducted in PubMed, Embase, CINAHL, Cochrane Library, and LILACS databases and registers of clinical trials from inception to November 1, 2022 (search terms: [Sydenham OR Sydenham's OR rheumatic OR minor] AND chorea).
STUDY SELECTION
Published articles that included patients with a final diagnosis of Sydenham chorea (in selected languages).
DATA EXTRACTION AND SYNTHESIS
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Individual patient data on clinical characteristics, treatments, chorea duration, relapse, and final outcome were extracted. Data from patients in the modern era (1945 through 2022) were entered into multivariable models and stratified by corticosteroid duration for survival analysis of chorea duration.
MAIN OUTCOMES AND MEASURES
The planned study outcomes were chorea duration at onset, monophasic course (absence of relapse after ≥24 months), and functional outcome (poor: modified Rankin Scale score 2-6 or persisting chorea, psychiatric, or behavioral symptoms at final follow-up after ≥6 months; good: modified Rankin Scale score 0-1 and no chorea, psychiatric, or behavioral symptoms at final follow-up).
RESULTS
In total, 1479 patients were included (from 307 articles), 1325 since 1945 (median [IQR] age at onset, 10 [8-13] years; 875 of 1272 female [68.8%]). Immunotherapy was associated with shorter chorea duration (hazard ratio for chorea resolution, 1.51 [95% CI, 1.05-2.19]; P = .03). The median chorea duration in patients receiving 1 or more months of corticosteroids was 1.2 months (95% CI, 1.2-2.0) vs 2.8 months (95% CI, 2.0-3.0) for patients receiving none (P = .004). Treatment factors associated with monophasic disease course were antibiotics (odds ratio [OR] for relapse, 0.28 [95% CI, 0.09-0.85]; P = .02), corticosteroids (OR, 0.32 [95% CI, 0.15-0.67]; P = .003), and sodium valproate (OR, 0.33 [95% CI, 0.15-0.71]; P = .004). Patients receiving at least 1 month of corticosteroids had significantly lower odds of relapsing course (OR, 0.10 [95% CI, 0.04-0.25]; P < .001). No treatment factor was associated with good functional outcome.
CONCLUSIONS AND RELEVANCE
In this meta-analysis of treatments and outcomes in patients with Sydenham chorea, immunotherapy, in particular corticosteroid treatment, was associated with faster resolution of chorea. Antibiotics, corticosteroids and sodium valproate were associated with a monophasic disease course. This synthesis of retrospective data should support the development of evidence-based treatment guidelines for patients with Sydenham chorea.
Topics: Humans; Female; Child; Adolescent; Chorea; Retrospective Studies; Valproic Acid; Disease Progression; Anti-Bacterial Agents; Adrenal Cortex Hormones; Recurrence
PubMed: 38625703
DOI: 10.1001/jamanetworkopen.2024.6792 -
International Journal of Molecular... Mar 2024Niemann-Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases... (Review)
Review
Niemann-Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, α-synuclein, TDP-43, and β-amyloid peptide. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing four principal mechanisms: synthesis, folding, maintenance of folding, and protein degradation. The dysregulation of these processes leads to excessive accumulation of abnormal proteins that impair cell function and trigger cytotoxicity. This comprehensive review delineates reported alterations across proteostasis mechanisms in NPC, encompassing changes in processes from synthesis to degradation. Additionally, it discusses therapeutic interventions targeting pharmacological facets of proteostasis in NPC. Noteworthy among these interventions is valproic acid, a histone deacetylase inhibitor (HDACi) that modulates acetylation during NPC1 synthesis. In addition, various therapeutic options addressing protein folding modulation, such as abiraterone acetate, DHBP, calnexin, and arimoclomol, are examined. Additionally, treatments impeding NPC1 degradation, exemplified by bortezomib and MG132, are explored as potential strategies. This review consolidates current knowledge on proteostasis dysregulation in NPC and underscores the therapeutic landscape targeting diverse facets of this intricate process.
Topics: Humans; Proteostasis; Niemann-Pick Disease, Type C; Lysosomal Storage Diseases; Protein Folding; Proteolysis
PubMed: 38612616
DOI: 10.3390/ijms25073806 -
Frontiers in Immunology 2024Coronavirus disease (COVID-19), caused by SARS-CoV-2, has emerged as a infectious disease, coexisting with widespread seasonal and sporadic influenza epidemics globally....
BACKGROUND
Coronavirus disease (COVID-19), caused by SARS-CoV-2, has emerged as a infectious disease, coexisting with widespread seasonal and sporadic influenza epidemics globally. Individuals living with HIV, characterized by compromised immune systems, face an elevated risk of severe outcomes and increased mortality when affected by COVID-19. Despite this connection, the molecular intricacies linking COVID-19, influenza, and HIV remain unclear. Our research endeavors to elucidate the shared pathways and molecular markers in individuals with HIV concurrently infected with COVID-19 and influenza. Furthermore, we aim to identify potential medications that may prove beneficial in managing these three interconnected illnesses.
METHODS
Sequencing data for COVID-19 (GSE157103), influenza (GSE185576), and HIV (GSE195434) were retrieved from the GEO database. Commonly expressed differentially expressed genes (DEGs) were identified across the three datasets, followed by immune infiltration analysis and diagnostic ROC analysis on the DEGs. Functional enrichment analysis was performed using GO/KEGG and Gene Set Enrichment Analysis (GSEA). Hub genes were screened through a Protein-Protein Interaction networks (PPIs) analysis among DEGs. Analysis of miRNAs, transcription factors, drug chemicals, diseases, and RNA-binding proteins was conducted based on the identified hub genes. Finally, quantitative PCR (qPCR) expression verification was undertaken for selected hub genes.
RESULTS
The analysis of the three datasets revealed a total of 22 shared DEGs, with the majority exhibiting an area under the curve value exceeding 0.7. Functional enrichment analysis with GO/KEGG and GSEA primarily highlighted signaling pathways associated with ribosomes and tumors. The ten identified hub genes included , , , , , , , , , and . Additionally, five crucial miRNAs (hsa-miR-8060, hsa-miR-6890-5p, hsa-miR-5003-3p, hsa-miR-6893-3p, and hsa-miR-6069), five essential transcription factors (CREB1, CEBPB, EGR1, EP300, and IRF1), and the top ten significant drug chemicals (estradiol, progesterone, tretinoin, calcitriol, fluorouracil, methotrexate, lipopolysaccharide, valproic acid, silicon dioxide, cyclosporine) were identified.
CONCLUSION
This research provides valuable insights into shared molecular targets, signaling pathways, drug chemicals, and potential biomarkers for individuals facing the complex intersection of COVID-19, influenza, and HIV. These findings hold promise for enhancing the precision of diagnosis and treatment for individuals with HIV co-infected with COVID-19 and influenza.
Topics: Humans; Influenza, Human; COVID-19; SARS-CoV-2; Computational Biology; MicroRNAs; Transcription Factors; Gene Expression Regulation; HIV Infections
PubMed: 38601162
DOI: 10.3389/fimmu.2024.1369311 -
Epilepsy & Behavior Reports 2024Traumatic brain injury (TBI) patients are recommended to receive anti-seizure medication (ASM) as posttraumatic seizure (PTS) prophylaxis. However, the utilization of...
Traumatic brain injury (TBI) patients are recommended to receive anti-seizure medication (ASM) as posttraumatic seizure (PTS) prophylaxis. However, the utilization of ASM, including the prescription patterns and associated clinical characteristics, is limited in Taiwan. Thus, this study aimed to investigate the ASM trends and clinical characteristics. This retrospective cohort study enrolled TBI patients who received levetiracetam, phenytoin, and valproic acid during hospitalization using the National Health Insurance Research Database between 2012 and 2019. The primary outcome was the trend of the ASMs based on the index year. The duration of levetiracetam prescription was categorized as short-term (seven days or less) or long-term (more than seven days). Logistic regression identified the factors associated with long-term usage. A total of 64,461 TBI patients were included. Levetiracetam usage increased yearly, while phenytoin declined. Among the levetiracetam users, 5681 (30.38%) were short-term users, and 13,016 (69.62%) were long-term users. Diagnoses of contusions, intracranial hemorrhage, other intracranial injuries, receiving operations, and a history of cerebrovascular disease were significantly associated with longer duration. Conclusions This study revealed the rising trend of levetiracetam usage, indicating its potential as an alternative to phenytoin. TBI patients with more severe conditions were more likely to receive longer prescriptions.
PubMed: 38590545
DOI: 10.1016/j.ebr.2024.100662 -
Scientific Reports Apr 2024Transcranial magnetic stimulation (TMS) is a neurostimulation device used to modulate brain cortex activity. Our objective was to enhance the therapeutic effectiveness...
Reversing valproic acid-induced autism-like behaviors through a combination of low-frequency repeated transcranial magnetic stimulation and superparamagnetic iron oxide nanoparticles.
Transcranial magnetic stimulation (TMS) is a neurostimulation device used to modulate brain cortex activity. Our objective was to enhance the therapeutic effectiveness of low-frequency repeated TMS (LF-rTMS) in a rat model of autism spectrum disorder (ASD) induced by prenatal valproic acid (VPA) exposure through the injection of superparamagnetic iron oxide nanoparticles (SPIONs). For the induction of ASD, we administered prenatal VPA (600 mg/kg, I.P.) on the 12.5th day of pregnancy. At postnatal day 30, SPIONs were injected directly into the lateral ventricle of the brain. Subsequently, LF-rTMS treatment was applied for 14 consecutive days. Following the treatment period, behavioral analyses were conducted. At postnatal day 60, brain tissue was extracted, and both biochemical and histological analyses were performed. Our data revealed that prenatal VPA exposure led to behavioral alterations, including changes in social interactions, increased anxiety, and repetitive behavior, along with dysfunction in stress coping strategies. Additionally, we observed reduced levels of SYN, MAP2, and BDNF. These changes were accompanied by a decrease in dendritic spine density in the hippocampal CA1 area. However, LF-rTMS treatment combined with SPIONs successfully reversed these dysfunctions at the behavioral, biochemical, and histological levels, introducing a successful approach for the treatment of ASD.
Topics: Pregnancy; Female; Rats; Animals; Humans; Valproic Acid; Autistic Disorder; Autism Spectrum Disorder; Transcranial Magnetic Stimulation; Social Behavior; Magnetic Iron Oxide Nanoparticles; Prenatal Exposure Delayed Effects; Disease Models, Animal; Behavior, Animal
PubMed: 38582936
DOI: 10.1038/s41598-024-58871-5 -
Journal of Clinical Laboratory Analysis Apr 2024This study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the...
OBJECTIVE
This study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA.
METHODS
We retrospectively reviewed data of hospitalized patients who were diagnosed with status epilepticus or epilepsy between 2010 and 2019. Patients co-administered VPA and MEPM during hospitalization were screened and assigned to the exposure group, while those co-administerd VPA and other broad-spectrum antibiotics were allocated to the control group.
RESULTS
The exposure group and control group included 50 and 11 patients, respectively. With a similar dosage of VPA, the plasma concentration of VPA significantly decreased during co-administration (24.6 ± 4.3 μg/mL) compared with that before co-administration (88.8 ± 13.6 μg/mL, p < 0.0001), and it was partly recovered with the termination of co-administration (39.8 ± 13.2 μg/mL, p = 0.163) in the exposure group. The inverse probability of treatment weighting estimated the treatment efficacy via changes in seizure frequency, seizure duration, and concomitant use of antiepileptic drugs, which were not significantly different between the exposure and control groups. In the exposure group, there was no significant differences in seizure frequency between the periods of before-during and before-after (p = 0.074 and 0.153, respectively). Seizure duration during VPA-MEPM co-administration was not significantly different from that before co-administration (p = 0.291).
CONCLUSIONS
In this study, the reduced plasma concentration of VPA induced by the co-administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted.
TRIAL REGISTRATION
Chinese Clinical Trial Registry: ChiCTR2000034567. Registered on 10 July 2020.
Topics: Humans; Valproic Acid; Anticonvulsants; Meropenem; Male; Female; Middle Aged; Retrospective Studies; Adult; Aged; Epilepsy; Drug Interactions; Anti-Bacterial Agents; Treatment Outcome
PubMed: 38563451
DOI: 10.1002/jcla.25025 -
Frontiers in Neuroscience 2024Autism is a complex neurodevelopmental condition characterized by deficits in social interaction, communication, and restricted repetitive behaviors. Hyperbaric oxygen...
INTRODUCTION
Autism is a complex neurodevelopmental condition characterized by deficits in social interaction, communication, and restricted repetitive behaviors. Hyperbaric oxygen therapy (HBOT) has emerged as a potential treatment for autism, although its effects on behavior and gene expression are not well understood. The gene, known for its involvement in encoding a glutamate receptor subunit crucial for neuron communication and associated with autism, was a focus of this study.
METHODS
Using a rat model induced by prenatal exposure to valproic acid, we examined the impact of HBOT on autism-like behaviors and gene expression. Male Wistar rats were categorized into four groups: control, VPA (valproic acid-exposed), VPA+HBOT [2 atmosphere absolute (ATA)], and VPA+HBOT (2.5 ATA). The rats underwent several behavioral tests to assess social behavior, anxiety, stereotype and exploratory behaviors, and learning. Following the behavioral tests, the HBOT groups received 15 sessions of HBOT at pressures of 2 and 2.5 (ATA), and their behaviors were re-evaluated. Subsequently, real-time PCR was employed to measure gene expression in the frontal lobe.
RESULTS
Our results indicated that HBOT significantly increased social interaction and exploratory behaviors in VPA-exposed rats, alongside elevated gene expression in their frontal lobe.
DISCUSSION
Our findings imply that HBOT might have a potential role in ameliorating autism-related behaviors in the VPA rat model of autism through potential modulation of gene expression. However, additional research is essential to fully comprehend the underlying mechanisms and refine the HBOT protocol for optimizing its effectiveness in improving autism-related symptoms.
PubMed: 38562305
DOI: 10.3389/fnins.2024.1385189 -
The Journal of Clinical Investigation Apr 2024Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally,...
Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/- mice and partially reversed gene expression changes in Kat6b+/- cortical neurons. Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.
Topics: Animals; Humans; Mice; Abnormalities, Multiple; Acetylation; Acetylcarnitine; Blepharophimosis; Chromatin; Congenital Hypothyroidism; Craniofacial Abnormalities; Exons; Facies; Heart Defects, Congenital; Histone Acetyltransferases; Histones; Intellectual Disability; Joint Instability
PubMed: 38557491
DOI: 10.1172/JCI167672 -
Journal of Investigative Medicine High... 2024Stevens-Johnson syndrome is an infrequent condition affecting the skin and mucous membranes, it involves cutaneous detachment with high mortality without adequate...
Stevens-Johnson syndrome is an infrequent condition affecting the skin and mucous membranes, it involves cutaneous detachment with high mortality without adequate treatment. We present the case of a 40-year-old male with a history of epilepsy treated with valproic acid and lamotrigine, previously diagnosed with dengue. Evaluation showed erythematous blisters on skin and mucosa with bleeding and desquamation, covering 10% of the body surface. The patient progressed favorably with the medical care received. Stevens-Johnson syndrome should be studied in association with arboviral diseases.
Topics: Male; Humans; Adult; Stevens-Johnson Syndrome; Peru; Anticonvulsants; Valproic Acid; Dengue
PubMed: 38546109
DOI: 10.1177/23247096241242574