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Frontiers in Veterinary Science 2024A 4-year-old male neutered Boston Terrier was presented with status epilepticus. He was diagnosed with idiopathic epilepsy and hospitalized with supportive care. During...
A 4-year-old male neutered Boston Terrier was presented with status epilepticus. He was diagnosed with idiopathic epilepsy and hospitalized with supportive care. During hospitalization, the patient developed both supraventricular and ventricular arrhythmias as well as focal left ventricular dyskinesis. Cardiac troponin I was significantly increased, which was supportive of myocardial damage. Neurogenic stunned myocardium was suspected, and the patient was treated and responded to esmolol. Follow-up echocardiography demonstrated the resolution of the ventricular dyskinesia. This report describes the clinical presentation, diagnostic findings, treatment, management, and outcome of the first reported case of naturally occurring neurogenic stunned myocardium in a dog. Electrocardiogram monitoring, cardiac troponin I, and echocardiography should be considered in patients presenting with seizure activity, especially when exhibiting cluster seizures or in status epilepticus.
PubMed: 38895716
DOI: 10.3389/fvets.2024.1376107 -
Sensors (Basel, Switzerland) Jun 2024The interpretability of gait analysis studies in people with rare diseases, such as those with primary hereditary cerebellar ataxia (pwCA), is frequently limited by the...
The interpretability of gait analysis studies in people with rare diseases, such as those with primary hereditary cerebellar ataxia (pwCA), is frequently limited by the small sample sizes and unbalanced datasets. The purpose of this study was to assess the effectiveness of data balancing and generative artificial intelligence (AI) algorithms in generating synthetic data reflecting the actual gait abnormalities of pwCA. Gait data of 30 pwCA (age: 51.6 ± 12.2 years; 13 females, 17 males) and 100 healthy subjects (age: 57.1 ± 10.4; 60 females, 40 males) were collected at the lumbar level with an inertial measurement unit. Subsampling, oversampling, synthetic minority oversampling, generative adversarial networks, and conditional tabular generative adversarial networks (ctGAN) were applied to generate datasets to be input to a random forest classifier. Consistency and explainability metrics were also calculated to assess the coherence of the generated dataset with known gait abnormalities of pwCA. ctGAN significantly improved the classification performance compared with the original dataset and traditional data augmentation methods. ctGAN are effective methods for balancing tabular datasets from populations with rare diseases, owing to their ability to improve diagnostic models with consistent explainability.
Topics: Humans; Female; Male; Middle Aged; Gait; Cerebellar Ataxia; Rare Diseases; Artificial Intelligence; Algorithms; Adult; Gait Analysis; Aged
PubMed: 38894404
DOI: 10.3390/s24113613 -
International Journal of Molecular... May 2024Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of... (Review)
Review
Neurodegenerative diseases are progressive disorders that affect the central nervous system (CNS) and represent the major cause of premature death in the elderly. One of the possible determinants of neurodegeneration is the change in mitochondrial function and content. Altered levels of mitochondrial DNA copy number (mtDNA-CN) in biological fluids have been reported during both the early stages and progression of the diseases. In patients affected by neurodegenerative diseases, changes in mtDNA-CN levels appear to correlate with mitochondrial dysfunction, cognitive decline, disease progression, and ultimately therapeutic interventions. In this review, we report the main results published up to April 2024, regarding the evaluation of mtDNA-CN levels in blood samples from patients affected by Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The aim is to show a probable link between mtDNA-CN changes and neurodegenerative disorders. Understanding the causes underlying this association could provide useful information on the molecular mechanisms involved in neurodegeneration and offer the development of new diagnostic approaches and therapeutic interventions.
Topics: Humans; Neurodegenerative Diseases; DNA, Mitochondrial; DNA Copy Number Variations; Mitochondria; Huntington Disease; Animals
PubMed: 38892250
DOI: 10.3390/ijms25116062 -
International Journal of Molecular... May 2024Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and retinal pigment epithelial atrophy, leading to severe visual...
Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and retinal pigment epithelial atrophy, leading to severe visual impairment or blindness. RP can be classified as nonsyndromic or syndromic with complex clinical phenotypes. Three unrelated Polish probands affected with retinitis pigmentosa coexisting with cerebellar ataxia were recruited for this study. Clinical heterogeneity and delayed appearance of typical disease symptoms significantly prolonged the patients' diagnostic process. Therefore, many clinical and genetic tests have been performed in the past. Here, we provide detailed clinical and genetic analysis results of the patients. Whole-exome sequencing (WES) and targeted NGS analysis allow the identification of four novel and two previously reported variants in the following genes: , , and The use of next-generation sequencing (NGS) methods finally allowed for confirmation of the clinical diagnosis. Ultra-rare diseases such as PHARC, PCARP, and Oliver-McFarlane syndromes were diagnosed in patients, respectively. Our findings confirmed the importance of the application of next-generation sequencing methods, especially in ultra-rare genetic disorders with overlapping features.
Topics: Humans; Retinitis Pigmentosa; Male; Female; Exome Sequencing; Pedigree; High-Throughput Nucleotide Sequencing; Adult; Cerebellar Ataxia; Membrane Transport Proteins; Monoacylglycerol Lipases; Mutation; Ataxia; Phenotype; Acyltransferases; Cataract; Phospholipases; Polyneuropathies
PubMed: 38891946
DOI: 10.3390/ijms25115759 -
Cells Jun 2024Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous, motile ciliopathy, characterized by neonatal respiratory distress, recurrent upper and lower... (Review)
Review
Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous, motile ciliopathy, characterized by neonatal respiratory distress, recurrent upper and lower respiratory tract infections, subfertility, and laterality defects. Diagnosis relies on a combination of tests for confirmation, including nasal nitric oxide (nNO) measurements, high-speed videomicroscopy analysis (HSVMA), immunofluorescent staining, axonemal ultrastructure analysis via transmission electron microscopy (TEM), and genetic testing. Notably, there is no single gold standard confirmatory or exclusionary test. Currently, 54 causative genes involved in cilia assembly, structure, and function have been linked to PCD; this rare disease has a spectrum of clinical manifestations and emerging genotype-phenotype relationships. In this review, we provide an overview of the structure and function of motile cilia, the emerging genetics and pathophysiology of this rare disease, as well as clinical features associated with motile ciliopathies, novel diagnostic tools, and updates on genotype-phenotype relationships in PCD.
Topics: Humans; Cilia; Ciliary Motility Disorders; Phenotype
PubMed: 38891105
DOI: 10.3390/cells13110974 -
Communications Biology Jun 2024Cognitive reserve is the ability to actively cope with brain deterioration and delay cognitive decline in neurodegenerative diseases. It operates by optimizing...
Cognitive reserve is the ability to actively cope with brain deterioration and delay cognitive decline in neurodegenerative diseases. It operates by optimizing performance through differential recruitment of brain networks or alternative cognitive strategies. We investigated cognitive reserve using Huntington's disease (HD) as a genetic model of neurodegeneration to compare premanifest HD, manifest HD, and controls. Contrary to manifest HD, premanifest HD behave as controls despite neurodegeneration. By decomposing the cognitive processes underlying decision making, drift diffusion models revealed a response profile that differs progressively from controls to premanifest and manifest HD. Here, we show that cognitive reserve in premanifest HD is supported by an increased rate of evidence accumulation compensating for the abnormal increase in the amount of evidence needed to make a decision. This higher rate is associated with left superior parietal and hippocampal hypertrophy, and exhibits a bell shape over the course of disease progression, characteristic of compensation.
Topics: Hippocampus; Humans; Decision Making; Cognitive Reserve; Male; Female; Huntington Disease; Middle Aged; Parietal Lobe; Hypertrophy; Adult; Neurodegenerative Diseases
PubMed: 38890487
DOI: 10.1038/s42003-024-06416-x -
Neuropharmacology Jun 2024Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that...
Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that sub-anesthetic ketamine produces acute anti-parkinsonian, and acute anti-dyskinetic effects in preclinical models of Parkinson's disease (PD). Ketamine is a multifunctional drug and exerts effects through blockade of N-methyl-d-aspartate receptors but also through interaction with the opioid system. In this report, we provide detailed pharmacokinetic rodent data on ketamine and its main metabolites following an intraperitoneal injection, and second, we explore the pharmacodynamic properties of ketamine in a rodent PD model with respect to the opioid system, using naloxone, a pan-opioid receptor antagonist, in unilateral 6-hydroxydopamine-lesioned male rats, treated with 6 mg/kg levodopa (l-DOPA) to establish a model of l-DOPA-induced dyskinesia (LID). As previously reported, we showed that ketamine (20 mg/kg) is highly efficacious in reducing LID and now report that the magnitude of this effect is resistant to naloxone (3 and 5 mg/kg). The higher naloxone dose of 5 mg/kg, however, led to an extension of the time-course of the LID, indicating that opioid receptor activation, while not a prerequisite for the anti-dyskinetic effects of ketamine, still exerts an acute modulatory effect. In contrast to the mild modulatory effect on LID, we found that naloxone added to the anti-parkinsonian activity of ketamine, further reducing the akinetic phenotype. In conclusion, our data show opioid receptor blockade differentially modulates the acute anti-parkinsonian and anti-dyskinetic actions of ketamine, providing novel mechanistic information to support repurposing ketamine for individuals with LID.
PubMed: 38889877
DOI: 10.1016/j.neuropharm.2024.110047 -
CNS Neuroscience & Therapeutics Jun 2024In absence of drug therapy options, standard treatment for spinocerebellar ataxia consists of symptomatic physiotherapy and speech therapy. New therapeutic options are... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In absence of drug therapy options, standard treatment for spinocerebellar ataxia consists of symptomatic physiotherapy and speech therapy. New therapeutic options are urgently needed. Transcranial magnetic stimulation is a promising therapeutic option, but applicability is limited by lengthy duration of stimulation protocols.
METHODS
In this randomized sham controlled clinical trial, patients were assigned to verum (n = 15) or sham (n = 18) cerebellar transcranial magnetic stimulation. To yield best possible treatment effects, both intervention groups received intensified physiotherapy for the duration of the study.
RESULTS
Ataxia severity was reduced by 1.6 points on the Scale for assessment and Rating of Ataxia among patients in the verum group (p < 0.001). Clinical improvement was significantly larger in the verum group, compared to the sham group (p < 0.01). The treatment effect was mainly carried by improved appendicular coordination. Patients in the verum group also significantly improved in the 8 Meter Walk Test (p < 0.05) and PATA rate (p < 0.01).
CONCLUSIONS
Cerebellar rTMS ameliorates ataxia severity in patient with spinocerebellar ataxia. Condensing treatment duration to only 5 days without reduction of treatment effects facilitates applicability and therefore broadens availability to larger patient populations.
Topics: Humans; Spinocerebellar Ataxias; Male; Female; Transcranial Magnetic Stimulation; Middle Aged; Adult; Cerebellum; Physical Therapy Modalities; Treatment Outcome; Combined Modality Therapy; Aged; Severity of Illness Index
PubMed: 38887169
DOI: 10.1111/cns.14797 -
Advanced Genetics (Hoboken, N.J.) Jun 2024The co-occurrence of sensorineural hearing loss and male infertility has been reported in several instances, suggesting potential shared genetic underpinnings. One such...
The co-occurrence of sensorineural hearing loss and male infertility has been reported in several instances, suggesting potential shared genetic underpinnings. One such example is the contiguous gene deletion of and genes, previously associated with deafness-infertility syndrome (DIS) in males. Fifteen males with both hearing loss and infertility from southern India after exclusion for the DIS contiguous gene deletion and the gene mutations are subjected to exome sequencing. This resolves the genetic etiology in four probands for both the phenotypes; In the remaining 11 probands, two each conclusively accounted for deafness and male infertility etiologies. Genetic heterogeneity is well reflected in both phenotypes. Four recessive () and one dominant () for the deafness; six recessive genes (, and ) for male infertility can be conclusively ascribed. and genes are implicated earlier only in mice models, while the gene is implicated in chronic destructive airway diseases due to primary ciliary dyskinesia. This study would be the first to document the role of these genes in the male infertility phenotype in humans. The result suggests that deafness and infertility are independent events and do not segregate together among the probands.
PubMed: 38884051
DOI: 10.1002/ggn2.202300206 -
Chest Jun 2024Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by the malfunction of motile cilia and a specific etiology of adult bronchiectasis of unknown...
BACKGROUND
Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by the malfunction of motile cilia and a specific etiology of adult bronchiectasis of unknown prevalence. A better understanding of the clinical phenotype of adults with PCD is needed to identify individuals for referral to diagnostic testing.
CLINICAL RESEARCH QUESTIONS
What is the frequency of PCD among adults with bronchiectasis; how do people with PCD differ from those with other etiologies; and which clinical characteristics are independently associated with PCD?
STUDY DESIGN AND METHODS
We investigated the proportion of PCD among the participants of the German Bronchiectasis Registry PROGNOSIS, applied multiple imputation to account for missing data in 64 (FEV), 58 (breathlessness), 26 (pulmonary exacerbations), and 2 subjects (BMI), respectively, and identified predictive variables from baseline data using multivariate logistic regression analysis.
RESULTS
We consecutively recruited 1,000 patients from 38 centers across all levels of the German healthcare system. Overall, PCD was the fifth most common etiology of bronchiectasis in 87 subjects (9%) after idiopathic, post-infective, COPD, and asthma. People with PCD showed a distinct clinical phenotype. In multivariate regression analysis, the chance of PCD being the etiology of bronchiectasis increased with the presence of upper airway disease (chronic rhinosinusitis and/or nasal polyps; aOR, 6.3; 95% CI 3.3-11.9; P < .001); age < 53 years (aOR, 5.3; 95% CI 2.7-10.4; P < .001); radiological involvement of any middle and lower lobe (aOR, 3.7; 95% CI 1.3-10.8; P = .016); duration of bronchiectasis > 15 years (aOR, 3.6; 95% CI 1.9-6.9; P < .001); and a history of Pseudomonas aeruginosa isolation from respiratory specimen (aOR, 2.4; 95% CI 1.3-4.5; P = .007).
INTERPRETATION
Within our nationally representative cohort, PCD was a common etiology of bronchiectasis. We identified few easy-to-assess phenotypic features, which may promote awareness for PCD among adults with bronchiectasis.
PubMed: 38880279
DOI: 10.1016/j.chest.2024.05.023