Freezing of gait (FOG) is a common and challenging clinical symptom in Parkinson’s disease. In this review, we summarise the recent insights into freezing of gait and highlight the strategies that ...should be considered to improve future treatment. There is a need to develop individualised and on-demand therapies, through improved detection and wearable technologies. Whilst there already exist a number of pharmacological (e.g., dopaminergic and beyond dopamine), non-pharmacological (physiotherapy and cueing, cognitive training, and non-invasive brain stimulation) and surgical approaches to freezing (i.e., dual-site deep brain stimulation, closed-loop programming), an integrated collaborative approach to future research in this complex area will be necessary to systematically investigate new therapeutic avenues. A review of the literature suggests standardising how gait freezing is measured, enriching patient cohorts for preventative studies, and harnessing the power of existing data, could help lead to more effective treatments for freezing of gait and offer relief to many patients.
BackgroundWhilst stridor related to bilateral vocal cord paralysis (BVCP) is a recognised complication of increased intracranial pressure, it typically resolves with ventricular-peritoneal (VP) ...shunting. We present a case where tracheostomy was needed after successful VP shunting.CaseA 33-year-old-man presented with headache, slurred speech and immobility. His background included resected medulloblastoma with head-neck radiotherapy (aged 8), long-term VP shunt, and post-treatment ataxia which had progressed over 2 years with development of intermittent nocturnal stridor. He underwent emergent shunt revision for a distally blocked shunt, with resolution of hydrocephalus. Two days afterwards, he developed hiccups and worsened stridor which progressed to respiratory obstruction over 24 hours. Laryngoscopy showed tightly adducted midline vocal folds with coarse pharyngeal, palatal, and tongue myorhythmia (3 Hz). There was no response to benzodiazepines and no epileptiform activity on EEG. He had loss of gag reflex on neurological examination with normal eye movements. A cerebral and neck MRI showed resolution of hydrocephalus and post-treatment changes related to previous medulloblastoma. There has unfortunately been no improvement in vocal fold movement over 3 weeks.DiscussionSubacute stridor may be due to pathological upper motor neurone activation of the branchial motor component of the vagal nerves with this person’s background brain injury.1 Tight acute midline cord positioning and myoclonus may be unusually caused by bilateral recurrent laryngeal nerve lesions secondary to changes in intracranial pressure,2 3 but is not the favoured sole mechanism here. Botulinum toxin therapy could provide benefit but may compromise a future safe swallow.ReferencesToland AD, Porubsky ES, Coker NJ, Adams HG. Velo-pharyngo-laryngeal myoclonus: evaluation of objective tinnitus and extrathoracic airway obstruction. Laryngoscope. 1984;94(5 Pt 1):691–5.Davis L, Ross N. Bilateral vocal cord palsy after ventricular drainage in a child. Anesth Analg. 2001;92(2):358–61.Mayhew JF, Miner ME, Denneny J. Upper airway obstruction following cyst-to-peritoneal shunt in a child with a Dandy-Walker cyst. Anesthesiology. 1985;62(2):183–4.
Abstract The expression of acetylcholinesterase (AChE), an enzyme hydrolyzes neurotransmitter acetylcholine at vertebrate neuromuscular junction, is regulated during myogenesis, indicating the ...significance of muscle intrinsic factors in controlling the enzyme expression. DNA methylation is essential for temporal control of myogenic gene expression during myogenesis; however, its role in AChE regulation is not known. The promoter of vertebrate ACHE gene carries highly conserved CG-rich regions, implying its likeliness to be methylated for epigenetic regulation. A DNA methyltransferase inhibitor, 5-azacytidine (5-Aza), was applied onto C2C12 cells throughout the myotube formation. When DNA methylation was inhibited, the promoter activity, transcript expression and enzymatic activity of AChE were markedly increased after day 3 of differentiation, which indicated the putative role of DNA methylation. By bisulfite pyrosequencing, the overall methylation rate was found to peak at day 3 during C2C12 cell differentiation; a SP1 site located at −1826 bp upstream of mouse ACHE gene was revealed to be heavily methylated. The involvement of transcriptional factor SP1 in epigenetic regulation of AChE was illustrated here: (i) the SP1-driven transcriptional activity was increased in 5-Aza-treated C2C12 culture; (ii) the binding of SP1 onto the SP1 site of ACHE gene was fully blocked by the DNA methylation; and (iii) the sequence flanking SP1 sites of ACHE gene was precipitated by chromatin immuno-precipitation assay. The findings suggested the role of DNA methylation on AChE transcriptional regulation and provided insight in elucidating the DNA methylation-mediated regulatory mechanism on AChE expression during muscle differentiation.
Adenosine 5′-triphosphate (ATP), a neurotransmitter and a neuromodulator, has been shown to be co-stored and co-released with acetylcholine (ACh) at the pre-synaptic vesicles in vertebrate ...neuromuscular junction (nmj). Several lines of studies demonstrated that binding of ATP to its corresponding P2Y1 receptors (P2Y1R) in muscle and neuron regulated the post-synaptic gene expressions. Indeed, the expression of acetylcholinesterase (AChE) in muscle was markedly decreased in P2Y1R−/− (P2Y1R knock-out) mice. In order to search for possible role of P2Y1R in cholinergic function of the brain, the expression of globular form AChE was determined in the brain of P2Y1R−/− mice. In contrast to that in muscle, the amounts of AChE activity, AChE catalytic subunit, structure subunit PRiMA and the amount of ACh, in the brain were not, significantly, altered, suggesting the role of P2Y1R in neuron could have different function as that in muscle. However, the expressions of a series of neuronal development markers, i.e. neurofilaments, were reduced in P2Y1R−/− mouse brain, indicating P2Y1R may be involved in neuronal development process.
•Dysfunction of P2Y1R did not alter the expressions of G4 AChE in mouse brain.•Dysfunction of P2Y1R did not affect the amount of ACh in mouse brain.•Reduced expressions of neurofilaments were found in P2Y1R−/− mouse brain.•ATP/P2Y1R signaling may play roles in neuronal differentiation.
In many databases, biocuration primarily involves literature curation, which usually involves retrieving relevant articles, extracting information that will translate into annotations and identifying ...new incoming literature. As the volume of biological literature increases, the use of text mining to assist in biocuration becomes increasingly relevant. A number of groups have developed tools for text mining from a computer science/linguistics perspective, and there are many initiatives to curate some aspect of biology from the literature. Some biocuration efforts already make use of a text mining tool, but there have not been many broad-based systematic efforts to study which aspects of a text mining tool contribute to its usefulness for a curation task. Here, we report on an effort to bring together text mining tool developers and database biocurators to test the utility and usability of tools. Six text mining systems presenting diverse biocuration tasks participated in a formal evaluation, and appropriate biocurators were recruited for testing. The performance results from this evaluation indicate that some of the systems were able to improve efficiency of curation by speeding up the curation task significantly (∼1.7- to 2.5-fold) over manual curation. In addition, some of the systems were able to improve annotation accuracy when compared with the performance on the manually curated set. In terms of inter-annotator agreement, the factors that contributed to significant differences for some of the systems included the expertise of the biocurator on the given curation task, the inherent difficulty of the curation and attention to annotation guidelines. After the task, annotators were asked to complete a survey to help identify strengths and weaknesses of the various systems. The analysis of this survey highlights how important task completion is to the biocurators' overall experience of a system, regardless of the system's high score on design, learnability and usability. In addition, strategies to refine the annotation guidelines and systems documentation, to adapt the tools to the needs and query types the end user might have and to evaluate performance in terms of efficiency, user interface, result export and traditional evaluation metrics have been analyzed during this task. This analysis will help to plan for a more intense study in BioCreative IV.
Abstract A bigenic MUC1.Tg/MIN mouse model was developed by crossing Apc/ MIN/+ (MIN) mice with human MUC1 transgenic mice to evaluate MUC1 antigen-specific immunotherapy of intestinal adenomas. The ...MUC1.Tg/MIN mice developed adenomas at a rate comparable to that of MIN mice and had similar levels of serum MUC1 antigen. A MUC1-based vaccine consisting of MHC class I-restricted MUC1 peptides, a MHC class II-restricted pan-helper peptide, unmethylated CpG oligodeoxynucleotide and GM-CSF caused flattening of adenomas and significantly reduced the number of large adenomas. Immunization was successful in generating a MUC1-directed immune response evidenced by increased MUC1 peptide-specific anti-tumor cytotoxicity and IFN-γ secretion by lymphocytes.
In health, most large language model (LLM) research has focused on clinical tasks. However, mobile and wearable devices, which are rarely integrated into such tasks, provide rich, longitudinal data ...for personal health monitoring. Here we present Personal Health Large Language Model (PH-LLM), fine-tuned from Gemini for understanding and reasoning over numerical time-series personal health data. We created and curated three datasets that test 1) production of personalized insights and recommendations from sleep patterns, physical activity, and physiological responses, 2) expert domain knowledge, and 3) prediction of self-reported sleep outcomes. For the first task we designed 857 case studies in collaboration with domain experts to assess real-world scenarios in sleep and fitness. Through comprehensive evaluation of domain-specific rubrics, we observed that Gemini Ultra 1.0 and PH-LLM are not statistically different from expert performance in fitness and, while experts remain superior for sleep, fine-tuning PH-LLM provided significant improvements in using relevant domain knowledge and personalizing information for sleep insights. We evaluated PH-LLM domain knowledge using multiple choice sleep medicine and fitness examinations. PH-LLM achieved 79% on sleep and 88% on fitness, exceeding average scores from a sample of human experts. Finally, we trained PH-LLM to predict self-reported sleep quality outcomes from textual and multimodal encoding representations of wearable data, and demonstrate that multimodal encoding is required to match performance of specialized discriminative models. Although further development and evaluation are necessary in the safety-critical personal health domain, these results demonstrate both the broad knowledge and capabilities of Gemini models and the benefit of contextualizing physiological data for personal health applications as done with PH-LLM.
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