-
Journal of Pediatric Urology Jun 2024Many pediatric urology conditions affect putatively normal tissues or appear too commonly to be based solely on specific DNA mutations. Understanding epigenetic...
INTRODUCTION
Many pediatric urology conditions affect putatively normal tissues or appear too commonly to be based solely on specific DNA mutations. Understanding epigenetic mechanisms in pediatric urology, therefore, has many implications that can impact cell and tissue responses to settings, such as environmental and hormonal influences on urethral development, uropathogenic infections, obstructive stimuli, all of which originate externally or extracellularly. Indeed, the cell's response to external stimuli is often mediated epigenetically. In this commentary, we highlight work on the critical role that epigenetic machinery, such as DNA methyltransferases (DNMTs), Enhancer of Zeste Polycomb Repressive Complex 2 Subunit (EZH2), and others play in regulating gene expression and cellular functions in three urological contexts.
DESIGN
Animal and cellular constructs were used to model clinical pediatric uropathology. The hypertrophy, trabeculation, and fibrosis of the chronically obstructed bladder was explored using smooth muscle cell models employing disorganised vs. normal extracellular matrix (ECM), as well as a new animal model of chronic obstructive bladder disease (COBD) which retains its pathologic features even after bladder de-obstruction. Cell models from human and murine hypospadias or genital tubercles (GT) were used to illustrate developmental responses and epigenetic dependency of key developmental genes. Finally, using bladder urothelial and organoid culture systems, we examined activity of epigenetic machinery in response to non uropathogenic vs. uropathogenic E.coli (UPEC). DNMT and EZH2 expression and function were interrogated in these model systems.
RESULTS
Disordered ECM exerted a principal mitogenic and epigenetic role for on bladder smooth muscle both in vitro and in CODB in vivo. Key genes, e.g., BDNF and KCNB2 were under epigenetic regulation in actively evolving obstruction and COBD, though each condition showed distinct epigenetic responses. In models of hypospadias, estrogen strongly dysregulated WNT and Hox expression, which was normalized by epigenetic inhibition. Finally, DNA methylation machinery in the urothelium showed specific activation when challenged by uropathogenic E.coli. Similarly, UPEC induces hypermethylation and downregulation of the growth suppressor p16INK4A. Moreover, host cells exposed to UPEC produced secreted factors inducing epigenetic responses transmissible from one affected cell to another without ongoing bacterial presence.
DISCUSSION
Microenvironmental influences altered epigenetic activity in the three described urologic contexts. Considering that many obstructed bladders continue to display abnormal architecture and dysfunction despite relief of obstruction similar to after resection of posterior valves or BPH, the epigenetic mechanisms described highlight novel approaches for understanding the underlying smooth muscle myopathy of this crucial clinical problem. Similarly, there is evidence for an epigenetic basis of xenoestrogen on development of hypospadias, and UTI-induced pan-urothelial alteration of epigenetic marks and propensity for subsequent (recurrent) UTI. The impact of mechanical, hormonal, infectious triggers on genitourinary epigenetic machinery activity invite novel avenues for targeting epigenetic modifications associated with these non-cancer diseases in urology. This includes the use of deactivated CRISPR-based technologies for precise epigenome targeting and editing. Overall, we underscore the importance of understanding epigenetic regulation in pediatric urology for the development of innovative therapeutic and management strategies.
PubMed: 38944627
DOI: 10.1016/j.jpurol.2024.06.008 -
Free Radical Biology & Medicine Jun 2024Due to an unexpected activation of different zinc (Zn) transporters in a recent prospective clinical study, we have revisited the role of Zn homeostasis and the...
Reactive oxygen species in skeletal muscle injury, fatigue, regeneration and ageing: In memory of John Faulkner The role of zinc and matrix metalloproteinases in myofibrillar protein degradation in critical illness myopathy.
Due to an unexpected activation of different zinc (Zn) transporters in a recent prospective clinical study, we have revisited the role of Zn homeostasis and the activation of matrix metalloproteinases (MMPs) in skeletal muscle exposed to the intensive care unit (ICU) condition (immobilization and mechanical ventilation). ICU patients exposed to 12 days ICU condition were followed longitudinally with six repeated muscle biopsies while they showed a progressive preferential myosin loss, i.e., the hallmark of Critical Illness Myopathy (CIM), in parallel with the activation of Zn-transporters. In this study, we have revisited the expression of Zn-transporters and the activation of MMPs in clinical as well as in experimental studies using an established ICU model. MMPs are a group Zn-dependent endopeptidases which do not only target and cleave extracellular proteins but also intracellular proteins including multiple sarcomeric proteins. MMP-9 is of specific interest since the hallmark of CIM, the preferential myosin loss, has also been reported in dilated cardiomyopathy and coupled to MMP-9 activation. Transcriptional activation of Zn-transporters was observed in both clinical and experimental studies as well as the activation of MMPs, in particular MMP-9, in various limb and respiratory muscles in response to long-term exposure to the ICU condition. The activation of Zn-transporters was paralleled by increased Zn levels in skeletal muscle which in turn showed a negative linear correlation with the preferential myosin loss associated with CIM, offering a potential intervention strategy. Thus, activation of Zn-transporters, increased intramuscular Zn levels, and activation of the Zn-dependent MMPs are forwarded as a probable mechanism involved in CIM pathophysiology. These effects were confirmed in different rat strains subjected to a model of CIM and exacerbated by old age. This is of specific interest since old age and muscle wasting are the two factors most strongly associated with ICU mortality.
PubMed: 38944212
DOI: 10.1016/j.freeradbiomed.2024.06.022 -
Journal of Neuromuscular Diseases Jun 2024Respiratory and bulbar dysfunctions (including swallowing, feeding, and speech functions) are key symptoms of spinal muscular atrophy (SMA), especially in its most...
BACKGROUND
Respiratory and bulbar dysfunctions (including swallowing, feeding, and speech functions) are key symptoms of spinal muscular atrophy (SMA), especially in its most severe forms. Demonstrating the long-term efficacy of disease-modifying therapies (DMTs) necessitates an understanding of SMA natural history.
OBJECTIVE
This study summarizes published natural history data on respiratory, swallowing, feeding, and speech functions in patients with SMA not receiving DMTs.
METHODS
Electronic databases (Embase, MEDLINE, and Evidence-Based Medicine Reviews) were searched from database inception to June 27, 2022, for studies reporting data on respiratory and/or bulbar function outcomes in Types 1-3 SMA. Data were extracted into a predefined template and a descriptive summary of these data was provided.
RESULTS
Ninety-one publications were included: 43 reported data on respiratory, swallowing, feeding, and/or speech function outcomes. Data highlighted early loss of respiratory function for patients with Type 1 SMA, with ventilatory support typically required by 12 months of age. Patients with Type 2 or 3 SMA were at risk of losing respiratory function over time, with ventilatory support initiated between the first and fifth decades of life. Swallowing and feeding difficulties, including choking, chewing problems, and aspiration, were reported in patients across the SMA spectrum. Swallowing and feeding difficulties, and a need for non-oral nutritional support, were reported before 1 year of age in Type 1 SMA, and before 10 years of age in Type 2 SMA. Limited data relating to other bulbar functions were collated.
CONCLUSIONS
Natural history data demonstrate that untreated patients with SMA experience respiratory and bulbar function deterioration, with a more rapid decline associated with greater disease severity. This study provides a comprehensive repository of natural history data on bulbar function in SMA, and it highlights that consistent assessment of outcomes in this area is necessary to benefit understanding and approval of new treatments.
PubMed: 38943396
DOI: 10.3233/JND-230248 -
GeroScience Jun 2024A growing body of research suggested that there was a link between poor periodontal health and systemic diseases, particularly with the early development of cognitive... (Review)
Review
A growing body of research suggested that there was a link between poor periodontal health and systemic diseases, particularly with the early development of cognitive disorders, dementia, and depression. This is especially true in cases of changes in diet, malnutrition, loss of muscular endurance, and abnormal systemic inflammatory response. Our study aimed to determine the extent of these associations to better target the multi-level healthy aging challenge investigating the impact of periodontal disease on cognitive disorders (cognitive impairment and cognitive decline), dementia, and depression. We conducted a comprehensive literature search up to November 2023 using six different electronic databases. Two independent researchers assessed the eligibility of 7363 records against the inclusion criteria and found only 46 records that met the requirements. The study is registered on PROSPERO (CRD42023485688). We generated random effects pooled estimates and 95% confidence intervals (CI) to evaluate whether periodontal disease increased the risk of the investigated outcomes. The quality assessment revealed moderate quality of evidence and risk of bias. Periodontal disease was found to be associated with both cognitive disorders (relative risk (RR) 1.25, 95% CI 1.11-1.40, in the analysis of cross-sectional studies); cognitive impairment (RR 3.01, 95% CI 1.52-5.95 for longitudinal studies, cognitive decline); and dementia (RR 1.22, 95% CI 1.10-1.36). However, no significant increased risk of depression among subjects with periodontal disease was found (RR 1.07, 95% CI 0.95-1.21). Despite the association with two of the three explored outcomes, the available evidence on periodontal diseases and dementia, cognitive disorders, and depression is controversial due to several limitations. Therefore, further investigations involving validated and standardized tools are required.
PubMed: 38943006
DOI: 10.1007/s11357-024-01243-8 -
British Dental Journal Jun 2024As temporomandibular disorders (TMDs) become ever more prevalent in both primary and secondary care settings, successful management is increasingly challenging in both...
As temporomandibular disorders (TMDs) become ever more prevalent in both primary and secondary care settings, successful management is increasingly challenging in both sectors. The authors aim to explore the dilemma of TMD management as the patient journeys through from primary to secondary care and offer educational tools to support practitioners in managing this complex patient cohort, as well as outlining alternative solutions for the delivery of TMD management strategies.
Topics: Humans; Temporomandibular Joint Disorders; Primary Health Care; Secondary Care
PubMed: 38942856
DOI: 10.1038/s41415-024-7506-5 -
British Dental Journal Jun 2024Temporomandibular joint dysfunction (TMD) is a common condition, with patients reporting symptoms to both dentists and doctors. The aetiology of TMD is likely to be...
Temporomandibular joint dysfunction (TMD) is a common condition, with patients reporting symptoms to both dentists and doctors. The aetiology of TMD is likely to be multifactorial, with occlusal, parafunctional and psychological factors all potentially playing a part to varying degrees in different individuals. A personal account by a dentist, suffering from TMD for over 40 years, chronicles their experience of different treatments and concludes that supporting a patient to 'learn to live' with TMD is pivotal to management.
Topics: Humans; Temporomandibular Joint Disorders; Chronic Disease
PubMed: 38942855
DOI: 10.1038/s41415-024-7507-4 -
American Journal of Medical Genetics.... Jun 2024Pseudo-TORCH Syndrome (PTS) encompasses a heterogeneous group of genetic disorders that may clinically and radiologically resemble congenital TORCH infections. These...
Pseudo-TORCH Syndrome (PTS) encompasses a heterogeneous group of genetic disorders that may clinically and radiologically resemble congenital TORCH infections. These mimickers present with overlapping features manifested as intracranial and systemic abnormalities. Collagen type IV alpha 1 chain (COL4A1)-related diseases, characterized by autosomal dominant inheritance, exhibit a diverse phenotypic spectrum involving cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities. Cerebrovascular manifestations range from small-vessel brain disease to large vessel abnormalities, resulting in intracerebral hemorrhage, periventricular leukoencephalopathy, and ventriculomegaly. Additional features include cortical malformations, eye defects, arrhythmias, renal disease, muscular abnormalities, and hematological manifestations. Age of onset varies widely, and phenotypic variability exists even among individuals with the same variant. In this study, we present two cases of COL4A1-related disorder mimicking congenital TORCH infections, highlighting the importance of recognizing genetic mimics in clinical practice.
PubMed: 38942733
DOI: 10.1002/ajmg.a.63804 -
RMD Open Jun 2024Fibromyalgia (FM) is a complex disorder with widespread pain and emotional distress, posing diagnostic challenges. FM patients show altered cognitive and emotional...
BACKGROUND
Fibromyalgia (FM) is a complex disorder with widespread pain and emotional distress, posing diagnostic challenges. FM patients show altered cognitive and emotional processing, with a preferential allocation of attention to pain-related information. This attentional bias towards pain cues can impair cognitive functions such as inhibitory control, affecting patients' ability to manage and express emotions. Sentiment analysis using large language models (LLMs) can provide insights by detecting nuances in pain expression. This study investigated whether open-source LLM-driven sentiment analysis could aid FM diagnosis.
METHODS
40 patients with FM, according to the 2016 American College of Rheumatology Criteria and 40 non-FM chronic pain controls referred to rheumatology clinics, were enrolled. Transcribed responses to questions on pain and sleep were machine translated to English and analysed by the LLM Mistral-7B-Instruct-v0.2 using prompt engineering targeting FM-associated language nuances for pain expression ('prompt-engineered') or an approach without this targeting ('ablated'). Accuracy, precision, recall, specificity and area under the receiver operating characteristic curve (AUROC) were calculated using rheumatologist diagnosis as ground truth.
RESULTS
The prompt-engineered approach demonstrated accuracy of 0.87, precision of 0.92, recall of 0.84, specificity of 0.82 and AUROC of 0.86 for distinguishing FM. In comparison, the ablated approach had an accuracy of 0.76, precision of 0.75, recall of 0.77, specificity of 0.75 and AUROC of 0.76. The accuracy was superior to the ablated approach (McNemar's test p<0.001).
CONCLUSION
This proof-of-concept study suggests LLM-driven sentiment analysis, especially with prompt engineering, may facilitate FM diagnosis by detecting subtle differences in pain expression. Further validation is warranted, particularly the inclusion of secondary FM patients.
Topics: Humans; Fibromyalgia; Female; Middle Aged; Male; Adult; ROC Curve; Natural Language Processing; Language; Emotions; Aged; Chronic Pain
PubMed: 38942593
DOI: 10.1136/rmdopen-2024-004367 -
Medicine Jun 2024Idiopathic inflammatory myopathies, especially antisynthetase syndrome, often appear outside of the muscles as interstitial lung disease (ILD). Another typical finding... (Observational Study)
Observational Study
Idiopathic inflammatory myopathies, especially antisynthetase syndrome, often appear outside of the muscles as interstitial lung disease (ILD). Another typical finding is the presence of mechanic's hands. The aim of the present study was to describe the clinical, functional, tomographic, and serological data of patients with ILD and mechanic's hands and their response to treatment and survival rates. This is a retrospective study of ILD with concurrent myopathy. Among the 119 patients initially selected, 51 had mechanic's hands. All the patients were screened for anti-Jo-1 antibodies. An expanded panel of myopathy autoantibodies was also performed in 27 individuals. Of the 51 patients, 35 had 1 or more antibodies. The most common were anti-Jo-1, anti-PL-7, and anti-PL-12, while of the associated antibodies, anti-Ro52 was present in 70% of the 27 tested individuals. A significant response to treatment was characterized by an increase in predicted forced vital capacity (FVC) of at least 5% in the last evaluation done after 6 to 24 months of treatment. A decrease in predicted FVC of at least 5%, the need for oxygen therapy, or death were all considered treatment failures. All patients were treated with corticosteroids, and 71% with mycophenolate. After 24 months, 18 patients had an increase in FVC, 11 had a decrease, and 22 remained stable. After a median follow-up of 58 months, 48 patients remained alive and three died. Patients with honeycombing on high-resolution chest tomography (log-rank = 34.65; P < .001) and a decrease in FVC ≥5% (log-rank = 18.28, P < .001) had a poorer survival rate. Patients with ILD and mechanic's hands respond well to immunosuppressive treatment.
Topics: Humans; Lung Diseases, Interstitial; Retrospective Studies; Male; Female; Middle Aged; Myositis; Aged; Treatment Outcome; Adult; Autoantibodies; Outpatients; Adrenal Cortex Hormones; Vital Capacity
PubMed: 38941439
DOI: 10.1097/MD.0000000000038642 -
Medicine Jun 2024Upper limb dysfunction is one of the most common sequelae of stroke and robotic therapy is considered one of the promising methods for upper limb rehabilitation. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Upper limb dysfunction is one of the most common sequelae of stroke and robotic therapy is considered one of the promising methods for upper limb rehabilitation.
OBJECTIVE
This study aimed to explore the clinical effectiveness of upper limb training using a rehabilitation robotic device (Rebless®) for patients with stroke.
METHODS
In this prospective, unblinded, randomized controlled trial, patients were randomly assigned to receive robotic training (experimental group, n = 15) or conventional therapy (control group, n = 15). Both groups received upper limb training lasting for 30 minutes per session with a total of 10 training sessions within 4 weeks. Motor function, functional evaluation, and spasticity were clinically assessed before and after the training. Cortical activation was measured using functional near-infrared spectroscopy at the 1st and 10th training sessions.
RESULTS
The experimental group demonstrated a significant improvement in the Fugl-Meyer assessment-upper extremity score and the modified Ashworth scale grade in elbow flexors. The cortical activity of the unaffected hemisphere significantly decreased after 10 training sessions in the experimental group compared with the control group.
CONCLUSIONS
The experimental group showed significant improvement in the Fugl-Meyer assessment-upper extremity score and spasticity of elbow flexors and had significantly decreased cortical activity of the unaffected hemisphere. Training with Rebless® may help patients with chronic stroke in restoring upper limb function and recovering the contralateral predominance of activation in motor function.
Topics: Humans; Stroke Rehabilitation; Male; Female; Upper Extremity; Middle Aged; Prospective Studies; Robotics; Aged; Stroke; Recovery of Function; Muscle Spasticity; Treatment Outcome; Chronic Disease; Exercise Therapy
PubMed: 38941364
DOI: 10.1097/MD.0000000000038753