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Journal of Neurology Jul 2024Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common genetically inherited myopathies in adults. It is characterized by incomplete penetrance and... (Review)
Review
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common genetically inherited myopathies in adults. It is characterized by incomplete penetrance and variable expressivity. Typically, FSHD patients display asymmetric weakness of facial, scapular, and humeral muscles that may progress to other muscle groups, particularly the abdominal and lower limb muscles. Early-onset patients display more severe muscle weakness and atrophy, resulting in a higher frequency of associated skeletal abnormalities. In these patients, multisystem involvement, including respiratory, ocular, and auditory, is more frequent and severe and may include the central nervous system. Adult-onset FSHD patients may also display some degree of multisystem involvement which mainly remains subclinical. In 95% of cases, FSHD patients carry a pathogenic contraction of the D4Z4 repeat units (RUs) in the subtelomeric region of chromosome 4 (4q35), which leads to the expression of DUX4 retrogene, toxic for muscles (FSHD1). Five percent of patients display the same clinical phenotype in association with a mutation in the SMCHD1 gene located in chromosome 18, inducing epigenetic modifications of the 4q D4Z4 repeated region and expression of DUX4 retrogene. This review highlights the complexities and challenges of diagnosing and managing FSHD, underscoring the importance of standardized approaches for optimal patient outcomes. It emphasizes the critical role of multidisciplinary care in addressing the diverse manifestations of FSHD across different age groups, from skeletal abnormalities in early-onset cases to the often-subclinical multisystem involvement in adults. With no current cure, the focus on alleviating symptoms and slowing disease progression through coordinated care is paramount.
PubMed: 38955828
DOI: 10.1007/s00415-024-12538-3 -
Supportive Care in Cancer : Official... Jul 2024The study investigates cryotherapy's efficacy in mitigating Chemotherapy-induced peripheral neuropathy (CIPN), an adverse effect of chemotherapy that often leads to... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The study investigates cryotherapy's efficacy in mitigating Chemotherapy-induced peripheral neuropathy (CIPN), an adverse effect of chemotherapy that often leads to dosage reduction or treatment discontinuation.
METHOD
The study was registered with PROSPERO (CRD42023428936). A literature search was conducted using the PubMed, Embase, and Cochrane Library databases. Randomized and nonrandomized controlled trials that investigated the effects of cryotherapy on CIPN were included for systematic review and meta-analysis. The primary outcome for prevention was the incidence of CIPN.
RESULTS
We identified 17 trials involving 2,851 patients. In total, 11 trials compared the incidence of CIPN between cryotherapy and control groups. Significant differences in the incidence of CIPN at the midpoint and end of chemotherapy were observed, with risk ratios (RRs) of 0.23 (95% confidence interval [CI] = 0.13 to 0.43) and 0.54 (95% CI = 0.33 to 0.88), respectively. Cryotherapy also significantly reduced the incidence of sensory CIPN, with an RR of 0.67 (95% CI = 0.49 to 0.92). Additionally, cryotherapy demonstrated a significant reduction in the incidence of CIPN in patients with gynecological cancers (RR = 0.24, 95% CI = 0.14 to 0.41). Significantly favorable global quality of life scores following chemotherapy (standardized mean difference = 1.43; 95% CI = 0.50 to 2.36) and relieved neuropathic symptoms were found with cryotherapy.
CONCLUSIONS
Cryotherapy demonstrates a pronounced preventive effect against the development of CIPN, providing substantial symptomatic relief and quality of life improvements for patients undergoing chemotherapy. The administration of cryotherapy through the use of frozen gloves and socks, or continuous-flow cooling systems, optimally initiated 15 min prior to and concluded 15 min following chemotherapy, is recommended for achieving maximum therapeutic efficacy.
Topics: Humans; Peripheral Nervous System Diseases; Cryotherapy; Antineoplastic Agents; Randomized Controlled Trials as Topic; Incidence; Neoplasms
PubMed: 38955817
DOI: 10.1007/s00520-024-08680-3 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Jul 2024
Topics: Humans; Child; Female; Male; Peripheral Nervous System Diseases
PubMed: 38955689
DOI: 10.3760/cma.j.cn112140-20240107-00027 -
FEBS Letters Jul 2024The poliovirus (PV) enters the central nervous system (CNS) via the bloodstream, suggesting the existence of a mechanism to cross the blood-brain barrier. Here, we...
The poliovirus (PV) enters the central nervous system (CNS) via the bloodstream, suggesting the existence of a mechanism to cross the blood-brain barrier. Here, we report that PV capsid proteins (VP1 and VP3) can penetrate cells, with VP3 being more invasive. Two independent parts of VP3 are responsible for this function. Both peptides can penetrate human umbilical cord vascular endothelial cells, and one peptide of VP3 could also penetrate peripheral blood mononuclear cells. In an in vitro blood-brain barrier model using rat-derived astrocytes, pericytes, and endothelial cells, both peptides were observed to traverse from the blood side to the brain side at 6 h after administration. These results provide insights into the molecular mechanisms underlying PV invasion into the CNS.
PubMed: 38955545
DOI: 10.1002/1873-3468.14974 -
Neurotoxicology Jun 2024The 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (MDPHP) is a synthetic cathinone closely related to 3,4-methylenedioxypyrovalerone (MDPV), one of the most common...
The 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (MDPHP) is a synthetic cathinone closely related to 3,4-methylenedioxypyrovalerone (MDPV), one of the most common synthetic cathinones present in the "bath salts". MDPHP has recently gained attention due to increasing seizures and involvement in human intoxications which occurred in Europe and Italy in the last years, but currently there is a lack of information about its pharmaco-toxicological effects. With the aim at filling this gap, the present study is endeavoured to (i) evaluate the effects of acute administration of MDPHP (0.01-20mg/kg; i.p.) on behaviour, cardiorespiratory and cardiovascular parameters in CD-1 male mice, comparing them to those observed after administration of MDPV; (ii) predict the ADMET profile of the two analogues using the Plus ADMET Predictor®; (iii) present clinical data related to MDPHP and MDPV-induced intoxications recorded between 2011 and 2023 by the Pavia Poison Control Centre (PCC) - National Toxicology Information Centre (Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Italy). Our results substantiated that MDPHP and MDPV similarly affect sensorimotor and behavioural responses in mice, importantly increased locomotion and induced aggressive behaviour, and, at higher dosage, increased heart rate and blood pressure. These findings are in line with those observed in humans, revealing severe toxidromes typically characterized by Central Nervous System (CNS) alterations (behavioural/neuropsychiatric symptoms), including psychomotor agitation and aggressiveness, cardiovascular and respiratory disorders (e.g. tachycardia, hypertension, dyspnoea), and other peripheral symptoms (e.g. hyperthermia, acidosis, rhabdomyolysis).
PubMed: 38955288
DOI: 10.1016/j.neuro.2024.06.014 -
Science Signaling Jul 2024Opioids trigger myelin insulation of reward circuit axons in a feedforward loop of addiction.
Opioids trigger myelin insulation of reward circuit axons in a feedforward loop of addiction.
Topics: Humans; Analgesics, Opioid; Animals; Axons; Myelin Sheath; Reward; Opioid-Related Disorders
PubMed: 38954639
DOI: 10.1126/scisignal.adr3505 -
MBio Jul 2024Neurotropic alphaherpesviruses, including herpes simplex virus type 1 and pseudorabies virus, establish a lifelong presence within the peripheral nervous system of their...
Neurotropic alphaherpesviruses, including herpes simplex virus type 1 and pseudorabies virus, establish a lifelong presence within the peripheral nervous system of their mammalian hosts. Upon entering cells, two conserved tegument proteins, pUL36 and pUL37, traffic DNA-containing capsids to nuclei. These proteins support long-distance retrograde axonal transport and invasion of the nervous system . To better understand how pUL36 and pUL37 function, recombinant viral particles carrying BioID2 fused to these proteins were produced to biotinylate cellular proteins in their proximity (<10 nm) during infection. Eighty-six high-confidence host proteins were identified by mass spectrometry and subsequently targeted by CRISPR-Cas9 gene editing to assess their contributions to early infection. Proteins were identified that both supported and antagonized infection in immortalized human epithelial cells. The latter included zyxin, a protein that localizes to focal adhesions and regulates actin cytoskeletal dynamics. Zyxin knockout cells were hyper-permissive to infection and could be rescued with even modest expression of GFP-zyxin. These results provide a resource for studies of the virus-cell interface and identify zyxin as a novel deterrent to alphaherpesvirus infection.IMPORTANCENeuroinvasive alphaherpesviruses are highly prevalent with many members found across mammals [e.g., herpes simplex virus type 1 (HSV-1) in humans and pseudorabies virus in pigs]. HSV-1 causes a range of clinical manifestations from cold sores to blindness and encephalitis. There are no vaccines or curative therapies available for HSV-1. A fundamental feature of these viruses is their establishment of lifelong infection of the nervous system in their respective hosts. This outcome is possible due to a potent neuroinvasive property that is coordinated by two proteins: pUL36 and pUL37. In this study, we explore the cellular protein network in proximity to pUL36 and pUL37 during infection and examine the impact of knocking down the expression of these proteins upon infection.
PubMed: 38953638
DOI: 10.1128/mbio.01445-24 -
British Journal of Clinical Pharmacology Jul 2024Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic...
Effects on cerebral blood flow after single doses of the β agonist, clenbuterol, in healthy volunteers and patients with mild cognitive impairment or Parkinson's disease.
AIMS
Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic transmission from the locus coeruleus. In pre-clinical models, β-adrenoceptor (β-AR) agonists increase cerebrocortical glucose metabolism, and may have therapeutic potential for neurodegenerative diseases. This study investigated the safety and effects on regional cerebral blood flow (rCBF) of the oral, brain-penetrant β-AR agonist, clenbuterol, in healthy volunteers (HV) and patients with mild cognitive impairment (MCI) or Parkinson's disease (PD).
METHODS
This study evaluated the safety and effects on cerebral activity of the oral, brain-penetrant, β-AR agonist clenbuterol (20-160 μg) in healthy volunteers and patients with MCI or PD. Regional CBF, which is tightly coupled to glucose metabolism, was measured by arterial spin labelling MRI in 32 subjects (25 HV and 8 MCI or PD) across five cohorts. In some cohorts, low doses of nadolol (1-5 mg), a β-AR antagonist with minimal brain penetration, were administered with clenbuterol to control peripheral β-AR responses.
RESULTS
Significant, dose-dependent increases in rCBF were seen in multiple brain regions, including hippocampus, amygdala and thalamus, following the administration of clenbuterol to HVs (mean changes from baseline in hippocampal rCBF of -1.7%, 7.3%, 22.9%, 28.4% 3 h after 20, 40, 80 and 160 μg clenbuterol, respectively). In patients with MCI or PD, increases in rCBF following 80 μg clenbuterol were observed both without and with 5 mg nadolol (in hippocampus, 18.6%/13.7% without/with nadolol). Clenbuterol was safe and well-tolerated in all subjects; known side effects of β-agonists, including increased heart rate and tremor, were mild in intensity and were blocked by low-dose nadolol.
CONCLUSIONS
The effects of clenbuterol on rCBF were evident both in the absence and presence of low-dose nadolol, suggesting central nervous system (CNS) involvement. Concomitant inhibition of the peripheral effects of clenbuterol by nadolol confirms that meaningful β-AR antagonism in the periphery was achieved without interrupting the central effects of clenbuterol on rCBF.
PubMed: 38953404
DOI: 10.1111/bcp.16160 -
Frontiers in Immunology 2024More than 350,000 chemicals make up the chemical universe that surrounds us every day. The impact of this vast array of compounds on our health is still poorly...
INTRODUCTION
More than 350,000 chemicals make up the chemical universe that surrounds us every day. The impact of this vast array of compounds on our health is still poorly understood. Manufacturers are required to carry out toxicological studies, for example on the reproductive or nervous systems, before putting a new substance on the market. However, toxicological safety does not exclude effects resulting from chronic exposure to low doses or effects on other potentially affected organ systems. This is the case for the microbiome-immune interaction, which is not yet included in any safety studies.
METHODS
A high-throughput in vitro model was used to elucidate the potential effects of environmental chemicals and chemical mixtures on microbiome-immune interactions. Therefore, a simplified human intestinal microbiota (SIHUMIx) consisting of eight bacterial species was cultured in a bioreactor that partially mimics intestinal conditions. The bacteria were continuously exposed to mixtures of representative and widely distributed environmental chemicals, i.e. bisphenols (BPX) and/or per- and polyfluoroalkyl substances (PFAS) at concentrations of 22 µM and 4 µM, respectively. Furthermore, changes in the immunostimulatory potential of exposed microbes were investigated using a co-culture system with human peripheral blood mononuclear cells (PBMCs).
RESULTS
The exposure to BPX, PFAS or their mixture did not influence the community structure and the riboflavin production of SIHUMIx . However, it altered the potential of the consortium to stimulate human immune cells: in particular, activation of CD8 MAIT cells was affected by the exposure to BPX- and PFAS mixtures-treated bacteria.
DISCUSSION
The present study provides a model to investigate how environmental chemicals can indirectly affect immune cells via exposed microbes. It contributes to the much-needed knowledge on the effects of EDCs on an organ system that has been little explored in this context, especially from the perspective of cumulative exposure.
Topics: Humans; Gastrointestinal Microbiome; Phenols; Benzhydryl Compounds; Fluorocarbons; Leukocytes, Mononuclear; Coculture Techniques; Environmental Pollutants; Bacteria
PubMed: 38953021
DOI: 10.3389/fimmu.2024.1298971 -
Clinical Interventions in Aging 2024To investigate association between optic disc parameters analyzed by optical coherence tomography (OCT) and occurrence of peripheral retinal tears in patients with...
BACKGROUND
To investigate association between optic disc parameters analyzed by optical coherence tomography (OCT) and occurrence of peripheral retinal tears in patients with symptomatic posterior vitreous detachment (PVD).
METHODS
This cross-sectional study enrolled 75 patients with symptoms of acute PVD, who were allocated into two groups based on whether a peripheral retinal tear occurred or not.
RESULTS
When comparing the average retinal nerve fiber layer (RNFL) thickness (μm) between retinal tear and control groups, it was shown that patients with a retinal tear have a significantly higher (87.18 [95% confidence interval (CI), 84.47 to 89.9] vs 81.14 [95% CI, 77.81 to 84.46], = 0.005) average RNFL thickness. Furthermore, we observed a significant difference (0.13, 0.06 to 0.22 vs 0.07, 0.04 to 0.1, = 0.036, Mann-Whitney -test) in the size of cup volume (mm) between the tear and control groups, respectively. Linear regression showed a significant decrease ( = 0.029) in average RNFL thickness with increasing age, but without a significant difference between the two groups. There was no statistically significant difference between the tear and control groups in terms of rim area, disc area, and average cup-to-disc ratio.
CONCLUSION
Patients with a higher average RNFL thickness and larger cup volume measured by OCT were more prone to develop a peripheral retinal tear. Increased peripapillary average RNFL thickness due to trauma and subsequent inflammation, possibly related to the more adherent posterior hyaloid membrane to the retina, may also indicate strengthened adhesions in the areas of the peripheral retina where retinal tears occur. OCT analysis of the optic nerve head may be used in everyday clinical practice as a predictor of the development of peripheral retinal tears in patients with symptomatic PVD.
Topics: Humans; Cross-Sectional Studies; Male; Tomography, Optical Coherence; Female; Vitreous Detachment; Middle Aged; Optic Disk; Retinal Perforations; Aged; Nerve Fibers; Adult; Linear Models
PubMed: 38952872
DOI: 10.2147/CIA.S466511