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PloS One 2024The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood.
BACKGROUND
The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood.
METHODS
Cardiac magnetic resonance (CMR) imaging was performed using a 1.5T scanner in subjects with FRDA who are homozygous for an expansion of an intron 1 GAA repeat in the FXN gene. Standard measurements were performed of LV mass (LVM), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). Native T1 relaxation time and the extracellular volume fraction (ECV) were utilised as markers of left ventricular (LV) diffuse myocardial fibrosis and late gadolinium enhancement (LGE) was utilised as a marker of LV replacement fibrosis. FRDA genetic severity was assessed using the shorter FXN GAA repeat length (GAA1).
RESULTS
There were 93 subjects with FRDA (63 adults, 30 children, 54% males), 9 of whom had a reduced LVEF (<55%). A LVEDV below the normal range was present in 39%, a LVM above the normal range in 22%, and an increased LVM/LVEDV ratio in 89% subjects. In adults with a normal LVEF, there was an independent positive correlation of LVM with GAA1, and a negative correlation with age, but no similar relationships were seen in children. GAA1 was positively correlated with native T1 time in both adults and children, and with ECV in adults, all these associations independent of LVM and LVEDV. LGE was present in 21% of subjects, including both adults and children, and subjects with and without a reduced LVEF. None of GAA1, LVM or LVEDV were predictors of LGE.
CONCLUSION
An association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA was present independently of FRDA-related LV structural changes. Localised replacement fibrosis was found in a minority of subjects with FRDA and was not associated with LV structural change or FRDA genetic severity in subjects with a normal LVEF.
Topics: Humans; Friedreich Ataxia; Male; Female; Adult; Gadolinium; Heart Ventricles; Child; Adolescent; Magnetic Resonance Imaging; Middle Aged; Young Adult; Contrast Media; Stroke Volume; Fibrosis; Frataxin
PubMed: 38814901
DOI: 10.1371/journal.pone.0303969 -
Disease Models & Mechanisms May 2024Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor...
Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.
Topics: Microglia; Amyotrophic Lateral Sclerosis; MicroRNAs; Animals; Female; Mice, Transgenic; Male; Mutation; Sex Characteristics; DNA-Binding Proteins; Mice; Extracellular Space; Humans; Lipopolysaccharides; Gene Expression Regulation
PubMed: 38813848
DOI: 10.1242/dmm.050638 -
Turkish Journal of Medical Sciences 2023Neuropathic pain (NP) is a type of chronic pain usually caused by damage to the somatosensory system. Bioactive antioxidant compounds, such as curcumin and ginger, are...
BACKGROUND/AIM
Neuropathic pain (NP) is a type of chronic pain usually caused by damage to the somatosensory system. Bioactive antioxidant compounds, such as curcumin and ginger, are widely preferred in the treatment of NP. However, the ingredient-based mechanism that underlies their pain-relieving activity remains unknown. The aim of this study was to investigate the therapeutic effects of trans-[6]-Shogaol and [6]-Gingerol active ingredients of the Roscoe extract on the spinal cord and cortex in the neuroinflammatory pathway in rats with experimental sciatic nerve injury.
MATERIALS AND METHODS
Forty-six volatile phenolic components were identified in ginger samples using gas chromatography-mass spectrometry analysis. Thirty 3-month-old male 250-300 g Wistar Albino rats were divided into three groups as (i) sham, (ii) chronic constriction injury (CCI), and (iii) CCI+ginger. NP was induced using the CCI model. A ginger extract treatment enriched with trans-[6]-shogaol and [6]-gingerol active ingredients was administered by gavage at 200 mg/kg/day for 7 days. On the 14th day of the experiment, locomotor activity was evaluated in open field and hyperalgesia in tail flick tests.
RESULTS
In behavioural experiments, a significant decrease was observed in the CCI group compared to the sham group, while a significant increase was observed in the CCI+ginger group compared to the CCI group (p < 0.05). In the spinal cord and cortex tissues, there was a significant increase in the TNF-α, IL-1β, and IL-18 neuroinflammation results of the CCI group compared to the sham group, while there was a significant decrease in the CCI+ginger group compared to the CCI group.
CONCLUSION
In this study, ginger treatment was shown to have a therapeutic effect on neuroinflammation against sciatic nerve damage.
Topics: Animals; Fatty Alcohols; Catechols; Neuralgia; Rats; Male; Rats, Wistar; Zingiber officinale; Disease Models, Animal; Cytokines; Plant Extracts; Sciatic Nerve; Spinal Cord
PubMed: 38813490
DOI: 10.55730/1300-0144.5728 -
Frontiers in Pharmacology 2024
PubMed: 38813111
DOI: 10.3389/fphar.2024.1421115 -
Turkish Journal of Medical Sciences 2023It is known that the correlation of pulmonary function tests (PFT) with muscle dysfunction is insufficient. Here, we aimed to evaluate the diaphragm functions in...
BACKGROUND/AIM
It is known that the correlation of pulmonary function tests (PFT) with muscle dysfunction is insufficient. Here, we aimed to evaluate the diaphragm functions in individuals with Friedreich's ataxia (FRDA) and to examine its relationship with respiratory parameters and disease severity.
MATERIALS AND METHODS
This prospective study, conducted between November and December 2022, at Erciyes University, included 14 individuals with genetically confirmed FRDA and an age- and gender-matched healthy control group of eight individuals. We examined pulmonary functions with spirometric methods and evaluated diaphragm excursion, and diaphragm thickness-expiratory (Tde) and - end of inspiration (Tdi) with ultrasonography during calm breathing. Thickening fraction (TF) calculated. Also, we examined PaCO2 at rest. The neurological status of individuals was assessed using the Scale for the Assessment and Rating of Ataxia (SARA).
RESULTS
The mean values of FEV1(lt), FEV1(%), FVC (lt), and FVC (%) were higher in the control group (p; <0.001, 0.013, <0.001, and 0.009, respectively). Also, mean Tdi, Tde, excursion and TF were lower in the FRDA group compared to the control group (p = 0.005, 0.294,0.005, and 0.019, respectively). The mean excursion value was 1.13 ± 0.54cm in the FRDA group and 1.71 ± 0.49cm in the control group. There is a strong, negative, and statistically significant correlation between SARA total score with excursion and TF (r = -0.7432, p = 0.002; r = -0.697, p = 0.008). There is no statistically significant relationship between excursion and BMI, standing-to-supine decrease in FVC, FEV1, and PaCO2. Also, the relationship between maximal inspiratory pressure (PImax) and excursion was moderate.
CONCLUSION
Diaphragm ultrasound may reveal respiratory dysfunction better than PFT. Diaphragm excursion and TF are associated with disease scores in individuals with FDRA. Further studies are needed regarding the detection of alveolar hypoventilation.
Topics: Humans; Friedreich Ataxia; Diaphragm; Male; Female; Ultrasonography; Prospective Studies; Adult; Respiratory Function Tests; Young Adult; Spirometry; Case-Control Studies
PubMed: 38812999
DOI: 10.55730/1300-0144.5696 -
Skeletal Muscle May 2024Intramuscular fat (IMAT) infiltration, pathological adipose tissue that accumulates between muscle fibers, is a shared hallmark in a diverse set of diseases including... (Comparative Study)
Comparative Study
Intramuscular fat (IMAT) infiltration, pathological adipose tissue that accumulates between muscle fibers, is a shared hallmark in a diverse set of diseases including muscular dystrophies and diabetes, spinal cord and rotator cuff injuries, as well as sarcopenia. While the mouse has been an invaluable preclinical model to study skeletal muscle diseases, they are also resistant to IMAT formation. To better understand this pathological feature, an adequate pre-clinical model that recapitulates human disease is necessary. To address this gap, we conducted a comprehensive in-depth comparison between three widely used mouse strains: C57BL/6J, 129S1/SvlmJ and CD1. We evaluated the impact of strain, sex and injury type on IMAT formation, myofiber regeneration and fibrosis. We confirm and extend previous findings that a Glycerol (GLY) injury causes significantly more IMAT and fibrosis compared to Cardiotoxin (CTX). Additionally, females form more IMAT than males after a GLY injury, independent of strain. Of all strains, C57BL/6J mice, both females and males, are the most resistant to IMAT formation. In regard to injury-induced fibrosis, we found that the 129S strain formed the least amount of scar tissue. Surprisingly, C57BL/6J of both sexes demonstrated complete myofiber regeneration, while both CD1 and 129S1/SvlmJ strains still displayed smaller myofibers 21 days post injury. In addition, our data indicate that myofiber regeneration is negatively correlated with IMAT and fibrosis. Combined, our results demonstrate that careful consideration and exploration are needed to determine which injury type, mouse model/strain and sex to utilize as preclinical model especially for modeling IMAT formation.
Topics: Animals; Male; Female; Mice, Inbred C57BL; Regeneration; Muscle, Skeletal; Mice; Adipose Tissue; Fibrosis; Disease Models, Animal; Sex Characteristics; Species Specificity; Glycerol; Mice, 129 Strain
PubMed: 38812056
DOI: 10.1186/s13395-024-00344-4 -
Translational Neurodegeneration May 2024Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.
Topics: Amyotrophic Lateral Sclerosis; Humans; Superoxide Dismutase-1; Mutation
PubMed: 38811997
DOI: 10.1186/s40035-024-00416-x -
Cureus Apr 2024Spinal subdural hematoma (SSDH) is a rare medical emergency that can cause permanent neurological deficits. The disease is characterized by sudden onset back pain,...
Spinal subdural hematoma (SSDH) is a rare medical emergency that can cause permanent neurological deficits. The disease is characterized by sudden onset back pain, sensorimotor changes, and bladder and autonomic dysfunction. This is often associated with the use of anticoagulants, blood dyscrasias, and recent spinal procedures. We present a case of a 63-year-old male maintained on rivaroxaban for nonvalvular atrial fibrillation clinically presenting with abrupt onset back pain that rapidly progressed to sensorimotor deficits and bladder dysfunction. Rivaroxaban, a selective inhibitor of factor Xa, has been approved by the Food and Drug Administration (FDA) for the reduction of stroke risk and systemic embolism in nonvalvular atrial fibrillation. We postulate that rivaroxaban played a major role in triggering the spinal hemorrhage. This case highlights the very limited documented cases of spontaneous subdural spinal hemorrhages associated with rivaroxaban use.
PubMed: 38807840
DOI: 10.7759/cureus.59208 -
Journal of Medical Case Reports May 2024Pneumomediastinum and pneumorrachis are rare complications following epidural analgesia, that can either be asymptomatic or rarely can produce mild to moderate severity...
BACKGROUND
Pneumomediastinum and pneumorrachis are rare complications following epidural analgesia, that can either be asymptomatic or rarely can produce mild to moderate severity symptoms. Most reported cases regarding the presentation of these two entities with epidural analgesia concern asymptomatic patients, however there are cases reporting post-dural puncture headache and respiratory manifestations.
CASE PRESENTATION
We present a case where a combined lumbar epidural and spinal anesthesia was performed using the loss of resistance to air technique (LOR), on a 78-year-old Greek (Caucasian) male undergoing a total hip replacement. Despite being hemodynamically stable throughout the operation, two hours following epidural analgesia the patient manifested a sudden drop in blood pressure and heart rate that required the administration of adrenaline to counter. Pneumomediastinum, pneumorrachis and paravertebral soft tissue emphysema were demonstrated in a Computed Tomography scan. We believe that injected air from the epidural space and surrounding tissues slowly moved towards the mediastinum, stimulating the para-aortic ganglia causing parasympathetic stimulation and therefore hypotension and bradycardia.
CONCLUSION
Anesthesiologists should be aware that epidural analgesia using the LOR to technique injecting air could produce a pneumomediastinum and pneumorrachis, which in turn could produce hemodynamic instability via parasympathetic stimulation.
Topics: Humans; Male; Mediastinal Emphysema; Aged; Analgesia, Epidural; Pneumorrhachis; Arthroplasty, Replacement, Hip; Hemodynamics; Tomography, X-Ray Computed; Anesthesia, Spinal
PubMed: 38807243
DOI: 10.1186/s13256-024-04588-y -
BMC Infectious Diseases May 2024To assess the immunogenicity of the current primary polio vaccination schedule in China and compare it with alternative schedules using Sabin or Salk-strain IPV (sIPV,...
BACKGROUND
To assess the immunogenicity of the current primary polio vaccination schedule in China and compare it with alternative schedules using Sabin or Salk-strain IPV (sIPV, wIPV).
METHODS
A cross-sectional investigation was conducted at four sites in Chongqing, China, healthy infants aged 60-89 days were conveniently recruited and divided into four groups according to their received primary polio vaccination schedules (2sIPV + bOPV, 2wIPV + bOPV, 3sIPV, and 3wIPV). The sero-protection and neutralizing antibody titers against poliovirus serotypes (type 1, 2, and 3) were compared after the last dose.
RESULTS
There were 408 infants completed the protocol. The observed seropositivity was more than 96% against poliovirus types 1, 2, and 3 in all groups. IPV-only groups induced higher antibody titers(GMT) against poliovirus type 2 (Median:192, QR: 96-384, P<0.05) than the "2IPV + bOPV" group. While the "2IPV + bOPV" group induced significantly higher antibody titers against poliovirus type 1 (Median:2048, QR: 768-2048, P<0.05)and type 3 (Median:2048, QR: 512-2048, P<0.05) than the IPV-only group.
CONCLUSIONS
Our findings have proved that the two doses of IPV with one dose of bOPV is currently the best polio routine immunization schedule in China.
Topics: Humans; Poliovirus Vaccine, Inactivated; Poliomyelitis; Infant; Poliovirus Vaccine, Oral; Male; Immunization Schedule; Female; Antibodies, Viral; Cross-Sectional Studies; China; Antibodies, Neutralizing; Poliovirus; Immunogenicity, Vaccine; Vaccination
PubMed: 38807038
DOI: 10.1186/s12879-024-09389-8