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Scientific Reports Jun 2024Hereditary spastic paraplegias are a diverse group of degenerative disorders that are clinically categorized as isolated; with involvement of lower limb spasticity, or...
Hereditary spastic paraplegias are a diverse group of degenerative disorders that are clinically categorized as isolated; with involvement of lower limb spasticity, or symptomatic, where spastic paraplegia is complicated by further neurological features. We sought to identify the underlying genetic causes of these disorders in the participating patients. Three consanguineous families with multiple affected members were identified by visiting special schools in the Punjab Province. DNA was extracted from blood samples of the participants. Exome sequencing was performed for selected patients from the three families, and the data were filtered to identify rare homozygous variants. ExomeDepth was used for the delineation of the copy number variants. All patients had varying degrees of intellectual disabilities, poor speech development, spasticity, a wide-based gait or an inability to walk and hypertonia. In family RDHR07, a homozygous deletion involving multiple exons and introns of SPG11 (NC000015.9:g.44894055_449028del) was found and correlated with the phenotype of the patients who had spasticity and other complex movement disorders, but not those who exhibited ataxic or indeterminate symptoms as well. In families ANMD03 and RDFA06, a nonsense variant, c.985C > T;(p.Arg329Ter) in DDHD2 and a frameshift insertion‒deletion variant of AP4B1, c.965-967delACTinsC;p.(Tyr322SerfsTer14), were identified which were homozygous in the patients while the obligate carriers in the respective pedigrees were heterozygous. All variants were ultra-rare with none, or very few carriers identified in the public databases. The three loss of function variants are likely to cause nonsense-mediated decay of the respective transcripts. Our research adds to the genetic variability associated with the SPG11 and AP4B1 variants and emphasizes the genetic heterogeneity of hereditary spastic paraplegia.
Topics: Humans; Male; Female; DNA Copy Number Variations; Pedigree; Spastic Paraplegia, Hereditary; Exons; Child; Adolescent; Adult; Exome Sequencing; Child, Preschool; Adaptor Protein Complex 4; Consanguinity; Homozygote; Phenotype; Young Adult; Proteins
PubMed: 38906889
DOI: 10.1038/s41598-024-64922-8 -
Medicine Jun 2024Fahr syndrome is a rare, degenerative neurological condition characterized by bilateral idiopathic calcification of the periventricular region, especially the basal...
RATIONALE
Fahr syndrome is a rare, degenerative neurological condition characterized by bilateral idiopathic calcification of the periventricular region, especially the basal ganglia. This condition is often misdiagnosed as other neurological or psychiatric disorders due to its rarity and overlapping symptoms.
PATIENT CONCERNS
A 34-year-old man had been experiencing seizures and cognitive dysfunction for few years, which were further compounded by slurred speech and motor difficulties as acute conditions.
DIAGNOSIS
After investigations, severe hypocalcemia, and hypoparathyroidism were detected and his brain computed tomography showed extensive bilateral calcifications in basal ganglia, thalamus, dentate nuclei, and some parts of subcortical white matter, suggestive of Fahr syndrome. Although, the patient was initially misdiagnosed due to a lack of information and the rarity of this disease.
INTERVENTION
The patient was treated with intravenous calcium gluconate, vitamin D3, l-ornithine l-aspartate syrup, and levetiracetam, replacing carbamazepine.
OUTCOME
His symptoms, including slurred speech, muscle pain, and stiffness improved, serum calcium normalized, and he was discharged with medications for memory deficit and depression.
LESSONS
This case underscores the importance of raising awareness among physicians, especially in areas with limited medical resources, about the significance of prompt diagnosis and appropriate symptomatic treatment in enhancing patient prognosis and quality of life.
Topics: Humans; Male; Adult; Seizures; Cognitive Dysfunction; Calcinosis; Afghanistan; Basal Ganglia Diseases; Hypoparathyroidism; Hypocalcemia; Tomography, X-Ray Computed; Neurodegenerative Diseases
PubMed: 38905413
DOI: 10.1097/MD.0000000000038542 -
Bioscience Reports Jun 2024Learning and memory impairment (LMI), a common degenerative central nervous system disease. Recently, more and more studies have shown that Ganoderma lucidum (GL) can...
Learning and memory impairment (LMI), a common degenerative central nervous system disease. Recently, more and more studies have shown that Ganoderma lucidum (GL) can improve the symptoms of LMI. The active ingredients in GL and their corresponding targets were screened through TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) and BATMAN-TCM (Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine) databases, and the potential LMI targets were searched for through GeneCard (GeneCards Human Gene Database) and DrugBank. Then, we construct a "main active ingredient-target" network and a protein-protein interaction (PPI) network diagram.The GO (Gene Ontology) functional enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway annotation analysis were performed on the common targets through DAVID (Database for Annotation Visualization and Integrated Discovery) to clarify the potential molecular mechanism of action of active ingredients in GL. The TNF protein was verified by western blot;Twenty one active ingredients in GL and 142 corresponding targets were screened out, including 59 targets shared with LMI. The 448 biological processes shown by the GO functional annotation results and 55 signal pathways shown by KEGG enrichment analysis were related to the improvement of LMI by GL, among which the correlation of Alzheimer disease pathway is the highest, and TNF was the most important protein; TNF can improve LMI.GL can improve LMI mainly by 10 active ingredients in it, and they may play a role by regulating Alzheimer disease pathway and TNF protein.
PubMed: 38904095
DOI: 10.1042/BSR20232068 -
International Journal of Biological... 2024Osteoarthritis (OA) is a challenging degenerative joint disease to manage. Previous research has indicated that cell-free fat extract (CEFFE) may hold potential for OA...
Osteoarthritis (OA) is a challenging degenerative joint disease to manage. Previous research has indicated that cell-free fat extract (CEFFE) may hold potential for OA treatment. This study investigated the role of Annexin A5 (AnxA5) within CEFFE in regulating macrophage polarization and protecting chondrocytes. experiments demonstrated that AnxA5 effectively inhibited M1 macrophage polarization by facilitating toll-like receptor (TLR) 4 internalization and lysosomal degradation through calcium-dependent endocytosis. This process decreased TLR4 expression, suppressed pro-inflammatory mediator release, and reduced the production of reactive oxygen species. Furthermore, AnxA5 displayed protective effects against chondrocyte necrosis and apoptosis. studies revealed that intra-articular administration of AnxA5 ameliorated pain symptoms in a monosodium iodoacetate-induced osteoarthritis rat model. Histological analyses indicated a decrease in synovial inflammation and mitigation of cartilage damage following AnxA5 treatment. These results underscored the potential of AnxA5 as a therapeutic option for OA due to its capacity to regulate macrophage polarization and maintain chondrocyte viability. Further investigation into the specific mechanisms and clinical applications of AnxA5 may help improve the management of OA.
Topics: Animals; Osteoarthritis; Rats; Macrophages; Annexin A5; Chondrocytes; Rats, Sprague-Dawley; Male; Toll-Like Receptor 4; Mice; RAW 264.7 Cells; Reactive Oxygen Species; Apoptosis
PubMed: 38904008
DOI: 10.7150/ijbs.92802 -
Military Medical Research Jun 2024Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and... (Review)
Review
Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.
Topics: Humans; Fibroblast Growth Factors; Signal Transduction; Osteoarthritis; Fibroblast Growth Factor-23; Intervertebral Disc Degeneration; Osteoporosis; Sarcopenia; Aging; Animals
PubMed: 38902808
DOI: 10.1186/s40779-024-00544-5 -
Pain Jul 2024Recent evidence highlights the importance of the neuroimmune interface, including periphery-to-central nervous system (CNS) neuroimmune crosstalk, in chronic pain....
Unraveling the neuroimmune interface in chronic pain-the association between cytokines in the cerebrospinal fluid and pain in patients with lumbar disk herniation or degenerative disk disease.
Recent evidence highlights the importance of the neuroimmune interface, including periphery-to-central nervous system (CNS) neuroimmune crosstalk, in chronic pain. Although neuroinflammatory processes have been implicated in central sensitization for a long time, their potential neuroprotective and analgesic effects remain relatively elusive. We have explored the relationships between cytokine expression and symptom severity, and candidates for periphery-to-CNS crosstalk. Patients with degenerative disk disease (DDD) (nociceptive pain) or patients with lumbar disk herniation (LDH) with radiculopathy (predominantly neuropathic pain) completed questionnaires regarding pain and functional disability, underwent quantitative sensory testing, and provided blood and cerebrospinal fluid (CSF) samples. Proximity extension assay (PEA) was used to measure the levels of 92 inflammatory proteins in the CSF and serum from a total of 160 patients and controls, and CSF/serum albumin quotients was calculated for patients with DDD and patients with LDH. We found signs of neuroimmune activation, in the absence of systemic inflammation. Regarding periphery-to-CNS neuroimmune crosstalk, there were significant associations between several cytokines and albumin quotient, despite the latter being primarily at subclinical levels. The cytokines CCL11, CD5, IL8, and MMP-10 were elevated in the CSF, had positive correlations between CSF and serum levels, and associated in a nonlinear manner with back, but not leg, pain intensity in the LDH, but not the DDD, group. In conclusion, we found evidence for neuroimmune activation in the CNS of both patient groups in the absence of systemic inflammation and signs of a communication between CSF and serum. Complex and disease-specific associations were found between cytokines in CSF and back pain intensity.
Topics: Humans; Male; Female; Cytokines; Middle Aged; Intervertebral Disc Displacement; Intervertebral Disc Degeneration; Adult; Chronic Pain; Aged; Lumbar Vertebrae; Pain Measurement; Neuroimmunomodulation
PubMed: 38900144
DOI: 10.1097/j.pain.0000000000003175 -
Cureus May 2024Introduction The neurovascular unit (NVU), comprising vascular and glial cells along with neurons, is vital for maintaining the blood-brain barrier (BBB) and cerebral...
Brain Vascular Expression of Monomeric C-Reactive Protein Is Blocked by C10M Following Intraperitoneal Injection in an ApoE-/- Murine Model of Dyslipidemia: An Immunohistochemical Analysis.
Introduction The neurovascular unit (NVU), comprising vascular and glial cells along with neurons, is vital for maintaining the blood-brain barrier (BBB) and cerebral homeostasis. Dysfunction of the NVU is implicated in key neurodegenerative disorders such as Alzheimer's disease (AD). Monomeric C-reactive protein (mCRP), the dissociated form of native, pentameric C-reactive protein (pCRP), is associated with enhanced pro-inflammatory responses in the vascular system, leading to increased permeability and potential NVU disruption. Methods This study utilized ApoE-/- mice receiving a high-fat diet which were injected intraperitoneally with either mCRP or mCRP together with a small molecule inhibitor (C10M) and investigated the deposition of mCRP and CD105 expression in the brain parenchyma and its localization within the microvasculature. Results Histological analysis revealed significant mCRP deposition in brain microvessels and neurons, indicating potential disruption of the BBB and neuronal damage. Moreover, co-administration of C10M effectively blocked mCRP accumulation in the brain parenchyma, suggesting its potential as a therapeutic agent for effectively inhibiting inflammation-associated degenerative changes. Immunohistochemical staining demonstrated co-localization of mCRP with CD105, indicating potential angiogenic activation and increased susceptibility to inflammatory insult. Discussion These findings provide evidence supporting the potential role of mCRP as a contributor to neuroinflammation in individuals with chronic systemic inflammation. Conclusion Further studies in human subjects should help validate the efficacy of C10M in preventing or halting neurodegeneration in conditions such as AD and stroke-associated dementia.
PubMed: 38899254
DOI: 10.7759/cureus.60682 -
Orthopaedic Surgery Jun 2024Three-level hybrid surgery (HS) consisting of cervical disc arthroplasty (CDA) and anterior cervical discectomy and fusion (ACDF) has been partly used for the treatment...
PURPOSE
Three-level hybrid surgery (HS) consisting of cervical disc arthroplasty (CDA) and anterior cervical discectomy and fusion (ACDF) has been partly used for the treatment of multi-level cervical degenerative disc disease (CDDD). The complications related to the implants and the collapse of the surgical vertebral bodies had been reported in multi-level anterior cervical spine surgery. Thus, this study aimed to explore the biomechanical effects on the prostheses and vertebrae in three-level HS.
METHODS
A FE model of cervical spine (C0-T1) was constructed. Five surgical models were developed. They were FAF model (ACDF-CDA-ACDF), AFA model (CDA-ACDF-CDA), FFF model (three-level ACDF), SF model (single-level ACDF), and SA model (single-level CDA). A 75-N follower load and 1.0-N·m moment was applied to produce flexion, extension, lateral bending, and axial rotation.
RESULTS
Compared with the intact model, the range of motion (ROM) of total cervical spine in FAF model decreased by 34.54%, 54.48%, 31.76%, and 27.14%, respectively, in flexion, extension, lateral bending, and axial rotation, which were lower than those in FFF model and higher than those in AFA model. The ROMs of CDA segments in FAF and AFA models were similar to the intact model and SA model. Compared with the intact model, the ROMs at C3/4 segment in FFF model increased from 5.71% to 7.85%, and increased from 5.31% to 6.81% at C7/T1 segment, following by FAF model, then the FAF model. The maximum interface pressures of the Prestige-LP in FAF model were similar to SA model, however the corresponding values were increased in AFA model. The maximum interface pressures of the Zero-P were increased in FAF and AFA model compared with those in SF and FFF models. The stress was mainly distributed on the screws. In AFA model, the maximum pressures of the ball and trough articulation in superior and inferior Prestige-LP were all increased compared with those in SA and FAF model. In FFF model, the maximum pressures of the vertebrae were higher than those in other models. The stress was mainly distributed on the anterior area of the vertebral bodies.
CONCLUSIONS
HS seemed to be more suitable than ACDF for the surgical treatment of three-level CDDD in consideration of the biomechanical effects, especially for the two-level CDA and one-level ACDF construct. But a more appropriate CDA prosthesis should be explored in the future.
PubMed: 38898370
DOI: 10.1111/os.14125 -
BioRxiv : the Preprint Server For... Jun 2024The retromer complex mediates retrograde transport of protein cargos from endosomes to the trans-Golgi network (TGN). γ-secretase is a multisubunit protease that...
The retromer complex mediates retrograde transport of protein cargos from endosomes to the trans-Golgi network (TGN). γ-secretase is a multisubunit protease that cleaves the transmembrane domain of its target proteins. Mutations in genes encoding subunits of retromer or γ-secretase can cause familial Alzheimer disease (AD) and other degenerative neurological diseases. It has been reported that retromer interacts with γ-secretase, but the consequences of this interaction are not known. Here, we report that retromer-mediated retrograde protein trafficking in cultured human epithelial cells is impaired by inhibition of γ-secretase activity or by genetic elimination of γ-secretase. γ-secretase inhibitor XXI and knockout of PS1, the catalytic subunit of γ-secretase, inhibit endosome to TGN trafficking of retromer-dependent retrograde cargos, divalent metal transporter 1 isoform II (DMT1-II), cation-independent mannose-6-phosphate receptor (CIMPR), and shiga toxin. Trafficking of retromer-independent cargos, such as cholera toxin and a CIMPR mutant that does not bind to retromer was not affected by γ-secretase inhibition. XXI treatment and PS1 KO inhibit interaction of γ-secretase with retromer but do not inhibit the association of cargo with retromer or with γ-secretase in intact cells. Similarly, these treatments do not affect the level of Rab7-GTP, which regulates retromer-cargo interaction. These results suggest that the γ-secretase-retromer interaction facilitates retromer-mediated retrograde trafficking.
PubMed: 38895404
DOI: 10.1101/2024.06.07.597932 -
Frontiers in Neuroscience 2024Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum... (Review)
Review
Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may disrupt a range of cellular processes, such as impaired protein quality control pathways, ion channel dysfunction, mitochondrial dysfunction, transcriptional dysregulation, DNA damage, loss of nuclear integrity, and ultimately, impairment of neuronal function and integrity which causes diseases. Many disease-modifying therapies, such as gene editing technology, RNA interference, antisense oligonucleotides, stem cell technology, and pharmacological therapies are currently under clinical trials. However, the development of curative approaches for genetic diseases remains a global challenge, beset by technical, ethical, and other challenges. Therefore, the study of the pathogenesis of spinocerebellar ataxia is of great importance for the sustained development of disease-modifying molecular therapies.
PubMed: 38894941
DOI: 10.3389/fnins.2024.1422442