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The Journal of Clinical Investigation May 2023Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of-function variants in the AP4M1 gene. SPG50 is...
Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of-function variants in the AP4M1 gene. SPG50 is characterized by progressive spastic paraplegia, global developmental delay, and subsequent intellectual disability, secondary microcephaly, and epilepsy. We preformed preclinical studies evaluating an adeno-associated virus (AAV)/AP4M1 gene therapy for SPG50 and describe in vitro studies that demonstrate transduction of patient-derived fibroblasts with AAV2/AP4M1, resulting in phenotypic rescue. To evaluate efficacy in vivo, Ap4m1-KO mice were intrathecally (i.t.) injected with 5 × 1011, 2.5 × 1011, or 1.25 × 1011 vector genome (vg) doses of AAV9/AP4M1 at P7-P10 or P90. Age- and dose-dependent effects were observed, with early intervention and higher doses achieving the best therapeutic benefits. In parallel, three toxicology studies in WT mice, rats, and nonhuman primates (NHPs) demonstrated that AAV9/AP4M1 had an acceptable safety profile up to a target human dose of 1 × 1015 vg. Of note, similar degrees of minimal-to-mild dorsal root ganglia (DRG) toxicity were observed in both rats and NHPs, supporting the use of rats to monitor DRG toxicity in future i.t. AAV studies. These preclinical results identify an acceptably safe and efficacious dose of i.t.-administered AAV9/AP4M1, supporting an investigational gene transfer clinical trial to treat SPG50.
Topics: Humans; Rats; Mice; Animals; Child; Spastic Paraplegia, Hereditary; Genetic Therapy; Dependovirus; Genetic Vectors; Paraplegia
PubMed: 36951961
DOI: 10.1172/JCI164575 -
Viruses Nov 2015First described in 1962 in children hospitalized for pneumonia and bronchiolitis, the Enterovirus D68 (EV-D68) is an emergent viral pathogen. Since its discovery, during... (Review)
Review
First described in 1962 in children hospitalized for pneumonia and bronchiolitis, the Enterovirus D68 (EV-D68) is an emergent viral pathogen. Since its discovery, during the long period of surveillance up to 2005, EV-D68 was reported only as a cause of sporadic outbreaks. In recent years, many reports from different countries have described an increasing number of patients with respiratory diseases due to EV-D68 associated with relevant clinical severity. In particular, an unexpectedly high number of children have been hospitalized for severe respiratory disease due to EV-D68, requiring intensive care such as intubation and mechanical ventilation. Moreover, EV-D68 has been associated with acute flaccid paralysis and cranial nerve dysfunction in children, which has caused concerns in the community. As no specific antiviral therapy is available, treatment is mainly supportive. Moreover, because no vaccines are available, conventional infection control measures (i.e., standard, for contacts and droplets) in both community and healthcare settings are recommended. However, further studies are required to fully understand the real importance of this virus. Prompt diagnosis and continued surveillance of EV-D68 infections are essential to managing and preventing new outbreaks. Moreover, if the association between EV-D68 and severe diseases will be confirmed, the development of adequate preventive and therapeutic approaches are a priority.
Topics: Disease Outbreaks; Enterovirus D, Human; Enterovirus Infections; Humans; Infection Control; Paraplegia; Respiratory Tract Infections
PubMed: 26610548
DOI: 10.3390/v7112925 -
Cells Feb 2020Spinal cord ischemia (SCI) is a clinical complication following aortic repair that significantly impairs the quality and expectancy of life. Despite some strategies,... (Review)
Review
Spinal cord ischemia (SCI) is a clinical complication following aortic repair that significantly impairs the quality and expectancy of life. Despite some strategies, like cerebrospinal fluid drainage, the occurrence of neurological symptoms, such as paraplegia and paraparesis, remains unpredictable. Beside the major blood supply through conduit arteries, a huge collateral network protects the central nervous system from ischemia-the paraspinous and the intraspinal compartment. The intraspinal arcades maintain perfusion pressure following a sudden inflow interruption, whereas the paraspinal system first needs to undergo arteriogenesis to ensure sufficient blood supply after an acute ischemic insult. The so-called steal phenomenon can even worsen the postoperative situation by causing the hypoperfusion of the spine when, shortly after thoracoabdominal aortic aneurysm (TAAA) surgery, muscles connected with the network divert blood and cause additional stress. Vessels are a conglomeration of different cell types involved in adapting to stress, like endothelial cells, smooth muscle cells, and pericytes. This adaption to stress is subdivided in three phases-initiation, growth, and the maturation phase. In fields of endovascular aortic aneurysm repair, pre-operative selective segmental artery occlusion may enable the development of a sufficient collateral network by stimulating collateral vessel growth, which, again, may prevent spinal cord ischemia. Among others, the major signaling pathways include the phosphoinositide 3 kinase (PI3K) pathway/the antiapoptotic kinase (AKT) pathway/the endothelial nitric oxide synthase (eNOS) pathway, the Erk1, the delta-like ligand (DII), the jagged (Jag)/NOTCH pathway, and the midkine regulatory cytokine signaling pathways.
Topics: Animals; Aortic Aneurysm, Thoracic; Arteries; Collateral Circulation; Humans; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase Type III; Paraplegia; Postoperative Complications; Receptors, Notch; Signal Transduction; Spinal Cord; Spinal Cord Ischemia; Vascular Endothelial Growth Factor A
PubMed: 32098337
DOI: 10.3390/cells9020501 -
Annals of Physical and Rehabilitation... Nov 2022Scientific evidence indicates the presence of secondary conditions (such as pressure injuries) after spinal cord injury (SCI). Treatment methods focusing on the... (Review)
Review
BACKGROUND
Scientific evidence indicates the presence of secondary conditions (such as pressure injuries) after spinal cord injury (SCI). Treatment methods focusing on the management of paraplegia and tetraplegia include systematic preventive follow-up. These advances have significantly improved the functional and vital prognosis of people with SCI, but some people may not have access to these specialized organizations or may not adhere closely to this medicalized vision. We used a narrative approach to explore the perceptions of people with SCI to better understand their adherence to follow-up.
OBJECTIVES
We aimed to determine the "common denominators" that lead to adherence or non-adherence to long-term follow-up after SCI.
METHODS
People with SCI who had completed their first rehabilitation period for > 1 year were included with regard to 2 variables: 1) an actual medical follow-up or not and 2) a history of pressure injury or not. A review of the literature was used as preparation for semi-directive interviews, which were prospectively analysed by using qualitative analysis software. Thematic saturation was reached at 28 interviews, and 32 interviews were ultimately completed.
RESULT
Three main areas concerning participants' perceptions emerged: people's readiness, appropriation and modulation of the systematic follow-up. We developed a broad conceptual framework representing follow-up and the promotion of the long-term health of people with SCI from their perspectives.
CONCLUSIONS
The medical environment should ensure that people with SCI are ready to actively consider the implementation of prevention strategies and should take into account their ability to establish their own truth, to integrate various life stages after SCI and to negotiate systematic follow-up. The implementation of data about functioning should be conducted using the concept of the Learning Health System.
Topics: Humans; Spinal Cord Injuries; Qualitative Research; Paraplegia; Quadriplegia; Software
PubMed: 35031498
DOI: 10.1016/j.rehab.2022.101629 -
Texas Heart Institute Journal Aug 2014
Topics: Aortic Dissection; Aortic Aneurysm; Arterial Occlusive Diseases; Humans; Male; Paraplegia; Thrombosis; Weight Lifting
PubMed: 25120409
DOI: 10.14503/THIJ-14-4526 -
Turkish Neurosurgery 2019To report the four most common spinal parasites for providing insight into definitive therapy.
AIM
To report the four most common spinal parasites for providing insight into definitive therapy.
MATERIAL AND METHODS
Twelve patients with spinal parasites were diagnosed between 2009 and 2016. A definite diagnosis was established in the form of histopathology (n=9) and response to drug therapy (n=3). The minimum follow-up was 0.9 years and ranged to a maximum of 8 years, with a median of 3 years.
RESULTS
Twelve patients aged between 8 and 69 years were reviewed, including nine hydatidosis and three non-hydatid cases. Occupational exposure to the endemic area and unclean food were the main routes of infestation. Spinal parasites can present symptoms that correlated with the level of the lesion. There was complete paraplegia in four patients and paraparesis in six patients before surgery. Seven hydatid patients underwent posterior decompression and pedicle screw fixation with posterolateral fusion. Two non-hydatid patients experienced laminoplasty after posterior decompression. Six hydatid patients had reoccurrences and two patients with intramedullary hydatidosis died of severe complications one year after surgery.
CONCLUSION
Spinal hydatidosis significantly differs from the three other non-hydatid parasites in diagnosis and treatment. The final prognosis of spinal hydatidosis remains poor, especially for intramedullary hydatidosis.
Topics: Adult; Aged; Animals; Child; Decompression, Surgical; Echinococcosis; Female; Humans; Laminoplasty; Male; Middle Aged; Paraplegia; Parasites; Pedicle Screws; Spinal Fusion; Spine
PubMed: 30649820
DOI: 10.5137/1019-5149.JTN.24369-18.2 -
Current Neurology and Neuroscience... Feb 2019Hereditary spastic paraplegias are a genetically heterogeneous group of neurological disorders. Patients present lower limb weakness and spasticity, complicated in... (Review)
Review
PURPOSE OF REVIEW
Hereditary spastic paraplegias are a genetically heterogeneous group of neurological disorders. Patients present lower limb weakness and spasticity, complicated in complex forms by additional neurological signs. We review here the major steps toward understanding the molecular basis of these diseases made over the last 10 years.
RECENT FINDINGS
Our perception of the intricate connections between clinical, genetic, and molecular aspects of neurodegenerative disorders has radically changed in recent years, thanks to improvements in genetic approaches. This is particularly true for hereditary spastic paraplegias, for which > 60 genes have been identified, highlighting (i) the considerable genetic heterogeneity of this group of clinically diverse disorders, (ii) the fuzzy border between recessive and dominant inheritance for several mutations, and (iii) the overlap of these mutations with other neurological conditions in terms of their clinical effects. Several hypotheses have been put forward concerning the pathophysiological mechanisms involved, based on the genes implicated and their known function and based on studies on patient samples and animal models. These mechanisms include mainly abnormal intracellular trafficking, changes to endoplasmic reticulum shaping and defects affecting lipid metabolism, lysosome physiology, autophagy, myelination, and development. Several causative genes affect multiple of these functions, which are, most of the time, interconnected. Recent major advances in our understanding of these diseases have revealed unifying pathogenic models that could be targeted in the much-needed development of new treatments.
Topics: Animals; Genetic Heterogeneity; Humans; Mutation; Paraplegia; Spastic Paraplegia, Hereditary
PubMed: 30820684
DOI: 10.1007/s11910-019-0930-2 -
Purinergic Signalling Dec 2018Purine metabolism is depending on a large amount of enzymes to ensure cellular homeostasis. Among these enzymes, we have been interested in the 5'-nucleotidase cN-II and... (Review)
Review
Purine metabolism is depending on a large amount of enzymes to ensure cellular homeostasis. Among these enzymes, we have been interested in the 5'-nucleotidase cN-II and its role in cancer biology and in response of cancer cells to treatments. This protein has been cited and studied in a large number of papers published during the last decade for its involvement in non-cancerous pathologies such as hereditary spastic paraplegia, schizophrenia, and blood pressure regulation. Here, we review these articles in order to give an overview of the recently discovered clinical relevance of cN-II.
Topics: 5'-Nucleotidase; Acid Phosphatase; Animals; Blood Pressure; GPI-Linked Proteins; Homeostasis; Humans; Paraplegia
PubMed: 30362044
DOI: 10.1007/s11302-018-9627-2 -
Spinal Cord Series and Cases Nov 2022Retrospective chart review.
STUDY DESIGN
Retrospective chart review.
OBJECTIVES
Sepsis is a leading preventable cause of death in patients with chronic spinal cord injury (SCI). Individuals with tetraplegia may exhibit different signs and symptoms of infection compared to those with paraplegia. In this study, we examine differences in vital signs (VS) and mental status between septic patients with tetraplegia and paraplegia with the goal of improving early identification of sepsis in this population.
SETTING
Veterans hospital in Washington, USA.
METHODS
Participants consisted of 19 patients with tetraplegia and 16 with paraplegia who were transferred from an SCI Service to a higher level of care with sepsis between June 1, 2010 and June 1, 2018 (n = 35). We compared VS between patients with tetraplegia and paraplegia at baseline and during sepsis including temperature, heart rate (HR), and blood pressure as well as presence/absence of altered mental status (AMS).
RESULTS
While there were no significant VS differences between groups at baseline, septic patients with tetraplegia had lower maximum temperature (38.2 °C versus 39.2 °C, p = 0.003), lower maximum HR (106 versus 124 beats/minute, p = 0.004), and more frequent AMS compared to septic patients with paraplegia (79% versus 31%, p = 0.007).
CONCLUSION
Patients with tetraplegia may not be able to mount fever and tachycardia to the same degree as patients with paraplegia and may be more prone to developing AMS during sepsis. These findings suggest that changes to VS parameter cut-offs may improve sensitivity and be useful in identifying sepsis earlier in the tetraplegic population.
Topics: Humans; Retrospective Studies; Quadriplegia; Paraplegia; Spinal Cord Injuries; Heart Rate; Sepsis
PubMed: 36433952
DOI: 10.1038/s41394-022-00553-3 -
Biochimica Et Biophysica Acta.... Jan 2020The endoplasmic reticulum (ER) is a continuous endomembrane system comprising the nuclear envelope, ribosome-studded sheets, dense peripheral matrices, and an extensive... (Review)
Review
The endoplasmic reticulum (ER) is a continuous endomembrane system comprising the nuclear envelope, ribosome-studded sheets, dense peripheral matrices, and an extensive polygonal network of interconnected tubules. In addition to performing numerous critical cellular functions, the ER makes extensive contacts with other organelles, including endosomes and lysosomes. The molecular and functional characterization of these contacts has advanced significantly over the past several years. These contacts participate in key functions such as cholesterol transfer, endosome tubule fission, and Ca exchange. Disruption of key proteins at these sites can result in often severe diseases, particularly those affecting the nervous system.
Topics: Animals; Calcium; Cholesterol; Endoplasmic Reticulum; Endosomes; Humans; Lysosomes; Paraplegia
PubMed: 31678515
DOI: 10.1016/j.bbalip.2019.158544