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1.
BMC Psychiatry ; 24(1): 532, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39049079

RESUMO

BACKGROUND: Adverse events (AEs) are commonly reported in clinical studies using the Medical Dictionary for Regulatory Activities (MedDRA), an international standard for drug safety monitoring. However, the technical language of MedDRA makes it challenging for patients and clinicians to share understanding and therefore to make shared decisions about medical interventions. In this project, people with lived experience of depression and antidepressant treatment worked with clinicians and researchers to co-design an online dictionary of AEs associated with antidepressants, taking into account its ease of use and applicability to real-world settings. METHODS: Through a pre-defined literature search, we identified MedDRA-coded AEs from randomised controlled trials of antidepressants used in the treatment of depression. In collaboration with the McPin Foundation, four co-design workshops with a lived experience advisory panel (LEAP) and one independent focus group (FG) were conducted to produce user-friendly translations of AE terms. Guiding principles for translation were co-designed with McPin/LEAP members and defined before the finalisation of Clinical Codes (CCs, or non-technical terms to represent specific AE concepts). FG results were thematically analysed using the Framework Method. RESULTS: Starting from 522 trials identified by the search, 736 MedDRA-coded AE terms were translated into 187 CCs, which balanced key factors identified as important to the LEAP and FG (namely, breadth, specificity, generalisability, patient-understandability and acceptability). Work with the LEAP showed that a user-friendly language of AEs should aim to mitigate stigma, acknowledge the multiple levels of comprehension in 'lay' language and balance the need for semantic accuracy with user-friendliness. Guided by these principles, an online dictionary of AEs was co-designed and made freely available ( https://thesymptomglossary.com ). The digital tool was perceived by the LEAP and FG as a resource which could feasibly improve antidepressant treatment by facilitating the accurate, meaningful expression of preferences about potential harms through a shared decision-making process. CONCLUSIONS: This dictionary was developed in English around AEs from antidepressants in depression but it can be adapted to different languages and cultural contexts, and can also become a model for other interventions and disorders (i.e., antipsychotics in schizophrenia). Co-designed digital resources may improve the patient experience by helping to deliver personalised information on potential benefits and harms in an evidence-based, preference-sensitive way.


Assuntos
Antidepressivos , Tomada de Decisão Compartilhada , Humanos , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Participação do Paciente/métodos , Internet
2.
Int J Mol Sci ; 25(11)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38891894

RESUMO

Traumatic spinal cord injury (SCI) is a life-threatening and life-altering condition that results in debilitating sensorimotor and autonomic impairments. Despite significant advances in the clinical management of traumatic SCI, many patients continue to suffer due to a lack of effective therapies. The initial mechanical injury to the spinal cord results in a series of secondary molecular processes and intracellular signaling cascades in immune, vascular, glial, and neuronal cell populations, which further damage the injured spinal cord. These intracellular cascades present promising translationally relevant targets for therapeutic intervention due to their high ubiquity and conservation across eukaryotic evolution. To date, many therapeutics have shown either direct or indirect involvement of these pathways in improving recovery after SCI. However, the complex, multifaceted, and heterogeneous nature of traumatic SCI requires better elucidation of the underlying secondary intracellular signaling cascades to minimize off-target effects and maximize effectiveness. Recent advances in transcriptional and molecular neuroscience provide a closer characterization of these pathways in the injured spinal cord. This narrative review article aims to survey the MAPK, PI3K-AKT-mTOR, Rho-ROCK, NF-κB, and JAK-STAT signaling cascades, in addition to providing a comprehensive overview of the involvement and therapeutic potential of these secondary intracellular pathways following traumatic SCI.


Assuntos
Transdução de Sinais , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/metabolismo , Humanos , Animais , Serina-Treonina Quinases TOR/metabolismo
3.
Mol Psychiatry ; 27(3): 1339-1349, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34819636

RESUMO

The gabapentinoids, gabapentin, and pregabalin, target the α2δ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage. We conducted a systematic review and meta-analysis of the evidence for three of their common psychiatric uses: bipolar disorder, anxiety, and insomnia. Fifty-five double-blind randomised controlled trials (RCTs) and 15 open-label studies were identified. For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified. A quantitative synthesis could not be performed due to heterogeneity in the study population, design and outcome measures. Across the anxiety spectrum, a consistent but not universal effect in favour of gabapentinoids compared to placebo was seen (standardised mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55, 95% CI -0.92 to -0.18) and gabapentin (SMD -0.92, 95% CI -1.32 to -0.52) were more effective than placebo in reducing preoperative anxiety. In insomnia, results were inconclusive. We conclude that there is moderate evidence of the efficacy of gabapentinoids in anxiety states, but minimal evidence in bipolar disorder and insomnia and they should be used for these disorders only with strong justification. This recommendation applies despite the attractive pharmacological and genetic rationale for targeting voltage-gated calcium channels.


Assuntos
Transtorno Bipolar , Ácidos Cicloexanocarboxílicos , Distúrbios do Início e da Manutenção do Sono , Aminas/uso terapêutico , Ansiedade/tratamento farmacológico , Transtorno Bipolar/tratamento farmacológico , Canais de Cálcio , Ácidos Cicloexanocarboxílicos/uso terapêutico , Gabapentina/uso terapêutico , Humanos , Pregabalina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico
4.
Environ Microbiol ; 24(3): 1308-1325, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34708512

RESUMO

Terpios hoshinota is an aggressive, space-competing sponge that kills various stony corals. Outbreaks of this species have led to intense damage to coral reefs in many locations. Here, the first large-scale 16S rRNA gene survey across three oceans revealed that bacteria related to the taxa Prochloron, Endozoicomonas, SAR116, Ruegeria, and unclassified Proteobacteria were prevalent in T. hoshinota. A Prochloron-related bacterium was the most dominant and prevalent cyanobacterium in T. hoshinota. The complete genome of this uncultivated cyanobacterium and pigment analysis demonstrated that it has phycobiliproteins and lacks chlorophyll b, which is inconsistent with the definition of Prochloron. Furthermore, the cyanobacterium was phylogenetically distinct from Prochloron, strongly suggesting that it should be a sister taxon to Prochloron. Therefore, we proposed this symbiotic cyanobacterium as a novel species under the new genus Candidatus Paraprochloron terpiosi. Comparative genomic analyses revealed that 'Paraprochloron' and Prochloron exhibit distinct genomic features and DNA replication machinery. We also characterized the metabolic potentials of 'Paraprochloron terpiosi' in carbon and nitrogen cycling and propose a model for interactions between it and T. hoshinota. This study builds a foundation for the study of the T. hoshinota microbiome and paves the way for better understanding of ecosystems involving this coral-killing sponge.


Assuntos
Antozoários , Cianobactérias , Microbiota , Poríferos , Animais , Antozoários/microbiologia , Recifes de Corais , Cianobactérias/metabolismo , Poríferos/genética , Prevalência , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Simbiose
5.
BMC Psychiatry ; 22(1): 228, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361184

RESUMO

BACKGROUND: People with substance use disorders may be at a greater risk of contracting COVID-19 infection and developing medical complications. Several institutional and governmental health agencies across the world developed ad hoc guidance for substance use disorder services and care of individuals misusing substances. We aimed to synthesise the best available recommendations on management and care of people with or at risk of substance use disorders during the COVID-19 pandemic from existing guidelines published in UK, USA, Australia, Canada, New Zealand, and Singapore. METHODS: We systematically searched existing guidelines and websites from 28 international institutions and governmental bodies in the context of the COVID-19 pandemic (May 4th 2021). We summarized the extracted data as answers to specific clinical questions. RESULTS: We organised the available recommendations from 19 sources in three sections. First, we focused on general advice and recommendations for people who misuse alcohol or drugs during the COVID-19 pandemic, the design of contingency plans, safeguarding issues for children and families of service users and advice to the public, patients, and carers. Then, we summarised specific guidelines for people who use illicit drugs and related services, such as opioid substitution treatment and needle and syringe programmes. Finally, we provided a synthesis on specific recommendations for services supporting people who misuse alcohol and key topics in the field, such as management of alcohol detoxification and safe transition between supervised and unsupervised consumption. CONCLUSIONS: Available guidance reflected different approaches, ranging from being extremely cautious in providing recommendations other than generic statements to proposing adaptation of previously available guidelines to confront the challenges of the COVID-19 pandemic. After the early phase, guidance focused on reduction of infection transmission and service delivery. Guidance did not provide advice on infection prevention via vaccination programmes and service access strategies tailored to individuals with substance use disorders.


Assuntos
Alcoolismo , COVID-19 , Transtornos Relacionados ao Uso de Substâncias , Alcoolismo/psicologia , Alcoolismo/terapia , Criança , Guias como Assunto , Pessoal de Saúde , Humanos , Pandemias , Transtornos Relacionados ao Uso de Substâncias/psicologia
6.
Int J Mol Sci ; 23(19)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36232808

RESUMO

Degenerative cervical myelopathy (DCM) is caused by age-related degeneration of the cervical spine, causing chronic spinal cord compression and inflammation. The aim of this study was to assess whether the natural progression of DCM is accompanied by hematological changes in the white blood cell composition. If so, these changes can be used for diagnosis complementing established imaging approaches and for the development of treatment strategies, since peripheral immunity affects the progression of DCM. Gradual compression of the spinal cord was induced in C57B/L mice at the C5-6 level. The composition of circulating white blood cells was analyzed longitudinally at four time points after induction of DCM using flow cytometry. At 12 weeks, serum cytokine levels were measured using a Luminex x-MAP assay. Neurological impairment in the mouse model was also assessed using the ladder walk test and CatWalk. Stepping function (* p < 0.05) and overground locomotion (*** p < 0.001) were impaired in the DCM group. Importantly, circulating monocytes and T cells were affected primarily at 3 weeks following DCM. T cells were two-fold lower in the DCM group (*** p < 0.0006), whereas monocytes were four-fold increased (*** p < 0.0006) in the DCM compared with the sham group. Our data suggest that changes in white blood cell populations are modest, which is unique to other spinal cord pathologies, and precede the development of neurobehavioral symptoms.


Assuntos
Compressão da Medula Espinal , Doenças da Medula Espinal , Animais , Vértebras Cervicais , Citocinas , Modelos Animais de Doenças , Leucócitos/patologia , Camundongos , Compressão da Medula Espinal/diagnóstico , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/patologia , Doenças da Medula Espinal/patologia
7.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575871

RESUMO

The pathobiology of traumatic and nontraumatic spinal cord injury (SCI), including degenerative myelopathy, is influenced by neuroinflammation. The neuroinflammatory response is initiated by a multitude of injury signals emanating from necrotic and apoptotic cells at the lesion site, recruiting local and infiltrating immune cells that modulate inflammatory cascades to aid in the protection of the lesion site and encourage regenerative processes. While peripheral immune cells are involved, microglia, the resident immune cells of the central nervous system (CNS), are known to play a central role in modulating this response. Microglia are armed with numerous cell surface receptors that interact with neurons, astrocytes, infiltrating monocytes, and endothelial cells to facilitate a dynamic, multi-faceted injury response. While their origin and essential nature are understood, their mechanisms of action and spatial and temporal profiles warrant extensive additional research. In this review, we describe the role of microglia and the cellular network in SCI, discuss tools for their investigation, outline their spatiotemporal profile, and propose translationally-relevant therapeutic targets to modulate neuroinflammation in the setting of SCI.


Assuntos
Inflamação/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Traumatismos da Medula Espinal/metabolismo , Animais , Astrócitos/metabolismo , Membrana Celular/metabolismo , Células Endoteliais/metabolismo , Humanos , Imunidade Inata , Inflamação/fisiopatologia , Macrófagos/metabolismo , Monócitos/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia
8.
Int J Mol Sci ; 22(23)2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34884738

RESUMO

Despite the debilitating consequences following traumatic spinal cord injury (SCI), there is a lack of safe and effective therapeutics in the clinic. The species-specific responses to SCI present major challenges and opportunities for the clinical translation of biomolecular and pharmacological interventions. Recent transcriptional analyses in preclinical SCI studies have provided a snapshot of the local SCI-induced molecular responses in different animal models. However, the variation in the pathogenesis of traumatic SCI across species is yet to be explored. This study aims to identify and characterize the common and inconsistent SCI-induced differentially expressed genes across species to identify potential therapeutic targets of translational relevance. A comprehensive search of open-source transcriptome datasets identified four cross-compatible microarray experiments in rats, mice, and salamanders. We observed consistent expressional changes in extracellular matrix components across the species. Conversely, salamanders showed downregulation of intracellular MAPK signaling compared to rodents. Additionally, sequence conservation and interactome analyses highlighted the well-preserved sequences of Fn1 and Jun with extensive protein-protein interaction networks. Lastly, in vivo immunohistochemical staining for fibronectin was used to validate the observed expressional pattern. These transcriptional changes in extracellular and MAPK pathways present potential therapeutic targets for traumatic SCI with promising translational relevance.


Assuntos
Sistema de Sinalização das MAP Quinases , Terapia de Alvo Molecular , Traumatismos da Medula Espinal/metabolismo , Ambystoma mexicanum , Animais , Modelos Animais de Doenças , Camundongos , Ratos , Traumatismos da Medula Espinal/terapia
9.
J Neuroinflammation ; 16(1): 141, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288834

RESUMO

BACKGROUND: Spinal cord injury (SCI) is a condition with few effective treatment options. The blood-spinal cord barrier consists of pericytes, astrocytes, and endothelial cells, which are collectively termed the neurovascular unit. These cells support spinal cord homeostasis by expressing tight junction proteins. Physical trauma to the spinal cord disrupts the barrier, which leads to neuroinflammation by facilitating immune cell migration to the damaged site in a process involving immune cell adhesion. Immunosuppressive strategies, including methylprednisolone (MPSS), have been investigated to treat SCI. However, despite some success, MPSS has the potential to increase a patient's susceptibility to wound infection and impaired wound healing. Hence, immunomodulation may be a more attractive approach than immunosuppression. Approved for modulating neuroinflammation in certain disorders, including Guillain-Barre syndrome, intravenous administration of human immunoglobulin G (hIgG) has shown promise in the setting of experimental SCI, though the optimal dose and mechanism of action remain undetermined. METHODS: Female adult Wistar rats were subjected to moderate-severe clip compression injury (35 g) at the C7-T1 level and randomized to receive a single intravenous (IV) bolus of hIgG (0.02, 0.2, 0.4, 1, 2 g/kg), MPSS (0.03 g/kg), or control buffer at 15 min post-SCI. At 24 h and 6 weeks post-SCI, molecular, histological, and neurobehavioral effects of hIgG were analyzed. RESULTS: At 24 h post-injury, human immunoglobulin G co-localized with spinal cord pericytes, astrocytes, and vessels. hIgG (2 g/kg) protected the spinal cord neurovasculature after SCI by increasing tight junction protein expression and reducing inflammatory enzyme expression. Improvements in vascular integrity were associated with changes in spinal cord inflammation. Interestingly, hIgG (2 g/kg) increased serum expression of inflammatory cytokines and co-localized (without decreasing protein expression) with spinal cord vascular cell adhesion molecule-1, a protein used by immune cells to enter into inflamed tissue. Acute molecular benefits of hIgG (2 g/kg) led to greater tissue preservation, functional blood flow, and neurobehavioral recovery at 6 weeks post-SCI. Importantly, the effects of hIgG (2 g/kg) were superior to control buffer and hIgG (0.4 g/kg), and comparable with MPSS (0.03 g/kg). CONCLUSIONS: hIgG (2 g/kg) is a promising therapeutic approach to mitigate secondary pathology in SCI through antagonizing immune cell infiltration at the level of the neurovascular unit.


Assuntos
Imunoglobulinas Intravenosas/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia , Junções Íntimas/efeitos dos fármacos , Animais , Medula Cervical/irrigação sanguínea , Medula Cervical/efeitos dos fármacos , Medula Cervical/patologia , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Distribuição Aleatória , Ratos , Ratos Wistar
10.
Int J Mol Sci ; 20(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374824

RESUMO

Spinal cord injury (SCI) is associated with an increased susceptibility to infections, such as pneumonia, which is the leading cause of death in these patients. This phenomenon is referred to as SCI immune deficiency syndrome (SCI-IDS), and has been shown to be more prevalent after high-level transection in preclinical SCI models. Despite the high prevalence of contusion SCIs, the effects of this etiology have not been studied in the context of SCI-IDS. Compared to transection SCIs, which involve a complete loss of supraspinal input and lead to the disinhibition of spinally-generated activity, contusion SCIs may cause significant local deafferentation, but only a partial disruption of sympathetic tone below the level of injury. In this work, we investigate the effects of thoracic (T6-7) and cervical (C6-7) moderate-severe contusion SCIs on the spleen by characterizing splenic norepinephrine (NE) and cortisol (CORT), caspase-3, and multiple inflammation markers at 3- and 7-days post-SCI. In contrary to the literature, we observe an increase in splenic NE and CORT that correspond to an increase in caspase-3 after thoracic SCI relative to cervical SCI. Further, we found differences in expression of leptin, eotaxin, IP-10, and IL-18 that implicate alterations in splenocyte recruitment and function. These results suggest that incomplete SCI drastically alters the level-dependence of SCI-IDS.


Assuntos
Vértebras Cervicais/fisiopatologia , Inflamação/etiologia , Traumatismos da Medula Espinal/complicações , Baço/fisiopatologia , Vértebras Torácicas/fisiopatologia , Animais , Vértebras Cervicais/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Inflamação/imunologia , Inflamação/fisiopatologia , Ratos Wistar , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/fisiopatologia , Baço/imunologia , Vértebras Torácicas/imunologia
11.
J Neuroinflammation ; 15(1): 222, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081922

RESUMO

BACKGROUND: Degenerative cervical myelopathy (DCM) is caused by degenerative or congenital changes to the discs and soft tissues of the cervical spine, which leads to chronic compression of the spinal cord. The current treatment for moderate to severe DCM consists of surgical decompression, which, while effective in most cases, can result in neuroinflammation and spinal cord reperfusion injury, leading to perioperative neurological complications and suboptimal neurological recovery. The primary objective of this study was to assess, in a translationally relevant animal model of DCM, the efficacy of perioperative methylprednisolone (MP) in enhancing neurological recovery and to evaluate its effect on the inflammatory response following decompression. METHODS: DCM was induced in C57BL/6 mice. Briefly, an aromatic polyether material was implanted underneath the C5-C6 laminae to cause progressive compression of the cervical spinal cord due to focal ossification. Decompressive surgery was undertaken at 12 weeks post initial biomaterial implantation. Animals received one dose of MP (30 mg/kg) or vehicle 30 min before decompression and at 2 weeks after decompression. Acute analysis of secreted cytokines and spinal cord microvasculature was complemented with immunohistochemistry for glial and neuronal cell markers. Locomotor outcomes were measured using the CatWalk system. The composition of circulating white blood cells was analyzed by flow cytometry. RESULTS: A single dose of MP before decompression significantly sped locomotor recovery (*p < 0.05) and reduced the incidence of perioperative motor complications, without affecting the composition of circulating white blood cells. Histological assessment of the spinal cord showed significant neuronal preservation and a modest reduction in parenchymal inflammation. CONCLUSIONS: Our data suggest that MP reduces perioperative neurological complications following decompressive surgery for DCM by protecting neurons from inflammation, without compromising the composition of circulating immune cells. We propose that MP, which is commonly used for neurological disorders including spinal cord injury, be considered as a perioperative adjunct to decompressive surgery to attenuate neurological complications.


Assuntos
Anti-Inflamatórios/uso terapêutico , Descompressão Cirúrgica/métodos , Metilprednisolona/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Compressão da Medula Espinal/tratamento farmacológico , Compressão da Medula Espinal/cirurgia , Análise de Variância , Animais , Células Sanguíneas/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/terapia , Fluxometria por Laser-Doppler , Leucócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Medula Espinal/metabolismo , Compressão da Medula Espinal/complicações , Fatores de Tempo
12.
J Neuroinflammation ; 15(1): 219, 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30075797

RESUMO

BACKGROUND: The spleen plays an important role in erythrocyte turnover, adaptive immunity, antibody production, and the mobilization of monocytes/macrophages (Mφ) following tissue injury. In response to trauma, the spleen initiates production of inflammatory cytokines, which in turn recruit immune cells to the inflamed tissue, exacerbating damage. Our previous work has shown that intravenous mesenchymal stromal cell (MSC) infusion has potent immunomodulatory effects following spinal cord injury (SCI), associated with the transplanted cells homing to and persisting within the spleen. Therefore, this work aimed to characterize the relationship between the splenic inflammatory response and SCI pathophysiology, emphasizing splenic involvement in MSC-mediated effects. METHODS: Using a rodent model of cervical clip-compression SCI, secondary tissue damage and functional recovery were compared between splenectomised rodents and those with a sham procedure. Subsequently, 2.5 million MSCs from the term human umbilical cord matrix cells (HUCMCs) were infused via tail vein at 1-h post-SCI and the effects were assessed in the presence or absence of a spleen. RESULTS: Splenectomy alone had no effect on lesion volume, hemorrhage, or inflammation. There was also no significant difference between the groups in functional recovery and those in lesion morphometry. Yet, while the infusion of HUCMCs reduced spinal cord hemorrhage and increased systemic levels of IL-10 in the presence of a spleen, these effects were lost with splenectomy. Further, HUCMC infusion was shown to alter the expression levels of splenic cytokines, suggesting that the spleen is an important target and site of MSC effects. CONCLUSIONS: Our results provide a link between MSC function and splenic inflammation, a finding that can help tailor the cells/transplantation approach to enhance therapeutic efficacy.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Citocinas/metabolismo , Células-Tronco Mesenquimais/fisiologia , Traumatismos da Medula Espinal/terapia , Baço/metabolismo , Cordão Umbilical/citologia , Animais , Modelos Animais de Doenças , Feminino , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/terapia , Fluxometria por Laser-Doppler , Transtornos Motores/etiologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/complicações
13.
Int J Mol Sci ; 19(8)2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30044384

RESUMO

While over half of all spinal cord injuries (SCIs) occur in the cervical region, the majority of preclinical studies have focused on models of thoracic injury. However, these two levels are anatomically distinct-with the cervical region possessing a greater vascular supply, grey-white matter ratio and sympathetic outflow relative to the thoracic region. As such, there exists a significant knowledge gap in the secondary pathology at these levels following SCI. In this study, we characterized the systemic plasma markers of inflammation over time (1, 3, 7, 14, 56 days post-SCI) after moderate-severe, clip-compression cervical and thoracic SCI in a rat model. Using high-throughput ELISA panels, we observed a clear level-specific difference in plasma levels of VEGF, leptin, IP10, IL18, GCSF, and fractalkine. Overall, cervical SCI had reduced expression of both pro- and anti-inflammatory proteins relative to thoracic SCI, likely due to sympathetic dysregulation associated with higher level SCIs. However, contrary to the literature, we did not observe level-dependent splenic atrophy with our incomplete SCI model. This is the first study to compare the systemic plasma-level changes following cervical and thoracic SCI using level-matched and time-matched controls. The results of this study provide the first evidence in support of level-targeted intervention and also challenge the phenomenon of high SCI-induced splenic atrophy in incomplete SCI models.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Inflamação/sangue , Traumatismos da Medula Espinal/sangue , Traumatismos Torácicos/sangue , Animais , Atrofia , Vértebras Cervicais/lesões , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/patologia , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/patologia , Baço/patologia , Traumatismos Torácicos/patologia , Vértebras Torácicas/lesões
14.
J Biol Chem ; 288(34): 24351-62, 2013 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-23846691

RESUMO

Embryonic stem cell (ESC) pluripotency is orchestrated by distinct signaling pathways that are often targeted to maintain ESC self-renewal or their differentiation to other lineages. We showed earlier that inhibition of PKC signaling maintains pluripotency in mouse ESCs. Therefore, in this study, we investigated the importance of protein kinase C signaling in the context of rat ESC (rESC) pluripotency. Here we show that inhibition of PKC signaling is an efficient strategy to establish and maintain pluripotent rESCs and to facilitate reprogramming of rat embryonic fibroblasts to rat induced pluripotent stem cells. The complete developmental potential of rESCs was confirmed with viable chimeras and germ line transmission. Our molecular analyses indicated that inhibition of a PKCζ-NF-κB-microRNA-21/microRNA-29 regulatory axis contributes to the maintenance of rESC self-renewal. In addition, PKC inhibition maintains ESC-specific epigenetic modifications at the chromatin domains of pluripotency genes and, thereby, maintains their expression. Our results indicate a conserved function of PKC signaling in balancing self-renewal versus differentiation of both mouse and rat ESCs and indicate that targeting PKC signaling might be an efficient strategy to establish ESCs from other mammalian species.


Assuntos
Células-Tronco Embrionárias/enzimologia , Células-Tronco Pluripotentes/enzimologia , Proteína Quinase C-épsilon/metabolismo , Transdução de Sinais/fisiologia , Animais , Células-Tronco Embrionárias/citologia , Indóis/farmacologia , Maleimidas/farmacologia , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Células-Tronco Pluripotentes/citologia , Proteína Quinase C-épsilon/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos
15.
Drug Metab Dispos ; 42(1): 94-104, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24131672

RESUMO

To accurately predict the modifications done during metabolic processes by cytochrome P450 (P450) 3A enzyme, selecting substrates that best represent a broad range of substrate substitutions and that follow the Michaelis-Menten kinetic properties is highly necessary. In the present study, the oxidative pathways of deoxyschizandrin (DS), the most abundant lignan in Fructus Schisandrae fruit extract, were characterized with liver microsomes from human (HLM) and rat (RLM). Only one monohydroxylated metabolite 7(S)-hydroxylated metabolite (isoschizandrin, ISZ), was identified using liquid chromatography-mass spectrometry and nuclear magnetic resonance techniques. CYP3A4 and CYP3A5 were found to be the major isoforms involved in the monohydroxylation of DS. Also, the kinetic studies showed that DS hydroxylation obeyed Michaelis-Menten kinetics both in HLM and in RLM. However, the subsequent metabolism of ISZ was nearly nonexistent when DS was present. More importantly, the interactions between DS and three well characterized CYP3A probe substrates, testosterone (TST), midazolam (MDZ), and nifedipine (NIF), were studied. TST and MDZ were shown to compete with DS for the mutual binding site, causing Km to be increased. The presence of DS also lowered the binding affinities for MDZ and TST. However, DS showed only slight inhibitory effects on nifedipine (NIF) oxidation even though NIF was able to inhibit DS hydroxylation in a noncompetitive fashion. These results show that DS is a good representative substrate of MDZ and TST primarily due to their shared, large binding regions on CYP3A. Therefore, DS is an attractive candidate as a novel CYP3A probe substrate for predicting the metabolic modifications in CYP3A activity.


Assuntos
Ciclo-Octanos/metabolismo , Citocromo P-450 CYP3A/metabolismo , Lignanas/metabolismo , Compostos Policíclicos/metabolismo , Animais , Biotransformação/fisiologia , Sistema Enzimático do Citocromo P-450 , Humanos , Hidroxilação/fisiologia , Cinética , Masculino , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Midazolam/metabolismo , Nifedipino/metabolismo , Oxirredução , Ratos , Ratos Wistar , Testosterona/metabolismo
16.
Stem Cell Reports ; 18(3): 672-687, 2023 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-36764296

RESUMO

The adult spinal cord contains a population of ependymal-derived neural stem/progenitor cells (epNSPCs) that are normally quiescent, but are activated to proliferate, differentiate, and migrate after spinal cord injury. The mechanisms that regulate their response to injury cues, however, remain unknown. Here, we demonstrate that excitotoxic levels of glutamate promote the proliferation and astrocytic fate specification of adult spinal cord epNSPCs. We show that glutamate-mediated calcium influx through calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (CP-AMPARs) in concert with Notch signaling increases the proliferation of epNSPCs via pCREB, and induces astrocytic differentiation through Hes1 upregulation. Furthermore, the in vivo targeting of this pathway via positive modulation of AMPARs after spinal cord injury enhances epNSPC proliferation, astrogliogenesis, neurotrophic factor production and increases neuronal survival. Our study uncovers an important mechanism by which CP-AMPARs regulate the growth and phenotype of epNSPCs, which can be targeted therapeutically to harness the regenerative potential of these cells after injury.


Assuntos
Ácido Glutâmico , Traumatismos da Medula Espinal , Humanos , Ácido Glutâmico/metabolismo , Cálcio/metabolismo , Medula Espinal , Receptores de AMPA/metabolismo , Traumatismos da Medula Espinal/metabolismo , Proliferação de Células
17.
Audiol Res ; 13(4): 600-614, 2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37622928

RESUMO

Conductive hearing losses are typically present in disorders of the external/middle ear. However, there is a rare group of inner ear conditions called third windows that can also generate a conductive hearing loss. This is due to an abnormal connection between the middle and the inner ear or between the inner ear and the cranial cavity. X-linked gusher disorder is an extremely rare congenital inner ear dysplastic syndrome with an abnormal connection due to a characteristic incomplete cochlear partition type III and an incomplete internal auditory meatus fundus. The disorder is inherited in an X-linked fashion due to the mutation of the POU3F4 gene. We present two siblings diagnosed with the condition and their long-term follow-ups. They both presented audiovestibular symptoms and showed progressive mixed losses and bilateral vestibular weakness. They were treated with cochlear implant, digital amplification and with vestibular rehabilitation. Significant others around them were involved in their journey with the medical team, and in both, a very favourable outcome was achieved. This is the first time that we have reported evolving audiovestibular function with vestibular quantification in X-linked gusher disorder and emphasize on the multidisciplinary holistic approach to manage these children effectively.

18.
JBJS Rev ; 11(6)2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37289916

RESUMO

¼ Lateral decubitus positioning is a nonanatomical position used for multiple orthopaedic procedures to obtain adequate surgical exposure.¼ Unique ophthalmologic, musculoskeletal, neurovascular, and hemodynamic complications may arise inadvertently from positioning.¼ Orthopaedic surgeons should be aware of the possible complications that may manifest from placing patients in the lateral decubitus position to adequately prevent and to properly manage them.


Assuntos
Procedimentos Ortopédicos , Ortopedia , Humanos , Procedimentos Ortopédicos/efeitos adversos , Procedimentos Ortopédicos/métodos
19.
Stem Cells Transl Med ; 12(9): 603-616, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37616288

RESUMO

Traumatic spinal cord injury (SCI) results in the loss of neurons, oligodendrocytes, and astrocytes. Present interventions for SCI include decompressive surgery, anti-inflammatory therapies, and rehabilitation programs. Nonetheless, these approaches do not offer regenerative solutions to replace the lost cells, fiber tracts, and circuits. Neural stem/progenitor cell (NPC) transplantation is a promising strategy that aims to encourage regeneration. However, NPC differentiation remains inconsistent, thus, contributing to suboptimal functional recovery. As such, we have previously engineered oligodendrogenically biased NPCs (oNPCs) and demonstrated their efficacy in a thoracic model of SCI. Since the majority of patients with SCI experience cervical injuries, our objective in the current study was to generate human induced pluripotent stem cell-derived oNPCs (hiPSC-oNPCs) and to characterize these cells in vitro and in vivo, utilizing a clinically relevant rodent model of cervical SCI. Following transplantation, the oNPCs engrafted, migrated to the rostral and caudal regions of the lesion, and demonstrated preferential differentiation toward oligodendrocytes. Histopathological evaluations revealed that oNPC transplantation facilitated tissue preservation while diminishing astrogliosis. Moreover, oNPC transplantation fostered remyelination of the spared tissue. Functional analyses indicated improved forelimb grip strength, gait, and locomotor function in the oNPC-transplanted rats. Importantly, oNPC transplantation did not exacerbate neuropathic pain or induce tumor formation. In conclusion, these findings underscore the therapeutic potential of oNPCs in promoting functional recovery and histopathological improvements in cervical SCI. This evidence warrants further investigation to optimize and advance this promising cell-based therapeutic approach.


Assuntos
Medula Cervical , Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Traumatismos da Medula Espinal , Humanos , Ratos , Animais , Traumatismos da Medula Espinal/terapia , Recuperação de Função Fisiológica
20.
N Am Spine Soc J ; 14: 100214, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37214263

RESUMO

Background: Google's People Also Ask feature uses various machine learning algorithms to distill the most frequently asked questions and link users to potential answers. The aim of this study is to investigate the most frequently asked questions related to commonly performed spine surgeries. Methods: This is an observational study utilizing Google's People Also Ask feature. A variety of search terms were entered into Google for anterior cervical discectomy and fusion (ACDF), discectomy, and lumbar fusion. Frequently asked questions and linked websites were extracted. Questions were categorized by topic based on Rothwell's Classification system, and websites were categorized by type. Pearson's chi-squared and Student t tests were performed as appropriate. Results: A total of 576 unique questions (181 ACDF, 148 discectomy, 309 lumbar fusion) were extracted with 372 unique websites and 177 domains. The most common website types were medical practice (41%), social media (22%), and academic (15%). The most popular question topics were specific activities & restrictions (22%), technical details (23%), and evaluation of surgery (17%). Questions related to technical details were more common in discectomy vs lumbar fusion (33% vs 24%, p=.03) and lumbar fusion vs ACDF (24% vs 14%, p=.01). Questions related to specific activities & restrictions were more common in ACDF vs discectomy (17% vs 8%, p=.02) and ACDF vs lumbar fusion (28% vs 19%, p=.016). Questions related to risks & complications were more common in ACDF vs lumbar fusion (10% vs 4%, p=.01). Conclusions: The most frequently asked questions on Google regarding spine surgery are related to technical details and activity restrictions. Surgeons may emphasize these domains in consultations and direct patients to reputable sources of further information. Much of the linked information provided originates from nonacademic and nongovernment sources (72%), with 22% from social media websites.

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