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OBJECTIVE: The objective of this study was to explore what non-pharmacological interventions have been examined for individuals with antiphospholipid syndrome (APS). METHODS: We conducted a systematic literature search of the databases PubMed, Embase, Scopus, Web of Science, CINAHL, and ClinicalTrials.gov from 1983-Feb. 2023. Our scoping review included studies that examined non-pharmacological interventions for individuals with APS using patient-reported outcome measures. We excluded studies that reported physiological outcomes only. RESULTS: The review yielded one case study on the safety and efficacy of an exercise program for a 15-year-old male with secondary APS using physiological and patient-reported outcome measures. Despite the lack of evidence of non-pharmacological interventions for individuals with APS, one excluded study reported that individuals with APS want guidance about physical activity and exercise. We also found several types of potentially relevant non-pharmacological interventions for individuals with lupus, a disease that often co-occurs with APS. CONCLUSIONS: Non-pharmacological interventions may offer a solution for addressing some non-thrombotic or non-obstetric APS symptoms, such as neurological, physical, and cognitive symptoms that are not well-controlled by anticoagulation. Due to the unique risks associated with APS, research is needed to determine the safety and efficacy of non-pharmacological interventions, particularly those involving exercise. Adopting a comprehensive, multidisciplinary approach to managing patients with APS and involving rehabilitation professionals, who are experts in the design and delivery of non-pharmacological interventions, may provide a foundation for developing and testing novel interventions that improve health outcomes while also fulfilling unmet needs reported by patients.
Assuntos
Síndrome Antifosfolipídica , Humanos , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/terapia , Síndrome Antifosfolipídica/reabilitação , Masculino , Terapia por Exercício/métodos , Medidas de Resultados Relatados pelo Paciente , Exercício Físico , AdolescenteRESUMO
Acute inflammation is a key feature of innate immunity that initiates clearance and repair in infected or damaged tissues. Alternatively, chronic inflammation is implicated in numerous disease processes. The contribution of neuroinflammation to the pathogenesis of neurological conditions, including infection, traumatic brain injury, and neurodegenerative diseases, has become increasingly evident. Potential drivers of such neuroinflammation include toll-like receptors (TLRs). TLRs confer a wide array of functions on different cell types in the central nervous system (CNS). Importantly, how TLR activation affects astrocyte functioning is unclear. In the present study, we examined the role of TLR2/4 signaling on various astrocyte functions (i.e., proliferation, pro-inflammatory mediator production, regulatory mechanisms, etc) by stimulating astrocytes with potent exogenous TLR2/4 agonist, bacterial lipopolysaccharide (LPS). Newborn astrocytes were derived from WT, Tnfα-/-, Il1α-/-/Il1ß-/-, and Tlr2-/-/Tlr4-/- mice as well as Sprague Dawley rats for all in vitro studies. LPS activated mRNA expression of different pro-inflammatory cytokines and chemokines in time- and concentration-dependent manners, and upregulated the proliferation of astrocytes based on increased 3H-thymidine update. Following LPS-mediated TLR2/4 activation, TNF-α and IL-1ß self-regulated and modulated the expression of pro-inflammatory cytokines and chemokines. Polyclonal antibodies against TNF-α suppressed TLR2/4-mediated upregulation of astrocyte proliferation, supporting an autocrine/paracrine role of TNF-α on astrocyte proliferation. Astrocytes perform classical innate immune functions, which contradict the current paradigm that microglia are the main immune effector cells of the CNS. TNF-α plays a pivotal role in the LPS-upregulated astrocyte activation and proliferation, supporting their critical roles in in CNS pathogenesis.
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Astrócitos/imunologia , Astrócitos/metabolismo , Imunidade Inata/fisiologia , Animais , Células Cultivadas , Citometria de Fluxo , Imunidade Inata/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , Ratos , Ratos Sprague-Dawley , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Amyloid beta (Aß) is a peptide cleaved from amyloid precursor protein that contributes to the formation of senile plaques in Alzheimer's disease (AD). The relationship between Aß and astrocyte proliferation in AD remains controversial. Despite pathological findings of increased astrocytic mitosis in AD brains, in vitro studies show an inhibitory effect of Aß on astrocyte proliferation. In this study, we determined the effect of an active fragment of Aß (Aß25-35) on the cell cycle progression of primary rat astrocytes. We found that Aß25-35 (0.3-1.0 µg/ml) enhanced astrocyte proliferation in vitro in a time- and concentration-dependent manner. Increased DNA synthesis by Aß25-35 was observed during the S phase of the astrocyte cell cycle, as indicated by proliferation kinetics and bromodeoxyuridine immunocytochemical staining. Aggregation of Aß25-35 abolished the upregulatory effect of Aß on astrocyte proliferation. Further examination indicated that Aß25-35 affected astrocyte proliferation during early or mid-G1 phase but had no effect on DNA synthesis at the peak of S phase. These results provide insight into the relationship between Aß25-35 and astrocyte cell cycling in AD.
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Neurogenesis is a highly-regulated process occurring in the dentate gyrus that has been linked to learning, memory, and antidepressant efficacy. MicroRNAs (miRNAs) have been previously shown to play an important role in the regulation of neuronal development and neurogenesis in the dentate gyrus via modulation of gene expression. However, this mode of regulation is both incompletely described in the literature thus far and highly multifactorial. In this study, we designed sensors and detected relative levels of expression of 10 different miRNAs and found miR-338-3p was most highly expressed in the dentate gyrus. Comparison of miR-338-3p expression with neuronal markers of maturity indicates miR-338-3p is expressed most highly in the mature neuron. We also designed a viral "sponge" to knock down in vivo expression of miR-338-3p. When miR-338-3p is knocked down, neurons sprout multiple primary dendrites that branch off of the soma in a disorganized manner, cellular proliferation is upregulated, and neoplasms form spontaneously in vivo. Additionally, miR-338-3p overexpression in glioblastoma cell lines slows their proliferation in vitro. Further, low miR-338-3p expression is associated with increased mortality and disease progression in patients with glioblastoma. These data identify miR-338-3p as a clinically relevant tumor suppressor in glioblastoma.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Diferenciação Celular , Glioblastoma/genética , Glioblastoma/patologia , MicroRNAs/genética , Neurônios/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Forma Celular , Giro Denteado/metabolismo , Giro Denteado/patologia , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Neurônios/metabolismo , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
We retrospectively analyzed electronic medical records of patients with Ehlers-Danlos Syndrome hypermobility type (HEDS), including demographic information, workup, rheumatological diagnoses in order to determine its association with rheumatological conditions. HEDS Patients were stratified according to level of workup received (no additional work (physical exam only) = NWU, limited workup = LWU, comprehensive workup = CWU)). HEDS patients were predominantly female (21:4, F:M). The percentage of patients with at least one rheumatological condition was significantly correlated with level of workup (NWU, 9.2%; LWU, 33.3%, CWU, 67.1%; p-value < 0.0001). The HLA-B27 antigen was more prevalent (p-value < 2.2 × 10-8) in the CWU HEDS patients (23.9%) than in the general population of the United States (6.1%). HEDS with CWU were associated with more rheumatological conditions (i.e. psoriasis, ankylosing spondylitis, rheumatoid arthritis, fibromyalgia) than those with NWU or LWU. In conclusion, HEDS is associated with complicated rheumatological conditions, which are uncovered by comprehensive workup. These conditions require different clinical management strategies than HEDS, and left untreated could contribute to the pain or even physical disability (i.e. joint erosions) in HEDS patients. While the mechanisms underlying these associations are unknown, it is important that all HEDS patients receive adequate workup to ensure a complete clinical understanding for the best care strategy possible.
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Síndrome de Ehlers-Danlos/epidemiologia , Doenças Reumáticas/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Síndrome de Ehlers-Danlos/complicações , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doenças Reumáticas/complicações , Adulto JovemRESUMO
Mammalian cells are amenable to the study of regulatory mechanisms dictating cell cycle progression in vitro by shifting them into the same phase of the cycle. Procedures to arrest cultured cells in specific phases of the cell cycle may be termed in vitro synchronization. The procedure described here was developed for the study of primary astrocytes and a glioma cell line, but is broadly applicable to other mammalian cells. Its application allows astrocytes to re-enter the cell cycle from a state of quiescence (G0) under carefully defined experimental conditions to move together into subsequent phases such as the G1 and S phases. A number of methods have been established to synchronize mammalian cell cultures, which include counterflow centrifugal elutriation, mitotic shake off, chemically induced cell cycle arrest, and newer live cell methods, such as cell permeable dyes. Yet, there are intrinsic limitations associated with these methods. In the present protocol, we describe a simple, reliable, and reversible procedure to synchronize astrocyte and glioma cultures from newborn rat brain by serum deprivation. The procedure is similar, and generally applicable, to other mammalian cells. This protocol consists essentially of two parts: (1) proliferation of astrocytes under optimal conditions in vitro until reaching desired confluence; and (2) synchronization and G0 phase arrest of cultures by serum down-shift. This procedure has been utilized to examine cell cycle control in astroglioma cells and astrocytes from injured adult brain. It has also been employed in precursor cloning studies in developmental biology, suggesting wide applicability.
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Técnicas de Cultura de Células/métodos , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Meios de Cultura Livres de Soro/farmacologia , Fase G1/genética , Glioma/genética , Ratos , Fase S/genéticaRESUMO
Alterations in cell cycle regulation underlie the unrestricted growth of neoplastic astrocytes. Chemotherapeutic interventions of gliomas have poor prognostic outcomes due to drug resistance and drug toxicity. Here, we examined the in vitro growth kinetics of C6 glioma (C6G) cells and primary astrocytes and their responses to 2 phase-specific inhibitors, lovastatin and hydroxyurea. C6G cells demonstrated a shorter G1 phase and an earlier peak of DNA synthesis in S phase than primary astrocytes. As C6G cells and primary astrocytes re-entered the cell cycle in the presence of lovastatin or hydroxyurea, they exhibited different sensitivities to the inhibitory effects of these agents, as measured by [3H]-thymidine incorporation. Compared to primary astrocytes, C6G cells were more sensitive to lovastatin, but less sensitive to hydroxyurea. Studies using 2 different paradigms of exposure uncovered dramatic differences in the kinetics of DNA synthesis inhibition by these 2 agents in C6G cells and primary astrocytes. One notable difference was the ability of C6G cells to more easily recover from the inhibitory effects of hydroxyurea following short exposure. Our results provide insight into C6 glioma drug resistance as well as the inhibitory effects of these 2 phase-specific inhibitors and their chemotherapeutic potential.
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Astrócitos/citologia , Ciclo Celular , Neoplasias/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , DNA/biossíntese , Hidroxiureia/farmacologia , Cinética , Lovastatina/farmacologia , Ratos Sprague-Dawley , SoroRESUMO
Biologics, both monoclonal antibodies (mAbs) and fusion proteins, have revolutionized the practice of medicine. This year marks the 30th anniversary of the Food and Drug Administration approval of the first mAb for human use. In this review, we examine the biotechnological breakthroughs that spurred the explosive development of the biopharmaceutical mAb industry, as well as how critical lessons learned about human immunology informed the development of improved biologics. We also discuss the most common mechanisms of action of currently approved biologics and the indications for which they have been approved to date.