RESUMO
Parkinson's disease is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular aetiology of the disease is still unclear. Several cellular pathways have been linked to Parkinson's disease, including the autophagy-lysosome pathway, α-synuclein aggregation and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal ß-glucocerebrosidase (GCase), and Parkinson's disease lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid build-up, disrupting lysosomal function and autophagy, thereby triggering α-synuclein accumulation. Additionally, α-synuclein aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-synuclein accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in Parkinson's disease pathogenesis and discuss promising examples of GCase-based therapeutics, such as gene and enzyme replacement therapies, small molecule chaperones and substrate reduction therapies, among others, as potential therapeutic interventions.
Assuntos
Glucosilceramidase , Lisossomos , Mitocôndrias , Doença de Parkinson , Humanos , Glucosilceramidase/metabolismo , Glucosilceramidase/genética , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Animais , alfa-Sinucleína/metabolismo , Autofagia/fisiologia , MutaçãoRESUMO
Recent studies of autophagic and lysosomal pathways have significantly changed our understanding of lysosomes; once thought to be simple degradative and recycling centers, lysosomes are now known to be organelles capable of influencing signal transduction, via the mammalian target of rapamycin complex 1 (mTORC1), and regulating gene expression, via transcription factor EB (TFEB) and other transcription factors. These pathways are particularly relevant to maintaining brain homeostasis, as dysfunction of the endolysosomal and autophagic pathways has been associated with common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, and lysosomal storage disorders, a group of inherited disorders characterized by the intralysosomal buildup of partially degraded metabolites. This review focuses on the cellular biology of lysosomes and discusses the possible mechanisms by which disruption of their function contributes to neurodegeneration. We also review and discuss how targeting TFEB and lysosomes may offer innovative therapeutic approaches for treating a wide range of neurological conditions.
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Autofagia/fisiologia , Encefalopatias/fisiopatologia , Encéfalo/fisiopatologia , Lisossomos/metabolismo , Animais , Encéfalo/metabolismo , Encefalopatias/metabolismo , Expressão Gênica/fisiologia , Homeostase/fisiologia , HumanosRESUMO
BACKGROUND: Arm restriction after cardiac implantable electronic device (CIED) placement is common practice despite minimal supporting evidence. Patients receive a range of restriction recommendations of variable durations with the goal of reducing complications such as wound dehiscence, infection, lead dislodgement, or hematoma formation. These movement limitations can lead to emotional stress and anxiety, complications such as frozen shoulder, and upper extremity venous thrombosis due to immobilization. There are no published clinical trials assessing the benefits and risks of arm restrictions post-CIED implant. OBJECTIVES: The randomized trial of lenient vs strict arm and activity instruction post-CIED surgery (LENIENT trial; NCT04915261) is a single center nonblinded randomized prospective study designed to evaluate lenient compared to restrictive post-CIED care instructions. We hypothesize that there will be no significant difference in complications between the arms. METHODS/DESIGN: All patients receiving a de novo CIED or those with upgrades and revisions requiring a new lead implant will be enrolled. Subjects are enrolled in a nonblinded randomized prospective trial with 6 randomly assigned 8-month periods, during which either a lenient or restrictive postoperative activity instructions will be given to all patients. Postoperative instructions are given at the time of discharge and further reinforced by recurrent interactive voice recognition (IVR) phone calls, text messages and emails. The requirement for individual consent has been waived. The primary end point is a composite of (1) lead dislodgement, (2) frozen shoulder, (3) upper extremity venous thrombosis, (4) clinically significant hematoma, and (5) infection occurring within 52 weeks of index surgery. The study is a noninferiority trial with a sample size of 1,250 per group. DISCUSSION: This is the first large randomized clinical trial designed to establish an evidence-based postoperative standard of care for patients undergoing CIED implantation. This will improve the quality of care provided to patients and help guide implanting physicians providing postoperative care instructions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04915261.
Assuntos
Desfibriladores Implantáveis , Trombose Venosa , Humanos , Estudos Prospectivos , Braço , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controleRESUMO
Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies.
Assuntos
Glicoesfingolipídeos , Doenças por Armazenamento dos Lisossomos , Animais , Camundongos , Glicoesfingolipídeos/metabolismo , Doenças por Armazenamento dos Lisossomos/metabolismo , Hidrolases/metabolismo , Lisossomos/metabolismoRESUMO
Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by cholesterol accumulation caused by loss-of-function mutations in the Npc1 gene. NPC disease primarily affects the brain, causing neuronal damage and affecting motor coordination. In addition, considerable liver malfunction in NPC disease is common. Recently, we found that the depletion of annexin A6 (ANXA6), which is most abundant in the liver and involved in cholesterol transport, ameliorated cholesterol accumulation in Npc1 mutant cells. To evaluate the potential contribution of ANXA6 in the progression of NPC disease, double-knockout mice (Npc1-/-/Anxa6-/-) were generated and examined for lifespan, neurologic and hepatic functions, as well as liver histology and ultrastructure. Interestingly, lack of ANXA6 in NPC1-deficient animals did not prevent the cerebellar degeneration phenotype, but further deteriorated their compromised hepatic functions and reduced their lifespan. Moreover, livers of Npc1-/-/Anxa6-/- mice contained a significantly elevated number of foam cells congesting the sinusoidal space, a feature commonly associated with inflammation. We hypothesize that ANXA6 deficiency in Npc1-/- mice not only does not reverse neurologic and motor dysfunction, but further worsens overall liver function, exacerbating hepatic failure in NPC disease.
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Anexina A6/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Hepatopatias/patologia , Longevidade , Animais , Comportamento Animal , Hepatopatias/etiologia , Hepatopatias/metabolismo , Camundongos , Camundongos Knockout , Proteína C1 de Niemann-PickRESUMO
We are all similar but a bit different. These differences are partially due to variations in our genomes and are related to the heterogeneity of symptoms and responses to treatments that patients exhibit. Most animal studies are performed in one single strain with one manipulation. However, due to the lack of variability, therapies are not always reproducible when treatments are translated to humans. Panels of already sequenced organisms are valuable tools for mimicking human phenotypic heterogeneities and gene mapping. This review summarizes the current knowledge of mouse, fly, and yeast panels with insightful applications for translational research.
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Saccharomyces cerevisiae , Pesquisa Translacional Biomédica , Animais , Mapeamento Cromossômico , Patrimônio Genético , Genoma , Humanos , Camundongos , Saccharomyces cerevisiae/genéticaRESUMO
BACKGROUND: The effectiveness, safety, and pulmonary vein (PV) reconnection patterns of point-by-point high-power, short-duration (HPSD) ablation relative to conventional force-time integral (FTI)-guided strategies for atrial fibrillation (AF) ablation are unknown. OBJECTIVES: To compare 1-year freedom from atrial arrhythmia (AA), complication rates, procedural times, and PV reconnection patterns with HPSD AF AF ablation versus an FTI-guided low-power, long-duration (LPLD) strategy. METHODS: We compared consecutive patients undergoing a first ablation procedure for paroxysmal or persistent AF. The HPSD protocol utilized a power of 50 W and durations of 6-8 s posteriorly and 8-10 s anteriorly. The LPLD protocol was FTI-guided with a power of ≤25 W posteriorly (FTI ≥ 300g·s) and ≤35 W anteriorly (FTI ≥ 400g·s). RESULTS: In total, 214 patients were prospectively included (107 HPSD, 107 LPLD). Freedom from AA at 1 year was achieved in 79% in the HPSD group versus 73% in the LPLD group (p = .339; adjusted hazard ratio with HPSD, 0.67; 95% confidence interval, 0.36-1.23; p < .004 for non-inferiority). Procedure duration was shorter in the HPSD group (229 ± 60 vs. 309 ± 77 min; p < .005). Patients undergoing repeat ablation had a higher propensity for reconnection at the right PV carina in the HPSD group compared with the LPLD group (14/30 = 46.7% vs. 7/34 = 20.6%; p = .035). There were no differences in complication rates. CONCLUSION: HPSD AF ablation resulted in similar freedom from AAs at 1 year, shorter procedure times, and a similar safety profile when compared with an LPLD ablation strategy. Patients undergoing HPSD ablation required more applications at the right carina to achieve isolation, and had a significantly higher rate of right carinal reconnections at redo procedures.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Humanos , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/cirurgia , Recidiva , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Current LBBB definitions cannot always distinguish LBBB from left ventricular conduction delay. Only patients with LBBB are expected to normalize with His bundle pacing. Patients who develop new LBBB immediately post transcatheter aortic valve replacement (TAVR) provide an excellent model to define electrocardiogram (ECG) features of LBBB. We sought to describe their ECG features and develop a new ECG definition of LBBB. METHODS: We screened ECGs from 264 consecutive patients who underwent TAVR at the University of Ottawa Heart Institute. Patients with a baseline QRS of ≤100â¯ms who developed QRS ≥120â¯ms immediately after TAVR were included. Two electrocardiologists reviewed all ECG independently. Baseline demographics and echocardiographic data were retrospectively collected. RESULTS: 36 patients were included in the analysis. The median age was 85.5â¯years (IQR, 81.8-89â¯years) and 52.8% were males. The minimum QRS duration was 126â¯ms. The median QRS axis was -18° (IQR, -40-4.5°), which is 18.5° leftward compared to the median QRS axis before TAVR. Fourteen patients (38.9%) had left axis deviation. All patients had a notched/slurred R wave in at least one lateral lead and an R wave duration of ≤20â¯ms in V1 when present. CONCLUSION: We developed a new ECG definition of LBBB that includes 2 novel findings: notching/slurring of the R wave in at least one lateral lead and an R wave ≤20â¯ms in V1. Further larger studies are warranted to confirm these findings.
Assuntos
Substituição da Valva Aórtica Transcateter , Idoso de 80 Anos ou mais , Bloqueio de Ramo/diagnóstico , Eletrocardiografia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Niemann-Pick type C (NPC), a lysosomal storage disorder, is mainly caused by mutations in the NPC1 gene. Niemann-Pick type C patients and mice show intracellular cholesterol accumulation leading to hepatic failure with increased inflammatory response. The complement cascade, which belongs to the innate immunity response, recognizes danger signals from injured tissues. We aimed to determine whether there is activation of the complement system in the liver of the NPC mouse and to assess the relationship between C3 activation, a final component of the pathway, and NPC liver pathology. Niemann-Pick type C mice showed high levels of C3 staining in the liver which unexpectedly decreased with aging. Using an inducible NPC1 hepatocyte rescue mouse model, we restored NPC1 expression for a short time in young mice. We found C3 positive cells only in non-rescued cells, suggesting that C3 activation in NPC cells is reversible. Then, we studied the effect of C3 ablation on NPC liver damage at two postnatal time points, P56 and P72. Deletion of C3 reduced the presence of hepatic CD68-positive cells at postnatal day 56 and prevented the increase of transaminase levels in the blood of NPC mice. These positive effects were abrogated at P72, indicating that the complement cascade participates only during the early stages of liver damage in NPC mice, and that its inhibition may serve as a new potential therapeutic strategy for the disease.
Assuntos
Complemento C3/metabolismo , Fígado/patologia , Doença de Niemann-Pick Tipo C/imunologia , Envelhecimento/patologia , Animais , Células Espumosas/metabolismo , Células Espumosas/patologia , Camundongos Endogâmicos C57BLRESUMO
Common forms of Parkinson's disease have long been described as idiopathic, with no single penetrant genetic factor capable of influencing disease aetiology. Recent genetic studies indicate a clear association of variants within several lysosomal genes as risk factors for idiopathic Parkinson's disease. The emergence of novel variants suggest that the aetiology of idiopathic Parkinson's disease may be explained by the interaction of several partially penetrant mutations that, while seemingly complex, all appear to converge on cellular clearance pathways. These newly evolving data are consistent with mechanistic studies linking α-synuclein toxicity to lysosomal abnormalities, and indicate that idiopathic Parkinson's disease resembles features of Mendelian lysosomal storage disorders at a genetic and biochemical level. These findings offer novel pathways to exploit for the development of disease-altering therapies for idiopathic Parkinson's disease that target specific components of the lysosomal system.
Assuntos
Doenças por Armazenamento dos Lisossomos/fisiopatologia , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Doença de Gaucher/genética , Doença de Gaucher/fisiopatologia , Humanos , Doenças por Armazenamento dos Lisossomos/genética , Lisossomos/genética , Lisossomos/fisiologia , Mitocôndrias/patologia , Doença de Parkinson/genética , Fatores de Risco , alfa-Sinucleína/metabolismoRESUMO
Niemannâ»Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the NPC1 or NPC2 genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with large numbers of foam cells; however, their role in disease pathogenesis has not been explored in depth. Here, we studied the consequences of gadolinium chloride (GdCl3) treatment, a well-known Kupffer/foam cell inhibitor, at late stages of NPC liver disease and compared it with NPC1 genetic rescue in hepatocytes in vivo. GdCl3 treatment successfully blocked the endocytic capacity of hepatic Kupffer/foam measured by India ink endocytosis, decreased the levels CD68-A marker of Kupffer cells in the liver-and normalized the transaminase levels in serum of NPC mice to a similar extent to those obtained by genetic Npc1 rescue of liver cells. Gadolinium salts are widely used as magnetic resonance imaging (MRI) contrasts. This study opens the possibility of targeting foam cells with gadolinium or by other means for improving NPC liver disease. Synopsis: Gadolinium chloride can effectively rescue some parameters of liver dysfunction in NPC mice and its potential use in patients should be carefully evaluated.
Assuntos
Gadolínio/farmacologia , Células de Kupffer/efeitos dos fármacos , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Endocitose , Gadolínio/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular , Células de Kupffer/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteína C1 de Niemann-Pick , Proteínas/genética , Proteínas/metabolismoRESUMO
The genetic basis of the phenotypic variability observed in patients can be studied in mice by generating disease models through genetic or chemical interventions in many genetic backgrounds where the clinical phenotypes can be assessed and used for genome-wide association studies (GWAS). This is particularly relevant for rare disorders, where patients sharing identical mutations can present with a wide variety of symptoms, but there are not enough number of patients to ensure statistical power of GWAS. Inbred strains are homozygous for each loci, and their single nucleotide polymorphisms catalogs are known and freely available, facilitating the bioinformatics and reducing the costs of the study, since it is not required to genotype every mouse. This kind of approach can be applied to pharmacogenomics studies as well.
Assuntos
Modelos Animais de Doenças , Medicina de Precisão , Animais , Mapeamento Cromossômico , Humanos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Great interest has been shown in understanding the pathology of Gaucher disease (GD) due to the recently discovered genetic relationship with Parkinson's disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid ß-glucosidase (GCase) using the irreversible inhibitor conduritol B-epoxide (CBE) is particularly attractive, although few systematic studies examining the effect of CBE on the development of symptoms associated with neurological forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on both the levels of accumulated lipids and the time at which their accumulation begins. Gene array analysis shows a remarkable similarity in the gene expression profiles of CBE-treated mice and a genetic GD mouse model, the Gba(flox/flox) ;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up-regulated in Gba(flox/flox) ;nestin-Cre mice. We also demonstrate that various aspects of neuropathology and some behavioural abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD. This is particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time-consuming crossing of mice. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Doença de Gaucher/patologia , Animais , Modelos Animais de Doenças , Doença de Gaucher/induzido quimicamente , Doença de Gaucher/genética , Perfilação da Expressão Gênica , Inositol/análogos & derivados , CamundongosRESUMO
Chronic systemic inflammation is thought to be a major contributor to metabolic and neurodegenerative diseases. Since inflammatory components are shared among different disorders, targeting inflammation is an attractive option for mitigating disease. To test the significance of inflammation in the lipid storage disorder (LSD) Niemann-Pick C (NPC), we deleted the macrophage inflammatory gene Mip1a/Ccl3 from NPC diseased mice. Deletion of Ccl3 had been reported to delay neuronal loss in Sandhoff LSD mice by inhibiting macrophage infiltration. For NPC mice, in contrast, deleting Ccl3 did not retard neurodegeneration and worsened the clinical outcome. Depletion of visceral tissue macrophages also did not alter central nervous system (CNS) pathology and instead increased liver injury, suggesting a limited macrophage infiltration response into the CNS and a beneficial role of macrophage activity in visceral tissue. Prevention of neuron loss or liver injury, even at late stages in the disease, was achieved through specific rescue of NPC disease in neurons or in liver epithelial cells, respectively. Local epithelial cell correction was also sufficient to reduce the macrophage-associated pathology in lung tissue. These results demonstrate that elevated inflammation and macrophage activity does not necessarily contribute to neurodegeneration and tissue injury, and LSD defects in immune cells may not preclude an appropriate inflammatory response. We conclude that inflammation remains secondary to neuronal and epithelial cell dysfunction and does not irreversibly contribute to the pathogenic cascade in NPC disease. Without further exploration of possible beneficial roles of inflammatory mediators, targeting inflammation may not be therapeutically effective at ameliorating disease severity.
Assuntos
Quimiocina CCL3/genética , Inflamação/patologia , Macrófagos/fisiologia , Neurônios/patologia , Doença de Niemann-Pick Tipo C/patologia , Proteínas/genética , Animais , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Quimiocina CCL3/biossíntese , Quimiocina CCL3/deficiência , Modelos Animais de Doenças , Células Epiteliais/patologia , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intracelular , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/imunologia , Doença de Niemann-Pick Tipo C/metabolismo , Proteínas/metabolismoRESUMO
Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal cholesterol storage disorder that arises from loss-of-f unction mutations in either the NPCI or NPC2 genes. Both genes code for proteins involved in lysosomal cholesterol efflux. NPC is often diagnosed in early childhood, with patients typically displaying cerebellar ataxia, difficulties in Unfortunately, to date, there is no curative treatment for this devastating and fatal disorder, although several symptomatic manifestations of NPC are treatable. In this review, we discuss the cell biology of the disease, clinical aspects, diagnostic approaches, and current and potential therapeutic strategies against NPC.
Assuntos
Colesterol , Mutação , Doença de Niemann-Pick Tipo C/diagnóstico , Proteínas de Transporte/genética , Glicoproteínas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Glicoproteínas de Membrana/genética , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/terapia , Proteínas de Transporte VesicularRESUMO
Background: Cardiac implantable electronic device (CIED) infection is a costly and highly morbid complication. Perioperative interventions, including the use of antibiotic pouches and intensified perioperative antibiotic regimens, have demonstrated marginal efficacy at reducing CIED infection. Additional research is needed to identify additional interventions to reduce infection risk. Objective: We sought to evaluate whether adherent skin barrier drape use is associated with a reduction in CIED infection. Methods: A prospective registry of all CIED implantation procedures was established at our institution in January 2007. The registry was established in collaboration with our hospital infection prevention team with a specific focus on prospectively identifying all potential CIED infections. All potential CIED infections were independently adjudicated by 2 physicians blinded to the use of an adherent skin barrier drape. Results: Over a 13-year period, 14,225 procedures were completed (mean age 72 ± 14 years; female 4,918 (35%); new implants 10,005 (70%); pulse generator changes 2585 (18%); upgrades 1635 (11%). Of those, 2469 procedures (17.4%) were performed using an adherent skin barrier drape. There were 103 adjudicated device infections (0.73%). The infection rate in patients in the barrier use groups was 8 of 2469 (0.32%) as compared with 95 of 11,756 (0.8%) in the nonuse group (P = .0084). In multivariable analysis, the use of an adherent skin barrier drape was independently associated with a reduction in infection (odds ratio 0.32; 95% confidence interval 0.154-0.665; P = .002). Conclusion: The use of an adherent skin barrier drape at the time of cardiac device surgery is associated with a lower risk of subsequent infection.
RESUMO
Niemann-Pick C disease (NPC) is a neuro-visceral lysosomal storage disorder mainly caused by genetic defects in the NPC1 gene. As a result of loss of NPC1 function large quantities of free cholesterol and other lipids accumulate within late endosomes and lysosomes. In NPC livers and brains, the buildup of lipids correlates with oxidative damage; however the molecular mechanisms that trigger it remain unknown. Here we study potential alterations in vitamin E (α-tocopherol, α-TOH), the most potent endogenous antioxidant, in liver tissue and neurons from NPC1 mice. We found increased levels of α-TOH in NPC cells. We observed accumulation and entrapment of α-TOH in NPC neurons, mainly in the late endocytic pathway. Accordingly, α-TOH levels were increased in cerebellum of NPC1 mice. Also, we found decreased mRNA levels of the α-TOH transporter, α-Tocopherol Transfer Protein (α-TTP), in the cerebellum of NPC1 mice. Finally, by subcellular fractionation studies we detected a significant increase in the hepatic α-TOH content in purified lysosomes from NPC1 mice. In conclusion, these results suggest that NPC cells cannot transport vitamin E correctly leading to α-TOH buildup in the endosomal/lysosomal system. This may result in a decreased bioavailability and impaired antioxidant function of vitamin E in NPC, contributing to the disease pathogenesis.
Assuntos
Lisossomos/metabolismo , Doença de Niemann-Pick Tipo C/metabolismo , Vitamina E/metabolismo , Animais , Antioxidantes/metabolismo , Disponibilidade Biológica , Transporte Biológico , Células Cultivadas , Cerebelo/metabolismo , Colesterol/metabolismo , Endocitose/fisiologia , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Fígado/metabolismo , Lisossomos/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/metabolismo , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/genética , Proteínas/genética , Proteínas/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Lysosomal storage diseases (LSDs), which are inborn errors of metabolism, encompass around 50 different inherited syndromes. Together, they have an incidence of 1/7000 newborns. LSDs are caused by deficiencies in lysosomal enzymes or transporters, resulting in intra-lysosomal buildup of under graded metabolites. Common features of LSDs include bone disease, organomegaly and central and peripheral nervous system degeneration. These diseases were first described in the 1880s. Despite more than an hundred years of study of the genetic and molecular bases of LSDs, little is known about the events that lead from intra-lysosomal accumulation to the distinctive cell dysfunction and pathology that is characteristic of each disease. This review focuses on the main historical discoveries in LSD biology, from the original descriptions of their phenotypes, to animal models, including therapeutic strategies and challenges to treat this family of devastating diseases.
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Predisposição Genética para Doença , Terapia Genética/métodos , Elastase de Leucócito/deficiência , Doenças por Armazenamento dos Lisossomos , Animais , Saúde Global , Humanos , Incidência , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/terapia , FenótipoRESUMO
Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. We propose that these factors should be considered when designing or repurposing treatments for this disease. Despite its seeming complexity, this proposition is not far-fetched, considering the expanding interest in precision medicine and easier access to multi-omics technologies.
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Background: Cardiac implantable electronic device (CIED) procedures can be associated with serious complications, including infection with significant mortality and morbidity, necessitating removal of the device and prolonged hospitalization. One potential pathophysiological mechanism is pocket contamination at the time of device implantation. Therefore, steps taken to prevent contamination at this stage can potentially reduce CIED infections.The barrier dressing, an adhesive material applied to the skin, has the potential to reduce the colonization of the surgical site with host flora that can predispose to infection. There are a limited number of randomized prospective studies on barrier dressing use during various surgeries, but it has never been systematically studied in CIED implantation. Objectives: Do Barrier Dressings Reduce Cardiac Implantable Device Infection? (BARRIER-PROTECT trial; NCT04591366) is a single-centre, prospective, double-armed, single-blinded, randomized controlled trial designed to evaluate the use of an intra-operative adhesive barrier dressing to reduce the risk of end-of-procedure pocket swab positivity. We hypothesize that adhesive draping during implant procedures will reduce the risk of contamination from the skin flora. Also, we aim to investigate if the end-of-procedure pocket swab culture positivity can be used as a potential surrogate marker of CIED infection. Methods and Design: Patients undergoing a second or later procedure on the same device pocket (pulse generator change, lead/pocket revision or upgrade) will be enrolled. Eligible and consenting patients will be equally randomized to the use of barrier dressing or not using an automated web-based system. Patients, but not the operator, will be blinded to the arm. The person performing the pocket swabs will also be blinded. The primary endpoint is the end-of-procedure pocket swab culture positivity. The main secondary endpoint is the CIED infection rate. Discussion: This is the first randomized controlled trial to assess the effectiveness of using a barrier adhesive draping on reducing the end-of-procedure pocket swab culture positivity. In this study, we are exploring a low-cost intervention that may significantly reduce CIED infection. Also, having a valid surrogate marker for CIED infection at the time of implant will facilitate design of future clinical trials.