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1.
J Vasc Interv Radiol ; 35(4): 558-562, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38181971

RESUMO

PURPOSE: To determine if symptom relief with celiac plexus block (CPB) is associated with favorable clinical outcomes after median arcuate ligament release (MALR) surgery. MATERIALS AND METHODS: A retrospective review was performed from January 2000 to December 2021. Fifty-seven patients (42 women, 15 men; mean age, 43 years [range, 18-84 years]) with clinical and radiographic features suggestive of median arcuate ligament syndrome (MALS) underwent computed tomography (CT)-guided percutaneous CPB for suspected MALS. Clinical outcomes of CPB and MALR surgery were correlated. Adverse events were classified according to the Society of Interventional Radiology (SIR) guidelines. RESULTS: CT-guided percutaneous CPB was successfully performed in all 57 (100%) patients with suspected MALS. A cohort of 38 (67%) patients showed clinical improvement with CPB. A subset of 28 (74%) patients in this group subsequently underwent open MALR surgery; 27 (96%) responders to CPB showed favorable clinical outcomes with surgery. There was 1 (4%) CPB-related mild adverse event. There were no moderate, severe, or life-threatening adverse events. CONCLUSIONS: Patients who responded to CPB were selected to undergo surgery, and 96% of them improved after surgery.


Assuntos
Plexo Celíaco , Síndrome do Ligamento Arqueado Mediano , Masculino , Humanos , Feminino , Adulto , Artéria Celíaca/diagnóstico por imagem , Artéria Celíaca/cirurgia , Plexo Celíaco/diagnóstico por imagem , Plexo Celíaco/cirurgia , Descompressão Cirúrgica/efeitos adversos , Síndrome do Ligamento Arqueado Mediano/diagnóstico por imagem , Síndrome do Ligamento Arqueado Mediano/cirurgia , Síndrome do Ligamento Arqueado Mediano/complicações , Ligamentos/diagnóstico por imagem , Ligamentos/cirurgia
2.
Gerontology ; 69(12): 1424-1436, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37793352

RESUMO

INTRODUCTION: Interventions targeting cholinergic neurotransmission like acetylcholinesterase (AChE) inhibition distinguish potential mechanisms to delay age-related impairments and attenuate deficits related to neurodegenerative diseases. However, the chronic effects of these interventions are not well described. METHODS: In the current study, global levels of cholinergic, cellular, synaptic, and inflammation-mediating proteins were assessed within the context of aging and chronic reduction of AChE activity. Long-term depletion of AChE activity was induced by using a mutant zebrafish line, and they were compared with the wildtype group at young and old ages. RESULTS: Results demonstrated that AChE activity was lower in both young and old mutants, and this decrease coincided with a reduction in ACh content. Additionally, an overall age-related reduction in AChE activity and the AChE/ACh ratio was observed, and this decline was more prominent in wildtype groups. The levels of an immature neuronal marker were upregulated in mutants, while a glial marker showed an overall reduction. Mutants had preserved levels of inhibitory and presynaptic elements with aging, whereas glutamate receptor subunit levels declined. CONCLUSION: Long-term AChE activity depletion induces synaptic and cellular alterations. These data provide further insights into molecular targets and adaptive responses following the long-term reduction of AChE activity that was also targeted pharmacologically to treat neurodegenerative diseases in human subjects.


Assuntos
Acetilcolinesterase , Doenças Neurodegenerativas , Animais , Humanos , Acetilcolinesterase/metabolismo , Peixe-Zebra/metabolismo , Encéfalo/metabolismo , Envelhecimento , Colinérgicos/metabolismo
3.
J Neurogenet ; 36(4): 89-97, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35997487

RESUMO

Telomerase is reactivated in the majority of cancers. For instance, in gliomas, it is common that the TERT promoter is mutated. Research on telomere promoter GC islands have been focused primarily on proximal TERT promoter but little is known about the distal promoter. Therefore, in this study, we investigated the proximal and distal TERT promoter, in terms of DNA methylation. We did bisulfite sequencing in zebrafish tissue samples for the distal tert promoter. In the zebrafish brain tissues, we identified a hypomethylation site in the tert promoter, and found that this hypomethylation was associated with aging and shortened telomeres. Through site directed mutagenesis in glioma cell lines, we changed 10 GC spots individually, cloned into a reporter vector, and measured promoter activity. Finally, we silenced DNMT3B and measured telomerase activity along with vidaza and adriamycin treatments. Site directed mutagenesis of glioma cell lines revealed that each of the 10 GC spots are critical for telomerase activity. Changing GC to AT abolished promoter activity in all spots when transfected into glioma cell lines. Then, through silencing of DNMT3B, we observed a reduction in hTERT expression levels, while hTR remained the same, and a major increase in senescence-associated beta-galactosidase activity. Finally, we propose a model regarding the efficacy of two chemotherapeutic drugs, adriamycin and azacytidine, on gliomas. Here, we show that distal TERT promoter is critical; changing even one GC to AT abolishes TERT promoter activity. DNMT3B, a de novo methyltransferase, together with GC islands in distal TERT promoter plays an important role in regulation of telomerase expression and senescence.


Assuntos
Glioma , Telomerase , Animais , Azacitidina/metabolismo , Metilação de DNA , Doxorrubicina , Glioma/genética , Telomerase/genética , Telomerase/metabolismo , Peixe-Zebra
4.
BMC Neurosci ; 16(1): 96, 2015 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-27390838

RESUMO

BACKGROUND: WDR81 (WD repeat-containing protein 81) is associated with cerebellar ataxia, mental retardation and disequilibrium syndrome (CAMRQ2, [MIM 610185]). Human and mouse studies suggest that it might be a gene of importance during neurodevelopment. This study aimed at fully characterizing the structure of the wdr81 transcript, detecting the possible transcript variants and revealing its expression profile in zebrafish, a powerful model organism for studying development and disease. RESULTS: As expected in human and mouse orthologous proteins, zebrafish wdr81 is predicted to possess a BEACH (Beige and Chediak-Higashi) domain, a major facilitator superfamily domain and WD40-repeats, which indicates a conserved function in these species. We observed that zebrafish wdr81 encodes one open reading frame while the transcript has one 5' untranslated region (UTR) and the prediction of the 3' UTR was mainly confirmed along with a detected insertion site in the embryo and adult brain. This insertion site was also found in testis, heart, liver, eye, tail and muscle, however, there was no amplicon in kidney, intestine and gills, which might be the result of possible alternative polyadenylation processes among tissues. The 5 and 18 hpf were critical timepoints of development regarding wdr81 expression. Furthermore, the signal of the RNA probe was stronger in the eye and brain at 18 and 48 hpf, then decreased at 72 hpf. Finally, expression of wdr81 was detected in the adult brain and eye tissues, including but not restricted to photoreceptors of the retina, presumptive Purkinje cells and some neurogenic brains regions. CONCLUSIONS: Taken together these data emphasize the importance of this gene during neurodevelopment and a possible role for neuronal proliferation. Our data provide a basis for further studies to fully understand the function of wdr81.


Assuntos
Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/genética , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Ataxia Cerebelar/genética , Biologia Computacional , Olho/crescimento & desenvolvimento , Olho/metabolismo , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Hibridização In Situ , Deficiência Intelectual/genética , Poliadenilação , Reação em Cadeia da Polimerase em Tempo Real , Peixe-Zebra/metabolismo
5.
BMC Neurosci ; 15: 29, 2014 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-24548546

RESUMO

BACKGROUND: Brain aging is a multi-factorial process due to both genetic and environmental factors. The zebrafish has recently become a popular model organism for examining aging and age-related diseases because as in humans they age gradually and exhibit cognitive decline. Few studies have examined the biological changes in the aging brain that may contribute to these declines and none have examined them within individuals with respect to gender. Our aim was to identify the main genetic pathways associated with zebrafish brain aging across gender. We chose males and females from specific age groups (young, 7.5-8.5 months and old, 31-36 months) based on the progression of cognitive decline in zebrafish. RNA was isolated from individual brains and subjected to microarray and qPCR analysis. Statistical analyses were performed using a two-way ANOVA and the relevant post-hoc tests. RESULTS: Our results demonstrated that in the brains of young and old male and female zebrafish there were over 500 differentially expressed genes associated with multiple pathways but most notably were those related to neurogenesis and cell differentiation, as well as brain and nervous system development. CONCLUSIONS: The gene expression of multiple pathways is altered with age and differentially expressed in males and females. Future studies will be aimed at determining the causal relationships of age-related changes in gene expression in individual male and female brains, as well as possible interventions that counteract these alterations.


Assuntos
Envelhecimento/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Feminino , Masculino , Caracteres Sexuais
6.
Behav Brain Res ; 460: 114812, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38104637

RESUMO

Numerous studies have shown that prior visual experiences play an important role in sensory processing and adapting behavior in a dynamic environment. A repeated and passive presentation of visual stimulus is one of the simplest procedures to manipulate acquired experiences. Using this approach, we aimed to investigate exposure-based visual learning of aging zebrafish and how cholinergic intervention is involved in exposure-induced changes. Our measurements included younger and older wild-type zebrafish and achesb55/+ mutants with decreased acetylcholinesterase activity. We examined both within-session and across-day changes in the zebrafish optomotor responses to repeated and passive exposure to visual motion. Our findings revealed short-term (within-session) changes in the magnitude of optomotor response (i.e., the amount of position shift by fish as a response to visual motion) rather than long-term and persistent effects across days. Moreover, the observed short-term changes were age- and genotype-dependent. Compared to the initial presentations of motion within a session, the magnitude of optomotor response to terminal presentations decreased in the older zebrafish. There was a similar robust decrease specific to achesb55/+ mutants. Taken together, these results point to short-term (within-session) alterations in the motion detection of adult zebrafish and suggest differential effects of neural aging and cholinergic system on the observed changes. These findings further provide important insights into adult zebrafish optomotor response to visual motion and contribute to understanding this reflexive behavior in the short- and long-term stimulation profiles.


Assuntos
Acetilcolinesterase , Peixe-Zebra , Animais , Peixe-Zebra/fisiologia , Atividade Motora/fisiologia , Envelhecimento , Colinérgicos
7.
Cardiovasc Intervent Radiol ; 47(7): 883-890, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38844684

RESUMO

PURPOSE: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare tumor with currently no established standard of care. This international multicenter retrospective study assesses the use of percutaneous irreversible electroporation (IRE) as an ablative tool to treat HEHE and provides a clinical overview of the current management and role of IRE in HEHE treatment. MATERIAL AND METHODS: Between 2017 and 2023, 14 patients with 47 HEHE tumors were treated with percutaneous IRE using CT-scan guidance in 23 procedures. Baseline patient and tumor characteristics were evaluated. Primary outcome measures included safety and effectiveness, analyzed using Common Terminology Criteria for Adverse Events (CTCAE) and treatment response by mRECIST criteria. Secondary outcome measures included technical success, post-treatment tumor sizes and length of hospital stay. Technical success was defined as complete ablation with an adequate ablative margin (intentional tumor free ablation margin > 5 mm). RESULTS: IRE treatment resulted in technical success in all tumors. Following a median follow-up of 15 months, 30 tumors demonstrated a complete response according to mRECIST criteria. The average tumor size pre-treatment was 25.8 mm, accompanied by an average reduction in tumor size by 7.5 mm. In 38 out of 47 tumors, there was no evidence of local recurrence. In nine tumors, residual tumor was present. There were no cases of progressive disease. Median length of hospital stay was one day. Only one grade 3 CTCAE event occurred, a pneumothorax requiring chest tube placement. CONCLUSION: The current study provides evidence that IRE is a safe and efficacious minimally invasive treatment option for HEHE.


Assuntos
Eletroporação , Hemangioendotelioma Epitelioide , Neoplasias Hepáticas , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Hemangioendotelioma Epitelioide/diagnóstico por imagem , Hemangioendotelioma Epitelioide/cirurgia , Hemangioendotelioma Epitelioide/terapia , Adulto , Eletroporação/métodos , Idoso , Resultado do Tratamento , Adulto Jovem
8.
Gene ; 851: 147026, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36332837

RESUMO

Overfeeding (OF) and obesity increase the risk for brain aging and neurodegenerative diseases due to increased oxidative stress and neuroinflammation, which likely contribute to cellular dysfunction. In contrast, caloric restriction (CR) is an intervention known for its effects on extending both life- and health-span. In the current study, the effects on the aging brain of two short-term feeding regimens, OF and CR, were investigated. We applied these diets for 12 weeks to both young and aged zebrafish. We performed protein and mRNA level analysis to examine diet-mediated effects on any potential age-related alterations in the brain. Markers implicated in the regulation of brain aging, cell cycle, proliferation, inflammation, and cytoskeleton were analyzed. The most prominent result observed was a downregulation in the expression levels of the stem cell marker, Sox2, in CR-fed animals as compared to OF-fed fish. Furthermore, our data highlighted significant age-related downregulations in Tp53, Myca, and L-plastin levels. The multivariate analyses of all datasets suggested that as opposed to OF, the adaptive mechanisms increasing lifespan via CR are likely exerting their effects by reinforcing the stem cell pool and downregulating inflammation. The data reveal important therapeutic targets with respect to the state of nutrient uptake for the slowing down of the detrimental effects of aging, resulting in a healthy and extended lifespan, as well as lowering the risk for neurodegenerative disease.


Assuntos
Restrição Calórica , Doenças Neurodegenerativas , Animais , Doenças Neurodegenerativas/metabolismo , Peixe-Zebra/metabolismo , Encéfalo/metabolismo , Envelhecimento/metabolismo , Biomarcadores/metabolismo , Inflamação/metabolismo , Células-Tronco/metabolismo , Proliferação de Células
9.
Neurobiol Aging ; 130: 12-21, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37419077

RESUMO

Various aspects of visual functioning, including motion perception, change with age. Yet, there is a lack of comprehensive understanding of age-related alterations at different stages of motion processing and in each motion system. To understand the effects of aging on second-order motion processing, we investigated optomotor responses (OMR) in younger and older wild-type (AB-strain) and acetylcholinesterase (achesb55/+) mutant zebrafish. The mutant fish with decreased levels of acetylcholinesterase have been shown to have delayed age-related cognitive decline. Compared to previous results on first-order motion, we found distinct changes in OMR to second-order motion. The polarity of OMR was dependent on age, such that second-order stimulation led to mainly negative OMR in the younger group while older zebrafish had positive responses. Hence, these findings revealed an overall aging effect on the detection of second-order motion. Moreover, neither the genotype of zebrafish nor the spatial frequency of motion significantly changed the response magnitude. Our findings support the view that age-related changes in motion detection depend on the activated motion system.

10.
J Am Chem Soc ; 134(32): 13448-57, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22866694

RESUMO

QS-21 is a potent immunostimulatory saponin that is currently under clinical investigation as an adjuvant in various vaccines to treat infectious diseases, cancers, and cognitive disorders. Herein, we report the design, synthesis, and preclinical evaluation of simplified QS-21 congeners to define key structural features that are critical for adjuvant activity. Truncation of the linear tetrasaccharide domain revealed that a trisaccharide variant is equipotent to QS-21, while the corresponding disaccharide and monosaccharide congeners are more toxic and less potent, respectively. Modification of the acyl chain domain in the trisaccharide series revealed that a terminal carboxylic acid is well-tolerated while a terminal amine results in reduced adjuvant activity. Acylation of the terminal amine can, in some cases, restore adjuvant activity and enables the synthesis of fluorescently labeled QS-21 variants. Cellular studies with these probes revealed that, contrary to conventional wisdom, the most highly adjuvant active of these fluorescently labeled saponins does not simply associate with the plasma membrane, but rather is internalized by dendritic cells.


Assuntos
Adjuvantes Imunológicos/farmacologia , Células Dendríticas/efeitos dos fármacos , Saponinas/química , Acilação , Adjuvantes Imunológicos/química , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular
11.
Ageing Res Rev ; 66: 101228, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33246078

RESUMO

Aging is a significant risk factor for cognitive decline associated with neurodegenerative diseases, which makes understanding what promotes 'healthy brain aging' very important. Studies suggest that caloric restriction (CR) is a non-genetic intervention that reliably extends life- and healthspan. Here, we review the CR literature related to both the subject of aging and alterations in cell cycle machinery, especially surrounding the regulation of the E2F/DP1 complex, to elucidate the cellular protection mechanisms in the brain induced via dietary applications. The alterations extending lifespan via CR appear to exert their effects by promoting survival of individual cells, downregulating cell proliferation, and inducing stem cell quiescence, which results in keeping the stem cell reserve for extreme needs. This survival instinct of cells is believed to cause some molecular adaptations for their maintenance of the system. Avoiding energy waste of proliferation machinery promotes the long term survival of the individual cells and this is due to adaptations to the limited nutrient supply in the environment. Such a protective mechanism induced by diet could be promoted via the downregulation of crucial cell cycle-related transcription activators. This review article aims to bring attention to the importance of molecular adaptations induced by diet that promote healthy brain aging. It will provide insights into alternative targets for new treatments or neuroprotective approaches against neurodegenerative pathophysiologies.


Assuntos
Restrição Calórica , Doenças Neurodegenerativas , Envelhecimento , Dieta , Humanos , Longevidade
12.
Exp Gerontol ; 149: 111346, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33838219

RESUMO

Progression of cognitive decline with or without neurodegeneration varies among elderly subjects. The main aim of the current study was to illuminate the molecular mechanisms that promote and retain successful aging in the context of factors such as environment and gender, both of which alter the resilience of the aging brain. Environmental enrichment (EE) is one intervention that may lead to the maintenance of cognitive processing at older ages in both humans and animal subjects. EE is easily applied to different model organisms, including zebrafish, which show similar age-related molecular and behavioral changes as humans. Global changes in cellular and synaptic markers with respect to age, gender and 4-weeks of EE applied with sensory stimulation were investigated using the zebrafish model organism. Results indicated that EE increases brain weight in an age-dependent manner without affecting general body parameters like body mass index (BMI). Age-related declines in the presynaptic protein synaptophysin, AMPA-type glutamate receptor subunits and a post-mitotic neuronal marker were observed and short-term EE prevents these changes in aged animals, as well as elevates levels of the inhibitory scaffolding protein, gephyrin. Gender-driven alterations were observed in the levels of the glutamate receptor subunits. Oxidative stress markers were significantly increased in the old animals, while exposure to EE did not alter this pattern. These data suggest that EE with sensory stimulation exerts its effects mainly on age-related changes in synaptic dynamics, which likely increase brain resilience through specific cellular mechanisms.


Assuntos
Disfunção Cognitiva , Peixe-Zebra , Idoso , Envelhecimento , Animais , Meio Ambiente , Humanos , Pessoa de Meia-Idade , Sinaptofisina
13.
Neurobiol Aging ; 106: 169-182, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34284260

RESUMO

Increased caloric intake (OF) impairs quality of life causing comorbidities with other diseases and cognitive deficits, whereas dietary restriction (DR) increases healthspan by preventing age-related deteriorations. To understand the effects of these opposing dietary regimens on the cellular and synaptic dynamics during brain aging, the zebrafish model, which shows gradual aging like mammals, was utilized. Global changes in cellular and synaptic markers with respect to age and a 12 week dietary regimen of OF and DR demonstrated that aging reduces the levels of the glutamate receptor subunits, GLUR2/3, inhibitory synaptic clustering protein, GEP, synaptic vesicle protein, SYP, and early-differentiated neuronal marker, HuC. DR significantly elevates levels of glutamate receptor subunits, GLUR2/3, and NMDA clustering protein, PSD95, levels, while OF subtly increases the level of the neuronal protein, DCAMKL1. These data suggest that decreased caloric intake within the context of aging has more robust effects on synapses than cellular proteins, whereas OF alters cellular dynamics. Thus, patterns like these should be taken into account for possible translation to human subjects.


Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Encéfalo/citologia , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Dietoterapia , Ingestão de Energia/fisiologia , Comportamento Alimentar/fisiologia , Hiperfagia/complicações , Hiperfagia/fisiopatologia , Plasticidade Neuronal/fisiologia , Animais , Proteína 4 Homóloga a Disks-Large/metabolismo , Quinases Semelhantes a Duplacortina/metabolismo , Envelhecimento Saudável , Modelos Animais , Receptores de AMPA/metabolismo , Fatores de Tempo , Peixe-Zebra
14.
Neurobiol Aging ; 98: 21-32, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33227566

RESUMO

Understanding the principles underlying age-related changes in motion perception is paramount for improving the quality of life and health of older adults. However, the mechanisms underlying age-related alterations in this aspect of vision, which is essential for survival in a dynamic world, still remain unclear. Using optomotor responses to drifting gratings, we investigated age-related changes in motion detection of adult zebrafish (wild-type/AB-strain and achesb55/+ mutants with decreased levels of acetylcholinesterase). Our results pointed out negative optomotor responses that significantly depend on the spatial frequency and contrast level of stimulation, providing supporting evidence for the visual motion-driven aspect of this behavior mainly exhibited by adult zebrafish. Although there were no significant main effects of age and genotype, we found a significant three-way interaction between contrast level, age, and genotype. In the contrast domain, the changes in optomotor responses and thus in the detection of motion direction were age- and genotype-specific. Accordingly, these behavioral findings suggest a strong but complicated relationship between visual motion characteristics and the cholinergic system during neural aging.


Assuntos
Acetilcolina/fisiologia , Envelhecimento/fisiologia , Comportamento Animal/fisiologia , Genótipo , Percepção de Movimento/fisiologia , Atividade Motora/fisiologia , Visão Ocular/fisiologia , Percepção Visual/fisiologia , Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Animais , Feminino , Masculino , Estimulação Luminosa , Receptores Colinérgicos/fisiologia
15.
Abdom Radiol (NY) ; 46(12): 5509-5512, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34223960

RESUMO

Radiology is a demanding career that requires a thorough understanding of evolving knowledge in both medical imaging and technology. Competing interests such as-familial obligations, clinical practice, committee meetings, and research projects-often leave little time for self-care and regular review of current medical literature. Healthy habits can be difficult to maintain, but micro-habits are more manageable and their benefits compound over time. Based on the book, Atomic Habits by James Clear, we discuss a micro-habit toolkit which includes: a two-minute rule, habit-stacking, environmental cues, task prioritization/automatization, habit tracking, and accountability. We offer practical suggestions for radiologists to incorporate this toolkit into their daily lives to become healthy life-long learners.


Assuntos
Hábitos , Radiologia , Sinais (Psicologia) , Humanos , Aprendizagem , Radiologistas
16.
Cardiovasc Intervent Radiol ; 44(10): 1510-1517, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34231013

RESUMO

As the field of interventional radiology assumes a larger role in patient care, the specialty has a growing responsibility to recognize and understand ethical dilemmas within the field. We present a case-based primer on common ethical issues in IR, including requests for potentially inappropriate procedures, surrogate decision making, informed consent, and managing conflicts of interest and procedural complications. This primer is intended to be used as a guide for discussion-based training in ethics in IR while inspiring further research in applied ethics in IR.


Assuntos
Consentimento Livre e Esclarecido , Radiologia Intervencionista , Humanos , Assistência ao Paciente
17.
J Am Chem Soc ; 132(38): 13114-6, 2010 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-20672823

RESUMO

We introduce a novel sensing mechanism for nitric oxide (NO) detection with a particular easily synthesized embodiment (NO(550)), which displays a rapid and linear response to NO with a red-shifted 1500-fold turn-on signal from a dark background. Excellent selectivity was observed against other reactive oxygen/nitrogen species, pH, and various substances that interfere with existing probes. NO(550) crosses cell membranes but not nuclear membranes and is suitable for both intra- and extracellular NO quantifications. Good cytocompatibility was found during in vitro studies with two different cell lines. The high specificity, dark background, facile synthesis, and low pH dependence make NO(550) a superior probe for NO detection when used as an imaging agent.


Assuntos
Corantes Fluorescentes/química , Óxido Nítrico/química , Concentração de Íons de Hidrogênio , Solubilidade
18.
J Am Chem Soc ; 132(6): 1939-45, 2010 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-20088518

RESUMO

The success of antitumor and antiviral vaccines often requires the use of an adjuvant, a substance that significantly enhances the immune response to a coadministered antigen. Only a handful of adjuvants have both sufficient potency and acceptable toxicity for clinical investigation. One promising adjuvant is QS-21, a saponin natural product that is the immunopotentiator of choice in many cancer and infectious disease vaccine clinical trials. However, the therapeutic promise of QS-21 adjuvant is curtailed by several factors, including its scarcity, difficulty in purification to homogeneity, dose-limiting toxicity, and chemical instability. Here, we report the design, synthesis, and evaluation of chemically stable synthetic saponins. These novel, amide-modified, non-natural substances exhibit immunopotentiating effects in vivo that rival or exceed that of QS-21 in evaluations with the GD3-KLH melanoma conjugate vaccine. The highly convergent synthetic preparation of these novel saponins establishes new avenues for discovering improved molecular adjuvants for specifically tailored vaccine therapies.


Assuntos
Adjuvantes Imunológicos/síntese química , Desenho de Fármacos , Quillaja/química , Saponinas/síntese química , Saponinas/imunologia , Vacinas/imunologia , Adjuvantes Imunológicos/isolamento & purificação , Animais , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Saponinas/isolamento & purificação
19.
Rejuvenation Res ; 23(6): 485-497, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32279604

RESUMO

Intermittent fasting (IF) and its mimetic, rapamycin extend lifespan and healthspan through mechanisms that are not fully understood. We investigated different short-term durations of IF and rapamycin on cellular and molecular changes in the brains of young (6-10 months) and old (26-31 months) zebrafish. Interestingly, our results showed that IF significantly lowered glucose levels while increasing DCAMKL1 in both young and old animals. This proliferative effect of IF was supported by the upregulation of foxm1 transcript in old animals. Rapamycin did not change glucose levels in young and old animals but had differential effects depending on age. In young zebrafish, proliferating cell nuclear antigen and the LC3-II/LC3-I ratio was decreased, whereas glial fibrillary acidic protein and gephyrin were decreased in old animals. The changes in proliferative markers and a marker of autophagic flux suggest an age-dependent interplay between autophagy and cell proliferation. Additionally, changes in glia and inhibitory tone suggest a suppressive effect on neuroinflammation but may push the brain toward a more excitable state. Mammalian target of rapamycin (mTOR) activity in the brain following the IF and rapamycin treatment was differentially regulated by age. Interestingly, rapamycin inhibited mTOR more potently in young animals than IF. Principal component analysis supported our conclusion that the regulatory effects of IF and rapamycin were age-specific, since we observed different patterns in the expression levels and clustering of young and old animals. Taken together, our results suggest that even a short-term duration of IF and rapamycin have significant effects in the brain at young and old ages, and that these are age and treatment dependent.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Jejum/metabolismo , Neuroglia/metabolismo , Neurônios/citologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Peixe-Zebra/metabolismo , Animais , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Feminino , Masculino , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Serina-Treonina Quinases TOR/metabolismo
20.
Neuroscience ; 436: 46-73, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278060

RESUMO

Aging occurs due to a combination of several factors, such as telomere attrition, cellular senescence, and stem cell exhaustion. The telomere attrition-dependent cellular senescence is regulated by increased levels of SMAD specific E3 ubiquitin protein ligase 2 (smurf2). With age smurf2 expression increases and Smurf2 protein interacts with several regulatory proteins including, Smad7, Ep300, Yy1, Sirt1, Mdm2, and Tp53, likely affecting its function related to cellular aging. The current study aimed at analyzing smurf2 expression in the aged brain because of its potential regulatory roles in the cellular aging process. Zebrafish were used because like humans they age gradually and their genome has 70% similarity. In the current study, we demonstrated that smurf2 gene and protein expression levels altered in a region-specific manner during the aging process. Also, in both young and old brains, Smurf2 protein was enriched in the cytosol. These results imply that during aging Smurf2 is regulated by several mechanisms including post-translational modifications (PTMs) and complex formation. Also, the expression levels of its interacting partners defined by the STRING database, tp53, mdm2, ep300a, yy1a, smad7, and sirt1, were analyzed. Multivariate analysis indicated that smurf2, ep300a, and sirt1, whose proteins regulate ubiquitination, acetylation, and deacetylation of target proteins including Smad7 and Tp53, showed age- and brain region-dependent patterns. Our data suggest a likely balance between Smurf2- and Mdm2-mediated ubiquitination, and Ep300a-mediated acetylation/Sirt1-mediated deacetylation, which most possibly affects the functionality of other interacting partners in regulating cellular and synaptic aging and ultimately cognitive dysfunction.


Assuntos
Ubiquitina-Proteína Ligases , Peixe-Zebra , Idoso , Animais , Encéfalo/metabolismo , Humanos , Processamento de Proteína Pós-Traducional , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Peixe-Zebra/metabolismo
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