RESUMO
You begin to hear distant rock music playing, people conversing about their weekend. Then the scalpel is requested-incision. Pain sends you reeling and you attempt to muster a scream. No one seems to hear you and you are unable to lift a finger. The scenario is so rare that numerous movies have been made about awareness under anesthesia. Awareness under anesthesia is a rare event, however, it is a complication that no one ever desires to occur. We will explore how frequent awareness is during surgery, what risk factors are involved, and what tools anesthesia providers utilize to ensure everyone undergoing surgery is adequately anesthetized.
Assuntos
Anestesia , Consciência no Peroperatório , Humanos , Anestesia/efeitos adversosRESUMO
Renal ischemia is among the leading causes of acute kidney injury (AKI). Previous studies have shown that extracellular adenosine is a prominent tissue-protective cue elicited during ischemia, including signaling events through the adenosine receptor 2b (Adora2b). To investigate the functional role of Adora2b signaling in cytokine-mediated inflammatory pathways, we screened wild-type and Adora2b-deficient mice undergoing renal ischemia for expression of a range of inflammatory cytokines. These studies demonstrated a selective and robust increase of TNF-α levels in Adora2b-deficient mice following renal ischemia and reperfusion. Based on these findings, we next sought to understand the contribution of TNF-α on ischemic AKI through a combination of loss- and gain-of-function studies. Loss of TNF-α, through either Ab blockade or study of Tnf-α-deficient animals, resulted in significantly attenuated tissue injury and improved kidney function following renal ischemia. Conversely, transgenic mice with overexpression of TNF-α had significantly pronounced susceptibility to AKI. Furthermore, neutrophil depletion or reconstitution of Adora2b(-/-) mice with Tnf-α-deficient neutrophils rescued their phenotype. In total, these data demonstrate a critical role of adenosine signaling in constraining neutrophil-dependent production of TNF-α and implicate therapies targeting TNF-α in the treatment of ischemic AKI.
Assuntos
Injúria Renal Aguda/imunologia , Injúria Renal Aguda/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptor A2B de Adenosina/fisiologia , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Injúria Renal Aguda/genética , Animais , Modelos Animais de Doenças , Predisposição Genética para Doença , Isquemia/genética , Isquemia/imunologia , Isquemia/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neutrófilos/patologia , Receptor A2B de Adenosina/deficiência , Receptor A2B de Adenosina/genética , Reperfusão/métodos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/deficiênciaRESUMO
A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) - a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1-/- mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications.
Assuntos
Injúria Renal Aguda/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Isquemia/metabolismo , Fluxo Sanguíneo Regional/fisiologia , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Adenosina/metabolismo , Animais , Linhagem Celular , Quimerismo , Dipiridamol/uso terapêutico , Transportador Equilibrativo 1 de Nucleosídeo/antagonistas & inibidores , Transportador Equilibrativo 1 de Nucleosídeo/genética , Humanos , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenômeno de não Refluxo , Proteínas de Transporte de Nucleosídeos/antagonistas & inibidores , Proteínas de Transporte de Nucleosídeos/metabolismo , Inibidores de Fosfodiesterase/uso terapêutico , Receptores Purinérgicos P1/genética , Receptores Purinérgicos P1/metabolismoRESUMO
The netrin family of secreted proteins provides migrational cues in the developing central nervous system. Recently, netrins have also been shown to regulate diverse processes beyond their functions in the brain, incluing the ochrestration of inflammatory events. Particularly netrin-1 has been implicated in dampening hypoxia-induced inflammation. Here, we hypothesized an anti-inflammatory role of endogenous netrin-1 in acute kidney injury (AKI). As homozygous deletion of netrin-1 is lethal, we studied mice with partial netrin-1 deletion (Ntn-1(+/-) mice) as a genetic model. In fact, Ntn-1(+/-) mice showed attenuated Ntn-1 levels at baseline and following ischemic AKI. Functional studies of AKI induced by 30 min of renal ischemia and reperfusion revealed enhanced kidney dysfunction in Ntn-1(+/-) mice as assessed by measurements of glomerular filtration, urine flow rate, urine electrolytes, serum creatinine and creatinine clearance. Consistent with these findings, histological studies indicated a more severe degree kidney injury. Similarly, elevations of renal and systemic inflammatory markers were enhanced in mice with partial netrin-1 deficiency. Finally, treatment of Ntn-1(+/-) mice with exogenous netrin-1 restored a normal phenotype during AKI. Taking together, these studies implicate endogenous netrin-1 in attenuating renal inflammation during AKI.
Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/fisiologia , Injúria Renal Aguda/metabolismo , Animais , Western Blotting , Células Cultivadas , Creatinina/sangue , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Taxa de Filtração Glomerular , Humanos , Técnicas Imunoenzimáticas , Rim/citologia , Rim/metabolismo , Testes de Função Renal , Camundongos , Camundongos Knockout , Fatores de Crescimento Neural/genética , Netrina-1 , Fenótipo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Supressoras de Tumor/genéticaRESUMO
OBJECTIVES: In 2006, the Centers for Disease Control and Prevention (CDC) published recommendations for HIV testing in health care settings, calling for nontargeted opt-out rapid HIV screening in most settings, including emergency departments (EDs). Although a number of ED-based testing strategies exist, it is unclear to what extent they are used. The objective of this study is to survey academic and community EDs throughout the United States to determine ED-based HIV testing practices. METHODS: This was a cross-sectional survey study of all academic EDs and a weighted random sample of all community-based EDs in the United States. A standardized survey instrument was developed and administered with an Internet-based survey platform, followed by direct contact and mail. The survey included domains related to perceived HIV testing barriers, whether HIV testing was performed and methods used, and familiarity with the CDC recommendations and whether they had been adopted. RESULTS: Of the 131 total academic sites and the 435 community sites, 99 (76%) and 150 (35%) completed the survey, respectively. A larger proportion of academic sites believed HIV testing was needed (P=.02) and a larger proportion actually provided HIV testing (65% versus 50%; P=.04). Among the academic and community EDs that provided testing, 74% and 62% performed diagnostic testing, 26% and 22% performed targeted screening, and 16% and 6% performed nontargeted screening, respectively. A larger proportion of academic EDs reported receiving external funding to support testing (23% versus 4%; P=.001), whereas a large proportion of community sites considered costs a significant barrier to testing (P=.03). A larger proportion of academic EDs reported being familiar with the 2006 CDC recommendations (64% versus 40%; P<.001), although only 26% and 37% reported having implemented any part of them, respectively. CONCLUSION: Academic EDs only make up approximately 3% of all EDs in the United States. Significant differences exist between academic and community EDs as they relate to performing HIV testing. Increased efforts should be made to improve the ability of community EDs to provide this service.
Assuntos
Serviço Hospitalar de Emergência , Infecções por HIV/diagnóstico , Sorodiagnóstico da AIDS/estatística & dados numéricos , Atitude do Pessoal de Saúde , Estudos Transversais , Serviço Hospitalar de Emergência/estatística & dados numéricos , Fidelidade a Diretrizes , Pesquisas sobre Atenção à Saúde , Humanos , Estados UnidosRESUMO
Acute kidney injury (AKI) is among the leading causes of morbidity and mortality in hospitalized patients. Particularly in the perioperative period, the most common cause of AKI is renal ischemia. At present, therapeutic modalities to prevent or treat AKI are extremely limited and the search for novel therapeutic interventions for ischemic AKI is an area of intense investigation. Recent studies implicate the endogenous signaling molecule, adenosine, in kidney protection from ischemia. As such, enzymatic production of adenosine from its precursor molecules ATP and AMP, and signaling events through adenosine receptors, play a critical role in attenuating renal inflammation and preserving kidney function during episodes of renal ischemia. Utilizing genetic mouse models with defects in adenosine generation or signaling provide strong evidence for the key role of extracellular adenosine in adapting renal tissues to limited oxygen availability and attenuating hypoxia-driven inflammation of the kidneys. Moreover, experimental therapeutics targeting individual adenosine receptors demonstrate strong prophylactic or therapeutic effects during murine AKI. If these experimental strategies can be translated into a clinical setting, adenosine receptor therapeutics may become an integral part in the prevention or treatment of AKI from renal ischemia.