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Recent documents in eScholarship@UMMS
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Double embolic protection during carotid artery stenting with persistent hypoglossal artery

Mon, 06/19/2017 - 10:54am

A woman presented with 75% stenosis of the right internal carotid artery (ICA) with extension to the origin of a persistent hypoglossal artery (PHA). The PHA is a rare fetal variant of carotid-basilar anastomosis that elevates the risk of ischemia and embolic infarction within the posterior cerebral circulation in patients with carotid disease proximal to the anastomosis. Our case is highly unique because of the extremely rare nature of the PHA with associated ICA stenosis that extended to the PHA. Additionally, a novel treatment approach was employed by stenting and angioplasty while protecting both the anterior and posterior cerebral circulations.

Bioactive versus bare platinum coils in the treatment of intracranial aneurysms: the MAPS (Matrix and Platinum Science) trial

Mon, 06/19/2017 - 10:54am

BACKGROUND AND PURPOSE: The ability of polymer-modified coils to promote stable aneurysm occlusion after endovascular treatment is not well-documented. Angiographic aneurysm recurrence is widely used as a surrogate for treatment failure, but studies documenting the correlation of angiographic recurrence with clinical failure are limited. This trial compares the effectiveness of Matrix(2) polyglycolic/polylactic acid biopolymer-modified coils with bare metal coils and correlates the angiographic findings with clinical failure (ie, target aneurysm recurrence), a composite end point that includes any incident of posttreatment aneurysm rupture, retreatment, or unexplained death.

MATERIALS AND METHODS: This was a multicenter randomized noninferiority trial with blinded end point adjudication. We enrolled 626 patients, divided between Matrix(2) and bare metal coil groups. The primary outcome was target aneurysm recurrence at 12 +/- 3 months.

RESULTS: At 455 days, at least 1 target aneurysm recurrence event had occurred in 14.6% of patients treated with bare metal coils and 13.3% of Matrix(2) (P = .76, log-rank test) patients; 92.8% of target aneurysm recurrence events were re-interventions for aneurysms that had not bled after treatment, and 5.8% of target aneurysm recurrence events resulted from hemorrhage or rehemorrhage, with or without retreatment. Symptomatic re-intervention occurred in only 4 (0.6%) patients. At 455 days, 95.8% of patients with unruptured aneurysms and 90.4% of those with ruptured aneurysms were independent (mRS ≤ 2). Target aneurysm recurrence was associated with incomplete initial angiographic aneurysm obliteration, presentation with rupture, and a larger aneurysmal dome and neck size.

CONCLUSIONS: Tested Matrix(2) coils were not inferior to bare metal coils. Endovascular coiling of intracranial aneurysms was safe, and the rate of technical success was high. Target aneurysm recurrence is a promising clinical outcome measure that correlates well with established angiographic measurements.

Human adipose-derived mesenchymal stem cells attenuate liver ischemia-reperfusion injury and promote liver regeneration

Mon, 06/19/2017 - 10:54am

BACKGROUND: Ischemia-reperfusion injury (IRI) of the liver is a well-known cause of morbidity and mortality after liver transplantation. Effective treatment strategies aimed at decreasing hepatic IRI injury and accelerating liver regeneration could offer major benefits in liver transplantation, especially in the case of partial allografts. Human adipose-derived mesenchymal stem cells (HADMSCs) are an attractive source for regenerative medicine because of their anti-inflammatory and regenerative properties. We hypothesized that HADMSCs attenuate IRI and promote liver regeneration.

METHODS: Mice were subjected to 60 minutes of partial IRI with or without 70% partial hepatectomy. Animals were treated with HADMSCs. Liver IRI was evaluated with serum levels of alanine aminotransferase, serum interleukin-6, and histopathology. Liver samples were stained for specific markers of liver regeneration.

RESULTS: Histology, serum interleukin-6, and alanine aminotransferase release revealed that treatment with HADMSCs attenuated liver injury compared with control patients. Improved animal survival and increased number of regenerating cells were observed in HADMSC-treated animals who underwent IRI and partial hepatectomy compared with the control group.

CONCLUSION: HADMSC represents a potential therapeutic strategy to decrease IRI and promote regeneration in liver transplantation.

Endovascular coiling of a ruptured basilar apex aneurysm with associated pseudoaneurysm

Mon, 06/19/2017 - 10:54am

Acute intracranial pseudoaneurysms secondary to aneurysmal rupture are a rare entity with no clear evidence-based guidelines for treatment to our knowledge. There are numerous examples of successful treatment of pseudoaneurysms both surgically and endovascularly, the latter mainly within the anterior circulation. Risk of pseudoaneurysm rupture in the acute state during endovascular procedures with subsequent difficulty in controlling the bleeding without sacrificing the feeder artery has led to some reservation in using endovascular treatments more broadly. We report a rare case of a 52-year-old-woman who presented with acute subarachnoid hemorrhage and was found to have a ruptured 5 mm x 8 mm bi-lobulated basilar apex aneurysm on CT angiography. Digital subtraction angiography demonstrated an associated anterior pseudoaneurysm that was formed secondary to the aneurysm rupture. The true aneurysm was successfully coiled with careful avoidance of the pseudoaneurysmal sac. Pseudoaneurysms are frequently identified for the first time during digital subtraction angiography. Recognizing their presence is essential for treatment planning. Acute pseudoaneurysms associated with true aneurysmal rupture can be safely and successfully treated by endovascular coiling of the true aneurysm. Care must be taken to avoid manipulation of the pseudoaneurysmal sac during the embolization.

Impaired cerebral autoregulation is associated with vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage

Mon, 06/19/2017 - 10:54am

BACKGROUND AND PURPOSE: Cerebral autoregulation may be impaired in the early days after subarachnoid hemorrhage (SAH). The purpose of this study was to examine the relationship between cerebral autoregulation and angiographic vasospasm (aVSP) and radiographic delayed cerebral ischemia (DCI) in patients with SAH. METHODS: Sixty-eight patients (54+/-13 years) with a diagnosis of nontraumatic SAH were studied. Dynamic cerebral autoregulation was assessed using transfer function analysis (phase and gain) of the spontaneous blood pressure and blood flow velocity oscillations on days 2 to 4 post-SAH. aVSP was diagnosed using a 4-vessel conventional angiogram. DCI was diagnosed from CT. Decision tree models were used to identify optimal cut-off points for clinical and physiological predictors of aVSP and DCI. Multivariate logistic regression models were used to develop and validate a risk scoring tool for each outcome. RESULTS: Sixty-two percent of patients developed aVSP, and 19% developed DCI. Patients with aVSP had higher transfer function gain (1.06+/-0.33 versus 0.89+/-0.30; P=0.04) and patients with DCI had lower transfer function phase (17.5+/-39.6 versus 38.3+/-18.2; P=0.03) compared with those who did not develop either. Multivariable scoring tools using transfer function gain>0.98 and phase<12.5 were strongly predictive of aVSP (92% positive predictive value; 77% negative predictive value; area under the receiver operating characteristic curve, 0.92) and DCI (80% positive predictive value; 91% negative predictive value; area under the curve, 0.94), respectively. CONCLUSIONS: Dynamic cerebral autoregulation is impaired in the early days after SAH. Including autoregulation as part of the initial clinical and radiographic assessment may enhance our ability to identify patients at a high risk for developing secondary complications after SAH.

Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue

Thu, 06/15/2017 - 12:31pm

OBJECTIVE: Insulin signaling plays a unique role in the regulation of energy homeostasis and the impairment of insulin action is associated with altered lipid metabolism, obesity, and Type 2 Diabetes. The main aim of this study was to provide further insight into the regulatory mechanisms governing the insulin signaling pathway by investigating the role of non-proteolytic ubiquitination in insulin-mediated activation of AKT.

METHODS: The molecular mechanism of AKT regulation through ubiquitination is first dissected in vitro in 3T3-L1 preadipocytes and then validated in vivo using mice with adipo-specific deletion of GPS2, an endogenous inhibitor of Ubc13 activity (GPS2-AKO mice).

RESULTS: Our results indicate that K63 ubiquitination is a critical component of AKT activation in the insulin signaling pathway and that counter-regulation of this step is provided by GPS2 preventing AKT ubiquitination through inhibition of Ubc13 enzymatic activity. Removal of this negative checkpoint, through GPS2 downregulation or genetic deletion, results in sustained activation of insulin signaling both in vitro and in vivo. As a result, the balance between lipid accumulation and utilization is shifted toward storage in the adipose tissue and GPS2-AKO mice become obese under normal laboratory chow diet. However, the adipose tissue of GPS2-AKO mice is not inflamed, the levels of circulating adiponectin are elevated, and systemic insulin sensitivity is overall improved.

CONCLUSIONS: Our findings characterize a novel layer of regulation of the insulin signaling pathway based on non-proteolytic ubiquitination of AKT and define GPS2 as a previously unrecognized component of the insulin signaling cascade. In accordance with this role, we have shown that GPS2 presence in adipocytes modulates systemic metabolism by restricting the activation of insulin signaling during the fasted state, whereas in absence of GPS2, the adipose tissue is more efficient at lipid storage, and obesity becomes uncoupled from inflammation and insulin resistance.

Properdin Levels in Individuals with Chemotherapy-Induced Neutropenia

Thu, 06/15/2017 - 12:30pm

BACKGROUND: Neutrophils produce and carry key components of the alternative pathway (AP) of complement, including properdin (P). The effect of chemotherapy-induced absolute neutropenia on circulating P levels and AP function has not been previously established.

METHODS: We prospectively measured free P levels in serum from 27 individuals expected to develop neutropenia after administration of chemotherapy for hematological malignancies in preparation for hematopoietic stem cell transplantation and here describe the relationship between serum P levels and the neutrophil count over time.

RESULTS: When the absolute neutrophil count (ANC) was > 500 cells/mm3 pre-chemotherapy, P levels were significantly higher than P levels associated with an ANC ≤500 cells/mm3 (median values 8392 ng/mL and 6355 ng/mL, respectively; P = .001). Pairwise comparison between pre-chemotherapy P levels and P levels at initial or last documented neutropenia before recovery showed a significant decline (P < .0001). No correlation was observed between P levels during neutropenia and after recovery of neutropenia in 20 subjects for which postneutropenia samples were obtained. A small but significant (P = .02) decrease in AP hemolytic activity was noted between baseline (preneutropenia) and samples obtained at the onset of neutropenia, but only with low (6.25%) and not higher (12.5 or 25%) serum concentrations.

CONCLUSIONS: A decline in P levels and AP activity could contribute to the increased risk of infection in neutropenic patients and warrants further study.

Evaluation of the impact of a prescribing guideline on the use of intraoperative dexmedetomidine at a tertiary academic medical center

Thu, 06/15/2017 - 12:30pm

Objective: To evaluate usage patterns of dexmedetomidine in the operating room after implementation of a prescribing guideline.

Methods: We conducted a retrospective analysis to evaluate the impact of a prescribing guideline on usage patterns of dexmedetomidine in the operating room at a tertiary, academic medical center during one-month period pre- (July 2010) and post-guideline (July 2011 and July 2012) implementation.

Results: A total of 267 patients received intraoperative dexmedetomidine during the study period. Dexmedetomidine use in surgical procedures decreased post-guideline implementation [5.7% (pre) vs. 1.9% and 3.3% (post)]. The most common guideline-based indication for intraoperative dexmedetomidine was for anesthesia during bariatric surgery (41% and 38% in 2011 and 2012, respectively). We estimated a cost-avoidance of $308,856 over the two-year period after guideline implementation.

Conclusion: Our results suggest that implementation of a prescribing guideline for the use of dexmedetomidine in the operating room is feasible and associated with improved utilization patterns.

Systemic administration of an HIV-1 broadly neutralizing dimeric IgA yields mucosal secretory IgA and virus neutralization

Thu, 06/15/2017 - 12:30pm

We investigated the mucosal distribution and neutralization potency of rhesus recombinant versions of the HIV-specific, broadly neutralizing antibody b12 (RhB12) following intravenous administration to lactating rhesus monkeys. IgG and dimeric IgA (dIgA) administration resulted in high plasma concentrations of broadly neutralizing antibody (bnAb), but the monomeric IgA (mIgA) was rapidly cleared from the systemic compartment. Interestingly, differences in the distribution of the RhB12 isoform were observed between the mucosal compartments. The peak concentration of RhB12 IgG was higher than dIgA in saliva, rectal, and vaginal secretions, but the bnAb concentration in milk was one to two logs higher after dIgA administration than with IgG or mIgA infusion. Neutralization was observed in plasma of all animals, but only those infused with RhB12 dIgA showed moderate levels of virus neutralization in milk. Remarkably, virus-specific secretory IgA was detected in mucosal compartments following dIgA administration. The high milk RhB12 dIgA concentration suggests that passive immunization with dIgA could be more effective than IgG to inhibit virus in breast milk.

Development of a Reporter System for In Vivo Monitoring of gamma-Secretase Activity in Drosophila

Thu, 06/15/2017 - 12:30pm

The gamma-secretase complex represents an evolutionarily conserved family of transmembrane aspartyl proteases that cleave numerous type-I membrane proteins, including the beta-amyloid precursor protein (APP) and the receptor Notch. All known rare mutations in APP and the gamma-secretase catalytic component, presenilin, which lead to increased amyloid betapeptide production, are responsible for early-onset familial Alzheimer's disease. beta-amyloid protein precursor-like (APPL) is the Drosophila ortholog of human APP. Here, we created Notch- and APPL-based Drosophila reporter systems for in vivo monitoring of gamma-secretase activity. Ectopic expression of the Notch- and APPL-based chimeric reporters in wings results in vein truncation phenotypes. Reporter-mediated vein truncation phenotypes are enhanced by the Notch gain-of-function allele and suppressed by RNAi-mediated knockdown of presenilin. Furthermore, we find that apoptosis partly contributes to the vein truncation phenotypes of the APPL-based reporter, but not to the vein truncation phenotypes of the Notch-based reporter. Taken together, these results suggest that both in vivo reporter systems provide a powerful genetic tool to identify genes that modulate gamma-secretase activity and/or APPL metabolism.

Fluoroscopic imaging overestimates the screw tip to subchondral bone distance in a cadaveric model of slipped capital femoral epiphysis

Thu, 06/15/2017 - 12:30pm

PURPOSE: Intra-operative imaging plays a key role in screw placement for slipped capital femoral epiphysis (SCFE). Complications have been associated with inadequate screw position. The purpose of this study was to evaluate computed tomography (CT) (3D fluoroscopy) and standard fluoroscopy (C-arm) images as compared with direct anatomic measurement to determine final screw position in a cadaveric SCFE model.

METHODS: Osteotomy with pinning was performed at the physeal scar in ten cadaveric hips. A standardised approach-withdrawal technique was performed with C-arm images taken at 15 degrees increments. We also obtained a CT (3D fluoroscopy) scan of each hip. The screw tip-subchondral bone (STSB) distance was measured on digital imaging software and also with a digital calliper directly when the femoral head was cut in plane to expose the STSB distance anatomically. Statistical analysis included t-tests and Fisher's exact test.

RESULTS: Moderate SCFE osteotomies were achieved with a mean Southwick angle (39.5 degrees +/- 7 degrees ). The 60 degrees fluoroscopic image was found to be the most representative image (41% of the time) compared with both anteroposterior (AP) and lateral images (8% and 21%). Both fluoroscopy (2.7 +/- 0.8 mm, p < 0.001) and CT (1.6 +/- 0.7 mm, p = 0.03) overestimated the STSB distance compared with direct measurement (0.94 +/- 0.51 mm). Two-thirds (67%) of CT measurements were within 1 mm of the cadaveric measurement, while only 20% of C-arm measurements fulfilled this criterion (p = 0.04).

CONCLUSIONS: Both standard fluoroscopy and CT overestimated the STSB distance when compared with direct measurement in a cadaveric model of SCFE. Surgeons should be aware of the limitations of intra-operative imaging to determine the STSB distance. We suggest that using the known pitch of a screw (2.9 mm in a 7.3-mm cannulated screw) as an intra-operative tool to help guide screw placement.

Prevalence of, and Resident and Facility Characteristics Associated With Antipsychotic Use in Assisted Living vs. Long-Term Care Facilities: A Cross-Sectional Analysis from Alberta, Canada

Thu, 06/15/2017 - 12:30pm

BACKGROUND: Potentially inappropriate antipsychotic use in long-term care (LTC) facilities has been the focus of significant policy and clinical attention over the past 20 years. However, most initiatives aimed at reducing the use of these medications have overlooked assisted living (AL) settings.

OBJECTIVE: We sought to compare the prevalence of antipsychotic use (including potentially inappropriate use) among older AL and LTC residents and to explore the resident and facility-level factors associated with use in these two populations.

METHODS: We performed cross-sectional analyses of 1089 residents (mean age 85 years; 77% female) from 59 AL facilities and 1000 residents (mean age 85 years; 66% female) from 54 LTC facilities, in Alberta, Canada. Research nurses completed comprehensive resident assessments at baseline (2006-2007). Facility-level factors were assessed using standardized administrator interviews. Generalized linear models were used to estimate odds ratios for associations, accounting for clustering by facility.

RESULTS: Over a quarter of residents in AL (26.4%) and LTC (31.8%) were using antipsychotics (p = 0.006). Prevalence of potentially inappropriate use was similar in AL and LTC (23.4 vs. 26.8%, p = 0.09). However, among users, the proportion of antipsychotic use deemed potentially inappropriate was significantly higher in AL than LTC (AL: 231/287 = 80.5%; LTC: 224/318 = 70.4%; p = 0.004). In both settings, comparable findings regarding associations between resident characteristics (including dementia, psychiatric disorders, frailty, behavioral symptoms, and antidepressant use) and antipsychotic use were observed. Few facility characteristics were associated with overall antipsychotic use, but having a pharmacist on staff (AL), or an affiliated physician (LTC) was associated with a lower likelihood of potentially inappropriate antipsychotic use.

CONCLUSION: Our findings illustrate the importance of including AL settings in clinical and policy initiatives aimed at reducing inappropriate antipsychotic use among older vulnerable residents.

HMGB1, IL-1alpha, IL-33 and S100 proteins: dual-function alarmins

Thu, 06/15/2017 - 12:30pm

Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline-encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein (HMGB1), interleukin (IL)-1alpha, IL-33 and the Ca2+-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.

Adeno-associated virus serotype rh.10 displays strong muscle tropism following intraperitoneal delivery

Thu, 06/15/2017 - 12:30pm

Recombinant adeno-associated virus (rAAV) is an attractive tool for basic science and translational medicine including gene therapy, due to the versatility in its cell and organ transduction. Previous work indicates that rAAV transduction patterns are highly dependent on route of administration. Based on this relationship, we hypothesized that intraperitoneal (IP) administration of rAAV produces unique patterns of tissue tropism. To test this hypothesis, we investigated the transduction efficiency of 12 rAAV serotypes carrying an enhanced green fluorescent protein (EGFP) reporter gene in a panel of 12 organs after IP injection. Our data suggest that IP administration emphasizes transduction patterns that are different from previously reported intravascular delivery methods. Using this approach, rAAV efficiently transduces the liver, pancreas, skeletal muscle, heart and diaphragm without causing significant histopathological changes. Of note, rAAVrh.10 showed excellent muscle transduction following IP administration, highlighting its potential as a new muscle-targeting vector.

Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study

Thu, 06/15/2017 - 12:30pm

Atrial fibrillation (AF) is the most common cardiac arrhythmia, but little is known about the molecular mechanisms associated with AF arrhythmogenesis. DNA methylation is an important epigenetic mechanism that regulates gene expression and downstream biological processes. We hypothesize that DNA methylation might play an important role in the susceptibility to develop AF. A total of 2,639 participants from the Offspring Cohort of Framingham Heart Study were enrolled in the current study. These participants included 183 participants with prevalent AF and 220 with incident AF during up to 9 years follow up. Genome-wide methylation was profiled using the Illumina Infinium HumanMethylation450 BeadChip on blood-derived DNA collected during the eighth examination cycle (2005-2008). Two CpG sites were significantly associated with prevalent AF, and five CpGs were associated with incident AF after correction for multiple testing (FDR < 0.05). Fourteen previously reported genome-wide significant AF-related SNP were each associated with at least one CpG site; the most significant association was rs6490029 at the CUX2 locus and cg10833066 (P = 9.5 x 10-279). In summary, we performed genome-wide methylation profiling in a community-based cohort and identified seven methylation signatures associated with AF. Our study suggests that DNA methylation might play an important role in AF arrhythmogenesis.

The Case for Adopting the "Species Complex" Nomenclature for the Etiologic Agents of Cryptococcosis

Thu, 06/15/2017 - 12:30pm

Cryptococcosis is a potentially lethal disease of humans/animals caused by Cryptococcus neoformans and Cryptococcus gattii. Distinction between the two species is based on phenotypic and genotypic characteristics. Recently, it was proposed that C. neoformans be divided into two species and C. gattii into five species based on a phylogenetic analysis of 115 isolates. While this proposal adds to the knowledge about the genetic diversity and population structure of cryptococcosis agents, the published genotypes of 2,606 strains have already revealed more genetic diversity than is encompassed by seven species. Naming every clade as a separate species at this juncture will lead to continuing nomenclatural instability. In the absence of biological differences between clades and no consensus about how DNA sequence alone can delineate a species, we recommend using "Cryptococcus neoformans species complex" and "C. gattii species complex" as a practical intermediate step, rather than creating more species. This strategy recognizes genetic diversity without creating confusion.

Recreational Physical Activity and Premenstrual Syndrome in Young Adult Women: A Cross-Sectional Study

Thu, 06/15/2017 - 12:30pm

INTRODUCTION: It is estimated that up to 75% of premenopausal women experience at least one premenstrual symptom and 8-20% meet clinical criteria for premenstrual syndrome. Premenstrual syndrome substantially reduces quality of life for many women of reproductive age, with pharmaceutical treatments having limited efficacy and substantial side effects. Physical activity has been recommended as a method of reducing menstrual symptom severity. However, this recommendation is based on relatively little evidence, and the relationship between physical activity, premenstrual symptoms, and premenstrual syndrome remains unclear.

METHODS: We evaluated the relationship between physical activity and premenstrual syndrome and premenstrual symptoms among 414 women aged 18-31. Usual premenstrual symptom experience was assessed with a modified version of the Calendar of Premenstrual Experiences. Total, physical, and affective premenstrual symptom scores were calculated for all participants. Eighty women met criteria for moderate-to-severe premenstrual syndrome, while 89 met control criteria. Physical activity, along with dietary and lifestyle factors, was assessed by self-report.

RESULTS: Physical activity was not significantly associated with total, affective, or physical premenstrual symptom score. Compared to the women with the lowest activity, women in tertiles 2 and 3 of activity, classified as metabolic equivalent task hours, had prevalence odds ratios for premenstrual syndrome of 1.5 (95% CI: 0.6-3.7) and 0.9 (95% CI: 0.4-2.4), respectively (p-value for trend = 0.85).

CONCLUSIONS: We found no association between physical activity and either premenstrual symptom scores or the prevalence of premenstrual syndrome.

Soluble Uric Acid Activates the NLRP3 Inflammasome

Thu, 06/15/2017 - 12:30pm

Uric acid is a damage-associated molecular pattern (DAMP), released from ischemic tissues and dying cells which, when crystalized, is able to activate the NLRP3 inflammasome. Soluble uric acid (sUA) is found in high concentrations in the serum of great apes, and even higher in some diseases, before the appearance of crystals. In the present study, we sought to investigate whether uric acid, in the soluble form, could also activate the NLRP3 inflammasome and induce the production of IL-1beta. We monitored ROS, mitochondrial area and respiratory parameters from macrophages following sUA stimulus. We observed that sUA is released in a hypoxic environment and is able to induce IL-1beta release. This process is followed by production of mitochondrial ROS, ASC speck formation and caspase-1 activation. Nlrp3-/- macrophages presented a protected redox state, increased maximum and reserve oxygen consumption ratio (OCR) and higher VDAC protein levels when compared to WT and Myd88-/- cells. Using a disease model characterized by increased sUA levels, we observed a correlation between sUA, inflammasome activation and fibrosis. These findings suggest sUA activates the NLRP3 inflammasome. We propose that future therapeutic strategies for renal fibrosis should include strategies that block sUA or inhibit its recognition by phagocytes.