Comparison of Radiologists and Deep Learning for US Grading of Hepatic Steatosis.

Background Screening for nonalcoholic fatty liver disease (NAFLD) is suboptimal due to the subjective interpretation of US images. Purpose To evaluate the agreement and diagnostic performance of radiologists and a deep learning model in grading hepatic steatosis in NAFLD at US, with biopsy as the reference standard. Materials and Methods This retrospective study included patients with NAFLD and control patients without hepatic steatosis who underwent abdominal US and contemporaneous liver biopsy from September 2010 to October 2019. Six readers visually graded steatosis on US images twice, 2 weeks apart. Reader agreement was assessed with use of κ statistics. Three deep learning techniques applied to B-mode US images were used to classify dichotomized steatosis grades. Classification performance of human radiologists and the deep learning model for dichotomized steatosis grades (S0, S1, S2, and S3) was assessed with area under the receiver operating characteristic curve (AUC) on a separate test set. Results The study included 199 patients (mean age, 53 years ± 13 [SD]; 101 men). On the test set (n = 52), radiologists had fair interreader agreement (0.34 [95% CI: 0.31, 0.37]) for classifying steatosis grades S0 versus S1 or higher, while AUCs were between 0.49 and 0.84 for radiologists and 0.85 (95% CI: 0.83, 0.87) for the deep learning model. For S0 or S1 versus S2 or S3, radiologists had fair interreader agreement (0.30 [95% CI: 0.27, 0.33]), while AUCs were between 0.57 and 0.76 for radiologists and 0.73 (95% CI: 0.71, 0.75) for the deep learning model. For S2 or lower versus S3, radiologists had fair interreader agreement (0.37 [95% CI: 0.33, 0.40]), while AUCs were between 0.52 and 0.81 for radiologists and 0.67 (95% CI: 0.64, 0.69) for the deep learning model. Conclusion Deep learning approaches applied to B-mode US images provided comparable performance with human readers for detection and grading of hepatic steatosis. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Tuthill in this issue.

Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation.

SET domain-containing proteins play a vital role in regulating gene expression during development through modifications in chromatin structure. Here we show that SET domain-containing 5 (Setd5) is divergently transcribed with Gt(ROSA26)Sor, is necessary for mammalian development, and interacts with the PAF1 co-transcriptional complex and other proteins. Setd5-deficient mouse embryos exhibit severe defects in neural tube formation, somitogenesis and cardiac development, have aberrant vasculogenesis in embryos, yolk sacs and placentas, and die between embryonic day 10.5 and 11.5. Setd5-deficient embryonic stem cells have impaired cellular proliferation, increased apoptosis, defective cell cycle progression, a diminished ability to differentiate into cardiomyocytes and greatly perturbed gene expression. SETD5 co-immunoprecipitates with multiple components of the PAF1 and histone deacetylase-containing NCoR complexes and is not solely required for major histone lysine methylation marks. In the absence of Setd5, histone acetylation is increased at transcription start sites and near downstream regions. These findings suggest that SETD5 functions in a manner similar to yeast Set3p and Drosophila UpSET, and that it is essential for regulating histone acetylation during gene transcription.

Probiotic treatment during neonatal age provides optimal protection against experimental asthma through the modulation of microbiota and T cells.

The incidence of allergic diseases, which increased to epidemic proportions in developed countries over the last few decades, has been correlated with altered gut microbiota colonization. Although probiotics may play a critical role in the restoration of gut homeostasis, their efficiency in the control of allergy is controversial. Here, we aimed to investigate the effects of probiotic treatment initiated at neonatal or adult ages on the suppression of experimental ovalbumin (OVA)-induced asthma. Neonatal or adult mice were orally treated with probiotic bacteria and subjected to OVA-induced allergy. Asthma-like symptoms, microbiota composition and frequencies of the total CD4+ T lymphocytes and CD4+Foxp3+ regulatory T (Treg) cells were evaluated in both groups. Probiotic administration to neonates, but not to adults, was necessary and sufficient for the absolute prevention of experimental allergen-induced sensitization. The neonatally acquired tolerance, transferrable to probiotic-untreated adult recipients by splenic cells from tolerant donors, was associated with modulation of gut bacterial composition, augmented levels of cecum butyrate and selective accumulation of Treg cells in the airways. Our findings reveal that a cross-talk between a healthy microbiota and qualitative features inherent to neonatal T cells, especially in the Treg cell subset, might support the beneficial effect of perinatal exposure to probiotic bacteria on the development of long-term tolerance to allergens.

Enhanced renewal of regulatory T cells in relation to CD4(+) conventional T lymphocytes in the peripheral compartment.

CD4(+) Foxp3(+) regulatory T (Treg) cells are necessary for the maintenance of self-tolerance and T-cell homeostasis. This population is kept at stable frequencies in secondary lymphoid organs for the majority of the lifetime, despite permanent thymic emigration or in the face of thymic involution. Continuous competition is expected to occur between recently thymus-emigrated and resident Treg cells (either natural or post-thymically induced). In the present work, we analysed the renewal dynamics of Treg cells compared with CD4(+) Foxp3- conventional T cells (Tconv), using protocols of single or successive T-cell transfers into syngeneic euthymic or lymphopenic (nu/nu or RAG2(-/-)) mice, respectively. Our results show a higher turnover for Treg cells in the peripheral compartment, compared with Tconv cells, when B cell-sufficient euthymic or nude hosts are studied. This increased renewal within the Treg pool, shown by the greater replacement of resident Treg cells by donor counterparts, correlates with augmented rates of proliferation and is not modified following temporary environmental perturbations induced by inflammatory state or microbiota alterations. Notably, the preferential substitution of Treg lymphocytes was not observed in RAG2(-/-) hosts. We showed that limited B-cell replenishment in the RAG2(-/-) hosts decisively contributed to the altered peripheral T-cell homeostasis. Accordingly, weekly transfers of B cells to RAG2(-/-) hosts rescued the preferential substitution of Treg lymphocytes. Our study discloses a new aspect of T-cell homeostasis that depends on the presence of B lymphocytes to regulate the relative incorporation of recently arrived Treg and Tconv cells in the peripheral compartment.

Metabolic Acidosis Assessment in High-Risk Surgeries: Prognostic Importance.

BACKGROUND: Metabolic acidosis frequently is present in surgical patients; however, different types of metabolic acidosis (hyperlactatemia, hyperchloremia, and others) may have different relationships to perioperative outcomes. We hypothesized that in postoperative surgical patients, distinctive types of metabolic acidosis would correlate differently with the outcomes of high-risk surgeries. METHODS: A prospective, multicenter observational study was performed in 3 different tertiary care hospitals. Patients who required postoperative admission to the intensive care unit (ICU) were included in this study. Patients with a short life expectancy (those with untreated cancer and limited treatment), hepatic failure, renal failure, or a diagnosis of diabetes were excluded. Patients were classified at ICU admission according to the presence and type of metabolic acidosis into 4 groups: those without acidosis, those with a base excess <-4 mmol/L and albumin-corrected anion gap ≤12 mmol/L (hyperchloremic), those with a base excess <-4 mmol/L and increased albumin-corrected anion gap >12 mmol/L, and those with a base excess <-4 mmol/L and hyperlactatemia >2 mmol/L. Furthermore, patients were reclassified 12 hours after admission to the ICU to verify the metabolic acidosis behavior and outcome differences among the groups. RESULTS: The study included 618 patients. The incidence of acidosis at ICU admission was 59.1%; 23.9% presented with hyperchloremia, 21.3% with hyperlactatemia, 13.9% with increased anion gap, and 40.9% of the patients presented without metabolic acidosis. Patients whose metabolic acidosis persisted for 12 hours had an incidence of ICU complications rates in hyperlactatemia group of 68.8%, increased anion gap of 68.6%, hyperchloremic of 65.8%, and those without acidosis over 12 hours of 59.3%. A Cox regression model for postoperative 30-day mortality showed: in hyperlactatemic acidosis, hazard ratio (HR) = 1.74, 95% confidence interval (CI) = 1.02-2.96; increased anion gap acidosis, HR = 1.68, 95% CI = 0.85-3.81; hyperchloremic acidosis, HR = 1.47, 95% CI = 0.75-2.89, and 10.3% of 30-day mortality rate in patients without acidosis. An adjusted survival curve by Cox regression found a worse 30-day survival in the hyperlactatemic group compared with the other groups (P = .03). Furthermore, in multiple comparisons among groups, patients with hyperlactatemic acidosis were more likely to develop renal dysfunction (P < .001) up to the seventh day postoperatively. CONCLUSIONS: We found that among patients with different types of acidosis, patients who developed hyperlactatemic metabolic acidosis postoperatively showed greater rates of renal dysfunction within 7 days and hyperlactatemic acidosis represented an independent factor on 30-day mortality in high-risk surgical patients.

Scrutinizing brain magnetic resonance imaging patterns in Angelman syndrome.

BACKGROUND: Global developmental delay, lack of speech, and severe epilepsy are the characteristic hallmarks of Angelman syndrome (AS). The purpose of this study was to explore the utility of brain magnetic resonance imaging (MRI) as an ancillary tool for the diagnosis of AS. MATERIAL AND METHODS: Brain MRI images of nine laboratory-confirmed patients with AS from a neurorehabilitation center in Rio de Janeiro were reviewed. Each MRI was assessed by a set of two experienced neuroradiologists following a predefined protocol. RESULTS: The main neuroimaging findings revealed in our study were: Thinning of the corpus callosum in five patients; enlargement of lateral ventricles in four patients; and, cerebral atrophy with frontal and temporal predominance in one patient. All patients presented with an increased signal intensity in T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences. CONCLUSION: The lack of specific changes in the brain MRI of children with AS observed in this case series rendered brain MRI a less helpful complementary test. Thus, a definitive diagnosis of AS could only be established on molecular biology that was undertaken based on the clinical suspicion of AS.

Simulating federated learning for steatosis detection using ultrasound images.

We aimed to implement four data partitioning strategies evaluated with four federated learning (FL) algorithms and investigate the impact of data distribution on FL model performance in detecting steatosis using B-mode US images. A private dataset (153 patients; 1530 images) and a public dataset (55 patient; 550 images) were included in this retrospective study. The datasets contained patients with metabolic dysfunction-associated fatty liver disease (MAFLD) with biopsy-proven steatosis grades and control individuals without steatosis. We employed four data partitioning strategies to simulate FL scenarios and we assessed four FL algorithms. We investigated the impact of class imbalance and the mismatch between the global and local data distributions on the learning outcome. Classification performance was assessed with area under the receiver operating characteristic curve (AUC) on a separate test set. AUCs were 0.93 (95% CI 0.92, 0.94) for source-based partitioning scenario with FedAvg, 0.90 (95% CI 0.89, 0.91) for a centralized model, and 0.83 (95% CI 0.81, 0.85) for a model trained in a single-center scenario. When data was perfectly balanced on the global level and each site had an identical data distribution, the model yielded an AUC of 0.90 (95% CI 0.88, 0.92). When each site contained data exclusively from one single class, irrespective of the global data distribution, the AUC fell in the range of 0.34-0.70. FL applied to B-mode US images provide performance comparable to a centralized model and higher than single-center scenario. Global data imbalance and local data heterogeneity influenced the learning outcome.

A proposal for analyzing the inflammatory and remodeling processes of mucosa in chronic rhinosinusitis with nasal polyposis through MRI.

OBJECTIVES: Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) is a disease characterized by chronic inflammation and tissue remodeling process. The remodeling process in nasal polyps has mainly been studied by histology analysis. However, it is limited to a polyp fragment and requires tissue removal. The present study aims to evaluate the ability of Magnetic Resonance Imaging (MRI) to depict and characterize the remodeling process in patients with CRSwNP. METHODS: 30 patients that met clinical diagnostic criteria for CRSwNP, without previous history of rhinosinusitis surgery were submitted to MRI scan (conventional, diffusion-weighted and DCE MRI) and compared with polyp tissue histological findings, IL-6 concentrations in the tissue and eosinophil count in the blood. The examinations were evaluated, independently, by two radiologists blinded to other radiological and histological data. The pathologist, blinded to MRI results, also compared the tissue sample from the most central and the most peripheral portion of the polypoid tissue adjacent to the floor of the nasal fossa. RESULTS: This study demonstrated a characteristic pattern of nasal polyps, whose peripheral portions of nasal polypoid tissue are edematous, whereas the central portions in the middle meatus and in the middle and upper ethmoid are predominantly fibrotic. ADC values found in the most anterior portion of the polyps may be a marker for radiological phenotyping the remodeling process. This non-invasive analysis presented a high degree of agreement in the fibrosis and edema rating by two radiologists and the histological analysis was concordant with the MRI findings. The polyps were characterized as eosinophilic, and no relationship was found between the severity of the eosinophilic inflammatory process or concentration of IL-6 and the remodeling process. CONCLUSION: MRI by using T2-weighted imaging sequence and ADCs values allows tissue characterization and is an effective tool for the differentiation of edematous and fibrotic components in CRSwNP.

Inflammatory Profile of Chronic Rhinosinusitis With Nasal Polyp Patients in Brazil: Multicenter Study.

OBJECTIVES: To determine the inflammatory profile of CRSwNP in Brazil and characterize the subgroups of CRSwNP patients in this population through cluster analysis. STUDY DESIGN: Multicenter cross-sectional study involving 15 centers representing different regions of Brazil. SUBJECTS AND METHODS: Clinical data of 166 patients and 80 controls, aged 18 to 70 years old, number of surgeries for CRS, history of asthma and aspirin sensitivity, and Lund-Mackay scores on CT scans. During nasal endoscopy, we obtained the Lund-Kennedy scores and collected 2 samples of nasal polyps: one for eosinophil and neutrophil tissue counts and one to quantify different cytokines. RESULTS: 79.6% of our patients had 10 or more eosinophils/HPF. CRSwNP groups exhibited significantly lower concentrations of TNF-alpha and significantly higher concentrations of IFN-gamma, CCL11/Eotaxin, CCL24/Eotaxin-2/MPIF-2, and CCL26/Eotaxin-3 versus the control group (Kruskal-Wallis test). Comparison between CRSwNP groups (≥10 vs <10 eosinophils/HPF) showed no difference in cytokine concentration (Mann-Whitney test). Hierarchical clustering and PCA according to cytokine concentrations revealed 2 main Clusters, with a significantly higher concentration of all cytokines in Cluster 1 (n = 35) than in Cluster 2 (n = 121), except IL-6 and IL-33 (Mann-Whitney test). According to ROC curve analysis the best cut-off to differentiate the 2 clusters was 43 eosinophils/HPF. The group with ≥43 presented a higher prevalence of men and a higher Lund-Mackay score (Mann-Whitney test). CONCLUSIONS: CRSwNP patients in Brazil present mixed inflammation, with 2 distinct groups (high and low inflammatory pattern) that can be distinguished by tissue eosinophilia of ≥43 eosinophils/HPF cut-off in nasal polyps.

The effect of excess fluid balance on the mortality rate of surgical patients: a multicenter prospective study.

INTRODUCTION: In some studies including small populations of patients undergoing specific surgery, an intraoperative liberal infusion of fluids was associated with increasing morbidity when compared to restrictive strategies. Therefore, to evaluate the role of excessive fluid infusion in a general population with high-risk surgery is very important. The aim of this study was to evaluate the impact of intraoperative fluid balance on the postoperative organ dysfunction, infection and mortality rate. METHODS: We conducted a prospective cohort study during one year in four ICUs from three tertiary hospitals, which included patients aged 18 years or more who required postoperative ICU after undergoing major surgery. Patients who underwent palliative surgery and whose fluid balance could change in outcome were excluded. The calculation of fluid balance was based on preoperative fasting, insensible losses from surgeries and urine output minus fluid replacement intraoperatively. RESULTS: The study included 479 patients. Mean age was 61.2 ± 17.0 years and 8.8% of patients died at the hospital during the study. The median duration of surgery was 4.0 (3.2 to 5.5) h and the value of the Simplified Acute Physiology Score (SAPS) 3 score was 41.8 ± 14.5. Comparing survivors and non-survivors, the intraoperative fluid balance from non-survivors was higher (1,950 (1,400 to 3,400) mL vs. 1,400 (1,000 to 1,600) mL, P <0.001). Patients with fluid balance above 2,000 mL intraoperatively had a longer ICU stay (4.0 (3.0 to 8.0) vs. 3.0 (2.0 to 6.0), P <0.001) and higher incidence of infectious (41.9% vs. 25.9%, P = 0.001), neurological (46.2% vs. 13.2%, P <0.001), cardiovascular (63.2% vs. 39.6%, P <0.001) and respiratory complications (34.3% vs. 11.6%, P <0.001). In multivariate analysis, the fluid balance was an independent factor for death (OR per 100 mL = 1.024; P = 0.006; 95% CI 1.007 to 1.041). CONCLUSIONS: Patients with excessive intraoperative fluid balance have more ICU complications and higher hospital mortality.

Assessment of macrobenthos diversity and a zoning proposal for Seixas coral reefs (northeastern Brazil).

Coral reefs worldwide are under severe threat due to their inherent fragility and urgent need for conservation. The escalating tourism in coral reefs significantly impacts the marine ecosystem's biodiversity and conservation. This study analyzed the diversity and conservation status of macrobenthos in the Seixas coral reef, located in northeastern Brazil, and proposed a zoning plan. We employed monitoring protocols adapted from the Reef Check Program, the Rapid Assessment Protocol for Atlantic and Gulf Reefs, and the Protocol for Monitoring Coastal Benthic Habitats. Species identification was carried out by analyzing 25 transects, each divided into 1 m2 grids, with photos recorded for each grid, totaling 625 photos. Margalef, Shannon-Weaver, Simpson, and Pielou indices were used to analyze species distribution and diversity. The results indicated Dictyotaceae, Sargassaceae, and Corallinaceae as prevalent families. This research offers decision-makers a snapshot of species distribution in the Seixas coral reefs, providing a non-destructive, efficient methodology for assessing environmental impacts on coastal coral reefs.

Transnasal endoscopy-guided percutaneous access to the sphenopalatine ganglion for neurostimulation in the treatment of primary headache: operative technique and feasibility.

OBJECTIVES: Cluster headache is considered a trigeminal autonomic cephalalgia and may present with characteristic symptoms of sympathetic/parasympathetic activation on the affected side of the face, such as nasal discharge, tearing, and conjunctival injection. Invasive therapies targeting the sphenopalatine ganglion have been performed in these headache syndromes and can have a medication-sparing effect, especially in refractory, difficult-to-manage cases. The gate control theory of pain suggests that electric pulses delivered to nerve tissues can modulate neuronal activity, thus aiding in management of nociceptive or neuropathic pain, and studies have demonstrated the efficacy and safety of sphenopalatine ganglion neurostimulation. Within this context, we sought to assess the feasibility of a new surgical technique for neurostimulation of the sphenopalatine ganglion in a cadaver dissection model. METHODS: The technique was developed through dissection of two cadaver heads. We divided the procedure into two stages: an endonasal endoscopic approach to expose the sphenopalatine ganglion and confirm electrode placement, and a cervicofacial approach to introduce the electrode array and position the internal pulse-generator unit. Computed tomography was performed to confirm implant placement at the end of the procedure. RESULTS: The pulse-generator unit was successfully placed through a retroauricular incision, as is already standard for cochlear implant placement. This should reduce the incidence of perioperative sequelae, especially pain and swelling in the oral region, which are a common complication of previous approaches used for this purpose. Control imaging confirmed proper electrode placement. The device used in this study allows the patient to modulate the intensity of the stimulus, reducing or even obviating the need for drug therapy. CONCLUSION: The novel technique described herein, based on percutaneous access guided by transmaxillary endoscopy, can provide great precision in electrode array positioning and decreased perioperative morbidity, combining the advantages of endoscopic approaches with those of the retroauricular route.

Analysis of marine diversity and anthropogenic pressures on Seixas coral reef ecosystem (northeastern Brazil).

Coral reefs, vital and ecologically significant ecosystems, are among the most jeopardized marine environments in the Atlantic Ocean, particularly along the northeastern coast of Brazil. The persistent lack of effective management and conservation has led to fragmented information on reef use and pressures, hindering the understanding of these ecosystems' health. Major difficulties and challenges include inadequate data, diverse anthropogenic pressures, and the complex interaction between marine species. This study sought to bridge this knowledge gap by conducting a comprehensive analysis of marine diversity and anthropogenic pressures, specifically focusing on Seixas coral reef near João Pessoa city, an area notably impacted by tourism. Utilizing 25 monitoring transects, subdivided into 1 m2 quadrants, the marine diversity was meticulously evaluated through innovative procedures including (a) sedimentological and geochemical field surveys, (b) application of Shannon-Weaver diversity and Simpson dominance indices, (c) cluster analysis, (d) species identification of macroalgae, coral, and fish, and (e) an examination of anthropogenic interactions and pressures on the coral reef. The assessment encompassed three distinct zones: Back Reef, Reef Top, and Fore Reef, and identified a total of 25 species across 15 genera and 10 fish families. The findings revealed the prevalence of brown macroalgae, fish, and coral, with heightened abundance of red macroalgae in the Fore Reef, which also exhibited the greatest diversity (2.816) and dominance (0.894). Original achievements include the identification of specific spatial variations, recognition of the anthropogenic factors leading to ecological changes, and the formulation of evidence-based recommendations. The study concludes that escalating urbanization and burgeoning daily tourist visits to the reef have exacerbated negative impacts on Seixas coral reef's marine ecosystem. These insights underscore the urgent need for strategic planning and resource management to safeguard the reef's biodiversity and ecological integrity.

Multi-proxy assessment of coral reef formation and biotic-abiotic diversity in an urban coastal reef ecosystem in northeastern Brazil.

Coral reefs are habitats with high animal and mineral diversity and are subject to both climate change and anthropogenic impacts. This article presents novel and relevant data on the Seixas coral reef environment's geological, sedimentological, mineralogical, and biotic aspects in Paraíba State, northeastern Brazil. The aim of this study is to evaluate the processes of reef formation and the diversity of coral reef species in urban coastal environments in northeastern Brazil using a multi-proxy approach. Materials and methods employed to analyze the formation and diversity of biotic and abiotic species include (a) bathymetric survey, (b) collection of sedimentological, mineralogical, and granulometric data, (c) geological and stratigraphic determination, and (d) identification of biotic and abiotic species. Mineralogical slide results reveal that the Seixas Reef is a recent biogenic coral-algal carbonate formation associated with coastline evolution, high coastal sedimentation, and changes that occurred alongside sea-level rise (Holocene-Quaternary period). The diversity results indicate that benthic organism settlement occurred on a consolidated arenite base, with the fauna undergoing continuous succession processes. It can be concluded that this coral reef is highly vulnerable due to the material of its formation and comprises subsectors with high diversity (fore reef) and others with low diversity (reef top), which are affected by both anthropogenic and natural factors. Studies of this nature can contribute to understanding the evolution of coastal reefs, as their proximity to the continent makes them more vulnerable, and they experience direct physical impacts from fishing and tourist activities.

Potential Biomarkers of impulsivity in mild traumatic brain injury: A pilot study.

Very few studies have investigated cognition and impulsivity following mild traumatic brain injury (mTBI) in the general population. Furthermore, the neurobiological mechanisms underlying post-TBI neurobehavioral syndromes are complex and remain to be fully clarified. Herein, we took advantage of machine learning based-modeling to investigate potential biomarkers of mTBI-associated impulsivity. Twenty-one mTBI patients were assessed within one-month post-TBI and their data were compared to 19 healthy controls on measures of impulsivity (Barratt Impulsiveness Scale - BIS), executive functioning, episodic memory, self-report cognitive failures and blood biomarkers of inflammation, vascular and neuronal damage. mTBI patients were significantly more impulsive than controls in BIS total and subscales. Serum levels of sCD40L, Cathepsin D, IL-4, Neuropilin-1, IFN-α2, and Copeptin were associated with impulsivity in mTBI patients. Besides showing that mTBI are associated with impulsivity in non-military people, we unveiled different pathophysiological pathways potentially implicated in mTBI-related impulsivity.

Inflammasome activation and assembly in Huntington's disease.

Huntington's disease (HD) is a rare neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Inflammasomes are multiprotein complexes capable of sensing pathogen-associated and damage-associated molecular patterns, triggering innate immune pathways. Activation of inflammasomes results in a pro-inflammatory cascade involving, among other molecules, caspases and interleukins. NLRP3 (nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3) is the most studied inflammasome complex, and its activation results in caspase-1 mediated cleavage of the pro-interleukins IL-1ß and IL-18 into their mature forms, also inducing a gasdermin D mediated form of pro-inflammatory cell death, i.e. pyroptosis. Accumulating evidence has implicated NLRP3 inflammasome complex in neurodegenerative diseases. The evidence in HD is still scant and mostly derived from pre-clinical studies. This review aims to present the available evidence on NLRP3 inflammasome activation in HD and to discuss whether targeting this innate immune system complex might be a promising therapeutic strategy to alleviate its symptoms.

Mature Naive B Cells Regulate the Outcome of Murine Acute Graft-versus-Host Disease in an IL-10-Independent Manner.

Graft-versus-host disease (GVHD) is the main complication of bone marrow transplantation (BMT). CD4+ T lymphocytes are the main effector cells for disease development, but other cell types can determine disease outcome through cytokine production and antigen presentation. B cells are abundant in BMT products and are involved in chronic GVHD immunopathogenesis. However, their role in acute GVHD is still unclear. Here we studied the role of donor resting B cells in a model of acute GVHD. Animals receiving transplants depleted of B cells developed more severe disease, indicating a protective role for B cells. Mice undergoing transplantation with IL-10 knockout B cells developed GVHD as severe as those receiving wild-type B cells. Moreover, mice that received MHC II-deficient B cells, and thus were unable to present antigen to CD4+ T cells, developed as severe GVHD as animals receiving transplants without B cells. This result suggests that the protection provided by mature naive B cells depends on antigen presentation and not on IL-10 production by B cells. Mice who underwent transplantation in the absence of donor B cells exhibited disorganized lymphoid splenic tissue. In addition, donor B cell depletion diminished the follicular T (Tfh)/effector T (Teff) cell ratio, suggesting that protection was correlated with a shift to Tfh differentiation, reducing the number of Teff cells. Importantly, the Tfh/Teff shift impacts disease outcome, with observed proinflammatory cytokine levels and tissue damage in target organs consistent with disease protection. The role of transplanted B cells in the outcome of BMT and the development of acute GVHD merits careful study, given that these cells are abundant in BMT products and are potent modulator and effector cells in the allogeneic response.

Enzyme biomarkers of renal tubular injury in arterial surgery patients.

OBJECTIVE: The aim of this study was to verify whether preoperative diabetes, hypertension, and renal function had any relationship with postoperative tubule function in patients submitted to anesthesia for arterial surgery. METHODS: Prospective observational study. One hundred and forty-four patients submitted to anesthesia for arterial surgery enrolled consecutively and divided into four groups: G1--diabetes and hypertension; G2--diabetes; G3--hypertension; and G4--without hypertension or diabetes. Urine was obtained for laboratory analysis of urinary creatinine (Ucr), alkaline phosphatase (AP), γ-glutamyltransferase (γGT), and blood for cystatin C and creatinine before the surgery (M1) and 24 h after the surgery (M2). RESULTS: Values of γGT, γGT/Ucr, and AP × Î³GT/Ucr increased at M2 in G4. Patients without renal function compromise (GFR ≥90 mL/min/1.73 m(2)) presented increased γGT/Ucr and AP × Î³GT/Ucr values at M2 and those with slightly compromised renal function (60-89 mL/min/1.73 m(2)) presented increased γGT values at M2. There was no correlation between deltaCystatin C and deltaAP, deltaγGT, deltaγGT/Ucr, deltaAP/Ucr, and deltaAP × Î³GT/Ucr. CONCLUSIONS: Diabetes, hypertension, and preoperative renal function seem to interfere in tubular enzymuria immediately after surgery in arteriopathic patients. However, when these markers do not increase in postoperative period, renal dysfunction cannot be discarded.

Chronic nutritional restriction of omega-3 fatty acids induces a pro-inflammatory profile during the development of the rat visual system.

Modern western diets have been associated with a reduced proportion of dietary omega-3 fatty acids leading to decreased levels of DHA (docosahexaenoic acid) in the brain. Low DHA content has been associated with altered development of visual acuity in infants and also with an altered time course of synapse elimination and plasticity in subcortical visual nuclei in rodents. Microglia has an active role in normal developmental processes such as circuitry refinement and plasticity, and its activation status can be modulated by omega-3 (ω3) and omega-6 (ω6) essential fatty acids. In the present study, we investigated the impact of dietary restriction of DHA (ω3-), through the chronic administration of a coconut-based diet as the only fat source. This dietary protocol resulted in a reduction in DHA content in the retina and superior colliculus (SC) and in a neuroinflammatory outcome during the development of the rodent visual system. The ω3- group showed changes in microglial morphology in the retina and SC and a corresponding altered pattern of pro-inflammatory cytokine expression. Early and late fish oil protocols supplementation were able to restore DHA levels. The early supplementation also decreased neuroinflammatory markers in the visual system. The present study indicates that a chronic dietary restriction of omega-3 fatty acids and the resulting deficits in DHA content, commonly observed in Western diets, interferes with the microglial profile leading to an inflamed microenvironment which may underlie a disruption of synapse elimination, altered topographical organization, abnormal plasticity, and duration of critical periods during brain development.

Does the choice of the halogenated anesthetic influence renal function during hemorrhagic shock and resuscitation?

INTRODUCTION: Halogenated anesthetics can cause changes in the variables that modify the cardiac output necessary to maintain renal hemodynamic during hemorrhagic shock and resuscitation. However, halogenated anesthetics seem to protect against renal ischemia-reperfusion injury. In a model of pressure-guided hemorrhagic shock in dogs, we studied the comparative effects of three halogenated anesthetics-halothane, sevoflurane, and isoflurane-at equipotent concentrations on renal responses after resuscitation. METHODS: Thirty dogs were anesthetized with 1.0 minimum alveolar anesthetic concentration (MAC) of halothane, sevoflurane, or isoflurane. The dogs were splenectomized and hemorrhaged to hold mean arterial pressure at 40-50 mm Hg over 45 min and then resuscitated with the shed blood volume. Hemodynamic variables were measured at baseline, after 45 min of hemorrhage, and 15 and 60 min after resuscitation. Renal variables were measured at baseline and 15 and 60 min after resuscitation. RESULTS: Hemorrhage induced reductions of mean arterial pressure, filling pressures, and cardiac index (p < 0.05), without significant differences among groups (p > 0.05). After 60 min of shed blood replacement, all groups restored hemodynamic and renal variables to the prehemorrhage levels (p > 0.05), without significant differences among groups (p > 0.05), with the exception of sodium fractional excretion, the values for which were significantly higher in isoflurane group, in relation to the other groups after 15 min of re-transfusion (p < 0.05), and renal vascular resistance, the values for which remain lower than baseline in halothane group (p < 0.05). CONCLUSIONS: We conclude that no difference could be detected between choosing equipotent doses of halothane, sevoflurane, or isoflurane in relation to renal variables in dogs submitted to pressure-adjusted hemorrhagic shock and resuscitation.