CD147 mediates the CD44s-dependent differentiation of myofibroblasts driven by transforming growth factor-ß1.

Progressive fibrosis leads to loss of organ function and affects many organs as a result of excessive extracellular matrix production. The ubiquitous matrix polysaccharide hyaluronan (HA) is central to this through association with its primary receptor, CD44, which exists as standard CD44 (CD44s) or multiple splice variants. Mediators such as profibrotic transforming growth factor (TGF)-ß1 and proinflammatory interleukin (IL)-1ß are widely associated with fibrotic progression. TGF-ß1 induces myofibroblast differentiation, while IL-1ß induces a proinflammatory fibroblast phenotype that promotes fibroblast binding to monocyte/macrophages. CD44 expression is essential for both responses. Potential CD44 splice variants involved, however, are unidentified. The TGF-ß1-activated CD44/epidermal growth factor receptor complex induces differentiation of metastatic cells through interactions with the matrix metalloproteinase inducer, CD147. This study aimed to determine the CD44 variants involved in TGF-ß1- and IL-1ß-mediated responses and to investigate the potential profibrotic role of CD147. Using immunocytochemistry and quantitative PCR, standard CD44s were shown to be essential for both TGF-ß1-induced fibroblast/myofibroblast differentiation and IL-1ß-induced monocyte binding. Co-immunoprecipitation identified that CD147 associated with CD44s. Using CD147-siRNA and confocal microscopy, we also determined that incorporation of the myofibroblast marker, αSMA, into F-actin stress fibers was prevented in the absence of CD147 and myofibroblast-dependent collagen gel contraction was inhibited. CD147 did not associate with HA, but removal of HA prevented the association of CD44s with CD147 at points of cell-cell contact. Taken together, our data suggest that CD44s/CD147 colocalization is essential in regulating the mechanical tension required for the αSMA incorporation into F-actin stress fibers that regulates myofibroblast phenotype.

Derivation of a prediction model for emergency department acute kidney injury.

BACKGROUND AND OBJECTIVE: Quality management of Acute Kidney Injury (AKI) is dependent on early detection, which is currently deemed to be suboptimal. The aim of this study was to identify combinations of variables associated with AKI and to derive a prediction tool for detecting patients attending the emergency department (ED) or hospital with AKI (ED-AKI). DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: This retrospective observational study was conducted in the ED of a tertiary university hospital in Wales. Between April and August 2016 20,421 adult patients attended the ED of a University Hospital in Wales and had a serum creatinine measurement. Using an electronic AKI reporting system, 548 incident adult ED-AKI patients were identified and compared to a randomly selected cohort of adult non-AKI ED patients (n = 571). A prediction model for AKI was derived and subsequently internally validated using bootstrapping. The primary outcome measure was the number of patients with ED-AKI. RESULTS: In 1119 subjects, 27 variables were evaluated. Four ED-AKI models were generated with C-statistics ranging from 0.800 to 0.765. The simplest and most practical multivariate model (model 3) included eight variables that could all be assessed at ED arrival. A 31-point score was derived where 0 is minimal risk of ED-AKI. The model discrimination was adequate (C-statistic 0.793) and calibration was good (Hosmer & Lomeshow test 27.4). ED-AKI could be ruled out with a score of <2.5 (sensitivity 95%). Internal validation using bootstrapping yielded an optimal Youden index of 0.49 with sensitivity of 80% and specificity of 68%. CONCLUSION: A risk-stratification model for ED-AKI has been derived and internally validated. The discrimination of this model is objective and adequate. It requires refinement and external validation in more generalisable settings.

Acute kidney injury demographics and outcomes: changes following introduction of electronic acute kidney injury alerts-an analysis of a national dataset.

BACKGROUND: Electronic alerts for acute kidney injury (AKI) have been widely advocated. Our aim was to describe the changes in AKI demographics and outcomes following implementation of a national electronic AKI alert programme. METHODS: A prospective national cohort study was undertaken to collect data on all cases of AKI in adult patients (≥18 years of age) between 1 April 2015 and 31 March 2019. RESULTS: Over the period of data collection, there were 193 838 AKI episodes in a total of 132 599 patients. The lowest incidence of AKI was seen in the first year after implementation of electronic alerts. A 30-day mortality was highest in Year 1 and significantly lower in all subsequent years. A direct comparison of mortality in Years 1 and 4 demonstrated a significantly increased relative risk (RR) of death in Year 1: RR = 1.08 [95% confidence interval (CI) 1.054-1.114 P < 0.001]. This translates into a number needed to treat in Year 4 for one additional patient to survive of 69.5 (95% CI 51.7-106.2) when directly comparing the outcomes across the 2 years. The increase in the number of cases and improved outcomes was more pronounced in community-acquired AKI, and was associated with a significant increase in patient hospitalization. CONCLUSIONS: This study represents the first large-scale dataset to clearly demonstrate that a national AKI alerting system which highlights AKI is associated with a change in both AKI demographics and patient outcomes.

Using electronic AKI alerts to define the epidemiology of acute kidney injury in renal transplants.

BACKGROUND: Little is known regarding the impact of acute kidney injury (AKI) on renal transplant outcome. Our aim was to define the incidence and outcome of AKI in renal transplant patients using data collected from a national AKI electronic alert system METHODS: The study represents a prospective national cohort study collecting data on 1224 renal transplants recipients with a functioning renal transplant, between April 2015 and March 2019. RESULTS: Four hundred forty patients experienced at least one episode of AKI giving an incidence rate of 35.4%. Sixty-four point seven% of episodes were AKI stage 1, 7.3% AKI stage 2 and 28% AKI stage 3. Only 6.2% of episodes occurred in the context of rejection. Forty-three point five% of AKI episodes were associated with sepsis. AKI was associated with pre-existing renal dysfunction, and a primary renal diagnosis of diabetic nephropathy. AKI was more prevalent in recipients from a donor after cardiac death (26.4% vs. 21.4%, p < 0.05) compared to the non-AKI cohort. Following AKI, 30-day mortality was 19.8% and overall mortality was 34.8%, compared to 8.4% in the non AKI cohort (RR 4.06, 95% CI 3.1-5.3, p < 0.001). Graft survival (GS), and death censored graft survival (DCGS) censored at 4 years, in the AKI cohort were significantly lower than in the non AKI group (p < 0.0001 for GS and DCGS). CONCLUSION: The study provides a detailed characterisation of AKI in renal transplant recipients highlighting its significant negative impact on patient and graft survival.

Gum Arabic (Acacia Senegal) Augmented Total Antioxidant Capacity and Reduced C-Reactive Protein among Haemodialysis Patients in Phase II Trial.

BACKGROUND: Oxidative processes might increase in patients with end-stage renal disease (ESRD) according to the current literature. Oxidative stress (OS) is a risk factor of atherosclerosis and cardiovascular complications, which are major causes of mortality among ESRD patients. Haemodialysis (HD) is life-saving procedure, nevertheless it is an active chronic inflammatory status that could augment cardiovascular disease and increase mortality. Gum Arabic (GA) has been claimed to act as an antioxidant and anti-inflammatory agent in experimental studies and clinical trials. Therefore, we assumed GA supplementation among haemodialysis patients would reduce oxidative stress and consequently reduce the state of chronic inflammatory activation associated with haemodialysis. METHODS: Forty end-stage renal failure (ESRF) patients aged 18-80 years who were on regular haemodialysis in Arif Renal Center, Omdurman, Sudan, were recruited. All recruited patients met the inclusion criteria and signed informed consent prior to enrolment. The patients received 30 g/day of GA for 12 weeks. C-reactive protein (CRP) and complete blood count (CBC) were measured as baseline and monthly. Total antioxidant capacity (TAC) and oxidative stress marker malondialdehyde (MDA) levels were measured before and after GA intake. Ethical approval from the National Medicines and Poisons Board was obtained. RESULTS: Gum Arabic significantly augmented total antioxidant capacity level (P < 0.001) (95% CI, 0.408-0.625) and also attenuated oxidative marker MDA and C-reactive protein (P < 0.001). CONCLUSIONS: GA has revealed potent antioxidative and anti-inflammatory properties in haemodialysis patients. Oral digestion of GA (30 g/day) decreased oxidative stress and inflammatory markers among haemodialysis patients. Trial registration. ClinicalTrials.gov Identifier: NCT03214692, registered 11 July 2017 (prospective registration).

Hyaluronidase-2 Regulates RhoA Signaling, Myofibroblast Contractility, and Other Key Profibrotic Myofibroblast Functions.

Hyaluronidase (HYAL)-2 is a weak, acid-active, hyaluronan-degrading enzyme broadly expressed in somatic tissues. Aberrant HYAL2 expression is implicated in diverse pathology. However, a significant proportion of HYAL2 is enzymatically inactive; thus the mechanisms through which HYAL2 dysregulation influences pathobiology are unclear. Recently, nonenzymatic HYAL2 functions have been described, and nuclear HYAL2 has been shown to influence mRNA splicing to prevent myofibroblast differentiation. Myofibroblasts drive fibrosis, thereby promoting progressive tissue damage and leading to multimorbidity. This study identifies a novel HYAL2 cytoplasmic function in myofibroblasts that is unrelated to its enzymatic activity. In fibroblasts and myofibroblasts, HYAL2 interacts with the GTPase-signaling small molecule ras homolog family member A (RhoA). Transforming growth factor beta 1-driven fibroblast-to-myofibroblast differentiation promotes HYAL2 cytoplasmic relocalization to bind to the actin cytoskeleton. Cytoskeletal-bound HYAL2 functions as a key regulator of downstream RhoA signaling and influences profibrotic myofibroblast functions, including myosin light-chain kinase-mediated myofibroblast contractility, myofibroblast migration, myofibroblast collagen/fibronectin deposition, as well as connective tissue growth factor and matrix metalloproteinase-2 expression. These data demonstrate that, in certain biological contexts, the nonenzymatic effects of HYAL2 are crucial in orchestrating RhoA signaling and downstream pathways that are important for full profibrotic myofibroblast functionality. In conjunction with previous data demonstrating the influence of HYAL2 on RNA splicing, these findings begin to explain the broad biological effects of HYAL2.

Acute Kidney Injury in Children Based on Electronic Alerts.

OBJECTIVE: To define the incidence and outcome of acute kidney injury (AKI) in pediatrics using data collected from a national electronic alert system. STUDY DESIGN: A prospective national cohort study was undertaken to collect data on all cases of pediatric AKI, excluding neonates, identified by an e-alert, from April 2015 to March 2019. RESULTS: There were 2472 alerts in a total of 1719 patients, giving an incidence of 77.3 per 100 000 person-years. Of the patients, 84.2% of all AKI were stage 1 and 58.3% occurred with a triggering creatinine within the reference range. The incidence of AKI was associated with measures of social deprivation. Thirty-day mortality was 1.7% but was significantly higher in hospital-acquired AKI (2.1%), compared with community-acquired AKI (0.8%, P < .001) and was associated with the severity of AKI at presentation. A significant proportion of patients had no repeat measure of creatinine (39.8%). This was higher in community-acquired AKI (69.7%) compared with hospital-acquired AKI (43.0%, P < .001), and higher in patients alerting with patients triggering with a creatinine within the reference range (48.4% vs 24.5%, P < .001). The majority of patients (84.7%) experienced only 1 AKI episode. Repeated episodes of AKI were associated with increased 30-mortaltiy (11.6% vs 4.6%, P < .001) and higher residual renal impairment (13.3% vs 5.4%, P < .001). CONCLUSIONS: The results suggest that the significance of the alert is missed in many cases reflecting that a large proportion of cases represent modest elevations in serum creatinine (SCr), triggered by a SCr level that may be interpreted as being normal despite a significant increase from the baseline for the patient.

Recurrent acute kidney injury: predictors and impact in a large population-based cohort.

BACKGROUND: This study examined the impact of recurrent episodes of acute kidney injury (AKI) on patient outcomes. METHODS: The Welsh National electronic AKI reporting system was used to identify all cases of AKI in patients ≥18 years of age between April 2015 and September 2018. Patients were grouped according to the number of AKI episodes they experienced with each patient's first episode described as their index episode. We compared the demography and patient outcomes of those patients with a single AKI episode with those patients with multiple AKI episodes. Analysis included 153 776 AKI episodes in 111 528 patients. RESULTS: Of those who experienced AKI and survived their index episode, 29.3% experienced a second episode, 9.9% a third episode and 4.0% experienced fourth or more episodes. Thirty-day mortality for those patients with multiple episodes of AKI was significantly higher than for those patients with a single episode (31.3% versus 24.9%, P < 0.001). Following a single episode, recovery to baseline renal function at 30 days was achieved in 83.6% of patients and was significantly higher than for patients who had repeated episodes (77.8%, P < 0.001). For surviving patients, non-recovery of renal function following any AKI episode was significantly associated with a higher probability of a further AKI episode (33.4% versus 41.0%, P < 0.001). Furthermore, with each episode of AKI the likelihood of a subsequent episode also increased (31.0% versus 43.2% versus 51.2% versus 51.7% following a first, second, third and fourth episode, P < 0.001 for all comparisons). CONCLUSIONS: The results of this study provide an important contribution to the debate regarding the need for risk stratification for recurrent AKI. The data suggest that such a tool would be useful given the poor patient and renal outcomes associated with recurrent AKI episodes as highlighted by this study.

Epidemiology of emergency department acute kidney injury.

AIM: The epidemiology of acute kidney injury (AKI) diagnosed in the emergency department (ED) is poorly described. This study describes the incidence, demographics and outcomes of patients diagnosed with AKI in the ED (ED-AKI). METHODS: A prospective cohort study was completed in a University Teaching Hospital, (UK) between April and August 2016. In total, 20 421 adult patients attended the ED and had a serum creatinine measurement. The incident ED-AKI patient episodes were compared with a randomly selected cohort of non-AKI ED patients. RESULTS: A total of 572 patients had confirmed eAlert ED-AKI (548 incident cases), incidence 2.8% (of all ED attendances). ED-AKI was associated with a 24.4% in-patient mortality (non-AKI 3.2%, P < .001) of which 22.3% of deaths occurred within 24 hours and 58% within 7 days. Progression of the admission AKI stage to a higher AKI stage was associated with a 38.8% mortality compared with a 21.4% mortality in those who did not progress (P < .001). In multivariate analysis, ED-AKI was an independent risk for mortality (hazard ratio, 6.293; 95% confidence interval, 1.887-20.790, P = .003). For those discharged from hospital, 20.4% of ED-AKI patients re-attend for acute assessment within 30-days post-discharge (non-AKI 7.6%, P < .001). At 90-days post-discharge, 10.0% of ED-AKI patients died (non-AKI 1.4%, P < .001). Twelve months post-discharge 17.8% of ED-AKI patients developed CKD progression or de-novo CKD (non-AKI 6.0%). CONCLUSION: The ED-AKI is an independent predictor of death. Mortality is predominantly in the early stages of hospital admission, but for those who survive to discharge have significant long-term morbidity and mortality.

Structural Characterization and Chain Conformation of Water-Soluble ß-Glucan from Wild Cordyceps sinensis.

Water-soluble ß-d-glucan was obtained from wild Cordyceps sinensis by alkali solution and ethanol precipitation. The structure characteristics were determined using high-performance anion-exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD), methylation combined with gas chromatography-mass spectrometry, and one-/two-dimensional nuclear magnetic resonance spectroscopy. Results showed that ß-d-glucan had a structure of every seven (1→3)-ß-d-Glcp backbone residues with two (1→6)-ß-d-Glcp branches. Additionally, conformation properties in different solvents were investigated by static light scattering, dynamic light scattering, and HPSEC with multiple detectors. It was found that ß-d-glucan in 0.5 M NaOH had a narrow unimodal distribution of hydrodynamic radius displaying a spherical coil conformation, whereas it formed severe aggregation in dimethyl sulfoxide. In 0.1 M NaNO3, ß-d-glucan mainly existed as a rod-like conformation corresponding to a helical structure together with small aggregates (10%). This work added more information to the understanding of C. sinensis polysaccharides.

Acute Kidney Injury, Age, and Socioeconomic Deprivation: Evaluation of a National Data Set.

INTRODUCTION: This study examined the relationship among age, measures of social deprivation, and incidence and outcome of acute kidney injury (AKI). METHODS: The Welsh National electronic AKI reporting system was used to identify all cases of AKI in patients 18 years or older between March 2015 and January 2017. Socioeconomic classification of patients was derived from the Welsh Index of Multiple Deprivation (WIMD). Patients were grouped according to their WIMD score, and Multivariate Cox proportional hazard modeling was used to adjust the data for age. The ranked data were categorized into percentiles and correlated with incidence, and measures of AKI severity and outcome. RESULTS: Analysis included 57,654 patients. For the whole cohort, the highest 90-day survival was associated with the most socially deprived cohorts. There was a significant negative relationship between age-adjusted incidence of AKI and the WIMD score. In patients 60 years or older, there was an inverse correlation between WIMD score and survival that was not evident in those younger than 60. AKI severity at presentation was worse in patients from areas of social deprivation. Social deprivation was associated with a significantly higher proportion of preexisting chronic kidney disease (CKD) in patients with AKI older than 60, but not in those younger than 60. CONCLUSION: Overall mortality following AKI was higher in least-deprived areas, reflecting an older patient cohort. In contrast, social deprivation was associated with higher age-adjusted AKI incidence and age-adjusted mortality following AKI. The excess mortality observed in more deprived areas was associated with more severe AKI and a higher proportion of preexisting CKD.

Utility of electronic AKI alerts in intensive care: A national multicentre cohort study.

BACKGROUND: Electronic AKI alerts highlight changes in serum creatinine compared to the patient's own baseline. Our aim was to identify all AKI alerts and describe the relationship between electronic AKI alerts and outcome for AKI treated in the Intensive Care Unit (ICU) in a national multicentre cohort. METHODS: A prospective cohort study was undertaken between November 2013 and April 2016, collecting data on electronic AKI alerts issued. RESULTS: 10% of 47,090 incident AKI alerts were associated with ICU admission. 90-day mortality was 38.2%. Within the ICU cohort 48.8% alerted in ICU. 51.2% were transferred to ICU within 7days of the alert, of which 37.8% alerted in a hospital setting (HA-AKI) and 62.2% in a community setting (CA-AKI). Mortality was higher in patients transferred to ICU following the alert compared to those who had an incident alert on the ICU (p<0.001), and was higher in HA-AKI (45.3%) compared to CA-AKI (39.5%) (35.0%, p=0.01). In the surviving patients, the proportion of patient recovering renal function following, was significantly higher in HA-AKI alerting (84.2%, p=0.004) and CA-AKI alerting patients (87.6%, p<0.001) compared to patients alerting on the ICU (78.3%). CONCLUSION: The study provides a nationwide characterisation of AKI in ICU highlighting the high incidence and its impact on patient outcome. The data also suggests that within the cohort of AKI patients treated in the ICU there are significant differences in the presentation and outcome between those patients that require transfer to the ICU after AKI is identified and those who develop AKI following ICU admission. Moreover, the study demonstrates that using AKI e-alerts provides a centralised resource which does not rely on clinical diagnosis of AKI or coding, resulting in a robust data set which can be used to define the incidence and outcome of AKI in the ICU setting.

Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype.

The cell surface protein CD44 is involved in diverse physiological processes, and its aberrant function is linked to various pathologies such as cancer, immune dysregulation, and fibrosis. The diversity of CD44 biological activity is partly conferred by the generation of distinct CD44 isoforms through alternative splicing. We identified an unexpected function for the ubiquitous hyaluronan-degrading enzyme, hyaluronidase 2 (HYAL2), as a regulator of CD44 splicing. Standard CD44 is associated with fibrotic disease, and its production is promoted through serine-arginine-rich (SR) protein-mediated exon exclusion. HYAL2 nuclear translocation was stimulated by bone morphogenetic protein 7, which inhibits the myofibroblast phenotype. Nuclear HYAL2 displaced SR proteins from the spliceosome, thus enabling HYAL2, spliceosome components (U1 and U2 small nuclear ribonucleoproteins), and CD44 pre-mRNA to form a complex. This prevented double-exon splicing and facilitated the inclusion of CD44 exons 11 and 12, which promoted the accumulation of the antifibrotic CD44 isoform CD44v7/8 at the cell surface. These data demonstrate previously undescribed mechanisms regulating CD44 alternative splicing events that are relevant to the regulation of cellular phenotypes in progressive fibrosis.

Understanding Electronic AKI Alerts: Characterization by Definitional Rules.

INTRODUCTION: Automated acute kidney injury (AKI) electronic alerts are based on comparing creatinine with historic results. METHODS: We report the significance of AKI defined by 3 "rules" differing in the time period from which the baseline creatinine is obtained, and AKI with creatinine within the normal range. RESULTS: A total of 47,090 incident episodes of AKI occurred between November 2013 and April 2016. Rule 1 (>26 µmol/l increase in creatinine within 48 hours) accounted for 9.6%. Rule 2 (≥50% increase in creatinine within previous 7 days) and rule 3 (≥50% creatinine increase from the median value of results within the last 8-365 days) accounted for 27.3% and 63.1%, respectively. Hospital-acquired AKI was predominantly identified by rules 1 and 2 (71.7%), and community-acquired AKI (86.3%) by rule 3. Stages 2 and 3 were detected by rules 2 and 3. Ninety-day mortality was higher in AKI rule 2 (32.4%) than rule 1 (28.3%, P < 0.001) and rule 3 (26.6%, P < 0.001). Nonrecovery of renal function (90 days) was lower for rule 1 (7.9%) than rule 2 (22.4%, P < 0.001) and rule 3 (16.5%, P < 0.001). We found that 19.2% of AKI occurred with creatinine values within normal range, in which mortality was lower than that in AKI detected by a creatinine value outside the reference range (22.6% vs. 29.6%, P < 0.001). DISCUSSION: Rule 1 could only be invoked for stage 1 alerts and was associated with acute on chronic kidney disease acquired in hospital. Rule 2 was also associated with hospital-acquired AKI and had the highest mortality and nonrecovery. Rule 3 was the commonest cause of an alert and was associated with community-acquired AKI.

Seasonal pattern of incidence and outcome of Acute Kidney Injury: A national study of Welsh AKI electronic alerts.

OBJECTIVES: To identify any seasonal variation in the occurrence of, and outcome following Acute Kidney Injury. METHODS: The study utilised the biochemistry based AKI electronic (e)-alert system established across the Welsh National Health Service to collect data on all AKI episodes to identify changes in incidence and outcome over one calendar year (1st October 2015 and the 30th September 2016). RESULTS: There were total of 48 457 incident AKI alerts. The highest proportion of AKI episodes was seen in the quarter of January to March (26.2%), and the lowest in the quarter of October to December (23.3%, P < .001). The same trend was seen for both community-acquired and hospital-acquired AKI sub-sets. Overall 90 day mortality for all AKI was 27.3%. In contrast with the seasonal trend in AKI occurrence, 90 day mortality after the incident AKI alert was significantly higher in the quarters of January to March and October to December compared with the quarters of April to June and July to September (P < .001) consistent with excess winter mortality reported for likely underlying diseases which precipitate AKI. CONCLUSIONS: In summary we report for the first time in a large national cohort, a seasonal variation in the incidence and outcomes of AKI. The results demonstrate distinct trends in the incidence and outcome of AKI.

The incidence of pediatric acute kidney injury is increased when identified by a change in a creatinine-based electronic alert.

A prospective national cohort study was undertaken to collect data on all cases of pediatric (under 18 yrs of age) acute kidney injury (AKI) identified by a biochemistry-based electronic alert using the Welsh National electronic AKI reporting system. Herein we describe the utility and limitation of using this modification of the KDIGO creatinine-based system data set to characterize pediatric AKI. Of 1,343 incident episodes over a 30-month period, 34.5% occurred in neonates of which 83.8% were AKI stage 1. Neonatal 30-day mortality was 4.1%, with 73.3% of this being accounted for by patients treated in an Intensive Care Unit. In the non-neonatal group, 76.1% were AKI stage 1. Hospital-acquired AKI accounted for 40.1% of episodes while community-acquired AKI represented 29.4% of cases within which 33.9% were admitted to hospital and 30.5% of cases were unclassified. Non-neonatal 30-day mortality was 1.2%, with half of this accounted for by patients treated in the Intensive Care Unit. Nonrecovery of renal function at 30 days occurred in 28% and was significantly higher in patients not admitted to hospital (45% vs. 20%). The reported incidence of AKI in children was far greater than previously reported in studies reliant on clinical identification of adult AKI or hospital coding data. Mortality was highest in neonates and driven by those in the Intensive Care Unit. Nonrecovery of renal function and persistent renal impairment was more common in non-neonates and was especially high in patients with community-acquired AKI who were not hospitalized.

Comparison of structural features and antioxidant activity of polysaccharides from natural and cultured Cordyceps sinensis.

Four polysaccharides (named as P1, P2, and P3 from three natural Cordyceps sinensis and P4 from cultured C. sinensis) were obtained by hot-water extraction and ethanol precipitation and their structural characteristics as well as antioxidant potentials were compared. Results revealed that the backbone of P1, P2, and P3 comprised α-1,4-glucose, with a branching point mainly at position 6 and terminating at glucose. On the other hand, the structure of P4 was highly complex, mainly comprising glucose, galactose, and mannose, with 1,4-glucose and 1,4-galactose as the main chain. For in vitro antioxidant assays, all the four polysaccharides showed similar scavenging capacity against DPPH and hydroxyl radicals, whereas P1 had a relatively low ferric reducing ability, possibly related to a combination of factors such as the phenolic compounds and amino acids that conjugated in polysaccharides.

Acute Kidney Injury in the Era of the AKI E-Alert.

BACKGROUND AND OBJECTIVES: Our aim was to use a national electronic AKI alert to define the incidence and outcome of all episodes of community- and hospital-acquired adult AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective national cohort study was undertaken in a population of 3.06 million. Data were collected between March of 2015 and August of 2015. All patients with adult (≥18 years of age) AKI were identified to define the incidence and outcome of all episodes of community- and hospital-acquired AKI in adults. Mortality and renal outcomes were assessed at 90 days. RESULTS: There was a total of 31,601 alerts representing 17,689 incident episodes, giving an incidence of AKI of 577 per 100,000 population. Community-acquired AKI accounted for 49.3% of all incident episodes, and 42% occurred in the context of preexisting CKD (Chronic Kidney Disease Epidemiology Collaboration eGFR); 90-day mortality rate was 25.6%, and 23.7% of episodes progressed to a higher AKI stage than the stage associated with the alert. AKI electronic alert stage and peak AKI stage were associated with mortality, and mortality was significantly higher for hospital-acquired AKI compared with alerts generated in a community setting. Among patients who survived to 90 days after the AKI electronic alert, those who were not hospitalized had a lower rate of renal recovery and a greater likelihood of developing an eGFR<60 ml/min per 1.73 m2 for the first time, which may be indicative of development of de novo CKD. CONCLUSIONS: The reported incidence of AKI is far greater than the previously reported incidence in studies reliant on clinical identification of adult AKI or hospital coding data. Although an electronic alert system is Information Technology driven and therefore, lacks intelligence and clinical context, these data can be used to identify deficiencies in care, guide the development of appropriate intervention strategies, and provide a baseline against which the effectiveness of these interventions may be measured.

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor ß1 (TGFß1)-dependent Fibroblast to Myofibroblast Differentiation.

Fibroblasts are central to wound healing and fibrosis through TGFß1-triggered differentiation into contractile, α-smooth muscle actin (α-SMA)-positive myofibroblasts. This is mediated by accumulation of a pericellular matrix of hyaluronan (HA) and the HA-dependent co-localization of CD44 with the epidermal growth factor receptor (EGFR). Interactions of HA with hyaladherins, such as inter-α-inhibitor (IαI) and tumor necrosis factor-stimulated gene-6 (TSG-6), are also essential for differentiation. This study investigated the mechanisms involved. TSG-6 and α-SMA had different kinetics of induction by TGFß1, with TSG-6 peaking before α-SMA Si CD44 or EGFR inhibition prevented differentiation but had no effect on TSG-6 expression. TSG-6 was essential for differentiation, and mAb A38 (preventing IαI heavy chain (HC) transfer), HA-oligosaccharides, cobalt, or Si bikunin prevented TSG-6 activity, preventing differentiation. A38 also prevented the EGFR/CD44 association. This suggested that TSG-6/IαI HC interaction was necessary for the effect of TSG-6 and that HC stabilization of HA initiated the CD44/EGFR association. The newly described HC5 was shown to be the principal HC expressed, and its cell surface expression was prevented by siRNA inhibition of TSG-6 or bikunin. HC5 was released by hyaluronidase treatment, confirming its association with cell surface HA. Finally, HC5 knockdown by siRNA confirmed its role in myofibroblast differentiation. The current study describes a novel mechanism linking the TSG-6 transfer of the newly described HC5 to the HA-dependent control of cell phenotype. The interaction of HC5 with cell surface HA was essential for TGFß1-dependent differentiation of fibroblasts to myofibroblasts, highlighting its importance as a novel potential therapeutic target.

17ß-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation.

Age-related defects in fibroblast differentiation and functionality were previously shown to be associated with impaired hyaluronan (HA) synthase 2 (HAS2) and epidermal growth factor receptor (EGFR) function, as a result of upregulated microRNA-7 (miR-7) expression. In aging fibroblasts, inhibiting miR-7 prevented the dysregulation of the HA-mediated CD44/EGFR signaling pathway. Here, we investigated transcriptional upregulation of miR-7 and implicated the age-associated over-activation of JAK/STAT1 as a primary candidate. STAT1 binding sites were identified on the putative miR-7 promoter and stimulation of fibroblasts with the inflammatory cytokine, interferon-γ (IFN-γ), significantly increased miR-7 transcriptional activity and resulted in upregulated miR-7 and loss of EGFR. Additionally, we demonstrated a role for the anti-inflammatory steroid, 17ß-estradiol (E2), in the attenuation of miR-7 expression. E2 stimulation promoted estrogen receptor (ER) interactions with the miR-7 putative promoter and suppressed miR-7 expression. E2 also attenuated STAT1 expression and activity. Furthermore, treatments with E2 restored fibroblast functionality, including proliferation, migration and differentiation, key events in effective wound healing. In light of our findings, we propose that the regulation of miR-7 by pro- and anti-inflammatory mediators plays a wider role than previously thought. The modulation of fibroblast functions and ultimately wound healing by miR-7 activators or inhibitors could provide realistic targets for the restoration of chronic wound healing capabilities in the elderly.