Novel KCNQ2 channel activators discovered using fluorescence-based and automated patch-clamp-based high-throughput screening techniques.

AIM: To establish an improved, high-throughput screening techniques for identifying novel KCNQ2 channel activators. METHODS: KCNQ2 channels were stably expressed in CHO cells (KCNQ2 cells). Thallium flux assay was used for primary screening, and 384-well automated patch-clamp IonWorks Barracuda was used for hit validation. Two validated activators were characterized using a conventional patch-clamp recording technique. RESULTS: From a collection of 80 000 compounds, the primary screening revealed a total of 565 compounds that potentiated the fluorescence signals in thallium flux assay by more than 150%. When the 565 hits were examined in IonWorks Barracuda, 38 compounds significantly enhanced the outward currents recorded in KCNQ2 cells, and were confirmed as KCNQ2 activators. In the conventional patch-clamp recordings, two validated activators ZG1732 and ZG2083 enhanced KCNQ2 currents with EC50 values of 1.04±0.18 µmol/L and 1.37±0.06 µmol/L, respectively. CONCLUSION: The combination of thallium flux assay and IonWorks Barracuda assay is an efficient high-throughput screening (HTS) route for discovering KCNQ2 activators.

The Differences in the Epidemiology and Predictors of Death between Candidemia Acquired in Intensive Care Units and Other Hospital Settings.

OBJECTIVE: The burden of candidemia is shifting from intensive care units (ICU) to non-ICU settings. This study aimed to define the differences in epidemiology and predictors of death between ICU-acquired candidemia (ICUAC) and non-ICUAC. METHODS: We conducted a retrospective study of 80 patients with ICUAC and 147 patients with non-IUCAC at five hospitals. RESULTS: The distribution of Candida species and resistance to antifungal agents did not differ between the ICUAC and non-ICUAC groups. ICUAC patients received more echinocandins and less triazoles, as well as more adequate antifungal therapy than non-ICUAC patients (all p<0.05). ICUAC patients had a significantly higher average acute physiology and chronic health evaluation (APACHE) II score (21.0±7.9 vs. 17.8±8.6; p<0.01), Sequential Organ Failure Assessment score (9.2±5.5 vs. 7.4±3.9; p<0.05) and day-90 mortality rate (52.5% vs. 36.7%; p<0.05) when compared to non-ICUAC patients. Using a multivariate logistic analysis, adequate antifungal therapy was found to be the only protective factor for death in both groups. Respiratory failure supported with invasive mechanical ventilation, renal failure supported with replacement therapy and an APACHE II score ≥20 were independent predictors of death in ICUAC patients, while age ≥60 years, concurrent bacteremia and APACHE II score ≥20 were independent predictors of death in non-ICUAC patients. CONCLUSION: The Candida species and antifungal resistance profiles in patients with ICUAC were similar to non-ICUAC patients, but led to worse outcomes. The protective and risk factors for death may therefore be relevant for the clinical management of patients with candidemia in ICU and non-ICU settings.

Antibiotics exposure, risk factors, and outcomes with Candida albicans and non-Candida albicans candidemia. Results from a multi-center study.

OBJECTIVE: To define the differences in antibiotics exposure, risk factors, and outcome in hospitalized patients with Candida albicans (C. albicans) and non-C. albicans candidemia. METHODS: This is a multi-center retrospective study of 132 patients with candidemia from 5 tertiary-care educational hospitals in Shandong, China conducted between January 2009 and June 2010. Fifty-six of 132 (42.4%) patients had candidemia due to C. albicans and 76/132 (57.6%) had non-C. albanians candidemia. RESULTS: Patients with non-C. albicans candidemia received anti-anaerobic agents more often (23.7% versus 8.9%; p=0.027) and beta-lactam/beta-lactamase inhibitors less often (34.2% versus 51.8%; p=0.043) than those with C. albicans candidemia. Independent risk factors of non-C. albicans candidemia were prior anti-anaerobic and antifungal therapies and central venous catheter placement. Overall, 30-day mortality was higher for patients with C. albicans than non-C. albicans candidemia (50% versus 31.6%; p=0.032). Multivariate logistic regression analysis revealed that C. albicans candidemia, advanced age, and concomitant bacteremia were associated with death due to candidemia. CONCLUSION: Patients who received anti-anaerobic or antifungal agents were likely to develop non-C. albicans candidemia. Candida albicans infection was associated with poorer prognosis. An awareness of these factors is needed to guide therapy and decrease the high mortality of candidemia.

[Use of the AKIN criteria to assess the incidence of acute renal injury, outcome and prognostic factors of ICU mortality in critically ill patients].

OBJECTIVE: To evaluate the value of the AKIN criteria of acute kidney injury (AKI) in the incidence and prognoses in critically ill patients, and to further identify risk factors associated with the prognoses of the critically ill patients. METHODS: We retrospectively studied 544 adult patients hospitalized for ≥24 h to a comprehensive ICU with 16 beds in teaching hospital from January 2008 to December 2009. Based on AKIN criteria, these patients were classified into four groups: NAKI (no AKI), AKII, AKIII, and AKIIII respectively. RESULTS: (1) Of the patients, 191 (35.5%) fulfilled the criteria for AKI (14.8% had AKI I 8.2% had AKI II and 11.9% had AKIIII). (2) Mortality in the ICU was much higher in patients with AKI than in patients with no AKI (48% vs 11%, OR 7.48, 95%CI 4.831-11.587, P<0.001). The mortality rate was 37% for AKII group, 51% for AKIII group and 60% for AKIIII group. (3) In multivariate analysis, each AKIN category was independently associated with ICU mortality. The other independent risk factors for ICU mortality included internal medical diseases, septic shock, pre-existing chronic illness, APACHEII score, the number of failed organs, mechanical ventilation and CRRT. CONCLUSIONS: The AKIN category closely relates to the prognoses in critically ill patients, even the mild degree of AKI with a much higher mortality rate than the patients without AKI. The AKIN criteria has some direction significance to the early detection and classification of AKI and to the prediction of clinical outcomes in critically ill patients.