Radiation induces cell cycle arrest and/or cell death in mammalian cells. In the present study, we show that Hip2, a ubiquitin-conjugating enzyme, can overcome radiation-induced G2/M cell cycle ...arrest and trigger the entry into mitosis. Ionizing radiation increased the levels of Hip2 by preventing its degradation but not its gene transcription. The stability of Hip2 in irradiated cells was further confirmed using live cell fluorescence imaging. Flow cytometric and molecular analyses revealed that Hip2 abrogated radiation-induced G2/M arrest, promoting entry into mitosis. Bimolecular fluorescence complementation assays and co-immunoprecipitation experiments showed that Hip2 interacted with and targeted p53 for degradation via the ubiquitin proteasome system, resulting in the activation of cdc2-cyclin B1 kinase to promote mitotic entry. These results contribute to our understanding of the mechanisms that regulate cell cycle progression and DNA damage-induced G2/M checkpoint cellular responses.
•Hip2 can overcome radiation-induced G2/M cell cycle arrest and trigger the entry into mitosis.•Hip2 interacted with p53.•Hip2 targeted p53 for degradation via the ubiquitin proteasome system.
Pharmacokinetic-pharmacodynamic (PK/PD) targets of vancomycin therapy have been recognized for methicillin-resistant Staphylococcus aureus infections but not for other gram-positive bacterial ...infections. Therefore, we investigated whether vancomycin concentration targets such as the trough level and ratio of the area under the curve to minimum inhibitory concentration (AUC/MIC) are associated with the treatment outcome in enterococcal bacteremia. A retrospective cohort analysis enrolled patients with bacteremia caused by vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis who were treated with vancomycin from January 2007 to December 2017 at a tertiary hospital located in Seoul, South Korea. Patients without vancomycin concentrations were excluded from the study. The primary outcome was 28-day all-cause mortality. A total of 37 patients were enrolled--26 with E. faecium infection and 11 with E. faecalis infection. The 28-day all-cause mortality rate was 21.6 %. In univariate analysis, vancomycin trough level (less than or equai to 15 microg/mL; p = 0.042), age (p = 0.044), and septic shock (p = 0.049) were associated with 28-day mortality but not AUC24/MIC (> 389; p = 0.479). In multivariate analysis, vancomycin trough concentration (less than or equai to 15 microg/mL; p = 0.041) and younger age (p = 0.031) were associated with 28-day mortality in patients with enterococcal bacteremia. In this study, a vancomycin trough level of 15 microg/mL or lower was associated with 28-day mortality in enterococcal bacteremia. However, relatively large prospective studies are needed to examine the efficacy of vancomycin PK/PD parameters in patients with enterococcal bacteremia.
Transcranial focused ultrasound (tFUS) is a promising technique of non-invasive brain stimulation for modulating neuronal activity with high spatial specificity. The medial prefrontal cortex (mPFC) ...has been proposed as a potential target for neuromodulation to prove emotional and sleep qualities. We aim to set up an appropriate clinical protocol for investigating the effects of tFUS stimulation of the bilateral mPFC for modulating the function of the brain-wide network using different sonication parameters. Seven participants received 20 min of 250 kHz tFUS to the bilateral mPFC with excitatory (70% duty cycle with sonication interval at 5 s) or suppressive (5% duty cycle with no interval) sonication protocols, which were compared to a sham condition. By placing the cigar-shaped sonication focus on the falx between both mPFCs, it was possible to simultaneously stimulate the bilateral mPFCs. Brain activity was analyzed using continuous electroencephalographic (EEG) recording during, before, and after tFUS. We investigated whether tFUS stimulation under the different conditions could lead to distinctive changes in brain activity in local brain regions where tFUS was directly delivered, and also in adjacent or remote brain areas that were not directly stimulated. This kind of study setting suggests that dynamic changes in brain cortical responses can occur within short periods of time, and that the distribution of these responses may differ depending on local brain states and functional brain architecture at the time of tFUS administration, or perhaps, at least temporarily, beyond the stimulation time. If so, tFUS could be useful for temporarily modifying regional brain activity, modulating functional connectivity, or reorganizing brain functions associated with various neuropsychiatric diseases, such as insomnia and depression.
Pulmonary tuberculosis (TB) is a known risk factor for lung cancer. However, a detailed analysis of lung cancer type, age, sex, smoking, and TB burden associated with geographic and socioeconomic ...status has not been performed previously. We systematically appraised relevant observational studies reporting an association between pulmonary TB and lung cancer. All studies were included in the primary analysis, and studies that used robust TB diagnostic methods, such as validated medical diagnostic codes, were included in the secondary analysis. Thirty-two articles were included. The association between the history of pulmonary TB and diagnosis of lung cancer was statistically significant (OR 2.09, 95% CI: 1.62-2.69,
< 0.001). There was a high heterogeneity (
= 95%), without any publication bias. The analysis indicated a high association in advanced articles describing stringent pulmonary TB diagnosis (OR 2.26, 95% CI: 1.29-3.94,
= 0.004). The subgroup analyses suggested a significant association in countries with medium or high TB burdens, from East Asia and the Pacific region, and upper-middle income countries. Heterogeneity within the subgroups remained high in a majority of the subgroup analyses. A meta-regression analysis revealed that younger patients showed a significantly higher association between TB and lung cancer (regression coefficient = 0.949,
< 0.001). The history of pulmonary TB is an independent risk factor for lung cancer, especially in younger patients diagnosed with pulmonary TB. Clinicians should be aware of this association while treating young patients with a history of pulmonary TB.
Abstract
Alzheimer’s disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene ...expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.
Aims
To evaluate the efficacy and safety of mirabegron in males with overactive bladder (OAB) symptoms.
Methods
In total, 464 males with OAB symptoms were enrolled from 14 institutes and were sorted ...into either the mirabegron 50 mg (n = 310) or placebo (n = 154) groups. The change in (i) the mean number of 24‐h micturition episodes; (ii) OAB Symptom Scale (OABSS); and (iii) International Prostate Symptom Score (IPSS) from baseline to 12 weeks of treatment were compared between the two groups. Safety assessments included treatment‐emergent adverse events, blood pressure, pulse rate, postvoid residual volume, and maximum urinary flow rate. After 12 weeks, the study was extended for 14 additional weeks by administering mirabegron 50 mg to both groups.
Results
The reduction in the mean number of 24‐h micturition episodes from baseline to 12 weeks of treatment was similar between the two groups. However, significantly greater changes from baseline to 12 weeks were observed in total OABSS, OABSS urgency incontinence score (Q4), IPSS storage subscore (Q2 + Q4 + Q7), and IPSS urgency score (Q4) in the mirabegron group (P = 0.01 for all). According to the extended study, the changes of all efficacy variables from baseline to 26 weeks were similar between both groups. The safety assessment results were also similar between the two groups at 12 and 26 weeks.
Conclusion
A daily 50 mg dose of mirabegron for 12 weeks reduced OAB symptoms in men, and no significant adverse events compared to the placebo group were noted.
The incidence of Proteus mirabilis antimicrobial resistance, especially that mediated by extended-spectrum β-lactamases (ESBLs), has increased. We investigated the impact of ESBL production on the ...mortality of patients with P. mirabilis bacteremia in Korea.
Patients diagnosed with P. mirabilis bacteremia between November 2005 and December 2013 at a 2000-bed tertiary care center in South Korea were included in this study. Phenotypic and molecular analyses were performed to assess ESBL expression. Characteristics and treatment outcomes were investigated among ESBL-producing and non-ESBL-producing P. mirabilis bacteremia groups. A multivariate analysis of 28-day mortality rates was performed to evaluate the independent impact of ESBLs.
Among 62 P. mirabilis isolates from 62 patients, 14 expressed ESBLs (CTX-M, 2; TEM, 5; both, 6; other, 1), and the 28-day mortality rate of the 62 patients was 17.74%. No clinical factor was significantly associated with ESBL production. The 28-day mortality rate in the ESBL-producing group was significantly higher than that in the non-ESBL-producing group (50% vs. 8.3%, p = 0.001). A multivariate analysis showed that ESBL production (odds ratio OR, 11.53, 95% confidence interval CI, 2.11-63.05, p = 0.005) was independently associated with the 28-day mortality rate in patients with P. mirabilis bacteremia.
ESBL production is significantly associated with mortality in patients with bacteremia caused by P. mirabilis. Rapid detection of ESBL expression and prompt appropriate antimicrobial therapy are required to reduce mortality caused by P. mirabilis bacteremia.
According to the new definition of septic shock, vasopressor therapy and hyperlactatemia are essential for diagnosis. However, there is controversy regarding the cutoff value for lactate, and ...prognostic factors in patients with septic shock and hypolactatemia. This study evaluated the prognostic significance of the cutoff value for lactate level in septic shock patients.
The retrospective observational cohort study enrolled 1043 patients aged ≥18 years who meet the revised definition of septic shock. Clinical outcomes of patients with hyperlactatemia were compared with hypolactatemia.
Of the 1022 eligible patients, 369 had an arterial lactate level ≤2 mmol/L. More patients in the high lactate group had poor prognosis than in the low lactate group. A high Sequential Organ Failure Assessment score (SOFA) score group was significant (p < 0.001) in predicting lactate levels. On the subgroup analysis of risk factors affecting mortality in the low lactate group, high Acute Physiology And Chronic Health Evaluation Ⅱ (APACHEⅡ) score (p = 0.003), high C-reactive protein (p = 0.034), and chronic heart failure (p = 0.001) were independently associated with 28-day mortality.
Arterial lactate is a very reliable diagnostic and prognostic predictor of septic shock. However, despite low arterial lactate, patients with a high APACHEⅡ score, high C-reactive protein levels, and chronic heart failure had a poorer prognosis.
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