Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH) has been shown to block the norepinephrine transporter (NET), and genetic investigations have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T) and G1287A polymorphisms with MPH response in ADHD. Methods This study enrolled 112 children and adolescents with ADHD. A response criterion was defined based on the Clinical Global Impression-Improvement (CGI-I) score, and the ADHD Rating Scale-IV (ARS) score was also assessed at baseline and 8 weeks after MPH treatment. Results We found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 G1287A polymorphism and response to ADHD treatment. Conclusion Our findings provide evidence for the involvement of the -3081(A/T) polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD

Prognostic value of neutrophil/lymphocyte ratio and mean platelet volume/platelet ratio for 1-year mortality in critically ill patients

Several studies have reported that the neutrophil to lymphocyte ratio (NLR) and mean platelet volume (MPV) are associated with poor prognosis. This study investigated whether NLR and/or the MPV/platelet ratio could function as predictive markers of mortality in critically ill patients. We retrospectively reviewed 1,154 patients admitted to the intensive care unit (ICU) between January 2017 and December 2017. Patients were divided into 2 groups according to 1-year mortality. We compared the NLR and MPV/platelet ratio on each day of ICU admission. Patients were classified into tertiles based on their NLR and MPV/platelet ratios, and the incidence of 1-year mortality was compared. Kaplan-Meier survival curves were plotted to evaluate their potential as prognostic factors for 1-year mortality. The NLR and MPV/platelet ratio were higher in the non-survivor group than in the survivor group. The incidence of 1-year mortality was the highest in the third tertile for both the NLR and MPV/platelet ratio. The MPV/platelet ratio was an independent predictor for 1-year mortality based on the Kaplan-Meier survival analysis. Our data showed that the MPV/platelet ratio is a predictive factor for 1-year mortality in critically ill patients.11Nsciescopu

Suppression of STAT3 and HIF-1 Alpha Mediates Anti-Angiogenic Activity of Betulinic Acid in Hypoxic PC-3 Prostate Cancer Cells

Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that betulinic acid (BA), a triterpene from the bark of white birch, had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. Methodology/Principal Findings: BA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1a (HIF-1a) under hypoxic condition. Consistently, BA blocked hypoxia-induced phosphorylation, DNA binding activity and nuclear accumulation of STAT3. In addition, BA significantly reduced cellular and secreted levels of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Furthermore, BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxic PC-3 cells, implying anti-angiogenic activity of BA under hypoxic condition. Of note, chromatin immunoprecipitation (ChiP) assay revealed that BA inhibited binding of HIF-1a and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia. Conclusions/Significance: Taken together, our results suggest that BA has anti-angiogenic activity by disturbing th

Quantitative prediction of oral bioavailability of a lipophilic antineoplastic drug bexarotene administered in lipidic formulation using a combined in vitro lipolysis/microsomal metabolism approach

For performance assessment of the lipid-based drug delivery systems (LBDDS), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilisation processes. Much of previous research on in vitro lipolysis have mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values (Foral,predicted) of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 1.6% and 36.2 2.6%, respectively, while the in vivo oral bioavailability (Foral) of BEX was tested as 31.5 13.4% and 31.4 5.2%, respectively. The Foral,predicted corresponded well with the Foral for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in [less than] 1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability

New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae

ABSTRACT Pharmacodynamics of a polymyxin B, meropenem, and rifampin triple combination were examined against Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) ST258. In time-kill experiments against three KPC-Kp isolates, triple combination generated 8.14, 8.19, and 8.29 log 10 CFU/ml reductions within 24 h. In the hollow-fiber infection model, the triple combination caused maximal killing of 5.16 log 10 CFU/ml at 78 h and the time required for regrowth was more than doubled versus the 2-drug combinations. Remarkably, combinations with a high single-dose polymyxin B burst plus rifampin preserved KPC-Kp polymyxin susceptibility (MIC 240 h = 0.5 mg/liter) versus the same combination with traditionally dosed polymyxin B, where resistance was amplified (MIC 240 h = 32 mg/liter)

Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity

Objectives: The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii . The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities. Methods: Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactam-resistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations. Results: Despite achieving colistin steady-state targets of an AUC 0-24 >60 mg·h/L and C avg of >2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam eradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth. Conclusions: To combat polymyxin-resistant A. baumannii , the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise

Micafungin prophylaxis for acute leukemia patients undergoing induction chemotherapy

Background Micafungin is a well-tolerated and effective prophylactic antifungal agent used in hematologic diseases. In this prospective trial, we evaluated the efficacy and safety of prophylactic micafungin during first induction chemotherapy in patients with acute leukemia. We also compared outcomes of prophylactic micafungin with those of prophylactic posaconazole in acute myeloid leukemia (AML). Methods Medically fit patients with newly diagnosed acute leukemia received 50 mg micafungin intravenously once daily from the initiation of first induction chemotherapy to recovery of neutrophil count, suspected fungal infection, or unacceptable drug-related toxicity (Clinicaltrials.gov number, NCT02440178). The primary end point was incidence of invasive fungal infection, and the secondary end points were adverse events of prophylactic micafungin and mortality during induction therapy. Results The 65 patients (median age = 51 years, male:female = 34:31) enrolled in this study had diagnoses of AML (33, 50.8%), acute lymphoblastic leukemia (31, 47.7%), and acute biphenotypic leukemia (1, 1.5%). Median duration of micafungin treatment was 24 days (range 1–68), with proven invasive fungal disease in one patient (1.5%) and possible fungal infection in two patients (3.1%). Three of the patients (4.6%) experienced the following adverse events, but all events were tolerable: liver function abnormality (Grade 2, n = 1; Grade 3, n = 1) and allergic reaction (Grade 2, n = 1). Three patients died during induction therapy, and invasive aspergillosis pneumonia was the cause of death for one of those patients. Overall, 19 patients (29.2%) discontinued prophylactic micafungin, and 18 (27.7%) patients switched to another antifungal agent. We observed no fungal infections caused by amphotericin B-resistant organisms. In AML patients, outcomes of prophylactic micafungin during induction chemotherapy did not differ significantly with those of prophylactic posaconazole with regard to incidence of fungal infections, rate of discontinuation, or safety. Conclusions Our study demonstrates that prophylactic micafungin is safe and effective in patients with acute leukemia undergoing induction chemotherapy. Outcomes in patients with AML were similar to those of prophylactic posaconazole, indicating the usefulness of micafungin as a prophylactic antifungal agent during induction chemotherapy for AML. Trial registration Clinicaltrials.gov NCT02440178, registered May 12th 2015.This study was funded by Astellas Pharma Korea, Inc. Funding source had no role in the study design, data collection, data analysis or data interpretation

Genome-Scale Profiling and High-Throughput Analyses Unravel the Genetic Basis of Arsenic Content Variation in Rice

Ionomics, the study of the composition of mineral nutrients and trace elements in organisms that represent the inorganic component of cells and tissues, has been widely studied to explore to unravel the molecular mechanism regulating the elemental composition of plants. However, the genetic factors of rice subspecies in the interaction between arsenic and functional ions have not yet been explained. Here, the correlation between As and eight essential ions in a rice core collection was analyzed, taking into account growing condition and genetic factors. The results demonstrated that the correlation between As and essential ions was affected by genetic factors and growing condition, but it was confirmed that the genetic factor was slightly larger with the heritability for arsenic content at 53%. In particular, the cluster coefficient of japonica (0.428) was larger than that of indica (0.414) in the co-expression network analysis for 23 arsenic genes, and it was confirmed that the distance between genes involved in As induction and detoxification of japonica was far than that of indica. These findings provide evidence that japonica populations could accumulate more As than indica populations. In addition, the cis-eQTLs of AIR2 (arsenic-induced RING finger protein) were isolated through transcriptome-wide association studies, and it was confirmed that AIR2 expression levels of indica were lower than those of japonica. This was consistent with the functional haplotype results for the genome sequence of AIR2, and finally, eight rice varieties with low AIR2 expression and arsenic content were selected. In addition, As-related QTLs were identified on chromosomes 5 and 6 under flooded and intermittently flooded conditions through genome-scale profiling. Taken together, these results might assist in developing markers and breeding plans to reduce toxic element content and breeding high-quality rice varieties in future

Risk factors for and clinical outcomes of carbapenem non-susceptible gram negative bacilli bacteremia in patients with acute myelogenous leukemia

Background Carbapenem is frequently used when gram negative bacilli (GNB) bacteremia is detected especially in neutropenic patients. Consequently, appropriate treatment could be delayed in GNB bacteremia cases involving organisms which are not susceptible to carbapenem (carba-NS), resulting in a poor clinical outcomes. Here, we explored risk factors for carba-NS GNB bacteremia and its clinical outcomes in patients with acute myelogenous leukemia (AML) that underwent chemotherapy. Methods We reviewed all GNB bacteremia cases that occurred during induction or consolidation chemotherapy, over a 15-year period, in a tertiary-care hospital. Results Among 489 GNB bacteremia cases from 324 patients, 45 (9.2%) were carba-NS and 444 (90.8%) were carbapenem susceptible GNB. Independent risk factors for carba-NS GNB bacteremia were: carbapenem use at bacteremia onset (adjusted odds ratio [aOR]: 91.2; 95% confidence interval [95%CI]: 29.3–284.1; P < 0.001); isolation of carbapenem-resistant Acinetobacter baumannii (aOR: 19.4, 95%CI: 3.4–112.5; P = 0.001) in the prior year; and days from chemotherapy to GNB bacteremia (aOR: 1.1 per day, 95%CI: 1.1–1.2; P < 0.001). Carba-NS bacteremia was independently associated with in-hospital mortality (aOR: 6.6, 95%CI: 3.0–14.8; P < 0.001). Conslusion Carba-NS organisms should be considered for antibiotic selection in AML patients having these risk factors