Beta-lactam antimicrobial dosing optimization in obese patients compared to non-obese patients using population pharmacokinetic/pharmacodynamic approach

Obesity is a significant global health problem and has been associated with altered pharmacokinetics and pharmacodynamics of many drugs. However, little is known regarding the effect of obesity on the pharmacokinetics and pharmacodynamics of many broad-spectrum, beta-lactam antibiotics such as piperacillin/tazobactam, meropenem, and cefepime. The objective of this study is to evaluate the population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam, meropenem, and cefepime in hospitalized obese patients in order to determine dosing regimens that provide similar exposures between obese and non-obese patients. ^ For piperacillin/tazobactam, a retrospective analysis was conducted using prospectively collected serum concentration-time data from two previous studies (Study 1 and Study 2) published by our research group. Hospitalized, adult patients who required antimicrobial therapy for a suspected or documented bacterial infection were eligible to participate in both studies. In Study 2, only patients with total body weight (TBW) greater than 120 kg were eligible to be enrolled. Patients were classified as either obese [body mass index (BMI) ¡Ý 30 kg/m2] or non-obese (BMI \u3c 30 kg/m2). In Study 1, all patients received piperacillin/tazobactam 4.5 g every 8 hours (q8h), infused over 4 hours. In Study 2, patients received piperacillin/tazobactam either 4.5 g or 6.75 g q8h, infused over 4 hours. After 2 or more days of therapy, serial blood samples were collected from an indwelling IV catheter immediately prior to drug administration, and at 1, 2, 3, 4 (end of infusion), 5, 6, 7 and 8 hours after the start of infusion. Piperacillin and tazobactam serum concentrations were determined by the previously validated high performance liquid chromatography (HPLC) method. Population pharmacokinetic parameters were estimated using NONMEM, and the final pharmacokinetic model was built by evaluating the effects of covariates on the pharmacokinetic parameters of piperacillin and tazobactam using the stepwise forward inclusion followed by the backward elimination process. Tested covariates included: 1) age; 2) sex; 3) body size descriptor, including TBW, ideal body weight (IBW), lean body weight (LBW), and BMI; 4) creatinine clearance (CRCL); and 5) admission to an intensive care unit (ICU; ICU=1, general medical ward=0). In the stepwise forward inclusion process, covariates that reduced the model objective function value (OFV) \u3e 3.84 (p \u3c 0.05; ¦Ö2 distribution; 1 df) were considered significantly associated with the pharmacokinetic parameters in the model. In the backward elimination process, a covariate was removed if its elimination increased the model OFV by \u3c 5.024 (p \u3e 0.025; ¦Ö2 distribution; 1 df). Using the final pharmacokinetic model, Monte Carlo simulations were performed for three 4-hour dosing regimens to calculate probability of target attainment (PTA) using ¡Ý 50%fT\u3eMIC. ^ Overall, a convenience sample of 27 patients (11 non-obese and 16 obese) were studied. TBW ranged from 60 kg to 211 kg, BMI from 19.7 kg/m2 to 72.9 kg/m2, and measured creatinine clearance (CRCL) from 23 mL/min to 260 mL/min. Patient demographics [median (range)] in non-obese vs. obese group are: age, 53 (27-76) vs. 48 (35-69) years; CRCL, 88 (23-148) vs. 111 (28-260) mL/min; height, 175 (163-190) vs. 175 (157-190) cm; TBW, 74 (60-100) vs. 151 (98-211) kg; LBW, 54 (39-72) vs. 78 (50-94) kg; IBW, 71 (55-84) vs. 71 (50-84) kg; BMI, 24.8 (19.7-29.4) vs. 50.1 (32.7-72.9) kg/m2. The number of male patients was seven in non-obese and ten in obese patient groups, and the number of patients admitted to an intensive care unit (ICU) was seven each in non-obese and obese patient groups. Compared to non-obese patients, obese patients had significantly larger TBW, LBW, and BMI (p \u3c 0.05); other demographics were similar between non-obese and obese patients. Observed serum concentration-time profiles of both piperacillin and tazobactam were best described by a one-compartment model with zero-order input and first-order, linear elimination. The final model for piperacillin was: clearance (CL; L/h) = 11.3 + [0.0646*(CRCL-105)] + [0.0579*(BMI-35)]; and volume of distribution (V; L) = 31.3 + [0.132*(TBW-120)]. The final model for tazobactam was: CL (L/h) = 10.1 + [0.0272*(CRCL-105)]; and V (L) = 34.3. For both piperacillin and tazobactam, obese patients had significantly increased CL and V compared to non-obese patients. The pharmacokinetic parameters [median (range)] in non-obese vs. obese patients were: piperacillin CL, 9.0 (4.8-14.2) vs. 13.1 (6.8-20.0) L/h (p=0.026); piperacillin V, 24.6 (17.1-37.8) vs. 32.5 (19.8-69.8) L (p=0.014); tazobactam CL, 6.8 (4.4-15.5) vs. 13.1 (5.6-26.4) L/h (p=0.005); and tazobactam V, 17.1 (9.4-70.3) vs. 45.5 (10.5-116.6) L (p=0.019). Based on the pharmacodynamic analysis using Monte Carlo simulation, at the piperacillin MICs ¡Ü 16 mg/L in the presence of tazobactam, which is the susceptibility breakpoint for Enterobacteriaceae and Pseudomonas aeruginosa, PTA was \u3e 90% for 4-hour infusion dosing regimens ¡Ý 3.375 g q8h in non-obese patients and ¡Ý 4.5 g q8h in obese patients, respectively. ^ For meropenem, a retrospective analysis was conducted using prospectively collected serum concentration-time data from three previous studies (Study 3, Study 4, and Study 5) published by our research group. Hospitalized, adult patients who required antimicrobial therapy for a suspected or documented bacterial infection were eligible to participate in all three studies. Although patients with CRCL less than 50 mL/min were eligible to participate in Study 3, they were excluded in Study 4 and 5 due to different study objectives. In Study 3, only patients with BMI ¡Ý 40 kg/m2 were enrolled, and in Study 4, only patients with BMI ¡Ý 40 kg/m2 or TBW ¡Ý 100 pounds over their IBW were enrolled. Patients were classified as either obese (BMI ¡Ý 30 kg/m2) or non-obese (BMI \u3c 30 kg/m2). In Study 3, patients received the following meropenem dosing regimens: 500 mg q6h if CRCL \u3e 60 mL/min; 500 mg q8h if CRCL was 40 to 60 mL/min; and 500 mg q12h if CRCL was 10 to 39 mL/min. In Study 4, all patients received either 500 mg or 1000 mg q6h. In Study 5, all patients received 1000 mg q8h. In all studies, all dosing regimens were infused over 30 minutes. After 2 or more days of therapy, serial blood samples were collected from an indwelling IV catheter as scheduled in each study: immediately prior to drug administration, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8 (if receiving q8h or q12h dosing regimens), and 12 hours (if receiving q12h dosing regimens) after the start of infusion in Study 3; prior to drug administration, 0.5 (end of infusion), 1, 2, 3, 4, and 6 hours after the start of infusion in Study 4; and prior to drug administration, 0.5 (end of infusion), 1, 1.5, 2, 3, 4, 5, 6, and 8 hours after the start of infusion in Study 5. Serum meropenem concentrations were determined by previously described analytical methods: HPLC in Study 3 and Study 4; and ultraperformance liquid chromatography in Study 5. Population pharmacokinetic parameters were estimated using NONMEM, and the final pharmacokinetic model was built by evaluating the effects of covariates on the meropenem pharmacokinetic parameters using the stepwise forward inclusion followed by the backward elimination process. Tested covariates included: 1) age; 2) sex; 3) body size descriptor, including TBW, IBW, LBW, and BMI; 4) CRCL; and 5) admission to an ICU (ICU=1, general medical ward=0). In the stepwise forward inclusion process, covariates that reduced the model OFV \u3e 3.84 (p \u3c 0.05; ¦Ö2 distribution; 1 df) were considered significantly associated with the pharmacokinetic parameters in the model. In the backward elimination process, a covariate was removed if its elimination increased the model OFV by \u3c 5.024 (p \u3e 0.025; ¦Ö2 distribution; 1 df). Using the final pharmacokinetic model, Monte Carlo simulations were performed for five different meropenem dosing regimens to calculate PTA using ¡Ý 40%fT\u3eMIC. Each dosing regimen was simulated as 30-minute infusion, 3-hour infusion for q6h regimens, and 4-hour infusion for q8h and q12h regimens. Overall, a convenience sample of 40 patients (11 non-obese and 29 obese) were studied. TBW ranged from 57 kg to 305 kg, BMI from 19.2 kg/m2 to 88.8 kg/m2, and CRCL from 15 mL/min to 186 mL/min. Patient demographics [median (range)] in non-obese vs. obese group are: age, 59 (20-79) vs. 57 (26-76) years; CRCL, 58 (15-182) vs. 87 (20-186) mL/min; height, 170 (165-183) vs. 170 (150-193) cm; TBW, 72 (57-88) vs. 149 (73-305) kg; LBW, 49 (40-66) vs. 66 (38-114) kg; IBW, 64 (57-78) vs. 64 (34-87) kg; BMI, 25.0 (19.2-28.6) vs. 53.7 (30.6-88.8) kg/m2. The number of male patients was seven in non-obese and 13 in obese patient groups, and the number of patients admitted to an intensive care unit (ICU) was seven in non-obese and 18 in obese patient groups. Compared to non-obese patients, obese patients had significantly larger TBW, LBW, and BMI (p \u3c 0.05); other demographics were similar between non-obese and obese patients. Observed serum concentration-time profiles of meropenem were best described by a two-compartment model with zero-order input and first-order, linear elimination from the central compartment. The final meropenem model was: CL (L/h) = 8.62*(CRCL/85)0.533; volume of distribution in the central compartment (V1; L) = 13.6; inter-compartmental distribution clearance (Q; L/h) = 11.8; and volume of distribution in the peripheral compartment (V2; L) = 14.5. There was no significant difference in CL, V1, Q, and V2 between non-obese and obese patient groups. The meropenem pharmacokinetic parameters [median (range)] in non-obese vs. obese patients were: CL, 5.5 (3.3-17.7) vs. 8.2 (3.0-18.1) L/h; V1, 14.3 (10.1-20.7) vs. 12.3 (5.6-47.4) L; Q, 10.8 (5.0-25.9) vs. 14.6 (0.6-66.4) L/h; and V2, 12.6 (9.7-20.1) vs. 14.5 (5.6-27.1) L. Based on the pharmacodynamic analysis using Monte Carlo simulation, at MICs ¡Ü 2 mg/L, which is the susceptibility breakpoint for Pseudomonas aeruginosa, PTA was \u3e 90% for dosing regimens ¡Ý 500 mg q8h in both non-obese and obese patient groups. ^ For cefepime, a retrospective analysis was conducted using prospectively collected serum concentration-time data from three previous studies (Study 6, Study 7, and Study 8) published by our research group. Hospitalized, adult patients who required antimicrobial therapy for a suspected or documented bacterial infection were eligible to participate in all three studies. In Study 8, only patients with BMI ¡Ý 40 kg/m2 were enrolled while in Study 6 and Study 7, there was no weight restriction in the inclusion and exclusion criteria. Patients were classified as either obese (BMI ¡Ý 30 kg/m2) or non-obese (BMI \u3c 30 kg/m2). In Study 6, patients received cefepime 1 g q6h if CRCL was ¡Ý 60 mL/min and 1 g q8h or q12h if CRCL was \u3c 60 mL/min. Patients received 1 g q8h in Study 7 and 2 g q8h in Study 8, respectively. All doses were infused over 30 minutes in Study 6 and over 4 hours in Study 7 and Study 8. After 2 or more days of therapy, serial blood samples were collected from an indwelling IV catheter as scheduled in each study: immediately prior to drug administration, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 6, 8 (if receiving q8h dosing regimens), and 12 hours (if receiving q12h dosing regimens) after the start of infusion in Study 6; and prior to drug administration, 1, 2, 3, 4 (end of infusion), 5, 6, 7, and 8 hours after the start of infusion in Study 7 and 8. Serum cefepime concentrations were determined by previously described HPLC method. Population pharmacokinetic parameters were estimated using NONMEM, and the final pharmacokinetic model was built by evaluating the effects of covariates on the cefepime pharmacokinetic parameters using the stepwise forward inclusion followed by the backward elimination process. Tested covariates included: 1) age; 2) sex; 3) body size descriptor, including TBW, IBW, LBW, and BMI; 4) CRCL; and 5) admission to an ICU (ICU=1, general medical ward=0). In the stepwise forward inclusion process, covariates that reduced the model OFV \u3e 3.84 (p \u3c 0.05; ¦Ö2 distribution; 1 df) were considered significantly associated with the pharmacokinetic parameters in the model. In the backward elimination process, a covariate was removed if its elimination increased the model OFV by \u3c 5.024 (p \u3e 0.025; ¦Ö2 distribution; 1 df). Using the final pharmacokinetic model, Monte Carlo simulations were performed for five different cefepime dosing regimens to calculate PTA using ¡Ý 60%fT\u3eMIC. Each dosing regimen was simulated as 30-minute infusion, 3-hour infusion for q6h regimens, and 4-hour infusion for q8h and q12h regimens. ^ Overall, a convenience sample of 30 patients (10 non-obese and 20 obese) were studied. TBW ranged from 54 kg to 276 kg, BMI from 18.5 kg/m2 to 92.5 kg/m2, and CRCL from 20 mL/min to 205 mL/min. Patient demographics [median (range)] in non-obese vs. obese group are: age, 44 (21-70) vs. 59 (32-81) years; CRCL, 101 (56-180) vs. 92 (20-205) mL/min; height, 178 (147-190) vs. 171 (147-183) cm; TBW, 74 (54-97) vs. 110 (81-276) kg; LBW, 60 (36-71) vs. 64 (42-96) kg; IBW, 73 (41-84) vs. 64 (41-78) kg; BMI, 22.5 (18.5-29.8) vs. 39.2 (30.9-92.5) kg/m2. The number of male patients was eight in non-obese and 13 in obese patient groups, and the number of patients admitted to an intensive care unit (ICU) was four in non-obese and 12 in obese patient groups. Compared to non-obese patients, obese patients were significantly older and had significantly larger TBW and BMI (p \u3c 0.05); other demographics were similar between non-obese and obese patients. Observed serum concentration-time profiles of cefepime were best described by a one-compartment model with zero-order input and first-order, linear elimination. The final cefepime model was: CL (L/h) = 8.06 + [0.0598*(CRCL-90)]; and V (L) = 39.2 + [0.323*(TBW-95)]. Obese patients had significantly increased V compared to non-obese patients (p \u3c 0.05), but CL was similar between non-obese and obese patients. The cefepime pharmacokinetic parameters [median (range)] in non-obese vs. obese patients were: CL, 8.0 (5.0-12.6) vs. 7.5 (3.6-27.9) L/h; and V, 27.6 (22.1-48.8) vs. 50.0 (19.3-94.5) L. Based on the pharmacodynamic analysis using Monte Carlo simulation, at MICs ¡Ü 2 mg/L, which is the susceptibility breakpoint for Enterobacteriaceae, PTA was \u3e 90% for dosing regimens ¡Ý 1 g q12h in both non-obese and obese patient groups. At an MIC of 4 mg/L, PTA was \u3e 90% for dosing regimens ¡Ý 1 g q8h in non- obese patients and ¡Ý 1 g q12h in obese patients. At an MIC of 8 mg/L, which is the susceptibility breakpoint for Pseudomonas aeruginosa, PTA was \u3e 90% for 30-minute infusions of 1 g q6h and 2 g q8h in non- obese patients and dosing regimens ¡Ý 1 g q8h in obese patients. When prolonging the infusion times to 3 to 4 hours, dosing regimens ¡Ý 1 g q12h achieved the PTA \u3e 90% at MICs ¡Ü 4 mg/L in both non-obese and obese patient groups. The PTA at an MIC of 8 mg/L was \u3e 90% for prolonged-infusion dosing regimens ¡Ý 1 g q8h in both non-obese and obese patient groups ^ In conclusion, piperacillin and tazobactam pharmacokinetics are altered in obesity, and larger doses (¡Ý 4.5 g q8h), infused over 4 hours, may be needed to provide similar exposures in obese patients compared with non-obese patients receiving ¡Ý 3.375 g q8h doses, infused over 4 hours. In contrast, meropenem pharmacokinetics are similar between obese and non-obese patients, so same dosages provide comparable pharmacodynamic exposures for susceptible organisms between obese and non-obese patients. Although cefepime pharmacokinetics are altered in obesity, same dosing regimens achieve similar pharmacodynamic exposures for susceptible organisms between obese and non-obese patients

Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillintazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of\u3e50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73m2, respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of\u3e90% at MICs of/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of\u3e90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of\u3e80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children

Development and Implementation of a Pharmacist-managed Outpatient Parenteral Antimicrobial Therapy Program

Purpose The development and implementation of a pharmacist-managed outpatient parenteral antimicrobial therapy (OPAT) program in a county teaching hospital are described. Summary A pharmacist-managed OPAT program was developed and implemented at a county teaching hospital to provide consistent evaluation, approval, and monitoring of patients requiring OPAT for the treatment of infection. The developmental and implementation stages of the OPAT program included (1) a needs assessment, (2) the identification of resources necessary for program operation, (3) delineation of general OPAT program operations and activities of individual OPAT clinicians, (4) the development of patient selection criteria, including a plan of care algorithm, and (5) acquisition of administrative support to approve the program. In this program, the OPAT pharmacist plays an integral role in the management and oversight of OPAT patients, working under a collaborative agreement with infectious diseases physicians. The OPAT pharmacist assists with appropriate patient and regimen selection, confirmation of orders on discharge, assuring that laboratory tests for safety surveillance are performed and evaluated, performing routine monitoring for adverse events and line complications, and assuring the removal of the vascular access device upon the completion of OPAT. Conclusion: The OPAT program provides structured monitoring, patient follow-up, and led to improvements in patient outcome with minimization of treatment and line-related adverse events

TRAO Survey of Nearby Filamentary Molecular clouds, the Universal Nursery of Stars (TRAO FUNS) I. Dynamics and Chemistry of L1478 in the California Molecular Cloud

"TRAO FUNS" is a project to survey Gould Belt's clouds in molecular lines. This paper presents its first results on the central region of the California molecular cloud, L1478. We performed On-The-Fly mapping observations using the Taedeok Radio Astronomy Observatory (TRAO) 14m single dish telescope equipped with a 16 multi-beam array covering $\sim$1.0 square degree area of this region using C$^{18}$O (1-0) mainly tracing low density cloud and about 460 square arcminute area using N$_{2}$H$^{+}$ (1-0) mainly tracing dense cores. CS (2-1) and SO $(3_{2}-2_{1})$ were also used simultaneously to map $\sim$440 square arcminute area of this region. We identified 10 filaments by applying the dendrogram technique to the C$^{18}$O data-cube and 8 dense N$_{2}$H$^{+}$ cores by using {\sc FellWalker}. Basic physical properties of filaments such as mass, length, width, velocity field, and velocity dispersion are derived. It is found that L1478 consists of several filaments with slightly different velocities. Especially the filaments which are supercritical are found to contain dense cores detected in N$_{2}$H$^{+}$. Comparison of non-thermal velocity dispersions derived from C$^{18}$O and N$_{2}$H$^{+}$ for the filaments and dense cores indicates that some of dense cores share similar kinematics with those of the surrounding filaments while several dense cores have different kinematics with those of their filaments. This suggests that the formation mechanism of dense cores and filaments can be different in individual filaments depending on their morphologies and environments.Comment: 25 pages, 15 figures, accepted for publication in Ap

Skin Aging and Photoaging Alter Fatty Acids Composition, Including 11,14,17-eicosatrienoic Acid, in the Epidermis of Human Skin

We investigated the alterations of major fatty acid components in epidermis by natural aging and photoaging processes, and by acute ultraviolet (UV) irradiation in human skin. Interestingly, we found that 11,14,17-eicosatrienoic acid (ETA), which is one of the omega-3 polyunsaturated acids, was significantly increased in photoaged human epidermis in vivo and also in the acutely UV-irradiated human skin in vivo, while it was significantly decreased in intrinsically aged human epidermis. The increased ETA content in the epidermis of photoaged human skin and acute UV-irradiated human skin is associated with enhanced expression of human elongase 1 and calcium-independent phophodiesterase A2. We demonstrated that ETA inhibited matrix metalloproteinase (MMP)-1 expression after UV-irradiation, and that inhibition of ETA synthesis using EPTC and NA-TCA, which are elongase inhibitors, increased MMP-1 expression. Therefore, our results suggest that the UV increases the ETA levels, which may have a photoprotective effect in the human skin

Programming effects of maternal stress on the circadian system of adult offspring

Maternal stress has long-lasting influences on the brain functions of offspring, and several brain regions have been proposed to mediate such programming. Although perinatal programming of crosstalk between the circadian and stress systems has been proposed, the functional consequences of prenatal stress on the circadian system and the underlying mechanisms remain largely unknown. Therefore, we investigated whether exposing pregnant mice to chronic restraint stress had prolonged effects on the suprachiasmatic nucleus (SCN), which bears the central pacemaker for mammalian circadian rhythms, of offspring. SCN explants from maternally stressed mice exhibited altered cyclic expression patterns of a luciferase reporter under control of the mouse Per1 promoter (mPer1::LUC), which manifested as a decreased amplitude and impaired stability of the rhythm. Bioluminescence imaging at the single-cell level subsequently revealed that impaired synchrony among individual cells was responsible for the impaired rhythmicity. These intrinsic defects appeared to persist during adulthood. Adult male offspring from stressed mothers showed advanced-phase behavioral rhythms with impaired stability as well as altered clock gene expression in the SCN. In addition to affecting the central rhythm, maternal stress also had prolonged influences on the circadian characteristics of the adrenal gland and liver, as determined by circulating corticosterone levels and hepatic glycogen content, and on canonical clock gene mRNA expression in those tissues. Taken together, our findings suggest that the SCN is a key target of the programming effects of maternal stress. The widespread effects of circadian disruptions caused by a misprogrammed clock may have further impacts on metabolic and mental health in later life. © 2020, The Author(s).1

Valosin-containing protein is a key mediator between autophagic cell death and apoptosis in adult hippocampal neural stem cells following insulin withdrawal

Background: Programmed cell death (PCD) plays essential roles in the regulation of survival and function of neural stem cells (NSCs). Abnormal regulation of this process is associated with developmental and degenerative neuronal disorders. However, the mechanisms underlying the PCD of NSCs remain largely unknown. Understanding the mechanisms of PCD in NSCs is crucial for exploring therapeutic strategies for the treatment of neurodegenerative diseases. Result: We have previously reported that adult rat hippocampal neural stem (HCN) cells undergo autophagic cell death (ACD) following insulin withdrawal without apoptotic signs despite their normal apoptotic capabilities. It is unknown how interconnection between ACD and apoptosis is mediated in HCN cells. Valosin-containing protein (VCP) is known to be essential for autophagosome maturation in mammalian cells. VCP is abundantly expressed in HCN cells compared to hippocampal tissue and neurons. Pharmacological and genetic inhibition of VCP at basal state in the presence of insulin modestly impaired autophagic flux, consistent with its known role in autophagosome maturation. Of note, VCP inaction in insulin-deprived HCN cells significantly decreased ACD and down-regulated autophagy initiation signals with robust induction of apoptosis. Overall autophagy level was also substantially reduced, suggesting the novel roles of VCP at initial step of autophagy. Conclusion: Taken together, these data demonstrate that VCP may play an essential role in the initiation of autophagy and mediation of crosstalk between ACD and apoptosis in HCN cells when autophagy level is high upon insulin withdrawal. This is the first report on the role of VCP in regulation of NSC cell death. Elucidating the mechanism by which VCP regulates the crosstalk of ACD and apoptosis will contribute to understanding the molecular mechanism of PCD in NSCs. © 2016 Yeo et al.1

Regulation of autophagic cell death by glycogen synthase kinase-3 beta in adult hippocampal neural stem cells following insulin withdrawal

Background: Neural stem cells (NSCs) hold great potential for the treatment of neurodegenerative diseases. However, programmed cell death (PCD) provoked by the harsh conditions evident in the diseased brain greatly undermines the potential of NSCs. Currently, the mechanisms of PCD that effect NSCs remain largely unknown. Results: We have previously reported that hippocampal neural stem (HCN) cells derived from the adult rat brain undergo autopahgic cell death (ACD) following insulin withdrawal without hallmarks of apoptosis despite their normal apoptotic capabilities. In this study, we demonstrate that glycogen synthase kinase 3β (GSK-3β) induces ACD in insulin-deprived HCN cells. Both pharmacological and genetic inactivation of GSK-3β significantly decreased ACD, while activation of GSK-3β increased autophagic flux and caused more cell death without inducing apoptosis following insulin withdrawal. In contrast, knockdown of GSK-3α barely affected ACD, lending further support to the critical role of GSK-3β. Conclusion: Collectively, these data demonstrate that GSK-3β is a key regulator of ACD in HCN cells following insulin withdrawal. The absence of apoptotic indices in GSK-3β-induced cell death in insulin-deprived HCN cells corroborates the notion that HCN cell death following insulin withdrawal represents the genuine model of ACD in apoptosis-intact mammalian cells and identifies GSK-3β as a key negative effector of NSC survival downstream of insulin signaling. © 2015 Ha et al.; licensee BioMed Central.1

Transcranial direct current stimulation for online gamers: A prospective single-arm feasibility study

Aim: Excessive use of online games can have negative influences on mental health and daily functioning. Although the effects of transcranial direct current stimulation (tDCS) have been investigated for the treatment of addiction, it has not been evaluated for excessive online game use. This study aimed to investigate the feasibility and tolerability of tDCS over the dorsolateral prefrontal cortex (DLPFC) in online gamers. Methods: A total of 15 online gamers received 12 active tDCS sessions over the DLPFC (anodal left/cathodal right, 2 mA for 30 min, 3 times per week for 4 weeks). Before and after tDCS sessions, all participants underwent 18F-fluoro-2-deoxyglucose positron emission tomography scans and completed the Internet Addiction Test (IAT), Brief Self Control Scale (BSCS), and Beck Depression Inventory-II (BDI-II). Results: After tDCS sessions, weekly hours spent on games (p = .02) and scores of IAT (p < .001) and BDI-II (p = .01) were decreased, whereas BSCS score was increased (p = .01). Increases in self-control were associated with decreases in both addiction severity (p = .002) and time spent on games (p = .02). Moreover, abnormal right-greater-than-left asymmetry of regional cerebral glucose metabolism in the DLPFC was partially alleviated (p = .04). Conclusions: Our preliminary results suggest that tDCS may be useful for reducing online game use by improving interhemispheric balance of glucose metabolism in the DLPFC and enhancing self-control. Larger sham-controlled studies with longer follow-up period are warranted to validate the efficacy of tDCS in gamers