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Background: The modified Marsh and Schnider pharmacokinetic models for propofol consistently produce negatively and positively biased predictions in underweight patients, respectively. We aimed to develop a new pharmacokinetic model of propofol in underweight patients., Methods: Twenty underweight (BMI<18.5 kg m -2 ) patients aged 20-68 yr were given an i.v. bolus of propofol (2 mg kg -1 ) for induction of anaesthesia. Anaesthesia was maintained with a zero-order infusion (8 mg kg -1 h -1 ) of propofol and target-controlled infusion of remifentanil. Arterial blood was sampled at preset intervals. A population pharmacokinetic analysis was performed using non-linear mixed effects modelling. The time to peak effect (t peak , maximally reduced bispectral index) was measured in 28 additional underweight patients receiving propofol 2 mg kg -1 ., Results: In total, 455 plasma concentration measurements from the 20 patients were used to characterise the pharmacokinetics of propofol. A three-compartment mammillary model well described the propofol concentration time course. BMI and lean body mass (LBM) calculated using the Janmahasatian formula were significant covariates for the rapid peripheral volume of distribution and for the clearance of the final pharmacokinetic model of propofol, respectively. The parameter estimates were as follows: V 1 (L)=2.02, V 2 (L)=12.9 (BMI/18.5) , V 3 (L)=139, Cl (L⋅min -1 )=1.66 (LBM/40) , Q 1 (L⋅min -1 )=1.44, Q 2 (L⋅min -1 )=0.87+0.0189×(LBM-40). The median t peak of propofol was 1.32 min (n=48)., Conclusions: A three-compartment mammillary model can be used to administer propofol via target effect-site concentration-controlled infusion of propofol in underweight patients., Clinical Trial Registration: KCT0001760., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: : In our preliminary study, the modified Marsh (M-Marsh) model caused an inadvertent underdosing of propofol in underweight patients. However, the predictive performance of the M-Marsh and Schnider models incorporated in commercially available target-controlled infusion (TCI) pumps was not evaluated in underweight patients., Methods: : Thirty underweight patients undergoing elective surgery were randomly allocated to receive propofol via TCI using the M-Marsh or Schnider models. The target effect-site concentrations (Ces) of propofol were, in order, 2.5, 3, 4, 5, 6 and 2 μg ml -1 . Arterial blood samples were obtained at least 7 min after achieving each pseudo-steady-state., Results: A total of 172 plasma samples were used to determine the predictive performance of both models. The pooled median (95% confidence interval) biases and inaccuracies at a target Ce ≤ 3 μg ml -1 were -22.6 (-28.8 to -12.6) and 31.9 (24.8-36.8) for the M-Marsh model and 9.0 (1.7-16.4) and 28.5 (21.7-32.8) for the Schnider model, respectively. These values at Ce ≥ 4 μg ml -1 were -9.6 (-16.0 to -6.0) and 24.7 (21.1-27.9) for the M-Marsh model and 19.8 (12.9-25.7) and 36.2 (31.4-39.7) for the Schnider model, respectively., Conclusions: The pooled biases and inaccuracies of both models were clinically acceptable. However, the M-Marsh and Schnider models consistently produced negatively and positively biased predictions, respectively, in underweight patients. In particular, the M-Marsh model showed greater inaccuracy at target Ce   ≤   3 μg ml -1 and the Schnider model showed greater inaccuracy at target Ce ≥ 4 μg ml -1 . Therefore, it is necessary to develop a new pharmacokinetic model for propofol in underweight patients., Clinical Trial Registration: KCT0001502., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cell), a molecular complex of human α-lactalbumin and oleic acid, is known to have selective cytotoxic activity against certain types of tumors. This cytotoxicity is known to stem from water-insoluble oleic acid. In this study, we manufactured an alternative complex using liposome as an oleic acid delivery vesicle. We named this nanolipoplex LIMLET (LIposome Made LEthal to Tumor cell). The LIMLET vesicle contained approximately 90,200 oleic acid molecules inserted into its lipophilic phospholipid bilayer and had a nominal mean diameter of 127nm. Using a WST-1 assay, its cytotoxicity against two cancer cell lines, MDA-MB-231 (human breast cancer) and A549 (human lung cancer), were tested. The results were compared with that of a normal cell line, Vero (from monkey kidney). We found that (1) LIMLET showed distinctive cytotoxicity against A549 and MDA-MB-231 cells, whereas bare liposomes (containing no oleic acid) had no toxicity, even at high concentrations, and (2) LIMLET demonstrated selective, concentration-dependent toxicity against the cancer cells: the LD50 values of MDA-MB-231 and A549 cells were 1.3 and 2.2nM LIMLET, respectively, whereas the LD50 of Vero was 5.7nM. The strength of the tumoricidal effect appeared to stem from the number of oleic acid molecules present. Our result suggests that LIMLET, like HAMLET, is an interesting nanolipoplex that can potentially be developed into tumor treatments., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Exenatide is a synthetic version of the 39-mer peptide of Exendin-4, which is an FDA-approved therapeutic against Type II diabetes mellitus. However, exenatide has a very short in-serum half-life and PEGylation have been performed to improve its in-serum stability. PEGylation often yields multivalent binding to non-specific residues, and the desired species should be carefully separated by chromatographies. In this study, we first devised an aqueous-phase, two-step PEGylation process. This consists of thiolation of Lys 12 and 27 residues followed by attachment of PEG-maleimide (10kD) to thiol groups. This process yields various species: mono-PEGylates with positional isomers, di-PEGylate, and other higher MW substances. A prep-grade cationic exchange chromatography (HiTrap SP) at pH 3.0 partially separated mono- and di-PEGylates based on the molar ratio of conjugated PEG and peptide and thus molecular weight of the conjugates. To further investigate the chromatographic separation of positional isomers of mono-PEGylates, we prepared two kinds of exenatide analogs by point mutation; K12C and K27C. Each analog was mono-PEGylated with very high yield (>95%). When a mixture of the two positional isomers of mono-PEGylates was applied to HiTrap SP chromatography, K12C-PEGylate and K27C-PEGylate eluted separately at 0.22M and 0.33M NaCl, respectively. When the proportions of acid and its conjugate base of the amino acid residues adjacent to the PEGylation site at pH 3.0 were analyzed, K27C-PEGylate shows stronger positive charge than K12C-PEGylate, and we propose the residence time difference between the two mono-PEGylates could be due to the charge difference. ELISA result shows that the immuno-binding activity of both analogs and their mono-PEGylates are well maintained. Furthermore, both mono-PEGylates of the analogs show higher than 50-fold improved anti-trypsin stability. We expect that mono-PEGylates of the exenatide analogs are alternatives to the conventional C40-PEG., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Guidelines recommend primary prophylaxis (PP) with granulocyte-colony-stimulating factors (G-CSF) for patients above a febrile neutropenia (FN) risk threshold of 20%. Practitioners often use FN rates of regimens based on data from randomized, controlled trials (RCTs), which are often comprised of highly selected patients. Patients in the community setting may be at higher risk of FN., Materials and Methods: A systematic literature search was conducted for full-length articles reporting FN rates for breast cancer-related chemotherapies between January 1996 and February 2014. A regimen was included if there was at least one RCT and one observational study. Meta-regression was used to model the odds of FN., Results: 130 studies involving 29 regimens and 50 069 patients were identified. Sixty-five observational study (n = 7812) and 110 RCT (n = 42 257) cohorts were included. The unadjusted FN rate was 11.7% in observational and 7.9% in RCT cohorts. The univariable odds ratio (OR) for FN in the observational study compared with RCT cohorts was 1.58 [95% confidence interval (CI) 1.09-2.28; P = 0.017]. The FN rates remained significantly higher in the observational study compared with RCT cohorts (OR = 1.74; 95% CI 1.15-2.62; P = 0.012) after adjusting for age, chemotherapy intent, and regimen; this meant that a 13% (95% CI 8.7% to 17.9%) FN rate in RCT would translate into 20% FN rate in observational study., Conclusions: FN rates in the observational studies are significantly higher than suggested by RCTs. Guidelines should clarify how FN rates from RCTs should be applied in clinical practice. Large population-based studies are needed to confirm FN rates in the real world., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Liposome is one of the frequently used carriers for active targeting systems in vivo. Such parameters as its size, surface charge, and surface modifiers are known to influence the liposome uptake by macrophage cells. In this study, we investigated the effects of liposome size and polyethylene glycol (PEG) surface modifier on the liposomal internalization to murine macrophage (RAW-264.7), by using an imaging analysis technique. Three different sized liposomes (100, 200, and 400 nm in nominal diameter) labeled with rhodamine fluorescence were used. Liposome internalization appeared to reach a pseudo-steady plateau in about 5h incubation, and most of the internalized liposomes were seen to accumulate in the cytosol including cellular extensions. The maximum fluorescent density from the internalized liposomes was similar between 100 nm and 200 nm liposomes. However, that of the larger 400 nm liposome was approximately 1.7 times higher than the others, confirming the previous report that the larger the liposomes are the higher the degree of internalization is. When the outside of the 200 nm liposomes was modified with biocompatible anchor molecule (BAM) consisting of PEG (ca. 2kD molecular weight) moiety, the endocytosis was indeed reduced by about 2.1-fold, despite the increase of the hydrodynamic size due to BAM conjugation. This fluorescence-based cellular imaging analysis can be used to quantitatively monitor and optimize cellular internalization systems., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: This study examined the influence of home and school environments, and individual health-risk behaviours on body weight outcomes in Korean adolescents., Study Design: This was a cross-sectional observational study., Methods: Quantile regression models to explore heterogeneity in the association of specific factors with body mass index (BMI) over the entire conditional BMI distribution was used. A nationally representative web-based survey for youths was used., Results: Paternal education level of college or more education was associated with lower BMI for girls, whereas college or more education of mothers was associated with higher BMI for boys; for both, the magnitude of association became larger at the upper quantiles of the conditional BMI distribution. Girls with good family economic status were more likely to have higher BMIs than those with average family economic status, particularly at the upper quantile of the conditional BMI distribution. Attending a co-ed school was associated with lower BMI for both genders with a larger association at the upper quantiles. Substantial screen time for TV watching, video games, or internet surfing was associated with a higher BMI with a larger association at the upper quantiles for both girls and boys. Dental prevention was negatively associated with BMI, whereas suicide consideration was positively associated with BMIs of both genders with a larger association at a higher quantile., Conclusions: These findings suggest that interventions aimed at behavioural changes and positive parental roles are needed to effectively address high adolescent BMI., (Copyright © 2015 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

In total, 39 clinical cases of fowl adenoviruses (FAdV) infection in chickens (28 broiler, 7 native, and 4 layer chickens) between 2007 and 2010 in Korea were investigated. The FAdV types 4, 8b, and 11 comprised 18, 9, and 12 clinical cases, respectively. All FAdV type 4 cases showed clinical hydropericardium (HPS) lesions as well as inclusion body hepatitis (IBH), whereas all FAdV types 8b and 11 cases exhibited IBH lesions without HPS. All 3 types were detected in broiler (9-30 d old) and layer chickens (23-112 d old), whereas most native chickens (14-65 d old) were affected only by FAdV type 4. Infectious bursal disease virus and chicken infectious anemia virus were complications in 51.3% of FAdV cases, with mortalities of 55% to <0.1%. Chicken infectious anemia virus was detected in all native chicken cases. These results indicate that preventive measures against FAdV infection and immunosuppressive diseases on poultry farms should be implemented.

Encapsulation of active proteins in the hydrophilic core of vesicular liposomes is important for developing a therapeutic protein carrier system. The efficiency of liposomal encapsulation of proteins is generally low. A better understanding of the fundamental mechanisms of encapsulation is needed to increase this efficiency. In this study we investigated the effects of operating parameters such as phospholipid concentration, buffer pH and ionic strength, protein size and surface charge, and liposome size on the enzyme encapsulation yield. Four model enzymes of different molecular weights and isoelectric points (trypsin, horseradish peroxidase, enterokinase and hyaluronidase) were encapsulated into three different sized liposomes (125 nm, 194 nm, and 314 nm in mean diameter). Relatively inert and neutral DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) was used as the main phospholipid in the liposomes. Size exclusion chromatography was used to separate the enzyme-encapsulated liposomes from the free enzyme, and the encapsulation yield was determined from the peak area. The encapsulation yield was generally low ranging from ca. 5% to 20%, and did not depend much on the molecular weight of the enzyme encapsulated. Larger liposomes had higher encapsulation yields. The electrostatic interaction between the phospholipid and enzyme was the most significant parameter in determining the encapsulation yield. Thus adjusting buffer pH and ionic strength and adding charged phospholipids to the liposome preparation to impart electric charge to the lipid bilayer could significantly improve the yield. This approach can be used to optimize the liposomal encapsulation of clinically significant proteins., (Copyright © 2012 Elsevier B.V. All rights reserved.)

SiO(2) surface was successfully modified with phospholipid bilayer for biocompatibility by covering the planar surface with vesicular liposomes. By applying heat to rupture the vesicle, they were converted into a planar form. To effectively decorate the bilayer with biological molecules such as a protein, BAM (biological anchor for membrane) was used as a linker. It is a linear assembly consisting of oleyl chain, polyethylene glycol, and NHS (N-hydroxysuccinimide). After a target protein (BSA) was conjugated with BAM by NHS replacement, the conjugate was effectively inserted to the phospholipid bilayer through the lipophilic interaction between the oleyl chain and the lipid bilayer. The entire process was monitored and quantitatively analyzed by QCM (quartz crystal microbalance). BSA-BAM conjugate showed approximately 12-fold higher binding efficiency to the lipid bilayer than BSA alone. From this result, we conclude that SiO(2) surface could be modified to a lipid bilayer surface so as to anchor a protein by the action of BAM.

Schwannoma is a slow-growing tumor that frequently occurs in the extremities, the trunk and the head region. Its occurrence in the breast is rare with only a few cases being reported. We present here the case of breast schwannoma in a 41-year-old woman who presented with a palpable mass in her right breast. This is the first report of breast schwannoma that showed massive exophytic growth with invasion of the skin, and it was initially presumed to be a breast cancer on preoperative mammography, ultrasonography and breast MRI examinations. Complete excision of the mass was done and pathology revealed a plexiform schwannoma.

Single direct partial sequencing of anonymous cDNA clones was performed to obtain genetic information on red algae Porphyra yezoensis of which genetic information is not available. This expressed sequence tags (EST) analysis revealed 81 clones (42%) had significant homologies to known genes in GenBank. Of these clones, eight are related to known algal genes, whereas above 90% of the EST clones were newly identified in algae. Putative functional categories of these clones showed that the most abundant genes were involved in stress and defense mechanisms and that the next abundant genes were associated with protein synthetic pathways.

Intravenous administration of two benzodiazepines, flurazepam and diazepam, had an inhibitory effect on the firing rates of neurons of the substantia nigra pars reticulata, a brain region with an identified GABAergic innervation. Diazepam was more potent than flurazepam. Bicuculline and picrotoxin, two drugs which block GABAergic transmission, and caffeine and theophylline, two methylxanthines which inhibit benzodiazepine binding, all reversed the inhibition produced by diazepam. The action of theophylline was less consistent than that of caffeine. Similarly, Ro 15-1788, an imidazodiazepine which putatively functions as a specific benzodiazepine antagonist, reversed the diazepam-induced inhibition. These findings are consistent with previous reports which suggest that the benzodiazepines may act through a GABAergic mechanism. In a separate group of experiments, caffeine or Ro 15-1788 was administered alone. While caffeine excited all reticulata, generally had little excitatory effect. These results suggest: 1) that cells of the substantia nigra pars reticulata may not receive a substantial, tonic inhibition mediated by an endogenous benzodiazepine-like substance; and 2) that the methylxanthines may increase reticulata cell firing, at least in part, through mechanisms unrelated to the blockade of benzodiazepine receptors.