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Abstract: Recent studies have suggested that extrasynaptic GABAA receptors, which contribute tonic conductance, are important targets for general anesthetics. We tested the hypothesis that manipulations designed to alter ambient GABA concentrations (tonic conductance) would affect hypnotic (as indicated by loss of righting reflex, LORR) and immobilizing (as indicated by loss of tail-pinch withdrawal reflex, LTWR) actions of sevoflurane, propofol, and midazolam. Two manipulations studied were 1) the genetic absence of glutamate decarboxylase (GAD) 65 gene (GAD65−/−), which purportedly reduced ambient GABA concentrations, and 2) the pharmacological manipulation of GABA uptake using GABA transporter inhibitor (NO-711). The influence of these manipulations on cellular and behavioral responses to the anesthetics was studied using behavioral and electrophysiological assays. HPLC revealed that GABA levels in GAD65−/− mice were reduced in the brain (76.7% of WT) and spinal cord (68.5% of WT). GAD65−/− mice showed a significant reduction in the duration of LORR and LTWR produced by propofol and midazolam, but not sevoflurane. NO-711 (3 mg/kg, ip) enhanced the duration of LORR and LTWR by propofol and midazolam, but not sevoflurane. Patch-clamp recordings revealed that sevoflurane (0.23 mM) slightly enhanced the amplitude of tonic GABA current in the frontal cortical neurons; however, these effects were not strong enough to alter discharge properties of cortical neurons. These results demonstrate that ambient GABA concentration is an important determinant of the hypnotic and immobilizing actions of propofol and midazolam in mice, whereas manipulations of ambient GABA concentrations minimally alter cellular and behavioral responses to sevoflurane. [Copyright &y& Elsevier]

The article presents a study on the impact of the excretion of mercapturic acid into the urine from dietary docosahexaenoic acid (DHA) intake. It mentions that Sprague-Dawley rats (SDRs) and Eisai hyperbilirubinuria rats (EHBRs) were used and that the analysis of variance (ANOVA) was performed to evaluate the interaction of multidrug resistance-associated protein (MRP2) and DHA intake. Results show that the excretion of mercapturic acid increases in MRP2-deficient EHBRs with DHA intake.

The article discusses the results of a study investigating the induction of the multidrug resistance-associated protein MRP3 in the liver of rats fed docosahexaenoic acid (DHA). High levels of DHA were found in the liver, kidney and heart of rats fed DHA versus group fed with linoleic acid. (LA) Tissue thiobarbituric acid values as an index of lipid peroxidation was significantly higher in the DHA-fed group than LA-fed group.

Abstract: Objectives: We examined the effects of ascorbic acid (AsA) and glutathione (GSH; experiment 1) and of GSH in acetaminophen-fed rats (experiment 2) on dietary docosahexaenoic acid (DHA)–induced tissue lipid peroxidation. Methods: In experiment 1, AsA-requiring Osteogenic Disorder Shionogi/Shi-od/od (ODS) rats were fed soybean protein diets containing DHA (10.0% total energy) and AsA at 50 (low) or 300 (normal) mg/kg without (low) or with (normal) methionine at 2 g/kg for 32 d. In experiment 2, ODS rats were fed diets containing DHA (7.8% total energy) and acetaminophen (4 g/kg) with different levels of dietary methionine (low, moderate, high, and excessive at 0, 3, 6, and 9 g/kg, respectively) for 30 d. Tissue lipid peroxides and antioxidant levels were determined. Results: In experiment 1, liver lipid peroxide levels in the low-AsA group were lower than those in the normal-AsA group, but kidney and testis lipid peroxide levels in the low-AsA group were higher than those in the normal-AsA group. Dietary methionine tended to decrease tissue lipid peroxide levels but did not decrease vitamin E (VE) consumption. In experiment 2, a high level of methionine (6 g/kg) decreased liver lipid peroxide levels and VE consumption. However, generation of tissue lipid peroxides and VE consumption were not decreased further by a higher dose of methionine (9 g/kg). Conclusions: Higher than normal levels of dietary methionine are not necessarily associated with decreased dietary DHA-induced generation of tissue lipid peroxides and VE consumption except that the GSH requirement is increased in a condition such as acetaminophen feeding. [Copyright &y& Elsevier]

Abstract: Little is known about the interaction of noradrenaline with volatile anesthetics in inhibitory synaptic transmission. The purpose of the present study was to investigate the interactions of noradrenaline and sevoflurane on inhibitory synaptic transmission mediated by GABA(A) receptors in the rat hippocampus. Pharmacologically isolated GABA(A) receptor-mediated IPSCs were recorded with whole-cell patch-clamp techniques in pyramidal neurons of the CA1 region of rat hippocampal slices. The actions of noradrenaline, noradrenaline analog, sevoflurane, and the interactions of these agents on the frequency and kinetics of spontaneous GABA(A) receptor-mediated IPSCs were studied. Noradrenaline (10 μM) caused an increase in the frequency of action potential-dependent sIPSCs. These effects were completely reversed by the addition of tetrodotoxin (1 μM), suggesting that noradrenaline produces the discharge of GABAergic interneurons innervating on pyramidal cells via adrenoceptors. Although sevoflurane (0.40 mM, 20 min) slightly depressed the amplitude of sIPSCs, sevoflurane significantly prolonged the decay time constant to 451.1 ± 89.0% of control (n = 9, P < 0.001) without affecting the rise time. In addition, sevoflurane increased the frequency of sIPSCs up to 3-fold. However, pretreatment of cadmium, multiple Ca channel blocker, abolished sevoflurane effects on the frequency whereas the effects on the decay were still observed. Application of both noradrenaline and sevoflurane produced a significant increase of the IPSC frequency than that of noradrenaline alone or sevoflurane alone with prolonged decays. These results provide evidence that both agents have additive effects on GABAergic synaptic transmission at the central nervous system via different mechanisms. [Copyright &y& Elsevier]

We examined the relationship between the transbilayer distribution of aminophospholipids, such as phosphatidylethanolamine (PE), PE plasmalogen and phosphatidylserine, and the oxidative stability of polyunsaturated fatty acids (PUFAs) in the aminophospholipids. To modulate the transbilayer distribution of aminophospholipid in liposomes, we used phosphatidylcholine (PC) with two types of acyl chain region: dipalmitoyl (PC16:0) or dioleoyl (PC18:1). In the smaller-sized liposomes, the proportions of aminophospholipid in the liposomal external layer were significantly higher in liposomes containing PC18:1 than in those containing PC16:0. Additionally, aminophospholipids in the external layer of smaller-sized liposomes were able to protect their component PUFAs from 2,2'-azobis(2-amidinopropane)dihydrochloride-mediated lipid peroxidation. [ABSTRACT FROM AUTHOR]

Rotational spectra of four rare isotopic species of OCS were observed in the 110–690 GHz region with a source-modulated submillimeter-wave spectrometer. Spectral lines of 18O13CS, O13C36S, 18OC36S, and 18O13C34S were measured in their natural abundances, 21.4, 1.51, 0.29, and 0.95 ppm, respectively. The rotational constants and centrifugal distortion constants were precisely determined from observed line frequencies by least squares methods. In order to facilitate sensitivity examination in the submillimeter-wave region, transition frequencies and peak absorption coefficients were calculated and tabulated for the spectral lines of the four species up to the 1000 GHz region. [Copyright &y& Elsevier]

We have proposed that incorporation of docosahexaenoic acid (DHA) into phosphatidylethanolamine (PE) might enhance resistance to lipid peroxidation in vivo. In this study, we examined the relationship between the transbilayer distribution of PE and the oxidative stability of DHA in PE. Liposomes composed of a phospholipid mixture were used as models for biological membranes. To modulate the transbilayer distribution of PE obtained from the liver of rats fed DHA (PE-DHA), we used phosphatidylcholine (PC) with two types of acyl chain region: dipalmitoyl (PC16:0) or dioleoyl (PC18:1). The proportion of PE-DHA in the liposomal external layer was significantly higher in liposomes containing PC18:1 than in those containing PC16:0. This tendency was more pronounced in liposomes extruded using a polycarbonate filter with smaller pore sizes. Additionally, PE-DHA in the external layer of liposomes prepared using a filter with smaller pore sizes could protect DHA itself from 2,2′-azobis(2-aminopropane)dihydrochloride-mediated lipid peroxidation. [Copyright &y& Elsevier]

Background/Aims: In order to clarify an appropriate intake of docosahexaenoic acid (DHA, 22:6n–3), from the viewpoint of safety and physiological efficacy, the potential changes in lipid peroxidation and antioxidant defense in serum and tissues as well as those in serum lipid levels were examined in matured rats at the age of 1 year. Methods: Rats were given the diets containing graded levels of purified DHA (0, 1.0, 3.1 and 8.4% of total energy, en%) for 30 days (control and 1.0, 3.1 and 8.4 en% groups). Lipid peroxides and α-tocopherol levels in serum and tissues, and lipid levels in serum were measured. Results: Serum α-tocopherol concentrations in the 3.1 and 8.4 en% groups were significantly lower than those in the control group. Liver lipid peroxide levels assessed using the microsomal conjugated dienes were significantly higher in the 3.1 and 8.4 en% groups than those in the control group, and the chemiluminescence intensity and thiobarbituric acid value were significantly greater in the 8.4 en% group than in the control group. The liver α-tocopherol level decreased in response to the increases in lipid peroxide levels, but a significant difference was recognized only in the 8.4 en% group. In the kidney, no changes in lipid peroxide levels were observed, but the α-tocopherol level was significantly lower in the 8.4 en% group than in the control group. The levels of all the serum lipids including total cholesterol, HDL-cholesterol, triacylglycerols and phospholipids decreased as the dietary DHA level increased, and total cholesterol and phospholipid concentrations were significantly lower in the 3.1 and 8.4 en% groups than in the control group. Conclusion: These experimental results suggest that the dietary intake of DHA should not be more than 3 en% in matured rats to avoid the potentially chronic deleterious influences caused by lipid peroxidation in serum and tissues, and that the amelioration of serum lipid levels is recognized in rats fed DHA at 3 en% and above.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In a previous study, we found that dietary docosahexaenoic acid (DHA)-stimulated tissue lipid peroxide formation was suppressed to a lesser extent than expected from the peroxidizability index of tissue total lipids. This suppression was presumed to be potentiated by mechanisms other than the lipid peroxide-scavenging system. In this study, we focused primarily on the incorporation of DHA into tissue nonphosphorus lipids and phospholipid species. DHA and different levels of dietary vitamin E (VE; 7.5, 54, 134 and 402 mg/kg of diet) were fed to rats for 32 d. In rats with poor VE status, liver chemiluminescence intensity and kidney and testis thiobarbituric acid (TBA) values correlated with the tissue's peroxidizability index. In rats with normal VE nutriture, liver lipid peroxide formation was suppressed to a level below that expected from the peroxidizability index, likely because DHA was present in nonphosphorus lipids and utilized preferentially for phosphatidylethanolamine synthesis. In the kidney, differences in the TBA values were associated with differences in the peroxidizability index of total lipids, even in the DHA groups fed VE at higher than normal levels. This may be because the levels of lipid peroxide scavengers were lower than those of liver and because DHA was utilized preferentially for phosphatidylcholine synthesis. In testis, the lipid peroxide levels were not as high as expected from the peroxidizability index, even in rats fed a high DHA diet containing the normal level of VE. This may be because the testis was composed of a high proportion of (n-6) polyunsaturated fatty acids (PUFA), which are low in unsaturation, and thus the proportion of DHA was low. In addition, in testis, VE and ascorbic acid, which act as antioxidants, were retained at higher levels in rats with particularly poor and normal VE nutriture than those of liver and kidney. These results suggest that antioxidant protection against dietary DHA-stimulated lipid peroxidation below the extent expected from the peroxidizability index of tissue total lipids differed from tissue to tissue. The suppression was likely due to not only the lipid peroxide scavenging system but also preferential incorporation of DHA into nonphosphorus lipids and phosphatidylethanolamine, particularly in liver. [ABSTRACT FROM AUTHOR]

This study evaluated the diagnostic value of a rapid whole-body fluorodeoxyglucose (FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) approach, combining Bayesian penalised likelihood (BPL) PET with an optimised β value and abbreviated MRI (abb-MRI). The study compares the diagnostic performance of this approach with the standard PET/MRI that utilises ordered subsets expectation maximisation (OSEM) PET and standard MRI (std-MRI). The optimal β value was determined by evaluating the noise-equivalent count (NEC) phantom, background variability, contrast recovery, recovery coefficient, and visual scores (VS) for OSEM and BPL with β100–1000 at 2.5-, 1.5-, and 1.0-min scans, respectively. Clinical evaluations were conducted for NECpatient, NECdensity, liver signal-to-noise ratio (SNR), lesion maximum standardised uptake value, lesion signal-to-background ratio, lesion SNR, and VS in 49 patients. The diagnostic performance of BPL/abb-MRI was retrospectively assessed for lesion detection and differentiation in 156 patients using VS. The optimal β values were β600 for a 1.5-min scan and β700 for a 1.0-min scan. BPL/abb-MRI at these β values was equivalent to OSEM/std-MRI for a 2.5-min scan. By combining BPL with optimal β and abb-MRI, rapid whole-body PET/MRI could be achieved in ≤1.5 min per bed position, while maintaining comparable diagnostic performance to standard PET/MRI. [ABSTRACT FROM AUTHOR]

Background: Coat color is important for registration and maintenance of livestock. Standard coat color of Kumamoto sub-breed of Japanese Brown cattle is solid brown, but individuals with diluted coat color have been observed recently. In this study, we attempted to identify polymorphism(s) responsible for coat color dilution by whole genome analysis. Results: One of the diluted cattle possessed 7302 exonic polymorphisms which could affect genes' function. Among them, 14 polymorphisms in 10 coat color-related genes were assumed to be specific for the diluted cattle. Subsequent genotyping with three diluted cattle and 74 standard cattle elucidated that PMEL p.Leu18del was the causative polymorphism for coat color dilution in this sub-breed. Individuals with del/del type of this polymorphism showed diluted coat color, but coat color of heterozygotes were intermediate with various dilution rates. Conclusions: Coat color dilution of Kumamoto sub-breed was caused by PMEL p.Leu18del. The causative del allele has been detected in several genetically distant cattle breeds, suggesting that PMEL p.Leu18del can be used as a DNA marker to control cattle coat color. [ABSTRACT FROM AUTHOR]

Docosahexaenoic acid (DHA) plays an important role in visual function but has a highly oxidation-prone chemical structure. Therefore, we investigated how dietary DHA affects the generation of lipid peroxides in rat retina under oxidative stress in diabetes with/without vitamin E (VE) deficiency. Streptozotocin-induced (50mg i.p./kg B.W.) diabetic Sprague-Dawley (SD) rats were assigned to four groups: (i) control/VE(+), (ii) DHA/VE(+), (iii) control/VE(-) and (iv) DHA/VE(-), and raised for 28 days. We then measured lipid peroxide levels in the retina, serum and liver. With a normal intake of VE, dietary DHA increased only the retinal level of thiobarbituric acid-reactive substances (TBARS) slightly. In contrast, in rats with VE deficiency, dietary DHA increased serum and liver lipid peroxide levels but not in the retina. These results suggest that dietary DHA does not necessarily promote lipid peroxidation in the retina even under high oxidative stress. [ABSTRACT FROM AUTHOR]

Purpose: To retrospectively assess the repeatability of physiological F-18 labeled fluorodeoxyglucose (FDG) uptake in the skin on positron emission tomography/magnetic resonance imaging (PET/MRI) and explore its regional distribution and relationship with sex and age. Methods: Out of 562 examinations with normal FDG distribution on whole-body PET/MRI, 74 repeated examinations were evaluated to assess the repeatability and regional distribution of physiological skin uptake. Furthermore, 224 examinations were evaluated to compare differences in the uptake due to sex and age. Skin segmentation on PET was performed as body-surface contouring on an MR-based attenuation correction map using an off-line reconstruction software. Bland–Altman plots were created for the repeatability assessment. Kruskal–Wallis test was performed to compare the maximum standardized uptake value (SUVmax) with regional distribution, age, and sex. Results: The limits of agreement for the difference in SUVmean and SUVmax of the skin were less than 30%. The highest SUVmax was observed in the face (3.09±1.04), followed by the scalp (2.07±0.53). The SUVmax in the face of boys aged 0–9 years and 10–20 years (1.33±0.64 and 2.05±1.00, respectively) and girls aged 0–9 years (0.98±0.38) was significantly lower than that of men aged ≥20 years and girls aged ≥10 years (p<0.001). In women, the SUVmax of the face (2.31±0.71) of ≥70-year-olds was significantly lower than that of 30–39-year-olds (3.83±0.82) (p<0.05). Conclusion: PET/MRI enabled the quantitative analysis of skin FDG uptake with repeatability. The degree of physiological FDG uptake in the skin was the highest in the face and varied between sexes. Although attention to differences in body habitus between age groups is needed, skin FDG uptake also depended on age. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the diagnostic performance of the lung zero-echo time (ZTE) sequence in FDG PET/MRI for detection and differentiation of lung lesions in oncologic patients in comparison with conventional two-point Dixon-based MR imaging. Methods: In this single-institution retrospective study approved by the institutional review board, 209 patients with malignancies (97 men and 112 women; age range, 17–89 years; mean age, 66.5 ± 12.9 years) underwent 18F-FDG PET/MRI between August 2017 and August 2018, with diagnostic Dixon and ZTE under respiratory gating acquired simultaneously with PET. Image analysis was performed for PET/Dixon and PET/ZTE fused images by two readers to assess the detectability and differentiation of lung lesions. The reference standard was pathological findings and/or the data from a chest CT. The detection and differentiation abilities were evaluated for all lesions and subgroups divided by lesion size and maximum standardized uptake value (SUVmax). Results: Based on the reference standard, 227 lung lesions were identified in 113 patients. The detectability of PET/ZTE was significantly better than that of PET/Dixon for overall lesions, lesions with a SUVmax less than 3.0 and lesions smaller than 4 mm (p < 0.01). The diagnostic performance of PET/ZTE was significantly better than that of PET/Dixon for overall lesions and lesions smaller than 4 mm (p < 0.01). Conclusions: ZTE can improve diagnostic performance in the detection and differentiation of both FDG-avid and non-FDG-avid lung lesions smaller than 4 mm in size, yielding a promising tool to enhance the utility of FDG PET/MRI in oncology patients with lung lesions. Key Points: • The detection rate of PET/ZTE for lesions with a SUVmax of less than 1.0 was significantly better than that of PET/Dixon. • The performance for differentiation of PET/ZTE for lesions that were even smaller than 4 mm in size were significantly better than that of PET/Dixon. • Inter-rater agreement of PET/ZTE for the differentiation of lesions less than 4 mm in size was substantial and better than that of PET/Dixon. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the usefulness of metabolic parameters obtained by F-FDG PET/CT for preoperative stratification of high-risk and low-risk endometrial carcinomas. Methods: Preoperative F-FDG PET/CT was performed in 56 women with endometrial cancer. Maximum standardized uptake values (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) of primary tumours were compared with clinicopathological features of surgical specimens. Diagnostic performance in terms of differentiation of low-risk disease (endometrioid histology, histological grade 1 or 2, invasion of less than half of the myometrium, and FIGO stage I) from high-risk disease was assessed. Results: MTV and TLG were significantly higher in patients with higher histological grade ( p = 0.0026 and p = 0.034), larger tumour size ( p = 0.002 and p = 0.0017), lymphovascular space involvement (LVSI; p = 0.012 and p = 0.0051), myometrial invasion ( p = 0.027 and p = 0.031), cervical stromal invasion ( p = 0.023 and p = 0.014), ovarian metastasis ( p = 0.00022 and p = 0.00034), lymph node metastasis ( p < 0.0001 and p < 0.0001), and higher FIGO stage ( p = 0.0011 and p = 0.00048). SUVmax was significantly higher in patients with larger tumour size ( p = 0.0025), LVSI ( p = 0.00023) and myometrial invasion ( p < 0.0001). The areas under the ROC curves (AUCs) for distinguishing high-risk from low-risk carcinoma were 0.625, 0.829 and 0.797 for SUVmax, MTV and TLG, respectively. AUCs for both MTV and TLG were significantly larger than that for SUVmax ( p = 0.0049 and p = 0.021). The optimal TLG cut-off value of 70.2, determined by ROC analysis, was found to have 72.0 % sensitivity and 74.2 % specificity for risk stratification. Conclusion: MTV and TLG of primary endometrial cancer show better correlations with clinicopathological features and are more useful for differentiating high-risk from low-risk carcinoma than SUVmax. [ABSTRACT FROM AUTHOR]

Abstract: Biomembranes and cytoplasm, a diffusion-limited region for nanoparticles are critical barriers to be overcome for the successful gene delivery. We herein report on a neutral, and intracellularly degradable lipid nanoparticle (LNP), containing encapsulated plasmid DNA (pDNA) that can be effectively delivered to the nucleus. A key material component in this particle is a vitamin A-scaffold SS-cleavable Proton-Activated Lipid-like Material (SSPalmA), which contains tertiary amine groups as proton sponge units that can respond to the acidic pH in endosomes, disulfide bonding for programmed collapse in the cytoplasm, and retinoic acid (RA) as a hydrophobic unit for assembly into LNP. LNP prepared using SSPalmA (LNPPalmA) exhibited a 15-fold higher gene expression activity compared to particles prepared with a simple acyl chain (myristoyl group)-scaffold one (LNPPalmM). Intracellular imaging studies revealed that LNPPalmA unexpectedly showed excessive endosome-disruptive characteristics. Furthermore, the decapsulation of pDNA slowly, but successively occurred in parallel with peri-nuclear accumulation. Nuclear targeting was blocked in the presence of native RA. Collectively, LNPPalmA is an intelligent particle that passes through the cytoplasm in particle form with the aid of the intrinsic nuclear transport system of RA, and thereafter releases its encapsulated pDNA for effective gene expression. [Copyright &y& Elsevier]

Abstract: For production of pH-sensitive liposomes, we developed pH-sensitive polymer-lipids that consists of pH-sensitive fusogenic polymer moieties such as 3-methyl glutarylated poly(glycidol) and 2-carboxycyclohexane-1-carboxylated poly(glycidol), connected to a phosphatidylethanolamine head group. Incorporation of these pH-sensitive polymer-lipids into egg yolk phosphatidylcholine liposomes produced highly pH-sensitive liposomes that were stable at neutral pH but which destabilized markedly in response to very small pH change in weakly acidic pH region. These liposomes delivered their contents (pyranine) into cytosol of dendritic cell-derived DC2.4 cells. When these polymer-lipid-incorporated liposomes loaded with antigenic protein ovalbumin (OVA) were administered subcutaneously to mice, the antigen-specific cellular immunity was induced efficiently in the mice. Furthermore, immunization of mice with these OVA-loaded pH-sensitive polymer-lipid-incorporated liposomes induced strong OVA-specific immunity, which achieved complete rejection of OVA-expressing E.G7-OVA cells and marked regression of E.G7-OVA tumors. [Copyright &y& Elsevier]