Efficient molecular doping of polymeric semiconductors driven by anion exchange.

The efficiency with which polymeric semiconductors can be chemically doped-and the charge carrier densities that can thereby be achieved-is determined primarily by the electrochemical redox potential between the π-conjugated polymer and the dopant species1,2. Thus, matching the electron affinity of one with the ionization potential of the other can allow effective doping3,4. Here we describe a different process-which we term 'anion exchange'-that might offer improved doping levels. This process is mediated by an ionic liquid solvent and can be pictured as the effective instantaneous exchange of a conventional small p-type dopant anion with a second anion provided by an ionic liquid. The introduction of optimized ionic salt (the ionic liquid solvent) into a conventional binary donor-acceptor system can overcome the redox potential limitations described by Marcus theory5, and allows an anion-exchange efficiency of nearly 100 per cent. As a result, doping levels of up to almost one charge per monomer unit can be achieved. This demonstration of increased doping levels, increased stability and excellent transport properties shows that anion-exchange doping, which can use an almost infinite selection of ionic salts, could be a powerful tool for the realization of advanced molecular electronics.

Characteristic Evaluation of a 11C-Labeled Leucine Analog, l-α-[5-11C]methylleucine, as a Tracer for Brain Tumor Imaging by Positron Emission Tomography.

Amino acid transporters are upregulated in many cancer cells, and system L amino acid transporters (LAT1-4), in particular, LAT1, which preferentially transports large, neutral, and branched side-chain amino acids, are considered a primary target for cancer positron emission tomography (PET) tracer development. Recently, we developed a 11C-labeled leucine analog, l-α-[5-11C]methylleucine ([5-11C]MeLeu), via a continuous two-step reaction of Pd0-mediated 11C-methylation and microfluidic hydrogenation. In this study, we evaluated the characteristics of [5-11C]MeLeu and also compared the sensitivity to brain tumors and inflammation with l-[11C]methionine ([11C]Met) to determine its potential for brain tumor imaging. Competitive inhibition experiments, protein incorporation, and cytotoxicity experiments of [5-11C]MeLeu were performed in vitro. Further, metabolic analyses of [5-11C]MeLeu were performed using a thin-layer chromatogram. The accumulation of [5-11C]MeLeu in tumor and inflamed regions of the brain was compared with [11C]Met and 11C-labeled (S)-ketoprofen methyl ester by PET imaging, respectively. Transporter assay with various inhibitors revealed that [5-11C]MeLeu is mainly transported via system L amino acid transporters, especially LAT1, into A431 cells. The protein incorporation assay and metabolic assay in vivo demonstrated that [5-11C]MeLeu was neither used for protein synthesis nor metabolized. These results indicate that MeLeu is very stable in vivo. Furthermore, the treatment of A431 cells with various concentrations of MeLeu did not change their viability, even at high concentrations (∼10 mM). In brain tumors, the tumor-to-normal ratio of [5-11C]MeLeu was more elevated than that of [11C]Met. However, the accumulation levels of [5-11C]MeLeu were lower than those of [11C]Met (the standardized uptake value (SUV) of [5-11C]MeLeu and [11C]Met was 0.48 ± 0.08 and 0.63 ± 0.06, respectively). In brain inflammation, no significant accumulation of [5-11C]MeLeu was observed at the inflamed brain area. These data suggested that [5-11C]MeLeu was identified as a stable and safe agent for PET tracers and could help detect brain tumors, which overexpress the LAT1 transporter.

Anatomical variability, multi-modal coordinate systems, and precision targeting in the marmoset brain.

Localising accurate brain regions needs careful evaluation in each experimental species due to their individual variability. However, the function and connectivity of brain areas is commonly studied using a single-subject cranial landmark-based stereotactic atlas in animal neuroscience. Here, we address this issue in a small primate, the common marmoset, which is increasingly widely used in systems neuroscience. We developed a non-invasive multi-modal neuroimaging-based targeting pipeline, which accounts for intersubject anatomical variability in cranial and cortical landmarks in marmosets. This methodology allowed creation of multi-modal templates (MarmosetRIKEN20) including head CT and brain MR images, embedded in coordinate systems of anterior and posterior commissures (AC-PC) and CIFTI grayordinates. We found that the horizontal plane of the stereotactic coordinate was significantly rotated in pitch relative to the AC-PC coordinate system (10 degrees, frontal downwards), and had a significant bias and uncertainty due to positioning procedures. We also found that many common cranial and brain landmarks (e.g., bregma, intraparietal sulcus) vary in location across subjects and are substantial relative to average marmoset cortical area dimensions. Combining the neuroimaging-based targeting pipeline with robot-guided surgery enabled proof-of-concept targeting of deep brain structures with an accuracy of 0.2 mm. Altogether, our findings demonstrate substantial intersubject variability in marmoset brain and cranial landmarks, implying that subject-specific neuroimaging-based localization is needed for precision targeting in marmosets. The population-based templates and atlases in grayordinates, created for the first time in marmoset monkeys, should help bridging between macroscale and microscale analyses.

Towards HCP-Style macaque connectomes: 24-Channel 3T multi-array coil, MRI sequences and preprocessing.

Macaque monkeys are an important animal model where invasive investigations can lead to a better understanding of the cortical organization of primates including humans. However, the tools and methods for noninvasive image acquisition (e.g. MRI RF coils and pulse sequence protocols) and image data preprocessing have lagged behind those developed for humans. To resolve the structural and functional characteristics of the smaller macaque brain, high spatial, temporal, and angular resolutions combined with high signal-to-noise ratio are required to ensure good image quality. To address these challenges, we developed a macaque 24-channel receive coil for 3-T MRI with parallel imaging capabilities. This coil enables adaptation of the Human Connectome Project (HCP) image acquisition protocols to the in-vivo macaque brain. In addition, we adapted HCP preprocessing methods to the macaque brain, including spatial minimal preprocessing of structural, functional MRI (fMRI), and diffusion MRI (dMRI). The coil provides the necessary high signal-to-noise ratio and high efficiency in data acquisition, allowing four- and five-fold accelerations for dMRI and fMRI. Automated FreeSurfer segmentation of cortex, reconstruction of cortical surface, removal of artefacts and nuisance signals in fMRI, and distortion correction of dMRI all performed well, and the overall quality of basic neurobiological measures was comparable with those for the HCP. Analyses of functional connectivity in fMRI revealed high sensitivity as compared with those from publicly shared datasets. Tractography-based connectivity estimates correlated with tracer connectivity similarly to that achieved using ex-vivo dMRI. The resulting HCP-style in vivo macaque MRI data show considerable promise for analyzing cortical architecture and functional and structural connectivity using advanced methods that have previously only been available in studies of the human brain.

Mapping vascular network architecture in primate brain using ferumoxytol-weighted laminar MRI.

Mapping the vascular organization of the brain is of great importance across various domains of basic neuroimaging research, diagnostic radiology, and neurology. However, the intricate task of precisely mapping vasculature across brain regions and cortical layers presents formidable challenges, resulting in a limited understanding of neurometabolic factors influencing the brain's microvasculature. Addressing this gap, our study investigates whole-brain vascular volume using ferumoxytol-weighted laminar-resolution multi-echo gradient-echo imaging in macaque monkeys. We validate the results with published data for vascular densities and compare them with cytoarchitecture, neuron and synaptic densities. The ferumoxytol-induced change in transverse relaxation rate (ΔR2*), an indirect proxy measure of cerebral blood volume (CBV), was mapped onto twelve equivolumetric laminar cortical surfaces. Our findings reveal that CBV varies 3-fold across the brain, with the highest vascular volume observed in the inferior colliculus and lowest in the corpus callosum. In the cerebral cortex, CBV is notably high in early primary sensory areas and low in association areas responsible for higher cognitive functions. Classification of CBV into distinct groups unveils extensive replication of translaminar vascular network motifs, suggesting distinct computational energy supply requirements in areas with varying cytoarchitecture types. Regionally, baseline R2* and CBV exhibit positive correlations with neuron density and negative correlations with receptor densities. Adjusting image resolution based on the critical sampling frequency of penetrating cortical vessels, allows us to delineate approximately 30% of the arterial-venous vessels. Collectively, these results mark significant methodological and conceptual advancements, contributing to the refinement of cerebrovascular MRI. Furthermore, our study establishes a linkage between neurometabolic factors and the vascular network architecture in the primate brain.

Protection by physical activity against deleterious effect of smoking on carotid intima-media thickness in young Japanese.

BACKGROUND: The hazardous effects of smoking and the favorable influence of physical activity on the progression of atherosclerosis have been well studied, but little is known about the interactions of these 2 factors. METHODS: A total of 1090 subjects who were screened for brain disease (at annual medical checkups) between April 2007 and March 2008 were studied to clarify the effects of smoking on maximum carotid intima-media thickness (IMT) in patients with different grades of physical activity. Univariate and multivariate analyses were performed to investigate relationships between maximum IMT and independent variables, such as smoking status, age, gender, coexisting disease, physical activity, alcohol drinking, family history, subjective symptoms, body mass index, systolic blood pressure, diastolic blood pressure, blood sugar, total cholesterol, high-density lipoprotein cholesterol, and triglycerides. RESULTS: Univariate analysis revealed only the low physical activity group to have a significant relationship between smoking and maximum IMT. When the subjects were divided into 3 age groups (≤49, 50-59, and ≤60 years of age, respectively), the same association was noted for high and moderate physical activity groups ≤49 years of age. Multivariate analysis further revealed smoking status to be a significant predictor of maximum IMT in the young low and moderate activity groups. CONCLUSIONS: In physically inactive young people, smoking might have detrimental effects on maximum IMT, while high physical activity may be protective.

Synthesis and Preclinical Evaluation of 18F-Labeled Ketoprofen Methyl Esters for Cyclooxygenase-1 Imaging in Neuroinflammation.

Cyclooxygenase (COX) is a rate-limiting enzyme in the synthesis of proinflammatory prostanoids from arachidonic acid. In vivo imaging of COX by PET is a potentially powerful tool for assessing the inflammatory response to injury, infection, and disease. We previously reported on a promising PET probe for COX imaging, 11C-labeled ketoprofen methyl ester, which can detect COX-1 activation in models of neuroinflammation and neurodegenerative disorders. In the current study, we aimed to design a fluorine-substituted benzoyl group of ketoprofen (FKTP) and to evaluate its racemate and enantiomers (18F-labeled ketoprofen methyl ester, [18F]FKTP-Me) as PET proradiotracers, potential radiopharmaceuticals for in vivo PET study of COX-1. Methods: We performed nucleophilic aromatic 18F-fluorination to obtain the desired racemic radiolabeled probe, (RS)-[18F]FKTP-Me, at a radiochemical yield of 11%-13%. Subsequent high-performance liquid chromatography separation with a chiral column yielded the desired enantiomerically pure (R)- and (S)-[18F]FKTP-Me. We examined the in vivo properties of (RS)-, (R)-, and (S)-[18F]FKTP-Me in PET studies using rats in which hemispheric inflammation was induced by intrastriatally injecting a lipopolysaccharide. Results: Racemic (RS)-[18F]FKTP-Me and enantiomeric (R)- or (S)-[18F]FKTP-Me were synthesized with radiochemical and chemical purities of more than 99%. The metabolite analysis revealed that the racemic (RS)-[18F]FKTP-Me crossed the blood-brain barrier and entered the brain, where it was subsequently hydrolyzed to its pharmacologically active acid form. PET images revealed a high accumulation of (R)-, (S)-, and (RS)-[18F]FKTP in the inflamed regions in rat brain. Moreover, the accumulated radioactivity of (S)-[18F]FKTP-Me was higher than that of (RS)-[18F]FKTP-Me and (R)-[18F]FKTP-Me, which was correlated with the stereospecific inhibitory activity of FKTP against COX-1. Conclusion: From the results of this study, we conclude that racemic (RS)-[18F]FKTP-Me and its enantiomers could act as proradiotracers of neuroinflammation in rat brain by the association of their hydrolyzed acid forms with COX-1 in inflamed regions. In particular, (S)-[18F]FKTP-Me demonstrated suitable properties as a COX-1-specific probe in PET imaging of neuroinflammation.

A novel Tungsten-based fiducial marker for multi-modal brain imaging.

BACKGROUND: Multi-modal brain image registration is a prerequisite for accurate mapping of brain structure and function in neuroscience. Image registration is commonly performed using automated software; however, its accuracy decreases when images differ in modality, contrast, uniformity, and resolution. This limitation could be overcome by using an external reference point; however, high-contrast agents in multi-modal imaging have not been previously reported. NEW METHODS: Here, we propose a novel multi-modal fiducial marker that contains Tungsten solution and provides high contrast in magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). The basic characteristics of this multi-modal marker were investigated by assessing major sources of image contrast in the following modalities: density and T1-, T2-relaxivity in comparison with conventional contrast agents. RESULTS: Tungsten solution had lower T1- and T2-relaxivity and high solubility, and showed high contrast in T1- and T2-weighted MR and CT images at a high-density concentration (˜3.0 g/mL), whereas other conventional solutions did not show sufficient contrast in either CT or MRI. COMPARISON WITH EXISTING METHODS: The use of this Tungsten-based multi-modal marker allowed more accurate registration than a software-only method in phantom and animal experiments. Application of this method demonstrated accurate cortical surface mapping of neurotransmitter function (dopamine transporter, DAT) using PET and MRI, and provided a neurobiologically relevant cortical distribution consistent with previous literature on histology-based DAT immunoreactivity. CONCLUSIONS: The Tungsten-based multi-modal fiducial marker is non-radioactive, easy to handle, and aids precise registration across different modalities of brain imaging.

Physicochemical and pharmacokinetic characterization of highly potent recombinant L-methionine gamma-lyase conjugated with polyethylene glycol as an antitumor agent.

A highly potent recombinant L-methionine gamma-lyase (METase) conjugated with polyethylene glycol (PEG) was characterized physicochemically and pharmacokinetically in vivo and in vitro. Pegylated METase (PEG-METase), which contains pyridoxal 5'-phosphate (PLP) as a cofactor in the molecule, is a potent anticancer agent that can deplete L-methionine from plasma. Although pegylation decreased its specific activity, dithiothreitol (DTT) treatment increased it over three times with the detachment of one PEG moiety modified with a cysteine residue. We can produce DTT-treated PEG-METase on a large scale in sufficient quality for therapeutic use. The superiority of DTT-treated PEG-METase was confirmed by the enhancement of L-methionine depletion and amelioration of pharmacokinetics in mice. The holoenzyme of DTT-treated PEG-METase gave a several times larger area under the plasma concentration curve than that of DTT-untreated PEG-METase, not because of an increase of the half-life but because of high specific activity. Conversely, simultaneous PLP infusion led to a greatly increased half-life of the holoenzyme. DTT-treated PEG-METase administration with PLP infusion was the most useful combination for maximizing the potency of the enzyme. We showed that serum albumin interfered with holoenzyme activity in vitro. The decrease of holoenzyme activity was dependent on the type of serum albumin. We concluded that PLP was released from PEG-METase by serum albumin in vivo and in vitro. The deleterious effect of PLP dissociation from PEG-METase could be improved by supplementing PLP and oleic acid. Their synergistic effect in preventing a decrease of the holoenzyme activity was also observed.

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer's Disease Model Mice.

UNLABELLED: Cyclooxygenase (COX), a prostanoid-synthesizing enzyme, is considered to be involved in the neuroinflammatory process of neurodegenerative diseases. However, the role of COX in the progression of neurodegeneration is not well understood. We hypothesized that in vivo imaging of COX by PET will contribute to elucidation of the function of COX during the neurodegenerative process in Alzheimer's disease (AD). (11)C-labeled ketoprofen methyl ester (racemic (RS)-(11)C-KTP-Me) developed recently by our group is a useful PET probe for in vivo imaging of COX-1 during neuroinflammation. The (S)-enantiomer of ketoprofen is known to be pharmacologically more active than the (R)-enantiomer. We thus synthesized (11)C-labeled (S)-ketoprofen methyl ester ((S)-(11)C-KTP-Me) as an improved PET probe specific for COX-1 and applied it for investigation of the changes in COX-1 during the progression of AD in a mouse model. METHODS: The specificity of (S)-(11)C-KTP-Me for COXs was examined in PET studies with rats that had intrastriatal injection of lipopolysaccharide. To determine the details of changes in COX-1 during progression of amyloid-ß (Aß) plaque formation in amyloid precursor protein transgenic (APP-Tg) mice, we performed immunohistochemical studies and ex vivo autoradiography with (S)-(11)C-KTP-Me. RESULTS: PET studies using hemispheric lipopolysaccharide injection into rats revealed that the sensitivity of (S)-(11)C-KTP-Me in neuroinflammation was much higher than that of (RS)-(11)C-KTP-Me and (R)-(11)C-KTP-Me; these results closely corresponded to the inhibitory activities of each enantiomer against COX-1 estimated by an in vitro assay. In APP-Tg mice, (S)-(11)C-KTP-Me administration resulted in progressive and significant increases in accumulation of radioactivity in the brain from 16 to 24 mo old in accordance with the histopathologic appearance of abundant Aß plaques and activated microglia, whereas few changes in radioactivity accumulation and few Aß plaques were seen in age-matched wild-type control mice. High-radioactivity accumulation by (S)-(11)C-KTP-Me was markedly observed in the frontal cortex and hippocampus in which COX-1-expressing activated microglia tightly surrounded and enclosed large and more intensely stained Aß plaques, indicating neuroinflammation that originated with Aß. CONCLUSION: (S)-(11)C-KTP-Me is a potent PET probe that is highly selective for COX-1. Studies using APP-Tg mice demonstrated that (S)-(11)C-KTP-Me could detect activated microglia that are associated with amyloid plaque progression, suggesting the involvement of COX-1 in the neuroinflammatory process in AD.

A novel (11)C-labeled thymidine analog, [(11)C]AZT, for tumor imaging by positron emission tomography.

BACKGROUND: Nucleoside analogs labeled with positrons, such as (11)C and (18)F, are considered valuable in visualizing the proliferative activity of tumor cells in vivo using positron emission tomography (PET). We recently developed the (11)C-labeled thymidine analogs [(11)C]zidovudine ([(11)C]AZT) and [(11)C]stavudine ([(11)C]d4T) via the Pd(0)-Cu(I) co-mediated rapid C-C coupling reaction. In this study, to examine whether [(11)C]AZT and [(11)C]d4T might be useful for visualization of tumors in vivo, we performed PET imaging, tissue distribution studies, and metabolite analysis in tumor-bearing mice. METHODS: Mice bearing tumors (rat glioma C6 and human cervical adenocarcinoma HeLa cells) were injected with 50 MBq of [(11)C]AZT or [(11)C]d4T, and PET was performed immediately thereafter. After PET imaging, the radioactivity in several tissues, including tumor tissues, was measured using a γ-counter. In addition, radioactive metabolites in plasma, bile, intestinal contents, and tumor were analyzed using thin layer chromatography (TLC). Cellular uptake of [(11)C]AZT in C6 was measured in the presence or absence of non-labeled thymidine (0.1 mM). RESULTS: In PET studies, C6 and HeLa tumors in mice were clearly visualized using [(11)C]AZT. Time-activity curves using [(11)C]AZT showed that the accumulation of radioactivity in tumors plateaued at 10 min after injection and persisted for 60 min, while most of the radioactivity in other tissues was rapidly excreted into the urine. In various tissues of the body, tumor tissue showed the highest radioactivity at 80 min after injection (five to six times higher uptake than that of blood). Compared with tumor tissue, uptake was lower in other proliferative tissues such as the spleen, intestine, and bone marrow, resulting in a high tumor-to-bone marrow ratio. Cellular uptake of [(11)C]AZT in C6 cells was completely blocked by the application of thymidine, strongly indicating the specific involvement of nucleoside transporters. In contrast, the time-activity curve of [(11)C]d4T in the tumor showed transient and rapid excretion with almost no obvious tumor tissue accumulation. CONCLUSIONS: Tumors can be detected by PET using [(11)C]AZT; therefore, [(11)C]AZT could be useful as a novel PET tracer for tumor imaging in vivo.

Immunoenzymometric assay for recombinant methioninase in biological fluids.

Immunoassay for recombinant methioninase (rMETase), an anti-cancer agent, in biological sample was developed. Antisera were produced by immunizing rabbits with rMETase. The antisera were evaluated using radioiodine-labeled rMETase and good antisera for sensitive immunoassay were obtained. Horseradish peroxidase (HRP) was coupled to reduced IgG of K232 antiserum through bridging agent, N-(epsilon -maleimidocaproyloxy) sulfosuccinimide ester (sulfo-EMCS), to prepare enzyme-labeled antibody. IgG fraction of K231 antiserum was immobilized on microplate well. Two-site sandwich immunoenzymometric assay (IEMA) was developed using these antibodies and had good standard curve between 0.4 and 12 ng per well. For determination of rMETase in mouse plasma, sample was diluted 100-fold with dilution buffer containing protease inhibitors, because about 10% of rMETase immunoreactivity was lost for 2 h at room temperature. rMETase in mouse plasma could be determined by the proposed method in the range of 0.5-8 microg/ml and the method was validated. This novel IEMA, in substitution for the measurement of its enzyme activity, should be very useful not only for preclinical studies of rMETase but also for the clinical studies.

Hypothermic circulatory arrest: renal protection by atrial natriuretic peptide.

Moderate hypothermic circulatory arrest with selective cerebral perfusion has been developed for cerebral protection during thoracic aortic surgery. However, visceral organs, particularly the kidneys, suffer greater tissue damage under moderate hypothermic circulatory arrest, and acute renal failure after hypothermic circulatory arrest is an independent risk factor for early and late mortality. This study investigated whether atrial natriuretic peptide could prevent the reduction in renal perfusion and protect renal function after moderate hypothermic circulatory arrest. Twelve pigs cooled to 30 degrees C during cardiopulmonary bypass were randomly assigned to a peptide-treated group of 6 and a control group of 6. Moderate hypothermic circulatory arrest was induced for 60 min. Systemic arterial mean pressure and renal artery flow did not differ between groups during the study. However, renal medullary blood flow increased significantly in the peptide-treated group after hypothermic circulatory arrest. Myeloperoxidase activity was significantly reduced in the medulla of the peptide-treated group. Renal medullary ischemia after hypothermic circulatory arrest was ameliorated by atrial natriuretic peptide which increased medullary blood flow and reduced sodium reabsorption in the medulla. Atrial natriuretic peptide also reduced the release of an inflammatory marker after ischemia in renal tissue.

Roles of bile acid conjugates and phospholipids in in vitro activation of pancreatic lipase by bear bile and cattle bile.

ETHNOPHARMACOLOGICAL RELEVANCE: Bear bile (BB) originally used as a traditional Chinese medicine has also been adopted in Japan as a traditional home remedy mainly for gastrointestinal problems due to impaired digestion. However, recently, efforts have been made to find alternatives to BB for ecological and ethical reasons. AIMS OF THE STUDY: To find alternatives to BB for facilitating fat digestion, we compared the potency of cattle bile (CB) or synthetic mixtures of major bile components to activate pancreatic lipase with that of BB. MATERIALS AND METHODS: The compositions of bile acid conjugates and phospholipids in BB and CB were determined by high-performance liquid chromatography and thin layer chromatography, respectively. The effects of BB and CB as well synthetic mixtures of bile acid conjugates and phospholipids on pancreatic lipase activity in vitro were examined. RESULTS: BB and CB contained markedly different types and quantities of bile acid conjugates and phospholipids, although the potencies of BB and CB to activate pancreatic lipase were not significantly different. The potency of BB to activate pancreatic lipase was reconstituted by the major bile acid conjugates and phospholipids found in BB. In contrast, only bile acid conjugates found in CB could reconstitute its potency to activate pancreatic lipase. CONCLUSIONS: Our observations indicate that CB or the synthetic mixture of bile components can be used as an alternative to BB for facilitating fat digestion.

Mitral valve repair for infective endocarditis.

OBJECTIVE: This study investigated the feasibility of mitral valve (MV) repair in patients with active or healed infective endocarditis (IE) with mitral regurgitation and evaluated effects on left ventricular (LV) function and structure. METHODS: Subjects comprised 19 patients who underwent MV operations for IE between December 2004 and September 2007. MV repair was performed for acute IE in 10 of 15 patients (67%) and for healed IE in 4 of 4 patients (100%). RESULTS: No early or late postoperative deaths were encountered. One patient underwent redo MV repair owing to severe mitral regurgitation 1 month postoperatively. Postoperative echocardiography after MV repair demonstrated less than trivial (acute IE in seven, healed IE in three) or mild (acute IE in three, healed IE in one) mitral regurgitation. In patients with MV replacement, the postoperative left atrial dimension (LAD) was decreased (51.5 +/- 39.2 vs. 39.2 +/- 1.9 mm, P = 0.007); however LV end-diastolic dimension (LVDD) and LV end-systolic dimension were unchanged. In patients with MV repair, LVDD (57.5 +/- 6.5 vs. 46.0 +/- 5.6 mm, P < 0.001), LV end-systolic dimension (36.1 +/- 5.2 vs. 32.4 +/- 6.2 mm, P = 0.04), LAD (43.1 +/- 8.1 vs. 33.6 +/- 7.7 mm, P = 0.003) were reduced. Postoperative ejection fraction (55.3 +/- 13.5% vs. 41.8% +/- 10.0%, P = 0.03) and fraction shortening (30.1% +/- 9.2% vs. 20.7% +/- 5.5%, P = 0.03) were better in patients with MV repair than those with MV replacement. CONCLUSIONS: MV repair is feasible in patients with both active and healed IE. MV repair preserves better LV function and structure postoperatively.

Quantitative glycomics of human whole serum glycoproteins based on the standardized protocol for liberating N-glycans.

Global glycomics of human whole serum glycoproteins appears to be an innovative and comprehensive approach to identify surrogate non-invasive biomarkers for various diseases. Despite the fact that quantitative glycomics is premised on highly efficient and reproducible oligosaccharide liberation from human serum glycoproteins, it should be noted that there is no validated protocol for which deglycosylation efficiency is proven to be quantitative. To establish a standard procedure to evaluate N-glycan release from whole human serum glycoproteins by peptide-N-glycosidase F (PNGase F) treatment, we determined the efficiencies of major N-glycan liberation from serum glycoproteins in the presence of reducing agents, surfactants, protease treatment, or combinations of pretreatments prior to PNGase F digestion. We show that de-N-glycosylation efficiency differed significantly depending on the condition used, indicative of the importance of a standardized protocol for the accumulation and comparison of glycomics data. Maximal de-N-glycosylation was achieved when serum was subjected to reductive alkylation in the presence of 2-hydroxyl-3-sulfopropyl dodecanoate, a surfactant used for solubilizing proteins, or related analogues, followed by tryptic digestion prior to PNGase F treatment. An optimized de-N-glycosylation protocol permitted relative and absolute quantitation of up to 34 major N-glycans present in serum glycoproteins of normal subjects for the first time. Moreover PNGase F-catalyzed de-N-glycosylation of whole serum glycoproteins was characterized kinetically, allowing accurate simulation of PNGase F-catalyzed de-N-glycosylation required for clinical glycomics using human serum samples. The results of the current study may provide a firm basis to identify new diagnostic markers based on serum glycomics analysis.

Coexistence of cystic medial necrosis and segmental arterial mediolysis in a patient with aneurysms of the abdominal aorta and the iliac artery.

Segmental arterial mediolysis is an unusual arterial lesion for which pathogenesis has remained controversial. We report on a 47-year-old Japanese woman who underwent surgery for an abdominal aortic aneurysm that was 10.5 cm in diameter and contiguous with a left common iliac aneurysm that was 2.3 cm in diameter; the aneurysms were considered to have progressed rapidly in size. Pathologic examinations of the respective aneurysms showed cystic medial necrosis in the aortic and segmental arterial mediolysis in the iliac aneurysm. Coexistence of these two pathologic findings indicates that there may be a strong relation between these two disease entities.