Differential effects on renal function and glucose metabolism of renal dependent bezafibrate and non-renal dependent pemafibrate in patients with hypertriglyceridemia.

OBJECTIVE: Among fibrates as triglyceride-lowering agents, bezafibrate and fenofibrate are predominantly renally excreted, while pemafibrate is mainly hepatically metabolized and biliary excreted. To elucidate possible different properties among fibrates, this retrospective observational study examined the changes in clinical laboratory parameters, including indices of renal function and glucose metabolism, in cases of switching from bezafibrate to pemafibrate. MATERIALS AND METHODS: In 93 patients with hypertriglyceridemia, the average values of laboratory parameters including serum creatinine, estimated glomerular filtration rate (eGFR), plasma glucose, and hemoglobin A1c on respective two occasions before and after switching from bezafibrate to pemafibrate were evaluated. RESULTS: Triglycerides, low-density and high-density lipoprotein cholesterol, creatine kinase, and uric acid did not change before and after switching from bezafibrate to pemafibrate. Serum creatinine significantly decreased and eGFR significantly increased after switching from bezafibrate to pemafibrate (p < 0.001, respectively). Plasma glucose tended to increase (p = 0.070) and hemoglobin A1c significantly increased (p < 0.001) after switching to pemafibrate. The degrees of changes in creatinine, eGFR, glucose, and hemoglobin A1c before and after drug switching were not affected by the presence or absence of coexisting disease, and with or without drug treatment including statin and renin-angiotensin system inhibitor. CONCLUSION: Our findings indicate that switching from bezafibrate to pemafibrate produces a significant decrease in serum creatinine and increases in eGFR and hemoglobin A1c in patients with hypertriglyceridemia, suggesting that the effects on renal function and glucose metabolism differ among fibrates.

Stereoisomer-Specific Induction of G2/M Phase Arrest and Apoptosis by 9-(E,Z)-Hydroxyoctadecadienoic Acid in Mouse Lymphoma Cells.

Hydroxyoctadecadienoic acids (HODEs) are generated by oxidation of linoleic acid in vivo and thought to mediate various pathophysiological responses. In this study, we examined the effects of HODEs on EL4 mouse lymphoma cell growth and found that 9-(E,Z)-HODE inhibited EL4 cell growth in a dose-dependent manner, whereas no such growth inhibition was observed with other isomers (9-(E,E)-, 13-(Z,E)-, or 13-(E,E)-HODE), suggesting that the growth-inhibitory effect of HODEs was stereospecific. Analysis by flow cytometry (FACS) with annexin V and propidium iodide (PI) staining showed that 9-(E,Z)-HODE induced apoptosis with G2/M phase arrest. We next examined the growth inhibition profile of 9-(E,Z)-HODE against a panel of 39 human cancer cell lines (JFCR39). The fingerprint of growth inhibition by 9-(E,Z)-HODE exhibited a high degree of similarity to that by MLN4924, an inhibitor of NEDD8-activating enzyme. The intracellular NEDD8 (ubiquitin-like protein) expression in EL4 cells was decreased by the treatment with 9-(E,Z)-HODE as assessed by immunoblotting and flow cytometry. In conclusion, 9-(E,Z)-HODE specifically induced G2/M phase arrest and apoptosis, and the decrease of NEDD8 expression might be involved in this effect.

Identification of the Fluvirucin B2 (Sch 38518) Biosynthetic Gene Cluster from Actinomadura fulva subsp. indica ATCC 53714: substrate Specificity of the ß-Amino Acid Selective Adenylating Enzyme FlvN.

Fluvirucins are 14-membered macrolactam polyketides that show antifungal and antivirus activities. Fluvirucins have the ß-alanine starter unit at their polyketide skeletons. To understand the construction mechanism of the ß-alanine moiety in fluvirucin biosyntheses, we have identified the biosynthetic cluster of fluvirucin B2 produced from Actinomadura fulva subsp. indica ATCC 53714. The identified gene cluster contains three polyketide synthases, four characteristic ß-amino acid-carrying enzymes, one decarboxylase, and one amidohydrolase. We next investigated the activity of the adenylation enzyme FlvN, which is a key enzyme for the selective incorporation of a ß-amino acid substrate. FlvN showed strong preference for l-aspartate over other amino acids such as ß-alanine. Based on these results, we propose a biosynthetic pathway for fluvirucin B2.

Contrast echocardiography for the diagnosis of left ventricular thrombus in anterior myocardial infarction.

Although detecting left ventricular thrombus in anterior myocardial infarction is important for the prevention of embolic events, imaging of apical thrombus is often difficult using conventional echocardiography. We examined whether contrast echocardiography improves sensitivity and specificity in detecting thrombus in the left ventricle in comparison with conventional echocardiography alone in patients with anterior myocardial infarction. Participants in this single-center prospective study comprised 392 patients with anterior myocardial infarction admitted between 2000 and 2006. After conventional echocardiography, all patients underwent contrast echocardiography (left ventricular opacification and myocardial contrast echocardiography) during intravenous drip infusion of contrast media at rest. Left ventricular thrombus was diagnosed based on left ventriculography or multidetector-row computed tomography (MDCT). Mural left ventricular thrombus was confirmed by left ventriculography and/or MDCT in 32 of 393 patients (8 %). Sensitivity and specificity of conventional echocardiography alone were 88 % and 96 %, respectively, compared with 100 % each with contrast echocardiography. Among the 32 patients with left ventricular thrombus, 25 patients (78 %) showed no perfusion in the anterior wall on myocardial contrast echocardiography, even with a four-beat interval. In conclusion, contrast echocardiography offers a clinically feasible and useful method for noninvasively evaluating left ventricular thrombus in anterior myocardial infarction.

Pulmonary artery aneurysm induced by lung abscess.

Physicians should consider a pulmonary artery aneurysm complication in patients presenting with hemoptysis during treatment for a pulmonary abscess. Contrast-enhanced CT or angiography is recommended for diagnosis, followed by pulmonary embolization for treatment.

Immune checkpoint inhibitor-induced asthma and chronic obstructive pulmonary disease overlap in patient with adenocarcinoma.

A 67-year-old current smoker Japanese man, with no history of asthma, was diagnosed with lung adenocarcinoma. He received first-line chemotherapy with carboplatin, pemetrexed, ipilimumab, and nivolumab in July 20XX-1, and subsequently a maintenance therapy with nivolumab. In October 20XX, he became aware of wheezy dyspnoea, and chest computed tomography demonstrated worsening bronchial wall thickenings. Eosinophilia was noted, and a pulmonary function test showed obstructive dysfunction insufficiently responding to beta-agonists, with 130 mL increase of forced expiratory volume in one second and high fractional exhaled nitric oxide level (85 ppb). He was clinically diagnosed with asthma and chronic obstructive pulmonary disease overlap, secondary to immune checkpoint inhibitors (ICIs). The inhibition of binding between programmed cell death-protein-1 (PD-1), expressed on T cells, and programmed cell death-ligand-2 (PD-L2), expressed on tumour and dendritic cells, can induce airway hyperresponsiveness. Physicians should be wary of asthmatic symptoms and chest image findings during ICIs therapy.

Shear-Viscosity-Dependent Effect of a Gum-Based Thickening Product on the Safety of Swallowing in Older Patients with Severe Oropharyngeal Dysphagia.

Fluid thickening is a valid therapeutic strategy for patients with oropharyngeal dysphagia (OD). The main aim of this study was to determine the therapeutic effect of the xanthan-gum-based thickener Tsururinko Quickly (TQ, Morinaga Milk Co., Tokyo, Japan) in older patients with severe OD. A total of 85 patients (83.32 ± 6.75 y) with OD and a penetration-aspiration score (PAS) of n ≥ 3 were studied by videofluoroscopy while swallowing duplicate 10 mL boluses at <50 mPa·s, 100, 200, 400, 800, and 1600 mPa·s, to assess the safety and efficacy of swallowing and the biomechanics of a swallowing response at each viscosity level. At <50 mPa·s, only 16.25% patients swallowed safely, 45% had penetrations (PAS 3-5), and 38.75% had aspirations (PAS 6-8). Fluid thickening with TQ greatly increased the prevalence of patients with safe swallowing from 62.90% at 100 mPa·s to 95.24% at 1600 mPa·s in a shear-viscosity-dependent manner. The penetrations and aspirations were significantly reduced to 3.60% and 1.19%, respectively, at 1600 mPa·s. The threshold viscosity was 100 mPa·s and the increasing viscosity above 800 mPa·s did not further improve the therapeutic effect significantly. Increasing the shear viscosity significantly reduced the time to laryngeal vestibule closure (-16.70%), increased the time to upper oesophageal sphincter opening (+26.88%), and reduced the pharyngeal bolus velocity (-31.62%) without affecting the pharyngeal residue. TQ has a strong shear-viscosity-dependent effect on the safety of swallowing in older patients with severe OD without increasing the pharyngeal residue. The therapeutic range for TQ is 100-800 mPa·s, with 200 and 800 mPa·s being the optimal doses to cover the needs of older patients with OD.

Gustatory sensation of (L)- and (D)-amino acids in humans.

Amino acids are known to elicit complex taste, but most human psychophysical studies on the taste of amino acids have focused on a single basic taste, such as umami (savory) taste, sweetness, or bitterness. In this study, we addressed the potential relationship between the structure and the taste properties of amino acids by measuring the human gustatory intensity and quality in response to aqueous solutions of proteogenic amino acids in comparison to D-enantiomers. Trained subjects tasted aqueous solution of each amino acid and evaluated the intensities of total taste and each basic taste using a category-ratio scale. Each basic taste of amino acids showed the dependency on its hydrophobicity, size, charge, functional groups on the side chain, and chirality of the alpha carbon. In addition, the overall taste of amino acid was found to be the combination of basic tastes according to the partial structure. For example, hydrophilic non-charged middle-sized amino acids elicited sweetness, and L-enantiomeric hydrophilic middle-sized structure was necessary for umami taste. For example, L-serine had mainly sweet and minor umami taste, and D-serine was sweet. We further applied Stevens' psychophysical function to relate the total-taste intensity and the concentration, and found that the slope values depended on the major quality of taste (e.g., bitter large, sour small).

Proposal for a Standard Protocol to Assess the Rheological Behavior of Thickening Products for Oropharyngeal Dysphagia.

Increasing shear viscosity (ShV) in thickening products (TP) is a valid therapeutic strategy for oropharyngeal dysphagia (OD). However, salivary amylase in the oral phase and shear rate in the pharyngeal phase of swallowing can change the viscosity of TPs when swallowed. This study aims to design and validate a rheological protocol to reproduce the oral and pharyngeal factors that affect the therapeutic effect of TPs and report the viscosity measurements in a standardized scientific and precise manner. We measured (a) the variability of the ShV measurements across several laboratories; (b) the in vitro and ex vivo properties of TPs and (c) the impact of the X-ray contrast Omnipaque, temperature and resting time on the rheological properties of TPs. A common protocol was applied in four international laboratories to assess five ShV values (100, 200, 400, 800 and 1600 mPa·s) for the xanthan-gum TP Tsururinko Quickly (TQ). The protocol included the dose (g/100 mL water), stirring procedure and standing time before measurement. Each value was characterized at the shear rate of 50 and 300 s-1 pre- and post-oral incubation in eight volunteers. The effect of temperature, standing time and Omnipaque was assessed. The main results of the study were: (a) The mean intra-laboratory variability on the ShV at all levels was very low: 0.85%. The mean inter-laboratory variability was higher: 9.3%; (b) The shear thinning of TQ at 300 s-1 was 75-80%. Increasing the temperature or standing time did not affect the ShV, and oral amylase caused a small decrease; (c) Omnipaque slightly decreased the dose of TP and hardly affected the amylase resistance or shear thinning. This study showed that different laboratories can obtain very accurate and similar ShV measurements using this protocol which uses scientific, universal SI units (mPa·s). Our protocol accurately reproduces oral and pharyngeal factors affecting the therapeutic effect of TPs. The addition of X-ray contrast did not produce significant changes.

Mutational Biosynthesis of Hitachimycin Analogs Controlled by the ß-Amino Acid-Selective Adenylation Enzyme HitB.

Hitachimycin is a macrolactam antibiotic with an (S)-ß-phenylalanine (ß-Phe) at the starter position of its polyketide skeleton. (S)-ß-Phe is formed from l-α-phenylalanine by the phenylananine-2,3-aminomutase HitA in the hitachimycin biosynthetic pathway. In this study, we produced new hitachimycin analogs via mutasynthesis by feeding various (S)-ß-Phe analogs to a ΔhitA strain. We obtained six hitachimycin analogs with F at the ortho, meta, or para position and Cl, Br, or a CH3 group at the meta position of the phenyl moiety, as well as two hitachimycin analogs with thienyl substitutions. Furthermore, we carried out a biochemical and structural analysis of HitB, a ß-amino acid-selective adenylation enzyme that introduces (S)-ß-Phe into the hitachimycin biosynthetic pathway. The KM values of the incorporated (S)-ß-Phe analogs and natural (S)-ß-Phe were similar. However, the KM values of unincorporated (S)-ß-Phe analogs with Br and a CH3 group at the ortho or para position of the phenyl moiety were high, indicating that HitB functions as a gatekeeper to select macrolactam starter units during mutasynthesis. The crystal structure of HitB in complex with (S)-ß-3-Br-phenylalanine sulfamoyladenosine (ß-m-Br-Phe-SA) revealed that the bulky meta-Br group is accommodated by the conformational flexibility around Phe328, whose side chain is close to the meta position. The aromatic group of ß-m-Br-Phe-SA is surrounded by hydrophobic and aromatic residues, which appears to confer the conformational flexibility that enables HitB to accommodate the meta-substituted (S)-ß-Phe. The new hitachimycin analogs exhibited different levels of biological activity in HeLa cells and multidrug-sensitive budding yeast, suggesting that they may target different molecules.

Application of umami taste stimulation to remedy hypogeusia based on reflex salivation.

Enjoying taste should be one of the greatest pleasures in human life. However, aging is sometimes associated with decreased taste sensitivity, also known as hypogeusia. The loss of taste not only affects quality of life, but can also cause weight loss and health problems in the elderly. Our recent study has shown that 37% of test subjects over 65 years of age exhibited hypogeusia. Further, whole saliva secretion, including minor salivary secretion, was significantly decreased in elderly patients with gustatory impairment, but was normal in all elderly subjects with normal taste thresholds. These data indicate that hyposalivation is closely related to hypogeusia. Moreover, clinical studies have shown that treatment of hyposalivation diminishes hypogeusia, indicating that salivation is essential to maintain normal taste function. However, many medications for relief of dry mouth, such as parasympathomimetic (cholinomimetic) drugs, have serious adverse effects. Palpitation, sweating, nausea, diarrhea and dizziness have all been observed in elderly patients taking parasympathomimetic drugs. To circumvent this problem, glutamate, which produces umami taste, was demonstrated to increase salivary secretion and thereby improve hypogeusia by enhancing the gustatory-salivary reflex. Our data suggests that umami is an effective tool for the relief of hypogeusia without the side effects of parasympathomimetic drugs.

Association between tissue characteristics assessed with optical coherence tomography and mid-term results after percutaneous coronary intervention for in-stent restenosis lesions: a comparison between balloon angioplasty, paclitaxel-coated balloon dilatation, and drug-eluting stent implantation.

AIMS: Morphological assessment of neointimal tissue using optical coherence tomography (OCT) is important for clarifying the pathophysiology of in-stent restenosis (ISR) lesions. The aim of this study was to determine the impact of OCT findings on recurrence of ISR after various types of percutaneous coronary intervention (PCI) including plain old balloon angioplasty (POBA), paclitaxel-coated balloon (PCB) dilatation, and drug-eluting stent (DES) implantation. METHODS AND RESULTS: Between June 2008 and August 2013, we performed PCI for 428 ISR lesions in 379 patients using POBA (78 lesions, POBA group), PCB dilatation (202 lesions, PCB group), and DES implantation (148 lesions, DES group). Morphological assessment of neointimal tissue at the minimum lumen area site to determine restenotic tissue structure (homogeneous, heterogeneous, or layered type) using OCT was performed. We examined the association between tissue structure and midterm results including ISR and target lesion revascularization (TLR) rates. The patients were 308 men and 71 women with a mean age of 68.9 ± 9.4 years. The mean follow-up period was 211 ± 40 days. ISR and TLR rates of lesions with a homogeneous structure were significantly higher in the POBA group than in the PCB group (ISR: 54.8 vs. 19.1%, P < 0.001; TLR: 38.7 vs. 10.6%, P < 0.001) and DES group (ISR: 54.8 vs. 19.6%, P = 0.002; TLR: 38.7 vs. 10.7%, P = 0.005), whereas there were no differences in ISR and TLR rates between the three groups in lesions with a heterogeneous structure. CONCLUSION: Morphological assessment of ISR tissue using OCT might suggest favourable types of PCI for ISR lesions.

Hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, mediate the endotoxin-induced suppression of the reproductive axis in rats.

It is well established that endotoxemia disrupts reproductive capability, and several proinflammatory cytokines, especially IL-1 beta, IL-6, and TNF-alpha in the brain, have been implicated in this endocrine aberration. However, no previous study has directly compared the effects of the three major proinflammatory cytokines (IL-1 beta, IL-6, and TNF-alpha) on the in vivo release of hypothalamic GnRH, a secretagogue of LH from the pituitary. Therefore, in this study, we addressed this issue with two complementary approaches involving push-pull perfusion in freely moving ovariectomized female rats. First, we examined the effects of systemic lipopolysaccharide (LPS) treatment on the release of plasma LH, and of GnRH, IL-1 beta, IL-6, and TNF-alpha in the hypothalamic medial preoptic area (MPOA), where the majority of GnRH neuronal perikarya are located. LPS inhibited the secretion of both LH and GnRH and concomitantly stimulated the release of all three cytokines. We next tested the effects of direct MPOA perfusion with the respective cytokines (at three different concentrations each) on the GnRH and LH secretion. IL-1 beta and TNF-alpha, at the concentrations that were observed in the MPOA after the LPS injection, were equipotent in inhibiting the GnRH-LH system, whereas IL-6 was ineffective (even at a supraphysiological concentration). These results strongly suggest that IL-1 beta and TNF-alpha may represent the major proinflammatory cytokines mediating the LPS-induced suppression of GnRH and LH release, whereas the role of IL-6 seems to be insignificant.

Development of an umami taste sensitivity test and its clinical use.

There is a close relationship between perception of umami, which has become recognized as the fifth taste, and the human physical condition. We have developed a clinical test for umami taste sensitivity using a filter paper disc with a range of six monosodium glutamate (MSG) concentrations. We recruited 28 patients with taste disorders (45-78 years) and 184 controls with no taste disorders (102 young [18-25 years] and 82 older [65-89 years] participants). Filter paper discs (5 mm dia.) were soaked in aqueous MSG solutions (1, 5, 10, 50, 100 and 200 mM), then placed on three oral sites innervated by different taste nerves. The lowest concentration participants correctly identified was defined as the recognition threshold (RT) for MSG. This test showed good reproducibility for inter- and intra-observer variability. We concluded that: (1) The RT of healthy controls differed at measurement sites innervated by different taste nerves; that is, the RT of the anterior tongue was higher than that of either the posterior tongue or the soft palate in both young and older individuals. (2) No significant difference in RT was found between young adults and older individuals at any measurement site. (3) The RT of patients with taste disorders was higher before treatment than that of the healthy controls at any measurement site. (4) The RT after treatment in these patients improved to the same level as that of the healthy controls. (5) The cutoff values of RT, showing the highest diagnostic accuracy (true positives + true negatives), were 200 mM MSG for AT and 50 mM MSG for PT and SP. The diagnostic accuracy at these cutoff values was 0.92, 0.87 and 0.86 for AT, PT and SP, respectively. Consequently, this umami taste sensitivity test is useful for discriminating between normal and abnormal umami taste sensations.

Association between tissue characteristics evaluated with optical coherence tomography and mid-term results after paclitaxel-coated balloon dilatation for in-stent restenosis lesions: a comparison with plain old balloon angioplasty.

AIMS: Morphological assessment of neointimal tissue using optical coherence tomography (OCT) is important for clarifying the pathophysiology of in-stent restenosis (ISR) lesions. The aim of this study was to determine the impact of OCT findings on recurrence of ISR after paclitaxel-coated balloon (PCB) dilatation compared with plain old balloon angioplasty (POBA). METHODS AND RESULTS: Between July 2008 and May 2012, we performed percutaneous coronary intervention for 214 ISR lesions using POBA + PCB (146 lesions, PCB group) or POBA only (68 lesions, POBA group). Morphological assessment of neointimal tissue using OCT, including assessment of restenotic tissue structure and restenotic tissue backscatter, was performed. We examined the association between lesion morphologies and mid-term (6-8 months) results including ISR and target lesion revascularization (TLR) rates. Both ISR and TLR rates of lesions with a homogeneous structure were significantly lower in the PCB group than those in the POBA group (ISR: 20.0 vs. 55.6%, P = 0.002, TLR: 12.7 vs. 37.0%, P = 0.019), but there was no difference between the two groups in ISR and TLR rates of lesions with a heterogeneous or layered structure. Both ISR and TLR rates of lesions with high backscatter were significantly lower in the PCB group than those in the POBA group (ISR: 19.8 vs. 52.5%, P < 0.001, TLR: 13.6 vs. 42.5%, P = 0.001), but there was no difference between the two groups in ISR and TLR rates of lesions with low backscatter. CONCLUSION: Morphological assessment of ISR tissue using OCT might be useful for identifying ISR lesions favourable for PCB dilatation.

Optical coherence tomography findings in lesions after sirolimus-eluting stent implantation with peri-stent contrast staining.

BACKGROUND: We have sometimes noted abnormal angiographic coronary dilatation, <50% of the reference vessel, at the site of sirolimus-eluting stent implantation, suggesting contrast staining outside the stent struts and named this finding peri-stent contrast staining (PSS). Little was known about optical coherence tomography findings of lesions with PSS. METHODS AND RESULTS: Between May 2008 and March 2010, we performed optical coherence tomography for 90 in-stent restenosis lesions after sirolimus-eluting stent implantation. We found PSS in 20 of the 90 lesions by coronary angiography. The differences in optical coherence tomography findings, including incomplete stent apposition, multiple interstrut hollows (MIH), strut coverage, and thrombus, were compared between lesions with PSS and those without PSS. PSS is defined as contrast staining outside the stent contour extending to >20% of the stent diameter measured by quantitative coronary angiography. MIH is defined as multiple hollows (the maximum depth >0.5 mm) existing between and outside well-apposed stent struts. Both incomplete stent apposition (60.0% versus 10%; P<0.001) and MIH (85.0% versus 25.7%; P<0.001) were frequently observed in lesions with PSS than in lesions without PSS. Among the 20 lesions with PSS, there was only 1 lesion in which we found neither MIH nor incomplete stent apposition, but only minor dissection. Uncovered struts (11.6% versus 3.9%; P=0.001), malapposed struts (2.0% versus 0.0%; P<0.001), and red thrombus (35% versus 10%; P=0.012) were frequently observed in lesions with PSS than in lesions without PSS. CONCLUSIONS: PSS might be closely associated with 2 different optical coherence tomography findings, MIH and incomplete stent apposition, in lesions after sirolimus-eluting stent implantation.

Contribution of umami taste substances in human salivation during meal.

The oral gustatory perception during a meal has very important physiological roles such as inducing appetite, smoothing mastication and swallowing, promoting digestion and each nutrient availability. One hundred years ago, L-glutamate was discovered as a new taste substance in Japan. Since then, Japanese taste physiologists have lead the research to establish L-glutamate as the prototype molecule for the fifth basic taste (umami taste), in addition to saltiness, sweetness, bitterness and sourness. Meanwhile, various lines of evidence demonstrated that taste perception is linked to taste stimuli-oral/pharyngeal reflexes. In this review, we focus on the efficacy of L-glutamate for human salivation and discuss the possible application of umami taste simulation to the nutritional management for the elderly due to amelioration of their quality of life (QOL).