Publications by authors named "Hiroyuki Kobayashi"

627 Publications

Determination of Brain Tumor Recurrence using C-methionine Positron Emission Tomography after Radiotherapy.

Cancer Sci 2021 Jun 1. Epub 2021 Jun 1.

Department of Nuclear Medicine, Hokkaido University Hospital, Sapporo, Japan.

We conducted a prospective multicenter trial to compare the usefulness of C-methioinine (MET) and F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both C-MET and F-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at three months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either C-MET or F-FDG underwent surgery; and 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in 1 of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of C-MET PET and F-FDG PET were 0.97 (32/33, 95% CI: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (p<0.0001). The diagnostic accuracy of C-MET PET was significantly better than that of F-FDG PET (87.5% vs. 69.6%, p=0.033). No examination-related adverse events were observed. The results of the study demonstrated that C-MET PET was superior to F-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis.
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http://dx.doi.org/10.1111/cas.15001DOI Listing
June 2021

Bioluminescence Resonance Energy Transfer (BRET) Imaging in Living Cells: Image Acquisition and Quantification.

Methods Mol Biol 2021 ;2274:305-314

Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC, Canada.

Bioluminescence resonance energy transfer (BRET) is an energy transfer phenomenon from a luciferase donor to a fluorescence acceptor and serves as an indicator of protein-protein interaction or protein proximity. BRET imaging is a powerful tool in the investigation of signaling proteins because it enables spatial analysis of such protein interactions. Here, we describe a method exerting high-resolution BRET imaging by combining bright-light output luciferases, such as NanoLuc , photon-counting EM-CCD, and unique algorithms for image correction and denoising.
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http://dx.doi.org/10.1007/978-1-0716-1258-3_26DOI Listing
June 2021

Examination of gender differences in patients with takotsubo syndrome according to left ventricular biopsy: two case reports.

J Med Case Rep 2021 May 21;15(1):281. Epub 2021 May 21.

Department of Cardiology, Tokai University School of Medicine, Isehara, Kanagawa, 259-1193, Japan.

Background: Takotsubo syndrome is a stress-induced disease that makes up 2-3% of acute coronary syndrome cases. However, its onset mechanism remains unclear. Although females are overwhelmingly affected, males end up having more cardiac complications.

Case Presentation: We examined the differences in stress responses in the myocardium between sexes in patients with takotsubo syndrome. We biopsied samples from an over 70-year-old Japanese male and an over 80-year-old Japanese female. Tissues from the left ventricle apex in the acute phase and the apical ballooning-type were examined using histopathology and deoxyribonucleic acid (DNA) microarray analysis. Our data showed that left ventricular ejection fractions were 38% and 56%, and peak creatinine kinase concentrations during hospitalization were 629 U/L and 361 U/L, for the male and female patient, respectively. The pulmonary capillary wedge pressure was 26 mmHg and 11 mmHg for the male and female patient, respectively. Negative T did not return to normal in the male subject after 6 months. Histopathology results indicated that contraction band necrosis and lymphocyte infiltration were more common in the male subject.

Conclusions: We noticed that possible differences may exist between male and female patients using pathological examination and some DNA analyses. In particular, it may help treat acute severity in males. We will elucidate the mechanism of takotsubo syndrome development by increasing the number of samples to support the reliability of the data in the future.
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http://dx.doi.org/10.1186/s13256-021-02856-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139097PMC
May 2021

BRET-based effector membrane translocation assay monitors GPCR-promoted and endocytosis-mediated G activation at early endosomes.

Proc Natl Acad Sci U S A 2021 May;118(20)

Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3T 1J4, Canada;

G protein-coupled receptors (GPCRs) are gatekeepers of cellular homeostasis and the targets of a large proportion of drugs. In addition to their signaling activity at the plasma membrane, it has been proposed that their actions may result from translocation and activation of G proteins at endomembranes-namely endosomes. This could have a significant impact on our understanding of how signals from GPCR-targeting drugs are propagated within the cell. However, little is known about the mechanisms that drive G protein movement and activation in subcellular compartments. Using bioluminescence resonance energy transfer (BRET)-based effector membrane translocation assays, we dissected the mechanisms underlying endosomal G trafficking and activity following activation of G-coupled receptors, including the angiotensin II type 1, bradykinin B, oxytocin, thromboxane A alpha isoform, and muscarinic acetylcholine M receptors. Our data reveal that GPCR-promoted activation of G at the plasma membrane induces its translocation to endosomes independently of β-arrestin engagement and receptor endocytosis. In contrast, G activity at endosomes was found to rely on both receptor endocytosis-dependent and -independent mechanisms. In addition to shedding light on the molecular processes controlling subcellular G signaling, our study provides a set of tools that will be generally applicable to the study of G protein translocation and activation at endosomes and other subcellular organelles, as well as the contribution of signal propagation to drug action.
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http://dx.doi.org/10.1073/pnas.2025846118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157916PMC
May 2021

Mirogabalin, a novel ligand for αδ subunit of voltage-gated calcium channels, improves cognitive impairments in repeated intramuscular acidic saline injection model rats, an experimental model of fibromyalgia.

Biomed Pharmacother 2021 Jul 30;139:111647. Epub 2021 Apr 30.

Specialty Medicine Research Laboratories I, Daiichi-Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address:

Mirogabalin is a novel potent and selective ligand for the αδ subunit of voltage-gated calcium channels, and shows potent and sustained analgesic effects in neuropathic pain and fibromyalgia models. Fibromyalgia is often associated with multiple comorbid symptoms, such as anxiety, depression and cognitive impairment. In the present study, we investigated the effects of mirogabalin on cognitive impairments in an experimental animal model for fibromyalgia, repeated intramuscular acidic saline injection model (Sluka model) rats. Male rats received two repeated intramuscular injections of pH 4 acidic saline into their gastrocnemius muscle. After developing mechanical hypersensitivity as identified in the von Frey test, the animals received the test substance orally once daily for 13 days and were subjected to four cognitive function tests, (Y-maze, novel object recognition, Morris water maze and step-through passive avoidance). Sluka model rats showed cognitive impairments in all four tests. Oral administration of mirogabalin (3 and 10 mg/kg) improved the cognitive impairments in these rats. In conclusion, mirogabalin improved the impaired cognitive function in Sluka model rats. It may thus also alleviate cognitive impairments as well as painful symptoms in fibromyalgia patients.
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http://dx.doi.org/10.1016/j.biopha.2021.111647DOI Listing
July 2021

Comparative dynamics of potassium and radiocesium in soybean with different potassium application levels.

J Environ Radioact 2021 Jul 12;233:106609. Epub 2021 Apr 12.

Agricultural Radiation Research Center, Tohoku Agricultural Research Center, NARO, 50 Harajuku-minami, Arai, Fukushima, Fukushima, 960-2156, Japan; Research Faculty of Agriculture, Hokkaido University, Kita 9, Nishi 9, Kita-ku, Sapporo, Hokkaido, 060-8589, Japan. Electronic address:

We conducted a field experiment in soybean with different levels of K application to elucidate the comparative dynamics of Cs and K. The inventory of K in the shoots increased substantially from the fifth trifoliate stage to the full seed stage, and as the absorption of K increased, so too did the absorption of Cs. Overall, the effect of K application was much greater in terms of Cs dynamics than K dynamics or biomass production. K application reduced not only the accumulation of Cs in the shoots, but also the distribution of Cs to the grains. However, the decrease of Cs distribution to the grain had a much smaller effect on Cs accumulation in the grains than Cs absorption. A positive correlation was also observed between the exchangeable Cs/K ratio in the soil and the Cs/K ratio in the shoots for each growth stage, and the Cs/K ratios in the shoots at the full seed and full maturity stage were much higher than those at the fifth trifoliate and full bloom stage under the same exchangeable Cs/K ratio in the soil. These findings suggest a decrease in the discrimination of Cs from K during absorption after the full bloom stage. As a result of this and the increase in soil-exchangeable Cs/K with growth, radiocesium was more transferable to the shoots after the full bloom stage. Overall, these results suggest that lowering the soil-exchangeable radiocesium/potassium ratio after the full bloom stage by increasing K availability could efficiently reduce the transfer of radiocesium to the grains.
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http://dx.doi.org/10.1016/j.jenvrad.2021.106609DOI Listing
July 2021

Primary Hepatic Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue in a Patient with Chronic Hepatitis B Virus Infection: Case Report and Summary of the Literature.

Medicina (Kaunas) 2021 Mar 18;57(3). Epub 2021 Mar 18.

Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.

Background: The incidence of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is low, at 7-8% of all non-Hodgkin lymphoma cases. The most common site of MALT lymphoma occurrence is the stomach. Primary hepatic extranodal marginal zone lymphoma of MALT is classified as a type of non-gastric MALT lymphoma and is considered extremely rare, with no consensus on imaging study findings or treatment due to a limited number of reports. We herein describe a rare case of primary hepatic extranodal marginal zone lymphoma of MALT with underlying hepatitis B infection (HBV) and present useful diagnostic findings of various imaging modalities, including contrast-enhanced ultrasonography (CEUS) with Sonazoid.

Case Presentation: A 66-year-old woman was diagnosed as being a non-active carrier of HBV at 51 years of age at the time of total hysterectomy and bilateral adnexectomy for uterine cervical cancer. She was admitted to our hospital following the incidental detection of two focal liver lesions on computed tomography. The lesions were considered malignant based on clinical and other radiologic imaging findings. Her CEUS results of hypo-enhancement in the portal and late phases were consistent with those of previously reported cases of hepatic extranodal marginal zone lymphoma of MALT, and histological liver biopsy findings were compatible with the diagnosis.

Conclusions: Primary hepatic extranodal marginal zone lymphoma of MALT is a rare condition that can appear in HBV carriers. Characteristic CEUS findings may help in disease diagnosis. Clinicians should bear primary hepatic extranodal marginal zone lymphoma of MALT in mind when encountering patients with focal liver lesions which exhibit image findings different from those of typical hepatocellular carcinoma.
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http://dx.doi.org/10.3390/medicina57030280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002959PMC
March 2021

Protocol: Prospective observational study investigating the prevalence and clinical outcome of portopulmonary hypertension in Japanese patients with chronic liver disease.

PLoS One 2021 1;16(4):e0249435. Epub 2021 Apr 1.

Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.

Background: Portopulmonary hypertension (PoPH) is a subtype of the pulmonary arterial hypertension (PAH) associated with portal hypertension. There is a dissociation between the proportion of PoPH in PAH and that of PoPH in patients with liver cirrhosis, suggesting PoPH underdiagnosis and an incomplete understanding of this entity in the clinical setting. Specifically, real-world data in Japan is largely unknown as compared with in Europe and the United States. The present study aims to elucidate the prevalence and etiology of PoPH in Japanese patients with chronic liver disease.

Methods And Design: In this prospective, single-center, observational investigation of PoPH patients with chronic liver disease, a targeted 2,500 Japanese adult patients regularly visiting Shinshu University Hospital in Matsumoto, Japan, for chronic liver disease will complete a standardized questionnaire on the presence of PoPH symptoms. If the respondent has signs of possible PoPH, ultrasound echocardiography (UCG) will be performed as a primary screening. In the case that UCG findings indicate pulmonary hypertension, the patient will be referred to a cardiologist for further evaluation, whereby a definitive diagnosis PoPH can be made. PoPH prevalence and etiology will be investigated at the time of diagnosis. Afterwards, patients with PoPH will be followed for five years for determination of survival rate.

Discussion: This study will reveal the prevalence, etiology, and 5-year survival rate of PoPH in Japanese patients with chronic liver disease.

Trial Registration: This study is being performed at Shinshu University following registration as UMIN 000042287 on October 29, 2020.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249435PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016266PMC
April 2021

Comprehensive Glycomic Approach Reveals Novel Low-Molecular-Weight Blood Group-Specific Glycans in Serum and Cerebrospinal Fluid.

J Proteome Res 2021 05 10;20(5):2812-2822. Epub 2021 Mar 10.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan.

ABO blood antigens on the human red blood cell membrane as well as different cells in various human tissues have been thoroughly studied. Anti-A and -B antibodies of IgM are present in serum/plasma, but blood group-specific glyco-antigens have not been extensively described. In this study, we performed comprehensive and quantitative serum glycomic analyses of various glycoconjugates and free oligosaccharides in all blood groups. Our comprehensive glycomic approach revealed that blood group-specific antigens in serum/plasma are predominantly present on glycosphingolipids on lipoproteins rather than glycoproteins. Expression of the ABO antigens on glycosphingolipids depends not only on blood type but also on secretor status. Blood group-specific glycans in serum/plasma were classified as type I, whereas those on RBCs had different structures including hexose and hexosamine residues. Analysis of free oligosaccharides revealed that low-molecular-weight blood group-specific glycans, commonly containing lacto--difucotetraose, were expressed in serum/plasma according to blood group. Furthermore, comprehensive glycomic analysis in human cerebrospinal fluid showed that many kinds of free oligosaccharides were highly expressed, and low-molecular-weight blood group-specific glycans, which existed in plasma from the same individuals, were present. Our findings provide the first evidence for low-molecular-weight blood group-specific glycans in both serum/plasma and cerebrospinal fluid.
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http://dx.doi.org/10.1021/acs.jproteome.1c00056DOI Listing
May 2021

Development of conformational BRET biosensors that monitor ezrin, radixin and moesin activation in real time.

J Cell Sci 2021 Apr 13;134(7). Epub 2021 Apr 13.

Cellular Mechanisms of Morphogenesis during Mitosis and Cell Motility lab, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, P.O. Box 6128, Station Centre-Ville, Montréal, QC H3C 3J7, Canada.

Ezrin, radixin and moesin compose the family of ERM proteins. They link actin filaments and microtubules to the plasma membrane to control signaling and cell morphogenesis. Importantly, their activity promotes invasive properties of metastatic cells from different cancer origins. Therefore, a precise understanding of how these proteins are regulated is important for the understanding of the mechanism controlling cell shape, as well as providing new opportunities for the development of innovative cancer therapies. Here, we developed and characterized novel bioluminescence resonance energy transfer (BRET)-based conformational biosensors, compatible with high-throughput screening, that monitor individual ezrin, radixin or moesin activation in living cells. We showed that these biosensors faithfully monitor ERM activation and can be used to quantify the impact of small molecules, mutation of regulatory amino acids or depletion of upstream regulators on their activity. The use of these biosensors allowed us to characterize the activation process of ERMs that involves a pool of closed-inactive ERMs stably associated with the plasma membrane. Upon stimulation, we discovered that this pool serves as a cortical reserve that is rapidly activated before the recruitment of cytoplasmic ERMs.
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http://dx.doi.org/10.1242/jcs.255307DOI Listing
April 2021

Clinical Outcome of Cytoreductive Surgery Prior to Bevacizumab for Patients with Recurrent Glioblastoma: A Single-center Retrospective Analysis.

Neurol Med Chir (Tokyo) 2021 Apr 4;61(4):245-252. Epub 2021 Mar 4.

Department of Neurosurgery, Faculty of Medicine, Hokkaido University.

Bevacizumab (BEV) is a key anti-angiogenic agent used in the treatment for recurrent glioblastoma multiforme (GBM). The aim of this study was to investigate whether cytoreductive surgery prior to treatment with BEV contributes to prolongation of survival for patients with recurrent GBM. We retrospectively analyzed the treatment outcomes of 124 patients with recurrent GBM who were initially treated with the Stupp protocol between 2006 and 2019. Given that BEV has only been available in Japan since 2013, we grouped the patients into two groups according to the time of first recurrence: the pre-BEV group (N = 51) included patients who had recurrence before BEV approval, and the BEV group (N = 73) included patients with recurrence after BEV approval. The overall survival after first recurrence (OS-R) was analyzed according to the treatment strategy. Among 124 patients, 27 patients (19.4%) received cytoreductive surgery. There were nine cases in the pre-BEV group and 18 cases in the BEV group. Although the mean extent of resection for both groups was almost equal, OS-R was significantly different. The median OS-R was 8.1 m in the pre-BEV group and 16.3 m in the BEV group (P = 0.007). Multivariate analysis revealed that the unavailability of BEV postoperatively (P = 0.03) and decreasing performance status by surgery (P = 0.01) were significant poor prognostic factors for survival after surgery. With the advent of BEV, cytoreductive surgery might provide superior survival benefit at the time of GBM recurrence, especially in cases where surgery can be performed without deteriorating the patient's condition.
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http://dx.doi.org/10.2176/nmc.oa.2020-0308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048115PMC
April 2021

Preoperative Texture Analysis Using C-Methionine Positron Emission Tomography Predicts Survival after Surgery for Glioma.

Diagnostics (Basel) 2021 Jan 28;11(2). Epub 2021 Jan 28.

Department of Diagnostic Imaging, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.

Background: Positron emission tomography with C-methionine (MET) is well established in the diagnostic work-up of malignant brain tumors. Texture analysis is a novel technique for extracting information regarding relationships among surrounding voxels, in order to quantify their inhomogeneity. This study evaluated whether the texture analysis of MET uptake has prognostic value for patients with glioma.

Methods: We retrospectively analyzed adults with glioma who had undergone preoperative metabolic imaging at a single center. Tumors were delineated using a threshold of 1.3-fold of the mean standardized uptake value for the contralateral cortex, and then processed to calculate the texture features in glioma.

Results: The study included 42 patients (median age: 56 years). The World Health Organization classifications were grade II (7 patients), grade III (17 patients), and grade IV (18 patients). Sixteen (16.1%) all-cause deaths were recorded during the median follow-up of 18.8 months. The univariate analyses revealed that overall survival (OS) was associated with age (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.01-1.08, = 0.0093), tumor grade (HR 3.64, 95% CI 1.63-9.63, = 0.0010), genetic status ( < 0.0001), low gray-level run emphasis (LGRE, calculated from the gray-level run-length matrix) (HR 2.30 × 10, 95% CI 737.11-4.23 × 10, = 0.0096), and correlation (calculated from the gray-level co-occurrence matrix) (HR 5.17, 95% CI 1.07-20.93, = 0.041). The multivariate analyses revealed OS was independently associated with LGRE and correlation. The survival curves were also significantly different (both log-rank < 0.05).

Conclusion: Textural features obtained using preoperative MET positron emission tomography may compliment the semi-quantitative assessment for prognostication in glioma cases.
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http://dx.doi.org/10.3390/diagnostics11020189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911154PMC
January 2021

Heterogeneity of eye drop use among symptomatic dry eye individuals in Japan: large-scale crowdsourced research using DryEyeRhythm application.

Jpn J Ophthalmol 2021 Mar 7;65(2):271-281. Epub 2021 Jan 7.

Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Purpose: To determine eye drop type and usage frequency and investigate risk factors for no eye drop use in individuals with symptomatic dry eye (DE) in Japan.

Study Design: Crowdsourced observational study.

Methods: This study was conducted using the DryEyeRhythm smartphone application between November 2016 and September 2019. Data collected included the type and frequency of eye drop use, demographics, medical history, lifestyle, and self-reported symptoms. Symptomatic DE was defined as an Ocular Surface Disease Index total score of ≥ 13. Risk factors for no eye drop use were identified using multivariate logistic regression analyses.

Results: Among 2619 individuals with symptomatic DE, 1876 did not use eye drops. The most common eye drop type was artificial tears (53.4%), followed by hyaluronic acid 0.1% (33.1%) and diquafosol sodium 3% (18.7%). Risk factors (odds ratio [95% confidence interval]) for no eye drop use were age (0.97 [0.97-0.98]), body mass index (1.04 [1.01-1.07]), brain disease (0.38 [0.15-0.98]), collagen disease (0.30 [0.13-0.68]), mental illness other than depression and schizophrenia (0.65 [0.45-0.93]), cataract surgery (0.12 [0.02-0.59]), ophthalmic surgery other than cataract and laser-assisted in situ keratomileusis (0.55 [0.34-0.88]), current (0.47 [0.38-0.57]) or past (0.58 [0.43-0.77]) contact lens use, >8 h screen exposure time (1.38 [1.05-1.81]), <6 h (1.24 [1.01-1.52]) and >9 h (1.34 [1.04-1.72]) sleep time, and water intake (0.97 [0.94-0.98]).

Conclusion: Many participants with symptomatic DE did not use optimized eye drop treatment and identified risk factors for no eye drop use. The DryEyeRhythm application may help improve DE treatment.
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http://dx.doi.org/10.1007/s10384-020-00798-1DOI Listing
March 2021

Laparoscopic Surgery for Colorectal Cancer in Super-Elderly Patients: A Single-Center Analysis.

Surg Laparosc Endosc Percutan Tech 2020 Nov 23;31(3):337-341. Epub 2020 Nov 23.

Department of Surgery, Kobe City Medical Center General Hospital, Chuo-ku, Kobe, Japan.

Background: Super-elderly patients with colorectal cancer are being encountered with increasing frequency in Japan. Laparoscopic surgery is considered a less invasive surgery in these patients; however, it is difficult to conduct controlled clinical trials in this super-elderly population. This study assessed the feasibility and safety of laparoscopic colorectal surgery in patients over 85 years old.

Materials And Methods: Open and laparoscopic surgeries for colorectal cancer in super-elderly patients (aged 85 y and older) were performed under general anesthesia in a single medical center. Records were retrospectively reviewed, and the clinicopathologic features of each patient and the surgical time and outcomes were recorded and analyzed.

Results: Records of colorectal surgery were reviewed for 108 super-elderly patients. Twenty-six open surgeries and 82 laparoscopic surgeries were performed. The mean operation times were 215 and 228 minutes in open and laparoscopic surgeries, respectively. Intraoperative bleeding in laparoscopic surgery was lesser than that in open surgery. There were 2 cases with major postoperative complications in open surgery, and mortality occurred in one case within 1 month after surgery. No major complications were observed in laparoscopic surgery. In survival analysis, disease-free survival did not differ between the 2 groups. The oldest patient was a man aged 102 years and 6 months who underwent laparoscopic anterior resection with lymph node dissection.

Conclusion: Laparoscopic surgery in super-elderly patients with colon cancer is feasible and safe. The authors report the success of laparoscopic colectomy for rectosigmoid colon cancer in the oldest known patient and the positive outcomes of laparoscopic colectomy in super-elderly patients.
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http://dx.doi.org/10.1097/SLE.0000000000000876DOI Listing
November 2020

Laparoscopic Colectomy for Splenic Flexure Cancer Approached from Four Directions.

J Laparoendosc Adv Surg Tech A 2020 Nov 23. Epub 2020 Nov 23.

Department of Surgery, Kobe City Medical Center General Hospital, Kobe, Japan.

Standardized protocols for laparoscopic surgery of splenic flexure cancer (SFC) have not been established yet. We described a standardized laparoscopic procedure for SFCs and examined its safety and feasibility. Laparoscopic colectomy for SFC was performed as follows. The sigmoid colon was mobilized to the descending mesocolon through the medial approach. After confirming the base of the inferior mesenteric artery, the left colic artery was dissected and resected at the base. Further dissection was carried out between the mesentery of the colon and the renal fascia until it exceeded the upper pole of the left kidney and the splenic flexure. The next dissection reached the white line at the lateral side and the sigmoid-descending colon junction. After making an incision at the greater omentum and gastrocolic ligament from the center of the transverse colon to the splenic flexure, the transverse mesocolon base was dissected from the inside splenic flexure for complete mobilization. This was performed by approaching from four directions toward the splenic flexure. Intestinal resection and anastomosis are performed. This procedure was performed in 70 patients with splenic flexure colon cancer (mean age 70 years). The mean operative time was 190 minutes, and the mean blood loss was 2.0 mL. No notable perioperative or postoperative complications were noted. Safe mobilization of the splenic flexure can be achieved by approaching from four directions, and standardization of left colectomy can facilitate complete mesenteric excision.
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http://dx.doi.org/10.1089/lap.2020.0709DOI Listing
November 2020

Are Genome-Wide Association Study Identified Single-Nucleotide Polymorphisms Associated With Sprint Athletic Status? A Replication Study With 3 Different Cohorts.

Int J Sports Physiol Perform 2020 Oct 15;16(4):489-495. Epub 2020 Oct 15.

Purpose: To replicate previous genome-wide association study identified sprint-related polymorphisms in 3 different cohorts of top-level sprinters and to further validate the obtained results in functional studies.

Methods: A total of 240 Japanese, 290 Russians, and 593 Brazilians were evaluated in a case-control approach. Of these, 267 were top-level sprint/power athletes. In addition, the relationship between selected polymorphisms and muscle fiber composition was evaluated in 203 Japanese and 287 Finnish individuals.

Results: The G allele of the rs3213537 polymorphism was overrepresented in Japanese (odds ratio [OR]: 2.07, P = .024) and Russian (OR: 1.93, P = .027) sprinters compared with endurance athletes and was associated with an increased proportion of fast-twitch muscle fibers in Japanese (P = .02) and Finnish (P = .041) individuals. A meta-analysis of the data from 4 athlete cohorts confirmed that the presence of the G/G genotype rather than the G/A+A/A genotypes increased the OR of being a sprinter compared with controls (OR: 1.49, P = .01), endurance athletes (OR: 1.79, P = .001), or controls + endurance athletes (OR: 1.58, P = .002). Furthermore, male sprinters with the G/G genotype were found to have significantly faster personal times in the 100-m dash than those with G/A+A/A genotypes (10.50 [0.26] vs 10.76 [0.31], P = .014).

Conclusion: The rs3213537 polymorphism found in the CPNE5 gene was identified as a highly replicable variant associated with sprinting ability and the increased proportion of fast-twitch muscle fibers, in which the homozygous genotype for the major allele (ie, the G/G genotype) is preferable for performance.
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http://dx.doi.org/10.1123/ijspp.2019-1032DOI Listing
October 2020

rs8192678 and rs6949152 Polymorphisms Are Associated with Muscle Fiber Composition in Women.

Genes (Basel) 2020 08 27;11(9). Epub 2020 Aug 27.

Graduate School of Health and Sports Science, Juntendo University, Chiba 270-1695, Japan.

rs8192678 G/A (Gly482Ser) and rs6949152 A/G polymorphisms have been associated with endurance athlete status, endurance performance phenotypes, and certain health-related markers of different pathologies such as metabolic syndrome, diabetes, and dyslipidemia. We hypothesized that they could be considered interesting candidates for explaining inter-individual variations in muscle fiber composition in humans. We aimed to examine possible associations of these polymorphisms with myosin heavy-chain (MHC) isoforms as markers of muscle fiber compositions in vastus lateralis muscle in a population of 214 healthy Japanese subjects, aged between 19 and 79 years. No significant associations were found in men for any measured variables. In contrast, in women, the rs8192678 A/A genotype was significantly associated with a higher proportion of MHC-I ( = 0.042) and with a lower proportion of MHC-IIx ( = 0.033), and the rs6949152 AA genotype was significantly associated with a higher proportion of MHC-I ( = 0.008) and with a lower proportion of MHC IIx ( = 0.035). In women, the genotype scores of the modes presenting the most significant results for rs8192678 G/A (Gly482Ser) and rs6949152 A/G polymorphisms were significantly associated with MHC-I ( = 0.0007) and MHC IIx ( = 0.0016). That is, women with combined A/A and A/A genotypes presented the highest proportion of MHC-I and the lowest proportion of MHC-IIx, in contrast to women with combined GG+GA and AG+GG genotypes, who presented the lowest proportion of MHC-I and the highest proportion of MHC-IIx. Our results suggest possible associations between these polymorphisms (both individually and in combination) and the inter-individual variability observed in muscle fiber composition in women, but not in men.
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http://dx.doi.org/10.3390/genes11091012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563119PMC
August 2020

Sialorphin Potentiates Effects of [Met]Enkephalin without Toxicity by Action other than Peptidase Inhibition.

J Pharmacol Exp Ther 2020 10 5;375(1):104-114. Epub 2020 Aug 5.

Departments of Anesthesiology (T.K., M.W., M.Mi., K.I., M.Ma., Ta.S., To.S.) and Clinical Pharmacology (M.Y., H.K.) and Education and Research Support Center (K.I.), Tokai University School of Medicine, Kanagawa, Japan.

This dose-response study investigated the effects of sialorphin on [Met]enkephalin (ME)-induced inhibition of contractions in mouse vas deferens and antinociception in male rats. Differences were compared among combinations of three chemical peptidase inhibitors: amastatin, captopril, and phosphoramidon. The ratio of potencies of ME in mouse vas deferens pretreated with both sialorphin (100 µM) and a mixture of the three peptidase inhibitors (1 µM each) was higher than that with the mixture of peptidase inhibitors alone at any dose. Intrathecal administration of sialorphin (100-400 nmol) significantly and dose dependently increased ME (3 nmol)-induced antinociception with the mixture of three peptidase inhibitors (10 nmol each). The degree of antinociception with a combination of any two of the peptidase inhibitors (10 nmol each) in the absence of sialorphin was less than that in the presence of sialorphin (200 nmol). Pretreatment with both sialorphin (200 nmol) and the mixture of three peptidase inhibitors (10 nmol each) produced an approximately 100-fold augmentation in ME (10 nmol)-induced antinociception, but without signs of toxicity such as motor dysfunction in rats. Radioligand receptor binding assay revealed that sialorphin did not affect either binding affinity or maximal binding capacity of [d-Ala,-MePhe,Gly-ol]enkephalin. These results indicate that sialorphin potentiates the effects of ME without toxicity by a mechanism other than peptidase inhibition and with no effect on its affinity to -opioid receptors. SIGNIFICANCE STATEMENT: Sialorphin is regarded as an endogenous peptidase inhibitor that interacts with enkephalin-degrading enzymes. The results of these in vitro and in vivo studies confirm that sialorphin potentiates the effects of [Met]enkephalin without toxicity by an action other than peptidase inhibition. This suggests that sialorphin offers the advantage of reducing or negating the side effects of opioid drugs and endogenous opioid peptides.
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http://dx.doi.org/10.1124/jpet.120.266080DOI Listing
October 2020

Discovery of a Novel Class of State-Dependent Na1.7 Inhibitors for the Treatment of Neuropathic Pain.

Chem Pharm Bull (Tokyo) 2020 ;68(7):653-663

R&D Division, Daiichi Sankyo Co., Ltd.

The discovery of a novel class of state-dependent voltage-gated sodium channel (Na)1.7 inhibitors is described. By the modification of amide or urethane bond in Na1.7 blocker III, structure-activity relationship studies that led to the identification of novel Na1.7 inhibitor 2i (DS01171986) were performed. Compound 2i exhibited state-dependent inhibition of Na1.7 without Na1.1, Na1.5 or human ether-a-go-go related gene (hERG) liabilities at concentrations up to 100 μM. Further biological profiling successfully revealed that 2i possessed potent analgesic properties in a murine model of neuropathic pain (ED: 3.4 mg/kg) with an excellent central nervous system (CNS) safety margin (> 600 fold).
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http://dx.doi.org/10.1248/cpb.c20-00126DOI Listing
February 2021

Internal hernia of the stomach associated with colostomy after laparoscopic surgery for rectal cancer: a case report.

Surg Case Rep 2020 Jun 3;6(1):127. Epub 2020 Jun 3.

Department of Surgery, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.

Background: Colostomy via the intraperitoneal route is often performed during laparoscopic Hartmann's operation or abdominoperineal resection. Internal hernia of the small intestine often occurs after colostomy. This report shows a rare case of internal hernia of the stomach associated with sigmoid colostomy after laparoscopic abdominoperineal resection for rectal cancer.

Case Presentation: The patient was a 79-year-old woman with a sigmoid colostomy. Computed tomography scan showed a markedly distended stomach in the space between the lifted sigmoid colon and the lateral abdominal wall. Laparoscopy revealed that the body of the stomach had passed through a hernia orifice located between the lifted sigmoid colon and the left lateral abdominal wall. The dislocated stomach was restored to its normal position, and the lateral defect was closed with the lateral peritoneum and the lifted sigmoid colon laparoscopically.

Conclusions: Internal hernia associated with colostomy can lead to not only obstruction of the small intestine, but also obstruction of the stomach. We reported a successful case of the suture repair for the internal hernia of the stomach associated with colostomy.
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http://dx.doi.org/10.1186/s40792-020-00889-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270322PMC
June 2020

Neuroendoscope-Assisted Aneurysm Trapping for Ruptured Intraventricular Aneurysms in Moyamoya Disease Patients.

World Neurosurg 2020 09 31;141:278-283. Epub 2020 May 31.

Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Kita, Sapporo, Japan.

Background: Intracranial hematomas associated with abnormal collateral vessels are observed in certain populations of adult patients with moyamoya disease (MMD). Of these, intraventricular hematomas resulting from rupture of intraventricular aneurysms, which are formed along an abnormal peripheral choroidal artery, are sometimes detected and could be severe. No appropriate treatment option for these ruptured aneurysms has been well established to date. Therefore in this report, we describe the case of an MMD patient with an intraventricular hematoma resulting from a ruptured intraventricular aneurysm arising along the abnormal collateral vessels near the lateral ventricular wall, which was successfully treated using a neuroendoscope.

Case Description: A 53-year-old female with MMD presented with an intraventricular hematoma. The patient had already undergone bilateral, combined direct/indirect cerebral revascularization surgery 3 years prior. Digital subtraction angiography revealed an aneurysm along the abnormal collateral choroidal artery near the posterior horn of the left lateral ventricle. A neuroendoscopic technique was applied to approach and treat the aneurysm; this was performed successfully by trapping using aneurysm clips without intraoperative or postoperative complications.

Conclusions: Neuroendoscopic aneurysm trapping using aneurysm clips is a treatment option for an intraventricular aneurysm that causes an intraventricular hematoma in patients with MMD. This technique is minimally invasive and offers good visibility of the surgical field.
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http://dx.doi.org/10.1016/j.wneu.2020.05.222DOI Listing
September 2020

Reduction in dietary lysine increases muscle free amino acids through changes in protein metabolism in chickens.

Poult Sci 2020 Jun 8;99(6):3102-3110. Epub 2020 May 8.

Graduate School of Science and Technology, Niigata University, Niigata 950-2181, Japan; Center for Transdisciplinary Research, Niigata University, Niigata 950-2181, Japan. Electronic address:

Taste is crucial to meat quality, and free Glu is an important taste-active component in meat. Our recent study showed that the short-term feeding of a low-Lys diet increases the concentration of free Glu and other free amino acids in chicken muscle and improves its taste. Here, we investigated the mechanisms by which the feeding of a low-Lys diet increases free Glu in chicken muscle. Two groups (n = 10 per group) of 28-day-old female Ross strain broiler chickens were fed diets with a graded Lys content of 90% or 100% of the recommended Lys requirement (according to National Research Council [1994] guidelines) for 10 D. Free amino acid concentrations and the mRNA abundance of protein metabolism-related genes were measured in breast muscle, and breast muscle metabolome analysis was conducted. Free Glu in muscle was increased by 51.8% in the Lys 90% group compared with the Lys 100% group (P < 0.01). Free threonine, glutamine, glycine, valine, isoleucine, leucine, tyrosine, phenylalanine, histidine, and 3-methyl-histidine concentrations in breast muscle were also increased in the Lys 90% group (P < 0.05). Metabolome analysis also showed that free amino acids were increased in the Lys 90% group. The mRNA abundance of μ-calpain, caspase-3, and 20S proteasome C2 subunit were increased in the Lys 90% group (P < 0.05). Moreover, the free Glu concentration in muscle was correlated with mRNA abundance of μ-calpain (r = 0.74, P < 0.01), caspase 3 (r = 0.69, P < 0.01), 20S proteasome C2 subunit (r = 0.65, P < 0.01), and cathepsin B (r = 0.52, P < 0.05). Our study suggests that the feeding of a low-Lys diet to chickens increased the free Glu content of breast muscle by promoting protein degradation.
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http://dx.doi.org/10.1016/j.psj.2019.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597547PMC
June 2020

Discovery of DS-1971a, a Potent, Selective Na1.7 Inhibitor.

J Med Chem 2020 09 26;63(18):10204-10220. Epub 2020 May 26.

R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

A highly potent, selective Na1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives ( and ) led to the discovery of novel series of cycloalkane derivatives with high Na1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00259DOI Listing
September 2020

Characterization of Postprandial Effects on CSF Metabolomics: A Pilot Study with Parallel Comparison to Plasma.

Metabolites 2020 May 6;10(5). Epub 2020 May 6.

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.

Cerebrospinal fluid (CSF) metabolites reflect biochemical diffusion/export from the brain and possibly serve as biomarkers related to brain disease severity, pathophysiology, and therapeutic efficacy/toxicity. Metabolomic studies using blood matrices have demonstrated interindividual and preanalytical variation of blood metabolites, whereas those of CSF metabolites remain unclear. In this study, we aimed to delineate the postprandial effects on CSF metabolites because fasting of patients with brain-related disorders is challenging. We collected pre- and postprandial (1.5, 3, and 6 h) plasma and CSF from nine healthy subjects. Using a mass-spectrometry-based global metabolomics approach, 150 and 130 hydrophilic metabolites and 263 and 340 lipids were detected in CSF and plasma, respectively. Principal component analysis of CSF hydrophilic metabolites and lipids primarily classified individual subjects at any time point, suggesting that the postprandial effects had a lower impact than interindividual variations on CSF metabolites. Individually, less than 10% of the CSF metabolites were putatively altered by postprandial effects (with either significant differences or over 2-fold changes, but not both) at any time point. Thus, global CSF metabolite levels are not directly associated with food intake, and except for several putatively altered CSF metabolites, postprandial effects are not a major concern when applying CSF metabolomics to screen biomarkers.
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http://dx.doi.org/10.3390/metabo10050185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281358PMC
May 2020

Challenges in treatment of disseminated nocardiosis in an elderly patient with renal failure on corticosteroids: a case report.

IDCases 2020 9;20:e00755. Epub 2020 Apr 9.

Department of Internal Medicine, Mito Kyodo General Hospital, University of Tsukuba, Japan.

We report the case of a 71-year-old Japanese man with a history of chronic kidney disease and sarcoidosis receiving chronic corticosteroids who presented with disseminated infection. He initially showed improvement with empiric antimicrobial therapy including trimethoprim-sulfamethoxazole. However, he deteriorated after modifying the empiric regimen due to complicated hyperkalemia and ultimately died. In general, elderly patients have decreased renal function. Standard therapy for nocardiosis with trimethoprim-sulfamethoxazole may not be used for a prolonged period of time. This case emphasizes the challenges and importance of prudent selection of empiric antimicrobial therapy for disseminated nocardiosis in elderly patients with underlying kidney disease.
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http://dx.doi.org/10.1016/j.idcr.2020.e00755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191206PMC
April 2020

Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.

J Neurooncol 2020 May 4;148(1):17-27. Epub 2020 May 4.

Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan.

Purpose: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonβ (IFNβ) plus temozolomide (TMZ) with that of TMZ alone.

Experimental: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations.

Results: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNβ + Radiotherapy (RT) group were found.

Conclusion: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNβ addition were identified.
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http://dx.doi.org/10.1007/s11060-020-03505-9DOI Listing
May 2020

Identification of chronic subdural hematoma types most responsive to Goreisan, Kampo medicine: A retrospective study.

J Clin Neurosci 2020 Aug 23;78:198-202. Epub 2020 Apr 23.

Department of Neurosurgery, Juntendo University, Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address:

Chronic subdural hematoma (CSDH) has a reported postoperative recurrence rate of 3-20% and the optimal therapeutic strategy remains controversial. Recently, in Japan, Goreisan (Kampo medicine) was used for preventing postoperative CSDH recurrence. Therefore, this study aimed to explore if Goreisan is effective against specific CSDH types by evaluating its effects on postoperative CSDH recurrence and reoperation rates based on its natural history and internal structure on CT images. This retrospective, single-center, cohort study was conducted at the Tokyo Metropolitan Hiroo Hospital. After applying the inclusion/exclusion criteria, data from 107 patients (70 men and 37 women; mean age, 77.1 ± 10.9 years), admitted for CSDH from January 2013 to December 2018, were included in the Goreisan group, whereas those of 122 patients (84 men and 38 women; mean age, 73.9 ± 13.3 years), admitted for CSDH from January 2007 to December 2012, were included in the control group. This corresponded to 114 lesions, with 14 reoperation lesions, in the Goreisan group and 108 lesions, with 16 reoperation lesions, in the control group. Lesions were categorized as homogeneous, laminar, separated, or trabecular type, and patients with homogeneous type lesions in the Goreisan group were approximately 50% less likely to undergo reoperation compared with those in the control group (7.3% versus 14%; odds ratio = 0.51; 95% confidence interval = 0.12-2.11). Thus, the homogeneous type CSDH was the most responsive to Goreisan, whereas the separated type was the least responsive. Therefore, selecting treatment strategies for preventing CSDH recurrence on CSDH type may contribute toward reducing reoperation rates.
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http://dx.doi.org/10.1016/j.jocn.2020.04.063DOI Listing
August 2020

Dehydroeffusol Rescues Amyloid β-Induced Spatial Working Memory Deficit.

Plant Foods Hum Nutr 2020 Jun;75(2):279-282

Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.

Amyloid β (Aβ) peptides produced from the amyloid precursor protein, a transmembrane protein, are neurotoxic and blocking the neurotoxicity may lead to prevention of Alzheimer's disease (AD). Here we tested whether Aβ-induced cognitive decline is rescued by treatment with dehydroeffusol, a phenanthrene isolated from Chinese medicine Juncus effusus. Dehydroeffusol (5 ~ 15 mg/kg body weight) was orally administered to mice for 6 days and Aβ (2 mM) was injected at the rate of 1 μl/min for 3 min into the lateral ventricle. Y-maze test was performed after dehydroeffusol administration for 12 days. Aβ impaired learning and memory in the test, while the impairment was dose-dependently rescued by dehydroeffusol administration. The present study indicates that treatment with dehydroeffusol is effective for rescuing Aβ-induced cognitive decline.
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http://dx.doi.org/10.1007/s11130-020-00816-0DOI Listing
June 2020

Analysis of the source of aggressiveness in gamecocks.

Sci Rep 2020 04 24;10(1):7005. Epub 2020 Apr 24.

Department of Clinical Pharmacology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.

Although the fighting behaviour in gamecocks has evolved because of artificial selection, it is unknown whether the selection for aggressiveness affects neurotransmitter levels in the avian central nervous system. We sought to identify the source and origin of this trait. We collected the brain samples from 6 female Shamo gamecocks and 5 Shaver Brown chickens (control; bred for egg production). The midbrain levels of norepinephrine (NE) were significantly higher in Shamo gamecocks (P = 0.0087) than in the controls. Moreover, alleles encoding adrenergic receptors differed between the breeds in terms of response to NE. Gene mutations specific to Shamo and potentially associated with fighting behaviour were in sites T440N of ADRα1D; V296I of ADRα2A; and T44I, Q232R, and T277M of ADRβ2. The evolutionary analysis indicated that the ADRβ2 (T44I and Q232R) mutations were heritable in all Galliformes, whereas the T440N mutation of ADRα1D and V296I mutations of ADRα2A were unique to Shamo and originated by artificial selection. A high NE level may confer a selective advantage by enabling gamecocks to be aggressive and pain tolerant. Therefore, the strong fighting behaviour of Shamo has resulted from a combination of naturally inherited and mutant genes derived by artificial selection.
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http://dx.doi.org/10.1038/s41598-020-63961-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181795PMC
April 2020