Publications by authors named "Yuko Hara"

100 Publications

Outcomes of endoscopic resection for superficial duodenal tumors: 10 years' experience in 18 Japanese high-volume centers.

Endoscopy 2021 Sep 8. Epub 2021 Sep 8.

Cancer Center, School of Medicine, Keio University, Tokyo, Japan.

Background And Study Aim: There is no enough data for endoscopic resection (ER) of superficial duodenal epithelial tumors (SDETs) due to its rarity. There are two main kinds of ER techniques for SDETs: EMR and ESD. In addition, modified EMR techniques, underwater EMR (UEMR) and cold polypectomy (CP), are getting popular. We conducted a large-scale retrospective multicenter study to clarify detailed outcomes of duodenal ER.

Patients And Methods: Patients with SDETs who underwent ER at 18 institutions from January 2008 to December 2018 were included. The rates of en bloc resection and delayed adverse events (AEs) (defined as delayed bleeding or perforation) were analyzed. Local recurrence was analyzed using Kaplan-Meier method.

Results: In total, 3107 patients (including 1017 receiving ESD) were included. En bloc resection rates were 79.1%, 78.6%, 86.8%, and 94.8%, and delayed AE rates were 0.5%, 2.2%, 2.8%, and 7.3% for CP, UEMR, EMR and ESD, respectively. The delayed AE rate was significantly higher for ESD group than non-ESD group among lesions less than 19 mm (7.4% vs 1.9%, p<0.0001), but not among lesions larger than 20 mm (6.1% vs 7.1%, p=0.6432). The local recurrence rate was significantly lower in ESD group than non-ESD group (p<0.001). Furthermore, for lesions larger than 30 mm, the cumulative local recurrence rate at 2 years was 22.6% in non-ESD group compared to only 1.6% in ESD group (p<0.0001).

Conclusions: ER outcomes for SDETs were generally acceptable. ESD by highly experienced endoscopists might be an option for very large SDETs.
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http://dx.doi.org/10.1055/a-1640-3236DOI Listing
September 2021

Psychotic Features Among Patients in the Prodromal Stage of Dementia with Lewy Bodies During Longitudinal Observation.

J Alzheimers Dis 2021 ;83(4):1917-1927

Sapporo Sato Hospital, Sapporo, Japan.

Background: Many cases of dementia with Lewy bodies (DLB) present with various psychotic features, including hallucinations, depression, catatonia, and delusions before the onset of cognitive impairment. However, the characteristic features of these psychotic symptoms in prodromal DLB have not been sufficiently described.

Objective: To clarify and describe the psychotic features of prodromal DLB before overt cognitive impairment.

Methods: The authors analyzed the characteristic psychotic features of prodromal DLB in 21 subjects who developed severe psychotic symptoms without dementia and were diagnosed as DLB after the longitudinal observation period. They were then confirmed to have DLB through indicative and supportive biomarkers of scintigraphy.

Results: The psychotic features included a wide variety of symptoms, but convergent to three principal categories: catatonia, delusions-hallucinations, and depression and/or mania. Catatonia was observed in nine cases, five were delusional-hallucinatory, and seven were manic and/or depressive. Seven of the 21 cases exhibited delirium during longitudinal observation. A psychotic state repeatedly appeared without any trigger in 20 of the 21 patients. All subjects developed cognitive impairment at 9.1±4.6 (mean±SD) years after the initial appearance of psychotic symptoms, and subsequently diagnosed with DLB at 71.3±6.1 (mean±SD) years.

Conclusion: Elderly patients with psychotic symptoms, such as catatonia, delusion-hallucination, manic and/or depressive features, and delirium without dementia, could indicate symptomatic psychosis or a prodromal stage of any neurocognitive disorder such as DLB. Therefore, further extensive workout (e.g., radioisotope neuroimaging) is required to avoid misdiagnosis.
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http://dx.doi.org/10.3233/JAD-210416DOI Listing
January 2021

Job characteristics, marital intentions, and partner-seeking actions: Longitudinal evidence from Japan.

Demogr Res 2020 Jul-Dec;43:1509-1544. Epub 2020 Dec 9.

University of Maryland, College Park.

Background: Most research linking jobs to marriage formation focuses on how job contexts and prospects affect singles' paces of entering marriage. Direct evidence on whether job traits shape singles' desire for marriage and actions toward forming a union remains scarce.

Objective: We examine how changes in a range of job characteristics correspond to alterations in never-married people's intention to marry and actions taken to meet romantic partners in Japan, a country with increasing inequality in job quality and declining marriage rates.

Methods: We use longitudinal data from the Japan Life Course Panel Survey to fit fixed-effects models, which take into account unobserved heterogeneity among people with differing jobs.

Results: We find that rises in job insecurity and workplace staffing shortages weaken, whereas increases in income and job autonomy strengthen, men's intention to marry. Moreover, men with a low marriage desire are especially likely to withdraw from partner-seeking activities when they have low-income jobs or face great deadline pressure at work. Job prospects and quality are generally less important to women's desire for marriage or partner-seeking actions. Nevertheless, being in workplaces where teamwork is prevalent, which could enhance singles' exposure to married and older coworkers, raises both women's intention to marry and their probability of using a formal method, such as employing a marriage agency, to find a partner.

Conclusions: For Japanese men, our results offer support for the argument that economic stagnation and deterioration of job quality are conducive to later and fewer marriages. The findings for women, however, are more consistent with the narrative focusing on values and social influences.

Contributions: This study enriches our understanding of singles' considerations of marriage and partner search and provides highly rigorous evidence on the roles of job conditions.
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http://dx.doi.org/10.4054/demres.2020.43.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143055PMC
December 2020

Association between Endoscopic Milk-White Mucosa, Epithelial Intracellular Lipid Droplets, and Histological Grade of Superficial Non-Ampullary Duodenal Epithelial Tumors.

Diagnostics (Basel) 2021 Apr 25;11(5). Epub 2021 Apr 25.

Department of Endoscopy, The Jikei University School of Medicine, Tokyo 105-8461, Japan.

We previously reported that superficial non-ampullary duodenal tumors (SNADETs) commonly had a whitish mucosal surface, named milk-white mucosa (MWM). The aim of this study was to evaluate the association of MWM with epithelial intracellular lipid droplets (immunohistochemically stained by adipose differentiation-related protein (ADRP)) and histological tumor grades. We reviewed endoscopic images and the histopathology of SNADETs resected en bloc endoscopically. We analyzed the correlation between the positive rates of endoscopic MWM in preoperative endoscopy and resected specimens, and ADRP-positive rates in the resected specimens. Associations between the MWM-positive rates and tumor grades, high-grade intraepithelial neoplasia (HGIN)/intramucosal carcinoma (IC), and low-grade intraepithelial neoplasia (LGIN) were analyzed. All the 92 SNADETs analyzed were <20 mm and histologically classified into 39 HGIN/IC and 53 LGIN. Spearman's rank correlation coefficient showed a significant correlation between MWM-positive and ADRP-positive rates ( < 0.001). MWM-positive rates were significantly lower in the HGIN/IC than in the LGIN in preoperative endoscopy ( < 0.001) and resected specimens ( = 0.02). Our results suggest that endoscopic MWM is closely associated with epithelial intracellular lipid droplets and that the MWM-positive rate may be a predictor of histological grade in small SNADETs.
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http://dx.doi.org/10.3390/diagnostics11050769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146723PMC
April 2021

Motherhood Penalties and Fatherhood Premiums: Effects of Parenthood on Earnings Growth Within and Across Firms.

Demography 2021 Feb;58(1):247-272

Department of Sociology, University of Maryland, College Park, MD, USA.

Despite much interest in how parenthood contributes to the gender pay gap, prior research has rarely explored firms' roles in shaping the parenthood pay penalty or premium. The handful of studies that investigated parenthood's effects within and across firms generally compared parents and their childless peers at a given time and failed to account for unobserved heterogeneity between the two groups. Such comparisons also cannot inform how having children may alter individuals' earnings trajectories within and across firms. Using 26 rounds of the National Longitudinal Survey of Youth 1979 and fixed-effects models, we examine how being a mother or father is linked to earnings growth within and across firms. We find that women's pay decreases as they become mothers and that the across-employer motherhood penalty is larger than the within-employer penalty. By contrast, fatherhood is associated with a pay premium, and the within-employer fatherhood premium is considerably greater than the across-employer one. We argue that these results are consistent with the discrimination explanation of the motherhood penalty and fatherhood premium. Because employers are likely to trust women who become mothers while working for them more than new recruits who are mothers, their negative bias against mothers would be more salient when evaluating the latter, which could result in a larger between-organizational motherhood penalty. Conversely, employers' likely greater trust in existing workers who become fathers than fathers they hire from elsewhere may amplify their positive bias favoring fathers in assessing the former, which could explain the greater within-firm fatherhood premium.
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http://dx.doi.org/10.1215/00703370-8917608DOI Listing
February 2021

Metabolomic Alteration of Oral Keratinocytes and Fibroblasts in Hypoxia.

J Clin Med 2021 Mar 10;10(6). Epub 2021 Mar 10.

Division of Biomimetics, School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan.

The oxygen concentration in normal human tissue under physiologic conditions is lower than the atmospheric oxygen concentration. The more hypoxic condition has been observed in the cells with wound healing and cancer. Somatic stem cells reside in a hypoxic microenvironment in vivo and prefer hypoxic culture conditions in vitro. Oral mucosa contains tissue-specific stem cells, which is an excellent tissue source for regenerative medicine. For clinical usage, maintaining the stem cell in cultured cells is important. We previously reported that hypoxic culture conditions maintained primary oral keratinocytes in an undifferentiated and quiescent state and enhanced their clonogenicity. However, the metabolic mechanism of these cells is unclear. Stem cell biological and pathological findings have shown that metabolic reprogramming is important in hypoxic culture conditions, but there has been no report on oral mucosal keratinocytes and fibroblasts. Herein, we conducted metabolomic analyses of oral mucosal keratinocytes and fibroblasts under hypoxic conditions. Hypoxic oral keratinocytes and fibroblasts showed a drastic change of metabolite concentrations in urea cycle metabolites and polyamine pathways. The changes of metabolic profiles in glycolysis and the pentose phosphate pathway under hypoxic conditions in the oral keratinocytes were consistent with those of other somatic stem cells. The metabolic profiles in oral fibroblasts showed only little changes in any pathway under hypoxia except for a significant increase in the antioxidant 2-oxoglutaric acid. This report firstly provides the holistic changes of various metabolic pathways of hypoxic cultured oral keratinocytes and fibroblasts.
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http://dx.doi.org/10.3390/jcm10061156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001958PMC
March 2021

Value-Generating Exploratory Trials in Neurodegenerative Dementias.

Neurology 2021 05 5;96(20):944-954. Epub 2021 Mar 5.

From the Alzheimer's Drug Discovery Foundation (L.G.F., N.M., Y.H., M.O., A.T., H.M.F.), New York; Chambers-Grundy Center for Transformative Neuroscience (J.L.C.), Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas; ADM Diagnostics (D.C.M.), Inc. Northbrook, IL; Servier Pharmaceuticals (J.Z.), Boston, MA; Global Alzheimer's Platform Foundation (R.C.M.), Washington, DC; AgeneBio (R.C.M.), Inc. Baltimore, MD; AbbVie Inc. (D.W.), North Chicago, IL; Pentara Corporation (S.B.H., S.P.D.), Salt Lake City, UT; Berry Consultants (M.Q.), Austin TX; Keck School of Medicine of the University of Southern California (L.S.S.), Los Angeles; Global R&D Partners (M.G.), LLC, University of California, San Diego, La Jolla; Department of Neurosciences (H.H.F.), University of California, San Diego, La Jolla; Albert Einstein College of Medicine (J.J.), Bronx, NY; CognitionMetrics (J.J.), LLC; Department of Clinical Neurological Sciences and Robarts Research Institute (E.C.F.), Schulich School of Medicine and Dentistry, University of Western Ontario; Parkwood Institute (E.C.F.), Lawson Health Research Institute, St. Josephs Health Care, London, Ontario, Canada; Rodin Therapeutics (J.M.R.), Boston, MA; Association for Frontotemporal Degeneration (D.N., S.L.-J.D.), Radnor, PA; and Modus Outcomes LLP (J.T.M.), Cambridge, MA.

Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.
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http://dx.doi.org/10.1212/WNL.0000000000011774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205472PMC
May 2021

Blood group O is a risk factor for delayed post-polypectomy bleeding.

Surg Endosc 2020 Nov 30. Epub 2020 Nov 30.

Department of Endoscopy, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.

Background: Blood group O of ABO blood group system is considered as a risk factor for various bleeding events, but the relationship with endoscopic treatment-associated bleeding has yet to be investigated. This study aimed to evaluate whether blood group O is associated with delayed bleeding after colorectal endoscopic resection.

Methods: This was a retrospective observational study based on medical records at four university hospitals in Japan. We reviewed the records for consecutive patients who underwent colorectal endoscopic resection from January 2014 through December 2017. The primary outcome was the incidence of delayed bleeding, defined as hematochezia or melena, requiring endoscopy, transfusion, or any hemostatic intervention up to 28 days after endoscopic resection. Multivariate logistic regression analysis was performed to adjust the impact of blood group O on the delayed bleeding.

Results: Among 10,253 consecutive patients who underwent colorectal endoscopic resection during the study period, 8625 patients met the criteria. In total, delayed bleeding occurred in 255 patients (2.96%). The O group had significantly more bleeding events compared with the non-O group (A, B, and AB) (relative risk, 1.62 [95% confidence interval, 1.24-2.10]; P < 0.001). In multivariate logistic regression analysis, blood group O remained an independent risk factor for the bleeding (adjusted odds ratio, 1.60 [95% confidence interval, 1.18-2.17]; P = 0.002).

Conclusions: Blood group O was associated with an increased risk of delayed bleeding in patients undergoing colorectal endoscopic resection. Preoperative screening for ABO blood group could improve risk assessments.
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http://dx.doi.org/10.1007/s00464-020-08195-yDOI Listing
November 2020

Gender differences in initial symptoms and symptoms at diagnosis in dementia with Lewy bodies.

Psychogeriatrics 2021 01 29;21(1):144-145. Epub 2020 Nov 29.

Department of Psychiatry, Nishi Kumagaya Hospital, Kumagaya, Japan.

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http://dx.doi.org/10.1111/psyg.12642DOI Listing
January 2021

Characteristics of initial symptoms and symptoms at diagnosis in probable dementia with Lewy body disease: incidence of symptoms and gender differences.

Psychogeriatrics 2020 Sep 2;20(5):737-745. Epub 2020 Aug 2.

Department of Psychiatry, Sapporo Sato Hospital, Sapporo, Japan.

Aim: Although dementia with Lewy bodies (DLB) is characterized by a variety of initial symptoms, there are almost no reports of the initial symptoms of DLB assessed in a large number of cases. We retrospectively evaluated the initial symptoms of 234 participants with DLB and DLB-related symptoms at diagnosis and characterized any gender differences in the symptom profiles.

Methods: This study consisted of 234 participants with probable DLB who met the diagnostic criteria outlined in the Fourth Consensus Report of the DLB Consortium (2017). DLB was confirmed based on several characteristic biomarkers for dopamine transporter imaging with I-N-omega-fluoropropyl-2-beta-carbomethoxy-3-beta (4-iodophenyl) nortropane single-photon emission computed tomography, I-metaiodobenzylguanidine myocardial scintigraphy, and brain perfusion measured with single photon emission computed tomography. In addition, core and supportive clinical features were considered in the diagnosis.

Results: Initial symptoms included cognitive impairment (41.9%) and psychiatric symptoms (i.e. visual and auditory hallucinations, delusions, and depression) (42.3%). Almost half of the women initially presented with psychiatric symptoms, with significantly more women than men presenting with auditory hallucinations. In contrast, men had a significantly higher rate of rapid eye movement sleep behaviour disorder (RBD) than women did. At diagnosis, DLB-related symptoms differed between men and women, with male patients exhibiting significantly more RBD, parkinsonism, hyposmia, and syncope than female patients. Moreover women presented significantly more often with auditory hallucinations than did men.

Conclusions: Our results indicate that there are gender differences in the initial symptoms of DLB, as well as in the presentation of subsequent symptoms observed at diagnosis. There was a higher incidence of RBD in men, whereas women had a higher incidence of psychotic symptoms.
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http://dx.doi.org/10.1111/psyg.12586DOI Listing
September 2020

Novel EGFP reporter cell and mouse models for sensitive imaging and quantification of exon skipping.

Sci Rep 2020 06 22;10(1):10110. Epub 2020 Jun 22.

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Duchenne muscular dystrophy (DMD) is a fatal X-linked disorder caused by nonsense or frameshift mutations in the DMD gene. Among various treatments available for DMD, antisense oligonucleotides (ASOs) mediated exon skipping is a promising therapeutic approach. For successful treatments, however, it is requisite to rigorously optimise oligonucleotide chemistries as well as chemical modifications of ASOs. To achieve this, here, we aim to develop a novel enhanced green fluorescence protein (EGFP)-based reporter assay system that allows us to perform efficient and high-throughput screenings for ASOs. We design a new expression vector with a CAG promoter to detect the EGFP fluorescence only when skipping of mdx-type exon 23 is induced by ASOs. Then, an accurate screening was successfully conducted in C57BL/6 primary myotubes using phosphorodiamidate morpholino oligomer or locked nucleic acids (LNA)/2'-OMe mixmers with different extent of LNA inclusion. We accordingly generated a novel transgenic mouse model with this EGFP expression vector (EGFP-mdx23 Tg). Finally, we confirmed that the EGFP-mdx23 Tg provided a highly sensitive platform to check the effectiveness as well as the biodistribution of ASOs for exon skipping therapy. Thus, the assay system provides a simple yet highly sensitive platform to optimise oligonucleotide chemistries as well as chemical modifications of ASOs.
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http://dx.doi.org/10.1038/s41598-020-67077-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308408PMC
June 2020

Publisher Correction: Modelling Duchenne muscular dystrophy in MYOD1-converted urine-derived cells treated with 3-deazaneplanocin A hydrochloride.

Sci Rep 2020 Feb 7;10(1):2462. Epub 2020 Feb 7.

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-59351-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005800PMC
February 2020

New approach to optimizing risk management of the sticking problem using scale-independent critical material attributes and the quantitative process parameter.

Int J Pharm 2020 Mar 15;577:119032. Epub 2020 Jan 15.

School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan. Electronic address:

In pharmaceutical manufacturing of solid formulations, blending with a lubricant is a key process in preventing sticking during compression. Sticking not only results in tablets with a disfigured appearance but also brings about the interruption of continuous operations. The aim of our study was to identify blending scale-independent critical material attributes (CMAs) in relation to the sticking problem to appropriately define the end-point of the blending process with magnesium stearate as lubricant. Results showed that the dispersive surface free energy (SFE) and the specific free energy absorptions (ΔGsp) of ethanol decreased during blending with magnesium stearate. As the two parameters decreased, the sticking problem was improved. In conclusion, we propose that the dispersive SFE and ΔGsp of ethanol are scale-independent CMAs, and that the minimum blending time (BT), which can be calculated from the two CMAs, of the quantitative process parameter show the minimum blending time required to achieve higher risk assessment of the sticking problem.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119032DOI Listing
March 2020

Gendered Emotional Support and Women's Well-Being in a Low-Income Urban African Setting.

Gend Soc 2018 Dec 20;32(6):837-859. Epub 2018 Jul 20.

University of Maryland.

Emotional support is crucial to the well-being of low-income, single women and their children in most contexts. Support women may be especially important for single mothers because of precarious ties to their children's fathers, the prevalence of extended matrifocal living arrangements, and gendered norms that place men as providers of financial rather than emotional support. However, in contexts marked by economic insecurity, spatial dispersion of families, and changing gender norms and kinship obligations, such an expectation may be problematic. Applying theories of emotional capital and family bargaining processes, we address three questions: 1) what is the gender composition of emotional support that single mothers receive? 2) how does gender composition change over time? and 3) does the gender composition of emotional support affect self-reported stress of single mothers? Drawing on data from a unique dataset on 462 low-income single mothers and their kin from Nairobi, Kenya, we uncover three key findings. One, whereas the bulk of strong emotional support comes from female kin, about 20% of respondents report having male dominant support networks. Two, nearly 30% of respondents report change in the composition of their emotional support over six months favoring men. Three, having a male dominant emotional support network is associated with lower stress. These results challenge what is commonly taken for granted about gender norms and kinship obligations in non-Western contexts.
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http://dx.doi.org/10.1177/0891243218786670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641544PMC
December 2018

Dye solution optimizing staining conditions for endocytoscopy for normal villi and superficial epithelial tumors in the duodenum.

Ann Gastroenterol 2019 Jul-Aug;32(4):378-386. Epub 2019 May 10.

Department of Innovative Interventional Endoscopy Research (Hisao Tajiri), The Jikei University School of Medicine, Tokyo, Japan.

Background: Vital staining is mandatory for endocytoscopy, which enables visualization of gastrointestinal mucosa at the cellular level. This study aimed to identify a dye solution that would optimize staining conditions for endocytoscopy in the duodenum, including normal villi and superficial non-ampullary duodenal epithelial tumors (SNADETs).

Methods: We performed endocytoscopy in 9 patients who had normal villi (27 sites) and 20 patients with SNADETs (20 sites). The normal sites were allocated to methylene blue (MB; 5/2.5/1%), toluidine blue (TB; 1/0.5/0.25%), and crystal violet (1/0.5/0.25%) staining. Based on the results of normal sites, we used 1% MB or 0.5% TB for staining SNADETs. Three reviewers, including endoscopists and pathologists, evaluated and scored the endocytoscopy images (1, poor; 2, moderate; 3, good) for general image quality and visibility of structure and nuclei. We calculated frequencies and compared the proportions of the highest score of 3 (good).

Results: The majority of scores of 3 for normal villi was given to 0.5% TB (81%), followed by 1% MB. For SNADETs, 1% MB showed significantly higher scores compared with 0.5% TB (P=0.035).

Conclusion: Among the dye solutions evaluated, 0.5% TB and 1% MB achieved the optimizing staining conditions for endocytoscopy for normal villi and SNADETs, respectively.
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http://dx.doi.org/10.20524/aog.2019.0382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595928PMC
May 2019

Intra-abdominal pressure during endoscopic full-thickness resection comparing manual and automatic control insufflation: a block-randomized porcine study.

Surg Endosc 2020 04 18;34(4):1625-1633. Epub 2019 Jun 18.

Department of Endoscopy, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan.

Background And Study Aims: An automatic carbon dioxide (CO) insufflating system (SPACE) was developed to stabilize intra-lumenal pressure (ILP) during endoscopic interventions. This study investigated whether SPACE could improve the control and monitoring of extra-lumenal intra-abdominal pressure (IAP) after establishing a perforation during endoscopic full-thickness resection (EFTR) of the gastric wall in porcine models.

Materials And Methods: After first establishing the optimal preset pressure for gastric EFTR in four pigs, we compared IAP dynamics during EFTR between manual insufflation and SPACE using a block-randomized study (n = 10). IAP was percutaneously monitored and plotted on a timeline graph every 5 s. The maximal IAP and the area under the IAP curve exceeding 10 mmHg (AUC) were compared between groups, with the agreement between IAP and endolumenally monitored ILP also analyzed for animals in the SPACE group.

Results: In the first study, 8 mmHg was identified as the most preferable preset pressure after establishment of the perforation. In the randomized study, the mean maximal IAP in the SPACE group was significantly lower than that in the manual insufflation group (11.0 ± 2.0 mmHg vs. 17.0 ± 3.5 mmHg; P = 0.03). The mean AUC was also significantly smaller in the SPACE group. Bland-Altman analysis demonstrated agreement between IAP and ILP within a range of ± 1.0 mmHg.

Conclusions: SPACE could be used to control and safely monitor IAP during gastric EFTR by measuring ILP during perforation of the gastric wall.
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http://dx.doi.org/10.1007/s00464-019-06927-3DOI Listing
April 2020

Modelling Duchenne muscular dystrophy in MYOD1-converted urine-derived cells treated with 3-deazaneplanocin A hydrochloride.

Sci Rep 2019 03 7;9(1):3807. Epub 2019 Mar 7.

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Duchenne muscular dystrophy (DMD) is a severe muscle disorder characterised by mutations in the DMD gene. Recently, we have completed a phase I study in Japan based on systemic administration of the morpholino antisense that is amenable to exon-53 skipping, successfully. However, to achieve the effective treatment of DMD, in vitro assays on patient muscle cells to screen drugs and patient eligibility before clinical trials are indispensable. Here, we report a novel MYOD1-converted, urine-derived cells (UDCs) as a novel DMD muscle cell model. We discovered that 3-deazaneplanocin A hydrochloride, a histone methyltransferase inhibitor, could significantly promote MYOGENIN expression and myotube differentiation. We also demonstrated that our system, based on UDCs from DMD patients, could be used successfully to evaluate exon-skipping drugs targeting DMD exons including 44, 50, 51, and 55. This new autologous UDC-based disease modelling could lead to the application of precision medicine for various muscle diseases.
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http://dx.doi.org/10.1038/s41598-019-40421-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405839PMC
March 2019

Short- and long-term outcomes of endoscopically treated superficial non-ampullary duodenal epithelial tumors.

World J Gastroenterol 2019 Feb;25(6):707-718

Department of Innovative Interventional Endoscopy Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan.

Background: It is widely recognized that endoscopic resection (ER) of superficial non-ampullary duodenal epithelial tumors (SNADETs) is technically challenging and may carry high risks of intraoperative and delayed bleeding and perforation. These adverse events could be more critical than those occurring in other levels of the gastrointestinal tract. Because of the low prevalence of the disease and the high risks of severe adverse events, the curability including short- and long-term outcomes have not been standardized yet.

Aim: To investigate the curability including short- and long-term outcomes of ER for SNADETs in a large case series.

Methods: This retrospective study included cases that underwent ER for SNADETs at our university hospital between March 2004 and July 2017. Short-term outcomes of ER were measured based on and R0 resection rates as well as adverse events. Long-term outcomes included local recurrence detected on endoscopic surveillance and disease-specific mortality in patients followed up for ≥ 12 mo after ER.

Results: In the study, 131 patients with 147 SNADETs were analyzed. The 147 ERs consisted of 136 endoscopic mucosal resections (EMRs) (93%) and 11 endoscopic submucosal dissections (ESDs) (7%). The median tumor diameter was 10 mm. The pathology diagnosis was adenocarcinoma (56/147, 38%), high-grade intraepithelial neoplasia (44/147, 30%), or low-grade intraepithelial neoplasia (47/147, 32%). The R0 resection rate was 68% (93/136) in the EMR group and 73% (8/11) in the ESD group, respectively. Cap-assisted EMR (known as EMR-C) showed a higher rate of R0 resection compared to the conventional method of EMR using a snare (78% 62%, = 0.06). No adverse event was observed in the EMR group, whereas delayed bleeding, intraoperative perforation, and delayed perforation in 3, 3, and 5 patients occurred in the ESD group, respectively. One patient with perforation required emergency surgery. In the 43 mo median follow-up period, local recurrence was found in four EMR cases and all cases were treated endoscopically. No patient died due to tumor recurrence.

Conclusion: Our findings suggest that ER provides good long-term outcomes in the patients with SNADETs. EMR is likely to become the safe and reliable treatment for small SNADETs.
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http://dx.doi.org/10.3748/wjg.v25.i6.707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378536PMC
February 2019

Scavenger Receptor Class A1 Mediates Uptake of Morpholino Antisense Oligonucleotide into Dystrophic Skeletal Muscle.

Mol Ther Nucleic Acids 2019 Mar 25;14:520-535. Epub 2019 Jan 25.

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan. Electronic address:

Exon skipping using phosphorodiamidate morpholino oligomers (PMOs) is a promising treatment strategy for Duchenne muscular dystrophy (DMD). The most significant limitation of these clinically used compounds is their lack of delivery systems that target muscles; thus, cell-penetrating peptides are being developed to enhance uptake into muscles. Recently, we reported that uptake of peptide-conjugated PMOs into myofibers was mediated by scavenger receptor class A (SR-A), which binds negatively charged ligands. However, the mechanism by which the naked PMOs are taken up into fibers is poorly understood. In this study, we found that PMO uptake and exon-skipping efficiency were promoted in dystrophin-deficient myotubes via endocytosis through a caveolin-dependent pathway. Interestingly, SR-A1 was upregulated and localized in juxtaposition with caveolin-3 in these myotubes and promoted PMO-induced exon skipping. SR-A1 was also upregulated in the skeletal muscle of mdx52 mice and mediated PMO uptake. In addition, PMOs with neutral backbones had negative zeta potentials owing to their nucleobase compositions and interacted with SR-A1. In conclusion, PMOs with negative zeta potential were taken up into dystrophin-deficient skeletal muscle by upregulated SR-A1. Therefore, the development of a drug delivery system targeting SR-A1 could lead to highly efficient exon-skipping therapies for DMD.
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http://dx.doi.org/10.1016/j.omtn.2019.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374502PMC
March 2019

Translating the biology of aging into novel therapeutics for Alzheimer disease.

Neurology 2019 01 7;92(2):84-93. Epub 2018 Dec 7.

From the Alzheimer's Drug Discovery Foundation, New York, NY.

Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer disease (AD), a progressive neurodegenerative disease with currently no therapies that prevent, slow, or halt disease progression. Like other chronic diseases of old age, the progressive pathology of AD begins decades before the onset of symptoms. Many decades of research in biological gerontology have revealed common processes that are relevant to understanding why the aging brain is vulnerable to AD. In this review, we frame the development of novel therapeutics for AD in the context of biological gerontology. The many therapies currently in development based on biological gerontology principles provide promise for the development of a new generation of therapeutics to prevent and treat AD.
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http://dx.doi.org/10.1212/WNL.0000000000006745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340342PMC
January 2019

Estrogen Alters the Synaptic Distribution of Phospho-GluN2B in the Dorsolateral Prefrontal Cortex While Promoting Working Memory in Aged Rhesus Monkeys.

Neuroscience 2018 12;394:303-315

Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; California National Primate Research Center, Davis, CA 95616, United States; Department of Neurology, School of Medicine, University of California, Davis, CA 95616, United States. Electronic address:

Age- and menopause-related deficits in working memory can be partially restored with estradiol replacement in women and female nonhuman primates. Working memory is a cognitive function reliant on persistent firing of dorsolateral prefrontal cortex (dlPFC) neurons that requires the activation of GluN2B-containing glutamate NMDA receptors. We tested the hypothesis that the distribution of phospho-Tyr1472-GluN2B (pGluN2B), a predominant form of GluN2B seen at the synapse, is sensitive to aging or estradiol treatment and coupled to working memory performance. First, ovariectomized young and aged rhesus monkeys (Macaca mulatta) received long-term cyclic vehicle (V) or estradiol (E) treatment and were tested on the delayed response (DR) test of working memory. Then, serial section electron microscopic immunocytochemistry was performed to quantitatively assess the subcellular distribution of pGluN2B. While the densities of pGluN2B immunogold particles in dlPFC dendritic spines were not different across age or treatment groups, the percentage of gold particles located within the synaptic compartment was significantly lower in aged-E monkeys compared to young-E and aged-V monkeys. On the other hand, the percentage of pGluN2B gold particles in the spine cytoplasm was decreased with E treatment in young, but increased with E in aged monkeys. In aged monkeys, DR average accuracy inversely correlated with the percentage of synaptic pGluN2B, while it positively correlated with the percentage of cytoplasmic pGluN2B. Together, E replacement may promote cognitive health in aged monkeys, in part, by decreasing the relative representation of synaptic pGluN2B and potentially protecting the dlPFC from calcium toxicity.
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http://dx.doi.org/10.1016/j.neuroscience.2018.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394848PMC
December 2018

Synaptic distributions of pS214-tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline.

J Comp Neurol 2019 03 4;527(4):856-873. Epub 2018 Dec 4.

Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Icahn School of Medicine at Mount Sinai, New York, New York.

Female rhesus monkeys and women are subject to age- and menopause-related deficits in working memory, an executive function mediated by the dorsolateral prefrontal cortex (dlPFC). Long-term cyclic administration of 17β-estradiol improves working memory, and restores highly plastic axospinous synapses within layer III dlPFC of aged ovariectomized monkeys. In this study, we tested the hypothesis that synaptic distributions of tau protein phosphorylated at serine 214 (pS214-tau) are altered with age or estradiol treatment, and couple to working memory performance. First, ovariectormized young and aged monkeys received vehicle or estradiol treatment, and were tested on the delayed response (DR) test of working memory. Serial section electron microscopic immunocytochemistry was then performed to quantitatively assess the subcellular synaptic distributions of pS214-tau. Overall, the majority of synapses contained pS214-tau immunogold particles, which were predominantly localized to the cytoplasm of axon terminals. pS214-tau was also abundant within synaptic and cytoplasmic domains of dendritic spines. The density of pS214-tau immunogold within the active zone, cytoplasmic, and plasmalemmal domains of axon terminals, and subjacent to the postsynaptic density within the subsynaptic domains of dendritic spines, were each reduced with age. None of the variables examined were directly linked to cognitive status, but a high density of pS214-tau immunogold particles within presynaptic cytoplasmic and plasmalemmal domains, and within postsynaptic subsynaptic and plasmalemmal domains, accompanied high synapse density. Together, these data support a possible physiological, rather than pathological, role for pS214-tau in the modulation of synaptic morphology in monkey dlPFC.
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http://dx.doi.org/10.1002/cne.24576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333519PMC
March 2019

Diagnostic efficacy of dual-focus endoscopy with narrow-band imaging using simplified dyad criteria for superficial esophageal squamous cell carcinoma.

J Gastroenterol 2019 Jun 8;54(6):501-510. Epub 2018 Nov 8.

Department of Innovative Interventional Endoscopy Research, The Jikei University School of Medicine, Tokyo, Japan.

Background: Our previous studies have shown the diagnostic utility of a newly developed dual-focus endoscope with narrow-band imaging (DF-NBI) and simplified dyad criteria for detection of superficial esophageal squamous cell carcinoma (SESCC). This clinical trial aimed to study the diagnostic efficacy of DF-NBI with dyad criteria for detecting SESCC compared to white light imaging (WLI).

Methods: This was a single-arm prospective comparative trial. We enrolled 170 consecutive high-risk patients for esophageal squamous cell carcinoma. Patients were initially examined with WLI by one independent endoscopist and then the other performed DF-NBI blinded to the WLI diagnosis to avoid a carry-over effect. Lesions showing proliferation and/or various shapes of intrapapillary capillary loops (IPCL) under DF-NBI (i.e., dyad criteria) were endoscopically diagnosed as SESCC including high-grade intraepithelial neoplasia. The primary endpoint was sensitivity of WLI and DF-NBI for detecting SESCC. The secondary endpoints were the diagnostic performance (i.e., specificity and accuracy) and inter/intra-observer concordance of DF-NBI with dyad criteria.

Results: A total 77 SESCCs were detected. The sensitivity of DF-NBI for SESCC was significantly higher than that of WLI (91% vs. 51%, P < 0.001). The specificity and accuracy of WLI and DF-NBI using dyad criteria were 100% vs. 84%, and 86% vs. 86%, respectively. Various shapes and proliferation of IPCL showed the highest value in inter-observer and intra-observer agreements (κ = 0.77 and 0.82, respectively).

Conclusion: DF-NBI combined with dyad criteria may be a promising technique with a high sensitivity for diagnosis of SESCC and high inter/intra-observer agreement.
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http://dx.doi.org/10.1007/s00535-018-1527-2DOI Listing
June 2019

Exon Skipping Using Antisense Oligonucleotides for Laminin-Alpha2-Deficient Muscular Dystrophy.

Methods Mol Biol 2018 ;1828:553-564

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.

Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is among the more promising approaches available for the treatment of several neuromuscular disorders, including Duchenne muscular dystrophy. The main weakness of this treatment arises from the low efficiency and sporadic nature of delivery of the neutrally charged PMO into muscle fibers, the mechanism of which is unknown.Recently, using wild-type and dystrophic mdx52 mice, we showed that muscle fibers took up PMO more efficiently during myotube formation. Interestingly, through in situ hybridization, we detected PMO mainly in embryonic myosin heavy chain-positive regenerating fibers. Next, we tested the therapeutic potential of PMO in laminin-alpha2 (laminin-α2) chain-null dy /dy mice, a model of merosin-deficient congenital muscular dystrophy 1A (MDC1A) with active muscle regeneration. We confirmed the recovery of the laminin-α2 chain following skipping of the mutated exon 4 in dy /dy mice, which prolonged the life span of the animals slightly. These findings support the theory that PMO entry into fibers is dependent on the developmental stage in myogenesis rather than on dystrophinless muscle membranes, and provide a platform for the future development of PMO-mediated therapies for a variety of muscular disorders, such as MDC1A, that involve active muscle regeneration. Herein, we describe the methods for PMO transfection/injection and evaluation of the efficacy of exon skipping in the laminin-α2-deficient dy /dy mouse model both in vitro and in vivo.
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http://dx.doi.org/10.1007/978-1-4939-8651-4_36DOI Listing
April 2019

In Vivo Evaluation of Single-Exon and Multiexon Skipping in mdx52 Mice.

Methods Mol Biol 2018 ;1828:275-292

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Exon-skipping therapy is an emerging approach that uses synthetic DNA-like molecules called antisense oligonucleotides (ASOs) to splice out frame-disrupting parts of mRNA, restore the reading frame, and produce truncated yet functional proteins. Phosphorodiamidate morpholino oligomer (PMO) is one of the safest among therapeutic ASOs for patients and has recently been approved under the accelerated approval program by the US Food and Drug Administration (FDA) as the first ASO-based drug for Duchenne muscular dystrophy (DMD). Multi-exon skipping utilizing ASOs can theoretically treat 80-90% of patients with DMD. Here, we describe the systemic delivery of a cocktail of ASOs to skip exon 51 and exons 45-55 in the mdx52 mouse, an exon 52 deletion model of DMD produced by gene targeting, and the evaluation of their efficacies in vivo.
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http://dx.doi.org/10.1007/978-1-4939-8651-4_17DOI Listing
April 2019

A Scale-up Approach for Film Coating Process Based on Surface Roughness as the Critical Quality Attribute.

AAPS PharmSciTech 2018 Apr 5;19(3):1243-1253. Epub 2018 Jan 5.

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

Scale-up approaches for film coating process have been established for each type of film coating equipment from thermodynamic and mechanical analyses for several decades. The objective of the present study was to establish a versatile scale-up approach for film coating process applicable to commercial production that is based on critical quality attribute (CQA) using the Quality by Design (QbD) approach and is independent of the equipment used. Experiments on a pilot scale using the Design of Experiment (DoE) approach were performed to find a suitable CQA from surface roughness, contact angle, color difference, and coating film properties by terahertz spectroscopy. Surface roughness was determined to be a suitable CQA from a quantitative appearance evaluation. When surface roughness was fixed as the CQA, the water content of the film-coated tablets was determined to be the critical material attribute (CMA), a parameter that does not depend on scale or equipment. Finally, to verify the scale-up approach determined from the pilot scale, experiments on a commercial scale were performed. The good correlation between the surface roughness (CQA) and the water content (CMA) identified at the pilot scale was also retained at the commercial scale, indicating that our proposed method should be useful as a scale-up approach for film coating process.
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http://dx.doi.org/10.1208/s12249-017-0940-9DOI Listing
April 2018

Exon Skipping Therapy Using Phosphorodiamidate Morpholino Oligomers in the mdx52 Mouse Model of Duchenne Muscular Dystrophy.

Methods Mol Biol 2018 ;1687:123-141

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8551, Japan.

Exon skipping therapy using synthetic DNA-like molecules called antisense oligonucleotides (ASOs) is a promising therapeutic candidate for overcoming the dystrophin mutation that causes Duchenne muscular dystrophy (DMD). This treatment involves splicing out the frame-disrupting segment of the dystrophin mRNA, which restores the reading frame and produces a truncated yet functional dystrophin protein. Phosphorodiamidate morpholino oligomer (PMO) is the safest ASO for patients among ASOs and has recently been approved under the accelerated approval pathway by the U.S. Food and Drug Administration (FDA) as the first drug for DMD. Here, we describe the methodology and protocol of PMO transfection and evaluation of the exon skipping efficacy in the mdx52 mouse, an exon 52 deletion model of DMD produced by gene targeting. The mdx52 mouse model offers advantages over the mdx mouse, a spontaneous DMD model with a nonsense mutation in exon 23, in terms of the deletion in a hotspot of deletion mutations in DMD patients, the analysis of caveolae and also Dp140 and Dp260, shorter dystrophin isoforms.
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http://dx.doi.org/10.1007/978-1-4939-7374-3_9DOI Listing
June 2018

Quantitative Antisense Screening and Optimization for Exon 51 Skipping in Duchenne Muscular Dystrophy.

Mol Ther 2017 11 28;25(11):2561-2572. Epub 2017 Jul 28.

Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; Muscular Dystrophy Canada Research Chair, Edmonton, AB T6G 2H7, Canada. Electronic address:

Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder, is caused by mutations in the dystrophin (DMD) gene. Exon skipping is a therapeutic approach that uses antisense oligonucleotides (AOs) to modulate splicing and restore the reading frame, leading to truncated, yet functional protein expression. In 2016, the US Food and Drug Administration (FDA) conditionally approved the first phosphorodiamidate morpholino oligomer (morpholino)-based AO drug, eteplirsen, developed for DMD exon 51 skipping. Eteplirsen remains controversial with insufficient evidence of its therapeutic effect in patients. We recently developed an in silico tool to design antisense morpholino sequences for exon skipping. Here, we designed morpholino AOs targeting DMD exon 51 using the in silico tool and quantitatively evaluated the effects in immortalized DMD muscle cells in vitro. To our surprise, most of the newly designed morpholinos induced exon 51 skipping more efficiently compared with the eteplirsen sequence. The efficacy of exon 51 skipping and rescue of dystrophin protein expression were increased by up to more than 12-fold and 7-fold, respectively, compared with the eteplirsen sequence. Significant in vivo efficacy of the most effective morpholino, determined in vitro, was confirmed in mice carrying the human DMD gene. These findings underscore the importance of AO sequence optimization for exon skipping.
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http://dx.doi.org/10.1016/j.ymthe.2017.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675502PMC
November 2017

Astrocytic tight junctions control inflammatory CNS lesion pathogenesis.

J Clin Invest 2017 Aug 24;127(8):3136-3151. Epub 2017 Jul 24.

Friedman Brain Institute.

Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocation of leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and then across the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJs), but the mechanisms that control access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier composed of reactive astrocyte TJs of claudin 1 (CLDN1), CLDN4, and junctional adhesion molecule A (JAM-A) subunits is induced at the GL. In a human coculture model, CLDN4-deficient astrocytes were unable to control lymphocyte segregation. In models of CNS inflammation and MS, mice with astrocyte-specific Cldn4 deletion displayed exacerbated leukocyte and humoral infiltration, neuropathology, motor disability, and mortality. These findings identify a second inducible barrier to CNS entry at the GL. This barrier may be therapeutically targetable in inflammatory CNS disease.
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http://dx.doi.org/10.1172/JCI91301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531407PMC
August 2017

Effect of Mandarin Orange Yogurt on Allergic Conjunctivitis Induced by Conjunctival Allergen Challenge.

Invest Ophthalmol Vis Sci 2017 06;58(7):2922-2929

Faculty of Agriculture, Ehime University, Matsuyama, Ehime, Japan.

Purpose: To evaluate the effects of mandarin orange yogurt containing nobiletin and β-lactoglobulin on the allergic conjunctivitis induced by a conjunctival allergen challenge (CAC).

Methods: Experiment 1 was performed on 26 asymptomatic patients (age, 25.3 ± 5.3 years) with proven seasonal allergic conjunctivitis due to cedar pollen. We compared the degree of conjunctivitis induced by CAC before and after ingesting mandarin orange yogurt for 2 weeks. Experiment 2 was a double-blind, placebo-controlled trial performed on 31 patients (age, 32.5 ± 12.2 years). A diet containing mandarin orange yogurt was compared to a diet containing yogurt lacking the mandarin orange on the conjunctivitis induced by CAC. The temperature of the inferior bulbar conjunctiva was measured before and 20 minutes after the CAC with an ocular surface thermographer (OST). The degree of conjunctival injection and chemosis was graded by slit-lamp biomicroscopy. The changes in the symptoms were evaluated by a questionnaire.

Results: In experiment 1, the scores of redness (3.07 ± 3.03 vs. 1.05 ± 1.70), chemosis (2.84 ± 2.27 vs. 0.81 ± 1.11), itching (4.34 ± 3.05 vs. 1.39 ± 2.12), and temperature (0.73 ± 0.42°C vs. 0.45 ± 0.43°C) were significantly lower (P < 0.001) after a diet of mandarin orange yogurt for 2 weeks. In experiment 2, the scores of redness (1.03 ± 0.18 vs. 1.28 ± 0.52; P = 0.0156), itching (1.93 ± 1.92 vs. 2.82 ± 2.21; P = 0.0133), and surface temperature (0.54 ± 0.21°C vs. 0.31 ± 0.25°C; P < 0.001) were significantly lower in the mandarin orange yogurt group than in the control yogurt group.

Conclusions: Mandarin orange yogurt can be an effective nutritional intervention for allergic conjunctivitis.
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http://dx.doi.org/10.1167/iovs.16-21206DOI Listing
June 2017
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