Ultrasonographic Screening of Carotid Artery in Patients with Vascular Retinopathies

Background and Purpose: Retinal vasculopathy is commonly found with complaintof burred vision by ophthalmologist and closely related to asymptomaticcerebrovascular disease. The purpose of this study was to evaluate patients withmicrovascular retinopathy by ultrasound sonography of neck carotid artery and to findhigh risk group for stroke at outpatient of ophthalmology with associated retinopathy.Methods: Between 1999 and 2001, a total of 480 consecutive patients visited atoutpatient of ophthalmology with a complaint of burred vision were evaluated byultrasound sonography of neck carotid artery. The patients were divided to withretinopathy (n=253) and without retinopathy (n=227). The former was subgrouped asfollows; central retinal vein occlusion (CRVO; n=11), branch of retinal vein occlusion(BRVO; n=71), retinal artery occlusion (RAO; n=8), hypertensive retinopathy group-I(according to Keith, Wagener and Barker's criteria) (HTN-R I; n=43) and group-II(HTN-R II; n=42), and diabetic retinopathy (DM-R; n=78). The latter group was withvarious ophthalmological diseases, mainly inflammation of cornea, with healthy retinalvessels and constituted as the control group.Results: There was no statistically significant difference between patients withretinopathy and the control group with respect to sex distribution, nor among theretinopathy groups. Patients with retinopathy had a mean age of 68 years, while thosewith HTN-R I and II were older with a mean age of 71 years. By ultrasonography,RAO showed pathology in intima-media thickness (IMT; 1.13 ± 0.55 vs. 0.81 ± 0.26 mmin control), average number of plaques (1.88 ± 0.99), degree of stenosis of internalcarotid artery (42.4 ± 28.5 %) and common carotid artery (27.4 ± 21.3 %). Those withDM-R had the second thickest IMT (0.96 ± 0.42 mm) and the second highest quantity ofplaque (1.23 ±1.23), and the second most stenotic common carotid artery (13.1 ±17.28%).Conclusion: Moderate sclerotic changes are found in ophthalmology patients withRAO and DM-R, although the degree pathology do not indicate medical nor surgicalprophylactic treatment. Retinal vein occlusion, that has been discussed with diminishedretinal blood circulation, does not show any differences in comparison with controlgroup and ultra sonography has less value for screening of asymptomatic carotidatherosclerosis

A novel Rac1-GSPT1 signaling pathway controls astrogliosis following central nervous system injury

Astrogliosis (i.e. glial scar), which is comprised primarily of proliferated astrocytes at the lesion site and migrated astrocytes from neighboring regions, is one of the key reactions in determining outcomes after CNS injury. In an effort to identify potential molecules/pathways that regulate astrogliosis, we sought to determine whether Rac/Rac-mediated signaling in astrocytes represents a novel candidate for therapeutic intervention following CNS injury. For these studies, we generated mice with Rac1 deletion under the control of the GFAP (glial fibrillary acidic protein) promoter (GFAP-Cre;Rac1(flox/flox)). GFAP-Cre;Rac1(flox/flox) (Rac1-KO) mice exhibited better recovery after spinal cord injury and exhibited reduced astrogliosis at the lesion site relative to control. Reduced astrogliosis was also observed in Rac1-KO mice following microbeam irradiation-induced injury. Moreover, knockdown (KD) or KO of Rac1 in astrocytes (LN229 cells, primary astrocytes, or primary astrocytes from Rac1-KO mice) led to delayed cell cycle progression and reduced cell migration. Rac1-KD or Rac1-KO astrocytes additionally had decreased levels of GSPT1 (G(1) to S phase transition 1) expression and reduced responses of IL-1β and GSPT1 to LPS treatment, indicating that IL-1β and GSPT1 are downstream molecules of Rac1 associated with inflammatory condition. Furthermore, GSPT1-KD astrocytes had cell cycle delay, with no effect on cell migration. The cell cycle delay induced by Rac1-KD was rescued by overexpression of GSPT1. Based on these results, we propose that Rac1-GSPT1 represents a novel signaling axis in astrocytes that accelerates proliferation in response to inflammation, which is one important factor in the development of astrogliosis/glial scar following CNS injury

Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2.

細胞老化から癌化への変換のカギとなる解糖系制御機構解明に成功 -代謝を標的とした新しい抗がん剤開発に期待-. 京都大学プレスリリース. 2014-02-24.Despite the well-documented clinical significance of the Warburg effect, it remains unclear how the aggressive glycolytic rates of tumor cells might contribute to other hallmarks of cancer, such as bypass of senescence. Here, we report that, during oncogene- or DNA damage-induced senescence, Pak1-mediated phosphorylation of phosphoglycerate mutase (PGAM) predisposes the glycolytic enzyme to ubiquitin-mediated degradation. We identify Mdm2 as a direct binding partner and ubiquitin ligase for PGAM in cultured cells and in vitro. Mutations in PGAM and Mdm2 that abrogate ubiquitination of PGAM restored the proliferative potential of primary cells under stress conditions and promoted neoplastic transformation. We propose that Mdm2, a downstream effector of p53, attenuates the Warburg effect via ubiquitination and degradation of PGAM

Jmjd5, an H3K36me2 histone demethylase, modulates embryonic cell proliferation through the regulation of Cdkn1a expression.

Covalent modifications of histones play an important role in chromatin architecture and dynamics. In particular, histone lysine methylation is important for transcriptional control during diverse biological processes. The nuclear protein Jmjd5 (also called Kdm8) is a histone lysine demethylase that contains a JmjC domain in the C-terminal region. In this study, we have generated Jmjd5-deficient mice (Jmjd5Δ/Δ) to investigate the in vivo function of Jmjd5. Jmjd5Δ/Δ embryos showed severe growth retardation, resulting in embryonic lethality at the mid-gestation stage. Mouse embryonic fibroblasts (MEFs) derived from Jmjd5 hypomorphic embryos (Jmjd5neo/neo) also showed the growth defect. Quantitative PCR analysis of various cell cycle regulators indicated that only Cdkn1a expression was upregulated in Jmjd5neo/neo MEFs and Jmjd5Δ/Δ embryos. A knockdown assay with Cdkn1a-specific small interfering RNAs revealed that the growth defect of Jmjd5neo/neo MEFs was significantly rescued. In addition, a genetic study using Jmjd5Δ/Δ; Cdkn1aΔ/Δ double-knockout mice showed that the growth retardation of Jmjd5Δ/Δ embryos was partially rescued by Cdkn1a deficiency. Chromatin immunoprecipitation analysis showed that increased di-methylated lysine 36 of histone H3 (H3K36me2) and reduced recruitment of endogenous Jmjd5 were detected in the transcribed regions of Cdkn1a in Jmjd5neo/neo MEFs. Taken together, these results suggest that Jmjd5 physiologically moderates embryonic cell proliferation through the epigenetic control of Cdkn1a expression.Accepted December 16, 2011

Detection of the Onset of Ischemia and Carcinogenesis by Hypoxia-Inducible Transcription Factor-Based In Vivo Bioluminescence Imaging

An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential

Familial brain arteriovenous malformation maps to 5p13-q14, 15q11-q13 or 18p11: linkage analysis with clipped fingernail DNA on high-density SNP array.

Familial arteriovenous malformations (AVM) in the brain is a very rare disease. It is defined as its occurrence in two or more relatives (up to third-degree relatives) in a family without any associated disorders, such as hereditary hemorrhagic telangiectasia. We encountered a Japanese family with brain AVM in which four affected members in four successive generations were observed. One DNA sample extracted from leukocytes of the proband and ten DNA samples from clipped finger nails of other members were available. A genome-wide linkage analysis was performed on this pedigree using Affymetrix GeneCip 10K 2.0 Xba Array and MERLIN software. We obtained sufficient performance of SNP genotyping in the fingernail samples with the mean SNP call rate of 92.49%, and identified 18 regions with positive LOD scores. Haplotype and linkage analyses with microsatellite markers at these regions confirmed three possible disease-responsible regions, i.e., 5p13.2-q14.1, 15q11.2-q13.1 and 18p11.32-p11.22. Sequence analysis was conducted for ten selected candidate genes at 5p13.2-q14.1, such as MAP3K1, DAB2, OCLN, FGF10, ESM1, ITGA1, ITGA2, EGFLAM, ERBB2IP, and PIK3R1, but no causative genetic alteration was detected. This is the first experience of adoption of fingernail DNA to genome-wide, high-density SNP microarray analysis, showing candidate brain AVM susceptible regions

Influenza H1N1 virus-associated pneumonia often resembles rapidly progressive interstitial lung disease seen in collagen vascular diseases and COVID-19 pneumonia; CT-pathologic correlation in 24 patients

To describe computed tomography (CT) findings of influenza H1N1 virus-associated pneumonia (IH1N1VAP), and to correlate CT findings to pathological ones. The study included 24 patients with IH1N1VAP. Two observers independently evaluated the presence, distribution, and extent of CT findings. CT features were divided into either classical form (C-form) or non-classical form (NC-form). C-form included: A.) broncho-bronchiolitis and bronchopneumonia type, whereas NC-forms included: B.) diffuse peribronchovascular type, simulating subacute rheumatoid arthritis-associated (RA) interstitial lung disease (ILD) and C.) lower peripheral and/or peribronchovascular type, resembling dermatomyositis-associated ILD and COVID-19 pneumonia. In 10 cases with IH1N1VAP where lung biopsy was performed, CT and pathology findings were correlated. The most common CT findings were ground-glass opacities (24/24, 100 %) and airspace consolidation (23/24, 96 %). C-form was found in 11 (46 %) patients while NC-form in 13 (54 %). Types A, B, and C were seen in 11(46 %), 4 (17 %), and 9 (38 %) patients, respectively. The lung biopsy revealed organizing pneumonia in all patients and 6 patients (60 %) showed incorporated type organizing pneumonia that was common histological findings of rapidly progressive ILD. In almost half of patients of IH1N1VAP, CT images show NC-form pneumonia pattern resembling either acute or subacute RA or dermatomyositis-associated ILD and COVID-19 pneumonia

Generation of medaka gene knockout models by target-selected mutagenesis

We have established a reverse genetics approach for the routine generation of medaka (Oryzias latipes) gene knockouts. A cryopreserved library of N-ethyl-N-nitrosourea (ENU) mutagenized fish was screened by high-throughput resequencing for induced point mutations. Nonsense and splice site mutations were retrieved for the Blm, Sirt1, Parkin and p53 genes and functional characterization of p53 mutants indicated a complete knockout of p53 function. The current cryopreserved resource is expected to contain knockouts for most medaka genes

Histologic factors associated with nintedanib efficacy in patients with idiopathic pulmonary fibrosis

Background Histopathologic factors predictive of nintedanib efficacy in idiopathic pulmonary fibrosis have not been studied. We aimed to describe the characteristics, focusing on histopathology, of idiopathic pulmonary fibrosis patients who did and did not respond to nintedanib. Methods This study retrospectively examined the clinicoradiopathologic features of 40 consecutive patients with surgical lung biopsy-confirmed idiopathic pulmonary fibrosis treated with nintedanib. Additionally, we compared the histopathologic scoring of 21 microscopic features between patients with functional or radiological progression and those with non-progression during 12 months of treatment. Results The histopathologic evaluation showed edematous changes in the interlobular septum as the only histologic finding observed more frequently in patients with both functional and radiological progression than in those without (58% vs. 14%, P = 0.007 and 50% vs. 0%, P = 0.003, respectively). Regarding per-year change, patients with edematous changes in the interlobular septum showed greater progression in median changes in spared area (-12%, interquartile range: [-25%-5%], vs. -3% [-7%-0%], P = 0.004) and reticular shadow (7% [3%-13%], vs. 0% [0%-5%], P = 0.041) on computed tomography. Functional and radiological progression-free survival were shorter in patients with edematous changes in the interlobular septum than in those without (6.6 months, 95% confidence interval: [5.9-25.3], vs. event <50%, [12.1-Not available], P = 0.0009, and 6.1 months, [5.2-6.6] vs. 14.5 months [7.8-not available], P<0.0001). Conclusions Edematous changes in the interlobular septum may indicate poor nintedanib efficacy in idiopathic pulmonary fibrosis. Further studies are needed to validate these findings and address the mechanism behind ECIS

Administration route-dependent induction of antitumor immunity by interferon-alpha gene transfer.

Type I interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis, and immunomodulation. We have demonstrated that intratumoral injection of an IFN-α-expressing adenovirus effectively induces cell death of cancer cells and elicits a systemic tumor-specific immunity in several animal models. On the other hand, reports demonstrated that an elevation of IFN in the serum following an intramuscular delivery of a vector is able to activate antitumor immunity. In this study, we compared the intratumoral and systemic routes of IFN gene transfer with regard to the effect and safety of the treatment. Intratumoral injection of an IFN-α adenovirus effectively activated tumor-responsive lymphocytes and caused tumor suppression not only in the gene-transduced tumors but also in distant tumors, which was more effective than the intravenous administration of the same vector. The expression of co-stimulatory molecules on CD11c+ cells isolated from regional lymph nodes was enhanced by IFN gene transfer into the tumors. Systemic toxicity such as an elevation of hepatic enzymes was much lower in mice treated by intratumoral gene transfer than in those treated by systemic gene transfer. Our data suggest that the intratumoral route of the IFN vector is superior to intravenous administration, due to the effective induction of antitumor immunity and the lower toxicity. © 2010 Japanese Cancer Association