The large and medium‐sized arteries in elderly people show varying degrees of intimal and medial change. The medial change is known as age‐related medial degeneration and sclerosis (ARMDS). The ARMDS ...results in systolic hypertension and left ventricular hypertrophy of the heart as a result of loss of arterial elasticity. It also causes aortic dilatation, or even aortic aneurysm. The ARMDS and atherosclerosis are distinct entities, but are often overlapped and confused with each other. The present review mainly focuses on ARMDS and briefly addresses atherosclerosis, and aging of arterioles, capillaries and veins. The smooth muscle cells in the inner half of the aortic media of elderly people degenerate and undergo apoptosis. This causes degradation of elastin fibers and the accumulation of collagen fibers in the media, but the inflammatory infiltrates are scarce. Biochemical studies showed an age‐related decrease of elastin and its crosslinks, and an increase of collagen and its crosslink. Because the turnover of elastin is very long, it likely suffers from glycation (Maillard reaction) and glyco‐oxidative reaction. The advanced glycation end‐products accumulate in the aortic media with increasing age. Alcian‐blue positive mucin accumulates in aortic media in elderly people. The major component of the increase of aortic mucin is chondroitin‐6‐sulfate. Microcalcification is frequent in the inner acellular portion of the aortic media in elderly people. Calcium contents increase with age. In conclusion, the ARMDS is a distinct pathological entity with clinical significance. The pathogenesis of ARMDS is unclear; the mechanical stress of elastin, endothelial dysfunction, and glycation of elastin are proposed. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S213–S220.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cause of death (COD) information taken from death certificates is often inaccurate and incomplete. However, the accuracy of Underlying CODs (UCODs) recorded on death certificates has not been ...comprehensively described when multiple diseases are present.
A total of 450 consecutive autopsies performed at a geriatric hospital in Japan between February 2000 and August 2002 were studied. We evaluated the concordance rate, sensitivity, and specificity of major UCODs (cancer, heart disease, and pneumonia) reported on death certificates compared with a reference standard of pathologist assessment based on autopsy data and clinical records. Logistic regression analysis was performed to assess the effect of sex, age, comorbidity, and UCODs on misclassification.
The concordance rate was relatively high for cancer (81%) but low for heart disease (55%) and pneumonia (9%). The overall concordance rate was 48%. Sex and comorbidity did not affect UCOD misclassification rates, which tended to increase with patient age, although the association with age was also not significant. The strongest factor for misclassification was UCODs (P < 0.0001). Sensitivity and specificity for cancer were very high (80% and 96%, respectively), but sensitivity for heart disease and pneumonia was 60% and 46%, respectively. Specificity for each UCOD was more than 85%.
Researchers should be aware of the accuracy of COD data from death certificates used as research resources, especially for cases of elderly patients with pneumonia.
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FFLJ, NUK, ODKLJ, UL, UM, UPUK
Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over ...60 genes, including RBM20, which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. RBM20
protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Diabetic nephropathy is a major complication of diabetes mellitus, and thus novel biomarkers are desired to evaluate the presence and progression of diabetic nephropathy. In this study, we sought to ...identify possible metabolites related to diabetic nephropathy among urinary eicosanoids and related mediators. Using liquid chromatogram-tandem mass spectrometry, we optimized the lipid extraction from urine using the Monospin C18 as a solid-phase extraction cartridge and measured the urinary lipid mediators in 111 subjects with type 2 diabetes mellitus as well as 33 healthy subjects. We observed that 14 metabolites differed significantly among the clinical stages of nephropathy. Among them, levels of tetranor-prostaglandin E metabolite (tetranor-PGEM), an arachidonic acid metabolite, were significantly higher in subjects with stage 1 nephropathy than in healthy subjects and increased with the progression of nephropathy. We also observed that levels of maresin-1, a docosahexaenoic acid metabolite, and leukotriene B4-ethanolamide, an arachidonoyl ethanolamide metabolite, were significantly lower in subjects with stage 3–4 nephropathy than in healthy subjects and those with stage 1–2 nephropathy. Finally, using a comprehensive analysis of urinary eicosanoids and related mediators, we concluded that tetranor-PGEM was capable of discriminating clinical stages of nephropathy and thus useful as a novel biomarker for diabetic nephropathy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The ends of human chromosome are protected by telomeres, which are composed of tandem repeats of DNA sequences. Telomeres can be damaged by a variety of environmental factors, ultimately resulting in ...cellular senescence and carcinogenesis. The purpose of this study was to clarify the relationship between telomere shortening in the skin and sun exposure. Using quantitative fluorescence in situ hybridization (Q-FISH), we examined telomere lengths (TL) in the epidermis and dermis of sun-exposed (SE) and sun non-exposed (NE) skin from the same individuals without any skin disease. There was a significant difference (p = 0.039) in epidermal TL between SE and NE samples, except for adolescents and young adults (AYA). Our results suggest that chronic sun exposure shortens the telomeres of the epidermis, which may explain the UV-associated acceleration of skin aging and skin disorders.
Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous bile duct cancer with a poor prognosis. Integrin αvβ6 (β6) has been shown to be upregulated in iCCA and is associated with its ...subclassification and clinicopathological features. In the present study, two ITGB6-knockout HuCCT1 CCA cell lines (ITGB6-ko cells) were established using the clustered regulatory interspaced short palindromic repeats (CRISPR), an associated nuclease 9 (Cas9) system, and single-cell cloning. RNA sequencing analysis, real-time polymerase chain reaction (PCR), and immunofluorescent methods were applied to explore possible downstream factors. ITGB6-ko cells showed significantly decreased expression of integrin β6 on flow cytometric analysis. Both cell lines exhibited significant inhibition of cell migration and invasion, decreased wound-healing capability, decreased colony formation ability, and cell cycle dysregulation. RNA sequencing and real-time PCR analysis revealed a remarkable decrease in podocalyxin-like protein 2 (PODXL2) expression in ITGB6-ko cells. Colocalization of PODXL2 and integrin β6 was also observed. S100 calcium-binding protein P and mucin 1, which are associated with CCA subclassification, were downregulated in ITGB6-ko cells. These results describe the successful generation of ITGB6-ko CCA cell clones with decreased migration and invasion and downregulation of PODXL2, suggesting the utility of integrin β6 as a possible therapeutic target or diagnostic marker candidate.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A quantification system for lysophospholipids (lysoPL) was developed, especially for blood samples, using liquid chromatography–tandem mass spectrometry (LC–MS/MS). However, the lysoPL measurement in ...cerebrospinal fluid (CSF) has not been validated. Therefore, the present study aimed to validate the lysoPL measurement using CSF samples and to elucidate the possible clinical significance of the lysoPL measurement in CSF. For the validation, we observed a good precision and linearity in a sample with high lysoPL levels. The concentrations of lysoPL changed after incubation but the changes were smaller than those observed for serum samples. Moreover, we observed that the CSF levels of 16:0, 18:0 lysophosphatidylcholine, and 18:0, 18:1, and 20:4 lysophosphatidic acid were significantly higher in subjects with central nervous system invasion caused by hematological malignancies or carcinoma than in subjects with no abnormal CSF test results. In conclusion, an LC–MS/MS quantification system for lysoPL in CSF might be useful and could be applied to clinical laboratory testing.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Histological identification of the human sinoatrial node (SAN) remains a challenge. Conventional identification methods, such as Lev’s method, have certain limitations. The aim of our study was to ...develop a new histological identification method that could properly identify the sinoatrial node, applicable to the immunohistochemical study of intra-nodal structures. Thirty-nine human autopsied hearts were included in this study. The cases included 23 men and 16 women ranging in age from 20 to 99 years. The sinoatrial area from eight control samples was cut in the vertical section using the conventional Lev’s method. In our new method, called the “En face one-block method,” the sinoatrial node was cut in “En face” at the junction of the right border of the right appendage and superior vena cava, placed in one long cassette, and serially cut using a microtome. Immunostaining was performed using primary antibodies against CD31, podoplanin (D2-40), S-100, and other proteins. The average area of the SAN on the slide glass in our new method was 32.2 mm
2
,
which was significantly larger than that (3.59 mm
2
) of the control samples by Lev’s method. The SAN area was positively correlated with age (
r
= 0.357;
p
= 0.026), especially in women (
r
= 0.626;
p
= 0.0095). The SAN group had significantly lower percentage of CD31-positive blood capillaries, higher percentage of podoplanin-positive lymphatic channels, and S-100-positive peripheral nerves. We successfully developed a novel cutting method applicable to immunohistochemical studies, with which we could provide a bird’s-eye view of the sinoatrial nodes.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Background Lifestyle-related diseases, such as obesity and dyslipidemia are important risk factors for atrial fibrillation (AF). However, the underlying mechanism linking these diseases and ...AF has not been fully investigated. Methods Adult male mice were fed a high-fat diet (HFD) or vehicle (NC) for 2 months. Electrocardiography and in vivo electrophysiological study were performed. Mice were then sacrificed for quantification of mRNA, microRNA, and protein in atria, in addition to histological analysis. Conduction velocity (CV) in right atrium was measured by optical mapping in Langendorff perfused hearts. Cultured atrial cardiomyocytes were treated with palmitate with or without a specific microRNA inhibitor. Twelve hours after stimulation, cells were lysed, and subjected to analysis with qPCR and Western blotting. Results HFD mice showed prolonged P wave duration, increased inducibility of sustained atrial tachycardia, and reduced atrial CV than NC mice. HFD mice also showed increased expression in inflammatory cytokines, whereas fibrotic area and signals relating fibrosis were not changed. HFD mice demonstrated reduced expression of Cx40 in mRNA and protein levels, and its lateralized expression in atria. MicroRNA array analysis revealed that miR-27b expression was up-regulated in HFD mice, and luciferase assay confirmed the direct interaction between miR-27b and Cx40 3′UTR. In palmitate-stimulated atrial cardiomyocytes, miR-27b up-regulation and Cx40 down-regulation were observed, while expression of inflammatory cytokines was not altered. Inhibition of miR-27b with antisense oligonucleotides reversed the alteration caused by palmitate stimulation. Conclusion HFD may increase the vulnerability to atrial arrhythmia by down-regulation of Cx40 via miR-27b, rather than fibrosis, which is independent of inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We have previously reported that promoter polymorphism of myocardin-related transcription factor A (MRTF-A) is associated with coronary atherosclerosis. However, the contribution of MRTF-A to the ...development of atherosclerosis remains unknown. Macrophages are known to be important mediators of atherosclerosis. It has been demonstrated that local proliferation and survival of macrophages are atherogenic. In this study, we found that MRTF-A was highly expressed in lesional macrophages in human carotid atherosclerotic plaque. We then investigated the role of macrophagic MRTF-A in the pathogenesis of atherosclerosis. ApoE null MRTF-A transgenic mice (ApoE−/−/MRTF-Atg/+), in which human MRTF-A was specifically overexpressed in monocytes/macrophages, were established and fed with normal diet to examine the progression of atherosclerosis. We found that ApoE−/−/MRTF-Atg/+ aggravated atherosclerosis and lesional macrophages were more prominently accumulated in the aortic sinus of ApoE−/−/MRTF-Atg/+ than in that of ApoE−/− littermates. We also found that MRTF-A promoted proliferation and mitigated apoptosis of macrophages both in vitro and in vivo, and down regulated the expression of cyclin-dependent kinase inhibitors. From these findings, we conclude that MRTF-A modulates functional properties of pro-atherogenic macrophages. Our study may play a valuable role in understanding the pathological role of macrophagic MRTF-A in the progression of atherosclerosis.
•Overexpression of MRTF-A in macrophages exacerbates atherosclerosis in ApoE knockout mice without altering plasma profile.•Overexpression of MRTF-A in macrophages facilitates local accumulation of lesional macrophages in atherosclerotic plaques.•MRTF-A mitigates apoptosis and promotes proliferation of macrophages.•MRTF-A regulates the expression level of cyclin-dependent kinase inhibitors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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