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Nakazawa A.,Tohto College of Health Sciences | Nakamura K.,Niigata University | Kitamura K.,Niigata University | Yoshizawa Y.,Niigata Council of Institutions for the Elderly
Journal of Epidemiology | Year: 2012

Background: We assessed the association between activities of daily living (ADL) and mortality among nursing home residents in Japan. Methods: This 1-year prospective cohort study investigated 8902 elderly adults in 140 nursing homes. Baseline measurements included age, sex, height, weight, body mass index (BMI), ADL, and dementia level. ADL levels were obtained by caregivers, using the Barthel Index (BI), after which total BI scores were calculated (higher scores indicate less dependence). Information on dates of discharge and mortality was also obtained to calculate personyears. The Cox proportional hazards model was used to estimate hazard ratios(HRs). Results: Mean age was 84.3 years, and mean total BI score was 38.5. The HRs of mortality adjusted for sex, age,BMI, and type of nursing home were 7.6 (95% CI: 3.3-17.8) for those with a BI score of 0 (totally dependent), 3.9 (1.7-9.0) for those with a score of 1 to 10, 3.5 (1.4-8.7) for those with a score of 11 to 40, 2.7 (1.4-5.1) for those with a score of 41 to 70, and 1.3 (0.7-2.4) for those with a score of 71 to 99 (P for trend <0.001), as compared with those with a score of 100. Multivariate analysis revealed that BI, sex, age, and BMI were significantly associated with mortality rate. Conclusions: There was a clear inverse association between ADL level and mortality. In conjunction with other risk factors, ADL level might effectively predict short-term mortality in institutionalized elderly adults. © 2012 by the Japan Epidemiological Association.

PubMed | Red Cross, Tokyo Women's Medical University, Juntendo University, Tohto College of Health Sciences and Keio University
Type: Journal Article | Journal: Pathology international | Year: 2016

The purpose of this article is to review the recent advances in renal cell carcinoma (RCC) from a pathological point of view. Because the genetic features and morphological characteristics have become major criteria for the classification of RCC, special techniques, such as immunohistochemistry, are essential to the differential diagnosis of renal tumors. Metastasis is frequently observed among the RCC patients with curative nephrectomy, and extracellular matrix-degrading enzymes, such as matrix metalloproteinases (MMP) and heparanase, play a key role in invasion and metastasis of RCC. Snail and Slug, transcription factors of epithelial-mesenchymal transition (EMT), accelerate cancer cell invasion through downregulation of E-cadherin and up-regulation of MMP. Therapies targeted at the vascular endothelial growth factor pathway have become the standard treatment of metastatic RCC. Although they lead to tumor shrinkage mainly by inhibiting angiogenesis, they have typically been associated with drug resistance. The mechanism of the resistance remains largely unknown, but complex events including re-activation of angiogenesis, EMT and cancer stem cells, and immune escape are implicated in the refractory response to the therapy. Recent advances of the research on RCC have caused the changes of classification and therapy, and pathologists should take overall view of these as integrated pathology.

PubMed | University of Florida, University of Tennessee at Knoxville, Tohto College of Health Sciences, U.S. Department of Agriculture and University Utrecht
Type: | Journal: Veterinary research | Year: 2015

To better understand the mechanisms involved in the dynamics of Johnes disease in dairy cattle, this paper illustrates a novel way to link a within-host model for Mycobacterium avium ssp. paratuberculosis with an epidemiological model. The underlying variable in the within-host model is the time since infection. Two compartments, infected macrophages and T cells, of the within-host model feed into the epidemiological model through the direct transmission rate, disease-induced mortality rate, the vertical transmission rate, and the shedding of MAP into the environment. The epidemiological reproduction number depends on the within-host bacteria load in a complex way, exhibiting multiple peaks. A possible mechanism to account for the switch in shedding patterns of the bacteria in this disease is included in the within-host model, and its effect can be seen in the epidemiological reproduction model.

PubMed | University of Sassari, Azabu University, 1 Sangenjaya Hospital, University of Tennessee at Knoxville and Tohto College of Health Sciences
Type: Journal Article | Journal: Foodborne pathogens and disease | Year: 2015

Mycobacterium avium subsp. paratuberculosis (MAP) is the established causative agent of Johnes disease in cattle and other ruminants, and it has also been speculated to be a putative etiological agent of several human autoimmune diseases. It is acknowledged that dairy products deriving from infected animals play a role (could be vehicles) in exposing humans to MAP. MAP could stimulate the human immune system by means of their complex antigen (in the case of lipids, multivalent antigens) and may modulate it, acting as adjuvant molecules such as Freunds complete adjuvant. The immune system might be abnormally stimulated by the constant presence of MAP antigens (for example, in the dairy products), and this might be particularly relevant in genetically predisposed individuals. However, there is limited understanding about the current human exposure to MAP. The present study analyzed the antibody recognition profile of MAP lipophilic antigens in a cohort of 126 healthy Japanese. We measured the serum levels of total immunoglobulin G (IgG) and subclasses targeting MAP surface antigens through ethanol vortex indirect enzyme-linked immunosorbent assay (EVELISA) by using serum absorbed with Mycobacterium phlei. Elevated IgG (especially IgG1 and IgG4) responses were observed in 14% of the sera. To assess the specificity of EVELISA, the same samples were analyzed by means of a commercially available Johnelisa II kit. It was noteworthy that a high degree of correlation was observed when comparing the two methodologies (rs=0.7, p<0.0001). Moreover, in order to investigate the specificity of the binding, inhibition assay experiments were carried out also searching for antibodies against Bacillus Calmette-Gurin antigens, but no cross-reaction was observed. The result obtained represents the first evidence implying that the Japanese population is exposed to MAP, and additionally the existence of a foodborne chain of exposure that transmits MAP antigens to humans.

PubMed | University of Tennessee at Knoxville, Tohto College of Health Sciences and University of Tennessee Health Science Center
Type: | Journal: Analytical biochemistry | Year: 2016

Mycobacterium avium subspecies paratuberculosis (MAP) causes chronic illnesses mostly in ruminants. MAP infection of intestinal tissue triggers a fatal inflammatory disorder, Johnes disease (paratuberculosis). Development of fast and reliable diagnostic methods for Johnes disease in clinically suspected ruminants requires the discovery of MAP-specific antigens that induce immune responses. Despite a longtime interest in finding such antigens that can detect serum antibody responses with high sensitivity, the antigens currently used for a diagnosis of the MAP infections are the crude extracts from the whole cell. We performed the serum antibody response assay-guided purification of the ethanol extract from MAP isolated from an infected cow. With the results of extensive fractionations and invitro assays, we identified that arachidyl-d-Phe-N-Me-l-Val-l-Ile-l-Phe-l-Ala-OH (named lipopeptide II, 3) exhibited the highest antibody binding activity in serum of a MAP-infected cattle compared with the other lipopeptides isolated from MAP. The absolute chemistry of 3 was determined unequivocally via our high-performance liquid chromatography (HPLC)-amino acid databases. -Amino lipopeptide II and its fluorescent probes were synthesized and evaluated in serum antibody binding activity assays. Lipopeptide II-(2S)-NH2 (9) and its dansyl and fluorescein isothiocyanate (FITC) probes (10 and 11) exhibited antibody-mediated binding activity; thus, such MAP-specific lipopeptide probes can be potential biomarkers for the development of rapid and accurate diagnosis of Johnes disease.

Kuribayashi T.,Azabu University | Seita T.,Azabu University | Momotani E.,Tohto College of Health Sciences | Yamazaki S.,Kanagawa University | And 2 more authors.
Inflammation | Year: 2015

The half-lives of typical acute phase proteins in rats and beagle dogs during acute inflammation were investigated. Acute inflammation was induced by injection of turpentine oil in rats and administration of indomethacin in beagle dogs. Serum concentrations of α2-macroglobulin (α2M) and C-reactive protein (CRP) were measured by enzyme-linked immunosorbent assay and α1-acid glycoprotein (AAG) was measured by single radial immunodiffusion. Half-life was calculated as 0.693/elimination rate constant (K). The mean half-lives in the terminal elimination phase of α2M and AAG were 68.1 and 164.8 h, respectively. The half-life of AAG was significantly longer than that of α2M. Mean half-lives in the terminal elimination phase of CRP and AAG were 161.9 and 304.4 h, respectively. The half-life of AAG was significantly longer than that of CRP in beagle dogs. No significant differences in the half-life of AAG were observed between rats and beagle dogs. Furthermore, serum concentrations in the terminal elimination phase could be simulated with the K data acquired in this study. © 2015, Springer Science+Business Media New York.

Kitamura K.,Niigata University of Health and Welfare | Nakamura K.,Niigata University | Nishiwaki T.,Niigata University of Health and Welfare | Ueno K.,Teikyo University | And 2 more authors.
Environmental Health and Preventive Medicine | Year: 2012

Objectives Serum albumin and activities of daily living (ADL) are associated with each other, but whether the association is causal is not known. The purpose of this study was to determine whether a causal association exists between serum albumin and ADL levels. Methods The subjects were 116 frail elderly individuals (34 men and 82 women; mean age 83.0 years). Demographic characteristics, serum albumin, ADL, and handgrip strength were measured at a baseline examination and at a follow-up examination 2 years later. Levels of ADL were assessed with the Barthel Index. Pearson's correlation coefficients were calculated for serum albumin, ADL, and handgrip strength for baseline values and for their 2-year changes (Δ). Results At baseline, the mean serum albumin concentration was 4.0 g/dL and the total score of the Barthel Index (baseline Barthel Index) was 71.1. The baseline serum albumin level correlated significantly with the baseline Barthel Index (r = 0.287) and baseline handgrip strength (r = 0.315), but not with Δ Barthel Index (r = 0.096) or Δ handgrip strength (r = - 0.058). The Δ serum albumin correlated significantly with Δ Barthel Index (r = 0.296), but not with Δ handgrip strength (r = 0.182), baseline Barthel Index (r = - 0.044), or baseline handgrip strength (r = 0.047). Conclusions This 2-year cohort study has demonstrated that a decrease in serum albumin levels is associated with a decrease in ADL levels. A third factor may play a role in adversely affecting both serum albumin and ADL levels in frail elderly people. © The Japanese Society for Hygiene 2011.

Mikami S.,Keio University | Oya M.,Keio University | Mizuno R.,Keio University | Kosaka T.,Keio University | And 2 more authors.
Medical Molecular Morphology | Year: 2014

Renal cell carcinoma (RCC) represents over 80 % of kidney cancer, and about 30 % of the patients with RCC develop metastasis after the surgery. Invasion of basement membrane (BM) and extracellular matrix (ECM) is an essential event in tumor invasion and metastasis. Matrix metalloproteinases (MMPs), which digest the main components of BM and ECM, are expressed in RCC. Heparanase, which degrades heparan sulfate proteoglycans, is predominantly expressed in high-grade RCCs with a positive correlation with pathological tumor stage and poor prognosis. Bone metastasis is common among the patients with RCC, and increased osteoclastic activity was observed at metastatic sites. Receptor activator of nuclear factor κB ligand (RANKL), which plays an important role in osteoclastogenesis, is predominantly expressed in high-grade RCC and its expression level is associated with bone metastasis and prognosis. Epithelial-mesenchymal transition (EMT), a switch of epithelial cells to sarcomatoid phenotype, is considered to be critical step during metastasis, and Snail, a major regulator of EMT, is predominantly expressed in high-grade RCC, and high Snail expression is a worse prognostic factor. Accordingly, heparanase, RANKL and Snail may be targets for the development of anti-tumor therapies for RCCs. © 2013 The Japanese Society for Clinical Molecular Morphology.

PubMed | Tokyo Medical and Dental University and Tohto College of Health Sciences
Type: Journal Article | Journal: PloS one | Year: 2016

Keratin subtypes are selectively expressed depending on the cell type. They not only provide structural support, but regulate the metabolic processes and signaling pathways that control the growth of the epithelium. KRT17 (keratin 17) is induced in the regenerative epithelium and acts on diverse signaling pathways. Here, we demonstrate that KRT17 is invariably and permanently induced in oral squamous cell carcinoma (OSCC), as revealed by immunohistochemistry and cDNA microarray analysis. Two representative OSCC cell lines; KRT17-weakly expressing Ca9-22 and KRT17-highly expressing HSC3 were used to establish KRT17-overexpressing Ca9-22 and KRT17-knockdown HSC3 cells. Analysis of these cells revealed that KRT17 promoted cell proliferation and migration by stimulating the Akt/mTOR pathway. KRT17 also upregulated the expression of SLC2A1 (solute carrier family 2 member 1/Glut1) and glucose uptake. To further investigate the effect of KRT17 on tumorigenesis, KRT17-knockout HSC3 cells were established and were transplanted to the cephalic skin of nude mice. The tumors that developed from KRT17-knockout HSC3 cells had a lower Ki-67 labeling index and were significantly smaller compared to the controls. These results indicate that KRT17 stimulates the Akt/mTOR pathway and glucose uptake, thereby facilitating tumor growth. We could not confirm the relationship between KRT17 and SFN (stratifin) in the cells examined in this study. However, our study reinforces the concept that the cellular properties of cancer are regulated by a series of molecules similar to those found in wound healing. In OSCC, KRT17 acts as a pathogenic keratin that facilitates tumor growth through the stimulation of multiple signaling pathways, highlighting the importance of KRT17 as a multifunctional promoter of tumorigenesis.

PubMed | Mukogawa Women's University and Tohto College of Health Sciences
Type: | Journal: Journal of cellular physiology | Year: 2017

Sox9, a master regulator of cartilage development, controls the cell fate decision to differentiate from mesenchymal to chondrogenic cells. In addition, Sox9 regulates the proliferation and differentiation of chondrocytes, as well as the production of cartilage-specific proteoglycans. The existence of Sox9-independent mechanisms in cartilage development remains to be determined. Here, we attempted to identify genes involved in such putative mechanisms via microarray analysis using a mouse chondrogenic cell line, N1511. We first focused on transcription factors that exhibited upregulated expression following Bmp2 treatment, which was not altered by subsequent treatment with Sox9 siRNA. Among these, we selected positive regulators for chondrogenesis and identified Iroquois-related homeobox 3 (Irx3) as one of the candidate genes. Irx3 expression gradually increased with chondrocyte terminal differentiation in a reciprocal manner to Sox9 expression, and promoted the chondrogenic differentiation of mesenchymal cells upon Bmp2 treatment. Furthermore, Irx3 partially rescued impaired chondrogenesis by upregulating the expression of epiphycan and lumican under reduced Sox9 expression. Finally, Irx3 was shown to act in concert with Bmp2 signaling to activate the p38 MAPK pathway, which in turn stimulated Sox9 expression, as well as the expression of epiphycan and lumican in a Sox9-independent manner. These results indicate that Irx3 represents a novel chondrogenic factor of mesenchymal cells, acts synergistically with Bmp2-mediated signaling, and regulates chondrogenesis independent of the transcriptional machinery associated with Sox9-mediated regulation. This article is protected by copyright. All rights reserved.

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