Publications by authors named "Hiroko Fujii"

49 Publications

Predictive factors of response to pulse methylprednisolone therapy in patients with alopecia areata: A follow-up study of 105 Japanese patients.

J Dermatol 2019 Jun 10;46(6):522-525. Epub 2019 Apr 10.

Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Pulse corticosteroid therapy is effective for alopecia areata (AA) in the early stage. The risk and efficacy of this therapy for patients with several backgrounds, however, remains controversial. To explore the predictive factors of the response and risk factors of this therapy, data from 105 AA patients treated with methylprednisolone (500 mg) i.v. for 3 days consecutively in our facility were retrospectively analyzed. Among good responders, longer time from the onset to therapy was correlated with longer time required for hair regrowth (P = 0.037, n = 27). Multivariate models demonstrated that "severity", "relapse" and longer "duration from the latest onset" were significantly and independently associated with poorer outcome (P < 0.01). "History of atopic dermatitis (AD)" was also associated with poorer outcome, but this correlation could be explained by the effect that duration from the latest onset of AA was longer among participants with AD. We propose that earlier initiation of pulse corticosteroid therapy is preferable for better outcome of AA, particularly among patients with AD. Clinicians should be mindful of the occurrence of mild adverse effects in the elderly patients.
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http://dx.doi.org/10.1111/1346-8138.14871DOI Listing
June 2019

DNA damage response induced by Etoposide promotes steroidogenesis via GADD45A in cultured adrenal cells.

Sci Rep 2018 06 25;8(1):9636. Epub 2018 Jun 25.

Department of Biochemistry, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.

Glucocorticoid production is regulated by adrenocorticotropic hormone (ACTH) via the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway in the adrenal cortex, but the changes in steroidogenesis associated with aging are unknown. In this study, we show that cell-autonomous steroidogenesis is induced by non-ACTH- mediated genotoxic stress in human adrenocortical H295R cells. Low-dose etoposide (EP) was used to induce DNA damage as a genotoxic stress, leading to cellular senescence. We found that steroidogenesis was promoted in cells stained with γH2AX, a marker of DNA damaged cells. Among stress-associated and p53-inducible genes, the expression of GADD45A and steroidogenesis-related genes was significantly upregulated. Immunofluorescence analysis revealed that GADD45A accumulated in the nuclei. Metabolite assay using cultured media showed that EP-treated cells were induced to produce and secrete considerable amounts of glucocorticoid. Knockdown of GADD45A using small interfering RNA markedly inhibited the EP-induced upregulation of steroidogenesis-related gene expression, and glucocorticoid production. A p38MAPK inhibitor, but not a PKA inhibitor, suppressed EP-stimulated steroidogenesis. These results suggest that DNA damage itself promotes steroidogenesis via one or more unprecedented non-ACTH-mediated pathway. Specifically, GADD45A plays a crucial role in the steroidogenic processes triggered by EP-stimulated genotoxic stress. Our study sheds new light on an alternate mechanism of steroidogenesis in the adrenal cortex.
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http://dx.doi.org/10.1038/s41598-018-27938-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018231PMC
June 2018

An Excess of CYP24A1, Lack of CaSR, and a Novel lncRNA Near the PTH Gene Characterize an Ectopic PTH-Producing Tumor.

J Endocr Soc 2017 Jun 3;1(6):691-711. Epub 2017 May 3.

Department of Biochemistry, Teikyo University School of Medicine, Tokyo 173-0003, Japan.

Thus far, only 23 cases of the ectopic production of parathyroid hormone (PTH) have been reported. We have characterized the genome-wide transcription profile of an ectopic PTH-producing tumor originating from a retroperitoneal histiocytoma. We found that the calcium-sensing receptor (CaSR) was barely expressed in the tumor. Lack of CaSR, a crucial braking apparatus in the presence of both intraparathyroid and, probably, serendipitous PTH expression, might contribute strongly to the establishment and maintenance of the ectopic transcriptional activation of the PTH gene in nonparathyroid cells. Along with candidate drivers with a crucial frameshift mutation or copy number variation at specific chromosomal areas obtained from whole exome sequencing, we identified robust tumor-specific cytochrome P450 family 24 subfamily A member 1 (CYP24A1) overproduction, which was not observed in other non-PTH-expressing retroperitoneal histiocytoma and parathyroid adenoma samples. We then found a 2.5-kb noncoding RNA in the PTH 3'-downstream region that was exclusively present in the parathyroid adenoma and our tumor. Such a co-occurrence might act as another driver of ectopic PTH-producing tumorigenesis; both might release the control of PTH gene expression by shutting down the other branches of the safety system ( CaSR and the vitamin D3-vitamin D receptor axis).
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http://dx.doi.org/10.1210/js.2017-00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686629PMC
June 2017

Disseminated Cryptococcosis with Adrenal Insufficiency and Meningitis in an Immunocompetent Individual.

Intern Med 2017 15;56(10):1259-1264. Epub 2017 May 15.

Department of Internal Medicine, Japan Self Defense Forces Central Hospital, Japan.

We present a case of cryptococcosis with adrenal insufficiency and meningitis in a healthy host without any risk factors. Antifungal therapy did not reduce the cryptococcal antigen titers of the cerebrospinal fluid and serum or the bilateral adrenal gland enlargement. It was suggested that the adrenal glands were the focus of persistent fungemia. Removal of both adrenal glands brought about a response to antifungal therapy. We conclude that if antifungal therapy is ineffective, bilateral adrenalectomy is an effective measure for treatment of such patients. Cryptococcosis is a possible cause of primary adrenal insufficiency in immunocompetent patients.
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http://dx.doi.org/10.2169/internalmedicine.56.7356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491828PMC
October 2017

Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages.

Sci Rep 2016 07 18;6:29914. Epub 2016 Jul 18.

Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.

Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.
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http://dx.doi.org/10.1038/srep29914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947927PMC
July 2016

Regulatory T Cells in Melanoma Revisited by a Computational Clustering of FOXP3+ T Cell Subpopulations.

J Immunol 2016 Mar 10;196(6):2885-92. Epub 2016 Feb 10.

Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, United Kingdom; and Immunobiology, University College London Institute of Child Health, London WC1N 1EH, United Kingdom

CD4(+) T cells that express the transcription factor FOXP3 (FOXP3(+) T cells) are commonly regarded as immunosuppressive regulatory T cells (Tregs). FOXP3(+) T cells are reported to be increased in tumor-bearing patients or animals and are considered to suppress antitumor immunity, but the evidence is often contradictory. In addition, accumulating evidence indicates that FOXP3 is induced by antigenic stimulation and that some non-Treg FOXP3(+) T cells, especially memory-phenotype FOXP3(low) cells, produce proinflammatory cytokines. Accordingly, the subclassification of FOXP3(+) T cells is fundamental for revealing the significance of FOXP3(+) T cells in tumor immunity, but the arbitrariness and complexity of manual gating have complicated the issue. In this article, we report a computational method to automatically identify and classify FOXP3(+) T cells into subsets using clustering algorithms. By analyzing flow cytometric data of melanoma patients, the proposed method showed that the FOXP3(+) subpopulation that had relatively high FOXP3, CD45RO, and CD25 expressions was increased in melanoma patients, whereas manual gating did not produce significant results on the FOXP3(+) subpopulations. Interestingly, the computationally identified FOXP3(+) subpopulation included not only classical FOXP3(high) Tregs, but also memory-phenotype FOXP3(low) cells by manual gating. Furthermore, the proposed method successfully analyzed an independent data set, showing that the same FOXP3(+) subpopulation was increased in melanoma patients, validating the method. Collectively, the proposed method successfully captured an important feature of melanoma without relying on the existing criteria of FOXP3(+) T cells, revealing a hidden association between the T cell profile and melanoma, and providing new insights into FOXP3(+) T cells and Tregs.
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http://dx.doi.org/10.4049/jimmunol.1402695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777917PMC
March 2016

Syringocystadenocarcinoma Papilliferum in the Perianal Area.

Case Rep Dermatol 2015 May-Aug;7(2):84-9. Epub 2015 May 7.

Department of Dermatology, Tenri Hospital, Tenri, Japan.

Syringocystadenocarcinoma papilliferum (SCACP) is a very rare cutaneous adnexal neoplasm. SCACP presents histologic variability, and it is difficult to establish the diagnosis from a punch biopsy. SCACP has an overall configuration similar to that of syringocystadenoma papilliferum (SCAP). When we diagnose SCACP, the histologic features of SCAP can be contributing and immunohistochemical staining is useful. Our case shows the histologic variability of SCACP and the pitfalls of a punch biopsy for the diagnosis of SCACP.
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http://dx.doi.org/10.1159/000381940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464026PMC
June 2015

Influenza virus-host interactome screen as a platform for antiviral drug development.

Cell Host Microbe 2014 Dec 20;16(6):795-805. Epub 2014 Nov 20.

ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA; Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan. Electronic address:

Host factors required for viral replication are ideal drug targets because they are less likely than viral proteins to mutate under drug-mediated selective pressure. Although genome-wide screens have identified host proteins involved in influenza virus replication, limited mechanistic understanding of how these factors affect influenza has hindered potential drug development. We conducted a systematic analysis to identify and validate host factors that associate with influenza virus proteins and affect viral replication. After identifying over 1,000 host factors that coimmunoprecipitate with specific viral proteins, we generated a network of virus-host protein interactions based on the stage of the viral life cycle affected upon host factor downregulation. Using compounds that inhibit these host factors, we validated several proteins, notably Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) and JAK1, as potential antiviral drug targets. Thus, virus-host interactome screens are powerful strategies to identify targetable host factors and guide antiviral drug development.
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http://dx.doi.org/10.1016/j.chom.2014.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451456PMC
December 2014

Marked cortisol production by intracrine ACTH in GIP-treated cultured adrenal cells in which the GIP receptor was exogenously introduced.

PLoS One 2014 21;9(10):e110543. Epub 2014 Oct 21.

Department of Biochemistry, Teikyo University School of Medicine, Tokyo, Japan.

The ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in the human adrenal gland causes significant hypercortisolemia after ingestion of each meal and leads to Cushing's syndrome, implying that human GIPR activation is capable of robustly activating adrenal glucocorticoid secretion. In this study, we transiently transfected the human GIPR expression vector into cultured human adrenocortical carcinoma cells (H295R) and treated them with GIP to examine the direct link between GIPR activation and steroidogenesis. Using quantitative RT-PCR assay, we examined gene expression of steroidogenic related proteins, and carried out immunofluorescence analysis to prove that forced GIPR overexpression directly promotes production of steroidogenic enzymes CYP17A1 and CYP21A2 at the single cell level. Immunofluorescence showed that the transfection efficiency of the GIPR gene in H295R cells was approximately 5%, and GIP stimulation enhanced CYP21A2 and CYP17A1 expression in GIPR-introduced H295R cells (H295R-GIPR). Interestingly, these steroidogenic enzymes were also expressed in the GIPR (-) cells adjacent to the GIPR (+) cells. The mRNA levels of a cholesterol transport protein required for all steroidogenesis, StAR, and steroidogenic enzymes, HSD3β2, CYP11A1, CYP21A2, and CYP17A1 increased 1.2-2.1-fold in GIP-stimulated H295R-GIPR cells. These changes were reflected in the culture medium in which 1.5-fold increase in the cortisol concentration was confirmed. Furthermore, the levels of adenocorticotropic hormone (ACTH) receptor and ACTH precursor proopiomelanocortin (POMC) mRNA were upregulated 2- and 1.5-fold, respectively. Immunofluorescence showed that ACTH expression was detected in GIP-stimulated H295R-GIPR cells. An ACTH-receptor antagonist significantly inhibited steroidogenic gene expression and cortisol production. Immunostaining for both CYP17A1 and CYP21A2 was attenuated in cells treated with ACTH receptor antagonists as well as with POMC siRNA. These results demonstrated that GIPR activation promoted production and release of ACTH, and that steroidogenesis is activated by endogenously secreted ACTH following GIP administration, at least in part, in H295R cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110543PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204891PMC
June 2015

Contact urticaria due to a face mask coated with disinfectant liquid spray.

Acta Derm Venereol 2015 May;95(5):628-9

Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

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http://dx.doi.org/10.2340/00015555-1962DOI Listing
May 2015

Linear basal cell carcinoma at the external genitalia.

J Dermatol 2014 Mar 31;41(3):275-6. Epub 2014 Jan 31.

Department of Dermatology, Tenri Hospital, Nara, Japan.

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http://dx.doi.org/10.1111/1346-8138.12403DOI Listing
March 2014

CD8⁺ tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma.

Int J Cancer 2014 May 18;134(10):2393-402. Epub 2013 Nov 18.

Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic factor in various cancers and are a promising target for immunotherapy. To investigate whether TILs have any impact on the prognosis of angiosarcoma patients, 55 non-treated patients (40 patients at stage 1 with cutaneous localized tumors, 4 patients at stage 2 with lymph node metastases and 11 patients at stage 3 with distant metastases) with angiosarcoma were evaluated retrospectively by immunohistochemistry stained CD4, CD8, FOXP3 and Ki67. The Kaplan-Meier method was used to estimate overall survival with patients at stage 1. Survival differences were analyzed by the log-rank test. Patients with higher numbers of CD8(+) TILs in their primary tumors survived significantly longer compared with patients with lower values. Moreover, the number of CD8 in TILs was positively correlated with a distant metastasis-free period. The total number of primary TILs (CD4 plus CD8) and CD8(+) primary TILs of stage 3 patients with distant metastases was positively correlated with their overall survival. To evaluate whether CD8(+) effector T cells are activated or differentiated, flow cytometric analysis of peripheral blood mononuclear cells (PBMC) was performed. The percentages of CD8(+) T cells producing IFN-γ in PBMC were significantly higher in patients with angiosarcoma (n = 10) compared not only with that of healthy controls (n = 20) but also patients with advanced melanoma (n = 11). These results suggest that anti-tumor immunity is clinically relevant in angiosarcoma.
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http://dx.doi.org/10.1002/ijc.28581DOI Listing
May 2014

Optimization of Ultrasound-mediated Anti-angiogenic Cancer Gene Therapy.

Mol Ther Nucleic Acids 2013 May 21;2:e94. Epub 2013 May 21.

Division of Cardiology, Department of Medicine, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Ultrasound-targeted microbubble destruction (UTMD) can be used to deliver silencing gene therapy to tumors. We hypothesized that UTMD would be effective in suppressing angiogenesis within tumors, and that modulation of the ultrasound pulsing intervals (PI) during UTMD would affect the magnitude of target knockdown. We performed UTMD of vascular endothelial growth factor receptor-2 (VEGFR2) short hairpin (sh)RNA plasmid in an heterotopic mammary adenocarcinoma model in rats, evaluating PIs of 2, 5, 10, and 20 seconds. We demonstrated that UTMD with a PI of 10 seconds resulted in the greatest knockdown of VEGFR2 by PCR, immunostaining, western blotting, smaller tumor volumes and perfused areas, and lower tumor microvascular blood volume (MBV) and flow by contrast-enhanced ultrasound (CEU) compared with UTMD-treated tumors at 2, 5, and 20 seconds, control tumors, tumors treated with intravenous shRNA plasmid and scrambled plasmid. CEU perfusion assessment using the therapeutic probe demonstrated that tumors were fully replenished with microbubbles within 10 seconds, but incompletely replenished at PI-2 and PI-5 seconds. In conclusion, for anti-VEGFR2 cancer gene therapy by UTMD, PI of 10 seconds results in higher target knockdown and a greater anti-angiogenic effect. Complete replenishment of tumor vasculature with silencing gene-bearing microbubbles in between destructive pulses of UTMD is required to maximize the efficacy of anti-angiogenic cancer gene therapy.Molecular Therapy - Nucleic Acids (2013) 2, e94; doi:10.1038/mtna.2013.20; published online 21 May 2013.
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http://dx.doi.org/10.1038/mtna.2013.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817934PMC
May 2013

Dronedarone and Captisol-enabled amiodarone in an experimental cardiac arrest.

J Cardiovasc Pharmacol 2013 May;61(5):385-90

Keenan Research Centre in the Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada.

Objective: To compare the energy required for defibrillation and postshock outcomes after the administration of dronedarone, amiodarone, and placebo in a porcine model of cardiac arrest.

Methods: Forty-two pigs were randomized to amiodarone, dronedarone, or control treatments. After induction of ventricular fibrillation, compressions and ventilations were performed for 3 minutes and treatment was administered over 30 seconds. If defibrillation was unsuccessful, cardiopulmonary resuscitation continued and repeated shocks were administered every 2 minutes with continual hemodynamic monitoring for a total duration of 30 minutes.

Results: The cumulative energy required for defibrillation was 570 ± 422 J for dronedarone, 441 ± 365 J for amiodarone, and 347 ± 281 J for control (P = not significant). Survival at 30 minutes was 1 (7.1%) for dronedarone compared with 11 (78.6%) for control (P = 0.001). Mortality in the dronedarone group was because of refibrillation in 3 (21.4%) cases, atrioventricular block in 1 (7.1%) case, and hypotension not because of bradycardia in 9 (64.3%) cases. Two minutes after successful defibrillation, systolic aortic pressure was lower in dronedarone versus control (86.6 ± 26.9 vs. 110 ± 15.1 mm Hg; P = 0.035).

Conclusions: The administration of dronedarone resulted in a significant reduction in survival and both systolic aortic and coronary perfusion pressure compared with control.
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http://dx.doi.org/10.1097/FJC.0b013e3182868750DOI Listing
May 2013

Treatment with a highly selective β₁ antagonist causes dose-dependent impairment of cerebral perfusion after hemodilution in rats.

Anesth Analg 2013 Mar 11;116(3):649-62. Epub 2013 Feb 11.

Department of Anesthesia, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, 30 Bond St., Toronto, ON M5B 1W8, Canada.

Background: Acute β-blockade has been associated with a dose-dependent increase in adverse outcomes, including stroke and mortality. Acute blood loss contributes to the incidence of these adverse events. In an attempt to link the risks of acute blood loss and β-blockade, animal studies have demonstrated that acute β-blockade impairs cerebral perfusion after hemodilution. We expanded on these findings by testing the hypothesis that acute β-blockade with a highly β(1)-specific antagonist (nebivolol) causes dose-dependent cerebral hypoxia during hemodilution.

Methods: Anesthetized rats and mice were randomized to receive vehicle or nebivolol (1.25 or 2.5 mg/kg) IV before hemodilution to a hemoglobin concentration near 60 g/L. Drug levels, heart rate (HR), cardiac output (CO), regional cerebral blood flow (rCBF, laser Doppler), and microvascular brain Po(2) (P(Br)O(2), G2 Oxyphor) were measured before and after hemodilution. Endothelial nitric oxide synthase (NOS), neuronal NOS (nNOS), inducible NOS, and hypoxia inducible factor (HIF)-1α were assessed by Western blot. HIF-α expression was also assessed using an HIF-(ODD)-luciferase mouse model. Data were analyzed using analysis of variance with significance assigned at P < 0.05, and corrected P values are reported for all post hoc analyses.

Results: Nebivolol treatment resulted in dose-specific plasma drug levels. In vehicle-treated rats, hemodilution increased CO and rCBF (P < 0.010) whereas P(Br)O(2) decreased to 45.8 ± 18.7 mm Hg (corrected P < 0.001; 95% CI 29.4-69.7). Both nebivolol doses comparably reduced HR and attenuated the CO response to hemodilution (P < 0.012). Low-dose nebivolol did not impair rCBF or further reduce P(Br)O(2) after hemodilution. High-dose nebivolol attenuated the rCBF response to hemodilution and caused a further reduction in P(Br)O(2) to 28.4 ± 9.6 mm Hg (corrected P = 0.019; 95% CI 17.4-42.7). Both nebivolol doses increased brain endothelial NOS protein levels. Brain HIF-1α, inducible NOS, and nNOS protein levels and brain HIF-luciferase activity were increased in the high-dose nebivolol group after hemodilution (P < 0.032).

Conclusions: Our data demonstrate that nebivolol resulted in a dose-dependent decrease in cerebral oxygen delivery after hemodilution as reflected by a decrease in brain tissue Po(2) and an increase in hypoxic protein responses (HIF-1α and nNOS). Low-dose nebivolol treatment did not result in worsened tissue hypoxia after hemodilution, despite comparable effects on HR and CO. These data support the hypothesis that acute β-blockade with a highly β(1)-specific antagonist causes a dose-dependent impairment in cerebral perfusion during hemodilution.
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http://dx.doi.org/10.1213/ANE.0b013e318280e26dDOI Listing
March 2013

Efficacy of a high dosage of donepezil for Alzheimer's disease as examined by single-photon emission computed tomography imaging.

Psychogeriatrics 2012 Sep;12(3):172-8

Department of Geriatric Medicine, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

Background: The efficacy of donepezil 10 mg/day against Alzheimer's disease (AD) was examined, with a primary focus on changes in cerebral blood flow (CBF) as determined by single-photon emission computed tomography imaging.

Methods: The subjects were 24 outpatients who had been diagnosed with probable AD, which had progressed to advanced AD. Mini-Mental State Examination and Alzheimer's Disease Assessment Scale (ADAS) scores were determined before and after the donepezil dosage increase. (99m) Tc-ethylcysteinate dimer single-photon emission computed tomography was performed to evaluate changes in CBF. Then, a comparative study evaluated changes after the donepezil dosage increased.

Results: After the donepezil dosage increase, adverse effects associated with gastrointestinal symptoms were observed in one patient, and irritability was observed in three. The average Mini-Mental State Examination score changed from 15.25 ± 6.24 to 14.67 ± 6.07; significant changes were not observed. Seventeen subjects were evaluated with the Alzheimer's Disease Assessment Scale-cognitive subscale. After the dosage increase, the average subscale score decreased from 24.52 ± 13.39 to 21.56 ± 9.14, and significant improvement was observed (P = 0.021). With respect to changes in the CBF, the values of all three indicators decreased after the higher dosage increased CBF. However, no significant differences were observed in CBF. Analysis performed after the donepezil dosage increase revealed significant increases in CBF in the right occipital and temporal lobes, left temporal lobe, right parietal lobe, and both parts of the posterior cerebellum.

Conclusion: Increasing the donepezil dosage from 5 mg/day to 10 mg/day is effective for the treatment of AD.
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http://dx.doi.org/10.1111/j.1479-8301.2011.00399.xDOI Listing
September 2012

Docosahexaenoic acid, but not eicosapentaenoic acid, supplementation reduces vulnerability to atrial fibrillation.

Circ Arrhythm Electrophysiol 2012 Oct 24;5(5):978-83. Epub 2012 Aug 24.

Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.

Background: The potential health benefits of ω-3 polyunsaturated fatty acids (PUFAs) usually are studied using a combination of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This combination reduces vulnerability to experimentally induced atrial fibrillation (AF). It is unknown whether EPA and DHA have differential effects when taken alone. Using a model of pacing-induced atrial hemodynamic overload, we investigated the individual effects of EPA and DHA on vulnerability to AF and atrial remodeling.

Methods And Results: Thirty-four dogs were randomized into 3 groups, all of which underwent simultaneous atrial and ventricular pacing at 220 beats per minute for 14 days. One group received purified DHA (≈1 g/d) orally for 21 days beginning 7 days before pacing began. Similarly, 1 group received ≈1 g/d purified EPA. In a third (control) group (No-PUFAs), 8 dogs received ≈1 g/d olive oil, and 12 were unsupplemented. Electrophysiological and echocardiographic measurements were taken at baseline and 21 days. Atrial tissue samples were collected at 21 days for histological and molecular analyses. Persistent AF inducibility was significantly reduced by DHA compared with No-PUFAs median [25-75 percentiles], 0% [0%-3%] for DHA versus 3.1% [2.2%-11%] for No-PUFAs; P=0.007) but not by EPA (3.4% [1.9%-8.9%]). DHA also reduced atrial fibrosis compared with No-PUFAs (11 ± 6% versus 20 ± 4%, respectively; P<0.05), whereas EPA did not (15 ± 5%; P>0.05).

Conclusions: DHA is more effective than EPA in attenuating AF vulnerability and atrial remodeling in structural remodeling-induced AF.
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http://dx.doi.org/10.1161/CIRCEP.112.971515DOI Listing
October 2012

Statin therapy prevents expansive remodeling in venous bypass grafts.

Atherosclerosis 2012 Jul 22;223(1):106-13. Epub 2012 Mar 22.

Schulich Heart Centre, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.

Background: Venous grafts (VG) have high failure rates by 10 years in aortocoronary bypass surgery. We have previously shown that expansive remodeling followed by increased LDL retention are early atherosclerotic changes in experimental VG placed in the arterial circulation. The objective of this study was to determine whether statin therapy prevents these expansive remodeling changes.

Methods And Results: Reversed jugular vein-to-common carotid artery interposition graft was constructed in 27 cholesterol-fed (0.5%) rabbits. Rabbits were randomized either to control or atorvastatin (5 mg/kg/day) groups, starting two weeks prior to vein graft implantation and continuing until sacrifice at 1 or 12 weeks post-surgery. Ultrasound measurements of arterial luminal cross-sectional area (CSA) were done at day 3 and at 4, 8 and 12 weeks post-surgery. Histomorphometric measurements were performed following sacrifice at 12 weeks. Atorvastatin treatment significantly decreased total plasma cholesterol levels at 4, 8 and 12 weeks (12 weeks: 6.7 ± 4.2 mmol/L versus control 38.7 ± 10.6 mmol/L, p<0.0002). Atorvastatin significantly reduced expansive remodeling at 4, 8 and 12 weeks (lumen CSA: 44.6 ± 6.6 mm(2) versus control 77.6 ± 10.7 mm(2), p<0.0001). Intimal CSA by histomorphometry was also significantly reduced by atorvastatin at 12 weeks (5.59 ± 2.19 mm(2) versus control 9.57 ± 2.43 mm(2), p<0.01). VG macrophage infiltration, MMP-2 activity and metalloelastase activity were reduced in the atorvastatin treated group.

Conclusion: Atorvastatin inhibits both expansive remodeling and intimal hyperplasia in arterialized VG, likely through inhibition of macrophage infiltration and reduction of tissue proteolytic activity. The mechanism proposed above may be important for preventing VG atherosclerosis and late VG failure.
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http://dx.doi.org/10.1016/j.atherosclerosis.2012.03.013DOI Listing
July 2012

N-3 polyunsaturated fatty acid supplementation does not reduce vulnerability to atrial fibrillation in remodeling atria.

Heart Rhythm 2012 Jul 15;9(7):1115-1122.e4. Epub 2012 Feb 15.

Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.

Background: Prophylactic supplementation with omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to atrial fibrillation (AF). The effect of PUFAs given after cardiac injury has occurred is unknown.

Objective: To investigate using a model of pacing-induced cardiac injury, the time course of development of injury and whether it was altered by postinjury PUFAs.

Methods: Sixty-five dogs were randomized to undergo simultaneous atrial and ventricular pacing (SAVP, 220 beats/min) for 0, 2, 7, or 14 days. Twenty-two dogs received PUFAs (850 mg/d) either prophylactically or after some pacing had occurred (postinjury). Electrophysiologic and echocardiographic measurements were taken at baseline and sacrifice. Atrial tissue samples were collected at sacrifice for histologic and molecular analyses.

Results: With no PUFAs, the inducibility of AF increased with pacing duration (P < .001). Postinjury PUFAs (started after 7 days of pacing) did not reduce the inducibility of AF after 14 days of pacing (9.3% ± 8.8% no PUFAs vs 9.7% ± 9.9% postinjury PUFAs; P = .91). Atrial myocyte size and fibrosis increased with pacing duration (P < .05). Postinjury PUFAs did not significantly attenuate the cell size increase after 14 days of pacing (no PUFAs 38% ± 30% vs postinjury PUFAs 19% ± 28%; P = .11). Similarly, postinjury PUFAs did not attenuate the increase in fibrosis after 14 days of pacing (no PUFAs 66% ± 51% vs postinjury PUFAs 63% ± 76%; P = .90).

Conclusion: PUFA supplementation begun after cardiac injury has already occurred does not reduce atrial structural remodeling or vulnerability to AF.
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http://dx.doi.org/10.1016/j.hrthm.2012.02.013DOI Listing
July 2012

Contrast ultrasound and targeted microbubbles: diagnostic and therapeutic applications for angiogenesis.

J Cardiovasc Transl Res 2011 Aug 3;4(4):404-15. Epub 2011 May 3.

Division of Cardiology, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Angiogenesis represents the formation of new capillaries from existing vasculature, and as such plays a critical role in the response to ischemia in the setting of chronic coronary artery and peripheral vascular disease. Recent technological advances in non-invasive imaging modalities now allow the molecular imaging of angiogenesis. One such technique is contrast-enhanced ultrasound using microbubbles targeted against molecular markers of the angiogenic process. The ability to non-invasively image the angiogenic process would be useful in risk stratifying patients with arterial occlusive disease and would aid in the evaluation of new therapies to promote angiogenesis in ischemic cardiac and skeletal muscle. Furthermore, ultrasound technologies have also been developed that allow targeted angiogenic gene therapy using high-power ultrasound and DNA-bearing microbubbles. This review will focus specifically on recent advances in (1) contrast-enhanced ultrasound molecular imaging techniques for the evaluation of angiogenesis and (2) ultrasound-mediated gene delivery for therapeutic angiogenesis, techniques that have potential for translation to clinical practice.
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http://dx.doi.org/10.1007/s12265-011-9282-2DOI Listing
August 2011

Olfactory ensheathing cell tumor: case report.

Skull Base 2010 Sep;20(5):357-61

Department of Neurosurgery, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Subfrontal schwannomas, sometimes referred to as olfactory groove schwannomas, are rare tumors (34 cases reported to date). Despite the name and several theories proposed in the literature, there is no officially recognized description of the tumor's cell origin. Yasuda proposed the concept of an olfactory ensheathing cell (OEC) tumor in 2006. Olfactory ensheathing cells are glial cells that ensheath the axons of the first cranial nerve. Microscopically, both olfactory ensheathing cells and Schwann cells have similar morphological and immunohistochemical features. However, immunohistochemically olfactory ensheathing cells are negative for Leu7 and Schwann cells positive. A 30-year-old woman presented with a subfrontal, extraaxial, enhancing tumor, and underwent gross total resection. Immunohistochemical reactivity data suggested a schwannoma (positive for S-100 and negative for epithelial membrane antigen). However, the tumor was negative for Leu7. Accordingly, our final diagnosis was that of an OEC tumor. Subfrontal schwannoma immunohistochemical staining, if negative for Leu7, is indicative of an OEC tumor. It is possible that schwannoma-like extraaxial tumors at the anterior skull base are OEC tumors, which negative Leu7 staining can confirm.
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http://dx.doi.org/10.1055/s-0030-1249572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023328PMC
September 2010

Impaired glucose metabolism in Japanese patients with acromegaly is restored after successful pituitary surgery if pancreatic {beta}-cell function is preserved.

Eur J Endocrinol 2011 Apr 1;164(4):467-73. Epub 2011 Feb 1.

Division of Endocrinology Pituitary Surgery, Toranomon Hospital Endocrine Center, 2-2-2 Toranomon Minato-ku, Tokyo 105-8470, Japan.

Objective: Impaired glucose metabolism is common in acromegaly, but it is not clear how glucose metabolism is impaired or what predicts its restoration after cure of the disease. To identify factors involved in the impairment of glucose metabolism in acromegaly, we evaluated clinical parameters before and immediately after surgical cure of the disease.

Design And Methods: We retrospectively analyzed clinical data of 92 consecutive Japanese patients with acromegaly who underwent successful pituitary surgery. Patients who had received medical therapy for acromegaly or insulin treatment for diabetes were excluded. We evaluated insulin resistance (IR) and pancreatic β-cell function in addition to GH and IGF1 levels before and after surgery. Results In this study of Japanese patients with acromegaly, average body mass index (BMI) was 23.4, and no patient had a BMI>30. IR was involved in the impairment of glucose metabolism, which was restored upon surgical cure of acromegaly if β-cell function was preserved. Insufficient β-cell function did not improve after normalization of GH/IGF1 and was associated with impaired glucose metabolism before and after surgery.

Results: of receiver operating characteristic analysis of preoperative clinical parameters suggest that insulinogenic index (IGI) >0.50 best predicts restoration of normal glucose metabolism upon cure of acromegaly in Japanese patients.

Conclusions: IR impairs glucose metabolism in acromegaly. Once β-cell function is impaired, abnormal glucose metabolism persists even after cure of acromegaly. IGI>0.50 indicates that β-cell function is preserved in non-obese Japanese patients with acromegaly.
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http://dx.doi.org/10.1530/EJE-10-1096DOI Listing
April 2011

Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair.

Eur Heart J 2011 Aug 31;32(16):2075-84. Epub 2010 Dec 31.

Division of Cardiovascular Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Aims: Ultrasound-targeted microbubble destruction (UTMD) uses ultrasound energy to selectively deliver genes into the myocardium using plasmids conjugated to microbubbles. We hypothesized that repeated delivery of stem cell-mobilizing genes could boost the ability of this therapy to enhance cardiac repair and ventricular function after a myocardial infarction.

Methods And Results: Beginning 7 days after coronary artery ligation, stem cell factor (SCF) and stromal cell-derived factor (SDF)-1α genes were administered to adult rats using 1, 3, or 6 UTMD treatments (repeat 1, 3, and 6 groups) at 2-day intervals (control=6 treatments with empty plasmid). Cardiac function (echocardiography) and myocardial perfusion (myocardial contrast echocardiography) were assessed on Days -7, 0, and 24 relative to the first treatment. Histological and biochemical assessments were performed on Day 24. Multiple UTMD treatments were associated with an increased presence of myocardial SCF and SDF-1α proteins and their receptors (vs. control and Repeat 1). All UTMD recipients exhibited increased vascular densities and smaller infarct regions (vs. control), with the highest ventricular densities in response to multiple treatments. Myocardial perfusion and ventricular function at Day 24 also improved progressively (vs. control) with the number of UTMD treatments.

Conclusions: Targeted ultrasound delivery of SCF and SDF-1α genes to the infarcted myocardium recruited progenitor cells and increased vascular density. Multiple UTMD treatments enhanced tissue repair, perfusion, and cardiac function. Repeated UTMD therapy may be applied to tailor the number of interventions required to optimize cardiac regeneration after an infarction.
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http://dx.doi.org/10.1093/eurheartj/ehq475DOI Listing
August 2011

Weight loss approach during routine follow-up is effective for obstructive sleep apnea hypopnea syndrome subjects receiving nasal continuous positive airway pressure treatment.

Ind Health 2010 ;48(4):511-6

Department of Public Health, Dokkyo Medical University School of Medicine, Kitakobayashi, Mibu, Shimotsuga, Tochigi.

The present study investigated the effectiveness of a weight loss program during routine medical follow-up with regularity on promoting weight reduction in obese obstructive sleep apnea hypopnea syndrome (OSAHS) subjects receiving continuous positive airway pressure treatment (CPAP). A total of 10 male obese OSAHS subjects treated with CPAP were enrolled in the present study that was an intervention study without a control and had a pre-post test study design. The age was 50.7 (7.8) (mean (SD)) years, and body mass index was 30.7 (2.5) kg/m(2). A 4-month weight loss program was developed, using a combined approach of diet and physical activity based on individual counseling with behavioral approach. At 4 months, weight was significantly decreased compared with the baseline value (88.4 (8.9) kg to 86.9 (8.8) kg, p=0.005), and the mean weight loss was a 1.7% decrease from the baseline. There was significantly higher percent weight loss in the group with a CPAP duration < 30 months, than in the group > or = 30 months (2.7 (1.6) % vs. 0.6 (0.5) %, p=0.032). The present study shows that a weight loss program may be useful in reducing weight for male obese OSAHS subjects treated with CPAP.
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http://dx.doi.org/10.2486/indhealth.ms1081DOI Listing
December 2010

Community-based lifestyle modification of cardiovascular disease risks in middle-aged Japanese: a 27-month update.

Tohoku J Exp Med 2010 Apr;220(4):307-18

Department of Public Health, Dokkyo Medical University School of Medicine, Shimotsuga, Tochigi, Japan.

Lifestyle modification is the cornerstone of preventive management for people with cardiovascular disease risks, such as obesity, hypertension, dyslipidemia and diabetes. This study investigated the effect of a 27-month community-based lifestyle intervention on the reduction of cardiovascular disease risks in middle-aged Japanese. Of 549 participants with cardiovascular disease risk factors of overweight, hypertension, dyslipidemia or diabetes enrolled in this non-randomized controlled study, 397 participants aged 39-71 years old completed all 3 serial surveys at baseline, 15 months and 27 months. For the intervention group (39 males and 174 females), 31 specific interventions including individual counselling and group sessions were conducted. The control group (64 males and 120 females) only received 7 newsletters providing health information and results of health checkups. Multiple logistic regression analysis adjusted for sex, each baseline risk category and age category showed that the proportion of those who were overweight or showed dyslipidemia risk were significantly lower in the intervention group only at 27 months [Odds ratio (OR): 0.43 (95% CI 0.20-0.94), OR: 0.43 (95% CI 0.21-0.87), respectively] and the proportion of those showing diabetes risk was significantly lower in the intervention group at both 15 months [OR: 0.42 (95% CI 0.18-0.97)] and 27 months [OR: 0.56 (95% CI 0.32-0.99)]. In conclusion, the 27-month community-based lifestyle modification of cardiovascular disease risks shows significant reductions in risks of diabetes, overweight and dyslipidemia in middle-aged Japanese.
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http://dx.doi.org/10.1620/tjem.220.307DOI Listing
April 2010

Changes in cognitive functions of patients with dementia of the Alzheimer type following long-term administration of donepezil hydrochloride: relating to changes attributable to differences in apolipoprotein E phenotype.

Geriatr Gerontol Int 2010 Jan;10(1):25-31

Department of Geriatric Medicine, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.

Aim: We conducted a study of changes in cognitive functions by long-term monitoring of dementia of Alzheimer type (DAT) patients to investigate the relationship between the progression of DAT symptoms and the presence of apolipoprotein (ApoE)4.

Methods: The subjects consisted of 40 DAT patients who had been treated with donepezil for 3 years or more. The Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale - Cognitive Subscale Japanese version (ADAS-Jcog), were conducted annually. The patients were categorized into ApoE4(+) and ApoE4(-) groups. Changes in initial cognitive function assessment score (0 years) were then studied longitudinally at each stage of the observation period (1, 2, 3 years) (Wilcoxon's signed-rank test). Moreover, the scores at each time period were compared cross-sectionally between the two groups (Mann-Whitney U-test).

Results: Significant decreases in MMSE scores were observed at the three time periods in both groups (P < 0.01) in the cross-sectional study. In the longitudinal study, the ApoE4(+) group demonstrated a lower trend (P < 0.1) after 1 year only. Significantly poorer ADAS-Jcog scores were observed in the ApoE4(+) group at the 3-year point both in the longitudinal and in the cross-sectional study (P < 0.05). For ADAS-Jcog sub-items, in the longitudinal study, orientation was demonstrated to be significantly poorer in the ApoE4(+) group in the third year (P < 0.05).

Conclusion: ApoE4 was suggested to not only be a risk factor for disease onset, but also a risk factor for exacerbation of symptoms with respect to long-term prognosis.
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http://dx.doi.org/10.1111/j.1447-0594.2009.00551.xDOI Listing
January 2010

Evaluation of the chemosensitivity of primary cultured malignant melanoma cells using the collagen gel droplet-embedded culture drug sensitivity test.

Exp Ther Med 2010 Jan 1;1(1):65-68. Epub 2010 Jan 1.

Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507;

Malignant melanoma usually shows resistance to a standard chemotherapy regimen. A useful in vitro method to evaluate individual chemosensitivity is required to select effective anti-cancer drugs. This study aimed to establish in vitro tumor response testing for malignant melanoma. We determined the chemosensitivity of primary cultured melanoma cells using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST). Nineteen tests were carried out for 15 cases of malignant melanoma. Primary cultured melanoma cells in collagen gel droplets were exposed to anti-cancer drugs, including cisplatin, adriamycin, dacarbazine, nimustine and vincristine. After a 7-day incubation in a serum-free medium, living melanoma cells in a collagen droplet were detected by image analysis after staining with Neutral red reagent. In vitro drug exposure conditions were determined to reproduce the value of the plasma area under the time-drug concentration curve in vivo. The rate of evaluation of the primary culture of melanoma cells was 78.9% (15/19 tests). The chemosensitivity of cisplatin, adriamycin, dacarbazine, nimustine and vincristine was 15, 62, 0, 0 and 62%, respectively. Dacarbazine was not suitable for CD-DST due to its prodrug characteristics. The CD-DST method was able to evaluate the chemosensitivity of malignant melanoma to anti-cancer drugs in vitro. This method can also be applied to estimate the efficacy of newly developed anti-cancer drugs in vitro.
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http://dx.doi.org/10.3892/etm_00000011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490383PMC
January 2010

High attendance at a lifestyle intervention program is important to reduce risks related to metabolic syndrome in middle-aged Japanese.

Tohoku J Exp Med 2009 Oct;219(2):155-64

Department of Public Health, Dokkyo Medical University School of Medicine, Japan.

Evaluating attendance at health education programs is important to obtain a more comprehensive evaluation of the program impact. This study investigated whether attendance at a lifestyle intervention program in a community setting would reduce risks related to metabolic syndrome. Of 545 subjects with risks related to metabolic syndrome, i.e. overweight, hypertension, dyslipidemia or diabetes, participated in this non-randomized control study, 389 subjects aged 40-71 years completed the surveys at baseline and 27 months. Intervention group (39 males and 168 females) was provided 3 individual counseling plus 28 group sessions conducted monthly on average, whereas control group (64 males and 118 females) received only 7 health information newsletters by mail. Intervention group was subcategorized into two groups according to the median attendance (87.1%): 106 subjects with high attendance (93.8 +/- 4.7%) and 101 subjects with low attendance (68.6 +/- 16.0%). Logistic regression analyses adjusted for age and baseline value showed that among males, the proportion with dyslipidemia risk was lower only in high attendance group compared with that in control group at 27 months [Odds ratio (OR): 0.11 (95%CI 0.02 - 0.51)] and among females, the proportion of overweight was lower only in high attendance group [OR: 0.24 (95%CI 0.07 - 0.81)]. In females, the mean total risk score calculated by adding the number of the 4 risks present decreased only in high attendance group (p < 0.001). In conclusion, high attendance at a lifestyle intervention program impacts the reduction of risks related to metabolic syndrome in a Japanese community setting.
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http://dx.doi.org/10.1620/tjem.219.155DOI Listing
October 2009

Ultrasound-targeted gene delivery induces angiogenesis after a myocardial infarction in mice.

JACC Cardiovasc Imaging 2009 Jul;2(7):869-79

Division of Cardiovascular Surgery, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario, Canada.

Objectives: This study evaluated the capacity of ultrasound-targeted microbubble destruction (UTMD) to deliver angiogenic genes, improve perfusion, and recruit progenitor cells after a myocardial infarction (MI) in mice.

Background: Angiogenic gene therapy after an MI may become a clinically relevant approach to improve the engraftment of implanted cells if targeted delivery can be accomplished noninvasively. The UTMD technique uses myocardial contrast echocardiography to target plasmid gene delivery to the myocardium and features low toxicity, limited immunogenicity, and the potential for repeated application.

Methods: Empty plasmids (control group) or those containing genes for vascular endothelial growth factor (VEGF), stem cell factor (SCF), or green fluorescent protein (to visualize gene delivery) were incubated with perflutren lipid microbubbles. The microbubble-deoxyribonucleic acid mixture was injected intravenously into C57BL/6 mice at 7 days after coronary artery ligation (MI). The UTMD technique facilitated transgene release into the myocardium. Twenty-one days after MI, myocardial perfusion and function were assessed by contrast echocardiography. Protein expression was quantified by Western blot and enzyme-linked immunosorbent assay. Flow cytometry quantified progenitor cell recruitment to the heart. Blood vessel density was evaluated immunohistochemically.

Results: Green fluorescent protein expression in the infarcted myocardium demonstrated gene delivery. Myocardial VEGF and SCF levels increased significantly in the respective groups (p < 0.05). The physiologic impact of VEGF and SCF gene delivery was confirmed by increased myocardial recruitment of VEGF receptor 2- and SCF receptor (c-kit)-expressing cells, respectively (p < 0.05). Consequently, capillary and arteriolar density (Factor VIII and alpha-smooth muscle actin staining), myocardial perfusion, and cardiac function were all enhanced (p < 0.01 relative to control group) in recipients of VEGF or SCF.

Conclusions: Noninvasive UTMD successfully delivered VEGF and SCF genes into the infarcted heart, increased vascular density, and improved myocardial perfusion and ventricular function. The UTMD technique may be an ideal method for noninvasive, repeated gene delivery after an MI.
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http://dx.doi.org/10.1016/j.jcmg.2009.04.008DOI Listing
July 2009