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Biomedical subjects

Tetsuya Nakamura

Publications and source records attributed to Tetsuya Nakamura.

At least 37 records · Page 2Linked to original sources
PubMed2005

Effect of transdermal hormone replacement therapy on the monocyte chemoattractant protein-1 concentrations and other vascular inflammatory markers and on endothelial function in postmenopausal women.

Monocyte chemoattractant protein-1 (MCP-1) is related to the progression of atherosclerosis. However, little is known about the effects of transdermal hormone replacement therapy (HRT) on circulating MCP-1, vascular inflammatory marker concentrations, and endothelial function in postmenopausal women. The effects of transdermal HRT on circulating MCP-1, vascular inflammatory marker concentrations, and endothelium-dependent vasodilation were investigated in postmenopausal women. Thirty-three women received transdermal HRT (continuous 17-beta estradiol patch 36 microg/day plus cyclic oral medroxyprogesterone acetate 2.5 mg/day for 12 days/month) for 12 months, and 27 control patients did not. Brachial artery flow-mediated vasodilation (FMD), assessed by ultrasound, and circulating MCP-1 and vascular inflammatory marker (C-reactive protein, intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], and E-selectin) concentrations were measured before and after 12 months of treatment. In the HRT group, MCP-1 concentrations decreased significantly (p <0.001), and ICAM-1, VCAM-1, and E-selectin concentrations decreased significantly (p <0.01 for all), but C-reactive protein concentrations did not change. MCP-1 and other marker concentrations did not change in the control group. FMD increased significantly in the HRT group (p <0.001) but did not change in the control group. Nitroglycerin-induced vasodilation did not change in either group. In conclusion, transdermal HRT decreased MCP-1 and cell adhesion molecule concentrations and improved endothelial function in postmenopausal women. Transdermal HRT may exert an antiatherosclerotic effect by improving MCP-1 and cell adhesion molecule expression and endothelial function.

Administration, Cutaneous↗
PubMed2005

IRF-1 mediates upregulation of LMP7 by IFN-gamma and concerted expression of immunosubunits of the proteasome.

An immunoproteasome subunit low molecular weight protein 7 (LMP7) plays critical roles in major histocompatibility complex class I antigen processing; however, the mechanism for its expression has remained unclear. We demonstrate that interferon (IFN) regulatory factor-1 (IRF-1) has a pivotal role in IFN-gamma-dependent LMP7 expression, as was shown for the other two immunosubunits. A tetracycline-inducible system for IRF-1 revealed its function in the LMP7 expression, and a genomic region functionally interacting with IRF-1 was also determined. Furthermore, the role of IRF-1 in IFN-gamma-inducible LMP7 transcription was confirmed by employing small interfering RNA experiments and IRF-1-/- mice. These results suggest that IRF-1 acts as a master regulator for the concerted expression of immunoproteasome components.

Animals↗
PubMed2005

Two nodal-responsive enhancers control left-right asymmetric expression of Nodal.

Asymmetric expression of Nodal in the lateral plate mesoderm (LPM) plays the major role in left-right (L-R) patterning. A Nodal-responsive enhancer located in the intron 1 (ASE) regulates asymmetric Nodal expression, but it is unknown how Nodal expression is initiated in the left LPM. Here, we have identified a second asymmetric enhancer (left side-specific enhancer, LSE) in the upstream region of mouse Nodal gene. LSE is also located in the corresponding region of human NODAL. L-R specificity of LSE is affected by iv and inv mutations. The requirement of a conserved FoxH1-binding sequence for LSE activity and the dependence of LSE activity on Nodal coreceptor Cryptic indicate that LSE is activated by Nodal signal. However, the mutant mouse lacking LSE does not show obvious L-R patterning defects. These results suggest that Nodal expression in the left LPM is induced by a combination of two Nodal-responsive autoregulatory enhancers, ASE and LSE.

Animals↗
PubMed2005

Questionnaire-based analysis of mefloquine chemoprophylaxis for malaria in a Japanese population.

Although mefloquine is the only drug licensed for malaria chemoprophylaxis in Japan, there have been few reports describing the effects of and adverse events in the prophylactic usage of mefloquine in a Japanese population. We therefore performed a questionnaire-based study in 21 travelers who were prescribed mefloquine for malaria chemoprophylaxis between October 2001 and December 2003. The study revealed that only 8 out of 21 (38.1%) of the travelers could complete the prophylaxis schedules. Another 8 travelers (38.1%) with incomplete adherence stated that they did not take mefloquine because of either actually experienced or anticipated adverse events. Twelve of the 16 travelers (75.0%) who took mefloquine complained of at least one adverse event probably related to mefloquine. As an overall impression about mefloquine chemoprophylaxis, 14 of the 21 travelers stated that they would take mefloquine again for the next travel to malaria-endemic areas, although 5 of them were concerned about adverse events. These results suggest that, although mefloquine is an indispensable drug for malaria prevention, other effective and well-tolerated chemoprophylactic antimalarials should be available for Japanese travelers who do not tolerate mefloquine.

Antimalarials↗
PubMed2005

Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestine.

BACKGROUND & AIMS: We have previously reported that bone marrow (BM)-derived cells contribute to the regeneration of the human intestinal epithelium. To analyze further how these cells arise, proliferate, and differentiate as epithelial cells, histologic analysis was conducted using endoscopic specimens. METHODS: Thirty biopsy specimens from 14 female, sex-mismatched BM-transplantation recipients were examined. BM-derived cells were identified by fluorescent in situ hybridization (FISH) for the Y chromosome and immunohistochemistry. Multicolor FISH was used to exclude cell fusion. These cells were further analyzed for various differentiation or proliferation markers. RESULTS: No evidence of cell fusion was detected. BM-derived cells did not distribute within the crypt as stem cells and rarely expressed Musashi-1. However, BM-derived epithelial cells frequently expressed Ki-67, and some of these cells appeared as pairs of adjacent cells. These cells also expressed markers of all 4 lineages of terminally differentiated cells. During regeneration following graft-vs-host disease, the number of BM-derived cells was substantially increased within Ki-67-positive cells. Interestingly, the number of cells expressing markers for secretory lineage cells was significantly increased within BM-derived cells. This change was unique for BM-derived cells, resulting in a significantly increased proportion of BM-derived cells among secretory lineage cells. CONCLUSIONS: BM-derived epithelial cells arise via a mechanism other than cell fusion and rarely give rise to stem cells. However, a small proportion of these cells express proliferation markers, and a majority reside as terminally differentiated cells. During regeneration BM-derived cells increase as secretory lineage cells, thereby contributing to restore epithelial functions.

Biopsy↗
PubMed2005

Genotyping of thiopurine methyltransferase using pyrosequencing.

Thiopurine methyltransferase (TPMT) metabolizes thiopurine drugs which are used in the treatment of leukemia and some autoimmune diseases. Previously, 11 mutant alleles of TPMT gene (TPMT*1S, *2, *3A, *3B, *3C, *3D, *4, *5, *6, *7, and *8) have been reported. These mutant alleles may cause life-threatening toxicity in patients exposed to thiopurine drugs, 6-mercaptopurine and azathioprine. We have developed a rapid and accurate protocol for TPMT genotype determination using Pyrosequencing(TM) technology in 96 Japanese subjects. Five fragments of the TPMT gene (exon 4, 5, 7, 8, 10) were amplified by PCR, and the 10 single-nucleotide polymorphisms (SNPs) for TPMT*1S, *2, *3A, *3B, *3C, *3D, *4, *5, *6, *7, and *8 were sequenced. The results of this pyrosequencing method corresponded exactly with those of the DNA sequencing method using BigDye terminator chemistry. We have demonstrated that typing of 10 SNPs can be performed within 30 min. Pyrosequencing has a wide application in the large-scale identification of individual TPMT genotypes.

Adult↗
PubMed2005

Fluvastatin ameliorates the hyperhomocysteinemia-induced endothelial dysfunction: the antioxidative properties of fluvastatin.

BACKGROUND: Hyperhomocysteinemia induces vascular endothelial dysfunction, contributing to a predisposition to the onset and/or progression of atherosclerosis. The major mechanism suggested for the adverse effect of homocysteine on vascular function seems to involve oxidative stress. Thus, we hypothesized that the administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin, which is experimentally demonstrated to have antioxidative properties as one of its pleiotropic effects, is a useful strategy for eliminating the detrimental events induced by hyperhomocysteinemia. METHODS AND RESULTS: In diet-induced hyperhomocysteinemic rats, we estimated oxidative stress and assessed endothelium-dependent vasodilatation. Hyperhomocysteinemia induced significant increases in urinary 8-isoprostaglandin F2alpha-III excretion and vascular superoxide generation, and impaired endothelium-dependent vasodilatation. Additional oral administration of the antioxidant fluvastatin or vitamin E, which normalized increased oxidative stress induced by hyperhomocysteinemia, ameliorated endothelial dysfunction. CONCLUSIONS: Hyperhomocysteinemia, even mild to moderate, induces endothelial dysfunction through its oxidative effect. The antioxidant fluvastatin was able to cancel out the oxidative stress induced by hyperhomocysteinemia and ameliorate endothelial dysfunction. Clinical use of fluvastatin might be a potent strategy for eliminating the detrimental events induced by hyperhomocysteinemia as well as hyperlipidemia. In addition to lowering homocysteine by means of folate supplementation, administration of the antioxidants is expected to be a potentially effective anti-homocysteine therapy.

Animals↗
PubMed2005

Selective angiotensin receptor antagonism with valsartan decreases arterial stiffness independently of blood pressure lowering in hypertensive patients.

Angiotensin II plays a key role in the development of vascular disease. We examined the long-term effects of selective angiotensin II receptor (ATR) blockade with valsartan on arterial wall stiffness. Brachial to ankle pulse wave velocity (baPWV) was measured in 28 women and 25 men with hypertension (mean age: 62+/-2 years). The measurements were repeated after 24 weeks of treatment with valsartan, 40 to 160 mg/day, with (n=10) or without (n=36) concomitant statin therapy. By multiple regression analysis, baseline baPWV was correlated with age (p<0.001), systolic blood pressure (SBP, p<0.0001), body mass index (p=0.018), and pulse pressure (p=0.005), but not with total cholesterol (p=0.446). Valsartan lowered mean SBP and diastolic blood pressure (DBP) from 155+/-3 to 140+/-3 mmHg and from 90+/-2 to 82+/-2 mmHg, respectively, and mean baPWV from 1,853+/-49 to 1,682+/-52 cm/s. Lowering of baPWV was not influenced by statin therapy. An overlap analysis was performed to separate the effect of angiotensin II receptor blockade from that of blood pressure (BP) lowering. The decrease in the baPWV value of 1,794+/-46 cm/s before valsartan (n=39) vs. 1,663+/-45 cm/s during valsartan (p=0.048, n=31) at a similar mean SBP level (149+/-2 vs. 146+/-3 mmHg, p=0.304) confirmed that ATR blockade had a beneficial effect independent of BP lowering. SBP strongly influences baPWV. However, the decrease in baPWV with valsartan was independent of BP lowering. Statins had no synergistic effect on baPWV. Lowering of baPWV may account for the therapeutic benefit conferred by valsartan independent of its BP-lowering effect.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Clinical characteristics of imported malaria in Japan: analysis at a referral hospital.

Imported malaria remains an important problem in Japan. We have reviewed the medical records of 170 cases of malaria in our hospital, which corresponds to 14.9% of the total cases in Japan. The predominant malarial species was Plasmodium falciparum (52.3%), and the most frequent area of acquisition was Africa (54.2%), followed by Asia (20.9%) and Oceania (19.6%). The most common reason for travel among Japanese patients was business. A significant proportion (22.2%) of vivax malaria cases experienced relapse despite standard primaquine therapy. Most primaquine failures were from Oceania. We also found that a substantial number of Japanese patients contracted malaria without chemoprophylaxis and consulted medical facilities with an unfavorably long delay from initial symptoms (median: 3.0 days). Direct education of travelers and travel companies, in addition to health care providers, is likely necessary to improve outcomes of imported malaria.

Adult↗
PubMed2005

[Preoperative combination chemotherapy with TS-1 is effective in a case gastric cancer with peritoneal dissemination].

We report a case of peritoneal cancer dissemination with Type 4 gastric cancer, successfully treated with combination chemotherapy with TS-1. The patient was a 59-year-old female, who complained of abdominal distension with pain, weight loss, and poor appetite. She was diagnosed as unresectable Type 4 gastric cancer, T3N2MOHOP1CY1M0, Stage IV with massive ascites (cytology: Class V). After 2 courses of combined chemotherapy with TS-1 and cisplatin (CDDP), primary tumor reduction was confirmed and no cancer cells were detected from a pathological investigation with biopsied specimens by endoscopy. As additional therapy for remained ascites, intraperitoneal administration of paclitaxel and docetaxel was performed, resulting in a remarkable decrease of ascites with cytological disappearance of cancer cells. The patients underwent total gastrectomy with lymph node dissection, pathological diagnosis of primary site and lymph nodes showed grade 2 effect, and no cancer cells were detected in ascites and peritoneum, microscopically. While she died of peritoneal recurrence after the surgery, the case suggested the clinical advantage of controlling the advanced cancer-bearing state by combination chemotherapy with TS-1, instead of surgery.

Adenocarcinoma↗
PubMed2005

[Capsule endoscopy].

Wireless capsule endoscopy is a new diagnostic tool in which a disposable video capsule is swallowed by the patient. This examination enables visualization of the small intestine that is not within the reach of conventional upper and lower endoscopy. The best indications include an obscure source of gastrointestinal bleeding, Crohn's disease, and small intestinal tumors. The disadvantage that biopsy cannot be performed is compensated for by employing double-balloon endoscopy. In particular, this examination can identify the origin of bleeding and diagnose the underlying disease, leading to prompt surgical treatment with better results. In future, capsule endoscopy will become a necessary examination for diagnosing digestive tract disease.

Endoscopes, Gastrointestinal↗
PubMed2004

IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4+ mucosal T cells in mice.

We have previously demonstrated that mucosal CD4(+) T cells expressing high levels of IL-7 receptor (IL-7R(high)) are pathogenic cells responsible for chronic colitis. Here we investigate whether IL-7 is directly involved in the expansion of IL-7R(high) memory CD4(+) mucosal T cells and the exacerbation of colitis. We first showed that CD4(+) lamina propria lymphocytes (LPLs) from wild-type, T cell receptor-alpha-deficient (TCR-alpha(-/-)), and recombinase-activating gene (RAG)-2(-/-)-transferred mice with or without colitis showed phenotypes of memory cells, but only CD4(+) LPLs from colitic mice showed IL-7R(high). In vitro stimulation by IL-7, but not by IL-15 and thymic stromal lymphopoietin, enhanced significant proliferative responses and survival of colitic CD4(+), but not normal CD4(+) LPLs. Importantly, in vivo administration of IL-7 mice accelerated the expansion of IL-7R(high) memory CD4(+) LPLs and thereby exacerbated chronic colitis in RAG-2(-/-) mice transferred with CD4(+) LPLs from colitic TCR-alpha(-/-) mice. Conversely, the administration of anti-IL-7R monoclonal antibody significantly inhibited the development of TCR-alpha(-/-) colitis with decreased expansion of CD4(+) LPLs. Collectively, the present data indicate that IL-7 is essential for the expansion of pathogenic memory CD4(+) T cells under pathological conditions. Therefore, therapeutic approaches targeting the IL-7R pathway may be feasible in the treatment of human inflammatory bowel disease.

Animals↗
PubMed2004

CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells.

It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only active suppression by regulatory T cells plays an important role in the normal intestinal homeostasis, but also its dysregulation leads to the development of inflammatory bowel disease. In this study, we demonstrate that the CD4(+)CD25(bright) T cells reside in the human intestinal lamina propria (LP) and functionally retain regulatory activities. All human LP CD4(+) T cells regardless of CD25 expression constitutively expressed CTLA-4, glucocorticoid-induced TNFR family-related protein, and Foxp3 and proliferate poorly. Although LP CD4(+)CD25(-) T cells showed an activated and anergic/memory phenotype, they did not retain regulatory activity. In LP CD4(+)CD25(+) T cells, however, cells expressing CD25 at high levels (CD4(+)CD25(bright)) suppressed the proliferation and various cytokine productions of CD4(+)CD25(-) T cells. LP CD4(+)CD25(bright) T cells by themselves produced fewer amounts of IL-2, IFN-gamma, and IL-10. Interestingly, LP CD4(+)CD25(bright) T cells with regulatory T activity were significantly increased in patients with active inflammatory bowel disease. These results suggest that CD4(+)CD25(bright) T cells found in the normal and inflamed intestinal mucosa selectively inhibit the host immune response and therefore may contribute to the intestinal immune homeostasis.

Antigens, CD↗
PubMed2004

Self-association of water-soluble fluorinated diblock copolymers in solutions.

The self-association of the fluorinated diblock copolymer, poly(methacrylic acid)-block-poly(perfluorooctylethyl methacrylate) (PMAA-b-PFMA), in water has been investigated by light scattering, potentiometry, atomic force microscopy, and transmission electron microscopy. The size of the polymer micelles increases, as the degree of dissociation of the PMAA blocks increases. Since the charged PMAA block takes the stretched structure, PMAA-b-PFMA can easily form large micelles due to the low steric hindrance of PMAA blocks. Addition of NaCl shielded electrostatic repulsion in the PMAA chain and induced the formation of smaller micelles than water without NaCl did because of the bulky structure of the PMAA chain in the shell of the micelles. The micelle of PMAA-b-PFMA in ethanol is larger than that of poly(t-butyl methacrylate)-block-poly(perfluorooctylethyl methacrylate) (PtBMA-b-PFMA) in ethanol as a result of the higher steric hindrance of the PtBMA block. The dimensions of the core and shell of the micelles were estimated. The micelle of PMAA-b-PFMA in water possesses a rather thick shell and a large volume per molecule, consistent with the extended PMAA chain. On the other hand, the shell of the micelle in an ethanol solution of PtBMA-b-PFMA is thin but has a large surface area. Facts are consistent with the shrunk structure of the PtBMA block in poor solvent.

Journal Article↗
PubMed2004

Aggregation states and surface wettability in films of poly(styrene-block-2-perfluorooctyl ethyl acrylate) diblock copolymers synthesized by atom transfer radical polymerization.

Well-defined poly(styrene-block-2-perfluorooctyl ethyl acrylate) [P(St-b-PFA)] copolymers with various chemical compositions were synthesized by atom transfer radical polymerization. Films of P(St-b-PFA) were structurally characterized, from bulk to surface, on the basis of transmittance electron microscopic observation and small-angle X-ray scattering, X-ray photoelectron spectroscopic, and contact angle measurements. For a comparison, poly(styrene-random-2-perfluorooctyl ethyl acrylate) [P(St-ran-PFA)] copolymers were also synthesized by conventional free radical polymerization. While P(St-b-PFA) with the 2-perfluorooctyl ethyl acrylate (PFA) content higher than 18.7 mol % formed a typical phase-separated cylinder structure, P(St-b-PFA) with a lower PFA content and P(St-ran-PFA) were in a miscible state. Since the perfluoroalkyl groups possess extremely low surface energy, they were preferentially segregated at the film surface, resulting in the formation of the PFA surface layer. This was the case for all P(St-b-PFA) films examined, although the aggregation state at the surface was strongly dependent on the PFA content. In the case of the P(St-b-PFA) with the PFA content higher than 18.7 mol %, both advancing and receding contact angles for water were 120 degrees and even larger with almost no hysteresis. In addition, extremely excellent oil-repellent surface properties such as advancing and receding contact angles for dodecane of 76 degrees and 75 degrees were also observed. However, these intriguing liquid-repellent properties were not observed for the films of miscible P(St-b-PFA) and P(St-ran-PFA). Therefore, it can be concluded that the internal structure beneath the surface as well as the surface itself should be deeply considered to design excellent and stable liquid-repellent materials.

Journal Article↗