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Biomedical subjects

T Sakane

Publications and source records attributed to T Sakane.

At least 19 recordsLinked to original sources
PubMed2001

An inhibitor of inducible nitric oxide synthase decreases forearm blood flow in patients with congestive heart failure.

OBJECTIVES: The functional activation of inducible nitric oxide synthase (iNOS) was evaluated as a source of nitric oxide (NO) in the forearm of patients with heart failure. BACKGROUND: Although endogenous NO is normally produced by constitutive NO synthase (cNOS) in patients with congestive heart failure (CHF), expression of iNOS provides an additional source of NO. However, there are no in vivo studies showing functional activation of iNOS in humans. METHODS: A nonselective NOS inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), and a selective inhibitor of iNOS, aminoguanidine, were administered intra-arterially in graded doses into the brachial arteries of 13 patients with CHF and 10 normal control subjects. Forearm blood flow (FBF) was measured simultaneously in the infused and noninfused arms by plethysmography. Arterial and venous plasma concentrations of nitrite/nitrate (NOx) were measured at baseline and at the highest dose of each drug. RESULTS: L-NMMA significantly reduced the FBF ratio between the infused and noninfused arms in both the control and patient groups (35 +/- 12% and 34 +/- 10%, respectively; both p < 0.001). Aminoguanidine at the same concentration significantly reduced the ratio in the patient group (15 +/- 9%, p < 0.01), with no change in the control group. The arterial NOx concentration was not affected by either drug; however, venous NOx concentrations were significantly decreased in both the control and patient groups by L-NMMA (18 +/- 5% and 18 +/- 17%, respectively; both p < 0.05) and in the patient group only by aminoguanidine (7 +/- 6%, p < 0.05). CONCLUSIONS: These findings suggest that NO production in the forearms of patients with CHF is induced partly by iNOS activation, whereas in normal subjects, it can be ascribed to cNOS activation.

Acetylcholine↗
PubMed2001

Analysis of IL-12 receptor beta 2 chain expression of circulating T lymphocytes in patients with atopic asthma.

Th2 cell predominance relative to Th1 cells contributes to pathological immune responses in patients with atopic asthma. IL-12 is a key cytokine in the induction of Th1 cells, and downregulation of IL-12 production is reported in these patients. However, IL-12 receptor expression of their T lymphocytes has not been clarified. In this study, expression of IL-12 receptor beta 2 on T cells and secretion of cytokines which affect IL-12 receptor beta 2 expression by their PBMC were examined. We found that IL-12 receptor beta 2 expression of the T cells is reduced. This is partly due to the diminished production of IL-12 and enhanced secretion of IL-4 by their PBMC. IL-18 production is not significantly modulated in these patients. Furthermore, intrinsic defects of the CD4(+) T cells, which reduce their IL-12 receptor beta 2 expression in response to IL-12 and/or IL-18 stimulation, are evident and are importantly involved in the Th1/Th2 imbalance of patients with atopic asthma.

Adolescent↗
PubMed2001

Diagnosis of cardiac sarcoidosis and evaluation of the effects of steroid therapy by gadolinium-DTPA-enhanced magnetic resonance imaging.

BACKGROUND: Cardiac involvement is an important prognostic factor in patients with sarcoidosis. In this study, we evaluated the usefulness of gadolinium-DTPA (diethylene triamine pentaacetic acid)-enhanced magnetic resonance imaging (Gd-MRI) for diagnosing cardiac sarcoidosis and evaluating the effects of steroid therapy. METHODS: Sixteen patients with sarcoidosis diagnosed by histology or by Japanese Ministry of Health and Welfare criteria for cardiac sarcoidosis underwent Gd-MRI with a 1.5-Tesla superconducting magnet system using a T1-weighted spin-echo sequence. RESULTS: Gd-MRI showed localized enhancement of signal intensity, indicating interstitial edema, in the left ventricle in 8 of the 16 patients. Two patients with enhancement also had thinning of the left ventricular septal wall. After 1 month of prednisolone therapy (60 mg every other day or 30 to 40 mg every day), the localized high-intensity signals were markedly diminished in all 8 patients. CONCLUSIONS: Images of the heart obtained by Gd-MRI may reflect active inflammation with interstitial edema in patients with sarcoidosis. Gd-MRI may be a useful noninvasive method for early detection of cardiac sarcoidosis and for evaluating the effects of steroid therapy.

Adult↗
PubMed2001

Atrial fibrillation impairs endothelial function of forearm vessels in humans.

BACKGROUND: Although there have been many studies on the effects of atrial fibrillation (AF) on cardiac function, few studies have been done on its effects on endothelial function. The present study was designed to examine the effects of AF on endothelial function in human subjects. METHODS AND RESULTS: Changes in forearm blood flow (FBF) induced by acetylcholine and nitroglycerin were measured by using plethysmography in 14 patients with lone AF, 13 patients with AF and underlying heart disease, and 12 normal control subjects. In the patients, these measurements were repeated after cardioversion. Although baseline FBF was the same in the 3 groups, acetylcholine-induced increases in FBF were significantly smaller in both patient groups than in the control group, and FBF increases were particularly depressed in AF patients with underlying heart disease. After restoration of sinus rhythm by cardioversion, FBF response to the highest dose of acetylcholine increased by 46% in patients with lone AF (n = 10) and by 90% in AF patients with underlying heart disease (n = 11). Nitroglycerin-induced vasodilatation was the same in all 3 groups and was not affected by cardioversion. CONCLUSIONS: These findings suggest that endothelium-dependent vasodilatation is impaired by AF and improves after sinus rhythm is restored.

Acetylcholine↗
PubMed2001

Pyloricidins, novel anti-helicobacterpylori antibiotics produced by Bacillus sp. I. Taxonomy, fermentation and biological activity.

Novel anti-Helicobacter pylori antibiotics, pyloricidins A, A1, A2, B, C and D, were discovered in the culture broth of two bacilli strains. Pyloricidins selectively inhibited the growth of H. pylori. Pyloricidin B was efficacious in the treatment of gastric infection caused by H. pylori in Mongolian gerbils and may be promising for cure of H. pylori infection as a single agent.

Amoxicillin↗
PubMed2001

Endorphin and enkephalin ameliorate excessive synovial cell functions in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether endorphin (END) and enkephalin (ENK) modulate excessive synovial cell functions in patients with rheumatoid arthritis (RA). METHODS: Effects of leucine-enkephalin (leu-ENK), methionine-enkephalin (met-ENK), and beta-endorphin (END) on proinflammatory cytokine and matrix metalloproteinase (MMP) production by RA synovial cells were analyzed by immunoblotting, and their mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR) using limiting dilution of complementary DNA. Expression of opioid receptors on RA synovial cells was assessed by immunohistochemical staining, radioreceptor assay, and RT-PCR. RESULTS: Leu-ENK, met-ENK, and END inhibited tumor necrosis factor-alpha and interleukin 1beta production at the level of mRNA expression. ENK and END inhibited MMP-9 production and its enzymatic activity by RA synovial cells. The mu-subtype opioid receptor was expressed in the RA synovial lining and sublining cells. Radioreceptor assay suggested expression of high affinity receptor for END on RA synovial cells. The mu-subtype opioid receptor-specific antagonist, naloxone, reversed the inhibitory effect of the opioid peptides. The opioid peptides inhibited nuclear translocation and phosphorylation of the transcription factor, cyclic AMP responsive element binding protein (CREB) in RA synovial cells. CONCLUSION: Leu-ENK, met-ENK, and END inhibited excessive RA synovial cell functions in vitro. The opioid hormones may have not only antinociceptive action, but also antiinflammatory effects on synovitis itself in RA.

Aged↗
PubMed2000

Contribution of endogenous nitric oxide to basal vasomotor tone of peripheral vessels and plasma B-type natriuretic peptide levels in patients with congestive heart failure.

OBJECTIVES: We examined whether a relationship exists between the vasoconstrictive response to endogenous nitric oxide (NO) synthesis inhibition and the severity of heart failure in patients with congestive heart failure (CHF). BACKGROUND: Controversy exists as to whether the vasoconstrictive response to NO synthesis inhibition in patients with CHF is comparable to that in normal subjects or is enhanced. METHODS: Forearm blood flow (FBF) and calculated forearm vascular conductance (FVC) were obtained using plethysmography before and after administration of the NO synthesis inhibitor L-NMMA (NG-monomethyl-L-arginine) in 40 patients with CHF due to dilated cardiomyopathy and in 16 normal control subjects. Basal plasma B-type natriuretic peptide (BNP) and nitric oxide concentrations were measured in all subjects. RESULTS: Plasma BNP and nitrite/nitrate (NOx) levels in the patients group were significantly greater and baseline FBF was significantly less. Administration of L-NMMA significantly decreased FBF and FVC in both groups. The percent changes in FBF (%FBF) and FVC (%FVC) from the baseline after L-NMMA correlated significantly with plasma BNP level (%FBF: r = 0.72; %FVC: r = 0.76; both p < 0.001). Percent changes in both FBF and FVC were greater in patients with BNP > or = 100 pg/ml than in normal subjects; however, in patients with BNP < 100 pg/ml they were comparable to those in normal subjects. CONCLUSIONS: Vasoconstrictive response to L-NMMA in patients with CHF was preserved or enhanced in proportion to the basal plasma BNP level, indicating a close relationship between the contribution of endogenous NO to basal vasomotor tone and the severity of heart failure.

Adult↗
PubMed2000

Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells.

The effects of various experimental conditions on in vitro drug permeability to Caco-2 monolayers were investigated to determine the optimized conditions for the prediction of intestinal drug absorption. Concerning the pH of the transport medium in the Caco-2 study, two different pH values, 6.0 and 7.4, were tested for the apical medium with the pH of the basolateral medium fixed to 7.4. The change in the apical pH showed pronounced effects on the permeability of both passively and actively transported drugs. It was found that the transport study under the condition of an apical pH value of 6.0 showed a better prediction of in vivo drug absorption in human. The appropriate conditions for determining the permeability of poorly soluble drugs were also examined. First, the effects of bile acids, surfactant and some agents used for solubilizing drugs on the permeability and transepithelial electrical resistance (TEER) of Caco-2 monolayers were investigated. Taurocholic and cholic acid showed no effects on the permeability of 3H-Dexamethasone (DEX) and TEER at 10 mM concentration, suggesting the possibility of use in the Caco-2 study. Polyethyleneglycol-400 and dimethylsulfoxide reduced the permeability of DEX concentration dependently, whereas ethanol induced no significant changes in the permeability. Furthermore, it was demonstrated that the addition of plasma protein (bovine serum albumin) to the basolateral medium apparently facilitated the transport of poorly soluble drugs with high lipophilicity across Caco-2 monolayers. These findings clearly suggest the importance of considering the physiological conditions of in vivo drug absorption in optimizing the in vitro experimental conditions for transport study using Caco-2 cells, in order to obtain a satisfactory in vitro-in vivo correlation.

Blood Proteins↗
PubMed2000

Impaired vasodilatation response to amrinone in the forearm of patients with congestive heart failure: role of endothelium-derived nitric oxide.

Recent in vitro experiments have shown that amrinone enhances the release of nitric oxide (NO) from the endothelium and induces NO mediated vasodilatation. This in vivo study examined whether amrinone causes vasodilatation mediated by endothelium-derived NO, and whether this effect is attenuated in patients with endothelial dysfunction. Eight patients with congestive heart failure and 10 age- and sex-matched healthy volunteers were studied. Forearm blood flow (FBF) was measured before and during infusion of drugs of acetylcholine, amrinone, and nitroglycerin in incremental doses. After the completion of these measurements, 100 micromol of N(G)-monomethyl-L-arginine (L-NMMA) was infused intraarterially. Thereafter, FBF measurement in response to incremental doses of amrinone was repeated. Infusion of incremental doses of amrinone caused a comparable increase in amrinone plasma concentration in both groups. Baseline FBF was 3.2+/-0.79 ml/min/100 ml in controls vs. 2.91+/-0.79 ml/min/100 ml in patients (p = 0.43). In both groups, FBF increased in response to acetylcholine, amrinone, and nitroglycerin. During infusion of the highest dose of nitroglycerin, FBF was not different between the two groups (p = 0.51); however, FBF during infusion of the highest doses of acetylcholine and amrinone was significantly less in patients than in controls: 9.75+/-2.69 vs. 24.87+/-8.65 ml/min/100 ml (p < 0.001) and 3.79+/-1.21 vs. 7.15+/-2.06 ml/min/100 ml (p < 0.001), respectively. L-NMMA significantly depressed the increase in FBF in response to amrinone in controls, but not in patients. In conclusion, the selective PDE III inhibitor, amrinone, has endothelium-derived NO-mediated vasodilating effects in addition to direct effects. This property may be impaired in patients with endothelial dysfunction.

Acetylcholine↗
PubMed2000

Characterization of tissue outgrowth developed in vitro in patients with rheumatoid arthritis: involvement of T cells in the development of tissue outgrowth.

BACKGROUND: The aim of this study was to analyze cellular and cytokine interactions governing the development of synovial tissue outgrowth in patients with rheumatoid arthritis (RA). METHODS: A single-cell suspension of dissociated synovial tissues of RA patients was cultured for a long period to develop tissue outgrowth. The resulting tissue outgrowth was characterized by immunohistochemical staining and ELISA. RESULTS: The tissue outgrowth developed in vitro included various cell types, such as macrophage-like synovial cells, fibroblast-like synovial cells and lymphocytes. Even after prolonged cultivation, synovial cells devoid of infiltrating T lymphocytes did not form tissue outgrowth. The outgrowth contained CD3+ cells, LeuM3 (CD14)+ cells and HLA-DR+ cells. The T cells expressed lymphocyte function-associated antigen (LFA)-1 and CD2, and the synovial cells expressed intracellular adhesion molecule (ICAM)-1 and LFA-3, suggesting possible interactions via LFA-1/ICAM-1 and CD2/LFA-3. Production of T-cell derived IFN-gamma and IL-17 and synovial-cell-derived fibroblast growth factor (FGF)-1 and IL-15 was confirmed in the tissue outgrowth as well as in RA synovial tissue. These cell types stimulate each other by secreting cytokines, leading to the secretion of proinflammatory cytokines and matrix metalloproteinase (MMP)-1 by the tissue outgrowth and proliferation of both lymphocytes and synovial cells. CONCLUSION: This study emphasizes the importance of cellular interactions between T cells and synovial cells, via adhesion molecules and the secretion of cytokines with stimulatory activity towards other cell types, for the hyperactivity of RA synovial cells.

Arthritis, Rheumatoid↗
PubMed2000

Novel approaches to Behçet's disease.

Behçet's disease is a systemic inflammatory disorder. The patients have repeated exacerbations and remissions of the symptoms. This disease may produce a wide variety of symptoms. In mild cases, mucocutaneous lesions are only the symptoms during the whole clinical course, whereas ocular lesions, which occur in about 70% of the patients, can cause blindness. Involvement of the gastrointestinal tract, CNS and large vessels is less frequent, but sometimes life-threatening. Colchicine, NSAIDs, corticosteroids and immunosuppressants are employed for the treatment of Behçet's disease with therapies tailored to individual patients depending on clinical manifestations. Cyclosporin A is the most effective drug for ocular lesions at the present, but its neurotoxicity, which occurs in 20-30% of patients receiving cyclosporin A, restricts usage of the agent. Many patients are still suffering from a severe form of uveitis and serious neurological symptoms, which are resistant to any conventional therapies. New drugs have been investigated for Behçet's disease. IFN-alpha therapy has shown significant efficacy for common symptoms including ocular lesions without any serious adverse effects. Thalidomide and its analogues also appear to be applicable to this disease. Monoclonal antibody to TNF-alpha is now in clinical trials. These novel therapeutic approaches may provide much needed treatment options for patients with Behçet's disease.

Antiviral Agents↗
PubMed2000

[Relationship between endothelial function and female hormone level in very old females: evaluation from ischemic reactive hyperemic response in forearm vessels].

Recently, the mechanism of longevity in females was proposed to be associated with female hormones. This study examined the effect of aging and sex on vascular endothelial function, and the relationship between female hormone level and endothelial function by ischemic reactive hyperemic response in the forearm using plethysmography. The study population consisted of 246 healthy subjects aged from 20 to 76 years (119 males, 127 females) and 20 healthy females aged 85 years and older (85 to 103 years; mean age 94 years) without distinct cardiovascular disease, hypertension, diabetes mellitus, renal disease, liver dysfunction or anemia. Levels of the female hormones, estradiol and estriol, were measured in females aged more than 85 years. The duration of reactive hyperemia decreased with aging, but the difference between males and females was not significant at any age. In females, the duration was markedly decreased from 110 +/- 36 sec in the fifties to 81 +/- 29 sec in the sixties or older (p < 0.05). Excess flow also showed similar changes to the duration of reactive hyperemia. The duration of reactive hyperemia and excess flow in females aged 85 years and older were similar to those in the fifties, but was significantly longer than those in females 60 years or older. The concentrations of estradiol (44.9 +/- 27.1 pg/ml) and estriol (22.1 +/- 13.4 pg/ml) in females aged 85 years were higher than in the sixties. There was a positive correlation between the duration of reactive hyperemia and the concentration of estradiol (r = 0.56, p < 0.01) or estriol (r = 0.57, p < 0.01). In summary, vascular endothelial function was impaired gradually with aging, but preservation of the function in healthy, very old females was closely associated with levels of female hormone.

Adult↗
PubMed2000

Current therapy in Behcet's disease.

Behçet's disease is an inflammatory disorder of unknown cause. There is often involvement of the gastrointestinal system, the central nervous system and large vessels, which can be life-threatening. As well, ocular lesions can cause blindness. Mucocutaneous symptoms are self-limiting but more frequent. Almost all the patients have recurrent oral aphthous ulcers, and more than 70% of the patients have genital ulcers and skin symptoms, which include erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules and a positive pathergy test. The pathergy test is felt to reflect cutaneous hypersensitivity. In general, topical treatment using corticosteroids is satisfactory for these mucocutaneous lesions unless eye and vital organs are involved.

Adrenal Cortex Hormones↗
PubMed2000

Neuro-endocrine-immune axis in human rheumatoid arthritis.

We present an overview of the role of neuro-endocrine-immune mechanisms in the pathophysiological responses of patients with rheumatoid arthritis (RA). In patients with RA, proinflammatory cytokines secreted by synovial cells provoke local inflammation in the joints and, simultaneously, initiate a systemic acute phase response. Thus, profound changes of the neuro-endocrine-immune axis could take place in the patients. Defects in the hypothalamus-pituitary-adrenal axis have been observed in patients with RA. Prolactin levels are often elevated and abnormal sex hormone levels have been described in RA patients. Defective neural regulation of inflammation involving neuropeptides at least partly plays a pathogenic role in RA. We and others have found that participants of the neuro-endocrine-immune interactions, such as hormones, neurotransmitters and neuropeptides, modulate RA synovial cell functions and that they are actually produced by, and their receptors are expressed on, cells within the inflammatory joint compartment. Thus, neuropeptides and hormones not only affect a systemic acute phase response of RA patients, but also modulate local inflammation directly in RA joints. These results suggest that defects in regulatory processes which are fundamental to RA may lie in the immune system, the nervous system, the endocrine system or the interactions of these. A better understanding of neuro-endocrine-immune interactions holds the promise of new approaches to the treatment of RA with the use of hormones, neurotransmitters, neuropeptides and/or their antagonists.

Arthritis, Rheumatoid↗