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F Suzuki

Publications and source records attributed to F Suzuki.

At least 73 records · Page 4Linked to original sources
PubMed2000

Carbon-11-labeled KF21213: a highly selective ligand for mapping CNS adenosine A(2A) receptors with positron emission tomography.

In vivo assessment of the adenosine A(2A) receptors localized in the striatum with positron emission tomography (PET) may offers us a new diagnostic tool for neurological disorders. We evaluated the potential of [7-methyl-(11)C](E)-8-(2,3-dimethyl-4-methoxystyryl)-1, 3,7-trimethylxanthine ([(11)C]KF21213) as a PET ligand for mapping adenosine A(2A) receptors in the central nervous system. KF21213 showed a high affinity for the adenosine A(2A) receptors in vitro (Ki = 3.0 nM) and a very low affinity for the A(1) receptors (Ki > 10,000 nM). In mice, the striatal uptake of [(11)C]KF21213 increased for the first 15 min and then gradually decreased, whereas the uptake in the reference regions such as the cortex and cerebellum rapidly decreased. The uptake ratio of striatum to cortex and striatum to cerebellum increased to 8.6 and 10.5, respectively, at 60 min postinjection. The striatal uptake was significantly blocked by co-injection of carrier KF21213 or each of three other A(2A) antagonists, but not by co-injection of A(1) antagonist. The specific uptake was not detected in the cortex or in the cerebellum. Ex vivo autoradiography and PET clearly visualized adenosine A(2A) receptors in the rat striatum. [(11)C]KF21213 was the most selective tracer for mapping adenosine A(2A) in the central nervous system by PET among the tracers proposed to date.

Animals↗
PubMed2000

Distinction between chronic hepatitis and liver cirrhosis in patients with hepatitis C virus infection. Practical discriminant function using common laboratory data.

In order to distinguish patients with cirrhosis from those with chronic hepatitis, multivariate discriminant analysis was performed using common laboratory data. A total of 205 consecutive patients were diagnosed by peritoneoscopy and biopsy as having chronic liver disease caused by hepatitis C virus (HCV), 168 with chronic hepatitis and 37 with cirrhosis. Twenty variables and their natural logarithmic transformation were employed in the multivariate analysis. After stepwise variable selection, the following function was finally obtained to discriminate the disease severity, z=0.120xgamma-globulin (%)+0.423xln (hyaluronate) (µg l(-1))-0.059xplatelet (x10(4) counts per mm(3))-0.364xsex (male, 1; female, 2)-3.953. Since the function contained an expression of logarithm and was slightly troublesome to apply, we prepared another discriminant function composed of usual figures without logarithmic transformation, z=0.124x(gamma-globulin (%))+0.001x(hyaluronate) (µg l(-1))-0.075x(platelet (x10(4) counts per mm(3)))-0.413xgender (male, 1; female, 2)-2.005. When a positive result is calculated in the latter equation, the diagnosis of the liver disease indicates cirrhosis, and negative result chronic hepatitis. Accuracy of the two discriminant functions was 90.3 and 91.2%, respectively. A concise linear discriminant function could successfully differentiate liver cirrhosis from chronic hepatitis with an accuracy of 91.2%.

Journal Article↗
PubMed2000

Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood-brain barrier using in vitro cultured cells and in vivo BUI studies.

PURPOSE: To prove the functional significance of monocarboxylic acid transporter, MCT1 at the blood-brain barrier (BBB) for the passage of both endogenous and exogenous monocarboxylic acids into the central nervous system. METHODS: Monocarboxylic acid transport at the BBB was studied in rats by using a newly established immortalized brain capillary endothelial cell (BCEC) line, RBEC1, and the results were compared with those obtained by using primary cultured BCECs, cells stably expressed with rat MCT1, and the in vivo brain uptake index (BUI) method. RESULTS: The cell line, RBEC1 meets various morphological and enzymatic criteria of BCECs and appears to be suitable for the study of BBB transport of monocarboxylic acids. The presence of MCT1-transcript in RBEC1 was confirmnned by the RT-PCR method, as previously observed in isolated brain capillaries. A typical substrate of MCT1, lactic acid, was taken up by RBEC1 in a stereospecific and saturable manner. The value of the kinetic parameter Km showed good agreement with values previously obtained in studies using an in vivo BUI and in vitro MCT1-transfected cells. An organic weak acid, benzoic acid, which has been considered to cross biological membranes by passive diffusion, exhibited carrier-mediated transport properties, such as saturation, pH dependence, and stereospecific inhibition in RBEC1, similar to those we observed in primary cultured rat BCECs. The Km values in RBEC1, in primary cultured BCECs and in the in vivo BUI method were comparable and well agreed with that obtained in MCT1-transfected cells, suggesting that the transport features of benzoic acid observed by in vitro methods well reflect the in vivo transport activity. Furthermore, hybrid depletion of MCT1 in RBEC1 using an antisense oligonucleotide against rat MCT1 abolished the saturable transport of benzoic acid. CONCLUSIONS: These observations show that MCT1 plays a significant role in the transport of monocarboxylic acids, including the exogenous organic weak acid benzoic acid, as well as native lactic acid.

Animals↗
PubMed2000

High-performance affinity beads for identifying drug receptors.

We have developed a method using novel latex beads for rapid identification of drug receptors using affinity purification. Composed of a glycidylmethacrylate (GMA) and styrene copolymer core with a GMA polymer surface, the beads minimize nonspecific protein binding and maximize purification efficiency. We demonstrated their performance by efficiently purifying FK506-binding protein using FK506-conjugated beads, and found that the amount of material needed was significantly reduced compared with previous methods. Using the latex beads, we identified a redox-related factor, Ref-1, as a target protein of an anti-NF-kappaB drug, E3330, demonstrating the existence of a new class of receptors of anti-NF-kappaB drugs. Our results suggest that the latex beads could provide a tool for the identification and analysis of drug receptors and should therefore be useful in drug development.

Amino Acid Sequence↗
PubMed2000

Splice isoforms of alpha(1a)-adrenoceptor in rabbit.

Two splice isoforms of rabbit alpha(1a)-adrenergic receptor (AR), (named alpha(1a)-OCU.2-AR and alpha(1a)-OCU.3-AR) have been isolated from the liver cDNA library in addition to the previously reported isoform (alpha(1a)-OCU.1-AR). Although they have the identical splice position with human alpha(1a)-AR isoforms, the C-terminal sequences are distinct from those of human isoforms. Among these rabbit alpha(1a)-AR isoforms, there are no significant differences in pharmacological properties: high affinity for prazosin, WB4101, KMD-3213 and YM617 and low affinity for BMY7378, using COS-7 cells expressing each isoform by radioligand binding assay. Competitive reverse transcription-polymerase chain reaction (RT - PCR) analysis revealed that mRNA of alpha(1a)-ARs was expressed in liver, thoracic aorta, brain stem and thalamus of rabbit. The splice isoforms exhibited a distinct distribution pattern in rabbit; alpha(1a)-OCU. 1-AR was expressed most abundantly in those tissues. CHO clones, stably expressing each isoforms with receptor density 740 fmol mg(-1) protein in alpha(1a)-OCU.1-AR, 1200 fmol mg(-1) in alpha(1a)-OCU.2-AR and 570 fmol mg(-1) in alpha(1a)-OCU.3-AR, respectively, showed a noradrenaline-induced increase in inositol trisphosphate which was suppressed by prazosin. Noradrenaline elicited a concentration-dependent increase in extracellular acidification rate (EAR) in the CHO clones with pEC(50) values of 6. 19 for alpha(1a)-OCU.1-AR, 6.49 for alpha(1a)-OCU.2-AR and 6.58 for alpha(1a)-OCU.3-AR, respectively. Noradrenaline caused a concentration-dependent increase in intracellular Ca(2+) concentration ([Ca(2+)]i) in the CHO clones with pEC(50) values of 6. 14 for alpha(1a)-OCU.1-AR, 7.25 for alpha(1a)-OCU.2-AR and 7.70 for alpha(1a)-OCU.3-AR, respectively. In conclusion, the present study shows the occurrence of three splice isoforms of rabbit alpha(1a)-AR, which are unique in C-terminal sequence and in tissue distribution. They show similar pharmacological profiles in binding studies but alpha(1a)-OCU.3-AR had the highest potency of noradrenaline in functional studies in spite of the lowest receptor density. These findings suggest that the structure of C-terminus of alpha(1a)-ARs may give the characteristic functional profile.

Alternative Splicing↗
PubMed2000

Inverse agonism and neutral antagonism at a constitutively active alpha-1a adrenoceptor.

We have studied the antagonist action of prazosin and KMD-3213 in a constitutively active mutant of the human alpha-1a adrenoceptor in which Ala(271) was substituted to Thr and was expressed in CHO cells. Inverse agonism was characterized by up-regulation of receptor density, a decrease in basal GTPgammaS binding, and a reduction in basal inositol-1,4,5-trisphosphate (IP(3)) level. According to the above criteria, prazosin acted as an inverse agonist, whilst KMD-3213 behaved as a neutral antagonist. Compared with the wild-type receptor, mutant receptor exhibited single affinity sites for [(3)H]-prazosin, [(3)H]-KMD and the non-radioactive ligands tested, and displayed significantly higher affinities for several agonists but not for the two antagonists. Administration of KMD-3213 to prazosin-treated CHO cells expressing the mutant receptor reversed the inverse agonism of prazosin resulting in rapid increases in cellular IP(3), in intracellular [Ca(2+)] and in the rate of extracellular acidification. These results indicated that a neutral antagonist can reverse the action of an inverse agonist at the receptor site. The distinct properties of inverse agonist and neutral antagonist in affecting receptor function may be important for the clinical use of such antagonists.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2000

Association of amino acid sequence in the PKR-eIF2 phosphorylation homology domain and response to interferon therapy.

Hepatitis C virus (HCV) genotype 1b and high pretreatment virus load are well known predictive factors of poor response to interferon (IFN) therapy. In addition, a sparsity of amino acid substitutions in the interferon sensitivity determining region (ISDR) is also predictive of a poor response to IFN in patients with genotype 1b, although this issue is still controversial. Recently, a 12 amino acid domain in the E2 protein of HCV (PKR-eIF2 alpha phosphorylation homology domain [PePHD]) has been reported to bind with and block the virus replication inhibition ability of PKR, suggesting that the interaction of E2 and PKR may be one mechanism by which HCV circumvents the antiviral effect of IFN. To clarify the significance of amino-acid sequences in this domain in predicting the effect of IFN therapy, we analyzed 82 patients with genotype 1b. Eleven patients (13.4%) responded to treatment whereas the remaining 71 patients (86.6%) were nonresponders. Multivariate analysis showed that only HCV load and amino-acid substitutions in the ISDR were predictive of sustained response to IFN. Amino-acid substitutions in the PePHD were detected in only eight of 82 patients (9.8%), and did not correlate with the therapeutic effect of IFN. However, amino-acid-sequence analyses of quasispecies before and after 1 week of IFN therapy showed elimination of clones with substitutions in this domain. Our results suggest that amino-acid sequences of the PePHD domain may be related to viral resistance to IFN but do not predict the outcome of IFN therapy as amino-acid substitutions in this domain are rare.

Adult↗
PubMed2000

Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer.

Because hepatocellular carcinoma often recurs after surgical resection or ethanol injection therapy, we conducted a prospective randomized controlled trial of interferon (IFN) in patients with chronic liver disease caused by hepatitis C virus (HCV). Twenty eligible patients with cirrhosis were randomized into two groups: 10 patients treated with 6 million units of natural IFN-beta twice a week for 36 months and 10 patients without IFN therapy. One patient within the treatment group discontinued interferon therapy after 19 months of treatment because of a mild degree of retinopathy. None of the patients in either group lost HCV-RNA until the end of the observation. Although 7 (70.0%) of 10 patients in the nontreatment group showed tumor recurrence, only 1 (10.0%) of 10 patients with IFN therapy developed tumor recurrence during a median observation period of 25.0 months. Cumulative recurrence rates of the treated and untreated groups were 0% and 62.5% at the end of the first year, and 0% and 100% at the second year, respectively (log-rank test, P =.0004). In conclusion, intermittent administration of IFN suppressed tumor recurrence after treatment with surgery or ethanol injection in patients with HCV-related chronic liver disease.

Aged↗
PubMed2000

Lanoconazole, a new imidazole antimycotic compound, protects MAIDS mice against encephalitis caused by Cryptococcus neoformans.

The protective effect of a new antifungal compound, lanoconazole, against Cryptococcus neoformans infection in C57BL/6 mice exposed to LP-BM5 murine leukaemia virus (MuLV) (MAIDS mice) was investigated. Mice were infected intratracheally with C. neoformans, strain 613D, 40 days after infection with LP-BM5 MuLV. They were treated orally with various doses of lanoconazole or with fluconazole 10 mg/kg (a positive control) once daily beginning 1 day after the fungal infection and continuing until the end of the experimental period. The number of C. neoformans cells in the lungs and brains of infected mice was determined. Lanoconazole and fluconazole had a similar inhibitory effect on the growth of C. neoformans in the brains and lungs of normal mice. Whereas lanoconazole inhibited the growth of C. neoformans in the brains and lungs of MAIDS mice, the pathogen grew in the brains of MAIDS mice treated with fluconazole. Lanoconazole reduced the number of C. neoformans in the brains of normal mice treated with a type 2 cytokine mixture, whereas fluconazole did not. A predominance of type 2 T-cell responses was demonstrated in MAIDS mice. Splenic T cells from MAIDS mice, but not those from normal mice, released interleukins 4 and 10 into the culture medium when they were stimulated with an anti-CD3 monoclonal antibody. These results suggest that lanoconazole may have the potential to inhibit the growth of C. neoformans in AIDS patients with a predominance of type 2 T-cell responses.

Animals↗
PubMed2000

Novel putative photoreceptor and regulatory genes Required for the positive phototactic movement of the unicellular motile cyanobacterium Synechocystis sp. PCC 6803.

Synechocystis: sp. PCC 6803 is a unicellular motile cyanobacterium, which shows positive or negative phototaxis on agar plates under lateral illumination. By gene disruption in a substrain showing of positive phototaxis, it was demonstrated that mutants defective in sll0038, sll0039, sll0041, sll0042 or sll0043 lost positive phototaxis but showed negative phototaxis away from the light source. Mutants of sll0040, which is located within the cluster of these genes, retained the capacity of positive phototaxis but to a lesser extent than the parent cells. These genes are homologous to che genes, which are involved in flagellar switching for bacterial chemotaxis. Interestingly, sll0041 (designated pisJ1) is predicted to have a chromophore-binding motif of phytochrome-like proteins and a signaling motif of chemoreceptors for bacterial chemotaxis. It is strongly suggested that the positive phototactic response was mediated by a phytochrome-like photoreceptor and CheA/CheY-type signal transduction system.

Amino Acid Sequence↗
PubMed2000

Prevalence of human papillomavirus infection and its correlation with cervical lesions in commercial-sex workers in Japan.

OBJECTIVE: To investigate the prevalence of the human papillomavirus (HPV) infection and its correlation with cervical lesions in commercial-sex workers (CSWs) who attended a sexually transmitted disease (STD) clinic in an entertainment area in Tokyo. METHODS: Surveys were conducted on 546 prostitutes and 233 control subjects. In all subjects, HPV detection was performed by the hybrid capture method. A cervical cytological examination was performed on 247 prostitutes and 233 control subjects. RESULTS: The HPV-positive rates in the two periods of study were higher (p < 0.01) in CSWs than in the control subjects. When the cytological grades were examined according to HPV-positive rates, the proportion of cytologic Class IIIa to Class IV was significantly higher (p < 0.01) in the HPV-positive CSWs than in the HPV-negative CSWs or in the normal subjects. CONCLUSION: The high frequencies of HPV infection and cervical dysplasia in the CSWs in the present series might predict a higher risk of cervical cancer in this group of subjects.

Adolescent↗
PubMed2000

Augmentation of QRS wave amplitudes in the precordial leads during narrow QRS tachycardia.

INTRODUCTION: QRS morphology during narrow QRS supraventricular tachycardia in patients without ventricular preexcitation generally is considered the same as that seen during sinus rhythm. This study presents a new ECG observation that the QRS amplitude increased significantly in leads V2 through V5 during tachycardia. METHODS AND RESULTS: Using the same ECG machine and the same electrode patches applied to the same electrode positions, 12-lead ECGs during sinus rhythm and narrow QRS tachycardia were analyzed comparatively in 23 patients without ventricular preexcitation. Precordial QRS amplitudes were measured as the vertical distance from the peak of the R to the nadir of the S wave. The amplitudes also were measured during atrial rapid pacing and extrastimulation. Furthermore, ventricular excitation during sinus rhythm and tachycardia was studied using body surface mapping. Body surface distributions of QRS potentials and ventricular activation time (VAT) were displayed as maps. Gross area of QRS (AQRS, equivalent to the QRS amplitude) was compared during sinus rhythm versus tachycardia. During tachycardia, QRS amplitude significantly increased in leads V2 through V5, without any noticeable change in the transitional zone or QRS wave duration. Increase of QRS amplitude also was noted during atrial rapid pacing and extrastimulation. Gross AQRS values during tachycardia significantly increased in the left parasternal area, whereas QRS isopotential and VAT isochronal maps were similar during sinus rhythm and tachycardia, suggesting a minimal role of conduction delay in the increase of QRS amplitude. CONCLUSION: QRS wave amplitude significantly increased in leads V2 through V5 during narrow QRS tachycardia compared with QRS waves in sinus rhythm. Increase of QRS amplitude seemed unlikely due to a conduction delay within the ventricular myocardium.

Adolescent↗
PubMed2000

Prevalence of human papillomavirus, Chlamydia trachomatis, and Neisseria gonorrhoeae in commercial sex workers in Japan.

OBJECTIVE: We used the hybrid capture assays to investigate the prevalence of human papillomavirus (HPV), Chlamydia trachomatis and Neisseria gonorrhoeae among commercial sex workers in Tokyo. METHODS: Five hundred forty-six consecutive commercial sex workers (CSW) who visited an STD clinic for STD checkup in 1998 and 1999 were studied. A control group consisted of 233 consecutive women who visited a general gynecological clinic for annual checkup. A cervical sample was obtained for hybrid capture assays for HPV-A (low-oncogenic-risk types), HPV-B (intermediate- and high-oncogenic-risk types), C. trachomatis, and N. gonorrhoeae. Fisher's exact test was used for statistical analyses. RESULTS: The positive rate for HPV-B among the CSW was 48.4%, significantly higher than the 6.0% among the control subjects. The positive rates for HPV-A, C. trachomatis, and N. gonorrhoeae were also significantly higher among the CSW than among the control subjects. Among the microorganisms tested, the positive rate for HPV-B was the highest in both the STD and control groups. CONCLUSIONS: The high prevalence of HPV, C. trachomatis, and N. gonorrhoeae infection in CSW poses a risk of further transmission of STD to the general public, suggesting the need for further education and screening for CSW and the general public. We found high- and intermediate-oncogenic-type HPV to be the most prevalent infection among both CSW and control subjects. Screening for HPV may be necessary in STD and general clinics to predict the risk of cervical malignancy. Hybrid capture assays, which permit simultaneous detection of HPV and other STD with high sensitivity, may be a useful diagnostic method.

Adolescent↗
PubMed2000

Relationship between five-year histological outcome and serial changes in serum alanine aminotransferase in patients with biochemical and virological relapse after interferon treatment for chronic hepatitis C.

OBJECTIVE: The aim of this study was to assess the correlation between serial changes in serum alanine aminotransferase (ALT) levels and histological outcome 5 years after treatment of patients with chronic hepatitis C with interferon (IFN). METHODS: We retrospectively evaluated 61 consecutive patients who underwent two liver biopsies, just before and 5 years after a 6-month course of IFN therapy, and who showed a relapse after therapy. The extent of liver fibrosis was estimated using a scale with seven grades. RESULTS: At the end of 6-month IFN therapy, 40 (65.6%) patients had normal serum ALT concentrations. However, 13 of the 40 patients relapsed within 6 months after IFN therapy. The average ALT during 5 years in 40 patients was less than or equal to 75 IU/l, while in the other 21 patients it was more than 75 IU/l. Among the 40 patients with a mean ALT less than 75 IU/l, 13 (33%) patients showed histological improvement, 26 (65%) showed no changes and only 1 patient (2%) showed worsening of liver fibrosis. On the other hand, among the 21 patients with a mean ALT of more than 75 IU/l, only 1 (5%) patient showed improvement, 8 (38%) showed no changes and 12 patients (57%) showed worsening of liver fibrosis. CONCLUSION: There is a significant relationship between 5-year histological outcome and serial changes in serum ALT in patients with biochemical and virological relapse after IFN treatment for chronic hepatitis C.

Adult↗
PubMed2000

Demonstration of phase-3 and phase-4 retrograde block in a second concealed accessory pathway after an initial successful radiofrequency ablation of a 'normal' concealed accessory pathway.

We report a patient with concealed Wolff-Parkinson-White syndrome who, following catheter ablation, demonstrated phase-3 and phase-4 retrograde block in a concealed accessory pathway. After an initial 'apparently successful' ablation, retrograde conduction was through the atrioventricular node during constant ventricular pacing. Ventricular extrastimulus testing was performed at a basic drive cycle length of 600 ms. Unexpectedly, ventricular extrastimuli at coupling intervals of 440-380 ms were conducted retrogradely over an accessory pathway, consistent with a phase-3 and phase-4 retrograde block in the accessory pathway. Residual accessory pathway conduction was eliminated in a single ablation session.

Catheter Ablation↗
PubMed2000

Diagnostic significance of the morphological change in the atrial electrogram during Para-Hisian pacing.

Para-Hisian pacing (PHP), a pacing method to differentiate between conduction occurring over an accessory pathway (AP) from that over the atrioventricular node (AVN), is assessed essentially by comparing the timing in the atrial electrogams. Morphological change in the atrial electrograms is often observed during PHP, but its significance has not been investigated. Prior to the catheter ablation procedure, PHP was performed in 52 patients with an AP and in 36 patients with AV nodal reentrant tachycardia (AVNRT). The morphological change in the atrial electrograms, which was retrospectively assessed between the His bundle and proximal right bundle branch (HB-RB) captured and non-captured beats, was identified in 15 of 52 patients with an AP and in 26 of 36 patients with AVNRT. The atrial electrogram in the 6 of these 15 AP patients changed its morphology without overlapping the ventricular electrogram. All 6 AP patients exhibited a PHP pattern with the presence of 2 retrograde conduction routes, an AP and the AVN. In the patients demonstrating no morphological change in the atrial electrogram, 33 of 37 AP patients and all 10 AVNRT patients had only one retrograde conduction route. Morphological change in the atrial electrogram without overlapping the ventricular electrogram seems to have diagnostic significance indicating the presence of both AP and AVN conduction.

Adolescent↗
PubMed2000

L-DOPA cyclohexyl ester is a novel potent and relatively stable competitive antagonist against L-DOPA among several L-DOPA ester compounds.

We explored L-DOPA esters with chemically bulky structures to find a potent stable competitive antagonist against L-DOPA, compared to DOPA methyl ester (DOPA ME). In anesthetized rats, DOPA cyclohexyl ester (DOPA CHE), DOPA cyclopentyl ester (DOPA CPE) and DOPA cyclopentyldimethyl ester (DOPA CPDME) at 1 microgram microinjected into depressor sites of the nucleus tractus solitarii elicited or tended to elicit more marked antagonism against depressor responses to 60 ng L-DOPA, compared to DOPA ME. At 100 ng, DOPA CHE elicited the most potent antagonism. At 1 microgram, duration of the antagonistic activity of DOPA CHE was approximately three times longer than that of DOPA ME. During microdialysis of the nucleus accumbens, conversion from DOPA CHE at 1 microM perfused via probes to extracellular L-DOPA was the lowest among these compounds and less than one half of that from DOPA ME. Binding studies showed that the recognition site for L-DOPA differs from ionotropic glutamatergic, dopaminergic D1 and D2 receptors. We recently found that L-DOPA evoked by transient ischemia may act as a DOPA CHE-sensitive causal factor for glutamate release and resultant neuronal cell death. DOPA CHE is the most potent, relatively stable competitive antagonist against L-DOPA and is a useful mother compound to develop neuroprotective drugs.

Animals↗