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Biomedical subjects

J Nishikawa

Publications and source records attributed to J Nishikawa.

At least 19 recordsLinked to original sources
PubMed1997

Drosophila TAF(II)230 and the transcriptional activator VP16 bind competitively to the TATA box-binding domain of the TATA box-binding protein.

The transcription initiation factor TFIID, consisting of the TATA box-binding protein (TBP) and many TBP-associated factors (TAFs), plays a central role in both basal and activated transcription. An intriguing finding is that the 80-residue N-terminal region of Drosophila TAF(II)230 [dTAF(II)230-(2-81)] can bind directly to TBP and inhibit its function. Here, studies with mutated forms of TBP demonstrate that dTAF(II)230-(2-81) binds to the concave surface of TBP, which is important for TATA box binding. Previously, it was reported that a point mutation (L114K) on this concave surface destroys the ability of TBP to bind VP16 and to mediate VP16-dependent activation in vitro, but has no effect on basal transcription. Importantly, the same TBP mutation eliminates TBP binding to dTAF(II)230-(2-81). Consistent with these effects of the L114K mutation, dTAF(II)230-(2-81) and the VP16 activation domain compete for binding to wild-type TBP. These results indicate that transcriptional regulation may involve, in part, competitive interactions between transcriptional activators and TAFs on the TBP surface.

Amino Acid Sequence↗
PubMed1996

Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis.

BACKGROUND: Reduced coronary flow reserve (CFR) in hypercholesterolemic patients without evidence of ischemia has been reported. However, it remains uncertain whether this abnormality occurs without overt coronary atherosclerosis. This study aimed to clarify whether CFR is impaired even in anatomically normal coronary arteries in hypercholesterolemic patients and to compare CFR between familial hypercholesterolemic (FH) patients and secondary hypercholesterolemic (SH) patients. METHODS AND RESULTS: Twenty-two patients with hypercholesterolemia (11 FH, 11 SH) and 11 control subjects were studied. Baseline myocardial blood flow (MBF) and MBF during dipyridamole loading were measured in segments perfused by angiographically normal coronary arteries with the use of positron emission tomography and 13N-ammonia, and CFR was calculated. Baseline MBF (mL/min per 100 g heart wt) in FH (81.3 +/- 31.4) and SH (70.0 +/- 20.7) patients was not different from that in control subjects (75.0 +/- 34.9). However, MBF during dipyridamole loading was significantly lower in FH patients (129 +/- 19.1) than in control subjects (322 +/- 174, P < .01) and SH patients (210 +/- 71.2, P < .01). CFR in FH patients (1.59 +/- 0.41) was also significantly lower compared with both control subjects (4.22 +/- 1.42, P < .01) and SH patients (3.00 +/- 0.96, P < .01). CFR in SH patients was also significantly lower than that in control subjects (P < .05). CFR correlated significantly with both plasma total cholesterol (r = .67, P < .01) and LDL cholesterol concentrations (r = .69, P < .01). CONCLUSIONS: CFR was decreased even in anatomically normal coronary arteries in hypercholesterolemic patients. This abnormality was more prominent in FH patients.

Blood Pressure↗
PubMed1996

A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A.

The adenoviral oncoprotein E1A induces progression through the cell cycle by binding to the products of the p300/CBP and retinoblastoma gene families. A new cellular p300/CBP-associated factor (P/CAF) having intrinsic histone acetylase activity has been identified that competes with E1A. Exogenous expression of P/CAF in HeLa cells inhibits cell-cycle progression and counteracts the mitogenic activity of E1A. E1A disturbs the normal cellular interaction between p300/CBP and its associated histone acetylase.

Acetyltransferases↗
PubMed1996

Isolation of a genomic DNA fragment having negative vitamin D response element.

The vitamin D receptor (VDR) binds to the vitamin D response element (VDRE) in the promoter region of target genes and acts as a ligand-dependent transcriptional regulator. In order to identify novel VDREs and new genes that are regulated by the active form of vitamin D [1,25-(OH)2D3], rat genomic DNA fragments bound by VDR were isolated. One of these fragments, designated as VBF5 was transcribed and the transcript was down-regulated by 1,25-(OH)2D3. These data strongly indicate that VBF5 may contain a VDRE regulating negatively an unidentified gene expression.

Animals↗
PubMed1996

Evaluation of gamma camera-based measurement of individual kidney function using iodine-123 orthoiodohippurate.

Gamma camera-based clearance techniques which use the renal uptake ratio (RUR) of the radiotracer are available to estimate the effective renal plasma flow (ERPF) and glomerular filtration rate. To evaluate the accuracy of these techniques, we measured RUR by an optimized procedure and compared it with standard ERPF. Iodine-123 orthoiodohippurate (OIH) scintigraphy and simultaneous para-aminohippurate clearance study for measuring standard ERPF were performed in three hospitals in 24 patients with normal or mildly impaired renal function. 123I-OIH was injected intravenously and 10-s consecutive imaging of the kidneys was started when the abdominal aorta was seen. The attenuation coefficient for 123I was measured in each hospital using the same water-equivalent absorption materials and used for the attenuation correction. After subtracting background radioactivity, RURs were defined as the count ratios of fractional renal uptakes based on the integral from 1 to 2, 2 to 3, 1.5 to 2.5 and 1 to 3 min after the injection of 123I-OIH in relation to injected doses using the following three procedures in respect of attenuation correction: (1) RUR without attenuation correction, (2) RUR with fractional renal uptake corrected by the measured attenuation coefficient, (3) RUR with the total injected dose corrected by the absorption material. To decide upon the appropriate correction method and time interval, RURs were compared with standard ERPF. Among the three correction methods, procedure 2 showed the highest correlation between RUR and standard ERPF, but the correlation coefficient was low (r=0.75). No significant difference was observed among the RURs of each time interval. Individual kidney function measured from early renal uptake may be inaccurate even when appropriate correction is made for attenuation, background activity or time lag between injection and data acquisition. Gamma camera-based measurement of renal function using 123I-OIH is limited with regard to accuracy and reproducibility, though it is convenient and non-invasive.

Adult↗
PubMed1996

Simple method to quantify myocardial glucose metabolism from MB ratio in myocardial FDG PET.

To provide a simple means of quantifying myocardial glucose metabolism, we tried to estimate the K complex (KC) from the myocardium to background ratio (MB ratio), which was obtained with a single static FDG scan and single venous sampling. In 48 fasting subjects and 74 subjects under oral glucose loading or insulin clamp, the reference KC was obtained from Patlak analysis by using an input function. We compared the reference KC with the MB ratio at 35 min 45 sec, 45 min 45 sec, and 55 min 45 sec, and with the FDG uptake index (FUI) reported by Tamaki. The correlation between KC and each index was very close during fasting (r = 0.97, 0.98, 0.98 and 0.97, respectively n = 48), and clinically acceptable during oral glucose loading and insulin clamp (r = 0.92, 0.91, 0.90 and 0.93, respectively n = 74). The average differences between the reference KC and KC estimated from the simple method were 13%, 10%, 8%, and 13%, respectively, during fasting, and 15%, 14%, and 16%, respectively, during oral glucose loading and insulin clamp. Both the MB ratio and FDG uptake index can be used for the simple estimation of myocardial glucose metabolism not only during fasting but also during oral glucose loading and insulin clamp, although the MB ratios at 45 min and at 55 min were slightly better than MB that at 35 min and the FDG uptake index during fasting.

Adult↗
PubMed1996

Use of whole-body imaging using Tc-99m RBC in patients with soft-tissue vascular lesions.

We investigated the usefulness of whole-body imaging as an adjunct to spot imaging in soft-tissue vascular lesions, such as hemangiomas and vascular malformations. Spot imaging of the known lesion and whole-body imaging were performed 1-3 hours after the injection of Tc-99m RBC in 42 patients with soft-tissue vascular lesions. Whole-body imaging was considered to be useful in only two patients, who had multiple distant occult lesions in addition to large known lesions. It was suggested that the routine addition of whole-body imaging is not cost effective in patients with soft-tissue vascular lesions, although it may be beneficial for detecting occult lesions in patients with hemangiomas.

Adolescent↗
PubMed1996

Reduced coronary flow reserve in familial hypercholesterolemia.

UNLABELLED: Familial hypercholesterolemia (FH) presents the highest risk for coronary artery disease (CAD) among patients with hyperlipidemia. Therefore, early detection of coronary arterial atherosclerosis is important for the treatment of FH patients. The aim of this study was to detect early coronary arterial abnormalities that may relate to future atherosclerosis in asymptomatic FH patients by measuring coronary flow reserve (CFR) using PET and 13N-ammonia. METHODS: Twenty-five patients with FH (14 men, 11 women) without a history of myocardial ischemia and 14 control subjects (9 men, 5 women) were studied. Total serum cholesterol (mmole/liter) was 5.33 +/- 0.66 in control subjects and 7.90 +/- 0.77 in FH patients (p < 0.01 versus control subjects). RESULTS: Myocardial blood flow (MBF) at rest and during dipyridamole loading was measured using PET, and CFR was calculated. MBF (ml/min/100 g weight heart) at rest in the FH group (79.0 +/- 20.0) was comparable to that in control subjects (70.0 +/- 17.0). However, MBF during dipyridamole loading was significantly lower in FH patients (163.0 +/- 67.0) than in control subjects (286.0 +/- 120.0, p < 0.01). CFR in FH patients (2.09 +/- 0.62) was also significantly lower than that in control subjects (4.13 +/- 1.38, p < 0.01). CFR showed a gender-specific variance in FH patients (1.85 +/- 0.40 in men versus 2.55 +/- 0.74 in women p < 0.05) but not in control subjects. Significant inverse correlations between CFR and the total plasma cholesterol level as well as plasma LDL cholesterol were observed. CONCLUSION: The CFR was reduced in patients with FH. This abnormality was more prominent in men than in women patients. Noninvasive assessment of CFR by 13N-ammonia PET was useful to detect early abnormalities of the coronary arteries in asymptomatic patients with FH.

Ammonia↗
PubMed1995

Induction of apoptotic cell death by pancreatitis-associated ascitic fluid in Madin-Darby canine kidney cells.

We investigated the cytotoxicity on Madin-Darby canine kidney (MDCK) cells of pancreatitis-associated ascitic fluid (PAAF) collected from rats with experimental necrotizing pancreatitis. PAAF reduced viability of MDCK cells in a time- and dose-dependent manner. We detected DNA fragmentation on the PAAF-treated MDCK cells, indicating that the cytocidal action of PAAF is via apoptosis. From the results obtained, we conclude that PAAF contains factor(s) inducing apoptosis on MDCK cells, and we assume that apoptotic cell death is involved in the mechanism of organ failure in acute pancreatitis.

Acute Disease↗
PubMed1995

Vitamin D receptor contains multiple dimerization interfaces that are functionally different.

The vitamin D receptor mediates the signal of 1 alpha, 25-dihydroxyvitamin D3 by binding to vitamin D responsive elements in DNA as a homodimer or as a heterodimer composed of one vitamin D receptor subunit and one retinoid X receptor subunit. We have mapped the dimerization interfaces of the vitamin D receptor that is involved in homo- or heterodimer formation in the absence of DNA. While deletion of the first zinc finger region of vitamin D receptor diminished homodimerization activity, it did not affect heterodimerization. In contrast, a deletion just beyond the zinc finger region affected heterodimerization with retinoid X receptor, but not homodimerization. The zinc finger region alone could form a homodimer with full-length vitamin D receptor, but not a heterodimer with retinoid X receptor. The carboxy-terminal region was also necessary for heterodimer formation. This region showed only a weak dimerization activity in the absence of ligand, but this was dramatically increased in the presence of ligand for both homo- and heterodimerization. These results suggest that the vitamin D receptor has at least three dimerization interfaces whose functions are apparently distinguishable. These are located in the first zinc finger region, the region just beyond this zinc finger and in the carboxy-terminal region.

Amino Acid Sequence↗
PubMed1995

Rabphilin-3A binds to a M(r) 115,000 polypeptide in a phosphatidylserine- and Ca(2+)-dependent manner.

Rabphilin-3A is a putative target protein for Rab3A/Smg 25A, which is a member of the Ras-related small GTP-binding protein and implicated in neurotransmitter release from the synapse. Rabphilin-3A is composed of two functionally different domains: the N-terminal Rab3A-binding and the C-terminal phosphatidylserine- and Ca(2+)-binding domains. The C-terminal domain has two copies of an internal repeat that are homologous to the C2 domains of protein kinase C, synaptotagmin, and phospholipase A2 and C-gamma 1, which are known to bind phosphatidylserine and Ca2+. In this study, we attempted to identify the Rabphilin-3A-interacting molecule in bovine brain by use of an overlay assay technique. The 32P-labeled C-terminal fragment of Rabphilin-3A (281-704 amino acids) bound to a protein molecule with a M(r) of about 115 kDa which was immobilized on a nitrocellulose sheet. This protein was highly purified and characterized. The binding of the 32P-labeled C-terminal fragment to this protein was dependent on both phosphatidylserine and Ca2+, and inhibited by an excess amount of the C-terminal fragment and the C2 domain fragment (396-704 amino acids) but not by the N-terminal fragment (1-280 amino acids). These results indicate that Rabphilin-3A binds to a protein molecule with a M(r) of 115 kDa through the C2 domain in the presence of phosphatidylserine and Ca2+.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Myocardial glucose metabolism in noninsulin-dependent diabetes mellitus patients evaluated by FDG-PET.

UNLABELLED: Diabetes mellitus (DM) is one of several factors influencing the assessment of myocardial viability using fluorine-18 fluorodeoxyglucose (FDG) PET. METHODS: To compare the myocardial glucose metabolism of normal subjects to patients with DM, we performed a quantitative FDG study during insulin clamp, oral glucose loading and fasting in nine normal volunteers and eight patients with noninsulin-dependent DM (NIDDM). RESULTS: During oral glucose loading, myocardium-to-background (MB) ratio remarkably deteriorated in NIDDM patients compared with normals because of high plasma glucose and low serum insulin. Myocardial glucose utilization (MGU) rates in NIDDM patients were also lower than those in normal volunteers. MB ratio of FDG remarkably improved with insulin clamp in NIDDM patients compared with oral glucose loading. MGU rates during insulin clamp were still slightly lower than in the normal volunteers despite low plasma glucose and adequate plasma insulin. CONCLUSION: The insulin clamp method may be very useful in NIDDM patients for improved myocardial FDG uptake compared to oral glucose loading or fasting, but slight decreases in MGU rates during insulin clamp in NIDDM patients may be because of insulin resistance (GluT4 abnormality).

Adult↗
PubMed1994

Difference and similarity of DNA sequence recognized by VDR homodimer and VDR/RXR heterodimer.

Nuclear receptors for the thyroid hormone and vitamin A and D cooperate with the retinoid X receptor (RXR) in activating the transcription. Although the hormone response elements for these receptors have been proposed in which spacing of the direct repeated motifs determine the specificity (so called 3-4-5 rule), vitamin D response elements (VDREs) in the natural context consist of often imperfect direct repeats. Vitamin D receptor (VDR) alone can bind to the mouse osteopontin (mSPP-1) VDRE, which contains a direct repeat separated by 3 nucleotides, but not to the rat osteocalcin (rOST) VDRE having inexact direct repeat. The presence of RXR not only allows the VDR to bind to the rOST VDRE, but also increases the binding affinity for the mSPP-1 VDRE. The RXR/VDR heterodimer exhibits the similar affinity constants for the mSPP-1 VDRE and the rOST VDRE, in spite of the apparently different affinities for two VDREs of the VDR homodimer. A random oligonucleotide selection procedure revealed that the consensus sequence selected by the RXR homodimer is the direct repeat spaced by one A residue. In contrast, the sequences preferentially selected by the VDR homodimer and the VDR/RXR heterodimer are similar, which are the direct repeats spaced by 3 nucleotides. The difference and similarity of DNA sequence recognition are discussed.

Animals↗
PubMed1994

Characterization of phe B gene encoding catechol 2,3-dioxygenase.

DNA sequence of the phe B gene isolated from a chromosome of the phenol degrading bacterium Pseudomonas putida BH is identical to that of the dmp B gene from the phenol degradative plasmid, pVI150. Catechol 2,3-dioxygenase encoded by phe B showed similar substrate specificity to that of xyl E. However, Phe B has much smaller Km values than Xyl E, indicating that Phe B is useful for treatment of low concentrations of catechol derivatives in waste water.

Biodegradation, Environmental↗
PubMed1993

Two functionally different domains of rabphilin-3A, Rab3A p25/smg p25A-binding and phospholipid- and Ca(2+)-binding domains.

Rabphilin-3A is a putative target molecule for rab3A p25/smg p25A, which is a member of a ras p21-related small GTP-binding protein and implicated in neurotransmitter release from the synapse. Rabphilin-3A has two copies of an internal repeat that are homologous to the C2 domains of protein kinase C, synaptotagmin, and phospholipase A2, which are known to bind to phospholipid in a Ca(2+)-dependent manner. In the current study, we have investigated the functional domains or rabphilin-3A by use of three recombinant proteins as follows: full rabphilin-3A (1-704 amino acids), an N-terminal fragment (1-280 amino acids), and a C-terminal fragment containing the C2 domains (281-704 amino acids). Both rabphilin-3A and the C-terminal fragment bound to phospholipid in the presence of Ca2+, but the N-terminal fragment did not bind to phospholipid. 45Ca2+ bound to rabphilin-3A and the C-terminal fragment only in the presence of phospholipid but did not bind to the N-terminal fragment. The GTP gamma S-bound form of rab3A p25 bound to both rabphilin-3A and the N-terminal fragment but did not bind to the C-terminal fragment. These results indicate that rabphilin-3A has at least two functionally different domains, the N-terminal rab3A p25-binding and C-terminal phospholipid- and Ca(2+)-binding domains.

Adaptor Proteins, Signal Transducing↗
PubMed1993

A measurement process for evaluating clinical teachers in internal medicine.

With input from faculty members and residents in the internal medicine residency training program at McMaster University, Hamilton, Ont., the authors developed a form to evaluate attending physicians in clinical teaching units according to 14 domains of performance. Although brief, the form included all main areas of teacher performance, allowed specification of attending physician behaviour and differentiated areas of strengths and weaknesses between and within attending physicians. The authors describe the new evaluation process and the results for 41 attending physicians.

Canada↗