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Biomedical subjects

K Hara

Publications and source records attributed to K Hara.

At least 253 records · Page 14Linked to original sources
PubMed1999

[Antinociceptive effects of intrathecally administered GABA agonists at the spinal cord level].

The present study was designed to investigate antinociceptive effect of GABA agonists regarding visceral as well as somatic noxious stimuli. Following the approval by the institutional animal care committee, an intrathecal catheter was implanted in the subarachnoid space at the L 4/5 level in male Sprague-Dawley rats. The tail flick (TF) test and the colorectal distension test (CD) were used to measure responses to somatic and visceral stimuli, respectively. Threshold in TF test and CD test were measured at 5, 10, 15, 20, 30, 60, 90, 120 and 180 min after the intrathecal injection of 0.1, 1, 5, 20 micrograms of muscimol, 0.01, 0.1, 0.3, 1 microgram of baclofen or normal saline. Percent of maximum possible effect (%MPE) and %area under the curve (%AUC) were calculated by transforming response threshold in TF and CD tests. Repeated measure ANOVA followed by Fisher's PLSD test were used for statistical analysis. Muscimol 0.1 microgram increased mean %MPE in TF test at 10 min to 15% but not in CD test. Muscimol 1, 5 and 20 micrograms significantly increased %MPE at 5 min in TF and CD tests. Muscimol 20 micrograms produced 100%MPE for 180 min after drug injection. Baclofen 0.1, 0.3 and 1 microgram significantly increased %MPE at 5 min in TF and CD test. Antinociceptive effect in TF test seems to be greater than that in CD test. Muscimol caused motor disturbance but baclofen did not. It is concluded that intrathecally administered muscimol and baclofen produced somatic and visceral antinociception in a dose dependent fashion.

Analgesics↗
PubMed1999

[Combined multimodal therapy for osteosarcoma--neoadjuvant chemotherapy].

Until the 1970s, the survival rate of osteosarcoma patients was less than 20%. By the 1990s, this had improved to 60% to 70%, and limb-sparing procedures have replaced amputation in many patients thanks to effective combination therapy. Neoadjuvant chemotherapy has become an accepted practice in the majority of institutions using protocols which include MTX, ADR, BCD and CDDP as the most active agents against this disease. Newer agents, particularly IFM and ETP, are increasingly incorporated into complex regimens. While several studies have reported multivariate analyses to identify prognostic factors, the histologic response to preoperative chemotherapy remains the most important prognostic factor. Pulmonary metastases are the primary cause of death in patients with osteosarcoma. Although current treatment regimens allow effective salvage therapy for the patients with pulmonary metastases, the actuarial survival rate is 30%. A more effective systemic treatment for those patients is needed. The current management of osteosarcoma is critically reviewed and a treatment strategy is proposed for discussion.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

[High creatine kinase MB concentration and activity in patients with rhabdomyosarcoma].

A 14-year-old boy with rhabdomyosarcoma (RMS) of the left palm showed increased concentration and activity of creatine kinase (CK; EC 2.7.3.2) MB in his serum. CK isoenzyme analysis revealed no extra band. Other laboratory data including high lactate dehydrogenase (LD) isoenzyme 2, CK isoenzyme BB and MB, neuron specific enolase (NSE), and clinical findings did not support the diagnosis of myocardial infarction. The high activity and concentration of CK-MB in serum is possibly originated from the tumor. We could follow his time-course and analyze laboratory data of him and other 6 patients with RMS. We concluded that CK-MB, both concentration and activity, was the more sensitive marker of disease states of RMS than NSE and LD to follow up the patients with RMS.

Adolescent↗
PubMed1999

[Clinical evaluation of biapenem in various infectious diseases].

The clinical usefulness of injectable biapenem (BIPM) was examined for various infectious diseases in the fields of internal medicine, urology, surgery, orthopedics, obstetrics and gynecology, otorhinolaryngology, ophthalmology, dermatology, oral surgery, and plastic surgery. BIPM was administered by intravenous drip infusion at a dose of 150, 300, or 600 mg twice a day. The concentrations in various body fluid and tissues were also examined. 1. In the total enrollment of 256 cases, the numbers subjected to the analyses for clinical efficacy, bacteriological efficacy, side effects and abnormal laboratory findings were 214, 170, 252 and 251 cases, respectively. 2. The clinical efficacy rate was 85.5% (183/214 cases) as a whole, being 2/2 for sepsis, 6/8 for cellulitis and lymphangitis, 76.2% (16/21) for traumatic, operative wound and burn infections, 4/6 for osteomyelitis and arthritis, 92.9% (13/14) for peritonsillar abscess and peritonsillitis, 83.3% (15/18) for chronic lower respiratory tract infection, 7/7 for pneumonia, 83.3% (30/36) for complicated urinary tract infection, 100% (14/14) for cholecystitis and cholangitis, 88.2% (15/17) for peritonitis, 86.5% (32/37) for internal genital infection, 8/9 for pelvic peritonitis, 2/4 for corneal ulcer, orbital infection and panophthalmitis, 1/2 for otitis media, 4/4 for sinustitis, 93.3% (14/15) for osteitis of jaw and cellulitis of mouth floor. The efficacy rate in the poor responders to the pretreatment by other antibiotics was 86.4% (70/81). 3. 300 strains of causative organisms were isolated from 170 cases which contained polymicrobial infections. The elimination rate of causative organisms was 85.3% (256/300 strains), in terms of bacteriological efficacy. 4. Side effects were noted in 11 of 252 cases (4.4%) with 11 events. The signs and symptoms were the skin symptoms (5 cases), gastro-intestinal symptoms (3 cases), interstitial pneumonia (2 cases), and feeling bad (1 case), all of which disappeared during treatment or after the discontinuation of treatment. The abnormal laboratory findings were observed in 31 of 251 cases (12.4%) with 50 events, and major ones were an increase in eosinophils, and elevations of AST, ALT, gamma-GTP and Al-p. 5. The concentrations of BIPM in body fluid and tissues were determined in 46 cases (212 samples) most of which were administered 300 mg of BIPM by intravenous drip infusion for 60 minutes. The concentrations in the sputum within 6 hours after administration were 0.1-2.5 micrograms/g. The maximum concentrations in body fluid and tissues were 0.2-1.8 micrograms/g or ml in the bile, middle ear mucosa, tonsillar tissue, aqueous humor and bone tissues and were 2.0-5.7 micrograms/g or ml in the gallbladder, maxillary sinus mucous membrane, ethmoidal sinus mucous membrane, oral tissues, skin, woman genitals, synovia, joint tissue, and the eschar. The concentrations in the uterine arterial plasma and retroperitoneal fluid were almost similar to those in the cubitl vein plasma. From the above-mentioned results of clinical efficacy, bacteriological efficacy, and safety, injectable BIPM was confirmed to be useful in the treatment of moderate, severe and/or refractory infections in various fields.

Adult↗
PubMed1998

Characterization of the phosphoproteins and protein kinase activity in mTOR immunoprecipitates.

The mammalian target of rapamycin, mTOR, has been shown to be an upstream regulator of translational effectors. In the present study, in order to detect potential molecules involved in the mTOR signaling, an in vitro phosphorylation assay using mTOR immunoprecipitates from HEK293 cells was carried out. In addition to the autophosphorylation of mTOR, 32P incorporation into 80-kDa (pp80) and 175-kDa (pp175) bands was observed in mTOR immunoprecipitates. The protein kinase activity toward the recombinant eIF-4E binding protein 1 (4E-BP1) was also detected as previously described. When mTOR immunoprecipitates from HEK293 cells were prepared in the presence of a detergent, Nonidet P-40, the 4E-BP1 kinase activity and 32P incorporation into pp175 dramatically diminished, while the phosphorylation of mTOR and 32P incorporation into pp80 did not change. These results raised a possibility that mTOR may associate with protein cofactors, some of which may be involved in the regulation of kinase activities associated with mTOR.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Molecular cloning and characterization of a novel p70 S6 kinase, p70 S6 kinase beta containing a proline-rich region.

A novel ribosomal S6 kinase, termed p70 S6 kinase beta (p70beta), which has a highly conserved amino acid sequence compared with that of p70/p85 S6 kinase (p70alpha) within the catalytic, kinase extension, and autoinhibitory pseudosubstrate domains, was identified. However, the amino acid sequence of p70beta differs from that of p70alpha in the noncatalytic amino-terminal region and in the carboxyl-terminal tail, which contains a proline-rich region. The majority of the regulatory phosphorylation sites identified in p70alpha are conserved in p70beta. Two isoforms of p70beta, referred to as beta1 (495 amino acids) and beta2 (482 amino acids), could be expressed from the single gene either by alternative mRNA splicing or by the use of alternative start codons. Here we report the characterization of p70beta2. Similarly to p70alpha, the catalytic activity of p70beta toward ribosomal protein S6 could be rapidly activated by serum, insulin, and phorbol ester in transiently transfected cells. The p70beta kinase was found to be significantly less sensitive to wortmannin and rapamycin than p70alpha. These results indicate that p70beta has the potential to participate in the regulation of protein synthesis and the cell cycle.

Amino Acid Sequence↗
PubMed1998

Effect of selective inhibition of cyclooxygenase 2 on temporary focal cerebral ischemia in rats.

Cyclooxygenase 2 (COX2) is the inducible isoform of COX but its involvement in ischemic neuronal injury is unclear. The effect of selective inhibition of COX2 was evaluated by intraperitoneal administration of NS-398, a selective COX2 inhibitor, before and after 2 h of temporary focal ischemia in rats. After 4 h of reperfusion, the infarct volume and the hemispheric concentration of prostaglandin E2 (PGE2), a major substance produced by COX2, were assessed. The infarct volume was unchanged by NS-398 administration. There was no difference in PGE2 levels between the ischemic and the contralateral hemispheres in the control group. However, PGE2 concentration significantly decreased in the ischemic hemisphere in the NS-398 group. The results are consistent with the previous observation that COX2 is induced in peri-ischemic areas and suggests that COX2 has a significant role in peri-ischemic pathophysiology.

Animals↗
PubMed1998

Regulation of protein phosphatase 2A catalytic activity by alpha4 protein and its yeast homolog Tap42.

Recent studies have revealed that the alpha4 protein, a mammalian homolog of yeast Tap42, is associated with the protein phosphatase 2A catalytic subunit (PP2A-C), however, effects of the association of alpha4 with PP2A-C on its phosphatase activity have not been examined, especially using physiologically relevant substrates in the signaling pathway of mTOR (the mammalian target of rapamycin) protein. Here, we report how this association affects the enzymatic activity of PP2A-C using the recombinant eIF-4E binding protein (4E-BP1) phosphorylated by immunoprecipitated mTOR as a substrate. PP2A-C dephosphorylated 4E-BP1 in vitro. The association of alpha4 and Tap42 with PP2A-C inhibited the phosphatase activity toward 4E-BP1. Rapamycin treatment, however, neither induced restoration of the phosphatase activity of PP2A-C nor caused dissociation of alpha4 and Tap42 from PP2A-C. Our study is the first report to reveal a potential regulatory role of alpha4 and Tap42 to inibit the phosphatase activity of PP2A-C toward the physiologically relevant substrate in the mTOR signaling.

Adaptor Proteins, Signal Transducing↗
PubMed1998

12-Hydroxyeicosatetraenoic acid directly potentiates angiotensin II-induced vascular contraction.

We studied whether 12-hydroxyeicosatetraenoic acid (HETE) affected the angiotensin II-induced contractile response in isolated hamster aorta. After preincubation with 10 nM 12-HETE for 1, 3, 5, 10 and 30 min, the angiotensin II-induced contractions were increased to 101%, 109%, 114%, 109% and 98%, respectively. The optimum preincubation time for the maximum effect of 12-HETE was 5 min. Under these conditions, 12-HETE increased dose dependently the contraction induced by 10 nM angiotensin II, and the concentration needed for the maximum effect was 30 nM, which increased contraction to 118% compared to the control angiotensin II-induced contraction. We demonstrated clearly that 12-HETE directly potentiates the angiotensin II-induced contraction.

Angiotensin II↗
PubMed1998

Determination of montelukast sodium in human plasma by column-switching high-performance liquid chromatography with fluorescence detection.

MK-0476 (montelukast sodium) is a potent and selective cysteinyl leukotriene receptor antagonist that is being investigated in the treatment of asthma. A simple and sensitive method for the determination of MK-0476 in human plasma was developed using column-switching high-performance liquid chromatography (HPLC) with fluorescence detection. A plasma sample was injected directly onto the HPLC system consisting of a pre-column (Capcell pak MF) and an analytical column (Capcell pak C18) which were connected with a six-port switching valve. The column eluate was monitored with a fluorescence detector (excitation at 350 nm; emission at 400 nm). The calibration curve was linear in a concentration range of 1-500 ng ml(-1) for MK-0476 in human plasma. The intra-day coefficients of variation of all concentrations within the range was less than 9.2%, and the intra-day accuracy values were between 97.2 and 114.6%. This method was used to measure the plasma concentration of MK-0476 following oral administration of the drug in humans.

Acetates↗
PubMed1998

Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism.

The present study identifies the operation of a signal tranduction pathway in mammalian cells that provides a checkpoint control, linking amino acid sufficiency to the control of peptide chain initiation. Withdrawal of amino acids from the nutrient medium of CHO-IR cells results in a rapid deactivation of p70 S6 kinase and dephosphorylation of eIF-4E BP1, which become unresponsive to all agonists. Readdition of the amino acid mixture quickly restores the phosphorylation and responsiveness of p70 and eIF-4E BP1 to insulin. Increasing the ambient amino acids to twice that usually employed increases basal p70 activity to the maximal level otherwise attained in the presence of insulin and abrogates further stimulation by insulin. Withdrawal of most individual amino acids also inhibits p70, although with differing potency. Amino acid withdrawal from CHO-IR cells does not significantly alter insulin stimulation of tyrosine phosphorylation, phosphotyrosine-associated phosphatidylinositol 3-kinase activity, c-Akt/protein kinase B activity, or mitogen-activated protein kinase activity. The selective inhibition of p70 and eIF-4E BP1 phosphorylation by amino acid withdrawal resembles the response to rapamycin, which prevents p70 reactivation by amino acids, indicating that mTOR is required for the response to amino acids. A p70 deletion mutant, p70Delta2-46/DeltaCT104, that is resistant to inhibition by rapamycin (but sensitive to wortmannin) is also resistant to inhibition by amino acid withdrawal, indicating that amino acid sufficiency and mTOR signal to p70 through a common effector, which could be mTOR itself, or an mTOR-controlled downstream element, such as a protein phosphatase.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Stimulatory effect of lymphocyte-derived factor on catecholamine efflux from cultured bovine adrenal medullary cells.

The effects of lymphocytes and their conditioned medium on catecholamine efflux and uptake were examined in cultured bovine adrenal medullary cells. Co-culture of adrenal medullary cells with lymphocytes for 3 days caused an increase in appearance of catecholamines in the culture medium. Treatment of adrenal medullary cells with a conditioned medium prepared from lymphocytes also enhanced the appearance of catecholamines in culture medium in time- (8-48 h) and concentration-dependent manners. Heat treatment of the conditioned medium at 60 and 100 degrees C for 10 min reduced its stimulatory effect to 59 and 20% of control, respectively. After gel filtration on a Sephadex G-25 column or dialysis (<8 kDa molecular mass cutoff), the stimulatory activity of the conditioned medium was found in a high molecular fraction. The conditioned medium had little effect on the activity of lactate dehydrogenase in the medium of cultured adrenal medullary cells and on desipramine-sensitive [3H]norepinephrine uptake by the cells. These findings suggest that lymphocytes release a heat-sensitive factor(s) (molecular mass of more than 8 kDa) which increases efflux of catecholamines from cultured adrenal medullary cells.

Adrenal Medulla↗
PubMed1998

Susceptibility of Opioid Peptides and Myofibrillar Proteins to Carp Cathepsin L.

The ability of carp cathepsin L to degrade opioid peptides and separate myofibrillar proteins was examined. The enzyme differentially released fragments from leucine-enkephalin, alpha-neoendorphin, and dynorphin, in which the common cleavage site of the enzyme was determined to be a Gly2-Gly3 bond. A Leu5-Arg6 bond in alpha-neoendorphin and dynorphin was also commonly cleaved by the enzyme. At a protein ratio of the enzyme to myofibrillar protein of 1:500, the preferences of the enzyme appeared to be myosin > tropomyosin > troponins T, I, and C > actin > alpha-actinin. Myosin heavy chain was completely degraded into some fragments by the enzyme within 30 min, and all of them underwent further degradation during subsequent incubation. Although troponins and tropomyosin were also completely degraded by the enzyme within 24 h, a small amount of actin and a large amount of alpha-actinin remained undegraded.

Journal Article↗
PubMed1998

Novel guide catheter for left coronary intervention via a right upper limb approach.

We designed a novel guide catheter specifically for interventions to the left coronary artery via a right upper limb approach. The catheter has a novel first loop design which utilizes the angle between the right subclavian and innominate arteries for support. The first loop introduces the catheter into the correct position and generates powerful and coaxial back-up power. We report successful implantation of Palmaz-Schatz stents in five cases using this 6 Fr. catheter.

Aged↗
PubMed1998

Effects of cilostazol on late lumen loss after Palmaz-Schatz stent implantation.

Cilostazol inhibits intimal hyperplasia after stent implantation into canine iliac arteries. To determine the antiproliferative effect of this agent, cilostazol or aspirin was randomly given for 6 mo to 36 patients treated with Palmaz-Schatz stent implantation. Initial success was obtained in 34 patients. Repeat angiography was performed in 33 patients, and the complete angiographic data were obtained in 22 lesions of the cilostazol group and in 21 lesions of the aspirin group. The reference diameter and minimal luminal diameter were similar in both groups before and immediately after stent implantation. At follow-up, minimal luminal diameters were significantly greater in the cilostazol group than in the aspirin group (P < 0.001). Late loss and loss index were significantly smaller in the cilostazol group than in the aspirin group (P < 0.001). These results suggest that cilostazol reduces angiographic late lumen loss and thereby may reduce the incidence of restenosis after Palmaz-Schatz stent implantation.

Aged↗
PubMed1998

Neoadjuvant chemotherapy with mitomycin C, etoposide, and cisplatin for adenocarcinoma of the cervix.

Between May 1990 and February 1995, 16 patients with adenocarcinoma or adenosquamous carcinoma of the uterine cervix were prescribed neoadjuvant chemotherapy consisting of cisplatin (50 mg/m2) on day 1, mitomycin C (10 mg/m2) on day 1, and etoposide (100 mg/m2) on days 1, 3, and 5 (MEP). In 2 patients stage was IB1, 5 were in stage IB2, 1 was in stage IIA, 5 were in stage IIB, 2 were in stage IIIB, and one was in stage IVB. A median of three courses of chemotherapy was given (range two to five). Of the 16 patients, 3 had a complete response and 5 had a partial response (response rate, 50%). Following termination of this chemotherapy, 12 patients with stage I or stage II carcinoma underwent radical hysterectomy. Three were given adjuvant radiotherapy because of positive pelvic nodes. One stage IIB patient, 1 stage IIIB patient and 1 stage IVB patient underwent standard radiotherapy and 1 stage IIIB patient underwent chemotherapy with another regimen because MEP therapy was without effect. Histopathological examinations revealed that changes as a result of the chemotherapy correlated well with clinical responses. Moderate or marked pathological changes occurred in 3 with a clinically complete response. The mean survival period of responders was 47.5 months while that of nonresponders was 28.3 months. Side effects of chemotherapy with MEP were within acceptable limits. The dose-limiting toxicity was myelosuppression and for only 1 patient the dose was reduced because of thrombocytopenia. Our preliminary study indicates that this chemotherapy regimen is effective for subjects with adenocarcinoma of the cervix. A prospective cooperative group trial on this regimen is ongoing.

Adenocarcinoma↗