Biomedical subjects
T Tashiro
Publications and source records attributed to T Tashiro.
[Acquisition of resistance associated with impairment of metabolic activation of anticancer drugs].
Some of anticancer drugs must undergo bioactivation in order to exert their anticancer activity. Those include most of antimetabolites, mitomycin C, cyclophosphamide and a camptothecin analog CPT-11. The latter two drugs are usually activated in liver or plasma, and the others are converted to active metabolites in the target cells. A number of biochemical mechanisms of resistance have been proposed and for the drugs to be activated in cancer cells impairment of activation enzymes were reported as one of the mechanisms; for example, deoxycytidine kinase for cytarabine and gemcitabine, orotate phosphoribosyl transferase for 5-fluorouracil, hypoxanthine-guanine phosphoribosyl transferase for 6-mercaptopurine, folylpolyglutamate synthetase for methotrexate and DT-diaphorase for mitomycin C were concerned.
[Inoperable esophageal carcinoma managed by combined chemotherapy (CBDCA, 5-FU and VDS) and radiotherapy].
Eleven inoperable patients with advanced esophageal carcinoma were treated with chemotherapy (carboplatin, 5-FU, vindesine) and concomitant radiotherapy. Two patients (T2) received this treatment due to their poor general condition and refusal of operation, and 9 patients for infiltration of tumor into the adjacent organs (T4). Administration of carboplatin (30 mg/body) and 5-FU (250 mg/body) together with radiotherapy (1.8 Gy/d) for 5 days a week was performed. This chemoradiation therapy was carried out for 5 consecutive weeks. In addition, vindesine (1-3 mg/body) was administered in the 1st and 4th week. After evaluation, endoscopic balloon dilatation was performed in 6 patients with stenosis of the esophagus. The general response rate was 80%. CR was noted in 2 patients of T2 but 1 patient of T4 developed severe leucopenia and immunosuppression, and died of septic MOF. All but the MOF case could take enough food orally following the endoscopic dilatation. The 1-year survival rate in the T4 group (45%) was significantly better than the non-treatment group (0%). In conclusion, this treatment is beneficial for patients with inoperable esophageal carcinoma to obtain a satisfactory QOL and survival rate.
[Postgadolinium MR angiography of normal intradural veins of the thoracolumbar spine].
To evaluate the normal intradural spinal veins, we used postgadolinium three-dimensional time-of-flight MR angiography (MRA) at 1.5T in 7 subjects. MR images and MR angiograms[32/6/1 (TR/TE/NEX)] were obtained after a bolus injection of Gd-DTPA (0.15-0.2 mmol/kg). We reconstructed images using an equipped function, so-called multiplanar reconstruction. The anterior median veins in 2 patients and the posterior median veins were shown in 2. The great medullary veins were demonstrated in 2. We successed in obtaining venous angiograms by postgadolinium MRA. Disseminated tumors and abnormal enhanced cauda equina are often indistinguishable from normal intradural veins. This study suggests that it is useful to know the MR angiographic features of normal intradural veins in order to evaluate enhanced intradural components.
[Coronary artery bypass surgery in patients older than 70 years of age].
From April 1994 to November 1996, coronary artery bypass grafting (CABG) was performed on 166 patients. Fifty-seven patients were older than 70 years of age (Group A), while 109 were younger than 70 years of age (Group B). In group A, such symptoms as severe stenosis of the left main coronary artery, a history of systemic hypertension, calcification of the ascending aorta, and postoperative respiratory complications with pneumonia were all significantly higher than in Group B. Regarding hospital mortality, the difference between the two groups was not significant. Based on these findings, the use of intensive respiratory care for elderly patients over than 70 years of age is thus considered to help reduce the occurrence of such complications.
[Analysis of chronic respiratory tract infection by using an intubation model--evaluation based on fluctuations in cytokine content].
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Reduced microtubule-nucleation activity of tau after dephosphorylation.
Based on video-enhanced differential interference contrast (DIC) microscopy, we developed a small-scale method which is capable of measuring both the lengths and the number densities of microtubules (MTs) assembled in vitro. With this method, effect of dephosphorylation on the activity of bovine brain tau protein to promote the assembly of tubulin at physiological concentration (15 microM) was quantitatively analyzed. The MT number density was selectively reduced when tau isolated directly in the presence of phosphatase inhibitors (N-tau) was dephosphorylated in vitro (DP-tau), without significant changes in the mean MT length or the binding affinity toward preformed MTs. Tau obtained from brain MTs (MT-tau) also exhibited lower nucleation activity in spite of its high MT-binding affinity. The results indicate that nucleation, elongation and MT-binding are distinct aspects of tau function which are differentially affected by the phosphorylation state of tau.
Coronary artery bypass grafting without cardiopulmonary bypass for high-risk patients.
Between January 1991 and June 1993, coronary artery bypass grafting was performed without either cardiopulmonary bypass or cardiac arrest in 23 patients. Most patients had several surgical risk factors, including age > or = 70 years, poor left ventricular function, left main coronary artery stenosis, chronic renal failure, and aortic aneurysm. Distal anastomoses were made under temporary interruption of coronary flow. A total of 37 distal anastomoses to the left anterior descending coronary artery and/or right coronary artery (mean 1.6 per patient) were made, 24 of which were internal thoracic arteries. The coronary occlusion time ranged from 7-14 min (mean 9.8 min). Combined cardiac or vascular operations were carried out in six patients (abdominal aortic aneurysm repair, thoracic aortic aneurysm repair, carotid endarterectomy, and coronary endarterectomy). There was one hospital death. Postoperative angiography was performed in 22 patients and showed a patency rate of 89%. In summary, coronary artery bypass grafting without cardiopulmonary bypass may improve the postoperative outcome of high-risk patients.
Increased contribution by myofibrillar protein to whole-body protein breakdown according to severity of surgical stress.
A study was conducted to clarify the contribution by myofibrillar protein to whole-body protein breakdown in surgically stressed patients. Thirteen patients who underwent esophagectomy (group E) and 22 who underwent gastric or colorectal operation (group GC) were studied. Patients were all male and younger than 65 y old. Whole-body protein breakdown was determined using constant infusion of 15N-glycine. Urinary excretion of total catecholamines and 3-methylhistidine (3-MH) were measured. Amino acid composition of femoral arterial and venous blood was also analyzed. All the patients were fed exclusively by total parenteral nutrition providing 1.5 g protein and 40 kcal.kg-1.d-1 throughout the study. Whole-body protein breakdown increased significantly in group E (P < 0.01) and group GC (P < 0.05) on the 3rd postoperative day. The increase was significantly greater in group E than group GC (P < 0.01). Urinary excretion of 3-MH also increased significantly in group E (P < 0.01) and in group GC (P < 0.01) on the 3rd postoperative day. The increase was also greater in group E than group GC (P < 0.01). The ratio of urinary 3-MH excretion to whole-body breakdown protein (mumol/g), which is a indicator for the contribution of myofibrillar protein to the whole-body protein breakdown, increased significantly from 0.84 +/- 0.30 of preoperative value to 1.79 +/- 0.38 in group E (mean +/- SD; P < 0.01) and 1.42 +/- 0.18 in group GC (P < 0.05) on the 3rd postoperative day. This ratio was significantly higher in group E (P < 0.05). Furthermore, the ratio of myofibrillar to whole-body protein breakdown correlated significantly with urinary excretion of total catecholamines (r = 0.546; P < 0.01). Therefore, the contribution of myofibrillar protein to whole-body protein breakdown increased proportionately with the severity of surgical stress. On the other hand, femoral-arteriovenous differences of BCAA, Ala, Gln, Tyr, and Phe correlated significantly with the urinary excretion of 3-MH. These data suggest that skeletal muscle protein degradation is proportional to the breakdown of total myofibrillar proteins and both correlate with the severity of stress. From these data, it may be suggested that the contribution of skeletal muscle to whole-body protein catabolism is increased postoperatively, and that the increase is correlated with the severity of surgical stress.
Differential axonal transport of soluble and insoluble tau in the rat sciatic nerve.
Axonal transport of microtubule-associated protein tau was studied in the motor fibers of the rat sciatic nerve 1-4 weeks after labeling of the spinal cord with [35S]methionine. As 60-70% of low molecular weight tau in this system was found to be insoluble in 1% Triton-containing buffer, labeled proteins in 6-mm consecutive nerve segments were first separated into Triton-soluble and insoluble fractions. Two-dimensional gel electrophoresis and immunoblotting with anti-tau antibody confirmed the presence of tau among labeled, transported proteins in both fractions. Isoform composition of labeled tau was similar to that of bulk axonal tau, the most acidic species with apparent molecular mass of 66 kDa being the major component. Transport profiles obtained by measuring radioactivities associated with this major isoform showed that soluble and insoluble tau were transported at different rates. Insoluble tau, which contained the majority of tau-associated radioactivity, was transported at 1.7 mm/day in slow component a (SCa), whereas soluble tau was transported faster, at 3 mm/day, corresponding to the rate of slow component b (SCb). Cotransport of insoluble tau with insoluble tubulin in SCa suggests its association with stable microtubules.
An orally active antitumor cyclohexanediamine-Pt(IV) complex: trans,cis,cis-bis(n-valerato)(oxalato)(1R,2R-cyclohexane diamine)Pt(IV).
In order to develop orally active antitumor platinum complexes, several cyclohexanediamine-Pt(IV) complexes of a general formula trans,cis,cis-[Pt(IV) (OCOCnHn+1)2 (oxalato)(1R,2R-cyclohexanediamine)] were synthesized by derivatizing oxaliplatin [Pt(II)(oxalato)(1R,2R-cyclohexanediamine), I-OHP], which is a potent antitumor cyclohexanediamine-Pt(II) complex we have prepared and now undergoing clinical trials. The I-OHP derivatives were found to be stable, lipophilic and reduced to yield I-OHP, an active species, quantitatively by ascorbate in vitro. All the derivatives were antitumor active against mouse lymphocytic leukemia L1210 when given i.p. In particular, trans-bis-valerato-oxalato-1R,2R-dach-Pt(IV), C5-OHP, showed markedly high activity. C5-OHP also exhibited significant antitumor activity against L1210 when orally administered. C5-OHP was considered to be a suitable candidate for the oral cancer chemotherapy agent to be developed.
[Invasive pulmonary aspergillosis caused by aspiration of polluted water after nearly drowning].
A 21-year-old male nearly drowned in a reservoir by a traffic accident and he aspirated a large mount of polluted water containing Aspergillus fumigatus. On admission to our hospital, he was alert but cyanotic. Chest rentogenograms showed scatter infiltrative shadows in bilateral lung fields. We administered methylpredonizolon and antimicrobial agents immediately because of respiratory failure which was rapidly progressing. During the following six days, infiltrative shadows diminished but multiple nodular shadows in both lung fields appeared. The diagnosis of pulmonary aspergillosis was confirmed by serological and microbiological studies. Intravenous amphotericin B and oral itraconazol were administrated, and clinical improvement was observed.
[Prevention of infections in a case with myelodysplastic syndrome by an intermittent subcutaneous administration of G-CSF].
An 83-year-old male was admitted to our hospital because of pancytopenia and low grade fever on April 19, 1993. On admission, hematological data were as follows: WBC 1,000/microliters with 19% neutrophils, RBC 367 x 10(4)/microliters, Hb 9.5 g/dl and platelets 6.7 x 10(4)/microliters. Bone marrow examination revealed 6.6% myeloblasts and 33.5% erythroblasts. Morphological abnormalities included hypersegmentation, degranulation and pseudo-Pelger's nuclear anomaly in neutrophils. Based on these findings the diagnosis of refractory anemia with excess of blasts (RAEB) of the myelodysplastic syndrome (MDS) was made and therapy with low dose Cytarabine (Ara-C) was initiated in April 1993. The patient had two episodes of severe pneumonia in June and July. Therefore, 75 micrograms/day of G-CSF was given in addition to antibiotic therapy for the second episode of infection in July. Thereafter the severe infection subsided, and G-CSF administration was switched to an intermittent schedule (75 micrograms twice a week) since September. Cytarabine ocfosfate (100 mg/day) was added for 10-14 days at interval 1-2 months from October,1993. He has been well with no episode of infection for more than two year. One major concern regarding the clinical application of G-CSF in MDS patients is related to the possible stimulation of leukemic cell proliferation. Frequent hematological monitoring is necessary in patients with RAEB who are prone to develop acute myeloid leukemia. However, we administered G-CSF at a relatively low dose twice a week for over two year and could successfully prevent infections without inducing the leukemic changes.
[Two cases of pulmonary dirofilariasis in Nagasaki Prefecture].
We reported two cases of pulmonary dirofilariasis in Nagasaki Prefecture. Each case was admitted to our hospitals for evaluation of an abnormal shadow on chest X-ray film taken for examination. We strongly suspected lung cancer before operation. It was resected in order to confirm the pathological diagnosis. There was a Dirofilaria immitis in the vessels surrounded by the necrotic tissues. The case of pulmonary dirofilariasis tends to increase in Japan, but the positive rate of dogs with Dirofilaria immitis tends to decrease, because of decreasing breeding places of mosquitoes by the spread of the public sewage system in Nagasaki City.
Relationship between rifampin MICs for and rpoB mutations of Mycobacterium tuberculosis strains isolated in Japan.
We analyzed the relationship between rifampin MICs and rpoB mutations of 40 clinical isolates of Mycobacterium tuberculosis. A point mutation in either codon 516, 526, or 531 was found in 13 strains requiring MICs of > or = 64 micrograms/ml, while 21 strains requiring MICs of < or = 1 microgram/ml showed no alteration in these codons. However, 3 of these 21 strains contained a point mutation in either codon 515 or 533. Of the other six strains requiring MICs between 2 and 32 micrograms/ml, three contained a point mutation in codon 516 or 526, while no alteration was detected in the other three. Our results indicate that the sequencing analysis of a 69-bp fragment in the rpoB gene is useful in predicting rifampin-resistant phenotypes.
Detection of Cryptococcus neoformans gene in patients with pulmonary cryptococcosis.
Pulmonary cryptococcosis was diagnosed by nested PCR. Extraction of DNA was performed by mechanical destruction of the capsules of Cryptococcus neoformans by the glass bead technique. Nested PCR was positive for 4 of 5 culture-positive specimens but negative for 1 culture-positive specimen, 10 culture-negative specimens, and 1 specimen with undetermined culture results.
New drug susceptibility test for Mycobacterium tuberculosis using the hybridization protection assay.
We developed a novel method for early detection of drug-resistant strains of Mycobacterium tuberculosis by using the hybridization protection assay (HPA). The number of viable bacteria during the incubation period correlated well with the number of relative light units measured by the HPA. In addition, the relative light unit values of susceptible strains on the first, third and fifth days of incubation were significantly different from those of resistant strains for both isoniazid and rifampin. Our results suggest that after isolation of the organism from clinical specimens, drug-resistant strains of M. tuberculosis are accurately detected by the HPA even after 1 day of incubation with the drug.
Enolase antigen, mannan antigen, Cand-Tec antigen, and beta-glucan in patients with candidemia.
We compared the specificities and sensitivities of four tests used for the serodiagnosis of candidemia in 39 patients with candidemia, including 10 patients with superficial Candida colonization, 10 patients with deep mycosis, and 20 healthy subjects. The results obtained by the dot immunoblotting assay for detecting the enolase antigen (48 kDa) were compared with those of assays for detecting mannan antigen, heat-labile antigen (a threshold titer of four times), and beta-glucan (> or = 60 pg/ml). Enolase antigen was detected in 28 (71.8%) patients with candidemia, while 30 (76.9%), 10 (25.6%), and 27 (84.4%) patients were positive for the heat-labile antigen by the Cand-Tec assay, the mannan antigen by the Pastorex Candida assay, and beta-glucan by the limulus test, respectively. Ten patients with superficial Candida colonization, 5 patients with invasive pulmonary aspergillosis, 5 patients with cryptococcosis, and 20 healthy subjects were negative for both enolase antigen and mannan antigen. Two patients with superficial Candida colonization, one patient with invasive pulmonary aspergillosis, and two patients with cryptococcosis were positive by the Cand-Tec assay. The beta-glucan concentration was more than 60 pg/ml in all patients with invasive pulmonary aspergillosis; however, it was less than 10 pg/ml in all patients with cryptococcosis. The specificity of enolase antigen in the serodiagnosis of candidemia was 100%, but the sensitivity was 71.8%. The specificity and sensitivity of Cand-Tec, the assay for mannan antigen, and the assay for beta-glucan were 76.9 and 87.5%, 25.6 and 100%, and 84.4 and 87.5%, respectively. Our results demonstrated that antigen detection tests are useful for the diagnosis of candidemia; however, none is satisfactory for the serodiagnosis of candidemia. We suggest that a combination of two assays may increase the accuracy of diagnosis of candidiasis.