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Biomedical subjects

M Takada

Publications and source records attributed to M Takada.

At least 19 recordsLinked to original sources

Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates.

Recombinant adeno-associated viral (rAAV) vector-mediated overexpression of alpha-synuclein (alphaSyn) protein has been shown to cause neurodegeneration of the nigrostriatal dopaminergic pathway in rodents and primates. Using serotype-2 rAAV vectors, we recently reported the protective effect of Parkin on alphaSyn-induced nigral dopaminergic neurodegeneration in a rat model. Here we investigated the neuronal specificity of alphaSyn toxicity and the effect of Parkin co-expression in a primate model. We used another serotype (type-1) of AAV vector that was confirmed to deliver genes of interest anterogradely and retrogradely to neurons in rats. The serotype-1 rAAV (rAAV1) carrying alphaSyn cDNA (rAAV1-alphaSyn), and a cocktail of rAAV1-alphaSyn and rAAV1 carrying parkin cDNA (rAAV1-parkin) were unilaterally injected into the striatum of macaque monkeys, resulting in protein expression in striatonigral GABAergic and nigrostriatal dopaminergic neurons. Injection of rAAV1-alphaSyn alone decreased tyrosine hydroxylase immunoreactivity in the striatum compared with the contralateral side injected with a cocktail of rAAV1-alphaSyn and rAAV1-parkin. Immunostaining of striatonigral GABAergic neurons was similar on both sides. Overexpression of Parkin in GABAergic neurons was associated with less accumulation of alphaSyn protein and/or phosphorylation at Ser129 residue. Our results suggest that the toxicity of accumulated alphaSyn is not induced in non-dopaminergic neurons and that the alphaSyn-ablating effect of Parkin is exerted in virtually all neurons in primates.

Animals↗

Study of an improved Allyl Di-Glycol carbonate sheet for high energy proton detection.

An allyl di-glycol carbonate (ADC) sheet which has been utilised as a neutron detector for personal dosimetry has recently been studied for its application as a device for radiation exposure control for astronauts in space, where protons are the dominant radiation. It is known that the fabrication process, modified by adding some kind of antioxidant to improve the sensitivity of ADC to high energy protons, causes a substantial increase in false tracks, which disturb the automatic counting of proton tracks using the auto-image analyser. This made clear the difficulty of fabricating ADC sheets which have sufficient sensitivity to high energy protons, while maintaining a good surface. In this study, we have tried to modify the fabrication process to improve the sensitivity to high energy protons without causing a deterioration of the surface condition of ADC sheets. We have successfully created fairly good products.

Carbonates↗

Serum amiodarone and desethylamiodarone concentrations following nasogastric versus oral administration.

OBJECTIVE: Hospitalized patients unable to ingest anything by mouth require nutritional support by enteral feeding and administration of drugs through a nasogastric tube inserted into the digestive tract. Nasogastric administration of amiodarone may not always be equivalent to oral administration of amiodarone. METHODS: We collected 162 observations of serum amiodarone and desethylamiodarone metabolite concentrations from 93 patients within 60 days of starting treatment with amiodarone. Eight patients were given the drug nasogastrically and 85 patients, orally. The two groups, were compared in terms of their serum concentration/(dose/weight) (C/D) value. A ratio of serum amiodarone concentration to serum desethylamiodarone concentration (AMD/DEA) was calculated for each sample. In addition, the percentage drug recovery after nasogastric administration of amiodarone was analysed. RESULTS: Significant differences were observed in C/D values of amiodarone and desethylamiodarone and in AMD/DEA values of patients given amiodarone orally when compared with those given the drug nasogastrically. The C/D values of patients who received their medication nasogastrically were approximately 30% of the C/D values of patients who received their medication orally. Approximately 70% of the drug was recovered after it had passed through the nasogastric tube. CONCLUSIONS: To achieve similar concentrations, an approximately 3-fold increase in dosage of amiodarone was required when patients were given the drug nasogastrically rather than orally. This suggests that the absorption of amiodarone following nasogastric administration is poor when compared with oral administration. Therapeutic drug monitoring is necessary to optimize dose particularly during the early stages of amiodarone therapy.

Administration, Oral↗

Carvedilol accelerate elevation of serum potassium in chronic heart failure patients administered spironolactone plus furosemide and either enalapril maleate or candesartan cilexetil.

OBJECTIVE: To retrospectively investigate the effect of carvedilol and spironolactone plus furosemide, administered concomitantly with an angiotensin II converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) to patients with chronic heart failure (CHF). METHODS: Patients with CHF, who visited Departments of Cardiovascular Internal Medicine at the National Hospital Organization Osaka Medical Center, were enrolled for this study. Serum potassium, blood urea nitrogen (BUN), serum creatinine (Scr) and serum sodium were measured in every patient at the time of start of treatment and after 3 and 12 months of treatment. Data from patients in groups A (20 mg/day carvedilol + 25 mg/day spironolactone + 40 mg/day furosemide + an ACE-I) and B (20 mg/day carvedilol + 25 mg/day spironolactone + 40 mg/day furosemide + ARB) were compared. RESULTS: When 20 mg/day carvedilol plus 25 mg/day spironolactone plus 5 mg/day enalapril maleate (enalapril, group A) or 8 mg/day candesartan cilexetil (candesartan, group B) plus 40 mg/day furosemide were used concomitantly, the mean serum potassium increased significantly in both groups of patients. Seven of 59 (11.9%) patients had hyperkalemia (>5.5 mEq/L) during 12 months of treatment whereas 8.5% of patients (five of 59) had hypokalemia (< or =3.5 mEq/L). CONCLUSION: When carvedilol is used concomitantly with spironolactone, furosemide and enalapril or candesartan, it is necessary to monitor serum potassium concentration, even if spironolactone is administered at a low dose of 25 mg/day.

Adult↗

Cutaneous plasmacytoma in three golden hamsters (Mesocrietus auratus).

Spontaneously occurring cutaneous tumours in three golden hamsters were characterized using histological, immunohistochemical and ultrastructural methods. Histologically, the tumours were composed of sheets of round to oval plasmacytoid cells with eccentrically placed nuclei. Tissue sections were weakly positive for anti-B lymphocyte antigen (BLA) staining. Ultrastructurally, large amounts of rough endoplasmic reticulum in the cytoplasm were observed. BLA positivity and characteristics of ultrastructure showed the plasma cell origin.

Animals↗

Differential absorbed dose distributions in lineal energy for neutrons and gamma rays at the mono-energetic neutron calibration facility.

Absorbed dose distributions in lineal energy for neutrons and gamma rays of mono-energetic neutron sources from 140 keV to 15 MeV were measured in the Fast Neutron Laboratory at Tohoku University. By using both a tissue-equivalent plastic walled counter and a graphite-walled low-pressure proportional counter, absorbed dose distributions in lineal energy for neutrons were obtained separately from those for gamma rays. This method needs no knowledge of energy spectra and dose distributions for gamma rays. The gamma-ray contribution in this neutron calibration field >1 MeV neutron was <3%, while for <550 keV it was >40%. The measured neutron absolute absorbed doses per unit neutron fluence agreed with the LA150 evaluated kerma factors. By using this method, absorbed dose distributions in lineal energy for neutrons and gamma rays in an unknown neutron field can be obtained separately.

Absorption↗

Irinotecan and etoposide for previously untreated extensive-disease small cell lung cancer: a phase II trial of West Japan Thoracic Oncology Group.

Irinotecan is a topoisomerase I inhibitor that is highly active against small cell lung cancer (SCLC). Etoposide is another drug that is effective for SCLC. Since combination of these two topoisomerase inhibitors revealed a synergistic effect in vitro and showed a safety in phase I study, we conducted a phase II study in patients with previously un-treated extensive disease (ED) SCLC to evaluate the efficacy and toxicity of this combination. Fifty patients with previously untreated ED-SCLC were enrolled. Irinotecan was administered intravenously at 60mg/m(2) on days 1, 8, and 15, while etoposide was given at 80mg/m(2) on days 2-4. Treatment was repeated every 4 weeks for four cycles. The overall response rate was 66.0%, with a complete response rate of 10.0%. The median survival time was 11.5 months and the 1- and 2-year survival rates were 43.2 and 14.4%, respectively. The major toxicity of this regimen was myelosuppression, including grade 3 or 4 neutropenia (62.9%), leukopenia (28.0%), and anemia (14%). The other grade 3 toxicity was diarrhea (2%). This irinotecan and etoposide regimen is active against ED-SCLC with relatively mild toxicity.

Adenocarcinoma↗

Experimental microdosimetric distributions of protons, from 19 to 65 MeV, using an A150-walled Low Pressure Proportional Counter.

Microdosimetric distributions of protons, from 19 to 65 MeV, were measured using an A150-walled Low Pressure Proportional Counter at the cyclotron facility in the National Institute of Radiological Sciences. The measured distributions were found to be very different from the spectra assumed by the Continuous Slowing Down Approximation. The measurements consisted of determining the energy deposition by direct incident protons, by secondary electrons produced in the wall of the detector and by scattered protons at the wall. The secondary electron and the scattered proton distributions were studied using analytical functions and the MCNPX Monte Carlo code, respectively.

Electrons↗

Natural killer cells in breast cancer cell growth and metastasis in SCID mice.

Natural killer (NK) cell is an important component of the innate immune system and plays a central role in host defense against tumor and virus-infected cells. This review briefly summarizes the role of murine NK cells in tumor growth and metastasis of breast cancer cells in severe combined immunodeficiency (SCID) mice. Conventional SCID and NOD-SCID strains have been used to study for xenotransplantion of human tumors. SCID mice models of cancer mimic human diseases and have provided valuable information. However, these mice strains have some residual immunity such as NK cells that somewhat limit post-transplantation growth and metastasis of human xenografts. In contrast, NOD/SCID/gammac(null) (NOG) mice without common gamma-chain inoculated with breast cancer cells were most efficient in the formation of a large tumor and metastasis. NOG mouse strain without NK activity appears to be more promising as tool for xenotransplantion of human cancer. This new xenotransplant model is relevant and can be recommended for use in clarifying the mechanism of growth of cancer cells as well as for developing new therapeutic strategies against cancer.

Animals↗

Measurements of the response functions of a large size NE213 organic liquid scintillator for neutrons up to 800 MeV.

The response functions of 25.4 cm (length) x 25.4 cm (diameter) NE213 organic liquid scintillator have been measured for neutrons in the energy range from 20 to 800 MeV at the Heavy-Ion Medical Accelerator in Chiba (HIMAC) and at the Research Center for Nuclear Physics (RCNP) of Osaka University. At HIMAC, white (continuous) energy spectrum neutrons were produced by the 400 MeV per nucleon carbon ion bombardment on a thick graphite target, whose energy spectrum has already been measured by Kurosawa et al., [Nucl. Sci. Eng. 132, 30 (1999)] and the response functions of the time-of-flight-gated monoenergetic neutrons in a wide energy range from 20 to 800 MeV were simultaneously measured. At RCNP, the quasi-monoenergetic neutrons were produced via 7Li(p,n)7Be reaction by 250 MeV proton beam bombardment on a thin 7Li target, and the TOF-gated 245 MeV peak neutrons were measured. The absolute peak neutron yield was obtained by the measurement of 478 keV gamma rays from the 7Be nuclei produced in a Li target. The measured results show that the response functions for monoenergetic neutrons < 250 MeV have a recoil proton plateau and an edge around the maximum light output, which increases with increasing incident neutron energy, on the other hand > 250 MeV, the plateau and the edge become unclear because the proton range becomes longer than the detector size and the escaping protons increase. It can be found that the efficiency of the 24.5 cm (diameter) x 25.4 cm (length) NE213 for the 250 MeV neutrons is -10 times larger than the 12.7 cm (length) x 12.7 cm (diameter) NE213, which is widely used as a neutron spectrometer.

Electrons↗

Appropriate dosing of antiarrhythmic drugs in Japan requires therapeutic drug monitoring.

OBJECTIVE: In general, drugs are used in accordance with an approved dosage regimen in expectation of an appropriate balance between efficacy and toxicity. However, dose control of drugs with a narrow therapeutic range and marked intersubject variability in pharmacokinetics should be established through individualization of dosing based on therapeutic drug monitoring (TDM). The purpose of this study was to examine differences between the approved dosage regimen and the doses of antiarrhythmic drugs and digoxin used in clinical practice and to examine the influence of TDM on dosing. METHODS: Prescription research of antiarrhythmic drugs was performed at five national hospitals in Japan. Prescriptions for antiarrhythmic drugs (cibenzoline, disopyramide, pirmenol, mexiletine, aprindine, flecainide, pilsicainide, amiodarone and digoxin) were counted for the study period. The mean dose and dose distribution of the drugs were determined in each hospital. Comparisons were made of mean dose obtained in the study with the dosage approved by the authority. In addition, the percentage of patients that received TDM was determined. RESULTS: A difference was seen between the approved dosage and the actual dose. For all drugs except flecainide, the mean dose was smaller than the approved dosage. For all drugs except digoxin, remarkable variations were seen in the dose distribution among the hospitals. Digoxin showed a similar dose distribution among the five hospitals. Overall, the percentage of patients that received TDM was low except for Hospital A. However, TDM of digoxin was relatively common at four of the hospitals. CONCLUSIONS: It is concluded that, with the exception of digoxin, the appropriate dosing regimen for antiarrhythmic drugs is not yet established. The establishment of appropriate dosing regimens for antiarrhythmic drugs requires the more widespread adoption of TDM.

Anti-Arrhythmia Agents↗

Appropriate dosing regimen of allopurinol in Japanese patients.

OBJECTIVE: Approved dosage regimens for prescription drug products are developed with a view to obtaining a favourable therapeutic index in the overall exposed population. The purpose of this study was to examine differences between the approved dosage regimen and the clinically prescribed doses of allopurinol in major hospitals in Japan. METHODS: The prescribing records for allopurinol were scrutinized at five national hospitals in Japan. Prescription information, including mean dose and the distribution of doses, was extracted for each hospital and the data compared with the dosage recommended in the approved labelling for the product. In addition, therapeutic drug monitoring (TDM) data were examined to evaluate relationships between dose administered, serum concentration of oxypurinol, and clinical efficacy. RESULTS: The mean dose of allopurinol prescribed in the five institutions, 131.7 mg/day, was lower than the approved dosage of 200-300 mg/day. There were no differences in the mean dose between the hospitals, and similar dose distributions were seen among the hospitals. Approximately 60-70% of patients were treated with 100 mg/day and 20-30% with 200 mg/day of allopurinol. The most frequent dosage of allopurinol used in clinical practice was 100 mg/day. In the TDM study, the mean trough serum concentrations of oxypurinol were 9.5+/-3.6 microg/mL (50 mg/day), 13.0+/-6.8 microg/mL (100 mg/day), 19.8+/-12.9 microg/mL (200 mg/day) and 15.7+/-7.3 microg/mL (300 mg/day). The mean values of creatinine clearance were 17.0+/-16.4 mL/min (50 mg/day), 33.5+/-32.8 mL/min (100 mg/day), 57.8+/-33.8 mL/min (200 mg/day) and 94.3+/-35.8 mL/min (300 mg/day, in patients with normal renal function), and showed a downward trend together with a reduction of dosage of allopurinol. Allopurinol was given to 91% (91/100) of patients at a daily dose of 100-200 mg, and the oxypurinol trough serum concentration attained (>4.6 microg/mL) was sufficient to maintain a therapeutic effect in 92.3% (84/91) of these patients. A daily dose of 100-200 mg may be enough to obtain therapeutic serum oxypurinol concentrations in most Japanese patients. CONCLUSIONS: Dose of 100-300 mg/day was an effective and commonly used dosing regimen for allopurinol in Japanese patients. The approved dosage range (200-300 mg/day) may be too high for patients with renal dysfunction, suggesting the recommended dosing regimen for allopurinol should be revised to include the lower doses.

Administration, Oral↗

Serum concentration of potassium in chronic heart failure patients administered spironolactone plus furosemide and either enalapril maleate, losartan potassium or candesartan cilexetil.

OBJECTIVE: To retrospectively investigate elevation of serum potassium when spironolactone (25 or 50 mg/day) and furosemide were administered concomitantly with an angiotensin II converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) to patients with chronic heart failure for 12 months and occurrence of hyperkalemia and hypokalemia because of concomitant administration of spironolactone plus an ACE-I or ARB and furosemide. METHODS: Patients with chronic heart failure, who visited departments of cardiovascular internal medicine and cardiovascular surgery at the National Hospital Organization Osaka Medical Center, were enrolled for this study. Serum potassium, blood urea nitrogen (BUN), serum creatinine, uric acid, and serum sodium were determined in every patient at the time of start of treatment and at 3 and 12 months of treatment. Data from patients in Groups A (25 mg/day spironolactone + 40 mg/day furosemide + an ACE-I or ARB) and B (50 mg/day spironolactone + 40 mg/day furosemide + an ACE-I or ARB) were analysed for differences with respect to the ACE-I and ARB used. RESULTS: When 50 mg/day spironolactone plus 5 mg/day enalapril maleate (enalapril) or 50 mg/day losartan potassium (losartan) or 8 mg/day candesartan cilexetil (candesartan) plus 40 mg/day furosemide were concomitantly used, the mean value of serum potassium was significantly elevated only in the group treated with 50 mg/day spironolactone regardless of the concomitant drug. The number of patients with hyperkalemia (>5.5 mEq/L) at 12 months of treatment was 12 (8.8%), while the number of patients with hypokalemia (<or=3.5 mEq/L) was 7 (5.1%). However, the occurrence of hyperkalemia was almost the same regardless of the dose of spironolactone or the ACE-I or ARB concomitantly administered. Therefore, if enalapril, losartan, or candesartan is concomitantly used, it is necessary to monitor the serum concentration of potassium, even if spironolactone is administered at a dose of 25 mg/day. CONCLUSION: The occurrence of hyperkalemia in patients administered spironolactone is influenced by the dose, but when it is used concomitantly with enalapril, losartan or candesartan, the occurrence of hyperkalemia exceeding 5.5 mEq/L may increase even if the dose of spironolactone is as low as 25 mg. Thus it is essential to always monitor serum potassium.

Adult↗

Down-regulation of metabotropic glutamate receptor 1alpha in globus pallidus and substantia nigra of parkinsonian monkeys.

Enhanced glutamatergic neurotransmission via the subthalamopallidal or subthalamonigral projection seems crucial for developing parkinsonian motor signs. In the present study, the possible changes in the expression of metabotropic glutamate receptors (mGluRs) were examined in the basal ganglia of a primate model for Parkinson's disease. When the patterns of immunohistochemical localization of mGluRs in monkeys administered systemically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were analysed in comparison with normal controls, we found that expression of mGluR1alpha, but not of other subtypes, was significantly reduced in the internal and external segments of the globus pallidus and the substantia nigra pars reticulata. To elucidate the functional role of mGluR1 in the control of pallidal neuron activity, extracellular unit recordings combined with intrapallidal microinjections of mGluR1-related agents were then performed in normal and parkinsonian monkeys. In normal awake conditions, the spontaneous firing rates of neurons in the pallidal complex were increased by DHPG, a selective agonist of group I mGluRs, whereas they were decreased by AIDA, a selective antagonist of group I mGluRs, or LY367385, a selective antagonist of mGluR1. These electrophysiological data strongly indicate that the excitatory mechanism of pallidal neurons by glutamate is mediated at least partly through mGluR1. The effects of the mGluR1-related agents on neuronal firing in the internal pallidal segment became rather obscure after MPTP treatment. Our results suggest that the specific down-regulation of pallidal and nigral mGluR1alpha in the parkinsonian state may exert a compensatory action to reverse the overactivity of the subthalamic nucleus-derived glutamatergic input that is generated in the disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Comparative study of electrothermal bipolar vessel sealer and ultrasonic coagulating shears in laparoscopic colectomy.

BACKGROUND: As an alternative to suture ligatures of the vessels, an electrothermal bipolar vessel sealer (EBVS) was recently developed. Meanwhile, ultrasonic coagulating shears (UCS) have been widely used clinically to provide hemostatic cutting in laparoscopic procedures. We conducted a comparative study to investigate the relative advantages of these two instruments. METHODS: The study included 30 patients with colon cancer who underwent laparoscopic colectomy using either the EBVS or the UCS. We performed a comparative analysis of the instruments by viewing videotapes showing their application in laparoscopic transverse colectomy and sigmoidectomy. RESULTS: Average patient age was 71.6 +/- 1.4 years. Average hospital stay was 14.2 +/- 1.0 days. There were no statistical differences between the groups in age and hospital stay. The incidence of rebleeding was significantly lower in the EBVS group than in the UCS group for both surgical procedures (0.3 vs 1.2 in transverse colectomy, 0.3 vs 2.0 in sigmoidectomy, respectively). In addition, the required time for mesocolon dissection was also significantly shorter when the EBVS was used in both laparoscopic transverse colectomy and sigmoidectomy (7.9 vs 18.4, 15.0 vs 27.6, respectively). CONCLUSION: The use of the EBVS will enable surgeons to reduce the total operating time for laparoscopic colectomy.

Aged, 80 and over↗

Modulation of thymidine phosphorylase by neoadjuvant chemotherapy in primary breast cancer.

The combination effect of docetaxel and capecitabine on tumour response rate and survival was demonstrated recently in metastatic breast cancer patients. This combination was based on an experimental hypothesis that taxane can increase tumour sensitivity to the effect of capecitabine through the upregulation of thymidine phosphorylase (TP), which is responsible for the metabolism of 5-fluorouracil (5-FU) and its derivatives, including capecitabine. To examine the alteration in TP expression before and after neoadjuvant chemotherapy, 92 patients with primary breast cancer (T2-4N0-1M0) were enrolled in this study; 14 were treated with adriamycin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC); 58 with 5-FU, adriamycin, and cyclophosphamide (FAC) or 5-FU, epirubicin, and cyclophosphamide (FEC); and 20 with FEC followed by docetaxel/taxotere (TXT-containing regimen). Thymidine phosphorylase upregulation was seen in 54.4% and 32.6% of patients in tumour cells and stromal cells, respectively. Increases in TP expression were found only in the AC/EC and TXT-containing regimen groups. In conclusion, it was strongly suggested that unlike 5-FU-containing regimens, the taxane and AC combination therapies upregulate TP expression in primary breast cancer. Thymidine phosphorylase upregulation by several anticancer drugs implies the importance of individualised strategies for sensitisation of tumour tissues to 5-FU and its derivatives.

Adult↗

Augmentation of interleukin-10 in pancreatic islets after brain death.

Clinical islet transplantation is now established as a treatment for patients with type I diabetes. Although organs from brain-dead (BD) donors are the main source for clinical transplantation, marginal status after BD produces deterioration of the organs followed by molecular activation. The effect of brain-death (BD) induction on the immunological status of donor islets was investigated using a rodent model of BD. BD animals showed decreased levels of peripheral white blood cells (WBC) compared to controls, indicating the extravasation of these cells (7270 +/- 500 vs 9570 +/- 370, respectively). In a densitometric study of RT-PCR products, the Th2 cytokine (IL-10) was significantly up-regulated in BD (2.91 +/- 0.26 vs 1.76 +/- 0.40), but a Th1 cytokine (IL-2) showed minimal change. Increased expression of IL-10 may inhibit macrophage function. As the marginal status after BD deteriorates, the islets of these donors may display early graft loss or poor long-term function. Integrative studies of immunomodulation might be necessary to eliminate islet infiltrates.

Animals↗

Microdosimetry of neutron field for boron neutron capture therapy at Kyoto university reactor.

Microdosimetric single event spectrum in a human body simulated by an acrylic phantom has been measured for the clinical BNCT field at the Kyoto University Reactor (KUR). The recoil particles resulting from the initial reaction and subsequent interactions, namely protons, electrons, alpha particles and carbon nuclei are identified in the microdosimetric spectrum. The relative contributions to the neutron dose from proton, alpha particles and carbon are estimated to be about 0.9, 0.07 and 0.3, respectively, four depths between 5 and 41 mm. We estimate that the dose averaged lineal energy, yD decreased with depth from 64 to 46 keV microm(-1). Relative biological effectiveness (RBE) of this neutron field using a response function for the microdosimetric spectrum was estimated to decrease from 3.6 to 2.9 with increasing depth.

Academic Medical Centers↗