[Physiological test].
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Autonomic Nervous System↗
Biomedical subjects
M Hirayama
Publications and source records attributed to M Hirayama.
[Pharmacological test].
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Arginine Vasopressin↗
Pharmacokinetics and metabolism of the new thromboxane A2 receptor antagonist ramatroban in animals. 1st communication: absorption, concentrations in plasma, metabolism, and excretion after single administration to rats and dogs.
The absorption, concentrations in plasma, metabolism and excretion of ramatroban ((+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid, CAS 116649-85-5, BAY u 3405) have been studied following a single intravenous, oral, or intraduodenal administration of 14C-labeled or nonlabeled compound to rats and dogs (dose range: 1-10 mg.kg-1). After intraduodenal administration of [14C]ramatroban, enteral absorption of radioactivity was rapid and almost complete both in bile duct-cannulated male rats (83%) and female dogs (95%). The oral bioavailability of ramatroban was complete in the dog but amounted to about 50% in the rat due to presystemic elimination. A marked food effect on the rate but not on the extent of absorption was observed in rats. The elimination of the parent compound from plasma occurred rapidly with total clearance of 1.2 l.h-1.kg-1 in male rats and 0.7 l.h-1.kg-1 in dogs. After oral administration to male rats AUC increased dose-proportionally between 1 and 10 mg.kg-1, whereas in Cmax an over-proportional increase was observed. Excretion of total radioactivity was fast and occurred predominantly via the biliary/fecal route in both species. The residues were low, 144 h after dosing less than 0.2% of the radioactivity remained in the body of rats. A considerable sex difference was found in rats following oral administration of ramatroban. In females a 3-fold higher AUC and a 1.7-fold longer half-life of unchanged compound, as well as 3-fold higher renal excretion of total radioactivity was observed. A marked species difference exists in the metabolism of ramatroban. In dogs the drug was almost exclusively metabolized via conjugation with glucuronic acid, whereas in rats oxidative phase I metabolism and glucuronidation were equally important. As a consequence enterohepatic circulation was much more pronounced in dogs (77%) than in rats (17% of the initial dose).
Administration, Oral↗
Pharmacokinetics and metabolism of the new thromboxane A2 receptor antagonist ramatroban in animals. 2nd communication: distribution to organs and tissues in male, female and pregnant rats, and characteristics of protein binding in plasma.
The distribution to organs and tissues, placental transfer and mammary excretion of ramatroban ((+)- (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9- carbazolepropanoic acid, CAS 116649-85-5, BAY u 3405) have been investigated in rats. Furthermore, the characteristics of protein binding in plasma of various species including man are described. After single oral administration of [14C]ramatroban to male rats, the radioactivity was preferentially localized in liver and kidneys, the tissue-to-plasma concentration ratios at tmax were 20 for liver and 6.3 for kidneys, respectively. For all other organs/tissues, a low to moderate affinity was detected. [14C]Ramatroban and its labeled metabolites did hardly penetrate the blood-brain barrier, and the brain-to-plasma concentration ratio was 0.03 at tmax. After repeated oral administration to male rats for 21 days, once daily, the radioactivity concentrations in organs and tissues showed only a slight tendency to accumulate. The AUC ratios in the dosing interval exhibited little or no increase, the highest accumulation factor was approximately 2. The steady-state of the trough levels in plasma was reached rapidly, with the third administration. The autoradiographic distribution pattern was not changed due to repeated administration. After receiving single oral doses of [14C]ramatroban, female rats showed almost identical autoradiographic distribution patterns of radioactivity compared with males. Although being similarly distributed, in most organs and tissues of pregnant rats (19th day of gestation) distinctly higher radioactivity concentrations were observed than in males. Maximal fetal concentrations occurred at 7 h after dosing. The distribution in fetuses was similar to that in maternal body, revealing relatively high concentrations in liver, kidneys, and gastrointestinal contents. The fetal AUC reached 68% of the AUC in maternal plasma. [14C]Ramatroban was excreted with the milk of lactating rats. The total amount within 24 h was estimated to be 1.7% of the maternal dose. [14C]Ramatroban is highly bound to plasma proteins in all species tested: rabbit (unbound fraction: 1.7-1.9%), rat (2.1-2.4%), man (2.0-2.7%), dog (2.4-2.8%), mouse (3.7-4.1%), guinea-pig (4.3-4.7%).
Administration, Oral↗
[Cervical spinal cord infarction in a patient with unilateral internal carotid artery occlusion and cervical spondylosis].
We report a 68-year-old male patient with right hemiparesis caused by cervical spinal cord infarction. Cerebral angiography revealed right internal carotid artery occlusion. The blood flow of right middle cerebral artery was fed by the basilar artery via right posterior communicating artery. In this case, the upper cervical spinal cord infarction might be induced by steal phenomenon of anterior spinal artery to the middle cerebral artery via posterior communicating artery in addition to the local ischemia by cervical spondylosis.
Aged↗
[The clinical utility of asbestos body counts in bronchoalveolar lavage fluid].
To assess the clinical utility of measuring the number of asbestos bodies (AB) present in bronchoalveolar lavage fluid (BALF), we counted the number of AB in BALF from 119 subjects using light microscopy. The results were analyzed according to occupational histories, radiological findings of asbestos-induced lung and pleural changes, and asbestos-related diseases. The 94 subjects in group 1 had a history of dust exposure, whereas group 2 subjects (n = 25) had no dust exposure. Group 1 was subdivided into subjects with obvious exposure to asbestos (group 1A, n = 61), and subjects with no known exposure to asbestos (group 1B, n = 33). The distribution of AB counts per ml of BALF (means +/- SEM) differed significantly between groups 1 and 2 (38.8 +/- 17.4 vs 0.06 +/- 0.04, p < 0.0001). The AB counts were significantly different between groups 1A and 1B (57.9 +/- 26.6 vs 3.4 +/- 1.2, p = 0.01). Subject, exposed to dust who had radiological evidence of pleural thickening had significantly higher AB counts than subjects in whom pleural thickening was absent (66.0 +/- 31.1 vs 5.1 +/- 4.2, p = 0.03). In group 1, the BALF was positive for AB in 7 of 14 patients with pulmonary fibrosis, 4 of 5 patients with lung cancer, all 6 patients with malignant mesothelioma, and all 4 patients with benign asbestos pleural effusion. We conclude that AB counts in BALF are useful for evaluating both the history of asbestos exposure in a population exposed to dust, as well as patients having asbestos-related diseases.
Adult↗
Natural killer cell recognition of "self" and "non-self" triggering antigens on normal lymphoblasts.
NK cell specificity for normal lymphoblasts was tested in mice by direct cytotoxicity and competitive inhibition assays. IL-2-activated NK cells lysed Hh-1 incompatible but not Hh-1 compatible or Hh-1[null] allogeneic and semisyngeneic lymphoblasts. NK cells also lysed some syngeneic blasts. NK alloreactivity was inhibited by unlabeled targets which shared at least one Hh-1 determinant with the labeled target. NK self-reactivity was inhibited by syngeneic cells as well as by some allogeneic cells. Class I molecule-deficient beta2m-/- blasts universally inhibited NK lysis of all normal blasts. Cold targets appeared to specifically inhibit NK lysis by competing for recognition by NK activatory receptors rather than by competing for NK lysis by sharing with hot targets the absence of MHC class I inhibitory molecules recognized by NK cell Ly49 molecules. Backcross analysis revealed that a single non-MHC-linked gene locus regulates the accessibility of some normal lymphoblast target antigens to recognition by triggering receptors on self-reactive BALB/c NK cells. The results suggest that target lymphoblast class I molecules may differentially control the accessibility of universally expressed polymorphic NK triggering antigens to positive recognition by distinct sets of alloreactive and self-reactive NK cells.
Animals↗
Augmented antitumor effects of killer cells induced by tumor necrosis factor gene-transduced autologous tumor cells from gastrointestinal cancer patients.
The purpose of this study was to determine the feasibility of a vaccine therapy using tumor necrosis factor (TNF) gene-transduced autologous tumor cells for the treatment of human gastrointestinal cancers, which tend to have lower immunogenicity than other cancers such as melanoma and renal cell carcinoma. We succeeded in establishing primary cultured tumor cells from 12/54 carcinomatous effusions (4 liver cancer patients, 5 gastric cancer patients, 1 pancreatic cancer patient, and 2 colon cancer patients) and in transducing the TNF gene to the tumor cells by using the retrovirus vector MFG-TNF. Even after irradiation, TNF production (0.3-3.5 U/ml per 10(6) cells per 72 hr) was confirmed for 10 of 12 transfectants, and the other two transduced cells were found to have approximately one TNF gene copy. In 7 of the 12 patients, the cytotoxic activity of killer cells to nontransduced autologous tumor cells incubated with these TNF gene transfectants was augmented. This activity was blocked with anti-HLA class I antibody or BrefeldinA (BFA), suggesting that the killer cells were cytotoxic T lymphocytes (CTL) and tumor antigens are presented with HLA class I molecules. Indeed, enhanced expression of HLA class I and/or ICAM-1 molecules on the surface of the TNF gene-transduced tumor cells were observed by fluorescence-activated cell sorting (FACS) analysis. Furthermore, natural killer (NK) and/or lymphokine-activated killer (LAK) activities determined by using K562 or Daudi cells as targets were also enhanced in some of these cases when they were incubated with TNF gene-transduced tumor cells. These findings indicate the feasibility of using TNF gene-transduced tumor cells as a vaccine in gastrointestinal cancer patients.
Carcinoma, Hepatocellular↗
Effect of casein phospho peptides and Ca2+ on penetration of boar spermatozoa into pig oocytes matured in vitro.
To investigate the promoting effect of casein phospho peptides (CPP) on the penetration of ejaculated boar spermatozoa into in vitro-matured oocytes, preincubated spermatozoa were coincubated with in vitro-matured oocytes in fertilization medium with or without CPP for 60-240 min. Sperm penetration into zona-intact oocytes was observed within 90 min of coincubation. The penetration rate reached a maximum earlier in the presence of CPP than in the absence of CPP. Furthermore, spermatozoa preincubated in fertilization medium with CPP before coincubation with matured oocytes retained the ability to penetrate oocytes for a longer time than spermatozoa preincubated in fertilization medium without CPP. In fertilization medium containing CPP, Ca2+ uptake by spermatozoa increased within 90 min of incubation, with a peak of 113 nm/1 x 10(7) cells. On the other hand, in fertilization medium with no CPP, the intracellular Ca2+ concentration remained constant or gradually decreased until 180 min of incubation. When preincubated spermatozoa were coincubated with oocytes for 5 h in a fertilization medium containing CPP and/or EGTA, or with no addition, EGTA decreased the rate of oocytes penetrated by spermatozoa and the number of spermatozoa penetrating each oocyte. On the other hand, when CPP was added to the medium containing EGTA, the inhibitory effect of EGTA was neutralized. These results indicate that CPP promotes Ca2+ uptake of boar spermatozoa, resulting in a more rapid and longer-lasting shift of a subpopulation of spermatozoa that can penetrate oocytes; the findings also suggest that CPP neutralizes the inhibitory effect of EGTA on sperm penetration.
Animals↗
Adverse events associated with MMR vaccines in Japan.
The largest nationwide active surveillance of four Measles-Mumps-Rubella (MMR) vaccines was conducted in Japan. A total of 1255 pediatricians actively participated in the study, which comprised 8.6% of all members of the Japanese Pediatric Society. The total number of registered recipients of MMR vaccines was 38 203. They were arbitrarily given one of the MMR vaccines produced by three makers (Takeda, Osaka city, Kitasato Minato-ku. Tokyo and Biken Suita city, Japan) or the standard MMR vaccine made of designated strains (Kitasato's measles-AIK-C, Biken's mumps-Urabe Am9 and Takeda's rubella-To336) produced by Takeda, Kitasato and Biken and were observed for 35 days. The rates of virologically confirmed aseptic meningitis per 10,000 recipients were 16.6, 11.6, 3.2 and 0 for the standard MMR, Takeda MMR, Kitasato MMR and Biken MMR vaccines, respectively. The incidence of convulsions between 15 and 35 days was the highest with the standard MMR vaccine and the incidence of fever associated with vomiting occurring between 15 and 35 days (symptoms relevant to aseptic meningitis) were also the highest with the standard MMR vaccine. The incidence of parotid swelling was the lowest with Takeda MMR vaccine. This surveillance revealed that incidences of aseptic meningitis after administration of the standard MMR vaccine and of Biken MMR vaccine were different. This posed questions about the manufacturing consistency of the Urabe Am9 mumps virus vaccines. On the other hand, the National Institute of Health found that the biological characteristics of the Urabe Am9 mumps virus contained in the standard MMR vaccine and in the Biken MMR vaccine were different. The Biken Company reported that the mumps vaccine in the standard MMR vaccine was a mixture of two Urabe Am9 mumps vaccine bulks; one identical to that contained in the Biken MMR vaccine and the other produced by a different manufacturing process.
Child↗
Orthostatic hypotension caused by a localised dorsal medullary tumour.
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Baroreflex↗
The integrative transformation of Pleurotus ostreatus using bialaphos resistance as a dominant selectable marker.
A plasmid pLC-bar containing the bialaphos resistance gene derived from Streptomyces hygroscopicus between the Lentinus edodes ras gene promoter and priA gene terminator was constructed. When protoplasts of Pleurotus ostreatus were mixed with the plasmid DNA in the presence of polyethylene glycol and CaCl2, bialaphos-resistant colonies were obtained. This indicated that transformation was successful. Southern blot analysis of total DNAs from transformants showed that the introduced plasmid DNA was integrated into the host chromosome and partly rearranged. A plasmid, pLC-GUS, containing the Escherichia coli beta-glucuronidase (GUS) gene under the control of the L. edodes ras gene promoter and priA gene terminator was constructed and introduced into protoplasts of P. ostreatus with pLC-bar by co-transformation. Two of 5 transformants obtained as bialaphos-resistant colonies showed two to twenty times higher specific activity of GUS than the recipient. Southern blot analysis of total DNAs from transformants indicated the presence of the GUS gene only in the two transformants. These results indicated that co-transformation of P. ostreatus was successful, and that the GUS gene was expressed in P. ostreatus. This transformation system will enable us to breed commercial strains of P. ostreatus at the molecular level.
DNA, Fungal↗
Hearing recovery and its process from the time of onset in sudden deafness.
A total of 547 patients with idiopathic sudden hearing loss were divided into eight groups according to the days (1-8 days) of their initial visit after onset, and initial hearing thresholds, hearing recovery and its process were investigated. There were no significant differences in initial hearing thresholds and hearing recovery among the eight groups. However, a difference was noticeable in the distribution of the thresholds at the initial visit and that on the 7th day between groups 1, 2 and 7. Many cases showed rapid recovery in groups 1, 2 and 7. We speculate that the treatment influenced the hearing recovery process in patients who showed relatively rapid recovery.
Deafness↗
Idiopathic bilateral sensorineural hearing loss: its clinical study in cases with rapidly progressed deafness.
In a series of 127 patients with idiopathic bilateral sensorineural hearing loss (IBSH) at the Hearing Clinic in the Department of Otolaryngology, Kitasato University Hospital, 20 cases showed rapid progression of hearing impairment. These patients had been treated with the same therapeutic regimen used in sudden deafness (SD). Improvement of hearing loss after treatment was generally less effective in the cases with rapidly progressed IBSH than in the cases with SD. However, hearing improvement was achieved in some cases with rapidly progressed IBSH when the treatment had started in the early stages after the onset of rapidly progressive hearing loss.
Adolescent↗
Prenatal diagnosis of compound heterozygous deficiency of protein C by direct detection of the mutation sites.
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Genetic Testing↗
[Gastrointestinal cancer and gene therapy].
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Animals↗
A scintigraphical qualitative analysis of peripheral vascular sympathetic function with meta-[123I]iodobenzylguanidine in neurological patients with autonomic failure.
In order to assess qualitatively the sympathetic functions of the peripheral vessels, we performed a scintigraphical study of the entire body with meta-[123I]iodobenzylguanidine (MIBG) in 13 patients with autonomic failure and 11 healthy subjects as control. The patients comprised seven with multiple system atrophy (MSA), two with pure autonomic failure (PAF), three with Parkinson's disease with autonomic failure (PD with AF) and one with familial amyloid polyneuropathy (FAP). No clinical evidence of vascular disease was noted in any of the patients and the control subjects. We investigated their autonomic functions using the head up tilt test as well as norepinephrine and isoproterenol infusion tests. We found that: (i) All of the control subjects showed satisfactory MIBG uptake; (ii) all of the patients with PAF and FAP, most of whom had postganglionic sympathetic lesions, showed supersensitivity and low MIBG uptake; (iii) almost all the patients with MSA, who were considered to have mainly preganglionic sympathetic lesions, showed supersensitivity and diminished MIBG uptake, although the patients with olivopontocerebellar atrophy showed supersensitivity but not diminished MIBG uptake. In conclusion, these results suggest that peripheral vascular scintigraphy using MIBG is useful in detecting peripheral adrenergic dysfunction.
3-Iodobenzylguanidine↗
Gastrointestinal dysfunction in Parkinson's disease detected by electrogastroenterography.
Electrogastroenterography (EGEG) is a method to record electrical activities of the stomach and the intestine using skin electrodes. We investigated whether this method could be used to detect gastrointestinal dysfunction in patients with idiopathic Parkinson's disease. EGEG recordings were done with ten patients with idiopathic Parkinson's disease and ten control subjects before and after a meal. The patients showed changes in EGEG that were markedly similar to those of acute stage of vagotomized patients reported previously. Patients' increase rate in amplitude of gastric activity after the meal (median: 1.19) was significantly (P < 0.05, Mann-Whitney test) smaller than that of the controls (median: 2.84), and normal temporal frequency decrease of gastric activity after the meal was not seen in the patient group. These results suggest vagal nerve dysfunction of patients with Parkinson's disease, though other possibilities could not be denied. EGEG may be useful to assess patients' gastrointestinal dysfunction though we need further study to elucidate the relation between pathophysiology of their symptoms and EGEG findings.
Aged↗