Biomedical subjects
Publications and source records attributed to M Fujii.
We examined three adult Japanese patients who had a history of decreased hepatic glucose-6-phosphatase activity. All three patients had increased bilateral subcutaneous (SC) fat in the lower eyelids and inverted eyelashes. One patient additionally showed retinal hemorrhages and microaneurysms in both fundi. The inverted eyelashes may have been related to type 1a glycogen storage disease.
Fractional rates (%/day) of degradation of muscle protein were determined by measuring the output of NT-methylhistidine (NT-MH) in the excreta at 2 and 10 weeks of age in three lines of quail, a random-bred line and two lines selected for body size, one for increased and the other for decreased size. In all lines, fractional rates of degradation of muscle protein at 2 weeks of age were higher than those at 10 weeks of age. The fractional rate of degradation at 2 weeks of age was highest for the RR line, 9.1-9.2%/day. However, at 10 weeks of age, the rank order changed, and the RR line showed the lowest rate, 1.8-1.9%/day. The SS line (5.8-6.2%/day at 2 weeks and 5.8-5.9%/day at 10 weeks of age) was significantly higher than the LL line (4.1-4.2%/day at 2 weeks and 2.1-2.2%/day at 10 weeks of age). Acid protease activities in supernatants of homogenized muscle of the three lines of quail at 2 and 10 weeks of age were measured. In all lines, the acid protease activities in supernatant of homogenized muscle decreased from 2 to 10 weeks of age. At 2 weeks, the protease activity of the RR line was significantly higher than that of the LL and SS lines, which did not differ significantly. However, at 10 weeks of age, the SS line had higher activity in both sexes than the LL and RR lines. The results suggest that selection for body size brings about significant changes in both fractional degradation rate and acid protease activity in the muscle.
The effects of chronic renal failure on the level of albumin mRNA and the transcription rate of the albumin gene were studied in seven of eight nephrectomized rats. A paired feeding procedure was employed to eliminate a nutritional difference between sham-operated control and uremic rats. Total RNA was isolated from the livers of control and uremic rats fasted for 24 or 48 hours. The mRNA level was measured by RNA-cDNA dot blot hybridization, and the transcription rate was measured by the "run-on" transcription assay in isolated nuclei. The albumin mRNA levels in uremic rat livers were reduced to 75% at the 24-hour fasted state, and to 45% at 48-hour fasted state compared with those in the respective control groups. There was no difference in the level of beta-actin mRNA between these groups. However, there was no difference in the transcription rate of the albumin gene between control and uremic rats. Northern analysis showed that albumin mRNA isolated from uremic rat liver was identical in size with that from the control. These results suggested that a posttranscriptional process, involving the destabilization of cytoplasmic mRNA, is responsible for the uremia-induced repression of albumin synthesis.
Interleukin-2 receptors (IL-2R) on mononuclear cells from human umbilical cord blood were investigated after stimulation by phytohemagglutinin (PHA) and anti-CD3 antibody. The proportion of cells expressing the Tac antigen (IL-2R alpha, p55) did not differ from that for adult mononuclear cells. However, the levels of high affinity IL-2R (H-IL-2R) and low affinity IL-2R (L-IL-2R) present on the PHA blasts of cord blood cells were shown to be twice and three times, respectively, that of adults by interleukin-2 (IL-2) binding assay. The level of low affinity IL-2R in the cord blood cells was approximately double that of adult cells after activation by anti-CD3 antibody, but no difference was observed in the levels of high affinity IL-2R. Functional investigation of IL-2R revealed that the amount of internalized IL-2 in PHA-stimulated cord blood mononuclear cells was twice that in adult mononuclear cells but there were no differences between them in the time course of internalization and degradation. Although there were significant numbers of H-IL-2R in premature (25 and 28 weeks) infants following PHA stimulation, there were markedly fewer following anti-CD3 stimulation. Prematurity of the T-cell activation system through the CD3 pathway at this stage is therefore indicated.
An embryonic olfactory bulb was heterotopically inserted and allowed to mature in young adult rat brains. The projection of the transplanted olfactory bulb to the host brain was examined by injections of peroxidase-labeled wheatgerm agglutinin into the host olfactory bulb (and anterior olfactory nucleus). Neurite elongation to the host olfactory area occurred most frequently from the transplant which had been inserted into the anterior horn of the lateral ventricle and fused medially with the lateral septum in host brains with no detectable damage of host olfactory connections. Transplants in the septum, olfactory tubercle, nucleus of the horizontal limb of the diagonal band, or anterior piriform cortex also showed the projection to the host olfactory area. These results indicate that the transplanted olfactory bulb projection neurons have potent abilities to detect the target and project to it even if there is a considerable distance (2-5 mm).
1. To study the effect of histamine on two different affinity sites in beta-adrenoceptors, we tested specific binding of [3H]befunolol to microsomal fractions from the guinea pig taenia caecum in the presence and absence of histamine (10(-5) M). 2. The Scatchard plot of data in the absence of histamine was recognized as two straight lines suggesting the existence of two different affinity sites: high and low. However, a curvilinear plot with upward concavity was observed in the presence of histamine (10(-5) M). 3. These results suggest the possibility that histamine alters the binding sites of beta-adrenoceptors into several classes of sites with lower affinity. 4. Further, an antagonism between isoprenaline and BFE-55, which interacts only with the high affinity site, was tested on the atria (beta 1-adrenoceptor predominant) and tracheae (beta 2-adrenoceptor predominant) of the guinea pig. The pA2-values in the atria were almost equal to those in the trachea, suggesting that both beta 1- and beta 2-adrenoceptors contained two different affinity sites.
1. Isoprenaline, a beta-adrenergic full agonist, and carteolol, befunolol and BFE-55, beta-adrenergic blockers with an intrinsic sympathomimetic action, induced dose-related increases in heart rate when administered intravenously (i.v.). 2. The beta-partial agonists administered i.v. shifted a dose-heart rate increased response curve of isoprenaline, suggesting a competitive antagonism. 3. In carteolol, doses to block beta-adrenoceptors were found to be 400-1000 times lower than that to induce agonistic action. In BFE-55, doses to block beta-adrenoceptors were equal to that to induce sympathomimetic action. The difference between doses of the befunolol to produce both actions was intermediate. 4. These results suggest that there may be a difference between doses blocking beta-adrenoceptors and inducing sympathomimetic action in some beta-adrenergic partial agonists and, therefore, that there may exist beta-partial agonists which do not induce sympathomimetic action in doses blocking beta-adrenoceptors.
The distribution of substance P-containing fibers in the cerebral cortex and the hippocampal formation of the Japanese monkey (Macaca fuscata fuscata) was studied by immunohistochemistry using a monoclonal antibody raised against substance P. The results were compared with the distribution in homologous regions of the rat brain. Substance P-containing fibers and cell bodies were observed in all regions of the cerebral cortex. In deep layers of the neocortex (IV-VI), substance P-immunoreactive fibers formed arrays that ran perpendicular to the surface. These immunoreactive fibers tended to branch as they approached the cortical surface in layers II and III, at which point they were oriented in many directions. The molecular layer (I) of the monkey neocortex contained many granular, substance P-immunoreactive structures, resembling terminal boutons. In contrast to the monkey, rat cortical areas contained substantially fewer substance P-containing fibers. The immunoreactive profiles, mostly fine dot-like structures, were seen uniformly in layers II and IV of the rat neocortex, although in the medial prefrontal cortex many thick, varicose fibers were also observed. Substance P-containing fibers were seen throughout the hippocampal formation of the monkey, including the subiculum and the parahippocampal regions. The regional distribution of immunoreactive fibers was most dense in the molecular layers of dentate gyrus, in the stratum moleculare of the CA1 region, and in the stratum pyramidalis of the CA2 region. In the rat, the hippocampus and dentate gyrus contained fewer immunoreactive fibers. Moderate densities were observed in the rat subiculum and entorhinal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of cholecystokinin receptor antagonist CR 1392 was studied in a model of mild acute pancreatitis induced in rats by four subcutaneous injections of the secretagogue caerulein. A single subcutaneous injection of 50 mg/kg body weight of CR 1392 caused a dramatic reduction in serum amylase concentration and pancreatic wet weight as well as histologic improvement of the caerulein-induced acute pancreatitis when given 30 min before the first caerulein injection. CR 1392 was also effective in reducing the elevated serum amylase activity, pancreatic weight, and histologic alterations even when administered after the pancreatitis had been induced. These present observations suggest that CR 1392 remains active for more than 3 h and blocks the action of caerulein on the pancreas.
We have studied the protective effect of OK-432, a biological response modifier (BRM) of Streptococcus pyogenes origin, on the lethal infection of mice with herpes simplex virus (HSV)-1. A single intraperitoneal (i.p.) injection of more than 10 micrograms of OK-432, when given at least two days before the infection, gave a marked effect yielding nearly 100% protection against ordinarily lethal infection. The protection was independent of the amount of infected virus inoculated. When given after the infection, the agent even at the maximal dose (100 micrograms), produced only a marginal effect. A single i.p. administration of OK-432 augmented the natural killer (NK) activity of peritoneal exudate cells and spleen mononuclear cells in mice 2 to 3 days after injection of OK-432, coinciding with the times when it induced a survival effect on HSV-infection. Treating OK-432-treated mice with a combination of an anti-macrophage agent, silica, and an anti-NK cell agent, anti-asialo GM1 serum, before infection diminished the antiviral effect of OK-432. The OK-432 protection against HSV infection was also markedly diminished in athymic nude mice. Thus, the protective effect of OK-432 on lethal HSV infection seems to be based on the activation of NK cells, macrophages, and T lymphocytes.
A promoter of the nuclear proto-oncogene fos was activated by cotransfection with the viral src gene. Ability to transactivate the c-fos promoter was dependent on tyrosine kinase activity, because (i) src mutants which have reduced tyrosine kinase activity due to mutation of Tyr-416 to Phe showed lower promoter activation, (ii) pp60c-src mutants which have increased tyrosine kinase activity due to mutation of Tyr-527 to Phe also augmented c-fos promoter induction, and (iii) mutation in the ATP-binding site of pp60v-src strongly suppressed c-fos promoter activation. Tyrosine kinase activity alone, however, was not sufficient for promoter activation, because of pp60v-src mutant which lacked its myristylation site and consequently membrane association showed no increased c-fos promoter activation. Both the tyrosine kinase- and membrane-association-defective mutants were also unable to induce transformation. Therefore, phosphorylation of membrane-associated substrates appears to be required for both gene expression and cellular transformation by the src protein. Two regions of the c-fos promoter located between positions -362 and -324 and positions -323 and -294 were responsive to src stimulation. We believe that protein tyrosine phosphorylation represents an important step of signal transduction from the membrane to the nucleus.
The effects of hydrocortisone treatment on the secretory abilities of pancreatic acini to various secretagogues were studied. Rats were given subcutaneous injections of hydrocortisone at doses of 1.25, 2.5, or 5.0 mg/kg body wt once daily for 7 days. Hydrocortisone led to a small dose-dependent increase in pancreatic wet weight per 100 g body wt, which was associated with an increase in both total protein and DNA contents. In acini prepared from hydrocortisone-treated rats, both the responsiveness and the sensitivity to cholecystokinin octapeptide (CCK-8) was increased. The concentration dependence of cellular Ca2+ mobilization in response to CCK-8 was also shifted to lower concentrations in acini from hydrocortisone-treated rats compared with control rat acini. In vivo administration of hydrocortisone caused a significant increase in the affinity of 125I-CCK-8 binding to high-affinity receptors. The secretory responsiveness to carbamylcholine and bombesin, but not to secretin, was also increased but without any change in the sensitivity. Moreover, the hydrocortisone treatment increased the secretory responsiveness of acini to the Ca2+ ionophore A23187 and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate but did not to an adenosine 3',5'-cyclic monophosphate analogue, 8-bromoadenosine 3',5'-cyclic monophosphate. The present observations suggest that in vivo glucocorticoid administration affects both the CCK receptors and a postreceptor loci.
The effects of proglumide analogue. CR 1392, on pancreatic exocrine secretion were studied in the isolated pancreatic acini and the isolated perfused pancreata of rats. In the isolated acini, CR 1392 caused a parallel rightward shift of the dose-response curve for amylase secretion stimulated by cholecystokinin octapeptide (CCK-8). CR 1392 inhibited maximally stimulated amylase release by CCK-8 (100 pM) in a concentration-dependent manner, with a half maximal inhibition (ID50) at 8.0 +/- 0.6 microM. CR 1409, another proglumide analogue, also caused a concentration-dependent inhibition (ID50: 3.2 +/- 0.4 microM). Although CR 1409 was about 2.5-fold more potent than CR 1392 in inhibiting the stimulated amylase release, 1 mM CR 1409 caused 107.4 +/- 0.9% increase in amylase release, suggesting acinar cell damage. CR 1392 (1 mM) also caused 19.9 +/- 2.3% increase in amylase release, but was less toxic than CR 1409. The antagonism produced by CR 1392 was selective for CCK and had no effect on amylase release stimulated by other receptor secretagogues or by agents bypassing receptors. CR 1392 added 20 min after the CCK-8 stimulation rapidly abolished pancreatic exocrine secretion in both isolated acini and isolated perfused pancreas. Although the inhibitory effect of CR 1392 was fully reversible in the isolated acini, the pancreata perfused with 100 microM CR 1392 for 20 min did not respond to the subsequent stimulation with CCK-8 for more than 20 min. These results indicate that CR 1392 is a potent, competitive, specific and long acting antagonist of CCK in rat pancreas.
We have recently treated an 8-year-old boy who had leukocoria, microcornea, cataract, and falciform retinal fold in the right eye and multiple grouped patches of pigmentation in the left retina. These were diagnosed as persistent hyperplastic primary vitreous in the right eye and congenital grouped pigmentation of the retina in the left. This patient had a different rare congenital anomaly in each eye.
Nerve fiber analyses were conducted on the human facial nerve with use of a new staining method (Luxol-PAS-hematoxylin stain; discriminative staining method) that permits simultaneous observation of the axon and surrounding myelin sheath. The following combination of equipment was employed in the study: an image-analyzing digitizer, a microscope with a drawing tube, and a computer for storing the data and performing statistical analyses. The numbers, transverse areas, and circularity ratios of axons were measured in 11 cases. The average number of axons composing one facial nerve was 6,254, and the average size of the axons was 6.23 microns 2. The results indicated that although the numbers of axons became reduced with age, the transverse areas and circularity ratios of the axons did not change with age.
The development and reversal of tolerance to the hemodynamic and anti-anginal effects of isosorbide dinitrate in a sustained release form (ISDN-SR) were investigated in 11 male patients (mean age 58.9 y.o.) with stable effort angina. Treadmill exercise test, evaluation of hemodynamic parameters and measurement of plasma ISDN concentrations were performed during the control period, on the 1st, 7th and 14th days of therapy with 40 mg of ISDN-SR orally every 8 h and, subsequently, on the day when ISDN-SR was re-administered after a 72 h placebo period (17th day). Initially, exercise tolerance time (ETT) was prolonged significantly (p less than 0.001) by ISDN-SR from 257 +/- 50 sec in the control period to 434 +/- 55 sec on day 1. This prolongation was significantly reduced with sustained therapy and ETT was shortened to 332 +/- 69 sec on the 7th day (p less than 0.01 vs day 1) and 326 +/- 73 sec on the 14th day (p less than 0.01 vs day 1). The effects of ISDN-SR initially observed were restored after a 72 h placebo period and ETT was prolonged to 432 +/- 57 sec on the 17th day. The resting heart rate was increased significantly (p less than 0.01 vs control) and systolic blood pressure was decreased (p less than 0.001 vs control) by ISDN-SR on day 1. These changes were also diminished significantly (p less than 0.01 vs day 1) with sustained therapy and were restored after a 72 h nitrate-free interval.(ABSTRACT TRUNCATED AT 250 WORDS)
To clarify the mechanical adaptation and interference of coronary vessels, we studied hemodynamics of coronary circulation in control and 4 different pacing rates (80, 100, 120, 150/min) in 5 patients with angina pectoris (AP) and in 5 patients with hypertrophic cardiomyopathy (HCM). Coronary sinus flow (CSF) was measured by a Webster's thermodilution catheter, and we applied ascorbic acid-platinum reaction for the mean transit time measurement in left coronary flow (t0-t2). Coronary vascular bed (CVB) was obtained by multiplying CSF and t0-t2. CSF in AP gradually increased from 104 +/- 21 ml/min at 72/min to 148 +/- 42 ml/min at 120/min, while CSF in HCM changed slightly from 91 +/- 25 ml/min at 64/min to 94 ml/min at 120/min. Average t0-t2 in HCM was 6.0 +/- 1.6 sec in control which was significantly lower than that in AP (7.8 +/- 0.7 sec). Calculated CVB in AP increased at any given heart rate up to 120/min (13.5 +/- 2.4, 15.8 +/- 1.7, 15.0 +/- 4.7, 15.1 +/- 4.3 ml), but CVB in HCM decreased from 9.1 +/- 2.3 ml at 64/min to 8.1 +/- 1.7 ml at 120/min. These data suggest that myocardial compression and suction at different heart rates and with different cardiac muscle structures play an important role for beat to beat adjustment of coronary circulation in cardiac cycle.
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