Chromosomal mapping of the T-helper immunodeficiency (thid) locus in LEC rats.
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Animals↗
Biomedical subjects
T Sakai
Publications and source records attributed to T Sakai.
Isolated ophthalmological manifestations due to malfunction of a lumboperitoneal shunt: shortening of the spinal catheter in three pediatric patients.
A long-term follow-up study was conducted in 28 pediatric patients treated with lumboperitoneal shunting. Shunt malfunction was observed in 3 patients (10.6%) who presented with isolated ophthalmological abnormalities 3, 5, and 11 years after surgery. The mechanism of this phenomenon is considered to be very slowly developing malfunction secondary to shortening of the spinal catheter associated with child's growth. The importance of periodic funduscopic examination in patients treated with lumboperitoneal shunting in infancy is stressed.
Adolescent↗
Nicotinamide adenine dinucleotide synthetase activity in erythrocytes as a tool for the biological monitoring of lead exposure.
OBJECTIVE: The objective of this study was to evaluate the usefulness of nicotinamide adenine dinucleotide synthetase (NADS) activity for the biological monitoring of lead exposure. METHODS: The subjects were 76 male lead workers and 13 normal volunteers (7 males and 6 females). NADS activity and blood lead concentration (Pb-B) was determined in each subject. Delta-aminolevulinic acid dehydratase (ALAD) activity was determined in 58 lead workers out of 76 subjects. RESULTS: NADS activity in the lead workers ranged from 0.08 to 1.1 mumol/h per g of hemoglobin (gHb) and decreased linearly (r = -0.867) as Pb-B increased up to 81.6 micrograms/dl. The pattern of depressed activity of NADS was different from that of ALAD activity, which decreased rapidly and reached a plateau at the Pb-B level between 40 and 60 micrograms/dl. The Pb-B levels inducing 50% inhibition of the enzyme activities were calculated to be 43 micrograms/dl and 20 micrograms/dl for NADS and ALAD, respectively. At the Pb-B level of 40 micrograms/dl, NADS activity showed high validity (1.77) with predictivity of 0.92 at the cut-off level of 0.4 mumol/h per gHb, which were higher than those of ALAD activity. CONCLUSIONS: These results show an apparent dose-effect relationship of NADS activity versus Pb-B. NADS activity can be used for the biological monitoring of lead exposure.
Adult↗
Role for protein kinase in Ca2+-dependent feedback modulation of divalent cation influx in internal-Ca2+-store-depleted rat parotid gland cells.
Divalent cation (Ca2+ and Mn2+) influx, stimulated by internal Ca2+ store depletion, into rat parotid acinar cells is inhibited by conditions which increase protein phosphorylation [T. Sakai and I.S. Ambudkar (1996) Am J Physiol 271:C284-C294]. The present study examines the involvement of this protein phosphorylation and Ca2+ in the store-dependent inactivation of divalent cation entry. Internal Ca2+ store depletion, achieved by incubation (30 min) of cells in nominally Ca2+-free medium containing either carbachol or thapsigargin, stimulated Ca2+, and Mn2+, influx into cells. In either case, inclusion of 1.5 mM Ca2+ for the last 5 min of incubation resulted in a decrease in Ca2+ (33-41%) and Mn2+ (50%) influx, which could not be accounted for by internal Ca2+ store refill. The inhibition was prevented when internal-store-depleted cells were treated (prior to incubation with Ca2+) with either staurosporine or K-252a, but not with H-7 or KN-93. Refilling of internal Ca2+ store(s) in carbachol-treated cells (incubation with Ca2++atropine) induced complete inhibition of divalent cation influx, which was not prevented by treatment with protein kinase inhibitors. These data suggest the staurosporine-sensitive (and K-252a-sensitive) protein phosphorylation is not involved in Ca2+-store-refilling-dependent inactivation of Ca2+ influx but mediates a Ca2+-dependent feedback modulation of divalent cation influx in rat parotid gland acinar cells.
Animals↗
Emergence and distribution of intimal smooth muscle cells in the postnatal rat aorta.
The distribution of aortic intimal smooth muscle cells in the normal rat during postnatal development was studied by electron microscopy and by staining with fluorescence-labeled phalloidin. The phenotypes of intimal and medial smooth muscle cells were almost identical at first; however, during development, the former remained synthetic, whereas the latter became contractile. Confocal laser scanning microscopy was utilized to observe intimal and medial cells separately. Intimal smooth muscle cells were rarely observed in neonatal rats, but appeared by 10 days of age and increased during postnatal development. A combination of confocal and conventional fluorescent microscopy clearly demonstrated that the intimal smooth muscle cells were preferentially distributed in: (1) the right-lateral and dorsal wall of the upper thoracic aorta, (2) the left-lateral and ventral wall of distal two-thirds of the descending aorta, and (3) the downstream side of branch orifices. Intimal smooth muscle cells in group (1) were oriented randomly, whereas most in group (2) ran longitudinally. Intimal smooth muscle cells at branches in group (3) ran obliquely from the edges at the downstream side in an upstream direction. They tended to accumulate in regions of the aortic wall considered to be under high tensile stress.
Age Factors↗
Fas-mediated cytotoxicity by intestinal intraepithelial lymphocytes during acute graft-versus-host disease in mice.
BACKGROUND & AIMS: Host-derived intestinal intraepithelial lymphocytes (IELs) increase in number during acute graft-versus-host disease (GVHD) in mice. In the present study, we examined Fas-mediated cytotoxicity by host-derived IELs against Fas-expressing target cells to see whether Fas/Fas ligand (Fas-L) interaction is involved in the pathogenesis of enteropathy during acute GVHD. METHODS: Acute GVHD was induced by injection of parental spleen cells into nonirradiated F1 mice. The expression of Fas antigen on the intestinal epithelial cells (IECs) was examined by flow cytometry, and the expression of messenger RNA (mRNA) for Fas-L, interleukin 2, and interferon gamma in host-derived IELs was assessed by reverse-transcription polymerase chain reaction. Fas-mediated cytotoxicity by host-derived IELs was assessed using Fas-transfected cells, IECs, and Fas immunoglobulin Fc fusion protein (Fas Fc). RESULTS: Fas antigen was constitutively expressed on the cell surface of IECs before and after GVHD induction. Although Fas-L mRNA was not detected or detected scarcely in either alphabeta or gammadelta IELs before GVHD induction, both IELs expressed high levels of mRNA for Fas-L and interferon gamma after GVHD induction. Host-derived IELs during acute GVHD showed cytotoxicity against Fas-transfected target cells and IECs, which was partly blocked by addition of Fas Fc. CONCLUSIONS: Fas/Fas-L-mediated cytotoxicity by host-derived IELs may be partly responsible for the enteropathy during acute GVHD.
Animals↗
Positron emission tomography (PET) in Machado-Joseph disease.
Positron emission tomography studies on the regional cerebral glucose metabolism (rCMRglc) and 18F-fluorodopa (18F-Dopa) uptake were performed in 3 patients with Machado-Joseph disease (MJD), a dominantly inherited degenerative disease in the cerebellum, brainstem and basal ganglia. The rCMRglc in MJD was found to be significantly decreased in the cerebellum, brainstem, striatum and whole cerebral cortex in comparison to that in normal subjects. These results of rCMRglc were different from those for dominantly inherited olivopontocerebellar atrophy (dOPCA) or cerebellar cortical degeneration (CCD), however they were similar to those for sporadic olivopontocerebellar atrophy (sOPCA) and multiple system atrophy (MSA). The 18F-Dopa uptake in MJD was found to be significantly decreased in the putamen and relatively spared in the caudate, which was different from that of MSA. In addition, these results indicate that MJD showed a dysfunction, not only in the regions with apparent pathological involvement such as cerebellum, brainstem and nigro-striatal dopaminergic system, but also in the cerebral cortex and the striatum where no pathology could be observed using conventional morphological techniques.
Adult↗
Mizoribine improves renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO)-treated rat by inhibiting the infiltration of macrophages and the expression of alpha-smooth muscle actin.
PURPOSE: Several lines of evidence suggest that the infiltration of macrophages and the expression of alpha-smooth muscle actin in myofibroblasts play important roles in the pathogenesis of tubulointerstitial fibrosis. However, the temporal sequence of these pathological changes or the dynamics in the expression of this cytoskeletal molecule in the process of tubulointerstitial fibrosis have not been precisely documented. MATERIALS AND METHODS: We investigated the infiltration of macrophages and the expression of alpha-smooth muscle actin in interstitial fibrosis caused by a unilateral ureteral obstruction (UUO) experimental model. RESULTS: The result showed that the macrophages were immobilized at the interstitium and alpha-smooth muscle actin was up-regulated in myofibroblasts of both cortex and medulla at day 3 when interstitial volume start to increase significantly. The highest expression of alpha-smooth muscle actin was detected at day 5 and the most intense infiltration of macrophages was noted at day 14 while the interstitial volume in renal cortex and medulla continued to increase until day 28. Furthermore, we investigated the effect of mizoribine, an immunosuppressive agent, on the interstitial fibrosis induced by UUO, demonstrating that mizoribine, but not prednisolone, significantly improves the tubulointerstitial fibrosis by suppressing the macrophage infiltration and the expression of alpha-smooth muscle actin. CONCLUSIONS: We discuss the pathological roles of macrophages and alpha-smooth muscle actin in tubulointerstitial fibrosis induced by UUO treatment. We also emphasize the pharmacological basis and clinical relevance of mizoribine in the treatment of interstitial fibrosis caused by obstructive nephropathy.
Actins↗
Expression of bcl-2 oncoprotein in gastrointestinal and uterine carcinomas and their premalignant lesions.
Expression of bcl-2 oncoprotein (Bcl-2) in carcinomas and their precursor lesions in the colon, stomach, uterine cervix (squamous and glandular epithelium), and endometrium was examined immunohistochemically using clone 124 monoclonal antibody. Most cases of premalignant lesions in the colon (adenoma, 80.6%), stomach (metaplastic gastritis, 77.1%, mainly positive in the proliferative zone), endocervix (glandular dysplasia, 87.5%) and endometrium (endometrial hyperplasia, 65.4%) showed intense immunoreactivity for Bcl-2, whereas fewer than 30% of adenocarcinomas in these tissues had no or weak Bcl-2 expression. In the stomach, adenomas with definite Bcl-2 expression were 37.5% of the cases examined. Conversely, most of both squamous intraepithelial neoplasia and squamous cell carcinoma of the uterine cervix showed weak or no Bcl-2 expression. These results suggest that upregulation of Bcl-2 in premalignant lesions and downregulation after malignant change is, to some extent, a common event in the glandular system, but not in the squamous epithelium of the uterine cervix. Bcl-2 may play an important role in keeping the transformed cells alive at the early stage of multistep carcinogenesis in the glandular tissue by an escape from a regulatory mechanism of apoptosis for further accumulation of gene abnormalities.
Adenoma↗
Detection of the soluble form of the Fas molecule in patients with multiple sclerosis and human T-lymphotropic virus type I-associated myelopathy.
We evaluated the presence of soluble Fas molecule (sFas) in the cerebrospinal fluids (CSF) and the sera of patients with multiple sclerosis (MS) or human T-lymphotropic virus type I (HTLV-I) associated myelopathy (HAM) using an enzyme-linked immunosorbent assay (ELISA). Patients with multiple sclerosis in the active phase had higher sFas serum levels than control (p < 0.005). In addition, significantly increased serum levels of sFas were found in patients with HAM (p < 0.005). We found a significantly increased CSF levels of sFas in patients with HAM and patients with MS in the active stage (p < 0.005). These results suggest that serum sFas may be related to clinical activity in patients with MS and that Fas may play an important role in the pathogenesis of HAM.
Adult↗
Phosphatidylserine suppresses Theiler's murine encephalomyelitis virus-induced demyelinating disease.
Intracerebral inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. Various cytokines may play an important role in the pathogenesis of this disease. Tumor necrosis factor (TNF)-alpha contributes to the further development of perivascular cellular infiltration and demyelination in the central nervous system (CNS). Phosphatidylserine (PS), a major anionic phospholipid of mammalian cells, has been proposed to function as a regulator of immune and inflammatory responses, especially reducing TNF-alpha production and release in mice. We studied the effect of PS on TMEV-induced demyelinating disease (TMEV-IDD). We injected TMEV intracerebrally into susceptible SJL/J mice and induced TMEV-IDD. PS were injected intraperitonealy, and clinical course and various immunological indicators were closely studied. The results show that when PS were administered in the effector phase. TMEV-IDD was significantly (P < 0.01) suppressed both clinically and histologically. In an ELISPOT assay, the number of TNF-alpha producing spleen cells was low in PS treated mice compared with saline treated control mice. mRNA of TNF-alpha was not detected in spleen cells of mice PS treated in the effector phase. These data suggest that administration of PS suppresses TMEV-IDD by suppressing TNF-alpha production in the effector phase.
Animals↗
Splanchnic and extrasplanchnic arterial hemodynamics in patients with cirrhosis.
BACKGROUND/AIMS: This study was designed to assess the contribution of splanchnic and extrasplanchnic vascular hemodynamics to the hyperdynamic circulation in patients with cirrhosis. METHODS: Cardiac index and flow volume index and pulsatility index (PI) of superior mesenteric artery (SMA) and femoral artery (FA) were measured with Doppler ultrasonography in 40 controls and 86 patients with cirrhosis (Child-Pugh grade A=41, grade B=30, and grade C=15). Mean arterial pressure was also recorded to calculate systemic vascular resistance index. RESULTS: Systemic vascular resistance index was significantly lower in each Child-Pugh group than in controls. SMA blood flow index was significantly higher in each Child-Pugh group than in controls and the increase in SMA blood flow index paralleled the degree of liver dysfunction. SMA-PI was significantly lower in each Child-Pugh group than in controls and the decrease in SMA-PI paralleled the degree of liver dysfunction. FA blood flow index was slightly higher in Child-Pugh grade A patients and significantly higher in grade B patients than in controls, whereas grade C patients had normal FA blood flow index. FA-PI was significantly lower in grade A and grade B patients than in controls, whereas grade C patients had normal FA-PI. When all patients were examined together, SMA-PI significantly correlated with systemic vascular resistance index (r=0.69, p<0.01). In contrast, FA-PI did not significantly correlate with systemic vascular resistance index (r=0.15, p=0.18). CONCLUSIONS: Splanchnic arterial vasodilatation plays an important role in the pathogenesis of decreased systemic vascular resistance seen in patients with cirrhosis.
Analysis of Variance↗
Effect of posture-induced blood volume expansion on systemic and regional hemodynamics in patients with cirrhosis.
BACKGROUND/AIMS: This study aimed to investigate the effects of posture-induced blood volume expansion on systemic and regional hemodynamics in patients with cirrhosis. METHODS: The mean arterial pressure, cardiac index, peripheral vascular resistance index, and flow volume index of the superior mesenteric artery (SMA) and femoral artery (FA) were measured in 10 patients with cirrhosis and portal hypertension and 10 controls after they had been standing for 2 h. Plasma atrial natriuretic peptide, plasma renin activity, and plasma glucagon levels were also determined. These measurements were repeated after 30 min and 60 min when the patients were recumbent. RESULTS: In the upright posture, systemic hemodynamics, FA blood flow index, plasma atrial natriuretic peptide level, and plasma renin activity level were similar in patients and controls. However, SMA blood flow index and plasma glucagon level were significantly higher in patients than in controls. On the assumption of the supine position, cardiac index and plasma atrial natriuretic peptide level significantly increased in the two groups, but the changes were greater in patients than in controls. Mean arterial pressure remained unchanged. The reduction in peripheral vascular resistance index was therefore greater in patients in controls. SMA and FA blood flow index increased significantly in the two groups, but the changes were greater in patients than in controls. Furthermore, SMA blood flow fraction (SMA blood flow index/cardiac index) was steady in controls, whereas it increased significantly in patients. In contrast, FA blood flow fraction (FA blood flow index/cardiac index) remained unchanged in the two groups. In patients, the change in peripheral vascular resistance index was correlated inversely with that of SMA blood flow index, but not with that of FA blood flow index. Plasma renin activity level dropped significantly, but the decline was similar in the two groups. Plasma glucagon level was not modified in either group. CONCLUSIONS: In patients with cirrhosis, splanchnic vasodilation appears to be present, even in the upright position, and further abnormal vasodilation occurs on recumbency-induced blood volume expansion. This abnormal shear-stress phenomenon observed in the splanchnic circulation seems to be mediated by a local vasodilator rather than a general vasodilator.
Blood Volume↗
Portal-hypertensive gastropathy develops less in patients with cirrhosis and fundal varices.
BACKGROUND/AIMS: The aim of this prospective study was to examine the association of portal-hypertensive gastropathy and fundal varices in patients with cirrhosis. METHODS: We carried out an endoscopic observation in 476 patients with cirrhosis (study 1), including 62 patients undergoing endoscopic obliteration of esophageal varices (study 2). In study 1, patients were classified into five subgroups: no esophagofundal varices (n=119), small esophagofundal varices (n=127), dominant esophageal varices (n=177), dominant fundal varices (n=27), and large esophagofundal varices (n=26). The severity of liver dysfunction was assessed by Pugh-Child classification: class A (n=222), class B (n=200), and class C (n=54). In study 2, two groups, poorly developed fundal varices (n=50) and well developed fundal (n=12), were distinguished and the follow-up endoscopic examinations were performed on the basis of 3-month intervals for 2 years. In each study, the severity of portal-hypertensive gastropathy was scored: 0 (absent), 1 (mild), 2 (severe), and 3 (bleeding). RESULTS: Study 1: One-way ANOVA showed that both variceal pattern and Pugh-Child class significantly influenced portal-hypertensive gastropathy score. However, two-way ANOVA indicated that variceal pattern was the only significant variable. Portal-hypertensive gastropathy score was significantly higher in patients with dominant esophageal varices than in either patients with no esophagofundal varices or patients with small esophagofundal varices. In contrast, portal-hypertensive gastropathy score in patients with dominant fundal varices was similar to that in patients with no esophagofundal varices and was significantly lower compared with that in patients with dominant esophageal varices. Furthermore, portal-hypertensive gastropathy score was significantly lower in patients with large esophagofundal varices than in patients with dominant esophageal varices. Study 2: After the obliteration of esophageal varices, portal-hypertensive gastropathy score in patients with poorly developed fundal varices became significantly higher at 3-, 6-, 9-months while it was not modified in patients with well developed fundal varices during the follow-up period. Furthermore, the integrated incremental change in portal-hypertensive gastropathy score during the first 1-year follow-up period was significantly lower in patients with well developed fundal varices than in patients with poorly developed fundal varices. CONCLUSIONS: These results indicate that both spontaneous and obliteration-induced portal-hypertensive gastropathy lesions develop less in patients with cirrhosis and fundal varices.
Endoscopy, Digestive System↗
Optical characterization of a novel GABA response in early embryonic chick brainstem.
To examine the functional expression of embryonic GABA receptors, the inhibitory effects were studied of GABA (GABA responses) on the excitatory postsynaptic potentials evoked by vagal stimulus in seven- to 10-day-old embryonic chick brainstem slice preparations. A multiple-site optical recording technique was used, with a multiple element photodiode array system and a fast voltage-sensitive merocyanine-rhodanine dye (NK2761). First, in the GABA response, three components were pharmacologically identified: component 1, related to GABA(A) receptors; component 2, related to GABA(B) receptors; and component 3 which is insensitive to GABA(A) and GABA(B) antagonists, but is stimulated by both GABA(A) and GABA(B) agonists. Subsequently. the embryogenesis and early development of the three components were investigated, and early developmental maps of regional distribution patterns of the three components were constructed. Components 1 and 3 have already emerged in the seven-day-old embryonic brainstem preparation; component 2 appeared in the eight-day-old preparations. No component related to GABA(C) receptors was observed in the seven- to 10-day-old embryonic stages. From the pharmacological properties of component 3, we suggest that it is related to a new subtype, the GABA(D) receptor.
Animals↗
Neuropathological findings in the cerebro-oculo-facio-skeletal (Pena-Shokeir II) syndrome.
An autopsy case is described of an infant with cerebro-oculo-facio-skeletal (COFS) (Pena-Shokeir II) syndrome who died of pneumonia at the age of 5 months, and the pathology of the CNS in this case and the cases in literature were reviewed. Neuropathological examination revealed a partial defect of the corpus callosum, lobulation of the caudate nucleus and putamen, polymicrogyria in the parietal lobes and neuronal heterotopia in the cerebral and cerebellar white matter. The migration disorders suggest that the onset starts in the early fetal period.
Agenesis of Corpus Callosum↗
Effects of fructose-induced hypertriglyceridemia on hepatorenal toxicity of acetaminophen in rats: role of pharmacokinetics and metabolism of acetaminophen.
Fructose-induced hypertriglyceridemic rats become resistant to hepatotoxicity and susceptible to nephrotoxicity of acetaminophen (APAP), as compared with normal ones. The present study was designed to test the hypothesis that alterations in the distribution of APAP and in the intrinsic susceptibility to toxicants are responsible for the alteration in hepatorenal toxicity of APAP in fructose-induced hypertriglyceridemic rats. Following APAP-administration (750 mg/kg, i.p.), fructose-pretreated rats (25% fructose in drinking water for 5 weeks) showed nephrotoxicity of APAP more promptly and more severely than normal ones. Renal APAP-concentrations at the early phase (15 and 30 min. after APAP-administration) were significantly greater in fructose-pretreated rats than those in normal ones. Plasma and hepatic APAP concentrations in fructose-pretreated rats were greater than those in normal ones only at the later phase (plasma; 6 hr, liver; 6 and 12 hr after APAP-administration). There were no significant differences in the APAP-induced depletion of hepatic and renal glutathione and in the basal hepatic and renal cytochrome P-450 contents between these rats. Fructose-pretreated rats were also more susceptible to p-aminophenol (PAP), a nephrotoxic metabolite of APAP, than normal rats. Therefore, enhanced susceptibility to APAP-nephrotoxicity in fructose-pretreated rats may be due, at least in part, to increased renal APAP concentration and increased intrinsic susceptibility to the metabolic nephrotoxicant.
Acetaminophen↗
Effects of fructose-induced hypertriglyceridemia on hepatorenal toxicity of acetaminophen in rats. II. Role of enhancement of fructose metabolism and overproduction of triglyceride in the liver and kidney on hepatorenal toxicity of acetaminophen.
Fructose-induced hypertriglyceridemic rats are resistant to hepatoxicity and susceptible to nephrotoxicity of acetaminophen (APAP) as compared with normal ones. The present studied were designed to evaluate how fructose-treatment affects the developmental mode of hepatorenal toxicity of APAP. First, following fructose-pretreatment for various durations (1 day, 1 week or 3 weeks), 1-day-fructose-pretreatment induced hypertriglyceridemia and enhancement of APAP-nephrectoxicity simultaneously. However, it took at least 3 weeks for fructose-pretreatment to reduce APAP-hepatotoxicity. Second, following fructose, sucrose or glucose-pretreatment for 3 weeks, fructose-pretreated rats showed marked hypertriglyceridemia and modification of APAP-hepatorenal toxicity. Sucrose-pretreated rats showed less effects than fructose-pretreated rats. Glucose-pretreated rats showed no changes in plasma triglyceride and APAP-hepatorenal toxicity. Third, rats with hypertriglyceridemia induced by olive oil or Triton WR-1339 which did not produce enhanced metabolism and triglyceride-overproduction in the liver and kidney showed no modification of APAP-hepatorenal toxicity. Pretreatment of glycerol which was metabolized in liver and kidney and induced an overproduction of triglyceride resulted in an enhancement of APAP-nephrotoxicity. These results indicate that an enhancement of fructose metabolism and an overproduction of triglyceride in liver and kidney are responsible for the modification of APAP-hepatorenal toxicity in fructose-induced hypertriglyceridemic rats.
Acetaminophen↗