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M Nishihara

Publications and source records attributed to M Nishihara.

At least 55 records · Page 3Linked to original sources
PubMed1999

Clinicopathological implications of parathyroid hormone-related protein in human colorectal tumours.

The purpose of the present study was to clarify the relationship of parathyroid hormone-related protein (PTHrP) to the oncogenesis and progression of colorectal adenocarcinoma. A total of 108 colorectal tumours, including 12 adenomas, six adenocarcinomas in adenomas, and 90 adenocarcinomas, were studied. Immunohistochemistry, in situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR) techniques were used to evaluate the expression of PTHrP. Positivity of immunostaining for PTHrP was defined as highly positive (++), slightly positive (+), and negative (-). None of the adenomas of background non-neoplastic mucosal epithelia showed immunostaining of PTHrP. In contrast, PTHrP was expressed in 85 (94.4 per cent) of 90 colorectal adenocarcinomas. Immunoreactivity of PTHrP was greater in poorly differentiated adenocarcinomas than in well-differentiated ones. Furthermore, advancing margins of primary tumours stained more intensely than other sites. Highly positive immunoreactivity of PTHrP, classified by histological invasiveness, was 22.6 per cent within the muscularis propria and 69.5 per cent beyond the muscularis propria. PTHrP expression was significantly correlated with differentiation, depth of invasion, lymphatic invasion, lymph node metastasis, hepatic metastases, and Dukes' classification. In carcinoma, PTHrP mRNA expression was evident in tumour cells by in situ hybridization. PTHrP transcripts were also detected in two resected human colorectal adenocarcinomas by RT-PCR. These findings suggest that PTHrP is related to carcinogenesis, differentiation, progression, and prognosis of colorectal adenocarcinomas.

Adenocarcinoma↗
PubMed1999

Genetic basis of autoimmune sialadenitis in MRL/lpr lupus-prone mice: additive and hierarchical properties of polygenic inheritance.

OBJECTIVE: To clarify the mode of inheritance of autoimmune sialadenitis in MRL/MpJ-lpr/lpr (MRL/lpr) lupus-prone mice and identify the susceptibility loci. METHODS: MRL/lpr, C3H/HeJ-lpr/lpr (C3H/lpr), (MRL/lpr x C3H/lpr)F1 intercross, and MRL/lpr x (MRL/lpr x C3H/lpr)F1 backcross mice were prepared, and sialadenitis in individual mice was analyzed by histopathologic grading. The genomic DNA of the backcross mice was examined by simple sequence-length polymorphism analysis, and the highly associated polymorphic microsatellite markers with sialadenitis were determined as sialadenitis susceptibility loci. RESULTS: Four susceptible gene loci recessively associated with sialadenitis were mapped on chromosomes 10, 18, 4, and 1, respectively. These loci manifested additive and hierarchical properties in the development of sialadenitis. CONCLUSION: The results indicate that sialadenitis in MRL/lpr mice is under the control of polygenic inheritance, possibly involving allelic polymorphism.

Animals↗
PubMed1999

VMH lesions reduce excessive running under the activity-stress paradigm in the rat.

We have previously shown that excitation of certain neurons in the ventromedial nucleus of the hypothalamus (VMH) of rats induces hyperrunning activity. The present study investigated the involvement of these VMH neurons in inducing excessive running under the activity-stress paradigm. The VMH of 6-week-old male rats was bilaterally lesioned by administration of kainic acid. Control animals received saline in the VMH. They were housed in running-wheel activity cages with free access to food for 6 days of the recovering period, and then fed 1 h each day for 6 days. Control animals exhibited marked increases in both running activity and its light/dark ratio, and developed stomach ulcers. In contrast, animals with bilateral VMH lesions showed a significantly attenuated increase in running activity and no change in light/dark ratio. VMH lesions also suppressed stomach ulceration. These results suggest that VMH neurons play a crucial role in inducing excessive running and stomach ulceration during exposure to the activity-stress paradigm.

Analysis of Variance↗
PubMed1999

Genetic dissection of the complex pathological manifestations of collagen disease in MRL/lpr mice.

An MRL strain of mice bearing a Fas-deletion mutant gene, lpr, MRL/MpJ-lpr/lpr (MRL/lpr) develops collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjögren's syndrome, respectively. Development of such lesions seems dependent on host genetic background since the congenic C3H/HeJ-lpr/lpr (C3H/lpr) mice rarely develop them. To identify the gene loci affecting each lesion, a genetic dissection of these complex pathological manifestations was carried out. First, histopathological features in MRL/lpr, C3H/lpr, (MRL/lpr x C3H/lpr) F1 intercross, and MRL/lpr x (MRL/lpr x C3H/lpr) F1 backcross mice were analyzed. Genomic DNA of the backcross mice were subjected to association studies by Chi-squared analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. As a result, gene loci recessively associated with each lesion were mapped on different chromosomal positions. We concluded that each of these lesions in MRL/lpr mice is under the control of a different set of genes, suggesting that the complex pathological manifestations of collagen disease result from polygenic inheritance.

Animals↗
PubMed1999

26-cholesterol hydroxylase in rat corpora lutea: A negative regulator of progesterone secretion.

From a subtracted cDNA library of rat luteal tissue, where cDNA fragments in functional luteal tissue were subtracted from those in regressing luteal tissue, a cDNA clone corresponding to 26-cholesterol hydroxylase (P450(C26)) was obtained. It is known that P450(C26) catalyzes the conversion of cholesterol to 26-hydroxycholesterol, which blocks cholesterol utilization in the cell, and that 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) catalyzes the conversion of progesterone to an inactive steroid, 20alpha-dihydroprogesterone (20alpha-OHP). Thus, using pseudopregnant rats as a model, physiological cooperation of P450(C26) and 20alpha-HSD in the reduction of progesterone release toward the end of the luteal phase was evaluated. Levels of P450(C26) and 20alpha-HSD mRNA were examined in corpora lutea from pseudopregnant rats by Northern blot or reverse transcription-polymerase chain reaction or both. P450(C26) mRNA was ubiquitously expressed in corpora lutea, and its expression increased toward the end of pseudopregnancy, while 20alpha-HSD was expressed in all corpora lutea on Day 16 (Day 0 = the day of after cervical stimulation) but not detected before Day 10. An inhibitor of 20alpha-HSD, STZ26 (D-homo-16-oxa-4-androstene-3,16alpha-dione), was administered at various doses to rats from Day 12 to 20, effectively suppressing the elevation of 20alpha-OHP in a dose-dependent manner but not the depletion of progesterone completely. The expression of P450(C26) mRNA was increased as STZ26 dose increased, which negatively correlated with the progesterone levels. These results strongly suggest that P450(C26) cooperated with 20alpha-HSD in the reduction of progesterone release from the rat luteal tissue at the end of the functional luteal phase.

20-Hydroxysteroid Dehydrogenases↗
PubMed1999

Does the Murphy eye reduce the reliability of chest auscultation in detecting endobronchial intubation?

UNLABELLED: Bilateral breath sounds are routinely auscultated after endotracheal intubation to verify that the endotracheal tube (ETT) tip is properly positioned. We conducted the present study to ascertain whether the eye of the Murphy tube has an influence on the reliability of auscultation of breath sounds in detecting endobronchial intubation. Twenty patients undergoing scheduled oral and maxillofacial surgery participated in this study. After the induction of general anesthesia, either the Magill tube or the Murphy tube was inserted through the nose into the trachea. The fiberoptic bronchoscope was inserted through the ETT, and the distance from the nares to the carina of the trachea was measured. When breath sounds from the left side of the chest changed and disappeared while the ETT was being advanced, the distance from the nares to the ETT tip was measured. Unilateral auscultatory change was not observed until the ETT tip was advanced beyond the carina and inserted 1.5+/-0.4 cm into the right mainstem bronchus when the Magill tube was used and 2.0+/-0.4 cm when the Murphy tube was used (P < 0.01). Breath sounds disappeared when the ETT tip was further advanced up to 3.2+/-0.3 cm from the carina. We demonstrated that the eye of the Murphy tube reduces the reliability of chest auscultation in detecting endobronchial intubation. IMPLICATIONS: The Murphy eye was designed to allow ventilation of the lung when the bevel of the endotracheal tube is occluded. We demonstrated that the eye of the Murphy tube reduces the reliability of chest auscultation in detecting endobronchial intubation.

Adult↗
PubMed1999

sn-glycerol-1-phosphate-forming activities in Archaea: separation of archaeal phospholipid biosynthesis and glycerol catabolism by glycerophosphate enantiomers.

In Methanobacterium thermoautotrophicum, sn-glycerol-1-phosphate (G-1-P) dehydrogenase is responsible for the formation of the Archaea-specific backbone of phospholipids, G-1-P, from dihydroxyacetonephosphate (DHAP). The possible G-1-P-forming activities were surveyed in cell-free extracts of six species of Archaea. All the archaeal cell-free homogenates tested revealed the ability to form G-1-P from DHAP. In addition, activities of G-3-P-forming glycerol kinase and G-3-P dehydrogenase were also detected in four heterotrophic archaea, while glycerol kinase activity was not detected in two autotrophic methanogens. These results show that G-1-P is produced from DHAP by G-1-P dehydrogenase in a wide variety of archaea while exogenous glycerol is catabolized via G-3-P.

Dihydroxyacetone Phosphate↗
PubMed1999

Electrophysiological correlates of pulsatile and surge gonadotrophin secretion.

The hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator governs intermittent discharges of GnRH into the pituitary portal circulation and, consequently, modulates the pulsatile pattern of gonadotrophin secretion. Electrophysiological correlates of pulsatile gonadotrophin secretion have been demonstrated in the mediobasal hypothalamus of monkeys, rats and goats by recording multiple unit activity. A temporal coincidence between characteristic increases in multiple unit activity and gonadotrophin pulses in the circulation is seen under a variety of physiological and experimental conditions in all three species examined, providing evidence that hypothalamic multiple unit activity originates in the GnRH pulse generator. During a preovulatory gonadotrophin surge induced by oestrogen in ovariectomized animals or occurring spontaneously in intact animals, GnRH pulse generator activity is decelerated, suggesting that it is not involved in generating the gonadotrophin surge. The gonadotrophin surge may be generated by an oestrogen-responsive neuronal complex intrinsically different from the GnRH pulse generator, the electrical operation of which remains unknown.

Animals↗
PubMed1999

[Usefulness of pharmacokinetic modulating chemotherapy (PMC) for the postoperative adjuvant therapy of colorectal carcinoma: a preliminary report].

Pharmacokinetic modulating chemotherapy (PMC) using oral UFT and continuous venous 5-FU infusion was administered to 22 resectable patients with Dukes' B2-D colorectal carcinomas. The regimen was arranged as follows: Group A (n = 12) UFT 300-450 mg/day, 5 days a week and 5-FU 440-600 mg/m2/24 hr (750-1,000 mg/body/24 hr) once a week, Group B (n = 10), UFT less than 300 mg/day, 5 days a week, and/ or 5-FU less than 440 mg/m2/24 hr (750 mg/body/ 24 hr) once a week. The control group (Group C, n = 26) was selected at random from among non-PMC cases matched for other background factors and in which surgery had been performed during the past 4 years. Fifteen out of 26 patients in Group C were treated with 5-FU masked compounds orally. The cumulative 2 year recurrent rates of Groups A, B and C were 8.3%, 52.0% and 50.0%, respectively; the rate of Group A was significantly lower than that of Group B (p < 0.05). Four patients who suffered from PMC-related side effects of grade 1-2 wanted to decrease their dosage of UFT and/or 5-FU. They were registered in Group B. These results suggest that the regimen of Group A was advantageous in improving the prognosis after resection of Dukes' B2-D colorectal carcinoma.

Administration, Oral↗
PubMed1998

Increased expression of rat ribosomal protein L4 mRNA in 5-azacytidine-treated PC12 cells prior to apoptosis.

5-Azacytidine (5AzC), a cytidine analogue, is thought to induce apoptosis in fetal neuronal cells and PC12 cells through DNA hypomethylation. However, apoptosis can be inhibited by adding protein synthesis inhibitors, indicating de novo protein synthesis may be partially responsible for apoptosis. Therefore, genes expressed just before apoptosis from 5AzC-treated PC12 cells were cloned. cDNA libraries were prepared from both 5AzC-treated and untreated PC12 cells and these libraries were subtracted. One clone overexpressed in 5AzC-treated PC12 cells was obtained, and was identified as the nearly full length (9 nt at 5' end and 1 nt at 3' end missing) rat ribosomal protein L4 (rpL4) gene. Time course study of Northern blot analysis in 5AzC-treated PC12 cells revealed that the peak of rat rpL4 gene expression preceded DNA fragmentation. COS-7 cells transfected with different amounts of cDNA from the subtracted clone expressed rat rpL4 dose-dependently. DNA fragmentation in the transfected COS-7 cells occurred proportional to the amount of the cDNA used for transfection. The present study indicates that rat rpL4 gene expression selectively increases in PC12 cells prior to 5AzC-induced apoptosis and that COS-7 cells transfected with and expressing the rat rpL4 gene also undergo apoptosis.

Animals↗
PubMed1998

Vasculitis-susceptible genes in mice with a deficit in Fas-mediated apoptosis.

Autoimmune diseases show complex pathological manifestations, which frequently involve systemic vasculitis. This complication is understood to be a manifestation of advanced disease, or to represent distinct entities, restricted by genetic and/or environmental factors. An MRL/Mp strain of mice bearing the Fas deletion mutant gene, lpr (MRL/lpr), spontaneously develop systemic vasculitis coincidentally with glomerulonephritis, arthritis and sialoadenitis, but a C3H/HeJ-lpr/lpr (C3H/lpr) strain does not. Thus, this is a suitable model for analyzing the genetic basis of vasculitis in autoimmune diseases. To genetically dissect these complex pathological manifestations, a linkage analysis of each lesion with polymorphic microsatellite markers was performed by using MRL/lpr x (MRL/lpr x C3H/lpr)F1 backcross mice. Vasculitis-susceptible gene loci were mapped on chromosomes 3 and 4, which were not associated with glomerulonephritis, arthritis and sialoadenitis. These results indicate that systemic vasculitis in MRL/lpr mice may be under the control of host genes which are different from those for other autoimmune diseases.

Animals↗
PubMed1998

Activity of ventromedial hypothalamic neurons suppressing heart rate is associated with paradoxical sleep in the rat.

Cardiovascular change is one of the common features of paradoxical sleep. Our study offers evidence that one of the central areas regulating the circulation during sleep is the ventromedial nucleus of the hypothalamus (VMH). We found a group of neurons in this hypothalamic nucleus of rats whose electrical activity was exclusively increased during paradoxical sleep, and was associated with a reduction in heart rate. The onset of this neural activity usually followed that of paradoxical sleep. The incidence and duration of paradoxical sleep was increased by means of microinjection of carbachol, a cholinergic agonist, into the pontine reticular formation, and the neural activity of the VMH still appeared in synchrony with carbachol-induced paradoxical sleep. These results suggest that the cholinergic paradoxical sleep-inducing mechanism in the pons facilitate the excitability of these neurons. We have previously shown that these VMH neurons suppress blood pressure and heart rate via inhibition of the vasomotor neurons in the medulla oblongata. Taken together, our findings suggest that a group of neurons in the VMH suppresses the circulatory system during paradoxical sleep.

Animals↗
PubMed1998

Crystal structures of reaction intermediates of L-2-haloacid dehalogenase and implications for the reaction mechanism.

Crystal structures of L-2-haloacid dehalogenase from Pseudomonas sp. YL complexed with monochloroacetate, L-2-chlorobutyrate, L-2-chloro-3-methylbutyrate, or L-2-chloro-4-methylvalerate were determined at 1.83-, 2.0-, 2.2-, and 2.2-A resolutions, respectively, using the complex crystals prepared with the S175A mutant, which are isomorphous with those of the wild-type enzyme. These structures exhibit unique structural features that correspond to those of the reaction intermediates. In each case, the nucleophile Asp-10 is esterified with the dechlorinated moiety of the substrate. The substrate moieties in all but the monochloroacetate intermediate have a D-configuration at the C2 atom. The overall polypeptide fold of each of the intermediates is similar to that of the wild-type enzyme. However, it is clear that the Asp-10-Ser-20 region moves to the active site in all of the intermediates, and the Tyr-91-Asp-102 and Leu-117-Arg-135 regions make conformational changes in all but the monochloroacetate intermediates. Ser-118 is located near the carboxyl group of the substrate moiety; this residue probably serves as a binding residue for the substrate carboxyl group. The hydrophobic pocket, which is primarily composed of the Tyr-12, Gln-42, Leu-45, Phe-60, Lys-151, Asn-177, and Trp-179 side chains, exists around the alkyl group of the substrate moiety. This pocket may play an important role in stabilizing the alkyl group of the substrate moiety through hydrophobic interactions, and may also play a role in determining the stereospecificity of the enzyme. Moreover, a water molecule, which is absent in the substrate-free enzyme, is present in the vicinities of the carboxyl carbon of Asp-10 and the side chains of Asp-180, Asn-177, and Ala-175 in each intermediate. This water molecule may hydrolyze the ester intermediate and its substrate. These findings crystallographically demonstrate that the enzyme reaction proceeds through the formation of an ester intermediate with the enzyme's nucleophile Asp-10.

Binding Sites↗
PubMed1998

Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion.

Interleukin (IL)-1 is a major mediator of inflammation and exerts pleiotropic effects on the neuro-immuno-endocrine system. To elucidate pathophysiological roles of IL-1, we have first produced IL-1alpha/beta doubly deficient (KO) mice together with mice deficient in either the IL-1alpha, IL-1beta, or IL-1 receptor antagonist (IL-1ra) genes. These mice were born healthy, and their growth was normal except for IL-1ra KO mice, which showed growth retardation after weaning. Fever development upon injection with turpentine was suppressed in IL-1beta as well as IL-1alpha/beta KO mice, but not in IL-1alpha KO mice, whereas IL-1ra KO mice showed an elevated response. At this time, expression of IL-1beta mRNA in the diencephalon decreased 1.5-fold in IL-1alpha KO mice, whereas expression of IL-1alpha mRNA decreased >30-fold in IL-1beta KO mice, suggesting mutual induction between IL-1alpha and IL-1beta. This mutual induction was also suggested in peritoneal macrophages stimulated with lipopolysaccharide in vitro. In IL-1beta KO mice treated with turpentine, the induction of cyclooxygenase-2 (EC 1.14.99.1) in the diencephalon was suppressed, whereas it was enhanced in IL-1ra KO mice. We also found that glucocorticoid induction 8 h after turpentine treatment was suppressed in IL-1beta but not IL-1alpha KO mice. These observations suggest that IL-1beta but not IL-1alpha is crucial in febrile and neuro-immuno-endocrine responses, and that this is because IL-1alpha expression in the brain is dependent on IL-1beta. The importance of IL-1ra both in normal physiology and under stress is also suggested.

Animals↗
PubMed1998

Direct antigen presentation through binding of donor intercellular adhesion molecule-1 to recipient lymphocyte function-associated antigen-1 molecules in xenograft rejection.

Cellular interactions that lead to graft rejection were examined in a rat-to-mouse xenogeneic combination using species-specific monoclonal antibodies (mAbs) against donor and recipient intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) molecules, respectively. Although both mAbs displayed moderate blocking activity in an in vitro mixed lymphocyte response assay, strong suppression was observed when anti-donor (rat) ICAM-1 mAb was combined with anti-recipient (mouse) LFA-1 mAb. Likewise, significant prolongation of islet xenograft survival was observed with these mAbs. Thus, 0.05 mg of anti-mouse LFA-1 mAb and anti-rat ICAM-1 mAb given on days 0 and 1 produced significant prolongation of graft survival over the control (51+/-20 days vs. 10+/-3 days, P<0.0001), but not when anti-mouse ICAM-1 mAb was combined with anti-mouse LFA-1 mAb (13+/-3 days). In this species combination, mouse T cells were able to proliferate in the presence of rat antigen-presenting cells (APCs) in a cell number-dependent manner, but not in the presence of mouse APCs. The binding assay showed that LFA-1 molecules on mouse T cells can bind immobilized rat ICAM-1 molecules. These results suggest that rat ICAM-1 molecules on APCs can interact with mouse LFA-1 molecules on T cells across a species barrier and that this binding generates the consequent immune responses leading to rejection. mAb treatment against these adhesion molecules of recipient as well as donor is crucial for preventing rejection in a xenogeneic transplantation model.

Animals↗