Biomedical subjects
Publications and source records attributed to Y Iwabuchi.
A new enantiocontrolled synthesis of a potent immunosuppressant(-)-mycestericin E has been accomplished by using cinchona alkaloid-catalyzed asymmetric Baylis-Hillman reaction of an aldehyde with 1,1,1,3,3,3-hexafluoroisopropyl acrylate and Lewis acid-promoted cyclisation of an epoxytrichloroacetimidate as the key steps.
Reaction of (S)-2-(tert-butyldiphenylsilyloxy)-5-(mesyloxy)pentanal with hydroxylamine in allyl alcohol brought about simultaneous 1,3-dipolar cycloaddition of the resulting nitrone to allyl alcohol to give three diastereoisomeric adducts, from which (+)-febrifugine and (+)-isofebrifugine, potent antimalarial alkaloids, were synthesized.
[figure: see text] This report describes a concise enantioselective synthesis of the A-ring synthon for the synthesis of 1 alpha-hydroxyvitamin D3 compounds. The synthesis involves two notable transformations: (I) stereoselective construction of the enol triflate from the vinyl ketone by Michael addition of Ph2P(O)Li followed by in situ triflation of the resulting enolate and (II) palladium-catalyzed Heck type cyclization of the enol triflate.
E4 allele of Apolipoprotein E (ApoE) is considered to be not only a risk factor for Alzheimer's disease (AD) but also a determinant of clinical features in AD. However, it is still controversial whether ApoE e4 allele is related to age at onset, severity of memory impairment or brain morphological changes in AD patients. The present study examined the issue in Japanese population: 1) ApoE genotype on in 38 normal controls and 32 AD patients; 2) association between e4 allele of ApoE and clinical features including Wechsler Memory Scale-Revised in 32 AD patients; and 3) association between e4 allele of ApoE and change in size of inferior horn in lateral ventricle (LV) in 13 out of 32 AD patients. The e4 allele of ApoE frequency was higher in AD patients than in normal controls. There was no significant difference in age at onset or neuropsychological results between AD with and without e4 allele of ApoE. Alteration per month of the inferior horn sizes in LV measured by MRI was similar in the AD patients with and without e4 allele of ApoE. These results suggest that e4 allele of ApoE is a risk factor but not a determinant of clinical features for AD in Japanese population.
A-ring diastereomers of 1alpha,25-dihydroxy-22-oxavitamin D3 (OCT) (2), 3-epi-1alpha,25-dihydroxy-22-oxavitamin D3 (3-epiOCT) (3) and 1,3-diepi-1alpha,25-dihydroxy-22-oxavitamin D3 (1,3-diepiOCT) (4) were synthesized by the convergent method. In vitro binding affinity for rat vitamin D binding protein and calf-thymus vitamin D receptor, differentiation-inducing activity on HL-60 cells, and transcriptional activity of 3-epiOCT (3) and 1,3-diepiOCT (4) were evaluated in comparison with OCT (2), 1-epi-1alpha,25-dihydroxy-22-oxavitamin D3 (1-epiOCT) (5) and 1alpha,25-dihydroxyvitamin D3 (1).
The characterization of new conjugated vitamin D metabolites in rat bile was performed using HPLC, liquid chromatography/tandem mass spectrometry combined derivatization, and GC-MS. After the administration of 24,25-dihydroxyvitamin D(3) to rats, 23, 25-dihydroxy-24-oxovitamin D(3) 23-glucuronide, 3-epi-24, 25-dihydroxyvitamin D(3) 24-glucuronide, and 24,25-dihydroxyvitamin D(3) 3-sulfate were obtained as new biliary metabolites together with 24,25-dihydroxyvitamin D(3) 3- and 24-glucuronides. The above metabolites, except 24,25-dihydroxyvitamin D(3) 3-glucuronide, were obtained from rats dosed with 25-hydroxyvitamin D(3). 23, 25-Dihydroxyvitamin D(3) 23-glucuronide was also obtained from the bile of rats administered 25-hydroxyvitamin D(3) in addition to its 3-glucuronide, 25-glucuronide, and 3-sulfate. Thus, it was found that 24,25-dihydroxyvitamin D(3) and 25-hydroxyvitamin D(3) were directly conjugated as glucuronide and sulfate, whereas at the C-23 position, they were hydroxylated and then conjugated. Furthermore, we found that the C-3 epimerization acts as one of the important pathways in vitamin D metabolism.
The Hic-5 protein is encoded by a transforming growth factor-beta1- and hydrogen peroxide-inducible gene, hic-5, and has striking similarity to paxillin, especially in their C-terminal LIM domains. Like paxillin, Hic-5 is localized in focal adhesion plaques in association with focal adhesion kinase in cultured fibroblasts. We carried out yeast two-hybrid screening to identify cellular factors that form a complex with Hic-5 using its LIM domains as a bait, and we identified a cytoplasmic tyrosine phosphatase (PTP-PEST) as one of the partners of Hic-5. These two proteins are associated in mammalian cells. From in vitro binding experiments using deletion and point mutations, it was demonstrated that the essential domain in Hic-5 for the binding was LIM 3. As for PTP-PEST, one of the five proline-rich sequences found on PTP-PEST, Pro-2, was identified as the binding site for Hic-5 in in vitro binding assays. Paxillin also binds to the Pro-2 domain of PTP-PEST. In conclusion, Hic-5 may participate in the regulation of signaling cascade through its interaction with distinct tyrosine kinases and phosphatases.
In a previous study we found that sensory regeneration was neurotropically selective regardless of the end organ, but motor regeneration was not, which made us doubt the existence of topographic specificity. The purpose of the present study was to confirm the existence of topographic specificity in rats. The proximal stump of either the peroneal or tibial nerve was inserted into the proximal limb of a silicone Y-chamber. Both distal stumps of peroneal and tibial nerve were inserted into the distal limbs. The gap between the stumps was set at either 4 mm (n = 8, on each subgroup) or 8 mm (n = 8, on each subgroup). Six weeks later the number of regenerated axons in the distal two limbs were counted and compared. The number of regenerated axons towards the distal tibial nerve side was significantly larger in every model. Regenerated axons from the proximal peroneal stump did not preferentially choose the distal peroneal stump. The existence of topographic specificity is unlikely.
A new metabolic pathway of (24R)-24,25-dihydroxyvitamin D3 [24,25(OH)2D3] was clarified in the in vivo experiments. After the administration of 24,25(OH)2D3 to rats, a new monoglucuronide of a vitamin D metabolite was obtained from the bile together with 24,25(OH)2D3 3- and 24-glucuronides. The genin of the metabolite was identified as 3-epi-24,25(OH)2D3 in comparison with the synthetic sample based on the data from 1H-NMR, GC/MS, and LC/atmospheric pressure chemical ionization-MS. The conjugation position was determined to be the 24-hydroxy group by the LC/electrospray ionization-MS and -MS/MS/MS combined with derivatization. To our knowledge, this is the first reported instance of the epimerization of the 3-hydroxy group of vitamin D compound with no hydroxy group at the 1alpha-position.
Four tachykinins were each administered at 20 micrograms/kg body wt. All the tachykinins had a positive effect on granular secretion from the lingual epithelium, and the loss of cytoplasm from cells of the lingual epithelium was greatest with physalaemin and eledoisin, moderate with neurokinin A, and smallest with substance P. These reactions were very different from those in mammals, in which tachykinins induce only watery secretions. Only physalaemin had a positive effect on protein secretion from the lingual gland. Transmission electron microscopy revealed that electron-dense granules in cells of the lingual epithelium were discharged during stimulation with physalaemin and eledoisin by typical exocytosis. Discharge of these granules was indistinct after the administration of substance P and of neurokinin A. Exocytosis of electron-dense granules from cells of the lingual gland was clearly detectable by electron microscopy after the administration of physalaemin, reflecting observations made by light microscopy. However, mucous granules in the lingual gland were secreted by an exocrine process only after administration of physalaemin.
1. The effects of rat calcitonin gene-related peptide (rCGRP), rat calcitonin (rCT) and salmon calcitonin (sCT) on the substance P-mediated (SP-mediated) secretion of fluid from the rat submandibular gland were investigated. 2. Rat CGRP potentiated and prolonged the SP-mediated secretion of fluid from the rat submandibular gland in a dose-dependent manner. CGRP also enhanced methacholine- and phenylephrine-mediated secretion of fluid. 3. The potentiating effect of the combination of rCGRP and SP was somewhat reduced by pretreatment with spantide, human CGRP8-37 and atropine but not by pretreatment with phentolamine or with propranolol. 4. Salmon CT at a low dose mimicked the effect of rCGRP on the SP-mediated secretion of fluid, but its potency was lower than that of rCGRP. However, rCT had no effect on the SP-mediated secretion of fluid. 5. These results suggest that the potentiating effects of rCGRP and SP might involve cholinergic receptors, as well as CGRP and tachykinin receptors, and that sCT, but not rCT, is able to mimic rCGRP in potentiating the secretion of fluid induced by SP.
We analyzed a case of malignant melanoma that resembled malignant peripheral nerve sheath tumor with marked neurotropism. The subungual tumor in the right ring finger extended along the ulnar nerve for a distance of 30 cm, as well as along the median and musculocutaneous nerves, with lymph nodal metastases. The tumor consisted of interlacing spindle-shaped cells with large nuclei and distinct nucleolei. Immunohistochemically, the tumor cells were diffusely positive for S-100 protein. Five years after forequarter amputation, the patient is alive without disease. Malignant melanoma has the potential of invading several major peripheral nerves and must be distinguished from malignant peripheral nerve sheath tumor, which rarely metastasizes to regional lymph nodes.
In vitro affinity maturation for evolving catalytic antibodies has been demonstrated by generating a diverse repertoire of the appropriate complementarity-determining regions on a phage surface. Phage display is followed by a selection based on binding to an altered antigen that was not used at the time of immunization, and provides variants with new catalytic activity and substrate specificity. This library format reduces the time needed to isolate the desired catalytic antibody fragments to under 2 weeks.
The interactions between substance P and beta-adrenergic agonists such as isoprenaline, dobutamine and terbutaline in the control of the secretion of fluid and protein from the rat submandibular gland have been examined. Substance P elicited large volumes of saliva whereas isoprenaline, dobutamine and terbutaline elicited small volumes only. The secretion of fluid in response to substance P was markedly enhanced when substance P was administered in combination with isoprenaline or dobutamine but not when it was administered in combination with terbutaline. Isoprenaline elicited large amounts of protein, whereas substance P elicited small amounts. The secretion of protein in response to isoprenaline did not change when isoprenaline was administered in combination with substance P. The secretion of fluid and protein induced by substance P in combination with isoprenaline was antagonized by metoprolol and by spantide, but it was unaffected by pretreatment with ICI118551. These results suggest that in the rat submandibular gland stimulation of beta1-adrenoceptors but not of beta2-adrenoceptors potentiates the secretion of fluid that is induced by stimulation of tachykinin receptors, whereas stimulation of tachykinin receptors does not enhance the secretion of protein that is induced by stimulation of beta1-adrenoceptors.
OBJECTIVE: To investigate the prevalence of abnormalities of the paranasal sinus detected by magnetic resonance imaging (MRI) in asymptomatic subjects. DESIGN: Prospective study. SETTING: Outpatient clinic. PATIENTS: A total of 325 patients who underwent MRI for suspected intracranial disease. Of those, 257 patients lacked nasal or sinus symptoms. RESULTS: Sinus abnormalities were seen on MRI in 153 (47.1%) of 325 patients, including 107 (41.6%) of the 257 asymptomatic patients. Subjects older than 50 years had a significantly higher frequency of sinus abnormalities on MRI (49.8%) vs those younger than 50 years (39.5%) (P < .05). The maxillary sinus abnormality was observed in 99 patients (38.5%) and the ethmoid sinus abnormality was observed in 52 (20.2%) (P < .01). The most common abnormality was mucosal thickening in the maxillary and ethmoid sinuses. CONCLUSION: A high prevalence of sinus abnormalities was detected in asymptomatic subjects on MRI.
Comparative observations of the effects of cholinergic and adrenergic agonists (such as pilocarpine, phenylephrine and isoproterenol) on the secretion of salivary fluid and of secretory granules from the lingual epithelium and the lingual gland in the Tokyo Daruma pond frog, Rana porosa porosa, were made by light and transmission electron microscopy. The effect of pilocarpine on the loss of cytoplasm in both the lingual epithelium and the lingual gland was the strongest, and that of isoproterenol was the weakest. Transmission electron microscopy revealed that electron-dense granules, located in cells in both the lingual epithelium and the lingual gland, were discharged by exocytosis after stimulation by phenylephrine and isoproterenol. Immediately before secretion of these granules, they became somewhat larger and round or distorted in shape. However, after administration of pilocarpine, no obvious discharge of electron-dense granules was apparent and, instead, granules in some cells began deteriorating within the cells and those in other cells developed electron-dense and electron-lucent areas. A dot-like pattern was recognized in the electron-dense areas of these granules. These phenomena were assumed to be secondary effects accompanying the secretion of salivary fluid from cells of the lingual epithelium and the lingual gland. By contrast, mucous granules in the lingual gland were secreted by a holocrine process.
The posterior interosseous cutaneous flap is characterized by its thinness and the adjustable length of its vascular pedicle. This flap can be used both as a free and reversed vascular pedicled flap. We applied the free flap mostly for reconstruction of the digits, and the reversed vascular pedicled flap for soft-tissue defects of the proximal hand. Of 17 free flaps, 16 survived completely, and 1 developed partial necrosis. Eleven flaps were elevated as reversed vascular pedicled flaps, three of which were combined with the lateral arm flap to cover large defects. In these three combined flaps, the posterior radial collateral artery was anastomosed to an artery in the recipient site to enhance circulation; all three flaps survived completely. Operative time was 30 to 40 minutes shorter for the reversed vascular pedicled flaps. Two of the remaining eight reversed vascular pedicled flaps developed partial necrosis. The flap success rate was thus higher in the free flaps than in the reversed vascular pedicled flaps.
The problems with the system for reconstructive surgery for head and neck cancers in our department where plastic surgeons are regularly invited from distant facilities were discussed. Especially, the importance of preoperative discussion between the plastic surgeons and ENT doctors was stressed. The computer system with Internet will play an important role in exchanging information such as CT scans and MRI scans between the plastic surgeons and ENT doctors. Moreover, the establishment of a system to prevent postoperative troubles such as closure of anastomosed vessels was stressed. Twenty-seven re-vascularized free flaps had been transferred with a 96.3% success rate (26 of 27 cases). We concluded that the system for reconstructive surgery under the multiple facility cooperation system worked well.