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Biomedical subjects

M Ohkubo

Publications and source records attributed to M Ohkubo.

At least 19 recordsLinked to original sources
PubMed2006

Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with polymyositis/dermatomyositis.

OBJECTIVES: To study the efficacy and safety of monthly intravenous pulse cyclophosphamide (IVCYC) therapy for progressive interstitial pneumonia in polymyositis/dermatomyositis (PM/DM). METHODS: Seventeen patients with PM/DM/amyopathic DM (mean age 51.4 +/- 10.4, mean follow-up 32 months) who received IVCYC for progressive interstitial pneumonia between August 1993 and October 2002 were studied. Nine patients had failed to respond to previous treatment with high-dose steroid and/or immunosuppressant. Cyclophosphamide (300-800 mg/m2) was given at least six times every 4 weeks. Oral prednisolone (0.5-1 mg/kg/day) was administered for the first 2 weeks and was gradually tapered. Response to treatment was evaluated based on the degree of exertional dyspnea, pulmonary function test and high-resolution computed tomography (HRCT). RESULTS: Eleven of 17 patients showed improvement in their dyspnea; six out of seven patients who had required oxygen treatment before IVCYC no longer did so after IVCYC. Eight of 17 patients had >or=10% improvement of vital capacity (VC)% and 9/17 had >or=10 point reduction in their HRCT score. Twelve patients had exhibited at least one result. Two patients with anti-Jo-1 antibodies showed a flare-up of interstitial pneumonia or myositis. After the IVCYC therapy, mean VC% improved by 15% (from 68 to 83%, P = 0.0034). The extent of abnormal lesions in HRCT was reduced from 24 to 13% (P = 0.0055). There was neither death nor severe toxicities observed. CONCLUSIONS: In this open-label study, IVCYC improved symptoms, pulmonary function tests and HRCT findings in patients with PM/DM. Longitudinal controlled studies are required to further confirm the efficacy of IVCYC.

Adult↗
PubMed2006

Parietal white matter abnormalities in obsessive-compulsive disorder: a magnetic resonance spectroscopy study at 3-Tesla.

OBJECTIVE: To identify a neurochemical basis for the hypothesis that an aberrant cortico-subcortical circuit underlies obsessive-compulsive disorder (OCD). The white matter was also investigated because of recent research which suggests the altered connectivity of axons. METHOD: Using 3-Tesla magnetic resonance spectroscopy, the relative concentrations of N-acetylaspartate (NAA) and choline-containing compounds (Cho) to creatine/phosphocreatine (Cr) were measured in the anterior cingulate, basal ganglia, thalamus, frontal and parietal white matter of 12 OCD patients, and 32 control subjects. RESULTS: The mean concentration of Cho/Cr was significantly higher in the patients than in the controls, but only in the parietal white matter, while no significant group differences in NAA/Cr were observed in any of the brain regions. Parietal Cho/Cr correlated positively with the severity of OCD symptoms. CONCLUSION: This finding provides indirect evidence for the parietal white matter involvement in OCD, thus suggesting a change in the phospholipids of myelinated axons and/or glia cells.

Adolescent↗
PubMed2005

High-resolution magnetic resonance of the extracranial facial nerve and parotid duct: demonstration of the branches of the intraparotid facial nerve and its relation to parotid tumours by MRI with a surface coil.

AIM: To investigate the usefulness of high-resolution MR imaging in the evaluation of the extracranial facial nerve, compared with surgical findings. MATERIALS AND METHODS: Thirteen patients with benign parotid tumours were studied on a 1.5-T MR system with a 3 in circular surface coil. High-resolution T1-weighted spin-echo, T2-weighted fast spin-echo, and three-dimensional gradient-recalled acquisition in the steady state (GRASS) images were obtained in the axial planes. Oblique reformatted images were generated. Tumours, parotid ducts and facial nerves were identified on these images. The relationship of the tumours to the facial nerves was confirmed at surgery. RESULTS: Facial nerves appeared as linear structures of low intensity on all pulse sequences. The main trunks and cervicofacial and temporofacial divisions of the facial nerves were identified in 100%, 84.1% and 53.8% of GRASS images, respectively. Parotid ducts appeared as structures of low intensity on T1-weighted (66.6%) and GRASS images (81.8%), and as structures of very high intensity on T2-weighted images (91.7%). The relationships of the tumours to the facial nerves were correctly diagnosed in 11 (91.7%) of 12 cases. CONCLUSION: High-resolution MR imaging depicts the extracranial facial nerve and the parotid duct, and is useful for preoperative evaluation of parotid gland tumours.

Adult↗
PubMed2004

Contribution of CD4+ and CD8+ T cells and interferon-gamma to the progress of chronic rejection of kidney allografts: the Th1 response mediates both acute and chronic rejection.

T cells mediating chronic rejection (CR) of human kidney allografts were characterized by comparing them with those mediating acute rejection (AR). Two lines of analysis were performed using biopsy specimens (23 CR and 8 AR). First, the extent of infiltration of CD4+ and CD8+ T cells into allografts was assessed from mRNA expression of CD4 and CD8. The group of CR specimens was not significantly different from the group of AR specimens in terms of the extent of CD4+ and CD8+ T cell infiltration, underlining the importance of the immunological contribution to the progress of CR. Second, Th1/Th2 polarization in infiltrating T cells was investigated by measuring mRNA expression of interferon gamma (IFN-gamma; a Th1 cytokine) and interleukin 4 (IL-4; a Th2 cytokine). IFN-gamma expression was detected in most CR specimens, and was not significantly different between the group of CR specimens and the group of AR specimens. On the other hand, IL-4 expression was detected in only two CR specimens and one AR specimen; from its pathological features, the AR in this last case was concomitant with CR. These results suggest that most cases of CR and of AR are mediated by Th1 mechanisms, although some cases of CR show features of both Th1 and Th2.

Acute Disease↗
PubMed2004

Clonality analysis of T cells mediating acute and chronic rejection in kidney allografts.

The clonality of T-cell populations mediating acute and chronic rejection (AR and CR, respectively) of kidney allografts was ascertained by investigating the diversity of TCRBV genes expressed by allograft-infiltrating T cells. Both oligoclonality and polyclonality cases were found in biopsy specimens of AR as well as CR. These results indicated that the T-cell clonality in each specimen did not correlate directly with the mode of rejection. When AR and CR specimens were compared, however, the CR specimen group was significantly more polyclonal (or less oligoclonal) than the AR group. This result may reflect the higher chance of epitope spreading in the more slowly progressing CR than in AR.

Clone Cells↗
PubMed2001

Synthesis and characterization of coronanes: multicyclopropane-fused macrocyclic arrays.

Stepwise macrocyclization of the all syn-trans-1,15-quinquecyclopropanedimethanol (4) with iso- and terephthaloyl chlorides and 4,4'-methanediyl-dibenzoic acid (28) gave the corresponding coronanes 22, 23, and 32. The same protocol was used with all syn-trans-1,21-septecyclopropanedimethanol (5) and 2,3-naphthalenedicarboxylic acid to obtain the macrolide 27. Direct macrocyclization of diol 4 and 1,10-phenanthroline-2,9-dicarbonyl chloride (33) and 2,2'-bipyridine-4,4'-dicarbonyl chloride (35) gave the coronanes 34 and 36, respectively. Ring closing metathesis (RCM) of the diene 42 using Cl2(Cy3P)2Ru=CHPh (48) (Grubbs's catalyst) gave the macrocyclic lactone 45. The structures of coronanes 22, 23, 32, 34, 36, and 45 were confirmed by X-ray crystallographic studies which showed the cyclopropyl chain to adopt very differing conformations throughout the series. Several of the macrocycles have significant free pathways through their ring centers, and in the case of compound 34 there is a water molecule hydrogen bonded within the ring. This latter compound has the potential to act as a chiral ligand to metal centers.

Crystallography, X-Ray↗
PubMed2001

A case of hypoplasia of the left hepatic lobe.

We report a case of hypoplasia of the left hepatic lobe in a 90-year-old woman. The left lobe was composed of three parts, central, anterior and lateral. The central part was equivalent to the hepatic hilum and consisted of 1/3 of a circle with a radius of about 30 mm and a maximum thickness of 8 mm. The anterior part had an elliptical shape of 65 mm x 33 mm, 21 mm thick. The lateral part had an elongated elliptical shape of 67 x 21 mm, also 16 mm thick. Sublobation was noted in the caudate and quadrate lobes. The caudate lobe was divided into two parts, and the quadrate lobe into three parts. The right lobe was bell-shaped with the top turned toward the diaphragm. The transverse diameter at the base was 108 mm, the antero-posterior diameter was 134 mm, and the distance from the bottom to the top was 95 mm. A deep groove paralleled the anterior rim at the base surface, where the gallbladder was in contact with the liver. No anomalous distribution of blood vessels or biliary canals was found. No atrophic feature was histologically recognized in any lobe.

Aged↗
PubMed2000

Purification of a novel serine proteinase inhibitor from the skeletal muscle of white croaker (Argyrosomus argentatus).

A novel serine proteinase inhibitor has been purified to homogeneity from the skeletal muscle of white croaker (Argyrosomus argentatus). The purification was carried out by ammonium sulfate fractionation, DEAE-Sephacel, heating treatment followed by column chromatographies on SP-Sepharose, Sephadex G-150 and gel-filtration high performance liquid chromatography. The molecular mass of the inhibitor was 55 kDa as estimated by SDS-PAGE and gel filtration. It specifically inhibited a myofibril-bound serine proteinase (MBSP) isolated from the skeletal muscle of lizard fish (Saurida wanieso). No inhibition, however, was detected toward other serine proteinases such as bovine trypsin, bovine chymotrypsin and a myofibril-bound serine proteinase from carp (Cyprinus carpio) muscle. Interestingly, the sequences of tryptic digested peptide fragments of MBSPI revealed high identity to that of porcine phosphoglucose isomerase (PGI) (76%) and other PGIs. Furthermore, purified MBSPI exhibits PGI activity, suggesting the inhibitor is a protein closely related to PGI. When rabbit muscle PGI was investigated, it also specifically suppressed the activity of MBSP. It thus strongly suggests that MBSPI is actually PGI and conversely, PGI is a specific inhibitor toward myofibril-bound serine proteinase(s).

Amino Acid Sequence↗
PubMed2000

Aberrant left gastric vein directly draining into the liver.

An aberrant left gastric vein found in dissection is reported here. The right gastric vein did not exist and only the left gastric vein originating from the lesser curvature of the stomach was present. It directly entered the liver without typically joining the trunk of the portal vein. After giving off a small branch to the liver parenchyma, the left gastric vein merged into the left branch of the portal vein. This aberrant left gastric vein may correspond to the phylogenetic and ontogenetic "left portal vein." The aberrant left gastric vein is considered to play an important role as a portal collateral pathway of the portal system, which is critical not only in anatomy but also in clinical diagnosis.

Cadaver↗
PubMed2000

A comparative study of simple methods to quantify cerebral blood flow with acetazolamide challenge by using iodine-123-IMP SPECT with one-point arterial sampling.

The aim of this study was to compare the accuracy of simplified methods for quantifying rCBF with acetazolamide challenge by using 123I-N-isopropyl-p-iodoamphetamine (IMP) and SPECT with one-point arterial sampling. After acetazolamide administration we quantified rCBF in 12 subjects by the following three methods: (a) the modified microsphere method, (b) the IMP-autoradiographic (ARG) method based on a two-compartment one-parameter model, and (c) the simplified method based on a two-compartment two-parameter model (functional IMP method). The accuracy of these methods was validated by comparing rCBF values with those obtained by the standard method: the super-early microsphere method with continuous withdrawal of arterial blood. On analyzing rCBF in each flow range (0-0.25, 0.25-0.5, 0.5-0.75 and more than 0.75 ml/g/min), rCBF values obtained by both methods (a) and (c) showed significant correlations (p < 0.01) with those obtained by the standard method in every range, but rCBF values obtained by method (b) did not significantly correlated in the high flow range (0.5-0.75 and more than 0.75 ml/g/min). Method (c) was found to be the most accurate, even though it needs two serial SPECT scans. When requiring one SPECT scan, method (a) was considered to be superior to method (b) because of its accuracy, especially in high flow regions loaded with acetazolamide.

Acetazolamide↗
PubMed2000

Studies on feline CD8+ T cell non-cytolytic anti-feline immunodeficiency virus (FIV) activity.

CD8+ T cells in FIV-infected cats inhibit feline immunodeficiency virus (FIV) replication by producing a soluble factor(s). In the present study, four SPF cats were experimentally infected with FIV. The period during which the anti-FIV activity of CD8+ T cells became detectable was investigated, and the presence or absence of this activity in the lymph nodes and spleen was examined. Furthermore, we investigated which step(s) of the FIV replication cycle are affected by this antiviral activity. This antiviral activity became detectable five weeks after FIV infection in early cases, and it was simultaneous with or one week after the induction of humoral immunity. All cats having CD8+ T cells with anti-FIV activity in the peripheral blood also possessed CD8+ T cells with anti-FIV activity in the lymph nodes. In contrast, CD8+ T cells from the spleens of some, but not all cats showed anti-FIV activity. CD8+ T cell-depleted peripheral blood mononuclear cells were cultured and reconstituted with CD8+ T cells on day 12 of culture after confirming FIV replication. The number of FIV proviral DNA copies in the cells did not change, but the amount of FIV p24 antigen production in the culture supernatant and the number of FIV mRNA copies in the cells decreased. These findings suggested that CD8+ T cell anti-FIV activity acts at the level of FIV mRNA synthesis from the FIV proviral DNA, inhibiting FIV replication by a non-cytolytic mechanism.

Animals↗
PubMed2000

Restenosis after balloon angioplasty of coarctation: relationship with ductus arteriosus.

BACKGROUND: Recently, balloon angioplasty (BA) has been used for the treatment of coarctation of the aorta (CoA) and the effectiveness of this treatment has been reported. However, the restenosis rate following BA in native CoA in the infant is high and the cause may be related to tissue properties at the origin of the ductus arteriosus (DA). However, the mechanisms responsible for restenosis remain uncertain. METHODS/RESULTS: The present study was designed to examine transformation of the smooth muscle cell (SMC) phenotypes using immunohistologic studies and to investigate the cause of restenosis of CoA following BA. A CoA model was surgically created in 15 newborn pigs (10-14-days-old; 2.4-4.1 kg). Balloon angioplasty was performed 1 month after the initial operation. One or 3 months after BA, animals were killed and immunohistologic studies on smooth muscle cell (SMC) antibodies against SM1, SM2 and SMemb of the myosin heavy chain (MHC) isoform were performed in the aorta at the CoA and DA. In the neointima, only SMemb was positive. In the SMC layer of the DA, only SM2 was positive. One month after BA, the external layer of the tunica media was strongly positive for SM2 only in the area around the origin of the DA. CONCLUSIONS: The first cause of restenosis is obstructive neointimal formation caused by the proliferation of undifferentiated SMC into the subendothelial tissue. This proliferation seems to be triggered by BA. The distribution of SM2 1 month after balloon angioplasty showed a similar pattern of proliferation of SMC in the external layer around the DA. This may represent a second mechanism of restenosis.

Angioplasty, Balloon↗
PubMed1999

Synthesis and biological activities of NB-506 analogues: Effects of the positions of two hydroxyl groups at the indole rings.

In the course of a study of 6-N-amino-substituted analogues of NB-506 (1), a more potent anticancer drug, J-109,404 (2), in which the formyl group of NB-506 was replaced with a 1,3-dihydroxypropane group, was reported. A study of further modification in the positions of two hydroxyl groups at the indole rings of 2 resulted in the discovery of a 2,10-dihydroxy analogue, J-107,088 (3), which is a promising anticancer agent with a broader therapeutic window than J-109,404.

Animals↗
PubMed1999

Mode of action of a new indolocarbazole anticancer agent, J-107088, targeting topoisomerase I.

J-107088 [6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]-carb azo le-5,7(6H)-dione] is a new derivative of NB-506, an indolocarbazole antitumor agent. J-107088 induced single-strand DNA cleavage only in the presence of topoisomerase I (top1) more effectively than NB-506 or camptothecin. The preferable sequences of the DNA cleaved by J-107088 were C/T / G as in the case of NB-506. This base-preference of J-107088 in top1-mediated cleavage was different from that of camptothecin, which was T / G/A. top1 poisons stabilize the complex between DNA and top1 (cleavable complex). This cleavable complex is released on addition of a high concentration of monovalent cation or removal of top1 poisons. The complex induced by J-107088 was quite stable; it was scarcely released on the addition of NaCl or dilution of J-107088, contrary to the case with camptothecin and NB-506. J-107088-inducing complexes were also stable in cultured cells, when the compound was added to the culture medium. These unique in vitro activities of J-107088 on top1 that differed from those of camptothecin and NB-506 may be relevant to its more potent in vivo antitumor efficacy in a human tumor xenographted nude mouse model.

Animals↗
PubMed1999

Substitution at the F-ring N-imide of the indolocarbazole antitumor drug NB-506 increases the cytotoxicity, DNA binding, and topoisomerase I inhibition activities.

The antitumor drug NB-506, which is currently undergoing phase I/II clinical trials, contains a DNA-intercalating indolocarbazole chromophore substituted with a glucose residue. In addition to interacting with DNA, the drug stabilizes the topoisomerase I-DNA covalent complex. To reinforce the DNA binding and anti-topoisomerase I activities of NB-506, an analogue containing a new substituent on the naphthalimide ring F was synthesized. The N-formylamino group of NB-506 has been replaced with a more hydrophilic group, N-bis(hydroxymethyl)methylamino. In this study we show that the incorporation of a longer substituent on the N6 position effectively reinforces both the interaction with DNA and the capacity of the drug to maintain the integrity of the topoisomerase I-DNA covalent complexes. The strength and the mode of binding of the drugs to DNA were studied by complementary biophysical techniques including absorption, fluorescence, and circular and linear dichroism. Various biochemical procedures were applied to investigate the effects on human topoisomerase I using plasmid DNA as well as restriction fragments. The drug binding sites and the positions of the topoisomerase I-mediated cleavage sites were mapped with nucleotide resolution using footprinting and sequencing techniques. Cytotoxicity measurements performed with various human cancer cell lines (HCT-116, DLD-1, MKN-45) indicate that the newly designed drug is 3 to 4 times more toxic to colon and gastric cancer cells than NB-506. Therefore, the results suggest that the antitumor activity of indolocarbazole-based drugs can be enhanced by incorporating DNA and/or topoisomerase I reactive groups. They also support the hypothesis that the substituent on the imide nitrogen on the F ring of NB-506 has direct interaction with the molecular target. The study helps to define the structure-activity relationships in the indolocarbazole series of antitumor agents targeting topoisomerase I.

Animals↗