Search PubMed⌕ Search

Biomedical subjects

K Sawada

Publications and source records attributed to K Sawada.

At least 73 records · Page 4Linked to original sources
PubMed2001

4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5alpha-reductase. III.

A novel series of indolizinebutyric acids with various benzoyl substituents was synthesized to develop nonsteroidal inhibitors of steroid 5alpha-reductase, and the structure-activity relationships in this series were studied. We previously reported the structure-activity relationships in a series of indolebutyric acids as well as the discovery of the novel nonsteroidal 5alpha-reductase inhibitor, FK143. We have now made other modifications to this compound to improve in vivo inhibitory activity. By altering the heterocyclic nucleus and changing the benzoyl substituent we have succeeded in identifying the strongly active compound, FK687, (S)-4-[1-[4-[[1-(4-isobutylphenyl)butyl]oxy]benzoyl]indolizin-3-yl]butyric acid, which displays strong in vitro inhibitory activity against the human enzyme and in vivo inhibitory activity against the castrated young rat model. This compound should be a useful agent for the treatment of benign prostatic hyperplasia.

5-alpha Reductase Inhibitors↗
PubMed2001

Interstitial pneumonia accompanying ulcerative colitis.

We report a patient with ulcerative colitis complicated with idiopatic interstitial pneumonia, in whom the etiology of interstitial pneumonia was unknown, but immunological disturbance might have been involved. There are many complications with ulcerative colitis, but interstitial pneumonia is quite rare and its prognosis is quite poor. Antibiotic and steroid treatment were given under respiration supported therapy, but no response could be obtained. In the treatment of patients with ulcerative colitis, we must be mindful of interstitial pneumonia because the prognosis is quite poor.

Biopsy↗
PubMed2001

Expression of tyrosine hydroxylase in cerebellar Purkinje cells of ataxic mutant mice: its relation to the onset and/or development of ataxia.

This report describes recent studies on tyrosine hydroxylase (TH) expression in Purkinje cells of the cerebellum of ataxic mutant mice. An increased expression of TH in some Purkinje cells has been observed in two allelic groups of mutant mice, tottering and dilute. TH-positive Purkinje cells appeared preceding the onset of ataxia. Northern blot analysis revealed 2.1 kb of TH mRNA in the mutant cerebella, and the size was identical to that of TH transcripts in other brain regions. However, TH in Purkinje cells did not seem to participate in catecholamine biosynthesis. In vitro studies showed that cultured non-catecholaminergic neurons expressed the TH transcripts following Ca2+ influx. Therefore, abnormal TH expression in the mutant Purkinje cells may indicate neuronal dysfunction caused by misregulation of intracellular Ca2+ concentrations.

Animals↗
PubMed2001

[Female paraurethral cyst: a case report].

We experienced a case of paraurethral cyst in a 42-year-old woman. A paraurethral cyst, the diameter of which was about 2 cm, was observed in the septum between urethra and vagina. No communication between the cyst and urthra or vagina was detected. The resected cyst did not reveal malignant findings. Sixty-one cases of paraurethral cyst in the Japanese literature are also reviewed.

Adult↗
PubMed2001

[Science in diabetes mellitus].

The Citizen Joint Symposium on "Science in Diabetes Mellitus" was held by the Hokkaido Medical Society at Hokkaido University Conference Hall on October 28, 2000. Six speakers, including three medical doctors, a health nurse, a nutritionist and a physical therapist presented the most-update information on diabetes mellitus based on their specialty. The aim of this symposium was to consider how to support the self-management of patients with diabetes mellitus to keep a quality of life.

Diabetes Mellitus↗
PubMed2001

[A case of traumatic rupture of the testis: usefulness of magnetic resonance imaging].

Traumatic rupture of the testis is rare because of the protection afforded by surrounding structures. Moreover, it is difficult to accurately diagnose preoperatively. A 17-year-old man was referred to our department with the complaint of painful swelling of the left testis after being hit by a basketball. Although ultrasonography and computed tomography did not reveal the rupture of the tunica albuginea, we preoperatively diagnosed the rupture of the left testis by magnetic resonance imaging (MRI). We repaired the tunica albuginea and preserved the left testis. In this report, the advantages of MRI for preoperative diagnosis of traumatic rupture of the testis are discussed. In addition, previous cases with traumatic rupture of the testis in the Japanese literature are also reviewed.

Adolescent↗
PubMed2001

Recognition and transport characteristics of nonpeptidic compounds by basolateral peptide transporter in Caco-2 cells.

Recent studies have revealed that diverse compounds lacking peptide bonds, such as valacyclovir and delta-aminolevulinic acid (delta-ALA), can be recognized by H+-coupled peptide transporters (PEPT1 and PEPT2). In the present study, recognition and transport characteristics of nonpeptidic compounds by the basolateral peptide transporter, which is distinct from PEPTs, were compared with those by PEPT1 using the human intestinal Caco-2 cells. [14C]Glycylsarcosine uptake via PEPT1 was inhibited by all nonpeptidic compounds tested. Similarly, most nonpeptidic compounds showed an inhibitory effect on [14C]glycylsarcosine uptake by the basolateral peptide transporter, although some kinds of nonpeptidic compounds, such as valine methyl ester, did not. Direct measurements of valacyclovir and delta-ALA transport revealed that both compounds were able to be transported by the basolateral peptide transporter. Because delta-ALA has been used recently in vitro and in clinical studies as an endogenous photosensitizer for photodynamic therapy, the intestinal transport characteristics of delta-ALA were further examined. Inhibition studies and Eadie-Hofstee plot analysis suggested that delta-ALA transport across the brush-border and basolateral membranes of the intestine was mainly mediated by peptide transporters. In addition, the apical-to-basolateral transport of delta-ALA was greater than that of the opposite direction. These findings provide the first evidence that the intestinal basolateral peptide transporter can recognize and transport nonpeptidic compounds, and play a definitive role in the absorption of delta-ALA.

ATP-Binding Cassette Transporters↗
PubMed2001

[Phase I study with irinotecan hydrochloride (CPT-11) for advanced neuroblastoma].

A Phase I trial of irinotecan hydrochloride (CPT-11) was performed to determine the maximum tolerated dose (MTD), the dose-limiting toxicities, and the incidence and severity of other toxicities in children with advanced neuroblastoma. Three children received 11 courses of CPT-11 administered as a 90-min i.v. infusion, daily for 3 days every 21 days. Doses ranged from 100 mg/m2 to 220 mg/m2. Two peaks in the total number of instances of diarrhea was observed, 25 stools at 3 days and 32 stools at 10 days. Myelosuppression was well controlled and of brief duration. One child achieved a clinical complete response (CR) and 2 had a partial response (PR). The MTD of CPT-11 administration was 180 mg/m2 for 3 days. These results indicate the usefulness of CPT-11 for the treatment of advanced neuroblastoma. Further investigation is necessary to establish its role in combination chemotherapeutic regimens.

Adrenal Gland Neoplasms↗
PubMed2000

Detection of triplet repeat expansion in the human genome by use of hybridization signal intensity.

Triplet repeat disease is a group of hereditary neurodegenerative disorders caused by expansion of trinucleotide repeats such as CAG/CTG, CGG/CCG, and GAA/TTC. Direct detection of the expansion in the patient's genome shortcuts the tedious process needed for identification of disease genes by conventional approaches. Here we describe a method to detect triplet repeat expansion from the hybridization signal intensity. Using a digoxigenin-labeled (CTG)9 probe, the hybridization intensity and number of repeats showed a good linear correlation. The technique detected expansion in genomic DNA in all cases with moderate or large expansion. Even in the case of a small expansion, this method could detect the mutant fragment. The technique has advantages over related techniques because it is more sensitive and can be applied to cases where a small repeat expansion is involved.

Alleles↗
PubMed2000

Intrahepatic anastomosis formation between the hepatic veins in the graft liver of the living related liver transplantation: observation by Doppler ultrasonography.

In living related liver transplantation, the right lobe has come to be used as a graft to meet the metabolic demands of adult or adolescent recipients. In harvesting the right lobe as a graft, however, there is controversy as to whether or not the middle hepatic vein (MHV) should be included and reconstructed. Anatomical intrahepatic anastomosis between the right hepatic vein (RHV) and MHV is considered to exist, but the formation process of this functional anastomosis has not been demonstrated by Doppler ultrasonography (US). In our case, a right lobe including a right branch of the MHV was used as a graft. In implanting, the RHV was anastomosed to the inferior vena cava and the right branch of the MHV was ligated. Using Doppler US, we checked the blood flow in the hepatic vein after transplantation. Within 3 days of surgery, no flow was detected in the right branch of the MHV. A flow around the right branch of the MHV was observed at postoperative day 6. At postoperative day 9, a reverse flow was detected in which the right branch of the MHV drained into the RHV via the anastomosis between them. Based on our results, it appears that a functional intrahepatic anastomosis between hepatic veins formed gradually within 10 days of ligation of an afferent branch, during which time the graft function did not deteriorate.

Adolescent↗
PubMed2000

A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of phosphatidylinositol 3-kinase-Akt activation pathway in erythropoietin signal transduction.

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is important for the regulation of a number of cellular responses. Serine/threonine kinase Akt (protein kinase B; PKB) is downstream of PI3K and activated by growth factors. This study found that erythropoietin (EPO) induced tyrosine phosphorylation of Akt in a time- and dose-dependent manner in EPO-dependent human leukemia cell line UT-7/EPO. In vitro kinase assay using histone H2B and glucose synthase kinase as substrates demonstrated that Akt was actually activated by EPO. EPO-induced phosphorylation of Akt was completely blocked by a PI3K-specific inhibitor, LY294002, at 10 micromol/L, indicating that activation of Akt by EPO is dependent on PI3K activity. In addition, overexpression of the constitutively active form of Akt on UT-7/EPO cells partially blocked apoptosis induced by withdrawal of EPO from the culture medium. This finding suggested that the PI3K-Akt activation pathway plays some role in the antiapoptotic effect of EPO. EPO induced phosphorylation of a member of the trancription factor Forkhead family, FKHRL1, at threonine 32 and serine 253 in a dose- and time-dependent manner in UT-7/EPO cells. Moreover, results showed that Akt kinase activated by EPO directly phosphorylated FKHRL1 protein and that FKHRL1 phosphorylation was completely dependent on PI3K activity as is the case for Akt. In conjunction with the evidence that FKHRL1 is expressed in normal human erythroid progenitor cells and erythroblasts, the results suggest that FKHRL1 plays an important role in erythropoiesis as one of the downstream target molecules of PI3K-Akt.

DNA-Binding Proteins↗
PubMed2000

Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2.

The novel oral hypoglycemic agent nateglinide (AY4166) is a nonsulfonylurea insulin secretagogue, and its pharmacokinetic features include rapid absorption and elimination. As nateglinide is a dipeptide-like drug, we investigated the interaction of nateglinide with peptide transporters PEPT1 and PEPT2, which mediate the absorption of various peptide-like drugs. Nateglinide exhibited a potent inhibitory effect on [14C]glycylsarcosine uptake by the human colon adenocarcinoma cell line Caco-2 and rat PEPT-transfectants. Kinetic analysis revealed that these inhibitory effects were noncompetitive. Na(+)-coupled alanine or threonine uptake by Caco-2 cells was not inhibited by nateglinide, suggesting that the inhibitory effect of nateglinide on peptide transporters was not due to nonspecific interaction. There was little uptake of [14C]nateglinide by peptide transporters. Various sulfonylureas, such as glibenclamide, also inhibited [14C]glycylsarcosine uptake by rat PEPT-transfectants. In conclusion, nateglinide as well as sulfonylureas inhibit the transport activity of PEPT1 and PEPT2, although nateglinide itself is not transported by these transporters.

Administration, Oral↗
PubMed2000

Splenomegaly and chronic disseminated intravascular coagulation in Osler-Weber-Rendu disease: a case report.

A 45-year-old Japanese woman with splenomegaly and thrombocytopenia was referred to our hospital. The diagnosis of Osler-Weber-Rendu disease (Osler's disease) was made because of spotty telangiectasia on her tongue, recurrent epistaxis since childhood, and a diathesis indicated by her family history. The patient's laboratory examination revealed anemia, thrombocytopenia, and other data consistent with chronic disseminated intravascular coagulation (DIC). Bone marrow examination was normal. Abdominal computed tomography showed marked enlargement of the spleen with deformity and calcified plaque, not homogeneously enhancing. Hypersplenism was not observed. Platelet scintigraphy indicated a remarkable uptake in the spleen. She was diagnosed as having chronic DIC associated with vascular lesions of Osler's disease in the spleen. Splenectomy was performed and the subsequent pathological findings indicated that fragility of the fine vascular architecture of the splenic red pulp might have been responsible for pathogenesis. The large pooling of blood with coagulation was thought to be secondary.

Disseminated Intravascular Coagulation↗
PubMed2000

On the nature of cell death during remodeling of hypertrophied human myocardium.

Cardiocyte loss during myocardial hypertrophy leads to progressive dysfunction in human hearts with chronic hemodynamic overload. The mechanism for such cell elimination is unknown. We examined lysosomal participation in cardiocytic degradation present in human cardiac biopsies, utilizing electron microscopic cytochemistry (acid phosphatase). Lysosomes were significantly increased in number (t-test, P<0.001) in 50 hemodynamically overloaded hearts (375+/-69, mean+/-s.e.m., per 5,000 microm(2) cardiocytic area; eight controls, 38+/-11). Secondary lysosomes were prominent near degenerative intracellular organelles in both hypertrophic and atrophic cardiocytes. Increased lysosomal and phagocytic activity in the cytoplasm without typical nuclear apoptosis resembled cytoplasmic degradation in developmental programmed cell death described in different tissues. We also demonstrated cardiocytic DNA degradation (in situ nick-end labeling) in autopsy hearts, including 299 nuclei normalized per 10(6) observed nuclei from five concentrically hypertrophied hearts, 1961 nuclei from five eccentrically hypertrophied hearts, and no positive nuclei in five controls. We postulate a chronic self-controlled cytoplasmic proteolysis in cardiocytes, not initially associated with either nuclear degradation or intercellular dehiscence but later possibly accompanied by apoptotic nuclear elimination, and leading to apoptotic cell death.

Acid Phosphatase↗
PubMed2000

Structural requirements for determining the substrate affinity of peptide transporters PEPT1 and PEPT2.

Peptide transporters PEPT1 and PEPT2 transport numerous compounds including small peptides, peptide-like drugs and nonpeptidic compounds such as valacyclovir. PEPT1 and PEPT2 show low and high affinity for most substrates, respectively, but beta-lactam antibiotics without an alpha-amino group are the only known substrates that prefer PEPT1 to PEPT2. The aim of this study was to compare the recognition and affinity of various substrates between rat PEPT1 and rat PEPT2, and to determine the structural requirements influencing the substrate affinity. [14C]Glycylsarcosine uptake by PEPT1- or PEPT2-expressing transfectant was inhibited by di- and tripeptides, but not by amino acids, tetrapeptides or most cyclic dipeptides. All dipeptides and tripeptides examined showed more potent inhibition of [14C]glycylsarcosine uptake via PEPT2 than via PEPT1, irrespective of their charge and structure. Modification of the alpha-amino group of dipeptides reduced their substrate affinity to both transporters, as compared to unmodified dipeptides, but these dipeptides still showed potent inhibitory effects on PEPT2. Among the nonpeptidic substrates tested, only the eight-amino-octanoic acid displayed stronger inhibition of [14C]glycylsarcosine uptake in PEPT1 than in PEPT2. These findings suggest that alpha- or beta-amino carbonyl function is the key structure responsible for the higher affinity for PEPT2 than for PEPT1.

Animals↗
PubMed2000

Antibiotic resistance among recent clinical isolates of Haemophilus influenzae in Japanese children.

From January 1997 to July 1999, a total of 867 isolates of Haemophilus influenzae were recovered in the microbiology laboratory of Chiba Children's Hospital. The overall prevalence of beta-lactamase production was 12.8%. Ampicillin-MICs for all of the 111 beta-lactamase-producing isolates was > or =4 microg/ml. A total of 26 beta-lactamase-negative isolates (3.4% of all beta-lactamase-negative isolates and 3.0% of all isolates) were found to be resistant to ampicillin. The prevalence of beta-lactamase negative ampicillin-resistant strains (BLNAR) increased remarkably to 8.9% during the last 7-month period. It is noteworthy that the MICs not only of penicillins but also of cephems for BLNAR were significantly higher than those for ampicillin-susceptible isolates. Eight beta-lactamase-producing isolates of H. influenzae (7.2% of all beta-lactamase-producing isolates) were resistant to amoxicillin-clavulanate (AMPC/CVA). Consequently, the overall resistance to ampicillin was 15.8%, and that to AMPC/CVA was 3.0%. The results of this study corroborate the findings of previous investigators in the US (Doern et al., 1997) regarding the emergence of BLNAR and beta-lactamase-producing AMPC/CVA-resistant strains (BLPACR) of H. influenzae. Continued monitoring of susceptibility trends will be required to guide appropriate chemotherapy.

Anti-Bacterial Agents↗
PubMed2000

N-terminal halves of rat H+/peptide transporters are responsible for their substrate recognition.

PURPOSE: Peptide transporters PEPT1 and PEPT2 differ substantially in their substrate affinity and recognition. The aim of this study is to define the structural domains which influence the functional characteristics of both transporters METHODS: Two kinds of chimeric peptide transporters (PEPT-N1C2 and PEPT-N2C1) were constructed, and their functional characteristics were compared with those of wild-type transporters in stable transfectants. RESULTS: PEPT-N1C2, the N-terminal half of rat PEPT1 and the C-terminal half of rat PEPT2, and the reciprocal chimera PEPT-N2C1 were functionally expressed in LLC-PK1 cells. The pH-profiles of [14C] glycylsarcosine uptake by PEPT-N1C2 and PEPT-N2C1 were close to those of PEPT1 and PEPT2, respectively. Substrate recognition for PEPT-N1C2 and PEPT-N2C1 was also similar to that of PEPT1 and PEPT2, respectively. However, substrate affinities for PEPT-N1C2 were higher than those for PEPT1, although those for PEPT-N2C1 and PEPT2 were comparable. CONCLUSIONS: These results indicate that functional regions which are associated with the extracellular pH changes and are responsible for substrate recognition of PEPT1 and PEPT2 may be located in the N-terminal halves of the proteins. In addition, it is suggested that the domain to affect the substrate affinity exists in the C-terminal as well as in the N-terminal half of rat PEPT2.

Animals↗