Biomedical subjects

M Baba

Publications and source records attributed to M Baba.

At least 109 records · Page 6Linked to original sources

PubMed2000

Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety.

The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [(125)I]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium moiety, which were synthesized to investigate new MCP-1 receptor antagonists. A series of novel anilide derivatives 1 with a quaternary ammonium moiety were designed, synthesized, and tested for their CCR5 antagonistic activity. Through the optimization of lead compounds, we have found N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6, 7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydr o-2 H-pyran-4-aminium chloride (1r, TAK-779) as a highly potent and selective nonpeptide CCR5 antagonist with a IC(50) value of 1.4 nM in the binding assay. Compound 1r also inhibited the replication of macrophage (M)-tropic HIV-1 (Ba-L strain) in both MAGI-CCR5 cells and PBMCs with EC(50) values of 1.2 and 3.7 nM, respectively. The synthesis and structure-activity relationships of 1r and its related compounds are detailed.

Amides↗

PubMed2000

Genistein attenuates peritoneal metastasis of azoxymethane-induced intestinal adenocarcinomas in Wistar rats.

The effects of the soybean isoflavonoid genistein on the development of bombesin-enhanced peritoneal metastasis from intestinal adenocarcinomas induced by azoxymethane (AOM) were investigated in male inbred Wistar rats. From the beginning of the experiment, rats were given 10 weekly s.c. injections of AOM (7.4 mg/kg body weight) and s.c. injections of bombesin (40 microg/kg body weight) every other day, and from week 16, s.c. injections of genistein (5 or 10 mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and of cancer metastasis to the peritoneum. Although genistein administered at either dose had little or no effect on the enhancement of intestinal carcinogenesis by bombesin or on the location, histologic type, depth of involvement, labeling index, or growth pattern of intestinal cancers, it significantly decreased the incidence of cancer metastasis. Genistein also significantly decreased the incidence of lymphatic vessel invasion of adenocarcinomas, which was enhanced by bombesin. Our findings indicate that genistein attenuates cancer metastasis by inhibiting cancer cell invasion into lymphatic vessels through activities that do not affect the growth of intestinal cancers.

Animals↗

PubMed2000

Suppression by Chai-hu-gui-zhi-tang of the development of liver lesions induced by N-nitrosomorpholine in Sprague-Dawley rats.

The effects of Chai-hu-gui-zhi-tang (TJ-10) on the development of liver lesions induced by N-nitrosomorpholine and on labeling and apoptotic indices were investigated in male Sprague-Dawley rats. Rats were given chow pellets containing 0.5 or 1.0% TJ-10 and, from the beginning of the experiment, were given drinking water containing N-nitrosomorpholine for 8 weeks. Visible white liver nodules, cellular alteration foci, and hepatic foci staining positively for glutathione-S-transferase, placental type, were examined macroscopically or histochemically. In week 16, TJ-10 at both dosages significantly reduced the incidence, and/or number of visible white nodules and hepatic lesions. Quantitative histologic analysis also showed that prolonged feeding of TJ-10 at both dosages significantly reduced the number of hepatic foci positive for glutathione-S-transferase, placental type. Administration of TJ-10 at both dosages also significantly decreased the labeling index of adjacent liver and significantly increased the apoptotic index of adjacent liver but had no significant effect on those of neoplastic lesions. These findings indicate that TJ-10 suppresses the development of liver lesions and suggest that this effect might be related to TJ-10's inhibition of cell proliferation and induction of apoptosis in adjacent hepatocytes.

Animals↗

PubMed2000

Evaluation and treatment of swallowing impairments.

Swallowing disorders are common, especially in the elderly, and may cause dehydration, weight loss, aspiration pneumonia and airway obstruction. These disorders may affect the oral preparatory, oral propulsive, pharyngeal and/or esophageal phases of swallowing. Impaired swallowing, or dysphagia, may occur because of a wide variety of structural or functional conditions, including stroke, cancer, neurologic disease and gastroesophageal reflux disease. A thorough history and a careful physical examination are important in the diagnosis and treatment of swallowing disorders. The physical examination should include the neck, mouth, oropharynx and larynx, and a neurologic examination should also be performed. Supplemental studies are usually required. A videofluorographic swallowing study is particularly useful for identifying the pathophysiology of a swallowing disorder and for empirically testing therapeutic and compensatory techniques. Manometry and endoscopy may also be necessary. Disorders of oral and pharyngeal swallowing are usually amenable to rehabilitative measures, which may include dietary modification and training in specific swallowing techniques. Surgery is rarely indicated. In patients with severe disorders, it may be necessary to bypass the oral cavity and pharynx entirely and provide enteral or parenteral nutrition.

Age Distribution↗

PubMed2000

Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways.

In nutrient-rich, vegetative conditions, the yeast Saccharomyces cerevisiae transports a resident protease, aminopeptidase I (API), to the vacuole by the cytoplasm to vacuole targeting (Cvt) pathway, thus contributing to the degradative capacity of this organelle. When cells subsequently encounter starvation conditions, the machinery that recruited precursor API (prAPI) also sequesters bulk cytosol for delivery, breakdown, and recycling in the vacuole by the autophagy pathway. Each of these overlapping alternative transport pathways is specifically mobilized depending on environmental cues. The basic mechanism of cargo packaging and delivery involves the formation of a double-membrane transport vesicle around prAPI and/or bulk cytosol. Upon completion, these Cvt and autophagic vesicles are targeted to the vacuole to allow delivery of their lumenal contents. Key questions remain regarding the origin and formation of the transport vesicle. In this study, we have cloned the APG9/CVT7 gene and characterized the gene product. Apg9p/Cvt7p is the first characterized integral membrane protein required for Cvt and autophagy transport. Biochemical and morphological analyses indicate that Apg9p/Cvt7p is localized to large perivacuolar punctate structures, but does not colocalize with typical endomembrane marker proteins. Finally, we have isolated a temperature conditional allele of APG9/CVT7 and demonstrate the direct role of Apg9p/Cvt7p in the formation of the Cvt and autophagic vesicles. From these results, we propose that Apg9p/Cvt7p may serve as a marker for a specialized compartment essential for these vesicle-mediated alternative targeting pathways.

Animals↗

PubMed2000

p21 expression is a prognostic factor in patients with p53-negative gastric cancer.

The expression of p21 and p53 proteins was analyzed by immunohistochemistry in 256 patients with advanced gastric cancer. The results showed that strong, weak and negative expression of p21 were detected in 22.2 (57/256), 68.0 (174/256) and 9.8% (25/256) of the patients, respectively. p53 expression was found in 28.9% (74/256). The expression of p21 was not associated with clinicopathological features. In p53 negative tumors, p21 expression was associated with the survival of patients who underwent curative operations (P = 0.007). The 5-year survival rates were 20.1, 36.6 and 59.8% in patients with p21-negative, -weakly positive and -strongly positive tumors, respectively. In contrast, in p53-positive tumors, prognosis did not differ in spite of p21 expression. Multivariate analysis showed that p21 expression was an independent factor in patients with p53-negative tumors. These results indicate that examination of p21 expression in p53 negative tumors will be useful for estimating the prognosis of patients with advanced gastric cancer.

Adult↗

PubMed2000

In vivo electroporetic transfer of bcl-2 antisense oligonucleotide inhibits the development of hepatocellular carcinoma in rats.

To investigate the potential use of a bcl-2 antisense oligonucleotide for therapy against hepatocellular carcinoma, we examined the effects of the electroporetic transfer of a bcl-2 antisense oligonucleotide on rat hepatocarcinogenesis induced by N-nitrosomorpholine (NNM). Sprague-Dawley rats were given water containing 175 mg/l NNM for 8 weeks and received intraperitoneal injections of a bcl-2 antisense phosphorothioate oligonucleotide, a sense oligonucleotide or a scrambled sequence oligonucleotide encapsulated in empty liposomes, at a dose of 150 microg oligonucleotide/kg body weight, every 4 weeks. One hour after injection, in vivo electroporation was performed on the liver to achieve selective transfer of the oligonucleotides. By week 16, the rats that had received the bcl-2 antisense oligonucleotide had significantly fewer and smaller precancerous liver lesions positive for glutathione-S-transferase (placental type), and a significantly lower incidence of hepatocellular carcinoma in the electroporation zone than rats that had received the sense or the scrambled oligonucleotides. Moreover, the bcl-2 antisense oligonucleotide significantly increased the apoptotic indices in foci, neoplastic nodules and in hepatocellular carcinomas. The expression of bcl-2 mRNA also decreased, and 3'-fragments of bcl-2mRNA produced by cleavage at the antisense target site were detected in rat liver. Mean cellular fluorescence in the liver increased with higher doses of fluorescein-isothiocyanate-labeled antisense or sense oligonucleotides. Our results show that the electroporetic transfer of bcl-2 antisense oligonucleotide can inhibit rat hepatocarcinogenesis.

Animals↗

PubMed2000

Constitutive phosphorylation of the Parkinson's disease associated alpha-synuclein.

alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease, since rare autosomal dominant mutations are associated with early onset of the disease and alpha-synuclein was found to be a major constituent of Lewy bodies. We have analyzed alpha-synuclein expression in transfected cell lines. In pulse-chase experiments alpha-synuclein appeared to be stable over long periods (t((1)/(2)) 54 h) and no endoproteolytic processing was observed. alpha-Synuclein was constitutively phosphorylated in human kidney 293 cells as well as in rat pheochromocytoma PC12 cells. In both cell lines phosphorylation was highly sensitive to phosphatases, since okadaic acid markedly stabilized phosphate incorporation. Phosphoamino acid analysis revealed that phosphorylation occurred predominantly on serine. Using site-directed mutagenesis we have identified a major phosphorylation site at serine 129 within the C-terminal domain of alpha-synuclein. An additional site, which was phosphorylated less efficiently, was mapped to serine 87. The major phosphorylation site was located within a consensus recognition sequence of casein kinase 1 (CK-1). In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by CK-1 and CK-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of CK-1 or CK-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its C terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.

Amino Acid Sequence↗

PubMed2000

Stability of N20 onset or peak latency in median somatosensory evoked potentials.

We analyzed onset and peak latencies of the N20 response of median nerve somatosensory evoked potentials (SEPs) in 21 healthy subjects by simultaneous recordings with noncephalic or ear reference from multiple scalp sites. The cortical onset was defined as the fork at which the contralateral parietal and frontal or ipsilateral parietal waves diverged. We found the N20 onset unchanged between noncephalic and ear reference recordings, or among the recordings around the contralateral centroparietal scalp. The N20 peak was prolonged when the recording position moved posteriorly. We suggest that N20 onset latency is more stable than N20 peak.

Adult↗

PubMed2000

Eicosapentaenoic acid reduces pulmonary edema in endotoxemic rats.

BACKGROUND: Recently, eicosapentaenoic acid (EPA) was found to have an anti-inflammatory effect attributable to diminished synthesis of arachidonic acid metabolites that initiate acute lung injury. We evaluated the ability of dietary EPA supplementation to prevent endotoxin-induced acute lung injury in rats. MATERIALS AND METHODS: Rats fed a standard diet were divided randomly into two groups: for 2 weeks one group additionally was fed 1000 mg/kg/day of EPA ethyl ester emulsion (EPA rats), while in the other group the diet was supplemented with vehicle alone (control rats). Fatty acid components of alveolar macrophages (AM) were measured, as well as leukotriene (LT) B(4) and LTB(5) production by AM exposed in vitro to calcium ionophore A23187. Plasma concentrations of thromboxane (Tx) B(2), a stable metabolite of TxA(2), were examined 1 h after inducing lung injury with endotoxin (2 mg/kg iv). At 6 h, wet/dry (W/D) weight ratios were calculated for the lungs to assess pulmonary edema, and neutrophils were counted in pulmonary parenchyma and peripheral blood. RESULTS: Arachidonic acid content and LTB(4) generation in AM were significantly lower in EPA rats than in controls; conversely, EPA content and LTB(5) generation in AM were significantly higher in the EPA group. Neutrophil counts in lung parenchyma and peripheral blood did not differ between groups, but W/D and plasma TxB(2) concentrations were significantly lower in EPA rats. CONCLUSIONS: EPA supplementation depressed arachidonic acid content and LTB(4) generation in AM and plasma TxB(2) in our model, leading to decreased pulmonary edema.

Animals↗

PubMed2000

ras p21 Isoprenylation inhibition induces flat colon tumors in Wistar rats.

PURPOSE: The effect of pravastatin, an inhibitor of ras p21 isoprenylation, on the gross type of colon tumors induced by azoxymethane was investigated in Wistar rats. METHODS: Rats received ten weekly subcutaneous injections of 7.4 mg/kg body weight of azoxymethane and intraperitoneal injections of 10 or 20 mg/kg body weight of pravastatin every other day until the end of the experiment at Week 45. RESULTS: Administration of pravastatin at both dosages had no significant effect on the incidence of colon tumors but significantly increased the incidence of rats with adenomas only. In contrast to the elevated adenomas in control rats, flat adenomas were significantly more prevalent in rats given pravastatin. Pravastatin at both doses significantly decreased the labeling index, but not the apoptotic index, of elevated adenomas, whereas it significantly decreased the labeling index but increased the apoptotic index of flat adenomas. Administration of pravastatin at both dosages also significantly decreased the amounts of membrane-associated ras p21 in colon tumors. CONCLUSIONS: These findings suggest that the ras oncogene may be closely related to the development of adenocarcinomas from adenomas and the development of elevated or polypoid tumors of the colon.

Adenocarcinoma↗

PubMed2000

Biological evaluation of undifferentiated carcinoma of the esophagus.

BACKGROUND: Patients with undifferentiated carcinoma of the esophagus (UEC) are rare and have a poor prognosis compared with those with differentiated squamous cell carcinomas (DECs). We compared clinicopathological and biological features of UEC and DEC, with emphasis on markers for epithelial cell origin, proliferation, and cell-cell adhesion. METHODS: Seven patients with UEC were compared with 21 with DEC. Immunohistochemical studies were performed by using monoclonal antibodies to cytokeratin, epithelial membrane antigen, p53, p21WAF1/CIP1, Ki-67, E-cadherin, desmoglein-1, and thrombomodulin. RESULTS: Patients with UEC had a poorer prognosis because of hematogenous metastasis at the time of presentation (mean survival, 6.5 +/- 6.2 vs. 35.5 +/- 28.9 months; P < .05). Immunohistochemical findings for cytokeratin and epithelial membrane antigen suggest that some UECs had epithelial origins. The following immunohistochemical profile of UEC was consistent with its highly malignant properties: (1) reduced or negative expression of cell-cell adhesion molecules such as E-cadherin, desmoglein-1, and thrombomodulin, (2) high positive rate for p53 and Ki-67, and (3) negative expression of p21WAF1/CIP1. CONCLUSIONS: The immunohistochemical findings for UEC showed its high cell-proliferative activity and a high potential for metastasis. Clinical features of UEC were supported by the results of immunohistochemical findings.

Adult↗

PubMed2000

A case of breast cancer diagnosed by inguinal lymph node metastasis.

We describe a case of a 58-year-old woman with right inguinal lymph node swelling and a T1 tumor in the right breast. She was referred with an 18-month history of the former complaint and a six-month history of the latter. Excisional biopsy of the inguinal lymph node revealed breast cancer metastasis. Radiographical examination showed no metastases to the lungs, liver or bone. Modified radical mastectomy was performed. Histological examination revealed solid tubular carcinoma, PT2, PM (axillary lymph node metastases 4/16), stage IV. Estrogen and progesterone receptors were negative. Three cycles of postoperative cyclophosphamide, adriamycin and 5-fluorouracil (CAF) chemotherapy were given, and the right inguinal area was irradiated with 40 Gy. The patient complained of swelling in both legs three years after surgery. Computed tomography revealed marked lymph node swellings in the pelvic cavity. She died six months later. Inguinal lymph node metastasis from breast cancer is very rare, although distant lymph node metastasis in the cervix occurs frequently. This case should help clarify how breast cancer metastasizes to distant lymph nodes.

Adenocarcinoma↗

PubMed2000

Relation between effective utilization of exogenous fat emulsion as energy substrate and oxygen metabolism after surgery.

It is known that fat oxidation is increased in patients who have sustained surgical stress, but it is not clear whether fat emulsion should be administered during the early postoperative period. The aim of this study was to evaluate the utilization of exogenous fat emulsion after major surgery. Total parenteral nutrition composed of glucose/amino acids or glucose/amino acids/fat was administered for 6 days to 18 patients who had undergone esophagectomy. The caloric intake was significantly less than the resting energy expenditure (REE), and there was no difference in substrate utilization in either group up to postoperative day (POD) 2. After POD 4, fat utilization was significantly increased in the fat group. The total ketone body concentration was higher in the fat group than in the glucose group on POD 1 and 2. The arterial ketone body ratio (AKBR), which reflects the rate of turnover of the Krebs cycle, was positively correlated with the caloric intake/REE ratio. It was negatively correlated with the oxygen delivery index, oxygen consumption, and lactate concentration between POD 0 and POD 2. The lactate concentration was decreased and the AKBR was increased by POD 4. Fat emulsion was effectively utilized as energy substrate after POD 4, after the relative tissue hypoxia had improved and the AKBR had increased. The utilization of exogenous fat emulsion was closely related to deficient caloric intake and oxygen metabolism.

Aged↗

PubMed2000

Crohn's disease of the esophagus: report of a case.

We report herein the case of a 27-year-old man with Crohn's disease of the esophagus. The patient presented with large ulcers in the esophagus for which treatment based on a diagnosis of reflux esophagitis was commenced. Although his symptoms were initially resolved, the ulcers did not improve and he was readmitted to hospital 3 months later for progressive heartburn. An esophagoscopy revealed large ulcers in the esophagus, and a colonoscopy revealed a longitudinal ulcer in the terminal ileum. Histological examination of specimens from the terminal ileum showed severe inflammation without granuloma formation, which led to a diagnosis of Crohn's disease. The oral administration of prednisolone and salazosulfapyridine controlled his symptoms and the esophageal ulcers were observed to be healing 2 weeks after this treatment was initiated. A review of the English literature revealed only 77 cases of this disease. Isolated esophageal lesions were reported in ten patients (13.0%), none of which were able to be diagnosed as Crohn's disease preoperatively. Ileocolic lesions developed after esophageal lesions in only five patients (6.5%) including ours. In the remaining 62 patients (80.5%), ileocolic lesions had existed synchronous with or prior to the esophageal lesions. This suggests that ileocolic lesions may often coexist in Crohn's patients with esophageal lesions, and that examination of the terminal ileum must be performed to confirm a diagnosis of Crohn's disease of the esophagus.

Adult↗

PubMed2000

Suppression by apigenin of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats.

The effect of a naturally occurring flavonoid apigenin on the development of bombesin-enhanced peritoneal metastasis from intestinal adenocarcinomas induced by azoxymethane was investigated in male Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of azoxymethane (7.4 mg/kg body weight) for 10 weeks and s.c. injection of bombesin (40 microg/kg body weight) every other day, and from week 16, s.c. injections of apigenin (0.75 or 1.5 mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of apigenin at either dose with bombesin had little or no effect on the enhancement of intestinal carcinogenesis by bombesin, the location, histologic type, depth of involvement, infiltrating growth patterns and labeling index, it was found to decrease significantly the incidence of cancer metastasis. Apigenin significantly decreased the incidence of lymphatic vessel invasion of adenocarcinomas, which was enhanced by bombesin. In vitro experiments revealed that apigenin inhibited bombesin-enhanced phosphorylation of mitogen-activated protein kinase (MAPK), but not matrix metalloprotease (MMP)-9 expression. Our findings indicate that apigenin inhibits cancer metastasis through inhibition of phosphorylation of MAPK.

Adenocarcinoma↗

PubMed2000

Survey of recognition and utilization of guidelines for the diagnosis and management of bronchial asthma in Japan.

BACKGROUND: In Japan in 1993, the Japanese Society of Allergology (JSA) developed guidelines for diagnosis and management of asthma (JGL), which were based on the concept that asthma is a chronic inflammatory disorder of the airway. METHODS: This survey study was intended to investigate the recognition and utilization of JGL among physicians who had treated asthma. The survey comprised two methods: a quantitative mail survey and a qualitative door-to-door survey conducted by trained interviewers. RESULTS: In the mail survey, a total of 1028 physicians responded; 552 members of the JSA and 476 nonmembers. Ninety-four percent of JSA members were aware of adult asthma management guidelines, while 53% of nonmembers were aware of them. Although approximately half of the physicians, both members and nonmembers, found differences between the asthma management policies in JGL and their previous policies, most of them utilized JGL once they read it. In the qualitative door-to-door survey, 80-90% of physicians evaluated JGL as good after they read it. CONCLUSIONS: JGL was recognized and utilized by most JSA members, but only half of nonmember physicians were aware of JGL, although they utilized JGL after they read it. Further action to implement JGL among nonspecialist physicians is needed to improve management of asthma.

Adult↗

PubMed2000

Bilateral testicular tumors in androgen insensitivity syndrome.

We report on a case of complete androgen insensitivity syndrome with bilateral testicular tumors and a point mutation in the androgen receptor gene. A bilateral gonadecotmy was performed and both of the resected tumors were histologically diagnosed as pure seminoma. Direct sequencing of amplified exons E-G of the androgen receptor gene from the resected tumor identified a CGA to CAA substitution in exon E, resulting in arginine to glutamine replacement at codon 752. To our knowledge, this is the first reported case of androgen insensitivity syndrome with bilateral testicular tumors.

Androgen-Insensitivity Syndrome↗