Biomedical subjects
Publications and source records attributed to Y Hamada.
Male breast cancer is a rare disease with an incidence between 0.5% and 2.4% of that in women. We report a case of intracystic papillary carcinoma of the breast in a 75-year-old Japanese man. The macroscopic features of the carcinoma could be accurately demonstrated by pneumocystography and ultrasonography preoperatively.
PROBLEM: The zona pellucida is a good target antigen for contraceptive vaccines due to its strong immunogenicity and high tissue specificity. However, this contraceptive effect is inevitably associated with ovarian failure. Therefore, it is necessary to define an epitope of the zona antigen to which the antibody produced inhibits fertilization without any undesirable side effects. METHOD OF STUDY: The DNA fragment coding for the NH2-terminal region of porcine zona pellucida proteins (ZPA) (1-198 amino acids) and human ZPA (1-206 amino acids) was prepared to produce recombinant porcine ZPA (r-ZPA), r-pZPA1-198 and r-hZPA1-206. Using Freund's complete adjuvant. antisera against these proteins were raised in rabbits. RESULTS: The resultant antisera to r-pZPA1-198 and r-hZPA1-206 were cross-reacted with each other on enzyme-linked immunosorbent assay and immunofluorescent staining. The antiserum to r-pZPA1-198 inhibited in vitro fertilization in pigs, but not human sperm binding to the zona pellucida, while the antiserum to r-hZPA1-206 inhibited the human sperm-binding assay. CONCLUSIONS: Antiserum to r-ZPA inhibited fertilization in the animal species possessing a homologous amino-acid sequence as an immunogen. The recombinant protein, r-hZPA1-206 seems to be a feasible candidate for the development of contraceptive vaccines for humans.
Delta1, Jagged1, and Jagged2, commonly designated Delta/Serrate/LAG-2 (DSL) proteins, are known to be ligands for Notch1. However, it has been less understood whether they are ligands for Notch receptors other than Notch1. Meanwhile, ligand-induced cleavage and nuclear translocation of the Notch protein are considered to be fundamental for Notch signaling, yet direct observation of the behavior of the Notch molecule after ligand binding, including cleavage and nuclear translocation, has been lacking. In this report, we investigated these issues for Notch2. All of the three DSL proteins bound to endogenous Notch2 on the surface of BaF3 cells, although characteristics of Jagged2 for binding to Notch2 apparently differed from that of Delta1 and Jagged1. After binding, the three DSL proteins induced cleavage of the membrane-spanning subunit of Notch2 (Notch2(TM)), which occurred within 15 min. In a simultaneous time course, the cleaved fragment of Notch2(TM) was translocated into the nucleus. Interestingly, the cleaved Notch2 fragment was hyperphosphorylated also in a time-dependent manner. Finally, binding of DSL proteins to Notch2 also activated the transcription of reporter genes driven by the RBP-Jkappa-responsive promoter. Together, these data indicate that all of these DSL proteins function as ligands for Notch2. Moreover, the findings of rapid cleavage, nuclear translocation, and phosphorylation of Notch2 after ligand binding facilitate the understanding of the Notch signaling.
To investigate the mechanism of human uterine smooth muscle relaxation, the activation of Ca2+-activated K+ channels in cultured myometrial cells obtained from human pregnant myometrium at term by nitric oxide was evaluated at the single cell level using the patch-clamp technique. The open probability of the K+ channel after the addition of 3 x 10(-3) M isosorbide dinitrate, a nitric oxide donor (0.116 +/- 0.048) was significantly higher than that before the addition (0.059 +/- 0.032; n = 9, p < 0.01). In myometrial cells pretreated with lipopolysaccharide, activation of K+ channels was also noted after the addition of L-arginine (10(-4) M; open probability increased from 0.179 +/- 0.076 to 0.380 +/- 0.105, n = 9, p < 0.01: 10(-3) M; open probability increased from 0.073 +/- 0.050 to 0.242 +/- 0.098, n = 12, p < 0.01). Either 10(-3) M N-nitro-L-arginine-methyl-ester, an inhibitor of nitric oxide synthase, or 10(-6) M methylene blue, an inhibitor of guanylate cyclase, abolished activation of the K+ channel by 10(-3) M L-arginine in pretreated myometrial cells with lipopolysaccharide. Application of 10(-3) M L-arginine to the intracellular surface of an excised inside-out patch in the myometrial cells pretreated with lipopolysaccharide failed to increase Ca2+-activated K+ channel activity, suggesting that the activation was mediated by intracellular messengers. These results indicate that nitric oxide should control human myometrial relaxation during pregnancy via activation of Ca2+-activated K+ channels.
Lipid peroxidation due to oxidative stress is accelerated under hyperglycemic conditions such as diabetes mellitus. The effect of 4-hydroxy-2-nonenal (HNE) and other lipid peroxidation products on the ability of isolated rat pancreatic islets to secrete insulin was examined in this study. HNE concentration- and time-dependently deteriorated glucose-induced insulin secretion: insulin secretion was decreased by 50% when measured after incubation of islets with 100 microM HNE for 1 h. Other lipid peroxidation products, e.g. 2-hexenal and 2-butenal, also inhibited glucose-induced insulin secretion. HNE at 100 microM lowered alpha-ketoisocaproate-induced insulin secretion, whereas leucine-induced insulin secretion was stimulated. Insulin secretion induced by 10 mM glyceraldehyde was slightly decreased by HNE. On the other hand, HNE severely decreased insulin secretion induced by 10 mM glyceraldehyde and 2.8 mM glucose. Glucose utilization and glucose oxidation were significantly lowered in islets treated with HNE. The amounts of fructose 1,6-bisphosphate and dihydroxyacetone phosphate in islets were decreased by treatment with HNE, whereas the amount of fructose 6-phosphate was increased. Our study indicates that HNE and other lipid peroxidation products impair insulin secretion induced by glucose probably through affecting both the glycolytic pathway and the citric acid cycle.
The mechanism of the liberation reaction of the N-oxide group has been studied and compared with the methylation reaction using a semi-empirical molecular orbital PM3 method. By comparing the calculated values of Gibbs free energy of activation, we can determine whether a liberation reaction or methylation reaction occurs.
1,4-Oxazepine formation reactions of 1,8-naphthyridine derivatives (1-4) with peroxy acid have been studied using a semiempirical MO method (AM1) and an ab initio molecular orbital method (Gaussian 94). The energies of molecules involved in the reaction paths were calculated and the transition states related to experimental products were obtained. For the reactions of 1-3, the calculated energies of the transition states predicted the previously obtained products. However, the calculated values for the reaction of 4 suggested a different type of oxazepine compound, which was verified in further experiments.
1, X-Naphthyridines (X = 5, 6, and 8) (1-3) were synthesized in a high yield by the Skraup reactions of 4-, 3-, and 2-aminopyridines with glycerol, in the presence of ferrous sulfate and boric acid. The improved syntheses were applied to the syntheses of 1,5-, 1,6-, and 1,8-naphthyridines (4-28), pyridonaphthyridines (31, 32), benzonaphthyridines (38-42), naphthonaphthyridines (44, 48, 49, 59). New synthetic methods of naphtho[1,2-b or 2,1-b][1,8]naphthyridine (62, 63), benzo[b][1,8]naphthyridine (41) and benzo[g]quinoline (67) were developed and their compounds obtained conveniently. Reissert reaction of 1,6-naphthyridine (2) using triethylbenzylammonium chloride (TEBA) produced Reissert compounds and ring-opened compounds. Reissert reaction of 1,7-naphthyridine (29), 4,7- (87), 4,6-phenanthroline (38) gave the Reissert compounds, and the compounds (2, 38) gave their pseudo bases (79, 90). Reissert-type reactions of benzo[f]quinoline (68), and 1,7-phenanthroline (105) with acyl chloride and phosphite, gave alpha- and gamma-phosphonate, and 87 produced alpha,alpha'-(108a-c) and alpha,gamma'-diphosphonates (109a-c). The structure of 108c-1 was determined to be trans-type by an X-ray analysis. Compounds 1-3, 29, and benzo[f or h]quinoline were treated with dimetyl sulfoxide in the presence of sodium hydride to give mainly methylated compounds at the position para to the ring-nitrogen. When benzo[f or h]quinoline N-oxide was treated with methylsulfinylmethyl carbanion in the usual procedure, a new reaction took place to produce phenanthrene in an excellent yield. The same reaction of 1,10-, 1,7-, or 4,7-phenanthroline N-oxides (143-145) resulted in the liberation of the N-oxide group to form benzo[f or h]quinoline, but isoquinoline N-oxide afforded to benzazepine derivatives (161). Reaction of quinaldine with methylsulfinylmethyl carbanion gave novel tricyclic compound (121a). The oxidation of 41, 62, and 63 with peroxy acids afforded novel products such as seven-membered 1,4-oxazepine derivatives.
The effect of addition of linoleic acid-albumin (LAA) to culture medium before freezing on the survival rate of bovine 16-cell embryos after freezing-thawing was investigated. Embryos were incubated in CR1aa containing LAA (0.25 mg/ml) for 4 days after insemination. A conventional slow cooling method was used, in which embryos were cooled at a rate of 0.3 degrees C/min to -30 degrees C in medium supplemented with 1.5 M ethylene glycol and 0.2 M trehalose. The developmental rate to the blastocyst stage of thawed embryos that had been cultured with LAA-containing medium before freezing was higher than that of these cultured without LAA (P<0.05). However, with fresh, non-frozen, embryos that were incubated under the same culture conditions (with and without LAA), no such difference was found.
A carcinogen-resistant inbred strain DRH/Sea has been developed from the Crj:Donryu strain. The rats had a very low incidence of liver tumors when they were fed diets containing a hepatocarcinogen such as 3'-methyl-4-dimethylamino-azobenzene (3'-Me-DAB). Despite using 3'-Me-DAB during the stage of selection, the DRH/Sea rats developed normally, reproduced and did not have any spontaneous tumor in the lung, liver or uterus at over 1 year of age. Although their growth curves were similar to the Crj:Donryu rats, the progression of polyploidization in the liver was significantly delayed when compared with Crj:Donryu rats. Mitogenic changes that occurred in the liver caused by either 3'-Me-DAB or lead nitrate were less significant in the DRH rats than in Crj:Donryu rats. Furthermore, the growth rate of cultured fibroblasts derived from the DRH rats was slower than that of Crj:Donryu rats. These results, together with our previous results, suggest that slow growth potential is present under certain conditions in DRH rats. These findings may explain partly the meaning of the different susceptibility to hepatocarcinogens.
A 61-year-old woman, who was diagnosed in 1982 as having polycythemia vera, was admitted to our hospital in July 1998 because of a splenic tumor in an enlarged spleen due to myelofibrosis. As it was difficult to identify the etiology of the splenic tumor, partial splenectomy was carried out. The resected tumor proved to be an extremely proliferative lesion as the result of extramedullary hematopoiesis. Since it is difficult to diagnose the etiology of splenic tumor, the collection and analysis of reports of relevant cases may well facilitate diagnosis.
OBJECTIVE: To clarify the role of the polyol pathway in the intracellular formation of advanced glycation end products in human tissues, we examined the effects of epalrestat, an aldose reductase inhibitor, on the level of Nepsilon-(carboxymethyl)lysine (CML) along with 3-deoxyglucosone (3-DG) and triosephosphates in erythrocytes from diabetic patients. Plasma thiobarbituric acid-reactive substances (TBARS) were also determined as indicators of oxidative stress. RESEARCH DESIGN AND METHODS: Blood samples were collected from 12 nondiabetic volunteers, 38 untreated type 2 diabetic patients, and 16 type 2 diabetic patients who had been treated with 150 mg epalrestat/day. Blood samples were also collected from 14 of the untreated type 2 diabetic patients before and after the administration of epalrestat for 2 months. The amount of erythrocyte CML was determined by a competitive enzyme-linked immunosorbent assay, and 3-DG was measured by high-performance liquid chromatography RESULTS: In diabetic patients not treated with epalrestat, the erythrocyte CML level was significantly elevated above levels seen in nondiabetic individuals (49.9 +/- 5.0 vs. 31.0 +/- 5.2 U/g protein, P < 0.05) and was significantly lower in patients receiving epalrestat (33.1 +/- 3.8 U/g protein, P < 0.05). Similar results were observed with 3-DG. The treatment of patients with epalrestat for 2 months significantly lowered the level of erythrocyte CML (46.2 +/- 5.6 at baseline vs. 34.4 +/- 5.0 U/g protein, P < 0.01) along with erythrocyte 3-DG (P < 0.05), triosephosphates (P < 0.05), fructose (P < 0.05), sorbitol (P < 0.05), and plasma TBARS (P < 0.05) without changes in plasma glucose and HbA(1c) levels. A positive correlation was evident between the erythrocyte CML and sorbitol (r = 0.49, P < 0.01) or fructose (r = 0.40, P < 0.05) levels in diabetic patients. CONCLUSIONS: The results indicate that epalrestat administration lowers CML and associated variables and that polyol metabolites are correlated with CML in the erythrocytes of diabetic patients. The observed results suggest that aldose reductase activity may play a substantial role in the intracellular formation of CML in the mediation of reactive intermediate metabolites and oxidative stress.
A 74-year-old man had an previous antero-septal and inferior myocardial infarction and an abdominal aortic aneurysm (AAA) 48 mm in diameter. Coronary angiography showed obstruction of the left anterior descending artery and of the right coronary artery, and 95% stenosis of the circumflex artery. The value of an ejection fraction of the left ventricle was 33%, measured by left venticulography. CABG and replacement of the aneurysm were performed simultaneously, because of the necessity of an intra-aortic balloon pumping (IABP) due to the impaired left ventricular function. First, CABG was performed under cardiac arrest. After declamping the ascending aorta, subsequently, replacement of AAA was performed while extracorporeal circulation (ECC) assisted heart beating. Weaning from ECC was smooth, and the operation was successful without using IABP. The patient was discharged 32 days after the operation. Consequently, cardiopulmonary bypass during AAA operation could decrease heart loads when hemodynamic states change in aortic clamping or after declamping. A simultaneous operation of CABG and AAA using ECC is safe and effective for impaired left ventricular function.
A 62-year-old man with synchronous multiple primary cancers involving the lung, stomach, and thyroid was admitted. Initially the patient's chest X-ray showed an abnormal shadow in the right middle-lobe indicating lung cancer. During preoperative examination, gastric cancer of the antrum and angle were detected. Excisional biopsy of the lymph node in the neck after chest surgery revealed thyroid cancer. A middle lobectomy with mediastinal lymph node dissection was performed for lung cancer and the histological diagnosis was moderately differentiated adenocarcinoma, pT4N2M0, stage IIIB. Gastric cancer was treated by endoscopic mucosal resection. Considering the relatively better prognosis of papillary thyroid cancer, we concluded that no further treatment to the thyroid lesion was necessary. In Japan, according to autopsy reports, triple primary cancers are gradually increasing. During the periods 1994 to 1996, the incidence of triple cancers was 0.81% of all autopsy cases reported.
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We report a case of 59-year-old man of descending necrotizing mediastinitis (DNM) secondary to peritonsillar abscess. A 59-year-old man with diabetes mellitus was admitted to a local hospital because of cervical swelling related to a peritonsillar abscess. Despite administration of antibiotics, swelling of the neck, dysphagia and dyspnea deteriorated. Therefore he was urgently undergone a tracheotomy and transferred to our hospital by an ambulance. The surgery consisted with neck and anterior mediastinal drainage through neck and cervical collar incision. Culture of drainage fluid showed clostridium difficile. On postoperative day 5, we started hyperbaric oxygen therapy (HBOT). After lavage and HBOT, the patient improved by degrees, and discharged on postoperative day 82. DNM is a rare but serious complication of otopharyngeal and deep neck infection that spreads down to the mediastinum through the cervical-facial planes. Its mortality rate remains high even with aggressive surgical drainage and appropriate antibiotics. Our patient was successfully treated with urgent surgical drainage, antibiotics and HBOT. HBOT might be of great value as an adjunctive management to control this fatal infection.
CD40 is a member of the tumor necrosis factor receptor super-family expressed by B cells, monocytes, dendritic cells, epithelial cells and hematopoietic progenitor cells. CD40 has recently been reported to be expressed on several epidermal tumors as well. CD40 on epidermal tumor cells interacts with lymphocytes expressing ligand for CD40 (CD40L) or monoclonal antibodies against CD40 with a significant decrease in proliferation. In this study, we examined the expression of CD40 and CD40L in Bowen's disease and squamous cell carcinoma (SCC). CD40 immunoreactivity was observed in a significantly lower proportion of tumor cells from SCC than from Bowen's disease. CD40L mRNA expression was detected in Bowen's disease and SCC by reverse transcriptase polymerase chain reaction (RT-PCR). CD40-CD40L interactions in epidermal tumors may play a role in the proliferation, and the lack of CD40 in tumor cells from SCC might be involved in the mechanisms of escape from the growth inhibitory effect.
Seven patients with pulmonary carcinoid including three with typical carcinoid and four with atypical carcinoid were reported. There were 3 males and 4 females, with an age range of 37 to 80 years. All patients with typical carcinoid had pathological stage I. Of the patients with atypical carcinoid, one patient had stage I, two stage IIIA and one stage IIIB. All but two patients underwent lobectomy and mediastinal lymph node dissection. Bronchoplastic operation or right pneumonectomy were performed in the two patients. All but one patient underwent absolute or relative curative operation. Only one patient died on the 4th postoperative day. One patient with atypical carcinoid died of cancer recurrence 4 years after surgery. One patient died of breast cancer. One patient underwent surgery for metachronous multiple lung cancer, and he is doing well without recurrence. In conclusion, a limited operation is thought to be acceptable only in patients with typical carcinoid in a peripheral lesion without lymph node metastasis. Lobectomy and mediastinal lymph node dissection is necessary for the atypical carcinoid case.