Biomedical subjects
Publications and source records attributed to N Iwai.
In age-matched controlled studies performed in Japan, enterotoxigenic Bacteroides fragilis was isolated from 14.9% of 114 children aged 1 to 14 years with antibiotic-unassociated diarrhea (AUD) and 6.5% of 108 children aged 1 to 6 years with antibiotic-associated diarrhea (AAD). The difference in comparison with control children, was significant for AUD children but not AAD children.
Changes in the renin-angiotensin system (RAS) mRNAs in the brain and the kidney of rats after administration of DOCA and/or sodium chloride were assessed by use of a competitive PCR method. Benzamil, a blocker of amiloride-sensitive sodium channels, was infused intracerebroventricularly or intravenously for 7 days in DOCA-salt or renal hypertensive rats, and the effects of benzamil on the brain RAS mRNAs were determined. Renin and ANG I-converting enzyme (ACE) mRNAs were not downregulated in the brain of rats administered DOCA and/or salt; however, these mRNAs were decreased in the kidney. Intracerebroventricular infusion of benzamil decreased renin, ACE, and ANG II type 1 receptor mRNAs in the brain of DOCA-salt hypertensive rats but not in the brain of renal hypertensive rats. The gene expression of the brain RAS, particularly renin and ACE, is regulated differently between the brain and the kidney in DOCA-salt hypertensive rats, and benzamil-blockable brain sodium channels may participate in the regulation of the brain RAS mRNAs.
Low-renin hypertension is characterized by a high ratio of aldosterone to plasma renin activity (ALD/PRA), which may suggest inappropriately increased aldosterone biosynthesis. The genes for the enzymes involved in aldosterone synthesis may contribute to low-renin hypertension. We investigated the associations between genetic variations of CYP11B2 (aldosterone synthase) T(-344)C and hypertension in 482 Japanese subjects. Subjects older than 50 years with a blood pressure <140/85 mm Hg were considered normotensive (n=227 subjects), and subjects younger than 65 years old with a BP >160/95 mm Hg were considered hypertensive (n=255 subjects). The frequency of the TC+CC genotypes in the normotensive group was significantly lower than in the hypertensive group. Logistic analysis on 482 subjects revealed that body mass index, gender, and the genotype of CYP11B2 T(-344)C were significantly associated with hypertension. ALD and PRA were assessed in 97 subjects with hypertension, and the TC+CC genotypes were significantly associated with higher ALD/PRA. Sixty-five subjects with hypertension were assessed by 24-hour ambulatory blood pressure monitoring, and the frequency of nondippers (a difference in mean blood pressure of <10% between the daytime [6 AM to 9 PM] and nighttime [9 PM to 6 AM] hours) was significantly higher in subjects with the TC+CC (hetero+homo mutation) genotype than in subjects with the TT (wild-type) genotype. Echocardiographic assessment (n=136) revealed that the ratio of left ventricular end-diastolic dimension to height tended to be higher in subjects with the TC+CC genotype than in subjects with the TT genotype. The present study suggests that the (-344)C allele of the CYP11B2 gene may be a genetic marker for low-renin hypertension in Japanese.
A newly identified 3'-untranslated region (UTR) polymorphism of the gene for skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 (PPP1R3) was associated with insulin resistance and type 2 diabetes in Pima Indians (Xia J, Scherers W, Cohen PTW, Majer M, Xi T, Norman RA, Knowler WC, Bogardus C, Prochazka M: A common variant in PP1R3 associated with insulin resistance and type 2 diabetes. Diabetes 47:1519-1524, 1998). Thus, we investigated the frequency of polymorphism of the adenine- and thymine-rich element (ARE-1 and its variant ARE-2) in 426 Japanese type 2 diabetic and 380 nondiabetic subjects using a polymerase chain reaction (PCR)-restriction enzyme fragment length polymorphism (RFLP) method. The allele frequency of the ARE-2 variant in diabetic subjects was higher than that in nondiabetic subjects (0.34 vs. 0.29; P < 0.05), even though its frequency in Japanese subjects was lower (P < 0.001) than the reported value in Pima Indians (0.56). An aspartate polymorphism at codon 905 was 100% coupled to the ARE-2 allele, and its allele frequency was higher also in diabetic subjects. Although a serine substitution at codon 883 was partially linked with the ARE-2 allele, there was no difference between diabetic and nondiabetic subjects. These results indicate that the frequency of polymorphism of the PPP1R3 gene (ARE-2 and Asp905) is different between two ethnic groups and is increased in Japanese people with type 2 diabetes, suggesting that these variants may be a possible marker for searching for diabetogenic genes.
The 4G allele of the plasminogen activator inhibitor (PAI-I) gene is associated with increased PAI-I levels. Increased PAI-I levels have been reported to be associated with atherothrombotic events. However, the significance of the 4G/5G polymorphism of the PAI-I gene in the pathogenesis of ischemic heart diseases has not been determined. We assessed the 4G/5G polymorphism of the PAI-I gene in 500 subjects including 148 normal controls, 23 subjects with normal coronary arteries, 28 subjects with a paradoxical acetylcholine response, 97 subjects with angina pectoris (AP) and 204 subjects with myocardial infarction (MI). We assessed the length of time between the first anginal pain and the onset of acute coronary syndromes (ACS) in the AP and MI subjects. Subjects who developed ACS within 2 months from the first anginal pain were categorized to have a rapid progression to ACS, and subjects who had had stable anginal pain more than 2 months were placed in the non-ACS group. Subjects in the ACS group were younger than those in non-ACS group (P = 0.012) The frequency of the 5G/5G genotype of the PAI-I gene was lower in the ACS (0.228) than in the non-ACS group (0.093) (P = 0.003). Multiple logistic analyses revealed that a younger age (P = 0.028, odds ratio = 1.03) and the (4G/5G + 4G/4G) genotype of the PAI-I gene (P = 0.008, odds ratio = 2.68) were associated with the ACS group. We also assessed plasma PAI-I antigen levels in 78 subjects. Plasma PAI-I antigen levels in the non-ACS group were significantly lower than those in the ACS group (P = 0.050). Multiple regression analyses revealed that plasma PAI-I levels were determined by plasma insulin (P < 0.001) and the genotype of the PAI-I gene (P = 0.019). Higher plasma insulin levels and the (4G/5G + 4G/4G) genotype of the PAI-I gene were associated with higher plasma PAI-I levels. The 4G/5G polymorphism of the PAI-I gene influenced not only plasma PAI-I antigen levels but also the time course of the progression to ACS in patients with coronary atherosclerosis.
BACKGROUND: Patients with multiple endocrine neoplasia (MEN) type 2B inherently present with gastrointestinal motility disorders as well as medullary thyroid carcinoma, adrenal pheochromocytoma, and Marfanoid habitus. METHODS: The authors examined gut motility function in a 7-year-old girl with MEN type 2B who had suffered from chronic constipation and recurrent acalculous cholecystitis since infancy. RESULTS: Results of total gastrointestinal barium meal and enema studies showed marked hypoperistalsis of the gut and entire colonic dilatation. Histopathologic study results of the gut wall from the stomach, duodenum, and rectum showed hyperplasia of the submucosal and intramuscular neural plexuses in all specimens. Anorectal manometry demonstrated disarrangement of the internal sphincter rhythmic wave and a complete absence of the rectoanal inhibitory reflex. CONCLUSION: These data suggest that gut motility disorders in MEN type 2B are caused by inadequately organized autonomic nervous system activity that originates from hyperplasia of the enteric nervous system.
The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is an uncommon neuromuscular disorder caused by mitochondrial dysfunctions that result in headaches, seizures, and progressive dementia. The authors describe a clinical case study of gastrointestinal manifestations in a pedigree with MELAS, in which all three children, ages 11, 8, and 6, demonstrated acute onset of intestinal obstruction. They unexpectedly showed severe abdominal distension and vomiting. Their parents had no clinical manifestation. The first female sibling underwent an emergent laparotomy because she was diagnosed to have intestinal strangulation. She had postoperative complications caused by progressive lactic acidosis and died the next day. The second and third sisters had similar onsets of the disease and were treated with gastrointestinal decompression and intravenous administration of lactate-free fluid and coenzyme Q10. Genetic testing using blood samples showed an A-to-G point mutation at nucleotide position 3243 in the tRNALeu(UUR) region in the mitochondrial DNA. In MELAS children who demonstrate acute onset of gastrointestinal manifestations, a careful review of family history and an elevation of serum lactate and pyruvate levels may enable a differential diagnosis to be made of acute abdomen to avoid unnecessary surgical intervention.
Severe osteolysis is a rare complication of lymphangioma. It can progress despite treatment and may be fatal. Four patients presented with massive osteolysis and serious related complications. Of these, two responded well to OK-432 therapy with arrest of the osteolysis. Complete recovery from life-threatening pleural effusion has been noted in one. Of the two nonresponders, one died of progressive osteolysis of the cervical and occipital bones, the other, despite therapy, still shows progressive osteolysis of the left leg from the femur to the phalanges. A boneless leg may be the outcome.
PURPOSE: To investigate the pathogenesis of anorectal malformations (ARM), the authors studied cell proliferation and programmed cell death (apoptosis) patterns in murine embryos that develop ARM as a result of administering an overdose of etretinate, a long-acting vitamin A analogue (retinoid). METHODS: Pregnant mice were fed 60 mg/kg of etretinate on the ninth gestational day (E9). Embryos were obtained between E9.5 and E13, and prepared for histological study. Cell proliferation was examined using proliferative cell-specific nuclear antigen (PCNA) expression. Apoptosis was identified by detecting in situ DNA fragmentation using the TdT-mediated dUTP-digoxigenin nick end-labeling (TUNEL) method. RESULTS: Over 95% of etretinate-treated embryos had ARM including rectoprostatic urethral or rectocloacal fistula. In the histological study, ARM embryos showed defective cell proliferation in the cloacal membrane and excessive apoptosis in the dorsocaudal region on E11, which resulted in a lack of apoptosis in the anal orifice and a short tail on E12, respectively. Cells forming the urorectal septum showed the same pattern of cell proliferation and apoptosis both in ARM embryos and the controls. These results suggest that impairments of embryonal cellular dynamics in the cloacal membrane and dorsocaudal region induce some types of ARM.
Intraoperative cholangiography revealed biliary tracts in 11 of 25 (44%) patients with biliary atresia. The outcome of these 11 patients was analyzed based on the cholangiographic patterns. In these 11 patients, 4 cases were the 1-cyst type, 3 showed a "cloudy shadow" pattern in the intrahepatic biliary tract, and 4 were subtype "a" pattern (distally patent common bile duct). Four patients showing the I-cyst type underwent hepaticojejunostomy with Rouxen-Y anastomosis, and all of the 4 became jaundice-free a few weeks after surgery. Three patients with the "cloudy shadow" pattern gained good bile drainage after hepatic portoenterostomy with Suruga II modification, all were complicated by ascending cholangitis. Three of the 4 subtype "a" pattern underwent hepatic portoenterostomy with Suruga II modification. Two became jaundice-free, while jaundice persisted in one. The subtype "a" patient who underwent hepatic porto-cholecystostomy showed poor bile drainage, and died of hepatic failure 17 months after surgery despite further surgery. From these results, we conclude that 1) hepatico-jejunostomy with Roux-en-Y anastomosis is indicated for I-cyst biliary atresia. 2) Prevention of ascending cholangitis is important in patients with the "cloudy shadow" pattern. 3) Hepatic porto-jejunostomy is indicated for the subtype "a" pattern rather than hepatic porto-cholecystostomy.
We utilized helical computed tomography (CT) in three infants (aged 1 to 5 months) with tracheomalacia after repair of esophageal atresia. Helical CT was used for preoperative diagnosis and operative planning. At the time of aortosternopexy, it is often difficult to determine the direction of suture traction to yield the largest tracheal lumen. The helical CT was useful not only for diagnosis of tracheomalacia but also for operative planning of aortosternopexy.
Prognosis of osteosarcoma has been improved markedly with the introduction of effective, intensive chemotherapy. However, there are many reports that indicate that the prognosis of osteosarcoma with pulmonary metastases at the initial presentation is poor. One hundred seventeen patients with osteosarcoma involving the extremities were treated at the Chiba Cancer Center from 1976 to 1995. Of these, nine (7.6%) patients had pulmonary metastases at initial presentation; these nine patients are the subjects of this article. There was an average of 0.9 pulmonary metastatic lesions at initial presentation seen on plain chest radiographs, an average 2.9 lesions seen on computed tomograms of the chest, and an average 12.7 lesions found at thoracotomy in these nine patients. The pulmonary metastatic lesions that could not be detected by computed tomography of the chest were resected by thoracotomy. Three patients died, and six patients are alive, with the 5-year survival being 64.8%. Intensive chemotherapy and aggressive surgical therapy were done for these patients with osteosarcoma with pulmonary metastases at initial presentation, and it is thought that this improved the prognosis of these patients. Pulmonary metastases of osteosarcoma at initial presentation do not always indicate a hopeless prognosis.
Toxigenic strains of Clostridium difficile have been reported to produce both toxins A and B nearly always, and nontoxigenic strains have been reported to produce neither of these toxins. Recent studies indicate that it is not always true. We established a PCR assay to differentiate toxin A-negative, toxin B-positive (toxin A-, toxin B+) strains from both toxin-positive (toxin A+, toxin B+) strains and both toxin-negative (toxin A-, toxin B-) strains as an alternative to cell culture assay and enzyme-linked immunosorbent assay (ELISA). By using the PCR primer set NK11 and NK9 derived from the repeating sequences of the toxin A gene, a shorter segment (ca. 700 bp) was amplified from toxin A-, toxin B+ strains compared to the size of the segment amplified from toxin A+, toxin B+ strains (ca. 1,200 bp), and no product was amplified from toxin A-, toxin B-strains. We examined a total of 421 C. difficile isolates by PCR. Of these, 48 strains showed a shorter segment by the PCR, were negative by ELISAs for the detection of toxin A, and were positive by cell culture assay. Although the cytotoxin produced by the toxin A-, toxin B+ strains was neutralized by anti-toxin B serum, the appearance of the cytotoxic effects on Vero cell monolayers was distinguishable from that of toxin A+, toxin B+ strains. By immunoblotting, the 44 toxin A-, toxin B+ strains were typed to serogroup F and the remaining four strains were serogroup X. Pulsed-field gel electrophoresis separated the 48 strains into 19 types. The PCR assay for the detection of the repeating sequences combined with PCR amplification of the nonrepeating sequences of either the toxin A or the toxin B gene is indicated to be useful for differentiating toxin A-, toxin B+ strains from toxin A+, toxin B+ and toxin A-, toxin B- strains and will contribute to elucidation of the precise role of toxin A-, toxin B+ strains in intestinal diseases.
Linkage analyses in the spontaneously hypertensive rat (SHR) suggest that a gene involved in blood pressure regulation may be located on rat chromosome 1, in the Sa region. To confirm this possibility, we replaced a region of chromosome 1 in the Wistar-Kyoto rat (WKY) defined by the markers D1Mit3 and MTPA with the corresponding chromosome segment from SHR. Genotyping using 65 polymorphic microsatellite markers throughout the entire genome confirmed the congenic status of this new strain designated WKY. SHR-D1Mit3/Rat57. In male WKY.SHR-D1Mit3/Rat57, mean blood pressures in the daytime and in the nighttime assessed by radiotelemetry were significantly higher than those in male progenitor WKY. Moreover, salt loading significantly increased the mean blood pressure in male WKY.SHR-D1Mit3/Rat57 but not in male progenitor WKY. The present study confirmed the existence of a gene that contributes to high blood pressure and salt sensitivity in this chromosomal segment. This congenic strain represents a new animal model for fine mapping and characterization of the gene in this region involved in salt-sensitive hypertension.
Recently, a molecular variant of alpha-adducin (with tryptophan instead of glycine at amino acid number 460) has been reported to be more common among Italian and French hypertensive individuals than among controls. Moreover, hypertensive individuals with Trp460 exhibit a greater sensitivity to changes in sodium balance and a greater fall in blood pressure in response to diuretic treatment. In the present study, we investigated the association between Gly460Trp polymorphism of the alpha-adducin gene and hypertension in Japanese subjects. The study population comprised 283 subjects enrolled at our outpatient clinic. The subjects were divided into normotensive (NT), borderline (B), and hypertensive (HT) groups. The alpha-adducin genotype was determined by allele-specific oligonucleotide hybridization. The genotype frequency of Gly460Trp polymorphism differed significantly among the NT, B, and HT groups (p=0.0113). The GG genotype of the adducin gene was more common in the NT group than in the HT group. Moreover, the Trp460 allele was significantly associated with lower plasma renin activity (p = 0.0075). However, this polymorphism was unrelated to left ventricular mass and height as assessed by echocardiography. The present study suggests that Gly460Trp polymorphism of the a-adducin gene may be involved in hypertension, particularly the low-renin type, in Japanese individuals.
PURPOSE: Among the pyrimidine nucleoside phosphorylases (PyNPase), thymidine phosphorylase (dThdPase) exists mainly in human tumor tissues, and is an enzyme which converts 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil. Recently, it was reported that dThdPase was identical to platelet-derived endothelial cell growth factor which was an antiogenetic factor, therefore. We think dThdPase may be a prognostic factor. METHODS: We investigated the possible correlation between PyNPase activities in tumor tissues and prognostic factors of histological findings, and examined influences of preoperative oral 5'-DFUR administration at a dose of 1,200 mg/body for 7 days on PyNPase activities and serum immunosuppressive acidic protein levels in patients with gastric cancer. RESULTS: Higher levels of PyNPase activities were especially observed in patients with v+ (p = 0.0161). PyNPase activities (p = 0.1668) and IAP (p = 0.0830) levels showed a decrease by 5'-DFUR administration. CONCLUSION: This study suggests that we must investigate in detail the possibility of PyNPase being prognostic factor, and 5'-DFUR administration may improve the prognosis of patients with gastric cancer.
The prognosis of lung cancer patients is generally poor even when they have undergone complete resection of primary tumors and systemic lymph node dissection. This is mainly attributed to micrometastases which have already developed by the time of surgery and the fact that local therapies cannot eliminate all cancer cells from the body. We developed a multimodality combination therapy for primary non-small cell lung cancer consisting of surgery, chemotherapy, and adoptive immunotherapy using interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells. The results of a randomized study indicated that the survival rate of the IL-2, LAK adoptive immunotherapy group was significantly higher than that of the control group. In conclusion, IL-2, LAK adoptive immunotherapy is an effective and promising modality which will compensate for the deficiencies of other therapies.
Pharmacokinetic, bacteriological and clinical studies were performed in pediatrics on tazobactam/piperacillin (TAZ/PIPC), a combined drug of a new beta-lactamase inhibitor tazobactam and piperacillin at a ratio of 1:4. 1. Serum levels and urinary excretions of TAZ, PIPC and desethyl piperacillin (DEt-PIPC), a metabolite of PIPC, after one shot intravenous administration of 50 mg/kg of TAZ/PIPC to two children (6-7 years old) were investigated. The serum TAZ level at 0.08 hour was 50.8-51.0 micrograms/ml after administration. Then TAZ concentrations gradually decreased with half-lives of 0.38-0.45 hour, and reached 1.0-1.4 micrograms/ml after 2 hours and was not detected after 3 hours and 6 hours. Serum PIPC levels at 0.08 hour was 167.0-231.0 micrograms/ml after administration. Then PIPC concentrations gradually decreased with half-lives of 0.41-0.55 hour, and reached 1.2-2.4 micrograms/ml after 3 hours and was not detected after 6 hours. DEt-PIPC was detected slightly in serum. A ratio of TAZ to PIPC was about 1 to 4 in serum at each time. Urinary recovery rates of TAZ in the first 6 hours after administration of TAZ/PIPC were 33.5-90.1% and those of PIPC were 41.9-77.8% and those of DEt-PIPC were 1.5-2.8%. 2. TAZ/PIPC was administered to 27 pediatric patients (their ages ranged between 2 months and 11 years old) with various infections, and clinical and bacteriological effects and adverse reactions were investigated. Single doses were 26.2-55.6 mg/kg, frequencies of administration were 3-4 times a day, and durations of administration were 3 1/3-7 1/3 days, and total dosages were 4.5-33.75 g. Clinical effects were evaluable in 26 cases. Responses were rated as "good" in acute purulent tonsillitis 1 case and acute purulent otitis media 1 case, as "excellent" in acute sinusitis 1 case, as "excellent" in 2 and "good" in 1 out of 3 cases of acute bronchitis, as "excellent" in 13 and "good" 2 out of 15 cases of acute pneumonia, as "excellent" in acute urinary tract infection 2 cases and as "excellent" in acute enteritis in 1 case, acute appendicitis in 1 case and lymphadentis in 1 case. In all cases, the results were rated as "good" or "excellent". Antimicrobial effects against a total of 10 strains identified or assumed to be pathogenic bacteria were evaluated. The 10 strains of bacteria included 4 strains of Streptococcus pneumoniae, 3 strains of Haemophilus influenzae (2 strains beta-lactamase producing), 2 strains of beta-lactamase producing Moraxella catarrhalis, 1 strain of beta-lactamase producing Morganella morganii. All the bacteria listed here were judged to have been eradicated. Adverse reaction was observed in 1 case with mild diarrhea. As abnormal changes in laboratory data, leucocytopenia in 1 case, elevation of GOT. GPT in 2 cases and eosinophilia in 1 case were observed. On the basis of the findings, TAZ/PIPC was considered to be effective and safe in the treatment of pediatric infections.