17ß-Estradiol induces proliferation of endometrial NK cells (CD56+) in postmenopausal women.

OBJECTIVE: The aim of this report was to evaluate the impact of hormone replacement therapy (HRT) on lymphocytic infiltration of the endometrium in postmenopausal women. METHOD: This study included 58 Japanese patients who had undergone hysterectomy at the University Hospital of Occupational and Environmental Health, Japan. Before surgery, nine patients had received 17ß-estradiol (E2), 0.72 mg transdermally for 2-8 weeks (E2 group); 16 patients had received an Estra-1,3,5(10)-triene-3,16α, 17ß-triol (E3) vaginal tablet 0.5 mg per month five times (E3 group); and 19 patients had received 17ß-estradiol, 0.62 mg, and norethindrone acetate (P), 2.70 mg for 3-16 weeks (E2 + P group). Fourteen patients received no HRT (control group). We examined uterine tissue specimens immunohistochemically for CD45+, CD3+, CD4+, CD8+, CD20+, CD56+, and Ki67 antigen-positive cells. RESULTS: The numbers of CD56 + cells were significantly increased in the E2 group compared with all other groups (E2 vs. E3: 7.0 vs. 0.75, p = 0.017; E2 vs. E2 + P: 7.0 vs. 0.58, p = 0.009; E2 vs. CONTROL: 7.0 vs. 0.43, p = 0.010). The numbers of CD3+ cells were significantly increased in the E2 group compared with the control group (149.3 vs. 42.6, p = 0.008). CONCLUSION: 17ß-Estradiol induced the proliferation of endometrial uterine natural killer cells (CD56+) in postmenopausal women.

Improvement of meal-related symptoms and epigastric pain in patients with functional dyspepsia treated with acotiamide was associated with acylated ghrelin levels in Japan.

BACKGROUND: The aim of this study is to clarify whether acotiamide and rabeprazole combination therapy can improve clinical symptoms, gastric emptying, and satisfaction with treatment in functional dyspepsia (FD) patients more effectively than acotiamide or rabeprazole monotherapy alone. We also aimed to determine whether acotiamide affects these changes via its effect on gastric emptying and appetite-related hormones such as ghrelin. METHODS: We used Rome III criteria to evaluate upper abdominal symptoms and anxiety by the State-Trait Anxiety Inventory (STAI). Gastric motility was evaluated by the (13) C-acetate breath test. Eighty-one FD patients were treated with acotiamide (300 mg/day) (n = 35), acotiamide (300 mg/day) and rabeprazole (10 mg/day) (n = 28), or rabeprazole (10 mg/day) (n = 18) for a period of 4 weeks and followed after 4 weeks of no treatment. Adenocorticotropic hormone (ACTH), cortisol, leptin and ghrelin levels were measured in all FD patients. KEY RESULTS: Acotiamide and rabeprazole combination therapy significantly improved postprandial distress syndrome (PDS)-like symptoms (p = 0.018, p = 0.04 and p = 0.041, respectively) and epigastric pain (p = 0.024) as wells as STAI-state scores (p = 0.04) compared to rabeprazole monotherapy. Both acotiamide monotherapy, and acotiamide taken in combination with rabeprazole, significantly (p = 0.001 and p = 0.02, respectively) improved satisfaction with treatment, compared to rabeprazole monotherapy. Acotiamide and rabeprazole combination therapy had no significant effect on ACTH and cortisol levels in FD patients. Of interest, acotiamide monotherapy, and acotiamide and rabeprazole combination therapy, significantly (p < 0.0001 and p = 0.018, respectively) increased acylated ghrelin/total ghrelin ratios and significantly (p = 0.04) improved impaired gastric emptying compared to rabeprazole monotherapy. CONCLUSIONS & INFERENCES: Further studies are warranted to clarify how acotiamide treatment improves clinical symptoms in FD patients.

Nizatidine improves clinical symptoms and gastric emptying in patients with functional dyspepsia accompanied by impaired gastric emptying.

BACKGROUND/AIMS: In this crossover study, we investigated whether nizatidine, a H(2)-receptor antagonist, can alleviate clinical symptoms and gastric emptying in patients with Rome III-based functional dyspepsia (FD) with or without impaired gastric emptying. METHODS: We enrolled 30 patients presenting with FD symptoms (epigastric pain syndrome, n = 6; postprandial distress syndrome, n = 24). Rome III-based FD patients were treated with nizatidine (300 mg/day) or placebo for 4 weeks in a crossover trial. Gastric motility was mainly evaluated with the T(max) value using the (13)C-acetate breath test. Meal-related symptoms were defined as postprandial fullness and early satiation. Gastroesophageal symptom was defined as a burning feeling rising from the stomach or lower chest up toward the neck. Acylated- and desacylated ghrelin levels were evaluated by the ELISA method. Clinical symptoms, gastric emptying and ghrelin levels were evaluated at three different points during the study (pretreatment, after 4 weeks former treatment and after 4 weeks later treatment). The primary end point of this study was to determine whether nizatidine would improve clinical symptoms and gastric emptying in FD patients with or without impaired gastric emptying via affecting ghrelin levels. RESULTS: Meal-related symptoms of the patients treated with nizatidine improved significantly (21/30; 70%) compared to those treated with placebo (3/30; 10%). In addition, nizatidine treatment also significantly improved gastroesophageal symptoms (16/30; 53%) compared to those treated with placebo (0/30; 0%). Nizatidine treatment in patients with FD accompanied by impaired gastric emptying significantly improved clinical symptoms and T(max) value as a marker of gastric emptying (10/11, 91%; 9/11, 82%) compared to placebo therapy, respectively. There were no significant differences in ghrelin levels between nizatidine treatment and placebo therapy. CONCLUSION: Nizatidine administration significantly improved both gastric emptying and clinical symptoms in FD patients with impaired gastric emptying.

Prognostic significance of BAF57 expression in patients with endometrial carcinoma.

This study was conducted to elucidate the prognostic significance of BAF57 in patients with endometrial carcinoma. We investigated the relationship between the immunohistochemical expression of BAF57 and various clinicopathological variables in 111 endometrial carcinomas. Both univariate and multivariate regression analyses were performed. The correlations between the BAF57 expression and the other variables including estrogen receptor (ER) and p53 were examined. The high nuclear BAF57 expression was detected in 42 (37.8%) endometrial carcinomas, and 69 (62.2%) endometrial carcinomas were defined as having low nuclear BAF57 expression. The BAF57 expression was significantly associated with the surgical stage, grade of the tumor, myometrial invasion, lympho-vascular space invasion (LVSI) and lymph node metastasis. The 10-year overall survival rates of patients with low and high BAF57 expression were 96.9% and 58.2%, respectively (p<0.001). A multivariate analysis identified BAF57 expression as an independent prognostic factor. The BAF57 expression was significantly correlated with p53 expression (r=0.312, P=0.001), but was not correlated with ER expression (r= -0.141, P=0.14). The high BAF57 expression is an independent marker of poor prognosis of the patients in endometrial carcinomas. The inhibition of BAF57 activity may be one of the candidates for endometrial cancer therapy, especially therapy for aggressive tumors showing overexpression of p53.

G-protein ß3 subunit 825CC genotype is associated with postprandial distress syndrome with impaired gastric emptying and with the feeling of hunger in Japanese.

BACKGROUND: G-protein dysfunction related alteration of intracellular signal transduction might be linked to various abnormalities of functional gastrointestinal (GI) disorders. Serotonin (5-hydroxytryptamine; 5-HT) as well as G-protein is also key signaling molecule sensorimotor functions in the GI tract. Thus, this study aims to evaluate the correlation between gastric emptying and GNß3 and 5-HTs polymorphisms in functional dyspepsia (FD) as defined by Rome III classification. METHODS: Seventy-four patients presenting with typical symptoms of FD (epigastric pain syndrome: EPS, n=24; postprandial distress syndrome: PDS, n = 51) and sixty-four healthy volunteers were enrolled. Gastric motility was evaluated with the T(max) value using the (13) C-acetate breath test. We used Rome III criteria to evaluate upper abdominal symptoms and SRQ-D scores to determine depression status. GNß3-C825T, 5-HT(1A) -C1019G, 5-HT(2A) -G1438A, 5-HT(3A) -C42T, and 5-HT(4A) -G353+6A polymorphisms were analyzed in DNA from blood samples of enrolled subjects. Genotyping was performed by polymerase chain reaction. KEY RESULTS: There was a significant relationship (P=0.045) between GNß3 825CC genotype and PDS patients without gastro-esophageal reflux symptoms with impaired gastric emptying. In Japanese, GNß3 825CC genotype in FD patients was significantly associated (P=0.0485) with the feeling of hunger compared with GNß3 825CT and TT genotypes. CONCLUSIONS & INFERENCES: Our results suggest that the GNß3 825CC genotype is significantly associated with PDS patients without gastro-esophageal reflux with impairments of gastric emptying and also with the feeling of hunger in patients with FD. Further studies are needed to clarify whether the GNß3 825CC genotype is linked to disturbances of gastric emptying via altered signal transduction responses.

Duodenogastric reflux induced by endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) may cause excessive duodenogastric reflux (DGR) in a similar manner to distal gastrectomy, particularly after antral resections. We aimed to examine the occurrence of DGR after ESD. PATIENTS AND METHODS: Patients with gastric neoplasm for whom ESD was indicated were categorized according to lesion site: the antral group (lower [L] stomach, n = 46) and the nonantral group (upper or middle [U or M] stomach, n = 49). Endoscopy was performed before ESD, the day after ESD, and 3 months after ESD, and the fasting bile acid concentration (BAC) in the gastric juice was analyzed. RESULTS: BAC values showed significant interaction between time point and group, although this association differed in the antral and nonantral groups. BACs on the day after ESD were higher in the antral group than in the nonantral group, but not the pre-ESD and 3 months post-ESD levels. In the antral group only, fasting BACs increased significantly the day after ESD and decreased to baseline levels 3 months post-ESD. There was also a correlation between BAC and lesion location in the antral subgroups, with significantly higher BACs found the day after ESD in patients with lesser curvature lesions. CONCLUSIONS: ESD of lesions in the antral lesser curvature may lead to a transient early increase in DGR. However, ESD does not result in long-term DGR, a factor that is known to increase the risk of carcinogenesis following gastrectomy.

Long-standing complications after treatment for cancer of the uterine cervix--clinical significance of medical examination at 5 years after treatment.

The purpose of this study is to investigate the side effect in patients who survived for more than 5 years after initial treatment for invasive cervical cancer. Between January 1984 and December 1997, 341 patients underwent primary treatment for invasive cervical cancer. One hundred nine patients who underwent medical examinations at 5 years after primary treatment were reviewed. The patients were divided into three groups: radical surgery alone (group A), radiotherapy alone (group B), and radical surgery with postoperative radiotherapy (group C). Dysuria was seen in 8%, and positive catheterized urine culture was noted in about 20% of groups A and C. Hydronephrosis was seen in 2% and 9% of groups A and B, respectively. Colitis or ulcer detected by proctosigmoidoscopy was noted in 15%, 50%, and 43% of groups A, B, and C, respectively, frequently observed in radiotherapy group (P= 0.0029). Lymphocyst was still present in 6% of group A, and leg edema was noted in 14%, 6%, and 15% of groups A, B, and C, respectively. Long-standing abnormal findings including urinary and bowel complications were presented in this study. Periodic physical examination after treatment should be performed because complications existed over a long time.

Neuropeptide W is present in antral G cells of rat, mouse, and human stomach.

Neuropeptide W (NPW) is a 30-amino-acid peptide initially isolated from the porcine hypothalamus as an endogenous ligand for the G protein-coupled receptors GPR7 and GPR8. An intracerebroventricular administration of NPW increased serum prolactin and corticosterone concentrations, decreased dark-phase feeding, raised energy expenditure, and lowered body weight. Peripherally, GPR7 receptors are abundantly expressed throughout the gastrointestinal tract; the presence of NPW in the gastrointestinal endocrine system, however, remains unstudied. Using monoclonal and polyclonal antibodies raised against rat NPW, we studied the localization of NPW in the rat, mouse, and human stomach by light and electron microscopy. NPW-immunoreactive cells were identified within the gastric antral glands in all three species. Double immunohistochemistry and electron-microscopic immunohistochemistry studies in rats demonstrated that NPW is present in antral gastrin (G) cells. NPW immunoreactivity localized to round, intermediate-to-high-density granules in G cells. NPW-immunoreactive cells accounted for 90% chromagranin A- and 85% gastrin-immunoreactive endocrine cells in the rat gastric antral glands. Using reversed-phase HPLC coupled with enzyme immunoassays specific for NPW, we detected NPW30 and its C-terminally truncated form, NPW23, in the gastric mucosa. Plasma NPW concentration of the gastric antrum was significantly higher than that of the systemic vein, suggesting that circulating NPW is derived from the stomach. Plasma NPW concentration of the gastric antrum decreased significantly after 15-h fast and increased after refeeding. This is the first report to clarify the presence of NPW peptide in the stomachs of rats, mice, and humans. In conclusion, NPW is produced in gastric antral G cells; our findings will provide clues to additional mechanisms of the regulation of gastric function by this novel brain/gut peptide.

Spiral terraces and spin frustration in layered antiferromagnetic Cr(001) films.

We have successfully fabricated a novel type of high-density spiral terraces on Cr(001) films. The influence of nanoscale spiral terraces on layered antiferromagnetic ordering of Cr(001) films has been studied at room temperature by direct imaging of both topographic and magnetic structures using spin-polarized scanning tunneling spectroscopy. Spin frustration and asymmetric magnetic ordering due to dense spiral terraces are observed. Sizable modification of the layered antiferromagnetic order is found to be originating from the topological asymmetry as confirmed by the continuum micromagnetic simulation.

Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction.

OBJECTIVES: This study was undertaken to assess whether prodromal angina could have beneficial effects in diabetic patients with acute myocardial infarction (AMI). BACKGROUND: Prodromal angina occurring shortly before the onset of AMI is associated with favorable outcomes by the mechanism of ischemic preconditioning. However, little is known about the impact of diabetes on ischemic preconditioning. METHODS: We studied 611 patients with a first anterior wall AMI who underwent emergency catheterization within 12 h after the onset of chest pain: 490 patients without diabetes and 121 patients with non-insulin treated diabetes. Prodromal angina was defined as angina episode(s) occurring within 24 h before the onset of AMI. Serial contrast left ventriculograms were obtained in 424 patients at the time of acute and predischarge catheterization. RESULTS: In non-diabetic patients, prodromal angina was associated with lower peak creatine kinase (CK) value (3,068 +/- 2,647 IU/l vs. 3,601 +/- 2,462 IU/l, p = 0.037), larger increase in left ventricular ejection fraction (LVEF) (10.1 +/- 13.0% vs. 5.8 +/- 13.4%, p = 0.004) and lower in-hospital mortality (3.4% vs. 9.3%, p = 0.015). On the contrary, in diabetic patients, there was no significant difference in peak CK value (3,382 +/- 2,520 IU/l vs. 3,233 +/- 2,412 IU/l, p = NS), the change in LVEF (6.7 +/- 13.8% vs. 7.1 +/- 12.4%, p = NS) and in-hospital mortality (8.8% vs. 11.0%, p = NS) between patients with and patients without prodromal angina. CONCLUSIONS: Prodromal angina limited infarct size, enhanced recovery of LV function and improved survival in non-diabetic patients with AMI. However, such beneficial effects of prodromal angina were not observed in diabetic patients, suggesting that diabetes might prevent ischemic preconditioning.

Impact of diabetes mellitus on long term survival after acute myocardial infarction in patients with single vessel disease.

OBJECTIVE: To assess the influence of diabetes on long term prognosis after reperfusion treatment and its interaction with multivessel disease. DESIGN: A retrospective observational study. SETTING: Hiroshima City Hospital. PATIENTS: 1660 consecutive patients with acute myocardial infarction who underwent coronary angiography within 24 hours after the onset of chest pain. MAIN OUTCOME MEASURES: Influence of diabetes on 10 year survival after infarction was assessed using the generalised Wilcoxon test and Cox's proportional hazards regression. Follow up was completed in 1622 patients (98%). RESULTS: Diabetic patients had more multivessel disease than non-diabetic patients (53% v 34%, p < 0.001). When only patients with single vessel disease were compared, diabetes was associated with a reduced 10 year survival after infarction (p = 0.002). On the other hand, in patients with multivessel disease there was no significant difference in survival between diabetic and non-diabetic patients (p = 0.70). Multivariate analysis also showed that diabetes was an independent risk factor related to 10 year mortality after infarction in patients with single vessel disease (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.27 to 2.54; p = 0.001) and not in patients with multivessel disease (OR 1.17, 95% CI 0.85 to 1.60; p = 0.34). CONCLUSIONS: Diabetes is an independent predictor of long term mortality after infarction in patients with single vessel disease. However, in the presence of multivessel disease, prognosis after infarction is impaired regardless of diabetes, and the influence of diabetes is less obvious.

Human tumor necrosis factor-alpha mutant RGD-V29 (F4614) shows potent antitumor activity and reduced toxicity against human tumor xenografted nude mice.

The antitumor effects of human tumor necrosis factor-alpha (TNF) mutant RGD-V29 (code no. F4614), that includes the cell adhesive sequence (4)Arg-(5)Gly-(6)Asp and (29)Arg-->Val substitution, were evaluated. The therapeutic index, a measure of the extent of the therapeutically-effective range, using three constitutive administrations of RGD-V29 in Meth A-bearing mice was 4.8, whereas that of recombinant human TNF (rhTNF) ((1)SSS(4)RTPSDK...(29)RR...(155)L) was 2.8, clearly indicating that the effective RGD-V29 dose-range was extended. Furthermore, RGD-V29 showed potent antitumor activity against human lung cancer Mqnu-1 xenografted nude mice without severe gastrointestinal and other organ toxicities, even when administered at the maximal tolerated dose (MTD). In contrast, rhTNF induced severe toxicity at the MTD. Direct cytotoxicity of RGD-V29 against Mqnu-1 cells was similar to that of rhTNF. In addition, a cytotoxicity assay using a tumor-derived endothelial-like cell (tEC)/normal endothelial cell (nEC) system used to study TNF antitumor effects on tumor-associated endothelial cells, suggested that RGD-V29 showed preferential cytotoxicity toward tumor-associated endothelial cells compared with rhTNF. Thus, RGD-V29 appears to be a low-toxicity mutant of rhTNF that shows preferential activity towards tumors, and therefore merits further investigation in pre-clinical and clinical studies.

[Long-term prognosis after reperfusion therapy for acute myocardial infarction in elderly patients].

Although it has been well demonstrated that TIMI grade 3 flow is associated with improved survival after acute myocardial infarction in non-elderly patients, its implication in elderly patients has not been clarified. To assess this issue, 1,115 patients with acute myocardial infarction who underwent coronary angiography within 24 hours after the onset of chest pain were studied: there were 131 elderly patients (age > or = 75 years) and 984 non-elderly patients (age < 75 years). Follow-up was achieved for 1,092 patients (98%). Elderly patients were associated with more female, Killip class > or = 2, 3 vessel disease and non-smokers. Although modality of reperfusion therapy was not different, final TIMI flow grade was less frequently obtained in elderly patients (53% vs 65%, p = 0.005). Elderly patients were associated with higher in-hospital mortality (25% vs 9%, p < 0.001) and lower 10 years cardiac death free rate (p < 0.001). Cox proportional hazards model showed that final TIMI flow grade 3 was an independent predictor of 10 years cardiac death free in elderly patients (odds ratio (OR) = 0.39, 95% confidence interval (CI) = 0.20-0.74, p = 0.004) as well as non-elderly patients (OR = 0.41, 95% CI = 0.29-0.58, p < 0.001). In conclusion, our data suggest that final TIMI grade 3 flow is an important determinant to improve short- and long-term survival after acute myocardial infarction in elderly patients as well as in non-elderly patients.

Myxoid leiomyosarcoma of the uterus. Report of a case with cytologic findings.

BACKGROUND: Myxoid leiomyosarcoma is a rare variant of uterine sarcoma, exhibiting malignant biologic behavior despite the absence of cytologic atypia and of significant mitotic activity. CASE: A 20-year-old female was referred with a cystic pelvic mass. At laparotomy, the tumor, weighed 2,200 g and originating in the left lateral uterine wall, was removed. Microscopic examination revealed well-differentiated smooth muscle cells without atypia and with a few mitotic figures in the copious myxoid matrix, suggesting myxoid leiomyosarcoma. Three years following laparotomy, an irregular mass around the uterus was noted on sonographic examination, suggesting local recurrence. Two years and six months later, the second operation was performed, and a locally recurrent, multicystic tumor weighing 3,500 g was excised. The histopathology was similar to that of the primary tumor. Cytologic findings on imprint material from the tumor revealed a few isolated or sheet like small cells consisting of spindle and polygonal cells with round and oval nuclei. Cytologic atypia was also minimal. CONCLUSION: Myxoid leiomyosarcoma should be included in the differential diagnosis of smooth muscle neoplasia.

Beneficial effect of prodromal angina pectoris is lost in elderly patients with acute myocardial infarction.

BACKGROUND: Prodromal angina pectoris occurring shortly before the onset of acute myocardial infarction is associated with a favorable outcome by the mechanism of ischemic preconditioning. Recent experiments have reported that the beneficial effect of ischemic preconditioning are reversed in the aged heart. METHODS: We studied 990 patients who underwent coronary angiography within 12 hours after the onset of acute myocardial infarction. Patients were divided into 2 groups: those aged <70 years (nonelderly patients, n = 722) and those aged >/=70 years (elderly patients, n = 268). Prodromal angina in the 24 hours before infarction was found in 190 of 722 nonelderly patients and in 66 of 268 elderly patients (26% vs 25%, P =.61). RESULTS: In nonelderly patients, prodromal angina was associated with lower peak creatine kinase levels (2438 +/- 1939 IU/L vs 2837 +/- 2341 IU/L, P =.04), lower in-hospital mortality rates (3.7% vs 8.8%, P =.02), and better 5-year survival rates (P =. 007). On the contrary, in elderly patients there was no significant difference in peak creatine kinase levels (2427 +/- 2142 IU/L vs 2256 +/- 1551 IU/L, P =.51), in-hospital mortality rate (21.2% vs 17. 4%, P =.49), and 5-year survival rates (P =.47). A multivariate analysis showed that prodromal angina in the 24 hours before infarction was associated with 5-year survival rate in nonelderly patients (odds ratio 0.49, P =.009) but not in elderly patients (odds ratio l.12, P =.65). CONCLUSIONS: In nonelderly patients, prodromal angina in the 24 hours before infarction was associated with a smaller infarct size and better short- and long-term survival, suggesting a relation to ischemic preconditioning. However, such a beneficial effect was not observed in elderly patients.