Association between gastroesophageal flap valve,reflux esophagitis,Barrett's epithelium,and atrophic gastritis assessed by endoscopy in Japanese patients

Background. Endoscopic grading of the gastroesophageal flap valve (GEFV) is a useful predictor of gastroesophageal reflux status; abnormal GEFV was associated with reflux esophagitis. Atrophic gastritis is often found in Japanese patients and is inversely related to reflux esophagitis. The aim of this study was to examine the association between GEFV, reflux esophagitis, Barrett's epithelium, and atrophic gastritis in Japanese patients by prospective endoscopic assessment. Methods. We enrolled 548 Japanese patients (296 men and 252 women; mean age, 57.3 years). GEFV was assessed by the classification of Hill and colleagues, reflux esophagitis was assessed by the Los Angeles classification, and the degree of atrophic gastritis was scored as: none, mild, moderate, or severe. Barrett's epithelium was recognized by the endoscopic detection of an upward shift in the columnar lining. Results. Reflux esophagitis and Barrett's epithelium were found in 42 (7.7%) and 67 (12.2%) patients, respectively. An increased prevalence of reflux esophagitis and Barrett's epithelium was correlated with an increased grade of GEFV. Abnormal GEFV (grades III and IV) was a risk for reflux esophagitis (adjusted odds ratio [OR]), 13.33 (95% confidence interval [CI], 6.08–29.25) and Barrett's epithelium (OR, 3.55 [95% CI, 2.04–6.20]), while the presence of atrophic gastritis was inversely associated with reflux esophagitis (OR, 0.15 [95% CI, 0.07–0.36]), but it was not associated with the prevalence of Barrett's epithelium (OR, 1.16 [95% CI, 0.67–2.01]). The prevalence of Barrett's epithelium and the severity of atrophic gastritis increased with age, while that of reflux esophagitis and abnormal GEFV did not change. Conclusions. Reflux esophagitis and Barrett's epithelium are associated with abnormal GEFV in Japanese patients. The presence of atrophic gastritis is inversely related to reflux esophagitis, but it is not related to Barrett's epithelium in Japanese patients. Received: June 14, 2002 / Accepted: November 22, 2002 RID="*" ID="*" Reprint requests to: Y. Fujiwara     

Endoscopic grading of gastroesophageal flap valve helps predict proton pump inhibitor response in patients with gastroesophageal reflux disease

Abstract

Objective. Limited information is available on predictors of the response to proton pump inhibitor (PPI) treatment in patients with gastroesophageal reflux disease (GERD). Endoscopic grading of gastroesophageal flap valve (GEFV) is simple and reproducible, and can provide useful information on patients with suspected reflux undergoing an endoscopy. The aim of this study was to prospectively identify predictors, including endoscopic findings such as GEFV, for PPI treatment outcomes in patients with GERD. Material and methods. One hundred and fifty consecutive patients with GERD were enrolled. All patients were treated with pantoprazole 40 mg daily for 8 weeks. Treatment response was defined as greater than 50% reduction in symptom scores between the two symptom assessments (i.e., over 4 or 8 weeks). Univariate and multivariate logistic regression analyses between responders and non-responders were performed to identify variables predicting response to pantoprazole treatment. Results. Of the 150 consecutive patients considered for this study, 31 were excluded based on exclusion criteria and/or refusal to participate, leaving 119 eligible patients. After 4-week pantoprazole treatment, 70 of 119 (58.8%) patients were classified as responders. Patients with obesity and Helicobacter pylori infection demonstrated a higher response rate to 4-week pantoprazole treatment (odds ratio (OR) 5.28, p = 0.008; OR 3.76, p = 0.023, respectively). Patients with abnormal GEFV showed a lower response rate to 4-week treatment (OR 0.17, p = 0.016). After 8-week treatment, 86 of 119 (72.3%) patients were classified as responders. Abnormal GEFV and aspirin intake were associated with a lower response rate to 8-week treatment (OR 0.17, p = 0.021; OR 0.11, p = 0.020, respectively). Conclusions. Abnormal GEFV was a significant independent factor predicting poor response to both 4-week and 8-week pantoprazole treatment. Endoscopic grading of GEFV provides useful information for predicting the response to PPI treatment in patients with GERD.     

Gastroesophageal flap valve is associated with gastroesophageal and gastropharyngeal reflux

Background The endoscopic grade of the gastroesophageal flap valve (GEFV) is suggested to be a good predictor of reflux status. The aim of this study was to investigate the association of the GEFV and gastroesophageal and gastropharyngeal reflux. Methods A total of 364 patients (151 men and 233 women; mean age, 52.2 years) who underwent endoscopy, esophageal manometry, and ambulatory 24-h dual-probe pH monitoring were included. GEFV was graded I through IV using Hill's classification; then, GEFV was classified into two groups: a normal GEFV group (grades I and II) and an abnormal GEFV group (grades III and IV). Findings of endoscopy, esophageal manometry, and ambulatory pH monitoring were compared between the groups. Results Increased GEFV grade was significantly associated with an increased prevalence of both reflux esophagitis and Barrett's epithelium (P < 0.001). Lower esophageal sphincter pressure was significantly lower in the abnormal GEFV group than in the normal GEFV group (P < 0.001). All variables showing gastroesophageal reflux in the distal probe were significantly higher in the abnormal GEFV group than in the normal GEFV group (P < 0.001). In addition, all variables, except the supine time of pH < 4, showing gastropharyngeal reflux in the proximal probe were significantly higher in the abnormal GEFV group than in the normal GEFV group (P < 0.001). The frequency of gastroesophageal reflux disease and of gastropharyngeal reflux disease was significantly higher in the abnormal GEFV group than in the normal GEFV group (P < 0.001). Conclusion Endoscopic grading of the GEFV is easy and provides useful information about the status of gastroesophageal and gastropharyngeal reflux.     

Abnormal gastroesophageal flap valve is highly associated with gastroesophageal reflux disease among subjects undergoing routine endoscopy in Taiwan

OBJECTIVE: Gastroesophageal flap valve (GEFV) grade predicts severe gastroesophageal reflux disease in Caucasians, but its role in other populations is unclear. This study evaluated the significance of endoscopic grading of the GEFV in Taiwanese subjects. METHODS: Five hundred and six consecutive patients undergoing routine check-ups at the National Taiwan University Hospital were enrolled. Symptoms of upper gastrointestinal disease and endoscopic severity of esophageal mucosal injury were correlated to GEFV grades according to the Hill classification. RESULTS: The frequency of abnormal valves (Hill grades III or IV) was 27.3%. Of these, 42.7% had erosive esophagitis (EE). The majority of patients with EE were classified as Los Angeles grades A and B (79.7 and 16.9%, respectively). The prevalence of EE, hiatal hernia and, to a lesser degree, non-erosive reflux disease, increased with altered GEFV. Patients with abnormal valves were younger and more likely to be male, overweight, and to have atypical and extraesophageal symptoms. CONCLUSIONS: Taiwanese patients with abnormal GEFVs share similar characteristics and risk factors with the patients who have EE. Endoscopic grading of the GEFV is highly associated with GERD, and in particular EE, in subjects undergoing routine endoscopy.     

化痰消瘀方加味治疗胃食管反流病伴慢性萎缩性胃炎的疗效观察

目的:观察化痰消瘀方加味治疗胃食管反流病(GERD)伴慢性萎缩性胃炎(CAG)的疗效.方法:选取反流性食管炎(RE)或非糜烂性反流病(NERD)同时伴有CAG的70例患者为研究对象.按随机数字表法分为2组,每组各35例.对照组采用西医抑酸、促胃动力治疗,治疗组在对照组治疗基础上加用化痰消瘀方加味.治疗后观察比较2组患者...     

Correlation of serum pepsinogens and gastrin-17 with atrophic gastritis in gastroesophageal reflux patients: a matched-pairs study

Background and Aim: An algorithm (GastroPanel) for the non‐invasive diagnosis of atrophic gastritis has been previously proposed, based on serum pepsinogen‐I, gastrin‐17, and Helicobacter pylori (H. pylori) antibodies. The aim of the present study was to evaluate whether serum markers correlate with and predict gastric atrophy in gastroesophageal reflux disease (GERD) patients. Methods: The baseline data of the prospective ProGERD study, a study on the long‐term course of GERD (n = 6215 patients), served to select patients with atrophic gastritis diagnosed in biopsies from gastric antrum and corpus, and control cases without atrophy. A total of 208 pairs were matched for age, sex, GERD status (erosive vs non‐erosive), presence of Barrett's esophagus, and histological H. pylori status were retrieved. Serum pepsinogen‐I, gastrin‐17, and H. pylori antibodies were determined using specific enzyme immunoassays. Results: A significant negative correlation was found between the degree of corpus atrophy and the level of serum pepsinogen‐I. A previously‐reported negative correlation between the degree of antral atrophy and serum gastrin‐17 could not be confirmed. The low sensitivity (0.32) and specificity (0.70) of the GastroPanel algorithm were mainly due to over diagnosis and under diagnosis of advanced atrophy in the antrum. Conclusion: The diagnostic validity of the GastroPanel algorithm to diagnose gastric atrophy non‐invasively is not sufficient for general use in GERD patients.     

胃食管阀瓣与反流性食管炎的关系初步探讨

目的 探讨胃食管阀瓣（GEFV）与反流性食管炎（RE）的关系.方法 分析2007年1月至2009年12月我院内镜诊断的BE 239例,按洛杉矶标准进行食管炎分级,按Hill分类法进行GEFV的分级.通过对照分析,探讨GEFV与RE之间的关系.结果 入组的960人中,异常GEFV发生率32.9%,RE发生率24.9%.重症RE（C级、D级）发生率GEFV异常组明显高于GEFV正常组（23.1%比2.4%,P=0.000）;RE分级与GEFV级别呈正相关（r=0.308,P=0.000）.RE患者的异常GEFV发生率高于非食管炎者（65.3%比22.2%,P=0.000）.RE患者和异常GEFV组均为男性多于女性（63.6%、60.1%比36.4%、39.9%,P=0.000）.各年龄段中,随着年龄的增长,RE巳的发生率逐渐升高,年龄增长与RE发生率呈正相关,（r=0.214,P=0.000）.30岁以上,随着年龄的增长,异常GEFV的发生率逐渐升高,年龄增长与异常GEFV的发生率呈正相关（r=0.129,P=0.000）.结论 GEFV异常和RE发生存在相关性,观察GEFV可作为评估和预测患者反流状态的有效方法.     

A prospective study of the prevalence of gastroesophageal reflux disease and confounding factors

Background The prevalence of gastroesophageal reflux disease (GERD) has reportedly risen in recent years. Difficulties associated with endoscopic diagnosis mean it is not easy to determine its precise prevalence. A prospective study of the prevalence of endoscopy-positive GERD (EP-GERD) was conducted at Higuchi Hospital, a general hospital in Northwestern Kyushu, Japan. The study also correlated factors that might affect prevalence (age, sex, and functions of the gastroesophageal junction). Methods From consecutive patients undergoing endoscopic examination at Higuchi Hospital between January 2000 and April 2003, 1234 patients without severe complications were examined for the possible presence of GERD. Patients were stratified by age and sex, and the prevalence in each group ascertained. EP-GERD was defined on the four-level scale of the Los Angeles classification. Endoscopic classification of gastroesophageal flap valve ([GEFV] functional anomalie; using a four-level scale), was done as proposed by Hill et al. in 1996, to assess flap-valve morphology. Six items were evaluated: (1) symptoms and primary diseases; (2) prevalence of development of EP-GERD classified by age and sex; (3) endoscopic morphology of the GEFV as an expression of the functions of the gastroesophageal junction, and its prevalence by age and sex; (4) regression analysis and Spearman's rank correlation of GEFV and EP-GERD grades; (5) prevalence of EP-GERD and GEFV stratified by age and analyzed; and (6) multiple regression analysis of EP-GERD and explanatory variables (age, sex, and GEFV). Results The overall prevalence of EP-GERD was 5.8% (72/1234) and this patient group was dominated by men. Aging had minimal effect on prevalence in men, but the prevalence rose among women as they aged. The age-stratified prevalence of GEFV functional anomalies was similar to the age-stratified prevalence of EP-GERD in both sexes. The correlation between EP-GERD and GEFV functional anomalies was high regardless of sex. Conclusions We postulate that the mechanisms leading to the development of GEFV functional anomalies in men are different from those in women. Future evaluations of EP-GERD should also observe GEFV function.     

胃镜下胃食管阀瓣分级与基于里昂共识的胃食管反流病证据等级及反流新参数的相关性

目的探讨胃镜下胃食管阀瓣(gastroesophageal flap valve, GEFV)分级与基于里昂共识的胃食管反流病(gastroesophageal reflux disease, GERD)证据等级、平均夜间基线阻抗(mean nocturnal baseline impedance, MNBI)、反流后吞咽诱发的蠕动波指数(post-reflux swallow-induced peristaltic wave index, PSPWI)的相关性。方法收集就诊于首都医科大学附属北京同仁医院消化内科有典型胃食管反流症状且完成胃镜、24 h食管pH-阻抗监测及食管高分辨测压(high-resolution manometry, HRM)的421例患者。回顾性分析胃镜下GEFV分级与基于里昂共识的GERD证据等级、食管pH-阻抗监测常规指标,即总反流次数、pH<4时间百分比[AET4(%)]、DeMeester评分及新参数(MNBI及PSPWI)的关系。结果异常GEFV(GEFVⅢ+Ⅳ级)占所有患者的29.5%,在确定性GERD证据组比例最高(49.6%)。GEFV异常组的男性比例、糜烂性食管炎比例、AET4(%)、总反流次数显著高于GEFV正常组,而MNBI、PSPWI显著降低(P<0.05)。男性、BMI、AET4(%)、DeMeester评分、总反流次数与GEFV分级呈显著正相关,MNBI、PSPWI与GEFV分级呈显著负相关(P<0.05)。结论基于里昂共识的确定性GERD证据的患者中GEFV异常比例最高,GEFV异常提示糜烂性食管炎发生率升高、更重的反流负荷、MNBI及PSPWI降低。     

原发性胆汁反流性胃炎与胃食管反流病的关系

目的:探讨原发性胆汁反流性胃炎(primary bile reflux gastritis,PBRG)与胃食管反流病(gastroesophageal reflux disease,GERD)之间的相关性.方法:选取我院确诊为PBRG的患者1060例为观察组,无痛胃镜下未查见有PBRG的体检者1060例为对照组,比较两组GERD的发生率;依据内镜下PBRG的诊断标准,将260例PBRG伴有GERD的患者分为轻度、中度及重度3组,对比各组食管黏膜损伤的程度以及GERD症状积分的分布.结果:PBRG组GERD的发生率高于对照组(24.5%vs9.8%,P<0.05).食管黏膜损伤程度加深的发生率随着PBRG程度的加重而增加.PBRG的程度与GERD症状分级无相关性.结论:PBRG与反流性食管炎(refluxe sophagitis,RE)形成存在正性相关,PBRG并非是引起GERD症状的主要原因.     

Inverse correlation between gastroesophageal reflux disease and atrophic gastritis assessed by endoscopy and serology

BACKGROUND Helicobacter pylori(H.pylori)infection is known to prevent the occurrence of gastroesophageal reflux disease(GERD)by inducing gastric mucosal atrophy.However,little is known about the relationship between atrophic gastritis(AG)and GERD.AIM To confirm the inverse correlation between AG and the occurrence and severity of GERD.METHODS Individuals receiving health checkups who underwent upper gastrointestinal endoscopy at Seoul National University Healthcare System Gangnam Center were included.The grade of reflux esophagitis was evaluated according to the Los Angeles classification.Endoscopic AG(EAG)was categorized into six grades.Serologic AG(SAG)was defined as pepsinogen I≤70 ng/m L and pepsinogen I/II ratio≤3.0.The association between the extent of EAG and SAG and the occurrence and severity of GERD was evaluated using multivariate logistic regression analysis.RESULTS In total,4684 individuals with GERD were compared with 21901 healthy controls.In multivariate logistic regression analysis,advanced age,male sex,body mass index>23 kg/m2,presence of metabolic syndrome,current smoking,and alcohol consumption were associated with an increased risk of GERD.Seropositivity for H.pylori immunoglobulin G antibodies was associated with a decreased risk of GERD.There was an inverse correlation between the extent of EAG and occurrence of GERD:Odds ratio(OR),1.01[95%confidence interval(CI):0.90-1.14]in C1,0.87(0.78-0.97)in C2,0.71(0.62-0.80)in C3,0.52(0.44-0.61)in O1,0.37(0.29-0.48)in O2,and 0.28(0.18-0.43)in O3.Additionally,the extent of EAG showed an inverse correlation with the severity of GERD.The presence of SAG was correlated with a reduced risk of GERD(OR=0.49,95%CI:0.28-0.87,P=0.014).CONCLUSION The extent of EAG and SAG exhibited strong inverse relationships with the occurrence and severity of GERD.AG followed by H.pylori infection may be independently protect against GERD.     

Endoscopic and laparoscopic treatment of gastroesophageal reflux

Gastroesophageal reflux is extremely common in Western countries. For selected patients, there is an established role for the surgical treatment of reflux, and possibly an emerging role for endoscopic antireflux procedures. Randomized trials have compared medical versus surgical management, laparoscopic versus open surgery and partial versus total fundoplications. However, the evidence base for endoscopic procedures is limited to some small sham-controlled studies, and cohort studies with short-term follow-up. Laparoscopic fundoplication has been shown to be an effective antireflux operation. It facilitates quicker convalescence and is associated with fewer complications, but has a similar longer term outcome compared with open antireflux surgery. In most randomized trials, antireflux surgery achieves at least as good control of reflux as medical therapy, and these studies support a wider application of surgery for the treatment of moderate-to-severe reflux. Laparoscopic partial fundoplication is an effective surgical procedure with fewer side effects, and it may achieve high rates of patient satisfaction at late follow-up. Many of the early endoscopic antireflux procedures have failed to achieve effective reflux control, and they have been withdrawn from the market. Newer procedures have the potential to fashion a surgical fundoplication. However, at present there is insufficient evidence to establish the safety and efficacy of endoscopic procedures for the treatment of gastroesophageal reflux, and no endoscopic procedure has achieved equivalent reflux control to that achieved by surgical fundoplication.     

慢性胃炎患者胃内24小时胆汁监测

目的　胆汁反流是导致胃黏膜炎症的重要因素 ,该文研究不同类型慢性胃炎患者胃内胆汁反流情况。方法　分别对 45例慢性胃炎患者 (慢性浅表性胃炎 17例 ,慢性糜烂性胃炎 2 1例 ,慢性萎缩性胃炎 7例 )行胃内 2 4h胆汁监测 ,获得胆汁反流指标。分析胆汁反流总时间百分比、胆汁反流次数、胆汁反流 >5min次数和最长反流持续时间。结果　不同类型慢性胃炎组之间各项胆汁监测指标相差显著。胆汁反流总时间百分比在慢性萎缩性胃炎组 (16 .2± 18.0 )和慢性糜烂性胃炎组 (14.2± 12 .1)明显高于慢性浅表性胃炎组 (5 .3± 14.1,P <0 .0 1)。结论　胆汁反流与慢性糜烂性胃炎、慢性萎缩性胃炎的发生有关     

胃食管阀瓣与反流性食管炎的关系初步探讨

目的 探讨胃食管阀瓣(GEFV)与反流性食管炎(RE)的关系.方法 分析2007年1月至2009年12月我院内镜诊断的BE 239例,按洛杉矶标准进行食管炎分级,按Hill分类法进行GEFV的分级.通过对照分析,探讨GEFV与RE之间的关系.结果 入组的960人中,异常GEFV发生率32.9%,RE发生率24.9%.重症RE(C级、D级)发生率GEFV异常组明显高于GEFV正常组(23.1%比2.4%,P=0.000);RE分级与GEFV级别呈正相关(r=0.308,P=0.000).RE患者的异常GEFV发生率高于非食管炎者(65.3%比22.2%,P=0.000).RE患者和异常GEFV组均为男性多于女性(63.6%、60.1%比36.4%、39.9%,P=0.000).各年龄段中,随着年龄的增长,RE巳的发生率逐渐升高,年龄增长与RE发生率呈正相关,(r=0.214,P=0.000).30岁以上,随着年龄的增长,异常GEFV的发生率逐渐升高,年龄增长与异常GEFV的发生率呈正相关(r=0.129,P=0.000).结论 GEFV异常和RE发生存在相关性,观察GEFV可作为评估和预测患者反流状态的有效方法.     

胃食管阀瓣与反流性食管炎的关系初步探讨

目的 探讨胃食管阀瓣(GEFV)与反流性食管炎(RE)的关系.方法 分析2007年1月至2009年12月我院内镜诊断的BE 239例,按洛杉矶标准进行食管炎分级,按Hill分类法进行GEFV的分级.通过对照分析,探讨GEFV与RE之间的关系.结果 入组的960人中,异常GEFV发生率32.9%,RE发生率24.9%.重症RE(C级、D级)发生率GEFV异常组明显高于GEFV正常组(23.1%比2.4%,P=0.000);RE分级与GEFV级别呈正相关(r=0.308,P=0.000).RE患者的异常GEFV发生率高于非食管炎者(65.3%比22.2%,P=0.000).RE患者和异常GEFV组均为男性多于女性(63.6%、60.1%比36.4%、39.9%,P=0.000).各年龄段中,随着年龄的增长,RE巳的发生率逐渐升高,年龄增长与RE发生率呈正相关,(r=0.214,P=0.000).30岁以上,随着年龄的增长,异常GEFV的发生率逐渐升高,年龄增长与异常GEFV的发生率呈正相关(r=0.129,P=0.000).结论 GEFV异常和RE发生存在相关性,观察GEFV可作为评估和预测患者反流状态的有效方法.     

胃黏膜下层食管胃黏膜单层吻合法的抗反流效果观察

目的观察经胃黏膜下层食管胃黏膜单层吻合法的抗反流效果。方法采用经胃黏膜下层食管胃黏膜单层吻合法施行食管癌、贲门癌手术305例。术后行X线吞钡、胃镜和食管pH检查。结果术后无1例早期死亡,未发生吻合口瘘,2例出现轻度胃食管反流。结论经胃黏膜下层食管胃黏膜单层吻合法具有明显的抗反流优势,且效果确切、可靠。     

Tolerance to H2 receptor antagonist correlates well with the decline in efficacy against gastroesophageal reflux in patients with gastroesophageal reflux disease

BACKGROUND AND AIM: The attenuated antisecretory activity of H2 receptor antagonists (H2RA) during continuous administration is known as the tolerance phenomenon. The authors recently clarified that presence or absence of Helicobacter pylori infection influences the occurrence of the tolerance phenomenon. The aim of this study was to clarify whether tolerance to H2RA is correlated with attenuation of the inhibitory effect against gastroesophageal acid reflux in patients with gastroesophageal reflux disease (GERD). METHODS: Ten male patients with GERD symptoms and abnormal gastroesophageal reflux were investigated by pH monitoring on days 1 and 15 of continuous oral famotidine administration at 20 mg twice daily, and H. pylori infection was examined using the urea breath test. RESULTS: Intragastric and intraesophageal acidity were significantly decreased on the first day of famotidine administration, but then increased during the 15-day administration period in seven patients who were negative for H. pylori. In contrast, the efficacy of famotidine against gastric acid secretion and gastroesophageal acid reflux was not attenuated in three H. pylori-positive patients. The changes in GERD symptoms were correlated with the change in the degree of gastroesophageal reflux. CONCLUSION: The presence or absence of tolerance to H2RA during 15-day administration is correlated with the efficacy for inhibition of gastroesophageal acid reflux.     

Reliability of 24-hour home esophageal ph monitoring in diagnosis of gastroesophageal reflux

Twenty-four-hour home esophageal pH monitoring is proposed in order to study gastroesophageal reflux (GER) so that prolonged use of costly hospital equipment and staff can be curtailed and the diagnostic accuracy of the examination improved. Eighty-six patients affected by GER symptoms and 20 healthy volunteers underwent 24-hr home esophageal pH monitoring, x-rays, and endoscopy of the upper gastrointestinal tract to investigate reliability of outpatient recording. Fifteen more patients consecutively underwent out- and inpatient recording to detect possible differences between these methods in the two daily periods. Outpatient monitoring was well tolerated in 94.7% of the patients; 14.3% of them markedly reduced their routine activities. The range of normality of outpatient recording does not differ from that of inpatients. In the 15 patients who consecutively underwent out-and inpatient monitoring, no significant differences were reported. The sensitivity of 24-hr home esophageal pH recording is 0.85, the specificity 1, the accuracy for negative prediction 0.68, and the accuracy for positive prediction 1. The reliability of 24-hr home esophageal pH monitoring is comparable to inpatient recording. It allows hospital cost reduction and is also better tolerated by patients but has not greatly improved the diagnostic accuracy of the gastroesophageal reflux pH monitoring.Supported by the Ministere Pubblica Istruzione, Rome; and Finanziamenti per studi e ricerche 40%, Com. 06, Cat 12-07 imp. 11515, University of Bologna.