A novel rat model to determine interaction between reflux oesophagitis and bronchial asthma.

BACKGROUND: Several studies have shown a strong association between reflux oesophagitis (RO) and bronchial asthma (BA). The precise mechanisms of interaction between RO and BA are uncertain, possibly due to lack of animal models. AIMS: We established a novel rat model and examined pathogenic interaction of RO and BA. METHODS: RO and BA were induced in Brown-Norway rats by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus, and by ovalbumin (OVA) sensitisation and challenge with OVA aerosol. Rats were divided into four groups: control, RO, BA, and RO+BA. OVA-induced airway inflammation was assessed by the number of infiltrating cells and cytokine levels in bronchoalveolar lavage fluid (BALF). Oesophageal lesion index, histology and expression of cytokine mRNA, as determined by real-time RT-PCR, were also examined. RESULTS: Significant increases in the number of cells, especially eosinophils, and IL13 but not IFN-gamma concentration in BALF were observed in the RO+BA group compared with the BA group. These enhancements of OVA-induced airway inflammation were prevented by treatment with rabeprazole. Although the oesophagitis lesion index in the RO+BA group did not differ from that in the RO group, eosinophilic infiltration in the oesophageal submucosa and levels of mRNA expression of cytokines such as IL5, IL10, IL13, and RANTES were significantly increased. CONCLUSION: We established a novel rat model of RO and BA, and found significant interactions of the two diseases. This model thus appears to be useful for examining the association between gastro-oesophageal reflux disease and bronchial asthma.

Roles of cyclooxygenase 2 and microsomal prostaglandin E synthase 1 in rat acid reflux oesophagitis.

BACKGROUND: Although prostaglandin E2 (PGE2), cyclooxygenase 2 (COX-2), and microsomal prostaglandin E synthase 1 (mPGES-1) are known to play a role in various inflammatory events, their roles in the pathogenesis of gastro-oesophageal reflux disease are not known. AIMS: We examined the dynamics of COX-1, COX-2, mPGES-1, mPGES-2, cytosolic PGES (cPGES), and PGE2 synthetic activity in rat acid reflux oesophagitis and the effects of COX-2 inhibitors on the severity of oesophagitis. METHODS: Acid reflux oesophagitis was induced by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus. Rats were killed on day 3 (acute phase) or day 21 (chronic phase) after induction of oesophagitis. RESULTS: Expression of COX-2 and mPGES-1 was markedly increased in oesophagitis while modest changes in COX-1, cPGES, and mPGES-2 expression were observed. COX-2 and mPGES-1 were colocalised in epithelial cells of the basal layer, as well as inflammatory and mesenchymal cells in the lamina propria and submucosa. COX-2 inhibitors significantly reduced the severity of chronic oesophagitis but did not affect acute oesophageal lesions. COX-2 inhibitors significantly inhibited the increase in PGE2 synthesis in oesophageal lesions on both days 3 and 21. Epithelial proliferation was significantly increased in the basal layer on day 21. Inflammatory cells and epithelial cells of the basal layer exhibited reactions for EP4 in oesophagitis. CONCLUSION: PGE2 derived from COX-2 and mPGES-1 plays a significant role in the pathogenesis of chronic acid reflux oesophagitis, and possibly in basal hyperplasia and persistent inflammatory cell infiltration.

Polarization dependence of femtosecond soliton-soliton interactions in dispersion-shifted fiber.

The polarization dependence of femtosecond soliton-soliton interaction in a dispersion-shifted fiber has been investigated in detail theoretically and experimentally. For 400-fs soliton pulses the input pulse separation at which the soliton-soliton interaction occurs is 1.6 ps for orthogonally polarized solitons as opposed to 2.3 ps when the polarizations are parallel. Similar to that in the parallel condition, the soliton self-frequency shift in the orthogonal case is accelerated through soliton-soliton interaction. However, the magnitude of the soliton self-frequency shift is reduced to one third of that in the parallel condition.

Broadband light generation by femtosecond pulse amplification with stimulated Raman scattering in a high-power erbium-doped fiber amplifier.

It is shown for the first time to our knowledge that short-pulse amplification in high-power erbium-doped fiber amplifiers, simultaneously accompanied by stimulated Raman scattering, generates a broadband optical spectrum at high output power (270 mW). At 20 dB down from the peak the continuum extended over 329 nm, from 1427 to 1756 nm. The FWHM bandwidth was 125 nm, centered at 1650 nm. The coherence was measured to be 15 fringes, which corresponds to a 25-microm coherence length.

[Long-term administration of carmofur as a post-operative adjuvant chemotherapy for cervical adenocarcinoma. Cervical Adenocarcinoma Cooperative Research Association].

Cervical adenocarcinoma and adenosquamous cell carcinoma are low in radiation sensitivity, and the prognosis is said to be inferior to that of squamous cell carcinoma. Eleven facilities nationwide participated in the historical control study on the recurrence prevention effect of carmofur (HCFU) administered at 300 mg/day for more than two years postoperatively as an adjuvant chemotherapy to patients with cervical adenocarcinoma or adenosquamous cell carcinoma for which radical operation is possible. Registered for the study was a total of 252 patients: 77 patients for whom administration of carmofur was begun during the period from January 1987 and March 1989, 71 patients (control 1) who were treated for the cancer after January 1982 but did not receive adjuvant chemotherapy, and 104 patients who received adjuvant chemotherapies with other than carmofur (control 2). In analyses with the Kaplan-Meier method, the carmofur administration group demonstrated a better cumulative survival rate and disease free rate than control 1 (no adjuvant chemotherapy), suggesting carmofur was effective in preventing the recurrence of cervical adenocarcinoma and adenosquamous cell carcinoma.

[Studies of prognostic factor and chemotherapeutic effect of epithelial ovarian cancer using Cox's proportional hazard model].

To make clear the prognostic factor and chemotherapeutic effect of epithelial ovarian cancer, a multiple-center study involving 22 hospitals in Japan was conducted using Cox's proportional hazard model. A total of 1,181 cases were reviewed. Clinical stage, histologic type, and residual tumor diameter were significant prognostic factors, but the degree of tissue differentiation was not. The effect of remission induction chemotherapy was assessed with or without CDDP, and a distinct prognostic difference was noted. Among the patients receiving CDDP + ADM + other chemotherapeutic agents (PA group), CDDP + other chemotherapeutic agents (PO group) and CDDP only (P group), the prognosis of the PO group was better than for the P group. The long-term prognosis improving effect of chemotherapy was assessed. Neither maintenance chemotherapy based on oral administration of pyrimidine fluoride nor immunotherapy had any long-term prognosis improving effect, while intermittent chemotherapy based on CDDP resulted in improved prognosis.

[Effect of chemotherapy on the prognosis of ovarian cancer].

Through the collaboration of 22 institutions nationwide, a total of 1,185 cases of ovarian cancer treated between January, 1980 and December, 1987, were investigated as to their prognosis from the aspect of the chemotherapeutic effect. (1) An excellent effect of the remission-induction chemotherapy was observed in a group receiving combination therapy with CDDP as the main ingredient. In particular a significant effect was seen in stages III and IV. In addition, the effect on the remaining tumors by diameter also showed a significant difference in cases of tumors of not less than 2 cm in diameter. (2) As to the effect on histological types, a comparison in stage III showed a favourable effect on endometroid, serous and mucinous adenocarcinomas, while no effect was observed in clear cell adenocarcinoma. (3) The effect of the remission induction chemotherapy did not always give rise to an improvement in the long-term prognosis of ovarian cancer, and the establishment of a therapeutic method aimed at the prevention of recurrence was desired. (4) To improve the long-term prognosis, intermittent (or cyclic) chemotherapy with CDDP as the main ingredient was found to be very effective, but maintenance chemotherapy with orally administered of 5-Fluorouracil or Tegaful was not effective. (5) The effect of the conventional immunotherapy was not observed at all.

[A group study on prognosis of ovarian cancer in Japan].

An assessment has been made, with the cooperation of 22 institutes, of 1,185 cases of ovarian cancer as subjects who were treated in the period from January, 1980, to December, 1987. As a result, (1) As for distribution by clinical staging at the initial examination, the cases in Stage III were the most numerous, followed by those in Stage I, and if classified according to the histological type, serous cystadenocarcinoma was the most frequently observed in Stage III, and undifferentiated and unclassified carcinomata were observed in Stages III and IV. (2) In the examination of prognostic factors, it was confirmed that the clinical stage, histological type and diameter of the remaining tumor after the initial operation were important factors. (3) A significant difference was observed between the grade of histomorphological differentiation and prognosis, the difference was chiefly due to the deviated distribution of clinical staging in each group of differentiation. (4) A favorable trend was observed in the prognosis by patient's age toward the younger layer. (5) When the starting time of the therapy is considered, a trend toward improvement has been seen year by year, and it is considered that the beneficial effect of chemotherapy with CDDP contributes to this.

[Changes in blood pressure in two types (absolute and relative) of pregnancy induced hypertension (hypertensive type of toxemia)].

The criteria for pregnancy induced hypertension (PIH: hypertensive type of toxemia) have been determined by the Japanese Obstetrics and Gynecology Society. Mild PIH is classified into two types. One is "Absolute PIH (A-PIH)" diagnosed by (1) systolic blood pressure (SBP) greater than or equal to 140 mmHg and less than 160 mmHg or (2) diastolic blood pressure (DBP) greater than or equal to 90 mmHg and less than 110 mmHg. The other one is "relative-PIH (R-PIH)" diagnosed by (3) an increase in SBP greater than or equal to 30 mmHg compared to the usual SBP or (4) an increase in DBP greater than or equal to 15 mmHg compared to the usual DBP (In this paper, blood pressure prior to the 12th gestational week is considered as "usual" blood pressure). However, there has been no report in which two types of PIH are assessed. Our hypothesis is that the pathophysiology of the two types of PIH is different. We have already reported the clinical background of two types of PIH. The purpose of this study is to clarify the pathophysiological difference by evaluating the blood pressure change during pregnancy. We evaluated 963 nullipara and 747 multipara whose pregnancies were recorded from the 1st trimester (multiple pregnancy and pre-term delivery before the 32nd gestational week were excluded). Among the nullipara, 765 women (79.4%) were diagnosed as having normal blood pressure (N-group), 7.1% as A-PIH, and 13.0% as R-PIH. Among the multipara, the N-group consisted of 632 women (84.6%), the A-PIH: 4.6% and R-PIH: 10.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

[Fetal growth in two types (absolute and relative) of pregnancy induced hypertension (hypertensive type of toxemia)].

The criteria for pregnancy induced hypertension ("PIH" which is a hypertensive type of toxemia) have been determined by the Japanese Obstetrics and Gynecology Society. Mild PIH is classified into two types. One is "Absolute PIH (A-PIH)" diagnosed by (1) systolic blood pressure (SBP) greater than or equal to 140 mmHg and less than 160 mmHg or (2) diastolic blood pressure (DBP) greater than or equal to 90 mmHg and less than 110 mmHg. The other one is "relative-PIH (R-PIH)" diagnosed by (3) an increase in SBP greater than or equal to 30 mmHg compared to usual SBP or (4) an increase in DBP greater than or equal to 15 mmHg compared to usual DBP (In this paper, blood pressure prior to the 12th gestational week is considered as "usual" blood pressure). We have already investigated the pathophysiological difference through the background and the change in blood pressure throughout pregnancy and puerperium in these two types of PIH. The purpose of this study is to clarify the pathophysiological difference by evaluating the influence of hypertension on fetal growth. We evaluated 963 nullipara and 747 multipara whose pregnancies were recorded from the 1st trimester (multiple pregnancy and pre-term delivery before the 32nd gestational week were excluded). Among nullipara, 765 women (79.4%) were diagnosed as having normal blood pressure (N-group), 7.1% as A-PIH, and 13.0% as R-PIH. Among multipara, the N-group consisted of 632 women (84.6%), A-PIH: 4.6% and R-PIH: 10.3%. There is no difference among the three groups in gestational days but the body weight, the chest circumference, and the abdominal girth at birth of A-PIH show a significant difference from those of the R-PIH and N-groups in both nullipara and multipara.(ABSTRACT TRUNCATED AT 250 WORDS)

[Significance of intermittent CDDP therapy for improving long-term prognosis in patients with advanced ovarian cancer].

In cases of advanced ovarian cancer, intermittent CDDP therapy (ICDDPT) was applied after the first operation and induction chemotherapy, and its efficacy and limit were studied. One cycle of this therapy involved consecutive 5 day CDDP treatment (25-30mg/body/day). The therapy was repeated at intervals of 3 months. In many cases, ovarian cancer was histologically rated as epithelial adenocarcinoma. The study included 18 cases in total. ICDDPT was applied to 13 cases in which no tumor mass was detected by second look operation (SLO) or which showed clinical remission after operation. Only 3 of these 13 cases showed recurrence, and all these 13 are still living. Of the 5 cases in which SLO disclosed a tumor mass or which did not show remission after the first operation, 2 died. When the survival rate after ICDDPT was compared by the Kaplan-Meier method with that of controls without CDDP therapy, the effectiveness of ICDDPT was demonstrated. The survival rate could therefore be improved by ICDDPT. The therapy particularly improved the long term prognosis of SLO negative cases and cases in clinical remission. It seems necessary to repeat this therapy for a long period to achieve satisfactory results. In SLO positive cases and cases without clinical remission, the therapy had only a limited effect.

[Clinical backgrounds in two kinds (absolute and relative) of mild pregnancy induced hypertension].

The criteria for pregnancy induced hypertension (PIH) have been determined by the Japanese Obstetrics and Gynecology Society. Mild PIH is classified into two types. One is "Absolute-PIH (A-PIH)" diagnosed by 1) systolic blood pressure (SBP) greater than = 140mmHg and less than 160mmHg or 2) diastolic blood pressure (DBP) greater than = 90mmHg and less than 110mmg. Another one is "Relative-PIH (R-PIH)" diagnosed by 3) an increase in SBP greater than = 30mmHg compared to normal SBP or 4) an increase in DBP greater than = 15mmHg compared to normal DBP. However, there has been no report in which two types of PIH are assessed. Our hypothesis is that the pathophysiology of two types of PIH is different. The purpose of this study is to clarify the pathophysiological difference by evaluating the clinical backgrounds. We evaluated 963 nullipara and 747 multipara whose pregnancies were recorded from the 1st trimester (multiple pregnancy and pre-term delivery before 32 gestational weeks were excluded). Among 765 nullipara women, 79.4% were diagnosed as having normal blood pressure (N-group), 7.1% as A-PIH, and 13.0% as R-PIH. In the multipara N-group, the figures were 632 women (84.6%), A-PIH, 4.6% and R-PIH, 10.3%. Clinical backgrounds showed that the incidence of hypertensive family history, high hematocrit (greater than = 39.0) before the 12th gestational week or obesity (Kaup index greater than = 24 before pregnancy) was significantly higher in A-PIH than in the N-group of nullipara and higher in the A-PIH than in the R-PIH and N-groups of multipara.(ABSTRACT TRUNCATED AT 250 WORDS)

[An early phase II study of CPT-11 in gynecologic cancers. Research Group of CPT-11 in Gynecologic Cancers].

An early Phase II study of CTP-11, a new derivative of Camptothecin, in gynecologic cancers was carried out by a cooperative study group of 9 institutions. Forty-six patients were enrolled, and there were 14 cases of ovarian cancers, 7 of cervical cancer, 6 of uterine body cancers and 1 of endometrial stromal sarcoma which satisfied study criteria. The response rate in ovarian cancers was 21.4%, and in cervical cancers 42.9%, among an overall rate of 21.4%. Three out of 6 patients with objective response had undergone previous chemotherapies including cisplatin, suggesting that CPT-11 was effective for patients with no response or refractory to these therapies. Leukopenia was a major adverse reaction with an incidence of 60.0% (grade 2 or more). Gastrointestinal symptoms such as nausea vomiting, anorexia and diarrhea were frequently observed (grade 2 or more; 13.3-43.3%). These were generally tolerable except in a few cases. Besides these reactions, alopecia was also observed (33.3%), but severe adverse reactions such as nephropathy were not. These results suggested that CPT-11 was effective against ovarian cancer and cervical cancer. The recommended dose regimen for a late phase II study is considered to be 100 mg/m2 once weekly and 150 mg/m2 once every 2 weeks.

[Influence of estrogen and progesterone on the vascular response to angiotensin-II in non-pregnant rabbit vessels--intact or denuded endothelium].

During pregnancy, vascular sensitivity to A-II is reduced and it was clarified that this refractoriness to A-II is due to a change in EDRF output in pregnant rabbits. The present study aimed at elucidating whether estrogen or progesterone is responsible for the augmentation of EDRF output. 17-OH-estradiol was administered (200 micrograms/kg/day) for 7 days to 8 non-pregnant rabbits, while progesterone was similarly administered (2,000 micrograms/kg/day) to 8 other non-pregnant rabbits. Twenty-four nonpregnant rabbits were employed as the controls. Common iliac arterial rings prepared from each group were compared for the isometric response to A-II. The arterial rings with intact endothelium prepared from the progesterone-treated group were found to have a smaller pD2 value and a smaller maximum response to A-II than the estrogen-treated group. On the other hand, no differences between the progesterone group and estradiol group were observed in these values for the endothelium-denuded arterial rings. These findings indicated that the augmentation of EDRF output during pregnancy is brought about by progesterone.

[Role of endothelial cells on refractoriness to angiotensin-II in pregnant and non-pregnant rabbits].

Vascular refractoriness to angiotensin-II (A-II) during pregnancy is well recognized. The present study was designed to evaluate how the response of endothelial cells of arterial rings to A-II changes in pregnant rabbits (n = 24) when compared with non-pregnant rabbits (n = 24). The response of the arterial rings with intact endothelium to A-II was markedly decreased in the pregnant rabbit group in comparison with the non-pregnant rabbit group. In contrast, in the case of the arterial rings whose endothelium had been removed, there was no difference between the two rabbit groups in the response to A-II. However, the maximum response of arterial rings to A-II was significantly lower in the pregnant group than the non-pregnant group under the presence of the endothelium. This study revealed that the arterial rings with intact endothelium prepared from the pregnant group shows markedly increased refractoriness to A-II, while no such difference is seen with rings from which the endothelium had been removed. That is, this study indicated that an endothelium-derived relaxing factor (EDRF) is deeply involved in refractoriness to A-II in pregnant rabbits.

[Clinicopathological, ultrastructural and immunohistochemical study on adenoma malignum of the uterine cervix].

A histological, cytological, immunohistochemical and electron microscopical study has been made on 9 cases of adenoma malignum of the cervix. Five patients out of 9 who received surgical treatment following correct diagnosis, and were followed by maintenance chemotherapy with tegafur have survived without evidence of recurrence for 15 to 60 months. The remaining 4 patients who were treated following incorrect diagnosis have died of the disease. Adenoma malignum is a potentially malignant tumor histologically characterized by adenomatous proliferation with structural abnormality in the shape and arrangement of the gland and budding invasive pattern into the stroma. The gland filled with mucous substance often ballooned and ruptured resulting in the leakage of mucous substance into the surrounding stromal tissue. Light and electron microscopical observation of the epithelial cells revealed that they were quite different from those of conventional adenocarcinoma. Excessive mucus-producing activity and variation in nuclear DNA content can lead to possible differential cytodiagnosis between tumorous and normal columnar cells. The finding of positive CEA in the cytoplasm of the tumor cell obtained in the immunohistochemical study led to further study to detect CEA in the cervical mucus in screening for this rare tumor.

[The effect on prognosis and the adverse drug reaction of intermittent cisplatin therapy in advanced ovarian cancer patients].

We examined the effects and adverse drug reaction (ADR) of intermittent cisplatin therapy (ICDDPT) on advanced ovarian cancer patients (OCP). Most OCPs had undergone surgical removal of primary lesion and induction chemotherapy, and histopathological analysis indicated epithelial tumors. Five OCPs were stage III, six were stage IV and one stage II (n = 12). After surgical treatment and induction chemotherapy, ICDDPT was initiated with a 25-30 mg/day dose of CDDP for 5 days, every 3 months. During the intervals, maintenance immunochemotherapy of Tegafur and OK-432 was applied. Following ICDDPT, all patients except one are alive. The longest survival, to date is 5 years 7 months, while the decreased case survived 4 years. ADR was analysed according to the total dose of CDDP i.e. under 500 mg, over 500 mg-under 1,000 mg, 1,000 mg-under 1,500 mg, and 1,500 mg and over. Abnormal laboratory findings were observed for WBC, platelet (thrombocytopenia), Hb, GOT and GPT. The abnormal values except for GOT and GPT reverted to normal just before next administration. Thereafter ADR of CDDP with regard to the renal tubulus were studied by observing urinary NAG and urinary and serum beta 2 microglobulin. These values, however, were restored to within normal limits after 1 week of CDDP administration. These ADR were no greater with the increasing dose, such that accumulative toxicity was not observed. Study of the histological concentration of platinum showed a high level in liver tissue. Therefore, liver damage should be noted as on ADR of CDDP. In conclusion, ICDDPT for OCP was seen to be effective because of a good survival rate and low ADR.

[Management of vulvar cancer].

In the treatment of vulvar malignancy surgery, chemotherapy, irradiation therapy and so on can be used. Actually, it was rarely performed only by a single method. For treatment by the stage of cancer progression, the superficial cancer was treated by wide local resection for the patients except old women who were done simple vulvectomy. For the invasive cancer, stage 1 or 2, the pre-operative bleomycin (BLM) was administered to reduce the tumor mass, thereafter, radical vulvectomy with inguinal lymph node resection was performed. If inguinal lymph nodes metastasis was found, area of resection was extended to pelvic lymph nodes. Recently, micro-invasive carcinoma was defined that the foci was below 2 cm and interstitial invasion below 1 mm. In this condition, it was needless to remove the lymph nodes. For the stage of 3 or 4 which was inoperable, chemotherapy (mainly BLM) combined with irradiation therapy was done. In the cases of good general condition, it was chosen by super-radical vulvectomy.