Milk/dairy products consumption, galactose metabolism and ovarian cancer: meta-analysis of epidemiological studies.

Ovarian cancer is the fifth most common cause of cancer death among women and the leading cause of gynaecological cancer death in the United States. Milk/dairy products consumption was considered to be a risk factor for ovarian cancer mainly because milk carbohydrate-lactose and galactose metabolism is toxic to oocytes. However, recent evidence does not support this hypothesis completely. We collected epidemiological studies related to the association between milk/dairy products consumption or galactose metabolism (lactose, galactose, galactose-1-phosphate uridyltransferase, lactose/transferase) and ovarian cancer published between January 1966 and August 2003 and found 27 items from 22 independent studies. Twenty studies were case-control studies and the other two were cohort studies. A meta-analysis method was conducted to estimate relative risk combining all relative data. In general, we did not find any association between milk/dairy products or galactose metabolism and ovarian cancer risk in this meta-analysis. The consumption of whole milk and butter, which contain relatively high amounts of fat, was positively (relative risk > 1.2), but not significantly, associated with an increased risk.

Pentobarbital anesthesia during the proestrous afternoon blocks lactotroph proliferation occurring on estrus in female rats.

Estradiol stimulates the synthesis and secretion of PRL and lactotroph proliferation, and its long-term administration induces PRL-secreting pituitary tumors. We examined changes in the number of proliferating lactotrophs throughout the estrous cycle in female rats and the involvement of the brain in the regulation of the lactotroph proliferation by anesthetizing with pentobarbital. Female rats revealing regular 4-day estrous cycles were injected ip with the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) 3 h before decapitation to label DNA-replicating cells. Dispersed anterior pituitary cells obtained from these rats were stained for PRL and BrdU with a double labeling immunofluorescence technique. The rate of lactotroph proliferation was represented by the BrdU-labeling index (BrdU-labeled lactotrophs as a percentage of total lactotrophs counted). Lactotrophs from rats injected with BrdU at 1000 h showed a high BrdU-labeling index of 2.6% on estrus, whereas they showed almost undetectable levels of the BrdU-labeling index during the other stages of the estrous cycle. The anterior pituitary cells other than lactotrophs were scarcely labeled during any stages. The BrdU-labeling index began to rise by the midnight between proestrus and estrus, peaked between 0800 and 1200 h, and returned to undetectable levels by the midnight between estrus and diestrus I. Pentobarbital (35 mg/kg, i.p.) injected at 1345 h on proestrus, which was effective in blocking ovulation on estrus, eliminated completely the increase in the BrdU-labeling index as determined by BrdU injection at 1000 h on estrus. In contrast, the high BrdU-labeling index on estrus was partly suppressed to a level of 1.4% by pentobarbital injection at 0900 or 2100 h on proestrus. The rats injected with pentobarbital at 1345 h on proestrus did not show any increases in the BrdU-labeling index even after BrdU injection was delayed from 1000 to 1400 h on estrus. However, a high BrdU-labeling index of 3.7% was obtained in these animals when BrdU was injected at 1000 h on diestrus I. We conclude that 1) lactotrophs of cycling female rats proliferate selectively on the day of estrus; and 2) the proliferation of lactotrophs on estrus is not due to a direct action on the anterior pituitary of estradiol secreted from the ovaries but triggered by neural events occurring during the proestrous afternoon, which are closely related with the regulation of preovulatory surges of gonadotropin and PRL secretion.

Estradiol-induced diurnal changes in lactotroph proliferation and their hypothalamic regulation in ovariectomized rats.

Pentobarbital anesthesia during the proestrous afternoon delays proliferation of lactotrophs of the anterior pituitary from estrus to diestrus 1 in cycling female rats. We determined whether estradiol treatment induced diurnal changes in rates of lactotroph proliferation in ovariectomized rats, and if so, examined whether hypothalamic neural activity was involved in the occurrence of the estradiol-induced diurnal changes. Dispersed anterior pituitary cells were obtained from ovariectomized rats bearing estradiol implants that had been treated with 5-bromo-2'-deoxyuridine (BrdU) 3 h before decapitation. BrdU-labeling indices representative of the proliferation rate of lactotrophs were determined by double immunofluorescence staining for BrdU and PRL. After treatment of ovariectomized rats with estradiol on day 0, BrdU-labeling indices of lactotrophs as determined by injecting BrdU at 1000 h increased markedly with time peaking on days 4-7. Levels of BrdU-labeling indices at 1000 h on day 4 were 2.8-fold higher than those at 2200 h on day 3 or 4 after estradiol treatment. However, levels of BrdU-labeling indices at 1000 h on day 14 were 35% lower than those at the same time on day 4 and did not differ from those at 2200 h on day 13 or 14. In addition, a difference in BrdU-labeling indices as observed between 1000 and 2200 h on day 4 in the ovariectomized rats was not detected in estradiol-treated orchidectomized male rats. Serial determinations of BrdU-labeling indices throughout day revealed that the difference in BrdU-labeling indices between 1000 and 2200 h on day 4 in the ovariectomized rats reflected estradiol-induced diurnal changes that were characterized by a peak between 0700-0900 h and a nadir between 1900-2200 h. Pentobarbital injected at 0900 or 2100 h on day 3 decreased slightly high levels of BrdU-labeling indices at 0800 h on day 4. However, pentobarbital injection at 1345 h on day 3, which was effective in blocking estradiolinduced surges of LH and PRL secretion, suppressed markedly the high levels at 0800 h on day 4. In these pentobarbital-blocked rats, the diurnal changes in BrdU-labeling indices whose peak would normally have occurred at 0700-0900 h on day 4 were delayed not by the time corresponding to the duration of pentobarbital anesthesia but exactly by 24 h. These results suggest that 1) hypothalamic and sexually dependent diurnal changes in lactotroph proliferation can be induced by short-term estradiol treatment in ovariectomized rats as well as in cycling rats, and 2) estradiol treatment for 14 days rather prevents the diurnal changes in lactotroph proliferation.

Liver microsomal mixed-function oxidases in response to dietary whole egg protein levels in rats.

Relation between the activity of liver microsomal mixed-function oxidase system and dietary protein level was investigated in rats using purified whole egg protein, i.e. free from limiting amino acids. The animals were given either a diet containing 0, 5, 10, 20 or 40% of protein (experiment 1) or a diet containing 5, 10, 15 or 20% of protein (experiment 2) for 16 days. In experiment 2, half of the rats of each group were intraperitoneally injected sodium phenobarbital (PB) to induce the mixed-function oxidase system. The cytochrome P-450 content plateaued even at 5% level of dietary protein in experiment 1 and in the PB-untreated groups of experiment 2. However, it showed the highest value at 15% protein level in the PB-treated groups of experiment 2, indicating a shift of the response peak to a higher protein level due to an increase in protein requirement. Cytochrome P-450 reflected most specifically the dietary protein levels when the enzyme system was induced by PB. The 15% protein level, equivalent to 14.1 protein calories %, is a little higher than the optimal dietary level of whole egg protein ever obtained by usual nutritional indices.

Judgments of emotion by nurses and students given double-bind information on a patient's tone of voice and message content.

We examined the communication process in a situation typical of the nursing setting by use of a double-bind communication. Our objective was to examine which of two cues in communications from a patient, tone of voice or verbal content, was more important in judging the speaker's emotional status and personality traits and in arousing the listening nurse's emotions. Subjects were 82 nurses who worked at the university hospital and 100 students who were studying at the Faculty of Nursing of the university. They were assigned into four groups at random, presented professionally tape-recorded scripts representing a patient's verbal report, and then completed a questionnaire concerning the speaker's emotional status as well as the listener's own emotional status. When the listeners judged the speaker's emotional status, they gave more attention to a negative emotional expression, and when the listeners formed an impression of the speaker's personality traits, they were influenced by the speaker's tone of voice rather than by the content of the speech.

Nurses' comprehension and recall process of a patient's message with double-bind information.

We examined nurses' comprehension and recall process of patients' passage with double-bind information. We focused on two modes of communication, tone of voice and content of speech. The experiment followed a 2 x 2 x 2 design with respect to listeners (nurse vs student), tone of voice (positive vs negative), and verbal content (positive vs negative). Subjects were 79 nurses who worked at the university hospital and 99 students who were studying at the Faculty of Nursing. Nurses and students were randomly divided into four subgroups; each was presented one of four professionally tape-recorded scripts representing one possible combination of tone of voice and verbal content on the part of a fictitious patient. Listeners then rated the passages on scales and were asked to recall the passages in detail. Listeners recalled and understood passages better when the modes of communication did not conflict. Accuracy in recall reflected comprehension of passages rather than the listener's feelings about the "patient," especially in double-bind situations. Listeners tended to judge the speaker's feelings by tone of voice rather than verbal content.

[A case of ovarian cancer with metastatic tumor in the liver with paclitaxel and carboplatin systemic chemotherapy was very effective].

An 82-year-old woman was admitted to the Dept. of Obstetrics and Gynecology, Yamanashi Medical University to try to identify the origin of a liver metastatic tumor. CT examination revealed a small tumor located adjacent to the uterine cervix in a cul-de-sac. With biopsy using MR, it was clearly shown histologically that the origin of the tumor was the ovary. Systemic chemotherapy with paclitaxel and carboplatin was selected as the most reasonable treatment for this case because of the patient's age. After 6 courses of this chemotherapy, the tumor in the cul-de-sac disappeared and the tumor in the liver decreased markedly. Furthermore, no severe side effects were seen during this treatment. This result indicated that systemic chemotherapy with paclitaxel and carboplatin is effective and safe in cases of advanced ovarian cancer.

Gastric mucin is expressed in a subset of endocervical tunnel clusters: type A tunnel clusters of gastric phenotype.

AIMS: Gastric mucin expression has been demonstrated in a group of endocervical glandular lesions. The aim of this study was to gain further insight into endocervical lesions with a gastric phenotype. METHODS AND RESULTS: Various types of tunnel clusters (TC) were examined for gastric mucin by alcian blue/periodic acid-Schiff staining and immunohistochemistry for HIK1083. Five of 34 cases of TC expressed gastric mucin defined by PAS dominant neutral mucin and immunopositivity for pyloric gland mucin. Histologically, TC expressing gastric mucin showed lobular arrangements of small to medium-sized glands composed of mucin-rich columnar cells and were classified as Flumann's type A TC. Neither type B TC nor normal endocervical glands expressed PAS dominant neutral mucin and none of them was immunopositive for pyloric gland mucin. Five patients with type A TC of gastric phenotype ranged in age from 33 to 79 years (mean 58 years) and were multiparous. Type A TC of gastric phenotype, ranging from 2 to 4 mm in maximum diameter, were incidental findings in hysterectomy specimens. CONCLUSION: Type A TC of gastric phenotype could be related to lobular endocervical glandular hyperplasia of gastric phenotype. The pathogenesis of gastric metaplasia in TC remains unclear.

D2 dopamine-receptor-mediated inhibition of proliferation of rat lactotropes in culture is accompanied by changes in cell shape.

Dopaminergic agonists are effective in vivo in inhibiting lactotrope proliferation and prolactin (PRL)-secreting pituitary tumors. The purpose of the present study was to demonstrate in vitro actions of dopaminergic agents on proliferation and cell shape of rat lactotropes. Anterior pituitary cells cultured with serum-free, chemically defined medium were treated with dopaminergic agents and were labeled with 5-bromo-2'-deoxyuridine (BrdU) for 3 h before the end of culture. BrdU-labeling indices indicative of the proliferation rate of lactotropes were determined by double immunofluorescence staining for BrdU and PRL. Treatment with dopamine for 21 h decreased BrdU-labeling indices of lactotropes in a dose-dependent manner with a nadir at 3 x 10(-7) M. The inhibitory action of 10(-5) M dopamine appeared 15 h after the initiation of treatment and became pronounced with time up to 33 h. The dopamine action was mimicked by treatment with the D2 receptor agonist bromocriptine at concentrations over 10(-9) M. Phase-contrast microscopy revealed that the flat polygonal cell shape of cultured lactotropes had changed to a round refractive cell shape after treatment with dopamine or bromocriptine, and that these changes in cell shape exactly paralleled those in the BrdU-labeling index. The changes in cell shape of lactotropes were accompanied by changes in subcellular distribution of actin filaments. Pretreatment with 10(-7) M eticlopride, a D2 receptor antagonist, blocked the dopamine- or bromocriptine-induced changes in both BrdU-labeling index and cell shape. These results suggest that (1) the in vitro experimental system established in the present study is a good model for studying the mechanism of the antiproliferative action of dopamine and (2) D2-receptor-mediated inhibition of proliferation of lactotropes in serum-free culture is closely related to changes in actin organization and cell shape.

A case of small cell carcinoma of the uterine cervix presenting Cushing's syndrome.

A proportion of small cell carcinoma of the uterine cervix is known to secrete a neuroendocrine substance. However, cases presenting Cushing's syndrome due to ACTH secreted from a cervical small cell carcinoma are extremely rare. Here, we report a case of small cell carcinoma of the uterine cervix that ectopically secreted ACTH and presented Cushing's syndrome. A 42-year-old woman was initially admitted to the endocrine unit for investigation of ectopic ACTH syndrome. Serum cortisol and plasma ACTH levels were elevated with no diurnal variation. After gynecologic examination, her original disease was found to be a stage IIb cervical small cell carcinoma. She underwent a radical hysterectomy and pelvic lymphadenectomy. The entire tumor was excised and post-TNM classification was T2bN1M0. Immunohistochemically, tumor cells stained strongly for ACTH and chromogranin. Electronmicroscopic pictures showed typical neurosecretory granules. Although plasma ACTH returned to normal after surgery, liver metastasis appeared during the course of postoperative irradiation. She died 9 months after operation in spite of vigorous systemic chemotherapy.

Mixed function oxidases in response to different types of dietary lipids in rats.

The influence of dietary lipids on the liver microsomal mixed function oxidase system and on pentobarbital-induced sleeping time was studied in rats. Giving diets containing (g/kg) 150 olive oil, 150 lard or 150 soya-bean oil for 21 d (Expt 1) increased the cytochrome P-450 content in the order: olive oil less than lard less than soya-bean oil. When diets containing (g/kg) 150 lard, 150 soya-bean oil, 150 sardine oil or an equal mixture of 50 of each oil were given for 15 d (Expt 2), the cytochrome P-450 content and aminopyrine N-demethylase activity were significantly higher in the sardine-oil and mixed-oil groups than in the lard group, and the activity of aminopyrine N-demethylase was also significantly higher in the soya-bean oil group compared with the lard group. A significantly higher activity of NADPH-cytochrome c reductase (EC 1.6.2.5) was observed in the sardine-oil group than in the other three groups. Aniline hydroxylase activity and cytochrome b5 content remained unchanged in all the groups. Pentobarbital-induced sleeping time measured on day 15 (Expt 2) varied inversely with the changes in cytochrome P-450 content and aminopyrine N-demethylase activity in the three single-fat groups, but not in the mixed-oil group, reflecting liver microsomal metabolic activity for pentobarbital in vivo. From these results, it appears that high intakes of polyunsaturated fatty acids (18:2n-6, 18:3n-3, 20:5n-3 and 22:6n-3) stimulate the liver microsomal mixed function oxidase system.

Cholesterol-lowering effects of soybean, potato and rice proteins depend on their low methionine contents in rats fed a cholesterol-free purified diet.

Rats were fed cholesterol-free purified diets containing casein, rice (RP), potato (PP) or soybean (SP) proteins having different amounts of methionine (25.9, 21.3, 16.2 and 10.9 g methionine/kg, respectively). Each protein was fed at 250 g/kg diet for 14 d. Growth rates of rats were the same in all groups. Serum total cholesterol concentrations were lower in rats fed SP, PP and RP than in those fed casein. Fecal bile acid plus neutral steroid excretion was significantly higher in rats fed the RP, PP and SP diets compared with those fed casein. There was a significant negative correlation between serum cholesterol concentration and fecal total steroid excretion (r = -0.490, P = 0.01). However, a stronger positive correlation was observed between serum cholesterol concentration and dietary methionine concentration (r = 0.674, P = 0.0003) or methionine:glycine ratios (r = 0.656, P = 0.0005). In a separate experiment in rats fed diets containing amino acid mixtures simulating the RP, PP and SP diets, serum total cholesterol concentrations were lower than in rats fed simulated casein. Fecal total steroid excretion was the same in all groups. A strong correlation was found between serum cholesterol concentration and dietary methionine concentration (r = 0.743, P = 0.0002) or the methionine:glycine ratio (r = 0.685, P = 0.0009) in rats fed the amino acid mixtures. Finally, we examined the hypocholesterolemic effects of 250 g SP or casein/kg diet with or without supplementation with 0.3 g/100 g sodium taurocholate (TC). Supplementation with TC did not alter the hypocholesterolemic effect of SP. These results support the view that RP, PP and SP lower serum cholesterol concentration in a similar manner.

Effect of concurrent intra-arterial infusion of platinum drugs for patients with stage III or IV uterine cervical cancer treated with radical radiation therapy.

PURPOSE: The purpose of this study was to explore the effect of concurrent intra-arterial infusion of platinum drugs in patients with stage III or IV uterine cervical cancer treated with radical radiation therapy. PATIENTS AND METHODS: Thirty-three patients with advanced (stage IIIA, 2; IIIB, 28; IVA, 3) uterine cervical squamous cell carcinoma were randomized into a concurrent intra-arterial infusion of platinum drugs with radiation therapy (IAPRT) group (18 patients) and a radiation therapy alone group (15 patients). After altering intrapelvic blood flow by embolization of the superior and inferior gluteal arteries under pelvic angiography, intra-arterial infusion of platinum drug through catheters inserted into both internal iliac arteries was performed concurrently with radiation therapy. One-shot infusion of cisplatin (100 mg/m2) twice with a 2- to 3-week interval was performed in eight patients, weekly infusion of carboplatin (100 mg/m2) via a reservoir five to six times was performed in four patients, and daily shot of cisplatin (10 mg/body) or 21 days via a reservoir was performed in six patients. Radiation therapy consisted of external-beam irradiation of 50 Gy/25 fractions/5 weeks for the whole pelvis with midline block after 30 Gy and intracavitary high-dose-rate brachytherapy using tandem and ovoids of 24 Gy/4 fractions/4 weeks to point A. RESULTS: The local complete response rate of the IAPRT group was 94% and was significantly higher than that of the radiation therapy group (67%). There were no significant differences in local response in the three drug delivery methods. Two- and 5-year overall survival rates were 54.5% and 44.4% in the IAPRT group, and 74.5% and 50.0% in the radiation therapy group, respectively. There was no significant difference between the two groups. In the IAPRT group, grade 3 or 4 acute bowel complications were seen in 33% of patients, grade 3 or 4 late bowel complications were seen 44%, and grade 3 or 4 myelosuppression was seen in 33%, and these complications were seen more in the IAPRT group than in the radiation therapy group and caused death in some patients. CONCLUSIONS: IAPRT had a better local response than radiation therapy but showed no proof of control over recurrence and had a poorer survival than radiation therapy. There were many local recurrences and distant metastases, contrary to the better first response of the IAPRT group over the radiation therapy group. Complications of the IAPRT group were very severe and made the patient's performance status and prognosis worse than in the radiation therapy group. We need to design some methods to decrease these complications to make use of the good local response acquired with IAPRT. Furthermore, we should re-examine the indication of IAPRT in patients with a large tumor because local recurrence and distant metastasis would be inevitable.