Association between low MCV in early pregnancy and perinatal mental health in the Japan Environment and Children's Study and the possible effect of iron deficiency.

BACKGROUND: Postpartum anemia and iron deficiency are associated with postpartum depression. This study investigated the association between a low mean corpuscular volume (MCV) without anemia (which implies early-stage iron deficiency) in early pregnancy and perinatal mental health outcomes. METHODS: The fixed data from the Japan Environment and Children's Study (JECS), a Japanese nationwide birth cohort, were used. Perinatal mental health was assessed using the Kessler 6-item psychological distress scale (K6) in mid-pregnancy and the Edinburgh Postnatal Depression Scale (EPDS) at 1- and 6-months postpartum. RESULTS: Among the 3635 women with MCVs <85 fL in early pregnancy, the proportions of women with K6 scores ≥13 in mid-pregnancy and EPDS scores ≥9 at 1- and 6-months postpartum were 2.7 %, 12.8 %, and 9.9 %, respectively, compared with the 33,242 women with MCVs ≥85 fL at 1.9 %, 11.9 %, and 9.0 %, respectively. Multivariate logistic regression models showed that an MCV <85 in early pregnancy was associated with a K6 score ≥ 13 in mid-pregnancy and an EPDS score ≥ 9 at 1- and 6-months postpartum (adjusted odds ratio (95 % confidence interval): 1.48 (1.16-1.87), 1.14 (1.01-1.28), and 1.09 (0.95-1.24), respectively). LIMITATIONS: Low MCV values do not necessarily represent iron deficiency. Ferritin, currently the best indicator of iron deficiency, was not measured in the JECS. CONCLUSIONS: This study results suggest that a low MCV without anemia in early pregnancy is associated with a slightly increased risk of perinatal mental health deterioration.

[Clinical reevaluation of continuous intravenous infusion of 5-fluorouracil--plasma concentrations and clinical dose by continuous intravenous and 60-min infusions].

Daily and intermittent continuous intravenous infusions [by gravity drip, (IVG) or infusion pump, (IVP)] and intermittent short-time intravenous drip infusion of 5-FU were carried out on advanced cancer patients. The MTD and dose-limiting toxicity were investigated in relation to the plasma concentrations of 5-FU determined by HPLC. Responses in eleven patients receiving IVG administration daily at 8-21 mg/kg/day were NC, but those given 5-FU alone showed no adverse reactions. Plasma concentrations were too low to be determined. In 9 patients receiving IVG or IVP administration weekly at 60 mg/kg for 24 hr, 1 of the 5 evaluable patients showed reduced hepatic metastatic lesions. One of 4 patients receiving IVP administration weekly at 120 mg/kg for 48 hr showed a disappearance of metastatic lesions in the skeletal muscle, but bone marrow suppression was observed as dose-limiting toxicity. Pharmacokinetics were more stable in IVP than in IVG with less individual difference in the plasma concentrations. Among the outpatients receiving short-time iv, IVG administration once or twice a week, 2 patients given weekly administrations at 20 mg/kg for 60 min showed slight adverse reactions. In 6 patients given high-dose administrations, bone marrow suppression was observed. When pharmacokinetics in the patients given 5-FU for 60 min were compared between the IVG and IVP groups, there were individual differences in plasma concentrations, but the differences were not significant. It was concluded from above results that the following practical dose schedules would be recommendable: 60 mg/kg for 24hr/week by IVP for inpatients and 20 mg/kg for 60 min/week by IVG for outpatients.

Cell kinetics and chemosensitivity of human carcinomas serially transplanted into nude mice.

Six human carcinoma xenografts serially transplanted into nude mice were used for the study of chemosensitivity and cell kinetics. Three gastric carcinomas (St-4, St-40 and H-111), two colon carcinomas (Co-3 and Co-4) and one breast carcinoma (MX-1) were inoculated into the subcutaneous tissue of BALB/cA nude mice. The maximum tolerable doses of mitomycin C (MMC), adriamycin (ADM), cyclophosphamide (CPA) and 5-fluorouracil (5-FU) were administered when the tumor weights reached 100-300 mg. The response rates of the tumor to these drugs were found to be 3/6 for MMC, 2/6 for 5-FU and 1/6 for ADM and CPA. Percent labeled mitosis curves obtained from 3H-thymidine pulse labeling were analyzed by the method of Quastler and Sherman. It was found that the antitumor effect of MMC was closely correlated with the growth fractions of the tumors (r = -0.98, P less than 0.001), and it appeared that the tumor cells were more sensitive to MMC in the resting stages during the proliferating phase than in the other cell cycle phases. Cell kinetics is considered to be an important factor in determining chemosensitivity, and the system of human tumor xenografts-nude mice seems to be a suitable experimental model for investigating the correlation between cell kinetics and chemosensitivity in vivo.

[Cell kinetics of human lung small cell carcinomas transplanted into nude mice].

Three human lung small cell carcinoma (SCC) xenografts serially transplanted into BALB/c nude mice were used for cell kinetic analysis. SCC strains, Lu-24, Lu-130 and Lu-134, were inoculated into the backs of nude mice, and when each tumor reached more than 300 mg, 50 microCi of 3H-thymidine per mouse was administered ip. The percentage labeled mitosis curve was obtained from the autoradiographic specimens which were labeled by the pulse-chase method. Cell cycle phase, growth fraction (GF) and cell loss factor (CL) were assessed by the methods of Quastler, Fujita and Steel, respectively. These cell kinetic parameters were compared with those of six control human gastrocolic and breast carcinoma xenografts which were previously reported by us. It was noticed that the cell cycle times (Tc) of SCC were statistically shorter than those of controls and this short Tc was found to be dependent on their short post-mitotic resting phases. GFs and labeling indices of SCC were observed to be statistically lower than those of controls, suggesting an incomplete adaptation of SCC xenografts to the host nude mice. Whereas some modifications by the host mice on the cell kinetics were supposed, the characteristics of SCC cell kinetics were thought to be essentially preserved in nude mice and these kinetic parameters were observed to be stable throughout the serial transfers. Accordingly, the SCC xenograft-nude mouse system was considered to be useful as an experimental therapeutic model of human lung small cell carcinomas.

[Experimental combination chemo-radiotherapy on human breast carcinoma (MX-1) transplanted into nude mice].

Experimental combination chemo-radiotherapy of mitomycin C (MMC) and Linac irradiation was performed on human breast carcinoma transplanted into nude mice. The treatment was started on 2 wks. after tumor inoculations and the effects were evaluated by T/C ratio of the tumor weight. Cell kinetic analysis was studied by flow cytometry, 3H-thymidine uptake labeling index (L.I.) and mitotic index (M.I.) on 24 hrs. after treatments. Effect of MMC (0.5, 1 and 2 mg/kg) and irradiation (500, 1000 and 2000 rads/mouse) revealed exponential linear dose response curves against T/C ratio which was significantly correlated with L.I. In combination therapy, the synergistic action was observed when 500 rads/mouse and 1 mg/kg were combined, and the effect was found to be more excellent when the radiation was performed 24 hrs. before MMC administration than the reversed sequence. By MMC and radiation, 2n and 3n cells increased with decrease of 4n cells. Whereas no change of M.I. was observed, L.I. was depressed. Increased 3n cells with depressed L.I. was supposed to be caused by S phase prolongation. As this change was more remarkable by radiation, the combination therapy was thought to be more effective when the radiation was performed before MMC administration. This nude mice-human tumor system was thought to be useful to analyze the combination chemoradiotherapy.

[Effect of chemotherapy on the interstitial tissue of a malignant human tumor transplanted into nude mice, with reference to microvessels].

Experimental chemotherapy of cyclophosphamide (CPA) was performed on a human malignant hemangiopericytoma serially transplanted into nude mice with a genetic background of BALB/c and the changes or histological findings and microangiograms (MAG) were investigated. The treatment was performed 2 weeks after tumor inoculation. Either 120 mg/kg or 240 mg/kg of CPA, dissolved in 0.2 ml of physiological saline, was administered once intraperitoneally. On days 1, 2, 4 and 7 after the treatment, mice were sacrificed and each tumor was examined in terms of histological findings and MAG. Although the tumors treated with 120 mg/kg of CPA were suppressed temporarily, the regrowth of the tumors were observed. The tumors treated with 240 mg/kg of CPA regressed without any regrowth. From the observations of MAG, the former showed an avascular area on day 4 after the treatment and the tumor vessels regenerated on day 7 after the treatment. On the other hand, in the latter group, it was found that the normal vascular network developed after the formation of an avascular area 2 days after the treatment. From the histological findings, the former showed to reduce mitotic indeces of 1 or 2 days after the treatment, however the mitotic indeces were found to recover 7 days after the treatment. Mitotic indeces of tumors treated with 240 mg/kg of CPA were observed to be depressed after the treatment. These results suggested that the changes of interstitial tissue were closely correlated well with the destruction and regrowth of tumor cells observed by the growth curve and histological findings. Tumor vessels were thought to play an important role in the cancer chemotherapy, not only as the transport systems of drugs but also as the target of antitumor agents.

Antitumor effect and metabolic activation of cyclophosphamide and 4-hydroperoxycyclophosphamide in the human breast carcinoma (MX-1)-nude mouse system.

The effects of cyclophosphamide (CPA) and its active form, 4-hydroperoxy-CPA, against human breast carcinoma transplanted into nude mice (BALB/c nu/nu) were evaluated in terms of the decreases of hepatic drug-metabolizing enzymes in nude mice. A human breast carcinoma, MX-1, was implanted into the subcutaneous tissue of nude mice and a drug was administered intravenously once at a dose of 0.05, 0.1 or 0.15 mmol/kg, 1 or 3 weeks after tumor inoculation. 4-Hydroperoxy-CPA was more effective than CPA as regards inhibition of tumor growth, and the difference in effect was greater when the drugs were administered 3 weeks after tumor inoculation. The activity of CPA was depressed by the decrease of the hepatic drug-metabolizing enzymes in proportion to the tumor-bearing period. Therefore, the effects of masked derivatives of CPA may correlate with the changes in drug-metabolizing activities of tumor-bearing mice. The human tumor xenografts-nude mice system is considered to be suitable for chemosensitivity tests with masked compounds.

[Immunological competence of nude mice on the growth of transplantable human tumors--with reference to natural killer cells].

Influences of natural killer cells on the transplantable human tumors was evaluated by using anti-asialo GM1 antibody. Two human gastric adenocarcinomas designated as St-4 (poorly differentiated) and St-40 (well differentiated) were inoculated into nude mice. The effects of anti-asialo GM1 antibody were assessed in terms of tumor doubling time (Td) and 3H-thymidine (3H-TdR) uptake labeling index (L.I.). Whereas the Td of St-4 was significantly shortened by administration of anti-asialo GM1 antibody, no noticeable changes were observed in St-40. This enhanced growth of St-4 was also supported by the elevation of L.I. both in flashing and repeating methods. On the other hand, as the repeated L.I. of St-40 was almost 100% in control tumors, repeated L.I. was not increased by the administration of anti-asialo GM1 antibody. It was supported that natural killer activity of nude mice regulated the growth of transplantable human tumors concerning with the growth fractions.

[Microvascular architecture of human tumors transplanted in nude mice--its relationship to sensitivity to antineoplastic agents].

Microangiographic study was performed with ten human tumors serially transplanted into nude mice to clarify the role of tumor vessels on the chemosensitivity of the human tumors. Five gastric carcinomas, two colon carcinomas, one breast carcinoma, one cholangiocarcinoma, and one hemangiopericytoma were used for the experiments. Seven tumors revealed hypervascular network of vessels, whereas hypovascular patterns of tumor vessels were observed in the other three tumors. It was found that the histologically differentiated tumors were hypervascular and undifferentiated tumors were hypovascular, with statistically significant differences (p less than 0.05). Each tumor possessed the vascular network similar to human tumors originated from the same organs. No discernible changes of microangiographic features were noticed by serial transfers. As the chemosensitivities of these tumors depended mainly on their original tissues, these chemosensitivities could not be explained only by tumor vascularities or drug transferences. However, in the tumors with similar chemosensitive spectra, less susceptible tumors were observed to possess the irregular vascular networks in comparison with sensitive strains. From these considerations, tumor vessels were thought to have some role on vascular flow and drug transference which affected chemosensitivity of human tumors.

[Effect of mitomycin C on human gastric and colon carcinomas serially transplanted to nude mice--with special reference to the start of drug administration].

Three human gastric carcinomas and one colon carcinoma serially transplanted to nude mice were used for experimental chemotherapy of mitomycin C (MMC) with special reference to the start of drug administration. BALB/c nu/nu male originated from the Central Institute for Experimental Animals were used. All the experiments were carried out under the specific pathogen-free conditions using laminar air flow racks. Tumors used for experiments were St-4; poorly differentiated adenocarcinoma of stomach, St-15; mucinous adenocarcinoma of stomach, KS-1; poorly differentiated adenocarcinoma of colon. MMC at the doses of 2 or 3 mg/kg were administered intraperiatoneally once a week for 3 or 4 times starting from 24 hours (DAY-1 Adm.) or 2 weeks (DAY-14 Adm.) after tumor inoculation. Response to chemotherapy was evaluated on the basis of growth curves, tumor weights, and histopathological changes. Whereas St-15, a sensitive strain to MMC, was suppressed by DAY-1 and DAY-14 administration. Similarly, DAY-1 administration revealed more excellent effect on the other three tumors than DAY-14 administration. These results indicated that MMC was more effective when the tumor mass was smaller, and also suggested that the adjuvant chemotherapy of surgical operation should be started as soon as possible after tumor resection or reduction. In the case of DAY-1 treatment, the false positive result by anti-vascularization effect of MMC could not be excluded, it seems to be adequate that drug administration should be started after the initiation of logarithmic growth phase of the tumors.