Takeyoshi Ohkura

Long-Term Estrogen Replacement Therapy in Female Patients with Dementia of the Alzheimer Type: 7 Case Reports

Seven female patients with mild to moderate dementia of the Alzheimer type (DAT) were treated with long-term, low-dose estrogen replacement therapy (ERT) over a period of 5-45 months. Five of the 7 patients were cases who had responded well to short-term ERT with 1.25 mg/day of conjugated equine estrogens (CEE) for 6 weeks. The 7 patients from 56 to 77 years of age received 0.625 mg/day of CEE for 21 days, followed by a pause of 7 days. A 28-day cycle of low-dose ERT was performed repeatedly. In 4 cases, these patients received 5 mg/day of medroxyprogesterone acetate (MPA) during the last 10-12 days of estrogen treatment. Therapeutic efficacy of estrogen was evaluated by psychometric assessments such as the Mini-Mental State Examination (MMSE) and the Hasegawa Dementia Scale (HDS) and a behavior rating scale of the Gottfries-Bråne-Steen geriatric rating scale (GBS). The MMSE and HDS evaluations were performed principally once in 2-4 weeks. In 4 out of the 7 patients, the MMSE and HDS scores were elevated above the pretreatment levels during ERT. The termination of ERT resulted in a decrease in both scores. Furthermore, the GBS scores and daily activities of the same 4 patients were improved during ERT. In these 4 patients cognitive functions were markedly improved throughout the treatment period, while the other 2 patients responded moderately well and another patient did not respond at all. These observations suggest that long-term, low-dose ERT improves cognitive functions, dementia symptoms and daily activities in women with mild to moderate DAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen Increases Cerebral and Cerebellar Blood Flows in Postmenopausal Women

Whole cerebral and cerebellar flow (CBF and Cb1BF) measurements with single-photon emission computed tomography were performed on 14 postmenopausal women 4 weeks after the discontinuation of hormone replacement therapy. After the first brain blood flow measurements, nine subjects received 0.625 mg of conjugated equine estrogens (CEE) orally twice a day continually for 3 weeks (study group). The remaining five did not receive CEE (control group). The second brain blood flow measurements were performed on all 14 subjects between 2 and 3 weeks after the first ones. The mean whole CBF value (&OV0335; ±; SE) in the study group was significantly increased from 45.9 ±;3.4 to 58.8 ±; 5.5 ml/100 g/min during estrogen replacement therapy (ERT) (p = 0.0382). The mean whole Cb1BF value was also significantly increased from 47.7 ±; 3.4 to 61.0 ±; 5.6/100 g/min during ERT (p = 0.0382). In the control group, there were no significant differences between the first and second flow measurements either in the mean whole CBF values (46.6 ±; 2.5 versus 44.6 ±; 5.4 ml/100 g/min) or in the mean whole Cb1BF values (46.3 ±; 2.2 versus 44.2 ±; 5.2 ml/100 g/min). The mean percent changes were 29.5 ±; 10.2% in CBF and 29.3 ±; 10.4% in Cb1BF. These results suggest that ERT significantly increases the whole cerebral and cerebellar blood flows in postmenopausal women.

Tumor Necrosis Factor‐α in the Placenta is not Elevated in Pre‐eclamptic Patients Despite its Elevation in Peripheral Blood

Problem:  Tumor necrosis factor‐α (TNF‐α) is present in human placental and uterine cells at the early and late stages of gestation and promotes the regulation of trophoblast growth and invasion. We evaluated whether TNF‐α levels in the placenta and blood of pre‐eclamptic women differed from those with normal pregnancies.

Characterization of five marker levels of the hemostatic system and endothelial status in normotensive pregnancy and pre-eclampsia

Abstract:  Objectives : Pre‐eclampsia is associated with changes in the hemostatic system and endothelial status. Urinary 11‐dehydrothromboxane B 2 /creatinine (11‐DTXB 2 /Cr) is a marker for platelet activation and vascular constriction, thrombin–antithrombin complex (TAT) for thrombin formation, serum thrombomodulin (TM) for endothelial damage, and β‐thromboglobulin (β‐TG) and platelet factor 4 (PF‐4) for platelet activation and releasing reaction. The present study attempted to evaluate these five markers in normotensive pregnancy and pre‐eclampsia. Methods: These five markers were simultaneously measured in urine and blood samples from 25 women who were not pregnant (group 1, controls), 31 women with normotensive pregnancy (group 2, second controls), 22 women with mild pre‐eclampsia (group 3), and 21 women with severe pre‐eclampsia (group 4). The average gestational age was 36 wk. Results: The 11‐DTXB2/Cr, TAT, and β‐TG levels were significantly higher (P < 0.01) in groups 2, 3, and 4 than in group 1. The TM and β‐TG levels were significantly higher (P < 0.05) in group 3 than in group 2. The TM, β‐TG, and PF‐4 levels were increased significantly (P < 0.05–0.01) in group 4 compared to those in groups 1, 2, and 3. Conclusions: Platelet aggregation, vascular constriction, and thrombin formation (detected by 11‐DTXB2/Cr and TAT) may be markedly enhanced even in group 2, but further enhancement may be relatively slight in groups 3 and 4. In contrast, endothelial damage (determined by TM) and platelet release of PF‐4 may not increase significantly in group 2, but they may increase in group 4. Platelet‐release of β‐TG may be enhanced in groups 2, 3, and 4. Endothelial damage and platelet‐releasing reaction (detected by PF‐4 and β‐TG) may be significantly more enhanced in group 4 than in group 3.

Increased Levels of Macrophage Colony‐Stimulating Factor in the Placenta and Blood in Preeclampsia

PROBLEM: Macrophage colony‐stimulating factor (M‐CSF) is considered an essential cytokine for placental growth and maintenance. We evaluated whether M‐CSF levels in the placenta and blood in preeclampsia differed from those in normal pregnancies.

Elevated levels of serum macrophage colony-stimulating factor in normotensive pregnancies complicated by intrauterine fetal growth restriction

OBJECTIVE Macrophage colony-stimulating factor (M-CSF) is considered an essential cytokine for placental growth and maintenance. M-CSF also may regulate trophoblast invasion into the placental bed. The aim of the present study was to evaluate whether serum M-CSF levels were altered in normotensive pregnancies complicated by intrauterine growth restriction (IUGR) arising from unknown factors. Plasma thrombin-antithrombin complex (TAT) levels and the pulsatility index (PI) values also were measured. PATIENTS AND METHODS This study enrolled 47 Japanese women experiencing normotensive pregnancies with single fetuses. Of these pregnancies, 20 were complicated by IUGR arising from unknown factors; these women later delivered small-for-gestational-age (SGA) infants. The other 27 women later delivered appropriate-for-gestational-age infants (controls). The womens ages and gestational ages did not differ significantly between the two groups. Maternal peripheral blood was collected, and the levels of serum M-CSF and plasma TAT were compared between two groups. The M-CSF level was determined by the sandwich enzyme-linked immunosorbent assay method and the TAT level by the enzyme immunoassay method. The PI value for the middle cerebral artery of the fetuses was calculated. RESULTS Serum levels of M-CSF were significantly higher (p < 0.005) in pregnancies complicated by IUGR that produced SGA infants than in controls. Plasma levels of TAT also were significantly higher (p < 0.02) in pregnancies that produced SGA infants than in controls. The PI values were significantly lower (p < 0.05) in pregnancies that produced SGA infants than in controls. CONCLUSIONS This study demonstrated significant increases in serum M-CSF levels in women with normotensive pregnancies complicated by IUGR arising from unknown factors who later delivered SGA infants. To the best of our knowledge, this is the first such report. Elevated serum M-CSF levels may be related to placental hypoxia leading to pregnancies complicated by IUGR.

Changes in Plasma Soluble CD26 and CD30 during Pregnancy: Markers of Th1/Th2 Balance?

The theory that the Th1 and Th2 cell ratio shifts towards Th2 dominance during pregnancy may improve fetal survival has gained support from recent studies. Also, the variation in the Th1/Th2 cell ratio is reportedly associated with intrauterine growth retardation and preeclampsia. On the basis of these findings, the analysis of the Th1/Th2 balance may be useful in predicting severe complications during pregnancy. However, simple methods for the analysis of Th1/Th2 balance are presently not available. Recently, it has been reported that regulation of CD26 cell surface expression correlates with the production of Th1-like cytokines. On the other hand, previous studies proposed that the sCD30 molecule is an activation marker useful for evaluation of a Th2 immune response. It is, therefore, possible that the analysis of the Th1/Th2 balance during pregnancy by measuring plasma sCD26 and sCD30 simultaneously is a simple and useful method. We herein demonstrate that combined analysis of sCD26 and sCD30 is a potent surrogate tool to evaluate the Th1/Th2 balance during pregnancy.

The levels of five markers of hemostasis and endothelial status at different stages of normotensive pregnancy

Background.  Urinary 11‐dehydrothromboxane B2/creatinine (11‐DTXB2/Cr) is a marker for in vivo platelet activation and vascular constriction, blood thrombomodulin (TM) for endothelial damage and associated thrombosis, thrombin–antithrombin complex (TAT) for thrombin formation, and β‐thromboglobulin (β‐TG) and platelet factor 4 (PF‐4) for in vivo platelet activation and releasing reaction. Little is known about the quantitative relationship among them during pregnancy. The present study investigated levels of five markers at different stages of normotensive pregnancy.

Elevation of serum macrophage colony-stimulating factor before the clinical manifestations of preeclampsia ☆

OBJECTIVE The purpose of this study was to determine whether the increase in serum macrophage colony-stimulating factor (M-CSF) levels preceded the onset of preeclampsia. STUDY DESIGN We selected 146 women, of whom 36 were nonpregnant women participating in the preliminary study and 110 were normotensive pregnant women at risk for preeclampsia who were carrying single fetuses at about 18 weeks of gestation. The blood was collected and serum was stored at -20 degrees C until assay. Sixteen women had preeclampsia develop at a later stage of pregnancy (preeclamptics), whereas 89 women continued to have normotensive pregnancies until delivery. Thirty-five of the 89 women with normotensive pregnancy who were matched for age and parity were selected to form a control group (controls). Serum M-CSF levels were determined by the sandwich enzyme-linking immunosorbent assay method with use of three antibodies. RESULTS Serum level of M-CSF was 1295 U/mL (median) in preeclamptics and 957 U/mL in controls. Serum M-CSF levels were significantly higher (P<.0001) in preeclamptics than in controls. CONCLUSION The increase in serum M-CSF levels markedly precedes the development of clinical manifestations of preeclampsia. Elevation of serum M-CSF supports M-CSF elevation in the placenta. This elevation at 18 weeks of gestation may be related to placental hypoxia, which is considered the cause of preeclampsia.

Plasma Levels of Soluble Fas during Normal Pregnancy

The Fas/Fas ligand system could reportedly help to identify a mechanism for maternal immunotolerance of the fetus in human pregnancy. However, there are few reports on soluble Fas (sFas) which is an inhibitor of apoptosis during normal pregnancy. Therefore, ascertaining plasma sFas levels during pregnancy would be of interest. The subjects studied were 10 nonpregnant healthy women and 20 healthy pregnant women in the first and third trimester with singleton gestations. The plasma sFas was measured by sandwich enzyme-linked immunosorbent assay. The mean concentration of sFas was significantly decreased in normal pregnant women in the first trimester compared to age-matched control subjects, and it did not differ significantly between normal pregnant women in the third trimester and age-matched control subjects. From these results, we presume that the decreased plasma sFas plays an important role in maternal immunotolerance in the first trimester of pregnancy.