Yoshitsugu Watanabe

Efficacy of a low-dose leuprolide acetate depot in the treatment of uterine leiomyomata in Japanese women*

OBJECTIVE To compare the efficacy of two different doses, 1.88 mg and 3.75 mg, of a monthly depot injection of a gonadotropin-releasing hormone agonist (GnRH-a) in the treatment of uterine leiomyomata. DESIGN A prospective randomized study. SETTING Hospital department of gynecology and obstetrics. PATIENTS Forty-one premenopausal Japanese women, 25 to 53 years of age, with uterine leiomyomata. INTERVENTIONS Depot type of GnRH-a, leuprolide acetate (LA) 1.88 mg or 3.75 mg was administered subcutaneously every 4 weeks for 24 weeks. MAIN OUTCOME MEASURES Efficacy of treatment was assessed in terms of uterine volume, serum levels of estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and adverse symptoms during treatment. RESULTS In both groups, a significant reduction in uterine volume, 52% in 1.88 mg group and 47% in 3.75 mg group, was obtained at week 24, with near maximal reduction (41%, 45%) apparent by 12 weeks. No significant difference was observed between the groups in percent uterine volume reduction at each treatment week. Both groups showed significant and equal suppression of serum levels of E2, LH, and FSH. In addition, the incidence of adverse symptoms was not significantly different between the two groups. CONCLUSIONS Monthly injection of 1.88 mg or 3.75 mg LA depot has equivalent treatment efficacy in reducing uterine volume. Twelve weeks of treatment is enough to obtain near maximal reduction.

Successful pregnancy after the noninvasive management of uterine arteriovenous malformation

A 22-year-old woman, gravida 2, para 0, showed massive vaginal bleeding and was admitted to our institution. She had persistent vaginal bleeding for 4 weeks after a secondary artificial abortion at 14 weeks’ gestation. When she was presented to our hospital, evaluation included negative urine hCG, and hemoglobin of 10.7 g/dl. Vaginal examination showed no uterine enlargement and no adnexal mass, but vaginal bleeding and some bloody coagula was recognized. Transvaginal ultrasound showed multiple tubular anechoic spaces without mass effect in the myometrium from the left anterior wall to the fundus. As dysfunction of uterine contraction due to retained products of conception, or trauma following artificial abortion was suspected, she was administered 0.2 mg of intramuscular methylergometrine maleate and 0.5 mg/day of oral methylergometrine maleate for 5 days. Vaginal bleeding decreased soon after the intramuscular injection, and she was discharged the next day with no vaginal bleeding. One week later, she was admitted again to our hospital with massive vaginal bleeding. Her hemoglobin was 6.9 g/dl. She was given only 0.5 mg/day of methylergometrine maleate orally for 7 days, which stopped the vaginal bleeding immediately. Her hemoglobin value subsequently rose by oral administration of iron alone. Percutaneous transfemoral angiography showed a 3¿2 cm hypervascular mass which looked like nidus in the left uterine wall (Fig. 1), and Color Doppler ultrasound revealed a mosaic pattern in the same area of the uterine wall, which was compatible with uterine AVM. Approximately one month later, angiography was performed again for embolization, but the procedure was not carried out because of an obvious reduction in the size of the lesion. Color Doppler ultrasonography also demonstrated the decreased size of the mosaic pattern area. After discharge, follow-up Color Doppler examinations showed no signs of abnormal findings, nor any abnormal bleeding. She conceived 8 months after her previous pregnancy. Her pregnancy progressed quite normally,

Impairment of T Cell-Mediated Immunity to Listeria monocytogenes in Pregnant Mice

In order to study pregnancy‐induced changes in cell‐mediated immunity to Listeria monocytogenes, acquired resistance and T cell functions in pregnant mice were compared with those in nonpregnant mice after immunization with viable listerial cells. Impaired generation of acquired resistance was evident in pregnant mice from the impaired elimination of bacteria and poor survival after secondary challenge. Delayed footpad reactivity to listerial antigen was also lower in the pregnant mice. When immune spleen cells were examined for their ability to produce macrophage activating factor in vitro, culture supernatants from pregnant‐mouse spleen cells with listerial antigen showed far less ability to render macrophages cytostatic for P815 mastocytoma cells. To elucidate further the impairment of listeria‐immune T cell generation in pregnant mice, a local transfer experiment was carried out. When a given number of immune spleen cells was transferred locally into the footpads of naive mice, both delayed footpad reaction and local protection were much lower in the pregnant mice. This local transferability of the reactions was abrogated after treatment of cells with anti‐Thy 1 antibody plus complement. These findings indicate that pregnancy impairs the generation of specific T cells capable of contributing to acquired resistance to L. monocytogenes. Possible mechanisms for this impairment and the relationship to macrophage functions are discussed.

Elevation of the phospholipase A2 activity in peritoneal fluid cells from women with endometriosis

OBJECTIVE To assess the prostaglandin (PG) production on peritoneal fluid (PF) cells, phospholipase A2 (PLA2) activity of those cells in women with endometriosis was measured and compared with that of women without endometriosis. DESIGN Prospective clinical controlled study. PATIENTS Women who underwent laparoscopy and were found either to have endometriosis (n = 15) or not (n = 9) were included in this study. Mononuclear cells obtained from the patients at laparoscopy were immediately separated by a Ficoll-Paque technique, lysed by nitrogen cavitation, and stored at -80 degrees C. INTERVENTIONS Phospholipase A2 activity was measured by Dole assay using 1-palmitoyl-2-[1-14C] palmitoyl phosphatidyl choline and assessed on a protein basis and a cell number basis. RESULTS There were at least four measurable kinds of PLA2 activity detected in the cells: two calcium-dependent pH optima 7.0 and 9.0 activities and two calcium-independent pH optima 7.5 and 8.5 activities. A calcium-dependent and pH optima 9.0 activity was the highest, and it was significantly higher in women with endometriosis when compared with those who did not have endometriosis. CONCLUSION These results indicate that the increase in the PGs in PF with endometriosis may be produced by PF cells in which PLA2 activity is elevated.

A significant role of the macrophage accumulation induced by MCF in the protection of mice against Listeria monocytogenes in vivo

Analysis was done on macrophage chemotactic factor (MCF) produced in the culture supernatant of spleen cells from mice immunized with Listeria monocytogenes. MCF was produced by Thy-1+, Lyt-1+ lymphocytes. MCF activity was resistant against pH 2 treatment and heating at 56 degrees C for 30 min, but was abolished by digestion with trypsin. G-100 gel filtration chromatography revealed that the approximate molecular weight of MCF was 15,000. MCF-rich fraction obtained by gel filtration chromatography showed neither MAF activity nor interferon activity. MCF activity in MCF-rich fraction was not affected by treatment with anti-rIFN-gamma antibody. An injection of MCF-rich fraction into the peritoneal cavity of mice induced a significant degree of accumulation of polymorphonuclear leukocytes (PMN) in a very short time after injection and macrophages thereafter. Resistance against listerial infection was augmented at the site where macrophage accumulation was provoked by the injection with MCF-rich fraction. It was shown that MCF plays an important role by itself in the protection against listerial infection by the accelerated accumulation of macrophages.

In vitro Primary Induction of T Cells Mediating Delayed Footpad Reaction and Acquired Cellular Resistance to Listeria monocytogenes

We established an in vitro system generating L. monocytogenes-specific T cells primarily from unprimed spleen cells of mice. Normal spleen cells were cultured for 5 days in the presence of L. monocytogenes in vitro. Viable cells were harvested and assessed for their capacity to confer acquired cellular resistance (ACR) and delayed footpad reaction (DFR) upon local passive transfer to naive syngeneic recipient mice. When normal spleen cells were stimulated with viable L. monocytogenes, the viable cells that were recovered after 5 days of culture conferred a high level of ACR and DFR. Negative selection revealed that the effector cells obtained in primary in vitro culture were Thy 1+, L3T4+, Lyt2- cells. T cells mediating ACR could not be generated in the culture of normal spleen cells with heat-killed bacteria; however, cells mediating only DFR were generated in the presence of a large number of killed L. monocytogenes. The expression of DFR and ACR by T cells generated in this primary culture system was Listeria-specific; reactions were not observed against unrelated bacterial antigens including S. typhimurium, S. aureus, E. coli and PPD. FACS analysis of the cells in culture showed that L3T4+ and Lyt2- T cells were being enriched during culture. The primary generation of antigen-specific T cells in vitro was also possible with spleen cells from NTx mice but not with cells from nude mice, suggesting the presence of Listeria-specific precursors in NTx mice.

Effects of two different doses of leuprolide acetate depot on uterine cavity area in patients with uterine leiomyomata.

OBJECTIVE To compare the effects of two different doses of a monthly depot injection of a GnRH agonist (GnRH-a) on uterine cavity area in patients with uterine leiomyomata. DESIGN Prospective, randomized study. SETTING Hospital department of obstetrics and gynecology. PATIENTS Thirty-six premenopausal women, 25 to 52 years of age, with uterine leiomyomata. INTERVENTION Leuprolide acetate (LA) depot, 1.88 or 3.75 mg, was administered SC every 4 weeks for 24 weeks. MAIN OUTCOME MEASURE Uterine cavity area before and after treatment was assessed by hysterosalpingography. RESULTS The 1.88- and 3.75-mg LA depots significantly reduced uterine cavity area by 40.8% and 40.2%, respectively. No significant difference was observed between the two groups. CONCLUSION Monthly injection of 1.88 or 3.75 mg LA depots appears to reduce uterine cavity area to a similar extent in patients with uterine leiomyomata.

Generation of Listeria monocytogenes-specific T cells mediating delayed footpad reaction and protection in neonatally thymectomized mice but not in nude mice

Neonatally thymectomized (NTx) mice, sham-operated control mice and congenitally athymic nude mice were immunized with viable Listeria monocytogenes and their spleen cells examined for the capacity to transfer both delayed footbad reaction and protection against challenge at the site of local transfer. Cells from immune NTx mice conferred significant degrees of delayed footpad reaction and protection comparable to sham mice, while cells from immune nude (nu/nu) mice did not. This abilty was completely eliminated by the treatment of cells with anti-Thy1, anti-Lytl or anti-L3T4 antibody plus complement but not with anti-Lyt2 antibody plus complement. These results indicated that NTx mice can normally mount the immunity to L. monocytogenes by generating Lyt1+2−, L3T4+ T cells. Immune competence of NTx mice and thymus dependency of various immune responses are discussed.

Allograft rejection and immune responses against allogeneic antigens in neonatally thymectomized mice

Skin allograft survival and immune responses against allogeneic antigens homologous to skin grafts were observed in BALB/c Cr Slc (BALB)3 mice (H-2d) thymectomized at 1 day after birth and grafted with sin from major histocompatibility complex (MHC)-incompatible, fully allogeneic C3H/HeN (C3H) (H-2k) or MHC-compatible allogeneic DBA/2 Cr Slc (DBA) mice (H-2d), at 14 weeks of age. In neonatally thymectomized (NTx) BALB mice, survival of C3H skin grafts was not prolonged at all, but survival of DBA skin grafts was prolonged significantly, although the survival periods of DBA skin grafts were very different among individual recipients. In NTx recipients grafted with C3H skin, delayed foot-pad reaction (DFR) was not reduced, but cytotoxic lymphocyte (CTL) activity and cytotoxic antibody (CTAb) production were appreciably depressed. CTL and CTAb were reduced profoundly and consistently in all NTz mice grafted with DBA skin, while DF was reduced to various degrees in each. The degrees of depression of DFR in these NTx mice correlated well with the prolongation of DBA skin survival, although the sample number was small. The rejection of skin allografts appears to be attributable largely to a T cell subset, the function of which can be expressed as DFR. Thymus dependency in the ontogenic development is low as compared with other T cell subsets.

Laparoscopic treatment of acute ovarian incarceration into the pelvic peritoneal sac.

Pelvic pain is a common symptom in women of reproductive age. Acute pelvic pain with rapid onset demands prompt diagnosis and treatment. We report the case of a patient with ovarian incarceration of acute onset. To our knowledge, this is the first report of ovarian incarceration into the pelvic peritoneal sac in a woman of reproductive age. In the present case, laparoscopy was useful in establishing the cause of pelvic pain. The patient reported severe lower right quadrant abdominal pain of sudden onset. At laparoscopic examination, the right fallopian tube was normal; however, the right ovary was not initially visible at the normal site. After the swollen right ovarian ligament was pulled aside using nontraumatic laparoscopic forceps, we were able to detect incarceration of the right ovary into the peritoneal sac in the medial to right uterosacral ligament. This case is unique because of ovarian incarceration into the peritoneal fenestration. We believe this condition was congenital because there was no other cause such as previous surgery, severe endometriosis, or pelvic inflammatory diseases.