Methotrexate versus hyperosomolar glucose in the treatment of extrauterine pregnancy.

The aim of this prospective, randomized, double blind study was to compare the efficacy of methotrexate and hyperosmolar glucose injected directly into the extra-uterine gestational sac under laparoscopic vision. The study included twenty women with ectopic pregnancy. Inclusion criteria were intact tubal pregnancy, not exceeding 4 cm in diameter, rising or plateauing betahCG levels, and no evidence of intra-abdominal bleeding. The patients were treated by laparoscopically guided injection of 3 mL fluid into the area containing the tubal pregnancy. The fluid contained either 25 mg methotrexate (n=9) or 50% glucose (n=9). Daily decrease in betahCG levels was faster in patients treated by methotrexate (median 8.7%) than in those treated by hyperosmolar glucose (median 4.8%), p=0.17. The study was discontinued due to a higher failure rate in the group treated by hyperosmolar glucose. In conclusion, local injection of methotrexate is superior to hyperosmolar glucose. It can be used as an alternative to salpingostomy or salpingotomy whenever laparoscopy is performed for the diagnosis and treatment of extra-uterine pregnancy.

The role of tamoxifen in the treatment of symptomatic uterine leiomyomata -- a pilot study.

OBJECTIVES: To determine the efficacy of tamoxifen in patients with leiomyomata complaining of abdominal pains and vaginal bleeding. STUDY DESIGN: Prospective, randomized, double blind study. A total of 10 patients received for 6 months 20 mg tamoxifen daily, and 10 women received placebo. All patients underwent serial pelvic and ultrasound exams and endometrial sampling was performed prior to initiation of treatment. After 5 years, the patients were interviewed again. RESULTS: Uterine size was not affected by the use of tamoxifen. Patients reported a blood loss decrease of 40--50% at the end of the study (P=0.0001). In the control group a slight increase in blood loss was reported. Hemoglobin levels remained unchanged in both groups. In the study group patients reported after 4 months of treatment a substantial decrease in the intensity of pain (P=0.018). Seven patients in the study group and one patient in the control group developed ovarian cysts. CONCLUSIONS: Treatment with tamoxifen added only marginal benefit while causing unacceptable side effects. Tamoxifen does not seem to be a useful adjunct in the treatment of symptomatic uterine leiomyomata and its use for this indication should be discouraged.

Fertility outcome following combined methotrexate treatment of unruptured extrauterine pregnancy.

OBJECTIVE: To assess the effectiveness of systemic treatment with methotrexate in combination with local injection for unruptured tubal pregnancy, and to evaluate reproductive function following treatment. DESIGN: Prospective, open clinical study. SETTING: University clinic. POPULATION: Sixty-seven women with unruptured tubal pregnancy. METHODS: Systemic methotrexate (intramuscular methotrexate 0.5 mg/kg for up to five days) in combination with local application of 12.5 mg methotrexate via laparoscopy. MAIN OUTCOME MEASURES: The subsequent surgical intervention required and future fertility. RESULTS: In 89.6% of women no further surgical intervention was required and 47 women (81%) experienced subsequently an intrauterine pregnancy. In 39 of 40 women who underwent hysterosalpingography following treatment, patency of the affected tube was observed. CONCLUSIONS: Combined local and systemic methotrexate treatment for unruptured tubal pregnancy seems to be more effective than each therapeutic modality alone.

Illness and treatment perceptions of Ethiopian immigrants and their doctors in Israel.

OBJECTIVES: Patient-provider misunderstandings arising from disparate medical and cultural concepts can impede health care among immigrant populations. This study assessed the extent of disagreement and identified the salient problems of communication between Israeli doctors and Ethiopian immigrant patients. METHODS: Semistructured interviews were conducted with 59 Ethiopian immigrants. Self-reports of health status and effectiveness of treatment were compared with evaluations by the primary care physician and supplemented by qualitative data from descriptions of illness, observations of medical visits, informant interviews, and participant observations conducted by the anthropologist. RESULTS: Health status and effectiveness of treatment were rated significantly higher by the doctor than by the patients. Low doctor-patient agreement occurred mainly for illnesses with stress-related or culture-specific associations. Qualitative data suggested that more long-term immigrants may alter their expectations of treatment but continue to experience symptoms that are culturally, but not biomedically, meaningful. CONCLUSIONS: Misunderstandings between immigrant patients and their doctors emerge from the biomedical system's limitations in addressing stress-related illnesses and from culture-based discrepancies in concepts of illness and healing. Including trained translators in medical teams can reduce medical misunderstandings and increase patient satisfaction among immigrant populations.

Exaggerated placental site erroneously diagnosed as non-metastatic trophoblastic disease. A case report.

BACKGROUND: Exaggerated placental site (EPS) is classified as a non-neoplastic trophoblastic lesion, and histologically it consists of endometrial and myometrial invasion of intermediate trophoblasts and syncytiotrophoblasts and it differs morphologically from placental site trophoblastic tumors and placental nodules. The purpose of this report is to increase physicians' awareness of this lesion. CASE: A 48-year-old woman with post-molar rising betahCG titers and a clinical diagnosis of non-metastatic trophoblastic disease underwent hysterectomy. Final histopathology showed exaggerated placental site--a lesion often unfamiliar to clinicians. CONCLUSION: It is suggested that operative hysteroscopy may be useful in the diagnosis and management of EPS.

An unusually high prevalence of asthma in Ethiopian immigrants to Israel.

BACKGROUND AND OBJECTIVES: The past 20 years have seen a large immigration of Ethiopian Jews to Israel, primarily in 2 airlifts, one in 1984-1985 and one in 1991. Infectious and parasitic diseases were the dominant health problems in the early years. Recently, we noticed changing health patterns in this population, particularly an increase in clinic visits for asthma, which contrasted with asthma rates of 2.5% reported among Ethiopian Jews at the time of immigration to Israel. This study evaluated the prevalence and characteristics of asthma in a population of Jews of Ethiopian origin who had been in Israel for 8-17 years. METHODS: We audited 302 files of adult patients of Ethiopian origin and 604 files of age- and gender-matched patients of non-Ethiopian origin. Each file was reviewed by 2 physicians. Asthma was defined by published clinical criteria as found in the patient file. Data on allergies and eosinophilia were collected as well. RESULTS: The average age of the 2 groups of asthmatics was 44.1 +/- 16.2 and 42.4 +/- 20.7 years, respectively. The prevalence of asthma in the patients of Ethiopian origin was 51/302 (17%), compared with 35/604 (5.8%) in the control group. Thirty-three percent of the Ethiopian asthmatics and 37% of the control group suffered from various allergic diseases. Among the patients of Ethiopian origin, the prevalence of eosinophilia was 44%, with no significant difference between asthmatics and non-asthmatic patients (49% versus 43%). Eosinophilia was found in 8.4% of the control group. Asthma was more prevalent among patients with eosinophilia (22%) than without eosinophilia (6.4%). CONCLUSIONS: Asthma is 3 times as prevalent in adults of Ethiopian origin, compared with the general population in our clinics, and markedly increased above the rate reported for newly immigrated Ethiopian Jews. We conclude that the move from the rural hills of Ethiopia to the more urban and industrialized setting of Israel has resulted in an increased prevalence of asthma in this population, but the specific cause is uncertain.

Pregnancy and delivery in a group of Israeli teenagers. A case-controlled study.

OBJECTIVE: To assess characteristics of an Israeli group of nulliparous teenagers and to compare selected variables of their course and outcome of pregnancy with controls. METHODS: Hospital records of 46 consecutive nulliparous teenagers younger than 17.5 years who delivered during a ten-year period and 84 matched adult controls were reviewed. RESULTS: The majority of the teenagers were older than 15 years, married and most were born in Israel or in the former Soviet Union with no obvious socio-economical deprivation. The rate of prenatal follow-up, hypertensive disorders, type of analgesia during labor and mode of delivery were similar in teenagers and controls. A statistically non-significant higher rate of anemia (hemoglobin, 10 gr%), preterm delivery and low birth weight were observed in teenagers. Only the rate of induction of labor and the rate of a hemoglobin level higher than 12 gr% were significantly lower in teenagers. CONCLUSIONS: The course and outcome of pregnancy were in most respects similar in this group of nulliparous teenagers and matched adult controls.

Ovarian carcinoma associated thrombocytosis. Correlation with prognostic factors and with survival.

OBJECTIVE: To assess the prevalence of thrombocytosis (platelets > or = 400,000 microliters) in ovarian cancer of epithelial origin as compared to benign controls consisting of benign ovarian cysts of epithelial origin and to correlate it with prognostic factors of ovarian cancer and survival. METHOD: Hospital records of 82 consecutive patients with ovarian carcinoma, 12 with low malignant potential tumors and 70 with invasive carcinoma, and of 32 patients with benign cysts of epithelial origin were reviewed. The clinical data and preoperative platelet counts were recorded. RESULTS: The prevalence of thrombocytosis in invasive ovarian carcinoma of epithelial origin was significantly higher than in benign controls (24.3% vs 2.9%; p = 0.006). No statistically significant correlation was found between thrombocytosis with age, grade and residual disease. A statistically non-significant excess of thrombocytosis was found among patients with advanced disease, but the survival of patients with thrombocytosis was significantly less favorable (p = 0.04). CONCLUSIONS: Thrombocytosis is significantly more prevalent in ovarian cancer patients than in benign controls and has a statistically significant correlation with poorer survival. The prevalence of thrombocytosis in ovarian carcinoma and its significance in various studies is inconsistent and should be elucidated in large prospective studies.

Incubation with sperm enhances in vitro maturation of the oocyte from the germinal vesicle to the M2 stage.

OBJECTIVE: To evaluate the effect of sperm in the culture medium on the rate of oocyte maturation in vitro from the germinal vesicle to the M2 stage. DESIGN: Prospective randomized controlled study. SETTING: The IVF Unit, Wolfson Medical Center, Holon, Israel. PATIENT(S): All women in whom oocytes were retrieved at the germinal vesicle stage between December 1995 and March 1996. INTERVENTION(S): Oocytes retrieved at the germinal vesicle stage were divided prospectively and randomly into four groups of incubation conditions: group 1, intact germinal vesicle with cumulus; group 2, intact germinal vesicle with sperm cells in the culture medium; group 3, stripped germinal vesicle; and group 4, stripped germinal vesicle with sperm cells. Oocytes were observed 24 hours after retrieval, and the stage of maturation was recorded. Oocytes that reached the M2 stage underwent the intracytoplasmic injection procedure, and the fertilization rate in each group was recorded at 48 hours. MAIN OUTCOME MEASURE(S): Maturation rate from the germinal vesicle to M2 stage and fertilization rate. RESULT(S): Each group contained 20 germinal vesicle oocytes. In groups 1 and 2, 2 (10%) and 9 (45%) oocytes, respectively, reached the M2 stage at 24 hours; at 48 hours, 1 (5%) and 8 (40%) embryos developed, respectively. The results in group 2 were significantly higher than in group 1. In groups 3 and 4, 6 (30%) and 16 (80%) oocytes, respectively, reached the M2 stage at 24 hours; at 48 hours, 5 (25%) and 14 (70%) embryos developed, respectively. Results in group 4 were significantly higher than those in groups 1, 2, and 3. CONCLUSION(S): Both methods of oocyte activation (i.e., addition of sperm to the culture medium or removal of the cumulus) enhance oocyte maturation in vitro, but the sperm-incubation method has a more pronounced effect. A combination of both methods leads to an exceptionally high rate of oocyte maturation, followed by a high fertilization rate.

[Gynecologic problems of the lower genital tract in children and young adolescents].

Hospital records of 46 girls under the age of 17 years, hospitalized for lower genital tract problems in 1986-95 were reviewed. The most common conditions were results of unintentional injuries (43.5%), imperforate hymen (28.2%) and infections (19.6%). The median age for unintentional injuries was significantly lower than for other conditions (7.0 vs 11.4; p < 0.001). Most injuries were external and occurred during outdoor activities. Mean volume of estimated bloody fluid drained in those with imperforate hymen was greater when the diagnosis was made after the age of 12 (783 vs 433; not significant). It has been suggested that hematocolpos and hematometra should be prevented, but the possible unfavorable sequelae have not been documented. The relative order of frequency of the various diagnostic groupings and the diagnoses of labial adhesions and imperforate hymen are specific for the age of the study group.

Normal and atypical butyrylcholinesterases in placental development, function, and malfunction.

1. In utero exposure to poisons and drugs (e.g., anticholinesterases, cocaine) is frequently associated with spontaneous absorption and placental malfunction. The major protein interacting with these compounds is butyrylcholinesterase (BuChE), which attenuates the effects of such xenobiotics by their hydrolysis or sequestration. Therefore, we studied BuChE expression during placental development. 2. RT-PCR revealed both BuChEmRNA and acetylcholinesterase (AChE) mRNA throughout gestation. However, cytochemical staining detected primarily BuChE activity in first-trimester placenta but AChE activity in term placenta. 3. As the atypical variant of BuChE has a narrower specificity for substrates and inhibitors than the normal enzyme, we investigated its interactions with alpha-solanine and cocaine, and sought a correlation between the occurrence of this variant and placental malfunction. 4. Atypical BuChE of serum or recombinant origin presented > 10-fold weaker affinities than normal BuChE for cocaine and alpha-solanine. However, BuChE in the serum of the heterozygote and a homozygous normal were similar in their drug affinities. Therefore, heterozygous serum or placenta can protect the fetus from drug or poison exposure, unlike homozygous atypical serum or placenta. 5. Genotype analyses revealed that heterozygous carriers of atypical BuChE were threefold less frequent among 49 patients with placental malfunction than among 76 controls of the entire Israeli population. These observations exclude heterozygote carriers of atypical BuChE from being at high risk for placental malfunction under exposure to anticholinesterases.

Cervical koilocytosis in hysterectomy specimens of Israeli residents and new immigrants.

There is an impression that the prevalence of cervical squamous cell carcinoma (SCC) among new immigrants from the former Soviet Union, is higher than among Israeli residents. Etiologically, SCC is associated with human papilloma virus infection (HPV). The purpose of the present study was to assess the prevalence of cervical HPV infection in new immigrants from the Soviet Union and in Israeli residents as indicated by the presence of koilocytosis in hysterectomy specimens. The study group consisted of 304 women (60 new immigrants and 244 Israeli residents who underwent hysterectomy for benign reasons). The original histological slides of the cervix were reviewed with special attention to the presence of koilocytosis. The two study subgroups differed, as expected, with regard to some characteristics, but koilocytosis was not present in any of the cervical specimens of new immigrants nor of residents. Although the study subgroups may be too small or selective, our findings do not support a possible higher HPV infection rate among new immigrants, yet may indicate a low reservoir of HPV in new immigrants and residents, in line with the low SCC incidence in Israeli women.

Overlapping drug interaction sites of human butyrylcholinesterase dissected by site-directed mutagenesis.

Butyrylcholinesterase [BuChE (acylcholine acyl hydrolase); EC 3.1.1.8] limits the access of drugs, including tacrine, to other proteins. The "atypical" BuChE variant, in which Asp70 at the rim of the active site gorge is substituted by glycine, displayed a more drastically weakened interaction with tacrine than with cocaine, dibucaine, succinylcholine, BW284c51 [1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide], or alpha-solanine. To delineate the protein domains that are responsible for this phenomenon, we mutated residues within the rim of the active site gorge, the region parallel to the peripheral site in the homologous enzyme acetylcholinesterase [AChE (acetylcholine acetyl hydrolase); EC 3.1.1.7], the oxyanion hole, and the choline-binding site. When expressed in microinjected Xenopus laevis oocytes, all mutant DNAs yielded comparable amounts of immunoreactive protein products. Most mutants retained catalytic activity close to that of wild-type BuChE and were capable of binding ligands. However, certain modifications in and around the oxyanion hole caused a dramatic loss in activity. The affinities for tacrine were reduced more dramatically than for all other ligands, including cocaine, in both oxyanion hole and choline-binding site mutants. Modified ligand affinities further demonstrated a peripheral site in residues homologous with those of AChE. BuChE mutations that prevented tacrine interactions also hampered its ability to bind other drugs and inhibitors, which suggests a partial overlap of the binding sites. This predicts that in addition to their genetic predisposition to adverse responses to tacrine, homozygous carriers of "atypical" BuChE will be overly sensitive to additional anticholinesterases and especially so when exposed to several anticholinesterases in combination.

O2 consumption in the in-vitro fetal side human placenta.

The relative dependence of placental O2 consumption (MO2) on O2 supply (SupO2) parameters, and the fraction of aerobic O2 utilization, was studied by in-vitro perfusion of the fetal side of term human placental lobes. Placental MO2 was a function of the combined effect of SupO2 parameters (PO2, perfusate flow rate, perfusate effective O2 solubility) and not of each separately. At SupO2 greater than 800 microliters/(min.lobe), MO2 saturated at 260 microliters/(min.lobe). No accumulation of O2 debt could be detected even after 2 h anoxia. Adding CN- or CO to perfusate did not abolish MO2, and a residual MO2 of 31-37% of control MO2 was measured. In its MO2, the placenta is a typical conformer tissue. This conformity enables conservation of O2 transfer to the embryo even when placental SupO2 is radically reduced. Only about 60-70% of placental MO2 is utilized in the aerobic respiratory pathway, while about 30-40% of the oxygen is used in other pathways.

Chorionic villus sampling safety. Report of World Health Organization/EURO meeting in association with the Seventh International Conference on Early Prenatal Diagnosis of Genetic Diseases, Tel-Aviv, Israel, May 21, 1994.

Accumulated experience of 138,996 cases of chorionic villus sampling shows that chorionic villus sampling is a safe procedure with an associated fetal loss rate comparable to that of amniocentesis. The chorionic villus sampling registry shows that chorionic villus sampling is currently performed primarily between 9 and 12 weeks' gestation and carried no increased risk of limb reduction defects: the overall incidence of limb reduction defects after chorionic villus sampling is 5.2 to 5.7 per 10,000, compared with 4.8 to 5.97 per 10,000 in the general population. Analysis of the pattern distribution of limb defects after chorionic villus sampling revealed no difference from the pattern in the general population. This applies specifically to transverse limb defects. Together with the overall incidence of limb reduction defects, these data provide no evidence for any risk for congenital malformation determined by chorionic villus sampling. Because chorionic villus sampling is currently performed generally after 8 completed weeks of pregnancy, few data are available for analysis of complications related to earlier procedures. Avoiding early chorionic villus sampling also excludes sampling in cases of early fetal death, which can be diagnosed reliably by ultrasonography at 9 weeks of pregnancy.

Autologous umbilical cord blood transfusion.

The purpose of this study was to examine some aspects of umbilical cord blood collection for autologous transfusion in premature infants. All 120 microbacterial cultures (aerobic and anaerobic) of cord blood samples as well as 30 cultures of mycoplasma were treated. Cord prothrombin fragment (F 1 + 2) concentrations were quantified at one and 10 minutes after clamping of the cord. F 1 + 2 concentrations assessed on 25 newborn infants were similar and no linear association with time of clamping could be drawn. This means that cord blood thrombosis is not activated for at least 10 minutes following clamping of the cord. As far as is known, the first newborn infant to benefit from this method of transfusion is reported here. The premature infant received two portions of autologous blood (on days 5 and 7). No untoward effects were noted. Blood, collected from the umbilical cord, is a safe source for autotransfusion, provided that bacteriological testing has been carried out.

Genetic predisposition to adverse consequences of anti-cholinesterases in 'atypical' BCHE carriers.

Normal butyrylcholinesterase (BuChE), but not several of its common genetic variants, serves as a scavenger for certain anti-cholinesterases (anti-ChEs). Consideration of this phenomenon becomes urgent in view of the large-scale prophylactic use of the anti-ChE, pyridostigmine, during the 1991 Persian Gulf War, in anticipation of nerve gas attack and of the anti-ChE, tacrine, for improving residual cholinergic neurotransmission in Alzheimer's disease patients. Adverse symptoms were reported for subjects in both groups, but have not been attributed to specific causes. Here, we report on an Israeli soldier, homozygous for 'atypical' BuChE, who suffered severe symptoms following pyridostigmine prophylaxis during the Persian Gulf War. His serum BuChE and recombinant 'atypical' BuChE were far less sensitive than normal BuChE to inhibition by pyridostigmine and several other carbamate anti-ChEs. Moreover, atypical BuChE demonstrated 1/200th the affinity for tacrine of normal BuChE or the related enzyme acetylcholinesterase (AChE). Genetic differences among BuChE variants may thus explain at least some of the adverse responses to anti-ChE therapies.