Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington's disease.

Huntington's disease (HD) is a hereditary, progressive and ultimately fatal neurodegenerative disorder. Excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. Recently we developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF(+) cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. Here, the efficacy of NTF(+) cells was evaluated using the quinolinic acid (QA) rat model for excitotoxicity. We show that NTF(+) cells transplanted into rat brains after QA injection survive transplantation (19% after 6 weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF(+) cells exhibit improved behavior; namely, perform 80% fewer apomorphine induced rotations than PBS-treated QA-injected rats. Importantly, we found that MSCs derived from HD patients can be induced to become NTF(+) cells and exert efficacious effects similarly to NTF(+) cells derived from healthy donors. To our knowledge, this is the first study to take adult bone marrow derived mesenchymal stem cells from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI we demonstrate in vivo that PBS-treated QA-injected striatae exhibit increasing T(2) values over time in lesioned regions, whereas T(2) values decrease in equivalent regions of QA-injected rats treated with NTF(+) cells. We conclude that NTF cellular treatment could serve as a novel therapy for managing HD.

Intracerebral adult stem cells transplantation increases brain-derived neurotrophic factor levels and protects against phencyclidine-induced social deficit in mice.

Stem cell-based regenerative therapy is considered a promising cellular therapeutic approach for the patients with incurable brain diseases. Mesenchymal stem cells (MSCs) represent an attractive cell source for regenerative medicine strategies for the treatment of the diseased brain. Previous studies have shown that these cells improve behavioral deficits in animal models of neurological disorders such as Parkinson's and Huntington's diseases. In the current study, we examined the capability of intracerebral human MSCs transplantation (medial pre-frontal cortex) to prevent the social impairment displayed by mice after withdrawal from daily phencyclidine (PCP) administration (10 mg kg(-1) daily for 14 days). Our results show that MSCs transplantation significantly prevented the PCP-induced social deficit, as assessed by the social preference test. In contrast, the PCP-induced social impairment was not modified by daily clozapine treatment. Tissue analysis revealed that the human MSCs survived in the mouse brain throughout the course of the experiment (23 days). Significantly increased cortical brain-derived neurotrophic factor levels were observed in the MSCs-treated group as compared with sham-operated controls. Furthermore, western blot analysis revealed that the ratio of phosphorylated Akt to Akt was significantly elevated in the MSCs-treated mice compared with the sham controls. Our results demonstrate that intracerebral transplantation of MSCs is beneficial in attenuating the social deficits induced by sub-chronic PCP administration. We suggest a novel therapeutic approach for the treatment of schizophrenia-like negative symptoms in animal models of the disorder.

Premalignant lesions of the uterine cervix in a large cohort of Israeli Jewish women.

Israeli Jewish women are at low risk for cancer of the uterine cervix. In view of absent screening programs in Israel, there are only scarce data available with regard to results of PAP smears. The aim of this study was to assess the incidence of premalignant cervical lesions in the largest sample of PAP smears reported so far from Israel. We retrospectively analyzed the results of 297,849 PAP smears, which had been examined in a single laboratory, during 9 years (1991-1999). The incidence of low- and high-grade squamous intraepithelial was 0.69% and 0.29%, respectively. Our data indicate similar incidence rates for premalignant lesions in Jewish Israeli women as observed in Western countries, but no increase during the study period. In spite of relatively high incidence rates for premalignant lesions of the uterine cervix, the incidence rate for invasive cervical cancer remains conspicuously low. For unknown reason the conversion rate from premalignant cervical lesions to invasive cancer is lower in Israeli Jewish women than in European and North American women. We discuss possible reasons for this phenomenon and suggest that at this time mass screening for cervical cancer in Israel may probably not be justified.

[The management of HIV patients during surgery and in the delivery ward: anesthetic considerations].

To date a total of more than 50 million individuals worldwide have been infected with HIV and more than 20 million have died from the disease. Two thirds of the known carriers of HIV 36 million worldwide, live in Africa. In Israel, as of December 31, 2000, there are a total of 2,843 reported carriers and 165 persons alive with AIDS. On the basis of future projections of increasing incidence of HIV/AIDS in obstetric patients undergoing anesthesia and surgery, obstetricians and anesthesiologists should be aware of the disease and its impact on anesthetic techniques and possible interactions between anesthetic drugs and HIV therapeutic agents. Surgical staff members should be knowledgeable and updated concerning safety precautions during surgical and anesthetic procedures.

Laparoscopic surgery for extrauterine pregnancy in hemodynamically unstable patients.

STUDY OBJECTIVE: To assess the feasibility and safety of laparoscopic surgery in treatment of ectopic pregnancy in hemodynamically unstable women. DESIGN: Three-year observational study (Canadian Task Force classification II-2). SETTING: Tertiary university hospital. PATIENTS: One hundred one women with ectopic pregnancy who underwent laparoscopic surgery, 18 with substantial intraabdominal bleeding and with clinical signs and symptoms of hemodynamic instability. INTERVENTION: Laparoscopic surgery. MEASUREMENTS AND MAIN RESULTS: Compared with stable patients, hemodynamically unstable women had significantly more free blood in the abdomen (1244 +/- 590 vs 173 +/- 301 ml, p <0.0001), had significantly lower hemoglobin levels (7.8 +/- 1.4 vs 11.9 +/-1.4 g%, p <0.0001), and required significantly more frequent blood transfusions (83% vs 3.6%, p <0.0001). Similarly, their hemodynamic values such as pulse rate and blood pressures were worse. Among these women, 15 (83%) had a tubal pregnancy, 2 had an interstitial pregnancy, and 1 had a tubal abortion. Those with tubal pregnancy who were hemodynamically unstable underwent salpingectomy. Only one required conversion to laparotomy. No major intraoperative or postoperative complications occurred, and all women made a full and uneventful recovery. CONCLUSION: Improved anesthesia and cardiovascular monitoring, together with advanced laparoscopic surgical skills and experience, justifies operative laparoscopy for surgical treatment of ectopic pregnancy even in women with hemodynamic instability.

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.

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.

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.

Screening efficacy of the subcutaneous tissue width/femur length ratio for fetal macrosomia in the non-diabetic pregnancy.

BACKGROUND: Antenatal weight estimations have limited sensitivity and specificity for the detection of macrosomia. The objective of our study was to examine the screening efficacy of the subcutaneous tissue width/femur length ratio for the intrapartum detection of fetal macrosomia in a non-diabetic population at term. STUDY DESIGN: Intrapartum sonographic measurements were performed in 178 well-dated gravidas at 37-41 weeks' gestation with negative glucose tolerance screens. The biparietal diameter, femur length (FL), abdominal circumference and subcutaneous tissue width of the thigh (SCT) were determined. Subsequently, predictions for macrosomia (actual birth weights above the 90th centile) were made using varying cut-off points of the examined parameters or estimated fetal weights. RESULTS: Macrosomia occurred in 27 newborns (15.1%). The SCT/FL ratio was independent of gestational age (r = -0.017). Maternal age, gravidity, parity, gestational age and the ratio of male-to-female infants were similar in pregnancies resulting in appropriate-for-gestational-age and macrosomic infants (NS). There was no difference in the SCT/FL ratio between these groups (p = 0.067; 99% power to detect 2 standard deviation differences). Comparison of screening efficacy by the univariate z score for the area under receiver operating characteristic (ROC) curves (theta) revealed that the abdominal circumference had the best sensitivity-specificity trade-off (theta = 0.8843; p < 0.0001 for comparison with SCT/FL ROC curve), followed by weight estimations based on the Hadlock formula (theta = 0.8773; p < 0.0005), the Shepard formula (theta = 0.8606; p < 0.0001), subcutaneous tissue thickness alone (theta = 0.6872; p < 0.01) and the SCT/FL ratio (theta = 0.6303). CONCLUSIONS: We conclude that the SCT/FL ratio is a poor sonographic predictor of fetal macrosomia in the non-diabetic pregnancy and does not improve fetal weight estimations by conventional sonographic parameters.

Air embolism due to pulmonary barotrauma in a patient undergoing cesarean section.

Air embolism may occur following criminal abortion, vaginal douching, powder insufflation as treatment for vaginal infections, and orogenital sex. The patient reported in this work deteriorated following pulmonary barotrauma. Diagnosis was made 16 h after the appearance of neurological signs. She was transferred immediately to the hyperbaric unit. The speed and completeness of recovery are directly related to the prompt diagnosis and commencement of therapy. Failure is more likely related to delay.

Endocrine profile associated with estrogen and progesterone receptors in leiomyoma and normal myometrium.

In leiomyoma and normal myometrium estrogen receptors act independently at low or high levels of the normal serum steroid range in the menstrual cycle. It might be an inherent characteristic of leiomyomas, which results in their progressive growth in the absence of any abnormal stimulation. In the secretory phase of the menstrual cycle, serum progesterone suppresses estrogen receptor concentrations in leiomyoma. In the present study serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) showed direct as well as inverse correlations with estrogen and progesterone receptors in different phases of the menstrual cycle.

Is it safe to prescribe hormonal contraception and replacement therapy to patients with premalignant and malignant uterine cervices?

The levels of estrogen and progesterone receptors in normal and abnormal uterine cervices were determined. The study group consisted of 14 patients with cervical intraepithelial neoplasia (CIN III) and 7 patients with invasive carcinoma of the cervix (stage IB-IIA). The control group included 23 patients who underwent total abdominal hysterectomy for menorrhagia, leiomyoma, etc. The concentration of total estrogen receptors in premalignant and malignant cervices did not differ from the patients with benign conditions of the cervix. The concentration of progesterone receptors was significantly higher in the nonaffected cervices than in the patients with preinvasive and invasive carcinoma of the cervix (P less than 0.05). We have shown that estrogen receptor concentrations do not differ between women with normal and abnormal uterine cervices. Therefore, we feel that the contraceptive pill is not contraindicated in women who have been treated for CIN III. We also maintain that hormone replacement therapy should be given, when indicated, to women who have been castrated following surgery and/or radiotherapy for invasive carcinoma of the cervix.

Management of tubal pregnancy with methotrexate.

Ten women with tubal ectopic pregnancy were treated by the injection of methotrexate into the gestational sac under direct laparoscopic vision followed by a course of intramuscular therapy including folinic acid rescue. One course of treatment induced resolution of the extrauterine pregnancy in eight women. Complete resolution (beta-hCG less than 10 miu/ml) was achieved within 6-47 days (mean 14.5 days). Serum beta-hCG levels started to decline 3.4 days from the beginning of therapy. Length of hospital stay was 5-11 days (mean 6.4 days). Treatment failed in two patients. One woman had a laparoscopic tubal clip sterilization concomitantly with methotrexate treatment. Tubal patency was demonstrated in all the other seven women (100%) tested subsequently. There is a need to establish criteria for patient selection before methotrexate becomes a routine treatment for tubal pregnancy.

PIP: 10 women with tubal ectopic pregnancy were treated with injections of methotrexate into the gestational sac under direct laparoscopic vision followed by a course of intramuscular therapy including folinic acid rescue. 1 course of treatment induced resolution of the extrauterine pregnancy in 8 women. Complete resolution (beta-HCG 10 miu/m1) was achieved within 6-47 days (mean 14.5 days). Serum beta-HCG levels started to decline 3-4 days from the beginning of therapy. The length of hospital stay was 5-11 days (mean 6.4 days). Treatment failed in 2 patients. 1 woman had a laparoscopic tubal clip sterilization concomitantly with the methotrexate treatment. Tubal patency was demonstrated in the other 7 women (100%) tested subsequently. There is a need to establish criteria for patient selection before methotrexate becomes a routine treatment for tubal pregnancy.

Ethnic variation in estrogen and progesterone receptor concentration in leiomyoma and normal myometrium.

The total content of 17-beta estradiol and progesterone receptors in human uterine leiomyoma and normal myometrium in a Caucasian population was determined. Estrogen receptor concentrations in leiomyoma and myometrium were not significantly different (p = 0.1401). The concentration of progesterone receptors in leiomyoma was higher than in myometrium (p = 0.0303). Negroid and Caucasian ethnic groups did not differ with respect to estrogen (p = 0.7040) or progesterone (p = 0.8494) receptor concentrations in leiomyoma, but estrogen (p less than 0.005) and progesterone (p less than 0.005) receptor concentrations in normal myometrium were significantly higher in Caucasian than in negroid patients. Leiomyoma in negroid and Caucasian patients appears to be histologically similar, but the biochemical pathway of its pathogenesis seems to differ. Genetic predisposition probably acts as an initiation factor in the myometrium of both ethnic groups, then estrogen receptor levels in negroids and alterations in steroid metabolism in Caucasians promote the growth of leiomyoma.

Oestrogen and progesterone receptor concentrations in leiomyoma and normal myometrium.

The content of cytoplasmic 17 beta oestradiol and progesterone receptors in human uterine leiomyoma and normal myometrium in the Negroid population was determined. Eighteen women of reproductive age, at various stages of the menstrual cycle, were included in the study. The serum oestrogen and progesterone concentrations were also measured. This is the first report in the literature in which oestrogen and progesterone receptors in leiomyoma are significantly higher than in normal myometrium (P = 0.0002). The steroid dependence of the growth of leiomyomas may be related to the steroid receptor level. The presence of persistently high concentrations of oestrogen and progesterone receptors in leiomyoma should be helpful in the treatment of this benign tumour.

Combined chemotherapy and irradiation therapy after radical surgery for leiomyosarcoma of the vulva. A case report.

Radical surgery failed to remove a leiomyosarcoma of the vulva completely, and residual tumour was left. Chemotherapy did not inhibit further local growth or the occurrence of secondary lesions in the lung. Irradiation therapy of the pelvis, including the area of the tumour, then successfully inhibited any further local growth, as evidenced by a marked decrease in size and eventual disappearance of the mass; however, the patient succumbed to distant metastasis.

Vaginal tumors in pregnancy. Case report and review of the literature.

A young patient with a vaginal tumor in early pregnancy is presented. The difficulty in diagnosis and subsequent management is discussed. Vaginal tumors with special reference to vaginal leiomyoma are reviewed and a differential diagnosis is presented.

Fine-needle aspiration of a ureteric stricture used to diagnose persistent cervical carcinoma. A case report.

Fine-needle aspiration of a ureteric obstruction diagnosed persistent disease in a 65-year-old woman who 2 years previously had had a Wertheim hysterectomy and postoperative irradiation for a stage lb cervical carcinoma.