Reduction of reticulata neuronal activity by zolpidem and alpidem, two imidazopyridines with high affinity for type I benzodiazepine receptors

Zolpidem and alpidem, two imidazopyridines with high affinity for the type I benzodiazepine recognition site, have recently been proposed as preferential hypnotic (zolpidem) and anxiolytic (alpidem) drugs notable for the minor incidence of side-effects. To further characterize the molecular mechanism involved in the action of these drugs, we studied their effects in comparison with those of diazepam on the spontaneous electrical activity of substantia nigra pars reticulata (SNR) neurons. These cells have been shown to be extremely sensitive to various positive and negative modulators of GABAergic transmission. All three drugs consistently produced a dose-dependent (0.03-8.0 mg/kg i.v.) inhibition of the firing of SNR cells when administered as a single bolus. However, zolpidem was more potent and efficacious than diazepam or alpidem. The ID50s were 0.076, 0.492 and 0.821 mg/kg, respectively. When the drugs were injected in exponentially (ratio 2) increasing doses up to 8.0 mg/kg, the rank order for tachyphylaxis was zolpidem much greater than diazepam greater than alpidem. Since the effects of the drugs were abolished and prevented by a small dose (0.5 mg/kg i.v.) of flumazenil (Ro 15-1788), it is likely that the effects were mediated through activation of benzodiazepine receptors. The results indicate that the hypnotic, zolpidem, has a more potent inhibitory action on SNR cell activity than the anxiolytics, alpidem and diazepam.     

Alterations in Notch signaling in neoplastic lesions of the human cervix.

The development of cancer is a cellular process that reflects and is partly driven by alterations in cell determination. Mutations in various molecules responsible for cell determination have been identified as being oncogenic, but little is known about the involvement of normal cell fate-determining mechanisms in the oncogenic process. The Notch pathway defines an evolutionarily conserved, general cell interaction mechanism that controls fundamental aspects of cell determination during vertebrate and invertebrate development. We have explored the involvement of the human Notch pathway in human cervical tissues, which define a cellular environment where cell fate changes take place and where neoplastic conditions have been well characterized. Our evidence suggests that Notch expression is associated with cell populations that are undergoing cell fate changes and that Notch activity can be used to monitor cell fate abnormalities in cervical as well as other epithelial neoplasias.     

Intermediate filamentous proteins in adult granulosa cell tumors. An immunohistochemical study of 25 cases.

Adult granulosa cell tumors (AGCTs) are classified as sex cord-stromal tumors of the ovary. However, they may be confused with other primary ovarian neoplasms. Intermediate filaments, specifically vimentin and cytokeratins, have been identified in AGCTs by immunohistochemistry performed on frozen and formalin-fixed, paraffin-embedded tissue and two-dimensional electrophoresis. Recently, however, immunohistochemical demonstration of cytokeratin has been used as supporting evidence of epithelial rather than sex cord-stromal differentiation in ovarian neoplasia. To investigate further intermediate filamentous proteins in AGCTs, 25 such tumors were studied by immunohistochemistry in formalin-fixed, paraffin-embedded sections. Cytoplasmic staining was observed, frequently in a distinct punctate, paranuclear pattern, in 14 of 25, 14 of 25, and seven of 17 tumors using monoclonal antibodies AE1/AE3, CAM 5.2, and 35BH11, respectively, which share the ability to detect low molecular weight cytokeratins. Staining for cytokeratin was not seen in any of the 17 tumors studied using the antibody 34BE12. Twenty-three of 25 tumors showed strong positivity for vimentin, characteristically seen as globoid paranuclear staining. Nine of 25 tumors contained desmin, which was restricted to the intermixed spindle cell, cortical type stromal component of the tumors. These patterns of immunoreactivity for intermediate filaments, particularly cytokeratins, are different than in common epithelial tumors of the ovary and may be useful in the differential diagnosis of ovarian neoplasia. Moreover, the immunohistochemical detection of cytokeratins should not be used as a criterion for excluding AGCT from the differential diagnosis of an ovarian neoplasm.     

Epithelioid trophoblastic tumor: clinicopathological features with an emphasis on uterine cervical involvement.

We report on the clinical and histological features of five cases of epithelioid trophoblastic tumor, with an emphasis on its involvement of the uterine cervix. All five patients were of reproductive age (median age 38.4 years) and all, except one, presented with vaginal bleeding 3 to 18 years after the most recent pregnancy. One patient presented with amenorrhea. Elevation of serum human chorionic gonadotropin (hCG) was seen in four cases. Pathologically, the tumor involved endocervix in three cases and involved uterine corpus in another two. All five tumors were invasive, nodular lesions consisting of epithelioid intermediate trophoblastic cells that were mononuclear with abundant eosinophilic cytoplasm, along with zones of hyaline material and necrotic debris. In three cases of cervical involvement, the neoplastic cells focally replaced endocervical surface and glandular epithelium, simulating high-grade squamous intraepithelial lesions. Immunohistochemically, all five tumors displayed focal positivity for human placental lactogen and hCG. Positive nuclear staining of p63 was seen in all five cases. All patients received total hysterectomy and various regimes of adjuvant chemotherapy. Three patients survived the tumor with no recurrences or metastases with follow-up periods of 3, 7 and 16 years. One patient is currently alive with lung metastasis 1 month after the surgery. One patient died of tumor metastasis 8 months after the diagnosis. In summary, with its unusual ability to simulate an invasive squamous cell carcinoma and other epithelioid neoplasms, epithelioid trophoblastic tumor frequently poses a diagnostic challenge, especially when involving the uterine cervix. High index of suspicion and an awareness of elevation of serum chorionic gonadotropin are crucial in reaching a correct diagnosis.     

Semen analysis and seminal plasma biochemistry in two brothers with familial reciprocal translocation 46,XY,t(8;9)(p10;p10) transmitted by the father

Here we report familial balanced translocation (46,XY,t(8;9)(p10;p10) inherited by two brothers from the father. The first subject, 33 years old, was examined after 3 years of childless marriage. Semen analysis showed severe oligozoospermia, hypomotility and teratozoospermia. His brother, 29 years old, volunteered to join this study. He had not yet tried to start a family. Semen analysis showed dyspermia, but the condition was much less serious than his brother's. In both subjects, the secretory function of the epididymis and the genital tract accessory glands did not seem to be affected by this particular translocation. This case report highlights the importance of cytogenetic analysis in dealing with infertile patients suffering from severe dyspermia apparently sine causa. This is particularly the case when certain Assisted Reproductive Technology (ART) programs are recommended, where natural selection of the sperm no longer takes place (e.g. ICSI). The possible risk of an increase in fetal chromosomal abnormalities would suggest genetic counselling in all such situations.