Incidence and potentiation of external and internal fetal anomalies resulting from chlordiazepoxide and amitriptyline alone and in combination

The teratogenic potential of a combination of chlordiazepoxide (Cdz) and amitriptyline (Amt) was examined with regard to both internal and external anomalies. Timed pregnant golden hamsters were given a single intraperitoneal injection on day 8 of gestation of one of the following: chlordiazepoxide hydrochloride (28.5 mg/kg), amitriptyline hydrochloride (70.3 mg/kg), Cdz-Amt combination (28.5 mg/kg Cdz + 70.3 mg/kg Amt, in order to retain the 1:2.5 dose ratio utilized in a clinically-used preparation of these agents), or saline vehicle (control). Fetuses were recovered on gestation day 15 following maternal sacrifice. Cranial malformations were analyzed in Bouin's-fixed fetuses by making 1-mm coronal sections through each head, whereas visceral anomalies were examined following general dissection of each body. Amt alone produced a significant (P less than 0.05) incidence of bent tail and encephalocele, whereas Cdz significantly (P less than 0.05) altered the male:female ratio of surviving fetuses when compared with saline-injected controls. The Cdz-Amt combination caused significant increases in cranial malformations, open eye, bent tail, abnormal lung, and urogenital anomalies. The teratogenic effects of potentiation between the components of this combination are discussed in terms of external and internal malformations.     

Galactose specific lectins from prostate tissue with different pathologies: biochemical and cellular studies

Background

Galectins—galactose-specific lectins are involved in various types of cell activities, including apoptosis, cell cycle regulation, inflammation and cell transformation. Galectins are implicated in prostate malignat transformation. It is not known yet if prostate glands with different grade of pathologies are expressing different galectins and if these galectins express different effects on the cell viability.

Methods

Cytosolic galactose-spesific lectin fractions from prostate tissue with different diagnosis were purified by affinity chromatography and analyzed by electrophoresis in polyacrylamide gel electrophoresis with sodium dodecyl sulphate. The lectin effects in a source-dependent maner were studied on cell viability on peripheral lymphocytes by MTT reduction method and on apoptosis by flow cytometry method.

Results

Affinity purified galactose-specific lectins fractions from normal and pathological tissue samples are characterized with different protein composition and they express different effects on cell viability and apoptosis.

Conclusion

The effects of cytosolic galactose-specific lectins depend on the source of lectin fraction (glandular tissue disease). We suppose that the released cytosolic galectins from prostatic high grade intraepithelial neoplasia and adenocarcinoma tissue could suppress the immune status of the host patients.

     

Proteomic and Systems Biology Analysis of Monocytes Exposed to Securinine,a GABAA Receptor Antagonist and Immune Adjuvant

Securinine, a GABA_A receptor antagonist, has been reported to enhance monocyte cell killing of Coxiella burnetii without obvious adverse effects in vivo. We employed multiplex 2D gel electrophoresis using Zdyes, a new generation of covalently linked fluorescent differential protein detection dyes to analyze changes in the monocyte proteome in response to Securinine. Securinine antagonism of GABA_A receptors triggers the activation of p38. We used the differential protein expression results to guide a search of the literature and network analysis software to construct a systems biology model of the effect of Securinine on monocytes. The model suggests that various metabolic modulators (fatty acid binding protein 5, inosine 5′-monophosphate dehydrogenase, and thioredoxin) are at least partially reshaping the metabolic landscape within the monocytes. The actin bundling protein L-plastin, and the Ca²⁺ binding protein S100A4 also appear to have important roles in the immune response stimulated by Securinine. Fatty acid binding protein 5 (FABP5) may be involved in effecting lipid raft composition, inflammation, and hormonal regulation of monocytes, and the model suggests that FABP5 may be a central regulator of metabolism in activated monocytes. The model also suggests that the heat shock proteins have a significant impact on the monocyte immune response. The model provides a framework to guide future investigations into the mechanisms of Securinine action and with elaboration may help guide development of new types of immune adjuvants.     

Comparative study of the teratogenic effects of chlordiazepoxide and diazepam in the fetal hamster

A single, intraperitoneal injection of either chlordiazepoxide (280–3100 mg/kg) or diazepam (120–980 mg/kg) was administered to pregnant hamsters on day 8 of gestation. These dosages produced a dose-dependent sedation of pregnant animals lasting up to 36 hours, and a combined maternal mortality rate of 21% (chlordiazepoxide) and 5% (diazepam). Animals were sacrificed on gestation day 12 and the fetuses were examined for gross malformations. Although there was a dose-related increase in the frequency of malformed fetuses (3.4%–54.7% for chlordiazepoxide, and 0–58.7% for diazepam), the lowest teratogenic dose was noted to be 280 mg/kg, i.e., almost 500 times and 1000 times the average daily recommended therapeutic doses for chlordiazepoxide and diazepam, respectively. The majority of fetal malformations observed with both compounds were either exencephaly or cranioschisis. The results of this study should be interpreted with caution in so far as their relevance to humans is concerned. The terata were observed at exceedingly high doses (700–7000 times the average human use dose), and the malformations noted by us have not been associated with the use of minor tranquilizers in human pregnancy. Also, although we found no gross anomalies in the litters of dams deprived of food and water for up to 72 hours, the confounding role of prolonged periods of sedation and resulting inactivity, and possible hypoxia and hypothermia needs to be explored further.     

The ABC of a Simple Method for Pulmonary Vein Angiography

Catheter-directed intervention to treat atrial fibrillation (AF) is becoming widely accepted procedure in current clinical practice. For assessment of pulmonary vein (PV) anatomy, angiography of left atrium (LA) and/or PV is often performed. We present a new, simple angiographic method for PVs and LA opacification using SL1 sheath. Total of 100 patients in our clinic underwent this procedure. In all of the cases good angiographic results were achieved. No immediate or late complications related to this procedure were observed.