Smoking in pregnancy: A survey from Northern Italy

Summary The prevalence of smoking in pregnancy was analyzed in a survey of women delivering between January and March 1989 in a large maternity clinic in Milan, Northern Italy. Out of the 528 women interviewed, 183 (35%) were current smokers before pregnancy and 99 stopped smoking during pregnancy. The probability of stopping smoking decreased with increasing age and was lower in less educated women, but these findings were not statistically significant. Considering persistent smokers only, the mean number of cigarettes per day fell from 13 before to 8 during pregnancy; this reduction was generally consistent in various subgroups of age and education. The reductions, however, are probably overestimated, since they are based on the women's reports only. Thus, there still appears to be ample scope for intervention on smoking in pregnancy, particularly in older and less educated women.

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Zusammenfassung Die Rauchprävalenz während der Schwangerschaft wurde in einer Querschnittstudie bei Frauen untersucht, welche zwischen Januar und März 1989 in einer grossen Frauenklinik in Mailand ein Kind zur Welt brachten. Von 528 befragten Frauen hatten 183 (35%) vor der Schwangerschaft geraucht, und 99 Frauen war es gelungen, während der Schwangerschaft mit Rauchen aufzuhören. Die Wahrscheinlichkeit für letzteres nahm mit zunehmendem Alter ab und war kleiner für Frauen mit geringer Ausbildung (statistisch nicht signifikant). Bei den Raucherinnen wurde eine Reduktion der mittleren Anzahl Zigaretten von 13 Stück vor der Schwangerschaft auf 8 während der Schwangerschaft festgestellt. Diese Reduktion fand sich in allen Alters- und Ausbildungsgruppen. Wahrscheinlich wurde die Reduktion aber überbewertet, weil sich ihre Berechnung nur auf die Aussagen der Frauen abstützte. Für Gesundheitsaktionen, die ein Rauchstopp während der Schwangerschaft zum Ziele haben, besteht immer noch ein grosser Bedarf, besonders bei älteren und weniger ausgebildeten Frauen.

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Résumé La prévalence du tabagisme durant la grossese a été étudiée lors d'une enquête des parturientes entre janvier et mars 1989 dans une grande maternité de Milan. Parmi les 528 femmes interrogées, 183 (35%) étaient tabagiques avant la grossesse et 99 avaient arrêté de fumer durant la grossesse. La probalité de cesser l'habitude diminue lorsque l'âge augmente, et est basse chez les femmes dont le niveau d'éducation est bas, sans significantion statistique. En considérant uniquement les parturientes tabagiques, le nombre quotidien de cigarettes fumées passe de 13 avant la grossesse à 8 durant la grossesse; cette diminution se retrouve dans tous les groupes d'âge et tous les niveaux d'éducation. Ces diminutions sont probablement surestimées, puisqu'elles sont basées sur les seules déclarations des parturientes. Cette enquête montre qu'il existe encore une large place por la prévention.

     

Partial Motor Epilepsy with "Negative Myoclonus"

Three children had both nocturnal unilateral motor seizures and daytime ipsilateral "negative myoclonus" which occurred so frequently that it resembled asterixis. Neurophysiologic studies demonstrated lateralized spike discharges that were time-locked to postural lapse in the contralateral outstretched arm. The clinical course was characterized by good seizure control with benzodiazepines.     

Molecular mechanisms of tolerance to and withdrawal of GABAA receptor modulators

Here, we summarize recent data pertaining to the effects of GABA_A receptor modulators on the receptor gene expression in order to elucidate the molecular mechanisms behind tolerance and dependence induced by these drugs. Drug selectivity and intrinsic activity seems to be important to evidence at the molecular level the GABA_A receptor tolerance. On the contrary, we suggested that all drug tested are equally potentially prone to induce dependence. Our results demonstrate that long-lasting exposure of GABA_A receptors to endogenous steroids, benzodiazepines and ethanol, as well as their withdrawal, induce marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and these drugs in modulating the functional activity of specific neuronal populations. We report here that endogenous steroids may play a crucial role in the action of ethanol on dopaminergic neurons.     

Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer.

PURPOSE: Up-regulation of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) enzymes has been reported in colorectal cancer. We aimed at evaluating the possible interaction between the nitric oxide and COX-2 pathways, and its effect on promoting tumor angiogenesis. EXPERIMENTAL DESIGN: Expression of iNOS, COX-2, vascular endothelial growth factor (VEGF), and CD31 was analyzed in tumor samples and corresponding normal mucosa obtained from 46 surgical specimens. We also evaluated iNOS activity, prostaglandin E(2) (PGE(2)), cyclic GMP and cyclic AMP production in the same specimens. Nitrite/nitrate levels, and PGE(2) and VEGF production were assessed in HCT116 and HT29 colon cancer cell lines after induction and selective inhibition of the two enzyme pathways. RESULTS: A significant correlation was found between iNOS and COX-2 immunohistochemical expression. PGE(2) production significantly correlated with iNOS activity and cGMP levels. A significant correlation was also found among PGE(2) production, microvessel density, and VEGF expression. Coinduction of both iNOS and COX-2 activities occurred after lipopolysaccharide (LPS) and epidermal growth factor (EGF) treatment in HCT116 and HT29 cells. Inhibition of iNOS by 1400W significantly reduced both LPS- and EGF-induced PGE(2) production. Treatment with LPS, EGF, and arachidonic acid significantly increased VEGF production in the iNOS-negative/COX-2-positive HT29 cells. This effect was completely reversed by treatment with the selective COX-2 inhibitor celecoxib. CONCLUSIONS: Our data showed a prominent role of nitric oxide in stimulating COX-2 activity in colorectal cancer. This interaction is likely to produce a cooperative effect in promoting angiogenesis through PGE(2)-mediated increase in VEGF production.     

Health-related quality of life parameters as prognostic factors in a nonmetastatic breast cancer population: an international multicenter study.

PURPOSE: The purpose of this research was to evaluate whether baseline health-related quality of life (HRQOL) parameters are prognostic factors for survival in locally advanced breast cancer patients. Although the literature highlights the important role of HRQOL parameters in predicting survival in advanced metastatic disease, little evidence exists for earlier stages. PATIENTS AND METHODS: The overall sample consisted of 448 patients randomly assigned to receive cyclophosphamide, epirubicin, and fluorouracil versus epirubicin, cyclophosphamide, and granulocyte colony-stimulating factor. Patients were enrolled in 12 countries. HRQOL baseline scores were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap resampling technique was used to assess the stability of the outcomes. Bootstrap results were then applied for model averaging purposes as a means to account for the observed model selection uncertainty. RESULTS: The final multivariate model retained inflammatory breast cancer (T4d) as the only factor predicting overall survival (OS) with a hazard ratio of 1.375 (95% CI, 1.027 to 1.840; P =.03). The presence of inflammatory breast cancer lowers the median survival time from 6.6 to 4.2 years (36% reduction). None of the preselected HRQOL variables were prognostic for OS or disease-free survival, in either the univariate or multivariate analysis. CONCLUSION: Our findings suggest that baseline HRQOL parameters have no prognostic value in a nonmetastatic breast cancer population.     

Targeted liposomal c-myc antisense oligodeoxynucleotides induce apoptosis and inhibit tumor growth and metastases in human melanoma models.

PURPOSE: Melanoma is a highly malignant and increasingly common tumor. Because the cure rate of metastatic melanoma by conventional treatment is very low, new therapeutic approaches are needed. We previously reported that coated cationic liposomes (CCL) targeted with a monoclonal antibody against the disialoganglioside (GD(2)) and containing c-myb antisense oligodeoxynucleotides (asODNs) resulted in a selective inhibition of the proliferation of GD(2)-positive neuroblastoma cells in vitro. EXPERIMENTAL DESIGN: Here, we tested the in vivo antitumor effects of this novel antisense liposomal formulation by targeting the c-myc oncogene on melanoma, a neuroectodermal tumor sharing with neuroblastoma the expression of GD(2). RESULTS: Our methods produced GD(2)-targeted liposomes that stably entrapped 90% of added c-myc asODNs. These liposomes showed a selective binding for GD(2)-positive melanoma cells in vitro. Melanoma cell proliferation was inhibited to a greater extent by GD(2)-targeted liposomes containing c-myc asODNs (aGD(2)-CCL-myc-as) than by nontargeted liposomes or free asODNs. The pharmacokinetic results obtained after i.v. injection of [(3)H]-myc-asODNs, free or encapsulated in nontargeted CCLs or GD(2)-targeted CCLs, showed that free c-myc-asODNs were rapidly cleared, with less than 10% of the injected dose remaining in blood at 30 min after injection. c-myc-asODNs encapsulated within either CCL or aGD(2)-CCL demonstrated a more favorable profile in blood, with about 20% of the injected dose of each preparation remaining in vivo at 24 h after injection. In an in vivo melanoma experimental metastatic model, aGD(2)-CCL-myc-as, at a total dose of only 10 mg of asODN per kilogram, significantly inhibited the development of microscopic metastases in the lung compared with animals treated with myc-asODNs, free or entrapped in nontargeted liposomes, or aGD(2)-CCL encapsulating scrambled asODNs (P < 0.01). Moreover, mice bearing established s.c. human melanoma xenografts treated with aGD(2)-CCL-myc-as exhibited significantly reduced tumor growth and increased survival (P < 0.01 versus control mice). The mechanism for the antitumor effects appears to be down-regulation of the expression of the c-myc protein and interruption of c-myc-mediated signaling: induction of p53 and inhibition of Bcl-2 proteins, leading to extensive tumor cell apoptosis. CONCLUSION: These results suggest that inhibition of c-myc proto-oncogene by GD(2)-targeted antisense therapy could provide an effective approach for the treatment of melanoma in an adjuvant setting.     

Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients.

PURPOSE: Imatinib (Glivec) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes chronic myelogenous leukemia (CML). alpha1 acid glycoprotein (AGP) binds to imatinib with high affinity and inhibits imatinib activity in vitro and in vivo in an animal model. A pharmacokinetics analysis of imatinib was undertaken in CML patients. EXPERIMENTAL DESIGN: Imatinib plasma concentrations were measured in 19 CML patients treated with imatinib (400 or 600 mg/day). Five patients received a concomitant short-term course of clindamycin (CLI). RESULTS: A positive correlation between AGP and imatinib plasma levels was observed. CLI administration decreased imatinib plasma concentrations, evaluated as area under the curve (AUC) and peak concentrations (C(max)). The effects of a bolus of CLI was studied in three patients on imatinib 23 h after the last imatinib dose. Within 5-10 min in three of three cases, CLI caused a decrease in imatinib plasma concentrations of 2.6-, 2.7-, and 4.7-fold, respectively. In vitro experiments using fresh blasts from CML patients showed that AGP, at concentrations observed in the patients, decreased imatinib intracellular concentrations up to 10 times and blocked imatinib activity. The incubation with CLI restored imatinib intracellular concentrations and biological activity. CONCLUSION: AGP exerts significant effects of the pharmacokinetics, plasma concentrations, and intracellular distribution of imatinib in CML patients; these data indicate that plasma imatinib levels represent unreliable indicators of the cellular concentrations of this molecule.