Maternal smoking during pregnancy and risks of suicidal acts in young offspring

Obstetric and neonatal complications have been associated with completed and attempted suicide (suicidal acts) in young offspring. Maternal smoking is one of the most important risk factors for obstetric complications, but the association between prenatal smoking exposure and offspring risk of suicidal acts is unknown. We performed a population-based study of 1,449,333 single births born in Sweden between 1983 and 1996, derived from linked registry data. Maternal smoking and risks of suicidal acts in offspring were estimated using hazard ratios, derived from proportional-hazard models, controlling for potential confounding of parental socio-demographic factors and psychiatric care in first degree relatives. To control for unmeasured familial confounding, a matched case-control analysis of suicidal acts was performed within sibling pairs discordant for prenatal smoking exposure. In the cohort analysis, the adjusted hazard ratio for completed suicide among offspring to women smoking 1-9 cigarettes and at least 10 cigarettes per day were 1.67, 95% confidence interval (CI), 1.29-2.16, and 1.54, 95% CI, 1.12-2.10. For suicidal acts, corresponding hazard ratios were 1.28, 95% CI 1.21-1.35 and 1.48, 95% CI 1.39-1.57, respectively. However, in sibling pairs discordant for suicidal acts and prenatal smoking exposure, we found no evidence that prenatal smoking exposure increased the risk of suicidal acts. We conclude that the association between prenatal smoking exposure and offspring risk of suicidal acts is probably confounded by unmeasured familial factors.     

Health inequalities for women living in rural regions: the prefecture of Xanthi, Greece

Gender equity with regard to access to health services has been set on a firm theoretical background but is far from reaching a resolution. Here we examine how geographic isolation affects the implementation of policies regarding equal access to health care by considering the case of the mountainous region of Xanthi, Greece. We determined that the characteristics of this mountainous region require additional measures to ensure truly equal access for women of all social and demographic groups. We also propose several interventions aimed at reducing health inequalities by involving the local population and broadening the target area.     

Anti-tumoral activities of dioncoquinones B and C and related naphthoquinones gained from total synthesis or isolation from plants

Dioncoquinones belong to a family of natural naphthoquinone products of interest due to their promising anti-tumoral and anti-infective activities. In particular, dioncoquinones A (5) and B (6) have been shown to be highly active against Leishmania major and multiple myeloma cells without any significant toxicity toward normal blood cells. Their effective concentrations against multiple myeloma cell lines were similar to those of melphalan, a well known DNA-alkylating agent used in a standard therapy against B cell lymphoma and multiple myeloma. We report on the first total synthesis of the highly oxygenated anti-tumoral agent dioncoquinone B (6) and the isolation of its new, even higher-oxygenated analogs, dioncoquinones C (7), D (8), and E (9), from cell cultures of Triphyophyllum peltatum. In addition, several derivatives of these compounds were synthesized, including dioncoquinone C (7), and a small library of naphthoquinones was created. Furthermore, the first structure-activity relationship (SAR) study on this class of compounds was conducted, showing that each of the three hydroxy groups, at C-3, C-5, and C-6, is required for improved anti-tumoral activities and decreased cytotoxicities.     

Comparison of direct antimicrobial susceptibility testing methods for rapid analysis of bronchial secretion samples in ventilator-associated pneumonia

Two hundred and fifty tracheal aspirates were subjected to direct antimicrobial susceptibility testing by disk diffusion, Etest and inoculation on antibiotic-enriched MacConkey agar plates. Results were compared with those obtained using an automated system on microorganisms recovered from standard quantitative culture. A total of 255 microorganisms were isolated from 194 positive samples by the standard quantitative procedure. A total of 85.1%, 82.5% and 72.5% agreement between direct disk diffusion, Etest and antibiotic-enriched MacConkey agar plates, respectively, and the standard procedure was observed in 64 microorganisms obtained from monomicrobial cultures that corresponded to 240 individual microorganism-antimicrobial agent combinations. Three (1.3%) and four (1.7%) very major errors for direct disk diffusion and Etest methods were observed, respectively. The antibiotic-enriched MacConkey agar plate method compared with the standard procedure demonstrated an unacceptable rate of very major (6.7%) and major errors (14.2%). Clinical evaluation of direct susceptibility tests based on the speculative impact on clinical practice by guiding patient's early treatment, if all positive cultures corresponded to infection, was correct in 79.9% for the direct disk diffusion test, 77.8% for the direct Etest method and 68.0% for antibiotic-enriched MacConkey agar plates. Direct diffusion tests (Etest or disk diffusion) applied on respiratory samples are rapid techniques that provide results comparable with standard antimicrobial susceptibility testing in <24 h.     

Polyethylenimines for RNAi-mediated gene targeting in vivo and siRNA delivery to the lung

RNA interference (RNAi) is a promising strategy to inhibit the expression of pathologically relevant genes, which show aberrant (over-)expression, e.g. in tumors or other pathologies. The induction of RNAi relies on small interfering RNAs (siRNAs), which trigger the specific mRNA degradation. Their instability and poor delivery into target tissues including the lung, however, so far severely limits the therapeutic use of siRNAs and requires the development of nanoscale delivery systems. Polyethylenimines (PEIs) are synthetic polymers, which are able to form non-covalent complexes with siRNAs. These nanoscale complexes (’nanoplexes’) allow the protection of siRNAs from nucleolytic degradation, their efficient cellular uptake through endocytosis and intracellular release through the ’proton sponge effect’. Chemical modifications of PEIs as well as the coupling of cell/tissue-specific ligands are promising approaches to increase the biocompatibility, specificity and efficacy of PEI-based nanoparticles.This review article gives a comprehensive overview of pre-clinical in vivo studies on the PEI-mediated delivery of therapeutic siRNAs in various animal models. It discusses the chemical properties of PEIs and PEI modifications, and their influences on siRNA knockdown efficacy, on adverse effects of the polymer or the nanoplex and on siRNA biodistribution in vivo. Beyond systemic application, PEI-based complexation allows the local siRNA application to the lung. Biodistribution studies demonstrate cellular uptake of PEI-complexed, but not of naked siRNAs in the lung with little systemic availability of the siRNAs, indicating the usefulness of this approach for the targeting of genes, which are pathologically relevant in lung tumors or lung metastases.Taken together, (i) PEI and PEI derivatives may represent an efficient delivery platform for siRNAs, (ii) siRNA-mediated induction of RNAi is a promising approach for the knockdown of pathologically relevant genes, and (iii) when sufficiently addressing biocompatibility issues, the locoregional delivery of PEI/siRNA complexes may become an attractive therapeutic strategy for the treatment of lung diseases with little systemic side effects.     

Translocation t(12;13)(p13;q14) in a patient with imatinib-sensitive MDS/MPD associated with resistance to treatment: review of the literature

The category of myelodysplastic syndromes/myeloproliferative diseases (MDS/MPD) is a relatively new group of malignant hematologic diseases developed by the World Health Organization. These hematologic disorders lack the BCR/ABL fusion gene, although they can be associated with chromosomal translocations that involve genes encoding other protein kinases. Imatinib mesylate was recognized as a potent inhibitor of some of those kinases. We present a patient with a previously treated acute myeloid leukemia, who, after a 9-year-long remission, developed an MDS/MPD with normal karyotype, which initially responded to imatinib mesylate. Translocation t(12;13)(p12;q14) was detected after loss of response to imatinib treatment. Translocation t(12;13) is rare. It has been described in several hematologic malignancies including chronic myelomonocytic leukemia but not in MDS/MPD, previously described as Philadelphia-negative chronic myelogenous leukemia. Moreover, the correlation of this molecular abnormality with loss of efficacy of imatinib is unique in the literature.     

Major furocoumarins in grapefruit juice I: Levels and urinary metabolite(s)

Furocoumarins are phototoxic and photogenotoxic natural plant constituents occurring in cosmetics, food and drugs. Grapefruit juice is considered as a major dietary source of furocoumarins although few is known about the variability of furocoumarins in grapefruit juice. We analyzed the major furocoumarins in eight commercial grapefruit juices and in freshly prepared juices made from pink grapefruit obtained from German retailers. Bergaptol was the major furocoumarin in commercial juices, followed by bergamottin and 6′,7′-dihydroxy-bergamottin (DHB), whereas an inverse picture (DHB > bergamottin > bergaptol) was obtained in freshly prepared juices. Results from different batches of a single brand of commercial juice, purchased over a period of 7 months, revealed a variability of about 50% for the individual furocoumarins and the sum. In a study with healthy volunteers, consumption of 900 ml commercial grapefruit juice (containing 12.5 mg bergaptol, 6.9 mg bergamottin, and 0.6 mg DHB) resulted in an average urinary excretion of 0.36 mg free plus 13.23 mg conjugated bergaptol within 6 h. Other furocoumarins were not found in urine. Thus, other grapefruit furocoumarins were obviously converted in the human body, at least in part, into bergaptol excreted in urine, since the excreted amount of bergaptol exceeded the consumed one.     

Synthesis and evaluation of 5-substituted 2'-deoxyuridine monophosphate analogues as inhibitors of flavin-dependent thymidylate synthase in Mycobacterium tuberculosis

A series of 5-substituted 2'-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC(50) value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC(50) > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.     

Daily Stress and Social Support among Women with CAD: Results from a 1-year Randomized Controlled Stress Management Intervention Study

Background  

Psychosocial stress may play a causative role in development and progression of coronary artery disease (CAD).