Risk Factors for Invasive Haemophilus influenzae Disease among Children 2-16 Years of Age in the Vaccine Era, Switzerland 1991-1993

Mūhlemann K (Institute of Medical Microbiology, Friedbūhistrasse 51, University of Berne, CH-3010 Berne, Switzerland), Alexander E R, Weiss N S, Pepe M, Schopfer K and the Swiss H.Influenzae Study Group. Risk factors for invasive Haemophilus influenzae disease among children aged 2-16 years of age in the vaccine era, Switzerland 1991-1993. International Journal of Epidemiology 1996; 25: 1280-1285. Background Continued surveillance, and detailed investigation of direct and indirect effects of conjugated vaccines and risk factors for invasive H. Influenzae serotype b (Hib) disease in the vaccine era are important Methods 143 cases with invasive disease between 1991 and 1993 aged 2-16 years were selected retrospectively from a large incidence trend study. Controls (n = 336) were recruited from local vital registries and matched to cases for age, gender, and residence. Hib vaccination histories among study subjects and their siblings and other sociodemographic variables were obtained by questionnaires completed by the parents of these children. Adjusted odds ratio (OR) estimates were calculated by conditional logistic regression analysis. Results Most vaccinated subjects had received the Polysacchande-Diphtheria Toxoid vaccine and estimated vaccine efficacy was high (95%; 95% confidence interval [Cl] 60-99%). Also, the results suggested that protection afforded by vaccination against Hib extended to the family members of vaccinated children. School attendance was found to be protective against invasive Hib disease (OR : 0.33; Cl : 0.14-0.75). Cases more often than controls reported sufferring from asthma and allergies (OR : 4.8; Cl: 1.2-19 4). Conclusions Post-licensure vaccine efficacy is high among children ≥2 years of age. The observed association between asthma and epiglottis is novel and deserves further investigatio

Saturated and monounsaturated fatty acids in membranes are determined by the gene expression of their metabolizing enzymes SCD1 and ELOVL6 regulated by the intake of dietary fat

Purpose: We investigated the effect of dietary fats on the incorporation of saturated (SAFAs) and monounsaturated dietary fatty acids (MUFAs) into plasma phospholipids and the regulation of the expression of lipid-metabolizing enzymes in the liver. Methods: Mice were fed different diets containing commonly used dietary fats/oils (coconut fat, margarine, fish oil, sunflower oil, or olive oil) for 4 weeks (n = 6 per diet group). In a second experiment, mice (n = 6 per group) were treated for 7 days with synthetic ligands to activate specific nuclear hormone receptors (NHRs) and the hepatic gene expression of CYP26A1 was investigated. Hepatic gene expression of stearoyl-coenzyme A desaturase 1 (SCD1), elongase 6 (ELOVL6), and CYP26A1 was examined using quantitative real-time PCR (QRT-PCR). Fatty acid composition in mouse plasma phospholipids was analyzed by gas chromatography (GC). Results: We found significantly reduced hepatic gene expression of SCD1 and ELOVL6 after the fish oil diet compared with the other diets. This resulted in reduced enzyme-specific fatty acid ratios, e.g., 18:1n9/18:0 for SCD1 and 18:0/16:0 and 18:1n7/16:1n7 for ELOVL6 in plasma phospholipids. Furthermore, CYP26A1 a retinoic acid receptor-specific target was revealed as a new player mediating the suppressive effect of fish oil-supplemented diet on SCD1 and ELOVL6 hepatic gene expression. Conclusion: Plasma levels of MUFAs and SAFAs strongly reflect an altered hepatic fatty acid-metabolizing enzyme expression after supplementation with different dietary fats/oils

Does the circulating ketoconazole metabolite N-deacetyl ketoconazole contribute to the drug-drug interaction potential of the parent compound?

Ketoconazole is a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and of P-glycoprotein (P-gp) and is often used as an index inhibitor especially for CYP3A4-mediated drug metabolism. A preliminary physiologically based pharmacokinetic (PBPK) model for drug-drug interactions indicated possible involvement of a metabolite to the perpetrator potential of ketoconazole. Still unknown for humans, in rodents, N-deacetyl ketoconazole (DAK) has been identified as the major ketoconazole metabolite. We therefore investigated in vitro, whether DAK also inhibits the human CYPs and drug transporters targeted by ketoconazole and quantified DAK in human plasma from healthy volunteers after receiving a single oral dose of 400 mg ketoconazole. Our data demonstrated that DAK also inhibits CYP3A4 (2.4-fold less potent than ketoconazole), CYP2D6 (13-fold more potent than ketoconazole), CYP2C19 (equally potent), P-gp (3.4-fold less potent than ketoconazole), breast cancer resistance protein (more potent than ketoconazole) and organic anion transporting polypeptide 1B1 and 1B3 (7.8-fold and 2.6-fold less potent than ketoconazole). After a single oral dose of 400 mg ketoconazole, maximum concentrations of DAK in human plasma were only 3.1 ‰ of the parent compound. However, assuming that DAK also highly accumulates in the human liver as demonstrated for rodents, inhibition of the proteins investigated could also be conceivable in vivo. In conclusion, DAK inhibits several CYPs and drug transporters, which might contribute to the perpetrator potential of ketoconazole

Identification of tumor-specific Salmonella Typhimurium promoters and their regulatory logic

Conventional cancer therapies are often limited in effectiveness and exhibit strong side effects. Therefore, alternative therapeutic strategies are demanded. The employment of tumor-colonizing bacteria that exert anticancer effects is such a novel approach that attracts increasing attention. For instance, Salmonella enterica serovar Typhimurium has been used in many animal tumor models as well as in first clinical studies. These bacteria exhibit inherent tumoricidal effects. In addition, they can be used to deliver therapeutic agents. However, bacterial expression has to be restricted to the tumor to prevent toxic substances from harming healthy tissue. Therefore, we screened an S. Typhimurium promoter-trap library to identify promoters that exclusively drive gene expression in the cancerous tissue. Twelve elements could be detected that show reporter gene expression in tumors but not in spleen and liver. In addition, a DNA motif was identified that appears to be necessary for tumor specificity. Now, such tumor-specific promoters can be used to safely express therapeutic proteins by tumor-colonizing S. Typhimurium directly in the neoplasi

microRNA Expression Profile of Purified Alveolar Epithelial Type II Cells

Alveolar type II (ATII) cells are essential for the maintenance of the alveolar homeostasis. However, knowledge of the expression of the miRNAs and miRNA-regulated networks which control homeostasis and coordinate diverse functions of murine ATII cells is limited. Therefore, we asked how miRNAs expressed in ATII cells might contribute to the regulation of signaling pathways. We purified "untouched by antibodies" ATII cells using a flow cytometric sorting method with a highly autofluorescent population of lung cells. TaqMan® miRNA low-density arrays were performed on sorted cells and intersected with miRNA profiles of ATII cells isolated according to a previously published protocol. Of 293 miRNAs expressed in both ATII preparations, 111 showed equal abundances. The target mRNAs of bona fide ATII miRNAs were used for pathway enrichment analysis. This analysis identified nine signaling pathways with known functions in fibrosis and/or epithelial-to-mesenchymal transition (EMT). In particular, a subset of 19 miRNAs was found to target 21 components of the TGF-β signaling pathway. Three of these miRNAs (miR-16-5p, -17-5p and -30c-5p) were down-modulated by TGF-β1 stimulation in human A549 cells, and concomitant up-regulation of associated mRNA targets (BMPR2, JUN, RUNX2) was observed. These results suggest an important role for miRNAs in maintaining the homeostasis of the TGF-β signaling pathway in ATII cells under physiological conditions

Highly diverse and antimicrobial susceptible Escherichia coli display a naïve bacterial population in fruit bats from the Republic of Congo

Bats are suspected to be a reservoir of several bacterial and viral pathogens relevant to animal and human health, but studies on Escherichia coli in these animals are sparse. We investigated the presence of E. coli in tissue samples (liver, lung and intestines) collected from 50 fruit bats of five different species (Eidolon helvum, Epomops franqueti, Hypsignathus monstrosus, Myonycteris torquata, Rousettus aegyptiacus) of two different areas in the Republic of Congo between 2009 and 2010. To assess E. coli pathotypes and phylogenetic relationships, we determined the presence of 59 virulence associated genes and multilocus sequence types (STs). Isolates were further tested for their susceptibility to several antimicrobial substances by agar disk diffusion test and for the presence of an Extended-Spectrum Beta- Lactamase phenotype. E. coli was detected in 60% of the bats analysed. The diversity of E. coli strains was very high, with 37 different STs within 40 isolates. Occasionally, we detected sequence types (e.g. ST69, ST127, and ST131) and pathotypes (e.g. ExPEC, EPEC and atypical EPEC), which are known pathogens in human and/or animal infections. Although the majority of strains were assigned to phylogenetic group B2 (46.2%), which is linked with the ExPEC pathovar, occurrence of virulence-associated genes in these strains were unexpectedly low. Due to this, and as only few of the E. coli isolates showed intermediate resistance to certain antimicrobial substances, we assume a rather naïve E. coli population, lacking contact to humans or domestic animals. Future studies featuring in depth comparative whole genome sequence analyses will provide insights into the microevolution of this interesting strain collection

Helicobacter pylori infection associates with fecal microbiota composition and diversity

Helicobacter (H.) pylori is the most important cause for peptic ulcer disease and a risk factor for gastric carcinoma. How colonization with H. pylori affects the intestinal microbiota composition in humans is unknown. We investigated the association of H. pylori infection with intestinal microbiota composition in the population-based cohort Study-of-Health-in-Pomerania (SHIP)-TREND. Anti-H. pylori serology and H. pylori stool antigen tests were used to determine the H. pylori infection status. The fecal microbiota composition of 212 H. pylori positive subjects and 212 matched negative control individuals was assessed using 16S rRNA gene sequencing. H. pylori infection was found to be significantly associated with fecal microbiota alterations and a general increase in fecal microbial diversity. In infected individuals, the H. pylori stool antigen load determined a larger portion of the microbial variation than age or sex. The highest H. pylori stool antigen loads were associated with a putatively harmful microbiota composition. This study demonstrates profound alterations in human fecal microbiota of H. pylori infected individuals. While the increased microbiota diversity associated with H. pylori infection as well as changes in abundance of specific genera could be considered to be beneficial, others may be associated with adverse health effects, reflecting the complex relationship between H. pylori and its human host

The MASCOT Magnetometer

The Mobile Asteroid Scout (MASCOT) is a small lander on board the Hayabusa2 mission of the Japan Aerospace Exploration Agency to the asteroid 162173 Ryugu. Among the instruments on MASCOT is a fluxgate magnetometer, the MASCOT Magnetometer (MasMag). The magnetometer is a lightweight ( ∼280 g∼280 g ) and low power ( ∼0.5 W∼0.5 W ) triaxial fluxgate magnetometer. Magnetic field measurements during the landing period and during the surface operational phase shall provide information about any intrinsic magnetic field of the asteroid and its remanent magnetization. This could provide important constraints on planet formation and the thermal and aqueous evolution of primitive asteroids.Thomas F. PetersonUnited States. National Aeronautics and Space Administration. Emerging Worlds Progra