Drug-target network in myocardial infarction reveals multiple side effects of unrelated drugs

The systems-level characterization of drug-target associations in myocardial infarction (MI) has not been reported to date. We report a computational approach that combines different sources of drug and protein interaction information to assemble the myocardial infarction drug-target interactome network (My-DTome). My-DTome comprises approved and other drugs interlinked in a single, highly-connected network with modular organization. We show that approved and other drugs may both be highly connected and represent network bottlenecks. This highlights influential roles for such drugs on seemingly unrelated targets and pathways via direct and indirect interactions. My-DTome modules are associated with relevant molecular processes and pathways. We find evidence that these modules may be regulated by microRNAs with potential therapeutic roles in MI. Different drugs can jointly impact a module. We provide systemic insights into cardiovascular effects of non-cardiovascular drugs. My-DTome provides the basis for an alternative approach to investigate new targets and multidrug treatment in MI

Comparison of Hepatic-like Cell Production from Human Embryonic Stem Cells and Adult Liver Progenitor Cells: CAR Transduction Activates a Battery of Detoxification Genes

In vitro production of human hepatocytes is of primary importance in basic research, pharmacotoxicology and biotherapy of liver diseases. We have developed a protocol of differentiation of human embryonic stem cells (ES) towards hepatocyte-like cells (ES-Hep). Using a set of human adult markers including CAAT/enhancer binding protein (C/EBPalpha), hepatocyte nuclear factor 4/7 ratio (HNF4alpha1/HNF4alpha7), cytochrome P450 7A1 (CYP7A1), CYP3A4 and constitutive androstane receptor (CAR), and fetal markers including alpha-fetoprotein, CYP3A7 and glutathione S-transferase P1, we analyzed the expression of a panel of 41 genes in ES-Hep comparatively with human adult primary hepatocytes, adult and fetal liver. The data revealed that after 21 days of differentiation, ES-Hep are representative of fetal hepatocytes at less than 20 weeks of gestation. The glucocorticoid receptor pathway was functional in ES-Hep. Extending protocols of differentiation to 4 weeks did not improve cell maturation. When compared with hepatocyte-like cells derived from adult liver non parenchymal epithelial (NPE) cells (NPE-Hep), ES-Hep expressed several adult and fetal liver makers at much greater levels (at least one order of magnitude), consistent with greater expression of liver-enriched transcription factors Forkhead box A2, C/EBPalpha, HNF4alpha and HNF6. It therefore seems that ES-Hep reach a better level of differentiation than NPE-Hep and that these cells use different lineage pathways towards the hepatic phenotype. Finally we showed that lentivirus-mediated expression of xenoreceptor CAR in ES-Hep induced the expression of several detoxification genes including CYP2B6, CYP2C9, CYP3A4, UDP-glycosyltransferase 1A1, solute carriers 21A6, as well as biotransformation of midazolam, a CYP3A4-specific substrate

Results of magnetic measurements and field integral compensation for the Elliptical Multipole Wiggler

A prototype of the Elliptical Multipole Wiggler (EMW) has been assembled, tested and tuned at the APS. This prototype has a period of 160 mm with 7 poles for the hybrid structure and 10 poles for the electromagnet part of the EMW. The hybrid structure of the EMW produces a vertical maenetic field of 0.83 T with K{sub y}= 12 for a cap of 27 mm, and the electromagnetic structure provides a horizontal field chancre up to 100 Hz with a maximum field of 0.12 T (I= 0.6 kA, K{sub x}= 1.6). The current pulse has a trapezium-type shape with a switching time to chancre the current polarity of about 2 ms. The measurements and tuning, were done for direct current (DC) mode and alternating current (AC) mode. Fine adjustment during the test at the NSLS X-ray ring, using the BPMs and active correction system allowed to achieve about 1 {mu}m of beam distortion. It corresponds to the peak-to-peak variations during, the time less than {plus_minus}0.5 G-cm and {plus_minus}100 G-cm{sup 2} of the first and second horizontal field integrals respectively

Magnetic measurements of the elliptical multipole wiggler prototype

A prototype of the elliptical multipole wiggler (EMW) has been assembled, tested, and magnetically tuned at the APS. This prototype has a period of 160 mm with seven poles for the hybrid structure (antisymmetric configuration) and ten poles for the electromagnetic part of the EMW (symmetric configuration). The hybrid structure of the EMW produces a vertical magnetic field of 0.83 T (K{sub y} = 12) for a gap of 27 mm, and the electromagnet structure provides a maximum horizontal field of 0.12 T (K{sub x} = 1.6) with AC frequency up to 100 Hz. The alternation time is about 3 ms. The requirements for electromagnetic field quality are very tight because the EMW introduces orbit perturbations in the vertical plane, where the emittance is smallest. Also the storage ring correction system cannot respond to perturbations of more than 10 Hz frequency. Thus the main effort during the magnetic tuning of the EMW was directed toward establishing time independence of the magnetic field integrals to better than 2 G-cm while the current was alternating through the electromagnet. This time independence has been achieved by implementing a special field integral compensation system and novel fast magnetic measurement techniques. Magnetic measurements of the EMW prototype have been performed at the APS insertion device magnetic measurement facility. A new fast acquisition system with a maximum sampling rate of 1 MHz has been developed and used for these measurements. Also a novel ``twisted coil`` technique has been used in order to make fast measurements of the second field integral. The field integral compensation on the order of 1 G-cm and 1,000 G-cm{sup 2} for the first and second integrals, respectively, has been achieved at electromagnet AC frequencies up to 100 Hz

Pneumopathie atypique chez un soudeur : sidérose pulmonaire ?

IntroductionPulmonary siderosis or welder's lung is an occupational lung disease that is usually observedafter chronic exposure to iron dust.ObservationA 55 years old welder visited hospital with dyspnea linked to occupational exposure.Pulmonary function studies revealed lung function abnormalities with decerase of FEV1 andTPC. Based on the chest Tomography CT results, he was diagnosed with obliteransbronchiolitis. A chest biopsy was performed and the specimen is for a pulmonary siderosisaspect.DiscussionThis case of pulmonary siderosis is an unusual one by symptoms, CT images and shortlatency of exposure. An intense inhalation of iron particles could explain this case andinflammatory process and it highlights need of histological analysis of chest biopsyIntroductionLa sidérose pulmonaire est une pneumoconiose de surcharge d’origine professionnellesecondaire à l’accumulation de particules de fer au niveau pulmonaire.ObservationUn soudeur de 55 ans a présenté une dyspnée à rythmicité professionnelle. Les Epreuvesfonctionnelles respiratoires montraient un trouble ventilatoire mixte, les imagesscanographiques un diagnostic radiologique de bronchiolite oblitérante. L’évolution estdéfavorable au niveau clinique et spirométriques malgré le traitement et l’éviction. Sur lespièces de biopsie pulmonaire, l’analyse histologique et minéralogique met en avant undiagnostic de sidérose.ConclusionCe cas décrit une pneumopathie, atypique pour une sidérose pulmonaire par l’intensité dessymptômes, les signes radiologiques et le court délai de latence de début d’exposition. Uneexposition massive à des particules de fer sur un terrain prédisposé serait à l’origine de ceprocessus inflammatoire et l’analyse histologique est nécessaire à la confirmation dudiagnostic

Beri-beri: the major cause of infant mortality in Karen refugees.

During a prospective evaluation of malaria prophylaxis in pregnancy in a refugee population on the north-western border of Thailand from 1987 to 1990, an extremely high infant mortality rate (18%) was documented despite good access to health care. Infantile beri-beri was recognized as the main cause of death accounting for 40% of all infant mortality. Thereafter, severe vitamin B1 deficiency in infants was diagnosed and treated promptly. The impact of this was assessed prospectively from 1993 to 1996 in a second cohort study. The case fatality of infantile beri-beri fell from almost 100% to 7%. The overall infant mortality rates declined from 183 to 78 per 1000 live births. Post-neonatal deaths fell by 79% (95% CI 65-87%) while neonatal mortality remained unchanged. Mortality resulting from acute respiratory infections did not change (15 and 11 per 1000, respectively), whereas mortality attributable to beri-beri decreased from 73 to 5 per 1000 (P < 0.0001). Before its recognition approximately 7% of all infants in this population died from infantile beri-beri. This lethal but preventable syndrome may be more common than hitherto recognized, particularly in refugee populations, in this populous region