Tumor growth is dependent in part on “neoangiogenesis.” Functional involvement of bone marrow (BM)-derived cells in this process has been demonstrated. However, it remains controversial as to whether ...tumor endothelium itself is BM derived. Here we sought to address this issue with an endothelial-specific, inducible transgenic model. We generated Cretransgenic mice (endothelial-SCL-Cre-ERT) using the tamoxifen-inducible Cre-ERTrecombinase driven by the 5′ endothelial enhancer of the stem cell leukemia (SCL) locus. These mice were intercrossed with Cre reporter strains in which β-galactosidase (LacZ) or enhanced yellow fluorescent protein (EYFP) are expressed upon Cre-mediated recombination. After tamoxifen administration, endothelial LacZ staining was observed in embryonic and adult tissues. Cre-mediated recombination was also observed in newly generated tumor endothelium. In adult BM cells we could only detect trace amounts of recombination by flow cytometry. Subsequently, BM from endothelial-SCL-Cre-ERT;R26R mice was transplanted into irradiated recipients. When tumors were grown in recipient mice, which received tamoxifen, no tumor LacZ staining was detected. However, when tumors were grown in endothelial-SCL-Cre-ERT;R26R mice 3 weeks after the cessation of tamoxifen treatment, there was widespread endothelial LacZ staining present. Thus, this genetic model strongly suggests that BM cells do not contribute to tumor endothelium and demonstrates the lineage relation between pre-existing endothelium and newly generated tumor endothelial cells. (Blood. 2004;104:1769-1777)
Objective: To explore self-confidence, and the respective facilitators and barriers, among intensive care specialists in Australia and New Zealand in relation to airway management. Design: A mixed ...methods study. Setting: 11 intensive care units across Australia and New Zealand. Participants: 48 intensive care specialists. Intervention: A structured online interview and the presentation of three discrete airway management clinical scenarios - routine endotracheal intubation, awake fibreoptic intubation (AFOI), and emergency front of neck access (FONA). Main outcome measures: Graded Likert scale responses regarding confidence in airway management were analysed, and perceptions of facilitators and barriers to confidence in each select scenario were obtained as free text. A deductive thematic analysis was done iteratively on free text entry and allowed for the development of a coding framework. NVivo software used the coding framework to run coding queries and cross-tabulations for comparison of relationships between themes and participant demographic characteristics. Results: Participants reported differing levels of confidence. Clinical experience, an anaesthetic qualification and training (including simulation) were the major facilitators to influencing confidence. Participants were more confident performing routine intubation than AFOI or FONA. Equipment, checklists or protocols, and availability of video-laryngoscopy were also identified as facilitators to confidence by most participants. Work relationships, teams and other staff availability were identified as further facilitators to confidence; lack of these factors were less commonly identified as barriers. Conclusions: Confidence in airway management among intensive care specialists in Australia and New Zealand varies, both between specialists and depending on clinical context. Multiple facilitators to improving this exist, including additional mandatory training.
The presence of the blood‐brain barrier (BBB), reduces the brain uptake of many drugs, peptides and other solutes from blood. Strategies for increasing the uptake of drugs and peptide‐based drugs ...include; structural modifications to increase plasma half‐life; improving passive penetration of the BBB by increasing the lipophilicity of the molecule; designing drugs which react with transporters present in the BBB; and reducing turnover and efflux from the central nervous system (CNS).
The present study evaluates immobilized artificial membrane (IAM) chromatography for predicting drug permeability across the blood-brain barrier (BBB) and outlines the potential and limitations of ...IAMs as a predictive tool by comparison with conventional methods based on octanol/water partitioning and octadecylsilane (ODS)-HPLC.
IAM-and ODS-HPLC capacity factors were determined in order to derive the hydrophobic indices log kIAM nad log kW for two sets of compounds ranging from very lipid soluble (steroids) to more hydrophilic agents (biogenic amines). The uptake of the compounds across the in vivo BBB expressed as brain uptake index (BUI) has been correlated with these HPLC capacity factors as well as octanol/ water partition (ClogP) and distribution coefficients (log D7.4).
For both test groups log kIAM correlates significantly with the respective log BUI of the drug (r2 = 0.729 and 0.747, p < 0.05), whereas with log kW, log D7.4 and ClogP there is only a correlation for the group of steroids (r2 = 0.789, 0.659 and 0.809, p < 0.05) but not for the group of biogenic amines. There is a good correlation between log kIAM and log kW. ClogP or log D7.4 for the group of steroids (r2 = 0.945.0867 and 0.974, p < 0.01) but not for the biogenic amines.
All physico-chemical descriptors examined in this study equally well describe brain uptake of lipophilic compounds, while log kIAM is superior over log D7.4, ClogP and log kW when polar and ionizable compounds are included. The predictive value of IAMs, combined with the power of HPLC holds thus great promise for the selection process of drug candidates with high brain penetration.
Summary
Sleep disturbances are a hallmark feature of post‐traumatic stress disorder (PTSD), and associated with poor clinical outcomes. Few studies have examined sleep quantitative ...electroencephalography (qEEG), a technique able to detect subtle differences that polysomnography does not capture. We hypothesized that greater high‐frequency qEEG would reflect ‘hyperarousal’ in combat veterans with PTSD (n = 16) compared to veterans without PTSD (n = 13). EEG power in traditional EEG frequency bands was computed for artifact‐free sleep epochs across an entire night. Correlations were performed between qEEG and ratings of PTSD symptoms and combat exposure. The groups did not differ significantly in whole‐night qEEG measures for either rapid eye movement (REM) or non‐REM (NREM) sleep. Non‐significant medium effect sizes suggest less REM beta (opposite to our hypothesis), less REM and NREM sigma and more NREM gamma in combat veterans with PTSD. Positive correlations were found between combat exposure and NREM beta (PTSD group only), and REM and NREM sigma (non‐PTSD group only). Results did not support global hyperarousal in PTSD as indexed by increased beta qEEG activity. The correlation of sigma activity with combat exposure in those without PTSD and the non‐significant trend towards less sigma activity during both REM and NREM sleep in combat veterans with PTSD suggests that differential information processing during sleep may characterize combat‐exposed military veterans with and without PTSD.
Gene targeting studies have shown that the transcription factor SCL is critically important for embryonic hematopoiesis, but the early lethality of SCL null mice has precluded the genetic analysis of ...its function in the adult. We have now generated a conditional knockout of SCL by using Cre/Lox technology and an IFN-inducible Cre transgenic mouse. Deletion of SCL in adult mice perturbed megakaryopoiesis and erythropoiesis with the loss of early progenitor cells in both lineages. This led to a blunted response to the hematopoietic stress induced by polyinosinic-polycytidylic acid, with a persistently low platelet count and hematocrit compared with controls. In contrast, progenitors of granulocyte and macrophage lineages were not affected, even in the setting of stress. Immature progenitor cells (day 12 colony-forming unit spleen) with multilineage capacity were still present in the SCL null bone marrow, but these progenitors had lost the capacity to generate erythroid and megakaryocyte cells, and colonies were composed of only myeloid cells. These results suggest that SCL is critical for megakaryopoiesis and erythropoiesis, but is dispensable for production of myeloid cells during adult hematopoiesis.
Abstract A retrospective analysis was conducted in one claims database and was confirmed in a second independent database (covering both commercial and government insurance plans between 11/2009 and ...9/2011) for the understanding of factors influencing antiepileptic drug (AED) use and the role of AEDs and other health-care factors in hospital encounters. In both datasets, epilepsy cases were identified by AED use and epilepsy diagnosis coding. Variables analyzed for effect on hospitalization rates were as follows: (1) use of first-generation AEDs or second-generation AEDs, (2) treatment changes, and (3) factors that may affect AED choice. Lower rates of epilepsy-related hospital encounters (encounters with an epilepsy diagnosis code) were associated with use of second-generation AEDs, deliberate treatment changes, and treatment by a neurologist. Epilepsy-related hospital encounters were more frequent for patients not receiving an AED and for those with greater comorbidities. On average, patients taking ≥ 1 first-generation AED experienced epilepsy-related hospitalizations every 684 days, while those taking ≥ 1 second-generation AED were hospitalized every 1001 days (relative risk reduction of 31%, p < 0.01). Prescriptions for second-generation AEDs were more common among neurologists and among physicians near an epilepsy center. Use of second-generation AEDs, access to specialty care, and deliberate efforts to change medications following epilepsy-related hospital encounters improved outcomes of epilepsy treatment based on average time between epilepsy-related hospital encounters. These factors may be enhanced by public health policies, private insurance reimbursement policies, and education of patients and physicians.
Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its ...relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF
). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.
Femtosecond laser pulses can be used to precisely debond the interface between transparent films and substrates, thus providing a critical tool for interface characterization. This paper presents a ...model for the dynamic response of the film in the debonded region due to excitation from the laser pulse. The model illustrates that the timescale for transfer of energy to the film is typically much smaller than the inertial timescale associated with film bending; in such cases, the film deflection is governed entirely by the impulse delivered to the film and is insensitive to the details of the pressure generated by the laser pulse. Results for the maximum stress in the film and the dynamic energy release rate for debonding are used to generate regime maps that indicate failure modes (e.g. film fracture or interface debonding) as a function of pulse characteristics and film properties. The model is shown to exhibit good agreement with experiments, and hence provides a simple framework to design laser experiments to generate precisely defined interface flaws while avoiding film failures.
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