Effect of mucolytic and bronchodilator aerosol therapy on airway resistance in mechanically ventilated patients

Nebulisation of a 10% solution of Mesna (Mistabron) in 10 postoperatively ventilated patients without preexisting pulmonary disease caused a significant increase in inspiratory resistance. This increase is effectively blocked by addition of a bronchodilator (i.e. Salbutamol) to the aerosol. No significant changes in airway resistance were observed in the 10 patients receiving salbutamol alone or isotonic saline. The expiratory resistance did not change suggesting that only the larger airways are involved in the constrictive effect of the drug. Although no patient showed clinical signs of bronchospasm, it is worth considering that even in patients without history of obstructive pulmonary disease nebulisation of Mesna should be performed in combination with a bronchodilator.     

Signal processing underlying extrinsic control of stem cell fate

PURPOSE OF REVIEW: Strategies to manipulate stem cells for therapeutic applications are limited by our inability to control or predict stem cell fate decisions in response to exogenous stimuli. This review focuses on the mechanisms by which exogenous stimuli influence cell fate. RECENT FINDINGS: Limitations in our ability to control cell fate arises from our primarily qualitative understanding of stem cell regulation, which proposes straightforward cue-fate relationships that appear to be the exception rather than the rule. Alternatively, consideration of the underlying quantitative, temporal, and spatial mechanisms governing extrinsic regulation of stem cell fate may enable novel approaches to control stem cell output predictively. SUMMARY: The authors review advances in the understanding of these underlying mechanisms, and discuss experimental and analytic tools necessary to investigate and use these mechanisms to control stem cell fate.     

Systematic engineering of 3D pluripotent stem cell niches to guide blood development

Pluripotent stem cells (PSC) provide insight into development and may underpin new cell therapies, yet controlling PSC differentiation to generate functional cells remains a significant challenge. In this study we explored the concept that mimicking the local in vivo microenvironment during mesoderm specification could promote the emergence of hematopoietic progenitor cells from embryonic stem cells (ESCs). First, we assessed the expression of early phenotypic markers of mesoderm differentiation (E-cadherin, brachyury (T-GFP), PDGFRα, and Flk1: +/−ETPF) to reveal that E−T+P+F+ cells have the highest capacity for hematopoiesis. Second, we determined how initial aggregate size influences the emergence of mesodermal phenotypes (E−T+P+F+, E−T−P+/−F+, and E−T−P+F−) and discovered that colony forming cell (CFC) output was maximal with ∼100 cells per PSC aggregate. Finally, we introduced these 100-cell PSC aggregates into a low oxygen environment (5%; to upregulate endogenous VEGF secretion) and delivered two potent blood-inductive molecules, BMP4 and TPO (bone morphogenetic protein-4 and thrombopoietin), locally from microparticles to obtain a more robust differentiation response than soluble delivery methods alone. Approximately 1.7-fold more CFCs were generated with localized delivery in comparison to exogenous delivery, while combined growth factor use was reduced ∼14.2-fold. By systematically engineering the complex and dynamic environmental signals associated with the in vivo blood developmental niche we demonstrate a significant role for inductive endogenous signaling and introduce a tunable platform for enhancing PSC differentiation efficiency to specific lineages.     

Selective decontamination of the digestive tract as infection prevention in the critically ill. A level 1 evidence-based strategy

Selective decontamination of the digestive tract (SDD) evolved into evidence-based medicine as a tool to prevent infections in critically ill patients. It significantly reduces mortality, pneumonia, bloodstream infections and the onset of resistance if the full four-component regimen is used. The use of only oral decontamination may reduce the incidence of pneumonia, but it has no significant impact on mortality. Moreover, the full SDD protocol significantly reduces the fecal carriage of multiresistant aerobic Gram-negative bacteria, whereas oral decontamination only is associated with increased carriage of multiresistant aerobic Gram-negative bacilli.     

Seeding bioreactor-produced embryonic stem cell-derived cardiomyocytes on different porous, degradable, polyurethane scaffolds reveals the effect of scaffold architecture on cell morphology

A successful regenerative therapy to treat damage incurred after an ischemic event in the heart will require an integrated approach including methods for appropriate revascularization of the infarct site, mechanical recovery of damaged tissue, and electrophysiological coupling with native cells. Cardiomyocytes are the ideal cell type for heart regeneration because of their inherent electrical and physiological properties, and cardiomyocytes derived from embryonic stem cells (ESCs) represent an attractive option for tissue-engineering therapies. An important step in developing tissue engineering-based approaches to cardiac cell therapy is understanding how scaffold architecture affects cell behavior. In this work, we generated large numbers of ESC-derived cardiomyocytes in bioreactors and seeded them on porous, 3-dimensional scaffolds prepared using 2 different techniques: electrospinning and thermally induced phase separation (TIPS). The effect of material macro-architecture on the adhesion, viability, and morphology of the seeded cells was determined. On the electrospun scaffolds, cells were elongated in shape, a morphology typical of cultured ESC-derived cardiomyocytes, whereas on scaffolds fabricated using TIPS, the cells retained a rounded morphology. Despite these gross phenotypic and physiological differences, sarcomeric myosin and connexin 43 expression was evident, and contracting cells were observed on both scaffold types, suggesting that morphological changes induced by material macrostructure do not directly correlate to functional differences.     

Suppression of Helicobacter pylori infection during intensive care stay: related to stress ulcer bleeding incidence?

Purpose: To assess the prevalence of active Helicobacter pylori infection in patients admitted to the intensive care unit, to determine the effect of selective gut decontamination on the persistence of this organism, and to explore the possible relationship between H. pylori infection and stress ulcer bleeding incidence. Materials and Methods: We determined in a prospective observational study of 300 consecutive, mechanically ventilated patients the activity of H. pylori infection and the incidence of stress ulcer–related upper gastrointestinal bleeding over time. H. pylori infection was detected by Laser-Assisted Ratio Analyzer (LARA)- ¹³C-urea breath test (Alimenterics, Inc., NJ) and serology. Stress ulcer prophylaxis was not prescribed. Endoscopy was performed in cases of upper gastrointestinal bleeding. Results: The prevalence of active H. pylori infection on admission was 38% as detected by urea breath test, and declined to 8% on the third day, and to 0% on the seventh day after admission as a result of antibiotic treatment. Stress ulcer–related upper gastrointestinal bleeding occurred in 1.0% (3 of 300) of the patients; none were infected with H. pylori on admission or at the time of bleeding. Conclusions: H. pylori infection monitored by LARA- ¹³C-urea breath test was rapidly suppressed during intensive care treatment, which can be explained by the routine use of antibiotics for gut decontamination.The low incidence of stress ulcer–related bleeding might be related to the prevention of H. pylori–associated stress lesions by effective suppression of this microorganism, but further studies are warranted to test this hypothesis. Copyright © 2002 by W.B. Saunders Company     

HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity

Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers. While documenting the enhanced therapeutic potential of HER2-targeted liposomal doxorubicin can be done with existing models, there has been no validated human cardiac cell-based assay system to rigorously assess the cardiotoxicity of anthracyclines. To understand if HER2-targeting of liposomal doxorubicin is possible with a favorable cardiac safety profile, we applied a human stem cell-derived cardiomyocyte platform to evaluate the doxorubicin exposure of human cardiac cells to HER2-targeted liposomal doxorubicin. To the best of our knowledge, this is the first known application of a stem cell-derived system for evaluating preclinical cardiotoxicity of an investigational agent. We demonstrate that HER2-targeted liposomal doxorubicin has little or no uptake into human cardiomyocytes, does not inhibit HER2-mediated signaling, results in little or no evidence of cardiomyocyte cell death or dysfunction, and retains the low penetration into heart tissue of liposomal doxorubicin. Taken together, this data ultimately led to the clinical decision to advance this drug to Phase I clinical testing, which is now ongoing as a single agent in HER2-expressing cancers.