A novel adaptive control system for noisy pressure-controlled ventilation: a numerical simulation and bench test study

Purpose

There is growing interest in the use of both variable and pressure-controlled ventilation (PCV). The combination of these approaches as “noisy PCV” requires adaptation of the mechanical ventilator to the respiratory system mechanics. Thus, we developed and evaluated a new control system based on the least-mean-squares adaptive approach, which automatically and continuously adjusts the driving pressure during PCV to achieve the desired variability pattern of tidal volume (V _T).

Methods

The controller was tested during numerical simulations and with a physical model reproducing the mechanical properties of the respiratory system. We applied step changes in respiratory system mechanics and mechanical ventilation settings. The time needed to converge to the desired V _T variability pattern after each change (t _c) and the difference in minute ventilation between the measured and target pattern of V _T (ΔMV) were determined.

Results

During numerical simulations, the control system for noisy PCV achieved the desired variable V _T pattern in less than 30 respiratory cycles, with limited influence of the dynamic elastance (E*) on t _c, except when E* was underestimated by >25%. We also found that, during tests in the physical model, the control system converged in <60 respiratory cycles and was not influenced by airways resistance. In all measurements, the absolute value of ΔMV was <25%.

Conclusion

The new control system for noisy PCV can prove useful for controlled mechanical ventilation in the intensive care unit.     

Alcohol, Signaling, and ECM Turnover

Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse.     

Immunostimulatory RNA oligonucleotides trigger an antigen-specific cytotoxic T-cell and IgG2a response

Single-stranded RNA oligonucleotides containing an immunostimulatory motif (immunostimulatory RNA [isRNA]) are potent inducers of interferon-alpha via the Toll-like receptor 7. We investigated the effect of isRNA on the development of an immune response. We show that isRNA activates dendritic cells and induces production of Th1-type cytokines both in vitro and in vivo. Cytokine production led to bystander activation of T and B cells. We further demonstrate that isRNA triggers the generation of antigen-specific cytotoxic T cells and of an IgG2a-biased antibody response to antigen in a sequence-dependent manner. In summary, we provide evidence for the first time that isRNA oligonucleotides can simultaneously activate the innate and adaptive arms of the immune system.     

Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging

Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways.Experimental dietary restriction (DR) is based on a 10–30% reduction in food intake without leading to malnutrition (Omodei and Fontana, 2011). DR has been intensively studied and was shown to elongate the lifespan of Caenorhabditis elegans, Drosophila melanogaster, and rats (Fontana et al., 2010). Studies on inbred laboratory mice revealed that DR elongates lifespan in some mouse strains, whereas in others, the effects of DR were neutral or even resulted in lifespan shortening compared with ad libitum (AL)–fed controls (Harper et al., 2006). In long-lived nonhuman primates, two studies reported on the consequences of long-term DR on overall lifespan (Colman et al., 2009; Mattison et al., 2012). In both studies, DR did not result in a significant elongation of the lifespan compared with AL controls when all primates were included in the analysis (Colman et al., 2009; Mattison et al., 2012). These results stand in contrast to multiple studies having unambiguously documented beneficial effects of DR on health parameters and disease prevention in both murine models and primates, including suppression of cancer development, memory loss, hearing impairments, type 2 diabetes, hypertension, and heart disease (Shimokawa et al., 1993; Mattson, 2005; Cohen et al., 2009; Colman et al., 2009; Omodei and Fontana, 2011; Mattison et al., 2012).To better understand the effects of DR on health and lifespan, it is important to characterize the cellular consequences of DR at the level of adult tissue stem cells. Adult stem cells exist in many mammalian organs and tissues. Given that stem cells play essential roles in the maintenance of tissue homeostasis and tissue regeneration after damage, it is believed that age-related changes in stem cell function impact tissue aging (Dorshkind et al., 2009; Jones and Rando, 2011; Goldberg et al., 2015). Indeed, age-related declines in stem cell functionality occur in various tissues (Liu and Rando, 2011). However, the effects of DR on stem cell functionality and aging remain to be characterized in greater detail. It was reported that DR enhances muscle stem cell maintenance and activity to regenerate damaged muscle (Cerletti et al., 2012). In addition, it was shown that DR augments stem cell activity in the intestinal epithelium by stimulating mammalian target of rapamycin complex 1 (mTORC1) signaling in the Paneth cells that form a niche for intestinal stem cells (Yilmaz et al., 2012).In the hematopoietic system, DR ameliorated aging-associated increases in the self-renewal of phenotypic hematopoietic stem cells (HSCs) with reduced functionality as well as defects in the clearance of nonproliferative (senescent) and damaged T lymphocytes (Spaulding et al., 1997a; Chen et al., 1998, 2003; Ertl et al., 2008). However, DR-fed mice exhibited an enhanced susceptibility to infections indicative of impaired immune functions (Peck et al., 1992; Gardner, 2005; Kristan, 2007; Goldberg et al., 2015). Mechanistically, the effects of DR on HSC functionality remain incompletely understood but are influenced by genetic factors (Ertl et al., 2008).In this study, we analyzed the short- and long-term effects of adult-onset 30% DR on the capacity of HSCs and progenitor cells in maintaining hematopoietic repopulation and B lymphopoiesis in C57BL/6J mice. The study provides the first experimental evidence that long-term DR alters the lymphoid cell differentiation potential of HSCs and progenitor cells, resulting in immune defects in the context of prolonged bacterial infection. However, long-term DR from young adulthood to midlife improves the maintenance of the repopulation capacity of HSCs by enhancing stem cell quiescence. The study identifies distinct stress signaling factors (IL-6 and IL-7) and growth factors (insulin-like growth factor 1 [IGF1]) that contribute to both the positive and adverse effects of DR on HSC functionality.     

Sensor-operated faucets: a possible source of nosocomial infection?

Recently, contamination of sensor-operated faucets (SOFs) with Pseudomonas aeruginosa was observed. To evaluate odds ratios, we conducted a case-control study in which handle-operated faucets served as controls. No statistically significant difference in P. aeruginosa counts was observed between SOFs and regular faucets in our study (odds ratio, 0.0; 95% confidence interval, 0.0 to 39.0; two-sided P exact = .99).     

Malaria in a holoendemic area of Burkina Faso: a cross-sectional study

A malaria survey of the entire population of a village in Western Burkina Faso (n=1,561) was conducted to assess malaria endemicity. The study population was examined for symptoms characteristic of malaria including fever, anaemia, splenomegaly and parasites present in thick blood films. In the overall study population, the prevalence of Plasmodium spp. infection by microscopic examination of thick blood films was 79.0% (1,233/1,561). In a subcohort with 201 individuals, PCR techniques found a prevalence rate for all Plasmodium spp. of 92.0% (185/201), while microscopy found one of 80.6% (162/201). A combination of both methods gives a rate of 95.5% (192/201). Though univariate logistic analyses of elevated body temperature, anaemia, splenomegaly and age showed them all to be predictors of or risk factors for an infection, only elevated body temperature and age were predictors in multivariate logistic analysis. However, the symptom of splenomegaly did show a highly significant association with infection by multiple species of Plasmodium.     

Migration of antibody secreting cells towards CXCL12 depends on the isotype that forms the BCR

Truncation of the cytoplasmic tail of membrane-bound IgE in vivo results in lower serum IgE levels, decreased numbers of IgE-secreting plasma cells and the abrogation of specific secondary immune responses. Here we present mouse strain KN1 that expresses a chimeric epsilon-gamma1 BCR, consisting of the extracellular domains of the epsilon gene and the transmembrane and cytoplasmic domains of the gamma1 gene. Thus, differences in the IgE immune response of KN1 mice reflect the influence of the "gamma1-mediated signalling" of mIgE bearing B cells. KN1 mice show an increased serum IgE level, resulting from an elevated number of IgE-secreting cells. Although the primary IgE immune response in KN1 mice is inconspicuous, the secondary response is far more robust. Most strikingly, IgE-antibody secreting cells with "gamma1-signalling history" migrate more efficiently towards the chemokine CXCL12, which guides plasmablasts to plasma cell niches, than IgE-antibody secreting cells with WT "epsilon-signalling history". We conclude that IgE plasmablasts have an intrinsic, lower chance to contribute to the long-lived plasma cell pool than IgG1 plasmablasts.     

Two-color FISH characterization of i(1q) and der(1;16) in human breast cancer cells

Two-color fluorescent in situ hybridizations using probes for alphoid (α) and classical satellite (CS) DNAs from chromosomes 1 and 16 were performed to characterize i(1q), der(1;16), and complex rearrangements observed in breast cancer cells from fresh tumors and established cell lines. Six of seven i(1q) occurred after breakage in the α1 containing region and one of seven was dicentric, with breakage in 1p11.2. The five der(1;16)(q10;p10) studied appeared to result from a variety of breakpoints involving α1, α16, CS1, and CS16 DNAs. All had conserved α16 DNA, suggesting a segregation of the der(1;16) leading to a loss of 16q and a gain of 1q in most cases. One complex rearrangement of chromosome 1 also appeared to involve chromosome 16, suggesting that a der(1;16) occurred first, followed by another rearrangement. Both the apparent preferential involvement of constitutive heterochromatin harboring α and CS DNAs and the variety of breakpoints spanning along heterochromatin suggest that the important consequence of the rearrangement is not the breakage per se but the resulting imbalance. © 1993 Wiley-Liss, Inc.