Tolerability of inhaled N-chlorotaurine in an acute pig streptococcal lower airway inflammation model

<p>Abstract</p> <p>Background</p> <p>Inhalation of N-chlorotaurine (NCT), an endogenous new broad spectrum non-antibiotic anti-infective, has been shown to be very well tolerated in the pig model recently. In the present study, inhaled NCT was tested for tolerability and efficacy in the infected bronchopulmonary system using the same model.</p> <p>Methods</p> <p>Anesthetized pigs were inoculated with 20 ml of a solution containing approximately 10⁸CFU/ml <it>Streptococcus pyogenes </it>strain d68 via a duodenal tube placed through the tracheal tube down to the carina. Two hours later, 5 ml of 1% NCT aqueous solution (test group, n = 15) or 5 ml of 0.9% NaCl (control group, n = 16) was inhaled via the tracheal tube connected to a nebulizer. Inhalation was repeated every hour, four times in total. Lung function and haemodynamics were monitored. Bronchoalveolar lavage samples were removed for determination of colony forming units (CFU), and lung samples for histology.</p> <p>Results</p> <p>Arterial pressure of oxygen (PaO₂) decreased rapidly after instillation of the bacteria in all animals and showed only a slight further decrease at the end of the experiment without a difference between both groups. Pulmonary artery pressure increased to a peak 1-1.5 h after application of the bacteria, decreased in the following hour and remained constant during treatment, again similarly in both groups. Histology demonstrated granulocytic infiltration in the central parts of the lung, while this was absent in the periphery. Expression of TNF-alpha, IL-8, and haemoxygenase-1 in lung biopsies was similar in both groups. CFU counts in bronchoalveolar lavage came to 170 (10; 1388) CFU/ml (median and 25 and 75 percentiles) for the NCT treated pigs, and to 250 (10; 5.5 × 10⁵) CFU/ml for NaCl treated pigs (p = 0.4159).</p> <p>Conclusions</p> <p>Inhaled NCT at a concentration of 1% proved to be very well tolerated also in the infected bronchopulmonary system. This study confirms the tolerability in this delicate body region, which has been proven in healthy pigs previously. Regarding efficacy, no conclusions can be drawn, mainly because of the limited test period of the model.</p

Oncogenic conversion of the thyroid hormone receptor by altered nuclear transport

Nuclear receptors (NRs) are transcription factors whose activity is modulated by ligand binding. These receptors are at the core of complex signaling pathways and act as integrators of many cellular signals. In the last decade our understanding of NRs has greatly evolved. In particular, regulation of NR subcellular dynamics has emerged as central to their activity. Research on the subcellular distribution of the thyroid hormone receptor (TR) has revealed new dimensions in the complexity of NR regulation, and points to the possibility that NR mislocalization plays a key role in oncogenesis. For many years, TR was thought to reside exclusively in the nucleus. It is now known that TR is a dynamic protein that shuttles between the nucleus and cytoplasm. TR is localized to the nucleus in a phosphorylated form, suggesting that compartment-specific phosphorylation mediates cross-talk between multiple cell signaling pathways. The oncoprotein v-ErbA, a viral-derived dominant negative variant of TR is actively exported to the cytoplasm by the CRM1 export receptor. Strikingly, the oncoprotein causes mislocalization of cellular TR and some of its coactivators by direct interaction. Here, we offer some perspectives on the role of subcellular trafficking in the oncogenic conversion of TR, and propose a new model for oncoprotein dominant negative activity

Mechanistic investigation of the effect of endoglucanases related to pulp refining

Endoglucanases are increasingly being touted as the ultimate solution for reducing energy consumption during the refining process in the pulp and paper industry. However, due to the high variety of endoglucanases in different enzyme formulations, these perform heterogeneously when applied to different pulps. In this study, the effect of four endoglucanases on softwood and hardwood pulp was studied using confocal laser scanning microscopy (CLSM) after addition of fluorescently labelled carbohydrate binding modules (CBMs). Nuclear magnetic resonance (NMR) analysis and high-performance liquid chromatography quantification of released oligo- and monosaccharides was performed for in-depth mechanistical investigation. Changes in the crystallinity levels caused by enzymatic degradation of amorphous regions were monitored by incubation with two different CBMs from Caldicellulosiruptor bescii and from Thermobifida fusca with high preference to either amorphous or crystalline regions of cellulose, respectively. When dosed at identical activity on the endoglucanase specific CellG5 substrate, CLSM analysis indicated the highest decrease of amorphous regions for those endoglucanases which were also most active in laboratory refining trials and which released highest amounts of cellooligomers from pulp. Using 13C-NMR analysis, an increase in para-crystalline cellulose caused by enzyme application was observed. Release of reducing sugars was determined at identical CellG5 dosage, indicating a high variance between the enzymes, especially when complex enzyme formulations were used. Scanning electron microscopy images were obtained for visualization of the endoglucanase activity. The results of mechanistical studies indicate that reduction of amorphous moieties of pulp by endoglucanases is especially beneficial for the refining proces

Tolerability of inhaled N-chlorotaurine in the pig model

<p>Abstract</p> <p>Background</p> <p>N-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic. Its antimicrobial activity can be enhanced by ammonium chloride. This study was designed to evaluate the tolerability of inhaled N-chlorotaurine (NCT) in the pig model.</p> <p>Methods</p> <p>Anesthetized pigs inhaled test solutions of 1% (55 mM) NCT (n = 7), 5% NCT (n = 6), or 1% NCT plus 1% ammonium chloride (NH₄Cl) (n = 6), and 0.9% saline solution as a control (n = 7), respectively. Applications with 5 ml each were performed hourly within four hours. Lung function, haemodynamics, and pharmacokinetics were monitored. Bronchial lavage samples for captive bubble surfactometry and lung samples for histology and electron microscopy were removed.</p> <p>Results</p> <p>Arterial pressure of oxygen (PaO₂) decreased significantly over the observation period of 4 hours in all animals. Compared to saline, 1% NCT + 1% NH₄Cl led to significantly lower PaO₂values at the endpoint after 4 hours (62 ± 9.6 mmHg vs. 76 ± 9.2 mmHg, p = 0.014) with a corresponding increase in alveolo-arterial difference of oxygen partial pressure (AaDO₂) (p = 0.004). Interestingly, AaDO₂was lowest with 1% NCT, even lower than with saline (p = 0.016). The increase of pulmonary artery pressure (PAP) over the observation period was smallest with 1% NCT without difference to controls (p = 0.91), and higher with 5% NCT (p = 0.02), and NCT + NH₄Cl (p = 0.05).</p> <p>Histological and ultrastructural investigations revealed no differences between the test and control groups. The surfactant function remained intact. There was no systemic resorption of NCT detectable, and its local inactivation took place within 30 min. The concentration of NCT tolerated by A549 lung epithelial cells <it>in vitro </it>was similar to that known from other body cells (0.25–0.5 mM).</p> <p>Conclusion</p> <p>The endogenous antiseptic NCT was well tolerated at a concentration of 1% upon inhalation in the pig model. Addition of ammonium chloride in high concentration provokes a statistically significant impact on blood oxygenation.</p

Young carers in England: findings from the 2018 BBC survey on the prevalence and nature of caring among young people

Background Many young people are involved in caring for parents, siblings, or other relatives who have an illness or disability. The aim of this study was to estimate the prevalence of caring by young people in England. Method A national survey of 925 English young people was conducted using the 18‐item survey version of the Multidimensional Assessment of Caring Activities Checklist for Young Carers. Results Around 7% of young people were identified as doing at least a high amount of caring activity and 3% a very high amount. Most frequently, caring by a young person is for a mother or a sibling, with a physical disability. Caring activity consisted mostly of domestic activities, household management, and emotional care. Conclusion This study provides the most up to date and methodologically sophisticated survey data on the prevalence of young caring in England, with implications for policy and practice

Intensive care nurse-family engagement from a global perspective: A qualitative multi-site exploration

Background: Critical illness is distressing for families, and often results in negative effects on family health that influence a family\u27s ability to support their critically ill family member. Although recent attention has been directed at improving care and outcomes for families of critically ill patients, the manner in which nurses engage with families is not fully understood. Objectives: To describe nurses’ perceptions and practices of family engagement in adult intensive care units from a global perspective. Design: A qualitative-descriptive multi-site design using content analysis. Settings: The study was conducted in 26 intensive care units of 12 urban, metropolitan, academic medical centers in ten countries, spanning five continents. Participants: A total of 65 registered nurses (77% women, age of M = 39.5, SD = 11.4 years) participated. Most held intensive care certification (72%) and had worked on average 10 (SD = 9.6) years in the ICU. Methods: Semi-structured, individual interviews (M = 38.4 min, SD = 12.0) were held with ICU nurses at the hospital (94%) or their home using an interview guide. Qualitative interview data were analysed using inductive content analysis. Results: We found that nurse-family engagement was an ebb and flow of relational power that needed to be carefully negotiated and balanced, with nurses holding and often exerting more power than families. Constant fluctuations in nurses’ practices of engagement occurred in day-to-day practice from shift-to-shift and from nurse-to-nurse. Family engagement was dependent on individual nurses’ attitudes and perceptions of family, the patient\u27s condition, and workload. Lastly, family engagement was shaped by the ICU context, with team culture, collaborative relationships, unit structures and organizational resources either enabling or limiting nurses’ ability to engage with families. Conclusions: This global study provides an in-depth understanding of the way nurses engage with families in ICU and reflects many different cultures and health systems. We found that nurse-family engagement was marked by a shifting, yet often unequal power distribution in the nurse-family relationship, inconsistent nurse engagement practices, both of which resulted in variable family engagement in intensive care. Our research contributes a detailed description of engagement as practiced in the everyday delivery of health care. A more concentrated team effort, based on a shared culture and defined framework of family care is needed to ensure that families of critically ill persons are fully engaged in all aspects of intensive care

Effects of anharmonic strain on phase stability of epitaxial films and superlattices: applications to noble metals

Epitaxial strain energies of epitaxial films and bulk superlattices are studied via first-principles total energy calculations using the local-density approximation. Anharmonic effects due to large lattice mismatch, beyond the reach of the harmonic elasticity theory, are found to be very important in Cu/Au (lattice mismatch 12%), Cu/Ag (12%) and Ni/Au (15%). We find that is the elastically soft direction for biaxial expansion of Cu and Ni, but it is for large biaxial compression of Cu, Ag, and Au. The stability of superlattices is discussed in terms of the coherency strain and interfacial energies. We find that in phase-separating systems such as Cu-Ag the superlattice formation energies decrease with superlattice period, and the interfacial energy is positive. Superlattices are formed easiest on (001) and hardest on (111) substrates. For ordering systems, such as Cu-Au and Ag-Au, the formation energy of superlattices increases with period, and interfacial energies are negative. These superlattices are formed easiest on (001) or (110) and hardest on (111) substrates. For Ni-Au we find a hybrid behavior: superlattices along and like in phase-separating systems, while for they behave like in ordering systems. Finally, recent experimental results on epitaxial stabilization of disordered Ni-Au and Cu-Ag alloys, immiscible in the bulk form, are explained in terms of destabilization of the phase separated state due to lattice mismatch between the substrate and constituents.Comment: RevTeX galley format, 16 pages, includes 9 EPS figures, to appear in Physical Review

An artificial intelligence algorithm is highly accurate for detecting endoscopic features of eosinophilic esophagitis

The endoscopic features associated with eosinophilic esophagitis (EoE) may be missed during routine endoscopy. We aimed to develop and evaluate an Artificial Intelligence (AI) algorithm for detecting and quantifying the endoscopic features of EoE in white light images, supplemented by the EoE Endoscopic Reference Score (EREFS). An AI algorithm (AI-EoE) was constructed and trained to differentiate between EoE and normal esophagus using endoscopic white light images extracted from the database of the University Hospital Augsburg. In addition to binary classification, a second algorithm was trained with specific auxiliary branches for each EREFS feature (AI-EoE-EREFS). The AI algorithms were evaluated on an external data set from the University of North Carolina, Chapel Hill (UNC), and compared with the performance of human endoscopists with varying levels of experience. The overall sensitivity, specificity, and accuracy of AI-EoE were 0.93 for all measures, while the AUC was 0.986. With additional auxiliary branches for the EREFS categories, the AI algorithm (AI-EoE-EREFS) performance improved to 0.96, 0.94, 0.95, and 0.992 for sensitivity, specificity, accuracy, and AUC, respectively. AI-EoE and AI-EoE-EREFS performed significantly better than endoscopy beginners and senior fellows on the same set of images. An AI algorithm can be trained to detect and quantify endoscopic features of EoE with excellent performance scores. The addition of the EREFS criteria improved the performance of the AI algorithm, which performed significantly better than endoscopists with a lower or medium experience level