Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Endotoxin-Induced Oxidation of Plasma Cysteine and Glutathione in Mice

Bone marrow-derived mesenchymal stem cells (BMDMSC) are emerging as a therapeutic modality in various inflammatory disease states, including acute lung injury (ALI). A hallmark of inflammation, and a consistent observation in patients with ALI, is a perturbation in the systemic redox environment. However, little is known about the effects of BMDMSC on the systemic redox status. The objective of the present study was to determine whether exogenously infused BMDMSC protect against endotoxin-induced oxidation of plasma cysteine (Cys) and glutathione (GSH) redox states. To determine the effect on the redox state if BMDMSC, mice received endotoxin intraperitoneally (1 mg/kg), followed by intravenous infusion of either 5 × 105 BMDMSC or an equal volume of saline solution. Control mice received intraperitoneal endotoxin followed by 5 × 105 lung fibroblasts given intravenously. Cys, cystine (CySS), GSH, and glutathione disulfide (GSSG) concentrations were determined by HPLC. Results showed sequential preservation of plasma Cys and GSH levels in response to BMDMSC infusion. The data show that BMDMSC infusion leads to a more reducing Cys and GSH redox state. The findings are the first to demonstrate that BMDMSC have antioxidant effects in vivo, and add to our understanding of the systemic effects of BMDMSC in lung injury

Altered prostanoid production by fibroblasts cultured from the lungs of human subjects with idiopathic pulmonary fibrosis

BACKGROUND: Prostanoids are known to participate in the process of fibrogenesis. Because lung fibroblasts produce prostanoids and are believed to play a central role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), we hypothesized that fibroblasts (HF) cultured from the lungs of patients with IPF (HF-IPF) have an altered balance between profibrotic (thromboxane [TX]A(2)) and antifibrotic (prostacyclin [PGI(2)]) prostaglandins (PGs) when compared with normal human lung fibroblasts (HF-NL). METHODS: We measured inducible cyclooxygenase (COX)-2 gene and protein expression, and a profile of prostanoids at baseline and after IL-1β stimulation. RESULTS: In both HF-IPF and HF-NL COX-2 expression was undetectable at baseline, but was significantly upregulated by IL-1β. PGE(2) was the predominant COX product in IL-1β-stimulated cells with no significant difference between HF-IPF and HF-NL (28.35 [9.09–89.09] vs. 17.12 [8.58–29.33] ng/10(6) cells/30 min, respectively; P = 0.25). TXB(2) (the stable metabolite of TXA(2)) production was significantly higher in IL-1β-stimulated HF-IPF compared to HF-NL (1.92 [1.27–2.57] vs. 0.61 [0.21–1.64] ng/10(6) cells/30 min, respectively; P = 0.007) and the ratio of PGI(2) (as measured by its stable metabolite 6-keto-PGF(1α)) to TXB(2) was significantly lower at baseline in HF-IPF (0.08 [0.04–0.52] vs. 0.12 [0.11–0.89] in HF-NL; P = 0.028) and with IL-1β stimulation (0.24 [0.05–1.53] vs. 1.08 [0.51–3.79] in HF-NL; P = 0.09). CONCLUSION: An alteration in the balance of profibrotic and antifibrotic PGs in HF-IPF may play a role in the pathogeneses of IPF

Integrating comparative effectiveness research programs into predictive health: A unique role for academic health centers

Abstract The growing burden of chronic disease, an aging population, and rising health care costs threaten the sustainability of our current model for health care delivery

CPUF - a chemical-structure-based polyurethane foam decomposition and foam response model.

A Chemical-structure-based PolyUrethane Foam (CPUF) decomposition model has been developed to predict the fire-induced response of rigid, closed-cell polyurethane foam-filled systems. The model, developed for the B-61 and W-80 fireset foam, is based on a cascade of bondbreaking reactions that produce CO2. Percolation theory is used to dynamically quantify polymer fragment populations of the thermally degrading foam. The partition between condensed-phase polymer fragments and gas-phase polymer fragments (i.e. vapor-liquid split) was determined using a vapor-liquid equilibrium model. The CPUF decomposition model was implemented into the finite element (FE) heat conduction codes COYOTE and CALORE, which support chemical kinetics and enclosure radiation. Elements were removed from the computational domain when the calculated solid mass fractions within the individual finite element decrease below a set criterion. Element removal, referred to as ?element death,? creates a radiation enclosure (assumed to be non-participating) as well as a decomposition front, which separates the condensed-phase encapsulant from the gas-filled enclosure. All of the chemistry parameters as well as thermophysical properties for the CPUF model were obtained from small-scale laboratory experiments. The CPUF model was evaluated by comparing predictions to measurements. The validation experiments included several thermogravimetric experiments at pressures ranging from ambient pressure to 30 bars. Larger, component-scale experiments were also used to validate the foam response model. The effects of heat flux, bulk density, orientation, embedded components, confinement and pressure were measured and compared to model predictions. Uncertainties in the model results were evaluated using a mean value approach. The measured mass loss in the TGA experiments and the measured location of the decomposition front were within the 95% prediction limit determined using the CPUF model for all of the experiments where the decomposition gases were vented sufficiently. The CPUF model results were not as good for the partially confined radiant heat experiments where the vent area was regulated to maintain pressure. Liquefaction and flow effects, which are not considered in the CPUF model, become important when the decomposition gases are confined

Inducible expression of Pisum sativum xyloglucan fucosyltransferase in the pea root cap meristem, and effects of antisense mRNA expression on root cap cell wall structural integrity

Mitosis and cell wall synthesis in the legume root cap meristem can be induced and synchronized by the nondestructive removal of border cells from the cap periphery. Newly synthesized cells can be examined microscopically as they differentiate progressively during cap development, and ultimately detach as a new population of border cells. This system was used to demonstrate that Pisum sativum L. fucosyl transferase (PsFut1) mRNA expression is strongly expressed in root meristematic tissues, and is induced >2-fold during a 5-h period when mitosis in the root cap meristem is increased. Expression of PsFut1 antisense mRNA in pea hairy roots under the control of the CaMV35S promoter, which exhibits meristem localized expression in pea root caps, resulted in a 50–60% reduction in meristem localized endogenous PsFut1 mRNA expression measured using whole mount in situ hybridization. Changes in gross levels of cell wall fucosylated xyloglucan were not detected, but altered surface localization patterns were detected using whole mount immunolocalization with CCRC-M1, an antibody that recognizes fucosylated xyloglucan. Emerging hairy roots expressing antisense PsFut1 mRNA appeared normal macroscopically but scanning electron microscopy of tissues with altered CCRC-M1 localization patterns revealed wrinkled, collapsed cell surfaces. As individual border cells separated from the cap periphery, cell death occurred in correlation with extrusion of cellular contents through breaks in the wall

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

In Vivo Assessment of Pulmonary Vascular Integrity in Experimental Pulmonary Edema

During single pass indicator studies across the lungs [(14)C]urea remains in the vascular compartment, but its molecular size and solubility suggest it might escape abnormally permeable vessels. To test the hypothesis that [(14)C]urea might be used to distinguish pulmonary edema due to acutely increased intravascular pressure from that due to vascular damage by alloxan, we studied [(51)Cr]erythrocytes (r), [(125)I]albumin (a), [(14)C]urea (u), and tritiated water as dilution indicators in the pulmonary circulation of anesthetized dogs. In addition, the adequacy of albumin as an intravascular indicator was evaluated. Indicator curves, blood gases, hematocrit, and vascular pressures were determined during a base-line period and repeated 30 and 60 min after treatment in five groups of dogs: (a) saline control. (b) alloxan edema. (c) epinephrine infusion, (d) volume overload, and (e) left atrial (LA) balloon obstruction. Groups b, d, and e developed a similar degree of edema judging by wet/dry lung weights and histology. Groups a and c did not develop edema. In alloxan edema, differences between the mean transit time volume of u and r (V(v-r)) increased over base line at 30 (P < 0.001) and 60 min (P < 0.02); the differences between the mean transit time volume of a and r (V(e-r)) increased slightly at 30 (P < 0.03) and 60 min (P < 0.02); and V(u-r) significantly exceeded V(a-r) at 30 (mean difference = 9 ml, P < 0.02) and 60 min (mean difference = 11, P < 0.04). In none of the other groups did V(u-r) significantly exceed V(a-r). Thus, comparison of V(u-r) with V(a-r) may permit distinction between “high pressure” and “increased permeability” pulmonary edema. Albumin was not a consistently reliable indicator of intravascular volume as compared with composite red cell and albumin curve