Zinc deficiency enhances sensitivity to influenza A associated bacterial pneumonia in mice.

Although zinc deficiency (secondary to malnutrition) has long been considered an important contributor to morbidity and mortality of infectious disease (e.g. diarrhea disorders), epidemiologic data (including randomized controlled trials with supplemental zinc) for such a role in lower respiratory tract infection are somewhat ambiguous. In the current study, we provide the first preclinical evidence demonstrating that although diet-induced acute zinc deficiency (Zn-D: ~50% decrease) did not worsen infection induced by either influenza A (H1N1) or methicillin-resistant staph aureus (MRSA), Zn-D mice were sensitive to the injurious effects of superinfection of H1N1 with MRSA. Although the mechanism underlying the sensitivity of ZnD mice to combined H1N1/MRSA infection is unclear, it was noteworthy that this combination exacerbated lung injury as shown by lung epithelial injury markers (increased BAL protein) and decreased genes related to epithelial integrity in Zn-D mice (surfactant protein C and secretoglobins family 1A member 1). As bacterial pneumonia accounts for 25%-50% of morbidity and mortality from influenza A infection, zinc deficiency may be an important pathology component of respiratory tract infections.

Telemedicine-Based Digital Cognitive Behavioral Intervention for Perioperative Anxiety and Depression for Total Knee Arthroplasty.

Introduction: Preoperative anxiety and depression have been shown to increase postoperative pain and opioid consumption by up to 50% in patients undergoing primary unilateral Total Knee Arthroplasty (TKA). We hypothesized that the use of a telemedicine-based digital Cognitive Behavioral Intervention program (RxWell®) started one month prior to surgery would control anxiety and depression prior to surgery. Materials and methods: This was a randomized, controlled trial that enrolled patients undergoing primary unilateral TKA. At least a month prior to surgery, patients who gave consent to participate were asked to complete PROMIS® (Patient-Reported Outcomes Measurement Information System) emotional anxiety short form 8a and PROMIS® emotional depression short form-8a questionnaires. Patients with T-scores of ≥ 57 were randomized to either a no intervention (control group) or a RxWell® program (treatment group) for a month prior to surgery. The primary outcome of this proof-of-concept study was the ability of the RxWell® to normalize patients' PROMIS anxiety T scores. Results: T scores for anxiety and depression among patients randomized to the RxWell® group significantly decreased from 64.3 ± 3.0 at the time of randomization to 58.5 ± 2.6 prior to surgery (n=5, p=0.006), whereas no changes in T scores were recorded in the control group (59.4 ± 4.2 at the time of randomization vs. 57.7 ± 6.2; n=6, p=0.559). Conclusion: These preliminary data suggest that the use of a RxWell® program represents an effective approach to control anxiety and depression prior to surgery. In contrast, it seems that in the absence of treatment, anxiety level remains similar over a month prior to surgery.

Prehabilitation: a narrative review focused on exercise therapy for the prevention of postoperative pulmonary complications following lung resection.

Extensive preventive strategies in the perioperative period are popular worldwide. Novel "prehabilitation" approaches are being defined for every individual surgical discipline. With intention to reduce perioperative morbidity, "prehabilitation" was developed to increase "physical wellness" considering exercise capacity, nutritional status, and psychological support. Thus, prehabilitation could be well-suited for patients undergoing lung cancer surgery. Theoretically, improving physical condition may increase the chances of having a better post-operative course, especially among frail patients. In this review, we describe the concept of prehabilitation with possible benefits, its role in the Enhanced Recovery After Surgery protocols, and its potential for the future.

Dichloroacetate-induced metabolic reprogramming improves lifespan in a Drosophila model of surviving sepsis.

Sepsis is the leading cause of death in hospitalized patients and beyond the hospital stay and these long-term sequelae are due in part to unresolved inflammation. Metabolic shift from oxidative phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome. We propose a shift from aerobic glycolysis to oxidative phosphorylation as a sepsis therapy by targeting the pathways involved in the conversion of pyruvate into acetyl-CoA via pyruvate dehydrogenase (PDH). Chemical manipulation of PDH using dichloroacetic acid (DCA) will promote oxidative phosphorylation over glycolysis and decrease inflammation. We tested our hypothesis in a Drosophila melanogaster model of surviving sepsis infected with Staphylococcus aureus. Drosophila were divided into 3 groups: unmanipulated, sham and sepsis survivors, all treated with linezolid; each group was either treated or not with DCA for one week following sepsis. We followed lifespan, measured gene expression of Toll, defensin, cecropin A, and drosomycin, and levels of lactate, pyruvate, acetyl-CoA as well as TCA metabolites. In our model, metabolic effects of sepsis are modified by DCA with normalized lactate, TCA metabolites, and was associated with improved lifespan of sepsis survivors, yet had no lifespan effects on unmanipulated and sham flies. While Drosomycin and cecropin A expression increased in sepsis survivors, DCA treatment decreased both and selectively increased defensin.

Metabolomics with Nuclear Magnetic Resonance Spectroscopy in a Drosophila melanogaster Model of Surviving Sepsis.

Patients surviving sepsis demonstrate sustained inflammation, which has been associated with long-term complications. One of the main mechanisms behind sustained inflammation is a metabolic switch in parenchymal and immune cells, thus understanding metabolic alterations after sepsis may provide important insights to the pathophysiology of sepsis recovery. In this study, we explored metabolomics in a novel Drosophila melanogaster model of surviving sepsis using Nuclear Magnetic Resonance (NMR), to determine metabolite profiles. We used a model of percutaneous infection in Drosophila melanogaster to mimic sepsis. We had three experimental groups: sepsis survivors (infected with Staphylococcus aureus and treated with oral linezolid), sham (pricked with an aseptic needle), and unmanipulated (positive control). We performed metabolic measurements seven days after sepsis. We then implemented metabolites detected in NMR spectra into the MetExplore web server in order to identify the metabolic pathway alterations in sepsis surviving Drosophila. Our NMR metabolomic approach in a Drosophila model of recovery from sepsis clearly distinguished between all three groups and showed two different metabolomic signatures of inflammation. Sham flies had decreased levels of maltose, alanine, and glutamine, while their level of choline was increased. Sepsis survivors had a metabolic signature characterized by decreased glucose, maltose, tyrosine, beta-alanine, acetate, glutamine, and succinate.

Are plasma mineral levels related to antibody response to influenza vaccination in older adults?

INTRODUCTION: An effective immune response to vaccination may be related to nutritional status. This study examined the association of plasma mineral levels with hemagglutination inhibition (HI) titers produced in response to influenza vaccine in older adults. METHODS: Prior to (Day 0) and 21 (range = 19-28) days after receiving the 2013-14 influenza vaccine, 109 adults ages 51-81 years, provided blood samples. Serum samples were tested for HI activity against the A/H1N1 and A/H3N2 2013-2014 vaccine virus strains. Plasma minerals were collected in zinc-free tubes and assayed by inductively coupled plasma mass spectrometry. HI titers were reported as seroprotection (≥1:40) and seroconversion (≥ 4-fold rise from Day 0 (minimum HI = 1:10) to Day 21). Both HI titers and mineral values were skewed and thus log2 transformed. Magnesium (Mg), phosphorus (P), zinc (Zn), copper (Cu), iron (Fe), potassium (K) and the Cu to Zn ratio were tested. Logistic regression analyses were used to determine the associations between mineral levels and seroconversion and seroprotection of HI titers for each influenza A strain. RESULTS: Participants were 61% white, 28% male, 39% diabetic, and 81% overweight/obese with a mean age of 62.6 y. In logistic regression, Day 21 A/H1N1 seroprotection was associated with P and Zn at Day 21(P < 0.05). Seroconversion of A/H1N1 was associated with Day 21 Cu, P, and Mg (P < 0.03). Day 21 A/H3N2 seroprotection and seroconversion were associated with Day 21 P (P < 0.05). CONCLUSIONS: Phosphorus was associated with seroprotection and seroconversion to influenza A after vaccination; these associations warrant additional studies with larger, more diverse population groups.

Cost of surviving sepsis: a novel model of recovery from sepsis in Drosophila melanogaster.

BACKGROUND: Multiple organ failure, wasting, increased morbidity, and mortality following acute illness complicates the health span of patients surviving sepsis. Persistent inflammation has been implicated, and it is proposed that insulin signaling contributes to persistent inflammatory signaling during the recovery phase after sepsis. However, mechanisms are unknown and suitable pre-clinical models are lacking. We therefore developed a novel Drosophila melanogaster model of sepsis to recapitulate the clinical course of sepsis, explored inflammation over time, and its relation to impaired mobility, metabolic disturbance, and changes in lifespan. METHODS: We used wild-type (WT), Drosomycin-green fluorescent protein (GFP), and NF-κB-luc reporter male Drosophila melanogaster 4-5 days of age (unmanipulated). We infected Drosophila with Staphylococcus aureus (infected without treatment) or pricked with aseptic needles (sham). Subsets of insects were treated with oral linezolid after the infection (infected with antibiotics). We assessed rapid iterative negative geotaxis (RING) in all the groups as a surrogate for neuromuscular functional outcome up to 96 h following infection. We harvested the flies over the 7-day course to evaluate bacterial burden, inflammatory and metabolic pathway gene expression patterns, NF-κB translation, and metabolic reserve. We also followed the lifespan of the flies. RESULTS: Our results showed that when treated with antibiotics, flies had improved survival compared to infected without treatment flies in the early phase of sepsis up to 1 week (81 %, p = 0.001). However, the lifespan of infected with antibiotics flies was significantly shorter than that of sham controls (p = 0.001). Among infected with antibiotic sepsis survivors, we observed persistent elevation of NF-κB in the absence of any obvious infection as shown by culturing flies surviving sepsis. In the same group, geotaxis had an early (18 h) and sustained decline compared to its baseline. Geotaxis in infected with antibiotics sepsis survivors was significantly lower than that in sham and age-matched unmanipulated flies at 18 and 48 h. Expression of antimicrobial peptides (AMP) remained significantly elevated over the course of 7 days after sepsis, especially drosomycin (5.7-fold, p = 0.0145) on day 7 compared to that of sham flies. Infected with antibiotics flies had a trend towards decreased Akt activation, yet their glucose stores were significantly lower than those of sham flies (p = 0.001). Sepsis survivors had increased lactate levels and LDH activity by 1 week, whereas ATP and pyruvate content was similar to that of the sham group. CONCLUSIONS: In summary, our model mimics human survivors of sepsis with persistent inflammation, impaired motility, dysregulated glucose metabolism, and shortened lifespan.

Effects of intra-abdominal sepsis on atherosclerosis in mice.

INTRODUCTION: Sepsis and other infections are associated with late cardiovascular events. Although persistent inflammation is implicated, a causal relationship has not been established. We tested whether sepsis causes vascular inflammation and accelerates atherosclerosis. METHODS: We performed prospective, randomized animal studies at a university research laboratory involving adult male ApoE-deficient (ApoE-/-) and young C57B/L6 wild-type (WT) mice. In the primary study conducted to determine whether sepsis accelerates atherosclerosis, we fed ApoE-/- mice (N = 46) an atherogenic diet for 4 months and then performed cecal ligation and puncture (CLP), followed by antibiotic therapy and fluid resuscitation or a sham operation. We followed mice for up to an additional 5 months and assessed atheroma in the descending aorta and root of the aorta. We also exposed 32 young WT mice to CLP or sham operation and followed them for 5 days to determine the effects of sepsis on vascular inflammation. RESULTS: ApoE-/- mice that underwent CLP had reduced activity during the first 14 days (38% reduction compared to sham; P < 0.001) and sustained weight loss compared to the sham-operated mice (-6% versus +9% change in weight after CLP or sham surgery to 5 months; P < 0.001). Despite their weight loss, CLP mice had increased atheroma (46% by 3 months and 41% increase in aortic surface area by 5 months; P = 0.03 and P = 0.004, respectively) with increased macrophage infiltration into atheroma as assessed by immunofluorescence microscopy (0.52 relative fluorescence units (rfu) versus 0.97 rfu; P = 0.04). At 5 months, peritoneal cultures were negative; however, CLP mice had elevated serum levels of interleukin 6 (IL-6) and IL-10 (each at P < 0.05). WT mice that underwent CLP had increased expression of intercellular adhesion molecule 1 in the aortic lumen versus sham at 24 hours (P = 0.01) that persisted at 120 hours (P = 0.006). Inflammatory and adhesion genes (tumor necrosis factor α, chemokine (C-C motif) ligand 2 and vascular cell adhesion molecule 1) and the adhesion assay, a functional measure of endothelial activation, were elevated at 72 hours and 120 hours in mice that underwent CLP versus sham-operations (all at P <0.05). CONCLUSIONS: Using a combination of existing murine models for atherosclerosis and sepsis, we found that CLP, a model of intra-abdominal sepsis, accelerates atheroma development. Accelerated atheroma burden was associated with prolonged systemic, endothelial and intimal inflammation and was not explained by ongoing infection. These findings support observations in humans and demonstrate the feasibility of a long-term follow-up murine model of sepsis.

Leukocyte capture and modulation of cell-mediated immunity during human sepsis: an ex vivo study.

INTRODUCTION: Promising preclinical results have been obtained with blood purification therapies as adjuvant treatment for sepsis. However, the mechanisms by which these therapies exert beneficial effects remain unclear. Some investigators have suggested that removal of activated leukocytes from the circulation might help ameliorate remote organ injury. We designed an extracorporeal hemoadsorption device capable of capturing both cytokines and leukocytes in order to test the hypothesis that leukocyte capture would alter circulating cytokine profiles and influence immunological cell-cell interactions in whole blood taken from patients with sepsis. METHODS: We performed a series of ex vivo studies in 21 patients with septic shock and 12 healthy volunteers. Blood circulated for four hours in closed loops with four specially designed miniaturized extracorporeal blood purification devices including two different hemoadsorption devices and a hemofilter in order to characterize leukocyte capture and to assess the effects of leukocyte removal on inflammation and immune function. RESULTS: Hemoadsorption was selective for removal of activated neutrophils and monocytes. Capture of these cells led to local release of certain cytokines, especially IL-8, and resulted in complex cell-cell interactions involved in cell-mediated immunity. Inhibition of cell adherence reversed the cytokine release and the effects on lymphocyte function. CONCLUSIONS: Monocyte and neutrophil capture using a sorbent polymer results in upregulation of IL-8 and modulation of cell-mediated immunity. Further studies are needed to understand better these cellular interactions in order to help design better blood purification therapies.