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Association of Sex With Clinical Outcome in Critically Ill Sepsis Patients A Retrospective Analysis of the Large Clinical Database MIMIC-III
Xu, Jinghong; Tong, Li; Yao, Jiyou; More
Shock. 52(2):146-151, August 2019.

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Introduction:
The objective of our study was to explore the association between sex and clinical outcome in sepsis patients in a large, diverse population.

Materials and Methods:
We analyzed 6,134 adult patients with sepsis from the critical care units of Beth Israel Deaconess Medical Center between 2001 and 2012. Study data were retrospectively extracted from Medical Information Mart for Intensive Care-III, a multiparameter intensive care database.

Results:
There were 2,677 (43.6%) female and 3,457 (56.4%) male patients. Compared with female patients, male patients with sepsis had a higher 1-year mortality rate (55.6% vs. 51.4%, P  = 0.001), and so did the 90-day mortality rate (45.1% vs. 42.1%, P  = 0.018). 33.8% of male and 31.3% of female patients with sepsis died during hospitalization ( P  = 0.041). The median length of hospitalization and intensive care unit (ICU) stay for male patients was 19.54 and 7.54 days, while that for female patients was 16.49 and 6.75 days ( P  < 0.001, P  = 0.002, respectively). Male patients were more likely to require dialysis therapy ( P  = 0.109), ventilation support ( P  = 0.012) and more vasoactive agents (dopamine P  = 0.113, norepinephrine P  = 0.016, and epinephrine P  = 0.093) during the ICU period than female patients. Our Cox proportional hazard regression model confirmed that the risk of death within 1 year of ICU admission in male patients is 1.083 times that in female.

Conclusion:
Female patients with sepsis have better clinical outcomes than male patients in terms of mortality and length of hospitalization and ICU stay.

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The Association of Fever and Antipyretic Medication With Outcomes in Mechanically Ventilated Patients A Cohort Study
Evans, Emily M.; Doctor, Rebecca J.; Gage, Brian F.; More
Shock. 52(2):152-159, August 2019.

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Background:
Fever is common in mechanically ventilated patients and may be uniquely detrimental in those with lung injury because of its injurious effects on pulmonary vascular permeability and alveolar epithelium. We evaluated the association of fever and antipyretic medication with mortality in mechanically ventilated emergency department (ED) patients.

Methods:
This is a retrospective cohort study of 1,264 patients requiring mechanical ventilation initiated in the ED with subsequent admission to an intensive care unit. Maximum body temperature was recorded for the first 24 h after ED admission and categorized into four categories: <37°C, 37°C to 38.2°C, 38.3°C to 39.4°C, and ≥39.5°C. The primary outcome was 28-day mortality. We conducted a planned subgroup analysis of patients with sepsis at the time of intubation. Multivariable Cox proportional hazard ratios (HRs) were used to assess the relationship between temperature, antipyretics, and mortality.

Results:
Multivariable Cox proportional HRs demonstrated that a maximum temperature ≥39.5°C was associated with increased mortality (adjusted hazard ratio [aHR] 1.59 [95% confidence interval, CI, 1.05–2.39]). In the subgroup of patients with sepsis, a maximum temperature of 38.3°C to 39.4°C was associated with survival (aHR 0.61 [95% CI, 0.39–0.99]). There was no difference in 28-day mortality between patients who did and did not receive antipyretic medication in either the overall cohort or the septic subgroup.

Conclusion:
High fever (≥39.5°C) was associated with increased risk for mortality in mechanically ventilated patients. However, in patients with sepsis, moderate fever (38.3°C–39.4°C) was protective. Antipyretic medication was not associated with changes in outcome. This suggests that fever may have different implications in septic versus nonseptic mechanically ventilated patients.

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Platelet–lymphocyte Ratio After Granulocyte Colony Stimulating Factor Administration an Early Prognostic Marker in Septic Shock Patients With Chemotherapy-Induced Febrile Neutropenia
Kim, Youn-Jung; Kang, Jihoon; Ryoo, Seung Mok; More
Shock. 52(2):160-165, August 2019.

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Introduction:
Chemotherapy-induced febrile neutropenia (FN) causes life-threatening complications, but little is known in septic shock patients with FN. The aim of this study was to investigate the prognostic value of inflammatory markers, including C-reactive protein level, immature granulocyte count, white blood cell (WBC) count, absolute neutrophil count (ANC), neutrophil–lymphocyte ratio (NLR), and platelet–lymphocyte ratio (PLR), in septic shock patients with FN at admission and after granulocyte colony-stimulating factor (G-CSF) administration.

Methods:
Data on consecutive adult septic shock patients with FN treated with G-CSF between June 2012 and June 2017 were extracted from a prospectively compiled septic shock registry. Clinical and serial laboratory data at admission and <24 h after G-CSF administration were compared between nonsurvivor and 1-month survivor groups.

Results:
Of 1,671 septic shock patients, 158 FN patients were treated with G-CSF and 114 (72.2%) survived for 1 month. At admission, no clinical and serial laboratory data were significant to predict survival. After G-CSF administration, PLR and APACHE II were independent predictors for 1-month survival. PLR after administration of G-CSF >100 (adjusted odds ratio [aOR], 9.394; 95% CI, 2.821–31.285, P < 0.001) showed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 89.4%, 46.2%, 82.9%, and 60.0%, respectively, and APACHE II <28 (aOR, 6.944; 95% CI, 2.351–20.511, P  < 0.001) showed sensitivity, specificity, PPV, and NPV of 86.8%, 63.6%, 86.1%, and 65.1%, respectively.

Conclusions:
After G-CSF administration in septic shock patients with chemotherapy-induced FN, PLR may be used as an early prognostic marker for mortality.

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Leukocyte Transcriptional Response in Sepsis
Skibsted, Simon; Bhasin, Manoj K.; Henning, Daniel J.; More
Shock. 52(2):166-173, August 2019.

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Background:
The complex host response to sepsis is incompletely understood. The aim of this investigation is to use leukocyte RNA sequencing to characterize biological functions, cellular pathways, and key regulatory molecules driving sepsis pathophysiology.

Methods:
This was a prospective, observational study of emergency department patients with sepsis, at an urban, academic, tertiary care center. In the derivation cohort, we collected blood at enrollment and 90 days after hospital discharge allowing each patient to serve as an internal control. We performed RNA sequencing to quantify transcriptional expression changes during sepsis and non-sepsis states. We then performed unsupervised and supervised analyses, as well as functional and pathway analyses. We selected the top down and upregulated genes and key regulatory molecules for validation. Validation occurred in a cohort of septic and non-septic using real-time PCR.

Results:
The derivation cohort included 5 patients, and RNA sequencing revealed 916 unique mRNA transcripts differentially expressed during sepsis. Among these, 673 (73%) genes were upregulated, and 243 (27%) were downregulated. Functional enrichment analysis revealed a highly dynamic downstream effect of the transcriptional activity during sepsis. Of the 43 functional cellular pathways activated during sepsis, the top pathways were closely associated with inflammation and response to infection. Validation occurred in 18 septic and 25 non-septic control patients, with 34/45 (76%) of identified genes validated. The regulatory analysis identified several key regulators of sepsis.

Conclusions:
Highly dynamic transcriptional activity occurs in leukocytes during sepsis, activating key cellular pathways and master regulatory molecules that drive the sepsis process.

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Remote Photoplethysmographic Assessment of the Peripheral Circulation in Critical Care Patients Recovering From Cardiac Surgery
Rasche, Stefan; Trumpp, Alexander; Schmidt, Martin; More
Shock. 52(2):174-182, August 2019.

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Purpose:
Camera-based photoplethysmography (cbPPG) remotely detects the volume pulse of cardiac ejection in the peripheral circulation. The cbPPG signal is sourced from the cutaneous microcirculation, yields a 2-dimensional intensity map, and is therefore an interesting monitoring technique. In this study, we investigated whether cbPPG is in general sufficiently sensitive to discern hemodynamic conditions.

Methods:
cbPPG recordings of 70 patients recovering from cardiac surgery were analyzed. Photoplethysmograms were processed offline and the optical pulse power (OPP) of cardiac ejection was calculated. Hemodynamic data, image intensity, and patient movements were recorded synchronously. The effects of hemodynamic parameters and measurement conditions on the patient's individual OPP variability and their actual OPP values were calculated in mixed-effects regression models.

Results:
Mean arterial pressure (MAP), pulse pressure (PP), heart rate (HR), and central venous pressure (CVP) significantly explained the individual OPP variability. PP had the highest explanatory power (19.9%). Averaged OPP significantly increased with PP and MAP ( P  < 0.001, respectively) and decreased with higher HR ( P  = 0.024). CVP had a 2-directional, nonsignificant effect on averaged OPP. Image intensity and patient movements did significantly affect OPP. After adjustment for hemodynamic covariables and measurement conditions, the effect of PP and HR remained unchanged, whereas that of MAP vanished.

Conclusion:
cbPPG is sensitive to hemodynamic parameters in critical care patients. It is a potential application for monitoring the peripheral circulation. Its value in a clinical setting has to be determined.

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Whole-Exome Sequencing of Adult and Pediatric Cohorts of the Rare Vascular Disorder Systemic Capillary Leak Syndrome
Pierce, Richard; Ji, Weizhen; Chan, Eunice C.; More
Shock. 52(2):183-190, August 2019.

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Objective:
Systemic capillary leak syndrome (SCLS) is a rare disorder that presents with episodes of hypovolemic shock. The extent to which genetic abnormalities contribute to SCLS is unknown. We identified pediatric and adult cohorts with characteristic clinical courses. We sought to describe the clinical characteristics of both cohorts, identify a possible genetic contribution to SCLS, and demonstrate that whole-exome sequencing (WES) may be conducted by critical care providers.

Design:
Prospective observational study of WES of nine adult and eight pediatric SCLS patients and available unaffected first-degree relatives.

Setting:
Tertiary children's hospitals and referral research laboratory.

Patients:
Children and adults with SCLS.

Interventions:
None.

Measurements:
Patients and available first-degree relatives underwent WES. Data were analyzed for rare homozygous, biallelic, de novo , and heterozygous variants with allelic enrichment and metabolic pathway analyses.

Main Results:
Children with SCLS presented at a younger age with episodes similar to those experienced by adults. All patients and available relatives underwent satisfactory WES. No overlapping gene variants or metabolic pathways were identified across all SCLS patients. Multiple candidate genes with homozygous or biallelic mutations were identified in individual subjects with SCLS. There was no significant enrichment of genes with rare heterozygous variants.

Conclusions:
The clinical characteristics of children and adults with SCLS are similar. We did not identify a uniform germline exomic genetic etiology for SCLS. WES identified several candidate genes in individual patients for future research. WES is a viable way for critical care providers to investigate the etiology of diseases with presumed genetic contributions.

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Association of Immune Cell Subtypes and Phenotype With Subsequent Invasive Candidiasis in Patients With Abdominal Sepsis
Arens, Christoph; Kramm, Timo; Decker, Sebastian; More
Shock. 52(2):191-197, August 2019.

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Background:
In nonneutropenic intensive care unit (ICU) patients, current risk stratification scores lack specificity to reliably predict the risk of a prospective invasive candidiasis (IC). We aimed to explore possible associations of distinct immunological markers with different degrees of Candida affection in patients with abdominal sepsis.

Methods:
The presented explorative, noninterventional diagnosis study recruited patients admitted to the surgical ICU at Heidelberg University Hospital with abdominal sepsis. Over 5 days, we determined white blood cell count, 1,3-β-D-glucan, and HLA-DR expression; the amount of Th1, Th17, regulatory T, T helper, and cytotoxic T cells; Dectin-1 and TLR2-expression; the amount of T, B, and NK cells; the ex vivo secretion of IL-8 upon stimulation with LPS, flagellin, and zymosan; and the distribution of distinct T-cell cytokines in a daily manner. On day 21, patients' Candida infection status was stratified in no colonization or IC, colonization or IC.

Results:
A total of 26 patients were included. On day 21, five patients showed no colonization or IC, in 13 patients a colonization was detected, and eight patients were diagnosed with IC. On study inclusion, the stratification groups showed comparable values in standard laboratory parameters and morbidity scores. Decreased B and NK cell counts, as well as reduced IL-8 secretion after ex vivo stimulation with LPS or flagellin seemed to be associated with a higher risk of subsequent Candida colonization. Even lower values could distinguish the therapy-relevant difference between prospective IC from colonization alone.

Conclusions:
We were able to show distinct immune system impairments in early abdominal sepsis by specific immune-based measurements. A possible association of these impairments with a subsequent Candida affection is shown.

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The Effectiveness and Safety of Corticosteroids Therapy in Adult Critical Ill Patients With Septic Shock A Meta-Analysis of Randomized Controlled Trials
Wen, Yongyao; Zhu, Yuhan; Jiang, Qimin; More
Shock. 52(2):198-207, August 2019.

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Objective:
To investigate the effectiveness and safety of corticosteroids therapy in adult critical ill patients with septic shock.

Methods:
The PUBMED, EMBASE, Web of Science, Cochrane Library databases were systematically searched from the inception dates to March 24, 2018. To identify randomized controlled trials that evaluating the role of corticosteroids therapy in adult critical ill patients with septic shock. The primary outcome was 28-day mortality. The second outcomes included 90-day mortality, intensive care unit (ICU) mortality, in-hospital mortality, length of stay in ICU, length of stay in hospital, reversal of shock, and superinfection.

Results:
A total of 18 randomized controlled trials involving 8,128 adult critical ill patients with septic shock fulfilled the inclusion criteria. The outcomes of this meta-analysis showed that corticosteroids therapy did not significantly reduce the 28-day mortality [RR = 0.94; 95% CI, 0.84–1.05; Z = 1.07 ( P  = 0.285)]. However, corticosteroids therapy was associated with a significantly shorter length of stay in ICU [WMD = −1.55; 95% CI, −2.19 to −0.91; Z = 4.74 ( P  = 0.000)]. 90-day mortality, ICU mortality, in-hospital mortality, length of stay in hospital, reversal of shock, and superinfection had no significant difference between the corticosteroids therapy and placebo therapy ( P  > 0.05). Similar results were obtained in subgroups of trials stratified according to the dose of corticosteroids (high dose or low does).

Conclusions:
Based on the results of this meta-analysis, corticosteroids therapy was associated with a significantly shorter length of stay in ICU among adult critical ill patients with septic shock. The mortality was similar between the corticosteroids therapy and placebo.

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Overexpression of Gilz Protects Mice Against Lethal Septic Peritonitis
Ballegeer, Marlies; Vandewalle, Jolien; Eggermont, Melanie; More
Shock. 52(2):208-214, August 2019.

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ABSTRACT
Sepsis in humans and experimental animals is characterized by an acute inflammatory response. glucocorticoids (GCs) are widely used for the treatment of many inflammatory disorders, yet their effectiveness in sepsis is debatable. One of the major anti-inflammatory proteins induced by GCs is glucocorticoid-induced leucine zipper (GILZ, coded by the TSC22D3 gene). We found that TSC22D3 mRNA expression is downregulated in white blood cells of human sepsis patients. Interestingly, transgenic GILZ-overexpressing mice (GILZ-tg) showed better survival rates in the cecal ligation and puncture (CLP) model of mouse sepsis. To our surprise, GILZ had only mild anti-inflammatory effects in this model, as the systemic proinflammatory response was not significantly reduced in GILZ-tg mice compared with control mice. During CLP, we observed reduced bacterial counts in blood of GILZ-tg mice compared with control mice. We found increased expression of Tsc22d3 mRNA specifically in peritoneal exudate cells in the CLP model, as well as increased capacity for bacterial phagocytosis of CD45 + GILZ-tg cells compared with CD45 + GILZ-wt cells. Hence, we believe that the protective effects of GILZ in the CLP model can be linked to a more efficient phagocytosis.

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Toll Like Receptor 4 Mediated Lymphocyte Imbalance Induces Nec-Induced Lung Injury
Jia, Hongpeng; Sodhi, Chhinder P.; Yamaguchi, Yukihiro; More
Shock. 52(2):215-223, August 2019.

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ABSTRACT
Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants, and is associated with the development of severe lung inflammation. The pathogenesis of NEC-induced lung injury remains unknown, yet infiltrating immune cells may play a role. In support of this possibility, we now show that NEC in mice and humans was associated with the development of profound lung injury that was characterized by an influx of Th17 cells and a reduction in T regulatory lymphocytes (Tregs). Importantly, the adoptive transfer of CD4 + T cells isolated from lungs of mice with NEC into the lungs of immune incompetent mice (Rag1 −/− mice) induced profound inflammation in the lung, while the depletion of Tregs exacerbated NEC induced lung injury, demonstrating that imbalance of Th17/Treg in the lung is required for the induction of injury. In seeking to define the mechanisms involved, the selective deletion of t oll- l ike r eceptor 4 (TLR4) from the Sftpc1 pulmonary epithelial cells reversed lung injury, while TLR4 activation induced the Th17 recruiting chemokine (C-C motif) ligand 25 (CCL25) in the lungs of mice with NEC. Strikingly, the aerosolized inhibition of both CCL25 and TLR4 and the administration of all trans retinoic acid restored Tregs attenuated NEC-induced lung injury. In summary, we show that TLR4 activation in S urfactant p rotein C - 1 (Sftpc1) cells disrupts the Treg/Th17 balance in the lung via CCL25 leading to lung injury after NEC and reveal that inhibition of TLR4 and stabilization of Th17/Treg balance in the neonatal lung may prevent this devastating complication of NEC.

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Therapeutic Hypothermia After Cardiac Arrest Involvement of the Risk Pathway in Mitochondrial PTP-Mediated Neuroprotection
Jahandiez, Vincent; Cour, Martin; Abrial, Maryline; More
Shock. 52(2):224-229, August 2019.

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ABSTRACT
Therapeutic hypothermia is neuroprotective after cardiac arrest (CA) via poorly understood mechanisms. It may prevent mitochondrial permeability transition pore (PTP) opening, an event which plays a pivotal role in ischemia-reperfusion injury. PTP is the main end-effector of the reperfusion injury salvage kinase (RISK) signaling pathway. We hypothesized that therapeutic hypothermia activates the RISK pathway, thereby preventing PTP opening and its deleterious neurological consequences after CA. Four groups of New Zealand White rabbits were subjected to 15 min of CA and 120 min of reperfusion: Control, HT (hypothermia at 32°–34°C), NIM (specific PTP inhibition with N-methyl-4-isoleucine-cyclosporine at the onset of reperfusion), and HT+NIM. A Sham group only underwent surgery. The following measurements were taken: pupillary reflexes and brain damage biomarkers (NSE and S100β), RISK pathway activation in brain cortex (total and phosphorylated forms of both protein kinase B [Akt] and extracellular signal-regulated kinase [ERK]) and PTP opening in isolated brain mitochondria. Therapeutic hypothermia and pharmacological PTP inhibition preserved the pupillary reflexes and prevented the increase in both NSE and S100β ( P  < 0.05 vs. controls). These two interventions also enhanced ( P  < 0.05 vs. controls) the phospho-Akt/Akt ratio to a similar extent while preventing a CA-induced increase in phospho-ERK/ERK ratio. This Akt activation in the HT and NIM groups was associated with an attenuation of CA-induced PTP opening. In this model, therapeutic hypothermia promoted the activation of the RISK signaling pathway via Akt and limited CA-induced brain injury by preventing PTP opening.

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The Mitochondria-Targeted H2S-Donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma
Wepler, Martin; Merz, Tamara; Wachter, Ulrich; More
Shock. 52(2):230-239, August 2019.

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ABSTRACT
Hemorrhagic shock (HS) accounts for 30% to 40% of trauma-induced mortality, which is due to multi-organ-failure subsequent to systemic hyper-inflammation, triggered by hypoxemia and tissue ischemia. The slow-releasing, mitochondria-targeted H 2 S donor AP39 exerted beneficial effects in several models of ischemia-reperfusion injury and acute inflammation. Therefore, we tested the effects of AP39-treatment in a murine model of combined blunt chest trauma (TxT) and HS with subsequent resuscitation.

Methods:
After blast wave-induced TxT or sham procedure, anesthetized and instrumented mice underwent 1 h of hemorrhage followed by 4 h of resuscitation comprising an i.v. bolus injection of 100 or 10 nmol kg −1 AP39 or vehicle, retransfusion of shed blood, fluid resuscitation, and norepinephrine. Lung mechanics and gas exchange were assessed together with hemodynamics, metabolism, and acid-base status. Blood and tissue samples were analyzed for cytokine and chemokine levels, western blot, immunohistochemistry, mitochondrial oxygen consumption (JO 2 ), and histological changes.

Results:
High dose AP39 attenuated systemic inflammation and reduced the expression of inducible nitric oxide synthase (iNOS) and IκBα expression in lung tissue. In the combined trauma group (TxT + HS), animals treated with high dose AP39 presented with the lowest mean arterial pressure and thus highest norepinephrine requirements and higher mortality. Low dose AP39 had no effects on hemodynamics, leading to unchanged norepinephrine requirements and mortality rates.

Conclusion:
AP39 is a systemic anti-inflammatory agent. In our model of trauma with HS, there may be a narrow dosing and timing window due to its potent vasodilatory properties, which might result in or contribute to aggravation of circulatory shock-related hypotension.

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Moderate Traumatic Brain Injury Alters the Gastrointestinal Microbiome in a Time-Dependent Manner
Nicholson, Susannah E.; Watts, Lora T.; Burmeister, David M.; More
Shock. 52(2):240-248, August 2019.

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ABSTRACT
The microbiome is defined as the collective genomes of the microbes (composed of bacteria, bacteriophage, fungi, protozoa, and viruses) that colonize the human body, and alterations have been associated with a number of disease states. Changes in gut commensals can influence the neurologic system via the brain-gut axis, and systemic insults such as trauma or traumatic brain injury (TBI) may alter the gut microbiome. The objective of this study was to evaluate the gut microbiome in a preclinical TBI cortical impact model. Male rats underwent craniotomy and randomized to a sham group (n = 4), or a moderate TBI (n = 10) using a pneumatic impactor. MRI and behavioral assessments were performed pre-TBI and on days 2, 7, and 14 days thereafter. Microbiome composition was determined with 16s rRNA sequencing from fecal sample DNA pre-TBI and 2 hrs, 1, 3, and 7 days afterward. Alpha- and β-bacterial diversity, as well as organizational taxonomic units (OTUs), were determined. Significant changes in the gut microbiome were evident as early as 2 h after TBI as compared with pre-injured samples and sham rats. While there were varying trends among the phylogenetic families across time, some changes persisted through 7 days in the absence of therapeutic intervention. While large structural lesions and behavioral deficits were apparent post-TBI, there were modest but significant decreases in α-diversity. Moreover, both changes in representative phyla and α-diversity measures were significantly correlated with MRI-determined lesion volume. These results suggest that changes in the microbiome may represent a novel biomarker to stage TBI severity and predict functional outcome.

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The lncRNA, H19 Mediates the Protective Effect of Hypoxia Postconditioning Against Hypoxia-Reoxygenation Injury to Senescent Cardiomyocytes by Targeting microRNA-29b-3p
Zhang, Xuan; Cheng, Long; Xu, Longhe; More
Shock. 52(2):249-256, August 2019.

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Background:
Ischemic postconditioning (I/Post) is an endogenous protection mechanism that reduces injury induced by ischemia-reperfusion (I/R). It remains controversial whether I/Post protects against I/R injury to the aging heart. The long non-coding RNA, H19 protects H9c2 cells against hypoxia-induced injury. This study aimed to elucidate the role of H19 in the hypoxic postconditioning (H/Post) of aged cardiomyocytes.

Methods:
Senescence induced by D-galactose in primary cardiomyocytes from neonatal Sprague–Dawley rats was measured by senescence-associated β-galactosidase staining. Hypoxic injury was evaluated by cell viability and apoptosis assays. H19 expression before and after hypoxia-reoxygenation (H/R) and H/Post was evaluated by real-time polymerase chain reactions. miR-29b-3p -binding sites in H19 and the cellular inhibitor of apoptosis protein 1 ( cIAP1 ) were predicted by bioinformatics analysis, and interaction was verified by luciferase assay. The effects of altered H19 , miR-29b-3p, and cIAP1 expression on the viability and apoptosis of senescent cardiomyocytes following H/Post were determined.

Results:
H/Post prevented H/R injury in normal but not senescent cardiomyocytes. H19 expression was remarkably down-regulated after H/Post in senescent compared with normal cardiomyocytes. Small interfering RNA-mediated knockdown of H19 in senescent cardiomyocytes increased H/Post-induced injury. miR-29b-3p was regulated by H19 and led to a greater injury. miR-29b-3p directly targeted the 3′-untranslated region of cIAP1 and suppressed its expression. Furthermore, knockdown of cIAP1 damaged senescent cardiomyocytes following H/Post.

Conclusions:
These findings suggest that H19 mediated the antiapoptotic effect of H/Post against H/R-induced injury to aged cardiomyocytes by inhibiting miR-29b-3p expression.

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Early Dynamics of Plasma Dna in a Mouse Model of Sepsis
Lauková, Lucia; Bertolo, Estera Maria Jana; Zelinková, Magdaléna; More
Shock. 52(2):257-263, August 2019.

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ABSTRACT
Concentration of extracellular DNA (ecDNA) in plasma of septic patients is higher in comparison to healthy controls and is associated with worse prognosis in intensive care patients. Decrease of ecDNA in plasma by treatment with deoxyribonuclease (DNase) showed to have beneficial effects in animal models of sepsis. A previously published study showed that timing of DNase application is crucial for the effect of DNase. No published study monitored plasma ecDNA dynamics during sepsis in detail yet. The aim of our study was to describe the early dynamics of plasma ecDNA but also plasma DNase activity in a mouse model of sepsis. Sepsis was induced using intraperitoneal injection of E. coli and mice were euthanized every hour to obtain sufficient volume of plasma. Our results show that the concentration of plasma ecDNA is rising continuously during the first 5 h after infection and is 20-fold higher 5 h after induction of sepsis in comparison to control mice. Subcellular origin of plasma ecDNA was analyzed but fundamental differences in dynamics between nuclear and mitochondrial ecDNA were not found. DNase activity in plasma seems to rise slowly until the fourth hour, but the interindividual variability is high. In conclusion, this is the first study that describes the dynamics of plasma ecDNA and DNase activity in early sepsis in detail. Our study is the basis for further studies focused on the timing of exogenous DNase treatment in sepsis. Additional studies will be needed to monitor plasma ecDNA in later time points that are more clinically relevant.

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Consequences of the Lack of IL-10 in Different Endotoxin Effects and its Relationship With Glucocorticoids
Córdoba-Moreno, Marlina O.; Todero, María Florencia; Fontanals, Adriana; More
Shock. 52(2):264-273, August 2019.

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ABSTRACT
Sepsis constitutes one of the major causes of death in ICUs. In sepsis induced by gram-negative, although lipopolysaccharide (LPS) initially induces an exacerbated secretion of proinflammatory cytokines leading to endotoxic shock and death resembling a septic shock, it is also capable of inducing refractoriness to subsequent challenge with LPS, a state known as endotoxin tolerance, which is considered the initial step of the immunosuppression found in septic patients. As we previously demonstrated the importance of glucocorticoids in endotoxin tolerance, the aim of this study was to evaluate the contribution of Interleukin-10 (IL-10) both in the endotoxic shock and in the development of the tolerance and its relationship with glucocorticoids. Our results show that, upon LPS challenge, IL-10 knockout mice (KO) mice had an enhanced LPS sensitivity, along with elevated levels of proinflammatory cytokines as tumor necrosis factor-α, IL-12 and interferon-γ, and enhanced tissue damage, despite the high levels of glucocorticoids. This effect may be because, in part, of the higher expression of tumor necrosis factor receptors in IL-10 KO mice. Further, the injection of dexamethasone did not protect IL-10 KO mice from a LPS lethal challenge. Although tolerance was achieved in the absence of IL-10, it was weaker and the elevated levels of glucocorticoids were not able to reverse the high sensitivity of IL-10 KO mice to LPS. Nevertheless, glucocorticoids would play a pivotal role in the establishment and maintenance of this partial tolerance in IL-10 KO mice. Finally, our results show that IL-10 and glucocorticoids could act in a bidirectional way influencing the inflammatory and anti-inflammatory periods.

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Augmenter of Liver Regeneration Protects Against Acetaminophen-Induced Acute Liver Injury in Mice by Promoting Autophagy
Hu, Ting; Sun, Hang; Deng, Wan-Yan; More
Shock. 52(2):274-283, August 2019.

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ABSTRACT
Most cases of acute liver failure are caused by acetaminophen (APAP) overdose. Oxidative stress is a key factor in APAP toxicity. Although augmenter of liver regeneration (ALR) has both antioxidative and antiapoptotic effects, its therapeutic potential in APAP hepatotoxicity remains unknown. The current study assessed the protective effects and associated mechanisms of ALR against APAP-induced acute liver injury in female BALB/c mice. We found that serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, intrahepatic hemorrhage and necrosis were increased at 3, 6, 12, 24, 48, and 72 h after 600 mg/kg APAP i.p. injection. During the early stages (before 12 h) of acute liver injury, ALR levels increased significantly, followed by a decrease to control level at 24 h after APAP administration. ALR treatment increased autophagosomes, promoted the conversion of LC3 I to LC3 II, and the degradation of p62. ALR attenuated APAP-stimulated increases in ALT, AST, myeloperoxidase (MPO), malondialdehyde (MDA), and reactive oxidative species (ROS) levels; intrahepatic hemorrhage; and necrosis as well as superoxide dismutase (SOD) and Glutathione (GSH) depletion. We found that APAP caused release of the mitochondrial intermembrane proteins apoptosis-inducing factor (AIF) and cytochrome c and that ALR inhibited this change. Meanwhile, ALR decreased expression of cleaved-caspase 3 and apoptotic cells. Subsequently, we investigated the significance of autophagy in APAP-induced acute liver injury by treatment with 3-methyladenine (3-MA), which were classical pharmaceuticals for suppressing autophagy. ALR directly induced autophagy flux; and the inhibition of autophagy reversed the beneficial effects of ALR on hepatotoxicity. Our findings suggest that ALR protects against APAP hepatotoxicity by activating the autophagy pathway.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com