Extensive Tissue Injury Research Articles

Fibrinogen binding to histones in circulation protects against adverse cellular and clinical outcomes

BackgroundCirculating histones are released by extensive tissue injury or cell death and play important pathogenic roles in critical illnesses. Their interaction with circulating plasma components and the potential roles in the clinical setting are not fully understood. ObjectivesWe aimed to characterize the interaction of histones with fibrinogen and explore its roles in vitro, in vivo, and in patient samples. MethodsHistone–fibrinogen binding was assessed by electrophoresis and enzyme-linked immunosorbent assay-based affinity assay. Functional significance was explored using washed platelets and endothelial cells in vitro and histone-infusion mouse models in vivo. To determine clinical translatability, a retrospective single-center cohort study was conducted on patients requiring intensive care admission (n = 199) and validated in a cohort of hospitalized patients with COVID-19 (n = 69). ResultsFibrinogen binds histones through its D-domain with high affinity (calf thymus histones, KD = 18.0 ± 5.6 nM; histone 3, KD = 2.7 ± 0.8 nM; and histone 4, KD = 2.0 ± 0.7 nM) and significantly reduces histone-induced endothelial damage and platelet aggregation in vitro and in vivo in a histone-infusion mouse model. Physiologic concentrations of fibrinogen can neutralize low levels of circulating histones and increase the cytotoxicity threshold of histones to 50 μg/mL. In a cohort of patients requiring intensive care, a histone:fibrinogen ratio of ≥6 on admission was associated with moderate–severe thrombocytopenia and independently predicted mortality. This finding was validated in a cohort of hospitalized patients with COVID-19. ConclusionFibrinogen buffers the cytotoxic properties of circulating histones. Detection and monitoring of circulating histones and histone:fibrinogen ratios will help identify critically ill patients at highest risk of adverse outcomes who might benefit from antihistone therapy.

The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study

BackgroundBreast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival.MethodsIn this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20).ResultsEx vivo cytokine production capacity of TNF, IL-6 and IL-1β was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1β after BCS (p = .041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p = .045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p = .003 and p = .041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p = .038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1β and TNF on POD3 (r = .408; p = .011 and r = .500; p = .001, respectively).ConclusionsThis pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation.

In Situ Rapid-Formation Sprayable Hydrogels for Challenging Tissue Injury Management.

Rapid-acting, convenient, and broadly applicable medical materials are in high demand for the treatment of extensive and intricate tissue injuries in extremely medical scarcity environment, such as battlefields, wilderness, and traffic accidents. Conventional biomaterials fail to meet all the high criteria simultaneously for emergency management. Here, a multifunctional hydrogel system capable of rapid gelation and in situ spraying, addressing clinical challenges related to hemostasis, barrier establishment, support, and subsequent therapeutic treatment of irregular, complex, and urgent injured tissues, is designed. This hydrogel can be fast formed in less than 0.5 s under ultraviolet initiation. The precursor maintains an impressively low viscosity of 0.018 Pa s, while the hydrogel demonstrates a storage modulus of 0.65MPa, achieving the delicate balance between sprayable fluidity and the mechanical strength requirements in practice, allowing flexible customization of the hydrogel system for differentiated handling and treatment of various tissues. Notably, the interactions between the component of this hydrogel and the cell surface protein confer upon its inherently bioactive functionalities such as osteogenesis, anti-inflammation, and angiogenesis. This research endeavors to provide new insights and designs into emergency management and complex tissue injuries treatment.

Altered Serum Alpha1-Antitrypsin Protease Inhibition before and after Clinical Hematopoietic Stem Cell Transplantation: Association with Risk for Non-Relapse Mortality.

α1-Antitrypsin (AAT), an acute-phase reactant not unsimilar to C-reactive protein (CRP), is a serine protease inhibitor that harbors tissue-protective and immunomodulatory attributes. Its concentrations appropriately increase during conditions of extensive tissue injury, and it induces immune tolerance, in part, by inhibiting the enzymatic activity of the inflammatory serine protease, proteinase 3 (PR3). Typically administered to patients with genetic AAT deficiency, AAT treatment was recently shown to improve outcomes in patients with steroid-refractory graft-versus-host disease (GVHD). GVHD represents a grave outcome of allogeneic hematopoietic stem cell transplantation (HSCT), a potentially curative intervention for hematological diseases. The procedure requires radio/chemotherapy conditioning of the prospective marrow recipient, a cytotoxic process that causes vast tissue injury and, in some formats, interferes with liver production of AAT. To date, changes in the functional profile of AAT during allogeneic HSCT, and during the cytotoxic intervention that precedes HSCT, are unknown. The present study followed 53 patients scheduled for allogeneic HSCT (trial registration NCT03188601). Serum samples were tested before and after HSCT for AAT and CRP levels and for intrinsic anti-proteolytic activity. The ex vivo response to clinical-grade AAT was tested on circulating patient leukocytes and on a human epithelial cell line treated with patient sera in a gap closure assay. According to the ex vivo experiments, circulating leukocytes responded to AAT with a favorable immune-regulated profile, and epithelial gap closure was enhanced by AAT in sera from GVHD-free patients but not in sera from patients who developed GVHD. According to serum collected prior to HSCT, non-relapse mortality was reliably predicted by combining three components: AAT and CRP levels and serum anti-proteolytic activity. Taken together, HSCT outcomes are significantly affected by the anti-proteolytic function of circulating AAT, supporting early AAT augmentation therapy for allogeneic HSCT patients.

Transforaminal Endoscopic Lumbar Foraminotomy for Juxta-Fusional Foraminal Stenosis.

Adjacent segment foraminal stenosis is a significant adverse event of lumbar fusion. Conventional revision surgery with an extended fusion segment may result in considerable surgical morbidity owing to extensive tissue injury. Transforaminal endoscopic lumbar foraminotomy (TELF) is a minimally invasive surgical approach for symptomatic foraminal stenosis. This study aimed to demonstrate the surgical technique and clinical outcomes of TELF for the treatment of juxta-fusional foraminal stenosis. Full-scale foraminal decompression was performed via a transforaminal endoscopic approach under local anesthesia. A total of 22 consecutive patients who had undergone TELF were evaluated. The included patients had unilateral foraminal stenosis at the juxta-fusional level of the previous fusion surgery, intractable lumbar radicular pain despite at least six months of non-operative treatment, and verified pain focus by imaging and selective nerve root block. The visual analog scale and Oswestry Disability Index scores significantly improved after the two-year follow-up period. The modified MacNab criteria were excellent in six patients (27.27%), good in 12 (55.55%), fair in two (9.09%), and poor in two (9.09%), with a 90.91% symptomatic improvement rate. No significant surgical complications were observed. The minimally invasive TELF is effective for juxta-fusional foraminal stenosis.

Comment on "Association of Intraoperative Red Blood Cell Transfusions With Venous Thromboembolism and Adverse Outcomes After Cardiac Surgery".

We read with great interest a recently published work by Raphael et al.1 Their primary hypothesis was to establish independent causality of intraoperative transfusion of red blood cells (RBCs) on venous thromboembolism (VTE) after coronary bypass grafting surgery (n = 751,893) using the database of the Society of Thoracic Surgeons. In their secondary analyses, they further explored the types of VTE, mortality, readmission rate, and length of hospital stay. Their analyses of these data were extensive; however, there are issues that warrant further discussion. First, the overall exposure to RBCs was reported as 17.8% in the current study, but it is important to note the authors handled missing data on intraoperative/postoperative blood products as “no transfusion.” Previous studies in similar patients have shown that intraoperative transfusion rates varied between 12.8% and 60.3% due to variations in institutional practice.2 Missing data labeled as “no transfusion” and omission of any postoperative transfusion before any VTE might have skewed the relationship between intraoperative RBCs and VTE. Second, 37% of women versus 12% of men received blood transfusion. The women were 3 times more likely to receive more than 3–4 units of transfusion than men; however, the adjusted odds ratio for VTE was 0.90 for women. Others also demonstrated that women were more likely to receive >4 U RBC transfusion.3 Women tend to have a lower body mass index (BMI) compared with men, and thus they are more prone to dilutional anemia, and subsequently RBC transfusion. A causality relationship between RBCs and VTE was not supported by the lower odds of VTE in women. As a related issue, we would like to discuss their use of conditional imputation for handling missing data. The extent or presumed pattern of missing data was not specified, but BMI was mentioned as an example of conditional imputation. BMI is known to have a wide variation, particularly by geographic location. Conditional imputation without consideration of regional clustering might have distorted the relationship of BMI (and other predictors) and transfusion in development of the propensity score.4,5 Third, the authors attempted to isolate the effect of intraoperative RBCs by addressing or adjusting all the other risk factors for VTE. From Table 3, the exposures to non-RBC components, recombinant activated factor VII, and factor VIII inhibitor bypassing agent were increased in those with increased RBC transfusion. Hemostatic components were treated as a confounder in the model, but there may be causal associations with both acute and subacute VTE and arterial thromboses.6,7 Patients with severe postoperative bleeding tend to have prolonged hospital stay. The authors showed that cohorts with ≥3 units of RBC had longer hospital stay (mean, 9.8–11.2 days) compared with nontransfused patients (mean, 6.6 days). Although not captured in the database, delayed thromboprophylaxis during a prolonged hospital stay may also exacerbate VTE risk. Lastly, the authors utilized inverse probability treatment weighting method using inverse probability of treatment weighting based on the matching as shown in their Table 2; however, the authors did not mention the handling of extreme weights, which may lead to undue influence of otherwise less common groups (ie, patients with 3 or 4+ units of RBCs) (Tables S1–S10, https://links.lww.com/SLA/E307). While inverse probability treatment weighting adequately accounted for measured confounders pertinent to transfusion (eg, cardiopulmonary bypass [CPB] time), it is speculated that there are residual confounders that impact VTE rates.8 For example, extensive tissue injury and CPB are well known to trigger activations of endothelial cells and leukocytes. Cross-talks between coagulation and immune systems are referred to as “thrombo-inflammation,” and it plays a pivotal role in the pathogenesis of VTE.9 Patient-level inflammation parameters are neither routinely measured nor captured in the database. The statistical adjustment for CPB time does not account for inter-individual variability in inflammation and VTE risk. Given the modest area under the curve statistics they reported for these models, it seems clear there remains an unmet need to improve precision of VTE prediction by including patient-level biomarkers with sufficient sensitivity and specificity. ACKNOWLEDGMENTS A.L.B. conceptualized the letter, and writing up of the first draft of the letter. E.C.W., K.A.T., and K.S. have helped write the letter, and approved the final article. All authors have written and reviewed the article, and approved the final article.

Neutrophil accumulation within tissues: A damage x healing dichotomy.

The abundance of neutrophils in human circulation, their fast mobilization from blood to tissues, along with their alleged short life-span led to the image of neutrophils as a homogeneous cell type designed to fight infections and die in the process. Additionally, their granule content and capacity to produce molecules with considerable cytotoxic potential, lead to the general belief that neutrophil activation inexorably results in side effect of extensive tissue injury. Neutrophil activation in fact causes tissue injury as an adverse effect, but it seems that this is restricted to particular pathological situations and more of an "exception to the rule". Here we review evidences arising especially from intravital microscopy studies that demonstrate neutrophils as cells endowed with sophisticated mechanisms and able to engage in complex interactions as to minimize damage and optimize their effector functions. Moreover, neutrophil infiltration may even contribute to tissue healing and repair which may altogether demand a reexamination of current anti-inflammatory therapies that have neutrophil migration and activation as a target.

Holistic Approach via Physiotherapeutic Intervention in a Complex Multiple Fracture Hampering a Middle-Class Man’s Life- a Case Report

Ankle fractures contribute to almost nine percent of all fractures of the weight-bearing joints, with uni, bi, and trimalleolar fractures being the most prevalent. Weber’s and (AO/ASIF) classifications are commonly used for easy analysis. Tibial plateau fractures can range in severity from stable to severely comminuted unstable fractures with extensive tissue injury, putting the extremities' at risk, according to the Schatzker grading system. The ulna is a long bone in the forearm that extends parallel to the radius and travels medially. The severity of proximal ulna fractures ranges from basic AO/OTA Classification fractures to severe Monteggia fractures or Monteggia-like lesions. After a road accident, a 35-year-old man with compound grade 3B ankle dislocation, Schatzker type 1 fracture of tibia, and proximal 1/3 ulnar shaft fracture of the left side were diagnosed on x-ray with external application of a delta fixator over the ankle, open reduction and internal fixation on the tibial plateau with screws and the nail was impacted over the ulna fracture. After the procedure, the patient was treated with physical therapy for 12 weeks, beginning with static regimens and proceeding to dynamic exercises, electrotherapeutic modalities, strengthening exercises, and gait exercises. The purpose of this study was to explore potential favorable rehabilitation effects in the use of exercises following operatively treated unstable ankle fractures requiring partial weight-bearing in the first six postoperative weeks.
 Conclusion: It could be shown that Immediate Postoperative Physical Therapy protocol in a proper scheduled manner helped the Patient to return to his daily activities with improved ranges, strength, and motivation to work again without any difficulties.

Immunometabolic Therapeutic Targets of Graft-versus-Host Disease (GvHD).

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option in the treatment of aggressive malignant and non-malignant blood disorders. However, the benefits of allo-HSCT can be compromised by graft-versus-host disease (GvHD), a prevalent and morbid complication of allo-HSCT. GvHD occurs when donor immune cells mount an alloreactive response against host antigens due to histocompatibility differences between the donor and host, which may result in extensive tissue injury. The reprogramming of cellular metabolism is a feature of GvHD that is associated with the differentiation of donor CD4+ cells into the pathogenic Th1 and Th17 subsets along with the dysfunction of the immune-suppressive protective T regulatory cells (Tregs). The activation of glycolysis and glutaminolysis with concomitant changes in fatty acid oxidation metabolism fuel the anabolic activities of the proliferative alloreactive microenvironment characteristic of GvHD. Thus, metabolic therapies such as glycolytic enzyme inhibitors and fatty acid metabolism modulators are a promising therapeutic strategy for GvHD. We comprehensively review the role of cellular metabolism in GvHD pathogenesis, identify candidate therapeutic targets, and describe potential strategies for augmenting immunometabolism to ameliorate GvHD.

Surgical treatment of children with extensive bone defects (Literature review)

BACKGROUND: Reconstruction of extensive defects to bone tissue is one of the important problems of orthopedics and traumatology. Especially in acuteis, the problem is associated with the restoration of bone tissue in conditions of its deficiency in pediatric patients.
 AIM: The aim of the study is to analyze modern methods of surgical treatment in children with extensive bone tissue injuries based on the published literature.
 MATERIALS AND METHODS: Our report presents a review of the literature of methods of surgical treatment of extensive bone defects. The literature search was carried out in several databases such as PubMed, ScienceDirect, E-library, GoogleScholar for the period from 2005 to 2020, using the keywords given below. As a result of the search, 105 foreign and 37 domestic sources were found. After exclusion, 56 articles were analyzed, all presented works were published in the last 15 years.
 RESULTS: The gold standard for replacing bone defects is still the use of autografts, including the use of technologies on a vascular pedicle. Various types of xenografts and allografts of bone tissue are increasingly being replaced by various kinds of synthetic implants.
 CONCLUSIONS: To date, there is no single generally accepted standard for the surgical treatment of extensive bone defects. The option of surgical treatment of extensive bone tissue defects using tissue-engineered bone implants with axial blood supply seems to be extremely interesting and promising.

Advances in Skin Tissue Bioengineering and the Challenges of Clinical Translation.

Skin tissue bioengineering is an emerging field that brings together interdisciplinary teams to promote successful translation to clinical care. Extensive deep tissue injuries, such as large burns and other major skin loss conditions, are medical indications where bioengineered skin substitutes (that restore both dermal and epidermal tissues) are being studied as alternatives. These may not only reduce mortality but also lessen morbidity to improve quality of life and functional outcome compared with the current standards of care. A common objective of dermal-epidermal therapies is to reduce the time required to accomplish stable closure of wounds with minimal scar in patients with insufficient donor sites for autologous split-thickness skin grafts. However, no commercially-available product has yet fully satisfied this objective. Tissue engineered skin may include cells, biopolymer scaffolds and drugs, and requires regulatory review to demonstrate safety and efficacy. They must be scalable for manufacturing and distribution. The advancement of technology and the introduction of bioreactors and bio-printing for skin tissue engineering may facilitate clinical products' availability. This mini-review elucidates the reasons for the few available commercial skin substitutes. In addition, it provides insights into the challenges faced by surgeons and scientists to develop new therapies and deliver the results of translational research to improve patient care.

Local Versus Systemic Use of Tranexamic Acid in Elective Cesarean Section

Abstract Background: Obstetric hemorrhage remains one of the major determinants of maternal death in both developed and developing countries. Because of its weight as a leading cause of maternal mortality and morbidity. Hemostatic drugs are not usually used as first-line treatment in post-partum hemor-rhage (PPH). It was authenticated that extensive tissue injury can direct the hemostatic equilibrium toward increased fibri-nolysis, leading to coagulopathy and bleeding. Antifibrinolytic drugs, named tranexamic acid (TXA) have been recognized to decrease blood loss and transfusion needs in various elective surgeries. Aim of Study: Evaluating the role of adjunctive IV Tran-examic acid versus topical Tranexamic acid infusion of the placental bed to prevent the postpartum hemorrhage. Patients and Method: It was a randomized clinical trial that extended from January 2019 to January 2020 and was done at Mansoura University Hospital, Obstetrics and Gyne-cology Department and it included a total of 164 pregnant subjects planning for cesarean section who were randomly divided into two groups; the initial group included cases who were subjected to local tranexamic acid administration (2gm), and the other one included cases who were commenced on the intravenous form (1gm). Before operation, all subjects were subjected to complete history taking, fulllaboratory investigations, detailed obstetric examination, and pelviab-dominal ultrasound. Cesarean section was performed in all cases using the standard procedure. Results: The mean age of the included cases was 35.3 and 33.89 years in the local and systemic groups respectively. There was no significant difference between the two groups regarding parity, number of gestations, the indication of cesarean section and the mean operative time. Blood loss was significantly increased in the systemic group versus local group (p < 0.001), hemoglobin levels showed significant de-crease in the systemic group. The change in both hemoglobin and hematocrit levels was significantly higher in the systemic group (p < 0.001). Conclusion: It is apparent that topical administration of TXA is associated with more effective to decrease blood lossv and causes less change in hematological parameters compared to its intravenous administration.

Rosmarinic acid prevents refractory bacterial pneumonia through regulating Keap1/Nrf2-mediated autophagic pathway and mitochondrial oxidative stress

Methicillin-resistant Staphylococcus aureus (MRSA) is the leading cause of bacterial pneumonia, featured with exuberant inflammatory cytokine production, extensive oxidative stress and tissue injury. The Keap1/Nrf2 system is the major apparatus essential for host defense against oxidative and electrophilic stresses of both exogenous and endogenous origins, representing a logical target for host-directed strategy to treat severe inflammatory diseases including MRSA-induced pneumonia. In an effort to search therapeutics for bacterial pneumonia, we identify rosmarinic acid (RA) as a covalent modifier of Keap1 and hence an activator of Nrf2. Specifically, RA forms a covalent bond with the cysteine 151 of Keap1 in BTB domain, and blocks its association with Nrf2 for proteasome-mediated degradation. Consequently, RA treatment caused the increased Nrf2 nuclear translocation to initiate antioxidant and mitochondrial biogenic programs, as well as macrophage bactericidal activity through inducing autophagic pathway, which eventually led to expedited bacterial eradication, inflammation resolution, and disease recovery. Collectively, our findings establish RA as a specific inducer of Nrf2 and show its potential to prevent MRSA pneumonia.

2167 Beyond diagnosis: Using ultrasound to affect tumor vasculature for hepatocellular carcinoma (HCC) therapy

OBJECTIVES/SPECIFIC AIMS: Preliminary animal studies showed that low-intensity ultrasound (US) coincident with intravascularly administered microbubbles locally disrupts tumor vasculature. This study translates the novel therapy of antivascular ultrasound (AVUS) into an autochthonous model of hepatocellular carcinoma (HCC). The differential effects produced by AVUS at low and high doses are evaluated. METHODS/STUDY POPULATION: HCC was induced in 12 Wistar rats by ingestion of 0.01% diethylnitrosamine in drinking water for 12 weeks. Rats received AVUS treatment at low and high doses. Low dose group (n=6) received 1 W/cm2 US for 1 minute with 0.2 mL microbubbles injected IV. High dose group (n=6) received 2 W/cm2 for 2 minute with 0.7 mL microbubbles IV. Perfusion was measured before and after AVUS with contrast-enhanced ultrasound (CE-US) and power Doppler (PD-US). Peak enhancement (PE) and perfusion index (PI) were measured from each US mode. Histology after sacrifice or natural death was compared to pre/post US. Analysis of H&amp;E and trichrome sections was evaluated for percent area of hemorrhage and findings of tissue injury and repair including inflammation, necrosis, and fibrosis. RESULTS/ANTICIPATED RESULTS: After high dose AVUS, PE, and PI of CE-US decreased from baseline by an average of 33.3% and 29.7%, respectively. Histology showed extensive tissue injury (hemorrhage, necrosis, fibrosis) in 58% of tumor cross-sectional area. Conversely, low dose AVUS increased PE and PI of CE-US by an average of 39.3% and 67.8%, respectively. Histology showed smaller areas of microhemorrhage Versus large pools of hemorrhage (only 17% area). PD-US changes were similar to CE-US. DISCUSSION/SIGNIFICANCE OF IMPACT: In summary, the opposing effects of AVUS observed at 2 doses allows for multiple roles in tumor therapy. Enhanced perfusion at a low dose may improve drug delivery or radiation therapy. Whereas, vascular disruption at high doses of AVUS may allow noninvasive ischemic therapy. Furthermore, AVUS is ripe for translation given the use its component parts clinically: low-intensity long-tone burst for physiotherapy and microbubbles as an US contrast agent. Thus, AVUS should be evaluated for translation of its differential effects into noninvasive therapies for HCC and other tumors.

Epidemiologic review of zika virus disease

Zika virus disease has resonated great concern globally. The World Health Organization declared it “a public health emergency of International concern” on 1st February, 2016. The recent outbreaks have become a major challenge due to a drift from its earlier known benign exanthematous spectrum to a causal link to microcephaly. Historically, the name Zika virus comes from the Zika Forest of Uganda. It was first identified in 1947 among Rhesus Macaque sub-population. Two genetically distinct isolates have been well characterized; the Asian and African strains. This virus is spread by bites of day-time-active Aedes mosquitoes; the Aedes aegypti and Aedes albopictus. Zika Virus appears to spread along a narrow equatorial belt of Africa to Asia through the Pacific Ocean to French Polynesia, New Caledonia (southwest Pacific Ocean), the Cook Islands (south Pacific), and Easter Island (a Chilean territory in Polynesia), and most recently to Mexico, Central America, the Caribbean, and South America, where today has assumed a pandemic proportion.Up to eighty percent of infections are asymptomatic. Symptomatic infections are characterized by a self-limiting febrile illness and maculopapular rash, arthralgia, conjunctivitis, back pain and mild headaches. Maternal Zika viral load is thought to be a significant risk factor to fetal infection leading to invasion of either trophoblasts or placental cells or both through maternal decidua. Zika viral RNA proteins and associated extensive selective tissue injuries have been demonstrated in the brains and spinal cords of abortuses. Diagnosis of Zika virus is essentially based on viral RNA detection from clinical specimens. Currently, licensed preventive medicines or vaccines are unavailable. With the wide spate of recent outbreaks and consequent neurologic morbidity and mortality, there is need for deployment of point-of-care equipment for screening of pregnant women in our environment. This is an ambitious call for advocacy by all relevant health care providers.Keywords: Zika Virus, disease outbreaks, microcephaly, Aedes mosquitoes

143 The roles and mechanisms of pore-forming toxins in cardiac injury

Cardiac injury, pore-forming toxins, calcium influxCardiac muscles and conduction system are very sensitive to interruption of plasma membrane integrity due to uncontrollable ion diffusion. There are many types of toxins...

The effect of intraoperative and 6-h postoperative intravenous administration of low-dose prostacyclin on the endothelium, hemostasis, and hemodynamics in patients undergoing a pancreaticoduodenoctemy: a randomized-controlled pilot study.

Capillary leakage, secondary to endothelial breakdown, is common in patients undergoing major surgical procedures with extensive tissue injury and this is associated with increased morbidity and mortality. Prostacyclin has been ascribed cytoprotective properties together with its vasodilatory and antiplatelet effects. The present pilot study investigated the safety and endothelial protective effects of low-dose prostacyclin infusion. A randomized placebo-controlled pilot study evaluating the effect of prostacyclin (iloprost) infusion (1.0 ng/kg/min) versus placebo (saline infusion) intraoperatively and 6 h postoperatively in patients undergoing a pancreaticoduodenoctemy was carried out. Hemodynamics were evaluated by Nexfin, hemostasis was evaluated by thrombelastography, and transfusion requirements were registered. Endothelial damage was evaluated by circulating sE-selectin, soluble thrombomodulin, and nucleosomes. Comparable baseline demography and surgical time were found. Hemodynamics were comparable between groups. The placebo group received more red blood cells, median 115 ml [interquartile range (IQR): 0-296 ml] versus 0 ml (IQR: 0-0 ml), P=0.027, at the postoperative ward and after 6 h. Thrombelastography maximum clot firmness decreased intraoperatively only in the placebo group (P=0.034)). Soluble thrombomodulin increased more in the placebo group postoperatively [1.63 ng/ml (IQR: 0.65-2.55 ng/ml) versus 0.40 ng/ml (IQR: 0.21-0.63 ng/ml), P=0.027] and 6 h postoperatively [1.83 (1.1-2.36) versus 0.67 (0.42-0.91), P=0.027]. Nucleosomes increased intraoperatively and postoperatively only in the placebo group; thus, the overall level of nucleosomes was higher in the placebo group (P=0.019). Intraoperative and postoperative low-dose prostacyclin infusion is safe and associated with reduced endothelial cell damage in patients undergoing a pancreaticoduodenoctemy compared with those receiving placebo.

Retinoic Acid-Loaded Collagen-Hyaluronate Scaffolds: A Bioactive Material for Respiratory Tissue Regeneration.

Clinical interventions for extensive tissue injury to the larger airways remain limited. Recently, respiratory tissue engineering strategies have emerged with a variety of biomimetic materials and tissue constructs to address these limitations, though rapid epithelialization of the construct with mucociliary function is still largely unresolved. The overall objective of this study was to manufacture an all-trans retinoic acid (atRA)-loaded bilayered collagen-hyaluronate (atRA-B) scaffold as a platform technology for tracheal tissue regeneration. atRA-loaded scaffolds were fabricated using a customized lyophilization process and characterized for drug loading and release properties using HPLC, followed by validation of their bioactivity using human primary tracheobronchial epithelial cells. atRA-loaded materials were reproducibly manufactured and exhibited the release of atRA following their hydration over 8-28 h that was significantly affected by collagen cross-linking. An optimal formulation consisting of 10 μg/mL atRA in a collagen-hyaluronate suspension to manufacture the scaffold film layer was identified and used to develop the atRA-B scaffold. Immunofluorescence studies and RT-PCR revealed that the atRA-loaded biomaterials increased the expression of two epithelial markers of mucociliary differentiation, MUC5AC and β-tubulin IV, via upregulation of MUC5AC and FOXJ1 genes, both in epithelial monoculture and in a 3D scaffold coculture system with lung fibroblasts. Overall, this study has demonstrated that the atRA-B scaffold can enhance functional epithelialization in primary tracheobronchial cells and can potentially pioneer the development of a novel and biocompatible device to address a currently unmet clinical need in tracheal replacement.

TLR and NLRP3 inflammasome expression deregulation in macrophages of adult rats subjected to neonatal malnutrition and infected with methicillin-resistant Staphylococcus aureus

ObjectivesNutritional aggression in critical periods may lead to epigenetic changes that affect gene expression. The aim of this study was to assess the effect of neonatal malnutrition on the expression of toll-like receptor (TLR)-2, TLR-4, and NLRP3 receptors, caspase-1 enzyme, and interleukin (IL)-1 β production in macrophages infected with methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) Staphylococcus aureus. MethodsWistar rats (N = 24) were divided in two distinct groups: nourished (17% casein) and malnourished (8% casein). Four systems were established after the isolation of mononuclear cells: negative control, positive control, MRSA, and MSSA. The plates were incubated at 37°C for 24 h in humidified atmosphere and 5% carbon dioxide. Tests were performed after this period to analyze the expression of standard recognition receptors, caspase-1 enzyme, and the production of IL-1 β. Student's t test and analysis of variance were used in the statistical analysis; P < 0.05 was statistically significant. ResultsMalnutrition reduced animal growth and the expression of TLR-2, TLR-4, and NLRP3 receptors, the caspase-1 enzyme, and the IL-1 β levels in macrophages infected with lipopolysaccharides in the present study. However, the interaction between the S. aureus and the macrophages promoted greater gene expression of receptors and enzymes. ConclusionThe neonatal malnutrition model compromised the expression of standard recognition receptors, of the caspase-1 enzyme as well as the production of IL-1 β. However, the S. aureus and neonatal malnutrition combination led to intense transcription of such innate immunity components. Therefore, the deregulation in the expression of TLR and NLRP3 receptors and of the caspase-1 enzyme may induce extensive tissue injury and favor the permanence and spread of these bacteria, especially those that are methicillin resistant.

Review of Research on Immunotherapy of Severe Surgical Infection

Abstract Severe surgical infection refers to infection after surgical treatment or surgical operation, accounting for approximately 30% of surgical diseases. This type of infection can cause extensive inflammation and tissue injury and reduce success rate of surgical treatments. Immune defense plays an important role in antiinfection treatment of hosts. Infection immunity is a series of physiological defense mechanisms for recognition of immune system and removal of pathogens. As for severe surgical infection, immunotherapy becomes an important and promising therapy for severe surgical infection. This study summarizes recent progresses achieved in immunization and immunotherapy of surgical infection.