Purpose
The abdomen is the second most common source of sepsis and is associated with unacceptably high morbidity and mortality. Recently, the essential definitions of sepsis and septic shock were ...updated (Third International Consensus Definitions for Sepsis and Septic Shock, Sepsis-3) and modified. The purpose of this review is to provide an overview of the changes introduced by Sepsis-3 and the current state of the art regarding the treatment of abdominal sepsis.
Results
While Sepsis-1/2 focused on detecting systemic inflammation as a response to infection, Sepsis-3 defines sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The Surviving Sepsis Campaign (SSC) guideline, which was updated in 2016, recommends rapid diagnosis and initiating standardized therapy. New diagnostic tools, the establishment of antibiotic stewardship programs, and a host of new-generation antibiotics are new landmark changes in the sepsis literature of the last few years. Although the “old” surgical source control consisting of debridement, removal of infected devices, drainage of purulent cavities, and decompression of the abdominal cavity is the gold standard of surgical care, the timing of gastrointestinal reconstruction and closure of the abdominal cavity (“damage control surgery”) are discussed intensively in the literature. The SSC guidelines provide evidence-based sepsis therapy. Nevertheless, treating critically ill intensive care patients requires individualized, continuous daily re-evaluation and flexible therapeutic strategies, which can be best discussed in the interdisciplinary rounds of experienced surgeons and intensive care medicals.
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Monocyte recruitment into the vessel wall at atherosclerosis predilection sites is essential for lesion development in the early phase of atherosclerosis. Platelets interacting with ...ultra-large von Willebrand Factor (ULVWF) multimers deposited after CD40 receptor ligation on the endothelial surface form adhesive bridges and facilitate monocyte diapedesis. We hypothesise that enhanced endothelial CD40 expression at arterial bifurcations is responsible for monocyte recruitment and that its absence reduces susceptibility to atherosclerosis.
Y-shaped channel slides covered with endothelial cells (HUVEC) and isolated perfused carotid artery bifurcations from different mouse lines were used for adhesion studies with isolated fluorescent dye-labelled platelets and monocytes. Monocyte adherence was quantified via fluorescence imaging. Oil Red O staining visualised aortic atherosclerotic plaques, and mRNA expression was determined by qRT-PCR.
In response to soluble CD40 ligand (sCD40L) stimulated ULVWF release, the number of monocytes bound distal to the bifurcation of the Y-slide was 1.8-fold greater than without stimulation. The number of adherent monocytes in sCD40L-treated carotid artery bifurcations was 6 to 12.3-fold greater in ApoE knockout mice as compared to bifurcations derived from CD40/ApoE-deficient or control mice. CD40 mRNA expression was 2-fold higher in carotid artery bifurcations of ApoE knockout mice as compared to the proximal unbranched segment. Introduction of the CD40 knockout into the ApoE-/- background reduced the atherosclerosis burden along the entire aorta of these mice by 60 %.
Our data demonstrate the importance of endothelial CD40 expression at atherosclerosis predilection sites for endothelial cell-platelet-monocyte interaction in the early phase of atherosclerosis.
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The CD40 receptor and its ligand CD154 are widely expressed in various immune-competent cells. Interaction of CD154 with CD40 is essential for B-cell growth, differentiation, and ...immunoglobulin class switching. Many other immune-competent cells involved in innate and adaptive immunity communicate through this co-stimulatory ligand-receptor dyad. CD40-CD154 interaction is involved in the pathogenesis of numerous inflammatory and autoimmune diseases. While CD40 and CD154 are membrane-bound proteins, their soluble counterparts are generated by proteolytic cleavage or alternative splicing.
This review summarises current knowledge about the impact of single nucleotide polymorphisms in the human CD40 gene and compensatory changes in the plasma level of the soluble CD40 receptor (sCD40) isoform in related pro-inflammatory diseases. It discusses regulation patterns of the disintegrin metalloprotease ADAM17 function leading to ectodomain shedding of transmembrane proteins, such as pro-inflammatory adhesion molecules or CD40. The role of sCD40 as a potential biomarker for chronic inflammatory diseases will also be discussed.
Since the eruption of the worldwide SARS-CoV-2 pandemic in late 2019/early 2020, multiple elective surgical interventions were postponed. Through pandemic measures, elective operation capacities were ...reduced in favour of intensive care treatment for critically ill SARS-CoV-2 patients. Although intermittent low-incidence infection rates allowed an increase in elective surgery, surgeons have to include long-term pulmonary and extrapulmonary complications of SARS-CoV-2 infections (especially “Long Covid”) in their perioperative management considerations and risk assessment procedures. This review summarizes recent consensus statements and recommendations regarding the timepoint for surgical intervention after SARS-CoV-2 infection released by respective German societies and professional representatives including DGC/BDC (Germany Society of Surgery/Professional Association of German Surgeons e.V.) and DGAI/BDA (Germany Society of Anesthesiology and Intensive Care Medicine/Professional Association of German Anesthesiologists e.V.) within the scope of the recent literature. The current literature reveals that patients with pre- and perioperative SARS-CoV-2 infection have a dramatically deteriorated postoperative outcome. Thereby, perioperative mortality is mainly caused by pulmonary and thromboembolic complications. Notably, perioperative mortality decreases to normal values over time depending on the duration of SARS-CoV-2 infection.
Although many organochlorine pesticides (OCPs) have been banned or restricted because of their persistence and linkage to neurodegenerative diseases, there is evidence of continued human exposure. In ...contrast, registered herbicides are reported to have a moderate to low level of toxicity; however, there is little information regarding their toxicity to humans or their combined effects with OCPs. This study aimed to characterize the mechanism of toxicity of banned OCP insecticides (aldrin, dieldrin, heptachlor, and lindane) and registered herbicides (trifluralin, triallate, and clopyralid) detected at a legacy contaminated pesticide manufacturing and packing site using SH-SY5Y cells. Cell viability, LDH release, production of reactive oxygen species (ROS), and caspase 3/7 activity were evaluated following 24 h of exposure to the biocides. In addition, RNASeq was conducted at sublethal concentrations to investigate potential mechanisms involved in cellular toxicity. Our findings suggested that aldrin and heptachlor were the most toxic, while dieldrin, lindane, trifluralin, and triallate exhibited moderate toxicity, and clopyralid was not toxic to SH-SY5Y cells. While aldrin and heptachlor induced their toxicity through damage to the cell membrane, the toxicity of dieldrin was partially attributed to necrosis and apoptosis. Moreover, toxic effects of lindane, trifluralin, and triallate, at least partially, were associated with ROS generation. Gene expression profiles suggested that decreased cell viability induced by most of the tested biocides was related to inhibited cell proliferation. The dysregulation of genes encoding for proteins with anti-apoptotic properties also supported the absence of caspase activation. Identified enriched terms showed that OCP toxicity in SH-SY5Y cells was mediated through pathways associated with the pathogenesis of neurodegenerative diseases. In conclusion, this study provides a basis for elucidating the molecular mechanisms of pesticide-induced neurotoxicity. Moreover, it introduced SH-SY5Y cells as a relevant in vitro model for investigating the neurotoxicity of pesticides in humans.
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•Aldrin and heptachlor induced their toxicity through damage to the cell membrane.•The toxicity of dieldrin was attributed to necrosis and apoptosis in SH-SY5Y cells.•Lindane, trifluralin, and triallate toxicity were associated with cell ROS generation.•OCP toxicity was mediated through pathways related to human neurodegenerative diseases.•SH-SY5Y is a relevant in vitro model for investigating the neurotoxicity of pesticides.
Background
If untreated, the abdominal compartment syndrome (ACS) has a mortality of nearly 100 %. Thus, its early recognition is of major importance for daily rounds on surgical intensive care ...units. Intraabdominal hypertension (IAH) is a poorly recognized entity, which occurs if intraabdominal pressure arises >12 mmHg. Measurement of the intravesical pressure is the gold standard to diagnose IAH, which can be detected in about one fourth of surgical intensive care patients.
Purpose
The aim of this manuscript is to outline the current diagnostic and therapeutic options for IAH and ACS. While diagnosis of IAH and ACS strongly depends on clinical experience, new diagnostic markers could play an important role in the future. Therapy of IAH/ACS consists of five treatment “columns”: intraluminal evacuation, intraabdominal evacuation, improvement of abdominal wall compliance, fluid management, and improved organ perfusion. If conservative therapy fails, emergency laparotomy is the most effective therapeutic approach to achieve abdominal decompression. Thereafter, patients with an open abdomen require intensive care and are permanently threatened by the quadrangle of fluid loss, muscle proteolysis, heat loss, and an impaired immune function. As a consequence, complication rate dramatically increases after 8 days of open abdomen therapy.
Conclusion
Despite many efforts, the mortality of patients with ACS remains unacceptably high. Permanent clinical education and surgical trials will be necessary to improve the outcome of our critically ill surgical patients.
Assessing a complex mixture of pesticides at the impacted sites has been challenging for risk assessors for 50 years. The default assumption is that at low concentrations, pesticides interact ...additively with one another; thus, the risk posed by each component of a complex mixture could be simply added up. The EPA interaction-based hazard index (HIInteraction) modifies this assumption using a binary weight-of-evidence (BINWOE). However, data gaps often preclude HIInteraction use at most sites. This study evaluated these assumptions using the BINWOE to estimate the hazard index (HI) of select pesticide mixtures. The lack of in vivo binary interaction data led us to use a cell line, SH-SY5Y, to obtain the data necessary for the BINWOE approach. In the risk assessment, we considered the most active exposure scenario inhaling a mixture of volatile pesticides from contaminated soil and groundwater. The potential interactions between pesticides in 15 binary mixtures were investigated using the MTT assay in SH-SY5Y cells. Our findings showed that 60% of the binary mixtures elicited synergism (in at least one concentration), 27% displayed antagonism, and 13% showed additive effects in SH-SY5Y cells. Combining human safety data with in vitro interaction data indicated that adults and toddlers were at the highest risk when considering industrial and commercial land use, respectively, compared to other subpopulations. Incorporating interaction data into the risk assessment either increased the risk by up to 20% or decreased the risk by 2%, depending on the mixture. Our results demonstrate the predominant synergistic interactions, even at low concentrations, altered risk characterization at the complex operating site. Most concerning, organochlorine pesticides with the same mechanism of action did not follow dose additivity when evaluated by SH-SY5Y cell lines. Based on our observations, we caution that current HI methods based on additivity assumptions may underestimate the risk of organochlorine mixtures.
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•The component-based risk assessment methods cannot adequately protect human health.•In vitro assays using human cells can create interaction data for risk assessment.•Pesticides with the same mechanism of action did not follow dose additivity in vitro.•The BINWOE approach can use in vitro interaction data to improve risk estimation.•Incorporating interaction data in risk assessment increased the risk of nine mixtures.
•HBCD generates a sigmoid curve of cytotoxicity in fathead minnow liver explants.•Expression of apoptotic genes was time- and concentration-dependent.•Expression of anti-ROS related genes was time- ...and concentration-dependent.•Apoptotic, anti-ROS, and xenobiotic pathways can explain the cytotoxicity of HBCD.
Hexabromocyclododecane (HBCD) is a ubiquitous environmental contaminant of current concern despite its global ban in 2013 due to its characteristics as a persistent organic pollutant. While the toxicity of HBDC in vertebrates has been extensively studied, the specific molecular mechanisms underlying its toxicity in fish are not fully understood to date. Therefore, the aim of this work was to determine the in vitro cytotoxicity of HBCD in the fathead minnow (Pimephales promelas) using liver explants, and to investigate the molecular mechanisms underlying these effects. Explants were incubated with nine different concentrations of HBCD (0.00032, 0.0016, 0.008, 0.04, 0.2, 1, 5, 25 and 125 mg HBCD/L) for 6 and 24 h, and cytotoxicity was tested by using the Lactate Dehydrogenase (LDH) assay. The expression of genes with a key role in the regulation of apoptosis, oxidative stress, cryoprotective responses to reactive oxygen species (ROS), and xenobiotic metabolism was also measured in liver explants after exposure to 0.00032, 0.0016, 0.008, 0.2, and 25 mg HBCD/L. After 6 h, a concentration-dependent significant increase in cytotoxicity was found between 0.008 and 1 mg/L HBCD, followed by a decrease between 1 and 25 mg/L. Cytotoxicity reached 100 % at a concentration of 125 mg/L HBCD. After 24 h, HBCD showed a biphasic response with a concentration-dependent decrease in cytotoxicity between 0.0016 and 1 mg/L that returned to baseline levels at 5 mg/L. Then, cytotoxicity increased at concentrations greater than 5 mg/L to reach a maximum value at 125 mg/L. Changes in the expression of genes related to apoptosis (apoEn, apoIn, caspase2, caspase9 and bax) were also time- and concentration-dependent. Genes related to antioxidant responses such as gst and catalase were generally decreased after 6 h of incubation and increased after 24 h. The same pattern was observed for cyp1a and cyp3a, both related to xenobiotic metabolism. The expression of genes related to cryoprotective responses anti ROS (akt and pi3k) decreased at almost all HBCD concentrations tested after 6 h but remained unaltered after 24 h. Overall, we demonstrated that the cytotoxic effect of HBCD in fathead minnow liver explant was not proportional to its concentration in the culture media. Cytotoxicity was highly dynamic and did not follow a typical concentration-response pattern, complicating its toxicological characterization.
Magnetically controlled growing rods (MCGR) are commonly implanted for the treatment of early-onset scoliosis. While most authors report favorable short-term results, little is known about long-term ...deformity correction. This prospective cohort study assesses spinal deformity control in a homogeneous spinal muscular atrophy (SMA) patient group treated with MCGR implants, a standardized lengthening protocol and a minimum follow-up of four years. 17 SMA patients with progressive scoliosis were treated with MCGR implanted parallel to the spine with rib-to-pelvis fixation. Radiologic measurements were performed before and after MCGR implantation and during external lengthening procedures. These included measurements of the scoliotic curve, kyphosis, lordosis, pelvic obliquity and the spinal length. Additional clinical data of the complications were also analyzed. 17 children (mean age 7.4 years) were surgically treated and underwent a total of 376 lengthenings. Complication rates were 3.5% in respect to all interventions or 41% of the patients had complications during 3.5% of the lengthening sessions. The initial implantation significantly reduced the main scoliotic curve by 59%, with the correction remaining constant throughout the follow-up. Pelvic obliquity was also significantly and permanently corrected by 72%, whereas kyphosis and lordosis were not influenced. The spinal length could be significantly increased mostly during the first year of treatment. Bilateral implantation of MCGRs for correction of spinal deformity in children with SMA showed no decrease of the lengthening potential during a four-year follow-up. Therefore, the previously described 'law of diminishing returns' could not be applied to this patient population.Level of Evidence/Clinical relevance: Therapeutic Level IV.
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Marfan syndrome (MFS) is a genetic disorder leading to medial aortic degeneration and life-limiting dissections. To date, there is no causal prevention or therapy. Rapamycin is a ...potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, regulating cell growth and metabolism. The mgR/mgR mice represent an accepted MFS model for studying aortic pathologies to understand the underlying molecular pathomechanisms. This study investigated whether rapamycin inhibits the development of thoracic aortic aneurysms and dissections in mgR/mgR mice.
Isolated primary aortic smooth muscle cells (mAoSMCs) from mgR/mgR mice were used for in vitro studies. Two mg kg/BW rapamycin was injected intraperitoneally daily for two weeks, beginning at 7–8 weeks of age. Mice were sacrificed 30 days post-treatment. Histopathological and immunofluorescence analyses were performed using adequate tissue specimens and techniques. Animal survival was evaluated accompanied by periodic echocardiographic examinations of the aorta.
The protein level of the phosphorylated ribosomal protein S6 (p-RPS6), a downstream target of mTOR, was significantly increased in the aortic tissue of mgR/mgR mice. In mAoSMCs isolated from these animals, expression of mTOR, p-RPS6, tumour necrosis factor α, matrix metalloproteinase-2 and -9 was significantly suppressed by rapamycin, demonstrating its anti-inflammatory capacity. Short-term rapamycin treatment of Marfan mice was associated with delayed aneurysm formation, medial aortic elastolysis and improved survival.
Short-term rapamycin-mediated mTOR inhibition significantly reduces aortic aneurysm formation and thus increases survival in mgR/mgR mice. Our results may offer the first causal treatment option to prevent aortic complications in MFS patients.
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