Role of necroptosis in the pathogenesis of solid organ injury.
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ABSTRACT:
SUBMITTER: Zhao H
PROVIDER: S-EPMC4670925 | biostudies-other | 2015 Nov
REPOSITORIES: biostudies-other
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Project description:Although nonoperative management has become the standard of care for solid organ injury, variability exists in the care patients receive, and there are limited data regarding nonoperative management in patients with high grades of organ injury and substantial overall injury. We aimed to evaluate operative intervention frequency, including splenectomy, and patient outcomes before and after institution of the pediatric solid organ injury pathway at Harborview Medical Center (HMC) in 2005.This is a retrospective cohort study conducted at HMC for all pediatric solid organ injury patients from 2001 to 2012. Patients were identified in the Harborview Trauma Registry via DRG International Classification of Diseases-9th Rev. (ICD-9) codes for the presence of liver and spleen injuries. Demographic information, clinical characteristics, and ICD-9 procedure codes were also obtained from the trauma registry. Outcomes including splenectomy, a related abdominal surgery (exploratory laparotomy, spleen or liver repair, or splenectomy), mortality, and length of stay were compared between periods before and after 2005, adjusted for Injury Severity Score (ISS).The pediatric solid organ injury population at HMC (n = 712) has a high frequency of high-grade injury (35% Grade IV or V) and a high level of overall injury severity (median ISS, 21). Splenectomy was rare and remained stable over time despite an increase in severity of injury (from 2.4% to 0.8%, p = 0.44, among patients with isolated injury and from 4.0% to 3.3%, p = 0.78, among patients with nonisolated injury). Other abdominal surgeries also remained stable over time. Mortality decreased among patients with nonisolated injury (from 11.2% to 4.8%, p = 0.01). Length of stay decreased among patients with isolated organ injury, from a median of 4 days (interquartile range, 3-5 days) to 2 days (interquartile range, 2-3 days) (p < 0.0005) as well as within the lower ISS strata among patients with nonisolated organ injury (from a median of 4 days to 2 days among ISS < 12, p = 0.007; from 5 days to 3 days among ISS of 12-20, p = 0.0001; and from 7 days to 4 days among ISS of 21-33, p = 0.003).Care in the recent period (2005-2012) was associated with a stable, low frequency of splenectomy; decreased mortality for patients with nonisolated injury; and decreased hospital length of stay among most subsets of patients, suggesting improved care despite an increase in patients' severity of injury.Therapeutic study, level IV; epidemiologic study, level III.
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Project description:Severe acute respiratory disease coronavirus 2 (SARS-CoV-2, formerly 2019-nCoV) is a novel coronavirus that has rapidly disseminated worldwide, causing the coronavirus disease 2019 (COVID-19) pandemic. As of January 6th, 2021, there were over 86 million global confirmed cases, and the disease has claimed over 1.87 million lives (a ∼2.2% case fatality rate). SARS-CoV-2 is able to infect human cells by binding its spike (S) protein to angiotensin-conversing enzyme 2 (ACE2), which is expressed abundantly in several cell types and tissues. ACE2 has extensive biological activities as a component of the renin-angiotensin-aldosterone system (RAAS) and plays a pivotal role as counter-regulator of angiotensin II (Ang II) activity by converting the latter to Ang (1-7). Virion binding to ACE2 for host cell entry leads to internalization of both via endocytosis, as well as activation of ADAM17/TACE, resulting in downregulation of ACE2 and loss of its protective actions in the lungs and other organs. Although COVID-19 was initially described as a purely respiratory disease, it is now known that infected individuals can rapidly progress to a multiple organ dysfunction syndrome. In fact, all human structures that express ACE2 are susceptible to SARS-CoV-2 infection and/or to the downstream effects of reduced ACE2 levels, namely systemic inflammation and injury. In this review, we aim to summarize the major features of SARS-CoV-2 biology and the current understanding of COVID-19 pathogenesis, as well as its clinical repercussions in the lung, heart, kidney, bowel, liver, and brain. We also highlight potential therapeutic targets and current global efforts to identify safe and effective therapies against this life-threatening condition.
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Project description:BackgroundPrevious studies have demonstrated protective effects of anti-receptor interacting protein kinase 1 (RIP1), a key necroptosis molecule. However, it is uncertain whether necroptosis has a crucial role in hepatic IR injury. Therefore, we evaluated the role of necroptosis in hepatic IR injury.MethodThe IR mice underwent 70% segmental IR injury induced by the clamping of the hepatic artery and portal vein for 1 hr followed by reperfusion for 4 hr. The key necroptosis molecules (RIP1, RIP3, and MLKL) and other key molecules of regulated necrosis (PGAM5 and caspase-1) were evaluated in the warm IR injury model. A RIP1 inhibitor (necrostain-1s) and/or an anti-mitochondrial permeability transition (MPT)-mediated necrosis mediator (cyclosporine A, CyA) were administered before clamping. Necrotic injury was quantified using Suzuki's scoring system. qRT-PCR and western blot were performed to evaluate RIP1, RIP3, MLKL and PGAM5 expressions.ResultsRIP1, RIP3, MLKL and PGAM5 expression did not change in the hepatic IR injury model. Moreover, Nec1s pretreatment did not improve histology or biochemical markers. The overall Suzuki score (cytoplasmic vacuolization, sinusoidal congestion and hepatocytes necrosis) was increased in the RIP3(-/-) mice compared to the IR group (3.5 vs. 5, p = 0.026). CyA pretreatment and/or RIP3(-/-) mice decreased Bax/Bcl2 expression; however, it did lead to an overall change in the levels of AST, ALT and LDH or necrotic injury. The Bax/Bcl2 ratio and the expression of caspase-1 and caspase-3 did not increase in our hepatic IR injury model.ConclusionKey necroptosis molecules did not increase in the necrosis-dominant hepatic IR injury model. Anti-necroptosis and/or cyclosporine-A treatment did not have an overall protective effect on necrosis-dominant hepatic IR injury.
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Project description:To investigate the use of abdominal CT scanning in the management of pediatric blunt abdominal trauma in pediatric and non-pediatric departments.In this observational cohort study, anonymized data were extracted from 2 large German statutory health insurances (∼5.9 million clients) in a 7-year period (2010-2016). All patients with inpatient International Classification of Diseases (ICD) codes S36.- and S37.- (injury of intra-abdominal organs; injury of urinary and pelvic organs) aged ≤18 years were included. Demographic and clinical data were analyzed by logistic regression analysis for associations with the use of abdominal CT.A total of 524 children with blunt abdominal trauma (mean age 11.0 ± 5.2 years; 62.6% males) were included; 164 patients (31.3%) received abdominal CT-imaging. There were no significant differences in traumatic non-intraabdominal comorbidity patterns (injuries of external causes; injuries to the head or thorax). There was substantial variability in the rate of abdominal CT imaging among different medical disciplines ranging from 11.6% to 44.5%. Patients admitted to pediatric departments (Pediatrics and Pediatric Surgery) underwent abdominal CT imaging significantly less frequently (19.7%; N = 55) compared to patients treated in non-pediatric departments (General/Trauma Surgery: 44.5%; N = 109) irrespective of concomitant injuries. The estimated OR for the use of abdominal CT by General/Trauma Surgery was 6.2-fold higher (OR: 6.15 [95-%-CI:3.07-13.21]; P < .001) compared to Pediatric Surgery. Other risk factors associated with the use of abdominal CT were traumatic extra-abdominal comorbidities, increasing age, male gender, and admission to a university hospital.Abdominal CT imaging was significantly less frequently used in pediatric departments. The substantial variability of the abdominal CT rate among different medical disciplines and centers indicates a potential for reduction of CT imaging by implementation of evidence-based guidelines. Furthermore, our study underlines the need for centralization of pediatric trauma care in Germany not only to improve patient outcome but to avoid radiation-induced cancer mortality.
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