Is the increased ozone dosage key factor for its anti-inflammatory effect in an experimental model of mesenteric ischemia?

BACKGROUND: Ischemia/reperfusion injury of the intestines is a severe surgical condition. This study aimed to reveal ozone therapy effects with relatively increased ozone dosage in a created ischemia/reperfusion injury model. METHODS: In this study, 24 albino Wistar rats were examined in three groups. Rats in the control group (CG, n=8) underwent only a laparotomy. In the sham group (SG, n=8) and ozone group (OG, n=8), the superior mesenteric artery (SMA) of the rats was occluded for 1 h. After deoccluding the SMA, the abdomen was closed, physiological saline was infused intraperitoneally in the SG, and an increased ozone/oxygen mixture dose (from 0.7 mg/kg to 1 mg/kg) was infused intraperitoneally in the OG. Small intestine samples were obtained at the 24th h for histopathological examination of intestinal mucosal injury and evaluated according to the Chiu score. In addition, Malondialdehyde and Myeloperoxidase levels were evaluated for oxidant levels, whereas, Glutathione (GSH) enzyme activity was measured to evaluate the tissue antioxidant system. RESULTS: Histopathologically, the Chiu score was the lowest in the CG. It was lower in the OG compared to the SG showing the ameliorating effect of ozone on the intestinal mucosa. Chiu score in the OG was higher compared to that in the CG, but not statistically significant. A significantly higher GSH level was observed in the OG compared to the SG, proving antioxidant activity. CONCLUSION: In this experimental model of ischemia/reperfusion in rats, treatment with an increased ozone level decreased the inflammatory process through antioxidant mechanisms and reduced intestinal mucosal damage. However, the effectiveness of ozone therapy depends on its dosages.

Acute mesenteric ischemia secondary to superior mesenteric vein thrombosis in a patient with liver cirrhosis: A case report.

RATIONALE: Acute mesenteric ischemia due to superior mesenteric vein (SMV) thrombosis is a rare yet potentially life-threatening emergency. Our case report explores this condition in the context of a patient with liver cirrhosis due to Wilson disease. We specifically highlight the complex derangement of the coagulative balance in liver cirrhosis. PATIENT CONCERNS: A 34-year-old female with Wilson disease-related cirrhosis presented with intractable abdominal pain, nausea, and vomiting that showed no response to antispasmodic medication. DIAGNOSES: A contrast-enhanced abdominal computed tomography scan and Doppler ultrasound confirmed an intraluminal filling defect in the SMV, leading to the diagnosis of SMV thrombosis. INTERVENTIONS: Prompt anticoagulation, intravenous fluids, and an antibiotic were initiated. Surgical consultation recommended conservative therapy with close monitoring. OUTCOMES: Over the following 2 days, the patient's condition improved considerably, with almost complete resolution of her symptoms. Genetic testing identified a 4G/4G homozygous genotype of the plasminogen activator inhibitor 1 gene, associated with a higher risk of thrombosis in the vessels of internal organs. After 2 months of sustained anticoagulant therapy, a follow-up contrast-enhanced computed tomography scan revealed near-complete recanalization of the SMV, and the patient remained symptom-free. LESSONS: This case underscores the importance of early detection and treatment of acute mesenteric ischemia in patients with liver cirrhosis, as well as the potential role of genetic factors in thrombosis.

Low-dose sumatriptan improves the outcome of acute mesenteric ischemia in rats via downregulating kynurenine.

BACKGROUND: Mesenteric ischemia has remained without effective pharmacological management for many years. Sumatriptan, an abortive medication for migraine and cluster headaches, has potent anti-inflammatory properties and ameliorated organ ischemia in previous animal studies. Similarly, inhibition of the kynurenine pathway ameliorated renal and myocardial ischemia/reperfusion (I/R) in many preclinical studies. Herein, we assessed the effect of sumatriptan on experimental mesenteric I/R and investigated whether kynurenine pathway inhibition is a mechanism underlying its action. METHODS: Ischemia was induced by ligating the origin of the superior mesenteric artery (SMA) and its anastomosis with the inferior mesenteric artery (IMA) with bulldog clamps for 30 min. Ischemia was followed by 1 h of reperfusion. Sumatriptan (0.1, 0.3, and 1 mg/kg ip) was injected 5 min before the reperfusion phase, 1-methyltryptophan (1-MT) (100 mg/kg iv) was used to inhibit kynurenine production. At the end of the reperfusion phase, samples were collected from the jejunum of rats for H&E staining and molecular assessments. RESULTS: Sumatriptan improved the integrity of intestinal mucosa after I/R, and 0.1 mg/kg was the most effective dose of sumatriptan in this study. Sumatriptan decreased the increased levels of TNF-α, kynurenine, and p-ERK but did not change the decreased levels of NO. Furthermore, sumatriptan significantly increased the decreased ratio of Bcl2/Bax. Similarly, 1-MT significantly decreased TNF-α and kynurenine and protected against mucosal damage. CONCLUSIONS: This study demonstrated that sumatriptan has protective effects against mesenteric ischemia and the kynurenine inhibition is potentially involved in this process. Therefore, it can be assumed that sumatriptan has the potential to be repurposed as a treatment for acute mesenteric ischemia.

Immediate postoperative parenteral anticoagulant therapy in patients with mesenteric ischemia after intestinal resection: a retrospective cohort study at a single institute.

BACKGROUND: Bowel gangrene represents a major fatal event in acute mesenteric ischemia. Intestinal resection is inevitable in patients with peritonitis and bowel gangrene. This retrospective study aimed to elucidate the benefit of postoperative parenteral anticoagulation in patients with intestinal resection. METHODS: Patients with acute mesenteric ischemia and bowel gangrene were recruited retrospectively between January 2007 and December 2019. All patients underwent bowel resection. They were categorized into two groups: patients without immediate parenteral anticoagulant therapy (Group A) and those with immediate parenteral anticoagulant therapy (Group B). Thirty-day mortality and survival were analyzed. RESULTS: A total of 85 patients were included, with 29 patients in Group A and 56 patients in Group B. Patients in Group B had lower 30-day mortality (16.1%) and a higher 2-year survival rate (45.4%) than patients in Group A (30-day mortality: 51.7%, p = 0.001; 2-year survival rate: 19.0%, p = 0.001). In the 30-day mortality multivariate analysis, patients in Group B had a better outcome (odds ratio = 0.080, 95% confidence interval between 0.011 and 0.605, p = 0.014). Patients in Group B also had a better outcome in the survival multivariate analysis (hazard ratio: 0.435, 95% confidence interval between 0.213 and 0.887, p = 0.022). CONCLUSIONS: Immediate postoperative parenteral anticoagulant therapy improves prognosis in patients with acute mesenteric ischemia treated by intestinal resection. Trial registration This research was retrospectively approved by the Institutional Review Board (IRB) I&II of Taichung Veterans General Hospital (TCVGH-IRB No.CE21256B) on July 28th, 2021. The informed consent waiver was also approved by IRB I&II of Taichung Veterans General Hospital. The Declaration of Helsinki and ICH-GCP guidelines were followed during this study.

COVID-19 induced mesenteric ischemia in a patient with ulcerative colitis and paroxysmal nocturnal haemoglobinuria despite thromboprophylaxis.

Inflammatory bowel disease and paroxysmal nocturnal hemoglobinuria (PNH) are both well-known prothrombotic states. However, ongoing thromboprophylaxis is usually effective in such conditions. We report an imbalance that was triggered by COVID-19 infection. There is evidence that COVID-19 infection leads to thrombosis of vessels. The thrombosis of mesenteric vessels can be multifocal and without respiratory symptoms and leads to devastating consequences like resection of large segments of the bowel and lifelong requirement of parenteral nutritional support. We report about a case of ulcerative colitis (in remission) and PNH where COVID-19 resulted in mesenteric ischemia.

Trombosis de vena mesentérica superior como complicación de apendicitis aguda: una entidad poco frecuente / Superior mesenteric vein thrombosis as a complication of acute appendicitis: a rare entity

Las complicaciones de la apendicitis aguda ha sido ampliamente descrita en la literatura; la trombosis venosa mesenterica es una manifestación poco común de esta patologia correspondiento a menos del 1 % de frecuencia, esto puede desorientar al cirujano general al coexistir en el cuadro de apendicitis aguda. Presentamos el caso de un paciente masculino de 58 años, con dolor abdominal de 5 días de evolución, con sintomatologia poco especifica para el diagnóstico concreto de apendicitis. Se realizó una tomografía computarizada de abdomen con hallazgos de apendicitis aguda y trombososis venosa mesenterica con un coágulo de 11.5 cm. Se hizó también apendicectomia abierta y se inició anticoagulación al egreso hospitalario.

The complications of acute appendicitis have been widely described in the literature; Mesenteric venous thrombosis is a rare manifestation of this pathology corresponding to less than 1% frequency, this can confuse the general surgeon as it coexists with acute appendicitis. We present the case of a 58-year-old male patient, with abdominal pain of 5 days of evolution, with symptoms that are not very specific for the specific diagnosis of appendicitis. Computed tomography of the abdomen was performed with findings of acute appendicitis and mesenteric venous thrombosis with a clot of 11.5 cm. An open appendectomy was performed and anticoagulation was started on hospital discharge.

Non-occlusive mesenteric ischemia during bevacizumab treatment for glioblastoma: a case report.

Glioblastoma is one of the most aggressive brain tumors in adults. The standard treatment is radiotherapy and chemotherapy based on the Stupp regimen after maximal safe resection. One effective chemotherapeutic drug is bevacizumab, which can prolong progression-free survival in glioblastoma patients but not overall survival. Adverse events of bevacizumab include hypertension, proteinuria, delayed wound healing, bleeding of the nose and gums, and thromboembolism resulting in gastrointestinal perforation. Herein, we describe an autopsy case of a patient with glioblastoma who died from non-occlusive mesenteric ischemia that was presumably caused by bevacizumab.

Albendazole ameliorates inflammatory response in a rat model of acute mesenteric ischemia reperfusion injury.

BACKGROUND: Acute mesenteric ischemia is known as a life threatening condition. Re-establishment of blood flow in this condition can lead to mesenteric ischemia reperfusion (MIR) injury which is accompanied by inflammatory response. Still, clear blueprint of inflammatory mechanism underlying MIR injury has not been provided. Interestingly, Albendazole has exhibited notable effects on inflammation and cytokine production. In this study, we aimed to evaluate outcomes of MIR injury following pretreatment with Albendazole with respect to assessment of mesenteric inflammation and ischemia threshold. METHODS: Male rats were randomly divided into sham operated, vehicle treated, Albendazole 100 mg/kg and Albendazole 200 mg/kg groups. MIR injury was induced by occlusion of superior mesenteric artery for 30 min followed by 120 min of reperfusion. Samples were utilized for assessment of epithelial survival and villous height. Immunohistochemistry study revealed intestinal expression of TNF-α and HIF-1-α. Gene expression of NF-κB/TLR4/TNF-α/IL-6 was measured using RTPCR. Also protein levels of inflammatory cytokines in serum and intestine were assessed by ELISA method. RESULTS: Histopathological study demonstrated that pretreatment with Albendazole could ameliorate decline in villous height and epithelial survival following MIR injury. Also, systemic inflammation was suppressed after administration of Albendazole. Analysis of possible participating inflammatory pathway could demonstrate that intestinal expression of NF-κB/TLR4/TNF-α/IL-6 is significantly attenuated in treated groups. Eventually, IHC study illustrated concordant decline in mesenteric expression of HIF-1-α/TNF-α. CONCLUSION: Single dose pretreatment with Albendazole could ameliorate inflammatory response and enhance ischemia threshold following induction of MIR injury. More studies would clarify existing causality in this phenomenon.

Predictors of response to intra-arterial vasodilatory therapy of non-occlusive mesenteric ischemia in patients with severe shock: results from a prospective observational study.

BACKGROUND: Non-occlusive mesenteric ischemia (NOMI) is a life-threatening condition occurring in patients with shock and is characterized by vasoconstriction of the mesenteric arteries leading to intestinal ischemia and multi-organ failure. Although minimal invasive local intra-arterial infusion of vasodilators into the mesenteric circulation has been suggested as a therapeutic option in NOMI, current knowledge is based on retrospective case series and it remains unclear which patients might benefit. Here, we prospectively analyzed predictors of response to intra-arterial therapy in patients with NOMI. METHODS: This is a prospective single-center observational study to analyze improvement of ischemia (indicated by reduction of blood lactate > 2 mmol/l from baseline after 24 h, primary endpoint) and 28-day mortality (key secondary endpoint) in patients with NOMI undergoing intra-arterial vasodilatory therapy. Predictors of response to therapy concerning primary and key secondary endpoint were identified using a) clinical parameters as well as b) data from 2D-perfusion angiography and c) experimental biomarkers of intestinal injury. RESULTS: A total of 42 patients were included into this study. At inclusion patients had severe shock, indicated by high doses of norepinephrine (NE) (median (interquartile range (IQR)) 0.37 (0.21-0.60) µg/kg/min), elevated lactate concentrations (9.2 (5.2-13) mmol/l) and multi-organ failure. Patients showed a continuous reduction of lactate following intra-arterial prostaglandin infusion (baseline: (9.2 (5.2-13) mmol/l vs. 24 h: 4.4 (2.5-9.1) mmol/l, p < 0.001) with 22 patients (52.4%) reaching a lactate reduction > 2 mmol/l at 24 h following intervention. Initial higher lactate concentrations and lower NE doses at baseline were independent predictors of an improvement of ischemia. 28-day mortality was 59% in patients with a reduction of lactate > 2 mmol/l 24 h after inclusion, while it was 85% in all other patients (hazard ratio 0.409; 95% CI, 0.14-0.631, p = 0.005). CONCLUSIONS: A reduction of lactate concentrations was observed following implementation of intra-arterial therapy, and lactate reduction was associated with better survival. Our findings concerning outcome predictors in NOMI patients undergoing intra-arterial prostaglandin therapy might help designing a randomized controlled trial to further investigate this therapeutic approach. Trial registration Retrospectively registered on January 22, 2020, at clinicaltrials.gov (REPERFUSE, NCT04235634), https://clinicaltrials.gov/ct2/show/NCT04235634?cond=NOMI&draw=2&rank=1 .

Vasoactive agents in acute mesenteric ischaemia in critical care. A systematic review.

Background: Acute mesenteric ischaemia (AMI) is a surgical emergency which has an associated high mortality.  The mainstay of active treatment includes early surgical intervention, with resection of non-viable bowel, and revascularisation of the ischaemic bowel where possible. Due to the physiological insult of AMI however, perioperative care often involves critical care and the use of vasoactive agents to optimise end organ perfusion. A number of these vasoactive agents are currently available with varied mechanism of action and effects on splanchnic blood flow. However, specific guidance on which is the optimal vasoactive drug to use in these settings is limited. This systematic review aimed to evaluate the current evidence comparing vasoactive drugs in AMI. Methods: A systematic search of Ovid Medline, Ovid Embase, Cochrane CENTRAL and the Cochrane Database of Systematic Review was performed on the 5th of November 2020 to identify randomised clinical trials comparing different vasoactive agents in AMI on outcomes including mortality. The search was performed through the Royal College of Surgeons of England (RCSEng) search support library. Results were analysed using the Rayyan platform, and independently screened by four investigators. Results: 614 distinct papers were identified. After screening, there were no randomised clinical trials meeting the inclusion criteria. Conclusions: This review identifies a gap in literature, and therefore recommends an investigation into current practice and clinician preference in relation to vasoactive agents in AMI. Multicentre randomised controlled trials comparing these medications on clinical outcomes will therefore be required to address this question.

Anti-inflammatory and antioxidant effects of the nanocomposite Fullerol decrease the severity of intestinal inflammation induced by gut ischemia and reperfusion.

Intestinal ischemia is a vascular emergency that arises when blood flow to the intestine is compromised. Reperfusion is necessary to restore intestinal function but might lead to local and systemic inflammatory responses and bacterial translocation, with consequent multiple organ dysfunction syndrome (MODS). During reperfusion occurs production of reactive oxygen species. These species contribute to intestinal injury through direct toxicity or activation of inflammatory pathways. Fullerol is a nanacomposite which has been shown to act as reactive oxygen species and reactive nitrogen species (RNS) scavengers. Thus, our aim was to evaluate whether Fullerol confer anti-inflammatory activity during intestinal ischemia and reperfusion (IIR). Intestinal ischemia was induced by total occlusion of the superior mesenteric artery. Groups were treated with vehicle or Fullerol 10 min before reperfusion. Mice were euthanized after 6 h of reperfusion, and small intestines were collected for evaluation of plasma extravasation, leukocyte influx, cytokine production and histological damage. Bacterial translocation to the peritoneal cavity and reactive oxygen and nitrogen species production by lamina propria cells were also evaluated. Our results showed that treatment with Fullerol inhibited bacterial translocation to the peritoneal cavity, delayed and decreased the lethality rates and diminished neutrophil influx and intestinal injury induced by IIR. Reduced severity of reperfusion injury in Fullerol-treated mice was associated with blunted reactive oxygen and nitrogen species production in leukocytes isolated from gut lamina propria and decreased production of pro-inflammatory mediators. Thus, the present study shows that Fullerol is a potential therapy to treat inflammatory bowel disorders associated with bacterial translocation, such as IIR.

Synergistic Effect of ß-alanine and Aprotinin on Mesenteric Ischemia.

BACKGROUND: Acute mesenteric ischemia arises through sudden interruption of mesenteric blood flow, mostly due to an occlusion of the superior mesenteric artery and is associated with a high mortality of approximately 50% to 90%. In previous studies, the single application of ß-alanine or aprotinin caused an ameliorated intestinal damage but without any systemic effects. METHODS: To analyze the combined effect of ß-alanine and aprotinin on acute ischemia and reperfusion of the small intestine, a model with anesthetized rats was used. Ischemia and reperfusion were initiated by occluding and reopening the superior mesenteric artery. After 120 min of ischemia and 180 min of reperfusion, the intestine was analyzed for tissue damage, the activity of the saccharase, and accumulation of granulocytes. In addition, systemic and metabolic as well as inflammatory parameters were measured in blood at certain points in time. RESULTS: The combination of ß-alanine and aprotinin resulted in a clearly stabilized mean arterial blood pressure and blood glucose level during the reperfusion period. Furthermore, the combined administration resulted in significantly reduced tissue damage parameters, cytokine and cell-free hemoglobin concentrations in blood plasma. In addition, the damage to the small intestine was significantly attenuated, so that the animals ultimately survived the entire test period because of the administration of both substances. CONCLUSIONS: Overall, the simultaneous application of both substances leads to a synergistic protection without the occurrence of undesirable side effects. The combined usage of ß-alanine and aprotinin can be seen as a promising approach to inhibit the onset of acute mesenteric ischemia.

Our early experience with mesenteric ischemia in COVID-19 positive patients.

Literature has been published stating that thrombosis is occurring at higher rates in patients who are positive for COVID-19. This experience is more with limb ischemia. Reports of mesenteric ischemia are coming in from different parts of the globe. We share our early experience of managing two patients with acute mesenteric ischemia.

Antiphospholipid syndrome with mesenteric vein thrombosis and hepatic nodular regenerative hyperplasia in a child: A case report.

RATIONALE: Hepatic nodular regenerative hyperplasia (NRH), a nonspecific change in the liver parenchyma, is very rare in children. Hepatic microvascular changes may be the cause, as these vascular changes are uncommon in children. Antiphospholipid syndrome (APS), an autoimmune disease characterized by vascular thromboembolism, is extremely unusual in children. PATIENT CONCERNS: A 13-year-old girl who presented with abdominal pain and elevated liver enzymes was transferred to our hospital. Abdominal computed tomography and magnetic resonance imaging showed a massive mesenteric venous thrombus and a malignant mass with liver metastasis. DIAGNOSES: Her immunological profile was positive for antinuclear antibodies (ANA) at a titer of 1/160 (nucleolar pattern), anticardiolipin antibodies (aCL) immunoglobulin G, and anti-histone antibody. A liver biopsy revealed hepatic NRH. INTERVENTIONS: The patient was initially started on heparin upon hospitalization and switched to warfarin and a vitamin K antagonist and continued treatment with international normalized ratio monitoring. OUTCOMES: Her symptoms improved after 9 months of anticoagulation therapy. LESSONS: In the presence of hepatic NRH or vascular thrombosis in children, we recommend that APS be differentially diagnosed using lupus anticoagulant and aCL and appropriate management be implemented.

Outcomes of long-term anticoagulant treatment for the secondary prophylaxis of splanchnic venous thrombosis.

BACKGROUND: Splanchnic vein thrombosis (SVT) is an uncommon but potentially life-threatening disease usually related to different underlying clinical conditions. The risk of SVT recurrences is high over time in patients with an underlying permanent prothrombotic condition. Vitamin K antagonists (VKA) represent the mainstay of treatment for SVT. Data about the efficacy and safety of direct oral anticoagulants (DOACs) are reported in the literature for the treatment of acute SVT, but less is known about their application for the secondary prophylaxis of venous thromboembolism (VTE). The aim of this study was to assess the efficacy and safety of long-term DOACs therapy in patients at high-risk of thrombosis, compared to VKA. METHODS: This is a retrospective single-centre study including 70 patients with SVT on long-term anticoagulant treatment with VKA followed-up at our Units between January 2017 and December 2019. All the patients were at high thrombotic risk defined as the presence of a permanent prothrombotic condition requiring long-term anticoagulation. During follow-up, 28 patients were shifted to DOACs and their clinical outcomes were compared to those of the patients who continued VKA therapy. All the arterial and venous thrombotic events of the splanchnic and extra-splanchnic districts as well as the haemorrhagic adverse events occurring during follow-up were recorded. RESULTS: Of the seventy patients enrolled in the study, 36 patients (51.4%) had a single-segment involvement thrombosis (28.5% of portal vein, 7.1% of superior mesenteric vein, 4.3% of splenic vein, 11.5% of hepatic veins) and 34 patients (48.6%) had multi-segment involvement at the time of diagnosis. 42 patients (60%) continued VKA therapy and 28 (40%) were switched to DOACs. Median follow-up was 6 years (range 2-8) during VKA and 1.9 years (range 1-5.2) during DOACs. The incidence of thrombotic events was similar between patients on VKA and those on DOACs. Patients on VKA developed deep vein thrombosis (DVT), and of the patients on DOACs 1 developed NSTEMI and 1 DVT. No major haemorrhagic events occurred. Minor bleedings occurred in 26% of patients on VKA and in none of the DOACs patients (P: 0.09). CONCLUSIONS: Our results highlight that DOACs could represent an effective and safe alternative to the VKA for secondary prophylaxis in SVT patients at high risk of thrombosis.

Protective Effects of Cinnamaldehyde against Mesenteric Ischemia-Reperfusion-Induced Lung and Liver Injuries in Rats.

The aim of this study was to characterize and reveal the protective effects of cinnamaldehyde (CA) against mesenteric ischemia-reperfusion- (I/R-) induced lung and liver injuries and the related mechanisms. Sprague-Dawley (SPD) rats were pretreated for three days with 10 or 40 mg/kg/d, ig of CA, and then induced with mesenteric ischemia for 1 h and reperfusion for 2 h. The results indicated that pretreatment with 10 or 40 mg/kg of CA attenuated morphological damage in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly restored the levels of aspartate transaminase (AST) and alanine transaminase (ALT) in mesenteric I/R-injured liver tissues, indicating the improvement of hepatic function. CA also significantly attenuated the inflammation via reducing myeloperoxidase (MOP) activity and downregulating the expression of inflammation-related proteins, including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), cyclooxygenase-2 (Cox-2), and tumor necrosis factor receptor type-2 (TNFR-2) in both lung and liver tissues of mesenteric I/R-injured rats. Pretreatment with CA significantly downregulated nuclear factor kappa B- (NF-κB-) related protein expressions (NF-κB p65, NF-κB p50, I kappa B alpha (IK-α), and inhibitor of nuclear factor kappa-B kinase subunit beta (IKKß)) in both lung and liver tissues of mesenteric I/R-injured rats. CA also significantly downregulated the protein expression of p53 family members, including caspase-3, caspase-9, Bax, and p53, and restored Bcl-2 in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly reduced TUNEL-apoptotic cells and significantly inhibited p53 and NF-κB p65 nuclear translocation in both lung and liver tissues of mesenteric I/R-injured rats. CA neither induced pulmonary and hepatic histological alterations nor affected the parameters of inflammation and apoptosis in sham rats. We conclude that CA alleviated mesenteric I/R-induced pulmonary and hepatic injuries via attenuating apoptosis and inflammation through inhibition of NF-κB and p53 pathways in rats, suggesting the potential role of CA in remote organ ischemic injury protection.