Taisuke Kitamura

The proteinase/proteinase-activated receptor-2/transient receptor potential vanilloid-1 cascade impacts pancreatic pain in mice

AIMS Proteinase-activated receptor-2 (PAR2) and transient receptor potential vanilloid-1 (TRPV1) are co-localized in the primary afferents, and the trans-activation of TRPV1 by PAR2 activation is involved in processing of somatic pain. Given evidence for contribution of PAR2 to pancreatic pain, the present study aimed at clarifying the involvement of TRPV1 in processing of pancreatic pain by the proteinase/PAR2 pathway in mice. MAIN METHODS Acute pancreatitis was created by repeated administration of cerulein in conscious mice, and the referred allodynia/hyperalgesia was assessed using von Frey filaments. Injection of PAR2 agonists into the pancreatic duct was achieved in anesthetized mice, and expression of Fos in the spinal cord was determined by immunohistochemistry. KEY FINDINGS The established referred allodynia/hyperalgesia following cerulein treatment was abolished by post-treatment with nafamostat mesilate, a proteinase inhibitor, and with capsazepine, a TRPV1 antagonist, in mice. Injection of trypsin, an endogenous PAR2 agonist, or SLIGRL-NH(2), a PAR2-activating peptide, into the pancreatic duct caused expression of Fos protein in the spinal superficial layers at T8-T10 levels in the mice. The spinal Fos expression caused by trypsin and by SLIGRL-NH(2) was partially blocked by capsazepine, the former effect abolished by nafamostat mesilate. SIGNIFICANCE Our data thus suggest that the proteinase/PAR2/TRPV1 cascade might impact pancreatic pain, in addition to somatic pain, and play a role in the maintenance of pancreatitis-related pain in mice.

Activation of sensory neurons contributes to reduce spinal cord injury in rats

We previously demonstrated that activation of sensory neurons increases endothelial prostaglandin I(2) (PGI(2)) production by releasing calcitonin gene-related peptide (CGRP). Since PGI(2) reduces post-traumatic spinal cord injury (SCI) by inhibiting tumor necrosis factor (TNF) production, activation of sensory neurons in the spinal cord tissue may ameliorate spinal cord injury. This study examines these possibilities using rat models of compression trauma-induced SCI. Both SB366791, a specific vanilloid receptor antagonist, and CGRP (8-37), a CGRP receptor antagonist, significantly inhibited trauma-induced increases in spinal cord tissue 6-keto-PGF(1alpha) levels. SB366791, CGRP (8-37) and indomethacin (IM) enhanced increases in spinal cord tissue TNF levels at 2h after trauma and exacerbated motor disturbances. Administration of CGRP significantly reduced motor disturbances and inhibited increases in spinal cord tissue TNF levels through enhancement of increases in tissue levels of 6-keto-PGF(1alpha). These observations strongly suggest that activation of sensory neurons might ameliorate compression trauma-induced SCI, inhibiting TNF production through enhancement of endothelial PGI(2) production. Thus, although the spinal cord sensory neurons function as nociceptive neurons, they could also be critically involved in the cytoprotective system that attenuates SCI development and, thus, pharmacological stimulation of spinal cord sensory neurons might contribute to reduce spinal cord injury.

Limaprost reduces motor disturbances by increasing the production of insulin-like growth factor I in rats subjected to spinal cord injury

Calcitonin gene-related peptide (CGRP) released from sensory neurons increases the production of a neuroprotective substance insulin-like growth factor I (IGF-I), and sensory neuron stimulation contributes to a reduction of spinal cord injury (SCI) by inhibiting inflammatory responses in rats. Because receptors for prostaglandin E₂ (EP receptors) are present on sensory neurons, it is possible that prostaglandin E₁ analog limaprost reduces SCI by increasing IGF-I production through sensory neuron stimulation. We examined this possibility in rats subjected to compression-trauma-induced SCI. Limaprost increased the CGRP release from dorsal root ganglion (DRG) neurons isolated from rats, and this increase was reversed by pretreatment with the EP4 receptor antagonist ONO-AE3-208. Spinal cord tissue levels of CGRP and IGF-I were increased after the induction of SCI, peaking at 2 h postinduction. The intravenous administration of limaprost enhanced increases of spinal cord tissue levels of CGRP, IGF-I, and IGF-I mRNA at 2 h after the induction of SCI. Increases of spinal cord tissue levels of tumor necrosis factor, caspase-3, myeloperoxidase, and the number of apoptotic nerve cells were inhibited by the administration of limaprost. Motor disturbances of hind legs in animals subjected to the compression-trauma-induced SCI were reduced by the administration of limaprost. These effects of limaprost were reversed completely by pretreatment with a specific transient receptor potential vanilloid 1 inhibitor SB366791 and by sensory denervation. These observations strongly suggest that limaprost may increase the IGF-I production by stimulating sensory neurons in the spinal cord, thereby ameliorating compression-trauma-induced SCI through attenuation of inflammatory responses.

Early predictors for massive transfusion in older adult severe trauma patients

BACKGROUND Many scoring systems for the early prediction of the need for massive transfusion (MT) have been reported; in most of these, vital signs are regarded as important. However, the validity of these scoring systems in older patients remains unclear because older trauma patients often present with normal vital signs. In this study, we investigated the effectiveness of previously described scoring systems, as well as risk factors that can provide early prediction of the need for MT in older severe trauma patients. METHODS We prospectively collected data from a cohort of severe trauma patients (ISS ≥16 and age ≥16years) admitted from January 2007 to March 2015. Trauma Associated Severe Hemorrhage (TASH), Assessment of Blood Consumption (ABC), and Prince of Wales Hospital (PWH) scores were compared between a younger and an older group. Furthermore, the predictors associated with MT in older severe trauma patients were assessed using multivariable logistic regression analyses. RESULTS The area under the curve (AUC) was significantly smaller for older group than for younger group for all three scoring systems (p<0.05). The most important risk factors to predict the need for MT were related to anatomical factors including FAST results (odds ratio (OR): 5.58, 95% confidence interval (CI): 2.10-14.99), unstable pelvic fracture (OR: 21.56, 95% CI: 6.05-90.78), and long bone open fracture of the lower limbs (OR: 12.21, 95% CI: 4.04-39.09), along with pre-injury anticoagulant agent use (OR: 5.22, 95% CI: 1.30-19.61), antiplatelet agent use (OR: 3.81, 95% CI: 1.57-9.04), lactate levels (OR: 1.20, 95% CI: 1.04-1.39) and shock index (OR: 2.67, 95% CI: 1.05-6.84). Traditional vital signs were not early risk factors. CONCLUSION We suggest that MT in older trauma patients should be considered on the basis of anatomical factors, pre-injury anticoagulant or antiplatelet agent use, lactate level and SI even if traditional vital signs are normal.

The impact of external fixation on mortality in patients with an unstable pelvic ring fracture: a propensity-matched cohort study

Aim There is not adequate evidence to establish whether external fixation (EF) of pelvic fractures leads to a reduced mortality. We used the Japan Trauma Data Bank database to identify isolated unstable pelvic ring fractures to exclude the possibility of blood loss from other injuries, and analyzed the effectiveness of EF on mortality in this group of patients. Patients and Methods This was a registry‐based comparison of 1163 patients who had been treated for an isolated unstable pelvic ring fracture with (386 patients) or without (777 patients) EF. An isolated pelvic ring fracture was defined by an Abbreviated Injury Score (AIS) for other injuries of < 3. An unstable pelvic ring fracture was defined as having an AIS ≥ 4. The primary outcome of this study was mortality. A subgroup analysis was carried out for patients who required blood transfusion within 24 hours of arrival in the Emergency Department and those who had massive blood loss (AIS code: 852610.5). Propensity‐score matching was used to identify a cohort like the EF and non‐EF groups. Results With the use of propensity‐score matching using the completed data, 346 patients were matched. When the propensity‐score matching was adjusted, EF was associated with a significantly lower risk of death (p = 0.047). In the subgroup analysis of patients who needed blood transfusion within 24 hours and those who had massive blood loss, EF was associated with a significantly lower risk of death in patients who needed blood transfusion within 24 hours (p = 0.014) and in those with massive blood loss (p = 0.016). Conclusion The use of EF to treat unstable pelvic ring fractures was associated with a significantly lower risk of death, especially in patients with severe fractures.

1398: PLASMINOGEN ACTIVATOR INHIBITOR-1 IS THE MOST PREDICTIVE MARKER OF MORTALITY IN SEPSIS.

Learning Objectives: Sepsis has poor outcome, and the mortality rate is 30%50% in patients with septic shock. Early diagnosis and treatment of sepsis are important for improving the prognosis. Sepsis is the most common disease associated with coagulopathy. Approximately 20%-40% of all sepsis patients are complicated with disseminated intravascular coagulation (DIC). Therefore, inflammation and coagulation are closely interrelated in sepsis. In 2016, new sepsis definition named SEPSIS-3 was published. We aimed to identify the most predictive marker of 28-day mortality using inflammation and coagulation markers. Methods: This was a single-center retrospective study and included 186 patients with sepsis from January 2013 to September 2015. The definition of sepsis was used according to SEPSIS-3. Inflammatory markers [C-reactive protein (CRP), procalcitonin (PCT), and presepsin (PSEP)] and coagulation markers [platelet count, prothrombin time-international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), antithrombin (AT), D-dimer, thrombin-antithrombin complex (TAT), plamin-2 plasmin inhibitor complex (PIC), protein C (PC), soluble fibrin (SF), and plasminogen activator inhibitor (PAI)-1] were assayed on ED admission. Univariate and multivariate logistic regression analyses were performed to identify independent predictive markers of 28-day mortality. The area under the curve (AUC) and the optimal cut-off value of the most predictive marker were examined. Results:The 28-day mortality rate was 19% (36/186). PSEP, TAT, PC, SF, and PAI-1 were found to be significant predictive markers of 28-day mortality according to univariate analysis. Subsequently, we performed multivariate logistic regression analysis using these five markers as explanatory variables. PAI-1 was found to be the only independent predictive marker of 28-day mortality (P <0.05). AUC of PAI-1 was 0.72, and the optimal cut-off value was 83 ng/ml, with sensitivity and specificity of 75% and 61%, respectively. Conclusions: In conclusion, PAI-1 may be a useful predictive marker of 28-day mortality for sepsis.