Identification of Ppy-lineage cells as a novel origin of pancreatic ductal adenocarcinoma.

The Ppy gene encodes pancreatic polypeptide (PP) secreted by PP- or γ-cells, which are a subtype of endocrine cells localised mainly in the islet periphery. For a detailed characterisation of PP cells, we aimed to establish PP cell lines. To this end, we generated a mouse model harbouring the SV40 large T antigen (TAg) in the Rosa26 locus, which is expressed upon Ppy-promoter-mediated Cre-loxP recombination. Whereas Insulin1-CreERT-mediated TAg expression in beta cells resulted in insulinoma, surprisingly, Ppy-Cre-mediated TAg expression resulted in the malignant transformation of Ppy-lineage cells. These mice showed distorted islet structural integrity at 5 days of age compared with normal islets. CK19+ duct-like lesions contiguous with the islets were observed at 2 weeks of age, and mice developed aggressive pancreatic ductal adenocarcinoma (PDAC) at 4 weeks of age, suggesting that PDAC can originate from the islet/endocrine pancreas. This was unexpected as PDAC is believed to originate from the exocrine pancreas. RNA-sequencing analysis of Ppy-lineage islet cells from 7-day-old TAg+ mice showed a downregulation and an upregulation of endocrine and exocrine genes, respectively, in addition to the upregulation of genes and pathways associated with PDAC. These results suggest that the expression of an oncogene in Ppy-lineage cells induces a switch from endocrine cell fate to PDAC. Our findings demonstrate that Ppy-lineage cells may be an origin of PDAC and may provide novel insights into the pathogenesis of pancreatic cancer, as well as possible therapeutic strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Association between lung contusion volume and acute changes in fibrinogen levels: A single-center observational study.

Aim: Organ tissue damage, including the lungs, may lead to acute coagulopathy. This study aimed to evaluate the association between lung contusion volume and serum fibrinogen level during the acute phase of trauma. Methods: We conducted an observational study using electronic medical records at a tertiary-care center between January 2015 and December 2018. We included patients with lung contusions on hospital arrival. We used three-dimensional computed tomography to calculate lung contusion volumes. The primary outcome was the lowest fibrinogen level measured within 24 h of hospital arrival. We evaluated the association between lung contusion volume and outcome with multivariable linear regression analysis. Also, we calculated the sensitivity and specificity of lung contusion volume in patients with a serum fibrinogen level of ≤150 mg/dL. Results: We identified 124 eligible patients. Their median age was 43.5 years, and 101 were male (81.5%). The median lung contusion volume was 10.9%. The median lowest fibrinogen level within 24 h from arrival was 188.0 mg/dL. After adjustment, lung contusion volume had a statistically significant association with the lowest fibrinogen level within 24 h from arrival (coefficient -1.6, 95% confidence interval -3.16 to -0.07). When a lung contusion volume of 20% was used as the cutoff, the sensitivity and specificity to identify fibrinogen depletion were 0.27 and 0.95, respectively. Conclusion: Lung contusion volume was associated with the lowest fibrinogen level measured within 24 h from hospital arrival. Measuring lung contusion volume may help to identify patients with a progression of fibrinogen depletion.

Zinc and iron dynamics in human islet amyloid polypeptide-induced diabetes mouse model.

Metal homeostasis is tightly regulated in cells and organisms, and its disturbance is frequently observed in some diseases such as neurodegenerative diseases and metabolic disorders. Previous studies suggest that zinc and iron are necessary for the normal functions of pancreatic ß cells. However, the distribution of elements in normal conditions and the pathophysiological significance of dysregulated elements in the islet in diabetic conditions have remained unclear. In this study, to investigate the dynamics of elements in the pancreatic islets of a diabetic mouse model expressing human islet amyloid polypeptide (hIAPP): hIAPP transgenic (hIAPP-Tg) mice, we performed imaging analysis of elements using synchrotron scanning X-ray fluorescence microscopy and quantitative analysis of elements using inductively coupled plasma mass spectrometry. We found that in the islets, zinc significantly decreased in the early stage of diabetes, while iron gradually decreased concurrently with the increase in blood glucose levels of hIAPP-Tg mice. Notably, when zinc and/or iron were decreased in the islets of hIAPP-Tg mice, dysregulation of glucose-stimulated mitochondrial respiration was observed. Our findings may contribute to clarifying the roles of zinc and iron in islet functions under pathophysiological diabetic conditions.

Establishment of an enzyme-linked immunosorbent assay for mouse pancreatic polypeptide clarifies the regulatory mechanism of its secretion from pancreatic γ cells.

Pancreatic polypeptide (PP), secreted from γ cells of the islets of Langerhans, is a 36 amino-acid peptide encoded by the Ppy gene. Although previous studies have reported that PP causes a decrease in appetite, the molecular mechanism that regulates PP secretion has not been fully elucidated. Lack of understanding of the regulatory mechanism of PP secretion may be partially owing to the lack of assay systems that can specifically detect PP. We recently developed the mouse monoclonal antibody 23-2D3 that specifically recognizes PP. In the present study, we developed a sandwich enzyme-linked immunosorbent assay for the measurement of mouse PP, and directly monitored intracellular Ca2+ concentrations in Ppy-expressing cells from a newly developed reporter mouse. Using these systems, we identified agonists, such as carbachol and glucose-dependent insulinotropic polypeptide (GIP), which stimulate PP secretion. We further demonstrated that, unlike the case of GIP-induced insulin secretion from ß cells, there is a unique mechanism by which PP secretion is triggered by an increase in intracellular Ca2+ concentrations via voltage-dependent calcium channels even in low-glucose conditions.

Assessing the impact of the national traffic safety campaign: a nationwide cohort study in Japan.

OBJECTIVES: This study aimed to examine the difference in mortality from serious road traffic injuries during the National Traffic Safety Campaign compared with other periods and identify the common mechanisms of injury by age group in Japan. DESIGN: A retrospective review of Japan Trauma Data Bank (JTDB). SETTING: A total of 280 participating major emergency institutions across Japan. PARTICIPANTS: Patients with road traffic injuries registered in JTDB between 2004 and 2018 were recruited in the study. We included patients injured by traffic crashes during the National Traffic Safety Campaigns and controls using a double control method. The National Traffic Safety Campaign comprises 10 consecutive days in spring and fall (20 days in each year), and controls was the same calendar days 2 weeks before and after the days in the National Traffic Safety Campaigns (40 days in each year) to control for weekday, seasonal and yearly trends. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was in-hospital mortality. The secondary outcome was the incidences of severe traffic injury. RESULTS: Among 126 857 patients recorded as road traffic injuries in JTDB, we identified 6181 patients (21 cases per day) with injuries occurring during the National Traffic Safety Campaigns and 12 382 controls (21 cases per day). The overall in-hospital mortality was 11.4%. We did not observe a significant difference in in-hospital mortality between the groups (11.8% vs 11.1%) with an adjusted OR of 1.05 (95% CI 0.95 to 1.16). The most common mechanism of injury in each age group was bicycle crash among children, motorcycle crash among adults and pedestrian among the elderly. CONCLUSIONS: We found no change in the incidence of severe traffic injury or in-hospital mortality during the National Traffic Safety Campaign in Japan. Serious road trauma was high for bicycles among children, motorcycles among adults and pedestrian among the elderly.

Effect of fluid administration on scene to traffic accident patients by EMS personnel: a propensity score-matched study using population-based ambulance records and nationwide trauma registry in Japan.

PURPOSE: The aim of this study was to assess the effect of fluid administration by emergency life-saving technicians (ELST) on the prognosis of traffic accident patients by using a propensity score (PS)-matching method. METHODS: The study included traffic accident patients registered in the JTDB database from January 2016 to December 2017. The main outcome was hospital mortality, and the secondary outcome was cardiopulmonary arrest on hospital arrival (CPAOA). To reduce potential confounding effects in the comparisons between two groups, we estimated a propensity score (PS) by fitting a logistic regression model that was adjusted for 17 variables before the implementation of fluid administration by ELST at the scene. RESULTS: During the study period, 10,908 traffic accident patients were registered in the JTDB database, and we included 3502 patients in this study. Of these patients, 142 were administered fluid by ELST and 3360 were not administered fluid by ELST. After PS matching, 141 patients were selected from each group. In the PS-matched model, fluid administration by ELST at the scene was not associated with discharge to death (crude OR: 0.859 [95% CI, 0.500-1.475]; p = 0.582). However, the fluid group showed statistically better outcome for CPAOA than the no fluid group in the multiple logistic regression model (adjusted OR: 0.231 [95% CI, 0.055-0.967]; p = 0.045). CONCLUSION: In this study, fluid administration to traffic accident patients by ELST was associated not with hospital mortality but with a lower proportion of CPAOA.

Patient age affects sex-based differences in post-traumatic mortality: a national trauma registry study in Japan.

PURPOSE: Sex-based differences in post-traumatic mortality have been widely discussed for quite some time. We hypothesized that age-related pathophysiologic changes would affect sex-based differences in post-traumatic mortality and aimed to verify the hypothesis using a nationwide trauma registry in Japan. METHODS: This was a retrospective analysis of trauma patients registered in The Japanese Trauma Data Bank. We stratified the study population into the following three subsets based on age: (1) pediatric subset (age ≤ 14), (2) adult subset (age 15-50) and (3) senior adult subset (age ≥ 51). We evaluated both sex-based differences in mortality in each subset separately using multivariate logistic regression analysis and the two-way interaction effect for predicted survival between the continuous increase of age and the sexes using a nonlinear multivariate regression model. RESULTS: We included 122,819 trauma patients who fulfilled the inclusion criteria and classified them into the 3 subsets according to age. Male patients were more likely to die compared to female patients only in the senior adult subset (adjusted odds ratio: 1.26; 95% confidence interval: 1.18-1.36), whereas there were no statistically significant differences in the other two subsets. Furthermore, non-linear logistic regression analysis revealed that predicted survival probability in male patients decreased more sharply in accordance with the increase of age compared to that in female patients (p for interaction: 0.051). CONCLUSION: Age-related change in post-traumatic mortality was significantly different between males and females, and male patients had a relatively higher risk of death in the older population.

Characteristics and outcomes of pediatric blunt renal trauma: a nationwide cohort study in Japan.

PURPOSE: The aim of this study was to describe epidemiologic features of pediatric blunt renal trauma. METHODS: We performed a retrospective analysis using the Japan Trauma Data Bank over 15 years. We included patients younger than 18 years with blunt renal trauma. We analyzed temporal trends and variations across age groups in patient characteristics, intervention, and in-hospital mortality. We also assessed factors associated with in-hospital mortality. RESULTS: We identified 435 pediatric patients with blunt renal trauma. Their median age was 14 years and median Injury Severity Score (ISS) was 17. The most common mechanism of injury was traffic accident in all age groups. Nephrectomy was performed in 3.2%, and the overall in-hospital mortality was 4.6%, both of which showed decreasing trends. The most common mechanism of injury by age group was a pedestrian accident in infants/toddlers/preschoolers (43.5%), pedestrian accident in middle childhood (18.5%), bicycle accident in young teens (24.7%), and motorcycle accident in teenagers (41.2%). Sports-related injury was common in young teens (23.3%) and teenagers (15.2%). Factors such as ISS, shock, concomitant injury, and nephrectomy were associated with high in-hospital mortality. CONCLUSIONS: We described decreasing trends in nephrectomy and in-hospital mortality in pediatric blunt renal trauma and found traffic accident and sports-related injury were common in the pediatric population in Japan.

Evaluation of urinary extravasation after non-operative management of traumatic renal injury: a multi-center retrospective study.

PURPOSE: Urinary extravasation is one of the major complications after non-operative management of traumatic renal injury and may lead to urinary tract infection and sepsis. The purpose of this study was to evaluate these factors in patients with traumatic renal injury. METHODS: This was a multi-center, retrospective, observational study performed at three tertiary referral hospitals in Osaka prefecture. We included patients with traumatic renal injury transported to the centers between January 2008 and December 2018. We excluded patients who either died or underwent nephrectomy within 24 h after admission. We investigated the occurrence of urinary extravasation and the related factors after traumatic renal injury using multivariable logistic regression analysis. RESULTS: In total, 146 patients were eligible for analysis. Their median age was 44 years and 68.5% were male. Their median Injury Severity Score was 17. Renal injuries were graded as American Association for Surgery of Trauma (AAST) grade I in 33 (22.6%), II in 27 (18.5%), III in 38 (26.0%), IV in 28 (19.2%), and V in 20 (13.7%) patients. Urinary extravasation was diagnosed in 26 patients (17.8%) and was statistically significantly associated with AAST grades IV-V (adjusted odds ratio, 33.8 [95% confidence interval 7.12-160], p < 0.001). CONCLUSION: We observed urinary extravasation in 17.8% of patients with non-operative management of traumatic renal injury and the diagnosed was made in mostly within 7 days after admission. In this study, the patients with AAST grade IV-V injury were associated with having urinary extravasation.

Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice.

AIMS/HYPOTHESIS: Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells. METHODS: We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca2+ imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin. RESULTS: Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12-15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca2+ signalling response and were increased in number in experimental diabetes models. CONCLUSIONS/INTERPRETATION: Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes. DATA AVAILABILITY: The single-cell RNA sequence (scRNA-seq) analysis datasets generated in this study have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE166164 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166164 ).

Factors associated with posttraumatic meningitis among traumatic head injury patients: a nationwide study in Japan.

PURPOSE: Posttraumatic meningitis is one of the severe complications that can result in increased mortality and longer hospital stay among trauma patients. Factors such as cerebrospinal fluid (CSF) fistula and basilar skull fracture are associated with posttraumatic meningitis. However, it remains unclear whether procedures such as burr hole surgery in the emergency department and decompressive craniectomy are associated with posttraumatic meningitis. The aim of this study was to assess factors associated with posttraumatic meningitis with a nationwide hospital-based trauma registry in Japan. METHODS: This was a retrospective observational study with a 12-year study period from January 2004 to December 2015. We included trauma patients registered in the Japanese Trauma Data Bank, whose head Abbreviated Injury Scale score was ≥ 3 in this study. The main endpoint was the occurrence of meningitis during hospitalization. Multivariable logistic regression analysis was used to assess independent parameters associated with posttraumatic meningitis such as CSF fistula, burr hole surgery in the emergency department, and decompressive craniectomy. RESULTS: Among 60,390 head injury patients with head AIS score 3 or more, 284 (0.5%) patients had posttraumatic meningitis. Factors associated with posttraumatic meningitis were burr hole surgery in the emergency department (adjusted odds ratio [AOR] 2.158 [95% confidence interval (CI) 1.401-3.325]), decompressive craniectomy (AOR 2.123 [95% CI 1.506-2.993]), external ventricular drainage (AOR 1.843 [95% CI, 1.157-2.935]), CSF leakage (AOR 3.328 [95% CI 2.205-5.022]), and basilar skull fracture (AOR 1.651 [95% CI 1.178-2.314]). CONCLUSIONS: In this population of trauma patients, burr hole surgery in the emergency department and decompressive craniectomy was associated with posttraumatic meningitis.

Pelvic angiography is effective for emergency pediatric patients with pelvic fractures: a propensity-score-matching study with a nationwide trauma registry in Japan.

PURPOSE: The aim of this study was to evaluate the association between the implementation of pelvic angiography (PA) and outcome in emergency pediatric patients with pelvic fracture. METHODS: We extracted data on pelvic fracture patients aged ≤ 19 years between 2004 and 2015 from a nationwide trauma registry in Japan. The main outcome was hospital mortality. We assessed the relationship between implementation of PA and hospital mortality using one-to-one propensity-score-matching analysis to reduce potential confounding effects in comparing the PA group with the non-PA group. RESULTS: In total, 1351 patients were eligible for our analysis, with 221 patients (16.4%) included in the PA group and 1130 patients (83.6%) included in the non-PA group. For all patients, the proportion of hospital mortality was higher in the PA group than in the non-PA group [13.6% (30/221) vs 7.1% (80/1130), crude odds ratio (OR) 2.062 (95% confidence interval (CI), 1.318-3.224); p = 0.002]. In the propensity-score-matched patients, the proportion of hospital mortality was lower in the PA group than in the non-PA group [10.5% (22/200) vs 18.2% (38/200), p = 0.027]. This finding was confirmed in both the multivariable logistic regression model [adjusted OR 0.392 (95% CI, 0.171-0.896); p = 0.026] and the conditional logistic regression model [conditional OR 0.484 (95% CI, 0.261-0.896); p = 0.021]. CONCLUSION: The implementation of PA was significantly associated with lower hospital mortality among emergency pediatric patients with pelvic fractures compared with the non-implementation of PA.

Assessment of the interaction effect between injury regions in multiple injuries: A nationwide cohort study in Japan.

BACKGROUND: There have been no clinical studies to sufficiently reveal the interaction effect generated by combinations of injury regions of multiple injuries. We hypothesized that certain combinations of trauma regions might lead to increased risk of traumatic death and aimed to verify this hypothesis using a nationwide trauma registry in Japan. MATERIALS AND METHODS: This was a retrospective study of trauma patients registered in the Japan Trauma Data Bank between 2004 and 2017. We included patients who suffered blunt trauma with an Injury Severity Score of 16 or more. The trauma was classified into four regions (head, chest, abdomen, and extremities), and a multivariable logistic regression analysis was performed that included interaction terms derived from the combination of two regions as covariates. RESULTS: We included 78,280 trauma patients in this study. Among them, 16,100 (20.6%) patients were discharged to death. Multivariable logistic regression showed the odds ratio (OR) of in-hospital death compared with patients without injury of an Abbreviated Injury Scale score of 3 or more in each injured region as follows: head score, 2.31 (95% confidence interval [CI], 2.13-2.51); chest score, 2.28 (95% CI, 2.17-2.39); abdomen score, 1.68 (95% CI, 1.56-1.82); and extremities score, 1.84 (95% CI, 1.76-1.93), respectively. In addition, the ORs of the statistically significant interaction terms were as follows: head-chest 1.29 (95% CI, 1.13-1.48), chest-abdomen 0.77 (95% CI, 0.67-0.88), chest-extremities 1.95 (95% CI, 1.77-2.14), and abdomen-extremities 0.70 (95% CI, 0.62-0.79), respectively. CONCLUSION: In this population, among patients with multiple injuries, a combination of head-chest trauma and chest-extremities trauma was shown to increase the risk of traumatic death. LEVEL OF EVIDENCE: Prognostic, Level III.

Trends and outcomes of blunt renal trauma management: a nationwide cohort study in Japan.

BACKGROUND: There is a paucity of information for predicting patient outcomes other than the American Association for the Surgery of Trauma (AAST) renal injury scale. The aim of this study was to evaluate the association between the patient characteristics and outcomes of patients with blunt renal trauma using a nationwide database in Japan. METHODS: We performed a retrospective analysis of the Japan Trauma Data Bank (JTDB) from 2004 to 2018. We identified patients with blunt renal trauma by AIS codes converted to AAST grades. We evaluated trends in patient characteristics and management and assessed factors associated with mortality and nephrectomy using a multivariable logistic regression analysis. RESULTS: We identified 3550 patients with blunt renal trauma. Their median age was 43 years and 74.2% were male. Nephrectomy was performed in 3.8%, and the overall mortality rate was 9.5%. We found increasing trends in age and emergency abdominal angiography and decreasing trends in nephrectomy and mortality over the 15-year period. The following factors were associated with mortality: age ≥ 65 years (adjusted OR 3.36); pedestrian accident (adjusted OR 1.94); fall from height (adjusted OR 1.91); shock on arrival (adjusted OR 4.02); concomitant injuries to the head/neck (adjusted OR 3.14), pelvis/lower-extremity (adjusted OR 1.59), liver (adjusted OR 1.68), spleen (adjusted OR 1.45), and gastrointestinal tract (adjusted OR 1.90); AAST grades III-V (adjusted ORs 1.42, 2.16, and 5.55); and emergency abdominal angiography (adjusted OR 0.70). The following factors were associated with nephrectomy: shock on arrival (adjusted OR 1.98), concomitant injuries to the thorax (adjusted OR 0.46) and spleen (adjusted OR 2.07), AAST grades III, IV, and V (adjusted ORs 18.40, 113.89, and 468.17), and emergency abdominal angiography (adjusted OR 0.28). CONCLUSIONS: We demonstrated that the AAST grade and emergency angiography were associated with mortality and nephrectomy in blunt renal trauma in the Japanese population.

Development of monoclonal mouse antibodies that specifically recognize pancreatic polypeptide.

Pancreatic polypeptide (PP) is a 36-amino acid peptide encoded by the Ppy gene, which is produced by a small population of cells located in the periphery of the islets of Langerhans. Owing to the high amino acid sequence similarity among neuropeptide Y family members, antibodies against PP that are currently available are not convincingly specific to PP. Here we report the development of mouse monoclonal antibodies that specifically bind to PP. We generated Ppy knockout (Ppy-KO) mice in which the Ppy-coding region was replaced by Cre recombinase. The Ppy-KO mice were immunized with mouse PP peptide, and stable hybridoma cell lines producing anti-PP antibodies were isolated. Firstly, positive clones were selected in an enzyme-linked immunosorbent assay for reactivity with PP coupled to bovine serum albumin. During the screening, hybridoma clones producing antibodies that cross-react to the peptide YY (PYY) were excluded. In the second screening, hybridoma clones in which their culture media produce no signal in Ppy-KO islets but detect specific cells in the peripheral region of wild-type islets, were selected. Further studies demonstrated that the selected monoclonal antibody (23-2D3) specifically recognizes PP-producing cells, not only in mouse, but also in human and rat islets. The monoclonal antibodies with high binding specificity for PP developed in this study will be fundamental for future studies towards elucidating the expression profiles and the physiological roles of PP.

Delay of computed tomography is associated with poor outcome in patients with blunt traumatic aortic injury: A nationwide observational study in Japan.

According to guidelines from the Eastern Association for the Surgery of Trauma, computed tomography (CT) with intravenous contrast is strongly recommended to diagnose clinically significant blunt traumatic aortic injury (BTAI). However, it remains unclear whether the timing of CT scanning is associated with the prognosis of BTAI patients.We extracted data on emergency patients who suffered a BTAI in the chest and/or the abdomen from 2004 to 2015 from the Japanese Trauma Data Bank, a nationwide trauma registry. The primary outcome was death in the emergency department (ED) and secondary outcome was discharge to death. In addition, we assessed the relationship between death in the ED and the timing of CT scanning by shock status in subgroup analysis. We divided these patients into the tertile groups of early (≤26 minutes), middle (27-40 minutes), and late (≥41 minutes) phases based on the time interval from hospital arrival to start of first CT scanning, and assessed death of BTAI patients in the ED by CT scanning time with the use of a multivariable logistic regression model.In total, 421 patients who suffered BTAI in the chest and/or the abdomen were eligible for our analysis. The proportion of patients dying at hospital admission was 7.7% (11/142) in the early group, 11.1% (15/135) in the middle group, and 17.6% (25/144) in the late group. In a multivariable logistic regression adjusted for confounding factors, the adjusted odds ratio (AOR) of death in the ED was 1.833 (95% confidence interval [CI]: 0.601-5.590, P = .287) in the middle group and 2.832 (95% CI: 1.007-7.960, P = .048) in the late group compared with the early group. Compared with the early group, the late group tended to have a higher rate of discharge to death (AOR: 1.438, 95% CI: 0.735-2.813). In the patients with shock, the AOR was 3.292 (95% CI: 0.495-21.902) in the middle group and 6.039 (95% CI: 0.990-36.837) in the late group compared with the early group.This study revealed that a longer time interval from hospital arrival to CT scanning was associated with higher mortality in the ED in patients with BTAI.

Role of the glucose-sensing receptor in insulin secretion.

Glucose is a primary stimulator of insulin secretion. It has been thought that glucose exerts its effect by a mechanism solely dependent on glucose metabolism. We show here that glucose induces rapid Ca2+ and cyclic AMP signals in ß-cells. These rapid signals are independent of glucose-metabolism and are reproduced by non-metabolizable glucose analogues. These results led us to postulate that glucose activates a cell-surface receptor, namely the glucose-sensing receptor. Rapid signals induced by glucose are blocked by inhibition of a sweet taste receptor subunit T1R3 and a calcium-sensing receptor subunit CaSR. In accordance with these observations, T1R3 and CaSR form a heterodimer. In addition, a heterodimer of T1R3 and CaSR is activated by glucose. These results suggest that a heterodimer of T1R3 and CaSR is a major component of the glucose-sensing receptor. When the glucose-sensing receptor is blocked, glucose-induced insulin secretion is inhibited. Also, ATP production is significantly attenuated by the inhibition of the receptor. Conversely, stimulation of the glucose-sensing receptor by either artificial sweeteners or non-metabolizable glucose analogue increases ATP. Hence, the glucose-sensing receptor signals promote glucose metabolism. Collectively, glucose activates the cell-surface glucose-sensing receptor and promotes its own metabolism. Glucose then enters the cells and is metabolized through already activated metabolic pathways. The glucose-sensing receptor is a key molecule regulating the action of glucose in ß-cells.

Glycan profiling using formalin-fixed, paraffin-embedded tissues: Hippeastrum hybrid lectin is a sensitive biomarker for squamous cell carcinoma of the uterine cervix.

AIM: Glycosylation of proteins is altered in cancer cells and distinctive glycan structures are associated with specific cancers, but little is known about the complete glycan profile of particular tumors. In this study, glycomic analysis of squamous cell carcinoma (SCC) of the uterine cervix was performed to search for useful markers. METHODS: A lectin microarray containing 45 lectins with different binding preferences that covered N- and O-linked glycans was coupled with evanescent field-activated fluorescent detection for glycomic analysis of SCC and normal squamous epithelium (NSE) of the cervix. Formalin-fixed, paraffin-embedded tissue specimens were obtained from 16 patients with uterine cervical cancer. Sections that included both tumor and non-tumor tissues were examined to detect alterations of glycans based on the lectin-binding pattern. RESULTS: Hippeastrum hybrid lectin was found to be a sensitive marker for distinguishing SCC of the cervix from NSE. It was the best lectin for discriminating SCC from other tissues according to receiver-operator curve analysis, as it showed a high sensitivity (81.8%), a high specificity (70.1%), and a large area under the curve (0.8182). Histochemistry confirmed specific cytoplasmic staining of SCC cells by Hippeastrum hybrid lectin, while there was little staining of cervical intraepithelial neoplasia and no staining of NSE. CONCLUSION: The present lectin microarray technique could be applied for tissue-based glycomic analysis of various tumors and for discovery of glycan-related biomarkers.

Sucralose, an activator of the glucose-sensing receptor, increases ATP by calcium-dependent and -independent mechanisms.

Sucralose is an artificial sweetener and activates the glucose-sensing receptor expressed in pancreatic ß-cells. Although sucralose does not enter ß-cells nor acts as a substrate for glucokinase, it induces a marked elevation of intracellular ATP ([ATP]c). The present study was conducted to identify the signaling pathway responsible for the elevation of [ATP]c induced by sucralose. Previous studies have shown that sucralose elevates cyclic AMP (cAMP), activates phospholipase C (PLC) and stimulates Ca(2+) entry by a Na(+)-dependent mechanism in MIN6 cells. The addition of forskolin induced a marked elevation of cAMP, whereas it did not affect [ATP]c. Carbachol, an activator of PLC, did not increase [ATP]c. In addition, activation of protein kinase C by dioctanoylglycerol did not affect [ATP]c. In contrast, nifedipine, an inhibitor of the voltage-dependent Ca(2+) channel, significantly reduced [ATP]c response to sucralose. Removal of extracellular Na(+) nearly completely blocked sucralose-induced elevation of [ATP]c. Stimulation of Na(+) entry by adding a Na(+) ionophore monensin elevated [ATP]c. The monensin-induced elevation of [ATP]c was only partially inhibited by nifedipine and loading of BAPTA, both of which completely abolished elevation of [Ca(2+)]c. These results suggest that Na(+) entry is critical for the sucralose-induced elevation of [ATP]c. Both calcium-dependent and -independent mechanisms are involved in the action of sucralose.

Glucose Evokes Rapid Ca2+ and Cyclic AMP Signals by Activating the Cell-Surface Glucose-Sensing Receptor in Pancreatic ß-Cells.

Glucose is a primary stimulator of insulin secretion in pancreatic ß-cells. High concentration of glucose has been thought to exert its action solely through its metabolism. In this regard, we have recently reported that glucose also activates a cell-surface glucose-sensing receptor and facilitates its own metabolism. In the present study, we investigated whether glucose activates the glucose-sensing receptor and elicits receptor-mediated rapid actions. In MIN6 cells and isolated mouse ß-cells, glucose induced triphasic changes in cytoplasmic Ca(2+) concentration ([Ca(2+)]c); glucose evoked an immediate elevation of [Ca(2+)]c, which was followed by a decrease in [Ca(2+)]c, and after a certain lag period it induced large oscillatory elevations of [Ca(2+)]c. Initial rapid peak and subsequent reduction of [Ca(2+)]c were independent of glucose metabolism and reproduced by a nonmetabolizable glucose analogue. These signals were also blocked by an inhibitor of T1R3, a subunit of the glucose-sensing receptor, and by deletion of the T1R3 gene. Besides Ca(2+), glucose also induced an immediate and sustained elevation of intracellular cAMP ([cAMP]c). The elevation of [cAMP]c was blocked by transduction of the dominant-negative Gs, and deletion of the T1R3 gene. These results indicate that glucose induces rapid changes in [Ca(2+)]c and [cAMP]c by activating the cell-surface glucose-sensing receptor. Hence, glucose generates rapid intracellular signals by activating the cell-surface receptor.