COX‐1‐dependent prostaglandin D2 in microglia contributes to neuropathic pain via DP2 receptor in spinal neurons

Cyclooxygenase (COX) enzyme synthesizes prostaglandins (PGs) from arachidonic acid and exists as two major isozymes, COX‐1 and COX‐2. The crucial role of prostaglandins in the pathogenesis of inflammatory pain in peripheral tissue and the spinal cord has been established; however its expression dynamics after peripheral nerve injury and its role in neuropathic pain are not clear. In this study, we examined the detailed expression patterns of genes for COX, PGD2 and thromboxane A2 synthases and their receptors in the spinal cord. Furthermore, we explored the altered gene expression of these molecules using the spared nerve injury (SNI) model. We also examined whether these molecules have a role in the development or maintenance of neuropathic pain. We found a number of interesting results in this study, the first was that COX‐1 was constitutively expressed in the spinal cord and up‐regulated in microglia located in laminae I‐II after nerve injury. Second, COX‐2 mRNA expression was induced in blood vessels after nerve injury. Third, TXA2 synthase and hematopoietic PGD synthase mRNAs were dramatically increased in the microglia after nerve injury. Finally, we found that intrathecal injection of a COX‐1 inhibitor and DP2 receptor antagonist significantly attenuated the mechanical allodynia. Our findings indicate that PGD2 produced by microglia is COX‐1 dependent, and that neurons in the spinal cord can receive PGD2 from microglia following peripheral nerve injury. We believe that PGD2 signaling via DP2 signaling pathway from microglia to neurons is one of the triggering factors for mechanical allodynia in this neuropathic pain model.     

Estimation of daily protein intake based on spot urine urea nitrogen concentration in chronic kidney disease patients

Background

Determination of daily protein intake in the management of chronic kidney disease (CKD) requires precision. Inaccuracies in recording dietary intake occur, and estimation from total urea excretion presents hurdles owing to the difficulty of collecting whole urine for 24 h. Spot urine has been used for measuring daily sodium intake and urinary protein excretion.

Methods

In this cross-sectional study, we investigated whether urea nitrogen (UN) concentration in spot urine can be used to predict daily protein intake instead of the 24-h urine collection in 193 Japanese CKD patients (Stages G1–G5). After patient randomization into 2 datasets for the development and validation of models, bootstrapping was used to develop protein intake estimation models.

Results

The parameters for the candidate multivariate regression models were male gender, age, body mass index (BMI), diabetes mellitus, dyslipidemia, proteinuria, estimated glomerular filtration rate, serum albumin level, spot urinary UN and creatinine level, and spot urinary UN/creatinine levels. The final model contained BMI and spot urinary UN level. The final model was selected because of the higher correlation between the predicted and measured protein intakes r = 0.558 (95 % confidence interval 0.400, 0.683), and the smaller distribution of the difference between the measured and predicted protein intakes than those of the other models.

Conclusion

The results suggest that UN concentration in spot urine may be used to estimate daily protein intake and that a prediction formula would be useful for nutritional control in CKD patients.

     

Involvement of Müller Glial Autoinduction of TGF-β in Diabetic Fibrovascular Proliferation Via Glial–Mesenchymal Transition

PurposeMüller glial–mesenchymal transition (GMT) is reported as the fibrogenic mechanism promoted by TGF-β–SNAIL axis in Müller cells transdifferentiated into myofibroblasts. Here we show the multifaceted involvement of TGF-β in diabetic fibrovascular proliferation via Müller GMT and VEGF-A production.MethodsSurgically excised fibrovascular tissues from the eyes of patients with proliferative diabetic retinopathy were processed for immunofluorescence analyses of TGF-β downstream molecules. Human Müller glial cells were used to evaluate changes in gene and protein expression with real-time quantitative PCR and ELISA, respectively. Immunoblot analyses were performed to detect TGF-β signal activation.ResultsMüller glial cells in patient fibrovascular tissues were immunopositive for GMT-related molecular markers, including SNAIL and smooth muscle protein 22, together with colocalization of VEGF-A and TGF-β receptors. In vitro administration of TGF-β1/2 upregulated TGFB1 and TGFB2, both of which were suppressed by inhibitors for nuclear factor-κB, glycogen synthase kinase-3, and p38 mitogen-activated protein kinase. Of the various profibrotic cytokines, TGF-β1/2 application exclusively induced Müller glial VEGFA mRNA expression, which was decreased by pretreatment with small interfering RNA for SMAD2 and inhibitors for p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Supporting these findings, TGF-β1/2 stimulation to Müller cells increased the phosphorylation of these intracellular signaling molecules, all of which were also activated in Müller glial cells in patient fibrovascular tissues.ConclusionsThis study underscored the significance of Müller glial autoinduction of TGF-β as a pathogenic cue to facilitate diabetic fibrovascular proliferation via TGF-β–driven GMT and VEGF-A–driven angiogenesis.     

The combination of the serum carbohydrate antigen 19-9 and carcinoembryonic antigen is a simple and accurate predictor of mortality in pancreatic cancer patients

Purpose

The aim of this study was to detect high-performance prognostic biomarkers of pancreatic cancer which would enable the identification of high-risk patients.

Methods

The subjects were 324 patients who underwent radical surgery for pancreatic ductal adenocarcinoma without neoadjuvant therapy. We evaluated the prognostic impact of four perioperative serum tumor markers, including carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). We also evaluated the indices by multiplying the values of two tumor markers (e.g., CA19-9 × CEA).

Results

The preoperative CA19-9 × CEA index had a strong correlation with the prognosis of patients with pancreatic cancer, even when the cut-off was set at the median value. CA19-9 × CEA ≥500 was an independent predictor of mortality (hazard ratio: 1.642, p = 0.021). In the ROC curve analysis of early mortality after surgery, the CA19-9 × CEA index had the highest goodness of fit. The presence of CA19-9 × CEA ≥500 had the largest attributable risk proportion because of its combined high predictive performance and prevalence. The postoperative CA19-9 × CEA index was also a significant predictive marker of mortality.

Conclusion

The CA19-9 × CEA index is a strong prognostic biomarker that could help identify pancreatic cancer patients expected to have a poor prognosis so that they can be administered appropriate multidisciplinary treatment.     

Prognostic Factors and Causes of Death in Patients Cured of Esophageal Cancer

Background

The number of patients cured of esophageal cancer after esophagectomy is gradually increasing owing to advances in surgical techniques, perioperative management, and adjuvant therapies. This study assessed the clinical course and sought to identify the prognostic factors of these patients.

Methods

A series of 220 consecutive patients who underwent esophagectomy and survived for more than 5 years with no relapse were enrolled. Survival analysis was performed using 25 variables including patient characteristics and operative and perioperative factors. Potential prognostic factors were identified by univariate and multivariate analyses, and the development of other primary cancers and the causes of death were retrospectively reviewed.

Results

The overall 10-, 15-, and 20-year survival rates were 71.6, 50.1, and 32.2 %, respectively, with a median survival time of 180 months (range, 61–315 months). The negative independent prognostic factors identified were age at surgery [hazard ratio (HR), 1.05; P < .01], being male (HR, 2.62; P = .02), pulmonary comorbidities (HR, 2.03; P = .02), synchronous presence of other cancers (HR, 2.35; P < .01), colonic/jejunal interposition (HR, 1.76; P = .03), perioperative blood transfusion (HR, 1.92; P = .02), development of pulmonary complications (HR, 1.71; P = .02), and adjuvant radiotherapy (HR, 2.13; P = .01). Pulmonary diseases and other primary cancers were found to be the most common causes of death.

Conclusions

Careful follow-up including the surveillance of other primary cancers is required for long-term survivors of esophageal cancer after esophagectomy.     

Comparison of prognosis and safety of pacemaker implantation in patients aged less than or 85 years and older

Journal of Interventional Cardiac Electrophysiology - Cardiac conduction disturbance necessitating pacemaker implantation is common among elderly patients. However, patients often have...     

Changes in arrhythmogenic properties and five‐year prognosis after carbon‐ion radiotherapy in patients with mediastinum cancer

Introduction

Carbon‐ion irradiation of rabbit hearts has improved left ventricular conduction abnormalities through upregulation of gap junctions. However, to date, there has been no investigation on the effect of carbon‐ion irradiation on electrophysiological properties in human. We investigated this effect in patients with mediastinum extra‐cardiac cancer treated with carbon‐ion radiotherapy that included irradiating the heart.

Methods and Results

In April–December 2009, eight patients were prospectively enrolled (including two male, aged 72.5 ± 13.0 years). They were treated with 44–72 Gray equivalent (GyE), with their hearts exposed to 1.3–19.1 GyE. High‐resolution ambulatory electrocardiography was performed before and after radiotherapy to investigate arrhythmic events, late potentials (LPs), and heart rate variability. Five patients had pre‐existing premature ventricular contraction (PVC)/atrial contraction (PAC) or paroxysmal atrial fibrillation (PAF)/AF; after irradiation, this improved in four patients with PVC/PAF/AF and did not deteriorate in one patient with PAC. Ventricular LP findings did not deteriorate and improved in one patient. In eight cases with available atrial LP findings, there was no deterioration, and two patients showed improvements. The low frequency/high frequency ratio of heart rate variability improved or did not deteriorate in the six patients who received radiation exposure to the bilateral stellate ganglions. During the five‐year follow‐up for the prognosis, six of the eight patients died because of cancer; there was no history of hospitalization for cardiac events.

Conclusion

Although this preliminary study has several limitations, carbon‐ion beam irradiation to the heart is not immediately cardiotoxic and demonstrates consistent signals of arrhythmia reduction.