Pancreas

The 49th Annual Meeting of the American Pancreatic Association in Collaboration With the International Association of Pancreatology No abstract available

Next-Generation Sequencing in Pancreatic Cancer Pancreatic ductal adenocarcinoma (PDAC) is lethal, and the majority of patients present with locally advanced or metastatic disease that is not amenable to cure. Thus, with surgical resection being the only curative modality, it is critical that disease is identified at an earlier stage to allow the appropriate therapy to be applied. Unfortunately, a specific biomarker for early diagnosis has not yet been identified; hence, no screening process exists. Recently, high-throughput screening and next-generation sequencing (NGS) have led to the identification of novel biomarkers for many disease processes, and work has commenced in PDAC. Genomic data generated by NGS not only have the potential to assist clinicians in early diagnosis and screening, especially in high-risk populations, but also may eventually allow the development of personalized treatment programs with targeted therapies, given the large number of gene mutations seen in PDAC. This review introduces the basic concepts of NGS and provides a comprehensive review of the current understanding of genetics in PDAC as related to discoveries made using NGS.

KRAS in Cyst Fluid Obtained by Endoscopic Ultrasound–Fine-Needle Aspiration in Pancreatic Cystic Lesions: A Systematic Review and Meta-analysis To evaluate the diagnostic accuracy of KRAS mutation in pancreatic cystic fluid and compare it with carcinoembryonic antigen and cytology, we identified studies with cyst fluid obtained by endoscopic ultrasound prior to surgery. We classified cysts as malignant, premalignant, and benign. A random-effects model was used for quantitative meta-analysis. Pooled sensitivities, specificities, and summary receiver operating characteristic curve analysis were conducted. We analyzed 16 studies, with 3429 patients, including 731 referred for surgery. Carcinoembryonic antigen was better for clinically significant cysts (premalignant and malignant) with sensitivity = 0.58 (95% confidence interval [CI], 0.53–0.65), specificity = 0.9 (95% CI, 0.76–0.97), and area under the curve (AUC) = 0.69. Cytology performed better in malignant cysts, with sensitivity = 0.37 (95% CI, 0.27–0.48), specificity = 0.96 (95% CI, 0.93–0.98), and AUC = 0.78. Isolated, KRAS mutation failed the diagnosis of malignant and significant cysts, with sensitivities = 0.43 (95% CI, 0.34–0.43) and 0.46 (95% CI, 0.42–0.51), specificities = 0.62 (95% CI, 0.56–0.68) and 0.97 (95% CI, 0.92–0.99), and AUCs = 0.56 and 0.53, respectively. Carcinoembryonic antigen and cytology are more accurate than KRAS. Additional studies are lacking to recommend KRAS as a single diagnostic test.

Animal Models: Challenges and Opportunities to Determine Optimal Experimental Models of Pancreatitis and Pancreatic Cancer At the 2018 PancreasFest meeting, experts participating in basic research met to discuss the plethora of available animal models for studying exocrine pancreatic disease. In particular, the discussion focused on the challenges currently facing the field and potential solutions. That meeting culminated in this review, which describes the advantages and limitations of both common and infrequently used models of exocrine pancreatic disease, namely, pancreatitis and exocrine pancreatic cancer. The objective is to provide a comprehensive description of the available models but also to provide investigators with guidance in the application of these models to investigate both environmental and genetic contributions to exocrine pancreatic disease. The content covers both nongenic and genetically engineered models across multiple species (large and small). Recommendations for choosing the appropriate model as well as how to conduct and present results are provided.

Frequency of Appropriate Use of Pancreatic Enzyme Replacement Therapy and Symptomatic Response in Pancreatic Cancer Patients Objectives Pancreatic cancer (PC) and its treatments can result in pancreatic exocrine insufficiency that requires pancreatic enzyme replacement therapy (PERT). Appropriate PERT usage is during meals and snacks. The aim was to determine the frequency of appropriate use of PERT and its impact on symptom alleviation in PC through a patient-reported outcomes online platform. Methods Users in the Pancreatic Cancer Action Network's Patient Registry were prompted to answer a standalone questionnaire about their experience with PERT. Results Two hundred sixty-two users completed the PERT questionnaire (January 2016–January 2018). Patients who reported taking PERT with meals had higher alleviation of symptoms compared with those taking PERT prior to or after meals. Specifically, "feeling of indigestion," "light-colored or orange stools," and "visible food particles in stool" were significantly decreased. Patients taking PERT with meals reported weight gain and less weight loss. Conclusions Of the 89% of PC patients prescribed PERT, 65% were prescribed PERT appropriately with all meals and snacks. Overall compliance with PERT administration guidelines was low (50% [105/208]). Improvement in symptoms significantly correlated with appropriate use of PERT. Increase in PC patient and provider education about appropriate PERT usage and administration is warranted.

Heme Oxygenase-1 Polymorphism Is Associated With the Development of Necrotic Acute Pancreatitis Via Vascular Cell Adhesion Molecule-1 and the E-Selectin Expression Regulation Pathway Objectives Severe acute pancreatitis can lead to systemic complications. Here, we explore the mechanisms based on our previous study associated with the deregulation of heme oxygenase-1 (HO-1) and development of severe acute pancreatitis. Methods Acute pancreatitis patients (n = 135) and age- and sex-matched healthy controls (n = 108) were studied. The polymerase chain reaction products were analyzed with an ABI 3130 genetic analyzer and GeneMapper software. A short allele was defined ≤27 dinucleotide (GT) repeats, whereas a long allele was defined >27 GT. Levels of 12 different cytokines in blood serum were measured by enzyme-linked immunosorbent assay. All samples in this study were consistently stored in −80°C. Results Patients with the long long genotype expressed E-selectin and vascular cell adhesion molecule-1 at statistically significantly higher levels in serum compared with short short genotype or short long genotypes. Vascular cell adhesion molecule-1 and E-selectin serum levels significantly correlate with the total allele length of the HO-1 promoter region. Conclusion Polymorphism of the GT repeats in the HO-1 promoter region may be a risk factor for developing acute necrotizing pancreatitis due to deregulation of the immune response.

Per Oral Pancreatoscopy Identification of Main-duct Intraductal Papillary Mucinous Neoplasms and Concomitant Pancreatic Duct Stones: Not Mutually Exclusive Objectives Per oral pancreatoscopy (POP) assists in the evaluation and treatment of select benign and neoplastic pancreatic disorders including main-duct intraductal papillary mucinous neoplasm (MD-IPMN). Although pancreatic duct stones are classically thought of as pathognomonic for chronic pancreatitis, its co-occurrence with MD-IPMN as identified via POP may help identify an alternative etiology for presumed idiopathic chronic pancreatitis. Methods This was a multicenter retrospective case series of patients found to have pancreatic duct stones with concomitant MD-IPMN by POP. Results Thirteen patients with presumed idiopathic chronic calcific pancreatitis were found on POP to have both pancreatic duct stones and MD-IPMN. All patients had a dilated pancreatic duct, and most (92.3%) were symptomatic. Conclusions Per-oral pancreatoscopy may identify MD-IPMN as an etiology for patients with presumed idiopathic chronic calcific pancreatitis and associated dilated pancreatic duct. Larger prospective studies are needed to validate these findings.

Ki-67 Index of 5% is Better Than 2% in Stratifying G1 and G2 of the World Health Organization Grading System in Pancreatic Neuroendocrine Tumors Objective The World Health Organization (WHO) grading system for the stratification of G1 and G2 pancreatic neuroendocrine tumors (pNETs) using an optimal Ki-67 index cutoff is still controversial. The present study aimed at finding one optimal Ki-67 cutoff value that distinguishes G1 and G2 tumors by analyzing the prognosis of patients with pNET in our center. Methods Data from 84 patients with pNET undergoing surgical resection in The First Affiliated Hospital of Sun Yat-sen University between March 2003 and October 2015 were retrospectively analyzed. Results The 5-year overall survival rate was 74.2%. Univariate analysis revealed that functional secretion, WHO grade, and TNM stage were significantly associated with long-term survival (all P < 0.05). Multivariate analysis demonstrated that WHO grade (P = 0.023) and TNM stage (P = 0.040) were independent prognostic factors. The receiver operating characteristic curve showed that the Ki-67 index of 5% had the best predictive ability (76.7%) for 5-year survival with a hazard ratio of 44.7. The hazard ratio was only 8.14 when the Ki-67 index cutoff was 2%. Conclusions TNM stage and WHO grade were independent prognostic factors of pNETs. A Ki-67 index of 5% is better than 2% in stratifying G1 and G2 pNET tumors.

Pancreatobiliary Versus Head and Neck Manifestations in Immunoglobulin G4–related Disease: Distinct Subsets of the Same Disease? Objectives We compared the clinical profiles and organ manifestations of the commonly encountered immunoglobulin G4–related diseases (IgG4-RDs) on either side of the diaphragm: head and neck (HN) versus pancreatobiliary (PB) in IgG4-RD. Methods From the Mayo Clinic, Rochester, database, we identified 53 HN and 88 PB IgG4-RD based on the first affected organ manifestation. Results Compared with HN IgG4-RD, subjects with PB IgG4-RD were likely to be older (median, 64.8 vs 50.2 years; P < 0.0001), male (83% vs 60.4%; P = 0.003), and with a shorter duration of follow-up (24.4 vs 48.7 months; P < 0.0001). In HN versus PB-IgG4-RD orbital, lacrimal gland, submandibular, parotid gland, asthma, and sinusitis manifestations were more common (77% vs 4.5%, 21% vs 0%, 32% vs 8%, 13% vs 0%, 36% vs 9%, and 51% vs 6.8%; P < 0.0001, respectively), whereas lung manifestations were similar (13.2% vs 5.6%; P = 0.12). In contrast, in PB versus HN IgG4-RD, pancreas and biliary were more frequent (98.8% vs 15%, 56.8% vs 3.7%; P < 0.0001), whereas renal lesions were similar (12.5% vs 7.5%; P = 0.36). Conclusion Pancreatobiliary and HN IgG4-RD have distinct clinical profiles. Proximity matters in other organ involvement in IgG4-RD, and organs involved tend to cluster close to each.

Deep Learning to Classify Intraductal Papillary Mucinous Neoplasms Using Magnetic Resonance Imaging Objective This study aimed to evaluate a deep learning protocol to identify neoplasia in intraductal papillary mucinous neoplasia (IPMN) in comparison to current radiographic criteria. Methods A computer-aided framework was designed using convolutional neural networks to classify IPMN. The protocol was applied to magnetic resonance images of the pancreas. Features of IPMN were classified according to American Gastroenterology Association guidelines, Fukuoka guidelines, and the new deep learning protocol. Sensitivity and specificity were calculated using surgically resected cystic lesions or healthy controls. Results Of 139 cases, 58 (42%) were male; mean (standard deviation) age was 65.3 (11.9) years. Twenty-two percent had normal pancreas; 34%, low-grade dysplasia; 14%, high-grade dysplasia; and 29%, adenocarcinoma. The deep learning protocol sensitivity and specificity to detect dysplasia were 92% and 52%, respectively. Sensitivity and specificity to identify high-grade dysplasia or cancer were 75% and 78%, respectively. Diagnostic performance was similar to radiologic criteria. Areas under the receiver operating curves (95% confidence interval) were 0.76 (0.70–0.84) for American Gastroenterology Association, 0.77 (0.70–0.85) for Fukuoka, and 0.78 (0.71–0.85) for the deep learning protocol (P = 0.90). Conclusions The deep learning protocol showed accuracy comparable to current radiographic criteria. Computer-aided frameworks could be implemented as aids for radiologists to identify high-risk IPMN. Review Surgical and Oncological Outcomes of Laparoscopic Versus Open Pancreaticoduodenectomy in Patients With Pancreatic Duct Adenocarcinoma Yin, Zi; Jian, Zhixiang; Hou, Baohua; More Pancreas. 48(7):861-867, August 2019. Abstract Favorites  PDF  Get Content & Permissions It is not clear which of the 2 principal treatments for patients with pancreatic duct adenocarcinoma (PDAC), laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD), has greater safety and efficacy. We performed the present meta-analysis to assess the efficacy of both treatments for PDAC patients undergoing LPD. Multiple electronic databases were systematically searched to identify studies (up to October 2018) comparing LPD with OPD for PDAC. Short- and long-term oncological outcomes were evaluated. Six studies were qualified for inclusion criteria in this meta-analysis with a total of 9144 PDAC participants. Regarding safety, there were fewer overall postoperative complications associated with LPD ( P = 0.005), but the results were similar in terms of pancreatic fistula and mortality. Laparoscopic pancreaticoduodenectomy was associated with a better trend of performance both in R0 resection (relative risk, 1.03; 95% confidence interval [CI], 1.00–1.07; P = 0.07) and preserved lymph nodes (median, 2.14; 95% CI, −0.21 to 4.49; P = 0.07). Long-term overall survival was comparable between LPD and OPD (hazard ratio, 1.03; 95% CI, 0.95–1.13; P = 0.49). In conclusion, LPD was found to be a suitable alternative to OPD in selected PDAC patients with respect to both surgical and oncological outcomes. BUY Table of Contents Outline | Back to Top  Collapse Box Original Articles New-Onset Diabetes Mellitus After Chronic Pancreatitis DiagnosisA Systematic Review and Meta-analysis Zhu, Xiangyun; Liu, Dechen; Wei, Qiong; More Pancreas. 48(7):868-875, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives The aim of this study was to assess the occurrence of new-onset diabetes mellitus (DM) after chronic pancreatitis (CP) diagnosis via systematic review and meta-analysis. Methods A systematic review of literature and meta-analysis of relevant reports were performed. The primary outcome measures studied were newly diagnosed DM and DM treated with insulin. For the binary outcomes, pooled prevalence and 95% confidence interval (CI) were calculated. Methods Fifteen studies involving 8970 patients were eligible. The incidence of new-onset DM after CP diagnosis was 30% (95% CI, 27%–33%). Among all patients, 17% (95% CI, 13%–22%) developed insulin-dependent new-onset DM. The prevalence of newly diagnosed DM after CP diagnosis increased from 15% within 36 months to 33% after 60 months. The proportion of alcoholic CP, sex, age, and body mass index had minimal effect on the studied outcomes. Conclusions This systematic review identified a clinically relevant risk of new-onset DM after CP diagnosis. Therefore, patients should be informed of the risk of DM and monitored. BUY Impact of Changes in the American Joint Committee on Cancer Staging Manual, Eighth Edition, for Pancreatic Ductal Adenocarcinoma Kassardjian, Ari; Stanzione, Nicholas; Donahue, Timothy R.; More Pancreas. 48(7):876-882, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objective Consistent and reliable tumor staging is a critical factor in determining treatment strategy, selection of patients for adjuvant therapy, and for therapeutic clinical trials. The aim of this study was to evaluate the number and extent of pancreatic ductal adenocarcinoma (PDAC) cases that would have a different pT, pN, and overall stages based on the new eighth edition American Joint Committee on Cancer staging system when compared with the seventh edition. Methods Patients diagnosed with PDAC who underwent pancreaticoduodenectomy, total pancreatectomy, or distal pancreatectomy from 2007 to 2017 were retrospectively reviewed. A total of 340 cases were included. Results According to the seventh edition, the vast majority of tumors in our cohort were staged as pT3 tumors (88.2%). Restaging these cases with the new size-based pT system resulted in a more equal distribution among the 3 pT categories, with higher percentage of pT2 cases (55%). Conclusions The newly adopted pT stage protocol for PDAC is clinically relevant, ensures a more equal distribution among different stages, and allows for a significant prognostic stratification. In contrast, the new pN classification (pN1 and pN2) based on the number of positive lymph nodes failed to show survival differences and remains controversial. BUY The Surveillance Patterns of Incidentally Detected Pancreatic Cysts Vary Widely and Infrequently Adhere to Guidelines Schenck, Robert J.; Miller, Frank H.; Keswani, Rajesh N. Pancreas. 48(7):883-887, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives We aimed to determine incidental pancreatic cyst ("cyst") surveillance patterns, predictors of receiving surveillance, and guideline adherence. Methods We performed a retrospective cohort study of all patients receiving longitudinal care at a single tertiary care center with a newly diagnosed incidental pancreatic cyst over a 2-year period (2010–2011). All follow-up care was abstracted over a 5-year period. Results Of 3241 eligible imaging studies reviewed, 100 patients with newly diagnosed incidental cysts eligible for surveillance were identified. A majority (53%) received no follow-up. We identified 4 predictors of cyst surveillance: radiology report conclusion mentioning the cyst (odds ratio [OR], 14.9; 95% confidence interval [CI], 1.9–119) and recommending follow-up (OR, 5.5; 95% CI, 2.1–13.9), pancreas main duct dilation (OR, 10.7; 95% CI, 1.3–89), and absence of multiple cysts (OR, 2.5; 95% CI, 1.1–10.0). Of the 47 patients who received surveillance, 66% met minimum surveillance imaging intervals of at least one guideline. Conversely, 21% of patients met the criteria for overutilization in at least one guideline. Conclusions Although guidelines recommend that surgically fit patients with incidental cysts undergo surveillance, most patients receive no follow-up. When follow-up occurs, surveillance patterns vary widely and infrequently conform to guidelines. Interventions to reduce care variation require study. BUY Acute Recurrent and Chronic Pancreatitis as Initial Manifestations of Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator–Related Disorders Baldwin, Christina; Zerofsky, Melissa; Sathe, Meghana; More Pancreas. 48(7):888-893, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives Recurrent pancreatitis is considered a rare manifestation of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction; this case series highlights that pancreatitis can be a presenting symptoms of cystic fibrosis (CF) or a CFTR-related disorder (CFTR-RD). Methods Retrospective review of patients younger than 30 years diagnosed as having acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) and subsequently diagnosed as having CF or CFTR-RD. Results Among 18 patients, median time from diagnosis of ARP/CP to diagnosis of CF was 0.4 years (range, 0–33 years). Eight were classified as having CF by elevated sweat chloride testing (SCT). Five had intermediate SCT (30–59 mmol/L) with 2 pathogenic mutations. Five had CFTR-RD with intermediate SCT and 0 to 1 pathogenic mutations. Eight patients (44%) had exocrine pancreatic insufficiency, and pancreatic fluid collections were more common in this group. Based on the CFTR mutation, 6 patients were eligible for CFTR potentiator therapy, although none received it during the study period. Nine of the 18 had ≥1 other likely CF manifestations, including sinusitis (33%), nasal polyps (11%), pneumonia (22%), and gallbladder disease (22%). Conclusions Cystic fibrosis or CFTR-RD can present as ARP/CP. Complete diagnostic testing for CFTR-RD in patients with ARP/CP will broaden treatment options and help to identify comorbid illness. BUY Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis Nadella, Sandeep; Burks, Julian; Huber, Matthew; More Pancreas. 48(7):894-903, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objective The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. Methods LSL-Kras G12D/+ ; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas. Results In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls. Conclusions This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis. BUY SDC The Importance of a Conjoint Analysis of Tumor-Associated Macrophages and Immune Checkpoints in Pancreatic Cancer Xu, Jun-Ying; Wang, Wang-Sheng; Zhou, Jing; More Pancreas. 48(7):904-912, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives Tumor-associated macrophages are dominant players in establishing the inmmunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC). Immune checkpoint inhibitor monotherapy has achieved limited clinical effectiveness. To date, the interaction of macrophages and checkpoint regulators and their correlation with clinicopathologic characteristics in PDAC have been largely unavailable. Methods Macrophages and immune checkpoint expression were assessed by immunohistochemistry from 80 PDAC samples. Clinicopathologic features and the prognostic value of each marker were evaluated. In vitro changes in the expression of immune markers in cocultured macrophages and PDAC cells were detected by Western blot and immunosorbance assays. Results The macrophages marker CD163 and the checkpoint marker programmed death-ligand 1 (PD-L1) remained as the independent prognostic factors for overall survival (hazard ratio, 2.543; P = 0.017 and hazard ratio, 2.389; P = 0.021). Furthermore, integrated analysis of CD163 and PD-L1 served as more optimal indicators of survival ( P = 0.000). In vitro coculture of macrophages and PDAC cells significantly increased the expression of CD163 and PD-L1, compared with monocultured counterpart ( P < 0.05). Conclusions Combined analysis of CD163 and PD-L1 was enhanced indicators of survival in PDAC patients. The interaction of macrophages and immune checkpoints implied the value of the combination therapy. BUY Induction Therapy in Localized Pancreatic Cancer Shaib, Walid L.; Sayegh, Layal; Zhang, Chao; More Pancreas. 48(7):913-919, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives Pancreatic cancer (PDAC) with localized stage includes resectable (RPC), borderline resectable (BRPC), or locally advanced unresectable (LAPC). Standard of care for RPC is adjuvant chemotherapy. There are no prospective randomized trials for best treatment of BRPC and LAPC. We evaluate the impact of induction chemotherapy on localized PDAC. Methods Charts of PDAC patients treated at Emory University between 2009 and 2016 were reviewed. The primary end point was overall survival (OS). Results A total of 409 localized PDACs were identified. Resectability was prospectively determined at a multidisciplinary tumor conference. Median age was 67 years (range, 30–92 years), 49% were male, 66% were white, 171 had RPC, 131 had BRPC, and 107 had LAPC. Median OSs for RPC, BRPC, and LAPC were 19.5, 16.1, and 12.7 months, respectively. Type of chemotherapy and age were predictors of OS. Induction chemotherapy was used in 106 with BRPC (81%) and 74 with RPC (56.5%); patients with BRPC who received combination chemotherapy and resection had a median OS of 31.5 compared with 19.5 months in patients with RPC ( P = 0.0049). Patients with LAPC had a median OS of 12.7 months. Conclusions In patients with BRPC who undergo resection after induction treatment, the OS was significantly better than in patients with RPC. Neoadjuvant treatment should be considered for all localized PDACs. BUY Comparisons of Outcomes of Real-World Patients With Advanced Pancreatic Cancer Treated With FOLFIRINOX Versus Gemcitabine and Nab-PaclitaxelA Population-Based Cohort Study Papneja, Neha; Zaidi, Adnan; Chalchal, Haji; More Pancreas. 48(7):920-926, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives The aim of this study was to compare the efficacy and safety of FOLFIRINOX (5-FU/leucovorin, irinotecan, and oxaliplatin) and gemcitabine/nab-paclitaxel (GnP) in patients with advanced pancreatic cancer. Methods Patients with newly diagnosed advanced pancreatic cancer in Saskatchewan, Canada, from 2011 to 2016, who received FOLFIRINOX or GnP were assessed. A Cox proportional multivariate analysis was performed to evaluate prognostic variables. Results One hundred nineteen eligible patients with median age of 61 years and male/female ratio of 70:49 were identified. Seventy-seven percent had metastatic disease. Of 119 patients, 86 (72%) received FOLFIRINOX and 33 (28%) were treated with GnP. Median progression-free survival of the FOLFIRINOX group was 6.0 months [95% confidence interval (CI), 4.5–7.5] versus 4.0 months (95% CI, 2.9–5.1) with GnP ( P = 0.39). The median overall survival of the FOLFIRINOX group was 9.0 months (95% CI, 7–11) compared with 9.0 months (95% CI, 4.2–13.8) with GnP ( P = 0.88). On multivariate analysis, albumin [hazard ratio (HR), 0.63; 95% CI, 0.41–0.97], male sex (HR, 0.65; 95% CI, 0.43–0.97), and second-line therapy (HR, 0.50; 95% CI, 0.28–0.86) were correlated with survival. Conclusions Our results showed that real-world patients with advanced pancreatic cancer treated with FOLFIIRNOX or GnP had comparable survival with different safety profile. BUY Alternate Week Gemcitabine and CapecitabineAn Effective Treatment for Patients With Pancreatic Adenocarcinoma Johns, Claire; Diaz, Celso L.; Hwang, Jimmy; More Pancreas. 48(7):927-930, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objective Determine whether a regimen of fixed dose rate gemcitabine plus capecitabine is effective and tolerable for advanced pancreatic adenocarcinoma. Methods We performed a retrospective analysis of 62 patients with locally advanced or metastatic pancreatic adenocarcinoma treated at the University of California San Francisco between 2008 and 2016. Treatment was an alternate week schedule of fixed dose rate 1000 mg/m 2 gemcitabine and capecitabine 1000 mg/m 3 (58 patients), 1200 mg/m 3 (12 patients), or 650 mg/m 3 (1 patient) for intended 12 cycles. We evaluated overall survival (OS), progression-free survival (PFS), radiologic response, and adverse events necessitating treatment modification. Results For metastatic patients, median OS was 10.3 months (95% confidence interval [CI], 6.7–12.1 months), and PFS was 5.6 months (95% CI, 2.6–7.7 months). In locally advanced patients, OS was 12.0 months (95% CI, 4.9–17.1 months), and PFS was 5.4 months (95% CI, 2.5–9.4 months). Radiologic response for metastatic disease (42 patients) was 19% objective response, 45% stable disease, and 36% progressive disease. Treatment required modification for 22 patients due to adverse events, most frequently hand-foot syndrome (18 patients). Conclusions Alternate week schedule of fixed dose rate gemcitabine and capecitabine was active and tolerable for advanced pancreatic adenocarcinoma. Overall survival and PFS were comparable to first-line treatments. Importantly, adverse effects appear less severe than first-line treatments. BUY Differences in Pancreatic Cancer Incidence Rates and Temporal Trends Across Asian Subpopulations in California (1988–2015) Liu, Lihua; Zhang, Juanjuan; Deapen, Dennis; More Pancreas. 48(7):931-933, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objective Ethnic disparities in pancreatic cancer (PanCan) incidence exist, but little is known about incidence trends in heterogeneous Asian Americans. We examined PanCan incidence and temporal patterns among detailed ethnic populations, including Asian American subgroups. Methods A total of 71,099 invasive exocrine PanCan cases were identified using the California Cancer Registry between 1988 and 2015. Cases were grouped into mutually exclusive groups of non-Hispanic (NH) white, NH black, Hispanic, NH Asian/Pacific Islander (API), and NH American Indian/Alaska Native (AIAN). Asians were further identified by specific ethnicity. Results The age-adjusted incidence rates (AAIRs, per 100,000) of PanCan varied significantly across racial/ethnic groups, ranging from the highest of 10.4 in NH blacks to 7.6 in NH whites, 7.1 in Hispanics, 6.2 in NH APIs, and to the lowest of 5.2 in NH AIAN. Despite the relatively low rate in the NH APIs, the rates across Asian subgroups varied significantly, with rates similar to NH whites in Japanese (8.1) and Koreans (7.5) to the low rate in South Asians (4.4). Conclusions Significant heterogeneity of PanCan incidence in disaggregated Asian Americans is a novel finding. These results fill a gap regarding PanCan burden in Asian Americans and underscore the importance of disaggregating ethnic populations in cancer research. BUY SDC Diagnostic and Management Challenges in Vasoactive Intestinal Peptide Secreting TumorsA Series of 15 Patients Angelousi, Anna; Koffas, Apostolos; Grozinsky-Glasberg, Simona; More Pancreas. 48(7):934-942, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives Vasoactive intestinal peptide–secreting tumors (VIPomas) are rare functioning neuroendocrine tumors often characterized by a difficult-to-control secretory syndrome and high potential to develop metastases. We hereby present the characteristics of 15 cases of VIPomas and provide a recent literature review. Methods This was a retrospective data analysis of 15 patients with VIPoma from 3 different centers and literature research through PubMed database during the last 10 years. Results Fifteen patients with VIPomas (9 with hepatic metastases at diagnosis) with watery diarrhea and raised VIP levels were studied. Ten patients (67%) had grade 2 tumors, 6 of 15 had localized disease and underwent potentially curative surgery, whereas the remaining 9 received multiple systemic therapies; 3 patients died during follow-up. The median overall survival was 71 months (range, 41–154 months). Patients who were treated with curative surgery (n = 7) had longer median overall survival compared with patients who were treated with other therapeutic modalities (44 vs 33 months). Conclusions The management of VIPomas is challenging requiring the application of multiple treatment modalities. Patients who underwent surgical treatment with curative intent appear to have higher survival rate. Central registration and larger prospective studies are required to evaluate the effect of currently employed therapies in these patients. BUY Significance of Lymph Node Metastasis in Resectable Well-differentiated Pancreatic Neuroendocrine Tumor Harimoto, Norifumi; Hoshino, Kouki; Muranushi, Ryo; More Pancreas. 48(7):943-947, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives Understanding the effect of lymph node metastasis (LNM) on prognosis in pancreatic neuroendocrine neoplasm is helpful for surgery and follow-up. In this study, we investigated the significance of LNM in well-differentiated pancreatic neuroendocrine tumors (PanNETs) according to the World Health Organization 2017 classification. Methods We retrospectively collected data for 95 consecutive patients with PanNET who underwent pancreatic resection with curative intent between January 2008 and December 2017 at 6 institutions. The clinicopathological factors were compared in patients with and without LNM, and prognostic factors were analyzed. Results Lymph node metastasis was significantly associated with malignant potential of PanNET, such as larger tumor size, higher Ki-67 index, higher tumor grade, and higher incidence of lymphatic, vessel, and neural invasion. Lymph node metastasis was also associated with disease-free but not overall survival. Multivariate analysis identified NET grade 2 (G2) and G3 as independent risk factors for recurrence after curative resection. Conclusions World Health Organization 2017 classification was the most independent prognostic factor in patients with resectable well-differentiated PanNETs. Patients with G2 and higher-grade tumors require lymph node dissection to improve prognosis. BUY Correlation of DOTATOC Uptake and Pathologic Grade in Neuroendocrine Tumors Chan, Hilary; Moseley, Christian; Zhang, Li; More Pancreas. 48(7):948-952, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives 68 Gallium (Ga)–DOTATOC is a somatostatin analog used to detect neuroendocrine tumors (NETs). Ki-67 proliferation index (Ki-67 PI) has been established as a prognostic factor in NETs. We aimed to evaluate whether a correlation exists between Ki-67 PI and somatostatin receptor positron emission tomography (SSTR-PET) uptake. Methods We retrospectively reviewed 238 DOTATOC PET scans between 2014 and 2016. Patients were excluded if DOTATOC PET was performed more than 365 days from the date of biopsy. Maximum standardized uptake values (SUV max ) of SSTR-PET from biopsied lesions were measured and correlated with Ki-67 PI using the Pearson correlation coefficient. Results Among 110 lesions from 90 patients, DOTATOC PET had 92.7% sensitivity and 100% specificity (102 true positives, 8 false negatives) for detection of NETs. Among 63 lesions from 54 patients with Ki-67 PI available, there were 27 grade 1 lesions [median Ki-67 PI, 1.0%; interquartile range (IQR), 1.0–2.0], 30 grade 2 lesions (median, Ki-67 PI 7.5%; IQR, 5–10), and 6 grade 3 lesions (median Ki-67 PI, 30%; IQR, 26–34). There was a correlation between Ki-67 PI and SUV max ( r 2 = −0.3 , P = 0.018). Conclusions Our analysis demonstrates an inverse correlation between Ki-67 PI and SUV max in NETs. Somatostatin receptor–PET provides additional information that can help guide management of NETs. BUY Gastric Emptying and Distal Gastrectomy Independently Enhance Postprandial Glucagon-Like Peptide-1 Release After a Mixed Meal and Improve Glycemic Control in Subjects Having Undergone Pancreaticoduodenectomy Steiner, Emanuel; Breuer, Robert; Kazianka, Lukas; More Pancreas. 48(7):953-957, August 2019. Abstract Favorites  PDF  Get Content & Permissions Objectives New-onset diabetes frequently resolves after pancreaticoduodenectomy (PD). Glucagon-like peptide-1 (GLP-1) conceivably is involved as its release is enhanced by rapid gastric emptying and distal bowel exposure to nutrients. We aimed at studying factors associated with GLP-1 release after PD. Methods Fifteen PD subjects with distal gastrectomy (Whipple) and 15 with pylorus preservation were evaluated. A test meal containing 1 g paracetamol to measure gastric emptying was ingested. Blood for the measurement of paracetamol, glucose, insulin, and GLP-1 was drawn at baseline and 10, 20, 30, 60, 90, 120, 150, and 180 minutes thereafter. The Matsuda index of insulin sensitivity was calculated. Results In univariate analysis, gastric emptying correlated with GLP-1. Glucagon-like peptide-1 responses to the modes of operation did not differ. Multiple regression analysis confirmed gastric emptying and Whipple versus pylorus-preserving pancreaticoduodenectomy as independent predictors of GLP-1 release. The Matsuda index of insulin sensitivity correlated with GLP-1 concentrations and inversely with body mass index. Patients after Whipple procedure revealed lower glycated hemoglobin as compared with pylorus-preserving pancreaticoduodenectomy. Conclusions Following PD, the postprandial GLP-1 release seems to be enhanced by rapid gastric emptying and to improve insulin sensitivity. Partial gastrectomy versus pylorus preservation enhanced the release of GLP-1, conceivably because of greater distal bowel exposure to undigested nutrients. BUY Table of Contents Outline | Back to Top  Collapse Box Letters to the Editor The Relationship of Acute Pancreatitis and Pancreatic Cancer Li, Jia-su; Liu, Feng Pancreas. 48(7):e57, August 2019. Favorites  PDF  Get Content & Permissions BUY Reply to The Relationship of Acute Pancreatitis and Pancreatic Cancer Phillips, Anna Evans; Yadav, Dhiraj; Brand, Randall E.; More Pancreas. 48(7):e57-e58, August 2019. Favorites  PDF  Get Content & Permissions BUY Mathematical Model and Study Design Could Be Optimized in Spatial Distribution Analysis of Pancreatic Stones Xu, Zheng-Lei; Yao, Jun; Wang, Li-Sheng Pancreas. 48(7):e58, August 2019. Favorites  PDF  Get Content & Permissions BUY Reply to Comment on Zeng et al, Spatial Distribution of Pancreatic Stones in Chronic Pancreatitis Zeng, Xiang-Peng; Xie, Ting; Li, Zhao-Shen; More Pancreas. 48(7):e59, August 2019. Favorites  PDF  Get Content & Permissions BUY

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

NeuroReport

Cellular, Molecular and Developmental Neuroscience
Offline beats online transcranial direct current stimulation timing influences on working memory
Friehs, Maximilian A.; Frings, Christian
NeuroReport. 30(12):795-799, August 14, 2019.

Abstract
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The n-back task is an established measure of an individual's working memory. In this task, participants have to continuously update their working memory to react to a stimulus correctly. For the verbal n-back task in particular, the left dorsolateral prefrontal cortex (lDLPFC) plays a key role in working memory updating and a higher activation of the lDLPFC has been linked to an increase in performance. Transcranial direct current stimulation (tDCS) has been used extensively to investigate its effect on working memory but it remains unclear whether online or offline tDCS produces the largest modulation of task performance. To tackle this question, we used anodal tDCS to stimulate the lDLPFC in a repeated measures design and compared offline, online and sham stimulation. A 9 cm 2 anode was always placed over the lDLPFC while the 35 cm 2 cathode was positioned over the left deltoid. In a sample of N = 63 healthy adults, we found a significantly larger performance improvement, in correct reaction times as well as accuracy rates, after offline tDCS compared to online or sham stimulation. This pattern of results provides evidence that the stimulation timing plays a crucial role in tDCS application and it confirms the role of the lDLPFC in verbal working memory performance.

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Human cytomegalovirus ie2 affects the migration of glioblastoma by mediating the different splicing patterns of RON through hnRNP A2B1
Liang, Shuzhen; Yu, Bo; Qian, Dongmeng; More
NeuroReport. 30(12):805-811, August 14, 2019.

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Glioblastoma is the most aggressive intracranial tumor and diffuse migration is the leading cause of death. Recent evidence has indicated that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNP A2B1) is overexpressed in human glioblastoma tissue and enhances glioblastoma invasion in vitro . We found by mass spectrometry that hnRNP A2B1 interacts with human cytomegalovirus (HCMV) immediate early 86 protein (IE86, ie2 gene-encoded) in malignant glioma cells (U87MG) infected with HCMV. However, the role of hnRNP A2 B1 in glioblastoma development remains poorly understood. Here, we report that hnRNP A2B1 is highly expressed in the HCMV· ie2 transgenic mice model. This phenomenon was confirmed in U87MG cell lines transfected with pEGFP-N3-ie2 plasmid. In addition, hnRNP A2B1 knockdown in U87MG cells inhibited tumor migration, and this effect might be mediated by hnRNP A2B1 through effects on splicing patterns of RON . Our data suggested that HCMV· ie2 promotes glioblastoma migration by regulating hnRNP A2B1 expression.

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Upregulation of microRNA-205 is a potential biomarker for intracranial aneurysms
Zhong, Zhigang; Wu, Jun; Yuan, Kui; More
NeuroReport. 30(12):812-816, August 14, 2019.

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Inhibition of microRNA-205 is considered to be a therapeutic target for abdominal aortic aneurysm in animal model. Hepatocyte growth factor also plays pivotal roles in the pathogenesis of intracranial aneurysms, and its expression can be regulated by different miRNAs in different processes. We investigated the involvement of microRNA-205 in intracranial aneurysms and explored is potential interaction with hepatocyte growth factor. We found that blood levels of microRNA-205 were significantly higher in patients with intracranial aneurysms than in healthy controls. High blood levels of microRNA-205 showed diagnostic values for intracranial aneurysms. MicroRNA-205 and hepatocyte growth factor were negatively correlated in patients with intracranial aneurysms. MicroRNA-205 overexpression inhibited hepatocyte growth factor expression and reduced cell viability. Therefore, microRNA-205 may participate in intracranial aneurysms and may serve as a diagnostic marker for this disease.

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LncRNA SAMMSON overexpression distinguished glioblastoma patients from patients with diffuse neurosarcoidosis
Xie, Jingwei; Wang, Xinjun; Liu, Shanshan; More
NeuroReport. 30(12):817-821, August 14, 2019.

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The MRI characteristics of diffuse neurosarcoidosis are similar to those of glioblastoma. Therefore, identification of novel biomarkers to distinguish these two diseases is needed. We found that lncRNA Survival Associated Mitochondrial Melanoma-Specific Oncogenic Non-Coding RNA (SAMMSON) was upregulated in plasma of glioblastoma patients but not in diffuse neurosarcoidosis patients comparing to healthy controls. Upregulated SAMMSON distinguished glioblastoma patients from diffuse neurosarcoidosis patients and healthy controls. MiR-622 in glioblastoma patients was inversely correlated with SAMMSON. SAMMSON overexpression caused the downregulated expression of miR-622 in glioblastoma cells, while miR-622 overexpression did not affect SAMMSON expression. SAMMSON overexpression mediated the increased proliferation rate of glioblastoma cells. MiR-622 overexpression played an opposite role and reduced the effects of SAMMSON overexpression. Therefore, plasma SAMMSON has diagnostic value for glioblastoma and SAMMSON overexpression may promote glioblastoma cell proliferation by downregulating miR-622.

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Association between imbalance of cortical brain activity and successful motor recovery in sub-acute stroke patients with upper limb hemiparesis a functional near-infrared spectroscopy study
Kinoshita, Shoji; Tamashiro, Hiroaki; Okamoto, Takatsugu; More
NeuroReport. 30(12):822-827, August 14, 2019.

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Objective:
This study was designed to determine the association between motor functional recovery and interhemispheric imbalance in cortical brain activity in sub-cortical stroke patients with moderate-to-severe upper limb hemiparesis admitted to the convalescent rehabilitation ward.

Subjects and methods:
The study included first-ever stroke patients with moderate-to-severe upper limb hemiparesis who received multidisciplinary rehabilitation therapy in the rehabilitation ward. Motor function of the affected upper extremity was evaluated by the Fugl-Meyer assessment and action research arm test at 1 (T1) and 3 months (T2) after stroke onset. We also conducted serial functional near-infrared spectroscopy at the same time points and calculated the laterality index, which is based on changes in oxyhaemoglobin in primary sensorimotor cortex (Brodmann Area 4), pre-motor cortex and supplementary motor cortex (PMC + SMA, BA6).

Results:
The study included eight patients (seven females, mean age: 68.8). Both the Fugl-Meyer assessment and action research arm test scores improved significantly during the study. Laterality index did not change significantly from T1 to T2. There was a no significant correlation between changes in laterality index in each region and improvement in Fugl-Meyer assessment score. In contrast, a significant and negative correlation was noted between ΔLI in Brodmann Area 4 and improvement in action research arm test score.

Conclusion:
Our results suggested that activation of the non-lesional hemisphere in sub-acute stroke associated with motor recovery in moderate-to-severe upper limb hemiparesis. A multidisciplinary rehabilitation of stroke patients with moderate-to-severe upper limb hemiparesis might enhance the compensatory movements and pre-existing motor network from the non-lesional motor cortex.

BUY
Decreased serotonin synthesis is involved in seizure-induced respiratory arrest in DBA/1 mice
Chen, Qinglan; Tian, Fafa; Yue, Qiang; More
NeuroReport. 30(12):842-846, August 14, 2019.

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A known cause of seizure-induced respiratory arrest is the deficiency in serotonergic neurotransmission. Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme of central serotonin (5-hydroxytryptamine) synthesis which converts l-tryptophan to 5-hydroxytryptophan. A recent study revealed a reduction in TPH2 protein expression in the brainstems of DBA/1 mice that developed recurrent seizure-induced respiratory arrest, whereas the activity of this protein was unexplored. Thus this study aims to investigate the association between intrinsic 5-hydroxytryptamine synthesis in the brainstem and the susceptibility for sudden unexpected death in epilepsy in DBA/1 mice. The effect of LY393558, a potent 5-hydroxytryptamine reuptake inhibitor with 5-HT 1B/1D receptor antagonist properties, on seizure-induced respiratory arrest evoked by acoustic stimulation was also examined in DBA/1 mice. ELISA results showed significantly decreased TPH2 activity in the brainstems of untreated DBA/1 mice than that of C57BL/6J mice. Moreover, the concentrations of 5-hydroxytryptamine, 5-hydroxytryptophan and 5-HIAA in the brainstems of DBA/1 mice with or without acoustic stimulation were significantly lower than that of C57BL/6J mice. Acute administration of LY393558 also significantly reduced seizure-induced respiratory arrest in DBA/1 mice. These observations provide novel evidences for the hypothesis that 5-hydroxytryptamine deficiency might be a potential cause of seizure-induced respiratory arrest.

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Table of Contents Outline | Back to Top
 Collapse Box Degeneration and Repair
Role of exosomes induced by remote ischemic preconditioning in neuroprotection against cerebral ischemia
Li, Yang; Ren, Changhong; Li, Haiyan; More
NeuroReport. 30(12):834-841, August 14, 2019.

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Remote ischemic preconditioning (RIPC) is an effective regimen for neuroprotection in ischemic stroke. Exosomes are extracellular vesicles released into the blood, where they can transfer signals throughout the body. Several studies have demonstrated that RIPC leads to many changes in circulating exosomes. However, the role of RIPC-induced exosomes in neuroprotection remains to be determined. In the current study, we demonstrate that infusion of enriched plasma exosomes from RIPC-treated mice significantly attenuates infarction size in a murine model of cerebral ischemia compared to control group receiving infusion of exosomes from non-RIPC-treated mice. Further studies show that infusion of RIPC-exosomes markedly improves neurological functions. In line with the above findings, we find that the level of hypoxia inducible transcription factor (HIF)-1α is significantly higher in plasma exosomes from mice subjected to RIPC than those from control mice, which could have contributed to the RIPC-exosome-induced neuroprotection through HIF-1α-induced signals including the enhanced tolerance to hypoxia. To our knowledge, this is the first to demonstrate RIPC protects against cerebral ischemia through inducing neuroprotective exosomes.

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Table of Contents Outline | Back to Top
 Collapse Box Integrative Systems
Physiological arousal and visuocortical connectivity predict subsequent vividness of negative memories
Kark, Sarah M.; Kensinger, Elizabeth A.
NeuroReport. 30(12):800-804, August 14, 2019.

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Relative to neutral memories, negative and positive memories both exhibit an increase in memory longevity, subjective memory re-experiencing and amygdala activation. These memory enhancements are often attributed to shared influences of arousal on memory. Yet, prior work suggests the intriguing possibility that arousal affects memory networks in valence-specific ways. Psychophysics work has shown that arousal-related heart rate deceleration (HRD) responses are related to enhanced amygdala-visual functional connectivity (AVFC) and visual perception of negative stimuli. However, in the memory realm, it is not known whether the effect of AVFC influences subsequent negative memory outcomes as a function of the magnitude of physiological arousal during encoding. Using psycho-autonomic interaction analyses and trial-level measures of HRD as an objective measure of arousal during encoding of emotional stimuli, our findings suggest that the magnitude of the HRD modulates the effect of AVFC on subsequent negative memory vividness. Specifically, AVFC effects in early visual regions predicted negative memory vividness, not neutral or positive vividness, but only in the presence of heightened physiological arousal. This novel approach was grounded in a replication of prior working showing enhanced HRD effects in the insula for negative stimuli. These findings demonstrate that the effect of arousal on emotional memory networks depends on valence and provide further evidence that negative valence may enhance the incorporation of visuo-sensory regions into emotional memory networks.

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SDC
Corticospinal excitability related to reciprocal muscles during the motor preparation period effect of movement repetition
Suzuki, Makoto; Suzuki, Takako; Tanaka, Satoshi; More
NeuroReport. 30(12):856-862, August 14, 2019.

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Objectives
Voluntary movements require a preparatory phase before action initiation to elaborate optimal motor commands. This study investigated the time course of change in corticospinal excitability related to each agonist or antagonist muscle during the motor preparation period and the influence of movement repetition on time course change in corticospinal excitability.

Methods
The participants were instructed to perform wrist flexion as quickly as possible in response to the appearance of a red circle. One hundred fifty milliseconds after the presentation of the red circle cue, we delivered transcranial magnetic stimulation at the primary motor cortex related to the agonist flexor and the antagonist extensor carpi radialis muscles.

Results
The motor evoked potential amplitudes for both the flexor and extensor carpi radialis during the motor preparation period which were regressed on the logarithm of time, and there were no significant differences in the slope of the logarithmic curves in the early half trials of movement repetition. However, the slope of the logarithmic curve of the flexor carpi radialis was steeper than that of the extensor carpi radialis in the late half trials of movement repetition.

Conclusion
These results implied that corticospinal excitability for agonist muscles during the motor preparation period is consistently modulated by movement repetition, whereas that for antagonist muscles is weakened by movement repetition.

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 Collapse Box Clinical Neuroscience
Scene processing following damage to the ventromedial prefrontal cortex
De Luca, Flavia; McCormick, Cornelia; Ciaramelli, Elisa; More
NeuroReport. 30(12):828-833, August 14, 2019.

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It has been suggested that the mental construction of scene imagery is a core process underpinning functions such as autobiographical memory, future thinking and spatial navigation. Damage to the ventromedial prefrontal cortex in humans can cause deficits in all of these cognitive domains. Moreover, it has also been reported that patients with ventromedial prefrontal cortex lesions are impaired at imagining fictitious scenes, although they seem able to describe specific scenes from autobiographical events. In general, not much is known about how ventromedial prefrontal cortex patients process scenes. Here, we deployed a recently-developed task to provide insights into this issue, which involved detecting either semantic (e.g. an elephant with butterflies for ears) or constructive (e.g. an endless staircase) violations in scene images. Identifying constructive violations typically provokes the formation of internal scene models in healthy control participants. We tested patients with bilateral ventromedial prefrontal cortex damage, brain-damaged control patients and healthy control participants. We found no evidence for statistically significant differences between the groups in detecting either type of violation. These results suggest that an intact ventromedial prefrontal cortex is not necessary for some aspects of scene processing, with implications for understanding its role in functions such as autobiographical memory and future thinking.

BUY
The inhibition process underlying correct rejection of lures under different attentional states an event-related potential study
Chen, Ying; Wang, Hailu; Zhang, Qin; More
NeuroReport. 30(12):847-851, August 14, 2019.

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This study explored the effects of different attentional states on correct rejection of lures (CRL) by studying event-related potentials. Healthy college students were recruited to complete a study–test task. Results showed that CRL processing was regulated by participants' attentional states. Under focused attention, CRL was confirmed using subsequent diagnostic monitoring. Under distracted attention, lures were identified using early-familiarity processing; in addition, subsequent processes of CRL under distracted attention might reflect subjects' confidence in making rejection judgments. Time–frequency results indicated that a top-down inhibition process from the frontal cortex to the hippocampus supported by theta oscillation might play an important role in CRL. These findings provide new inspiration and directions for future research on CRL neural mechanisms.

BUY
Atypical frontal midline theta activity during cognitive control in heroin addicts
Li, Shifeng; Xu, Qiongying
NeuroReport. 30(12):852-855, August 14, 2019.

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Deficiency in cognitive control has been proposed as a core issue in addictive behavior, and recent advancements in cognitive neuroscience have suggested that frontal midline theta is a mechanism for cognitive control. This study examined frontal midline theta deficits in patients with heroin dependence during a Go/No-go task which explicitly involved cognitive control. Electroencephalography readings were collected from 15 male heroin addicts and 17 demographically matched healthy controls during an equal probability Go/No-go task. The findings revealed that heroin addicts responded significantly slower to the Go stimulus as compared to the healthy control. Heroin addicts also showed less frontal midline theta modulations between the Go and No-go conditions. These findings provided further evidence toward understanding the nature of drug addiction-related cognitive dysfunction.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Shock

 Collapse Box Clinical Science Aspects
Association of Sex With Clinical Outcome in Critically Ill Sepsis Patients A Retrospective Analysis of the Large Clinical Database MIMIC-III
Xu, Jinghong; Tong, Li; Yao, Jiyou; More
Shock. 52(2):146-151, August 2019.

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Introduction:
The objective of our study was to explore the association between sex and clinical outcome in sepsis patients in a large, diverse population.

Materials and Methods:
We analyzed 6,134 adult patients with sepsis from the critical care units of Beth Israel Deaconess Medical Center between 2001 and 2012. Study data were retrospectively extracted from Medical Information Mart for Intensive Care-III, a multiparameter intensive care database.

Results:
There were 2,677 (43.6%) female and 3,457 (56.4%) male patients. Compared with female patients, male patients with sepsis had a higher 1-year mortality rate (55.6% vs. 51.4%, P  = 0.001), and so did the 90-day mortality rate (45.1% vs. 42.1%, P  = 0.018). 33.8% of male and 31.3% of female patients with sepsis died during hospitalization ( P  = 0.041). The median length of hospitalization and intensive care unit (ICU) stay for male patients was 19.54 and 7.54 days, while that for female patients was 16.49 and 6.75 days ( P  < 0.001, P  = 0.002, respectively). Male patients were more likely to require dialysis therapy ( P  = 0.109), ventilation support ( P  = 0.012) and more vasoactive agents (dopamine P  = 0.113, norepinephrine P  = 0.016, and epinephrine P  = 0.093) during the ICU period than female patients. Our Cox proportional hazard regression model confirmed that the risk of death within 1 year of ICU admission in male patients is 1.083 times that in female.

Conclusion:
Female patients with sepsis have better clinical outcomes than male patients in terms of mortality and length of hospitalization and ICU stay.

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The Association of Fever and Antipyretic Medication With Outcomes in Mechanically Ventilated Patients A Cohort Study
Evans, Emily M.; Doctor, Rebecca J.; Gage, Brian F.; More
Shock. 52(2):152-159, August 2019.

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Background:
Fever is common in mechanically ventilated patients and may be uniquely detrimental in those with lung injury because of its injurious effects on pulmonary vascular permeability and alveolar epithelium. We evaluated the association of fever and antipyretic medication with mortality in mechanically ventilated emergency department (ED) patients.

Methods:
This is a retrospective cohort study of 1,264 patients requiring mechanical ventilation initiated in the ED with subsequent admission to an intensive care unit. Maximum body temperature was recorded for the first 24 h after ED admission and categorized into four categories: <37°C, 37°C to 38.2°C, 38.3°C to 39.4°C, and ≥39.5°C. The primary outcome was 28-day mortality. We conducted a planned subgroup analysis of patients with sepsis at the time of intubation. Multivariable Cox proportional hazard ratios (HRs) were used to assess the relationship between temperature, antipyretics, and mortality.

Results:
Multivariable Cox proportional HRs demonstrated that a maximum temperature ≥39.5°C was associated with increased mortality (adjusted hazard ratio [aHR] 1.59 [95% confidence interval, CI, 1.05–2.39]). In the subgroup of patients with sepsis, a maximum temperature of 38.3°C to 39.4°C was associated with survival (aHR 0.61 [95% CI, 0.39–0.99]). There was no difference in 28-day mortality between patients who did and did not receive antipyretic medication in either the overall cohort or the septic subgroup.

Conclusion:
High fever (≥39.5°C) was associated with increased risk for mortality in mechanically ventilated patients. However, in patients with sepsis, moderate fever (38.3°C–39.4°C) was protective. Antipyretic medication was not associated with changes in outcome. This suggests that fever may have different implications in septic versus nonseptic mechanically ventilated patients.

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Platelet–lymphocyte Ratio After Granulocyte Colony Stimulating Factor Administration an Early Prognostic Marker in Septic Shock Patients With Chemotherapy-Induced Febrile Neutropenia
Kim, Youn-Jung; Kang, Jihoon; Ryoo, Seung Mok; More
Shock. 52(2):160-165, August 2019.

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Introduction:
Chemotherapy-induced febrile neutropenia (FN) causes life-threatening complications, but little is known in septic shock patients with FN. The aim of this study was to investigate the prognostic value of inflammatory markers, including C-reactive protein level, immature granulocyte count, white blood cell (WBC) count, absolute neutrophil count (ANC), neutrophil–lymphocyte ratio (NLR), and platelet–lymphocyte ratio (PLR), in septic shock patients with FN at admission and after granulocyte colony-stimulating factor (G-CSF) administration.

Methods:
Data on consecutive adult septic shock patients with FN treated with G-CSF between June 2012 and June 2017 were extracted from a prospectively compiled septic shock registry. Clinical and serial laboratory data at admission and <24 h after G-CSF administration were compared between nonsurvivor and 1-month survivor groups.

Results:
Of 1,671 septic shock patients, 158 FN patients were treated with G-CSF and 114 (72.2%) survived for 1 month. At admission, no clinical and serial laboratory data were significant to predict survival. After G-CSF administration, PLR and APACHE II were independent predictors for 1-month survival. PLR after administration of G-CSF >100 (adjusted odds ratio [aOR], 9.394; 95% CI, 2.821–31.285, P < 0.001) showed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 89.4%, 46.2%, 82.9%, and 60.0%, respectively, and APACHE II <28 (aOR, 6.944; 95% CI, 2.351–20.511, P  < 0.001) showed sensitivity, specificity, PPV, and NPV of 86.8%, 63.6%, 86.1%, and 65.1%, respectively.

Conclusions:
After G-CSF administration in septic shock patients with chemotherapy-induced FN, PLR may be used as an early prognostic marker for mortality.

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Leukocyte Transcriptional Response in Sepsis
Skibsted, Simon; Bhasin, Manoj K.; Henning, Daniel J.; More
Shock. 52(2):166-173, August 2019.

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Background:
The complex host response to sepsis is incompletely understood. The aim of this investigation is to use leukocyte RNA sequencing to characterize biological functions, cellular pathways, and key regulatory molecules driving sepsis pathophysiology.

Methods:
This was a prospective, observational study of emergency department patients with sepsis, at an urban, academic, tertiary care center. In the derivation cohort, we collected blood at enrollment and 90 days after hospital discharge allowing each patient to serve as an internal control. We performed RNA sequencing to quantify transcriptional expression changes during sepsis and non-sepsis states. We then performed unsupervised and supervised analyses, as well as functional and pathway analyses. We selected the top down and upregulated genes and key regulatory molecules for validation. Validation occurred in a cohort of septic and non-septic using real-time PCR.

Results:
The derivation cohort included 5 patients, and RNA sequencing revealed 916 unique mRNA transcripts differentially expressed during sepsis. Among these, 673 (73%) genes were upregulated, and 243 (27%) were downregulated. Functional enrichment analysis revealed a highly dynamic downstream effect of the transcriptional activity during sepsis. Of the 43 functional cellular pathways activated during sepsis, the top pathways were closely associated with inflammation and response to infection. Validation occurred in 18 septic and 25 non-septic control patients, with 34/45 (76%) of identified genes validated. The regulatory analysis identified several key regulators of sepsis.

Conclusions:
Highly dynamic transcriptional activity occurs in leukocytes during sepsis, activating key cellular pathways and master regulatory molecules that drive the sepsis process.

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Remote Photoplethysmographic Assessment of the Peripheral Circulation in Critical Care Patients Recovering From Cardiac Surgery
Rasche, Stefan; Trumpp, Alexander; Schmidt, Martin; More
Shock. 52(2):174-182, August 2019.

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Purpose:
Camera-based photoplethysmography (cbPPG) remotely detects the volume pulse of cardiac ejection in the peripheral circulation. The cbPPG signal is sourced from the cutaneous microcirculation, yields a 2-dimensional intensity map, and is therefore an interesting monitoring technique. In this study, we investigated whether cbPPG is in general sufficiently sensitive to discern hemodynamic conditions.

Methods:
cbPPG recordings of 70 patients recovering from cardiac surgery were analyzed. Photoplethysmograms were processed offline and the optical pulse power (OPP) of cardiac ejection was calculated. Hemodynamic data, image intensity, and patient movements were recorded synchronously. The effects of hemodynamic parameters and measurement conditions on the patient's individual OPP variability and their actual OPP values were calculated in mixed-effects regression models.

Results:
Mean arterial pressure (MAP), pulse pressure (PP), heart rate (HR), and central venous pressure (CVP) significantly explained the individual OPP variability. PP had the highest explanatory power (19.9%). Averaged OPP significantly increased with PP and MAP ( P  < 0.001, respectively) and decreased with higher HR ( P  = 0.024). CVP had a 2-directional, nonsignificant effect on averaged OPP. Image intensity and patient movements did significantly affect OPP. After adjustment for hemodynamic covariables and measurement conditions, the effect of PP and HR remained unchanged, whereas that of MAP vanished.

Conclusion:
cbPPG is sensitive to hemodynamic parameters in critical care patients. It is a potential application for monitoring the peripheral circulation. Its value in a clinical setting has to be determined.

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Whole-Exome Sequencing of Adult and Pediatric Cohorts of the Rare Vascular Disorder Systemic Capillary Leak Syndrome
Pierce, Richard; Ji, Weizhen; Chan, Eunice C.; More
Shock. 52(2):183-190, August 2019.

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Objective:
Systemic capillary leak syndrome (SCLS) is a rare disorder that presents with episodes of hypovolemic shock. The extent to which genetic abnormalities contribute to SCLS is unknown. We identified pediatric and adult cohorts with characteristic clinical courses. We sought to describe the clinical characteristics of both cohorts, identify a possible genetic contribution to SCLS, and demonstrate that whole-exome sequencing (WES) may be conducted by critical care providers.

Design:
Prospective observational study of WES of nine adult and eight pediatric SCLS patients and available unaffected first-degree relatives.

Setting:
Tertiary children's hospitals and referral research laboratory.

Patients:
Children and adults with SCLS.

Interventions:
None.

Measurements:
Patients and available first-degree relatives underwent WES. Data were analyzed for rare homozygous, biallelic, de novo , and heterozygous variants with allelic enrichment and metabolic pathway analyses.

Main Results:
Children with SCLS presented at a younger age with episodes similar to those experienced by adults. All patients and available relatives underwent satisfactory WES. No overlapping gene variants or metabolic pathways were identified across all SCLS patients. Multiple candidate genes with homozygous or biallelic mutations were identified in individual subjects with SCLS. There was no significant enrichment of genes with rare heterozygous variants.

Conclusions:
The clinical characteristics of children and adults with SCLS are similar. We did not identify a uniform germline exomic genetic etiology for SCLS. WES identified several candidate genes in individual patients for future research. WES is a viable way for critical care providers to investigate the etiology of diseases with presumed genetic contributions.

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Association of Immune Cell Subtypes and Phenotype With Subsequent Invasive Candidiasis in Patients With Abdominal Sepsis
Arens, Christoph; Kramm, Timo; Decker, Sebastian; More
Shock. 52(2):191-197, August 2019.

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Background:
In nonneutropenic intensive care unit (ICU) patients, current risk stratification scores lack specificity to reliably predict the risk of a prospective invasive candidiasis (IC). We aimed to explore possible associations of distinct immunological markers with different degrees of Candida affection in patients with abdominal sepsis.

Methods:
The presented explorative, noninterventional diagnosis study recruited patients admitted to the surgical ICU at Heidelberg University Hospital with abdominal sepsis. Over 5 days, we determined white blood cell count, 1,3-β-D-glucan, and HLA-DR expression; the amount of Th1, Th17, regulatory T, T helper, and cytotoxic T cells; Dectin-1 and TLR2-expression; the amount of T, B, and NK cells; the ex vivo secretion of IL-8 upon stimulation with LPS, flagellin, and zymosan; and the distribution of distinct T-cell cytokines in a daily manner. On day 21, patients' Candida infection status was stratified in no colonization or IC, colonization or IC.

Results:
A total of 26 patients were included. On day 21, five patients showed no colonization or IC, in 13 patients a colonization was detected, and eight patients were diagnosed with IC. On study inclusion, the stratification groups showed comparable values in standard laboratory parameters and morbidity scores. Decreased B and NK cell counts, as well as reduced IL-8 secretion after ex vivo stimulation with LPS or flagellin seemed to be associated with a higher risk of subsequent Candida colonization. Even lower values could distinguish the therapy-relevant difference between prospective IC from colonization alone.

Conclusions:
We were able to show distinct immune system impairments in early abdominal sepsis by specific immune-based measurements. A possible association of these impairments with a subsequent Candida affection is shown.

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The Effectiveness and Safety of Corticosteroids Therapy in Adult Critical Ill Patients With Septic Shock A Meta-Analysis of Randomized Controlled Trials
Wen, Yongyao; Zhu, Yuhan; Jiang, Qimin; More
Shock. 52(2):198-207, August 2019.

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Objective:
To investigate the effectiveness and safety of corticosteroids therapy in adult critical ill patients with septic shock.

Methods:
The PUBMED, EMBASE, Web of Science, Cochrane Library databases were systematically searched from the inception dates to March 24, 2018. To identify randomized controlled trials that evaluating the role of corticosteroids therapy in adult critical ill patients with septic shock. The primary outcome was 28-day mortality. The second outcomes included 90-day mortality, intensive care unit (ICU) mortality, in-hospital mortality, length of stay in ICU, length of stay in hospital, reversal of shock, and superinfection.

Results:
A total of 18 randomized controlled trials involving 8,128 adult critical ill patients with septic shock fulfilled the inclusion criteria. The outcomes of this meta-analysis showed that corticosteroids therapy did not significantly reduce the 28-day mortality [RR = 0.94; 95% CI, 0.84–1.05; Z = 1.07 ( P  = 0.285)]. However, corticosteroids therapy was associated with a significantly shorter length of stay in ICU [WMD = −1.55; 95% CI, −2.19 to −0.91; Z = 4.74 ( P  = 0.000)]. 90-day mortality, ICU mortality, in-hospital mortality, length of stay in hospital, reversal of shock, and superinfection had no significant difference between the corticosteroids therapy and placebo therapy ( P  > 0.05). Similar results were obtained in subgroups of trials stratified according to the dose of corticosteroids (high dose or low does).

Conclusions:
Based on the results of this meta-analysis, corticosteroids therapy was associated with a significantly shorter length of stay in ICU among adult critical ill patients with septic shock. The mortality was similar between the corticosteroids therapy and placebo.

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Overexpression of Gilz Protects Mice Against Lethal Septic Peritonitis
Ballegeer, Marlies; Vandewalle, Jolien; Eggermont, Melanie; More
Shock. 52(2):208-214, August 2019.

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ABSTRACT
Sepsis in humans and experimental animals is characterized by an acute inflammatory response. glucocorticoids (GCs) are widely used for the treatment of many inflammatory disorders, yet their effectiveness in sepsis is debatable. One of the major anti-inflammatory proteins induced by GCs is glucocorticoid-induced leucine zipper (GILZ, coded by the TSC22D3 gene). We found that TSC22D3 mRNA expression is downregulated in white blood cells of human sepsis patients. Interestingly, transgenic GILZ-overexpressing mice (GILZ-tg) showed better survival rates in the cecal ligation and puncture (CLP) model of mouse sepsis. To our surprise, GILZ had only mild anti-inflammatory effects in this model, as the systemic proinflammatory response was not significantly reduced in GILZ-tg mice compared with control mice. During CLP, we observed reduced bacterial counts in blood of GILZ-tg mice compared with control mice. We found increased expression of Tsc22d3 mRNA specifically in peritoneal exudate cells in the CLP model, as well as increased capacity for bacterial phagocytosis of CD45 + GILZ-tg cells compared with CD45 + GILZ-wt cells. Hence, we believe that the protective effects of GILZ in the CLP model can be linked to a more efficient phagocytosis.

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Toll Like Receptor 4 Mediated Lymphocyte Imbalance Induces Nec-Induced Lung Injury
Jia, Hongpeng; Sodhi, Chhinder P.; Yamaguchi, Yukihiro; More
Shock. 52(2):215-223, August 2019.

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ABSTRACT
Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants, and is associated with the development of severe lung inflammation. The pathogenesis of NEC-induced lung injury remains unknown, yet infiltrating immune cells may play a role. In support of this possibility, we now show that NEC in mice and humans was associated with the development of profound lung injury that was characterized by an influx of Th17 cells and a reduction in T regulatory lymphocytes (Tregs). Importantly, the adoptive transfer of CD4 + T cells isolated from lungs of mice with NEC into the lungs of immune incompetent mice (Rag1 −/− mice) induced profound inflammation in the lung, while the depletion of Tregs exacerbated NEC induced lung injury, demonstrating that imbalance of Th17/Treg in the lung is required for the induction of injury. In seeking to define the mechanisms involved, the selective deletion of t oll- l ike r eceptor 4 (TLR4) from the Sftpc1 pulmonary epithelial cells reversed lung injury, while TLR4 activation induced the Th17 recruiting chemokine (C-C motif) ligand 25 (CCL25) in the lungs of mice with NEC. Strikingly, the aerosolized inhibition of both CCL25 and TLR4 and the administration of all trans retinoic acid restored Tregs attenuated NEC-induced lung injury. In summary, we show that TLR4 activation in S urfactant p rotein C - 1 (Sftpc1) cells disrupts the Treg/Th17 balance in the lung via CCL25 leading to lung injury after NEC and reveal that inhibition of TLR4 and stabilization of Th17/Treg balance in the neonatal lung may prevent this devastating complication of NEC.

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Therapeutic Hypothermia After Cardiac Arrest Involvement of the Risk Pathway in Mitochondrial PTP-Mediated Neuroprotection
Jahandiez, Vincent; Cour, Martin; Abrial, Maryline; More
Shock. 52(2):224-229, August 2019.

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ABSTRACT
Therapeutic hypothermia is neuroprotective after cardiac arrest (CA) via poorly understood mechanisms. It may prevent mitochondrial permeability transition pore (PTP) opening, an event which plays a pivotal role in ischemia-reperfusion injury. PTP is the main end-effector of the reperfusion injury salvage kinase (RISK) signaling pathway. We hypothesized that therapeutic hypothermia activates the RISK pathway, thereby preventing PTP opening and its deleterious neurological consequences after CA. Four groups of New Zealand White rabbits were subjected to 15 min of CA and 120 min of reperfusion: Control, HT (hypothermia at 32°–34°C), NIM (specific PTP inhibition with N-methyl-4-isoleucine-cyclosporine at the onset of reperfusion), and HT+NIM. A Sham group only underwent surgery. The following measurements were taken: pupillary reflexes and brain damage biomarkers (NSE and S100β), RISK pathway activation in brain cortex (total and phosphorylated forms of both protein kinase B [Akt] and extracellular signal-regulated kinase [ERK]) and PTP opening in isolated brain mitochondria. Therapeutic hypothermia and pharmacological PTP inhibition preserved the pupillary reflexes and prevented the increase in both NSE and S100β ( P  < 0.05 vs. controls). These two interventions also enhanced ( P  < 0.05 vs. controls) the phospho-Akt/Akt ratio to a similar extent while preventing a CA-induced increase in phospho-ERK/ERK ratio. This Akt activation in the HT and NIM groups was associated with an attenuation of CA-induced PTP opening. In this model, therapeutic hypothermia promoted the activation of the RISK signaling pathway via Akt and limited CA-induced brain injury by preventing PTP opening.

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The Mitochondria-Targeted H2S-Donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma
Wepler, Martin; Merz, Tamara; Wachter, Ulrich; More
Shock. 52(2):230-239, August 2019.

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ABSTRACT
Hemorrhagic shock (HS) accounts for 30% to 40% of trauma-induced mortality, which is due to multi-organ-failure subsequent to systemic hyper-inflammation, triggered by hypoxemia and tissue ischemia. The slow-releasing, mitochondria-targeted H 2 S donor AP39 exerted beneficial effects in several models of ischemia-reperfusion injury and acute inflammation. Therefore, we tested the effects of AP39-treatment in a murine model of combined blunt chest trauma (TxT) and HS with subsequent resuscitation.

Methods:
After blast wave-induced TxT or sham procedure, anesthetized and instrumented mice underwent 1 h of hemorrhage followed by 4 h of resuscitation comprising an i.v. bolus injection of 100 or 10 nmol kg −1 AP39 or vehicle, retransfusion of shed blood, fluid resuscitation, and norepinephrine. Lung mechanics and gas exchange were assessed together with hemodynamics, metabolism, and acid-base status. Blood and tissue samples were analyzed for cytokine and chemokine levels, western blot, immunohistochemistry, mitochondrial oxygen consumption (JO 2 ), and histological changes.

Results:
High dose AP39 attenuated systemic inflammation and reduced the expression of inducible nitric oxide synthase (iNOS) and IκBα expression in lung tissue. In the combined trauma group (TxT + HS), animals treated with high dose AP39 presented with the lowest mean arterial pressure and thus highest norepinephrine requirements and higher mortality. Low dose AP39 had no effects on hemodynamics, leading to unchanged norepinephrine requirements and mortality rates.

Conclusion:
AP39 is a systemic anti-inflammatory agent. In our model of trauma with HS, there may be a narrow dosing and timing window due to its potent vasodilatory properties, which might result in or contribute to aggravation of circulatory shock-related hypotension.

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Moderate Traumatic Brain Injury Alters the Gastrointestinal Microbiome in a Time-Dependent Manner
Nicholson, Susannah E.; Watts, Lora T.; Burmeister, David M.; More
Shock. 52(2):240-248, August 2019.

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ABSTRACT
The microbiome is defined as the collective genomes of the microbes (composed of bacteria, bacteriophage, fungi, protozoa, and viruses) that colonize the human body, and alterations have been associated with a number of disease states. Changes in gut commensals can influence the neurologic system via the brain-gut axis, and systemic insults such as trauma or traumatic brain injury (TBI) may alter the gut microbiome. The objective of this study was to evaluate the gut microbiome in a preclinical TBI cortical impact model. Male rats underwent craniotomy and randomized to a sham group (n = 4), or a moderate TBI (n = 10) using a pneumatic impactor. MRI and behavioral assessments were performed pre-TBI and on days 2, 7, and 14 days thereafter. Microbiome composition was determined with 16s rRNA sequencing from fecal sample DNA pre-TBI and 2 hrs, 1, 3, and 7 days afterward. Alpha- and β-bacterial diversity, as well as organizational taxonomic units (OTUs), were determined. Significant changes in the gut microbiome were evident as early as 2 h after TBI as compared with pre-injured samples and sham rats. While there were varying trends among the phylogenetic families across time, some changes persisted through 7 days in the absence of therapeutic intervention. While large structural lesions and behavioral deficits were apparent post-TBI, there were modest but significant decreases in α-diversity. Moreover, both changes in representative phyla and α-diversity measures were significantly correlated with MRI-determined lesion volume. These results suggest that changes in the microbiome may represent a novel biomarker to stage TBI severity and predict functional outcome.

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The lncRNA, H19 Mediates the Protective Effect of Hypoxia Postconditioning Against Hypoxia-Reoxygenation Injury to Senescent Cardiomyocytes by Targeting microRNA-29b-3p
Zhang, Xuan; Cheng, Long; Xu, Longhe; More
Shock. 52(2):249-256, August 2019.

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Background:
Ischemic postconditioning (I/Post) is an endogenous protection mechanism that reduces injury induced by ischemia-reperfusion (I/R). It remains controversial whether I/Post protects against I/R injury to the aging heart. The long non-coding RNA, H19 protects H9c2 cells against hypoxia-induced injury. This study aimed to elucidate the role of H19 in the hypoxic postconditioning (H/Post) of aged cardiomyocytes.

Methods:
Senescence induced by D-galactose in primary cardiomyocytes from neonatal Sprague–Dawley rats was measured by senescence-associated β-galactosidase staining. Hypoxic injury was evaluated by cell viability and apoptosis assays. H19 expression before and after hypoxia-reoxygenation (H/R) and H/Post was evaluated by real-time polymerase chain reactions. miR-29b-3p -binding sites in H19 and the cellular inhibitor of apoptosis protein 1 ( cIAP1 ) were predicted by bioinformatics analysis, and interaction was verified by luciferase assay. The effects of altered H19 , miR-29b-3p, and cIAP1 expression on the viability and apoptosis of senescent cardiomyocytes following H/Post were determined.

Results:
H/Post prevented H/R injury in normal but not senescent cardiomyocytes. H19 expression was remarkably down-regulated after H/Post in senescent compared with normal cardiomyocytes. Small interfering RNA-mediated knockdown of H19 in senescent cardiomyocytes increased H/Post-induced injury. miR-29b-3p was regulated by H19 and led to a greater injury. miR-29b-3p directly targeted the 3′-untranslated region of cIAP1 and suppressed its expression. Furthermore, knockdown of cIAP1 damaged senescent cardiomyocytes following H/Post.

Conclusions:
These findings suggest that H19 mediated the antiapoptotic effect of H/Post against H/R-induced injury to aged cardiomyocytes by inhibiting miR-29b-3p expression.

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Early Dynamics of Plasma Dna in a Mouse Model of Sepsis
Lauková, Lucia; Bertolo, Estera Maria Jana; Zelinková, Magdaléna; More
Shock. 52(2):257-263, August 2019.

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ABSTRACT
Concentration of extracellular DNA (ecDNA) in plasma of septic patients is higher in comparison to healthy controls and is associated with worse prognosis in intensive care patients. Decrease of ecDNA in plasma by treatment with deoxyribonuclease (DNase) showed to have beneficial effects in animal models of sepsis. A previously published study showed that timing of DNase application is crucial for the effect of DNase. No published study monitored plasma ecDNA dynamics during sepsis in detail yet. The aim of our study was to describe the early dynamics of plasma ecDNA but also plasma DNase activity in a mouse model of sepsis. Sepsis was induced using intraperitoneal injection of E. coli and mice were euthanized every hour to obtain sufficient volume of plasma. Our results show that the concentration of plasma ecDNA is rising continuously during the first 5 h after infection and is 20-fold higher 5 h after induction of sepsis in comparison to control mice. Subcellular origin of plasma ecDNA was analyzed but fundamental differences in dynamics between nuclear and mitochondrial ecDNA were not found. DNase activity in plasma seems to rise slowly until the fourth hour, but the interindividual variability is high. In conclusion, this is the first study that describes the dynamics of plasma ecDNA and DNase activity in early sepsis in detail. Our study is the basis for further studies focused on the timing of exogenous DNase treatment in sepsis. Additional studies will be needed to monitor plasma ecDNA in later time points that are more clinically relevant.

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Consequences of the Lack of IL-10 in Different Endotoxin Effects and its Relationship With Glucocorticoids
Córdoba-Moreno, Marlina O.; Todero, María Florencia; Fontanals, Adriana; More
Shock. 52(2):264-273, August 2019.

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ABSTRACT
Sepsis constitutes one of the major causes of death in ICUs. In sepsis induced by gram-negative, although lipopolysaccharide (LPS) initially induces an exacerbated secretion of proinflammatory cytokines leading to endotoxic shock and death resembling a septic shock, it is also capable of inducing refractoriness to subsequent challenge with LPS, a state known as endotoxin tolerance, which is considered the initial step of the immunosuppression found in septic patients. As we previously demonstrated the importance of glucocorticoids in endotoxin tolerance, the aim of this study was to evaluate the contribution of Interleukin-10 (IL-10) both in the endotoxic shock and in the development of the tolerance and its relationship with glucocorticoids. Our results show that, upon LPS challenge, IL-10 knockout mice (KO) mice had an enhanced LPS sensitivity, along with elevated levels of proinflammatory cytokines as tumor necrosis factor-α, IL-12 and interferon-γ, and enhanced tissue damage, despite the high levels of glucocorticoids. This effect may be because, in part, of the higher expression of tumor necrosis factor receptors in IL-10 KO mice. Further, the injection of dexamethasone did not protect IL-10 KO mice from a LPS lethal challenge. Although tolerance was achieved in the absence of IL-10, it was weaker and the elevated levels of glucocorticoids were not able to reverse the high sensitivity of IL-10 KO mice to LPS. Nevertheless, glucocorticoids would play a pivotal role in the establishment and maintenance of this partial tolerance in IL-10 KO mice. Finally, our results show that IL-10 and glucocorticoids could act in a bidirectional way influencing the inflammatory and anti-inflammatory periods.

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Augmenter of Liver Regeneration Protects Against Acetaminophen-Induced Acute Liver Injury in Mice by Promoting Autophagy
Hu, Ting; Sun, Hang; Deng, Wan-Yan; More
Shock. 52(2):274-283, August 2019.

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ABSTRACT
Most cases of acute liver failure are caused by acetaminophen (APAP) overdose. Oxidative stress is a key factor in APAP toxicity. Although augmenter of liver regeneration (ALR) has both antioxidative and antiapoptotic effects, its therapeutic potential in APAP hepatotoxicity remains unknown. The current study assessed the protective effects and associated mechanisms of ALR against APAP-induced acute liver injury in female BALB/c mice. We found that serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, intrahepatic hemorrhage and necrosis were increased at 3, 6, 12, 24, 48, and 72 h after 600 mg/kg APAP i.p. injection. During the early stages (before 12 h) of acute liver injury, ALR levels increased significantly, followed by a decrease to control level at 24 h after APAP administration. ALR treatment increased autophagosomes, promoted the conversion of LC3 I to LC3 II, and the degradation of p62. ALR attenuated APAP-stimulated increases in ALT, AST, myeloperoxidase (MPO), malondialdehyde (MDA), and reactive oxidative species (ROS) levels; intrahepatic hemorrhage; and necrosis as well as superoxide dismutase (SOD) and Glutathione (GSH) depletion. We found that APAP caused release of the mitochondrial intermembrane proteins apoptosis-inducing factor (AIF) and cytochrome c and that ALR inhibited this change. Meanwhile, ALR decreased expression of cleaved-caspase 3 and apoptotic cells. Subsequently, we investigated the significance of autophagy in APAP-induced acute liver injury by treatment with 3-methyladenine (3-MA), which were classical pharmaceuticals for suppressing autophagy. ALR directly induced autophagy flux; and the inhibition of autophagy reversed the beneficial effects of ALR on hepatotoxicity. Our findings suggest that ALR protects against APAP hepatotoxicity by activating the autophagy pathway.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Pediatric Infectious Diseases

Multidrug-resistant Gram-negative Bacterial Bloodstream Infections in Children's Hospitals in Japan, 2010–2017 Background: The risk factors of multidrug-resistant (MDR) Gram-negative bacilli (GNB) bloodstream infection (BSI) are not yet known in children. Our aim was to evaluate risk factors and outcomes associated with MDR GNB BSI in children. Methods: Patients with GNB BSI were enrolled between April 2010 and March 2017 at 8 children's hospitals in Japan. Clinical and microbiologic data were collected retrospectively. The risk factors and outcomes of MDR and non-MDR GNB BSI were compared. Results: In total, 629 GNB BSI episodes met the case definition. The median age and proportion of males were 2 years (interquartile range, 0.3–8.7) and 50.7%, respectively. An underlying disease was found in 94% of patients. The proportion of BSI cases that developed >48 hours after admission was 76.2%. MDR comprised 24.5% of BSI cases. The MDR rate did not change over time (P = 0.540). The effective coverage rate of the initial empiric therapy for the MDR and non-MDR BSI cases was 60.4% and 83.4%, respectively (P < 0.001). The all-cause mortality rate at 28 days for all BSI, MDR-BSI and non-MDR BSI cases was 10.7%, 13.6% and 9.7%, respectively (P = 0.167). MDR BSI was independently associated with cancer chemotherapy within 30 days (odds ratio [OR] 43.90), older age (OR 1.05) and admission to the neonatal ward (OR 0.019). Conclusions: One-fourth of GNB BSI cases were MDR. Cancer chemotherapy and older age were risk factors for MDR GNB BSI in children's hospitals. MDR did not increase the all-cause mortality rate.

Improved Clinical Outcome After Treatment of Mycobacterium abscessus Complex Pulmonary Disease in Children With Cystic Fibrosis Background: Mycobacterium abscessus complex pulmonary disease (M. abscessus PD) in cystic fibrosis (CF) is challenging to treat. Current guideline therapeutic regimens involving an intensive phase of intravenous (IV) antibiotics followed by a consolidation phase of inhaled and oral antibiotics are not evidence-based. The objectives of this study were to characterize the clinical outcomes and clearance of Mycobacterium abscessus complex (M. abscessus) from respiratory cultures in children with CF M. abscessus PD. Methods: This retrospective longitudinal cohort analysis evaluated the first course of treatment for M. abscessus PD in 33 children in Queensland, Australia between 2001 and 2015. Spirometry and nutritional outcomes 2 years pretreatment and 1 year posttreatment were compared with clearance or relapse/persistence of Mycobacterium abscessus complex from respiratory cultures. Results: Nine of 18 children who completed therapy, cleared infection. Three of 7 children who completed only intensive therapy cleared sputum compared with 0/8 children who did not. The trajectory of the percent predicted forced expiratory volume in 1 s and age standardized body mass index significantly improved posttreatment in those that cleared sputum (P < 0.0001). Conclusions: These results suggest that current treatment recommendations for M. abscessus PD are associated with some success in clearing infection in children with CF and improvement in lung function and body mass index. Clinical trials are required to determine the best treatment approaches.

Incidence, Risk Factors and Outcomes Among Children With Acute Flaccid Myelitis: A Population-based Cohort Study in a California Health Network Between 2011 and 2016 Background: Acute flaccid myelitis (AFM) is defined as an acute onset of limb weakness with longitudinal spinal gray matter lesions. Reporting bias and misdiagnosis confound epidemiologic studies of AFM. We mitigated these confounders by using a large data set to assess AFM incidence, risk factors and outcomes in a fixed population. Methods: A retrospective cohort study was conducted within Kaiser Permanente Northern California population among children 1–18 years. Cases met radiographic and clinical criteria for AFM and were confirmed by two clinicians. Clinical and demographic data were assessed. Results: A total of 28 patients met study criteria for AFM between January 1, 2011 and December 31, 2016, an overall rate of 1.46 per 100,000 person-years. Incidence increased from 0.30 to 1.43 cases/per 100,000 person-years between 2011 and 2016, respectively. Median age was 9 years. Risk factors included male sex, Asian ancestry and history of asthma, atopic dermatitis or head injury. Risk factors associated with poliomyelitis were absent. Prodromal illness was common; enterovirus was the most common pathogen detected (n = 5). Among the 27 patients with 12-month follow-up, most demonstrated some improvement, 11 (41.0%) had full recovery, but several had significant deficits with one death reported after the study period. Conclusions: We employed a closed-population study to generate AFM incidence, risk and outcome data. Our findings support previous reports of male sex and atopy as risk factors. Interval increase in incidence, predisposing Asian ancestry and history of head injury were unique findings to this study. Overall prognosis was better than prior reports, but recovery was incomplete in several patients.

A Population-based Observational Study of Childhood Encephalitis in Children Admitted to Pediatric Intensive Care Units in England and Wales Background: Encephalitis is a serious neurologic condition that can result in admission to intensive care. Yet, there are no studies on pediatric intensive care unit (PICU) admission rates and usage of intensive care resources by children with encephalitis in England and Wales. The objectives of this study were to (1) define the PICU incidence and mortality rates for childhood encephalitis, (2) describe the usage of intensive care resources by children with encephalitis admitted to PICU and (3) explore the associated cost from PICU encephalitis admissions. Methods: Retrospective analysis of anonymized data for 1031 children (0–17 years) with encephalitis admitted (January 2003 to December 2013) to PICU in England and Wales. Results: The PICU encephalitis incidence was 0.79/100,000 population/yr (95% confidence interval [CI]: 0.74–0.84), which gives an annual total of 214 bed days of intensive care occupancy for children admitted with encephalitis and an estimated annual PICU bed cost of £414,230 (interquartile range: 198,111–882,495) for this cohort. PICU encephalitis admissions increased during the study period (annual percentage change = 4.5%, 95% CI: 2.43%–6.50%, P ≤ 0.0001). In total, 808/1024 (78.9%) cases received invasive ventilation while 216/983 (22.0%) and 50/890 (5.6%) cases received vasoactive treatment and renal support, respectively. There were 87 deaths (8.4%), giving a PICU encephalitis mortality rate of 0.07/100,000 population (0–17 years)/yr (95% CI: 0.05–0.08). Conclusions: These data suggest that encephalitis places a significant burden to the healthcare service. More work is needed to improve outcomes for children with encephalitis.

RSVpredict: An Online Tool to Calculate the Likelihood of Respiratory Syncytial Virus Infection in Children Hospitalized With Acute Respiratory Disease Background: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection in young children. Early detection of RSV infection can avoid unnecessary diagnostic and therapeutic intervention and is required to prevent the nosocomial spread of RSV infection in pediatric hospitals. We developed a web tool to calculate the probability of RSV infection in children hospitalized with acute respiratory tract infection (ARTI) (RSVpredict). Methods: During winter seasons 2014/2015 to 2017/2018, 1545 children hospitalized with clinical symptoms of ARTI at the University Hospital Heidelberg/Germany were prospectively included. Medical information was reported on a standardized data sheet, and nasopharyngeal swabs were obtained for multiplex real-time polymerase chain reaction analyses. We applied logistic regression to develop a prediction model and developed a web-based application to predict the individual probability of RSV infection. Results: Duration of clinical symptoms ≥2 days on admission, calendar month of admission, admission for lower respiratory tract infection, the presence of cough and rale and younger age were associated with RSV infection (P < 0.05). Those data were included in the prediction model (RSVpredict, https://web.imbi.uni-heidelberg.de/rsv/). RSVpredict is a web-based application to calculate the risk of RSV infection in children hospitalized with ARTI. The prediction model is based on easily accessible clinical symptoms and predicts the individual probability of RSV infection risk immediately. Conclusions: Pediatricians might use the RSVpredict to take informed decisions on further diagnostic and therapeutic intervention, including targeted RSV testing in children with relevant RSV infection risk.

Bacterial Colonization of the Hospitalized Newborn: Competition Between: Staphylococcus aureus: and: Staphylococcus epidermidis Background: In adults, Staphylococcus epidermidis and Staphylococcus aureus compete for colonization of the nasal mucosa and S. epidermidis strains that produce the Esp serine protease eradicate S. aureus nasal colonization. Whether similar phenomena are seen in newborn infants is unknown. Methods: Nasal swabs were obtained on admission and discharge from newborn infants (n = 90 and 83, respectively) in the neonatal intensive care unit at UC Davis Children's Hospital. Swabs were cultured for S. aureus and S. epidermidis. S. epidermidis isolates were tested for Esp expression, overall secreted protease activity and biofilm inhibition. Results: No infant had S. aureus on admission. S. epidermidis colonization was rare on admission in inborn infants (2.5%), but common in infants transferred from referring hospitals (50%). At discharge, most infants (96%) were colonized by staphylococci. S. aureus colonization was less common in infants with S. epidermidis colonization (9%) and more common in infants without S. epidermidis (77%) (relative risk of S. aureus colonization in infants colonized with S. epidermidis 0.18, 95% confidence interval: 0.089–0.34, P < 0.0001). Compared with S. epidermidis strains from infants without S. aureus, S. epidermidis from infants co-colonized with S. aureus had lower total proteolytic enzyme activity and decreased biofilm inhibition capacity, but did not have lower frequency of Esp positivity. Conclusions: In hospitalized neonates, S. epidermidis colonization has a protective effect against S. aureus colonization. Secretion of proteases by S. epidermidis is a possible mechanism of inhibition of S. aureus colonization; however, in this cohort of neonates, the source of major protease activity is likely other than Esp.

Enterovirus D68 Causing Acute Respiratory Infection: Clinical Characteristics and Differences With Acute Respiratory Infections Associated With Enterovirus Non-D68 Background: Enterovirus (EV) D68 is mainly associated with acute respiratory infection (ARI). Since 2014, when outbreaks in different countries were observed, this emerging virus was considered a potential threat to public health. Methods: During 2015–2017, the presence of enterovirus RNA was investigated in all respiratory samples of children younger than 15 years of age with ARI, obtained for virologic studies in the Pediatric Emergency Care Units and wards of 2 hospitals in Gipuzkoa (Spain), using a commercial multiplex real-time polymerase chain reaction. When enterovirus was detected, a polymerase chain reaction to amplify a specific viral polyprotein (VP1) gene region of EV-D68 was performed. Results: In 2016, EV-D68 circulation was associated to ARI, with the highest incidence in the spring months. EV-D68 was detected in 44 children, mean age 30.1 ± 31.7 months old, 23 (52.3%) of them females and 17 (38.6%) with underlying respiratory medical conditions. Thirty-two patients (72%) required hospital admission, receiving the discharge diagnosis of recurrent wheezing (37.5%), asthmatic crisis (37.5%) or bronchiolitis (12.5%). Seven children (15.9%) needed the support of the pediatric intensive care unit. When coinfections were excluded, children with EV-D68 infection presented with increased work of breathing, recurrent wheezing or asthmatic crisis, more frequently than those with ARI associated with EV non-D68. Moreover, clinical outcomes (hospitalization, respiratory support) were more severe. All 44 EV-D68 strains detected belonged to lineage B3. Conclusions: EV-D68 circulated widely in Gipuzkoa during 2016 and was associated with severe ARI. In children with severe ARI of unknown etiology, the presence of EV-D68 should be considered.

Intrafamilial Transmission of Hepatitis C Virus Among Families of Infected Pediatric Oncology Patients Background: Hepatitis C virus (HCV) is the most commonly encountered blood transmittable hepatitis among cancer patients. Several studies have reported clustering of HCV infections in families or household contacts of infected cases. Data about the epidemiologic aspects of intrafamilial transmission from pediatric cancer patients are scarce and still debated. We aimed to identify the magnitude of horizontal intrafamilial transmission of HCV from infected pediatric oncology patients; its prevalence, risk factors and possible routes of transmission. Methods: One hundred fifty-seven (86 HCV positive, 71 HCV negative) pediatric oncology patients who received treatment and follow-up at Zagazig university Hospital-Egypt and their household family contacts (751) were enrolled in this cross-sectional case-control study. Blood samples were collected from 450 relatives of HCV infected cases (group 1) and 301 household contacts of HCV-negative cases (group 2) for analysis of HCV antibodies and HCV RNA to confirm positivity. Family contacts of HCV-infected cases were interviewed, and close-ended questionnaire was completed for each participant to determine risk factors and possible routes of HCV intrafamilial transmission. Results: Significantly higher HCV prevalence and chronicity rates were documented among relatives of HCV-infected cases as compared with contacts of HCV-negative cases (12.6% and 10.6% for group 1 vs. 7% and 5.3% for group 2, respectively). Risk factors of infection were calculated by univariate and logistic regression analysis among contacts of HCV-infected cases. Female caregivers, particularly mother (OR 5.1, 95% CI: 2–13.5), contact with index cases blood, either directly without using personal protective equipment (OR 7.8, 95% CI: 2.9–23.8) or indirectly through common use of sharps (razors, scissors) (OR 8.9, 95% CI: 3.5–20.5) and nail clippers (OR 2.1, 95% CI: 1.1–5.4) and giving care to infected cases (OR 2.9, 95% CI: 1.3–16.6) represented the real predictors of intrafamilial HCV infection. Conclusions: Intrafamilial transmission of HCV from infected children to their relatives does occur. Parenteral route is the only documented way of transmission either directly or indirectly.

The Clinical Presentation of Pediatric Mycoplasma pneumoniae Infections—A Single Center Cohort Background: Mycoplasma pneumoniae (MP) is a major cause of community-acquired upper and lower respiratory infections in school-age children; however, there is increasing recognition that younger children are also affected. Clinical manifestations vary from asymptomatic, to severe complicated pneumonia sometimes with extrapulmonary manifestations. Methods: We reviewed the medical records of all MP positive pediatric patients admitted to the Hadassah-Hebrew University Medical Center. MP positive case was defined if MP polymerase chain reaction was positive from an oropharyngeal swab sent from 2007 to 2017. Results: During the study period, we identified 353 MP positive pediatric cases, of which 51.3% (181 of 353) were younger than 6 years old. Full clinical data were available for 332 of 353 (94%). The median age was 5.7 years (range, 3 weeks to 18 years). Disease presentation differed between younger and older children. Children older than 6 years were more likely to have chest radiograph confirmed pneumonia (66% vs. 52%; P = 0.009), while younger children were more likely to have other respiratory manifestations (37% vs. 25%; P = 0.017). The duration of hospitalization and pediatric intensive care unit admission rate, however, did not differ between age groups. The rate of extrapulmonary manifestations were also similar. Conclusions: MP-associated infection is a significant cause of hospitalization in the pediatric population including younger children (<6 years old). However, the clinical presentation in younger age is less typical than is thought. These findings should prompt clinicians to consider MP infections also in children younger than 6 admitted with fever even without pneumonia.

Pediatric Infectious Sacroiliitis: Characterization and Differentiation from Noninfectious Etiologies Background: Pediatric sacroiliitis (SI) is an uncommon entity of infectious or inflammatory etiology. Recent data regarding pediatric SI are scarce. The study objective was to describe and compare the clinical features of pediatric infectious and noninfectious SI. Methods: We reviewed files of children ≤18 years of age, admitted with SI in 2004–2017. Patients were grouped by etiology, infectious versus noninfectious. Clinical and laboratory indices, imaging, treatment protocols and outcome were compared. Results: Study population included 40 patients with infectious SI (range: 3–192 months, median age: 15 months, 45% female) and 13 patients with noninfectious SI (range: 30–216 months, median age: 168 months, 62% females). Duration of symptoms before admission averaged 5.9 ± 7.5 days in the infectious group and 54.2 ± 96 days in the noninfectious group (P = 0.003). Symptoms observed solely in the infectious group included refusal to stand (n = 27, 77%); walk or crawl (n = 24, 65%); irritability (n = 20, 50%) and recent constipation event (n = 8, 20%). No significant differences in laboratory results were found. Infectious SI patients had uneventful medical history, rapid response to antibiotics and a higher rate of complete resolution of symptoms without recurrences. Conclusions: An acute unilateral presentation in young patients ≤2 years of age, without chronic medical conditions, suggests an infectious etiology of SI anticipated to completely resolve with antibiotic treatment, not necessitating further workup for noninfectious etiologies.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com