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Abstract Background High-risk neuroblastoma has an overall five-year survival of less than 40%, indicating a need for new treatment strategies such as angiogenesis inhibition. Recent studies have shown that chemotherapeutic drugs can inhibit angiogenesis if administered in a continuous schedule. The aim of this study was primarily to characterize tumor spread in an orthotopic, metastatic model for aggressive, MYCN-amplified neuroblastoma and secondarily to study the effects of daily administration of the chemotherapeutic agent CHS 828 on tumor angiogenesis, tumor growth, and spread. Methods MYCN-amplified human neuroblastoma cells (IMR-32, 2 × 106) were injected into the left adrenal gland in SCID mice through a flank incision. Nine weeks later, a new laparotomy was performed to confirm tumor establishment and to estimate tumor volume. Animals were randomized to either treatment with CHS 828 (20 mg/kg/day; p.o.) or vehicle control. Differences between groups in tumor volume were analyzed by Mann-Whitney U test and in metastatic spread using Fisher's exact test. Differences with p < 0.05 were considered statistically significant. Results The orthotopic model resembled clinical neuroblastoma in respect to tumor site, growth and spread. Treatment with CHS 828 resulted in tumor regression (p < 0.001) and reduction in viable tumor fraction (p < 0.001) and metastatic spread (p < 0.05) in correlation with reduced plasma levels of the putative tumor marker chromogranin A (p < 0.001). These effects were due to increased tumor cell death and reduced angiogenesis. No treatment-related toxicities were observed. Conclusion The metastatic animal model in this study resembled clinical neuroblastoma and is therefore clinically relevant for examining new treatment strategies for this malignancy. Our results indicate that daily scheduling of CHS 828 may be beneficial in treating patients with high-risk neuroblastoma.

Background: The role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the early treatment of patients with non-ST-elevation acute coronary syndrome (NSTACS) has been evaluated in 6 large studies that include >12,000 patients.Methods and Results: These studies convincingly show that this marker of cardiac performance is associated strongly with death and the risk of future congestive heart failure and carry important prognostic information that is independent from previous known risk factors in NSTACS. As such, NT-proBNP can be added to existing risk stratification models and multimarker approaches. There is some data that indicate that this marker might also be helpful in guiding decisions about coronary revascularization in these patients, but further studies are needed.Conclusion: Before routine use of NT-proBNP in NSTACS, the extra cost of adding this new marker to the current routine markers and its impact on selection of treatment should be considered. [ABSTRACT FROM AUTHOR]

Abstract. Ärnlöv J, Lind L, Stridsberg M, Andrén B, Lithell H (University of Uppsala, Sweden). N-terminal atrial natriuretic peptide and left ventricular geometry and function in a population sample of elderly males. J Intern Med 2000; 247: 699–708. Objectives. To investigate the relationships between N-terminal atrial natriuretic peptide (N-ANP) and left ventricular geometry and function. Design. A cross-sectional study of a population-based cohort. Setting. Follow-up of a health survey in Uppsala county, Sweden. Subjects. Two hundred and five men aged 70. Main outcome measures. A Delfia sandwich immunoassay was used to measure the plasma levels of N-ANP. M-mode and Doppler echocardiographic examinations were used to measure left ventricular dimensions, mass, geometry and systolic function and to classify the subjects into four groups (normal geometry, concentric remodelling, concentric hypertrophy or eccentric hypertrophy). Left ventricular systolic dysfunction was defined as a left ventricular ejection fraction ≤ 0.40. Results. Plasma levels of N-ANP were significantly increased in subjects with left ventricular dysfunction compared to healthy subjects (702 ± 486, n = 14 vs. 277 ± 201 pmol L-1, n = 118, P < 0.0001), but there was a great overlap between the groups. N-ANP differed significantly between the four different left ventricular geometric groups (P = 0.02) with the highest N-ANP levels in the subjects with left ventricular eccentric hypertrophy (n = 40). However, N-ANP levels were no longer significantly associated with left ventricular geometry when taking the ejection fraction into account. Conclusions. This study showed that N-ANP levels were significantly elevated in subjects with left ventricular dysfunction, as well as in subjects with left ventricular hypertrophy. However, the increase in N-ANP seen in the eccentric hypertrophy group was mainly due to a decreased ejection fraction. [ABSTRACT FROM AUTHOR]

The acrosyringium is the target for inflammation in the chronic and intensely inflammatory skin disease palmoplantar pustulosis (PPP). The sweat-gland apparatus seems to be an immunocompetent structure that probably contributes to skin defence. Furthermore, the sweat gland and duct may be a hitherto unrecognized neuroendocrine organ. To obtain further information about the neuroendocrine properties of the sweat-gland apparatus by examining expression of the somatostatin receptors (SSTRs) 1-5 in healthy palmar skin and in PPP skin. Biopsy specimens were taken from 25 patients with PPP and 25 healthy controls. Immunohistochemical analysis was used to investigate expression of SSTRs 1-5. SSTRs 1-5 were expressed in both epidermal and endothelial structures. The staining intensity of the sweat-gland apparatus was more pronounced than that of the epidermis. Expression differed significantly between lesional PPP and normal plantar skin, with increased expression of SSTRs 3 and 4 in ducts in epidermis, and decreased expression of SSTR 1 in ducts in both papillary and reticular dermis. In specimens with pronounced inflammation, numerous dendritic cells with strong expression of SSTRs 1, 2 and 4 were seen, especially in the papillary dermis. The presence of SSTRs in palmoplantar skin, and specifically at high density in the sweat glands and ducts, might be of particular importance in skin neuroimmunoendocrinology. Although the relevance of the changes in SSTR expression in PPP skin compared with normal skin is unclear, our hypothesis is that these differences might influence the function of both the neuroendocrine and neuroimmunological properties of palmoplantar skin, especially in the sweat-gland apparatus. [ABSTRACT FROM AUTHOR]

Background: Activated protein C has recently been shown in a multicentre trial to significantly reduce mortality in patients with septic shock. There are also some case reports and minor studies demonstrating promising results with the unactivated form of protein C. However, in children with severe meningococcal infection, skin biopsies have demonstrated low expression of endothelial thrombomodulin and protein C receptors, suggesting low protein C activation capacity in severe meningococcal sepsis.Methods: A patient with meningococcal septic shock was treated with two doses of the unactivated form of protein C, the first during intense activation of the coagulation system and the second during a phase of low grade or no activation. Repeated plasma samples were analysed for protein C concentration, which made it possible to compare pharmacokinetics and half-lives of the two administrations. A shorter half-life during intense coagulation was expected if there was an activation and consumption of the protein C administered.Results: The calculated half-lives of protein C during intense and low grade activation were 32 h and 19 h, respectively, a magnitude similar to that reported in protein C-deficient patients without infection.Conclusion: The result indicates that whole body utilisation of the unactivated protein C was low. Endothelial impairment of protein C activation does not seem to be restricted to the skin vessels only. [ABSTRACT FROM AUTHOR]

BackgroundSerum chromogranin A (CgA), a marker of neuroendocrine neoplasia, increases during profound gastric acid inhibition, possibly reflecting the trophic effect of gastrin on the enterochromaffin-like (ECL) cells. AimsThis study investigated the clinical value of serum CgA as a screening test for gastric fundic enterochromaffin-like (ECL) cell hyperplasia during acid-suppressive therapy. MethodA consecutive series of 230 dyspeptic patients referred for upper gastrointestinal endoscopy was investigated in a cross-sectional design. They were 154 patients on continuous medium-term (6 weeks to one year) or long-term (longer than one year) acid inhibition with either proton pump inhibitors (PPIs, n = 117) or histamine2-receptor antagonists (H2RAs, n = 37) for gastro-oesophageal reflux disease, and 76 nontreated subjects, with normal endoscopic findings (control group). Fasting blood samples were analysed for gastrin and CgA. Gastric biopsy specimens (oxyntic mucosa) were examined for histological evaluation of gastritis (Sydney classification) and of ECL cell hyperplasia (Solcia classification). ResultsSerum CgA levels correlated positively with serum gastrin, following a quadratic function (r = 0·78, P < 0·0001). Elevated serum CgA values during long-term acid inhibition correlated with the presence and severity of fundic ECL cell hyperplasia. Multivariate analysis identified hypergastrinaemia (P < 0·0001), duration of acid inhibition (P < 0·0001), H. pylori infection (P = 0·008), ECL cell hyperplasia (P = 0·012), and body gland atrophy (P = 0·043) as independent predictors of elevated serum CgA. In subjects on long-term acid inhibition (n = 123), serum CgA was equally sensitive but more specific than serum gastrin for the detection of ECL cell hyperplasia (sensitivity, 91·3% for both; specificity, 73% vs. 43%, P < 0·0001). ConclusionsDuring long-term gastric acid inhibition, serum CgA levels... [ABSTRACT FROM AUTHOR]

Background: The polymorphic enzyme CYP2C19 is of importance for the metabolism and effects of omeprazole during short-term treatment. Aim: To investigate the relationship between CYP2C19 genotype and the effects of long-term omeprazole treatment. Material and methods: A total of 180 patients with acid related disorders were genotyped for wild type and mutated CYP2C19 alleles by allele-specific PCR amplification. Gastrin and chromogranin A were assessed by radioimmunoassays, and pepsinogen I and H. pylori serology were assessed by ELISA methods. Results: In 108 of the patients, who received a single dose of 20 mg omeprazole, there was no difference in gastrin and chromogranin A concentrations between the three CYP2C19 genotypes. In 72 patients on long-term treatment (> 1 year) with 20 mg omeprazole daily, serum gastrin as well as plasma chromogranin A concentrations (mean ± s.e.) were both about threefold higher in the wild type/mutated (52.1 ± 7.6 pM and 7.3 ± 1.3 nM (n=19), respectively) compared to wild type/wild type (14.7 ± 0.9 pM and 2.5 ± 0.1 nM (n=52), respectively; both comparisons P=0.0001). In a single mutated/mutated patient on long-term treatment, both gastrin and chromogranin A were high (88 pM and 13.7 nM, respectively). Serum pepsinogen I concentration was significantly lower in wild type/mutated (n=19) patients on long-term treatment, compared with the corresponding wild type/wild type (n=49) group (147 ± 19 μg/L vs. 193 ± 12 μg/L, P=0.04). Conclusion: Patients with one (and probably also with two) mutated CYP2C19 allele(s) on long-term treatment with omeprazole had significantly affected serum gastrin and pepsinogen I and plasma chromogranin A concentrations compared with patients with two normal alleles. This indicates that changes in gastric mucosal morphology during omeprazole treatment might be dependent upon the degree of the individual’s capacity to metabolize omeprazole. [ABSTRACT FROM AUTHOR]

Abstract: Background: Chromogranin (Cg) A is expressed in neuroendocrine and neuronal tissues. It is involved in the generation of secretory granules and is cleaved to form biologically active peptides. Targeted ablation of the Chga gene resulted in increased plasma catecholamines, high blood pressure, and decreased size and number of adrenal medullary chromaffin granules. The aim of this study was to determine whether Chga null mice display changes in the morphology and function of the endocrine pancreas. Materials and methods: Sections of pancreata from Chga−/−, Chga+/− and Chga+/+ mice, were immunostained with antibodies against synaptophysin, CgA, CgB, secretogranin II and the four major pancreatic islet hormones. Plasma was analysed for glucose, insulin, glucagon, somatostatin and pancreatic polypeptide (PP). Results: CgA epitopes were undetectable in the islets of Chga−/− animals. CgB and secretogranin II epitopes were expressed in the islets of all animal groups albeit with decreased expression in Chga−/− islets. The islet number and size were decreased in the Chga−/− animals compared with Chga+/+. The proportion of insulin cells was decreased but somatostatin and PP cells were increased in Chga−/− mice compared to Chga+/+ mice. The nuclear size was decreased in insulin cells and increased in somatostatin cells in Chga−/− mice. Plasma insulin level was markedly decreased in the Chga−/− mice although fasting plasma glucose and glucagon were normal. Conclusion: Ablation of the Chga gene affected the islet volume, the composition, distribution and nuclear size of islet cell types and plasma insulin concentration. Our data indicate decreased insulin cell function and increased glucagon cell function. Our study shows that CgA exerts a significant influence on the endocrine pancreas with importance in maintaining islet volume, cellular composition and function. [Copyright &y& Elsevier]

Objectives: We aimed to determine whether the common variation at the chromogranin A (CHGA) locus increases susceptibility to hypertension.Background: CHGA regulates catecholamine storage and release. Previously we systematically identified genetic variants across CHGA.Methods: We carried out dense genotyping across the CHGA locus in >1,000 individuals with the most extreme blood pressures (BPs) in the population, as well as twin pairs with autonomic phenotypes. We also characterized the function of a trait-associated 3'-untranslated region (3'-UTR) variant with transfected CHGA 3'-UTR/luciferase reporter plasmids.Results: CHGA was overexpressed in patients with hypertension, especially hypertensive men, and CHGA predicted catecholamines. In individuals with extreme BPs, CHGA genetic variants predicted BP, especially in men, with a peak association occurring in the 3'-UTR at C+87T, accounting for up to approximately 12/ approximately 9 mm Hg. The C+87T genotype predicted CHGA secretion in vivo, with the +87T allele (associated with lower BP) also diminishing plasma CHGA by approximately 10%. The C+87T 3'-UTR variant also predicted the BP response to environmental (cold) stress; the same allele (+87T) that diminished basal BP in the population also decreased the systolic BP response to stress by approximately 12 mm Hg, and the response was smaller in women (by approximately 6 mm Hg). In a chromaffin cell-transfected CHGA 3'-UTR/luciferase reporter plasmid, the +87T allele associated with lower BP also decreased reporter expression by approximately 30%. In cultured chromaffin cells, reducing endogenous CHGA expression by small interfering ribonucleic acid caused approximately two-thirds depletion of catecholamine storage vesicles.Conclusions: Common variant C+87T in the CHGA 3'-UTR is a functional polymorphism causally associated with hypertension especially in men of the population, and we propose steps ("intermediate phenotypes") whereby in a sex-dependent fashion this genetic variant influences the ultimate disease trait. These observations suggest new molecular strategies to probe the pathophysiology, risk, and rational treatment of hypertension. [ABSTRACT FROM AUTHOR]

In this pilot study, the predictive value of Octreotide scintigraphy (Octreoscan) and/or Chromogranin-A (CgA) was investigated in patients with hormone-refractory prostate cancer treated with Octreotide acetate. In total, 20 patients with progressive disease and bone metastases entered the trial. At baseline Octreoscan, CgA, PSA, alkaline phosphates (ALP) and two self-administered questionnaires (EORTC QLQ C-30 (v3) and brief pain index) were performed and a diary of the pharmaceutical was started. The treatment consisted of Octreotide (Sandostatin LAR) acetate 30 mg intramuscular injection every month. The blood samples and questionnaires were repeated every month until 3 months. Clinical responder was defined as a patient with increased global health score more than 10 units and stable or decreased pain score without an increase in analgesic. In all, 17 patients were treated per protocol, and four were assessed as clinical responders. Six patients developed a reduction in ALP (median −26%, range −5 to −78%). All patients increased in PSA. At baseline, three patients had a negative Octreoscan and the patients with positive lesions, demonstrated uptake of low intensity. At baseline the CgA was elevated above the normal range in 15 of the patients, and during treatment five patients decreased their CgA to the normal range. Neither baseline Octreoscan nor CgA could identify the clinical reponders. A minority of patients improves their health-related quality of life. The decrease and normalization of CgA levels in five patients during therapy indicates therapeutic activity but Octreoscan and CgA could not identify clinical responders.Prostate Cancer and Prostatic Diseases (2006) 9, 92–98. doi:10.1038/sj.pcan.4500843; published online 18 October 2005 [ABSTRACT FROM AUTHOR]

This study demonstrates the expression of functional somatostatin receptor (sstr) subtypes in human circular and longitudinal colonic smooth muscle cells (SMC). Native somatostatin (SS) and sstr subtype-specific analogues were used to characterize the sstr subtypes present in both cell types by contraction/relaxation studies. Qualitative and quantitative mRNA analysis and immunohistochemistry of sstr subtypes were also carried out. sstr subtype 2 mRNA was expressed in circular SMC, and various levels of subtypes 1, 2 and 3 mRNA were expressed in longitudinal colonic SMC. Native SS and each subtype-specific analogue exerted a modest, but significant, contraction, although inhibition of carbachol-induced contraction (relaxation) was the main effect on SMC from both layers. CH-288, a sstr subtype 1-specific analogue, and octreotide, a sstr subtype 2-specific analogue, were the most effective relaxant analogues on longitudinal and circular SMC, respectively. sstr subtypes display a distinct expression pattern on human colonic SMC; on circular SMC, subtype 2 is the only sstr, whereas sstr subtypes 1, 2 and 3 are expressed on human SMC isolated from the longitudinal layer. The contractile effects of SS are mediated through sstr subtype 2 and sstr subtype 1 on circular and longitudinal human colonic SMC, respectively. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Elevated serum gastrin and a low pepsinogen A/C ratio are well-recognized markers for atrophic body gastritis (ABG). We have shown that the presence of body atrophy is also associated with elevated serum pro-inflammatory cytokines. This study tested the hypothesis that serum cytokines provide additional information to gastrin and pepsinogens in screening for ABG. Methods Two hundred and twenty-six consecutive patients were investigated on referral for upper gastrointestinal endoscopy: 150 were patients with gastro-oesophageal reflux disease, receiving acid inhibitory medication either with proton pump inhibitors (n = 113) or with histamine 2 -receptor antagonists ( n = 37), and 76 were nontreated controls, who had normal endoscopic findings. Gastric mucosal biopsies were sampled for histological examination (Sydney classification). Serum samples were analyzed for gastrin, chromogranin A (CgA), and pepsinogens A and C by RIA, and for the interleukins (IL)-1β, IL-6, and IL-8 by ELISA. Results Subjects with ABG had significantly higher serum gastrin (P < 0·01) and serum CgA ( P < 0·01) levels and significantly lower pepsinogen A/C ratios ( P < 0·001) than those without ABG. Additionally, serum IL-1β, IL-6 and, especially, IL-8 levels were significantly higher in the subjects with than in those without ABG ( P < 0·0001, for all cytokines). To optimize the detection of body atrophy we defined the ABG index: the ratio between the simultaneously measured IL-8 and pepsinogen A/C. The area under the ROC curve for the ABG index was significantly greater than that for serum gastrin and for serum pepsinogen A/C alone (0·91 ± 0·029 vs. 0·72 ± 0·042, and vs. 0·83 ± 0·031, P = 0·018 and P = 0·049). Using the ABG index at a cut-off value of 1·8 pg mL -1 , 91% of the cases were classified correctly. Conclusions The ratio between serum IL-8... [ABSTRACT FROM AUTHOR]

Objective: Our aim was to analyse the chromogranin A-derived peptides vasostatin and catestatin in serum from wild boar (Sus scrofa) captured in a corral trap. Acute capture-related stress quickly leads to a release of adrenalin and noradrenalin, but these hormones have a short half-life in blood and are difficult to measure. Chromogranin A (CgA), a glycoprotein which is co-released with noradrenalin and adrenalin, is relatively stable in circulation and the CgA-derived peptides catestatin and vasostatin have been measured in domestic species, but not yet in wildlife., Results: Vasostatin and catestatin could be measured and the median (range) serum concentrations were 0.91 (0.54-2.86) and 0.65 (0.35-2.62) nmol/L, respectively. We conclude that the CgA-derived peptides vasostatin and catestatin can be measured in wild boar serum and may thus be useful as biomarkers of psychophysical stress., (© 2021. The Author(s).)

Background: Circulating secretoneurin (SN) concentrations, as measured by established radioimmunoassay (RIA), risk stratify patients with cardiovascular disease. We now report data for a recently developed research-use-only SN enzyme-linked immunosorbent assay (ELISA) in patients with suspected acute coronary syndrome (ACS)., Methods: SN ELISA was developed according to industry standards and tested in 401 unselected chest pain patients. Blood samples were drawn <24 h from admission, and we adjudicated all hospitalizations as ACS or non-ACS. The mean follow-up was 6.2 years., Results: SN ELISA with 2 monoclonal sheep anti-SN antibodies has a measuring range of 10-250 pmol/L and demonstrates excellent analytical precision and accuracy across the range of SN concentrations. SN measured by ELISA and RIA correlated in the chest pain patients: rho = 0.39, p < 0.001. SN concentrations were higher in ACS patients (n = 161 [40%]) than in non-ACS patients (n = 240) for both assays, with an area under the curve (AUC) of 0.66 (95% CI: 0.61-0.71) for ELISA and 0.59 (0.54-0.65) for RIA. SN concentrations were also higher in nonsurvivors (n = 65 [16%]) than survivors, with an AUC of 0.72 (0.65-0.79) for ELISA versus 0.64 (0.56-0.72) for RIA, p = 0.007, for difference between assays. Adjusting for age, sex, blood pressure, previous myocardial infarction, atrial fibrillation, and heart failure in multivariable analysis, SN concentrations as measured by ELISA, but not RIA, remained associated with mortality, with a hazard ratio of 1.71 (1.03-2.84), p = 0.038., Conclusions: The novel SN ELISA has excellent performance, higher AUC for diagnosis, and superior prognostic accuracy compared to the established RIA in chest pain patients., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: The protein chromogranin A (CgA) is stored and co-released with catecholamines from the stimulated adrenal glands. Increased plasma concentrations of CgA have been shown in people with heart disease. The aim of the study was to investigate whether plasma concentrations of the CgA-derived biologically active peptides catestatin and vasostatin were associated with the severity of myxomatous mitral valve disease (MMVD) in dogs and to assess potential associations between these blood variables and dog characteristics, echocardiographic variables, heart rate (HR), blood pressure (BP) and plasma N-terminal-proBNP (NT-proBNP) concentration. Sixty-seven privately owned dogs with or without MMVD were included. The dogs underwent physical examination, blood pressure measurement, blood sample collection, and echocardiographic examination. Plasma concentrations of catestatin and vasostatin were analyzed using radioimmunoassay., Results: Catestatin concentration decreased with increasing left atrial and ventricular size (R 2  ≤ 0.09, P ≤ 0.019), and increased with increasing systolic and diastolic blood pressures (R 2  ≤ 0.08, P ≤ 0.038). Regression analyses showed no significant associations for vasostatin. No differences in plasma concentrations of catestatin or vasostatin were found between the disease severity groups used in the study., Conclusions: In the present dog population, the catestatin concentration showed weak negative associations with left atrial and ventricular sizes, both of which are known to increase with increasing severity of MMVD. Furthermore, the catestatin concentration showed weak positive associations with blood pressure.

Background: Secretoneurin (SN) concentrations provide important prognostic information in patients with myocardial dysfunction. Whether preoperative SN concentrations improve risk assessment in patients with moderate to severe aortic stenosis (AS) is unknown., Methods: We included 57 patients with moderate to severe AS referred for presurgical evaluation. All patients were examined with comprehensive echocardiography, electrocardiogram (ECG), and biochemical measurements and compared to 10 age- and sex-matched healthy subjects., Results: Median (quartile 1-3) SN concentrations were 141 (121-163) pmol/L in AS patients and 132 (106-148) pmol/L in control subjects (p = .17). Lower estimated creatinine clearance and use of diuretics, but not standard ECG or echocardiographic indices and cardiac biomarkers, were associated with increasing SN concentrations. Fifteen patients (26%) died during 3.5 years median follow-up. SN concentrations were higher in non-survivors than survivors: 156 (133-209) vs. 140 (116-155) pmol/L, p = .007. Higher SN concentrations were associated with increased risk of mortality also after adjustment for established risk indices, biomarkers, and status regarding valvular surgery: hazard ratio per ln SN 15.13 (95% CI 1.05-219.00); p = .046. Receiver operating characteristics area under the curve for SN to predict mortality was 0.74 (95% CI 0.60-0.88) compared to 0.73 (0.59-0.87) for high-sensitivity cardiac troponin T and 0.67 (0.51-0.82) for N-terminal pro-B-type natriuretic peptide. The previously identified cut-off of SN >204 pmol/L in cardiac surgical patients predicted mortality also in this cohort., Conclusions: SN concentrations improve risk assessment in patients with moderate to severe AS by providing additional prognostic information to established risk indices such as echocardiography, ECG, and established cardiac biomarkers., (Copyright © 2019 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objectives: Secretoneurin is associated with cardiomyocyte Ca handling and improves risk prediction in patients with acute myocardial dysfunction. Whether secretoneurin improves risk assessment on top of established cardiac biomarkers and European System for Cardiac Operative Risk Evaluation II in patients undergoing cardiac surgery is not known., Design: Prospective, observational, single-center sub-study of a multicenter study., Setting: Prospective observational study of survival in patients undergoing cardiac surgery., Patients: A total of 619 patients undergoing cardiac surgery., Interventions: Patients underwent either isolated coronary artery bypass graft surgery, single noncoronary artery bypass graft surgery, two procedures, or three or more procedures. Procedures other than coronary artery bypass graft were valve surgery, surgery on thoracic aorta, and other cardiac surgery., Measurements and Main Results: We measured preoperative and postoperative secretoneurin concentrations and adjusted for European System for Cardiac Operative Risk Evaluation II, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T concentrations in multivariate analyses. During 961 days of follow-up, 59 patients died (9.5%). Secretoneurin concentrations were higher among nonsurvivors compared with survivors, both before (168 pmol/L [quartile 1-3, 147-206 pmol/L] vs 160 pmol/L [131-193 pmol/L]; p = 0.039) and after cardiac surgery (173 pmol/L [129-217 pmol/L] vs 143 pmol/L [111-173 pmol/L]; p < 0.001). Secretoneurin concentrations decreased from preoperative to postoperative measurements in survivors, whereas we observed no significant decrease in secretoneurin concentrations among nonsurvivors. Secretoneurin concentrations were weakly correlated with established risk indices. Patients with the highest postoperative secretoneurin concentrations had worse outcome compared with patients with lower secretoneurin concentrations (p < 0.001 by the log-rank test) and postoperative secretoneurin concentrations were associated with time to death in multivariate Cox regression analysis: hazard ratio lnsecretoneurin 2.96 (95% CI, 1.46-5.99; p = 0.003). Adding postoperative secretoneurin concentrations to European System for Cardiac Operative Risk Evaluation II improved patient risk stratification, as assessed by the integrated discrimination index: 0.023 (95% CI, 0.0043-0.041; p = 0.016)., Conclusions: Circulating postoperative secretoneurin concentrations provide incremental prognostic information to established risk indices in patients undergoing cardiac surgery.

Background: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKIIδ (Ca 2+ /calmodulin-dependent protein kinase IIδ) activity, we hypothesized that upregulation of SN in patients protects against cardiomyocyte mechanisms of arrhythmia., Methods: Circulating levels of SN and other biomarkers were assessed in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; n=8) and in resuscitated patients after ventricular arrhythmia-induced cardiac arrest (n=155). In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using adeno-associated virus-9-induced overexpression. Interactions between SN and CaMKIIδ were mapped using pull-down experiments, mutagenesis, ELISA, and structural homology modeling. Ex vivo actions were tested in Langendorff hearts and effects on Ca 2+ homeostasis examined by fluorescence (fluo-4) and patch-clamp recordings in isolated cardiomyocytes., Results: SN levels were elevated in patients with CPVT and following ventricular arrhythmia-induced cardiac arrest. In contrast to NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity troponin T), circulating SN levels declined after resuscitation, as the risk of a new arrhythmia waned. Myocardial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9-induced overexpression of SN attenuated arrhythmic induction during stress testing with isoproterenol. Mechanistic studies mapped SN binding to the substrate binding site in the catalytic region of CaMKIIδ. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKIIδ in Langendorff hearts and inhibited CaMKIIδ-dependent RyR phosphorylation. In line with CaMKIIδ and RyR inhibition, SN treatment decreased Ca 2+ spark frequency and dimensions in cardiomyocytes during isoproterenol challenge, and reduced the incidence of Ca 2+ waves, delayed afterdepolarizations, and spontaneous action potentials. SN treatment also lowered the incidence of early afterdepolarizations during isoproterenol; an effect paralleled by reduced magnitude of L-type Ca 2+ current., Conclusions: SN production is upregulated in conditions with cardiomyocyte Ca 2+ dysregulation and offers compensatory protection against cardiomyocyte mechanisms of arrhythmia, which may underlie its putative use as a biomarker in at-risk patients.

Background: Granins have been implicated in the pathophysiology of irritable bowel syndrome (IBS) in adults. We sought to determine whether fecal granins are altered in children with IBS and associated with symptoms., Methods: Children (7-12 years of age) with IBS and healthy controls (HC) kept daily pain and stool diaries for 2 weeks. Stool samples were analyzed for chromogranins A and B (CgA, CgB) and secretogranins II and III (SgII, SgIII). Children also completed psychological measures to assess anxiety, depression, somatization, and internalizing symptoms., Key Results: Fecal CgB and SgIII concentrations were higher in all the boys (IBS plus HC, n = 48) than in all the girls (IBS plus HC, n = 75) (P = 0.02 and P = 0.046, respectively). CgA and SgIII were greater in children with IBS (n = 52) vs HC (n = 69) (P = 0.01, P = 0.017, respectively). CgB and SgII did not differ between groups. In children with IBS, the number of pain episodes per week and mean daily pain rating correlated positively with all four granins. The number of stools per day correlated positively with CgB and SgII, and the percent of diarrheal stools (6 or 7 on the Bristol Scale) correlated inversely with all four granins in boys but not in girls. Fecal granins did not correlate with psychological measures., Conclusions and Inferences: As measured by fecal granins, there is evidence of neuroimmune activation in children with IBS. Granins are related to abdominal pain symptoms, stooling frequency, and stool form in children with IBS. Sex influences the fecal concentration of CgB and SgIII., (© 2018 John Wiley & Sons Ltd.)

Altered fecal levels of chromogranins (Cg) and secretogranins (Sg) are demonstrated in irritable bowel syndrome (IBS), but their role in IBS pathophysiology remains unknown. This study aimed to determine if granins are associated with bacterial composition, immune activation and IBS symptoms. Protein levels of fecal granins (CgA, CgB, SgII and SgIII) were analysed with immunoassays. Mucosal mRNA expression of granins, TPH1 and immune markers were evaluated with RT-qPCR. 16S rRNA gene sequencing was performed on fecal and mucosal bacteria. The intestinal granin profile, based on fecal protein levels and mucosal mRNA expression, could not discriminate between IBS patients (n = 88) and healthy subjects (HS, n = 33). IBS patients dominated by high fecal or mucosal granin levels, respectively, did not differ in symptom or immune profiles. Fecal-dominated and mucosal-dominated granin clusters of IBS patients and HS, demonstrated separate fecal and mucosal bacterial profiles and high fecal abundance of granins were associated with a less diverse bacterial composition and the Bacteroides enterotype. The intestinal granin profiles of IBS patients and HS are linked to the intestinal bacterial composition, diversity and enterotypes. These findings suggest that granins may be one of several host-produced factors regulating the microbiota composition of the intestine.

Objectives: Secretoneurin directly influences cardiomyocyte calcium handling, and circulating secretoneurin levels seem to improve risk prediction in patients with myocardial dysfunction by integrating information on systemic stress, myocardial function, and renal function. Accordingly, in this study, we hypothesized that secretoneurin would improve risk prediction in patients with sepsis and especially in patients with septic shock as these patients are more hemodynamically unstable., Design: Multicenter, interventional randomized clinical trial., Setting: Multicenter, pragmatic, open-label, randomized, prospective clinical trial testing fluid administration with either 20% human albumin and crystalloids or crystalloid solutions alone in patients with severe sepsis or septic shock (The Albumin Italian Outcome Sepsis)., Patients or Subjects: In total, 540 patients with septic shock and 418 patients with severe sepsis., Interventions: Either 20% human albumin and crystalloids or crystalloid solutions alone., Measurements and Main Results: We measured secretoneurin on days 1, 2, and 7 after randomization and compared the prognostic value of secretoneurin for ICU and 90-day mortality with established risk indices and cardiac biomarkers in septic shock and severe sepsis. High secretoneurin levels on day 1 were associated with age and serum concentrations of lactate, bilirubin, creatinine, and N-terminal pro-B-type natriuretic peptide. Adjusting for established risk factors and cardiovascular biomarkers, secretoneurin levels on day 1 were associated with ICU (odds ratio, 2.27 [95% CI, 1.05-4.93]; p = 0.04) and 90-day mortality (2.04 [1.02-4.10]; p = 0.04) in patients with septic shock, but not severe sepsis without shock. Secretoneurin levels on day 2 were also associated with ICU (3.11 [1.34-7.20]; p = 0.008) and 90-day mortality (2.69 [1.26-5.78]; p = 0.01) in multivariate regression analyses and improved reclassification in patients with septic shock, as assessed by the net reclassification index. Randomized albumin administration did not influence the associations between secretoneurin and outcomes., Conclusions: Secretoneurin provides early and potent prognostic information in septic patients with cardiovascular instability.