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1.  Ovary ecdysteroidogenic hormone functions independently of the insulin receptor in the yellow fever mosquito, Aedes aegypti 
Insect biochemistry and molecular biology  2013;43(12):10.1016/j.ibmb.2013.09.004.
Most mosquito species must feed on the blood of a vertebrate host to produce eggs. In the yellow fever mosquito, Aedes aegypti, blood feeding triggers medial neurosecretory cells in the brain to release insulin-like peptides (ILPs) and ovary ecdysteroidogenic hormone (OEH). Theses hormones thereafter directly induce the ovaries to produce ecdysteroid hormone (ECD), which activates the synthesis of yolk proteins in the fat body for uptake by oocytes. ILP3 stimulates ECD production by binding to the mosquito insulin receptor (MIR). In contrast, little is known about the mode of action of OEH, which is a member of a neuropeptide family called neuroparsin. Here we report that OEH is the only neuroparsin family member present in the Ae. aegypti genome and that other mosquitoes also encode only one neuroparsin gene. Immunoblotting experiments suggested that the full-length form of the peptide, which we call long OEH (lOEH), is processed into short OEH (sOEH). The importance of processing, however, remained unclear because a recombinant form of lOEH (rlOEH) and synthetic sOEH exhibited very similar biological activity. A series of experiments indicated that neither rlOEH nor sOEH bound to ILP3 or the MIR. Signaling studies further showed that ILP3 activated the MIR but rlOEH did not, yet both neuropeptides activated Akt, which is a marker for insulin pathway signaling. Our results also indicated that activation of TOR signaling in the ovaries required co-stimulation by amino acids and either ILP3 or rlOEH. Overall, we conclude that OEH activates the insulin signaling pathway independently of the MIR, and that insulin and TOR signaling in the ovaries is coupled.
doi:10.1016/j.ibmb.2013.09.004
PMCID: PMC3885182  PMID: 24076067
2.  Pancreatic stone protein (PSP) and pancreatitis-associated protein (PAP): a protocol of a cohort study on the diagnostic efficacy and prognostic value of PSP and PAP as postoperative markers of septic complications in patients undergoing abdominal surgery (PSP study) 
BMJ Open  2014;4(3):e004914.
Introduction
Major abdominal surgery leads to a postoperative systemic inflammatory response, making it difficult to discriminate patients with systemic inflammatory response syndrome from those with a beginning postoperative infectious complication. At present, physicians have to rely on their clinical experience to differentiate between the two. Pancreatic stone protein (PSP) and pancreatitis-associated protein (PAP), both secretory proteins produced by the pancreas, are dramatically increased during pancreatic disease and have been shown to act as acute-phase proteins. Increased levels of PSP have been detected in polytrauma patients developing sepsis and PSP has shown a high diagnostic accuracy in discriminating the severity of peritonitis and in predicting death in intensive care unit patients. However, the prognostic value of PSP/PAP for infectious complications among patients undergoing major abdominal surgery is unknown.
Methods and analysis
160 patients undergoing major abdominal surgery will be recruited preoperatively. On the day before surgery, baseline blood values are attained. Following surgery, daily blood samples for measuring regular inflammatory markers (c-reactive protein, procalcitonin, interleukin-6, tumour necrosis factor-α and leucocyte counts) and PSP/PAP will be acquired. PSP/PAP will be measured using a validated ELISA developed in our research laboratory. Patient's discharge marks the end of his/her trial participation. Complication grade including mortality and occurrence of infectious postoperative complications according to validated diagnostic criteria will be correlated with PSP/PAP values. Total intensive care unit days and total length of stay will be recorded as further outcome parameters.
Ethics and dissemination
The PSP trial is a prospective monocentric cohort study evaluating the prognostic value of PSP and PAP for postoperative infectious complications. In addition, a comparison with established inflammatory markers in patients undergoing major abdominal surgery will be performed to help evaluate the role of these proteins in predicting and diagnosing infectious and other postoperative complications.
Institution ethics board approval ID
KEKZH-Nr. STV 11-2009.
Trial registration
ClinicalTrials.gov: NCT01258179.
doi:10.1136/bmjopen-2014-004914
PMCID: PMC3948573  PMID: 24604486
3.  Effects of hepatocyte nuclear factor-1A and -4A on pancreatic stone protein/regenerating protein and C-reactive protein gene expression: implications for maturity-onset diabetes of the young 
Background
There is a significant clinical overlap between patients with hepatocyte nuclear factor (HNF)-1A and HNF4A maturity-onset diabetes of the young (MODY), two forms of monogenic diabetes. HNF1A and HNF4A are transcription factors that control common and partly overlapping sets of target genes. We have previously shown that elevated serum pancreatic stone protein / regenerating protein A (PSP/reg1A) levels can be detected in subjects with HNF1A-MODY. In this study, we investigated whether PSP/reg is differentially regulated by HNF1A and HNF4A.
Methods
Quantitative real-time PCR (qPCR) and Western blotting were used to validate gene and protein expression in cellular models of HNF1A- and HNF4A-MODY. Serum PSP/reg1A levels and high-sensitivity C-reactive protein (hsCRP) were measured by ELISA in 31 HNF1A- and 9 HNF4A-MODY subjects. The two groups were matched for age, body mass index, diabetes duration, blood pressure, lipid profile and aspirin and statin use.
Results
Inducible repression of HNF1A and HNF4A function in INS-1 cells suggested that PSP/reg induction required HNF4A, but not HNF1A. In contrast, crp gene expression was significantly reduced by repression of HNF1A, but not HNF4A function. PSP/reg levels were significantly lower in HNF4A subjects when compared to HNF1A subjects [9.25 (7.85-12.85) ng/ml vs. 12.5 (10.61-17.87) ng/ml, U-test P = 0.025]. hsCRP levels were significantly lower in HNF1A-MODY [0.22 (0.17-0.35) mg/L] compared to HNF4A-MODY group [0.81 (0.38-1.41) mg/L, U-test P = 0.002], Parallel measurements of serum PSP/reg1A and hsCRP levels were able to discriminate HNF1A- and HNF4A-MODY subjects.
Conclusion
Our study demonstrates that two distinct target genes, PSP/reg and crp, are differentially regulated by HNF1A and HNF4A, and provides clinical proof-of-concept that serum PSP/reg1A and hsCRP levels may distinguish HNF1A-MODY from HNF4A-MODY subjects.
doi:10.1186/1479-5876-11-156
PMCID: PMC3707779  PMID: 23803251
HNF1A; HNF4A; MODY; PSP/reg; HsCRP; Gene regulation
4.  Sepsis biomarkers in unselected patients on admission to intensive or high-dependency care 
Critical Care  2013;17(2):R60.
Introduction
Although many sepsis biomarkers have shown promise in selected patient groups, only C-reactive protein and procalcitonin (PCT) have entered clinical practice. The aim of this study was to evaluate three promising novel sepsis biomarkers in unselected patients at admission to intensive care. We assessed the performance of pancreatic stone protein (PSP), soluble CD25 (sCD25) and heparin binding protein (HBP) in distinguishing patients with sepsis from those with a non-infective systemic inflammatory response and the ability of these markers to indicate severity of illness.
Methods
Plasma levels of the biomarkers, PCT and selected inflammatory cytokines were measured in samples taken from 219 patients during the first six hours of admission to intensive or high dependency care. Patients with a systemic inflammatory response were categorized as having sepsis or a non-infective aetiology, with or without markers of severity, using standard diagnostic criteria.
Results
Both PSP and sCD25 performed well as biomarkers of sepsis irrespective of severity of illness. For both markers the area under the receiver operating curve (AUC) was greater than 0.9; PSP 0.927 (0.887 to 0.968) and sCD25 0.902 (0.854 to 0.949). Procalcitonin and IL6 also performed well as markers of sepsis whilst in this intensive care unit (ICU) population, HBP did not: PCT 0.840 (0.778 to 0.901), IL6 0.805 (0.739 to 0.870) and HBP 0.607 (0.519 to 0.694). Levels of both PSP and PCT reflected severity of illness and both markers performed well in differentiating patients with severe sepsis from severely ill patients with a non-infective systemic inflammatory response: AUCs 0.955 (0.909 to 1) and 0.837 (0.732 to 0.941) respectively. Although levels of sCD25 did not correlate with severity, the addition of sCD25 to either PCT or PSP in a multivariate model improved the diagnostic accuracy of either marker alone.
Conclusions
PSP and sCD25 perform well as sepsis biomarkers in patients with suspected sepsis at the time of admission to intensive or high dependency care. These markers warrant further assessment of their prognostic value. Whereas previously published data indicate HBP has clinical utility in the emergency department, it did not perform well in an intensive-care population.
doi:10.1186/cc12588
PMCID: PMC3672658  PMID: 23531337
5.  The value of pancreatic stone protein in predicting acute appendicitis in patients presenting at the emergency department with abdominal pain 
BMC Gastroenterology  2012;12:154.
Background
Pancreatic Stone Protein (PSP) is a protein naturally produced mainly in the pancreas and the gut. There is evidence from experimental and clinical trials that blood PSP levels rise in the presence of inflammation or infection. However, it is not known whether PSP is superior to other established blood tests (e.g. White Blood Count, Neutrophils or C - reactive protein) in predicting appendicitis in patients presenting with abdominal pain and a clinical suspicion of appendicitis at the emergency room.
Methods/design
The PSP Appendix Trial is a prospective, multi-center, cohort study to assess the value of PSP in the diagnostic workup of acute appendicitis. 245 patients will be prospectively recruited. Interim analysis will be performed once 123 patients are recruited. The primary endpoint of the study concerns the diagnostic accuracy of PSP in predicting acute appendicitis and therefore the evidence of appendicitis on the histopathological specimen after appendectomy.
Discussion
The PSP Appendix Trial is a prospective, multi-center, cohort study to assess the value of PSP in the diagnostic workup of acute appendicitis.
Trial registration
ClinicalTrials.gov: NCT01610193; Institution Ethical Board Approval ID: KEKZH- Nr. 2011–0501
doi:10.1186/1471-230X-12-154
PMCID: PMC3503734  PMID: 23098130
PSP; Pancreatic stone protein; Acute appendicitis; Abdominal pain
6.  Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward 
Background
Mutations in the transcription factor hepatocyte nuclear factor-1-alpha (HNF1A) result in the commonest type of maturity onset diabetes of the young (MODY). HNF1A-MODY carriers have reduced pancreatic beta cell mass, partially due to an increased rate of apoptosis. To date, it has not been possible to determine when apoptosis is occurring in HNF1A-MODY.We have recently demonstrated that beta cell apoptosis stimulates the expression of the pancreatic stone protein/regenerating (PSP/reg) gene in surviving neighbour cells, and that PSP/reg1A protein is subsequently secreted from these cells. The objective of this study was to determine whether serum levels of PSP/reg1A are elevated during disease progression in HNF1A-MODY carriers, and whether it may provide information regarding the onset of beta-cell apoptosis.
Methods
We analysed serum PSP/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY), and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed.
Results
PSP/reg1A serum levels were significantly elevated in HNF1A-MODY (n = 37) subjects compared to controls (n = 60) (median = 12.50 ng/ml, IQR = 10.61-17.87 ng/ml versus median = 10.72 ng/ml, IQR = 8.94-12.54 ng/ml, p = 0.0008). PSP/reg1A correlated negatively with insulin levels during OGTT, (rho = −0.40, p = 0.02). Interestingly we noted a significant positive correlation of PSP/reg1A with age of the HNF1A-MODY carriers (rho = 0.40 p = 0.02) with an age of 25 years separating carriers with low and high PSP/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP/reg1A compared to controls, however this was independent of the duration of diabetes.
Conclusion
Our data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25 years and over. PSP/reg1A may be developed as a serum marker to detect increased beta-cell apoptosis, or its therapeutic response.
doi:10.1186/1472-6823-12-13
PMCID: PMC3433346  PMID: 22808921
Maturity onset diabetes of the young (MODY); Apoptosis; Serum biomarker; Beta-Cell; Type 1 diabetes; Pancreatic stone protein (PSP); Regenerating gene 1A (reg1A)
7.  Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management 
Critical Care  2012;16(4):R114.
Introduction
Biomarkers, such as C-reactive protein [CRP] and procalcitonin [PCT], are insufficiently sensitive or specific to stratify patients with sepsis. We investigate the prognostic value of pancreatic stone protein/regenerating protein (PSP/reg) concentration in patients with severe infections.
Methods
PSP/reg, CRP, PCT, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL1-β), IL-6 and IL-8 were prospectively measured in cohort of patients ≥ 18 years of age with severe sepsis or septic shock within 24 hours of admission in a medico-surgical intensive care unit (ICU) of a community and referral university hospital, and the ability to predict in-hospital mortality was determined.
Results
We evaluated 107 patients, 33 with severe sepsis and 74 with septic shock, with in-hospital mortality rates of 6% (2/33) and 25% (17/74), respectively. Plasma concentrations of PSP/reg (343.5 vs. 73.5 ng/ml, P < 0.001), PCT (39.3 vs. 12.0 ng/ml, P < 0.001), IL-8 (682 vs. 184 ng/ml, P < 0.001) and IL-6 (1955 vs. 544 pg/ml, P < 0.01) were significantly higher in patients with septic shock than with severe sepsis. Of note, median PSP/reg was 13.0 ng/ml (IQR: 4.8) in 20 severely burned patients without infection. The area under the ROC curve for PSP/reg (0.65 [95% CI: 0.51 to 0.80]) was higher than for CRP (0.44 [0.29 to 0.60]), PCT 0.46 [0.29 to 0.61]), IL-8 (0.61 [0.43 to 0.77]) or IL-6 (0.59 [0.44 to 0.75]) in predicting in-hospital mortality. In patients with septic shock, PSP/reg was the only biomarker associated with in-hospital mortality (P = 0.049). Risk of mortality increased continuously for each ascending quartile of PSP/reg.
Conclusions
Measurement of PSP/reg concentration within 24 hours of ICU admission may predict in-hospital mortality in patients with septic shock, identifying patients who may benefit most from tailored ICU management.
doi:10.1186/cc11406
PMCID: PMC3580689  PMID: 22748193
8.  Perception of surgical complications among patients, nurses and physicians: a prospective cross-sectional survey 
Background
Several scores grade the severity of post-operative complications but it is unclear whether such scores truly reflect the perception of patients and practicing nurses and physicians.
Study Design
227 patients, 143 nurses and 245 physicians independently rated the severity of 30 common post-operative complications on a numerical analogue scale from 0 (not severe at all) to 100 (extremely severe) while being blinded towards the Clavien-Dindo classification. We considered a difference in ratings of >10 to be clinically important in distinguishing between grades of severity and groups. We evaluated the level of reproducibility of responses by calculating intraclass correlation coefficients (ICC) and compared scores across severity grades and between groups using the generalized estimating equations.
Results
Reproducibility of the ratings was good for all three groups (ICCpatients 0.71 (95%-CI 0.64-0.76), ICCnurses 0.83 (0.78-0.87) and ICCphysicians 0.87 (0.83-0.90)). The participants' perceptions of the severity of complications reflected the Clavien-Dindo classification (median of grade I: 20 (IQR 10-30), grade II: 40 (31.3-52.5), grade IIIa: 50 (40-60), grade IIIb: 70 (60-75), grade IVa: 85 (80-90) and grade IVB: 95 (90-100)). Although patients' perception differed significantly from those of physicians (average difference -8.7 (95%-CI -10.4 to -6.9, p < 0.001) and nurses (difference -2.8 (-4.8 to -0.8, p = 0.007) they did not reach our thresholds for clinical importance.
Conclusions
The severity of post-operative complications is perceived similarly by patients, nurses and physicians and reflects the Clavien-Dindo classification well. Our results support the use of Clavien-Dindo classification system as part of the shared or informed decision making process.
doi:10.1186/1754-9493-5-30
PMCID: PMC3284430  PMID: 22107603
Perception; surgical complications; patients; nurses and physicians
9.  INS-1 Cells Undergoing Caspase-Dependent Apoptosis Enhance the Regenerative Capacity of Neighboring Cells 
Diabetes  2010;59(11):2799-2808.
OBJECTIVE
In diabetes, β-cell mass is not static but in a constant process of cell death and renewal. Inactivating mutations in transcription factor 1 (tcf-1)/hepatocyte nuclear factor1a (hnf1a) result in decreased β-cell mass and HNF1A–maturity onset diabetes of the young (HNF1A-MODY). Here, we investigated the effect of a dominant-negative HNF1A mutant (DN-HNF1A) induced apoptosis on the regenerative capacity of INS-1 cells.
RESEARCH DESIGN AND METHODS
DN-HNF1A was expressed in INS-1 cells using a reverse tetracycline-dependent transactivator system. Gene(s)/protein(s) involved in β-cell regeneration were investigated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Pancreatic stone protein/regenerating protein (PSP/reg) serum levels in human subjects were detected by enzyme-linked immunosorbent assay.
RESULTS
We detected a prominent induction of PSP/reg at the gene and protein level during DN-HNF1A–induced apoptosis. Elevated PSP/reg levels were also detected in islets of transgenic HNF1A-MODY mice and in the serum of HNF1A-MODY patients. The induction of PSP/reg was glucose dependent and mediated by caspase activation during apoptosis. Interestingly, the supernatant from DN-HNF1A–expressing cells, but not DN-HNF1A–expressing cells treated with zVAD.fmk, was sufficient to induce PSP/reg gene expression and increase cell proliferation in naïve, untreated INS-1 cells. Further experiments demonstrated that annexin-V–positive microparticles originating from apoptosing INS-1 cells mediated the induction of PSP/reg. Treatment with recombinant PSP/reg reversed the phenotype of DN-HNF1A–induced cells by stimulating cell proliferation and increasing insulin gene expression.
CONCLUSIONS
Our results suggest that apoptosing INS-1 cells shed microparticles that may stimulate PSP/reg induction in neighboring cells, a mechanism that may facilitate the recovery of β-cell mass in HNF1A-MODY.
doi:10.2337/db09-1478
PMCID: PMC2963538  PMID: 20682686
10.  Caerulein-induced acute pancreatitis in mice that constitutively overexpress Reg/PAP genes 
BMC Gastroenterology  2006;6:16.
Background
The cystic fibrosis (CF) mouse pancreas has constitutively elevated expression of the Reg/PAP cell stress genes (60-fold greater Reg3α, and 10-fold greater PAP/Reg3β and Reg3γ). These genes are suggested to be involved in protection or recovery from pancreatic injury.
Methods
To test this idea the supramaximal caerulein model was used to induce acute pancreatitis in wild type and CF mice. Serum amylase, pancreatic water content (as a measure of edema), pancreatic myeloperoxidase activity, and Reg/PAP expression were quantified.
Results
In both wild type and CF mice caerulein induced similar elevations in serum amylase (maximal at 12 h), pancreatic edema (maximal at 7 h), and pancreatic myeloperoxidase activity (MPO, a marker of neutrophil infiltration; maximal at 7 h). By immunohistochemistry, Reg3α was strongly expressed in the untreated CF pancreas but not in wild type. During pancreatitis, Reg3α was intensely expressed in foci of inflamed tissue in both wild type and CF.
Conclusion
These data demonstrate that the severity of caerulein-induced pancreatitis is not ameliorated in the CF mouse even though the Reg/PAP stress genes are already highly upregulated. While Reg/PAP may be protective they may also have a negative effect during pancreatitis due to their anti-apoptotic activity, which has been shown to increase the severity of pancreatitis.
doi:10.1186/1471-230X-6-16
PMCID: PMC1479353  PMID: 16700916

Results 1-10 (10)