Serum Protein Signatures Differentiating Autoimmune Pancreatitis versus Pancreatic Cancer

Autoimmune pancreatitis (AIP) is defined by characteristic lymphoplasmacytic infiltrate, ductal strictures and a pancreatic enlargement or mass that can mimic pancreatic cancer (PaCa). The distinction between this benign disease and pancreatic cancer can be challenging. However, an accurate diagnosis may pre-empt the misdiagnosis of cancer, allowing the appropriate medical treatment of AIP and, consequently, decreasing the number of unnecessary pancreatic resections.Mass spectrometry (MS) and two-dimensional differential gel electrophoresis (2D-DIGE) have been applied to analyse serum protein alterations associated with AIP and PaCa, and to identify protein signatures indicative of the diseases. Patients'' sera were immunodepleted from the 20 most prominent serum proteins prior to further 2D-DIGE and image analysis. The identity of the most-discriminatory proteins detected, was performed by MS and ELISAs were applied to confirm their expression. Serum profiling data analysis with 2D-DIGE revealed 39 protein peaks able to discriminate between AIP and PaCa. Proteins were purified and further analysed by MALDI-TOF-MS. Peptide mass fingerprinting led to identification of eleven proteins. Among them apolipoprotein A-I, apolipoprotein A-II, transthyretin, and tetranectin were identified and found as 3.0-, 3.5-, 2-, and 1.6-fold decreased in PaCa sera, respectively, whereas haptoglobin and apolipoprotein E were found to be 3.8- and 1.6-fold elevated in PaCa sera. With the exception of haptoglobin the ELISA results of the identified proteins confirmed the 2D-DIGE image analysis characteristics. Integration of the identified serum proteins as AIP markers may have considerable potential to provide additional information for the diagnosis of AIP to choose the appropriate treatment.     

Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors

NY-ESO-1 and LAGE-1 are cancer testis antigens with an ideal profile for tumor immunotherapy, combining up-regulation in many cancer types with highly restricted expression in normal tissues and sharing a common HLA-A*0201 epitope, 157–165. Here, we present data to describe the specificity and anti-tumor activity of a bifunctional ImmTAC, comprising a soluble, high-affinity T-cell receptor (TCR) specific for NY-ESO-1_157–165 fused to an anti-CD3 scFv. This reagent, ImmTAC-NYE, is shown to kill HLA-A2, antigen-positive tumor cell lines, and freshly isolated HLA-A2- and LAGE-1-positive NSCLC cells. Employing time-domain optical imaging, we demonstrate in vivo targeting of fluorescently labelled high-affinity NYESO-specific TCRs to HLA-A2-, NY-ESO-1_157–165-positive tumors in xenografted mice. In vivo ImmTAC-NYE efficacy was tested in a tumor model in which human lymphocytes were stably co-engrafted into NSG mice harboring tumor xenografts; efficacy was observed in both tumor prevention and established tumor models using a GFP fluorescence readout. Quantitative RT-PCR was used to analyze the expression of both NY-ESO-1 and LAGE-1 antigens in 15 normal tissues, 5 cancer cell lines, 10 NSCLC, and 10 ovarian cancer samples. Overall, LAGE-1 RNA was expressed at a greater frequency and at higher levels than NY-ESO-1 in the tumor samples. These data support the clinical utility of ImmTAC-NYE as an immunotherapeutic agent for a variety of cancers.     

Metal Concentrations in Cerebrospinal Fluid and Blood Plasma from Patients with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative disorder of motor neurons. The cause of this degeneration is unknown, and different causal hypotheses include genetic, viral, traumatic and environmental mechanisms. In this study, we have analyzed metal concentrations in cerebrospinal fluid (CSF) and blood plasma in a well-defined cohort (n?=?17) of ALS patients diagnosed with quantitative electromyography. Metal analyses were performed with high-resolution inductively coupled plasma mass spectrometry. Statistically significant higher concentrations of manganese, aluminium, cadmium, cobalt, copper, zinc, lead, vanadium and uranium were found in ALS CSF compared to control CSF. We also report higher concentrations of these metals in ALS CSF than in ALS blood plasma, which indicate mechanisms of accumulation, e.g. inward directed transport. A pattern of multiple toxic metals is seen in ALS CSF. The results support the hypothesis that metals with neurotoxic effects are involved in the pathogenesis of ALS.     

Determining Allocation: From Paper to Practice in the Distribution of Fishing Rights Between Countries

This article discusses the allocation problem in international fisheries management, which is critical to effective resource management. A number of cases where allocation problems exist are reviewed and trends identified. It is concluded that power relationships between the states involved are an important determinant of allocation outcomes. While this may seem a frustrating conclusion, it nevertheless reflects the realities of international cooperation.     

Individualized closed-loop control of propofol anesthesia: A preliminary study

This paper proposes an individualized approach to closed-loop control of depth of hypnosis during propofol anesthesia. The novelty of the paper lies in the individualization of the controller at the end of the induction phase of anesthesia, based on a patient model identified from the dose–response relationship during induction of anesthesia. The proposed approach is shown to be superior to administration of propofol based on population-based infusion schemes tailored to individual patients. This approach has the potential to outperform fully adaptive approaches in regards to controller robustness against measurement variability due to surgical stimulation. To streamline controller synthesis, two output filters were introduced (inverting the Hill dose–response model and the linear time-invariant sensor model), which yield a close-to-linear representation of the system dynamics when used with a compartmental patient model. These filters are especially useful during the induction phase of anesthesia in which a nonlinear dose–response relationship complicates the design of an appropriate controller. The proposed approach was evaluated in simulation on pharmacokinetic and pharmacodynamic models of 44 patients identified from real clinical data. A model of the NeuroSense, a hypnotic depth monitor based on wavelet analysis of EEG, was also included. This monitor is similar to the well-known BIS, but has linear time-invariant dynamics and does not introduce a delay. The proposed scheme was compared with a population-based controller, i.e. a controller only utilizing models based on demographic covariates for its tuning. On average, the proposed approach offered 25% improvement in disturbance attenuation, measured as the integrated absolute error following a step disturbance. The corresponding standard deviation from the reference was also decreased by 25%. Results are discussed and possible directions of future work are proposed.     

Risk of Inflammatory Bowel Disease According to Self-Rated Health,Pregnancy Course,and Pregnancy Complications: A Study within the Danish National Birth Cohort

Background

Poor self-rated health (SRH) has been connected to immunological changes, and pregnancy complications have been suggested in the etiology of autoimmune diseases including inflammatory bowel disease (IBD). We evaluated the impact of self-rated pre-pregnancy health and pregnancy course, hyperemesis, gestational hypertension, and preeclampsia on risk of IBD.

Methods

Information was collected by questionnaires from The Danish National Birth Cohort (enrolment 1996–2002) at 16^th and 30^th week of pregnancy and 6 months postpartum. A total of 55,699 women were followed from childbirth until development of IBD (using validated National Hospital Discharge Register diagnoses), emigration, death, or end of follow-up, 31^st of October, 2011. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards models adjusting for age and evaluating pre-pregnancy BMI, parity, alcohol and tobacco consumption, and socio-occupational status as potential confounders.

Results

Risk of IBD increased with decreasing level of self-rated pre-pregnancy health (p = 0.002) and was elevated in women with poor self-rated pregnancy course (HR, 1.61, 95% CI 1.22–2.12). Associations persisted for more than 5 years postpartum. Hyperemesis and preeclampsia were not significantly associated with risk of IBD.

Conclusions

This is the first prospective observational study to suggest that poor self-rated health – in general and in relation to pregnancy – is associated with increased risk of IBD even in the long term though results needs further confirmation. Symptoms of specific pregnancy complications were, on the other hand, not significantly associated with risk of IBD.     

Weight loss maintenance in severely obese adults after an intensive lifestyle intervention: 2- to 4-year follow-up

Objective: To evaluate the long‐term weight loss maintenance after 2 to 4 years in severely obese subjects after a lifestyle intervention at a weight loss camp in Denmark. Research Methods and Procedures: In a retrospective follow‐up study, we assessed weight loss after 21 weeks of treatment at a weight loss camp, weight loss maintenance after 2 to 4 years, and numbers of subjects with a weight loss maintenance of ≥10% of a total number of 435 severely obese adults participating in an intensive lifestyle intervention with a primary focus on physical activity. Results: We obtained follow‐up data of 249 subjects (180 women and 69 men) with an initial body weight of 142 ± 32 kg. After 21 weeks at the camp, the subjects had reduced their body weight with a mean of 21.9 ± 13 kg (corresponding to a 15% weight loss). The average weight loss maintenance was 5.3% at a follow‐up after 2 to 4 years, and 28.3% had maintained a weight loss above 10% after 4 years of follow‐up. Discussion: Weight loss camps are a relatively new commercial approach in treating severely obese subjects. However, the results demonstrate that even with a multidisciplinary intensive setting with focus on diet, exercise, and psychological counseling, only 28% had maintained a weight loss above 10% after 4 years. This emphasizes that obesity is a chronic condition that needs additional strategies after a weight loss intervention in the efforts to maintain a sufficient weight loss.     

Food Size Spectra and Species Replacement within Herbivorous Zooplankton

The relationship between two commonly co-occurring filter-feeders; Bosmina longirostris and Eudiaptomus gracilis at different nutrient levels, was investigated in bag experiments in Lake Gjersjøen. At the start of the experiment, the numerical relationship between Bosmina and Eudiaptomus was less than 1 : 10, but during the experimental period, a strong increase in Bosmina and a corresponding decrease in Eudiaptomus and medium-sized algae (5–25 μm) was observed. The shift from Eudiaptomus to Bosmina was probably due to strong competition on mediumsized algae while Bosmina in addition may utilize smaller algae and bacteria, not available to Eudiaptomus. Their coexistence in the lake at much lower densities is probably due to a strong selective fish predation, suppressing Bosmina. Daphnia longispina, not naturally occurring in the lake, showed strong competitive abilities in a fish-free bag.     

Are doping tests in sports trustworthy?: Athletes suffer from insufficiently defined criteria for doping tests

The lack of clearly defined criteria for doping tests carries a great risk of punishing innocent athletes and undermines the fight against doping in international sports. Subject Categories: Economics, Law & Politics, Methods & Resources

The World Anti‐Doping Agency (WADA) uses analytic, science‐based methods to detect doping, but it does not always adhere to scientific principles when it evaluates the results from their tests. The criteria for determining whether a sample is positive for an illegal substance often appear to be ambiguous with the risk of rendering evaluations subjective. Statements from WADA laboratories such as “you need to be an expert to clearly identify it” and “we know it when we see it” indicate such subjectivity. Subjective evaluations are troublesome because they erode the trust in WADA’s fight against doping, and have potentially dramatic consequences for athletes.