Proteombasierte diagnostische und prognostische Biomarker beim Prostatakarzinom

Background

Due to comprehensive PSA screening, the incidence for prostate cancer (PCa) is rising. Therefore, there is an urgent need for improved PCa diagnostics and prognostic tools to differentiate between insignificant and aggressive, fast growing tumors.

Methods

With the proteome-based method presented here, we were able to distinguish PCa from BPH, chronic prostatitis and healthy controls with 83?% sensitivity and 67?% specificity. Furthermore, the methods discerned advanced PCa from local, organ-confined PCa in a group of patients with gleason score 7 (80?% sensitivity, 82?% specificity).

Results

Our proteomic approach is based on the analysis of low molecular weight polypeptides, identified as the endpoint of the naturally occuring liquefaction cascade in seminal plasma. For the first time using seminal plasma as a source, we analysed a complex network of interacting proteases and specific inhibitors, reflecting tumor biology specificity. Our diagnostic and prognostic tool is robust and easy to handle, and therefore it is well suitable for the laboratory and medical practice.     

Structural Brain Alterations Associated With Schizophrenia Preceded by Conduct Disorder: A Common and Distinct Subtype of Schizophrenia?

Conduct disorder (CD) prior to age 15 is a precursor of schizophrenia in a minority of cases and is associated with violent behavior through adulthood, after taking account of substance misuse. The present study used structural magnetic imaging to examine gray matter (GM) volumes among 27 men with schizophrenia preceded by CD (SZ+CD), 23 men with schizophrenia but without CD (SZ–CD), 27 men with CD only (CD), and 25 healthy (H) men. The groups with schizophrenia were similar in terms of age of onset and duration of illness, levels of psychotic symptoms, and medication. The 2 groups with CD were similar as to number of CD symptoms, lifelong aggressive behavior, and number of criminal convictions. Men with SZ+CD, relative to those with SZ–CD, displayed (1) increased GM volumes in the hypothalamus, the left putamen, the right cuneus/precuneus, and the right inferior parietal cortex after controlling for age, alcohol, and drug misuse and (2) decreased GM volumes in the inferior frontal region. Men with SZ+CD (relative to the SZ–CD group) and CD (relative to the H group) displayed increased GM volumes of the hypothalamus and the inferior and superior parietal lobes, which were not associated with substance misuse. Aggressive behavior, both prior to age 15 and lifetime tendency, was positively correlated with the GM volume of the hypothalamus. Thus, among males, SZ+CD represents a distinct subtype of schizophrenia. Although differences in behavior emerge in childhood and remain stable through adulthood, further research is needed to determine whether the differences in GM volumes result from abnormal neural development distinct from that of other males developing schizophrenia.Key words: conduct problems, antisocial behavior, violence, structural brain alterationsMany years ago, Lee Robins found that conduct disorder (CD) was a precursor of schizophrenia ¹ and later confirmed this finding. ^{2 , 3} Subsequent evidence concurs. For example, a prospective investigation that followed a birth cohort to age 26 determined that 40% of the cohort members who developed schizophreniform disorders had displayed CD prior to age 15. ⁴ The CD modules of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental (DSM) disorders (fourth edition, DSM-IV), SCID in short, were designed to diagnose CD prior to age 15 among adults. ⁵ Several studies have used this interview protocol, some supplementing self-reports with information from family members, school, social service, and justice files, to diagnose CD among adults with schizophrenia. Among men and women with schizophrenia in general psychiatric services, the prevalence of CD prior to age 15 ranged from 20% to 45%, ^{6 , 7} with higher rates in samples recruited from forensic hospitals and correctional facilities. ⁶ CD is a precursor of schizophrenia, and it is more common among people with schizophrenia than in the general population. ⁶ Among people with schizophrenia, CD prior to age 15 continues to be associated with antisocial and violent behavior through adult life after taking account of past and current substance misuse. ^6–12 Among people with schizophrenia, ^{10 , 13–17} as in the general population, ^18–20 those who present CD in childhood commit a disproportionate number of violent crimes. While some studies show that positive symptoms are associated with aggressive behavior even after taking account of CD, ²¹ those with CD are not distinguished from other patients with schizophrenia by profiles of positive and negative symptoms. ²² Prospective investigations show that adults with schizophrenia and prior CD (SZ+CD) displayed aggressive behavior, psychotic-like experiences as children, ²³ and poor academic achievement. ²⁴ Retrospective studies report that adults with SZ+CD, as compared to those with SZ–CD, obtained lower-than-average marks in elementary school, failed to graduate from secondary school, abused substances in adolescence, and experienced physical abuse. ^{6 , 24–27} Criminality and substance misuse are elevated among fathers and brothers of men with SZ+CD, whereas rates of mental illness are similar to that found among patients with SZ–CD. ^{6 , 27 , 28} Among the non–mentally ill men, a small group present CD from an early age, persistent antisocial and aggressive behavior through adulthood, and abnormalities in brain structure relative to healthy men. ^29–37 Results of structural magnetic resonance imaging studies (sMRI) measuring gray matter (GM) volumes are inconsistent regarding the type (larger or smaller) and regions of abnormality. ^{32 , 35–37} Among men with SZ+CD, however, there no studies. ^{38 , 39} A few studies of brain structure have been conducted among men with schizophrenia who display different ages of onset and patterns of aggressive behavior, including persistent aggressive behavior and poor response to antipsychotic medication, no previous aggressive behavior and 1 violent offence, no aggressive behavior prior to onset followed by persistent aggression, and finally the largest group comprising those who show conduct problems from childhood that persist across their life span. The extant literature is limited and difficult to aggregate, but it does suggest differences specific to each pattern of violent behavior. ^38–43 Two studies examined male offenders with schizophrenia: one compared those with and without comorbid antisocial personality disorder (ASPD), which requires, by definition, CD prior to age 15; ⁴⁴ and another compared those with and without high psychopathy scores. ⁴⁵ Both included small samples and reported fewer neuropsychological deficits among the antisocial participants in tests tapping the dorsolateral prefrontal and the orbital frontal cortex (OFC) functions. ³⁸ A recent meta-analysis reported that among persons with schizophrenia, those defined very broadly as antisocial, as compared to the nonantisocial, were characterized by lower intelligence quotients (IQs) and memory dysfunction, whereas compared to non–mentally ill antisocial participants, they exhibited deficits in IQ, attention, executive function, and memory. ⁴⁶ Among patients with schizophrenia, scores on the Life History of Aggression (LHA) measure were associated with increased diffusivity in the inferior frontal white matter and lower functional connectivity between the amygdala and the ventral prefrontal cortex. ³⁹ Diffusivity has been associated with increased cerebrospinal fluid (CSF). ⁴⁷ Functional MRI (fMRI) studies of violent offenders with schizophrenia observed decreased frontal basal activation during a Go/NoGo task, increased activity in the motor, premotor, and anterior cingulate regions among those with ASPD, ⁴⁸ and attenuated amygdala activation to fearful faces among those with high psychopathy scores. ⁴⁹ Thus, among men with schizophrenia, at least one in five people presents CD prior to age 15 and persistent antisocial and aggressive behavior. Identifying distinctive subtypes of schizophrenia may facilitate etiological research ⁵⁰ and inform the development of effective treatments for both the illness and the antisocial and aggressive behavior. ⁵¹ Both schizophrenia ⁵² and CD ^{53 , 54} are neurodevelopmental disorders. In both disorders, from conception onwards, combinations of genes, in addition and in interaction with environmental events, are thought to modify brain structure and function. Thus, we reasoned that when schizophrenia develops in parallel with CD, neurodevelopment would be distinct from both that associated with schizophrenia and that associated with CD. We hypothesized that in adulthood, men with SZ+CD would show cognitive and structural brain abnormalities relative to healthy men, and both similarities and differences relative to men with SZ–CD and those with CD and no mental illness.Almost all persons with childhood onset of CD and persistence of antisocial and aggressive behavior in adulthood also display childhood onset and persistent pattern of substance misuse. ^55–57 This is true among those with and without schizophrenia. ^{22 , 26–28} Although substance misuse is an integral part of a heritable pattern of lifelong antisocial behavior, ⁵⁸ disentangling the cognitive and structural abnormalities consequent to substance use from those associated with persistent antisocial and aggressive behavior is necessary to understand the mechanisms underlying these behaviors. However, neither statistical controls nor studying groups of antisocial persons without substance misuse provide an ideal solution to this problem. ⁵⁹ Further, prospective studies indicate that heavy cannabis use in adolescence may play a causal role in schizophrenia ^{60 , 61} by altering brain development, ^{62 , 63} and 1 study has shown that among persons experiencing a first episode of psychosis, CD increased the likelihood of cannabis use before age 14. ⁶⁴ In addition, histories of substance misuse that can be obtained from middle-aged adults are imprecise measures of different phenomena—past and current use by type, combinations, and doses of substances. This led us to obtain careful histories of use of substances and to statistically control for group differences in use.Four groups of men, with SZ+CD, SZ–CD, CD, and no schizophrenia or history of CD (H), were compared on sociodemographic, clinical, and forensic characteristics, and their GM brain volumes were assessed using sMRI.     

Prioritization of livestock transboundary diseases in Belgium using a multicriteria decision analysis tool based on drivers of emergence

During the past decade, livestock diseases have (re‐)emerged in areas where they had been previously eradicated or never been recorded before. Drivers (i.e. factors of (re‐)emergence) have been identified. Livestock diseases spread irrespective of borders, and therefore, reliable methods are required to help decision‐makers to identify potential threats and try stopping their (re‐)emergence. Ranking methods and multicriteria approaches are cost‐effective tools for such purpose and were applied to prioritize a list of selected diseases (N = 29 including 6 zoonoses) based on the opinion of 62 experts in accordance with 50 drivers‐related criteria. Diseases appearing in the upper ranking were porcine epidemic diarrhoea, foot‐and‐mouth disease, low pathogenic avian influenza, African horse sickness and highly pathogenic avian influenza. The tool proposed uses a multicriteria decision analysis approach to prioritize pathogens according to drivers and can be applied to other countries or diseases.     

Molecular diagnosis of kidney transplant failure based on urine

In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor’s disease of oral‐facial‐digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next‐generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long‐term outcome was enabled for 5 recipients.     

Massive blood transfusion after the first cut in liver transplantation predicts renal outcome and survival

Introduction

Transfusion requirements of blood products may provide useful prognostic factors for the prediction of short-term patient mortality and renal outcome after liver transplantation.

Patients and methods

Two hundred ninety-one consecutive liver transplants in adults were analysed retrospectively. Combined and living-related liver transplants were excluded. The amount of transfused packed red blood cells (PRBC) and units of platelets (UP) within the first 48 h were investigated as prognostic factors to predict short-term patient mortality and renal outcome. Receiver operating characteristic (ROC) curve analysis with area under the curve (AUC), Hosmer-Lemeshow tests and Brier scores were used to calculate overall model correctness, model calibration and accuracy of prognostic factors. Cut-off values were determined with the best Youden index.

Results

The potential clinical usefulness of PRBC as a prognostic factor to predict 30-day mortality (cut-off 17.5 units) and post-transplant haemodialysis (cut-off 12.5 units) could be demonstrated with AUCs >0.7 (0.712 and 0.794, respectively). Hosmer-Lemeshow test results and Brier scores indicated good overall model correctness, model calibration and accuracy. The UP proved as an equally clinically useful prognostic factor to predict end-stage renal disease (cut-off 3.5 units; AUC?=?0.763). The association of cut-off levels of PRBC with patient survival (p?<?0.001, log-rank test) and dialysis-free survival (p?<?0.001, log-rank test) was significant (cut-off levels 17.5 and 12.5 units, respectively) as well as the association of UP with dialysis-free survival (p?<?0.001, log-rank test) (cut-off level 3.5 units).

Conclusions

The impressive discriminative power of these simple prognostic factors for the prediction of outcome after liver transplantation emphasizes the relevance of strategies to avoid excessive transfusion requirements.     

Expression of hybrid class I genes of the major histocompatibility complex in mouse L cells.

The class I genes of the major histocompatibility complex of the mouse can be divided into two categories: those encoding the transplantation antigens and those encoding the Qa and Tla antigens. The inbred BALB/c mouse has 28 potential Qa/Tla genes. The sites of tissue expression, developmental regulation, and functions of these genes are virtually unknown. We have used the technique of exon shuffling to construct hybrid genes between each of three Qa region genes (Q5, Q7, and Q8) and two other class I genes (H-2Ld and Q6). The hybrid genes have been transfected into mouse L cells, in which intact transplantation antigen genes generally are expressed and in which intact Qa genes generally are not expressed. Analysis of expression of the hybrid gene constructs indicates that the 5' half of two of the Qa genes (Q5 and Q8) can readily be expressed in the context of a hybrid molecule, whereas the 3' half prevents cell-surface expression. The exon shuffling approach described here will be useful in characterizing Qa/Tla genes and in identifying or producing new reagents to study the Qa/Tla gene products, their tissue distribution, their developmental stages of expression, and, ultimately, their functions.     

Oral supplementation with physiological doses of leptin during lactation in rats improves insulin sensitivity and affects food preferences later in life

We have previously described that neonate rats supplemented with physiological doses of oral leptin during lactation become more protected against overweight in adulthood. The purpose of this study was to characterize further the long-term effects on glucose and leptin homeostasis and on food preferences. Neonate rats were supplemented during lactation with a daily oral dose of leptin or the vehicle. We followed body weight and food intake of animals until the age of 15 months, and measured glucose, insulin, and leptin levels under different feeding conditions: ad libitum feeding, 14-h fasting, and 3-h refeeding after fasting. An oral glucose tolerance test and a leptin resistance test were performed. Food preferences were also measured. Leptin-treated animals were found to have lower body weight in adulthood and to eat fewer calories than their controls. Plasma insulin levels were lower in leptin-treated animals than in their controls under the different feeding conditions, as was the increase in insulin levels after food intake. The homeostatic model assessment for insulin resistance index was significantly lower in leptin-treated animals, and the oral glucose tolerance test also indicated higher insulin sensitivity in leptin-treated animals. In addition, these animals displayed lower plasma leptin levels under the different feeding conditions and were also more responsive to exogenous leptin administration. Leptin-treated animals also showed a lower preference for fat-rich food than their controls. These observations indicate that animals supplemented with physiological doses of oral leptin during lactation were more protected against obesity and metabolic features of the metabolic syndrome.     

High-dose intravenous gammaglobulin in alloimmunized platelet transfusion recipients

High-dose intravenous gammaglobulin (polyvalent immunoglobulin G) has been shown to be of benefit in some patients with immune thrombocytopenic purpura (ITP), possibly by producing reticuloendothelial system blockade. We studied this approach in patients refractory to random donor platelet transfusion using an IV IgG preparation manufactured by the Swiss Red Cross. Eleven adult patients with acute leukemia received either 0.4 g IgG/kg/d intravenously X five days (four patients) or 0.6 g/kg/d X five days (seven patients). All patients had high levels of lymphocytotoxic antibody and poor responses to random donor platelets. Except for mild headaches in two patients, there were no side effects related to the IgG infusions. All patients had significant elevations of serum IgG on the day after completion of treatment. Either random donor or partially HLA-matched platelet transfusions were administered the day after and, in some cases, during the IgG therapy. No patient had an improvement in one hour posttransfusion platelet count increments. Two additional patients received pooled platelet concentrates incubated for 30 minutes at 37 degrees C with IgG at a final concentration of 3 g% prior to transfusions. These results indicate that high-dose IgG, an extremely expensive treatment, cannot be recommended for alloimmunized adults with leukemia.