Probation and effective rehabilitation – an alternative to incarceration? Using neuroscience to facilitate rehabilitation methods

In recent years critiques of collective sentencing and imprisonment have gained importance. Alarming numbers of overcrowded prisons and extraordinary high rates of recidivism have drawn attention towards legal proceedings and the imposition of sanctions and sentences. Moreover, assessments of forensic psychologists appeared to be of rather less accuracy in terms of predicting the propensity of a perpetrator to reoffend. At the same time, the field of neuroscience has experienced significant progress in exploring our brains and the connection to our minds. More precisely, the research on correlations between specific brain functioning and appertaining human behaviour has remarkably advanced in recent years. Certain methods have been developed allowing for brain imagining and lie detection to a certain extent. For this reason, the field of ‘neurolaw’ has emerged with emphasis on the impact of neuroscience on law. Proponents of the latter suggest that neuroscience may serve as evidence to support solving questions of guilt and punishment and help to advance the forecast of future criminal behaviour. Especially in the light of emerging neuroscientific findings both legal and neuroscientific scholars have argued for a reform of the justice systems towards more individualized litigation and a greater focus on rehabilitation instead of incarceration

Rolle der von Willebrand-Faktor-spaltenden-Protease ADAMTS-13 bei Patienten mit systemischer Inflammation

Eine generalisierte Inflammationsreaktion steht häufig im Zusammenhang mit einer gesteigerten Gerinnungsaktivierung. Bei der sepsis-assoziierten endothelialen Dysfunktion kommt es zur vermehrten Freisetzung des Akutphase-Proteins von Willebrand-Faktor (VWF). Native ultralange VWF-Multimere (ULVWF) werden vorwiegend durch die VWF spaltende Protease ADAMTS-13 gespalten. ULVWF-Multimere führen bei verminderter Enzymaktivität zur spontanen Aktivierung der Thrombozyten und bilden die molekulare Basis der thrombotischen Mikroangiopathie. Es wurde untersucht, ob eine verminderte ADAMTS-13 Aktivität bei Patienten mit systemischer Inflammation auftritt, sowie ob eine mögliche Präsenz von ULVWF-Multimeren für die Entwicklung des septischen Organversagens relevant sein könnte. In einer prospektiven Longitudinalstudie fanden wir im Citratplasma von 11 thrombozytopenischen Patienten mit septischem Schock eine erniedrigte ADAMTS13 Aktivität im gesamten Tagesverlauf. Hierbei traten Unterschiede zwischen Überlebenden und Nicht-Überlebenden auf, indem die ADAMTS13 Aktivität bei den Überlebenden im Zeitverlauf anstieg. Bei einem weiteren Patientenkollektiv von 22 Patienten mit postoperativem systemischem Inflammationssyndrom war die ADAMTS-13 Aktivität an den ersten 5 postoperativen Tagen erniedrigt. Eine erniedrigte ADAMTS-13 Aktivität war in beiden Kollektiven sowohl mit dem Auftreten von ULVWF-Multimeren als auch mit erhöhten inflammationsrelevanten Parametern und erhöhtem „Sequential Organ Failure Assessment“-(SOFA)-Score assoziiert. Die über ULVWF-Multimere vermittelte Thrombozytenaggregation spielt eine potentielle Rolle bei der Entstehung eines Organversagens im Rahmen von systemischen Inflammationsreaktionen

Shrinking Cities, Growing Adversaries: The Politics of Territory for Community Nonprofits in \u27Shrinking City\u27 Planning Processes

Political institutions in ‘shrinking cities’ undergo transformative restructuring when depopulation and disinvestment threaten public capacity. Using a New Institutionalism approach, this chapter explores historical impacts of changing institutions on community nonprofit organization (CNPO) behaviors, and highlights applications to Detroit’s current ‘right-sizing’ planning processes. It explores influences of foundations, intermediaries and anchor institutions on CNPO roles in decision making and concludes that Detroit illustrates governance without government, challenging CNPOs to impact deliberations increasingly led by the independent sector, where communities and CNPOs lack formal access. The chapter presents one case of counter-institutional response, that of LEAP, an innovative alternative CNPO plan

Introduction

This essay collection marks the conclusion of the MARBLE (Maastricht University Research Based Learning) for Excellence project on Neurolaw in 2013. Its objective was to address some of the complexities arising from the intersection of law and science. In particular, our attention was focused on the possible contributions that neuroimaging and neuroscience in general could yield to the field of law. The consequent research addressed the issue from a variety of perspectives – legal philosophy, criminal procedure, as well as human rights and rehabilitation

The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis

Introduction: Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficacy of a novel polyethylene glycol (PEG)-clustered Tie2 agonist peptide, vasculotide (VT), to protect against vascular leakage and mortality in a murine model of polymicrobial abdominal sepsis. Methods: Polymicrobial abdominal sepsis in C57BL6 mice was induced by cecal-ligation-and-puncture (CLP). Mice were treated with different dosages of VT or equal volume of phosphate-buffered saline (PBS). Sham-operated animals served as time-matched controls. Results: Systemic administration of VT induced long-lasting Tie2 activation in vivo. VT protected against sepsis-induced endothelial barrier dysfunction, as evidenced by attenuation of vascular leakage and leukocyte transmigration into the peritoneal cavity. Histological analysis revealed that VT treatment ameliorated leukocyte infiltration in kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression. VT-driven effects were associated with significantly improved organ function and reduced circulating cytokine levels. The endothelial-specific action of VT was supported by additional in vitro studies showing no effect of VT on either cytokine release from isolated peritoneal macrophages, or migratory capacity of isolated neutrophils. Finally, administration of VT pre-CLP (hazard ratio 0.39 [95% confidence interval 0.19-0.81] P < 0.001) and post-CLP reduced mortality in septic mice (HR 0.22 [95% CI 0.06-0.83] P < 0.05). Conclusions: We provide proof of principle in support of the efficacious use of PEGylated VT, a drug-like Tie2 receptor agonist, to counteract microvascular endothelial barrier dysfunction and reduce mortality in a clinically relevant murine sepsis model. Further studies are needed to pave the road for clinical application of this therapeutic concept

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis

The pathophysiology of sepsis involves activation of acid sphingomyelinase (SMPD1) with subsequent generation of the bioactive mediator ceramide. We herein evaluate the hypothesis that the enzyme exerts biological effects in endothelial stress response. Plasma-secreted sphingomyelinase activity, ceramide generation and lipid raft formation were measured in human microcirculatory endothelial cells (HMEC-1) stimulated with serum obtained from sepsis patients. Clustering of receptors relevant for signal transduction was studied by immunostaining. The role of SMPD1 for macrodomain formation was tested by pharmacological inhibition. To confirm the involvement of the stress enzyme, direct inhibitors (amino bisphosphonates) and specific downregulation of the gene was tested with respect to ADAMTS13 expression and cytotoxicity. Plasma activity and amount of SMPD1 were increased in septic patients dependent on clinical severity. Increased breakdown of sphingomyelin to ceramide in HMECs was observed following stimulation with serum from sepsis patients in vitro. Hydrolysis of sphingomyelin, clustering of receptor complexes, such as the CD95L/Fas-receptor, as well as formation of ceramide enriched macrodomains were abrogated using functional inhibitors (desipramine and NB6). Strikingly, the stimulation of HMECs with serum obtained from sepsis patients or mixture of proinflammatory cytokines resulted in cytotoxicity and ADAMTS13 downregulation which was abrogated using desipramine, amino bisphosphonates and genetic inhibitors. SMPD1 is involved in the dysregulation of ceramide metabolism in endothelial cells leading to macrodomain formation, cytotoxicity and downregulation of ADAMTS13 expression. Functional inhibitors, such as desipramine, are capable of improving endothelial stress response during sepsis and might be considered as a pharmacological treatment strategy to obtain a favorable outcome