Statistical inferences for the Cauchy distribution based on maximum likelihood estimators

Various estimators of the location and scale parameters in the Cauchy distribution are investigated, and the superiority of the maximum likelihood estimators is established. Tables based on maximum likelihood estimators are presented for use in making statistical inferences for the Cauchy distribution. Those areas considered include confidence intervals, tests of hypothesis, power of the tests, and tolerance intervals. Both one- and two-sample problems are considered. Tables for testing the hypothesis of whether a sample came from a normal distribution or a Cauchy distribution are presented. The problems encountered in finding maximum likelihood estimators for the Cauchy parameters are discussed, and a computer program for obtaining the estimates is included --Abstract, page ii

Delineation of the cellular responses to MDA-modified proteins in macrophages

Malondialdehyd (MDA) ist ein hochreaktives Aldehyd, das während der Peroxidation von Lipi-den (Fettsäuren) produziert wird. Es reagiert sofort mit Acetaldehyd und freien Aminogruppen und bildet dabei eine Reihe verschiedener chemischer Strukturen (Epitope). Ein sehr häufig ge-bildetes Epitop ist das Malondialdehyd-Acetaldehyd-Addukt (MAA). Dieses bezeichnet vorran-gig eine Ring-Struktur namens 4-methyl-1,4-dihydropyridine-3,5-dicarbaldehyde (MDHDC). MAA Epitope findet man an der Oberfläche von apoptotischen und nekrotischen Zellen, sowie an der Oberfläche von Mikropartikeln. In dieser Master Thesis zeigen wir, dass eine Stimulation mit MAA schon nach kurzer Zeit Makrophagen und Monozyten zur Sekretion von inflammatorischen Chemokinen veranlasst. Unsere Resultate weisen darauf hin, dass Macrophagen MAA mittels TLR2 und TLR4 erkennen. CD14 scheint dabei ebenso eine wichtige Funktion zu erfüllen. Weiters zeigen wir mittels in vitro Bindungsstudien, dass MAA an TLR2 bindet. Überraschenderweise fanden wir auch her-aus, dass MAA an TREM1 bindet. Bisher ist kein TREM1 Ligand bekannt, daher ist MAA der erste nachgewiesene, direkte Interaktionspartner. Wir zeigen, dass nach Bindung an diese Pattern-Recognition-Rezeptoren (PRRs) MAPK-pathways hochreguliert werden. Eine Stimulation mit MAA führte zu einer erhöhten Phosphory-lierung von ERK1/2. Inhibition von ERK mit einem künstlichen Inhibitor führte zu einer redu-zierten Sekretion von Chemokinen nach MAA-BSA Stimulation. Zusammenfassend, beschreiben wir ein neues damage-associated-molecular-pattern (DAMP), welches in vielen Krankheitsbildern vorkommt. Ein besseres Verständnis, von den von MAA ausgelösten Immunreaktionen, könnte in Zukunft zu einer besseren Behandlung von Krankhei-ten führen, in denen MAA eine wichtige Rolle spielt.Malondialdehyde (MDA) per se is a highly reactive aldehyde generated during lipid breakdown that forms adducts on amino groups. One of the main generated adducts is the Malondialdehyde-acetaldehyde-adduct, further named MAA. MAA mainly consists of the ring structure 4-methyl-1,4-dihydropyridine-3,5-dicarbaldehyde (MDHDC). These epitopes are found on the surface of apoptotic and necrotic cells and on the surface of apoptotic blebs (microparticles) and accumu-late in many diseases, such as atherosclerosis. We show that MAA causes a fast and complex inflammatory response in vitro and in vivo. Macrophages and monocytes immediately respond to this epitope by secreting various pro-inflammatory chemokines. The recognition of MAA by macrophages involves the pattern-recognition-receptors (PRRs) TLR4 and TLR2. Additionally, CD14 is crucial for eliciting a re-sponse to MAA. Conducted binding assays prove a direct binding of MAA to TLR2 as well as to TREM1. Moreover, competition assays suggest a role for scavenger receptor A (SR-A) in MAA-signalling. We show that stimulation with MAA-BSA leads to an upregulation of MAPK pathways on the genomic level. Specifically, ERK1/2 is phosphorylated in response to MAA-BSA treatment. Using an ERK-specific inhibitor, we show that the response to MAA-BSA is ERK-dependent. Taken together we present evidence that MAA represents a novel damage-associated-molecular-pattern (DAMP) which is abundant in inflammatory conditions and diseases associated with it. A better understanding of MAA signalling could identify novel therapeutical targets and thereby lead to a better treatment of these diseases

Chiasma

Newspaper reporting on events at the Boston University School of Medicine in the 1960s

Modulation of Liver Inflammation and Fibrosis by Interleukin-37

Background and Aims: Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-beta. TGF-beta promotes liver fibrosis via the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-beta signaling cascade to modulate liver fibrogenesis. Methods: The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity. Results: Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl4-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-beta-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1 beta stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis. Conclusions: Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis

The use of influential power in ocean governance

Ensuring inclusivity, especially the meaningful participation of diverse actors, is a key component of good governance. However, existing ocean governance frameworks have not yet achieved an equitable and fair playing field and are indeed often characterized by inequitable practices. In this perspective piece, we argue that one of the reasons for this lack of inclusion are the existing power frameworks and ways in which power is exercised within fora nominally intended to foster inclusion and cooperation. By focusing on four case studies of basic ocean governance processes, we explore how influential and interactive power is exercised in intergovernmental meetings, international conferences, and regional negotiations. These case studies demonstrate how specific exercises of power that undermine procedural inclusivity influence decision-making and the setting of agendas, and exclude important voices from ocean governance fora. This perspective piece contributes to the existing literature on power by highlighting how power is exercised within fundamental aspects of ocean governance. This paper merely scratches the surface, and more actions and research are needed to uncover and, more importantly, reverse deeply-rooted and self-perpetuating power structures in ocean governance

Mechanical Mitral Valve Replacement:A Multicenter Study of Outcomes With Use of 15-to 17-mm Prostheses

Background. The aim of this study was to evaluate early and mid-term outcomes (mortality and prosthetic valve reintervention) after mitral valve replacement with 15- to 17-mm mechanical prostheses. Methods. A multicenter, retrospective cohort study was performed among patients who underwent mitral valve replacement with a 15- to 17-mm mechanical prosthesis at 6 congenital cardiac centers: 5 in The Netherlands and 1 in the United States. Baseline, operative, and follow-up data were evaluated. Results. Mitral valve replacement was performed in 61 infants (15 mm, n = 17 [28%]; 16 mm, n = 18 [29%]; 17 mm, n = 26 [43%]), of whom 27 (47%) were admitted to the intensive care unit before surgery and 22 (39%) required ventilator support. Median age at surgery was 5.9 months (interquartile range [IQR] 3.2-17.4), and median weight was 5.7 kg (IQR, 4.5-8.8). There were 13 in-hospital deaths (21%) and 8 late deaths (17%, among 48 hospital survivors). Major adverse events occurred in 34 (56%). Median follow-up was 4.0 years (IQR, 0.4-12.5) First prosthetic valve replacement (n = 27 [44%]) occurred at a median of 3.7 years (IQR, 1.9-6.8). Prosthetic valve endocarditis was not reported, and there was no mortality related to prosthesis replacement. Other reinterventions included permanent pacemaker implantation (n = 9 [15%]), subaortic stenosis resection (n = 4 [7%]), aortic valve repair (n = 3 [5%], and aortic valve replacement (n = 6 [10%]). Conclusions. Mitral valve replacement with 15- to 17-mm mechanical prostheses is an important alternative to save critically ill neonates and infants in whom the mitral valve cannot be repaired. Prosthesis replacement for outgrowth can be carried out with low risk. (C) 2020 by The Society of Thoracic Surgeons. Published by Elsevier Inc

Mechanical Mitral Valve Replacement: A Multicenter Study of Outcomes with Use of 15- to 17-mm Prostheses

Background: The aim of this study was to evaluate early and mid-term outcomes (mortality and prosthetic valve reintervention) after mitral valve replacement with 15- to 17-mm mechanical pr