ACTH-Bestimmungen im Plasma aus dem Bulbus cranialis venae jugularis

Der Anstieg der Corticosteroninkretion in das Nebennierenvenenblut frisch hypophysektomierter Ratten diente zur Bestimmung von ACTH-Spiegeln in 1 ml nativen, menschlichen Plasma. Normale ACTH-Plasmaspiegel sind sowohl bei Punktion der Vena cubitalis als auch des Bulbus cranialis venae jugularis durch diese Methode nicht oder nur ungenau zu erfassen. Bei Patienten mit pathologisch erhöhten ACTH-Spiegeln in der Vena cubitalis sind die ACTH-Spiegel im Bulbus cranialis venae jugularis signifikant höher. Es ließ sich eine Beziehung zwischen ACTH-Spiegel in der Peripherie (Vena cubitalis), Differenz der ACTH-Spiegel zwischen Bulbus cranialis venae jugularis und Vena cubitalis und biologischer Halbwertszeit von endogenem ACTH aufstellen. Nach den Ergebnissen der Bestimmung von ACTH-Spiegeln bei Nebennierengesunden läßt sich folgern, daß die biologische Halbwertszeit von endogenem ACTH größer als 4 min sein muß. Bei Patienten mit erhöhten ACTH-Spiegeln ließ sich die biologische Halbwertszeit von endogenem ACTH größenordnungsmäßig mit ca. 40 min berechnen. Bei diesen Patienten betrug die mittlere tägliche ACTH-Inkretion ca. 100 E.ACTH-contents of 1 ml specimens of human plasma were assayed by measurement of increases of corticosterone output in the adrenal vein of acutely hypophysectomized rats. This procedure is not sensitive enough to measure normal ACTH-levels acurately, neither when blood was drawn from the bulbus cranialis venae jugularis, nor from the vena cubitalis. In patients having pathologically elevated ACTH-levels, the ACTH-content of plasma is significantly higher in the bulbus cranialis venae jugularis than in peripheral venous blood. An equation is presented formulating the relation of peripheral ACTH-levels, differences of ACTH-levels between bulbus cranialis venae jugularis and vena cubitalis, and of the biological halflife of endogenous ACTH. On the basis of the results of the determinations of socalled normal ACTH-levels it can be concluded, that the biological halflife of endogenous ACTH is longer than 4 min. From the data of patients with elevated ACTH-levels a halflife of approximately 40 min and a mean ACTH-secretion of approx. 100 units per day could be calculated

The role of sex in the pathophysiology of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II). Female susceptibility to PAH has been known for some time, and most recent figures show a female-to-male ratio of 4:1. Variations in the female sex hormone estrogen and estrogen metabolism modify FPAH risk, and penetrance of the disease in BMPR-II mutation carriers is increased in females. Several lines of evidence point towards estrogen being pathogenic in the pulmonary circulation, and thus increasing the risk of females developing PAH. Recent studies have also suggested that estrogen metabolism may be crucial in the development and progression of PAH with studies indicating that downstream metabolites such as 16α-hydroxyestrone are upregulated in several forms of experimental pulmonary hypertension (PH) and can cause pulmonary artery smooth muscle cell proliferation and subsequent vascular remodelling. Conversely, other estrogen metabolites such as 2-methoxyestradiol have been shown to be protective in the context of PAH. Estrogen may also upregulate the signalling pathways of other key mediators of PAH such as serotonin

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

Phenotypic and functional analysis of monocyte populations in cattle peripheral blood identifies a subset with high endocytic and allogeneic T-cell stimulatory capacity

International audienceAbstractCirculating monocytes in several mammalian species can be subdivided into functionally distinct subpopulations based on differential expression of surface molecules. We confirm that bovine monocytes express CD172a and MHC class II with two distinct populations of CD14+CD16low/-CD163+ and CD14−CD16++CD163low- cells, and a more diffuse population of CD14+CD16+CD163+ cells. In contrast, ovine monocytes consisted of only a major CD14+CD16+ subset and a very low percentage of CD14−CD16++cells. The bovine subsets expressed similar levels of CD80, CD40 and CD11c molecules and mRNA encoding CD115. However, further mRNA analyses revealed that the CD14−CD16++ monocytes were CX3CR1highCCR2low whereas the major CD14+ subset was CX3CR1lowCCR2high. The former were positive for CD1b and had lower levels of CD11b and CD86 than the CD14+ monocytes. The more diffuse CD14+CD16+ population generally expressed intermediate levels of these molecules. All three populations responded to stimulation with phenol-extracted lipopolysaccharide (LPS) by producing interleukin (IL)-1β, with the CD16++ subset expressing higher levels of IL-12 and lower levels of IL-10. The CD14−CD16++ cells were more endocytic and induced greater allogeneic T cell responses compared to the other monocyte populations. Taken together the data show both similarities and differences between the classical, intermediate and non-classical definitions of monocytes as described for other mammalian species, with additional potential subpopulations. Further functional analyses of these monocyte populations may help explain inter-animal and inter-species variations to infection, inflammation and vaccination in ruminant livestock

Rapid identification of bovine MHCI haplotypes in genetically divergent cattle populations Using Next-Generation Sequencing

The major histocompatibility complex (MHC) region contains many genes that are key regulators of both innate and adaptive immunity including the polymorphic MHCI and MHCII genes. Consequently, the characterisation of the repertoire of MHC genes is critical to understanding the variation that determines the nature of immune responses. Our current knowledge of the bovine MHCI repertoire is limited with only the Holstein-Friesian breed having been studied in any depth. Traditional methods of MHCI genotyping are of low resolution and laborious and this has been a major impediment to a more comprehensive analysis of the MHCI repertoire of other cattle breeds. Next-generation sequencing (NGS) technologies have been used to enable high throughput and much higher resolution MHCI typing in a number of species. In this study we have developed a MiSeq platform approach and requisite bioinformatics pipeline to facilitate typing of bovine MHCI repertoires. The method was validated initially on a cohort of Holstein-Friesian animals and then demonstrated to enable characterisation of MHCI repertoires in African cattle breeds, for which there was limited or no available data. During the course of these studies we identified >140 novel classical MHCI genes and defined 62 novel MHCI haplotypes, dramatically expanding the known bovine MHCI repertoire