The importance of FcRn in neuro-immunotherapies: From IgG catabolism, FCGRT gene polymorphisms, IVIg dosing and efficiency to specific FcRn inhibitors.

The neonatal Fc receptor (FcRn) binds endogenous IgG and protects it from lysosomal degradation by transporting it back to the cell surface to re-enter the circulation, extending the serum IgG life span. FcRn plays a role in the function of IVIg because the supraphysiological IgG levels derived from IVIg administrations saturate the FcRn allowing the endogenous IgG to be degraded, instead of being recycled, resulting in high levels of infused IgG ensuring IVIg efficiency. New data in myasthenia gravis patients suggest that the that the Variable Number of Tandem 3/2 (VNTR3/2) polymorphisms in FCGRT, the gene that encodes FcRn, may affect the duration of infused IgG in the circulation and IVIg effectiveness. This review addresses these implications in the context of whether the FCGRT genotype, by affecting the half-life of IVIg, may also play a role in up to 30% of patients with autoimmune neurological diseases, such as Guillain-Barré syndrome, CIDP or Multifocal Motor Neuropathy, who did not respond to IVIg in controlled trials. The concern is of practical significance because in such patient subsets super-high IVIg doses may be needed to achieve high IgG levels and ensure efficacy. Whether FCGRT polymorphisms affect the efficacy of other therapeutic monoclonal antibodies by influencing their distribution clearance and pharmacokinetics, explaining their variable effectiveness, is also addressed. Finally, the very promising effect of monoclonal antibodies that inhibit FcRn, such as efgartigimod, rozanolixizumab and nipocalimab, in treating antibody-mediated neurological diseases is discussed along with their efficacy in the IgG4 subclass of pathogenic antibodies and their role in the blood-brain barrier endothelium, that abundantly expresses FcRn

Hereditary angioedema (HAE) in children and adolescents : a consensus on therapeutic strategies

Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis

New GABA amides activating GABAa-receptors

We have prepared a series of new and some literature-reported GABA-amides and determined their effect on the activation of GABA A -receptors expressed in CHO cells. Special attention was paid to the purification of the target compounds to remove even traces of GABA contaminations, which may arise from deprotection steps in the synthesis. GABA-amides were previously reported to be partial, full or superagonists. In our hands these compounds were not able to activate GABA A -receptor channels in whole-cell patch-clamp recordings. New GABA-amides, however, gave moderate activation responses with a clear structure-activity relation- ship suggesting some of these compounds as promising molecular tools for the functional analysis of GABA A -receptor

Evaluation der Experimentierklausel nach § 6c SGB II - Untersuchungsfeld 4: Makroanalyse und regionale Vergleiche: Endbericht

"Der Beitrag von Untersuchungsfeld 4 - Makroanalyse und regionale Vergleiche - zu den Arbeiten des Forschungsverbundes zur Evaluation der Experimentierklausel nach § 6c SGB II besteht in einer Analyse der Wirkungen unterschiedlicher Formen der Aufgabenwahrnehmung im SGB II auf regionaler Ebene unter Berücksichtigung von regionalen Besonderheiten und gesamtwirtschaftlichen Wirkungszusammenhänge, darunter insbesondere interregionale Verflechtungen sowie Substitutions-, Verdrängungs- und Mitnahmeeffekte. Im Vordergrund steht dabei ein Performancevergleich von Arbeitsgemeinschaften (ARGEn) und zugelassenen kommunalen Trägern (zkT), zugespitzt in der Frage: 'Was wäre geschehen, wenn deutschlandweit entweder das ARGE-Modell oder die kommunale Trägerschaft eingeführt worden wäre?' Zur Beantwortung dieser Frage sind, über rein deskriptive Vergleiche hinaus, Untersuchungen zu den Einflussfaktoren für die Wahl der Form der Aufgabenwahrnehmung und zu den Effekten erforderlich, die sich auf der Ebene der verschiedenen Grundsicherungsstellen bezüglich der Zielsetzungen des SGB II ergeben und der jeweiligen Form der Aufgabenwahrnehmung kausal zugerechnet werden können." (Textauszug

Swabian MOSES 2021: An interdisciplinary field campaign for investigating convective storms and their event chains

The Neckar Valley and the Swabian Jura in southwest Germany comprise a hotspot for severe convective storms, causing tens of millions of euros in damage each year. Possible reasons for the high frequency of thunderstorms and the associated event chain across compartments were investigated in detail during the hydro-meteorological field campaign Swabian MOSES carried out between May and September 2021. Researchers from various disciplines established more than 25 temporary ground-based stations equipped with state-of-the-art in situ and remote sensing observation systems, such as lidars, dual-polarization X- and C-band Doppler weather radars, radiosondes including stratospheric balloons, an aerosol cloud chamber, masts to measure vertical fluxes, autosamplers for water probes in rivers, and networks of disdrometers, soil moisture, and hail sensors. These fixed-site observations were supplemented by mobile observation systems, such as a research aircraft with scanning Doppler lidar, a cosmic ray neutron sensing rover, and a storm chasing team launching swarmsondes in the vicinity of hailstorms. Seven Intensive Observation Periods (IOPs) were conducted on a total of 21 operating days. An exceptionally high number of convective events, including both unorganized and organized thunderstorms such as multicells or supercells, occurred during the study period. This paper gives an overview of the Swabian MOSES (Modular Observation Solutions for Earth Systems) field campaign, briefly describes the observation strategy, and presents observational highlights for two IOPs

Evaluation der Experimentierklausel nach § 6c SGB II - Untersuchungsfeld 4: Makroanalyse und regionale Vergleiche: Zwischenbericht 2007

"Im Rahmen der Evaluation der Experimentierklausel nach Paragraph 6c SGB II umfasst die Aufgabenstellung des Forschungsfeldes 4 - Makroanalyse und regionale Vergleiche - eine Analyse der regionalen Wirkungen von ARGEn und zkT (zugelassene kommunale Träger), die Analyse der gesamtwirtschaftlichen Wirkungen und ein Performancevergleich der Regionen. Insbesondere im Rahmen der Makroanalyse gilt es die Frage zu beantworten, 'Was wäre geschehen, wenn zum 1. 1. 2005 deutschlandweit entweder das ARGE-Modell oder die kommunale Trägerschaft eingeführt worden wäre?' und zwar unter besonderer Berücksichtigung regionaler Besonderheiten und Verflechtungen, sowie Substitutions-, Verdrängungs- und Mitnahmeeffekten. Bei einem Vergleich der ARGEn mit den zkT muss berücksichtigt werden, ob sich Kreise mit spezifischen Merkmalen für die eine oder die andere Form der Aufgabenwahrnehmung entschieden haben. Auf Grundlage der Vorarbeiten des Paragraph 6c-Forschungsverbundes dürften folgende Faktoren die Optionsneigung beeinflusst haben: Lokale Arbeitsmarktlage, Größe der Kommune, Finanzkraft, Sozio-geographische Merkmale, Politische Merkmale und Vorerfahrungen. Die regionalen Vergleiche dienen der Darstellung und der deskriptiven Beschreibung der Entwicklung zentraler Indikatoren für die Zielgrößen 'Integration in Erwerbstätigkeit', 'Verbesserung der Beschäftigungsfähigkeit' und 'soziale Stabilisierung' im Vergleich der drei Formen der Aufgabenwahrnehmung sowie der unterschiedlichen Organisationstypen." (Autorenreferat

The international WAO/EAACI guideline for the management of hereditary angioedema - The 2021 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients

Clinical Use and Therapeutic Potential of IVIG/SCIG, Plasma-Derived IgA or IgM, and Other Alternative Immunoglobulin Preparations

Intravenous and subcutaneous immunoglobulin preparations, consisting of IgG class antibodies, are increasingly used to treat a broad range of pathological conditions, including humoral immune deficiencies, as well as acute and chronic inflammatory or autoimmune disorders. A plethora of Fab- or Fc-mediated immune regulatory mechanisms has been described that might act separately or in concert, depending on pathogenesis or stage of clinical condition. Attempts have been undertaken to improve the efficacy of polyclonal IgG preparations, including the identification of relevant subfractions, mild chemical modification of molecules, or modification of carbohydrate side chains. Furthermore, plasma-derived IgA or IgM preparations may exhibit characteristics that might be exploited therapeutically. The need for improved treatment strategies without increase in plasma demand is a goal and might be achieved by more optimal use of plasma-derived proteins, including the IgA and the IgM fractions. This article provides an overview on the current knowledge and future strategies to improve the efficacy of regular IgG preparations and discusses the potential of human plasma-derived IgA, IgM, and preparations composed of mixtures of IgG, IgA, and IgM