Therapeutic strategies in preclinical stages of rheumatoid arthritis.

Modern therapies and treatment algorithms like treat to target have significantly improved outcomes in rheumatoid arthritis over the past decades. Moreover, the "window of opportunity" concept has led to early diagnosis and treatment with improved outcomes. Nevertheless, individuals are still impacted by progressive disease courses, which also inflict a socioeconomic burden. Therefore, novel concepts of treatment are investigated. One of those is the concept of primary prevention: treating patients at risk for developing rheumatoid arthritis for a short period of time so they do not develop the full disease. The initiation of treatment in preclinical phases of rheumatoid arthritis is expected to delay, halt or even prevent the disease onset or progression in the long term. This review summarizes the concept itself, current studies with their therapeutic algorithm and findings and provides a critical evaluation of pharmacological therapy in the preclinical stages of rheumatoid arthritis.

Prevalence and effects of Vitamin D receptor polymorphism on bone mineral density and metabolism in patients with systemic sclerosis: a preliminary study.

Patients with systemic sclerosis (SSc) have a disproportionately high prevalence of reduced bone mineral density (BMD). Polymorphisms of the vitamin D receptor (VDR) gene have been associated with osteoporosis in patients with autoimmune diseases. The aim of this study was to investigate the prevalence and possible effects of VDR polymorphism on BMD and bone metabolism in patients with SSc. In patients with SSc measurement of BMD was performed using dual-energy X-ray absorptiometry. VDR polymorphisms (FokI, BsmI) were genotyped using restriction fragment length polymorphism analysis. Markers of bone metabolism (calcium, osteocalcin, ß-crosslaps) were determined. Primary endpoint was the prevalence of VDR gene polymorphisms and the association with reduced BMD. Secondary endpoints included associations between bone metabolism and VDR gene polymorphism. 79 Caucasian patients with SSc were included. Overall, 83.5% had reduced BMD (51.9% osteopenia, 31.6% osteoporosis). The prevalence of VDR gene polymorphism (73% BsmI, 77% FokI) was comparable to studies in healthy and rheumatic populations. The homozygous presence of FokI polymorphism, but not BsmI, was significantly associated with reduced axial BMD. Fokl polymorphism was significantly associated with reduced CTX levels, although changes remained within the reference limits. VDR polymorphisms can frequently be found in patients with SSc in comparable prevalence to healthy and rheumatic populations. The homozygous presence of FokI polymorphism, but not BsmI, was significantly associated with reduced axial BMD. This could be a possible contributor for the high prevalence of reduced BMD in 83.5% of patients with SSc in this study.Trial registration. DRKS00032768, date: 05.10.2023, retrospectively registered.

Heat therapy in rheumatic and musculoskeletal diseases - an overview of clinical and molecular effects.

Rheumatic and musculoskeletal diseases (RMDs) usually lead to morphological and functional deficits of various extend, increased morbidity and a considerable loss of quality of life. Modern pharmacological treatment has become effective and can stop disease progression. Nonetheless, disease progression is often only slowed down. Moreover, pharmacological treatment does not improve functionality per se. Therefore, multimodal treatment of rheumatic disorders with physical therapy being a key element is of central importance for best outcomes. In recent years, research into physical medicine shifted from a sole investigation of its clinical effects to a combined investigation of clinical effects and potential changes in the molecular level (e.g., inflammatory cytokines and the cellular autoimmune system), thus offering new explanations of clinical effects of physical therapy. In this review we provide an overview of studies investigating different heat applications in RMDs, their effect on disease activity, pain and their influence on the molecular level.

[Lifestyle medication vitamin D. What evidence is available?] / Lifestyle-Medikament Vitamin D. Was gibt es an Evidenz?

An undersupply of 25-(OH) vitamin D3 (calcifediol) exists in many countries with moderate sunlight, long winters and only moderate fish consumption. Risk groups for vitamin D3 deficiency are older persons over 65 years, geriatric persons in nursing homes, infants and children/adolescents. Therefore, there are also many situations in Germany which justify vitamin D substitution; however, vitamin D3 is currently praised as a "magic bullet" against everything. But what do the data look like? Where can it help and where can it not help?

Cardiovascular effects of bufotenin on human 5-HT4 serotonin receptors in cardiac preparations of transgenic mice and in human atrial preparations.

It is unclear whether bufotenin (= N,N-dimethyl-serotonin = 5-hydroxy-N,N-dimethyl-tryptamine), a hallucinogenic drug, can act on human cardiac serotonin 5-HT4 receptors. Therefore, the aim of the study was to examine the cardiac effects of bufotenin and for comparison tryptamine in transgenic mice that only express the human 5-HT4 receptor in cardiomyocytes (5-HT4-TG), in their wild-type littermates (WT) and in isolated electrically driven (1 Hz) human atrial preparations. In 5-HT4-TG, we found that both bufotenin and tryptamine enhanced the force of contraction in left atrial preparations (pD2 = 6.77 or 5.5, respectively) and the beating rate in spontaneously beating right atrial preparations (pD2 = 7.04 or 5.86, respectively). Bufotenin (1 µM) increased left ventricular force of contraction and beating rate in Langendorff perfused hearts from 5-HT4-TG, whereas it was inactive in hearts from WT animals, as was tryptamine. The positive inotropic and chronotropic effects of bufotenin and tryptamine were potentiated by an inhibitor of monoamine oxidases (50 µM pargyline). Furthermore, bufotenin concentration- (0.1-10 µM) and time-dependently elevated force of contraction in isolated electrically stimulated musculi pectinati from the human atrium and these effects were likewise reversed by tropisetron (10 µM). We found that bufotenin (10 µM) increased the phosphorylation state of phospholamban in the isolated perfused hearts, left and right atrial muscle strips of 5-HT4-TG but not from WT and in isolated human right atrial preparations. In summary, we showed that bufotenin can increase the force of contraction via stimulation of human 5-HT4 receptors transgenic mouse cardiac preparations but notably also in human atrial preparations.

Carbon's Three-Center, Four-Electron Tetrel Bond, Treated Experimentally.

Tetrel bonding is the noncovalent interaction of group IV elements with electron donors. It is a weak, directional interaction that resembles hydrogen and halogen bonding yet remains barely explored. Herein, we present an experimental investigation of the carbon-centered, three-center, four-electron tetrel bond, [N-C-N]+, formed by capturing a carbenium ion with a bidentate Lewis base. NMR-spectroscopic, titration-calorimetric, and reaction-kinetic evidence for the existence and structure of this species is reported. The studied interaction is by far the strongest tetrel bond reported so far and is discussed in comparison with the analogous halogen bond. The necessity of the involvement of a bidentate Lewis base in its formation is demonstrated by providing spectroscopic and crystallographic evidence that a monodentate Lewis base induces a reaction rather than stabilizing the tetrel bond complex. A vastly decreased Lewis basicity of the bidentate ligand or reduced Lewis acidity of the carbenium ion weakens-or even prohibits-the formation of the tetrel bond complex, whereas synthetic modifications facilitating attractive orbital overlaps promote it. As the geometry of the complex resembles the SN2 transition state, it provides a model system for the investigation of fundamental reaction mechanisms and chemical bonding theories.

NMR Determination of the Binding Constant of Ionic Species: A Caveat.

Determination of the dissociation constant of ionic complexes with the standard NMR titration and NMR dilution techniques may yield a severely compromised result, due to the typically unconsidered chemical shift alteration induced by the gradual change of the ionic strength during the experiment. We show that the reliability of an NMR titration experiment is markedly improved upon keeping the overall ionic strength constant.

Refined SMD Parameters for Bromine and Iodine Accurately Model Halogen-Bonding Interactions in Solution.

Motivated by the need to calculate liquid-phase free energies of species and equilibria involving halogen bonding, recent experimental data were used to optimize new Coulomb radii for Br and I for use in the SMD universal solvation model for calculating free energies of solvation. The use of the SMD model with these parameters for Br and I and the SMD values of all other parameters is called SMD18. After parametrization, the SMD18 model was tested for data not used in the parametrization. These data are standard-state free energies (equivalent to equilibrium constants) for 18 ionic equilibria involving Cl, Br, and I halogen bonding in acetonitrile, and the agreement of theory and experiment is satisfactory. The SMD18 model is then used to compare hydrogen bonding to halogen bonding and to reassess the interpretation of recent experiments.

The Interaction Modes of Haloimidazolium Salts in Solution.

We performed a comparative study on the interaction modes of 2-haloimidazolium salts with anions in solution, particularly with regard to halogen bonding, hydrogen bonding and anion-π interactions. The syntheses and solid-state analyses of a series of sterically and electronically modified 2-haloimidazolium structures are presented. Detailed isothermal titration calorimetry (ITC) measurements, quantum mechanics/molecular mechanics (QM/MM), classical molecular dynamics simulations (MD) and free-energy calculations together with NMR spectroscopy were used to elucidate the binding modes in solution. Our work reveals the absence of a potential anion-π interaction between the cationic imidazolium ring and the Lewis basic counteranion, and corroborates a formation of halogen bonding via the Lewis acidic iodine moiety and hydrogen bonding via the backbone hydrogen atoms, with repercussions in the field of organocatalysis.