[The judgment of the Federal Social Court on the involvement of psychological psychotherapists in interdisciplinary multimodal pain therapy : A critical comment]. / Das Urteil des Bundessozialgerichts zur Einbindung von Psychologischen Psychotherapeuten in die interdisziplinäre multimodale Schmerztherapie : Eine kritische Kommentierung.

In the context of their offer of interdisciplinary multimodal pain therapy (day-patient and inpatient), hospitals repeatedly have to contend with strict detailed checks of the procedure codes (OPS 8-918.xx; 8-91c) by health insurers and the medical service. The necessity of day-patient or inpatient treatment in the respective sector, documented therapy components, and the qualifications of the therapists are regularly reviewed. On 27 October 2020, the Federal Social Court ruled on the specific qualification of psychological psychotherapists (BSG, 27 October 2020, Ref.: B 1 KR 25/19 R). The ruling and its potential impact are explained and discussed in this overview.

Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver.

BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life-threatening acute neurovisceral attacks due to the induction of hepatic δ-aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks. OBJECTIVE: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks. METHODS: A follow-up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs-/- mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients. RESULTS: The introduction of hemin into the pharmacopeia has coincided with a 4.4-fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence. CONCLUSION: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP.

The KID Study VI: diabetic complications and associated diseases in younger type 2 diabetics still performing a profession. Prevalence and correlation with duration of diabetic state, BMI and C-peptide.

A sub-study evaluated 698 younger (54.5 +/- 6.9 years) type 2 diabetics of the KID Study participants to establish the prevalence of diabetic complications and associated diseases and their correlation with body mass index (BMI), duration of disease and to C-peptide levels. Only 19.8% of the type 2 diabetics had a normal weight. In all weight subgroups, the average age of diabetes manifestation were around age 45. In 46.6% of all type 2 diabetics we could already demonstrate microangiopathic complications. Strikingly, 15.9% of the patients already had proliferative retinopathies and 12.6% had albuminuria of more than 1000 mg/dl. 74.7% of our type 2 diabetics presented with the well-known risk cluster of the metabolic syndrome: In every other patient, we found hypertension and/or hyperlipoproteinaemia. Accordingly, the prevalence of the macroangiopathic diabetic complications, coronary artery disease and peripheral vascular disease was 17.8%, which is high for a relatively young population with a mean age of 53.9 years and goes conform with recent literature (Lowel et al., 1999). An increase in BMI correlated significantly with deterioration of HbA1, a decrease in HDL cholesterol, an increase in triglycerides and with a higher prevalence of hypertension. The frequency of nephropathy increase significantly up to a BMI of 30-35 kg/m2. Retinopathies and polyneuropathies were associated with BMI but increased significantly with the duration of the diabetic state. In contrast to microangiopathic diabetic complications, there was already a high prevalence of nephropathy after a comparatively short duration of disease. The prevalence of hyperlipoproteinaemia and hypertension did not depend from the duration of diabetes. These concomitant diseases already were frequent early in the disease and did not increase with the duration of disease. However, there was a strong correlation between increasing hyperlipoproteinaemia and hypertension and higher C-peptide levels. We found no coincidence between C-peptide levels and microangiopathic diabetic complications.

Delayed fetal development in two models of disturbed pregnancy of rats. Effect on mortality, body mass development, blood urea nitrogen (BUN) and urinary ammonium concentrations during the first week of extrauterine life.

To induce pregnancy disturbance, two models were used ("endotoxin-model" and "stress-model"), both causing decreased fetal body mass. Fetuses were delivered by Caesarean section in the morning of the 21st gestational day. Postnatal mortality rate during rearing for one week amounted to 12% in controls and was enhanced in the endotoxin- and stress-models (to approximately 25% and approximately 30%, respectively). During this period body mass gain of surviving pups was significantly delayed in the stress-model (approximately 140% of birth mass), compared with controls or pups of the endotoxin-model (160% and 155%, respectively). Additionally, decreased BUN concentrations were registered in newborns as well as 7-day-old pups of the stress-model. Urinary ammonium concentrations were not changed significantly. Possible alterations of metabolic processes in pups of the stress-model are discussed.

Airway structural cells regulate TLR5-mediated mucosal adjuvant activity.

Antigen-presenting cell (APC) activation is enhanced by vaccine adjuvants. Most vaccines are based on the assumption that adjuvant activity of Toll-like receptor (TLR) agonists depends on direct, functional activation of APCs. Here, we sought to establish whether TLR stimulation in non-hematopoietic cells contributes to flagellin's mucosal adjuvant activity. Nasal administration of flagellin enhanced T-cell-mediated immunity, and systemic and secretory antibody responses to coadministered antigens in a TLR5-dependent manner. Mucosal adjuvant activity was not affected by either abrogation of TLR5 signaling in hematopoietic cells or the presence of flagellin-specific, circulating neutralizing antibodies. We found that flagellin is rapidly degraded in conducting airways, does not translocate into lung parenchyma and stimulates an early immune response, suggesting that TLR5 signaling is regionalized. The flagellin-specific early response of lung was regulated by radioresistant cells expressing TLR5 (particularly the airway epithelial cells). Flagellin stimulated the epithelial production of a small set of mediators that included the chemokine CCL20, which is known to promote APC recruitment in mucosal tissues. Our data suggest that (i) the adjuvant activity of TLR agonists in mucosal vaccination may require TLR stimulation of structural cells and (ii) harnessing the effect of adjuvants on epithelial cells can improve mucosal vaccines.

Chromatin code, local non-equilibrium dynamics, and the emergence of transcription regulatory programs.

Chromatin is a, if not the, hallmark of eukaryotic life. Any molecular process entailing genomic DNA or the nucleus by default provokes or depends on chromatin structural dynamics on various space and time scales. Chromatin dynamics are result of changes in the physico-chemical properties of the chromatin constituents themselves or the nuclear environment. Chromatin has been found in the former case to undergo many different covalent enzyme-mediated chemical modifications. Their identification sheds light on the molecular mechanisms and the physico-chemical properties underlying chromatin dynamics, and allows the development of quantitative models for the chromatin fiber. The abundance of the different modifications, their dynamics, and short- as well as long-range correlation phenomena between different modifications also point to a second layer of genomic coding implemented at the level of chromatin. Especially, gene regulatory coding seems to depend on such a second-level code. The information-theoretical properties of chromatin in the context of gene regulatory coding are discussed. A model for the emergence of cellular differentiation from the intricate interplay between genomic and chromatin code is presented and discussed in light of recent experimental insights.

Chromatin physics: Replacing multiple, representation-centered descriptions at discrete scales by a continuous, function-dependent self-scaled model.

This commentary on the inspiring works and ideas by Langowski, Mangeol et al., Lee et al., Bundschuh and Gerland, Schiessel, Vaillant et al., Lesne and Victor, Claudet and Bednar, Fuks, Allemand et al., and Blossey, all appearing in this issue (Eur. Phys. J. E 19 (2006)), expresses our felt need of novel approaches to chromatin modeling.

Synergy between estrogen receptor alpha activation functions AF1 and AF2 mediated by transcription intermediary factor TIF2.

The activation function AF2 in the ligand-binding domain of estrogen receptors ER alpha and ER beta signals through the recruitment of nuclear receptor coactivators. Recent evidence indicates that coactivators, such as the transcription intermediary factor TIF2, also bind to and transactivate the N-terminal AF1 function of the two ERs. We have generated TIF2 mutant proteins that are deficient in either AF1 or AF2 interaction and use these mutants to investigate the relative contribution of both AFs to TIF2 recruitment and transactivation. We observe that TIF2 is capable of interacting simultaneously with both the isolated N- and C-terminus of ER alpha in transfected mammalian cells and in vitro, indicating that TIF2 can bridge both receptor domains. The concomitant interaction of TIF2 with both AFs results in synergistic activation of transcription. Thus, synergy between ER alpha AF1 and AF2 is a result of the cooperative recruitment of TIF2 and/or other members of the p160 coactivator family.

Ligand-dependent activation of transcription in vitro by retinoic acid receptor alpha/retinoid X receptor alpha heterodimers that mimics transactivation by retinoids in vivo.

All-trans and 9-cis retinoic acids (RA) signals are transduced by retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers that act as functional units controlling the transcription of RA-responsive genes. With the aim of elucidating the underlying molecular mechanisms, we have developed an in vitro transcription system using a chromatin template made up of a minimal promoter and a direct repeat with 5-spacing-based RA response element. RARalpha and RXRalpha were expressed in and purified from baculovirus-infected Sf9 cells, and transcription was carried out by using naked DNA or chromatin templates. Transcription from naked templates was not affected by the presence of RA and/or RAR/RXR heterodimers. In contrast, very little transcription occurred from chromatin templates in the absence of RA or RAR/RXR heterodimers whereas their addition resulted in a dosage-dependent stimulation of transcription that never exceeded that occurring on naked DNA templates. Most importantly, the addition of synthetic agonistic or antagonistic retinoids to the chromatin transcription system mimicked their stimulatory or inhibitory action in vivo, and activation by a RXR-specific retinoid was subordinated to the binding of an agonist ligand to the RAR partner. Moreover, the addition of the p300 coactivator generated a synergistic enhancement of transcription. Thus, the dissection of this transcription system ultimately should lead to the elucidation of the molecular mechanisms by which RAR/RXR heterodimers control transcription in a ligand-dependent manner.

Retinoic acid receptors interact physically and functionally with the T:G mismatch-specific thymine-DNA glycosylase.

The pleiotropic effects of retinoids are mediated by nuclear receptors that are activated by 9-cis- or all-trans-retinoic acid to function as ligand-dependent transcription factors. In a yeast one-hybrid screen for proteins capable of interacting with native retinoic acid receptor (RAR), we have isolated the T:G mismatch-specific thymine-DNA glycosylase (TDG), which initiates the repair of T:G mismatches caused by spontaneous deamination of methylated cytosines. Here, we report that TDG can interact with RAR and the retinoid X receptor (RXR) in a ligand-independent manner, both in yeast and in vitro. Mapping of the binding sites revealed interaction with a region of the ligand binding domain harboring alpha-helix 1 in both RAR and RXR. In transient transfection experiments, TDG potentiated transactivation by RXR from a direct repeat element spaced by one nucleotide (DR1) and by RXR/RAR heterodimers from a direct repeat element spaced by five nucleotides (DR5). In vitro, TDG enhanced RXR and RXR/RAR binding to their response elements. These data indicate that TDG is not only a repair enzyme, but could also function in the control of transcription.

The yeast Ada complex mediates the ligand-dependent activation function AF-2 of retinoid X and estrogen receptors.

Nuclear receptors can function as ligand-inducible transregulators in both mammalian and yeast cells, indicating that important features of control of transcription have been conserved throughout evolution. Here, we report the isolation and characterization of a yeast protein that exhibits properties expected for a coactivator/mediator of the ligand-dependent activation function AF-2 present in the ligand-binding domain (LBD, region E) of the retinoid X (RXRalpha) and estrogen (ERalpha) receptors. This protein is identical to Ada3, a component of the yeast Ada coactivator complex. We demonstrate that: (1) the region encompassing residues 347-702 of Ada3 interacts with the LBD of RXRalpha and ERalpha in a ligand-dependent manner in yeast; (2) this interaction corresponds to a direct binding and requires the integrity of the core of the AF-2 activating domain (AF-2 AD) of both RXRalpha and ERalpha; (3) Ada3 as well as Ada2 and Gcn5, two other components of the Ada complex, are required for maximal AF-2 activity in yeast; and (4) Ada3 is able to enhance the AF-2 activity of RXRalpha and ERalpha when overexpressed in yeast and mammalian cells. Taken together, these data indicate that ligand-dependent transactivation by RXRalpha and ERalpha in yeast is mediated at least in part by the Ada complex, in which the Ada3 subunit directly binds to the holoreceptor LBD.