How to determine whether conceptual endophenotypes can improve clinical outcomes in patients suffering from major depression: An exploratory approach.

Depression is a complex mental health disorder, resulting in a high degree of disability. Since symptom constellation, course, and outcome are heterogeneous in these patients, current research initiatives are striving to establish stratified diagnostic and treatment approaches. In the past two decades, Dirk Hellhammer and his team introduced Neuropattern, a new diagnostic concept, which is based on conceptual endophenotypes of the stress response network. We explore how to use this concept in clinical practice in order to ultimately determine whether it brings any value over standard care. In view of the novelty of the concept and the difficulties dealing with such a concept at a practical level, it was necessary to initiate an exploratory study to determine key factors for planning future clinical trials. We report results and knowledge gained from an exploratory single-site study investigating the use and potential benefits of Neuropattern in standard care. Inpatients (ICD-10 diagnosis F32, F33; Nö=ö178) were allocated to either treatment as usual (standard group, SG) or a novel Neuropattern oriented exploratory treatment (intervention group, IG). Symptom severity was assessed with psychometric tests at admission to hospital, during the first six weeks, and upon discharge from the hospital. In addition, direct and indirect costs were assessed for the 3-month-intervals prior to and after the hospital stay. Compared to the SG, depression scores of patients in the IG showed a faster decline once psychotherapeutic and pharmacological treatment were based on an individualized explanatory model. The patients in the IG with an F33 diagnosis showed a more pronounced reduction of depression severity during the stay in the hospital and a stronger and quicker reduction of general symptom severity. Comparing the average depression scores at the start of the study and after six weeks, symptom severity was reduced in all Neuropattern groups. Some limitations of the study have to be mentioned: The study was not blinded, was single-site, included highly depressed inpatients only, and was conducted for no longer than 8 months. The results highlight some important issues regarding taking the Neuropattern approach to the bedside and researching its efficacy and effectiveness to support personalized treatments in clinical care.

Molecular dissection of the mouse interleukin-4 promoter.

Understanding the molecular mechanisms regulating the expression of interleukin 4 (IL-4) may shed light on the differentiation of lymphokine-producing phenotypes of CD4+ T cells. We have identified two DNA segments that are necessary for full phorbol 12-myristate 13-acetate (PMA)-induced activity of the IL-4 promoter region in the thymoma cell line EL4. Through deletion and mutation analyses, one of these segments (-57 through -47) was shown to be indispensable for promoter function. We designated this sequence consensus sequence 1 (CS1), as it shares homology with a sequence (ATTTTCCNNTG) that appears five times in the proximal 302-base-pair (bp) region 5' of the gene. We examined CS1 in further detail, as well as a second consensus sequence, CS2, located at nucleotides -75 through -65; both are within a minimal 83-bp construct that expresses full promoter activity. CS1- and CS2-spanning oligonucleotides bound apparently distinct PMA-inducible, sequence-specific factors in mobility-shift assays. Multimer constructs linking CS1- or CS2-spanning oligonucleotides to a heterologous promotor revealed that the CS1 construct had the greater enhancer activity in EL4 cells. Mutating the CS1 sequence within the context of the 302-bp promoter abolished all activity of the promoter, while mutating the CS2 sequence alone had little effect. Furthermore, a CS1 multimer could drive a heterologous promoter in an IL-4-producing [helper T-cell type 2 (TH2-type)] T-cell clone but not in a non-IL-4-producing (TH1-type) clone, suggesting a mechanism by which IL-4 production could be differentially regulated in TH subsets.

Interaction between NF-kappa B- and serum response factor-binding elements activates an interleukin-2 receptor alpha-chain enhancer specifically in T lymphocytes.

We find that a short enhancer element containing the NF-kappa B binding site from the interleukin-2 receptor alpha-chain gene (IL-2R alpha) is preferentially activated in T cells. The IL-2R alpha enhancer binds NF-kappa B poorly and is only weakly activated by the NF-kappa B site alone. Serum response factor (SRF) binds to a site adjacent to the NF-kappa B site in the IL-2R enhancer, and both sites together have strong transcriptional activity specifically in T cells. Surprisingly, the levels of SRF constitutively expressed in T cells are consistently higher than in other cell types. Overexpression of SRF in B cells causes the IL-2R enhancer to function as well as it does in T cells, suggesting that the high level of SRF binding in T cells is functionally important.