Impact of nonalcoholic fatty liver disease-related metabolic state on depression.

Nonalcoholic fatty liver disease (NAFLD), also recently referred as metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by hepatocyte steatosis in the setting of metabolic risk conditions and in the absence of an underlying precursor, for instance alcohol consumption, hepatotropic viruses and hepatotoxic drugs. A possible association between NAFLD and depression has been proposed, owing to intersecting pathophysiological pathways. This narrative review aimed to summarize the current evidence that illustrate the potential pathophysiological and clinical linkage between NAFLD-related metabolic state and depression. Prefrontal cortex lesions are suggested to be a consequence of liver steatosis-associated systematic hyperinflammatory state, a phenomenon also occurring in depression. In addition, depressive symptoms are present in neurotransmitter imbalances. These abnormalities seem to be correlated with NAFLD/MAFLD, in terms of insulin resistance (IR), ammonia and gut dysbiosis' impact on serotonin, dopamine, noradrenaline levels and gamma aminobutyric acid receptors. Furthermore, reduced levels of nesfatin-1 and copine-6-associated BDNF (brain-derived neurotrophic factor) levels have been considered as a probable link between NAFLD and depression. Regarding NAFLD-related gut dysbiosis, it stimulates mediators including lipopolysaccharides, short-chain fatty acids and bile acids, which play significant role in depression. Finally, western diet and IR, which are mainstay components of NAFLD/MAFLD, are, also, substantiated to affect neurotransmitters in hippocampus and produce neurotoxic lipids that contribute to neurologic dysfunction, and thus trigger emotional disturbances, mainly depressive symptoms.

CXCR4 and CD74 together enhance cell survival in response to macrophage migration-inhibitory factor in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of small, mature CD5+ B lymphocytes in the blood, marrow, and lymphoid organs. Cell survival depends on interaction with the leukemic microenvironment. However, the mechanisms controlling CLL cell survival are still incompletely understood. Macrophage migration-inhibitory factor (MIF), a pro-inflammatory and immunoregulatory chemokine-like cytokine, interacts with CXCR4, a major chemokine receptor, as well as with CD74/invariant chain, a single-pass type II receptor. In this study, we analyzed the roles of CXCR4, CD74, and MIF in CLL. Mononuclear cells from patients with hematological malignancies were analyzed for coexpression of CXCR4 and CD74 by flow cytometry. Strong co- and overexpression of CXCR4 and CD74 were observed on B cells of CLL patients (n = 10). Survival and chemotaxis assays indicated that CXCR4 and CD74 work together to enhance the survival and migration of malignant cells in CLL. Blockade of the receptors, either individually or in combination, promoted cell death and led to an abrogation of MIF-driven migration responses in murine and human CLL cells, suggesting that joint activation of both receptors is crucial for CLL cell survival and mobility. These findings indicate that the MIF/CXCR4/CD74 axis represents a novel therapeutic target in CLL.

Establishment of a Palliative Care Consultation Service (PCCS) in an Acute Hospital Setting.

Background and study aims: Acute health service requires focused palliative care (PC). This study was performed to provide guidance for the establishment of a palliative care consultation service (PCCS). Patients and methods: This study was conceived as a retrospective single-center study for observing, analyzing and evaluating the initial setup of a PCCS from 1 May 2015 to 31 May 2018. Patients from Muenster University Hospital with advanced life-limiting diseases, identified to require PC, were included. Results: PCCS was requested from various departments, for between 20 and 80 patients per month, corresponding to a total of 2359 for the study period. Requests were highest in internal medicine (27.3%), gynecology (18.1%) and radiotherapy (17.6%). Time to referral was significantly shorter in departments with special PCCS ward rounds (6 ± 9 vs. 12 ± 22 days, p < 0.001). The most frequently reported symptoms were fatigue, pain and loss of appetite. Pain was frequently localized in the stomach (20.4%), back (17.1%), or in the head and neck area (14.9%). After the first PCCS consultation, 254 patients (90%) reported sufficient pain relief after 48 h. An introduction/modification of painkiller medication, which was recommended for 142 inpatients, was implemented in 57.0% of cases by the respective departments. Overall, the direct realization of PCCS recommendations reached only 50% on average. Conclusions: Besides an analysis of the ability to address the symptoms of the referred patients by the PCCS, this study highlights the importance of the interaction between PCCS and other departments. It further elucidates the role and possibilities of this service both in regular ward rounds and individual staff contacts.

Identification of an Arg-Leu-Arg tripeptide that contributes to the binding interface between the cytokine MIF and the chemokine receptor CXCR4.

MIF is a chemokine-like cytokine that plays a role in the pathogenesis of inflammatory and cardiovascular disorders. It binds to the chemokine-receptors CXCR2/CXCR4 to trigger atherogenic leukocyte migration albeit lacking canonical chemokine structures. We recently characterized an N-like-loop and the Pro-2-residue of MIF as critical molecular determinants of the CXCR4/MIF binding-site and identified allosteric agonism as a mechanism that distinguishes CXCR4-binding to MIF from that to the cognate ligand CXCL12. By using peptide spot-array technology, site-directed mutagenesis, structure-activity-relationships, and molecular docking, we identified the Arg-Leu-Arg (RLR) sequence-region 87-89 that - in three-dimensional space - 'extends' the N-like-loop to control site-1-binding to CXCR4. Contrary to wildtype MIF, mutant R87A-L88A-R89A-MIF fails to bind to the N-terminal of CXCR4 and the contribution of RLR to the MIF/CXCR4-interaction is underpinned by an ablation of MIF/CXCR4-specific signaling and reduction in CXCR4-dependent chemotactic leukocyte migration of the RLR-mutant of MIF. Alanine-scanning, functional competition by RLR-containing peptides, and molecular docking indicate that the RLR residues directly participate in contacts between MIF and CXCR4 and highlight the importance of charge-interactions at this interface. Identification of the RLR region adds important structural information to the MIF/CXCR4 binding-site that distinguishes this interface from CXCR4/CXCL12 and will help to design MIF-specific drug-targeting approaches.