Primary sclerosing cholangitis – The arteriosclerosis of the bile duct?

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of unknown aetiology affecting the large bile ducts and characterized by periductal fibrosis and stricture formation, which ultimately result in biliary cirrhosis and liver failure. Arteriosclerosis involves the accumulation of altered lipids and lipoproteins in large arteries; this drives inflammation and fibrosis and ultimately leads to narrowing of the arteries and hypoperfusion of dependent organs and tissues. Knowledge of the causative factors is crucial to the understanding of disease mechanisms and the development of specific treatment. Based on pathogenetic similarities between PSC and arteriosclerosis, we hypothesize that PSC represents "arteriosclerosis of the bile duct" initiated by toxic biliary lipids. This hypothesis is based on common molecular, cellular, and morphological features providing the conceptual framework for a deeper understanding of their pathogenesis. This hypothesis should stimulate translational research to facilitate the search for novel treatment strategies for both diseases

Azobenzene-based inhibitors of human carbonic anhydrase II

Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small library of nine photochromic sulfonamides towards hCAII. All molecules are azobenzene-4-sulfonamides, which are substituted by different functional groups in the 4 '-position and were characterized by X-ray crystallography. We aimed to investigate the influence of electrondonating or electron-withdrawing substituents on the inhibitory constant Ki. With the aid of an hCAII crystal structure bound to one of the synthesized azobenzenes, we found that the electronic structure does not strongly affect inhibition. Taken together, all compounds are strong blockers of hCAII with K-i = 25-65 nM that are potentially photochromic and thus combine studies from chemical synthesis, crystallography and enzyme kinetics

Towards a nationwide implementation of a standardized nutrition and dietetics terminology in clinical practice: a pre-implementation focus group study including a pretest and using the consolidated framework for implementation research

BACKGROUND & AIMS In order to assure high quality of nutrition and dietetic care as well as research, the implementation of a standardized terminology, such as the World Health Organization (WHO) International Classification of Functioning, Disability and Health for Dietetics (ICF-Dietetics) is indispensable. The aim of this study was to explore the clinical practicability and applicability of the ICF-Dietetics in the field of nutrition and dietetic practice prior to the implementation in order to develop criteria (points to consider) for a targeted implementation strategy. METHODS A focus group study including a pretest of the ICF-Dietetics was conducted. Subsequently, facilitators and barriers for a nationwide implementation of the ICF-Dietetics in clinical nutrition and dietetic practice were identified and linked to interventions (combining theory-based and group-based approach) using the Consolidated Framework of Implementation Research (CFIR) to organize and represent data and summarized in a logic model. RESULTS In the pretest 55 clinical documentations which consisted of 248 different ICF-Dietetics categories were received. In four focus groups with 22 health professionals, 66 relevant higher-level themes and implementation strategy criteria (points to consider) were identified. These themes referred to all five domains of the CFIR, namely intervention characteristics, inner setting, outer setting, characteristics of individuals and implementation process and contained important barriers and facilitators that were linked to six implementation objectives as well as six context requirements and five main actors. CONCLUSIONS This study provides facilitators and barriers to be addressed when implementing the ICF-Dietetics in clinical practice and shows potential interventions based on this analysis. A nationwide implementation was mainly seen as a great advantage for enhancing quality and continuity of care and for providing comparable data. However, it requires further refinements and a multifaceted implementation strategy where the engagement of leadership of institutions plays a crucial role. These results have provided a foundation for a targeted implementation strategy to increase the success, reproducibility and comparability

Optical control of AMPA receptors using a photoswitchable quinoxaline-2,3-dione antagonist

AMPA receptors respond to the neurotransmitter glutamate and play a critical role in excitatory neurotransmission. They have been implicated in several psychiatric disorders and have rich pharmacology. Antagonists of AMPA receptors have been explored as drugs and one has even reached the clinic. We now introduce a freely diffusible photoswitchable antagonist that is selective for AMPA receptors and endows them with light-sensitivity. Our photoswitch, ShuBQX-3, is active in its dark-adapted trans-isoform but is significantly less active as its cis-isoform. ShuBQX-3 exhibits a remarkable red-shifting of its photoswitching properties through interactions with the AMPA receptor ligand binding site. Since it can be used to control action potential firing with light, it could emerge as a powerful tool for studying synaptic transmission with high spatial and temporal precision

Photopharmacologic Vision Restoration Reduces Pathological Rhythmic Field Potentials in Blind Mouse Retina

Photopharmacology has yielded compounds that have potential to restore impaired visual responses resulting from outer retinal degeneration diseases such as retinitis pigmentosa. Here we evaluate two photoswitchable azobenzene ion channel blockers, DAQ and DAA for vision restoration. DAQ exerts its effect primarily on RGCs, whereas DAA induces light-dependent spiking primarily through amacrine cell activation. Degeneration-induced local field potentials remain a major challenge common to all vision restoration approaches. These 5-10 Hz rhythmic potentials increase the background firing rate of retinal ganglion cells (RGCs) and overlay the stimulated response, thereby reducing signal-to-noise ratio. Along with the bipolar cell-selective photoswitch DAD and second-generation RGC-targeting photoswitch PhENAQ, we investigated the effects of DAA and DAQ on rhythmic local field potentials (LFPs) occurring in the degenerating retina. We found that photoswitches targeting neurons upstream of RGCs, DAA (amacrine cells) and DAD (bipolar cells) suppress the frequency of LFPs, while DAQ and PhENAQ (RGCs) had negligible effects on frequency or spectral power of LFPs. Taken together, these results demonstrate remarkable diversity of cell-type specificity of photoswitchable channel blockers in the retina and suggest that specific compounds may counter rhythmic LFPs to produce superior signal-to-noise characteristics in vision restoration

Prognostic impact of ICG-PDR in patients with hypoxic hepatitis

Background: Hepatic impairment is found in up to 20 % in critically ill patients. Hypoxic/ischemic hepatitis (HH) is a diffuse hepatic damage associated with high morbidity and mortality. Indocyanine green plasma disappearance rate (ICG-PDR) is an effective tool assessing liver function in acute and chronic hepatic diseases. Aim of this study was to evaluate the prognostic impact of ICG-PDR in comparison to established parameters for risk stratification. Methods: Patients with HH were included in this prospective observational study and compared to cirrhosis, acute liver failure (ALF) and patients without underlying liver disease. ICG-PDR, measured non-invasively by finger pulse densitometry, was assessed on admission and in patients with HH serially and results were compared between groups. Diagnostic test accuracy of ICG-PDR predicting 28-day mortality was analyzed by receiver operating characteristics (ROC). Results: ICG-PDR on admission was significantly lower in patients with liver diseases than in patients without hepatic impairment (median 5.7 %/min, IQR 3.8-7.9 vs. 20.7 %/min, IQR 14.1-25.4 %/min;p = 9.0 %/min 48 h after admission. Conclusions: ICG-PDR is an independent predictor of mortality in patients with liver disease. Diagnostic test accuracy of ICG-PDR was superior to standard liver function parameters and established scoring systems in patients with HH

Pathophysiological mechanisms of liver injury in COVID-19

The recent outbreak of coronavirus disease 2019 (COVID‐19), caused by the Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) has resulted in a world‐wide pandemic. Disseminated lung injury with the development of acute respiratory distress syndrome (ARDS) is the main cause of mortality in COVID‐19. Although liver failure does not seem to occur in the absence of pre‐existing liver disease, hepatic involvement in COVID‐19 may correlate with overall disease severity and serve as a prognostic factor for the development of ARDS. The spectrum of liver injury in COVID‐19 may range from direct infection by SARS‐CoV‐2, indirect involvement by systemic inflammation, hypoxic changes, iatrogenic causes such as drugs and ventilation to exacerbation of underlying liver disease. This concise review discusses the potential pathophysiological mechanisms for SARS‐CoV‐2 hepatic tropism as well as acute and possibly long‐term liver injury in COVID‐19

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis

Objective Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies. Design Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations. Results Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63–68) and 86% (84–87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37–39) and specificity of 90% (89–91) with 19% needing biopsy. Conclusion Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies