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Purpose Recombinant erythropoietin (EPO) administered for traumatic brain injury (TBI) may increase short-term survival, but the long-term effect is unknown. Methods We conducted a pre-planned long-term follow-up of patients in the multicentre erythropoietin in TBI trial (2010-2015). We invited survivors to follow-up and evaluated survival and functional outcome with the Glasgow Outcome Scale-Extended (GOSE) (categories 5-8 = good outcome), and secondly, with good outcome determined relative to baseline function (sliding scale). We used survival analysis to assess time to death and absolute risk differences (ARD) to assess favorable outcomes. We categorized TBI severity with the International Mission for Prognosis and Analysis of Clinical Trials in TBI model. Heterogeneity of treatment effects were assessed with interaction p-values based on the following a priori defined subgroups, the severity of TBI, and the presence of an intracranial mass lesion and multi-trauma in addition to TBI. Results Of 603 patients in the original trial, 487 patients had survival data; 356 were included in the follow-up at a median of 6 years from injury. There was no difference between treatment groups for patient survival [EPO vs placebo hazard ratio (HR) (95% confidence interval (CI) 0.73 (0.47-1.14) p = 0.17]. Good outcome rates were 110/175 (63%) in the EPO group vs 100/181 (55%) in the placebo group (ARD 8%, 95% CI [Formula omitted] 3 to 18%, p = 0.14). When good outcome was determined relative to baseline risk, the EPO groups had better GOSE (sliding scale ARD 12%, 95% CI 2-22%, p = 0.02). When considering long-term patient survival, there was no evidence for heterogeneity of treatment effect (HTE) according to severity of TBI (p = 0.85), presence of an intracranial mass lesion (p = 0.48), or whether the patient had multi-trauma in addition to TBI (p = 0.08). Similarly, no evidence of treatment heterogeneity was seen for the effect of EPO on functional outcome. Conclusion EPO neither decreased overall long-term mortality nor improved functional outcome in moderate or severe TBI patients treated in the intensive care unit (ICU). The limited sample size makes it difficult to make final conclusions about the use of EPO in TBI., Author(s): Markus B. Skrifvars [sup.1], Nora Luethi [sup.2], Michael Bailey [sup.3], Craig French [sup.4], Alistair Nichol [sup.3] [sup.5], Tony Trapani [sup.3], Colin McArthur [sup.6], Yaseen M. Arabi [sup.7], Stepani Bendel [...]

The design of potent indoleamine 2,3-dioxygenase 1 (IDOl) enzyme inhibitors targeting immunopathic neuroinflammation has emerged as an area of interest for the treatment of Alzheimer's disease (AD); additionally, recent findings on the clinical benefits of antibodies preventing [beta]-amyloid (Aft) aggregation have renewed efforts to discover small molecule anti-aggregants targeting proteopathic protein misfolding. Exploiting an endogenous tryptophan-like scaffold, we describe the design and synthesis of small-molecule inhibitors of both immunopathic and proteopathic processes, thus presenting the possibility of single therapeutics acting simultaneously on multiple AD pathogeneses. Specifically, investigations on compounds that inhibit both IDOl (in human recombinant enzyme, transfected HEK293 cells, and interferon-[gamma] stimulated human microglia assays) and Aft aggregation (in thioflavin-T and biotinylated-A[beta] oligomeric assays) are presented. Five compounds have been identified with high potency against both targets, identifying (E)-3-styryl indoles as useful tool compounds for developing Alzheimer's therapeutics. Brain penetration of these compounds via passive diffusion or active transport was predicted using Blood-Brain Barrier Score and Brain Exposure Efficiency Score calculations, respectively; the effects of efflux (pgp, BCRP), and influx (OCT1, OCT2) transporters were similarly predicted. Structure-activity relationships were rationalised with molecular docking and molecular dynamics simulations, which also provide insights for future lead compound optimisation. Key words: Alzheimer's disease, tryptophan, IDO-1, amyloid-[beta], neuroinflammation, neuroimmunology La conception de puissants inhibiteurs de l'indoleamine 2,3 dioxygenase 1 (IDOl) ciblant la neuro-inflammation immunopathique constitue desormais un nouveau champ d'interet pour le traitement de la maladie d'Alzheimer (alzheimer). En outre, des donnees recentes sur les bienfaits cliniques des anticorps empechant l'agregation de la beta-amyloide (Aft) ont ravive les efforts visant a decouvrir de petites molecules antiagregantes qui ciblent le mauvais repliement proteopathique des proteines. En exploitant une structure endogene de type tryptophane, nous avons concu et synthetise des inhibiteurs a petite molecule qui ciblent a la fois les processus immunopathiques et proteopathiques, ouvrant ainsi la voie a des monotherapies agissant simultanement sur plusieurs processus pathogenes de l'alzheimer. En particulier, nous presentons des experiences portant sur des composes qui inhibent a la fois IDOl (dans des essais avec des enzymes recombinantes humaines, des cellules HEK293 transferees et des microglies humaines stimulees par 1'interferon [gamma]) et l'agregation de l'A[beta] (dans des essais de liaison avec la thioflavine-T et d'inhibition de l'oligomerisation de l'A[beta] biotinylee). Nous avons identifie cinq composes presentant une forte affinite pour les deux cibles, ce qui nous a permis de definir les (E) 3 styrylindoles comme des composes pouvant servir d'outils pour le developpement d'agents therapeutiques contre l'alzheimer. La penetration cerebrale de ces composes par diffusion passive ou transport actif a ete estimee a l'aide de calculs de l'indice penetration de la barriere hematoencephalique (<< Score BBB >>) et de l'indice d'efficacite de l'exposition cerebrale (<< Score BEE >>), respectivement. Les effets des transporteurs d'efflux (P gp, BCRP) et d'influx (OCT1, OCT2) ont ete egalement ete estimes par calculs. Nous avons rationalise les relations structure-activite a l'aide de simulations d'amarrage moleculaire et de dynamique moleculaire, qui fournissent egalement des informations pour roptimisation d'eventuels composes tetes de serie. [Traduit par la Redaction] Mots-cles : maladie d'Alzheimer, tryptophane, IDOl, beta-amyloide, neuro-inflammation, neuro-immunologie, Introduction The neuropathology of Alzheimer's disease (AD) involves the brain's innate and adaptive immune systems, resulting in a complex inflammatory state that involves not only aggregation of [beta]-amyloid (Aft) and [...]

Context.--Amyloidosis is an uncommon but important entity. A protein-based classification of amyloidosis defines the underlying disease process, directing clinical management and providing prognostic information. However, in routine surgical pathology there often is no attempt to classify amyloid other than staining to determine light chain-associated amyloidosis. Systemic and localized amyloidosis vary with respect to frequency of organ involvement by different amyloid types, and most amyloid proteins have commercial antibodies available for identification. Objective.--To provide a guide for the likelihood of amyloid type by organ system. Data Sources.--Literature review based on PubMed searches containing the word amyloid, specifically addressing the prevalence and significance of amyloid proteins in each organ system other than the brain, and the authors' practice experience. Conclusions.--In patients with amyloidosis, determination of the responsible protein is critical for appropriate patient care. In large subspecialty practices and reference laboratories with experience in using and analyzing relevant immunohistochemistry, most amyloid proteins can be identified with an organ-specific algorithm. Referring to an organ-based algorithm may be helpful in providing clinicians with a more specific differential diagnosis regarding amyloid type to help guide clinical evaluation and treatment. When the protein cannot be characterized, mass spectrometry can be performed to definitively classify the amyloid type. (Arch Pathol Lab Med. 2020;144:379-387; doi: 10.5858/ arpa.2018-0509-RA), Amyloidosis is defined as tissue deposition of protein fibrils that form insoluble [beta]-pleated sheets. It has a reported prevalence of 20 per million with an incidence of 10 to 13 [...]