Evaluation of the cardiac amyloidosis clinical pathway implementation: A real-world experience

AIMS: The aim of this study is to evaluate the implementation of the cardiac amyloidosis (CA) clinical pathway on awareness among referring cardiologists, diagnostic delay, and severity of CA at diagnosis. METHODS AND RESULTS: Patients with CA were retrospectively included in this study and divided into two periods: pre-implementation of the CA clinical pathway (2007–18; T1) and post-implementation (2019–20; T2). Patients’ and disease characteristics were extracted from electronic health records and compared. In total, 113 patients (mean age 67.8 ± 8.5 years, 26% female) were diagnosed with CA [T1 (2007–18): 56; T2 (2019–20): 57]. The number of CA diagnoses per year has increased over time. Reasons for referral changed over time, with increased awareness of right ventricular hypertrophy (9% in T1 vs. 36% in T2) and unexplained heart failure with preserved ejection fraction (22% in T1 vs. 38% in T2). Comparing T1 with T2, the diagnostic delay also improved (14 vs. 8 months, P < 0.01), New York Heart Association Class III (45% vs. 23%, P = 0.03), and advanced CA stage (MAYO/Gillmore Stage III/IV; 61% vs. 33%, P ≤ 0.01) at time of diagnosis decreased. CONCLUSION: After implementation of the CA clinical pathway, the awareness among referring cardiologists improved, diagnostic delay was decreased, and patients had less severe CA at diagnosis. Further studies are warranted to assess the prognostic impact of CA clinical pathway implementation

Wartenberg’s migrant sensory neuritis: a prospective follow-up study

Migrant sensory neuropathy (Wartenberg’s migrant sensory neuritis) is characterized by sudden numbness in the distribution of one or multiple cutaneous nerves. To study disease course and outcome, we prospectively followed 12 patients who presented to our tertiary referral neuromuscular outpatient clinic between January 2003 and January 2004. Medical history, neurological, laboratory and electrophysiological examinations were obtained from all patients. All patients were reviewed a second time in 2007, and five had a follow-up electrophysiological examination. At the first visit, 50% described an episode of stretching preceding the sensory complaints. All but three described pain in the affected area before or concomitant with sensory loss. At clinical examination a median of six skin areas were affected, and in 75% this could be confirmed by nerve conduction studies in at least one nerve. Forty-two percent had involvement of the trigeminal nerve. After a mean disease duration of 7.5 years, three patients reported a complete disappearance of sensory complaints and five that the pain had disappeared, but numbness remained. Three patients still had both painful and numb sensory deficits. One patient developed a distal symmetric sensory polyneuropathy. In conclusion, Wartenberg’s sensory neuritis is a distinct, exclusively sensory, neuropathy, marked by pain preceding numbness in affected nerves. An episode of stretching preceding pain is not necessary for the diagnosis. Wartenberg’s sensory neuritis often retains its spotty, exclusively sensory characteristics after long term follow-up

Nodes of Ranvier and Paranodes in Chronic Acquired Neuropathies

Chronic acquired neuropathies of unknown origin are classified as chronic inflammatory demyelinating polyneuropathies (CIDP) and chronic idiopathic axonal polyneuropathies (CIAP). The diagnosis can be very difficult, although it has important therapeutic implications since CIDP can be improved by immunomodulating treatment. The aim of this study was to examine the possible abnormalities of nodal and paranodal regions in these two types of neuropathies. Longitudinal sections of superficial peroneal nerves were obtained from biopsy material from 12 patients with CIDP and 10 patients with CIAP and studied by immunofluorescence and in some cases electron microscopy. Electron microscopy revealed multiple alterations in the nodal and paranodal regions which predominated in Schwann cells in CIDP and in axons in CIAP. In CIDP paranodin/Caspr immunofluorescence was more widespread than in control nerves, extending along the axon in internodes where it appeared intense. Nodal channels Nav and KCNQ2 were less altered but were also detected in the internodes. In CIAP paranodes, paranodin labeling was irregular and/or decreased. To test the consequences of acquired primary Schwann cells alteration on axonal proteins, we used a mouse model based on induced deletion of the transcription factor Krox-20 gene. In the demyelinated sciatic nerves of these mice we observed alterations similar to those found in CIDP by immunofluorescence, and immunoblotting demonstrated increased levels of paranodin. Finally we examined whether the alterations in paranodin immunoreactivity could have a diagnosis value. In a sample of 16 biopsies, the study of paranodin immunofluorescence by blind evaluators led to correct diagnosis in 70±4% of the cases. This study characterizes for the first time the abnormalities of nodes of Ranvier in CIAP and CIDP, and the altered expression and distribution of nodal and paranodal proteins. Marked differences were observed between CIDP and CIAP and the alterations in paranodin immunofluorescence may be an interesting tool for their differential diagnosis

In vitro epithelial-to-mesenchymal transformation in human adult epicardial cells is regulated by TGFβ-signaling and WT1

Adult epicardial cells are required for endogenous cardiac repair. After myocardial injury, they are reactivated, undergo epithelial-to-mesenchymal transformation (EMT) and migrate into the injured myocardium where they generate various cell types, including coronary smooth muscle cells and cardiac interstitial fibroblasts, which contribute to cardiac repair. To understand what drives epicardial EMT, we used an in vitro model for human adult epicardial cells. These cells have an epithelium-like morphology and markedly express the cell surface marker vascular cell adhesion marker (VCAM-1). In culture, epicardial cells spontaneously undergo EMT after which the spindle-shaped cells now express endoglin. Both epicardial cells before and after EMT express the epicardial marker, Wilms tumor 1 (WT1). Adding transforming growth factor beta (TGFβ) induces loss of epithelial character and initiates the onset of mesenchymal differentiation in human adult epicardial cells. In this study, we show that TGFβ-induced EMT is dependent on type-1 TGFβ receptor activity and can be inhibited by soluble VCAM-1. We also show that epicardial-specific knockdown of Wilms tumor-1 (WT1) induces the process of EMT in human adult epicardial cells, through transcriptional regulation of platelet-derived growth factor receptor alpha (Pdgfrα), Snai1 and VCAM-1. These data provide new insights into the process of EMT in human adult epicardial cells, which might provide opportunities to develop new strategies for endogenous cell-based cardiac repair

Ancient chicken remains reveal the origins of virulence in Marek's disease virus

This is the author accepted manuscript. The final version is available from the American Association for the Advancement of Science via the DOI in this recordData and materials availability: All MDV sequence data generated have been deposited in GenBank under accession PRJEB64489. Code is available at GitHub (https://github.com/antonisdim/MDV) and archived at Zenodo (https://zenodo.org/records/10022436) (25).The pronounced growth in livestock populations since the 1950s has altered the epidemiological and evolutionary trajectory of their associated pathogens. For example, Marek's disease virus (MDV), which causes lymphoid tumors in chickens, has experienced a marked increase in virulence over the past century. Today, MDV infections kill >90% of unvaccinated birds, and controlling it costs more than US$1 billion annually. By sequencing MDV genomes derived from archeological chickens, we demonstrate that it has been circulating for at least 1000 years. We functionally tested the Meq oncogene, one of 49 viral genes positively selected in modern strains, demonstrating that ancient MDV was likely incapable of driving tumor formation. Our results demonstrate the power of ancient DNA approaches to trace the molecular basis of virulence in economically relevant pathogens.European Research Council (ERC)Wellcome TrustOxford Martin School Pandemic Genomics ProgrammeArts and Humanities Research Council (AHRC)European Union Horizon 2020Biotechnology and Biological Sciences Research Council (BBSRC)Research Foundation–Flanders (Fonds voor Wetenschappelijk Onderzoek