High salt intake increases copeptin but salt sensitivity is associated with fluid induced reduction of copeptin in women.

This study investigated if copeptin is affected by high salt intake and whether any salt-induced changes in copeptin are related to the degree of salt sensitivity. The study was performed on 20 men and 19 women. In addition to meals containing 50 mmol NaCl daily, capsules containing 100 mmol NaCl and corresponding placebo capsules were administered during 4 weeks each, in random order. Measurements of 24 h blood pressure, body weight, 24 h urinary volume, and fasting plasma copeptin were performed at high and low salt consumption. Copeptin increased after a high compared to low dietary salt consumption in all subjects 3,59 ± 2,28 versus 3,12 ± 1,95 (P = 0,02). Copeptin correlated inversely with urinary volume, at both low (r = -0,42; P = 0,001) and high (r = -0,60; P < 0,001) salt consumption, as well as with the change in body weight (r = -0,53; P < 0,001). Systolic salt sensitivity was inversely correlated with salt-induced changes of copeptin, only in females (r = -0,58; P = 0,017). As suppression of copeptin on high versus low salt intake was associated with systolic salt sensitivity in women, our data suggest that high fluid intake and fluid retention may contribute to salt sensitivity

Electrophysiological abnormalities in patients with paroxysmal atrial fibrillation in the absence of overt structural heart disease

AbstractPurposeThe aim of the present study was to define the atrial electrical substrate in patients with paroxysmal atrial fibrillation (AF) occurring in the absence of overt structural heart disease and to assess if electrophysiological parameters could predict AF recurrence after radiofrequency ablation in this population.Methods and results45 consecutive patients (39 male, age 59 ± 10 years) with paroxysmal AF and without overt structural heart disease, referred for radiofrequency catheter ablation, were prospectively enrolled. A cohort of 12 age-matched patients without a history of AF, served as a control group. Atrial electrical substrate was assessed by P-wave signal-averaging, intracardiac conduction delays and refractory periods. Total P wave duration during signal-averaging was longer in patients with paroxysmal AF than in controls (140 ± 19 ms vs 123 ± 13 ms, p = 0.004). Patients with paroxysmal AF showed an increase in right intra-atrial (40.2 ± 11.3 ms vs 31.7 ± 11.8 ms, p = 0.02) and inter-atrial conduction delays (87.93 ± 22.0 ms vs 65.3 ± 15.6 ms, p = 0.001) in sinus rhythm. Refractory periods in the right atrium were longer in patients with paroxysmal AF (265 ± 44 ms vs 222 ± 32 ms, p = 0.002). After ablation, 22 patients had AF recurrence but showed no differences in electrophysiological parameters compared to patients without recurrence.ConclusionElectrophysiological abnormalities are present in patients with paroxysmal AF without overt structural heart disease. Neither signal-averaged P-wave duration nor intracardiac atrial electrophysiology could predict arrhythmia recurrence after pulmonary vein isolation

Industrial Development of Standardized Fetal Progenitor Cell Therapy for Tendon Regenerative Medicine: Preliminary Safety in Xenogeneic Transplantation.

Tendon defects require multimodal therapeutic management over extensive periods and incur high collateral burden with frequent functional losses. Specific cell therapies have recently been developed in parallel to surgical techniques for managing acute and degenerative tendon tissue affections, to optimally stimulate resurgence of structure and function. Cultured primary human fetal progenitor tenocytes (hFPT) have been preliminarily considered for allogeneic homologous cell therapies, and have been characterized as stable, consistent, and sustainable cell sources in vitro. Herein, optimized therapeutic cell sourcing from a single organ donation, industrial transposition of multi-tiered progenitor cell banking, and preliminary preclinical safety of an established hFPT cell source (i.e., FE002-Ten cell type) were investigated. Results underlined high robustness of FE002-Ten hFPTs and suitability for sustainable manufacturing upscaling within optimized biobanking workflows. Absence of toxicity or tumorigenicity of hFPTs was demonstrated in ovo and in vitro, respectively. Furthermore, a 6-week pilot good laboratory practice (GLP) safety study using a rabbit patellar tendon partial-thickness defect model preliminarily confirmed preclinical safety of hFPT-based standardized transplants, wherein no immune reactions, product rejection, or tumour formation were observed. Such results strengthen the rationale of the multimodal Swiss fetal progenitor cell transplantation program and prompt further investigation around such cell sources in preclinical and clinical settings for musculoskeletal regenerative medicine

Development of Standardized Fetal Progenitor Cell Therapy for Cartilage Regenerative Medicine: Industrial Transposition and Preliminary Safety in Xenogeneic Transplantation

Diverse cell therapy approaches constitute prime developmental prospects for managing acute or degenerative cartilaginous tissue affections, synergistically complementing specific surgical solutions. Bone marrow stimulation (i.e., microfracture) remains a standard technique for cartilage repair promotion, despite incurring the adverse generation of fibrocartilagenous scar tissue, while matrix-induced autologous chondrocyte implantation (MACI) and alternative autologous cell-based approaches may partly circumvent this effect. Autologous chondrocytes remain standard cell sources, yet arrays of alternative therapeutic biologicals present great potential for regenerative medicine. Cultured human epiphyseal chondro-progenitors (hECP) were proposed as sustainable, safe, and stable candidates for chaperoning cartilage repair or regeneration. This study describes the development and industrial transposition of hECP multi-tiered cell banking following a single organ donation, as well as preliminary preclinical hECP safety. Optimized cell banking workflows were proposed, potentially generating millions of safe and sustainable therapeutic products. Furthermore, clinical hECP doses were characterized as non-toxic in a standardized chorioallantoic membrane model. Lastly, a MACI-like protocol, including hECPs, was applied in a three-month GLP pilot safety evaluation in a caprine model of full-thickness articular cartilage defect. The safety of hECP transplantation was highlighted in xenogeneic settings, along with confirmed needs for optimal cell delivery vehicles and implantation techniques favoring effective cartilage repair or regeneration

Industrial Development of Standardized Fetal Progenitor Cell Therapy for Tendon Regenerative Medicine: Preliminary Safety in Xenogeneic Transplantation

Tendon defects require multimodal therapeutic management over extensive periods and incur high collateral burden with frequent functional losses. Specific cell therapies have recently been developed in parallel to surgical techniques for managing acute and degenerative tendon tissue affections, to optimally stimulate resurgence of structure and function. Cultured primary human fetal progenitor tenocytes (hFPT) have been preliminarily considered for allogeneic homologous cell therapies, and have been characterized as stable, consistent, and sustainable cell sources in vitro. Herein, optimized therapeutic cell sourcing from a single organ donation, industrial transposition of multi-tiered progenitor cell banking, and preliminary preclinical safety of an established hFPT cell source (i.e., FE002-Ten cell type) were investigated. Results underlined high robustness of FE002-Ten hFPTs and suitability for sustainable manufacturing upscaling within optimized biobanking workflows. Absence of toxicity or tumorigenicity of hFPTs was demonstrated in ovo and in vitro, respectively. Furthermore, a 6-week pilot good laboratory practice (GLP) safety study using a rabbit patellar tendon partial-thickness defect model preliminarily confirmed preclinical safety of hFPT-based standardized transplants, wherein no immune reactions, product rejection, or tumour formation were observed. Such results strengthen the rationale of the multimodal Swiss fetal progenitor cell transplantation program and prompt further investigation around such cell sources in preclinical and clinical settings for musculoskeletal regenerative medicine

Revisiting the Immune Trypanolysis Test to Optimise Epidemiological Surveillance and Control of Sleeping Sickness in West Africa

Human African trypanosomiasis (HAT) due to Trypanosoma brucei (T.b.) gambiense is usually diagnosed using two sequential steps: first the card agglutination test for trypanosomiasis (CATT) used for serological screening, followed by parasitological methods to confirm the disease. Currently, CATT will continue to be used as a test for mass screening because of its simplicity and high sensitivity; however, its performance as a tool of surveillance in areas where prevalence is low is poor because of its limited specificity. Hence in the context of HAT elimination, there is a crucial need for a better marker of contact with T.b. gambiense in humans. We evaluated here an existing highly specific serological tool, the trypanolysis test (TL). We evaluated TL in active, latent and historical HAT foci in Guinea, Côte d'Ivoire and Burkina Faso. We found that TL was a marker for exposure to T.b. gambiense. We propose that TL should be used as a surveillance tool to monitor HAT elimination

Should I Get Screened for Sleeping Sickness? A Qualitative Study in Kasai Province, Democratic Republic of Congo

Active screening strategies are common disease control interventions in the context of poor and remote rural communities with no direct access to healthcare facilities. For such activities to be as effective as possible, it is necessary that they are well adapted to local socio-economic and cultural settings. Our aim was to gain insight into the barriers communities in the Kasai-Oriental province of the Democratic Republic of Congo experience in relation to their participation in active screening activities for African sleeping sickness. Participation rates seem to be especially low in this province compared to other endemic regions in the country. We found several important factors to be in play, a number of which could be addressed by adapting the operational procedures of the mobile teams that perform the active screening activities (e.g., improved confidentiality during the screening procedure). However, more profound considerations were found in the form of regional beliefs related to the treatment of the disease. Although not based on rational grounds, these prohibitions seem to pose a significant barrier in a person's decision to seek diagnosis and treatment. A better understanding of these prohibitions and their origin could lead to improved participation rates for sleeping sickness screening in Kasai-Oriental

2,4-Diaminopyrimidines as Potent Inhibitors of Trypanosoma brucei and Identification of Molecular Targets by a Chemical Proteomics Approach

The protozoan parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT) or sleeping sickness, a fatal disease affecting nearly half a million people in sub-Saharan Africa. Current treatments for HAT have very poor safety profiles and are difficult to administer. There is an urgent need for new, safe and effective treatments for sleeping sickness. This work describes the discovery of 2,4-diaminopyrimidines, exemplified by 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid phenylamide or SCYX-5070, as potent inhibitors of T. brucei growth in vitro and also in animal models for HAT. To determine the parasite proteins responsible for interaction with SCYX-5070 and related compounds, affinity pull-downs were performed followed by sequence analysis and parasite genome database searching. The work revealed that mitogen-activated protein kinases (MAPKs) and cdc2-related kinases (CRKs) are the major proteins specifically bound to the immobilized compound, suggesting their potential participation in the pharmacological effects of 2,4-diaminopyrimidines against trypanosomatid protozoan parasites. These data strongly support the use of 2,4-diminipyrimidines as leads for the development of new drug candidates for the treatment of HAT