Risk willingness in multiple system atrophy and Parkinson’s disease understanding patient preferences

Disease-modifying therapeutics in the α-synucleinopathies multiple system atrophy (MSA) and Parkinson’s Disease (PD) are in early phases of clinical testing. Involving patients’ preferences including therapy-associated risk willingness in initial stages of therapy development has been increasingly pursued in regulatory approval processes. In our study with 49 MSA and 38 PD patients, therapy-associated risk willingness was quantified using validated standard gamble scenarios for varying severities of potential drug or surgical side effects. Demonstrating a non-gaussian distribution, risk willingness varied markedly within, and between groups. MSA patients accepted a median 1% risk [interquartile range: 0.001–25%] of sudden death for a 99% [interquartile range: 99.999–75%] chance of cure, while PD patients reported a median 0.055% risk [interquartile range: 0.001–5%]. Contrary to our hypothesis, a considerable proportion of MSA patients, despite their substantially impaired quality of life, were not willing to accept increased therapy-associated risks. Satisfaction with life situation, emotional, and nonmotor disease burden were associated with MSA patients’ risk willingness in contrast to PD patients, for whom age, and disease duration were associated factors. An individual approach towards MSA and PD patients is crucial as direct inference from disease (stage) to therapy-associated risk willingness is not feasible. Such studies may be considered by regulatory agencies in their approval processes assisting with the weighting of safety aspects in a patient-centric manner. A systematic quantitative assessment of patients’ risk willingness and associated features may assist physicians in conducting individual consultations with patients who have MSA or PD by facilitating communication of risks and benefits of a treatment option

Acute cellular rejection in small-bowel transplantation impairs NCR+ innate lymphoid cell subpopulation 3/interleukin 22 axis

Acute cellular rejection (ACR) remains as one of the main causes of graft loss and death in intestinal transplant (ITx) patients. ACR promotes intestinal injury, disruption of the mucosal barrier, bacterial translocation, and organ dysfunction. As epithelial regeneration is critical in reversing these consequences, the functional axis between the innate lymphoid cell subpopulation 3 (ILC3) and interleukin 22 plays an essential role in that process. Natural-cytotoxic-receptor–positive (NCR+) ILC3 cells have been demonstrated to induce intestinal-stem-cell proliferation along with an IL-22–dependent expansion of that population in several intestinal pathologies, though thus far not after ITx. Therefore, we intended to determine the impact of chronic immunosuppression and ACR on ILC3 cells and interleukin-22 (IL-22) production in the lamina propria after that intervention. Materials and methods We compared biopsies from healthy volunteers with biopsies from ITx recipients without or with mild-to-moderate ACR, using flow cytometry and the quantitative-PCR. Results NCR+ ILC3 cells were found to be unaffected by immunosuppression at different time points posttransplant when patients did not experience ACR, but were diminished upon the occurrence of ACR independently of the post-ITx time. Moreover, IL-22–expression levels were notably reduced in ACR. Conclusion The NCR+-ILC3/IL-22 axis is impaired during ACR contributing to a delay in or lack of a complete and efficient epithelial regeneration. Thus, our findings reveal that IL-22 analogues could potentially be used as a new complementary therapeutic approach, in conjunction with immunosuppressant drugs, in order to promote mucosal regeneration upon ACR.Consejo Nacional de Investigaciones Científicas y TécnicasInstituto de Estudios Inmunológicos y Fisiopatológico

Acute cellular rejection in small-bowel transplantation impairs NCR+ innate lymphoid cell subpopulation 3/interleukin 22 axis

Acute cellular rejection (ACR) remains as one of the main causes of graft loss and death in intestinal transplant (ITx) patients. ACR promotes intestinal injury, disruption of the mucosal barrier, bacterial translocation, and organ dysfunction. As epithelial regeneration is critical in reversing these consequences, the functional axis between the innate lymphoid cell subpopulation 3 (ILC3) and interleukin 22 plays an essential role in that process. Natural-cytotoxic-receptor–positive (NCR+) ILC3 cells have been demonstrated to induce intestinalstem-cell proliferation along with an IL-22–dependent expansion of that population in several intestinal pathologies, though thus far not after ITx. Therefore, we intended to determine the impact of chronic immunosuppression and ACR on ILC3 cells and interleukin-22 (IL-22) production in the lamina propria after that intervention. Materials and methods: We compared biopsies from healthy volunteers with biopsies from ITx recipients without or with mild-to-moderate ACR, using flow cytometry and the quantitative-PCR. Results: NCR+ ILC3 cells were found to be unaffected by immunosuppression at different time points posttransplant when patients did not experience ACR, but were diminished upon the occurrence of ACR independently of the post-ITx time. Moreover, IL-22–expression levels were notably reduced in ACR. Conclusion: The NCR+-ILC3/IL-22 axis is impaired during ACR contributing to a delay in or lack of a complete and efficient epithelial regeneration. Thus, our findings reveal that IL-22 analogues could potentially be used as a new complementary therapeutic approach, in conjunction with immunosuppressant drugs, in order to promote mucosal regeneration upon ACR.Fil: Pucci Molineris, Melisa Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina. Universidad Favaloro; ArgentinaFil: González Polo, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina. Universidad Favaloro; ArgentinaFil: Rumbo, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Fuxman, Claudia. Universidad Favaloro; ArgentinaFil: Abate Daga, Carlos Rubén. Universidad Favaloro; ArgentinaFil: Nachman, Fabio. Universidad Favaloro; ArgentinaFil: Rumbo, Martín. Universidad Favaloro; ArgentinaFil: Gondolesi, Gabriel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina. Universidad Favaloro; ArgentinaFil: Meier, Dominik. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina. Universidad Favaloro; Argentin

Risk willingness in multiple system atrophy and Parkinson’s disease understanding patient preferences

Abstract Disease-modifying therapeutics in the α-synucleinopathies multiple system atrophy (MSA) and Parkinson’s Disease (PD) are in early phases of clinical testing. Involving patients’ preferences including therapy-associated risk willingness in initial stages of therapy development has been increasingly pursued in regulatory approval processes. In our study with 49 MSA and 38 PD patients, therapy-associated risk willingness was quantified using validated standard gamble scenarios for varying severities of potential drug or surgical side effects. Demonstrating a non-gaussian distribution, risk willingness varied markedly within, and between groups. MSA patients accepted a median 1% risk [interquartile range: 0.001–25%] of sudden death for a 99% [interquartile range: 99.999–75%] chance of cure, while PD patients reported a median 0.055% risk [interquartile range: 0.001–5%]. Contrary to our hypothesis, a considerable proportion of MSA patients, despite their substantially impaired quality of life, were not willing to accept increased therapy-associated risks. Satisfaction with life situation, emotional, and nonmotor disease burden were associated with MSA patients’ risk willingness in contrast to PD patients, for whom age, and disease duration were associated factors. An individual approach towards MSA and PD patients is crucial as direct inference from disease (stage) to therapy-associated risk willingness is not feasible. Such studies may be considered by regulatory agencies in their approval processes assisting with the weighting of safety aspects in a patient-centric manner. A systematic quantitative assessment of patients’ risk willingness and associated features may assist physicians in conducting individual consultations with patients who have MSA or PD by facilitating communication of risks and benefits of a treatment option

Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

International audienceThe accumulation of amyloid Tau aggregates is implicated in Alzheimer’s disease (AD) andother tauopathies. Molecular chaperones are known to maintain protein homeostasis. Herewe show that an ATP-dependent human chaperone system disassembles Tau fibrils invitro. We found that this function is mediated by the core chaperone HSC70, assisted byspecific co-chaperones, in particular class B J-domain proteins and a heat shock protein110 (Hsp110)-type nucleotide exchange factor (NEF). The Hsp70 disaggregation machineryprocessed recombinant fibrils assembled from all six Tau isoforms as well as sarkosylresistant Tau aggregates extracted from cell cultures and human AD brain tissues, demonstrating the ability of the Hsp70 machinery to recognize a broad range of Tau aggregates. However, the chaperone activityreleased monomeric and small oligomeric Tau species, which induced the aggregation of selfpropagating Tau conformers in a Tau cell culture model. We conclude that the activity of the Hsp70 disaggregation machinery is a double-sided sword, as it eliminates Tau amyloids at the cost of generating new seeds

Intestinal transplantation from the clinic to translational research

Uno de los mayores avances de la gastroenterología y la ci­rugía de los últimos 50 años ha sido el poder trasplantar los distintos órganos del aparato digestivo abdominal por separa­do o en su conjunto. La complejidad del trasplante intestinal llevó a la necesidad de crear equipos multidisciplinarios dedi­cados al manejo de pacientes con insuficiencia intestinal para definir la necesidad de soporte nutricional, rehabilitación o trasplante intestinal. Asimismo, cabe agregar que como parte de este núcleo se debe contar con áreas de investigación básica que permitan dar respuestas a problemas de la clínica aún no resueltos. El objetivo del siguiente trabajo es el de establecer la situación actual del trasplante intestinal, presentar los avan­ces y resultados alcanzados en nuestro centro, enfatizando el desarrollo logrado en el área clínica y las contribuciones he­chas como producto de estudios de investigación traslacional y de la inmunología de mucosas en una unidad integral de in­suficiencia intestinal, rehabilitación y trasplante. Lo reporta­do en el mismo permitirá mostrar que el trasplante intestinal se ha establecido como una opción terapéutica en nuestro país y Latinoamérica con resultados a largo plazo que ubican a nuestro servicio al nivel de los mejores centros del mundo con publicaciones clínicas, básicas y traslacionales que nos han permitido constituirnos como referentes en la especialidad.One of the greatest achievements in gastroenterology and sur­gery of the last 50 years has been the capability to transplant different abdominal organs of the digestive system separately or as a whole. The complexity of the intestinal transplanta­tion demands a multidisciplinary team engaged in the ma­ nagement of patients with intestinal failure responsible for defining the need for nutritional support, rehabilitation, or intestinal transplantation. This team should include a basic research area to provide answers to unresolved clinical pro­blems. The aim of this work is to update the current status of intestinal transplantation, and to show the progress and re­sults of our center; emphasizing our achievements in the cli­nical area, and the contributions of the translational research and mucosal immunology studies as part of the integral unit of intestinal failure, rehabilitation and transplantation. The data reported here demonstrate that the intestinal transplan­tation has been established as a therapeutic option in our country and Latin America, with long term results that have ranked our service at the level of the best centers in the world positioning us as referent in the specialty.Fil: Gondolesi, Gabriel Eduardo. Fundación Favaloro; Argentina. Cedars Sinai Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Meier, Dominik. Fundación Favaloro; ArgentinaFil: Rumbo, Carolina. Fundación Favaloro; ArgentinaFil: Ramisch, Diego. Fundación Favaloro; ArgentinaFil: Echevarria, Constanza. Fundación Favaloro; ArgentinaFil: Nachman, Fabio. Fundación Favaloro; ArgentinaFil: Pucci Molineris, Melisa Eliana. Fundación Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Martínez, María Inés. Fundación Favaloro; ArgentinaFil: Barros Schelotto, Pablo. Fundación Favaloro; ArgentinaFil: Cabanne, Ana. Fundación Favaloro; ArgentinaFil: Solar, Héctor. Fundación Favaloro; ArgentinaFil: Rumbo, Martín. Fundación Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

NSs amyloid formation is associated with the virulence of Rift Valley fever virus in mice

International audienceAmyloid fibrils result from the aggregation of host cell-encoded proteins, many giving rise to specific human illnesses such as Alzheimer's disease. Here we show that the major virulence factor of Rift Valley fever virus, the protein NSs, forms filamentous structures in the brain of mice and affects mortality. NSs assembles into nuclear and cytosolic disulfide bond-dependent fibrillary aggregates in infected cells. NSs structural arrangements exhibit characteristics typical for amyloids, such as an ultrastructure of 12 nm-width fibrils, a strong detergent resistance, and interactions with the amyloid-binding dye Thioflavin-S. The assembly dynamics of viral amyloid-like fibrils can be visualized in real-time. They form spontaneously and grow in an amyloid fashion within 5 hours. Together, our results demonstrate that viruses can encode amyloid-like fibril-forming proteins and have strong implications for future research on amyloid aggregation and toxicity in general