Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms

The globular to fibrillar transition of proteins represents a key pathogenic event in the development of amyloid diseases. Although systemic amyloidoses share the common characteristic of amyloid deposition in the extracellular matrix, they are clinically heterogeneous as the affected organs may vary. The observation that precursors of amyloid fibrils derived from circulating globular plasma proteins led to huge efforts in trying to elucidate the structural events determining the protein metamorphosis from their globular to fibrillar state. Whereas the process of metamorphosis has inspired poets and writers from Ovid to Kafka, protein metamorphism is a more recent concept. It is an ideal metaphor in biochemistry for studying the protein folding paradigm and investigating determinants of folding dynamics. Although we have learned how to transform both normal and pathogenic globular proteins into fibrillar polymers in vitro, the events occurring in vivo, are far more complex and yet to be explained. A major gap still exists between in vivo and in vitro models of fibrillogenesis as the biological complexity of the disease in living organisms cannot be reproduced at the same extent in the test tube. Reviewing the major scientific attempts to monitor the amyloidogenic metamorphosis of globular proteins in systems of increasing complexity, from cell culture to human tissues, may help to bridge the gap between the experimental models and the actual pathological events in patients

Plasminogen activation triggers transthyretin amyloidogenesis in vitro

Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibers, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both WT and genetic variants of the normal plasma protein transthyretin (TTR) form amyloid, but neither the misfolding leading to fibrillogenesis nor the anatomical localization of TTR amyloid deposition are understood. We have previously shown that, under physiological conditions, trypsin cleaves human TTR in a mechano-enzymatic mechanism that generates abundant amyloid fibrils in vitro. In sharp contrast, the widely used in vitro model of denaturation and aggregation of TTR by prolonged exposure to pH 4.0 yields almost no clearly defined amyloid fibrils. However, the exclusive duodenal location of trypsin means that this enzyme cannot contribute to systemic extracellular TTR amyloid deposition in vivo. Here, we therefore conducted a bioinformatics search for systemically active tryptic proteases with appropriate tissue distribution, which unexpectedly identified plasmin as the leading candidate. We confirmed that plasmin, just as trypsin, selectively cleaves human TTR between residues 48 and 49 under physiological conditions in vitro. Truncated and full-length protomers are then released from the native homotetramer and rapidly aggregate into abundant fibrils indistinguishable from ex vivo TTR amyloid. Our findings suggest that physiological fibrinolysis is likely to play a critical role in TTR amyloid formation in vivo. Identification of this surprising intersection between two hitherto unrelated pathways opens new avenues for elucidating the mechanisms of TTR amyloidosis, for seeking susceptibility risk factors, and for therapeutic innovation

High Risk of Secondary Infections Following Thrombotic Complications in Patients With COVID-19

Background. This study’s primary aim was to evaluate the impact of thrombotic complications on the development of secondary infections. The secondary aim was to compare the etiology of secondary infections in patients with and without thrombotic complications. Methods. This was a cohort study (NCT04318366) of coronavirus disease 2019 (COVID-19) patients hospitalized at IRCCS San Raffaele Hospital between February 25 and June 30, 2020. Incidence rates (IRs) were calculated by univariable Poisson regression as the number of cases per 1000 person-days of follow-up (PDFU) with 95% confidence intervals. The cumulative incidence functions of secondary infections according to thrombotic complications were compared with Gray’s method accounting for competing risk of death. A multivariable Fine-Gray model was applied to assess factors associated with risk of secondary infections. Results. Overall, 109/904 patients had 176 secondary infections (IR, 10.0; 95% CI, 8.8–11.5; per 1000-PDFU). The IRs of secondary infections among patients with or without thrombotic complications were 15.0 (95% CI, 10.7–21.0) and 9.3 (95% CI, 7.9–11.0) per 1000-PDFU, respectively (P = .017). At multivariable analysis, thrombotic complications were associated with the development of secondary infections (subdistribution hazard ratio, 1.788; 95% CI, 1.018–3.140; P = .043). The etiology of secondary infections was similar in patients with and without thrombotic complications. Conclusions. In patients with COVID-19, thrombotic complications were associated with a high risk of secondary infections

The Role of Narcissistic Vulnerability in Predicting Adult Posttraumatic Symptoms from Childhood Sexual Abuse

Abstract The aim of the present study is to determine whether narcissistic vulnerability can aid in clarifying the debate regarding the relationship between childhood sexual abuse (CSA) and adulthood adjustment to traumatic events. 157 survivors (mean age = 31.1, SD = 10.9) of a traumatic event (war activities and road and work accidents) were assessed 1 week, 1, and 4 months following the event. Of the 157 participants, 15 reported experiencing CSA, and 26 reported experiencing childhood physical abuse (CPA). In the first-week assessment, patients were administered the Narcissistic Vulnerability Scale (NVS) and the Beck Depression Inventory (BDI). In the follow-up assessments, subjects were interviewed on the ClinicianAdministered PTSD Scale. Narcissistic vulnerability was found, both in 1-and 4-month follow-ups, to increase the likelihood of participants who experienced CSA to develop PTSD symptoms later in their adult life, when exposed to other additional trauma. Narcissistic vulnerability, in both follow-ups, did not increase the likelihood of participants who experienced CPA to develop PTSD symptoms later in their life when exposed to other additional trauma. The NVS predicted the development of PTSD symptoms in the whole sample, both in the 1-and 4-month follow-ups, above and beyond the prediction of the BDI. In other words, narcissistic vulnerability can add additional information above and beyond general negative emotionality. In conclusion, it is recommended to take into consideration the interplay between CSA and the individual's narcissistic vulnerability when assessing the long term effects of CSA such as acute or chronic PTSD

Child Poverty: concepts and indicators

Tema del mesDiversos trabajos han documentado cómo la situación de la infancia en una sociedad, condiciona lo que le ocurra en etapas posterioresy por lo tanto es un factor preponderante en sus posibilidades globales de desarrollo. Uno de los problemas más acuciantes y aún no resueltos en Uruguay, al igual que ocurre en otros países latinoamericanos, es la situación de los niños que nacen, viven, crecen y se desarrollan en contextos de pobreza.Se trata de una cuestión altamente relevante en tanto configura un grupo específico, en el que la desigualdad de oportunidades llega a su máximo nivel. Se ha destacado que las necesidades de los niños son diferentes a las necesidades de los adultos. Los niños tienen sus propias prioridades, su visión del futuro, su valoración de las cosas, los eventos y las instituciones sociales. Su visibilidad depende, entre otras cosas, de que se constituyan por sí mismos en “unidad de observación”. El Centro Interdisciplinario de Infancia y Pobreza (CIIP) del Espacio Interdisciplinario de la Universidad de la República, intenta avanzar en conocimientos que den bases científicas a las intervenciones dirigidas a la infancia, en particular aquellas que buscan dar respuesta a la pobreza infantil y sus repercusiones. Se apoya en un paradigma multidimensional y complejo, donde se integran al menos conceptualmente, desde los recientes aportes de las neurociencias y el efecto del estrés sobre el Sistema Nervioso Central, hasta los múltiples componentes macro sociales. Este trabajo interdisciplinario implica el establecimiento de algunos acuerdos básicos en torno a la temática, adoptando definiciones consensuadas respecto a los ejes claves. El Centro actualmente se concentra en el estudio del crecimiento, el desarrollo integral y el bienestar de los niños menores de 5 años y sus familias, que viven en situación de pobreza, llegando a acuerdos en algunas definiciones y conceptualizaciones relevantes, aun cuando las mismas tengan carácter provisorio y niveles de consenso no homogéneos. Igualmente trabaja en la identificación de indicadores que aporten a la construcción de un Sistema Integrado de Monitorización de Crecimiento, Desarrollo y Bienestar Infantil (SINADIBI). El presente artículo presenta un marco conceptual, construido desde la interdisciplina, sobre la pobreza infantil y su impacto en el crecimiento, el desarrollo y el bienestar de los niños y sus familias. Igualmente se revisan algunos aspectos destacados de la discusión teórica, acerca de qué utilidad tienen los indicadores y cuáles deberían ser incluidos en un sistema de monitoreo de la situación de la infancia.Several studies have documented how the situation of children in a society determines what happens in later stages and therefore is a major factor in its overall development possibilities. One of the most pressing and unresolved problems in Uruguay, as occurs in other Latin American countries, is the situation of children born, living, growing and developing in contexts of poverty. This is a highly relevant issue as it configures a specific group where inequality of opportunity is at its highest level. It was noted that the needs of children differ from adults’ needs. Children have their own priorities, vision of the future, perspectives of things, events and social institutions. Their visibility depends, among other things, on that in themselves constitute an “observation unit”. The Interdisciplinary Center for Children and Poverty (CIIP)- Interdisciplinary Space- University of the Republic- attempts to advance in knowledge in order to give a scientific basis for interventions aimed at children, particularly those that aim to child poverty and its impact. Its work relies on a comprehensive, multidimensional and complex paradigm which integrates, at least conceptually, from the recent contributions of neuroscience and the effect of stress on the central nervous system to multiple social macro components. Interdisciplinary work involves establishing some basic agreements regarding the subject, adopting consensus definitions on key axes. In this regard, the Centre now has concentrated on the study of growth, comprehensive development and welfare of children under 5 and their families living in poverty, agreeing on some relevant definitions and concepts, even when they have provisional and non-homogeneous levels of consensus. Also is working on identifying indicators that contribute to the construction of an Integrated Monitoring of Growth, Development and Child Welfare (SINADIBI). This article presents a conceptual framework, built over an interdisciplinary process, of child poverty and its impact on growth, development and welfare of children and their families. It also review some highlights from the theoretical discussion about how useful are the indicators and what should be included in a monitoring of the situation of children

Delay in schistosomiasis diagnosis and treatment: a multicenter cohortstudy in Italy

14noBACKGROUND: Barriers to access to care, different diagnostic strategies, and low awareness remain challenging issues in the fight against schistosomiasis.Our study aims to examine management of schistosomiasis in migrants attending large tertiary hospitals in Italy, in order to call for a comprehensive approach. METHODS: A retrospective review of schistosomiasis cases was carried out between January 1, 2016 and December 31, 2017 in five large Infectious Disease Centers in Italy. We included all patients diagnosed with schistosomiasis. We differentiated among i) asymptomatic patients diagnosed by serology either as healthy 'migrant evaluation' or as 'late evaluation' in patients followed because of a different infection and ii) patients tested because of a suggestive clinical presentation. Patients characteristics and clinical data were recorded. RESULTS: 149 patients were included, 137 (91.9%) were male, the median age was 26 years and 70% of them came from Sub-Saharan Africa.Thirty-eight asymptomatic patients (25.5%) were diagnosed by serology [15, (10.1%) among 'migrant evaluation' and 23 (15.4%) among 'late evaluation' group] and 111 (74.5%) presented with signs/symptoms.The median diagnostic delay from arrival in Italy was 31 months: 110 for asymptomatic group and 16 months for symptomatic patients. Among the 111 symptomatic patients, 41 individuals were already followed in our Clinics and they never underwent screening before appearance of evident disease. Among patients with positive serology who were tested by microscopy, 32/86 (37.2%) had confirmed diagnosis. Forty-five (37.8%) patients presented radiologic abnormalities. Praziquantel was the treatment of choice (70.1% for 3 days and 29.9% in a single-day dose) and 77 (51.7%) were lost to follow-up. CONCLUSION: In our centers, a high proportion of patients were tested late after arrival and most of them presented with clinical apparent disease. Well-defined strategies and implementation of recent guidelines are needed to improve early diagnosis and to overcome heterogeneity of practice.nonenoneComelli, Agnese; Riccardi, Niccolò; Canetti, Diana; Spinicci, Michele; Cenderello, Giovanni; Magro, Paola; Nicolini, Laura Ambra; Marchese, Valentina; Zammarchi, Lorenzo; Castelli, Francesco; Bartoloni, Alessandro; Di Biagio, Antonio; Caligaris, Silvio; Gaiera, GiovanniComelli, Agnese; Riccardi, Niccolò; Canetti, Diana; Spinicci, Michele; Cenderello, Giovanni; Magro, Paola; Nicolini, Laura Ambra; Marchese, Valentina; Zammarchi, Lorenzo; Castelli, Francesco; Bartoloni, Alessandro; Di Biagio, Antonio; Caligaris, Silvio; Gaiera, Giovann