Distinctive Toll-like receptors gene expression and glial response in different brain regions of natural scrapie

Prion diseases are chronic and fatal neurodegenerative diseases characterized by the accumula-tion of disease-specific prion protein (PrPSc), spongiform changes, neuronal loss, and gliosis. Growing evidence shows that the neuroinflammatory response is a key component of prion diseases and contributes to neurodegeneration. Toll-like receptors (TLRs) have been proposed as important mediators of innate immune responses triggered in the central nervous system in other human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. However, little is known about the role of TLRs in prion dis-eases, and their involvement in the neuropathology of natural scrapie has not been studied. We assessed gene expression of ovine TLRs in four anatomically distinct brain regions in natural scrapie-infected sheep and evaluated possible correlations between gene expression and patho-logical hallmarks of prion disease. We observed significant changes in TLR expression in scra-pie-infected sheep that correlate with the degree of spongiosis, PrPSc deposition, and gliosis in each of the regions studied. Remarkably, TLR4 was the only gene upregulated in all regions, re-gardless of the severity of neuropathology. In the hippocampus, we observed milder neuropa-thology associated with a distinct TLR gene expression profile and the presence of a peculiar microglial morphology, called rod microglia, described here for the first time in the brain of scrapie-infected sheep. The concurrence of these features suggests partial neuroprotection of the hippocampus. Finally, comparison of findings in naturally-infected sheep versus an ovinized mouse model (tg338 mice) revealed distinct patterns of TLR gene expression.This research was funded by “Departamento de Ciencia, Universidad y Sociedad del Conocimiento” (Aragon Government) through the project “A05_20R: Enfermedades Priónicas, Vecto- riales y Zoonosis Emergentes”

[Responding to the sexual and reproductive health needs of Venezuelan migrant women in LimaResposta às necessidades de saúde sexual e reprodutiva de migrantes venezuelanas em Lima].

OBJECTIVES: To present and analyze the Peruvian health system's response to the sexual and reproductive health needs of Venezuelan women living in the city of Lima, Peru, and to identify some of the reasons underlying this response. METHODS: Information was collected through semi-structured, in-depth telephone interviews with 30 Venezuelan women, 10 healthcare workers, and two Ministry of Health officials. RESULTS: Based on the experiences of Venezuelan women who sought care through these services during 2019-2020 and the perspectives of healthcare personnel and health authorities, we present an analysis of the public health services' capacity and limitations in meeting the sexual and reproductive health needs of this population. Migrant women's testimonies reported a positive experience with a health system that, despite shortcomings, responds to the most common sexual and reproductive health needs. These perspectives parallel the testimonies of healthcare personnel and authorities who emphasized the existence of priority policies for sexual and reproductive health care. CONCLUSION: This study shows how a national priority framework (reducing maternal mortality), accompanied by operational mechanisms for social protection (such as the Comprehensive Health Insurance program), represent complementary instruments that have a positive impact on and extend benefits to migrants, even though this population was not considered when designing these policies

Responding to the sexual and reproductive health needs of Venezuelan migrant women in Lima=Resposta às necessidades de saúde sexual e reprodutiva de migrantes venezuelanas em Lima

Objetivo. Presentar y analizar la respuesta que el sistema de salud peruano viene dando a las necesidades en salud sexual y reproductiva de las mujeres venezolanas que radican en la ciudad de Lima, Perú e identificar algunas de las razones que nos permite entender esta respuesta. Métodos. La información se recogió mediante entrevistas a profundidad semiestructuradas por vía telefónica a 30 mujeres venezolanas, 10 trabajadores de salud y 2 funcionarios del Ministerio de Salud. Resultados. A partir de las experiencias de mujeres venezolanas que acudieron a estos servicios durante el 2019-2020 y de las perspectivas del personal y autoridades de salud presentamos un análisis de la capacidad y limitaciones que los servicios de salud públicos tienen para atender las necesidades de salud sexual y reproductiva de esta población. Los testimonios de las mujeres migrantes reportan una experiencia positiva con un sistema de salud que, a pesar de las deficiencias, responde a las necesidades de salud sexual y reproductiva más comunes. Estas coinciden con los testimonios del personal de salud y con las de las autoridades quienes enfatizan la existencia de políticas prioritarias para la atención de la Salud Sexual y Reproductiva. Conclusión. Este estudio muestra cómo un marco de prioridad nacional (disminuir la mortalidad materna), acompañado de mecanismos operativos de protección social (como el Seguro Integral de Salud), se convierten en instrumentos complementarios, que repercute de manera positiva y extiende beneficios para las y los migrantes, a pesar de no haber considerado a esta población durante el diseño de estas políticas

In vitro and in vivo evidence towards fibronectin’s protective effects against prion infection

A distinctive signature of the prion diseases is the accumulation of the pathogenic isoform of the prion protein, PrPSc, in the central nervous system of prion-affected humans and animals. PrPSc is also found in peripheral tissues, raising concerns about the potential transmission of pathogenic prions through human food supplies and posing a significant risk to public health. Although muscle tissues are considered to contain levels of low prion infectivity, it has been shown that myotubes in culture efficiently propagate PrPSc. Given the high consumption of muscle tissue, it is important to understand what factors could influence the establishment of a prion infection in muscle tissue. Here we used in vitro myotube cultures, differentiated from the C2C12 myoblast cell line (dC2C12), to identify factors affecting prion replication. A range of experimental conditions revealed that PrPSc is tightly associated with proteins found in the systemic extracellular matrix, mostly fibronectin (FN). The interaction of PrPSc with FN decreased prion infectivity, as determined by standard scrapie cell assay. Interestingly, the prion-resistant reserve cells in dC2C12 cultures displayed a FN-rich extracellular matrix while the prion-susceptible myotubes expressed FN at a low level. In agreement with the in vitro results, immunohistopathological analyses of tissues from sheep infected with natural scrapie demonstrated a prion susceptibility phenotype linked to an extracellular matrix with undetectable levels of FN. Conversely, PrPSc deposits were not observed in tissues expressing FN. These data indicate that extracellular FN may act as a natural barrier against prion replication and that the extracellular matrix composition may be a crucial feature determining prion tropism in different tissues

Hidden Sylvatic Foci of the Main Vector of Chagas Disease Triatoma infestans: Threats to the Vector Elimination Campaign?

Triatoma infestans, a highly domesticated species and historically the main vector of Trypanosoma cruzi, is the target of an insecticide-based elimination program in the southern cone countries of South America since 1991. Only limited success has been achieved in the Gran Chaco region due to repeated reinfestations. We conducted full-coverage spraying of pyrethroid insecticides of all houses in a well-defined rural area in northwestern Argentina, followed by intense monitoring of house reinfestation and searches for triatomine bugs in sylvatic habitats during the next two years, to establish the putative sources of new bug colonies. We found low-density sylvatic foci of T. infestans in trees located within the species' flight range from the nearest infested house detected before control interventions. Using multiple methods (fine-resolution satellite imagery, geographic information systems, spatial statistics, genetic markers and wing geometric morphometry), we corroborated the species identity of the sylvatic bugs as T. infestans and found they were indistinguishable from or closely related to local domestic or peridomestic bug populations. Two sylvatic foci were spatially associated to the nearest peridomestic bug populations found before interventions. Sylvatic habitats harbor hidden foci of T. infestans that may represent a threat to vector suppression attempts

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030