Multivalency drives interactions of alpha-synuclein fibrils with tau.

Age-related neurodegenerative disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by deposits of protein aggregates, or amyloid, in various regions of the brain. Historically, aggregation of a single protein was observed to be correlated with these different pathologies: tau in AD and α-synuclein (αS) in PD. However, there is increasing evidence that the pathologies of these two diseases overlap, and the individual proteins may even promote each other's aggregation. Both tau and αS are intrinsically disordered proteins (IDPs), lacking stable secondary and tertiary structure under physiological conditions. In this study we used a combination of biochemical and biophysical techniques to interrogate the interaction of tau with both soluble and fibrillar αS. Fluorescence correlation spectroscopy (FCS) was used to assess the interactions of specific domains of fluorescently labeled tau with full length and C-terminally truncated αS in both monomer and fibrillar forms. We found that full-length tau as well as individual tau domains interact with monomer αS weakly, but this interaction is much more pronounced with αS aggregates. αS aggregates also mildly slow the rate of tau aggregation, although not the final degree of aggregation. Our findings suggest that co-occurrence of tau and αS in disease are more likely to occur through monomer-fiber binding interactions, rather than monomer-monomer or co-aggregation.

Myocardial Infarction During Treatment of Crotalinae Envenomation: A Case Report.

While myocardial infarction is a rare, but known, potential side effect of snakebite envenomation, snake antivenom has thus far not been associated with any cardiovascular adverse events. We report the case of a 71-year-old man who developed an anterolateral MI during administration of Crotalidae immune F(ab')2 (equine) (ANAVIP), given as treatment for Crotalidae envenomation. The patient required cardiac catheterization with stenting of the left anterior descending artery and was discharged two days later on long-term clopidogrel and aspirin. Treatment of MI in the setting of envenomation should mirror typical management, with consideration of additional antivenom if the ischemia is determined to be venom-induced. Clinicians should have a high index of suspicion for patients with chest pain after snake envenomation or administration of antivenom.

Evaluation of the International Society on Thrombosis and Haemostasis definition of major bleeding in Arizona rattlesnake bites.

INTRODUCTION: In 2023, a group of experts proposed that a definition of major bleeding in pharmaceutically anticoagulated patients be used in all snakebite trials. This includes bleeding that results in death, is life-threatening, causes chronic sequelae, or consumes major healthcare resources, including bleeding into a major area or hemoglobin concentration decrease ≥20 g/L. We hypothesized that a decline in hemoglobin concentration ≥20 g/L is common but rarely clinically significant in our population of Arizona rattlesnake bite patients. METHODS: Poison center records of rattlesnake bites in humans from 2018 through 2022 were retrospectively reviewed and assessed for major bleeding by the above criteria. RESULTS: Four hundred and eighty-one patients met the inclusion criteria, of whom 265 (55.1%) had a hemoglobin concentration decrease ≥20 g/L. No patients died, and there was no evidence of bleeding into a critical organ. Three patients (1.1%) received blood transfusions. A decrease in hemoglobin concentration ≥20 g/L was 100% sensitive for identifying the major bleeding-associated outcomes; however, specificity was only 45.2%. Measures of healthcare utilization and chronic sequelae were somewhat higher in patients with a decrease in hemoglobin concentration ≥20 g/L. DISCUSSION: Laboratory manifestations of hemotoxicity were common in this population, but hemorrhage was rare. While over half of patients met the major bleeding criterion of a decline in hemoglobin concentration ≥20 g/L, only 1.1% had bleeding that was potentially life-threatening as measured by receipt of a red blood cell transfusion. None died or had bleeding into a critical area. While nonspecific for major bleeding, a drop in hemoglobin concentration correlated with worse envenomation severity: these patients received more vials of antivenom, had a higher medical bill, a longer hospital stay, and were less likely to report full recovery at 90 days. CONCLUSIONS: A decrease in hemoglobin concentration ≥20 g/L should not be used as evidence of major bleeding for Arizona rattlesnake envenomation studies, but it may have a role as an indirect marker of envenomation severity.

Twenty-five years of suspected rattlesnake encounters in Arizona.

INTRODUCTION: Rattlesnake (Crotalus spp., Sistrurus spp.) bites in the southwestern United States are associated with significant morbidity. This study aims to describe 25 years of rattlesnake encounters reported to the Arizona Poison and Drug Information Center to identify vulnerable populations and circumstances where encounters occur to create public education to reduce future bites. METHODS: Cases of suspected rattlesnake encounters in Arizona reported to the Arizona Poison and Drug Information Center between 1999 and 2023 were analyzed to identify populations and circumstances associated with encounters. RESULTS: A total of 3,808 cases were analyzed overall and by age subgroups. Most encounters occurred in men (69.9%), during the evening (16:00-21:59; 49.2%), in summer (41.9%), and close to home (38.2%). Most bites occurred to the lower extremity (51%). Children 0 to 12-years-old have more encounters than those 13-years-old and older in rural zip codes (27.7% versus 14.8%; P = 0.005), during spring (31.8% versus 22.3%; P = 0.0005), and during the evening (64.4% versus 48.1%; P < 0.001). DISCUSSION: Rattlesnakes are encountered when rattlesnake and human behavior patterns overlap. Many people spend time outside during evening hours in the summer, and valuable resources like food, water, and shelter can be found near houses where humans spend much of their time. Most age groups have similar encounter circumstances but encounters among children 0 to 12-years-old differ in time of day, season, and urbanization level than encounters of those 13-years-old and older. Limitations of this study include underreporting of encounters, incomplete case details, potential reporting bias, potential snake misidentification, and geographic coverage of the poison center. CONCLUSION: Prevention of rattlesnake bites by reducing encounters is the most effective way to reduce suffering and healthcare costs. Future steps include creating and disseminating targeted public health education using the data collected.

Perceived worsening of obsessive-compulsive disorder symptoms after childbirth in women and men: An understudied phenomenon.

The aim of this study was to examine worsening of OCD symptoms after childbirth in individuals seeking assessment or treatment of OCD. The postpartum period may make parents biologically and psychologically vulnerable to OCD symptoms. Participants included 222 parents with OCD who completed surveys through a self-help website. Most women and almost half of men with self-reported OCD reported an increase in OCD symptoms following childbirth. Retrospective report of perceived worsening of OCD symptoms after childbirth was associated with more aggressive obsessions for both men and women, in comparison to individuals whose OCD symptoms did not worsen around childbirth. Women whose OCD symptoms worsened after childbirth reported more impairment in social functioning than individuals whose symptoms did not worsen. These results highlight the need to develop a better understanding of aggressive obsessions in parents, and improve education about prevalence, content, assessment, and intervention for aggression-focused intrusive thoughts.

Large-scale releases and establishment of wMel Wolbachia in Aedes aegypti mosquitoes throughout the Cities of Bello, Medellín and Itagüí, Colombia.

BACKGROUND: The wMel strain of Wolbachia has been successfully introduced into Aedes aegypti mosquitoes and has been shown to reduce the transmission of dengue and other Aedes-borne viruses. Here we report the entomological results from phased, large-scale releases of Wolbachia infected Ae. aegypti mosquitoes throughout three contiguous cities located in the Aburrá Valley, Colombia. METHODOLOGY/PRINCIPAL FINDINGS: Local wMel Wolbachia-infected Ae. aegypti mosquitoes were generated and then released in an initial release pilot area in 2015-2016, which resulted in the establishment of Wolbachia in the local mosquito populations. Subsequent large-scale releases, mainly involving vehicle-based releases of adult mosquitoes along publicly accessible roads and streets, were undertaken across 29 comunas throughout Bello, Medellín and Itagüí Colombia between 2017-2022. In 9 comunas these were supplemented by egg releases that were undertaken by staff or community members. By the most recent monitoring, Wolbachia was found to be stable and established at consistent levels in local mosquito populations (>60% prevalence) in the majority (67%) of areas. CONCLUSION: These results, from the largest contiguous releases of wMel Wolbachia mosquitoes to date, highlight the operational feasibility of implementing the method in large urban settings. Based on results from previous studies, we expect that Wolbachia establishment will be sustained long term. Ongoing monitoring will confirm Wolbachia persistence in local mosquito populations and track its establishment in the remaining areas.

The Effects of Lipids on α-Synuclein Aggregation In Vitro.

The small neuronal protein α-synuclein (αS) is found in pre-synaptic terminals and plays a role in vesicle recycling and neurotransmission. Fibrillar aggregates of αS are the hallmark of Parkinson's disease and related neurodegenerative disorders. In both health and disease, interactions with lipids influence αS's structure and function, prompting much study of the effects of lipids on αS aggregation. A comprehensive collection (126 examples) of aggregation rate data for various αS/lipid combinations was presented, including combinations of lipid variations and mutations or post-translational modifications of αS. These data were interpreted in terms of lipid structure to identify general trends. These tabulated data serve as a resource for the community to help in the interpretation of aggregation experiments with lipids and to be potentially used as inputs for computational models of lipid effects on aggregation.

Combining non-canonical amino acid mutagenesis and native chemical ligation for multiply modifying proteins: A case study of α-synuclein post-translational modifications.

The Parkinson's disease associated protein α-synuclein (αS) has been found to contain numerous post-translational modifications (PTMs), in both physiological and pathological states. One PTM site of particular interest is serine 87, which is subject to both O-linked ß-N-acetylglucosamine (gS) modification and phosphorylation (pS), with αS-pS87 enriched in Parkinson's disease. An often-overlooked aspect of these PTMs is their effect on the membrane-binding properties of αS, which are important to its role in regulating neurotransmitter release. Here, we show how one can study these effects by synthesizing αS constructs containing authentic PTMs and labels for single molecule fluorescence correlation spectroscopy measurements. We synthesize αS-gS87 and αS-pS87 by combining native chemical ligation with genetic code expansion approaches. We introduce the fluorophore by a click reaction with a non-canonical amino acid. Beyond the specific problem of PTM effects on αS, our studies highlight the value of this combination of methods for multiply modifying proteins.

Symptom Prevalence in Spanish and Colombian Oncology Patients Measured with the MSAS.

Cancer patients experience several symptoms throughout their illness and the treatments they receive. While this pathology represents a worldwide health problem, knowing the symptom prevalence in oncology patients remains a challenge; validated tools to obtain this information are essential. Furthermore, this prevalence information would help health professionals to establish appropriate treatments. The objective of this study was to ascertain the symptom prevalence in cancer patients from Spain and Colombia to improve future approaches. The frequency, severity, and distress of 32 symptoms from a validated scale experienced by cancer patients from Spain and Colombia were measured. Two hundred and forty-six patients (49.7%) who attended the Day University Hospital of Salamanca (Spain) and two hundred and forty-nine outpatients (50.3%) of the San Diego Cancer Center (Colombia) between 2016 and 2019 participated in the study. All patients filled in the Assessment Scale only once. Four hundred and ninety-five patients (333 women (67.3%) and 162 men (32.7%)) completed the Memorial Symptom Assessment Scale (Spanish version). The most frequent symptom for both samples (Spanish and Colombian) was "lack of energy" (38.4% and 13.7%, respectively). The most severe symptoms for the Spanish and Colombian samples were "problems with sexual interest or activity" (38.4%) and "dry mouth" (13.7%), respectively, and both samples agreed on the most distressing symptom: "hair loss" (Spanish, 38%; Colombian, 10.1%). The Spanish version of the MSAS has proven to be a valid and reliable tool in Spanish-speaking countries to obtain the most prevalent, severe, and distressing symptoms in Spanish and Colombian oncology patients. The prevalence of symptoms was demonstrated to be similar across both countries, and the results will help to design and adapt treatments for cancer patients, targeting these symptoms to reduce or avoid them and thus improving their quality of life.

Escala de evaluación de síntomas Memorial 10-18: Adaptación cultural y validez para oncología pediátrica Colombia / Memorial symptom assessment scale 10-18: Cultural adaptation and validity for pediatric oncology Colombia

Objetivo principal: Adaptar culturalmente y validar en el componente de validez facial y de contenido la escala de evaluación de síntomas Memorial 10-18 años en pediatría oncológica en Colombia. Metodología: Estudio de validación de escalas en dos fases: 1. Adaptación cultural al contexto colombiano 2. Validación facial y de contenido. Los participantes eran adolescentes sanos y con diagnóstico oncológico entre 10 a 18 años de edad. Resultados principales: Se obtuvo versión adaptada de la MSAS 10-18 al contexto colombiano para escenarios de oncología pediátrica, con comprensibilidad global de ítems mayor al 85 % e índice de validez de contenido de 0.71. Conclusión principal: La escala de evaluación de síntomas Memorial 10-18 años proporciona cumple con propiedades psicométricas para su aplicación en la práctica, contribuyendo a mejorar la calidad de vida al niño con cáncer y su familia.(AU)

Objective: Culturally adapt and validate in the component of facial validity and content the Memorial Symptom Assessment Scale 10-18 years in oncological pediatrics in Colombia. Methods: Scale validation study in two phases: 1. Cultural adaptation of the MSAS 10-18 to the Colombian, 2. Facial and content validation with experts in the phenomenon and children with cancer between the ages described. Participants were healthy adolescents and with oncological diagnosis between 10 and 18 years of age. Results: An adapted version of the Memorial Symptom Assessment Scale 10-18 was obtained for the Colombian context for pediatric oncology scenarios, with an overall comprehensibility of the items greater than 85 % and a content validity index of 0.71. Conclusions: Having specific scales adapted to the age group and the context in which they are applied, provides theoretical and disciplinary knowledge to guide the practice, contributing to improve the quality of life and comprehensive care for children with cancer and their family.(AU)