Abnormal Iron Homeostasis and Neurodegeneration
Inclusion Bodies, Iron, oxidative stress, neurodegeneration, ferritin, neuroferritinopathy
Abnormal iron metabolism is observed in many neurodegenerative diseases, however only two have shown dysregulation of brain iron homeostasis as the primary cause of neurodegeneration. Herein, we review one of these - hereditary ferritinopathy (HF) or neuroferritinopathy, which is an autosomal dominant, adult onset degenerative disease caused by mutations in the ferritin light chain (FTL) gene. HF has a clinical phenotype characterized by a progressive movement disorder, behavioral disturbances, and cognitive impairment. The main pathologic findings are cystic cavitation of the basal ganglia, the presence of ferritin inclusion bodies (IBs), and substantial iron deposition. Mutant FTL subunits have altered sequence and length but assemble into soluble 24-mers that are ultrastructurally indistinguishable from those of the wild type. Crystallography shows substantial localized disruption of the normally tiny 4-fold pores between the ferritin subunits because of unraveling of the C-termini into multiple polypeptide conformations. This structural alteration causes attenuated net iron incorporation leading to cellular iron mishandling, ferritin aggregation, and oxidative damage at physiological concentrations of iron and ascorbate. A transgenic murine model parallels several features of HF, including a progressive neurological phenotype, ferritin IB formation, and misregulation of iron metabolism. These studies provide a working hypothesis for the pathogenesis of HF by implicating (1) a loss of normal ferritin function that triggers iron accumulation and overproduction of ferritin polypeptides, and (2) a gain of a toxic function through radical production, ferritin aggregation, and oxidative stress. Importantly, the finding that ferritin aggregation can be reversed by iron chelators and oxidative damage can be inhibited by radical trapping may be used for clinical investigation. This work provides new insights into the role of abnormal iron metabolism in neurodegeneration.
Neurosciences. Biological psychiatry. Neuropsychiatry
Comparative pathogenesis of three human and zoonotic SARS-CoV strains in cynomolgus macaques.
The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. While there were significant differences in the number of host genes differentially regulated during the host responses between the three SARS-CoV strains, the top pathways and functions were similar and only apparent early during infection with the majority of genes associated with interferon signaling pathways. This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use.
Barry Rockx, Friederike Feldmann, Douglas Brining, Don Gardner, Rachel LaCasse, Lisa Kercher, Dan Long, Rebecca Rosenke, Kimmo Virtaneva, Daniel E. Sturdevant, Stephen F. Porcella, John Mattoon, Michael Parnell, Ralph S. Baric, Heinz Feldmann
Bart L. Haagmans, Albert D.M.E. Osterhaus
Livestock Susceptibility to Infection with Middle East Respiratory Syndrome Coronavirus
livestock, pig, coronavirus, MERS-CoV, Middle East respiratory syndrome, MERS
Middle East respiratory syndrome (MERS) cases continue to be reported, predominantly in Saudi Arabia and occasionally other countries. Although dromedaries are the main reservoir, other animal species might be susceptible to MERS coronavirus (MERS-CoV) infection and potentially serve as reservoirs. To determine whether other animals are potential reservoirs, we inoculated MERS-CoV into llamas, pigs, sheep, and horses and collected nasal and rectal swab samples at various times. The presence of MERS-CoV in the nose of pigs and llamas was confirmed by PCR, titration of infectious virus, immunohistochemistry, and in situ hybridization; seroconversion was detected in animals of both species. Conversely, in sheep and horses, virus-specific antibodies did not develop and no evidence of viral replication in the upper respiratory tract was found. These results prove the susceptibility of llamas and pigs to MERS-CoV infection. Thus, the possibility of MERS-CoV circulation in animals other than dromedaries, such as llamas and pigs, is not negligible.
Bart L. Haagmans, Marta Muñoz, Judith M.A. van den Brand, Júlia Vergara-Alert, Albert Bensaid, Joaquim Segalés, W. Widagdo, Debby Schipper, David Solanes, Stalin Raj, Ivan Cordón
Centers for Disease Control and Prevention
Infectious and parasitic diseases, Medicine
Sargramostim to treat patients with acute hypoxic respiratory failure due to COVID-19 (SARPAC): A structured summary of a study protocol for a randomised controlled trial
GM-CSF, Randomised controlled trial, protocol, COVID-19, sargramostim, leukine®
Abstract Objectives The hypothesis of the proposed intervention is that Granulocyte-macrophage colony-stimulating factor (GM-CSF) has profound effects on antiviral immunity, and can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. Sargramostim is a man-made form of the naturally-occurring protein GM-CSF. Trial design A phase 4 academic, prospective, 2 arm (1:1 ratio), randomized, open-label, controlled trial. Participants Patients aged 18-80 years admitted to specialized COVID-19 wards in 5 Belgian hospitals with recent (< 2 weeks prior to randomization) confirmed COVID-19 infection and acute respiratory failure defined as a PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen. Patients were excluded from the trial in case of (1) known serious allergic reactions to yeast-derived products, (2) lithium carbonate therapy, (3) mechanical ventilation prior to randomization, (4) peripheral white blood cell count above 25.000/μL and/or active myeloid malignancy, (5) high dose systemic steroid therapy (> 20 mg methylprednisolone or equivalent), (6) enrolment in another investigational study, (7) pregnant or breastfeeding or (8) ferritin levels > 2000 μg/mL. Intervention and comparator Inhaled sargramostim 125 μg twice daily for 5 days in addition to standard care. Upon progression of disease requiring mechanical ventilation or to acute respiratory distress syndrome (ARDS) and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125 μg/m2 body surface area once daily until the 5 day period is reached. From day 6 onwards, progressive patients in the active group will have the option to receive an additional 5 days of IV sargramostim, based on the treating physician's assessment. Intervention will be compared to standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards in the standard of care group will have the option (clinician's decision) to initiate IV sargramostim 125m μg/m2 body surface area once daily for 5 days. Main outcomes The primary endpoint of this intervention is measuring oxygenation after 5 days of inhaled (and intravenous) treatment through assessment of a change in pretreatment and post-treatment ratio of PaO2/FiO2 and through measurement of the P(A-a)O2 gradient (PAO2= Partial alveolar pressure of oxygen, PaO2=Partial arterial pressure of oxygen; FiO2= Fraction of inspired oxygen). Randomisation Patients will be randomized in a 1:1 ratio. Randomization will be done using REDCap (electronic IWRS system). Blinding (masking) In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. Numbers to be randomised (sample size) A total of 80 patients with confirmed COVID-19 and acute hypoxic respiratory failure will be enrolled, 40 in the active and 40 in the control group. Trial Status SARPAC protocol Version 2.0 (April 15 2020). Participant recruitment is ongoing in 5 Belgian Hospitals (i.e. University Hospital Ghent, AZ Sint-Jan Bruges, AZ Delta Roeselare, University Hospital Brussels and ZNA Middelheim Antwerp). Participant recruitment started on March 26th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. Trial registration The trial was registered on Clinical Trials.gov on March 30th, 2020 (ClinicalTrials.gov Identifier: NCT04326920) - retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT04326920?term=sarpac&recrs=ab&draw=2&rank=1 and on EudraCT on March 24th, 2020 (Identifier: 2020-001254-22). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
Bart Lambrecht, Karel Van Damme, Marnik Vuylsteke, Stefaan Vandecasteele, Cedric Bosteels, Bastiaan Maes, Stefanie Vermeersch, Elisabeth De Leeuw, Jozefien Declercq, Anja Delporte, Bénédicte Demeyere, Joren Willaert, Laura Bollé, Yuri Vanbiervliet, Jana Decuypere, Frederick Libeer, Isabelle Peene
Predictability and epidemic pathways in global outbreaks of infectious diseases: the SARS case study
Abstract Background The global spread of the severe acute respiratory syndrome (SARS) epidemic has clearly shown the importance of considering the long-range transportation networks in the understanding of emerging diseases outbreaks. The introduction of extensive transportation data sets is therefore an important step in order to develop epidemic models endowed with realism. Methods We develop a general stochastic meta-population model that incorporates actual travel and census data among 3 100 urban areas in 220 countries. The model allows probabilistic predictions on the likelihood of country outbreaks and their magnitude. The level of predictability offered by the model can be quantitatively analyzed and related to the appearance of robust epidemic pathways that represent the most probable routes for the spread of the disease. Results In order to assess the predictive power of the model, the case study of the global spread of SARS is considered. The disease parameter values and initial conditions used in the model are evaluated from empirical data for Hong Kong. The outbreak likelihood for specific countries is evaluated along with the emerging epidemic pathways. Simulation results are in agreement with the empirical data of the SARS worldwide epidemic. Conclusion The presented computational approach shows that the integration of long-range mobility and demographic data provides epidemic models with a predictive power that can be consistently tested and theoretically motivated. This computational strategy can be therefore considered as a general tool in the analysis and forecast of the global spreading of emerging diseases and in the definition of containment policies aimed at reducing the effects of potentially catastrophic outbreaks.
Barthélemy Marc, Barrat Alain, Colizza Vittoria, Vespignani Alessandro
HIV and SARS-Coronavirus-2 Epidemics: Possible Interactions and Need for Studies, Especially in Africa
HIV, Africa, SARS-CoV-2, COVID-19, antiretrovirals (ARVs)
Bartholomew Dzudzor, Sandro Vento, Massimiliano Lanzafame, Adonis Goushchi, Francesca Cainelli, Sirika Chhem
La Huerta de Cabra es un referente ineludible de los paisajes y regadíos tradicionales del interior de la España meridional. Situadas en el contacto entre la campiña y la Subbética cordobesa, deben su existencia al importante caudal que brota de la surgencia kárstica (Fuente del Río) que permite el riego del piedemonte (Huertas Altas) y, aguas abajo, de la terraza aluvial del río Cabra (Huertas Bajas). De origen inmemorial aunque tuvieron gran esplendor en época árabe, se consolidaron en el siglo XVI. Desde entonces conformaron un vergel de geométricas explotaciones minifundistas y rico y variado policultivo, que abastecía de frutas y verduras a un amplio entorno, siendo su ameno paisaje glosado en la literatura y en la percepción de propios y extraños. La orientación productivista de los años sesenta del siglo XX las encauzó hacia la transformación e intensificación de las prácticas agrícolas, llegando a alcanzar su zénit de ingresos y rendimientos. Pero pronto acusaron la incapacidad para competir y adaptarse a los nuevos mercados, de ahí que en las últimas décadas hayan entrado en una dinámica que las hacen casi irreconocibles con respecto al pasado cercano. Las Huertas Altas han sido presa de una urbanización poco controlada, y las Huertas Bajas objeto del abandono y cautivas del monocultivo. La pérdida del patrimonio que ello ha supuesto es dolorosa e irreparable, y ambas son hoy un paisaje roto: las Huertas Altas por la pérdida del suelo rústico a favor de la ocupación urbana y las Huertas Bajas por la pérdida de su función de auténticas huertas.
COVID-19 Pandemisi Sırasında Türkiye’de Acil Servislerin Organizasyonu ve Değişen Hasta Profili
Organizasyon, acil servis, adli olgu, COVID-19, Pandemi, Acil Hasta
COVID-19 salgını sırasında acil servisler hastaların tanımlanması, izolasyonu, hastane içi enfeksiyonları önlenme ve halk sağlığı otoritelerini bilgilendirmede önemli görevler üstlenir. Olası olgunun hızlı tanımlanması ve diğer hastalardan izole edilmesi gereklidir. Acil servisler doğası gereği afet durumlarında dahi hasta alımının devam etmesi gereken bakım alanlarıdır ve birçok ülkede acil servisler normal rutinlerinde maksimum kapasite ile çalışmaktadır. Tüm bu nedenlerle sağlık merkezlerinde yayılmayı önlemek ve kontrol altına almak için, özellikle acil servislerde kalabalıklığın önlenmesi ve mümkünse hastaların hastane başvurusundan önce tanımlanmasına yönelik politikalar gereklidir. Bu çalışmada COVID-19 Pandemisi ile birlikte bir üniversite hastanesi acil servisinin organizasyonun nasıl düzenlendiği paylaşılmış, acil servise başvuran acil, enfekte hasta ve adli olguların organizasyonu anlatılmıştır.