H-ferritin ferroxidase induces cytoprotective pathways and inhibits microvascular stasis in transgenic sickle mice

Hemolysis, oxidative stress, inflammation, vaso-occlusion and organ infarction are hallmarks of sickle cell disease (SCD). We have previously shown that increases in heme oxygenase-1 (HO-1) activity detoxify heme and inhibit vaso-occlusion in transgenic mouse models of SCD. HO-1 releases Fe2+ from heme, and the ferritin heavy chain (FHC) ferroxidase oxidizes iron to catalytically-inactive Fe3+ inside ferritin. FHC overexpression has been shown to be cytoprotective. In this study, we hypothesized that overexpression of FHC and its ferroxidase activity will inhibit inflammation and microvascular stasis in transgenic sickle mice in response to stroma-free hemoglobin. We utilized a Sleeping Beauty transposase plasmid to deliver a human wild-type-ferritin heavy chain (wt-hFHC) transposable element by hydrodynamic tail vein injections to NY1DD SCD mice. Control mice were infused with the same volume of lactated Ringer's solution (LRS) or a triple missense human FHC (ms-hFHC) plasmid with no ferroxidase activity. Eight weeks later, LRS-injected mice had ~40% microvascular stasis (% non-flowing venules) when infused with stroma-free hemoglobin at 1 h, while mice overexpressing wt-hFHC had only 5% stasis (p< 0.05), and ms-hFHC mice had 33% stasis suggesting vascular protection by ferroxidase active wt-hFHC. The wt-hFHC SCD mice had marked increases in splenic hFHC mRNA and hepatic hFHC protein, light chain ferritin, 5-aminolevulinic acid synthase (5-ALA-synthase), heme content, ferroportin, nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear hFHC, and microsomal HO-1 activity and protein, and a decrease in activated nuclear phosho-nuclear factor-kappa B (NF-κB) p65. HO-1 activity was not essential for the protection by FHC. We conclude that wt-hFHC ferroxidase activity enhances cytoprotective Nrf2-regulated proteins including HO-1, thereby resulting in decreased NF-κB-activation, inflammation and microvascular stasis in transgenic SCD mice

A case study using 2019 pre-monsoon snow and stream chemistry in the Khumbu region, Nepal

This case study provides a framework for future monitoring and evidence for human source pollution in the Khumbu region, Nepal. We analyzed the chemical composition (major ions, major/trace elements, black carbon, and stable water isotopes) of pre-monsoon stream water (4300–5250 m) and snow (5200–6665 m) samples collected from Mt. Everest, Mt. Lobuche, and the Imja Valley during the 2019 pre-monsoon season, in addition to a shallow ice core recovered from the Khumbu Glacier (5300 m). In agreement with previous work, pre-monsoon aerosol deposition is dominated by dust originating from western sources and less frequently by transport from southerly air mass sources as demonstrated by evidence of one of the strongest recorded pre-monsoon events emanating from the Bay of Bengal, Cyclone Fani. Elevated concentrations of human-sourced metals (e.g., Pb, Bi, As) are found in surface snow and stream chemistry collected in the Khumbu region. As the most comprehensive case study of environmental chemistry in the Khumbu region, this research offers sufficient evidence for increased monitoring in this watershed and surrounding areas

Burden of Psychosocial and Cognitive Impairment in Patients With Atrial Fibrillation

BACKGROUND: Impairments in psychosocial status and cognition relate to poor clinical outcomes in patients with atrial fibrillation (AF). However, how often these conditions co-occur and associations between burden of psychosocial and cognitive impairment and quality of life (QoL) have not been systematically examined in patients with AF. METHODS: A total of 218 patients with symptomatic AF were enrolled in a prospective study of AF and psychosocial factors between May 2013 and October 2014 at the University of Massachusetts Medical Center. Cognitive function, depression, and anxiety were assessed at baseline and AF-specific QoL was assessed 6 months after enrollment using validated instruments. Demographic and clinical information were obtained from a structured interview and medical record review. RESULTS: The mean age of the study participants was 63.5 +/- 10.2 years, 35% were male, and 81% had paroxysmal AF. Prevalences of impairment in 1, 2, and 3 psychosocial/cognitive domains (eg, depression, anxiety, or cognition) were 75 (34.4%), 51 (23.4%), and 16 (7.3%), respectively. Patients with co-occurring psychosocial/cognitive impairments (eg, \u3e 1 domain) were older, more likely to smoke, had less education, and were more likely to have heart failure (all P \u3c 0.05). Compared with participants with no psychosocial/cognitive impairments, AF-specific QoL at 6 months was significantly poorer among participants with baseline impairment in 2 (B = -13.6, 95% CI: -21.7 to -5.4) or 3 (B = -15.1, 95% CI: -28.0 to -2.2) psychosocial/cognitive domains. CONCLUSION: Depression, anxiety, and impaired cognition were common in our cohort of patients with symptomatic AF and often co-occurred. Higher burden of psychosocial/cognitive impairment was associated with poorer AF-specific QoL

A novel computer adaptive word list memory test optimized for remote assessment: Psychometric properties and associations with neurodegenerative biomarkers in older women without dementia

Introduction: This study established the psychometric properties and preliminary validity of the Stricker Learning Span (SLS), a novel computer adaptive word list memory test designed for remote assessment and optimized for smartphone use. Methods: Women enrolled in the Mayo Clinic Specialized Center of Research Excellence (SCORE) were recruited via e-mail or phone to complete two remote cognitive testing sessions. Convergent validity was assessed through correlation with previously administered in-person neuropsychological tests (n = 96, ages 55-79) and criterion validity through associations with magnetic resonance imaging measures of neurodegeneration sensitive to Alzheimer\u27s disease (n = 47). Results: SLS performance significantly correlated with the Auditory Verbal Learning Test and measures of neurodegeneration (temporal meta-regions of interest and entorhinal cortical thickness, adjusting for age and education). Test-retest reliabilities across two sessions were 0.71-0.76 (two-way mixed intraclass correlation coefficients). Discussion: The SLS is a valid and reliable self-administered memory test that shows promise for remote assessment of aging and neurodegenerative disorders

Defining imaging biomarker cut points for brain aging and Alzheimer's disease

AbstractIntroductionOur goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness.MethodsWe examined five methods for determining cut points.ResultsThe reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal.DiscussionIn the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method

Prefacing unexplored archives from Central Andean surface-to-bedrock ice cores through a multifaceted investigation of regional firn and ice core glaciochemistry.

Shallow firn cores, in addition to a near-basal ice core, were recovered in 2018 from the Quelccaya ice cap (5470 m a.s.l) in the Cordillera Vilcanota, Peru, and in 2017 from the Nevado Illimani glacier (6350 m a.s.l) in the Cordillera Real, Bolivia. The two sites are ~450 km apart. Despite meltwater percolation resulting from warming, particle-based trace element records (e.g. Fe, Mg, K) in the Quelccaya and Illimani shallow cores retain well-preserved signals. The firn core chronologies, established independently by annual layer counting, show a convincing overlap indicating the two records contain comparable signals and therefore capture similar regional scale climatology. Trace element records at a ~1?4 cm resolution provide past records of anthropogenic emissions, dust sources, volcanic emissions, evaporite salts and marine-sourced air masses. Using novel ultra-high-resolution (120 ?m) laser technology, we identify annual layer thicknesses ranging from 0.3 to 0.8 cm in a section of 2000-year-old radiocarbon-dated near-basal ice which compared to the previous annual layer estimates suggests that Quelccaya ice cores drilled to bedrock may be older than previously suggested by depth-age models. With the information collected from this study in combination with past studies, we emphasize the importance of collecting new surface-to-bedrock ice cores from at least the Quelccaya ice cap, in particular, due to its projected disappearance as soon as the 2050s

Cervical Screening within HIV Care: Findings from an HIV-Positive Cohort in Ukraine

HIV-positive women have an increased risk of invasive cervical cancer but cytologic screening is effective in reducing incidence. Little is known about cervical screening coverage or the prevalence of abnormal cytology among HIV-positive women in Ukraine, which has the most severe HIV epidemic in Europe

Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts

<p>Abstract</p> <p>Background</p> <p>NF-κB is a survival signaling transcription factor complex involved in the malignant phenotype of many cancers, including squamous cell carcinomas (SCC). The citrus coumarin, auraptene (AUR), and the ethno-medicinal ginger (Alpinia galanga) phenylpropanoid, 1'-acetoxychavicol acetate (ACA), were previously shown to suppress 12-<it>O</it>-tetradecanoylphorbol-13-acetate (TPA) induced mouse skin tumor promotion. The goal of the present study was to determine whether AUR and ACA are effective either alone or in combination with all-<it>trans </it>retinoic acid (ATRA) for suppressing SCC tumor growth.</p> <p>Methods</p> <p>We first determined the effects of orally administered ACA (100 mg/kg bw) and AUR (200 mg/kg bw) on lipopolysaccharide (LPS)-induced NF-κB activation in NF-κB-RE-luc (Oslo) luciferase reporter mice. Dietary administration of AUR and ACA ± ATRA was next evaluated in a xenograft mouse model. Female SCID/bg mice were fed diets containing the experimental compounds, injected with 1 × 10⁶SRB12-p9 cells s.c., palpated and weighed twice a week for 28 days following injection.</p> <p>Results</p> <p>Both ACA and AUR suppressed LPS-induced NF-κB activation in the report mice. In the xenograft model, AUR (1000 ppm) and ACA (500 ppm) modestly suppressed tumor volume. However, in combination with ATRA at 5, 10, and 30 ppm, ACA 500 ppm significantly inhibited tumor volume by 56%, 62%, and 98%, respectively. The effect of ATRA alone was 37%, 33%, and 93% inhibition, respectively. AUR 1000 ppm and ATRA 10 ppm were not very effective when administered alone, but when combined, strongly suppressed tumor volume by 84%.</p> <p>Conclusions</p> <p>Citrus AUR may synergize the tumor suppressive effects of ATRA, while ACA may prolong the inhibitory effects of ATRA. Further studies will be necessary to determine whether these combinations may be useful in the control of human SCC.</p

Gerschenkron revisited: The new corporate Russia

© 2015, Journal of Economic Issues / Association for Evolutionary Economics. Our analysis is based on firm-specific data compiled from the Russian Trading System stock exchange and SKRIN (CKP-H in Russian) database. We seek to identify the factors behind Russias dramatically improved corporate sector performance from the beginning of the 2000s to December 2007. We argue that improved long-term corporate performance was a consequence of several policy initiatives associated with the state-dominated banking sector, which enabled statesubsidized investment funds to be channeled from a structurally reengineered energy sector to targeted investment projects located in other industries. We claim that Russias industrial strategy closely conforms to Alexander Gerschenkrons catch-up theory