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While there is increasing recognition that social processes in cities like gentrification have ecological consequences, we lack nuanced understanding of the ways gentrification affects urban biodiversity. We analyzed a large camera trap dataset of mammals (>500 g) to evaluate how gentrification impacts species richness and community composition across 23 US cities. After controlling for the negative effect of impervious cover, gentrified parts of cities had the highest mammal species richness. Change in community composition was associated with gentrification in a few cities, which were mostly located along the West Coast. At the species level, roughly half (11 of 21 mammals) had higher occupancy in gentrified parts of a city, especially when impervious cover was low. Our results indicate that the impacts of gentrification extend to nonhuman animals, which provides further evidence that some aspects of nature in cities, such as wildlife, are chronically inaccessible to marginalized human populations.
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Biodiversidad , Segregación Residencial , Animales , Humanos , Ciudades , Mamíferos , Animales Salvajes , EcosistemaRESUMEN
PURPOSE: To investigate if metformin use reduces the odds of developing new neovascular AMD (nAMD). METHODS: This is a case-control study of 86,930 subjects with new diagnoses of nAMD and 86,918 matched control subjects using the Merative Marketscan Research Databases. Subjects were analyzed using multivariable conditional logistic regression to identify the risks of various exposures on developing nAMD. A subgroup analysis of 22,117 diabetic cases and 21,616 diabetic control subjects was also performed. RESULTS: Metformin use was associated with reduced odds ratio of developing nAMD (odds ratio 0.95, 95% confidence interval 0.91-0.98) in full sample and diabetic cohort particularly in patients without any diabetic retinopathy-an effect that persisted after Bonferroni correction. In the diabetic cohort without diabetic retinopathy, reduced odds ratio was observed at 24-month cumulative doses of 1 to 300 g, 301 to 630 g, and 631 to 1,080 g. CONCLUSION: Metformin use was associated with reduced odds ratio of nAMD, particularly in patients without diabetic retinopathy. The protective effect was noted for 24-month cumulative doses below 1,080 g. Metformin may be a novel preventive strategy for nAMD.
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Retinopatía Diabética , Metformina , Degeneración Macular Húmeda , Humanos , Retinopatía Diabética/epidemiología , Inhibidores de la Angiogénesis , Estudios de Casos y Controles , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/epidemiología , Metformina/uso terapéutico , MetildopaRESUMEN
PURPOSE: A previous study from our group demonstrated protective effects of the use of metformin in the odds of developing age-related macular degeneration (AMD). This is a subgroup analysis in a cohort of patients with diabetes to assess the interaction of metformin and other medications in protecting diabetic patients against developing AMD. METHODS: This is a case-control analysis using data from the Merative MarketScan Commercial and Medicare databases. Patients were 55 years and older with newly diagnosed AMD and matched to controls. We performed multivariable conditional logistic regressions, which adjusted for known risk factors of AMD and tested multiple interaction effects between metformin and 1) insulin, 2) sulfonylureas, 3) glitazones, 4) meglitinides, and 5) statins. RESULTS: The authors identified 81,262 diabetic cases and 79,497 diabetic controls. Metformin, insulin, and sulfonylureas demonstrated independent protective effects against AMD development. Sulfonylureas in combination with metformin demonstrated further decreased odds of AMD development compared with metformin alone. The other medication group (exenatide, sitagliptin, and pramlintide) slightly increased the odds of developing AMD when taken alone, but the combination with metformin alleviated this effect. CONCLUSION: The authors believe that their results bring them one step closer to finding an optimal effective hypoglycemic regimen that also protects against AMD development in diabetic patients.
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Diabetes Mellitus , Degeneración Macular , Metformina , Humanos , Anciano , Estados Unidos/epidemiología , Metformina/uso terapéutico , Medicare , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/epidemiología , Compuestos de Sulfonilurea/uso terapéutico , Insulina/uso terapéutico , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/prevención & control , Degeneración Macular/inducido químicamenteRESUMEN
PURPOSE: To investigate if metformin use reduces the odds of developing new neovascular AMD (nAMD). METHODS: This is a case-control study of 86,930 subjects with new diagnoses of nAMD and 86,918 matched controls using the Merative™ Marketscan® Research Databases. Subjects were analyzed using multivariable conditional logistic regression to identify the risks of various exposures on developing nAMD. A subgroup analysis of 22,117 diabetic cases and 21,616 diabetic controls was also performed. RESULTS: Metformin use was associated with reduced odds ratio (OR) of developing nAMD (OR 0.95, 95% confidence interval 0.91-0.98) in full sample and diabetic cohort particularly in patients without any diabetic retinopathy (DR) -an effect that persisted after Bonferroni correction. In the diabetic cohort without DR, reduced OR was observed at 24-month cumulative doses of 1 to 300g, 301 to 630g, and 631 to 1080g. CONCLUSIONS: Metformin use was associated with reduced OR of nAMD, particularly in patients without DR. The protective effect was noted for 24-month cumulative doses below 1080g. Metformin may be a novel preventive strategy for nAMD.
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The Covid-19 pandemic has greatly disrupted the education of first-generation college students (first-gens)-those whose parents did not complete a college degree. With campuses closed, activities canceled, and support services curtailed, many first-gens have increasingly relied on their parents for mental, emotional, and logistical support. At the same time, their parents face compounding stresses and challenges stemming from the prolonged effects of the Covid pandemic. We examined the role that relational dynamics between first-gens and their parents played in how they weathered the first 2 years of the Covid pandemic together. We draw upon journals submitted by self-identified first-gens and parents of first-gens to the Pandemic Journaling Project between October 2021 and May 2022 as part of a pilot study of first-gen family experiences of Covid-19, along with a series of interviews conducted with three student-parent dyads. We argue that what we term the micropractices of care-the "little things," like a kind word, small gift, or car ride, that were regularly exchanged between parents and students-played a key role in mental wellness and educational persistence. We find that when there is synchrony between practices offered by one dyad member and their reception by the other, mental wellbeing is preserved. When there is asynchrony, mental health is destabilized. These findings reflect the strategies on which first-gen families have creatively relied to maintain shared mental wellness and student success during a time of crisis. We show how everyday mental wellness is forged in the intersubjective space between two people engaged in achieving shared life goals.
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Acute and long-term paraquat (PQ) exposure produces hippocampal neurodegeneration and cognition decline. Although some mechanisms involved in these effects were found, the rest are unknown. PQ treatment, for 1 and 14 days, upregulated interferon-gamma signaling, which reduced insulin levels and downregulated the insulin pathway through phosphorylated-c-Jun N-terminal-kinase upregulation, increasing glucose levels and the production of Aß1-42 and phosphorylated-tau, by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) overexpression and phosphorylated-GSK3ß (p-GSK3ß; ser9) level reduction, respectively, which induced primary hippocampal neuronal loss. This novel information on the PQ mechanisms leading to hippocampal neurodegeneration could help reveal the PQ actions that lead to cognition dysfunction.
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Paraquat , Proteínas tau , Proteínas tau/metabolismo , Paraquat/toxicidad , Paraquat/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/farmacología , Insulina/metabolismo , Regulación hacia Arriba , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/farmacología , Péptidos beta-Amiloides/metabolismo , Hipocampo , Muerte CelularRESUMEN
This study aimed to test the effects of the drug r-met-hu-G-CSF (filgrastim) on spermatogenic efficiency in prepubertal Brahman bulls. Twelve intact, healthy prepubertal bulls were administered 0, 1 (LD = low dose) or 4 (HD = high dose) µg/Kg r-met-hu-G-CSF (daily for 4 days), and haematological analysis was performed. Bulls were castrated (D0 or D60). BW (body weight) and SC (scrotal circumference) were recorded. Testis weight and volume were taken at castration with samples for testis histology and stereology: germ cell types, spermatids count and DSP (daily sperm production per gram)/g of testicular parenchyma. Testicular weight, volume, BW, SC and gonadosomatic index (GSI) were NS (LD-HD; p > .05). At D0 (age 11 months), the most advanced germ cell types (maGCt) ranged from intermediate spermatogonia to pachytene spermatocytes. After 2 months, control animals had round spermatids as maGCt, LD animals 75% round spermatids and 25% elongated spermatids, and HD animals round spermatids. Spermatids/testis were higher in LD (1.23 ± 0.2 millions) than in controls (0.65 ± 0.1 millions, p < .05). Spermatogenic efficiency (DSP/g) was higher in LD (5.4 ± 0.4 million) than in controls (3.2 ± 0.2 million, p < .01). In conclusion, r-met-hu-G-CSF raises spermatogenic efficiency in prepubertal Brahman bulls.
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Factor Estimulante de Colonias de Granulocitos , Espermatogénesis , Animales , Bovinos , Filgrastim/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Masculino , Espermátides , Espermatozoides , TestículoRESUMEN
The biocide chlorpyrifos (CPF) was described to increase breast cancer risk in humans, to produce breast cancer in animals, and to induce cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment. The entire mechanisms related to these CPF actions remain unknown. CPF induced cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment by AhR activation through the PGE2/Wnt/ß-catenin pathway and HSP90 and HSP70 overexpression. Our results reveal new information on CPF toxic mechanisms induced in human breast cancer cell lines, which could assist in elucidating its involvement in breast cancer.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Proliferación Celular/efectos de los fármacos , Cloropirifos/toxicidad , Desinfectantes/toxicidad , Proteínas de Choque Térmico/metabolismo , Receptores de Hidrocarburo de Aril/agonistas , Vía de Señalización Wnt/efectos de los fármacos , Línea Celular Tumoral , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Prion diseases are a group of incurable neurodegenerative disorders that affect humans and animals via infection with proteinaceous particles called prions. Prions are composed of PrPSc, a misfolded version of the cellular prion protein (PrPC). During disease progression, PrPSc replicates by interacting with PrPC and inducing its conversion to PrPSc As PrPSc accumulates, cellular stress mechanisms are activated to maintain cellular proteostasis, including increased protein chaperone levels. However, the exact roles of several of these chaperones remain unclear. Here, using various methodologies to monitor prion replication (i.e. protein misfolding cyclic amplification and cellular and animal infectivity bioassays), we studied the potential role of the molecular chaperone heat shock protein 70 (HSP70) in prion replication in vitro and in vivo Our results indicated that pharmacological induction of the heat shock response in cells chronically infected with prions significantly decreased PrPSc accumulation. We also found that HSP70 alters prion replication in vitro More importantly, prion infection of mice lacking the genes encoding stress-induced HSP70 exhibited accelerated prion disease progression compared with WT mice. In parallel with HSP70 being known to respond to endogenous and exogenous stressors such as heat, infection, toxicants, and ischemia, our results indicate that HSP70 may also play an important role in suppressing or delaying prion disease progression, opening opportunities for therapeutic intervention.
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Proteínas HSP70 de Choque Térmico/metabolismo , Enfermedades por Prión/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Progresión de la Enfermedad , Retículo Endoplásmico/fisiología , Estrés del Retículo Endoplásmico/fisiología , Femenino , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Priónicas/metabolismo , Priones/metabolismo , Pliegue de ProteínaRESUMEN
Ubiquitylation of Nrf2 by the Keap1-Cullin3/RING box1 (Cul3-Rbx1) E3 ubiquitin ligase complex targets Nrf2 for proteasomal degradation in the cytoplasm and is an extensively studied mechanism for regulating the cellular level of Nrf2. Although mechanistic details are lacking, reports abound that Nrf2 can also be degraded in the nucleus. Here, we demonstrate that Nrf2 is a target for sumoylation by both SUMO-1 and SUMO-2. HepG2 cells treated with As2O3, which enhances attachment of SUMO-2/3 to target proteins, increased SUMO-2/3-modification (polysumoylation) of Nrf2. We show that Nrf2 traffics, in part, to promyelocytic leukemia-nuclear bodies (PML-NBs). Cell fractions harboring key components of PML-NBs did not contain biologically active Keap1 but contained modified Nrf2 as well as RING finger protein 4 (RNF4), a poly-SUMO-specific E3 ubiquitin ligase. Overexpression of wild-type RNF4, but not the catalytically inactive mutant, decreased the steady-state levels of Nrf2, measured in the PML-NB-enriched cell fraction. The proteasome inhibitor MG-132 interfered with this decrease, resulting in elevated levels of polysumoylated Nrf2 that was also ubiquitylated. Wild-type RNF4 accelerated the half-life (t½) of Nrf2, measured in PML-NB-enriched cell fractions. These results suggest that RNF4 mediates polyubiquitylation of polysumoylated Nrf2, leading to its subsequent degradation in PML-NBs. Overall, this work identifies Nrf2 as a target for sumoylation and provides a novel mechanism for its degradation in the nucleus, independent of Keap1.
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Leucemia Promielocítica Aguda/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Nucleares/metabolismo , Estrés Oxidativo , Núcleo Celular/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Genes Reporteros , Células Hep G2 , Humanos , Cuerpos de Inclusión Intranucleares/metabolismo , Microscopía Fluorescente , Estructura Terciaria de Proteína , Sumoilación , Factores de Transcripción/metabolismoRESUMEN
Importance: Metformin use may protect against the development of age-related macular degeneration (AMD) based on results from observational studies. However, its potential effectiveness among patients without diabetes remains unclear. Objective: To assess the association between metformin use and the development of AMD in patients without diabetes. Design, Setting, and Participants: This case-control study used data from 2006 to 2017 in the Merative MarketScan Research Database, a nationwide insurance claims database that includes between 27 and 57 million patients in the US with primary or Medicare supplemental health insurance. Cases with AMD and controls without AMD aged 55 years or older were matched 1:1 by year, age, anemia, hypertension, region, and Charlson Comorbidity Index score. Then, cases and matched controls without a diagnosis of diabetes were selected. In subgroup analyses, cases with dry AMD and their matched controls were identified to explore the association between metformin use and AMD staging in patients without diabetes. Data were analyzed between March and September 2023. Exposures: Exposure to metformin in the 2 years prior to the index date (ie, date of AMD diagnosis in cases and date of a randomly selected eye examination for controls) was assessed from the claims database and categorized into quartiles based on cumulative dose (1-270, 271-600, 601-1080, and >1080 g/2 y). Exposure to other antidiabetic medications was also noted. Main Outcomes and Measures: Odds of new-onset AMD development as assessed by multivariable conditional logistic regression after adjusting for known risk factors for AMD, including female sex, hyperlipidemia, smoking, and exposures to other antidiabetic medications. Asymptotic Cochran-Armitage tests for trend were also performed. Results: We identified 231â¯142 patients with any AMD (mean [SD] age, 75.1 [10.4] years; 140 172 females [60.6%]) and 232 879 matched controls without AMD (mean [SD] age, 74.9 [10.5] years; 133 670 females [57.4%]), none of whom had a diagnosis of diabetes. The sample included 144 147 cases with dry AMD that were matched to 144 530 controls. In all, 2268 (1.0%) cases and 3087 controls (1.3%) were exposed to metformin in the 2 years before their index visit. After data adjustment, exposure to any metformin was associated with reduced odds of any AMD development (adjusted odds ratio [AOR], 0.83; 95% CI, 0.74-0.87), specifically in the dosing quartiles of 1 to 270, 271 to 600, and 601 to 1080 g/2 y. Any metformin use was also associated with a reduced odds of developing dry AMD (AOR, 0.85; 95% CI, 0.79-0.92), specifically in the dosing quartiles of 1 to 270 and 271 to 600 g/2 y. Adjusted odds ratios for any AMD and dry AMD development did not differ across the dosing quartiles. Asymptotic Cochran-Armitage tests for trend revealed 2-sided P = .51 and P = .66 for the any and dry AMD samples, respectively. Conclusions and Relevance: In this case-control study of a population without a diagnosis of diabetes, metformin use was associated with reduced odds of developing AMD. This association does not appear to be dose dependent. These findings provide further impetus to study metformin's usefulness in protecting against AMD in prospective clinical trials.
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Diabetes Mellitus , Atrofia Geográfica , Degeneración Macular , Metformina , Anciano , Femenino , Humanos , Estudios de Casos y Controles , Diabetes Mellitus/tratamiento farmacológico , Atrofia Geográfica/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Degeneración Macular/diagnóstico , Degeneración Macular/epidemiología , Degeneración Macular/tratamiento farmacológico , Medicare , Metformina/uso terapéutico , Estudios Prospectivos , Factores de Riesgo , Estados Unidos/epidemiología , Masculino , Anciano de 80 o más Años , Persona de Mediana EdadRESUMEN
Purpose: Metformin has been suggested to protect against the development of age-related macular degeneration (AMD) in multiple observational studies. However, the association between metformin and geographic atrophy (GA), a debilitating subtype of AMD, has not been analyzed. Methods: We conducted a case-control study of patients ages 60 years and older with new-onset International Classification of Diseases (ICD) coding of GA in the Merative MarketScan Commercial and Medicare Databases between 2017 and 2021. Cases were matched with propensity scores estimated by age, region, hypertension, and Charlson Comorbidity Index to a control without GA of the same year. Exposure to metformin was assessed for cases and controls in the year prior to their index visit. Conditional multivariable logistic regression, adjusting for AMD risk factors, was used to calculate odd ratios and 95% confidence intervals (CIs). This study design and analysis were repeated in a sample of patients without diabetes. Results: In the full sample, we identified 10,505 cases with GA and 10,502 matched controls without GA. In total, 1149 (10.9%) cases and 1277 (12.2%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 12% (95% CI, 0.79-0.99). In the sample of patients without diabetes, we identified 7611 cases with GA and 7608 matched controls without GA. Twenty-nine (0.4%) cases and 63 (0.8%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 47% (95% CI, 0.33-0.83). Conclusions: Metformin may hold promise as a noninvasive, alternative agent to prevent the development of GA. This finding is notable due to shortcomings in recently approved therapeutics for GA and metformin's overall ease of use and few adverse effects. Additional studies are required to explore our findings further and motivate a clinical trial.
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Diabetes Mellitus , Atrofia Geográfica , Degeneración Macular , Metformina , Anciano , Humanos , Estudios de Casos y Controles , Atrofia Geográfica/diagnóstico , Clasificación Internacional de Enfermedades , Degeneración Macular/prevención & control , Medicare , Metformina/uso terapéutico , Estados Unidos/epidemiología , Persona de Mediana EdadRESUMEN
Chlorpyrifos (CPF) biocide, exposure to which is mainly produced in the human population through diet, induces several neurotoxic effects. CPF single and repeated exposure induces memory and learning disorders, although the mechanisms that produce these outcomes are complex and not well understood. CPF treatment (single and repeated) of cholinergic septal SN56 cells induced an increase in phosphorylated-P38α levels that led to WNT/ß-Catenin and NGF/P75NTR/TrkA pathways disruption and cell death. These results provide new knowledge on the mechanisms that mediate CPF basal forebrain cholinergic neuronal loss induced by CPF single and repeated exposure and can help unravel the way through which this compound produces cognitive decline and develop efficient treatments against these effects.
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Volunteering has long held a vaunted position in the United States, which has only increased in the wake of welfare reform and the retraction of the state from the provision of public goods. This article explores how immigrant-origin Latinx youth in Nashville, Tennessee, who are active community volunteers linked volunteering to moral personhood and their claims to national membership. This linkage is based on an internalized deficit perception of the Latinx immigrant person as an immoral national interloper and a stigmatization and racialization of economic need. However, youth also engaged in a reframing of the meanings of membership and volunteering rooted in their relational commitments to each other and their undocumented peers' blocked paths to citizenship. These socially reproductive and more transformative understandings of volunteering, and their links to self-as-citizen, reveal the contingent value of civic engagement for immigrant-origin Latinx youth. It also reveals their central roles in defining the parameters of membership in an era of increased nativist racism and decreased state social service provision in the United States.
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Purpose: The widespread use of antibiotics has many well-documented impacts on the human microbiome, which may be associated with the development of various inflammatory diseases. Despite age-related macular degeneration (AMD) featuring an inflammatory pathogenesis, the relationship between antibiotics and AMD has remained unexplored. We conducted the first study to determine the association between antibiotic exposure and a new-onset International Classification of Diseases (ICD) diagnosis of AMD. Methods: We performed a case-control analysis of patients aged 55 and older with new-onset AMD between 2008 and 2017 from a nationwide commercial health insurance claims database. Exposure to antibiotics in the two years before the index date was determined for cases and controls matched one-to-one by age, year, region, anemia, hypertension, and a comorbidity index. Conditional multivariable logistic regression, adjusted for AMD risk factors, was performed to calculate odd ratios (OR) and 95% confidence intervals (CI). Results: Among the antibiotic classes, exposure to aminoglycosides (OR = 1.24; 95% CI, 1.22-1.26) and fluoroquinolones (OR = 1.13; 95% CI, 1.12-1.14) was associated with the greatest odds of a new-onset ICD code diagnosis of AMD. Broad-spectrum antibiotics were associated with nearly three times greater odds of a new-onset ICD code diagnosis of AMD (OR = 1.15; 95% CI, 1.13-1.16) compared to narrow-spectrum antibiotics (OR = 1.05; 95% CI, 1.03-1.07). We also identified a frequency- and duration-dependent association, with a greater cumulative number of antibiotic prescriptions or day supply of antibiotics conferring increased odds of a new-onset ICD code diagnosis of AMD. Conclusions: Greater cumulative exposure to antibiotics, particularly fluoroquinolones, aminoglycosides, and those with broader-spectrum coverage, may be associated with the development of AMD, a finding that requires further investigation using prospective studies.
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Antibacterianos , Degeneración Macular , Humanos , Antibacterianos/efectos adversos , Clasificación Internacional de Enfermedades , Estudios de Casos y Controles , Estudios Prospectivos , Aminoglicósidos , Fluoroquinolonas , Degeneración Macular/diagnóstico , Degeneración Macular/epidemiologíaRESUMEN
BACKGROUND: Sympathetic stress stimulates norepinephrine (NE) release from sympathetic nerves. During pregnancy, it modifies the fetal environment, increases NE to the fetus through the placental NE transporter, and affects adult physiological functions. Gestating rats were exposed to stress, and then the heart function and sensitivity to in vivo adrenergic stimulation were studied in male progeny. METHODS: Pregnant Sprague-Dawley rats were exposed to cold stress (4 °C/3 h/day); rats' male progeny were euthanized at 20 and 60 days old, and their hearts were used to determine the ß-adrenergic receptor (ßAR) (radioligand binding) and NE concentration. The in vivo arterial pressure response to isoproterenol (ISO, 1 mg/kg weight/day/10 days) was monitored in real time (microchip in the descending aorta). RESULTS: Stressed male progeny presented no differences in ventricular weight, the cardiac NE was lower, and high corticosterone plasma levels were recorded at 20 and 60 days old. The relative abundance of ß1 adrenergic receptors decreased by 36% and 45%, respectively (p < 0.01), determined by Western blot analysis without changes in ß2 adrenergic receptors. A decrease in the ratio between ß1/ß2 receptors was found. Displacement of 3H-dihydroalprenolol (DHA) from a membrane fraction with propranolol (ß antagonist), atenolol (ß1 antagonist), or zinterol (ß2 agonist) shows decreased affinity but no changes in the ß-adrenergic receptor number. In vivo exposure to ISO to induce a ß-adrenergic overload provoked death in 50% of stressed males by day 3 of ISO treatment. CONCLUSION: These data suggest permanent changes to the heart's adrenergic response after rat progeny were stressed in the uterus.
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Madres , Placenta , Ratas , Femenino , Masculino , Embarazo , Animales , Humanos , Ratas Sprague-Dawley , Placenta/metabolismo , Norepinefrina , Receptores Adrenérgicos beta/metabolismo , AdrenérgicosRESUMEN
Purpose: The pathogenesis of age-related macular degeneration (AMD) likely implicates the dysregulation of immune response pathways. Several studies demonstrate that the pathogenic elements of AMD resemble those of autoimmune diseases, yet the association between AMD development and most autoimmune diseases remain unexplored. Methods: We conducted a case-control analysis of patients ages 55 and older with new-onset International Classification of Diseases (ICD) coding of dry, wet, or unspecified AMD between 2005 and 2019 in the Merative MarketScan Commercial and Medicare Databases. The diagnosis of an autoimmune disease was defined by an outpatient or inpatient claim with a relevant ICD code in the 12 months before the index visit. Conditional multivariable logistic regression, adjusted for AMD risk factors, was used to calculate odd ratios and 95% confidence intervals. Results: We identified 415,027 cases with new-onset ICD coding for AMD matched with propensity scores to 414,853 controls. In total, 16.1% of cases and 15.9% of controls were diagnosed with any autoimmune disease. The diagnosis of any autoimmune disease did not affect the odds of new-onset ICD coding for AMD in multivariable regression (OR = 1.01; 95% CI, 0.999-1.02). Discoid lupus erythematosus (OR = 1.29; 95% CI, 1.12-1.48), systemic lupus erythematosus (SLE) (OR = 1.21; 95% CI, 1.15-1.27), giant cell arteritis (OR = 1.19; 95% CI, 1.09-1.30), Sjogren's syndrome (OR = 1.17; 95% CI, 1.09-1.26), and Crohn's disease (OR = 1.13; 95% CI, 1.06-1.22) increased the odds of a new-onset ICD coding for AMD. Conclusions: Most autoimmune diseases do not affect the odds of developing AMD but several common autoimmune disorders such as SLE and Crohn's disease were associated with modestly increased odds of AMD. Further studies are needed to validate and investigate the underlying mechanisms of these associations.
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Enfermedades Autoinmunes , Enfermedad de Crohn , Lupus Eritematoso Sistémico , Degeneración Macular , Estados Unidos/epidemiología , Humanos , Anciano , Medicare , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/epidemiología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/epidemiología , Degeneración Macular/diagnóstico , Degeneración Macular/epidemiología , Degeneración Macular/etiologíaRESUMEN
PURPOSE: Recruiting patients for clinical research is challenging, especially for underrepresented populations, and may be influenced by patients' relationships with their physicians, care experiences, and engagement with care. This study sought to understand predictors of enrollment in a research study among socioeconomically diverse participants in studies of care models that promote continuity in the doctor-patient relationship. METHOD: A study of the effects of vitamin D levels and supplementation on COVID-19 risk and outcomes was implemented from 2020 to 2022 within 2 studies of care models at the University of Chicago that promoted continuity of inpatient and outpatient care from the same physician. Hypothesized predictors of vitamin D study enrollment included patient-reported measures of the care experience (quality of relationship with the doctor and their staff, timely receipt of care), engagement in care (scheduling and completing outpatient visits), and engagement with these "parent" studies (follow-up survey completion). The authors used univariate tests and multivariable logistic regression to examine the association of these predictors with enrollment in the vitamin D study among participants in the parent study intervention arms. RESULTS: Among 773 eligible participants, 351/561 (63%) in the parent study intervention arms enrolled in the vitamin D study, versus 35/212 (17%) in the control arms. Among intervention arm participants, vitamin D study enrollment was not associated with reported quality of communication with or trust in the doctor, or helpful/respectful office staff, but was associated with report of receiving timely care, more completed clinic visits, and higher parent study follow-up survey completion. CONCLUSIONS: Study enrollment may be high in care models with high levels of continuity in the doctor-patient relationship. Rates of clinic involvement, parent study engagement, and experience of receiving timely access to care may better predict enrollment than quality of the doctor-patient relationship.
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COVID-19 , Relaciones Médico-Paciente , Humanos , COVID-19/epidemiología , Atención Ambulatoria , Padres , Vitamina DRESUMEN
Cadmium (Cd) produces cognition decline following single and repeated treatment, although the complete mechanisms are still unrevealed. Basal forebrain (BF) cholinergic neurons innervate the cortex and hippocampus, regulating cognition. Cd single and repeated exposure induced BF cholinergic neuronal loss, partly through thyroid hormones (THs) disruption, which may cause the cognition decline observed following Cd exposure. However, the mechanisms through which THs disruption mediate this effect remain unknown. To research the possible mechanisms through which Cd-induced THs deficiency may mediate BF neurodegeneration, Wistar male rats were treated with Cd for 1- (1 mg/kg) or 28-days (0.1 mg/kg) with or without triiodothyronine (T3, 40 µg/kg/day). Cd exposure promoted neurodegeneration, spongiosis, gliosis and several mechanisms related to these alterations (increased H202, malondialdehyde, TNF-α, IL-1ß, IL-6, BACE1, Aß and phosphorylated-Tau levels, and decreased phosphorylated-AKT and phosphorylated-GSK-3ß levels). T3 supplementation partially reversed the effects observed. Our results show that Cd induces several mechanisms that may be responsible for the neurodegeneration, spongiosis and gliosis observed in the rats' BF, which are partially mediated by a reduction in THs levels. These data may help to explain the mechanisms through which Cd induces BF neurodegeneration, possibly leading to the cognitive decline observed, providing new therapeutic tools to prevent and treat these damages.
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Prosencéfalo Basal , Cadmio , Animales , Masculino , Ratas , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Prosencéfalo Basal/metabolismo , Cadmio/toxicidad , Gliosis/inducido químicamente , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Inflamación , Ratas Wistar , Especies Reactivas de Oxígeno , Proteínas tau/metabolismo , Hormonas TiroideasRESUMEN
The widely used plasticizer bisphenol-A (BPA) is well-known for producing neurodegeneration and cognitive disorders, following acute and long-term exposure. Although some of the BPA actions involved in these effects have been unraveled, they are still incompletely known. Basal forebrain cholinergic neurons (BFCN) regulate memory and learning processes and their selective loss, as observed in Alzheimer's disease and other neurodegenerative diseases, leads to cognitive decline. In order to study the BPA neurotoxic effects on BFCN and the mechanisms through which they are induced, 60-day old Wistar rats were used, and a neuroblastoma cholinergic cell line from the basal forebrain (SN56) was used as a basal forebrain cholinergic neuron model. Acute treatment of rats with BPA (40 µg/kg) induced a more pronounced basal forebrain cholinergic neuronal loss. Exposure to BPA, following 1- or 14-days, produced postsynaptic-density-protein-95 (PSD95), synaptophysin, spinophilin, and N-methyl-D-aspartate-receptor-subunit-1 (NMDAR1) synaptic proteins downregulation, an increase in glutamate content through an increase in glutaminase activity, a downregulation in the vesicular-glutamate-transporter-2 (VGLUT2) and in the WNT/ß-Catenin pathway, and cell death in SN56 cells. These toxic effects observed in SN56 cells were mediated by overexpression of histone-deacetylase-2 (HDAC2). These results may help to explain the synaptic plasticity, cognitive dysfunction, and neurodegeneration induced by the plasticizer BPA, which could contribute to their prevention.