RESUMO
Horse domestication revolutionized warfare and accelerated travel, trade, and the geographic expansion of languages. Here, we present the largest DNA time series for a non-human organism to date, including genome-scale data from 149 ancient animals and 129 ancient genomes (≥1-fold coverage), 87 of which are new. This extensive dataset allows us to assess the modern legacy of past equestrian civilizations. We find that two extinct horse lineages existed during early domestication, one at the far western (Iberia) and the other at the far eastern range (Siberia) of Eurasia. None of these contributed significantly to modern diversity. We show that the influence of Persian-related horse lineages increased following the Islamic conquests in Europe and Asia. Multiple alleles associated with elite-racing, including at the MSTN "speed gene," only rose in popularity within the last millennium. Finally, the development of modern breeding impacted genetic diversity more dramatically than the previous millennia of human management.
Assuntos
Cavalos/genética , Animais , Ásia , Evolução Biológica , Cruzamento/história , DNA Antigo/análise , Domesticação , Equidae/genética , Europa (Continente) , Feminino , Variação Genética/genética , Genoma/genética , História Antiga , Masculino , FilogeniaRESUMO
Cancer metabolism is a marvellously complex topic, in part, due to the reprogramming of its pathways to self-sustain the malignant phenotype in the disease, to the detriment of its healthy counterpart. Understanding these adjustments can provide novel targeted therapies that could disrupt and impair proliferation of cancerous cells. For this very purpose, genome-scale metabolic models (GEMs) have been developed, with Human1 being the most recent reconstruction of the human metabolism. Based on GEMs, we introduced the genetic Minimal Cut Set (gMCS) approach, an uncontextualized methodology that exploits the concepts of synthetic lethality to predict metabolic vulnerabilities in cancer. gMCSs define a set of genes whose knockout would render the cell unviable by disrupting an essential metabolic task in GEMs, thus, making cellular proliferation impossible. Here, we summarize the gMCS approach and review the current state of the methodology by performing a systematic meta-analysis based on two datasets of gene essentiality in cancer. First, we assess several thresholds and distinct methodologies for discerning highly and lowly expressed genes. Then, we address the premise that gMCSs of distinct length should have the same predictive power. Finally, we question the importance of a gene partaking in multiple gMCSs and analyze the importance of all the essential metabolic tasks defined in Human1. Our meta-analysis resulted in parameter evaluation to increase the predictive power for the gMCS approach, as well as a significant reduction of computation times by only selecting the crucial gMCS lengths, proposing the pertinency of particular parameters for the peak processing of gMCS.
Assuntos
Neoplasias , Humanos , Neoplasias/genética , Proliferação de Células , Expressão Gênica , Nível de Saúde , FenótipoRESUMO
Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.
Assuntos
Neoplasias da Mama , Animais , Feminino , Humanos , Camundongos , Adipócitos/metabolismo , Neoplasias da Mama/patologia , Células Endoteliais/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Rosiglitazona/farmacologiaRESUMO
The Hippo signaling is instrumental in regulating organ size, regeneration, and carcinogenesis. The cytoskeleton emerges as a primary Hippo signaling modulator. Its structural alterations in response to environmental and intrinsic stimuli control Hippo signaling pathway activity. However, the precise mechanisms underlying the cytoskeleton regulation of Hippo signaling are not fully understood. RAP2 GTPase is known to mediate the mechanoresponses of Hippo signaling via activating the core Hippo kinases LATS1/2 through MAP4Ks and MST1/2. Here we show the pivotal role of the reciprocal regulation between RAP2 GTPase and the cytoskeleton in Hippo signaling. RAP2 deletion undermines the responses of the Hippo pathway to external cues tied to RhoA GTPase inhibition and actin cytoskeleton remodeling, such as energy stress and serum deprivation. Notably, RhoA inhibitors and actin disruptors fail to activate LATS1/2 effectively in RAP2-deficient cells. RNA sequencing highlighted differential regulation of both actin and microtubule networks by RAP2 gene deletion. Consistently, Taxol, a microtubule-stabilizing agent, was less effective in activating LATS1/2 and inhibiting cell growth in RAP2 and MAP4K4/6/7 knockout cells. In summary, our findings position RAP2 as a central integrator of cytoskeletal signals for Hippo signaling, which offers new avenues for understanding Hippo regulation and therapeutic interventions in Hippo-impaired cancers.
Assuntos
Via de Sinalização Hippo , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Animais , Humanos , Camundongos , Citoesqueleto/metabolismo , Microtúbulos/metabolismo , Paclitaxel/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas rap de Ligação ao GTP/metabolismo , Proteínas rap de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , FosforilaçãoRESUMO
The soluble flavoprotein oleate hydratase (OhyA) hydrates the 9-cis double bond of unsaturated fatty acids. OhyA substrates are embedded in membrane bilayers; OhyA must remove the fatty acid from the bilayer and enclose it in the active site. Here, we show that the positively charged helix-turn-helix motif in the carboxy terminus (CTD) is responsible for interacting with the negatively charged phosphatidylglycerol (PG) bilayer. Super-resolution microscopy of Staphylococcus aureus cells expressing green fluorescent protein fused to OhyA or the CTD sequence shows subcellular localization along the cellular boundary, indicating OhyA is membrane-associated and the CTD sequence is sufficient for membrane recruitment. Using cryo-electron microscopy, we solved the OhyA dimer structure and conducted 3D variability analysis of the reconstructions to assess CTD flexibility. Our surface plasmon resonance experiments corroborated that OhyA binds the PG bilayer with nanomolar affinity and we found the CTD sequence has intrinsic PG binding properties. We determined that the nuclear magnetic resonance structure of a peptide containing the CTD sequence resembles the OhyA crystal structure. We observed intermolecular NOE from PG liposome protons next to the phosphate group to the CTD peptide. The addition of paramagnetic MnCl2 indicated the CTD peptide binds the PG surface but does not insert into the bilayer. Molecular dynamics simulations, supported by site-directed mutagenesis experiments, identify key residues in the helix-turn-helix that drive membrane association. The data show that the OhyA CTD binds the phosphate layer of the PG surface to obtain bilayer-embedded unsaturated fatty acids.
Assuntos
Ácido Oleico , Peptídeos , Staphylococcus aureus , Microscopia Crioeletrônica , Ácidos Graxos Insaturados , Bicamadas Lipídicas/metabolismo , Fosfatos , Staphylococcus aureus/enzimologia , Staphylococcus aureus/genéticaRESUMO
BACKGROUND: Tools for mortality prediction in patients with the severe hypercholesterolemia phenotype (low-density lipoprotein cholesterol ≥190 mg/dL) are limited and restricted to specific racial and ethnic cohorts. We sought to evaluate the predictors of long-term mortality in a large racially and ethnically diverse US patient cohort with low-density lipoprotein cholesterol ≥190 mg/dL. METHODS: We conducted a retrospective analysis of all patients with a low-density lipoprotein cholesterol ≥190 mg/dL seeking care at Montefiore from 2010 through 2020. Patients <18 years of age or with previous malignancy were excluded. The primary end point was all-cause mortality. Analyses were stratified by age, sex, and race and ethnicity. Patients were stratified by primary and secondary prevention. Cox regression analyses were used to adjust for demographic, clinical, and treatment variables. RESULTS: A total of 18 740 patients were included (37% non-Hispanic Black, 30% Hispanic, 12% non-Hispanic White, and 2% non-Hispanic Asian patients). The mean age was 53.9 years, and median follow-up was 5.2 years. Both high-density lipoprotein cholesterol and body mass index extremes were associated with higher mortality in univariate analyses. In adjusted models, higher low-density lipoprotein cholesterol and triglyceride levels were associated with an increased 9-year mortality risk (adjusted hazard ratio [HR], 1.08 [95% CI, 1.05-1.11] and 1.04 [95% CI, 1.02-1.06] per 20-mg/dL increase, respectively). Clinical factors associated with higher mortality included male sex (adjusted HR, 1.31 [95% CI, 1.08-1.58]), older age (adjusted HR, 1.19 per 5-year increase [95% CI, 1.15-1.23]), hypertension (adjusted HR, 2.01 [95% CI, 1.57-2.57]), chronic kidney disease (adjusted HR, 1.68 [95% CI, 1.36-2.09]), diabetes (adjusted HR, 1.79 [95% CI, 1.50-2.15]), heart failure (adjusted HR, 1.51 [95% CI, 1.16-1.95]), myocardial infarction (adjusted HR, 1.41 [95% CI, 1.05-1.90]), and body mass index <20 kg/m2 (adjusted HR, 3.36 [95% CI, 2.29-4.93]). A significant survival benefit was conferred by lipid-lowering therapy (adjusted HR, 0.57 [95% CI, 0.42-0.77]). In the primary prevention group, high-density lipoprotein cholesterol <40 mg/dL was independently associated with higher mortality (adjusted HR, 1.49 [95% CI, 1.06-2.09]). Temporal trend analyses showed a reduction in statin use over time (P<0.001). In the most recent time period (2019-2020), 56% of patients on primary prevention and 85% of those on secondary prevention were on statin therapy. CONCLUSIONS: In a large, diverse cohort of US patients with the severe hypercholesterolemia phenotype, we identified several patient characteristics associated with increased 9-year all-cause mortality and observed a decrease in statin use over time, in particular for primary prevention. Our results support efforts geared toward early recognition and consistent treatment for patients with severe hypercholesterolemia.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Humanos , Masculino , Pessoa de Meia-Idade , Hipercolesterolemia/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos Retrospectivos , LDL-Colesterol , HDL-Colesterol , Fenótipo , Fatores de RiscoRESUMO
BACKGROUND: HIV and hepatitis C virus (HCV) are associated with increased risk of carotid artery atherosclerotic plaque and stroke. We examined associations of HIV- and HCV-related factors with echomorphologic features of carotid artery plaque. METHODS: This cross-sectional study included participants from the MACS (Multicenter AIDS Cohort Study)/WIHS (Women's Interagency HIV Study) Combined Cohort Study who underwent high-resolution B-mode carotid artery ultrasound. Plaques were characterized from 6 areas of the right carotid artery. Poisson regression controlling for demographic and cardiometabolic risk factors determined adjusted prevalence ratios (aPRs) and 95% CIs for associations of HIV- and HCV-related factors with echomorphologic features. RESULTS: Of 2655 participants (65% women, median age 44 [interquartile range, 37-50] years), 1845 (70%) were living with HIV, 600 (23%) were living with HCV, and 425 (16%) had carotid plaque. There were 191 plaques identified in 129 (11%) women with HIV, 51 plaques in 32 (7%) women without HIV, 248 plaques in 171 (28%) men with HIV, and 139 plaques in 93 (29%) men without HIV. Adjusted analyses showed that people with HIV and current CD4+ count <200 cells/µL had a significantly higher prevalence of predominantly echolucent plaque (aPR, 1.86 [95% CI, 1.08-3.21]) than those without HIV. HCV infection alone (aPR, 1.86 [95% CI, 1.08-3.19]) and HIV-HCV coinfection (aPR, 1.75 [95% CI, 1.10-2.78]) were each associated with higher prevalence of predominantly echogenic plaque. HIV-HCV coinfection was also associated with higher prevalence of smooth surface plaque (aPR, 2.75 [95% CI, 1.03-7.32]) compared with people without HIV and HCV. CONCLUSIONS: HIV with poor immunologic control, as well as HCV infection, either alone or in the presence of HIV, were associated with different echomorphologic phenotypes of carotid artery plaque.
Assuntos
Doenças das Artérias Carótidas , Estenose das Carótidas , Coinfecção , Infecções por HIV , Hepatite C , Placa Aterosclerótica , Adulto , Feminino , Humanos , Masculino , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/epidemiologia , Doenças das Artérias Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/epidemiologia , Estenose das Carótidas/complicações , Estudos de Coortes , Coinfecção/diagnóstico por imagem , Coinfecção/epidemiologia , Coinfecção/complicações , Estudos Transversais , Hepacivirus , Hepatite C/complicações , Hepatite C/diagnóstico por imagem , Hepatite C/epidemiologia , Infecções por HIV/complicações , Infecções por HIV/diagnóstico por imagem , Infecções por HIV/epidemiologia , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/epidemiologia , Placa Aterosclerótica/complicações , Fatores de Risco , Pessoa de Meia-Idade , Estudos Multicêntricos como AssuntoRESUMO
Leptospirosis is a common but underdiagnosed zoonosis. We conducted a 1-year prospective study in La Guaira State, Venezuela, analyzing 71 hospitalized patients who had possible leptospirosis and sampling local rodents and dairy cows. Leptospira rrs gene PCR test results were positive in blood or urine samples from 37/71 patients. Leptospira spp. were isolated from cultured blood or urine samples of 36/71 patients; 29 had L. interrogans, 3 L. noguchii, and 4 L. venezuelensis. Conjunctival suffusion was the most distinguishing clinical sign, many patients had liver involvement, and 8/30 patients with L. interrogans infections died. The Leptospira spp. found in humans were also isolated from local rodents; L. interrogans and L. venezuelensis were isolated from cows on a nearby, rodent-infested farm. Phylogenetic clustering of L. venezuelensis isolates suggested a recently expanded outbreak strain spread by rodents. Increased awareness of leptospirosis prevalence and rapid diagnostic tests are needed to improve patient outcomes.
Assuntos
Surtos de Doenças , Leptospira , Leptospirose , Filogenia , Roedores , Animais , Leptospirose/epidemiologia , Leptospirose/veterinária , Leptospirose/microbiologia , Leptospirose/diagnóstico , Humanos , Venezuela/epidemiologia , Bovinos , Leptospira/genética , Leptospira/isolamento & purificação , Leptospira/classificação , Feminino , Roedores/microbiologia , Adulto , Masculino , Pessoa de Meia-Idade , Doenças dos Bovinos/microbiologia , Doenças dos Bovinos/epidemiologia , Adolescente , Leptospira interrogans/genética , Leptospira interrogans/isolamento & purificação , Leptospira interrogans/classificação , Adulto Jovem , Estudos Prospectivos , Criança , Idoso , Doenças Endêmicas , Zoonoses/epidemiologia , Zoonoses/microbiologia , Pré-EscolarRESUMO
Focal adhesion kinase (FAK) is a key component of the membrane proximal signaling layer in focal adhesion complexes, regulating important cellular processes, including cell migration, proliferation, and survival. In the cytosol, FAK adopts an autoinhibited state but is activated upon recruitment into focal adhesions, yet how this occurs or what induces structural changes is unknown. Here, we employ cryo-electron microscopy to reveal how FAK associates with lipid membranes and how membrane interactions unlock FAK autoinhibition to promote activation. Intriguingly, initial binding of FAK to the membrane causes steric clashes that release the kinase domain from autoinhibition, allowing it to undergo a large conformational change and interact itself with the membrane in an orientation that places the active site toward the membrane. In this conformation, the autophosphorylation site is exposed and multiple interfaces align to promote FAK oligomerization on the membrane. We show that interfaces responsible for initial dimerization and membrane attachment are essential for FAK autophosphorylation and resulting cellular activity including cancer cell invasion, while stable FAK oligomerization appears to be needed for optimal cancer cell proliferation in an anchorage-independent manner. Together, our data provide structural details of a key membrane bound state of FAK that is primed for efficient autophosphorylation and activation, hence revealing the critical event in integrin mediated FAK activation and signaling at focal adhesions.
Assuntos
Proteínas Aviárias/química , Proteína-Tirosina Quinases de Adesão Focal/química , Membranas/química , Multimerização Proteica , Animais , Proteínas Aviárias/metabolismo , Galinhas , Ativação Enzimática , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Células HEK293 , Humanos , Membranas/enzimologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is increasingly recognized. Clinical outcomes have evolved over time amid changes in the diagnostic pathway and advances in therapeutics. We sought to evaluate clinical outcomes over time of patients with ATTR-CA with access to disease-modifying therapy. METHODS AND RESULTS: This is a retrospective cohort study of 419 patients diagnosed with ATTR-CA during 2001-2021, comparing clinical characteristics across eras. The primary end point was composite all-cause mortality or orthotopic heart transplantation (OHT). Time-to-event analysis was performed using Cox proportional hazard modeling controlling for differences among cohorts. Patients diagnosed in the more recent years had higher median age (2017-2021, 78 years; 2014-2016, 75 years; 2001-2013, 74 years) and more often had wild-type ATTR (81.9% vs 82.5% vs 56.4%), but less severe phenotypes as evidenced by more individuals with Columbia stage I disease (47.6% vs 35.9% vs 22.4%), owing to lower biomarkers, more patients in New York Heart Association functional classes I and II (68.9% vs 47.6% vs 43.6%), and lower use of loop diuretics (67.0% vs 78.6% vs 89.1%). Over time, patients were treated more frequently with tafamidis (74% vs 37% vs 32%). On multivariable analysis, greater Columbia score (hazard ratio 1.42, 95% confidence interval 1.30-1.54, P < .001) was predictive of death or OHT, whereas tafamidis (hazard ratio 0.31, 95% confidence interval 0.22-0.44, P < .001) was associated with greater survival and freedom from OHT. CONCLUSIONS: Patients recently diagnosed with ATTR-CA have earlier stage disease and substantially lower mortality. Tafamidis is associated with significantly improved survival and freedom from OHT.
RESUMO
BACKGROUND: The Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations study seeks to determine the prevalence of transthyretin cardiac amyloidosis (ATTR-CA) among older Black or Caribbean Hispanic individuals with heart failure and an increased wall thickness. We noticed varied recruitment percentages across the recruiting sites and sought to determine the factors associated with greater percentage enrollment of eligible participants. METHODS: The percentage of enrolled to eligible participants was calculated across study sites. Baseline demographic and clinical characteristics, health literacy, trust in providers, perceived discrimination, area deprivation index (ADI) and English proficiency were compared by site using Kruskal-Wallis's test or one-way ANOVA for continuous variables and the Chi-Square test or Fisher's exact test for categorical variables. Wilcoxon rank sum and Chi-Square tests, with multiple comparisons correction using the false discovery rate (FDR) method, were used as post-hoc analysis when results were statistically significant. RESULTS: Among the four recruiting sites, Boston Medical Center, Columbia University Irving Medical Center, Harlem Hospital and Yale University, which employed different recruitment approaches, the percentage of participants enrolled among eligible participants differed, with the highest rate at Harlem Hospital (n=149 of 310, 48%), followed by Yale University (n=27 of 67, 40%), Boston University (n=247 of 655, 38%), and Columbia University (n=137of 442, 32%), p <0.01. Direct recruitment by the primary cardiovascular care team providing clinical care was associated with higher percent enrolled across sites as were higher education levels and English proficiency. Enrollment differences across sites were not associated with the number of chronic diseases, physician trust, perceived discrimination, or health literacy. CONCLUSIONS: Recruitment of eligible under-represented minorities (URMs) in SCAN-MP was associated with approaches employed in recruitment, including direct initial contact by the primary cardiovascular care team providing the potential participant's clinical care. Such data may help improve approaches to more successful recruitment of URMs in clinical research.
RESUMO
BACKGROUND: Studies assessing equity in the prevention of atherosclerotic cardiovascular disease (ASCVD) for Latinos living in the USA collectively yield mixed results. Latino persons are diverse in many ways that may influence cardiovascular health. The intersection of Latino nativity and ASCVD prevention is understudied. OBJECTIVE: To determine whether disparities in ASCVD screening, detection, and prescribing differ for US Latinos by country of birth. DESIGN: A retrospective cohort design utilizing 2014-2020 electronic health record data from a network of 320 community health centers across 12 states. Analyses occurred October 1, 2022, to September 30, 2023. PARTICIPANTS: Non-Hispanic White and Latino adults age 20-75 years, born in Cuba, Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, and the USA. EXPOSURES: Ethnicity and country of birth. MAIN MEASURES: Outcome measures included prevalence of statin eligibility, of having insufficient data to establish eligibility, odds of having a documented statin prescription, and rates of statin prescriptions and refills. We used covariate-adjusted logistic and generalized estimating equations logistic and negative binomial regressions to generate absolute and relative measures. KEY RESULTS: Among 108,672 adults, 23% (n = 25,422) were statin eligible for primary or secondary prevention of ASCVD using American College of Cardiology/American Heart Association guidelines. Latinos, born in and outside the USA were more likely eligible than Non-Hispanic White patients were (US-born Latino OR = 1.55 (95% CI = 1.37-1.75); non-US-born Latino OR = 1.63 (95% CI = 1.34-1.98)). The eligibility criteria that was met differed by ethnicity and nativity. Latinos overall were less likely missing data to establish eligibility and differences were again observed by specific non-US country of origin. Among those eligible, we observed no statistical difference in statin prescribing between US-born Latinos and non-Hispanic White persons; however, disparities varied by specific non-US country of origin. CONCLUSION: Efforts to improve Latino health in the USA will require approaches for preventing and reversing cardiovascular risk factors, and statin initiation that are Latino subgroup specific.
Assuntos
Aterosclerose , Hispânico ou Latino , Prevenção Primária , Prevenção Secundária , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Hispânico ou Latino/estatística & dados numéricos , Estudos Retrospectivos , Idoso , Aterosclerose/prevenção & controle , Aterosclerose/etnologia , Prevenção Secundária/métodos , Adulto Jovem , Estados Unidos/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos de Coortes , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/etnologiaRESUMO
Aniridia is a panocular condition characterized by a partial or complete loss of the iris. It manifests various developmental deficits in both the anterior and posterior segments of the eye, leading to a progressive vision loss. The homeobox gene PAX6 plays an important role in ocular development and mutations of PAX6 have been the main causative factors for aniridia. In this study, we assessed how Pax6-haploinsufficiency affects retinal morphology and vision of Pax6Sey mice using in vivo and ex vivo metrics. We used mice of C57BL/6 and 129S1/Svlmj genetic backgrounds to examine the variable severity of symptoms as reflected in human aniridia patients. Elevated intraocular pressure (IOP) was observed in Pax6Sey mice starting from post-natal day 20 (P20). Correspondingly, visual acuity showed a steady age-dependent decline in Pax6Sey mice, though these phenotypes were less severe in the 129S1/Svlmj mice. Local retinal damage with layer disorganization was assessed at P30 and P80 in the Pax6Sey mice. Interestingly, we also observed a greater number of activated Iba1+ microglia and GFAP + astrocytes in the Pax6Sey mice than in littermate controls, suggesting a possible neuroinflammatory response to Pax6 deficiencies.
Assuntos
Aniridia , Microftalmia , Humanos , Camundongos , Animais , Fator de Transcrição PAX6/genética , Fatores de Transcrição Box Pareados/genética , Doenças Neuroinflamatórias , Camundongos Endogâmicos C57BL , Microftalmia/genética , Aniridia/genética , Proteínas de Homeodomínio/genética , Proteínas do Olho/genéticaRESUMO
INTRODUCTION: Stroke is a leading cause of morbidity and mortality in the USA and has implications on the financial health of patients, families, and healthcare systems. The objective of this study aimed to determine the economic perspective of stroke on the national healthcare system for the past 2 decades. METHODS: This retrospective study of inpatient subjects from 2000 to 2020 with stroke was collected from the Healthcare Cost and Utilization Project (HCUP). We queried patients admitted primarily for ischemic or hemorrhagic stroke. Patients were evaluated for demographics, length of stay (LOS), mortality, and hospital charges. Statistical Z-testing with a significance of p < 0.05 was conducted for the analysis. RESULTS: During the study period, 12,158,747 stroke subjects were studied, with 51.9% female and a mean age of 70.08 (±0.16) years old. The mean rate of stroke discharges per 100,000 persons was 187.71 (±3.44), decreasing from 200 to 193 during the study (p = 0.16). The mean percentage of deaths was 8.78% (±0.17), which decreased from 10.96% to 6.81% (p = 0.00). The mean LOS was 6.28 days (±0.08), which increased from 6.70 to 7.15 (p = 0.00). During the study period, the aggregated national bill was USD 725 billion. The mean hospital charges per patient were USD 57,178 (±1,504), increasing from USD 19,647 to USD 121,765 per person during the study period (p = 0.00), while mean hospital costs per stay were USD 15,781 (±330). These data closely conform to an exponential growth pattern, and forecasting per patient charges for the next 10 years demonstrates a cost of USD 287,836 by 2030. CONCLUSIONS: Our data show that the rate and mortality of stroke have decreased, but its charges and costs are increasing. The improvement in outcomes could be multifactorial such as establishment of comprehensive stroke centers and evolving treatment modalities. Ironically, the charges per patient increased more than sixfold with a national bill almost equal to the annual Medicare budget. Thus, the significance of preventive medicine, such as controlling hypertension, diabetes, and smoking cessation, cannot be understated. With such a dramatically increasing financial burden, improvements in mitigating risk factors, educational programs, and access to care may be a more cost-effective option.
Assuntos
Medicare , Acidente Vascular Cerebral , Humanos , Feminino , Idoso , Estados Unidos/epidemiologia , Masculino , Estudos Retrospectivos , Hospitalização , Tempo de Internação , Custos de Cuidados de Saúde , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapiaRESUMO
The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep-wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons.
Assuntos
Ácidos Araquidônicos , Ketamina , Morfolinas , Neurônios , Receptor CB1 de Canabinoide , Animais , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Masculino , Ratos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ketamina/farmacologia , Ácidos Araquidônicos/farmacologia , Morfolinas/farmacologia , Pirazóis/farmacologia , Endocanabinoides/farmacologia , Endocanabinoides/metabolismo , Ratos Wistar , Piperidinas/farmacologia , Benzoxazinas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Alcamidas Poli-Insaturadas/farmacologia , Naftalenos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Anestésicos Dissociativos/farmacologiaRESUMO
INTRODUCTION: Asthma is a chronic inflammatory disease of the lower airways that affects more than 260 million people worldwide and has been related to more than 460,000 deaths a year. It is estimated that in 60% of asthma cases, the symptoms are not adequately controlled. The objective of this study was to determine the association between some comorbidities, habits, and health risk behaviors with uncontrolled asthma in a sample of young people with asthma. METHODS: Through a cross-sectional study, data from 1,078 young people aged 17 to 19 years were analyzed. Information was collected through physical examination, direct questioning, and the application of a self-administered questionnaire. RESULTS: In the group of young people with asthma, the prevalence of uncontrolled asthma was 20.6%, of which 53.8% were women, 76.9% suffered from rhinitis, 46.2% were overweight and 23.1% were obese. In the group of young with uncontrolled asthma, gingivitis was detected in 53.8% and alcohol consumption in 84.6%. Logistic regression analysis showed a significant association between allergic rhinitis, gingivitis, carbohydrate intake, alcohol consumption, overweight, and obesity with uncontrolled asthma. CONCLUSIONS: Parents and members of the health team need to identify on time the risk factors associated with uncontrolled asthma in young people with asthma to limit its development and the negative effects it generates. The results of this study should be used to strengthen programs that promote the comprehensive health of adolescents.
RESUMO
BACKGROUND: Combat casualties are frequently injured in austere settings where modern imaging modalities are unavailable. Exploratory laparotomies are often performed in these settings when there is suspicion for intra-abdominal injury. Prior studies of combat casualties reported non-therapeutic laparotomy (NTL) rates as high as 32%. Given improvements in combat casualty care over time, we evaluated NTLs performed during later years of the wars in Iraq and Afghanistan. METHODS: Military personnel with combat-related injuries (6/1/2009-12/31/2014) who underwent exploratory laparotomy based on concern for abdominal injury (i.e. not performed for proximal vascular control or fecal diversion) and were evacuated to Landstuhl Regional Medical Center (Germany) before being transferred to participating U.S. military hospitals were assessed. An NTL was defined as a negative laparotomy without substantial intra-abdominal injuries requiring repair. Characteristics, indications for laparotomy, operative findings, and outcomes were examined. RESULTS: Among 244 patients who underwent laparotomies, 41 (16.8%) had NTLs and 203 (83.2%) had therapeutic laparotomies (i.e. positive findings). Patients with NTLs had more computed tomography scans concerning for injury (48.8% vs 27.1%; p = 0.006), less penetrating injury mechanisms (43.9% vs 71.9%; p < 0.001), and lower Injury Severity Scores (26 vs 33; p = 0.003) compared to patients with therapeutic laparotomies. Patients with NTLs were also less likely to be admitted to the intensive care unit (70.7 vs 89.2% for patients with therapeutic laparotomies; p = 0.007). No patients with NTLs developed abdominal surgical site infections (SSI) compared to 16.7% of patients with therapeutic laparotomies (p = 0.002). There was no significant difference in mortality between the groups (p = 0.198). CONCLUSIONS: Our proportion of NTLs was lower than reported from earlier years during the wars in Iraq and Afghanistan. No infectious complications from NTLs (i.e. abdominal SSIs) were identified. Nevertheless, surgeons should continue to have a low threshold for exploratory laparotomy in military patients in austere settings with concern for intra-abdominal injury.
RESUMO
PURPOSE: To assess the possible benefits of the use of perceptual learning and dichoptic therapy combined with patching in children with amblyopia over the use of only patching. METHODS: Quasi-experimental multicentric study including 52 amblyopic children. Patients who improved their visual acuity (VA) by combining spectacles and patching were included in patching group (PG: 20 subjects), whereas those that did not improved with patching performed visual training (perceptual learning + dichoptic therapy) combined with patching, being assigned to the visual treatment group (VT: 32 subjects). Changes in VA, contrast sensitivity (CS), and stereopsis were monitored during a 6-month follow-up in each group. RESULTS: Significant improvements in VA were found in both groups at 1 month (p < 0.01). The total improvement of VA was 0.18 ± 0.16 and 0.31 ± 0.35 logMAR in PG and VT groups, respectively (p = 0.317). The Wilcoxon effect size was slightly higher in VT (0.48 vs. 0.54) at 6 months. An enhancement in CS was observed in the amblyopic eye of the VT group for all spatial frequencies at 1 month (p < 0.001). Likewise, the binocular function score also increased significantly in VT group (p = 0.002). A prediction equation of VA improvement at 1 month in VT group was obtained by multiple linear regression analysis (p < 0.001, R2 = 0.747). CONCLUSIONS: A combined treatment of visual training and patching is effective for obtaining a predictable improvement of VA, CS, and binocularity in patching-resistant amblyopic children.
RESUMO
Non-tuberculosis infections in immunocompromised patients represent a cause for concern, given the increased risks of infection, and limited treatments available. Herein, we report that molecules for binding to the catalytic site of histone deacetylase (HDAC) inhibit its activity, thus increasing the innate immune response against environmental mycobacteria. The action of HDAC inhibitors (iHDACs) was explored in a model of type II pneumocytes and macrophages infection by Mycobacterium aurum. The results show that the use of 1,3-diphenylurea increases the expression of the TLR-4 in M. aurum infected MDMs, as well as the production of defb4, IL-1ß, IL-12, and IL-6. Moreover, we observed that aminoacetanilide upregulates the expression of TLR-4 together with TLR-9, defb4, CAMP, RNase 6, RNase 7, IL-1ß, IL-12, and IL-6 in T2P. Results conclude that the tested iHDACs selectively modulate the expression of cytokines and antimicrobial peptides that are associated with reduction of non-tuberculous mycobacteria infection.
Assuntos
Citocinas , Reposicionamento de Medicamentos , Inibidores de Histona Desacetilases , Imunidade Inata , Infecções por Mycobacterium não Tuberculosas , Imunidade Inata/efeitos dos fármacos , Humanos , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Inibidores de Histona Desacetilases/farmacologia , Citocinas/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Micobactérias não Tuberculosas/efeitos dos fármacos , Micobactérias não Tuberculosas/imunologia , Mycobacterium/imunologia , Mycobacterium/efeitos dos fármacosRESUMO
The need for urgent or emergent cardiovascular imaging in children is rare when compared to adults. Patients may present from the neonatal period up to adolescence, and may require imaging for both traumatic and non-traumatic causes. In children, coronary pathology is rarely the cause of an emergency unlike in adults where it is the main cause. Radiology, including chest radiography and computed tomography in conjunction with echocardiography, often plays the most important role in the acute management of these patients. Magnetic resonance imaging can occasionally be useful and may be suitable in more subacute cases. Radiologists' knowledge of how to manage and interpret these acute conditions including knowing which imaging technique to use is fundamental to appropriate care. In this review, we will concentrate on the most common cardiovascular emergencies in the thoracic region, including thoracic traumatic and non-traumatic emergencies and pulmonary vascular emergencies, as well as acute clinical disorders as a consequence of primary and postoperative congenital heart disease. This review will cover situations where cardiovascular imaging may be acutely needed, and not strictly emergencies only. Imaging recommendations will be discussed according to the different clinical presentations and underlying pathology.