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BACKGROUND: Hybrid closed-loop insulin therapy has shown promise for management of type 1 diabetes during pregnancy; however, its efficacy is unclear. METHODS: In this multicenter, controlled trial, we randomly assigned pregnant women with type 1 diabetes and a glycated hemoglobin level of at least 6.5% at nine sites in the United Kingdom to receive standard insulin therapy or hybrid closed-loop therapy, with both groups using continuous glucose monitoring. The primary outcome was the percentage of time in the pregnancy-specific target glucose range (63 to 140 mg per deciliter [3.5 to 7.8 mmol per liter]) as measured by continuous glucose monitoring from 16 weeks' gestation until delivery. Analyses were performed according to the intention-to-treat principle. Key secondary outcomes were the percentage of time spent in a hyperglycemic state (glucose level >140 mg per deciliter), overnight time in the target range, the glycated hemoglobin level, and safety events. RESULTS: A total of 124 participants with a mean (±SD) age of 31.1±5.3 years and a mean baseline glycated hemoglobin level of 7.7±1.2% underwent randomization. The mean percentage of time that the maternal glucose level was in the target range was 68.2±10.5% in the closed-loop group and 55.6±12.5% in the standard-care group (mean adjusted difference, 10.5 percentage points; 95% confidence interval [CI], 7.0 to 14.0; P<0.001). Results for the secondary outcomes were consistent with those of the primary outcome; participants in the closed-loop group spent less time in a hyperglycemic state than those in the standard-care group (difference, -10.2 percentage points; 95% CI, -13.8 to -6.6); had more overnight time in the target range (difference, 12.3 percentage points; 95% CI, 8.3 to 16.2), and had lower glycated hemoglobin levels (difference, -0.31 percentage points; 95% CI, -0.50 to -0.12). Little time was spent in a hypoglycemic state. No unanticipated safety problems associated with the use of closed-loop therapy during pregnancy occurred (6 instances of severe hypoglycemia, vs. 5 in the standard-care group; 1 instance of diabetic ketoacidosis in each group; and 12 device-related adverse events in the closed-loop group, 7 related to closed-loop therapy). CONCLUSIONS: Hybrid closed-loop therapy significantly improved maternal glycemic control during pregnancy complicated by type 1 diabetes. (Funded by the Efficacy and Mechanism Evaluation Program; AiDAPT ISRCTN Registry number, ISRCTN56898625.).
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Glicemia , Diabetes Mellitus Tipo 1 , Hipoglicemiantes , Sistemas de Infusão de Insulina , Insulina , Gravidez em Diabéticas , Adulto , Feminino , Humanos , Gravidez , Glicemia/análise , Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/efeitos adversos , Insulina/uso terapêutico , Sistemas de Infusão de Insulina/efeitos adversos , Gravidez em Diabéticas/sangue , Gravidez em Diabéticas/tratamento farmacológico , Resultado do TratamentoRESUMO
We examined associations between sexist beliefs and tolerance of violence against women in India using a nationally representative probability sample of adults (n = 133,398). Research consistently indicates that hostile sexism fosters tolerance of violence against women. However, benevolent sexism is sometimes associated with higher tolerance and sometimes with lower tolerance of violence. We proposed that this inconsistency could be resolved by considering the source of violence: Is violence perpetrated by outsiders or intimate partners? Results of a multigroup structural equation model showed that endorsement of hostile sexism was related to greater tolerance of violence regardless of the source. In contrast, endorsement of benevolent sexism was associated with lower tolerance of violence from outsiders but was simultaneously associated with higher tolerance of spousal violence. These opposing processes indicate that although benevolent sexism promises women protection from violence, the very same ideology legitimizes spousal violence, thereby reinforcing men's power within intimate relationships.
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Sexismo , Humanos , Índia , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Hostilidade , Violência por Parceiro Íntimo/estatística & dados numéricos , Violência por Parceiro Íntimo/psicologia , AdolescenteRESUMO
This paper introduces a novel approach to measure deformations in geomaterials using the recently developed 'Smart Pebble' sensors. Smart Pebbles were included in triaxial test specimens of unbound aggregates stabilized with geogrids. The sensors are equipped with an aggregate particle/position tracking algorithm that can manage uncertainty arising due to signal noise and random walk effects. Two Smart Pebbles were placed in each test specimen, one at specimen's mid-height, where a geogrid was installed in the mechanically stabilized specimen, and one towards the top of the specimen. Even with simple raw data processing, the trends on linear vertical acceleration indicated the ability of Smart Pebbles to assess the geomaterial configuration and applied stress states. Employing a Kalman filter-based algorithm, the Smart Pebble position coordinates were tracked during testing. The specimen's resilient deformations were simultaneously recorded. bender element shear wave transducer pairs were also installed on the specimens to further validate the Smart Pebble small-strain responses. The results indicate a close agreement between the BE sensors and Smart Pebbles estimates towards local stiffness enhancement quantification in the geogrid specimen. The study findings confirm the viability of using the Smart Pebbles in describing the resilient behavior of an aggregate material under repeated loading.
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Given the powerful implications of relationship quality for health and well-being, a central mission of relationship science is explaining why some romantic relationships thrive more than others. This large-scale project used machine learning (i.e., Random Forests) to 1) quantify the extent to which relationship quality is predictable and 2) identify which constructs reliably predict relationship quality. Across 43 dyadic longitudinal datasets from 29 laboratories, the top relationship-specific predictors of relationship quality were perceived-partner commitment, appreciation, sexual satisfaction, perceived-partner satisfaction, and conflict. The top individual-difference predictors were life satisfaction, negative affect, depression, attachment avoidance, and attachment anxiety. Overall, relationship-specific variables predicted up to 45% of variance at baseline, and up to 18% of variance at the end of each study. Individual differences also performed well (21% and 12%, respectively). Actor-reported variables (i.e., own relationship-specific and individual-difference variables) predicted two to four times more variance than partner-reported variables (i.e., the partner's ratings on those variables). Importantly, individual differences and partner reports had no predictive effects beyond actor-reported relationship-specific variables alone. These findings imply that the sum of all individual differences and partner experiences exert their influence on relationship quality via a person's own relationship-specific experiences, and effects due to moderation by individual differences and moderation by partner-reports may be quite small. Finally, relationship-quality change (i.e., increases or decreases in relationship quality over the course of a study) was largely unpredictable from any combination of self-report variables. This collective effort should guide future models of relationships.
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Relações Interpessoais , Aprendizado de Máquina , Características da Família , Feminino , Humanos , Estudos Longitudinais , Masculino , AutorrelatoRESUMO
Background and Purpose: Brain tissue-resident microglia and monocyte-derived macrophages (MDMs) are innate immune cells that contribute to the inflammatory response, phagocytosis of debris, and tissue repair after injury. We have previously reported that both microglia and MDMs transition from proinflammatory to reparative phenotypes over days after an intracerebral hemorrhage (ICH). However, their individual functional properties in the brain remain largely unknown. Here we characterized the differences between microglia and MDMs and further elucidate their distinct activation states and functional contributions to the pathophysiology and recovery after ICH. Methods: Autologous blood injection was used to model ICH in mice. Longitudinal transcriptomic analyses on isolated microglia and MDMs from mice at days 1, 3, 7 and 10 after ICH and naive controls identified core transcriptional programs that distinguish these cells. Imaging flow cytometry and in vivo phagocytosis assays were used to study phagocytic ability of microglia and MDMs. Antigen presentation was evaluated by ovalbumin-OTII CD4 T-cell proliferation assays with bone marrowderived macrophages and primary microglia cultures. Results: MDMs had higher phagocytic activity and higher erythrophagocytosis in the ICH brain. Differential gene expression revealed distinct transcriptional signatures in the MDMs and microglia after ICH. MDMs had higher expression of MHCII (major histocompatibility complex class II) genes than microglia at all time points and greater ability to induce antigen-specific T-cell proliferation. Conclusions: The different ontogeny of microglia and MDMs lead to divergent responses and functions in the inflamed brain as these 2 cell populations differ in phagocytic functions and antigen-presenting capabilities in the brain after ICH.
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Encéfalo/metabolismo , Hemorragias Intracranianas/metabolismo , Macrófagos/metabolismo , Fagocitose/fisiologia , Animais , Proliferação de Células/fisiologia , Modelos Animais de Doenças , Camundongos , Microglia/metabolismoRESUMO
The terminal cadmium hydride compound, [κ3-TismPriBenz]CdH, which features the tris[(1-isopropylbenzimidazol-2-yl)dimethylsilyl]methyl ligand, may be obtained via the reactions of either [κ3-TismPriBenz]CdN(SiMe3)2 or [TismPriBenz]CdOSiPh3 with PhSiH3. The Cd-H bond of [κ3-TismPriBenz]CdH undergoes (a) metathesis reactions with MeI, Me3SiX (X = Cl, Br, I, NCO), and Me3SnX (X = Cl, Br, I) to afford the corresponding [TismPriBenz]CdX derivative, (b) insertion with CO2 and CS2 to afford respectively [TismPriBenz]Cd(κ1-O2CH) and [TismPriBenz]Cd(κ1-S2CH), and (c) hydride abstraction with B(C6F5)3 to afford {[TismPriBenz]Cd}[HB(C6F5)3] that possesses a rare trigonal monopyramidal geometry for cadmium.
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The hydrodefluorination of CF3-substituted alkenes can be catalyzed by a nickel(II) hydride bearing a pincer ligand. The catalyst loading can be as low as 1 mol%. gem-Difluoroalkenes containing a number of functional groups can be formed in good to excellent yields by a radical mechanism initiated by H⢠transfer from the nickel hydride. The relative reactivity of various substrates supports the proposed mechanism, as does a TEMPO trapping experiment.
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Alcenos/síntese química , Complexos de Coordenação/química , Hidrocarbonetos Fluorados/síntese química , Níquel/química , Silanos/química , Catálise , Modelos Químicos , Estrutura MolecularAssuntos
Fibrose Pulmonar Idiopática , Polimorfismo de Nucleotídeo Único , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Importance: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited treatment options. Patients with IPF have altered lung microbiota, with bacterial burden within the lungs associated with mortality; previous studies have suggested benefit with co-trimoxazole (trimethoprim-sulfamethoxazole). Objective: To determine the efficacy of co-trimoxazole in patients with moderate and severe IPF. Design, Setting, and Participants: Double-blind, placebo-controlled, parallel randomized trial of 342 patients with IPF, breathlessness (Medical Research Council dyspnea scale score >1), and impaired lung function (forced vital capacity ≤75% predicted) conducted in 39 UK specialist interstitial lung disease centers between April 2015 (first patient visit) and April 2019 (last patient follow-up). Interventions: Study participants were randomized to receive 960 mg of oral co-trimoxazole twice daily (n = 170) or matched placebo (n = 172) for between 12 and 42 months. All patients received 5 mg of folic acid orally once daily. Main Outcomes and Measures: The primary outcome was time to death (all causes), lung transplant, or first nonelective hospital admission. There were 15 secondary outcomes, including the individual components of the primary end point respiratory-related events, lung function (forced vital capacity and gas transfer), and patient-reported outcomes (Medical Research Council dyspnea scale, 5-level EuroQol 5-dimension questionnaire, cough severity, Leicester Cough Questionnaire, and King's Brief Interstitial Lung Disease questionnaire scores). Results: Among 342 individuals who were randomized (mean age, 71.3 years; 46 [13%] women), 283 (83%) completed the trial. The median (interquartile range) duration of follow-up was 1.02 (0.35-1.73) years. Events per person-year of follow-up among participants randomized to the co-trimoxazole and placebo groups were 0.45 (84/186) and 0.38 (80/209), respectively, with a hazard ratio of 1.2 ([95% CI, 0.9-1.6]; P = .32). There were no statistically significant differences in other event outcomes, lung function, or patient-reported outcomes. Patients in the co-trimoxazole group had 696 adverse events (nausea [n = 89], diarrhea [n = 52], vomiting [n = 28], and rash [n = 31]) and patients in the placebo group had 640 adverse events (nausea [n = 67], diarrhea [n = 84], vomiting [n = 20], and rash [n = 20]). Conclusions and Relevance: Among patients with moderate or severe IPF, treatment with oral co-trimoxazole did not reduce a composite outcome of time to death, transplant, or nonelective hospitalization compared with placebo. Trial Registration: ISRCTN Identifier: ISRCTN17464641.
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Fibrose Pulmonar Idiopática/tratamento farmacológico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Administração Oral , Idoso , Tosse/etiologia , Método Duplo-Cego , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/mortalidade , Transplante de Pulmão , Masculino , Náusea/induzido quimicamente , Gravidade do Paciente , Falha de Tratamento , Combinação Trimetoprima e Sulfametoxazol/efeitos adversosRESUMO
The leukodystrophies are a heterogeneous group of inherited diseases characterized by progressive demyelination of the central nervous system leading to devastating neurologic symptoms and premature death. Hematopoietic stem cell transplantation (HSCT) has been successfully used to treat certain leukodystrophies, including adrenoleukodystrophy, globoid leukodystrophy (Krabbe disease), and metachromatic leukodystrophy, over the past 30 years. To date, these complex patients have primarily been transplanted at a limited number of pediatric centers. As the number of cases identified through pregnancy and newborn screening is increasing, additional centers will be required to treat these children. Hunter's Hope created the Leukodystrophy Care Network in part to create and standardize high-quality clinical practice guidelines to guide the care of affected patients. In this report the clinical guidelines for the care of pediatric patients with leukodystrophies undergoing treatment with HSCT are presented. The initial transplant evaluation, determination of patient eligibility, donor selection, conditioning, supportive care, and post-transplant follow-up are discussed. Throughout these guidelines the need for early detection and treatment and the role of the partnership between families and multidisciplinary providers are emphasized.
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Transplante de Células-Tronco Hematopoéticas , Leucodistrofia de Células Globoides/terapia , Leucodistrofia Metacromática/terapia , Aloenxertos , Humanos , Recém-Nascido , Guias de Prática Clínica como AssuntoRESUMO
A series of tris(oxoimidazolyl)hydroborato ligands, which serve as L2X [O3] donors, have been employed to obtain organometallic zirconium compounds in an uncommon oxygen-rich coordination environment. For example, Cp[ToMeBenz]ZrCl2 has been synthesized via the reaction of [ToMeBenz]Na with CpZrCl3 and bears a structural resemblance to the bent metallocene dichloride derivative Cp2ZrCl2. In addition, the half-sandwich counterparts [ToMeBenz]ZrCl3 and [ToBut]ZrCl3 have been obtained by metathesis of ZrCl4 with [ToMeBenz]Na and [ToBut]Na, respectively. The structurally related zirconium benzyl compounds [ToRBenz]Zr(CH2Ph)3 (R = Me, But, 1-Ad) have also been synthesized via the reactions of [ToRBenz]Tl with Zr(CH2Ph)4, and X-ray diffraction studies demonstrate that the benzyl ligands in these compounds are conformationally flexible and exhibit a large range of Zr-CH2-Ph bond angles (94.7-131.7°). Protolytic cleavage of one of the benzyl ligands of [ToRBenz]Zr(CH2Ph)3 (R = But, 1-Ad) may be achieved by treatment with [PhNHMe2][B(C6F5)4] to generate {[ToRBenz]Zr(CH2Ph)2}[B(C6F5)4], which are catalysts for the polymerization of ethylene. The molecular structure of the ether adduct, {[ToButBenz]Zr(CH2Ph)2(OEt2)}[B(C6F5)4], has been determined by X-ray diffraction. In addition to the use of tris(oxoimidazolyl)hydroborato ligands, bis(oxoimidazolyl)hydroborato ligands have also been used to obtain zirconium benzyl compounds in oxygen-rich environments, namely, [BoMeBenz]2Zr(CH2Ph)2 and [BoAdBenz]2Zr(CH2Ph)2.
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BACKGROUND: Loneliness has many negative physical and mental health ramifications and is most prevalent among vulnerable social groups. However, little is known about how loneliness is grouped within the population and the characteristics of those groups. METHODS: We conducted a Latent Profile Analysis on 18,264 participants from the fifth wave of the New Zealand Attitudes and Values Study to identify the number of distinct loneliness profiles in the population. Secondary analyses then determined the representation of various demographic and psychosocial characteristics of participants within each profile. RESULTS: Analyses identified four distinct loneliness profiles: 'high-loneliness' (5.7%), 'low-loneliness' (57.9%), 'appreciated outsiders' (29.1%; who received acceptance from others but felt like social outsiders) and 'superficially connected' (7.2%; who showed the opposite pattern). 'High-loneliness' were the most introverted, emotionally unstable and poorest in wellbeing. 'Appreciated outsiders' and 'superficially connected' had moderate wellbeing, but 'appreciated outsiders' were relatively higher in wellbeing despite greater introversion and neuroticism. CONCLUSION: This research provides a typology of loneliness in New Zealand and identifies groups more likely to experience loneliness. The 'appreciated outsiders' and 'superficially connected' profiles provide fresh insight into how loneliness may manifest and the relative influences of quality and quantity of social contacts on wellbeing.
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Análise de Classes Latentes , Solidão , Rede Social , Apoio Social , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Inquéritos e QuestionáriosRESUMO
A series of bis- and tris(oxobenzimidazolyl)hydroborato compounds, namely, [BoRBenz]Na and [ToRBenz]-Na (R = Me, But, Ad), which feature uncommon sterically demanding LX [O2] and L2X [O3] donor ligands, have been obtained via the reactions of NaBH4 with 1-R-1,3-dihydro-2H-benzimidazol-2-ones. Evidence that the alkyl substituents are suitably located to have a significant impact on the coordination environment is provided by the observation that the methyl derivative [ToMeBenz]Na(κ3-diglyme) exhibits κ3-coordination of the diglyme, whereas the t-butyl and adamantyl derivatives, [ToButBenz]Na(κ2-diglyme) and [ToAdBenz]Na(κ2-diglyme), exhibit κ2-coordination. The [BoRBenz] and [ToRBenz] ligands also allow for isolation of discrete mononuclear thallium compounds, [BoRBenz]Tl and [ToRBenz]Tl, for which the steric demands of the ligands have been quantified in terms of both cone angle and buried volume concepts.
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In this study, we asked participants to "describe their sexual orientation" in an open-ended measure of self-generated sexual orientation. The question was included as part of the New Zealand Attitudes and Values Study (N = 18,261) 2013/2014 wave, a national probability survey conducted shortly after the first legal same-sex marriages in New Zealand. We present a two-level classification scheme to address questions about the prevalence of, and demographic differences between, sexual orientations. At the most detailed level of the coding scheme, 49 unique categories were generated by participant responses. Of those who responded with the following, significantly more were women: bisexual (2.1 % of women, compared to 1.5 % of men), bicurious (0.7 % of women, 0.4 % of men), and asexual (0.4 % of women and less than 0.1 % of men). However, significantly fewer women than men reported being lesbian or gay (1.8 % of women, compared to 3.5 % of men). Those openly identifying as bicurious, bisexual, or lesbian/gay were significantly younger than those with a heterosexual orientation. This study shows diversity in the terms used in self-generated sexual orientations, and provides up-to-date gender, age, and prevalence estimates for the New Zealand population. Finally, results reveal that a substantial minority of participants may not have understood the question about sexual orientation.
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Sexualidade/psicologia , Sexualidade/estatística & dados numéricos , Adulto , Feminino , Humanos , Masculino , Nova Zelândia/epidemiologia , PrevalênciaRESUMO
There is debate about the abstractness of young children's self-concepts-specifically, whether they include representations of (a) general traits and abilities and (b) the global self. Four studies (N = 176 children aged 4-7) suggested these representations are indeed part of early self-concepts. Studies 1 and 2 reexamined prior evidence that young children cannot represent traits and abilities. The results suggested that children's seemingly immature judgments in previous studies were due to peculiarities of the task context not the inadequacy of children's self-concepts. Similarly, Studies 3 and 4 revealed that, contrary to claims of immaturity in reasoning about the global self, young children update their global self-evaluations in flexible, context-sensitive ways. This evidence suggests continuity in the structure of self-concepts across childhood.
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Desenvolvimento Infantil , Personalidade , Autoimagem , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
Intracerebral hemorrhage (ICH) is a devastating type of stroke that lacks a specific treatment. An intense immune response develops after ICH, which contributes to neuronal injury, disability, and death. However, the specific mediators of inflammation-induced injury remain unclear. The objective of the present study was to determine whether blood-derived CCR2+ Ly6C(hi) inflammatory monocytes contribute to disability. ICH was induced in mice and the resulting inflammatory response was quantified using flow cytometry, confocal microscopy, and neurobehavioral testing. Importantly, blood-derived monocytes were distinguished from resident microglia by differential CD45 staining and by using bone marrow chimeras with fluorescent leukocytes. After ICH, blood-derived CCR2+ Ly6C(hi) inflammatory monocytes trafficked into the brain, outnumbered other leukocytes, and produced tumor necrosis factor. Ccr2(-/-) mice, which have few circulating inflammatory monocytes, exhibited better motor function following ICH than control mice. Chimeric mice with wild-type CNS cells and Ccr2(-/-) hematopoietic cells also exhibited early improvement in motor function, as did wild-type mice after inflammatory monocyte depletion. These findings suggest that blood-derived inflammatory monocytes contribute to acute neurological disability. To determine the translational relevance of our experimental findings, we examined CCL2, the principle ligand for the CCR2 receptor, in ICH patients. Serum samples from 85 patients were collected prospectively at two hospitals. In patients, higher CCL2 levels at 24 h were independently associated with poor functional outcome at day 7 after adjusting for potential confounding variables. Together, these findings suggest that inflammatory monocytes worsen early disability after murine ICH and may represent a therapeutic target for patients.
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Antígenos Ly/genética , Hemorragia Cerebral/imunologia , Encefalite/imunologia , Monócitos/imunologia , Receptores CCR2/genética , Doença Aguda , Animais , Antígenos Ly/imunologia , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Movimento Celular/imunologia , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Quimiocina CCL2/sangue , Avaliação da Deficiência , Encefalite/patologia , Encefalite/fisiopatologia , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/patologia , Transtornos dos Movimentos/imunologia , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/fisiopatologia , Estudos Prospectivos , Receptores CCR2/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologiaRESUMO
BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is swiftly followed by an inflammatory response. A key component of this response is the recruitment of leukocytes into the brain, which promotes neurological injury in rodent models. However, the mechanisms by which leukocytes transmigrate across the endothelium into the injured brain are unclear. The present study examines leukocyte adhesion molecules (α4 integrin, L-selectin, and αLß2 integrin) on 4 leukocyte subtypes to determine which are important for leukocyte recruitment after ICH. METHODS: We used the blood injection mouse model of ICH, whereby 25 µL of blood was injected into the striatum. Flow cytometry was used to quantify leukocyte populations and adhesion molecule expression in brain and blood. An α4 integrin-blocking antibody was administered to evaluate the contribution of α4 integrin in leukocyte migration and neurological injury. RESULTS: α4 integrin was elevated on all leukocyte populations in brain after ICH, whereas L-selectin was unchanged and αLß2 was increased only on T cells. Antagonism of α4 resulted in decreased leukocyte transmigration and lessened neurobehavioral disability. CONCLUSIONS: α4 integrin is an important cell adhesion molecule involved in neuroinflammation after ICH.
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Hemorragia Cerebral/metabolismo , Integrina alfa4/metabolismo , Leucócitos/metabolismo , Animais , Hemorragia Cerebral/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Selectina L/metabolismo , Leucócitos/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Metformin is currently the first-line treatment drug for type 2 diabetes. Metformin is a well-known activator of AMP-activated protein kinase (AMPK). In experimental studies, metformin has been shown to exert direct vascular effects by increasing vascular endothelial growth factor expression and improving microvascular density. As stroke is the leading cause of long-term disability and angiogenesis is implicated as an important mechanism in functional recovery, we hypothesized that chronic metformin treatment would improve post-stroke functional recovery by enhancing functional microvascular density. For this study, C57BL/6N male mice were subjected to a 60-min middle cerebral artery occlusion, and were given 50 mg/kg/day metformin beginning 24 h post-stroke for 3 weeks. Behavioral recovery was assessed using adhesive-tape removal and the apomorphine-induced turning test. The role of angiogenesis was assessed by counting vessel branch points from fluorescein-conjugated lectin-perfused brain sections. Importantly even if metformin treatment was initiated 24 h after injury it enhanced recovery and significantly improved stroke-induced behavioral deficits. This recovery occurred in parallel with enhanced angiogenesis and with restoration of endogenous cerebral dopaminergic tone and revascularization of ischemic tissue. We assessed if the effects on recovery and angiogenesis were mediated by AMPK. When tested in AMPK α-2 knockout mice, we found that metformin treatment did not have the same beneficial effects on recovery and angiogenesis, suggesting that metformin-induced angiogenic effects are mediated by AMPK. The results from this study suggest that metformin mediates post-stroke recovery by enhancing angiogenesis, and these effects are mediated by AMPK signaling.
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Infarto da Artéria Cerebral Média/tratamento farmacológico , Metformina/farmacologia , Atividade Motora/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apomorfina/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Neovascularização Patológica/patologia , Neovascularização Patológica/fisiopatologia , Neuroglia/efeitos dos fármacos , Neuroglia/fisiologia , Estimulação Física , Distribuição Aleatória , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
We report a case of previously undescribed medial unicompartmental knee arthroplasty failure due to femoral component implant fracture. The patient experienced sudden pain and locking while ambulating 8 years postoperatively. Radiographs revealed catastrophic femoral component failure with a transverse break through the metal. The patient underwent revision to total knee arthroplasty. At 1-year follow-up, the patient had no pain and a range of motion of 130 degrees. Particular attention should be paid to obtaining adequate femoral component posterior flange fixation during unicompartmental knee arthroplasty. Patient education regarding maintaining a healthy weight is crucial to preventing this complication.
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The current research examined the phenomenon of fading affect bias - the tendency for affect associated with negative events to fade more than affect associated with positive events - within the context of romantic relationships. Participants recalled and evaluated positive and negative relationship-specific and non-relationship autobiographical events. Participants also completed measures of attachment avoidance and anxiety. Multi-level modeling demonstrated fading affect bias for relationship and non-relationship events, but that affect fade was shaped by attachment orientations. Specifically, higher attachment anxiety, and lower attachment avoidance predicted greater importance of relationship events which predicted lower fading of affective intensity of memories. Thus, attachment anxiety sustained, while attachment avoidance suppressed the affect of relational memories. We discuss implications of these findings for relationship maintenance.