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1.
Calcif Tissue Int ; 106(2): 180-193, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31583426

RESUMO

Radiation therapy and estrogen deficiency can damage healthy bone and lead to an increased fracture risk. The goal of this study is to develop a mouse model for radiation therapy using a fractionated biologically equivalent dose for cervical cancer treatment in both pre- and postmenopausal women. Thirty-two female C57BL/6 mice 13 weeks of age were divided into four groups: Sham + non-irradiated (SHAM + NR), Sham + irradiated (SHAM + IRR), ovariectomy + non-irradiated (OVX + NR) and ovariectomy + irradiated (OVX + IRR). The irradiated mice received a 6 Gy dose of X-rays to the hindlimbs at Day 2, Day 4 and Day 7 (18 Gy total). Tissues were collected at Day 35. DEXA, microCT analysis and FEA were used to quantify structural and functional changes at the proximal tibia, midshaft femur, proximal femur and L1 vertebra. There was a significant (p < 0.05) decline in proximal tibia trabecular BV/TV from (1) IRR compared to NR mice within Sham (- 46%) and OVX (- 41%); (2) OVX versus Sham within NR mice (- 36%) and IRR mice (- 30%). With homogenous material properties applied to the proximal tibia mesh using FEA, there was (1) an increase in whole bone (trabecular + cortical) structural stiffness from IRR compared to NR mice within Sham (+ 10%) and OVX (+ 15%); (2) a decrease in stiffness from OVX versus Sham within NR mice (- 18%) and IRR mice (- 14%). Fractionated irradiation and ovariectomy both had a negative effect on skeletal microarchitecture. Ovariectomy had a systemic effect, while skeletal radiation damage was largely specific to trabecular bone within the X-ray field.

2.
J Exp Med ; 217(2)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31841125

RESUMO

Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.

3.
Bone ; 127: 91-103, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31055118

RESUMO

Chronic kidney disease (CKD) is a common disease of aging and increases fracture risk over advanced age alone. Aging and CKD differently impair bone turnover and mineralization. We thus hypothesize that the loss of bone quality would be greatest with the combination of advanced age and CKD. We evaluated bone from young adult (6 mo.), middle-age (18 mo.), and old (24 mo.) male C57Bl/6 mice three months following either 5/6th nephrectomy, to induce CKD, or Sham procedures. CKD exacerbated losses of cortical and trabecular microarchitecture associated with aging. Aging and CKD each resulted in thinner, more porous cortices and fewer and thinner trabeculae. Bone material quality was also reduced with CKD, and these changes to bone material were distinct from those due to age. Aging reduced whole-bone flexural strength and modulus, micrometer-scale nanoindentation modulus, and nanometer-scale tissue and collagen strain (small-angle x-ray scattering [SAXS]. By contrast, CKD reduced work to fracture and variation in bone tissue modulus and composition (Raman spectroscopy), and increased percent collagen strain. The increased collagen strain burden was associated with loss of toughness in CKD. In addition, osteocyte lacunae became smaller, sparser, and more disordered with age for Sham mice, yet these age-related changes were not clearly observed in CKD. However, for CKD, larger lacunae positively correlated with increased serum phosphate levels, suggesting that osteocytes play a role in systemic mineral homeostasis. This work demonstrates that CKD reduces bone quality, including microarchitecture and bone material properties, and that loss of bone quality with age is compounded by CKD. These findings may help reconcile why bone mass does not consistently predict fracture in the CKD population, as well as why older individuals with CKD are at high risk of fragility.

4.
Proc Natl Acad Sci U S A ; 116(24): 12007-12012, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31118285

RESUMO

Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates translation of numerous mRNA targets, some of which are present at synapses. While protein synthesis deficits have long been postulated as an etiology of FXS, how FMRP loss affects distributions of newly synthesized proteins is unknown. Here we investigated the role of FMRP in regulating expression of new copies of the synaptic protein PSD95 in an in vitro model of synaptic plasticity. We find that local BDNF application promotes persistent accumulation of new PSD95 at stimulated synapses and dendrites of cultured neurons, and that this accumulation is absent in FMRP-deficient mouse neurons. New PSD95 accumulation at sites of BDNF stimulation does not require known mechanisms regulating FMRP-mRNA interactions but instead requires the PI3K-mTORC1-S6K1 pathway. Surprisingly, in FMRP-deficient neurons, BDNF induction of new PSD95 accumulation can be restored by mTORC1-S6K1 blockade, suggesting that constitutively high mTORC1-S6K1 activity occludes PSD95 regulation by BDNF and that alternative pathways exist to mediate induction when mTORC1-S6K1 is inhibited. This study provides direct evidence for deficits in local protein synthesis and accumulation of newly synthesized protein in response to local stimulation in FXS, and supports mTORC1-S6K1 pathway inhibition as a potential therapeutic approach for FXS.

5.
J Clin Immunol ; 39(2): 148-158, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30911953

RESUMO

"This porridge is too hot!" she exclaimed. So, she tasted the porridge from the second bowl. "This porridge is too cold," she said. So, she tasted the last bowl of porridge. "Ahhh, this porridge is just right," she said happily and she ate it all up. While this describes the adventures of Goldilocks in the classic fairytale "The Story of Goldilocks and the Three Bears," it is an ideal analogy for the need for balanced signaling mediated by phosphatidylinositol-3-kinase (PI3K), a key signaling hub in immune cells. Either too little or too much PI3K activity is deleterious, even pathogenic-it needs to be "just right"! This has been elegantly demonstrated by the identification of inborn errors of immunity in key components of the PI3K pathway, and the impact of these mutations on immune regulation. Detailed analyses of patients with germline activating mutations in PIK3CD, as well as the parallel generation of novel murine models of this disease, have shed substantial light on the role of PI3K in lymphocyte development and differentiation, and mechanisms of disease pathogenesis resulting not only from PIK3CD mutations but genetic lesions in other components of the PI3K pathway. Furthermore, by being able to pharmacologically target PI3K, these monogenic conditions have provided opportunities for the implementation of precision medicine as a therapy, as well as to gain further insight into the consequences of modulating the PI3K pathway in clinical settings.

6.
J Allergy Clin Immunol ; 144(1): 236-253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30738173

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8+ T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4+ T cells in disease pathogenesis. OBJECTIVE: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4+ T-cell function. METHODS: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4+ T cells and a novel murine disease model caused by overactive PI3K signaling. RESULTS: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (TFH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human TFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH cell function were cell intrinsic. CONCLUSION: Our studies reveal that CD4+ T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations.

7.
J Allergy Clin Immunol ; 143(1): 276-291.e6, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800648

RESUMO

BACKGROUND: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown. OBJECTIVE: Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies. METHODS: We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV. RESULTS: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70. CONCLUSIONS: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Classe I de Fosfatidilinositol 3-Quinases , Infecções por Vírus Epstein-Barr , Mutação com Ganho de Função , Doenças Genéticas Inatas/imunologia , Herpesvirus Humano 4/imunologia , Células Matadoras Naturais/imunologia , Adolescente , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/genética , Senescência Celular/genética , Senescência Celular/imunologia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Vigilância Imunológica/genética , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade
8.
Conf Proc IEEE Eng Med Biol Soc ; 2018: 1747-1750, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30440733

RESUMO

Astronauts and patients on bedrest are subject to a combination of bone strength losses and muscle atrophy due to microgravity and unloading. In this study, mice were subject to both hind limb suspension and cast mediated immobilization. Pre-treatment and post-treatment microCT scans were utilized to create finite element models. Both pre-treatment and posttreatment scans were then cropped, rotated and threedimensional image registration was performed to eliminate inconsistency in alignment. A hexahedral finite element mesh was then generated from this 3D data. Finite element analysis was conducted to perform simulated physiological loading of the femoral neck to assess bone strength through bone structural morphology. Hind limb suspension combined with Cast Mediated Immobilization caused a 7.9% decrease in bone FEA stiffness compared to the in-vivo pre-treatment control. No differences were found in bone volume or structural efficiency.


Assuntos
Osso e Ossos , Moldes Cirúrgicos , Análise de Elementos Finitos , Elevação dos Membros Posteriores , Ausência de Peso , Animais , Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/fisiologia , Imobilização , Camundongos , Modelos Biológicos , Atrofia Muscular , Microtomografia por Raio-X
9.
Conf Proc IEEE Eng Med Biol Soc ; 2018: 1763-1766, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30440736

RESUMO

As the duration of manned missions outside of the Earth's protective shielding increase, astronauts are at risk for exposure to space radiation. Various organ systems may be damaged due to exposure. This study investigates the bone strength changes using finite element modeling of Long Evans rats (n=85) subjected to graded, head-only proton (0, 10, 25, and 100 cGy, 150 MeV/n) and 28silicon (0, 10, 25, and 50 cGy, 300 MeV/n) radiation. The strength of the femoral neck will be examined due its clinical relevance to hip fractures. It has been shown in previous studies that bone mineral density was not reduced at the site of fracture. These findings question whether measurements of bone mineral density may be used to assess risk of hip fracture. The mechanisms leading to the irregular relationship between bone density and strength are still uncertain within literature and investigated to greater extent in clinical applications. Finite element analysis within this study simulated physiological loading of the femoral neck. No significant changes in femoral neck strength were found across doses of proton or 28silicon head-only radiation. Future work includes performing mechanical testing of the bone samples. Moving from mouse to larger animal models may also provide the increased lifespan for assessing the long-term outcomes of radiation exposure.


Assuntos
Radiação de Fundo , Densidade Óssea , Colo do Fêmur , Análise de Elementos Finitos , Modelos Biológicos , Animais , Densidade Óssea/efeitos da radiação , Colo do Fêmur/efeitos da radiação , Fraturas do Quadril , Camundongos , Ratos , Ratos Long-Evans
10.
J Exp Med ; 215(8): 2073-2095, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30018075

RESUMO

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.


Assuntos
Linfócitos B/citologia , Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação em Linhagem Germinativa/genética , Fosfatidilinositol 3-Quinases/genética , Animais , Afinidade de Anticorpos/imunologia , Células da Medula Óssea/citologia , Diferenciação Celular , Proliferação de Células , Criança , Mutação com Ganho de Função/genética , Humanos , Switching de Imunoglobulina , Imunoglobulinas/metabolismo , Interleucinas/farmacologia , Camundongos , Modelos Animais , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Plasmócitos/metabolismo , Transdução de Sinais
13.
Neurosurg Focus ; 43(2): E6, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28760031

RESUMO

OBJECTIVE The objective of this study was to describe the use of a minimally invasive surgical treatment of lumbar spondylolysis in athletes by a fluoroscopically guided direct pars screw placement with recombinant human bone morphogenetic protein-2 (rhBMP-2) and to report on clinical and radiographic outcomes. METHODS A retrospective review was conducted of all patients treated surgically for lumbar spondylolysis via a minimally invasive direct pars repair with cannulated screws. Demographic information, clinical features of presentation, perioperative and intraoperative radiographic imaging, and postoperative data were collected. A 1-cm midline incision was performed for the placement of bilateral pars screws utilizing biplanar fluoroscopy, followed by placement of a fully threaded 4.0-mm-diameter titanium cannulated screw. A tubular table-mounted retractor was utilized for direct pars fracture visualization and debridement through a separate incision. The now-visualized pars fracture could then be decorticated, with care taken not to damage the titanium screw when using a high-speed drill. Local bone obtained from the curettage was then placed in the defect with 1.05 mg rhBMP-2 divided equally between the bilateral pars defects. RESULTS Nine patients were identified (mean age 17.7 ± 3.42 years, range 14-25 years; 6 male and 3 female). All patients had bilateral pars fractures of L-4 (n = 4) or L-5 (n = 5). The mean duration of preoperative symptoms was 17.22 ± 13.2 months (range 9-48 months). The mean operative duration was 189 ± 29 minutes (range 151-228 minutes). The mean intraoperative blood loss was 17.5 ± 10 ml (range 10-30 ml). Radiographic follow-up was available in all cases; the mean length of time from surgery to the most recent imaging study was 30.8 ± 23.3 months (range 3-59 months). The mean hospital length of stay was 1.13 ± 0.35 days (range 1-2 days). There were no intraoperative complications. CONCLUSIONS Lumbar spondylolysis treatment with a minimally invasive direct pars repair is a safe and technically feasible option that minimizes muscle and soft-tissue dissection, which may particularly benefit adolescent patients with a desire to return to a high level of physical activity.


Assuntos
Proteína Morfogenética Óssea 2/administração & dosagem , Parafusos Ósseos , Vértebras Lombares/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Espondilólise/cirurgia , Fator de Crescimento Transformador beta/administração & dosagem , Adolescente , Parafusos Ósseos/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Monitorização Neurofisiológica Intraoperatória/métodos , Vértebras Lombares/diagnóstico por imagem , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos/instrumentação , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos , Espondilólise/diagnóstico por imagem , Adulto Jovem
14.
Ecol Evol ; 7(24): 10963-10973, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29299273

RESUMO

Forest loss has been associated with reduced survival in many vertebrates, and previous research on amphibians has mostly focused on effects at early life stages. Paramesotriton hongkongensis is a tropical newt that breeds in streams but spends up to 10 months per year in terrestrial habitats. Populations are threatened by habitat degradation and collection for the pet trade, but the cryptic terrestrial lifestyle of this newt has limited our understanding of its population ecology, which inhibits development of a species-specific conservation plan. We conducted an eight-year (2007-2014) mark-recapture study on four P. hongkongensis populations in Hong Kong and used these data to evaluate relationships between forest cover, body size, and rainfall on survival and to estimate population sizes. Hong Kong has been subjected to repeated historic territory-wide deforestation, and thus, we wanted to determine whether there was a link between forest extent as a proxy of habitat quality and newt demography. Annual survival was positively associated with forest cover within core habitat of all populations and negatively related to body size. Mean annual survival (~60%) was similar to that of other stream-dwelling amphibians, but varied among years and declined substantially in 2012-2013, perhaps due to illegal collection. Despite the link between forest extent and survival, population sizes declined at the most forested site by 40% and increased by 104% and 134% at two others. Forest protection and consequential secondary succession during recent decades in Hong Kong may have been responsible for persistence of P. hongkongensis populations.

15.
Arthritis Rheumatol ; 69(2): 352-361, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27564840

RESUMO

OBJECTIVE: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is elevated in the serum and synovial fluid of patients with osteoarthritis (OA). This study was undertaken to investigate the potential role of MIF in OA in human joint tissues and in vivo in mice with age-related and surgically induced OA. METHODS: MIF in conditioned media from human chondrocytes and meniscal cells and from cartilage explants was measured by enzyme-linked immunosorbent assay. The severity of OA was analyzed histologically in male wild-type and MIF-/- mice at 12 and 22 months of age and following destabilization of the medial meniscus (DMM) surgery in 12-week-old MIF-/- mice as well as in wild-type mice treated with a neutralizing MIF antibody. Synovial hyperplasia was graded in S100A8-immunostained histologic sections. Bone morphometric parameters were measured by micro-computed tomography. RESULTS: Human OA chondrocytes secreted 3-fold higher levels of MIF than normal chondrocytes, while normal and OA meniscal cells produced equivalent amounts. Compared to age- and strain-matched controls, the cartilage, bone, and synovium in older adult mice with MIF deletion were protected against changes of naturally occurring age-related OA. No protection against DMM-induced OA was seen in young adult MIF-/- mice or in wild-type mice treated with anti-MIF. Increased bone density in 8-week-old mice with MIF deletion was not maintained at 12 months. CONCLUSION: These results demonstrate a differential mechanism in the pathogenesis of naturally occurring age-related OA compared to injury-induced OA. The inhibition of MIF may represent a novel therapeutic target in the reduction of the severity of age-related OA.


Assuntos
Deleção de Genes , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Osteoartrite/genética , Fatores Etários , Animais , Células Cultivadas , Humanos , Masculino , Camundongos , Índice de Gravidade de Doença
17.
Can J Hosp Pharm ; 69(6): 454-459, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28123191

RESUMO

BACKGROUND: Symptomatic venous thromboembolism (VTE) occurs in about 1% of patients within 3 months after admission to a medical unit. Recent evidence for thromboprophylaxis in an unselected medical inpatient population has suggested only a modest net benefit. Consequently, guidelines recommend careful risk stratification to guide thromboprophylaxis. OBJECTIVES: To compare candidacy for thromboprophylaxis according to 4 risk stratification models: a regional preprinted order (PPO) set used in the study institution, the Padua Prediction Score, and the IMPROVE predictive and associative risk assessment models. METHODS: A retrospective review of health records was undertaken for patients with no contraindication to pharmacologic thromboprophylaxis who were admitted to the internal medicine service of a teaching hospital between April and July 2013. RESULTS: Of the 298 patients in the study cohort, 238 (80.0%) received pharmacologic thromboprophylaxis on admission, ordered according to the regional PPO. However, according to the Padua and the IMPROVE predictive risk assessment models, only 64 (21.5%) and 21 (7.0%) of the patients, respectively, were eligible for thromboprophylaxis at the time of admission. On the basis of risk factors identified during the subsequent hospital stay, 54 (18.1%) of the patients were eligible for thromboprophylaxis according to the IMPROVE associative model. Chance-corrected agreement between the PPO and the published risk assessment models was generally poor, with kappa coefficients of 0.109 for the PPO compared with the Padua Prediction Score and 0.013 for the PPO compared with the IMPROVE predictive model. CONCLUSIONS: These data suggest that quantitative models such as the Padua Prediction Score and the IMPROVE models identify more patients at low risk of venous thromboembolism than do in-hospital qualitative risk assessment models. Adoption of these guideline-based risk assessment models for predicting thromboembolic risk in medical inpatients could reduce the use of pharmacologic thromboprophylaxis from 80% to as low as 7%. Further external prognostic validation of risk assessment models and impact analysis studies may show improvements in safety and resource utilization.

18.
Macromol Biosci ; 15(12): 1744-54, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26259625

RESUMO

A simple and versatile methodology, which employs a combination of ring-opening polymerization and alkyne-azide click chemistry to synthesize amphiphilic AB3 miktoarm stars, is reported. Their aqueous self-assembly behavior was studied using dynamic light scattering, fluorescence, and asymmetrical flow field-flow fractionation (AF4). AB3 miktoarm stars form micelles which incorporate curcumin with high efficiency, and significantly reduce the viability of glioblastoma cells in spheroids. We demonstrate that AF4 is an effective technique to determine the size distribution of self-assembled structures exposed to a biological medium. The ease, with which asymmetric AB3 miktoarm polymers are constructed, provides a platform that can be widely employed to deliver a variety of lipophilic drugs.


Assuntos
Plásticos Biodegradáveis , Química Click , Curcumina , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/farmacocinética , Plásticos Biodegradáveis/farmacologia , Linhagem Celular Tumoral , Curcumina/química , Curcumina/farmacocinética , Curcumina/farmacologia , Humanos , Micelas
19.
J Exp Med ; 212(6): 855-64, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25941256

RESUMO

Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.


Assuntos
Fator de Transcrição STAT3/metabolismo , Linfócitos T/citologia , Separação Celular , Citocinas/metabolismo , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Interleucinas/metabolismo , Células Matadoras Naturais/citologia , Leucócitos Mononucleares/citologia , Linfócitos/citologia , Mutação , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina-12/metabolismo , Receptores de Interleucina-21/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
20.
Appl Microbiol Biotechnol ; 99(14): 5855-61, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25904130

RESUMO

This study investigated the characterization and flocculation mechanism of a bioflocculant prepared using potato starch wastewater. The optimal culture conditions of this strain were determined as 4 g K2HPO4, 2 g KH2PO4, 0.2 g MgSO4, 0.1 g NaCl, and 2.0 g urea dissolved in 1.0 L potato starch wastewater with no need of adding carbon sources or adjusting pH value. Production of this bioflocculant was positively associated with cell growth, and a highest value of 0.81 g/L was obtained. During the kaolin suspension flocculation, charge neutralization and interparticle bridging were proposed as the main reasons for enhanced performance. Further, with potato starch wastewater, chemical oxygen demand (COD) and turbidity removal rates reached 52.4 and 81.7 %, respectively, at pH 7.5 when the bioflocculant dose was adjusted to 30 mg/L.


Assuntos
Resíduos Industriais , Solanum tuberosum/química , Amido/química , Águas Residuárias/química , Águas Residuárias/microbiologia , Meios de Cultura/química , Floculação , Concentração de Íons de Hidrogênio
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