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Plasma fibronectin (pFN) is a hepatocyte-derived circulating extracellular matrix protein that affects cell morphology, adipogenesis, and insulin signaling of adipocytes in vitro. In this study, we show pFN accrual to adipose tissue and its contribution to tissue homeostasis in mice. Hepatocyte-specific conditional Fn1 knockout mice (Fn1-/-ALB) show a decrease in adipose tissue FN levels and enhanced insulin sensitivity of subcutaneous (inguinal), visceral (epididymal) adipose tissue on a normal diet. Diet-induced obesity model of the Fn1-/-ALB mouse showed normal weight gain and whole-body fat mass, and normal adipose tissue depot volumes and unaltered circulating leptin and adiponectin levels. However, Fn1-/-ALB adipose depots showed significant alterations in adipocyte size and gene expression profiles. The inguinal adipose tissue on a normal diet, which had alterations in fatty acid metabolism and thermogenesis suggesting browning. The presence of increased beige adipocyte markers Ucp1 and Prdm16 supported this. In the inguinal fat, the obesogenic diet resulted in downregulation of the browning markers and changes in gene expression reflecting development, morphogenesis, and mesenchymal stem cell maintenance. Epididymal adipose tissue showed alterations in developmental and stem cell gene expression on both diets. The data suggests a role for pFN in adipose tissue insulin sensitivity and cell profiles.
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Fibronectinas , Resistência à Insulina , Animais , Camundongos , Fibronectinas/metabolismo , Fibronectinas/genética , Masculino , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Adipogenia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/genética , Obesidade/sangue , Diferenciação Celular , Dieta HiperlipídicaRESUMO
OBJECTIVE: This cross-sectional study investigated the relationship between metacognition and mood symptoms four years post-stroke and examined fatigue as a potential moderator for this relationship. METHODS: A number of 143 participants completed a survey that included the Hospital Anxiety and Depression Scale (HADS), the Metacognition Questionnaire-30 (MCQ-30), the Fatigue Severity Scale (FSS), and the modified Rankin Scale (mRS) (functional status) four years after stroke. Multiple regression analyses adjusting for demographic and stroke-specific covariates were performed with anxiety and depression as dependent variables and fatigue as a moderator. RESULTS: The proportions of participants satisfying the caseness criteria for anxiety and depression were 20% and 19%, respectively, and 35% reported severe fatigue. Analysed separately, all MCQ-30 subscales contributed significantly to anxiety, whereas only three MCQ-30 subscales contributed significantly to depression. In the adjusted analyses, the MCQ-30 subscales 'positive beliefs' (p < 0.05) and 'uncontrollability and danger' (p < 0.001), as well as fatigue (p < 0.001) and functional status at four years (p < 0.05) were significantly associated with anxiety symptoms. Similarly, the MCQ-30 subscales 'cognitive confidence' (p < 0.05) and 'self-consciousness' (p < 0.05), as well as fatigue (p < 0.001), stroke severity at baseline (p < 0.01), and functional status at four years (p < 0.01) were significantly associated with depression symptoms. Fatigue did not significantly moderate the relationship between any MCQ-30 subscale and HADS scores. CONCLUSION: Maladaptive metacognitions were associated with the mood symptoms of anxiety and depression, independent of fatigue, even after controlling for demographic and stroke-specific factors. Future studies should implement longitudinal designs to determine whether metacognitions precede anxiety or depression after a stroke, and more strongly indicate the potential of metacognitive therapy for improving the mental health of individuals after a stroke.
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Afeto , Ansiedade , Depressão , Fadiga , Metacognição , Acidente Vascular Cerebral , Humanos , Fadiga/psicologia , Fadiga/etiologia , Masculino , Feminino , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/psicologia , Pessoa de Meia-Idade , Idoso , Depressão/psicologia , Depressão/etiologia , Metacognição/fisiologia , Estudos Transversais , Ansiedade/psicologia , Afeto/fisiologia , Inquéritos e Questionários , AdultoRESUMO
OBJECTIVE: To explore trajectories that describe change in post-stroke health-related quality of life with fatigue as outcome. DESIGN: Observational and prospective study. SUBJECTS: Stroke survivors (N = 144) with predominantly mild or moderate strokes. METHODS: The multidimensional Stroke-Specific Quality of Life scale was used at 1 and 4 years, and the Fatigue Severity Scale at 4 years post-stroke. Latent class growth analyses were used as person-oriented analyses to identify meaningful trajectories. Socio-demographic and stroke-related covariables provided customary adjustment of the outcome, as well as prediction of class membership. RESULTS: The latent class growth analysis models were estimated for "physical health", "visual-language", and "cognitive-social-mental" components of the Stroke-Specific Quality of Life scale, which extracted trajectories describing a variation in stable, deteriorating and improving functional patterns. The stable, well-functioning trajectory was most frequent across all components. More pronounced fatigue was associated with trajectories describing worse functioning, which was more prominent among females compared with males. Living alone implied more fatigue in the "cognitive-social-mental" component. Within the "visual-language" components' trajectories, younger and older participants reported more fatigue compared with middle-aged participants. CONCLUSION: Most participants belonged to the stable, well-functioning trajectories, which showed a consistently lower level of fatigue compared with the other trajectories.
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Qualidade de Vida , Acidente Vascular Cerebral , Feminino , Masculino , Pessoa de Meia-Idade , Humanos , Seguimentos , Estudos Prospectivos , Fadiga/etiologia , Idioma , Acidente Vascular Cerebral/complicaçõesRESUMO
PURPOSE: Chest wall injury taxonomy and nomenclature are important components of chest wall injury classification and can be helpful in communicating between providers for treatment planning. Despite the common nature of these injuries, there remains a lack of consensus regarding injury description. The Chest Wall Injury Society (CWIS) developed a taxonomy among surgeons in the field; however, it lacked consensus and clarity in critical areas and collaboration with multidisciplinary partners. We believe an interdisciplinary collaboration between CWIS and American Society of Emergency Radiology (ASER) will improve existing chest wall injury nomenclature and help further research on this topic. METHODS: A collaboration between CWIS and ASER gathered feedback on the consensus recommendations. The workgroup held a series of meetings reviewing each consensus statement, refining the terminology, and contributing additional clarifications from a multidisciplinary lens. RESULTS: After identifying incomplete definitions in the CWIS survey, the workgroup expanded on and clarified the language proposed by the survey. More precise definitions related to rib and costal cartilage fracture quality and location were developed. Proposed changes include more accurate characterization of rib fracture displacement and consistent description of costal cartilage fractures. CONCLUSIONS: The 2019 consensus survey from CWIS provides a framework to discuss chest wall injuries, but several concepts remained unclear. Creating a universally accepted taxonomy and nomenclature, utilizing the CWIS survey and this article as a scaffolding, may help providers communicate the severity of chest wall injury accurately, allow for better operative planning, and provide a common language for researchers in the future.
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Fraturas Ósseas , Radiologia , Traumatismos Torácicos , Parede Torácica , Humanos , Parede Torácica/diagnóstico por imagem , Traumatismos Torácicos/diagnóstico por imagemRESUMO
Osteoclasts are multinucleated, bone-resorbing giant cells derived from monocyte-macrophage cell lines. Increased bone resorption results in loss of bone mass and osteoporosis. Osteoclast and bone marrow macrophages have been shown to express three TG enzymes (TG2, Factor XIII-A, and TG1) and TG activity to regulate osteoclast differentiation from bone marrow macrophages in vitro. In vivo and in vitro studies have demonstrated that the deletion of TG2 causes increased osteoclastogenesis and a significant loss of bone mass in mice (Tgm2-/- mice). Here, we confirm that TG2 deficiency results in increased osteoclastogenesis in vitro and show that this increase can be reversed by a TG inhibitor, NC9, suggesting that other TGs are responsible for driving osteoclastogenesis in the absence of TG2. An assessment of total TG activity with 5-(biotinamido)-pentylamine, as well as TG1 and FXIII-A activities using TG-specific Hitomi peptides (bK5 and bF11) in Tgm2-/- bone marrow flushes, bone marrow macrophages, and osteoclasts, showed a significant increase in total TG activity and TG1 activity. Factor XIII-A activity was unchanged. Aspartate proteases, such as cathepsins, are involved in the degradation of organic bone matrix and can be produced by osteoclasts. Moreover, Cathepsin D was shown in previous work to be increased in TG2-null cells and is known to activate TG1. We show that Pepstatin A, an aspartate protease inhibitor, blocks osteoclastogenesis in wild-type and Tgm2-/- cells and decreases TG1 activity in Tgm2-/- osteoclasts. Cathepsin D protein levels were unaltered in Tgm2-/-cells and its activity moderately but significantly increased. Tgm2-/- and Tgm2+/+ bone marrow macrophages and osteoclasts also expressed Cathepsin E, and Renin of the aspartate protease family, suggesting their potential involvement in this process. Our study brings further support to the observation that TGs are significant regulators of osteoclastogenesis and that the absence of TG2 can cause increased activity of other TGs, such as TG1.
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Ácido Aspártico Proteases , Osteoclastos , Animais , Camundongos , Osteogênese , Catepsina D , Transglutaminases/genética , Ácido Aspártico , Fator XIIIRESUMO
Transglutaminases (TGs) are a family of protein cross-linking enzymes that are capable of stiffening and insolubilizing proteins and creating protein networks, and thereby altering biological functions of proteins. Their role in fibrosis progression has been widely investigated with a focus on kidney, lung, liver, and heart where activity is triggered by various stimuli including hypoxia, inflammation, and hyperglycemia. TG2 has been considered one of the key enzymes in the pathogenesis of fibrosis mainly through transforming growth factor beta (TGF-beta) signaling and matrix cross-linking mechanisms. Although TG2 has been most widely studied in this context, the involvement of other TGs, TG1 and Factor XIII-A (FXIII-A), is beginning to emerge. This mini-review highlights the major steps taken in the TG and fibrosis research and summarizes the most recent advances and contributions of TG2, TG1, and FXIII-A to the progression of fibrosis in various animal models. Also, their mechanisms of action as well as therapeutic prospects are discussed.
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Hiperglicemia , Transglutaminases , Animais , Fígado , Hipóxia , FibroseRESUMO
The globally increasing prevalence of obesity is associated with the development of metabolic diseases such as type 2 diabetes, dyslipidemia, and fatty liver. Excess adipose tissue (AT) often leads to its malfunction and to a systemic metabolic dysfunction because, in addition to storing lipids, AT is an active endocrine system. Adipocytes are embedded in a unique extracellular matrix (ECM), which provides structural support to the cells as well as participating in the regulation of their functions, such as proliferation and differentiation. Adipocytes have a thin pericellular layer of a specialized ECM, referred to as the basement membrane (BM), which is an important functional unit that lies between cells and tissue stroma. Collagens form a major group of proteins in the ECM, and some of them, especially the BM-associated collagens, support AT functions and participate in the regulation of adipocyte differentiation. In pathological conditions such as obesity, AT often proceeds to fibrosis, characterized by the accumulation of large collagen bundles, which disturbs the natural functions of the AT. In this review, we summarize the current knowledge on the vertebrate collagens that are important for AT development and function and include basic information on some other important ECM components, principally fibronectin, of the AT. We also briefly discuss the function of AT collagens in certain metabolic diseases in which they have been shown to play central roles.
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Factor XIIIa (FXIIIa) is a transglutaminase of major therapeutic interest for the development of anticoagulants due to its essential role in the blood coagulation cascade. While numerous FXIIIa inhibitors have been reported, they failed to reach clinical evaluation due to their lack of metabolic stability and low selectivity over transglutaminase 2 (TG2). Furthermore, the chemical tools available for the study of FXIIIa activity and localization are extremely limited. To combat these shortcomings, we designed, synthesised, and evaluated a library of 21 novel FXIIIa inhibitors. Electrophilic warheads, linker lengths, and hydrophobic units were varied on small molecule and peptidic scaffolds to optimize isozyme selectivity and potency. A previously reported FXIIIa inhibitor was then adapted for the design of a probe bearing a rhodamine B moiety, producing the innovative KM93 as the first known fluorescent probe designed to selectively label active FXIIIa with high efficiency (kinact/KI = 127,300 M-1 min-1) and 6.5-fold selectivity over TG2. The probe KM93 facilitated fluorescent microscopy studies within bone marrow macrophages, labelling FXIIIa with high efficiency and selectivity in cell culture. The structure-activity trends with these novel inhibitors and probes will help in the future study of the activity, inhibition, and localization of FXIIIa.
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Fator XIIIa , Transglutaminases , Transglutaminases/química , Fator XIIIa/química , Fator XIIIa/metabolismo , Corantes Fluorescentes , Técnicas de Cultura de Células , Macrófagos/metabolismoRESUMO
PURPOSE: To assess the healing of costal cartilage fractures (CCFX) in patients with blunt polytrauma with follow-up imaging and clinical examination. Effect on physical performance and quality of life (QoL) was also evaluated. METHODS: The study group comprised twenty-one patients with diagnosed CCFX in trauma CT. All the patients underwent MRI, ultrasound, ultra-low-dose CT examinations, and clinical status control. The patients completed QoL questionnaires. Two radiologists evaluated the images regarding fracture union, dislocation, calcifications, and persistent edema at fracture site. An attending trauma surgeon clinically examined the patients, with emphasis on focal tenderness and ribcage mobility. Trauma registry data were accessed to evaluate injury severity and outcome. RESULTS: The patients were imaged at an average of 34.1 months (median 36, range 15.8-57.7) after the initial trauma. In 15 patients (71.4%), CCFX were considered stable on imaging. Cartilage calcifications were seen on healed fracture sites in all the patients. The fracture dislocation had increased in 5 patients (23.8%), and 1 patient (4.8%) showed signs of a non-stable union. Four patients (19.0%) reported persistent symptoms from CCFX. CONCLUSION: Non-union in CCFX is uncommon but may lead to decreased stability and discomfort. Both clinical and radiological examinations play an important part in the post-traumatic evaluation of CCFX. CT and MRI visualize the healing process, while dynamic ultrasound may reveal instability. No significant difference in QoL was detected between patients with radiologically healed and non-healed CCFX. Post-traumatic disability was mostly due to other non-thoracic injuries.
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Fraturas de Cartilagem , Traumatismo Múltiplo , Fraturas das Costelas , Ferimentos não Penetrantes , Seguimentos , Humanos , Traumatismo Múltiplo/diagnóstico por imagem , Estudos Prospectivos , Qualidade de Vida , Tomografia Computadorizada por Raios X/métodos , Ferimentos não Penetrantes/diagnóstico por imagemRESUMO
IL-17 plays important roles in host defense against Candida albicans at barrier surfaces and during invasive infection. However, the role of IL-17 in host defense after colonization of the epidermis, a main site of C. albicans infection, remains poorly understood. Using a murine model of epicutaneous candidiasis without skin abrasion, we found that skin inflammation triggered by epidermal C. albicans colonization was self-limiting with fungal clearance completed by day 7 after inoculation in wild-type mice or animals deficient in IL-17A or IL-17F. In contrast, marked neutrophilic inflammation in the epidermis and impaired fungal clearance were observed in mice lacking both IL-17A and IL-17F. Clearance of C. albicans was independent of Dectin-1, Dectin-2, CARD9 (caspase-recruitment domain family, member 9), TLR2 (Toll-like receptor 2) and MyD88 in the epidermal colonization model. We found that group 3 innate lymphoid cells (ILC3s) and γδT cells were the major IL-17 producers in the epicutaneous candidiasis model. Analyses of Rag2-/- mice and Rag2-/-Il2rg-/- mice revealed that production of IL-17A and IL-17F by ILC3s was sufficient for C. albicans clearance. Finally, we found that depletion of neutrophils impaired C. albicans clearance in the epidermal colonization model. Taken together, these findings indicate a critical and redundant function of IL-17A and IL-17F produced by ILC3s in host defense against C. albicans in the epidermis. The results also suggest that epidermal C. albicans clearance is independent of innate immune receptors or that these receptors act redundantly in fungal recognition and clearance.
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Candida albicans , Candidíase , Interleucina-17/imunologia , Animais , Proteínas Adaptadoras de Sinalização CARD , Epiderme/metabolismo , Imunidade Inata , Inflamação , Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Adipose tissue is a central regulator of metabolic health and its failure in obesity is a major cause of weight associated comorbidities, such as type 2 diabetes. Many extracellular matrix proteins, represented by matrisome, play a critical role in balancing adipose tissue health and dysfunction. Extracellular matrix components, produced by different cell types of adipose tissue, can modulate adipocyte function, tissue remodeling during expansion, angiogenesis, and inflammation and also form fibrotic lesions in the tissue. In this study, we investigated changes in matrisome of whole adipose tissue and adipocytes in human obesity. We investigated further the networks and biological pathways of the genes related to the changes and their association to development of metabolic dysfunction linked to type 2 diabetes. We used transcriptome data and clinical metabolic parameters from a rare weight-discordant MZ twin cohort. The Heavy-Lean differential matrisome gene expression (Δmatrisome) and differential metabolic parameters reflect changes in adipose tissue upon weight gain and changes in whole body glucose, insulin metabolism, as well as lipid status. We report that obesity Δmatrisome shows high specificity with 130 and 71 of the 1068 matrisome genes showing altered expression in the adipose tissue and adipocytes of heavier co-twin, respectively. The Δmatrisome differs considerably between adipose tissue vs adipocytes which reflects inflammation of hypertrophic adipocytes and the remodeling activity of the rest of the tissue resident cells. The obesity Δmatrisome is discussed extensively in the light of existing evidence and novel significant associations to obesity are reported to matrisome genes; cathepsin A, cathepsin O, FAM20B and N-glycanase1.
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Diabetes Mellitus Tipo 2 , Transcriptoma , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Obesidade/genética , Obesidade/metabolismoRESUMO
The rare decay K_{L}âπ^{0}νν[over ¯] was studied with the dataset taken at the J-PARC KOTO experiment in 2016, 2017, and 2018. With a single event sensitivity of (7.20±0.05_{stat}±0.66_{syst})×10^{-10}, three candidate events were observed in the signal region. After unveiling them, contaminations from K^{±} and scattered K_{L} decays were studied, and the total number of background events was estimated to be 1.22±0.26. We conclude that the number of observed events is statistically consistent with the background expectation. For this dataset, we set an upper limit of 4.9×10^{-9} on the branching fraction of K_{L}âπ^{0}νν[over ¯] at the 90% confidence level.
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The bone regenerative capacity of synthetic calcium phosphates (CaPs) can be enhanced through the enrichment with selected metal trace ions. However, defining the optimal elemental composition required for bone formation is challenging due to many possible concentrations and combinations of these elements. We hypothesized that the ideal elemental composition exists in the inorganic phase of the bone extracellular matrix (ECM). To study our hypothesis, we first obtained natural hydroxyapatite through the calcination of bovine bone, which was then investigated its reactivity with acidic phosphates to produce CaP cements. Bioceramic scaffolds fabricated using these cements were assessed for their composition, properties, and in vivo regenerative performance and compared with controls. We found that natural hydroxyapatite could react with phosphoric acid to produce CaP cements with biomimetic trace metals. These cements present significantly superior in vivo bone regenerative performance compared with cements prepared using synthetic apatite. In summary, this study opens new avenues for further advancements in the field of CaP bone biomaterials by introducing a simple approach to develop biomimetic CaPs. This work also sheds light on the role of the inorganic phase of bone and its composition in defining the regenerative properties of natural bone xenografts.
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Biomimética , Regeneração Óssea/efeitos dos fármacos , Fosfatos de Cálcio/farmacologia , Cerâmica/farmacologia , Metais/farmacologia , Oligoelementos/farmacologia , Animais , Cimentos Ósseos/química , Fosfatos de Cálcio/química , Bovinos , Ácido Cítrico/farmacologia , Força Compressiva , Cristalografia por Raios X , Durapatita/química , Durapatita/isolamento & purificação , Feminino , Teste de Materiais , Metais/análise , Metais/uso terapêutico , Ácidos Fosfóricos/farmacologia , Ratos , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacos , Tíbia/lesões , Oligoelementos/análise , Oligoelementos/uso terapêutico , Microtomografia por Raio-XRESUMO
Transglutaminases TG2 and FXIII-A have recently been linked to adipose tissue biology and obesity, however, human studies for TG family members in adipocytes have not been conducted. In this study, we investigated the association of TGM family members to acquired weight gain in a rare set of monozygotic (MZ) twins discordant for body weight, i.e., heavy-lean twin pairs. We report that F13A1 is the only TGM family member showing significantly altered, higher expression in adipose tissue of the heavier twin. Our previous work linked adipocyte F13A1 to increased weight, body fat mass, adipocyte size, and pro-inflammatory pathways. Here, we explored further the link of F13A1 to adipocyte size in the MZ twins via a previously conducted TWA study that was further mined for genes that specifically associate to hypertrophic adipocytes. We report that differential expression of F13A1 (ΔHeavy-Lean) associated with 47 genes which were linked via gene enrichment analysis to immune response, leucocyte and neutrophil activation, as well as cytokine response and signaling. Our work brings further support to the role of F13A1 in the human adipose tissue pathology, suggesting a role in the cascade that links hypertrophic adipocytes with inflammation.
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Adipócitos/patologia , Tecido Adiposo/imunologia , Fator XIIIa/genética , Imunidade/genética , Obesidade/genética , Transglutaminases/fisiologia , Adipócitos/imunologia , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Composição Corporal/genética , Fator XIIIa/metabolismo , Feminino , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Hipertrofia/genética , Masculino , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/patologia , Proteína 2 Glutamina gama-Glutamiltransferase , Transglutaminases/genética , Transglutaminases/metabolismo , Gêmeos Monozigóticos/genéticaRESUMO
BACKGROUND: As part of a randomised controlled trial of treatment with placebo versus 3â days of amoxicillin for nonsevere fast-breathing pneumonia among Malawian children aged 2-59â months, a subset of children was hospitalised for observation. We sought to characterise the progression of fast-breathing pneumonia among children undergoing repeat assessments to better understand which children do and do not deteriorate. METHODS: Vital signs and physical examination findings, including respiratory rate, arterial oxygen saturation measured by pulse oximetry (S pO2 ), chest indrawing and temperature were assessed every 3â h for the duration of hospitalisation. Children were assessed for treatment failure during study visits on days 1, 2, 3 and 4. RESULTS: Hospital monitoring data from 436 children were included. While no children had S pO2 90-93% at baseline, 7.4% (16 of 215) of children receiving amoxicillin and 9.5% (21 of 221) receiving placebo developed S pO2 90-93% during monitoring. Similarly, no children had chest indrawing at enrolment, but 6.6% (14 of 215) in the amoxicillin group and 7.2% (16 of 221) in the placebo group went on to develop chest indrawing during hospitalisation. CONCLUSION: Repeat monitoring of children with fast-breathing pneumonia identified vital and physical examination signs not present at baseline, including S pO2 90-93% and chest indrawing. This information may support providers and policymakers in developing guidance for care of children with nonsevere pneumonia.
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Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.
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Actínio/uso terapêutico , Imunoconjugados/uso terapêutico , Antígeno Prostático Específico/imunologia , Neoplasias da Próstata/terapia , Calicreínas Teciduais/metabolismo , Partículas alfa , Animais , Biomarcadores Tumorais , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias Experimentais/terapiaRESUMO
BACKGROUND: Use of gastrointestinal (GI) contrast material for computed tomography (CT) diagnosis of hollow viscus injury (HVI) after penetrating abdominal trauma is still controversial. PURPOSE: To assess the sensitivity of CT and GI contrast material use in detecting HVI after penetrating abdominal trauma. MATERIAL AND METHODS: Retrospective analysis (2013-2016) of patients with penetrating abdominal trauma. Data from the local trauma registry, medical records, and imaging from PACS were reviewed. CT and surgical findings were compared. RESULTS: Of 636 patients with penetrating trauma, 177 (163 men, 14 women) had abdominal trauma (mean age 34 years, age range 16-88 years): 155/177 (85%) were imaged with CT on arrival; 128/155 (83%) were stab wounds and 21/155 (14%) were gunshot wounds; 47/155 (30%) had emergent surgery after CT. Two patients were imaged using oral, rectal and i.v. contrast; 23 with rectal and i.v. contrast; and 22 with i.v. contrast only. Surgery revealed HVI in 26 patients. CT had an overall sensitivity 69.2%, specificity 90.5%, PPV 90.0%, and NPV 70.4%. CT with oral and/or rectal contrast (n = 25) had sensitivity 66.7%, specificity 71.4%, PPV 85.7%, and NPV 45.5%. CT with i.v. contrast only (n = 22) had 75% sensitivity, 100% specificity, PPV 100%, and NPV 87.5%. No statistically significant difference was found between sensitivity of CT with GI contrast material and i.v. contrast only (P = 1). CONCLUSION: Stab wounds were the most common cause of penetrating abdominal trauma. CT had 69.2% sensitivity and 90.5% specificity in detecting HVI. CT with GI contrast had similar sensitivity as CT with i.v. contrast only.
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Traumatismos Abdominais/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Ferimentos Penetrantes/diagnóstico por imagem , Traumatismos Abdominais/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Sensibilidade e Especificidade , Suécia , Centros de Traumatologia , Ferimentos Penetrantes/cirurgiaRESUMO
Short sleep duration is a known risk factor for suicidality in the general population, yet it is unclear how short sleep interacts with autism traits in predicting suicidality. In this cross-sectional online study, a general population sample (N = 650) completed measures assessing autism traits, suicidal ideation, and sleep duration. Moderated hierarchical regressions demonstrated that higher autism traits and shorter sleep were independent predictors of increased suicide ideation. However, sleep duration did not significantly moderate the autism trait to suicide ideation relationship. Future work should explore this relationship longitudinally using objective measures before considering intervention work to increase sleep duration in those with elevated autism traits.
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Transtorno Autístico/diagnóstico , Transtorno Autístico/psicologia , Sono/fisiologia , Ideação Suicida , Tentativa de Suicídio/psicologia , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Suicídio/psicologia , Fatores de Tempo , Adulto JovemRESUMO
Immunomodulation strategies are believed to improve the integration and clinical performance of synthetic bone substitutes. One potential approach is the modification of biomaterial surface chemistry to mimic bone extracellular matrix (ECM). In this sense, we hypothesized that coating synthetic dicalcium phosphate (DCP) bioceramics with bone ECM proteins would modulate the host immune reactions and improve their regenerative performance. To test this, we evaluated the in vitro proteomic surface interactions and the in vivo performance of ECM-coated bioceramic scaffolds. Our results demonstrated that coating DCP scaffolds with bone extracts, specifically those containing calcium-binding proteins, dramatically modulated their interaction with plasma proteins in vitro, especially those relating to the innate immune response. In vivo, we observed an attenuated inflammatory response against the bioceramic scaffolds and enhanced peri-scaffold new bone formation supported by the increased osteoblastogenesis and reduced osteoclastogenesis. Furthermore, the bone extract rich in calcium-binding proteins can be 3D-printed to produce customized hydrogels with improved regeneration capabilities. In summary, bone extracts containing calcium-binding proteins can enhance the integration of synthetic biomaterials and improve their ability to regenerate bone probably by modulating the host immune reaction. This finding helps understand how bone allografts regenerate bone and opens the door for new advances in tissue engineering and bone regeneration. STATEMENT OF SIGNIFICANCE: Foreign-body reaction is an important determinant of in vivo biomaterial integration, as an undesired host immune response can compromise the performance of an implanted biomaterial. For this reason, applying immunomodulation strategies to enhance biomaterial engraftment is of great interest in the field of regenerative medicine. In this article, we illustrated that coating dicalcium phosphate bioceramic scaffolds with bone-ECM extracts, especially those rich in calcium-binding proteins, is a promising approach to improve their surface proteomic interactions and modulate the immune responses towards such biomaterials in a way that improves their bone regeneration performance. Collectively, the results of this study may provide a conceivable explanation for the mechanisms involved in presenting the excellent regenerative efficacy of natural bone grafts.
Assuntos
Regeneração Óssea/efeitos dos fármacos , Osso e Ossos , Fosfatos de Cálcio/farmacologia , Cerâmica , Misturas Complexas/farmacologia , Hidrogéis/farmacologia , Fatores Imunológicos , Osteogênese/efeitos dos fármacos , Impressão Tridimensional , Alicerces Teciduais/química , Animais , Osso e Ossos/química , Osso e Ossos/fisiologia , Cerâmica/química , Cerâmica/farmacologia , Misturas Complexas/química , Feminino , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , RatosRESUMO
A search for the rare decay K_{L}âπ^{0}νν[over ¯] was performed. With the data collected in 2015, corresponding to 2.2×10^{19} protons on target, a single event sensitivity of (1.30±0.01_{stat}±0.14_{syst})×10^{-9} was achieved and no candidate events were observed. We set an upper limit of 3.0×10^{-9} for the branching fraction of K_{L}âπ^{0}νν[over ¯] at the 90% confidence level (C.L.), which improved the previous limit by almost an order of magnitude. An upper limit for K_{L}âπ^{0}X^{0} was also set as 2.4×10^{-9} at the 90% C.L., where X^{0} is an invisible boson with a mass of 135 MeV/c^{2}.