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This study investigated the long-term survival and incidence of secondary fractures after fragility hip fractures. The 5-year survival rate was 62%, and the mortality risk was seen in patients with GNRI < 92. The 5-year incidence of secondary fracture was 22%, which was significantly higher in patients with a BMI < 20. BACKGROUND: Malnutrition negatively influences the postoperative survival of patients with fragility hip fractures (FHFs); however, little is known about their association over the long term. OBJECTIVE: This study evaluated the ability of the geriatric nutritional risk index (GNRI) as a risk factor for long-term mortality after FHFs. METHODS: This study included 623 Japanese patients with FHFs over the age of 60 years. We prospectively collected data on admission and during hospitalization and assessed the patients' conditions after discharge through a questionnaire. We examined the long-term mortality and the incidence of secondary FHFs and assessed the prognostic factors. RESULTS: The mean observation period was 4.0 years (range 0-7 years). The average age at the time of admission was 82 years (range 60-101 years). The overall survival after FHFs (1 year, 91%; 5 years, 62%) and the incidence of secondary FHFs were high (1 year, 4%; 5 years, 22%). The multivariate Cox proportional hazard analysis revealed the risk factors for mortality as older age (hazard ratio [HR] 1.04), male sex (HR 1.96), lower GNRI score (HR 0.96), comorbidities (malignancy, HR 2.51; ischemic heart disease, HR 2.24; revised Hasegawa dementia scale ≤ 20, HR 1.64), no use of active vitamin D3 on admission (HR 0.46), and a lower Barthel index (BI) (on admission, HR 1.00; at discharge, HR 0.99). The GNRI scores were divided into four risk categories: major risk (GNRI, < 82), moderate risk (82-91), low risk (92-98), and no risk (> 98). Patients at major and moderate risks of GNRI had a significantly lower overall survival rate (p < 0.001). Lower body mass index (BMI) was also identified as a prognostic factor for secondary FHFs (HR 0.88 [p = 0.004]). CONCLUSIONS: We showed that older age, male sex, a lower GNRI score, comorbidities, and a lower BI are risk factors for mortality following FHFs. GNRI is a novel and simple predictor of long-term survival after FHFs.
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Fraturas do Quadril , Desnutrição , Humanos , Masculino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Avaliação Nutricional , Prognóstico , Desnutrição/complicações , Desnutrição/epidemiologia , Fraturas do Quadril/etiologia , Fatores de Risco , Avaliação Geriátrica , Estado Nutricional , Estudos RetrospectivosRESUMO
INTRODUCTION: Volunteering presupposes having free time and refers to the provision of services without the motivation of material reward, for the benefit of society. In this study, we aimed to provide insight into the impact of economic crisis on blood donors and their motivation to donate blood during that period. STUDY DESIGN AND METHODS: We asked blood donors about their blood donation activity and motivation to donate using a standardized, anonymous questionnaire (n = 3000). Descriptive analysis was performed for the consideration of donor turnout during this economic period. The results were analyzed using the χ2 test and Spearman's correlation coefficient. RESULTS: Regarding gender, 68.2% were males, while 31.8% were females. Most blood donors donated voluntarily (75.8%) and only 24.2% were replacement or family blood donors. The economic crisis has affected the inhabitants of Athens more than the inhabitants of the province (χ2 = 9.910,p = 0.007). The influence of economic crisis on the regular blood donors' quality of life was greater than the non-regular donors (χ2 = 16.227,p < 0.001). According to our results, the economic crisis reduced the quality of life, but it did not affect the frequency of blood donations in a percentage of 87,3%. Not any significant difference was found between employment status, economic crisis and blood donation. CONCLUSION: Although the economic crisis has affected the lives of blood donors, it does not seem to affect the frequency of blood donation. We suggest that blood collection services should consider specialist campaigns that focus on the altruistic motivation of donors during an economic crisis.
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Doadores de Sangue , Recessão Econômica , Masculino , Feminino , Humanos , Grécia , Qualidade de Vida , Altruísmo , Motivação , Inquéritos e QuestionáriosRESUMO
Psoriasis is characterized by excessive growth and aberrant differentiation of epidermal keratinocytes due to persistent inflammation. However, the underlying mechanism that triggers immune activation in psoriasis is not clear. In this study, we explored excessive DNA as a potential trigger of psoriasis using cultured human keratinocytes and psoriatic skin tissues. We demonstrated that human genomic DNA fragments induced tumour necrosis factor (TNF)-α expression, hyperproliferation and over-expression of heparin-binding epidermal-like growth factor (HB-EGF) and transforming growth factor (TGF)-α, accompanied by defective expression of keratins 1 and 10 in cultured normal human epidermal keratinocytes, which have a similar phenotype to that of keratinocytes in psoriatic skin lesions. In psoriatic lesions, we found high levels of double-stranded (ds)DNA fragments, accompanying keratinocytes expressing Ki-67, HB-EGF and TNF-α. In addition, we showed that 1,25-dihydroxyvitamin D3 inhibited genomic DNA fragment-induced TNFA and interleukin-1ß (IFNB) expression in human keratinocytes, and an intact function of cathelicidin anti-microbial peptide (CAMP) was required for this effect. These results suggest that excessive dsDNA fragments probably act as a risk factor for immune activation in psoriasis, and the active form of vitamin D can prevent genomic DNA-mediated skin inflammation via CAMP.
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Proliferação de Células , Fragmentação do DNA , DNA/metabolismo , Queratinócitos/metabolismo , Psoríase/metabolismo , Linhagem Celular , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/biossíntese , Humanos , Interleucina-1beta/biossíntese , Queratinócitos/patologia , Antígeno Ki-67/biossíntese , Psoríase/patologia , Fator de Crescimento Transformador alfa/biossíntese , Fator de Necrose Tumoral alfa/biossínteseRESUMO
AIMS: We investigated the potential cooperative effects of carotenoid-producing Bacillus aquimaris SH6 and nonpigmented Bacillus subtilis SH23 on white-leg shrimp growth and health. METHODS AND RESULTS: SH6, SH23 and a combination of both spores (1 × 106 CFU per g pellet) were administered in shrimp. The growth rate (2·36% day-1 ), red-colour score (25) and astaxanthin concentration (3·5 µg g-1 shrimp) were maximum in two-spore-administered shrimp. Immune-related Rho mRNA expression level and phenoloxidase and superoxidase dismutase activities were higher in two-spore-administered shrimp than in control shrimp, with Rho mRNA expression level being 55-fold higher in two-spore-administered shrimp than in SH6-administered shrimp and phenoloxidase activity being 1·2-fold higher in two-spore-administered shrimp than in SH23-administered shrimp. Although live SH6 count was 2·7-fold lower, SH6 germination level was 3·5-fold higher in the combination group than in SH6 group. CONCLUSIONS: When both SH6 and SH23 spores were administered, SH6 spore germination was enhanced and cooperative improvement was seen in growth, astaxanthin level and red-colour score of white-leg shrimp; however, immune-related parameters were induced in a noncooperative manner. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report showing the cooperative probiotic activities of Bacillus strains and their possible mechanisms in a shrimp model.
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Bacillus/fisiologia , Microbioma Gastrointestinal , Penaeidae/química , Penaeidae/crescimento & desenvolvimento , Probióticos , Animais , Bacillus/metabolismo , Carotenoides/metabolismo , Penaeidae/microbiologia , Pigmentação , Frutos do Mar/análise , Frutos do Mar/microbiologia , Esporos Bacterianos/metabolismo , Esporos Bacterianos/fisiologia , Xantofilas/análiseRESUMO
BACKGROUND: Despite universal administration of erythropoiesis-stimulating agents, patients with end-stage renal disease (ESRD) are at high risk for presenting persistent anemia. Due to ambiguities in optimal hemoglobin targets and evidence of recombinant human erythropoietin (EPO)-related toxicity, an increase in blood transfusions has been observed in chronic renal disease over the past years. The probable effects of uremic plasma on the performance of stored red blood cells (RBCs) after transfusion have not been investigated. STUDY DESIGN AND METHODS: Leukoreduced RBCs after short or long storage in CPD-SAGM (n = 5) were assessed for hemolysis, surface removal signaling, reactive oxygen species (ROS) accumulation, and shape distortions before and after reconstitution with healthy (n = 10) or uremic plasma from ESRD patients (n = 20) for 24 hours at physiologic temperature, by using a previously reported in vitro model of transfusion. RESULTS: Temperature and cell environment shifts from blood bag to plasma independently and in synergy affected the RBC physiology. Outcome measures at transfusion-simulating conditions might not be analogous to timing of storage lesion. The uremic plasma ameliorated the susceptibility of stored RBCs to hemolysis, phosphatidylserine externalization, and ROS generation after stimulation by oxidants, but negatively affected shape homeostasis versus healthy plasma. Creatinine, uric acid, and EPO levels had correlations with the performance of stored RBCs in ESRD plasma. CONCLUSION: Renal insufficiency and EPO supplementation likely affect the recovery of donor RBCs and the reactivity of RBCs after transfusion by exerting both toxic and cytoprotective influences on them. ESRD patients constitute a specific recipient group that deserves further examination.
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Transfusão de Eritrócitos/normas , Eritrócitos/fisiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Transplantados , Uremia/sangue , Preservação de Sangue , Forma Celular , Eritrócitos/citologia , Hemólise/fisiologia , Humanos , Técnicas In Vitro , Falência Renal Crônica/complicações , Espécies Reativas de Oxigênio/metabolismo , Diálise Renal , Resultado do Tratamento , Uremia/etiologiaRESUMO
Concentration of essential (Se, Zn and Cu) and non-essential (As, Cd, Hg and Pb) trace elements were measured in selected tissues of two dead whale sharks (Rhincodon typus) stranded in the Gulf of California (GC) in 2017 and 2018. Concentrations of Cd and Pb in the skeletal muscle of the whale shark from La Paz Bay, GC were higher compared to a previous study on whale shark from China. The shark from La Paz Bay also presented higher concentration of Pb in the epidermis, compared to the same tissue of the other whale shark stranded in Punta Bufeo, GC. The Hg in all analysed tissues was lower than those documented in carnivorous sharks. Molar ratio Se:Hg shows an excess of Se over Hg in all the tissues sampled in both sharks.
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Monitoramento Ambiental/métodos , Epiderme/química , Metais Pesados/análise , Músculo Esquelético/química , Tubarões/metabolismo , Oligoelementos/análise , Poluentes Químicos da Água/análise , Animais , Baías/química , México , Oceano PacíficoRESUMO
We report the first observation of the hadronic transition Ï(4S)âη^{'}Ï(1S), using 496 fb^{-1} data collected at the Ï(4S) resonance with the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We reconstruct the η^{'} meson through its decays to ρ^{0}γ and to π^{+}π^{-}η, with ηâγγ. We measure B(Ï(4S)âη^{'}Ï(1S))=[3.43±0.88(stat)±0.21(syst)]×10^{-5}, with a significance of 5.7σ.
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The OPERA experiment was designed to study ν_{µ}âν_{τ} oscillations in the appearance mode in the CERN to Gran Sasso Neutrino beam (CNGS). In this Letter, we report the final analysis of the full data sample collected between 2008 and 2012, corresponding to 17.97×10^{19} protons on target. Selection criteria looser than in previous analyses have produced ten ν_{τ} candidate events, thus reducing the statistical uncertainty in the measurement of the oscillation parameters and of ν_{τ} properties. A multivariate approach for event identification has been applied to the candidate events and the discovery of ν_{τ} appearance is confirmed with an improved significance level of 6.1σ. |Δm_{32}^{2}| has been measured, in appearance mode, with an accuracy of 20%. The measurement of the ν_{τ} charged-current cross section, for the first time with a negligible contamination from ν[over ¯]_{τ}, and the first direct evidence for the ν_{τ} lepton number are also reported.
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BACKGROUND: Previous investigations in leukoreduced units of red blood cells (RBCs) in mannitol additive solution revealed the close association of uric acid (UA) levels in vivo with the susceptibility of RBCs to storage lesion markers. In this study, we examined whether UA has a similar correlation with the capability of RBCs to cope with the oxidative provocations of storage under different conditions, namely, in CPDA-1 and in the absence of leukoreduction. STUDY DESIGN AND METHODS: The UA-dependent antioxidant capacity of the supernatant was measured in nonleukoreduced units of RBCs in CPDA (n = 47). The possible effect of UA variability on the storage lesion profile was assessed by monitoring several physiologic properties of RBCs and supernatant, including cell shape, reactive oxygen species, and size distribution of extracellular vesicles, in units exhibiting the lowest or highest levels of UA activity (n = 16) among donors, throughout the storage period. RESULTS: In stored RBC units, the UA-dependent antioxidant activity of the supernatant declined as a function of storage duration but always in strong relation to the UA levels in fresh blood. Contrary to units of poor-UA activity, RBCs with the highest levels of UA activity exhibited better profile of calcium- and oxidative stress-driven modifications, including a significant decrease in the percentages of spherocytes and of 100- to 300-nm-sized vesicles, typically associated with the exovesiculation of stored RBCs. CONCLUSION: The antioxidant activity of UA is associated with donor-specific differences in the performance of RBCs under storage in nonleukoreduced CPDA units.
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Doadores de Sangue , Preservação de Sangue/métodos , Eritrócitos/citologia , Ácido Úrico/sangue , Adenina/farmacologia , Adolescente , Adulto , Antioxidantes/análise , Biomarcadores , Cálcio/sangue , Citratos/farmacologia , Difusão Dinâmica da Luz , Eritrócitos/efeitos dos fármacos , Eritrócitos Anormais/ultraestrutura , Vesículas Extracelulares/ultraestrutura , Glucose/farmacologia , Hemólise , Humanos , Masculino , Manitol/farmacologia , Estresse Oxidativo , Fosfatos/farmacologia , Espécies Reativas de Oxigênio , Adulto JovemRESUMO
Detailed information on the nutrition of free-ranging mammals contributes to the understanding of life history requirements, yet is often quite limited temporally for most species. Reliable dietary inferences can be made by analyzing the stable carbon (C) and nitrogen (N) isotopic values (δ13C and δ15N) of some consumer tissues; exactly which tissue is utilized dictates the inferential scope. Steller sea lion (SSL) vibrissae are grown continuously without shedding and thus provide a continuous multi-year record of dietary consumption. We applied a novel kernel density approach to compare the δ13C and δ15N values along the length of SSL vibrissae with δ13C and δ15N distributions of potential prey species. This resulted in time-series of proportion estimates of dietary consumption for individual SSL. Substantial overlap in δ13C and δ15N distributions for prey species prevented a discrete species-scale assessment of SSL diets; however, a post hoc correlational analysis of diet proportion estimates revealed grouping by trophic level. Our findings suggest that adult female SSL diets in the western and central Aleutian Islands shift significantly according to season: diets contain a higher proportion of lower trophic level species (Pacific Ocean perch, northern rockfish, Atka mackerel and walleye pollock) in the summer, whereas in the winter SSL consume a much more diverse diet which includes a greater proportion of higher trophic level species (arrowtooth flounder, Kamchatka flounder, darkfin sculpin, Pacific cod, Pacific octopus, rock sole, snailfish, and yellow Irish lord).
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Perciformes , Leões-Marinhos , Alaska , Animais , Dieta , Feminino , VibrissasRESUMO
Hemodiafiltration (HDF) is a renal replacement therapy that is based on the principles of diffusion and convection for the elimination of uremic toxins. A significant and increasing number of end-stage renal disease (ESRD) patients are treated with HDF, even in the absence of definite and conclusive survival and anemia treatment data. However, its effects on red blood cell (RBC) physiological features have not been examined in depth. In this study, ESRD patients under regular HDF or conventional hemodialysis (cHD) treatment were examined for RBC-related parameters, including anemia, hemolysis, cell shape, redox status, removal signaling, membrane protein composition, and microvesiculation, in repeated paired measurements accomplished before and right after each dialysis session. The HDF group was characterized by better redox potential and suppressed exovesiculation of blood cells compared with the cHD group pre-dialysis. However, HDF was associated with a temporary but acute, oxidative-stress-driven increase in hemolysis, RBC removal signaling, and stomatocytosis, probably associated with the effective clearance of dialyzable natural antioxidant components, including uric acid, from the uremic plasma. The nature of these adverse short-term effects of HDF on post-dialysis plasma and RBCs strongly suggests the use of a parallel antioxidant therapy during the HDF session.
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Eritrócitos/patologia , Hemodiafiltração/métodos , Idoso , Anemia/complicações , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9)-/- and myeloid differentiation primary response gene 88 (MyD88)-/- mice. We also performed in-vitro studies with vascular and monocytic cells and vascular tissues. A histopathological analysis showed that both cyclosporin A and tacrolimus exacerbated the NOD1-mediated coronary arteritis in a dose-dependent manner. Cyclosporin A induced the exacerbation of coronary arteritis in mice only in high doses, while tacrolimus exacerbated it within the therapeutic range in humans. Similar effects were obtained in SCID and CARD9-/- mice but not in MyD88-/- mice. CNIs enhanced the expression of adhesion molecules by endothelial cells and the cytokine secretion by monocytic cells in our KD model. These data indicated that both vascular and monocytic cells were involved in the exacerbation of coronary arteritis. Activation of MyD88-dependent inflammatory signals in both vascular cells and macrophages appears to contribute to their adverse effects. Particular attention should be paid to the development of coronary artery lesions when using CNIs to treat refractory KD.
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Arterite/tratamento farmacológico , Inibidores de Calcineurina/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/metabolismo , Oligopeptídeos/uso terapêutico , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Vasos Coronários/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Fator 88 de Diferenciação Mieloide/genética , Células RAW 264.7 , Transdução de SinaisRESUMO
OBJECTIVE: Modified, bioreactive red blood cells (RBCs) and RBC-derived microvesicles (MVs) likely contribute to the hematological and cardiovascular complications in end-stage renal disease (ESRD). This study assesses the physiological profile of RBCs in patients with ESRD receiving standard or high doses of recombinant human erythropoietin (rhEPO). METHOD: Blood samples from twenty-eight patients under sustained hemodialysis, responsive, or not to standard rhEPO administration were examined for RBC morphology, fragility, hemolysis, redox status, removal signaling, membrane protein composition, and microvesiculation before and after dialysis. Acute effects of uremic plasma on RBC features were examined in vitro through reconstitution experiments. RESULTS: Overall, the ESRD RBCs were characterized by pathological levels of shape distortions, surface removal signaling, and membrane exovesiculation, but reduced fragility compared to healthy RBCs. Irreversible transformation of RBCs was found to be a function of baseline Hb concentration. The more toxic uremic context in non-responsive patients compared to rhEPO responders was blunted in part by the antioxidant, antihemolytic, and anti-apoptotic effects of high rhEPO doses, and probably, of serum uric acid. A selective lower expression of RBC membrane in complement regulators (CD59, clusterin) and of CD47 "marker-of-self" was detected in non-responders and responders, respectively. Evidence for different short-term dialysis effects and probably for a different erythrocyte vesiculation mechanism in rhEPO responsive compared to non-responsive patients was also revealed. CONCLUSION: Deregulation of RBC homeostasis might involve diverse molecular pathways driving erythrocyte signaling and removal in rhEPO non-responders compared to responsive patients.
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Eritrócitos/efeitos dos fármacos , Eritropoetina/uso terapêutico , Falência Renal Crônica/terapia , Proteínas Recombinantes/uso terapêutico , Diálise Renal , Idoso , Idoso de 80 Anos ou mais , Antígeno CD47/sangue , Antígeno CD47/genética , Antígenos CD59/sangue , Antígenos CD59/genética , Estudos de Casos e Controles , Forma Celular/efeitos dos fármacos , Clusterina/sangue , Clusterina/genética , Contagem de Eritrócitos , Eritrócitos/metabolismo , Eritrócitos/patologia , Vesículas Extracelulares/efeitos dos fármacos , Feminino , Expressão Gênica , Hemoglobinas/metabolismo , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/patologia , Masculino , Fragilidade Osmótica/efeitos dos fármacos , Resultado do Tratamento , Ácido Úrico/sangueRESUMO
Although 3-field lymph node dissection (3-FLD) is often performed for thoracic esophageal squamous cell carcinoma (ESCC), the clinical effects of cervical lymph node dissection in addition to mediastinal and abdominal dissections on postoperative complications remain unclear. A total of 367 ESCC patients who underwent curative esophagectomy for thoracic esophageal cancer in our hospital from 2010 to 2015 were included in the study: 157 patients who underwent 2-field lymph node dissection (2-FLD) and 210 patients who underwent 3-FLD. Clinicopathological parameters and postoperative complications based on the Clavien-Dindo classification were compared between the two groups. We performed propensity score matching (PSM) analyses to compare the groups with well-balanced backgrounds. In terms of patient background, clinical T (p < 0.001), N (p < 0.001), and M (p = 0.002) stage of tumor was significantly more advanced; therefore, preoperative treatment was more frequently performed in the 3-FLD group than in the 2-FLD group (91.0% vs. 79.0%, P< 0.001). However, perioperative parameters including operation time, blood loss, and the number of dissected mediastinal and abdominal lymph nodes did not differ between the groups. In terms of postoperative complications, the occurrence rate of pneumonia increased significantly in patients with 3-FLD compared to 2-FLD (grade III or higher: 10.5% vs. 3.2%, P= 0.025). Although the duration of systemic inflammatory response syndrome (SIRS) was longer in the 3-FLD group than in the 2-FLD group (median 3 days vs. 2 days, P= 0.025), other postoperative parameters (including the highest level of postoperative serum C-reactive protein, intensive care unit stay, re-operation rate, and postoperative hospital stay) were similar between the groups. After PSM, the differences in the background between the groups disappeared. PSM analysis showed that there was no significant difference in each complication between the groups. The duration of SIRS tended to be longer in the 3-FLD group than in the 2-FLD group, but the difference was not significant. The field of lymphadenectomy negatively impacted the short-term outcome in ESCC patients in terms of pneumonia and inflammatory response. However, because the results of the PSM analyses indicate that the short-term outcome was similar between the two groups, 3-FLD could be as feasible as 2-FLD in ESCC patients.
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Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Complicações Pós-Operatórias/etiologia , Abdome , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Tempo de Internação , Linfonodos/patologia , Masculino , Mediastino , Pessoa de Meia-Idade , Pescoço , Duração da Cirurgia , Pneumonia/etiologia , Período Pós-Operatório , Pontuação de Propensão , Estudos Prospectivos , Estudos Retrospectivos , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
X-linked agammaglobulinemia (XLA) is one of the most common humoral immunodeficiencies, which is caused by mutations in Bruton's tyrosine kinase (BTK) gene. To examine the possibility of using gene therapy for XLA, we constructed a helper-dependent adenovirus/adeno-associated virus BTK targeting vector (HD-Ad.AAV BTK vector) composed of a genomic sequence containing BTK exons 6-19 and a green fluorescence protein-hygromycin cassette driven by a cytomegalovirus promoter. We first used NALM-6, a human male pre-B acute lymphoblastic leukemia cell line, as a recipient to measure the efficiency of gene targeting by homologous recombination. We identified 10 clones with the homologous recombination of the BTK gene among 107 hygromycin-resistant stable clones isolated from two independent experiments. We next used cord blood CD34⺠cells as the recipient cells for the gene targeting. We isolated colonies grown in medium containing cytokines and hygromycin. We found that the targeting of the BTK gene occurred in four of the 755 hygromycin-resistant colonies. Importantly, the gene targeting was also observed in CD19⺠lymphoid progenitor cells that were differentiated from the homologous recombinant CD34⺠cells during growth in selection media. Our study shows the potential for the BTK gene therapy using the HD-Ad.AAV BTK vector via homologous recombination in hematopoietic stem cells.
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Dependovirus/genética , Marcação de Genes , Vetores Genéticos/genética , Vírus Auxiliares/genética , Recombinação Homóloga , Proteínas Tirosina Quinases/genética , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/genética , Agamaglobulinemia/terapia , Linhagem Celular Tumoral , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Terapia Genética , Humanos , Masculino , MutaçãoRESUMO
Kawasaki disease (KD) is an acute systemic vasculitis of childhood that does not have a known cause or aetiology. The epidemiological features (existence of epidemics, community outbreaks and seasonality), unique age distribution and clinical symptoms and signs of KD suggest that the disease is caused by one or more infectious environmental triggers. However, KD is not transmitted person-to-person and does not occur in clusters within households, schools or nurseries. KD is a self-limited illness that is not associated with the production of autoantibodies or the deposition of immune complexes, and it rarely recurs. Regarding the underlying pathophysiology of KD, innate immune activity (the inflammasome) is believed to play a role in the development of KD vasculitis, based on the results of studies with animal models and the clinical and laboratory findings of KD patients. Animal studies have demonstrated that innate immune pathogen-associated molecular patterns (PAMPs) can cause vasculitis independently of acquired immunity and have provided valuable insights regarding the underlying mechanisms of this phenomenon. To validate this concept, we recently searched for KD-specific PAMPs and identified such molecules with high specificity and sensitivity. These molecules have structures similar to those of microbe-associated molecular patterns (MAMPs), as shown by liquid chromatography-tandem mass spectrometry. We propose herein that KD is an innate immune disorder resulting from the exposure of a genetically predisposed individual to microbe-derived innate immune stimulants and that it is not a typical infectious disease.
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Síndrome de Linfonodos Mucocutâneos/etiologia , Animais , Meio Ambiente , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Imunidade Inata , Síndrome de Linfonodos Mucocutâneos/metabolismoRESUMO
We measure the decay B_{s}^{0}âK^{0}K[over ¯]^{0} using data collected at the Ï(5S) resonance with the Belle detector at the KEKB e^{+}e^{-} collider. The data sample used corresponds to an integrated luminosity of 121.4 fb^{-1}. We measure a branching fraction B(B_{s}^{0}âK^{0}K[over ¯]^{0})=[19.6_{-5.1}^{+5.8}(stat)±1.0(syst)±2.0(N_{B_{s}^{0}B[over ¯]_{s}^{0}})]×10^{-6} with a significance of 5.1 standard deviations. This measurement constitutes the first observation of this decay.
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We report the analysis of the three-body e^{+}e^{-}âBB[over ¯]π^{±}, BB[over ¯]^{*}π^{±}, and B^{*}B[over ¯]^{*}π^{±} processes, including the first observations of the Z_{b}^{±}(10610)â[BB[over ¯]^{*}+c.c.]^{±} and Z_{b}^{±}(10650)â[B^{*}B[over ¯]^{*}]^{±} transitions that are found to dominate the corresponding final states. We measure Born cross sections for the three-body production of σ(e^{+}e^{-}â[BB[over ¯]^{*}+c.c.]^{±}π^{∓})=[17.4±1.6(stat)±1.9(syst)] pb and σ(e^{+}e^{-}â[B^{*}B[over ¯]^{*}]^{±}π^{∓})=[8.75±1.15(stat)±1.04(syst)] pb and set a 90% C.L. upper limit of σ(e^{+}e^{-}â[BB[over ¯]]^{±}π^{∓})<2.9 pb. The results are based on a 121.4 fb^{-1} data sample collected with the Belle detector at a center-of-mass energy near the Ï(10860) peak.
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Using data collected with the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider, we measure the energy dependence of the e^{+}e^{-}âh_{b}(nP)π^{+}π^{-} (n=1, 2) cross sections from thresholds up to 11.02 GeV. We find clear Ï(10860) and Ï(11020) peaks with little or no continuum contribution. We study the resonant substructure of the Ï(11020)âh_{b}(nP)π^{+}π^{-} transitions and find evidence that they proceed entirely via the intermediate isovector states Z_{b}(10610) and Z_{b}(10650). The relative fraction of these states is loosely constrained by the current data: The hypothesis that only Z_{b}(10610) is produced is excluded at the level of 3.3 standard deviations, while the hypothesis that only Z_{b}(10650) is produced is not excluded at a significant level.
RESUMO
BACKGROUND: Previous studies have shown that baseline hematologic characteristics concerning or influencing red blood cell (RBC) properties might affect storage lesion development in individual donors. This study was conducted to evaluate whether variation in hemolysis, microparticle accumulation, phosphatidylserine (PS) exposure, and other storage lesion-associated variables might be a function of the prestorage hematologic and biologic profiles of the donor. STUDY DESIGN AND METHODS: Ten eligible, regular blood donors were paired and studied before donation (fresh blood) and during storage of RBCs in standard blood banking conditions. Plasma and cellular characteristics and modifications were evaluated by standard laboratory and biochemical or biologic analyses as well as by statistical and network analysis tools. RESULTS: Nitrate/nitrite and other bioactive factors exhibited high interdonor variability, which further increased during storage in a donor-specific manner. Storage lesion evaluators, including RBC fragility and PS exposure, fluctuated throughout the storage period in proportion to their values in fresh blood. Donors' levels of phosphatidylserine exposure and hemoglobin F correlated with stored cells' mean cell (RBC) Hb concentration, oxidative stress markers, and cellular fragility. DISCUSSION: Storage lesion indicators change in an orderly fashion, namely, by following donor-related prestorage attributes. These correlations are illustrated for the first time in "prestorage versus storage" biologic networks, which might help determine the best candidates for in vivo biomarkers of storage quality and provide deeper insight into the apparently complex donor variation effect on the RBC storage lesion.