RESUMO
Many neurodegenerative diseases are characterized by the accumulation of insoluble protein aggregates, including neurofibrillary tangles comprised of tau in Alzheimer's disease and Lewy bodies composed of α-synuclein in Parkinson's disease. Moreover, different pathological proteins frequently codeposit in disease brains. To test whether aggregated α-synuclein can directly cross-seed tau fibrillization, we administered preformed α-synuclein fibrils assembled from recombinant protein to primary neurons and transgenic mice. Remarkably, we discovered two distinct strains of synthetic α-synuclein fibrils that demonstrated striking differences in the efficiency of cross-seeding tau aggregation, both in neuron cultures and in vivo. Proteinase K digestion revealed conformational differences between the two synthetic α-synuclein strains and also between sarkosyl-insoluble α-synuclein extracted from two subgroups of Parkinson's disease brains. We speculate that distinct strains of pathological α-synuclein likely exist in neurodegenerative disease brains and may underlie the tremendous heterogeneity of synucleinopathies.
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Neurônios/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Amiloide/química , Amiloide/metabolismo , Animais , Células Cultivadas , Embrião de Mamíferos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Doença de Parkinson/metabolismo , Proteínas Recombinantes/metabolismo , alfa-Sinucleína/químicaRESUMO
Adoptive cell therapy (ACT), especially with CD4+ regulatory T cells (CD4+ Tregs), is an emerging therapeutic strategy to minimize immunosuppression and promote long-term allograft acceptance, although much research remains to realize its potential. In this study, we investigated the potency of novel Ab-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp) in comparison with conventional CD25highFoxp3+CD4+ Tregs for suppression of humoral alloimmunity in a murine kidney transplant (KTx) model of Ab-mediated rejection (AMR). We examined quantity of peripheral blood, splenic and graft-infiltrating CD8+ TAb-supp, and CD4+ Tregs in KTx recipients and found that high alloantibody-producing CCR5 knockout KTx recipients have significantly fewer post-transplant peripheral blood and splenic CD8+ TAb-supp, as well as fewer splenic and graft-infiltrating CD4+ Tregs compared with wild-type KTx recipients. ACT with alloprimed CXCR5+CD8+ T cells reduced alloantibody titer, splenic alloprimed germinal center (GC) B cell quantity, and improved AMR histology in CCR5 knockout KTx recipients. ACT with alloprimed CD4+ Treg cells improved AMR histology without significantly inhibiting alloantibody production or the quantity of splenic alloprimed GC B cells. Studies with TCR transgenic mice confirmed Ag specificity of CD8+ TAb-supp-mediated effector function. In wild-type recipients, CD8 depletion significantly increased alloantibody titer, GC B cells, and severity of AMR pathology compared with isotype-treated controls. Anti-CD25 mAb treatment also resulted in increased but less pronounced effect on alloantibody titer, quantity of GC B cells, and AMR pathology than CD8 depletion. To our knowledge, this is the first report that CD8+ TAb-supp cells are more potent regulators of humoral alloimmunity than CD4+ Treg cells.
Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Transplante de Rim , Linfócitos T Reguladores , Animais , Camundongos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Rejeição de Enxerto/imunologia , Isoanticorpos , Transplante de Rim/efeitos adversos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores CXCR5/imunologia , Imunidade Humoral/imunologiaRESUMO
CD8+ T cells have conventionally been studied in relationship to pathogen or tumor clearance. Recent reports have identified novel functions of CXCR5+CD8+ T cells that can home to lymphoid follicles, a key site of antibody production. In this review we provide an in-depth analysis of conflicting reports regarding the impact of CXCR5+CD8+ T cells on antibody production and examine the data supporting a role for antibody-enhancement (B cell "helper") and antibody-downregulation (antibody-suppressor) by CXCR5+CD8+ T cell subsets. CXCR5+CD8+ T cell molecular phenotypes are associated with CD8-mediated effector functions including distinct subsets that regulate antibody responses. Co-inhibitory molecule PD-1, among others, distinguish CXCR5+CD8+ T cell subsets. We also provide the first in-depth review of human CXCR5+CD8+ T cells in the context of clinical outcomes and discuss the potential utility of monitoring the quantity of peripheral blood or tissue infiltrating CXCR5+CD8+ T cells as a prognostic tool in multiple disease states.
Assuntos
Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Anticorpos/metabolismo , Formação de Anticorpos , Humanos , Imunomodulação , Ativação Linfocitária , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismoRESUMO
INTRODUCTION: Complement C5 inhibitor eculizumab is the first approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder caused by uncontrolled terminal complement activation. Approximately 50% of patients with aplastic anemia (AA) have PNH cells. Limited data are available for patients with AA-PNH taking concomitant immunosuppressive therapy (IST) and eculizumab. METHODS: Data from the International PNH Registry (NCT01374360) were used to evaluate the safety and effectiveness of eculizumab and IST in patients taking IST followed by concomitant eculizumab (IST + c-Ecu) or eculizumab followed by concomitant IST (Ecu + c-IST). RESULTS: As of January 1, 2018, 181 Registry-enrolled patients were included in the eculizumab effectiveness analyses (n = 138, IST + c-Ecu; n = 43, Ecu + c-IST); 87 additional patients received IST alone. Reductions from baseline with eculizumab were observed in the least squares mean lactate dehydrogenase ratio (IST + c-Ecu, -3.4; Ecu + c-IST, -3.5); thrombotic event incidence rates were similar between groups (IST + c-Ecu, 1.3; Ecu + c-IST, 0.7). Red blood cell transfusion rate ratios decreased from baseline for IST + c-Ecu (0.7) and increased for Ecu + c-IST (1.2); there were none for IST alone. Hematological parameters generally improved for IST + c-Ecu and IST alone, and changed minimally or worsened for Ecu + c-IST. Safety signals were generally consistent with those previously described for the respective therapies. DISCUSSION/CONCLUSION: Although some intergroup differences were seen, concomitant eculizumab and IST were safe and effective regardless of treatment sequence.
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Anemia Aplástica , Hemoglobinúria Paroxística , Humanos , Anemia Aplástica/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Terapia de Imunossupressão , Sistema de RegistrosRESUMO
We use single-molecule techniques to characterize the dynamics of prokaryotic DNA repair by non-homologous end-joining (NHEJ), a system comprised only of the dimeric Ku and Ligase D (LigD). The Ku homodimer alone forms a â¼2 s synapsis between blunt DNA ends that is increased to â¼18 s upon addition of LigD, in a manner dependent on the C-terminal arms of Ku. The synapsis lifetime increases drastically for 4 nt complementary DNA overhangs, independently of the C-terminal arms of Ku. These observations are in contrast to human Ku, which is unable to bridge either of the two DNA substrates. We also demonstrate that bacterial Ku binds the DNA ends in a cooperative manner for synapsis initiation and remains stably bound at DNA junctions for several hours after ligation is completed, indicating that a system for removal of the proteins is active in vivo. Together these experiments shed light on the dynamics of bacterial NHEJ in DNA end recognition and processing. We speculate on the evolutionary similarities between bacterial and eukaryotic NHEJ and discuss how an increased understanding of bacterial NHEJ can open the door for future antibiotic therapies targeting this mechanism.
Assuntos
Proteínas de Bactérias/metabolismo , Reparo do DNA por Junção de Extremidades , Autoantígeno Ku/metabolismo , Bacillus subtilis/genética , Proteínas de Bactérias/química , DNA/metabolismo , DNA Ligases/metabolismo , Autoantígeno Ku/química , Multimerização ProteicaRESUMO
Objective: To investigate the clinical characteristics of patients with acquired aplastic anemia (AA) accompanied by abnormal antinuclear antibody (ANA) and autoantibodies and their effects on the efficacy of immunosuppressive therapy (IST). Method: A retrospective case-control study was conducted, analyzing the clinical data of 291 patients with AA who underwent IST and were screened for autoantibodies at initial diagnosis between January 2018 and December 2019 at Blood Diseases Hospital, Chinese Academy of Medical Sciences. According to the titer of ANA at the initial diagnosis, extracted nuclear antigen antibodies (ENAs) abnormality and the change of ANA titer after treatment, the treatment responses of 3 months and 6 months after IST were compared. The correlation between clinical features and ANA abnormality was analyzed by univariate and multivariate logistic regression analysis. The parameters of univariate analysis P<0.1 were included in multivariate analysis, stepwise regression analysis and subgroup analysis. Results: A total of 291 patients were included in the study, of which 145 (49.83%) were male. Among all patients, 147 (50.52%) tested positive for ANA at initial diagnosis, with titers of 1â¶100, 1â¶320, and 1â¶1 000 observed in 94, 47, and 6 cases, respectively. Female gender, older age, presence of paroxysmal nocturnal hemoglobinuria (PNH) clone, and higher levels of IgG, IgA, and thyroid hormone were significantly associated with ANA positivity at initial diagnosis, while white cell counts, reticulocytes, and free triiodothyronine were significantly lower than that of ANA-negatively patients (all P<0.05). Furthermore, logistic regression analyses revealed that female gender (OR=1.980, 95%CI 1.206-3.277), older age (OR=1.017, 95%CI 1.003-1.032), and presence of PNH clone (OR=1.875, 95%CI 1.049-3.408) were independent risk factors for ANA positivity at initial diagnosis. Subgroup analysis indicated that the risk of ANA positivity at initial diagnosis was even higher in PNH clone-positive patients in the subgroups of females (OR=1.24, 95%CI 1.02-1.51), severe AA (OR=1.26, 95%CI 1.07-1.47), and age≥40 years (OR=1.26, 95%CI 1.05-1.52) (all P<0.05). However, ANA titers at initial diagnosis, presence of other abnormal ENAs, and changes in ANA titers after treatment with IST were not correlated with treatment response (all P>0.05). Conclusions: Approximately 50% of patients with AA had abnormal ANA, and their presence was significantly associated with female gender, older age, and presence of PNH clone at initial diagnosis. However, the presence of abnormal ANA and changes in ANA titers after treatment did not affect the efficacy of IST in patients with AA.
Assuntos
Anemia Aplástica , Autoanticorpos , Humanos , Feminino , Masculino , Adulto , Anemia Aplástica/tratamento farmacológico , Estudos de Casos e Controles , Estudos Retrospectivos , Terapia de ImunossupressãoRESUMO
CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H-2b ) were transplanted with A/J kidneys (H-2a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5+ CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5+ CD8+ T cells and CD8-mediated cytotoxicity to alloprimed IgG+ B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5+ CD8+ T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG+ B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5+ CD8+ T cells (but not alloprimed CXCR5- CD8+ or third-party primed CXCR5+ CD8+ T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5+ CD8+ T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT.
Assuntos
Transplante de Rim , Animais , Linfócitos T CD8-Positivos , Rejeição de Enxerto/patologia , Imunoglobulina G , Isoanticorpos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
BACKGROUND: The effects of eculizumab treatment in paroxysmal nocturnal hemoglobinuria (PNH) patients with or without high-disease activity (HDA), defined by LDH ≥ 1.5 × ULN and history of major adverse vascular events (MAVEs; including thrombotic events [TEs]); anemia; and/or physician-reported abdominal pain, dyspnea, dysphagia, erectile dysfunction, fatigue, and/or hemoglobinuria, in the International PNH Registry were evaluated. METHODS: Registry patients were stratified by baseline HDA and eculizumab-treatment status. Longitudinal changes in laboratory and clinical PNH-related endpoints were evaluated using linear mixed models (continuous variables) or Poisson regression (incidence rates). RESULTS: As of May 1, 2017, 3009 patients (HDA/eculizumab-treated, n = 913; HDA/never-treated, n = 651; no-HDA/eculizumab-treated, n = 173; no-HDA/never-treated, n = 1272) were analyzed. Higher proportions of eculizumab-treated patients had HDA and history of MAVEs. In patients with and without HDA, respectively, eculizumab treatment resulted in reductions from baseline for (1) LDH ratio (mean [SD]: -5.3 [4.0] and -2.3 [3.8]); (2) incidence rate ratio (IRR) for MAVEs (-80% and -70%); (3) IRR for TEs (-80% for both); and (4) units of red blood cell transfusions per year (from 6.8 to 2.8 and 3.6 to 2.5 units). CONCLUSIONS: Eculizumab treatment in a real-world setting improved outcomes, including substantial decreases in hemolysis, MAVE rates, TEs, and transfusions in PNH patients regardless of HDA.
Assuntos
Hemoglobinúria Paroxística , Anticorpos Monoclonais Humanizados/efeitos adversos , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos , Masculino , Sistema de RegistrosRESUMO
Mechanistic studies in DNA repair have focused on roles of multi-protein DNA complexes, so how long non-coding RNAs (lncRNAs) regulate DNA repair is less well understood. Yet, lncRNA LINP1 is over-expressed in multiple cancers and confers resistance to ionizing radiation and chemotherapeutic drugs. Here, we unveil structural and mechanistic insights into LINP1's ability to facilitate non-homologous end joining (NHEJ). We characterized LINP1 structure and flexibility and analyzed interactions with the NHEJ factor Ku70/Ku80 (Ku) and Ku complexes that direct NHEJ. LINP1 self-assembles into phase-separated condensates via RNA-RNA interactions that reorganize to form filamentous Ku-containing aggregates. Structured motifs in LINP1 bind Ku, promoting Ku multimerization and stabilization of the initial synaptic event for NHEJ. Significantly, LINP1 acts as an effective proxy for PAXX. Collective results reveal how lncRNA effectively replaces a DNA repair protein for efficient NHEJ with implications for development of resistance to cancer therapy.
Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Autoantígeno Ku/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HeLa , Humanos , Ligação Proteica , Multimerização ProteicaRESUMO
Respiratory pandemics, such as COVID19, may be transmitted by several modes. The present work focuses on the transmission through small droplets released by people from their mouth by breathing, speaking, coughing, sneering, and possibly aspirated by other people around through their respiration. An analysis of droplet evolution in simplified situations shows that the droplets reach very quickly a quasi-equilibrium temperature before encompassing an isothermal evaporation process. The removal of droplets from suspension is thus piloted by balance between evaporation and sedimentation. It is shown that ambient relative humidity is a major factor influencing the lifetime of droplets and the distance they may travel. As a consequence, and independently of any other health consideration linked to ambient humidity, it is seen that a dry air is a favourable factor for limiting risk of contamination from COVID19. Further investigation is made using computational fluid dynamics (CFD) in a classroom geometry. Several ventilation strategies are investigated: classical regulatory mechanical ventilation, open window natural ventilation and displacement natural ventilation. Ventilation has several effects which influence contamination risk: by introducing fresh air, it reduces droplet concentration; humidity released by human occupants is also limited. However, these effects are not uniform in space, and depend on ventilation strategy. Application of a dose-effect model calibrated for COVID19 to CFD results allows to estimate contamination risk. It is shown that contamination risk is higher for regulatory mechanical ventilation, and may be reduced, using natural ventilation in the absence of wind, by a factor 2.3 to nearly 3 when the teacher is sick, and by a factor 6 to 500 when a student is sick. In the presence of wind, the reduction factor is as high as 13 when the teacher is sick and 17 when a student is sick.
RESUMO
To study the clinical features of myeloperoxidase(MPO) antineutrophil cytoplasmic antibody (ANCA) associated hypertrophic pachymeningitis (HP). Clinical data of 15 cases diagnosed with MPO-ANCA vasculitis complicated with HP were retrospectively analyzed. Nine cases were males and the other 6 were females, with an average age of (58±8) years. All cases presented with chronic headache. Contrast-enhanced magnetic resonance imaging (MRI) scan showed local or diffused thickening of cerebral and/or spinal dura matter while brain parenchyma were normal. Nine cases developed multiple cranial nerve paralysis, with trigeminal nerve and auditory nerve involved most commonly. The main clinical manifestations were facial pain, hearing loss and tinnitus. Two cases were complicated with hypertrophic spinal pachymeningitis (HSP) and 4 cases were complicated with pulmonary diseases. Positive serum perinuclear pattern ANCA (pANCA) and MPO could be found in all cases, positive serum IgG4 was seen in two patients. erythrocyte sedimentation rate(ESR;25-116 mm/1h) and C-reactive protein (CRP;29.02-146.00 mg/L) were both elevated in 14 cases. Nine cases had elevated intracranial pressure[180-235 mmH2O (1 mmH2O=0.009 8 kPa)] and abnormal protein level (457.6-3710.0 mg/L) in cerebrospinal fluid. Six cases were treated with glucocorticoids (prednisone 20-60 mg/d) and 9 cased with glucocorticoids and immunosuppressants (methotrexate 15 mg/week or cyclophosphamide 100 mg/d po). All patients achieved remission. MPO-ANCA associated HP is a special type of central nervous system involvement in ANCA associated vasculitis (AAV). It rarely involves the lung or kidney. Steroids and immunosuppressive agents are effective. In HP with unknown underlying diseases, it is suggested to screen ANCA and IgG4 tests for AAV or IgG4-related disease.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Meningite , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Anticorpos Anticitoplasma de Neutrófilos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hipertrofia/complicações , Hipertrofia/tratamento farmacológico , Imunoglobulina G , Imunossupressores/uso terapêutico , Masculino , Meningite/diagnóstico , Meningite/tratamento farmacológico , Meningite/etiologia , Pessoa de Meia-Idade , Peroxidase , Estudos RetrospectivosRESUMO
Objective: To evaluate the diagnostic efficacy of stress-strain index (SSI) for different stages or degrees of keratoconus and changes of SSI and stiffness parameter A1 (SPA1) after corneal collagen cross-linking (CXL) surgery. Methods: Cross-sectional study and retrospective case series study. Ninety-four patients (113 eyes) diagnosed as clinical keratoconus (CKC) in Qingdao Eye Hospital from July 2019 to August 2021 were enrolled in the CKC group, including 69 males and 25 females, aged (20.82±4.53) years, and further divided into subgroups of mild (35 patients, 36 eyes), moderate (36 patients, 40 eyes) and severe (33 patients, 37 eyes) CKC. Fifty-six unaffected eyes of monocular keratoconus patients were enrolled in the subclinical keratoconus (SKC) group. Ninety-one healthy subjects (91 eyes) were recruited as the control group. All subjects were examined by Pentacam topography and Corvis ST measurements to obtain mean keratometry, maximal keratometry, deformation amplitude (DA) ratio at 2 mm, integrated radius (IR), Ambrósio's relational thickness to the horizontal profile, corneal central thickness, SPA1 and SSI for comparison. Forty-eight CKC patients (65 eyes) underwent CXL surgery, and the above parameters were recorded before and 3, 6 and 12 months after operation. Data were analyzed by the ANOVA test, Kruskal-Wallis H test, paired sample test, receiver operating characteristic curves and Pearson correlation. Results: The value of SPA1 in the SKC group accounted for 85.53% (87.92±12.38 vs. 102.79±11.74; t=-6.614, P<0.001) compared with the control group, but the value of SSI had no difference in the two groups (t=0.105, P=0.916). The value of SPA1 in the CKC group accounted for 52.87% (54.35±14.70 vs. 102.79±11.74; t=25.985, P<0.001) compared with the control group. The value of SSI in the CKC group accounted for 67.96% (0.70±0.14 vs. 1.03±0.14; t=-15.305, P<0.001) compared with the control group. The more severe the disease was, the smaller the SPA1 and SSI values were 64.27±12.12, 55.22±12.23, 43.75±12.33; 0.78±0.14, 0.71±0.11, 0.61±0.09, and there were significant statistical differences among groups (mild vs. moderate, mild vs. severe, moderate vs. severe; SPA1: t=3.257, -7.249, -4.159; all P<0.001. SSI: t=2.383, 5.065, 2.798; P=0.018,<0.001,=0.006). Receiver operating characteristic analysis showed that SPA1 had good diagnostic efficiency for subclinical patients [area under curve (AUC)=0.802], while the SSI had no diagnostic value (P=0.802). SPA1 had better diagnostic efficiency than the SSI for keratoconus in different stages, especially in the mild CKC and SKC groups (AUC: 0.914 vs. 0.847). The SSI had a significant positive correlation with SPA1 and a significant negative correlation with DA ratio and IR in the control, SKC and CKC groups (r=0.278, 0.368, 0.550; r=-0.346, -0.462, -0.547; r=-0.612, -0.591, -0.718; P<0.01). For patients who received CXL, maximal keratometry decreased significantly at 6 and 12 months postoperatively (t=4.029, 3.633; all P<0.001), whereas SPA1 increased significantly (t=-3.960, -4.500; all P<0.001). However, the SSI only increased significantly at 3 months (t=-2.577, P=0.012) and returned to the preoperative level at 6 and 12 months postoperatively, with no statistical difference compared with the preoperative level (t=-0.544, -0.257; P=0.589, 0.798). Conclusions: While there was no significant change in the SSI of SKC, the SSI of CKC decreased, and the more severe the disease was, the smaller the value was. The SSI was significantly and consistently correlated with DA ratio, IR and SPA1. The SSI compared with SPA1 had a lower degree of identification in different stages and degrees of keratoconus. The consistency of SPA1 with clinical effects after CXL surgery was higher than that of the SSI parameter.
Assuntos
Ceratocone , Colágeno , Córnea/cirurgia , Topografia da Córnea , Reagentes de Ligações Cruzadas , Estudos Transversais , Feminino , Humanos , Ceratocone/diagnóstico , Masculino , Fármacos Fotossensibilizantes , Estudos Retrospectivos , Riboflavina , Raios UltravioletaRESUMO
With aging and pathology, cells of the nucleus pulposus (NP) de-differentiate towards a fibroblast-like phenotype, a change that contributes to degeneration of the intervertebral disc (IVD). Laminin isoforms are a component of the NP extracellular matrix during development but largely disappear in the adult NP tissue. Exposing human adult NP cells to hydrogels made from PEGylated-laminin-111 (PEGLM) has been shown to regulate NP cell behaviors and promote cells to assume a biosynthetically active state with gene/protein expression and morphology consistent with those observed in juvenile NP cells. However, the mechanism regulating this effect has remained unknown. In the present study, the integrin subunits that promote adult degenerative NP cell interactions with laminin-111 are identified by performing integrin blocking studies along with assays of intracellular signaling and cell phenotype. The findings indicate that integrin α3 is a primary regulator of cell attachment to laminin and is associated with phosphorylation of signaling molecules downstream of integrin engagement (ERK 1/2 and GSK3ß). Sustained effects of blocking integrin α3 were also demonstrated including decreased expression of phenotypic markers, reduced biosynthesis, and altered cytoskeletal organization. Furthermore, blocking both integrin α3 and additional integrin subunits elicited changes in cell clustering, but did not alter the phenotype of single cells. These findings reveal that integrin- mediated interactions through integrin α3 are critical in the process by which NP cells sense and alter phenotype in response to culture upon laminin and further suggest that targeting integrin α3 has potential for reversing or slowing degenerative changes to the NP cell.
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Integrinas/metabolismo , Laminina/farmacologia , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Adolescente , Adulto , Idoso , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Humanos , Hidrogéis/farmacologia , Disco Intervertebral/efeitos dos fármacos , Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/tratamento farmacológico , Degeneração do Disco Intervertebral/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Adulto JovemRESUMO
Objective: To report the risk factors, clinical characteristics and treatment courses of pulmonary mucormycosis after lung transplantation(LT). Methods: We included 3 cases with pulmonary mucormycosis after LT from March 2017 to July 2020 in the centre for lung transplantation of China-Japan Friendship Hospital. Twelve cases from Chinese and English literature from China National Knowledge Infrastructure (CNKI), China Biomedical Literature Service System and Pubmed Database from March 1980 to July 2020 were added. The risk factors, clinical characteristics and treatment courses of all cases were summarized and analyzed. Results: Pulmonary mucormycosis occurred in 1.06% (3/284) in our centre. A total of 15 cases with 12 cases from literature included 10 males and 5 females with a mean age of(47±20)years. Thirteen cases occurred after LT, and 2 cases occurred after heart-lung transplantation (HLT). Nine probable cases were diagnosed by positive isolation of the pathogen from bronchoalveolar lavage fluid or sputum. Three proven cases were diagnosed by transbronchial lung biopsy. Meanwhile, the other 3 proven cases diagnosed by CT-guided percutaneous lung biopsy, autopsy and surgical operation respectively. Ten cases (66.7%) were diagnosed with pulmonary mucormycosis within 90 days after lung transplantation. The mortality was as high as 46.67% (7/15), but if it occurred within 90 days, the mortality reached 70% (7/10). The average interval between transplantation and positive isolation of the pathogen was 112.3 (5-378) days. Conclusions: The clinical and radiographic features of pulmonary mucormycosis after LT were nonspecific. It had a high mortality, especially in those occurred within 90 days after LT. The combination of antifungal therapy and surgical resection may contribute to a better outcome of the disease.
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Pneumopatias Fúngicas , Transplante de Pulmão , Mucormicose , Adulto , Idoso , Antifúngicos/uso terapêutico , Líquido da Lavagem Broncoalveolar , Feminino , Humanos , Pulmão , Pneumopatias Fúngicas/tratamento farmacológico , Transplante de Pulmão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mucormicose/tratamento farmacológico , Mucormicose/etiologiaRESUMO
OBJECTIVE: United Nations Programme on human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome and World Health Organization believe that some of the benchmark numbers collected may be inaccurate when using the multiplier method to estimate the size of populations most at risk of acquiring HIV. Here, study data have been evaluated to characterize the inaccurate benchmark numbers. STUDY DESIGN: The study design used is a systematic review. METHODS: Studies published from 1 January 2004 to 1 December 2019 using the multiplier method to estimate the population proportions of men who have sex with men (MSM) and female sex workers (FSWs) in China were reviewed. Five electronic bibliographic databases were searched: Medline, the China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, Wanfang Data, and the Chinese BioMedical Literature Database. RESULTS: In all eight studies of FSW, six of the estimated population proportions fell within the range of national estimates. However, the estimated MSM population proportions of all 18 studies fell outside the range of national estimates. CONCLUSIONS: When estimating the MSM population, the use of benchmark numbers from homosexual websites or MSM-frequented sites usually led to an inaccurate estimation. Therefore, benchmark numbers from services/programs that meet fundamental needs, such as those dealing with health and wellness, should be used.
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Coleta de Dados/métodos , Infecções por HIV/epidemiologia , Síndrome da Imunodeficiência Adquirida/epidemiologia , Adolescente , Adulto , China/epidemiologia , Feminino , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População/métodos , Fatores de Risco , Profissionais do Sexo/estatística & dados numéricos , Minorias Sexuais e de Gênero/estatística & dados numéricos , Adulto JovemRESUMO
We recently developed a blood-brain barrier (BBB)-penetrating enzyme transport vehicle (ETV) fused to the lysosomal enzyme iduronate 2-sulfatase (ETV:IDS) and demonstrated its ability to reduce glycosaminoglycan (GAG) accumulation in the brains of a mouse model of mucopolysaccharidosis (MPS) II. To accurately quantify GAGs, we developed a plate-based high-throughput enzymatic digestion assay coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to simultaneously measure heparan sulfate and dermatan sulfate derived disaccharides in tissue, cerebrospinal fluid (CSF) and individual cell populations isolated from mouse brain. The method offers ultra-high sensitivity enabling quantitation of specific GAG species in as low as 100,000 isolated neurons and a low volume of CSF. With an LOD at 3 ng/mL and LLOQs at 5-10 ng/mL, this method is at least five times more sensitive than previously reported approaches. Our analysis demonstrated that the accumulation of CSF and brain GAGs are in good correlation, supporting the potential use of CSF GAGs as a surrogate biomarker for brain GAGs. The bioanalytical method was qualified through the generation of standard curves in matrix for preclinical studies of CSF, demonstrating the feasibility of this assay for evaluating therapeutic effects of ETV:IDS in future studies and applications in a wide variety of MPS disorders.
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Biomarcadores/metabolismo , Glicosaminoglicanos/isolamento & purificação , Iduronato Sulfatase/genética , Mucopolissacaridose II/diagnóstico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Cromatografia Líquida , Dermatan Sulfato/farmacologia , Dissacarídeos/química , Modelos Animais de Doenças , Glicosaminoglicanos/genética , Glicosaminoglicanos/metabolismo , Heparitina Sulfato/farmacologia , Humanos , Iduronato Sulfatase/metabolismo , Camundongos , Mucopolissacaridose II/genética , Mucopolissacaridose II/patologia , Espectrometria de Massas em TandemRESUMO
Objective: To investigate the corneal topographic characteristics of the parents of patients with keratoconus (KC) and the correlation with their offspring. Methods: Case-control study. Twenty-six patients (49 eyes) with KC, who were 15 males and 11 females, and (18.83±2.74) years old, 48 parents (96 eyes) of patients with KC, who were 23 males and 25 females, and (44.14±1.70) years old, and 44 controls (88 eyes), who were 22 males and 22 females, and (42.81±4.03) years old, were enrolled in Qingdao Eye Hospital. The indexes in the Belin/Ambrósio Enhanced Ectasia Display were acquired with Pentacam topography. The basic indicators were flat K/steep K/maximum K (Kmax) curvature and astigmatism, thinnest pachymetry (TP), and front/back elevation (Ef/Eb); the Belin indexes included deviation of normality of the front/back elevation (Df/Db), deviation of average pachymetry progression/normality of corneal thinnest point/normality of relational thickness (Dp/Dt/Da), overall deviation of normality (Do), minimum/maximum/average pachymetric progression indices (PPImin/PPImax/PPIave), and Ambrósio's average and maximum relational thickness indices (ARTave/ARTmax). All parameters in the groups of parents and controls were compared by Mann-Whitney U test. The ROC curve was used to analyze the differential value of each abnormal index. In addition, the ratio of abnormal indicators in the Belin/Ambrósio Enhanced Ectasia Display was statistically analyzed. Partial correlation analysis was used to find the correlation between the parameters of KC patients and their parents, and binary logistics regression analysis was used to predict the prevalence in children through the parental indicators. Results: Clinical KC was diagnosed in 1 of the 48 parents (2.08%) of patients with KC. There was no statistically significant difference in anterior surface parameters such as K1, K2, Kmax, astigmatism and Ef, but differences in the thickness [522.00 (493.00, 542.75) µm versus 540.00 (523.25, 559.50) µm] and posterior surface elevation value [8.00 (4.00, 11.00) µm versus 5.00 (3.00, 8.00) µm] were statistically significant. Except for Df, the other Belin/Ambrósio indicators such as Do (Z=-4.551, P=0.000), PPImax (Z=-3.959, P=0.000) and ARTave (Z=-4.792, P=0.000) indicated significant difference. The ROC curve analyses showed ARTave had the greatest value in the identification of KC patients (AUC=0.705), PPImax had the best sensitivity (0.845), and Eb had the best specificity (0.837). The ratio of suspicious indicators between the parents' group and the control group was 1.5â¶1, and the ratio of pathological indicators was 3â¶1. There was a correlation in multiple parameters between KC patients and their parents (all P>0.05). Do/Eb/TP indices of mothers and Do/Kmax indices of fathers were the major influence factors for the disease in the offspring, with a diagnosis rate of 85.6%. Conclusions: The corneal topographic map of the parents of patients with KC showed that the index of the anterior surface was normal, but the thickness was thinner and the posterior surface was higher. According to Belin's analysis, all indicators except Df were abnormal. Moreover, the ratio of suspected and pathological indicators increased. These data suggested that the corneal topography of parents of patients with KC had features of subclinical KC. Compared with the traditional index, ARTave was of the highest value in the identification of subclinical KC. There was a strong correlation between parents of patients with KC and offspring. The Do and Kmax indices of paternal parents and the Do, Eb and TP indices of maternal parents were good predictors of children's disease. (Chin J Ophthalmol, 2020, 56:456-464).
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Ceratocone , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Córnea , Paquimetria Corneana , Topografia da Córnea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pais , Curva ROC , Adulto JovemRESUMO
Objective: To explore the prevalence and risk factors of ischemic stroke in rural areas of Liaoning province. Methods: The study was a cross-sectional survey. From September 2017 to May 2018, a total of 10 926 rural residents aged ≥40 years were investigated in Chaoyang county, Lingyuan, Liaoyang county and Donggang city of Liaoning province. The investigation included questionnaire survey, physical examination and laboratory examination.Univariate and multivariate logistic regression models were used to analyze the risk factors of ischemic stroke. Results: The prevalence of ischemic stroke in the rural areas of Liaoning province was 5.51% (602/10 926), and the standardized prevalence rate was 4.04%. The standardized prevalence rate of male (5.05%) is higher than that of female (3.44%). The prevalence of ischemic stroke increased with age in both males (P<0.01) and females (P<0.01). Multivariate logistic regression analysis showed that age increase(compared with 40-49 years old group, 50-59 years old, OR=2.08, 95%CI 1.31-3.30, P=0.02; 60-69 years old, OR=3.90, 95%CI 2.51-6.05, P<0.01; 70-79 years old, OR=5.32, 95%CI 3.37-8.34, P<0.01; ≥80 years old, OR=3.64, 95%CI 2.00-6.62, P<0.01), male(OR=2.35, 95%CI 1.95-2.84, P<0.01),family history of stroke(OR=2.18, 95%CI 1.83-2.60, P<0.01),coronary heart disease (OR=2.01, 95%CI 1.52-2.66, P<0.01), hypertension (OR=2.82, 95%CI 2.21-3.60, P<0.01), diabetes mellitus (OR=1.36, 95%CI 1.11-1.67, P=0.03) and overweight/obese (OR=1.22, 95%CI 1.02-1.47, P=0.03) were the major risk factors of ischemic stroke. Conclusions: The prevalence of ischemic stroke in rural areas of Liaoning province is high. Age, male, family history of stroke, coronary heart disease, hypertension, diabetes mellitus, overweight/obesity are the risk factors of ischemic stroke in rural areas of Liaoning province.
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Isquemia Encefálica , Acidente Vascular Cerebral , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/epidemiologia , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipertensão , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , População Rural , Acidente Vascular Cerebral/epidemiologiaRESUMO
Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based on long-term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient-years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy-six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit-risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Inativadores do Complemento/efeitos adversos , Hemoglobinúria Paroxística/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Pré-Escolar , Inativadores do Complemento/uso terapêutico , Bases de Dados Factuais , Fadiga/induzido quimicamente , Feminino , Febre/induzido quimicamente , Hemoglobinas/deficiência , Humanos , Lactente , Recém-Nascido , Masculino , Infecções Meningocócicas/induzido quimicamente , Pessoa de Meia-Idade , Infecções Oportunistas/induzido quimicamente , Farmacovigilância , Gravidez , Complicações na Gravidez/tratamento farmacológico , Resultado da Gravidez , Adulto JovemRESUMO
BACKGROUND: Spinal cord stimulation (SCS) is a well-established therapy for chronic pain syndromes, with growing applicability to other conditions. Restless legs syndrome (RLS) is a widespread, chronic movement disorder managed primarily and incompletely by medication, and its etiology can be classified as idiopathic or secondary. METHODS: Three patients underwent SCS implantation for chronic back and/or leg pain with concomitant targeting of RLS: (1) a 34-year-old man with sporadic RLS symptoms that strongly intensified after military-related spinal fractures, (2) a 54-year-old man with RLS likely secondary to meralgia paresthetica, and (3) a 42-year-old man with low back and right lower extremity pain after a military motor vehicle accident. RESULTS: Continuing through 40-month, 2-month, and 28-month follow-ups, respectively, the patients experienced exemplary relief of their RLS symptoms. Notably in the case of patient 1, this benefit appears separate from his pain relief, as during the 5-month period directly after surgery but before adjusted targeting, he only experienced pain alleviation. CONCLUSIONS: To our knowledge, this is the first reported case of using SCS as a potentially long-lasting, safe, and highly effective therapy for RLS of mixed etiology. Additionally, 2 patients with RLS possibly secondary to chronic pain also benefited from the therapy. This success may be due to increased inhibition from hypothalamic cells controlling dopaminergic input to the spine.