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Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)-ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3-ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3-ANCA was transient, but could recur. In the second cohort, IgM PR3-ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3-ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3-ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.
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Autoanticorpos/imunologia , Granulomatose com Poliangiite/imunologia , Imunoglobulina M/imunologia , Poliangiite Microscópica/imunologia , Mieloblastina/imunologia , Adulto , Idoso , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Biomarcadores , Feminino , Granulomatose com Poliangiite/diagnóstico , Humanos , Imunoglobulina G/imunologia , Masculino , Poliangiite Microscópica/diagnóstico , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥ 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 ± 13.9 vs. 46.8 ± 17.3 years), had higher Birmingham vasculitis activity score (19.5 ± 9.1 vs. 16.9 ± 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.
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Granulomatose com Poliangiite/epidemiologia , Poliangiite Microscópica/epidemiologia , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Distribuição por Idade , Idoso , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Estudos de Coortes , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/imunologia , Humanos , Nefropatias/etiologia , Masculino , Poliangiite Microscópica/complicações , Poliangiite Microscópica/imunologia , Pessoa de Meia-Idade , Mieloblastina/imunologia , Otorrinolaringopatias/etiologia , Seleção de Pacientes , Peroxidase/imunologia , Índice de Gravidade de DoençaRESUMO
BACKGROUND: BK virus (BKV) is an important cause of renal dysfunction in kidney transplant (KTX) recipients. Immunosuppression intensity is a major risk factor for BKV replication in these patients. The prevalence of BKV replication in immunosuppressed patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) without transplant is not known. METHODS: Consecutive patients (n = 37) with a diagnosis of GPA (n = 25) or MPA (n = 12) without history of KTX were evaluated for plasma BKV replication by quantitative PCR (group A). Descriptive data were collected. BKV replication in this nontransplant immunosuppressed vasculitis cohort was compared with a historical cohort of vasculitis KTX recipients (group B). RESULTS: Group A patients had mean disease duration of 75 months. Mean age was 57 years and 54% were female. Mean time from vasculitis onset to BKV testing was 36 months, and 19/37 patients were tested within 24 months of induction therapy. At the time of BKV testing, 73% were on prednisone (P) with azathioprine, mycophenolate mofetil (MMF), methotrexate or leflunomide. None of the nontransplanted vasculitis patients had detectable plasma BKV. Among 35 patients in group B, 16 were tested for BKV; 5/16 (31%) had detectable virus in plasma at a mean of 6 months after TX (p = 0.002). Most (94%) were on maintenance therapy with MMF, P and tacrolimus. CONCLUSION: Immunosuppressed patients with GPA/MPA without KTX had no evidence of plasma BKV. However, BKV was common in GPA/MPA patients after KTX, suggesting that replication may be related to differences in immunosuppression, alloimmune activation or differences in host defense mechanisms.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/virologia , Vírus BK/fisiologia , Infecções por Polyomavirus/diagnóstico , Adulto , Idoso , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Fatores de Risco , Replicação ViralRESUMO
OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.
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Anticorpos Monoclonais Murinos/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Imunossupressores/uso terapêutico , Poliangiite Microscópica/tratamento farmacológico , Indução de Remissão/métodos , Adulto , Anticorpos Monoclonais Murinos/administração & dosagem , Azatioprina/administração & dosagem , Azatioprina/uso terapêutico , Estudos Cross-Over , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Rituximab , Resultado do TratamentoRESUMO
The workshop "Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS) Based Biowaivers" was held virtually on December 6, 2021, organized by the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), and the Food and Drug Administration (FDA). The workshop focused on the industrial, academic, and regulatory experiences in generating and evaluating permeability data, with the aim to further facilitate implementation of the BCS and efficient development of high-quality drug products globally. As the first international permeability workshop since the BCS based biowaivers was finalized as the ICH M9 guideline, the workshop included lectures, panel discussions, and breakout sessions. Lecture and panel discussion topics covered case studies at IND, NDA, and ANDA stages, typical deficiencies relating to permeability assessment supporting BCS biowaiver, types of evidence that are available to demonstrate high permeability, method suitability of a permeability assay, impact of excipients, importance of global acceptance of permeability methods, opportunities to expand the use of biowaivers (e.g. non-Caco-2 cell lines, totality-of-evidence approach to demonstrate high permeability) and future of permeability testing. Breakout sessions focused on 1) in vitro and in silico intestinal permeability methods; 2) potential excipient effects on permeability and; 3) use of label and literature data to designate permeability class.
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Biofarmácia , Relatório de Pesquisa , Preparações Farmacêuticas , Biofarmácia/métodos , Equivalência Terapêutica , Excipientes , Permeabilidade , SolubilidadeRESUMO
NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Adolescente , Adulto , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Doxorrubicina/administração & dosagem , Combinação de Medicamentos , Feminino , Dissulfeto de Glutationa/administração & dosagem , Humanos , Imunidade Celular/efeitos dos fármacos , Estimativa de Kaplan-Meier , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Estadiamento de Neoplasias , Taxoides/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
Experimental observations assisted by 2-D imaging diagnostics on the KSTAR tokamak show that a solitary perturbation (SP) emerges prior to a boundary burst of magnetized toroidal plasmas, which puts forward SP as a potential candidate for the burst trigger. We have constructed a machine learning (ML) model based on a convolutional deep neural network architecture for a statistical study to identify the SP as a boundary burst trigger. The ML model takes sequential signals detected from 19 toroidal Mirnov coils as input and predicts whether each temporal frame corresponds to an SP. We trained the network in a supervised manner on a training set consisting of real signals with manually annotated SP locations and synthetic burst signals. The trained model achieves high performances in various metrics on a test data set. We also demonstrated the reliability of the model by visualizing the discriminative parts of the input signals that the model recognizes. Finally, we applied the trained model to new data from KSTAR experiments, which were never seen during training, and confirmed that the large burst at the plasma boundary that can fatally damage the fusion device always involves the emergence of SP. This result suggests that the SP is a key to understanding and controlling of the boundary burst in magnetized toroidal plasmas.
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The systemic vasculitides are multisystem disorders with considerable mortality and morbidity and frequent relapses. In the absence of reliable serological markers, accurate clinical tools are required to assess disease activity and damage for treatment decisions, and for the performance of clinical trials. This article reviews and summarises the development and use of disease assessment tools for determining activity and damage in systemic vasculitis and reports ongoing initiatives for further development of disease assessment tools. A literature search was conducted using PubMed and reference lists for vasculitis, assessment, clinical trials, outcome and prognosis. The findings indicate that comprehensive disease assessment in vasculitis requires documentation of disease activity, chronic irreversible damage and impairment of function.
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Vasculite/diagnóstico , Ensaios Clínicos como Assunto , Efeitos Psicossociais da Doença , Sistemas de Apoio a Decisões Clínicas , Previsões , Humanos , Qualidade de Vida , Medição de Risco/métodos , Inquéritos e QuestionáriosRESUMO
We describe the design, construction, and performance of three generations of superconducting Ioffe magnetic traps. The first two are low current traps, built from four racetrack shaped quadrupole coils and two solenoid assemblies. Coils are wet wound with multifilament NbTi superconducting wires embedded in epoxy matrices. The magnet bore diameters are 51 and 105 mm with identical trap depths of 1.0 T at their operating currents and at 4.2 K. A third trap uses a high current accelerator-type quadrupole magnet and two low current solenoids. This trap has a bore diameter of 140 mm and tested trap depth of 2.8 T. Both low current traps show signs of excessive training. The high current hybrid trap, on the other hand, exhibits good training behavior and is amenable to quench protection.
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We have discovered transposase sequences in the bull frog (Rana catesbeiana) and in the clawed frog (Xenopus laevis), which demonstrates that there are DNA-mediated transposons in Amphibia. The DNA sequences of 11 new Xenopus elements describe two new vertebrate transposon families. Phylogenetic analysis, using these sequences along with previously defined vertebrate and invertebrate elements, reveals at least five families of Tc1-like elements in Vertebrata. Some of these families co-exist in the same genome. Furthermore, the grouping of one of the amphibian transposon families with a branch of the teleost transposons raises the possibility of horizontal transfer.
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Elementos de DNA Transponíveis/genética , Rana catesbeiana/genética , Xenopus laevis/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA/genética , DNA Nucleotidiltransferases/genética , Bases de Dados Factuais , Dados de Sequência Molecular , Filogenia , Alinhamento de Sequência , Transposases , Vertebrados/genéticaRESUMO
SUM1 (sea urchin myogenic factor 1) is a sea urchin homologue of the myogenic basic helix-loop-helix transcription factors of the MyoD family. SUM1 was initially cloned from Lytechinus variegatus where immunocytochemistry demonstrated restricted expression in precursors of the circumesophageal muscles, the only identified muscle cells in the early embryo. Subsequent in situ hybridization analysis indicates that SUM1 embryonic expression is not restricted to the myogenic lineage; a distinct population of nonmyogenic cells also expresses SUM1. For comparative purposes, we cloned the SUM1 orthologue in the distantly related sea urchin, Strongylocentrotus purpuratus, where we found SpSUM1 transcripts in the same population of nonmyogenic cells.
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Regulação da Expressão Gênica no Desenvolvimento , Músculos/embriologia , Proteína MyoD/genética , Ouriços-do-Mar/embriologia , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Linhagem da Célula , Embrião não Mamífero , Indução Embrionária/genética , Sequências Hélice-Alça-Hélice/genética , Hibridização In Situ , Dados de Sequência Molecular , Desenvolvimento Muscular , Ouriços-do-Mar/genética , Ouriços-do-Mar/crescimento & desenvolvimento , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/metabolismoRESUMO
We have developed a new type of field-expansion spectrometer to measure the neutron beta decay correlations (a, b, B, and A). A precision measurement of these correlations places stringent requirements on charged particle detectors. The design employs large area segmented silicon detectors to detect both protons and electrons in coincidence. Other requirements include good energy resolution (< 5 keV), a thin dead layer to allow observation of 30-keV protons, fast timing resolution (~1 ns) to reconstruct electron-backscattering events, and nearly unity efficiency. We report results of testing commercially available surface-barrier silicon detectors for energy resolution and timing performance, and measurement of the dead-layer thickness of ion-implanted silicon detectors with a 3.2 MeV alpha source.
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The NPDGamma collaboration has completed the construction of a pulsed cold neutron beam line on flight path12 at the Los Alamos Neutron Science Center (LANSCE). We describe the new beam line and characteristics of the beam. We report results of the moderator brightness and the guide performance measurements. FP12 has the highest pulsed cold neutron intensity for nuclear physics in the world.
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We are developing an experiment to measure the correlations a, A, and B, and the Fierz interference term b in neutron decay, with a precision of approximately 10(-4). The experiment uses an electromagnetic spectrometer in combination with two large-area segmented silicon detectors to detect the proton and electron from the decay in coincidence, with 4π acceptance for both particles. For the neutron-polarization-dependent observables A and B, precision neutron polarimetry is achieved through the combination of a pulsed neutron beam, under construction at the SNS, and a polarized (3)He neutron polarizer. Measuring a and A in the same apparatus provides a redundant determination of λ = gA/gV . Uncertainty in λ dominates the uncertainty of CKM unitarity tests.
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The NPDGamma experiment will measure the parity-violating directional gamma ray asymmetry A γ in the reaction [Formula: see text]. Ultimately, this will constitute the first measurement in the neutron-proton system that is sensitive enough to challenge modern theories of nuclear parity violation, providing a theoretically clean determination of the weak pion-nucleon coupling. A new beam-line at the Los Alamos Neutron Science Center (LANSCE) delivers pulsed cold neutrons to the apparatus, where they are polarized by transmission through a large volume polarized (3)He spin filter and captured in a liquid para-hydrogen target. The 2.2 MeV gamma rays from the capture reaction are detected in an array of CsI(Tl) scintillators read out by vacuum photodiodes operated in current mode. We will complete commissioning of the apparatus and carry out a first measurement at LANSCE in 2004-05, which would provide a statistics-limited result for A γ accurate to a standard uncertainty of ±5 × 10(-8) level or better, improving on existing measurements in the neutron-proton system by a factor of 4. Plans to move the experiment to a reactor facility, where the greater flux would enable us to make a measurement with a standard uncertainty of ±1 × 10(-8), are actively being pursued for the longer term.
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The NPDGamma γ-ray detector has been built to measure, with high accuracy, the size of the small parity-violating asymmetry in the angular distribution of gamma rays from the capture of polarized cold neutrons by protons. The high cold neutron flux at the Los Alamos Neutron Scattering Center (LANSCE) spallation neutron source and control of systematic errors require the use of current mode detection with vacuum photodiodes and low-noise solid-state preamplifiers. We show that the detector array operates at counting statistics and that the asymmetries due to B4C and (27)Al are zero to with- in 2 × 10(-6) and 7 × 10(-7), respectively. Boron and aluminum are used throughout the experiment. The results presented here are preliminary.
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OBJECTIVES: Advancing age is a risk factor for treatment-related side effects and mortality in AAV patients treated with cyclophosphamide (CYC) and glucocorticoids (GC) for remission induction. The efficacy and safety of rituximab (RTX) in elderly AAV patients has not been well described. METHODS: We performed a single center retrospective review of 31 consecutive AAV patients aged 60 or more at the time of RTX use for remission induction. All patients received RTX with GC for remission induction. Four patients received concomitant CYC for a mean duration of 52 days. We evaluated clinical and laboratory variables at diagnosis, rates of complete remission defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG) = 0 and patient survival, renal survival, infections requiring hospitalization, and vasculitis relapse 24 months following RTX use. RESULTS: Of the 31 patients, 77% were Caucasian, 68% female, mean age was 71 ± 6 years, 58% were MPO ANCA positive, and 42% had relapsing disease. The mean BVAS/WG score entry was 4.4 ± 1.5, 71% had glomerulonephritis (GN) and 10% had alveolar hemorrhage. The mean baseline e-GFR was 40 ± 28ml/min/1.73m(2). Thirty patients achieved remission with a mean time to remission of 57 ± 27 days. The single patient with refractory vasculitis responded to CYC. The mean prednisone dose at 6 months was 5.6 ± 4mg. Remission maintenance therapy was started within 12 months of RTX induction in 6 patients (4 with RTX, 1 with azathioprine, and 1 with mycophenolate mofetil). One patient suffered a limited relapse 10 months post RTX use. Among the 22 patients with GN at baseline, 1 developed ESRD. One-year patient survival among 25 patients with at least 1 year of follow-up was 100%. There were no episodes of infusion reaction or leukopenia. There were 3 episodes of bacterial pneumonia, 1 episode of candida pneumonia, and 1 episode of disseminated cutaneous zoster. CONCLUSIONS: This study demonstrates that rituximab is effective for remission induction in elderly patients with AAV. Furthermore, we observed a high incidence of infectious complications. Our experience was limited by its retrospective design, and further studies are needed to evaluate the efficacy and safety of RTX in elderly AAV patients.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. METHODS: RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. RESULTS: Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). CONCLUSION: Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.
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Glucocorticoides/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Poliangiite Microscópica/tratamento farmacológico , Prednisona/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Monoclonais Murinos/uso terapêutico , Autoanticorpos/imunologia , Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Feminino , Granulomatose com Poliangiite/imunologia , Humanos , Imunossupressores/uso terapêutico , Quimioterapia de Manutenção , Masculino , Poliangiite Microscópica/imunologia , Mieloblastina/imunologia , Peroxidase/imunologia , Recidiva , Indução de Remissão , Rituximab , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
AUDIENCE: This article is intended for primary care providers who care for patients requiring anticoagulation therapy. GOAL: To provide the reader with a basic understanding of the pharmacology and uses of low molecular weight heparin, including its potential to reduce the length of hospitalization for a variety of indications. OBJECTIVES: 1. To describe the pharmacology of low molecular weight heparin. 2. To outline studies examining the use of low molecular weight heparin for the treatment of deep venous thrombosis and acute coronary syndromes. 3. To discuss the cost-effectiveness of low molecular weight heparins, as well as therapeutic considerations associated with their use. 4. To discuss the possible use of low molecular weight heparin in patients with mechanical prosthetic valves.
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Anticoagulantes/uso terapêutico , Doença das Coronárias/tratamento farmacológico , Heparina de Baixo Peso Molecular/uso terapêutico , Tromboembolia/tratamento farmacológico , Doença Aguda , Anticoagulantes/economia , Doença das Coronárias/economia , Educação Médica Continuada , Heparina de Baixo Peso Molecular/economia , Humanos , Tromboembolia/economiaRESUMO
BACKGROUND: Atopic dermatitis is a chronically relapsing, common inflammatory skin disease, which significantly affects quality of life negatively in many respects. Topical steroids are the mainstay of atopic dermatitis treatment but they carry the risk of local side effects. A topical formulation of tacrolimus, a macrolide calcineurin inhibitor, has recently been developed. OBJECTIVE: To evaluate the efficacy and safety of 0.03% tacrolimus ointment for the treatment of moderate to severe atopic dermatitis in Korea. METHODS: An open, non-comparative, multi-center study with 4 weeks' follow-up was performed. A total of 180 patients (aged 2-57 years old) were enrolled. Tacrolimus ointment (0.03%) was applied to all involved areas twice daily. Efficacy was evaluated by an investigator's global assessment, the eczema area and severity index score, and by the patient's assessment of pruritus and clinical response at baseline, and after weeks 1, 2 and 4. Dermatology life quality index (DLQI), children's DLQI (CDLQI) and toddler's DLQI were assessed at baseline and at week 4. The safety assessment included monitoring all adverse events and clinical laboratory values. RESULTS: All efficacy parameters were improved. The mean EASI (eczema area and severity index) score was 19.7 at baseline and reduced to 8.0 at the end of the study. Moderate improvement was observed by the investigator's global assessment after 4 weeks' treatment. A marked decrease of pruritus was observed, and mild or moderate improvement was observed by patients' global assessments after the treatment period. Significant benefits in terms of quality of life in adults and children with atopic dermatitis were obtained. The most common adverse events associated with tacrolimus treatment were transient skin burning sensation (45.3%) and pruritus (41.6%) at the site of application. CONCLUSION: 0.03% tacrolimus ointment should be considered effective and safe in both Korean children and adults with moderate to severe atopic dermatitis.