RESUMO
ABSTRACT: Caplacizumab prevents the interaction between von Willebrand factor and platelets and is used to treat immune thrombotic thrombocytopenic purpura (iTTP). Its administration has been associated with a delay in ADAMTS13 activity restoration after plasma exchange (PEX) suspension. We analyzed the outcomes of 113 iTTP episodes, 75 of which were treated with caplacizumab, in 108 patients from the Spanish Registry of Thrombotic Thrombocytopenic Purpura. Caplacizumab shortened the time to platelet count normalization and reduced PEX requirement, exacerbations, and relapses. There was no difference in the time to achieve ADAMTS13 activity ≥20% after PEX end between caplacizumab-treated and nontreated episodes (median [interquartile range], 14.5 [7.7-27.2] vs 13.0 [8.0-29.0] days, P = .653). However, considering the 36 episodes in which caplacizumab was started ≤3 days after iTTP diagnosis, the time for ADAMTS13 restoration from PEX end was higher than in those episodes in which caplacizumab was started >3 days after iTTP diagnosis (20.0 [12.0-43.0] vs 11.0 [3.5-20.0] days, P = .003) or than in non-caplacizumab-treated episodes (P = .033). This finding could be related to a significantly shorter duration of PEX in early caplacizumab-treated episodes than in late caplacizumab-treated episodes (5.5 [4.0-9.0] vs 15.0 [11.0-21.5] days, P < .001) or non-caplacizumab-treated episodes (11.0 [6.0-26.0] days, P < .001). There were no differences in time to ADAMTS-13 restoration from PEX start (28.0 [17.2-47.5], 27.0 [19.0-37.5] and 29.5 [15.2-45.0] days in early caplacizumab-treated, late caplacizumab-treated and non-caplacizumab-treated episodes). Early administered caplacizumab does not prevent the requirement for immunosuppression but has beneficial effects by shortening PEX requirement without major safety concerns.
Assuntos
Proteína ADAMTS13 , Troca Plasmática , Púrpura Trombocitopênica Trombótica , Anticorpos de Domínio Único , Humanos , Proteína ADAMTS13/sangue , Proteína ADAMTS13/metabolismo , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Púrpura Trombocitopênica Trombótica/terapia , Masculino , Feminino , Anticorpos de Domínio Único/uso terapêutico , Adulto , Pessoa de Meia-Idade , Contagem de Plaquetas , Doença Aguda , Resultado do Tratamento , IdosoRESUMO
Cardioembolic stroke is one of the most devastating complications of nonischemic dilated cardiomyopathy (NIDCM). However, in clinical trials of primary prevention, the benefits of anticoagulation are hampered by the risk of bleeding. Indices of cardiac blood stasis may account for the risk of stroke and be useful to individualize primary prevention treatments. We performed a cross-sectional study in patients with NIDCM and no history of atrial fibrillation (AF) from two sources: 1) a prospective enrollment of unselected patients with left ventricular (LV) ejection fraction <45% and 2) a retrospective identification of patients with a history of previous cardioembolic neurological event. The primary end point integrated a history of ischemic stroke or the presence intraventricular thrombus, or a silent brain infarction (SBI) by imaging. From echocardiography, we calculated blood flow inside the LV, its residence time (TR) maps, and its derived stasis indices. Of the 89 recruited patients, 18 showed a positive end point, 9 had a history of stroke or transient ischemic attack (TIA) and 9 were diagnosed with SBIs in the brain imaging. Averaged TR, [Formula: see text] performed well to identify the primary end point [AUC (95% CI) = 0.75 (0.61-0.89), P = 0.001]. When accounting only for identifying a history of stroke or TIA, AUC for [Formula: see text] was 0.92 (0.85-1.00) with odds ratio = 7.2 (2.3-22.3) per cycle, P < 0.001. These results suggest that in patients with NIDCM in sinus rhythm, stasis imaging derived from echocardiography may account for the burden of stroke.NEW & NOTEWORTHY Patients with nonischemic dilated cardiomyopathy (NIDCM) are at higher risk of stroke than their age-matched population. However, the risk of bleeding neutralizes the benefit of preventive oral anticoagulation. In this work, we show that in patients in sinus rhythm, the burden of stroke is related to intraventricular stasis metrics derived from echocardiography. Therefore, stasis metrics may be useful to personalize primary prevention anticoagulation in these patients.
Assuntos
Cardiomiopatia Dilatada , Humanos , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Transversais , Estudos Retrospectivos , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/etiologia , Infarto Encefálico/fisiopatologia , Ecocardiografia , Função Ventricular Esquerda , Fatores de Risco , Estudos Prospectivos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/prevenção & controle , AVC Embólico/etiologia , AVC Embólico/prevenção & controle , AVC Embólico/diagnóstico por imagem , Doenças Assintomáticas , Volume SistólicoRESUMO
Immuno Thrombotic thrombocytopenic purpura (iTTP) is a rare and potentially fatal disorder characterized by systemic microvascular thrombosis because of a severe deficiency of ADAMTS13. It is difficult to generate knowledge about TTP because of its low incidence and the lack of clinical trials. Most of the evidence on diagnosis, treatment, and prognosis has been generated from real-world data registries. In 2004, the Spanish Apheresis Group (GEA) implemented the Spanish registry of TTP (REPTT) with 438 patients suffering 684 acute episodes in 53 hospitals up to January 2022. REPTT has studied several aspects of TTP in Spain. The iTTP incidence in Spain our country is 2.67 (95 % CI 1.90-3.45) and the prevalence is 21.44 (95 % CI % 19.10-23.73) patients per million inhabitants. The refractoriness incidence is 4.8 % and exacerbation incidence was 8.4 %, with a median of follow-up of 131.5 months (IQR: 14-178 months). In a 2018 review, the mortality in the first episode due to TTP was 7.8 %. We have also found that de novo episodes require fewer PEX procedures than relapses. Since June 2023, REPTT will involve Spain and Portugal, with a recommended sampling protocol and new variables to improve the neurological, vascular and quality of life evaluation of these patients. The main strength of this project will be the involvement of a combined population of more than 57 million inhabitants, which implies an annual incidence of close to 180 acute episodes per year. This will allow us to provide better answers to questions like treatment efficacy, associated morbidity and mortality, and the possible neurocognitive and cardiac sequelae.
Assuntos
Púrpura Trombocitopênica Trombótica , Trombose , Humanos , Púrpura Trombocitopênica Trombótica/epidemiologia , Púrpura Trombocitopênica Trombótica/terapia , Púrpura Trombocitopênica Trombótica/complicações , Qualidade de Vida , Prognóstico , Sistema de Registros , Proteína ADAMTS13RESUMO
OBJECTIVE: To investigate whether the classification of a patient's caries activity based on lesion activity assessment can predict the increment and progression of coronal and root caries lesions among adults. METHODS: This population-based prospective cohort study followed 413 individuals (mean age 54.1) from southern Brazil for 4 years. Data collection included a questionnaire and clinical examination to record coronal/root caries and gingival recession. The main outcomes were caries increment measured as decayed, missing and filled tooth surfaces (DMFS) and caries progression (surface-level analysis). The main predictor variable was patients' caries activity at baseline ("caries-inactive" or "caries-active"). Negative binomial regression models (unadjusted and adjusted) were used. RESULTS: Caries-active individuals were more likely to present DMFS increment than caries-inactive ones when migrations among DMFS components were considered (IRR [incidence risk ratio] = 1.26, 95%CI [confidence interval] = 1.01-1.58). On the other hand, no such association was found when these migrations were disregarded. The risk for coronal caries progression on filled surfaces was 90% higher among caries-active patients (IRR=1.9; 95%CI=1.4-2.6). In addition, patient's caries activity was able to predict higher risk for root caries progression in newly exposed root surfaces (IRR=1.9; 95%CI=1.0-3.6). CONCLUSION: The classification of a patient's caries activity based on lesion activity was able to foresee lesion progression on the coronal and root surfaces more susceptible to caries among adults. Clinical relevance Classifying a patient's caries activity is a useful tool for the clinical management of dental caries in adults.
Assuntos
Cárie Dentária , Retração Gengival , Cárie Radicular , Humanos , Adulto , Pessoa de Meia-Idade , Suscetibilidade à Cárie Dentária , Estudos Prospectivos , Índice CPORESUMO
BACKGROUND: Huntington's disease is a neurodegenerative disorder characterized by clinical alterations in the motor, behavioral, and cognitive domains. However, the structure and disruptions to large-scale brain cognitive networks have not yet been established. OBJECTIVE: We aimed to profile changes in large-scale cognitive networks in premanifest and symptomatic patients with Huntington's disease. METHODS: We prospectively recruited premanifest and symptomatic Huntington's disease mutation carriers as well as healthy controls. Clinical and sociodemographic data were obtained from all participants, and resting-state functional connectivity data, using both time-averaged and dynamic functional connectivity, was acquired from whole-brain and cognitively oriented brain parcellations. RESULTS: A total of 64 gene mutation carriers and 23 healthy controls were included; 21 patients with Huntington's disease were classified as premanifest and 43 as symptomatic Huntington's disease. Compared with healthy controls, patients with Huntington's disease showed decreased network connectivity within the posterior hubs of the default-mode network and the medial prefrontal cortex, changes that correlated with cognitive (t = 2.25, P = 0.01) and disease burden scores (t = -2.42, P = 0.009). The salience network showed decreased functional connectivity between insular and supramarginal cortices and also correlated with cognitive (t = 2.11, P = 0.02) and disease burden scores (t = -2.35, P = 0.01). Dynamic analyses showed that network variability was decreased for default-central executive networks, a feature already present in premanifest mutation carriers (dynamic factor 8, P = 0.02). CONCLUSIONS: Huntington's disease shows an early and widespread disruption of large-scale cognitive networks. Importantly, these changes are related to cognitive and disease burden scores, and novel dynamic functional analyses uncovered subtler network changes even in the premanifest stages.
Assuntos
Doença de Huntington , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Cognição , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/genética , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Allogeneic stem cell transplantation is the treatment of choice for acute myeloid leukemia (AML) patients. Unmanipulated haploidentical transplantation (Haplo-HSCT) is commonly used for those AML patients who need a timely transplant and do not have a suitable matched donor, but relapse rates are still high, and improvements are needed. Adoptive immunotherapy using natural killer cells (NK cells) could be a promising tool to improved Haplo-HSCT but, to date, no optimal infusion and manufacturing protocols have been developed. STUDY DESIGN AND METHODS: In this study, we describe a quick and reproducible protocol for clinical-grade production of haploidentical donor NK cells using double immunomagnetic depletion and enrichment protocol and overnight IL-15 stimulation. RESULTS: Thus, we have obtained 8 viable and functional NK cell products that have been safely infused to five AML patients undergoing unmanipulated Haplo-HSCT. DISCUSSION: Our results demonstrate the safety and feasibility of manufactured NK IL15 cells obtained from an adult allogeneic donor in the setting of haploidentical transplantation for AML patients.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Interleucina-15 , Células Matadoras Naturais , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
BACKGROUND: Molecular glioblastomas (i.e. without the histological but with the molecular characteristics of IDH-wild-type glioblastoma) frequently lack contrast enhancement, which can wrongly lead to suspect a lower-grade glioma. Herein, we aimed to assess the diagnostic value of gyriform infiltration as an imaging marker for molecular glioblastomas. METHODS: Two independent investigators reviewed the MRI scans from patients with newly diagnosed gliomas for the presence of a gyriform infiltration defined as an elective cortical hypersignal on MRI FLAIR sequence. Diagnostic test performance of this sign for the diagnosis of molecular glioblastoma were calculated. RESULTS: A total of 426 patients were included, corresponding to 31 molecular glioblastoma, 294 IDH-wild-type glioblastoma, 50 IDH-mutant astrocytoma, and 51 IDH-mutant 1p19q-codeleted oligodendroglioma. A gyriform infiltration was observed in 16/31 (52%) molecular glioblastoma, 40/294 (14%) IDH-wild-type glioblastoma, and none of the IDH-mutant glioma. All the 56 gyriform-infiltration-positive tumors were IDH-wild-type and all but two had a TERT promoter mutation. The inter-rater agreement was good (κ = 0.69, p < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the presence of a gyriform infiltration for the diagnosis of molecular glioblastoma were 52%, 90%, 29%, 96%, respectively. The median overall survival was better for gyriform-infiltration-negative patients compared to gyriform-infiltration-positive patients in the whole series and in patients with non-enhancing lesions (n = 95) (25.6 vs 16.9 months, p = 0.005 and 20.2 months vs not reached, p < 0.001). CONCLUSION: Gyriform infiltration is a specific imaging marker of molecular glioblastomas that can help distinguishing these tumors from IDH-mutant lower-grade gliomas.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Biomarcadores , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , MutaçãoRESUMO
Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (TR1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into TR1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.
Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Antígenos CD11/imunologia , Diferenciação Celular , Citocinas/imunologia , Feminino , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Nanomedicina , Nanopartículas/química , Nanopartículas/uso terapêutico , Especificidade de Órgãos , Prevalência , Solubilidade , Linfócitos T Reguladores/citologiaRESUMO
Infections are one of the well-known precipitating factors for relapses in patients with immune thrombocytopenia (ITP). Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can sometimes lead to or be associated with thrombocytopenia due to an increase in peripheral platelet destruction from inflammatory hyperactivation. Currently, we do not know if SARS-CoV-2 infection modifies the natural evolution of chronic or persistent ITP or if previous immunosuppression of patients with ITP influences the incidence and severity of coronavirus disease 2019 (COVID-19) in this group. The present study was an observational, multicentre, national series of 32 adult patients with pre-existing ITP and subsequent SARS-CoV-2 infection, collected by the Spanish ITP Group [Grupo Español de Trombocitopenia Inmune (GEPTI)].
Assuntos
COVID-19/epidemiologia , Púrpura Trombocitopênica Idiopática/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Espanha/epidemiologiaRESUMO
The objective of this observational study was to evaluate the efficacy and safety of duloxetine in a cohort of 100 cancer survivors with chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN was graded employing the TNSc and the NCI-CTCv4. The Patient Global Impression of Change (PGIC) scale measured the efficacy of duloxetine (1: no benefit; to 7: excellent response). A clinically meaningful response was considered a PGIC > 4. Median age was 62 (29-81) years and 42% were male. CIPN was graded as grades 1, 2 and 3 in 20, 66, and 14% of patients, respectively. Median time to duloxetine initiation was 6 (1-63) months after chemotherapy. Fifty-seven patients early dropped out from duloxetine, due to lack of efficacy (20%) or side effects (37%). Male patients more frequently discontinued duloxetine due to lack of efficacy (35.7 vs. 8.6% P = 0.001). PGIC scores were higher in female patients (4 vs. 1, P = 0.001), taxane-treated patients (4 vs. 1, P = 0.042) and with short-lasting (<6 months) CIPN (4 vs. 1, P = 0.008). Patients with long-lasting CIPN had a higher rate of adverse events (47 vs. 27%, P = 0.038) and discontinuation (54.8 vs. 45.1%, P = 0.023). In the multivariate analysis, female gender and short-lasting CIPN were independently associated with a favorable response to duloxetine. Low tolerability, male gender, and long-lasting CIPN significantly limited duloxetine use in daily practice setting. A minority of cancer survivors with CIPN treated with duloxetine had a meaningful CIPN improvement, and tolerability was overall low. Female gender and short-term CIPN were independently associated with a favorable response to duloxetine.
Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Cloridrato de Duloxetina/efeitos adversos , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/patologia , Doenças do Sistema Nervoso Periférico/patologia , Qualidade de Vida , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Síndromes Neurotóxicas/etiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Prognóstico , Estudos ProspectivosRESUMO
AIM: To describe changes in gingival recession (GR) at buccal and palatal sites in adults over an average follow-up of 4 years. MATERIALS AND METHODS: Baseline data were obtained from a multistage probabilistic representative sample of 1023 individuals aged ≥35 years from Porto Alegre, Brazil. Buccal and palatal/lingual GR were analysed. RESULTS: 402 individuals (6,862 teeth) were followed. At baseline, 3,356 (48.9%) teeth did not have GR at the buccal site and 1206 developed the condition overtime (incidence =35.9%; 95% CI 32.6-38.9). Percentage of incident teeth was higher among individuals with (42.3%) than those without (29.5%) periodontitis stages III/IV. Also, 38.5% of teeth with proximal attachment loss at follow-up had incident GR compared to 7.6% of those without proximal attachment loss. Incidence of palatal GR was observed in 32.5% of teeth (95% CI 29.7-35.3). Mean buccal and palatal/lingual GR incidence was 2.11 mm and 2.33 mm, whereas buccal and palatal/lingual GR progression equalled 0.40 mm and 0.48 mm. The prevalence of GR ≥3 mm increased in individuals with (from 35.9% to 47.4%) and without (from 25.2 to 41.5%) periodontitis. CONCLUSION: Incidence and progression of GR are high in a general urban Brazilian population of adults.
Assuntos
Retração Gengival , Periodontite , Adulto , Idoso , Brasil/epidemiologia , Retração Gengival/epidemiologia , Humanos , Incidência , Estudos LongitudinaisRESUMO
Acquired thrombotic thrombocytopenic purpura (aTTP) is still associated with a 10% to 20% death rate and its clinical course is characterized by recurrent episodes in up to 50% of cases. Over the last decade, mortality predicting models like the French TMA Reference Center Score and the Mortality In TTP Score (MITS) have been developed in an attempt to personalize treatment. The objective of the present study was to compare the results in both scores of de novo and relapsed aTTP episodes. For such purpose, a total of 29 episodes of aTTP (16 de novo and 13 relapses) were analyzed. All patients were homogeneously diagnosed and treated. First episodes had a higher score in both models in comparison with relapsed aTTP, (MITS median, 1 r: 1-4 vs 0 r: 1-2, P = .038 and French TMA Reference Center Score median, 2 r: 1-3 vs 1 r: 0-1, P = .006). The prevalence of neurological symptoms was significantly higher in the first episodes (P = .001) and patients >60 years old were more common in this group (P = .013), which may have been related to the results. Platelet count at presentation was higher in recurrences than in the first disease episode (P = .016) and ADAMTS13 activity <5% was more frequent in the last group (P = .016). There was no significant difference in the rate of refractoriness or exacerbations. In conclusion, first aTTP episodes had a higher probability of short-term mortality compared to relapsed aTTP episodes according to the MITS and French TMA Reference Center Score.
Assuntos
Púrpura Trombocitopênica Trombótica/terapia , Proteína ADAMTS13/análise , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Púrpura Trombocitopênica Trombótica/mortalidade , Estudos Retrospectivos , Atenção Terciária à SaúdeRESUMO
BACKGROUND: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease characterized by the presence of anti-ADAMTS13 autoantibodies. Achieving accurate information on incidence and customary disease management is important to provide appropriate diagnostic and therapeutic resources. The aim of this study was to determine the incidence and outcomes of iTTP in Spain. STUDY DESIGN AND METHODS: A cross-sectional survey was carried out among Spanish hospitals, focused on iTTP patients ≥16 years old attended between 2015 and 2017, and those at follow-up before that interval. Incidence, prevalence, mortality, refractoriness, exacerbations, treatment complications, relapses, and sequelae were estimated. RESULTS: Forty-two hospitals covering roughly 20 million inhabitants answered the survey and reported 203 episodes (138 newly-diagnosed and 65 relapses), of which 193 (95.1%) were treated. Incidence was 2.67 (95% CI 1.90-3.45) patients per million inhabitants per year and prevalence 21.44 (95% CI% 19.10-23.73) patients per million inhabitants. At diagnosis, ADAMTS13 activity and anti-ADAMTS13 autoantibody were measured in 97% and 84.3% of reported episodes, respectively. Fifteen patients (7.4%) died as a direct consequence of iTTP, 6 of them before receiving any iTTP-specific treatment. Thirty-one (16.1%) of the 193 treated episodes were refractory to plasma exchange and corticosteroids, and 51 (26.4%) suffered at least one exacerbation. CONCLUSION: iTTP incidence and prevalence were somewhat higher than those documented in neighboring countries. Together with data on treatments and outcomes, this information will allow us to better estimate what is needed to improve diagnosis and prognosis of iTTP patients in Spain.
Assuntos
Hematologia/organização & administração , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/epidemiologia , Púrpura Trombocitopênica Trombótica/terapia , Proteína ADAMTS13/química , Adulto , Autoanticorpos/química , Estudos Transversais , Hospitalização , Hospitais , Humanos , Incidência , Avaliação de Resultados em Cuidados de Saúde , Troca Plasmática , Prevalência , Sistema de Registros , Estudos Retrospectivos , Espanha/epidemiologia , Inquéritos e Questionários , Resultado do TratamentoRESUMO
The formal insertion of alkenes into aromatic chloro- and bromoalkynes takes place under cationic gold catalysis. This haloalkynylation reaction can be performed with cyclic, gem-disubstituted and monosubstituted alkenes, using BINAP, triazolo[4,3-b]isoquinolin-3-ylidene ligands or SPhos, respectively. The products were isolated in moderate to excellent yields and with complete diastereo- and regioselectivity; the halogen atom bonding the more substituted carbon of the alkene. Preliminary experiments showed that the enantioselective haloalkynylation of cyclopentene can be performed with (S)-BINAP to afford the insertion products with moderate to good enantioselectivities.
RESUMO
BACKGROUND: Abnormal coagulation parameters have been reported in COVID-19-infected patients. Although the underlying mechanism of COVID-19 coagulopathy remains unknown, it has been suggested to be a form of disseminated intravascular coagulation (DIC). OBJECTIVES: The aim of our study was to analyze the coagulation parameters of patients with COVID-19, determine whether coagulation factors consumption occurs and identify potential prognostic biomarkers of the disease. PATIENTS/METHODS: Blood samples from hospitalized patients with COVID-19 pneumonia were collected. We performed basic coagulation tests and quantification of coagulation factors and physiological inhibitor proteins. Laboratory data were compared with clinical data and outcomes. RESULTS: The study involved 206 patients (63.6% male). D-dimer was particularly elevated (median 450 ng/mL; IQR 222.5-957.3). Free protein S levels were below the normal range (median 56.6%; IQR: 43.6-68.9), and factor VIII showed an increasing trend (median 173.4%; IQR: 144.1-214.9). However, all coagulation factors were within normal limits. We found no correlation between abnormal coagulation parameters and thrombosis, except for higher D-dimer (HR 1.99; 95% CI 1.3-3.1; P = .002). CONCLUSIONS: COVID-19 is associated with coagulopathy that correlates with poor prognosis. However, we did not demonstrate a consumption of coagulation factors, as seen in DIC.
Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Fator VIII/metabolismo , Pneumonia Viral/complicações , Trombose Venosa/complicações , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Testes de Coagulação Sanguínea , Plaquetas/patologia , Plaquetas/virologia , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/mortalidade , Coagulação Intravascular Disseminada/virologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Prognóstico , Proteína S/metabolismo , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Análise de Sobrevida , Trombose Venosa/diagnóstico , Trombose Venosa/mortalidade , Trombose Venosa/virologiaRESUMO
Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.
Assuntos
Doenças Autoimunes do Sistema Nervoso/imunologia , Autoimunidade , Glutamato Descarboxilase/imunologia , Neurônios/enzimologia , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/terapia , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/imunologia , Ataxia Cerebelar/terapia , Humanos , Encefalite Límbica/diagnóstico , Encefalite Límbica/imunologia , Encefalite Límbica/terapia , Neurônios/imunologia , Rigidez Muscular Espasmódica/diagnóstico , Rigidez Muscular Espasmódica/imunologia , Rigidez Muscular Espasmódica/terapiaRESUMO
Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD-MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level-1 Movement Disorders Society-Task Force Criteria. Voxel-based morphometry, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD-MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD.
Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Idoso , Cognição/fisiologia , Disfunção Cognitiva/psicologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/psicologiaRESUMO
BACKGROUND: Minor hallucinations and well-structured hallucinations are considered in the severity continuum of the psychotic spectrum associated with Parkinson's disease. Although their chronological relationship is largely unknown, the spatial patterns of brain atrophy in these 2 forms of hallucinations partially overlap, suggesting they share similar pathophysiological processes. Functional connectivity studies show that disruption of functional networks involved in perception and attention could be relevant in the emergence of well-structured hallucinations. However, functional neuroimaging studies in patients with isolated minor hallucinations are lacking. The objectives of this study were to explore the structural and functional changes underlying minor hallucinations. METHODS: We compared patients with (n = 18) and without (n = 14) minor hallucinations using a multimodal structural (gray-matter volume voxel-based morphometry) and functional (seed-to-whole-brain resting-state functional MRI) neuroimaging study. RESULTS: Coincident with previously described structural changes in well-structured hallucinations in Parkinson's disease, patients with minor hallucinations exhibited gray-matter atrophy with significant voxel-wise differences in visuoperceptual processing areas and core regions of the default mode network. Functional connectivity changes consisted of altered connectivity within the default mode network, reduced negative correlation with task-positive network, and aberrant connectivity between posterior regions of the default mode network and visual-processing areas. These changes are in accordance with the attentional networks hypothesis proposed for well-structured hallucinations. CONCLUSIONS: Although longitudinal studies are needed to assess the potential role of minor hallucinations as an early clinical biomarker of progression to well-structured hallucinations, the present findings show that the 2 phenomena share similar structural and functional brain correlates. © 2018 International Parkinson and Movement Disorder Society.
Assuntos
Atenção/fisiologia , Encéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Doença de Parkinson/fisiopatologia , Idoso , Encéfalo/patologia , Mapeamento Encefálico/métodos , Transtornos Cognitivos/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
BACKGROUND: Contrast enhancement (CE) is found in 10-60% of low-grade gliomas. Its prognostic significance is controversial, and its correlation with IDH mutations and 1p/19q codeletion is elusive. The aim of this study is to investigate whether CE is associated with molecular characteristics of low-grade gliomas and uncover its prognostic value. MATERIALS AND METHODS: All confirmed histological cases of low-grade gliomas diagnosed at our institution between years 2000-2016 were reviewed (n = 102). Spinal and brainstem localization, only-biopsied tumours with ring-like enhancement and incomplete medical records were excluded. RESULTS: Mean age was 42 years ( ± 13.9 years), and 63.6% were male. The median follow-up time was 79.8 months. CE was present on 25% of preoperative MRI, and 25% of patients were considered high-risk according to Pignatti score. Most were astrocytomas (67%) and 87.2% were surgically removed. IDH mutation was found in 64.6% of tumour samples, and 18.8% had a 1p/19q codeletion. No subgroup differences were observed according to CE except for presurgical performance status and postoperative chemotherapy. IDH status and 1p/19q codeletion were evenly distributed. On univariate analysis, age, size > 6 cm, CE, extent of resection, Pignatti score, IDH mutation and 1p/19q codeletion were significantly associated to OS. On multivariate analysis, only CE and IDH status were independently associated to OS. CE remained a significant prognostic factor in IDH-mutant non-codeleted tumours when analysed by tumour subtype. CONCLUSION: CE in low-grade gliomas provides prognostic information in IDH-mutant non-codeleted tumours, although its meaning remains uncertain in IDH-wildtype gliomas.
Assuntos
Deleção Cromossômica , Meios de Contraste , Glioma/patologia , Aumento da Imagem/métodos , Isocitrato Desidrogenase/genética , Mutação , Adulto , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Terapia Combinada , Feminino , Seguimentos , Glioma/genética , Glioma/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Taxa de SobrevidaRESUMO
Pungent chemical compounds originating from decaying tissue are strong drivers of animal behavior. Two of the best-characterized death smell components are putrescine (PUT) and cadaverine (CAD), foul-smelling molecules produced by decarboxylation of amino acids during decomposition. These volatile polyamines act as 'necromones', triggering avoidance or attractive responses, which are fundamental for the survival of a wide range of species. The few studies that have attempted to identify the cognate receptors for these molecules have suggested the involvement of the seven-helix trace amine-associated receptors (TAARs), localized in the olfactory epithelium. However, very little is known about the precise chemosensory receptors that sense these compounds in the majority of organisms and the molecular basis of their interactions. In this work, we have used computational strategies to characterize the binding between PUT and CAD with the TAAR6 and TAAR8 human receptors. Sequence analysis, homology modeling, docking and molecular dynamics studies suggest a tandem of negatively charged aspartates in the binding pocket of these receptors which are likely to be involved in the recognition of these small biogenic diamines.