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1.
World J Surg Oncol ; 19(1): 161, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082777

RESUMO

BACKGROUND: Breast cancer (BC) is the most commonly malignant tumor among women worldwide. Many studies have reported that circular RNAs (circRNAs) were participated in the regulation of multiple cancers development. However, the mechanism underlying hsa_circ_0001982 in breast cancer development is still unclear. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the levels of circ_0001982, microRNA-1287-5p (miR-1287-5p), and mucin 19 (MUC19) in BC tissues and cells under hypoxia. Moreover, glycolysis was evaluated by glucose consumption, lactic acid production, and hexokinase II (HK2) protein levels. The protein levels of cyclin D1, proliferating cell nuclear antigen (PCNA), and HK2 were determined by western blot assay. Cell proliferation, migration, and invasion were assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-h-tetrazolium bromide (MTT) and transwell assays, respectively. The relationship between miR-1287-5p and circ_0001982 or MUC19 was predicted using starbase v3.0 or Targetscan, and verified by dual-luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay. The xenograft model in nude mice was established to examine the effect of circ_0001982 in vivo. RESULTS: The levels of circ_0001982 and MUC19 were upregulated, while miR-1287-5p was downregulated in BC tissues and cells under hypoxia. Knockdown of circ_0001982 hindered glycolysis, cell viability, migration, and invasion of BC cells under hypoxia. Mechanistic studies discovered that circ_0001982 could act as a sponge for miR-1287-5p to enhance MUC19 expression in BC cells. In addition, circ_0001982 silencing reduced xenograft tumor growth by regulating miR-1287-5p/MUC19 axis. CONCLUSION: Circ_0001982 affected BC cells glycolysis, proliferation, migration, and invasion through miR-1287-5p/MUC19 axis under hypoxia.


Assuntos
Neoplasias da Mama/genética , Hipóxia , MicroRNAs , Mucinas/genética , RNA Circular/genética , Animais , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/genética , Camundongos , Camundongos Nus , MicroRNAs/genética , Transplante de Neoplasias , Prognóstico
2.
Sci Rep ; 11(1): 11524, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075155

RESUMO

Nearly 5% of patients suffering from COVID-19 develop acute respiratory distress syndrome (ARDS). Extravascular lung water index (EVLWI) is a marker of pulmonary oedema which is associated with mortality in ARDS. In this study, we evaluate whether EVLWI is higher in patients with COVID-19 associated ARDS as compared to COVID-19 negative, ventilated patients with ARDS and whether EVLWI has the potential to monitor disease progression. EVLWI and cardiac function were monitored by transpulmonary thermodilution in 25 patients with COVID-19 ARDS subsequent to intubation and compared to a control group of 49 non-COVID-19 ARDS patients. At intubation, EVLWI was noticeably elevated and significantly higher in COVID-19 patients than in the control group (17 (11-38) vs. 11 (6-26) mL/kg; p < 0.001). High pulmonary vascular permeability index values (2.9 (1.0-5.2) versus 1.9 (1.0-5.2); p = 0.003) suggested a non-cardiogenic pulmonary oedema. By contrast, the cardiac parameters SVI, GEF and GEDVI were comparable in both cohorts. High EVLWI values were associated with viral persistence, prolonged intensive care treatment and in-hospital mortality (23.2 ± 6.7% vs. 30.3 ± 6.0%, p = 0.025). Also, EVLWI showed a significant between-subjects (r = - 0.60; p = 0.001) and within-subjects correlation (r = - 0.27; p = 0.028) to Horowitz index. Compared to non COVID-19 ARDS, COVID-19 results in markedly elevated EVLWI-values in patients with ARDS. High EVLWI reflects a non-cardiogenic pulmonary oedema in COVID-19 ARDS and could serve as parameter to monitor ARDS progression on ICU.


Assuntos
COVID-19/complicações , Água Extravascular Pulmonar/imunologia , Edema Pulmonar/mortalidade , Síndrome do Desconforto Respiratório/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/mortalidade , Permeabilidade Capilar , Progressão da Doença , Água Extravascular Pulmonar/virologia , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Monitorização Fisiológica/estatística & dados numéricos , Prognóstico , Edema Pulmonar/diagnóstico , Edema Pulmonar/imunologia , Edema Pulmonar/virologia , Respiração Artificial , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , Medição de Risco/métodos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Termodiluição/métodos , Termodiluição/estatística & dados numéricos , Adulto Jovem
3.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065857

RESUMO

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Neoplasias/genética , Progressão da Doença , Complexo I de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Predisposição Genética para Doença , Humanos , Mutação , Neoplasias/metabolismo , Polimorfismo Genético , Espécies Reativas de Oxigênio/metabolismo
4.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065952

RESUMO

White adipose tissue (WAT) is a heterogeneous tissue that is composed of adipocytes and several non-adipocyte cell populations, including adipose progenitors, fibroblasts, endothelial and infiltrating immune cells [...].


Assuntos
Tecido Adiposo Branco/metabolismo , Neoplasias da Mama/patologia , Adipogenia , Animais , Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos
5.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065983

RESUMO

Dysregulation of messenger RNA (mRNA) processing-in particular mRNA splicing-is a hallmark of cancer. Compared to normal cells, cancer cells frequently present aberrant mRNA splicing, which promotes cancer progression and treatment resistance. This hallmark provides opportunities for developing new targeted cancer treatments. Splicing of precursor mRNA into mature mRNA is executed by a dynamic complex of proteins and small RNAs called the spliceosome. Spliceosomes are part of the supraspliceosome, a macromolecular structure where all co-transcriptional mRNA processing activities in the cell nucleus are coordinated. Here we review the biology of the mRNA splicing machinery in the context of other mRNA processing activities in the supraspliceosome and present current knowledge of its dysregulation in lung cancer. In addition, we review investigations to discover therapeutic targets in the spliceosome and give an overview of inhibitors and modulators of the mRNA splicing process identified so far. Together, this provides insight into the value of targeting the spliceosome as a possible new treatment for lung cancer.


Assuntos
Neoplasias Pulmonares/genética , Splicing de RNA , Spliceossomos/metabolismo , Processamento Alternativo , Núcleo Celular/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo
6.
Med Clin North Am ; 105(4): 723-735, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34059247

RESUMO

Cellulitis is a common skin infection resulting in increasing hospitalizations and health care costs. There is no gold standard diagnostic test, making cellulitis a potentially challenging condition to distinguish from other mimickers. Physical examination typically demonstrates poorly demarcated unilateral erythema with warmth and tenderness. Thorough history and clinical examination can narrow the differential diagnosis of cellulitis and minimize unnecessary hospitalization. Antibiotic selection is determined by patient history and risk factors, severity of clinical presentation, and the most likely microbial culprit.


Assuntos
Celulite (Flegmão)/diagnóstico , Celulite (Flegmão)/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Dermatopatias Infecciosas/patologia , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Gestão de Antimicrobianos/métodos , Celulite (Flegmão)/fisiopatologia , Diagnóstico Diferencial , Progressão da Doença , Eritema/patologia , Custos de Cuidados de Saúde/estatística & dados numéricos , Hospitalização/economia , Humanos , Exame Físico/métodos , Valor Preditivo dos Testes , Fatores de Risco , Índice de Gravidade de Doença , Dermatopatias Infecciosas/microbiologia
7.
J BUON ; 26(2): 303-305, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34076972

RESUMO

COVID-19 pandemic has obviously affected patients' behavior towards seeking medical help as well as physicians' decision in the management of emergencies. Our recent experience as surgeons at a COVID-19 referral hospital revealed cases which share an alerting characteristic: the delay in appropriate management. Unfortunately for COVID-19 negative patients a "coronacentric" health system has been adopted. In view of measures applied to avoid spread of the disease, a significant delay in patients' presentation as well as in their in-hospital management is observed. We present cases where delay in appropriate management affected the patients' outcome and underline the fact that balancing between COVID-19 safety measures and a patient who needs urgent treatment can be very challenging and stressful.


Assuntos
Abscesso Abdominal/cirurgia , Teste para COVID-19 , COVID-19/diagnóstico , Atenção à Saúde , Aceitação pelo Paciente de Cuidados de Saúde , Tempo para o Tratamento , Abscesso Abdominal/diagnóstico , Adulto , Idoso de 80 Anos ou mais , Apendicite/diagnóstico , Apendicite/cirurgia , COVID-19/prevenção & controle , COVID-19/transmissão , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/cirurgia , Perfuração Intestinal/diagnóstico , Perfuração Intestinal/cirurgia , Tempo de Internação , Abscesso Hepático/diagnóstico , Abscesso Hepático/terapia , Masculino , Megacolo/diagnóstico , Megacolo/cirurgia , Pessoa de Meia-Idade , Segurança do Paciente , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
8.
NPJ Prim Care Respir Med ; 31(1): 33, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083541

RESUMO

Accurate prediction of the risk of progression of coronavirus disease (COVID-19) is needed at the time of hospitalization. Logistic regression analyses are used to interrogate clinical and laboratory co-variates from every hospital admission from an area of 2 million people with sporadic cases. From a total of 98 subjects, 3 were severe COVID-19 on admission. From the remaining subjects, 24 developed severe/critical symptoms. The predictive model includes four co-variates: age (>60 years; odds ratio [OR] = 12 [2.3, 62]); blood oxygen saturation (<97%; OR = 10.4 [2.04, 53]); C-reactive protein (>5.75 mg/L; OR = 9.3 [1.5, 58]); and prothrombin time (>12.3 s; OR = 6.7 [1.1, 41]). Cutoff value is two factors, and the sensitivity and specificity are 96% and 78% respectively. The area under the receiver-operator characteristic curve is 0.937. This model is suitable in predicting which unselected newly hospitalized persons are at-risk to develop severe/critical COVID-19.


Assuntos
COVID-19/diagnóstico , Hospitalização/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , COVID-19/patologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Prognóstico , Tempo de Protrombina , Curva ROC , Medição de Risco , Sensibilidade e Especificidade , Adulto Jovem
9.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072544

RESUMO

The development and progression of atherosclerosis (ATH) involves lipid accumulation, oxidative stress and both vascular and blood cell dysfunction. Erythrocytes, the main circulating cells in the body, exert determinant roles in the gas transport between tissues. Erythrocytes have long been considered as simple bystanders in cardiovascular diseases, including ATH. This review highlights recent knowledge concerning the role of erythrocytes being more than just passive gas carriers, as potent contributors to atherosclerotic plaque progression. Erythrocyte physiology and ATH pathology is first described. Then, a specific chapter delineates the numerous links between erythrocytes and atherogenesis. In particular, we discuss the impact of extravasated erythrocytes in plaque iron homeostasis with potential pathological consequences. Hyperglycaemia is recognised as a significant aggravating contributor to the development of ATH. Then, a special focus is made on glycoxidative modifications of erythrocytes and their role in ATH. This chapter includes recent data proposing glycoxidised erythrocytes as putative contributors to enhanced atherothrombosis in diabetic patients.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Suscetibilidade a Doenças , Eritrócitos/metabolismo , Animais , Aterosclerose/patologia , Biomarcadores , Citofagocitose , Progressão da Doença , Membrana Eritrocítica/imunologia , Membrana Eritrocítica/metabolismo , Heme/metabolismo , Hemoglobinas/metabolismo , Hemólise , Humanos , Estresse Oxidativo
10.
Cochrane Database Syst Rev ; 5: CD013029, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-34097768

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is one of the leading causes of blindness in high-income countries. The majority of cases of AMD are of the non-exudative type. Experts have proposed photobiomodulation (PBM) therapy as a non-invasive procedure to restore mitochondrial function, upregulate cytoprotective factors and prevent apoptotic cell death in retinal tissue affected by AMD. OBJECTIVES: To assess the effectiveness and safety of PBM compared to standard care, no treatment or sham treatment for people with non-exudative AMD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 5, 2020), Ovid MEDLINE, Embase, ISRCTN, ClinicalTrials.gov and the WHO ICTRP to 11 May 2020 with no language restrictions. SELECTION CRITERIA: The review included randomised controlled trials (RCTs) on participants receiving any type of PBM therapy for non-exudative AMD compared to standard care, sham treatment or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We considered the following outcome measures at 12 months: best-corrected visual acuity (BCVA) ; contrast sensitivity; near vision; low luminance density score; reading speed; vision-related quality of life score; and adverse events such as progression of AMD and conversion to exudative AMD. We graded the certainty of the evidence using GRADE. MAIN RESULTS: We included two published RCTs from single centres in the UK and Canada, which recruited 60 participants (60 eyes) and 30 participants (46 eyes) respectively. Participants in these trials were people with non-exudative AMD with Age-Related Eye Disease Study (AREDS) categories 2 to 4. One study compared single wavelength PBM with no treatment. This study was at risk of performance bias because the study was not masked, and there was attrition bias. One study compared multi-wavelength PBM with sham treatment and conflicts of interest were reported by study investigators. We also identified three eligible ongoing RCTs from searching the clinical trials database. When comparing PBM with sham treatment or no treatment for non-exudative AMD, there was no evidence of any meaningful clinical difference in BCVA at 12 months (mean difference (MD) 0.02 logMAR, 95% confidence interval (CI) -0.02 to 0.05; 2 RCTs, 90 eyes; low-certainty evidence). One study comparing multi-wavelength PBM with sham treatment showed an improvement in contrast sensitivity at Level E (18 cycles/degree) at 12 months (MD 0.29 LogCS, 95% CI 0.23 to 0.35; 1 RCT, 46 eyes; low-certainty evidence). Visual function and health-related quality of life scores were comparable between single wavelength PBM and no treatment groups at 12 months (VFQ-48 score MD 0.43, 95% CI -0.17 to 1.03; P = 0.16; 1 RCT, 47 eyes; low-certainty evidence). When comparing PBM with sham treatment or no treatment for non-exudative AMD, there was no evidence of any meaningful clinical difference in conversion to exudative AMD (risk ratio (RR) 0.97, 95% CI 0.17 to 5.44; 2 RCTs, 96 eyes; very low-certainty evidence) at 12 months. There was inconclusive evidence that single wavelength PBM prevents the progression of AMD (RR 0.79, 95% CI 0.41 to 1.53; P = 0.48; 1 RCT, 50 eyes; low-certainty evidence). Disease progression was defined as the development of advanced AMD or significant increase in drusen volume. No included study reported near vision, low luminance vision or reading speed outcomes. AUTHORS' CONCLUSIONS: Currently there remains uncertainty whether PBM treatment is beneficial in slowing progression of non-exudative macular degeneration. There is a need for further well-designed controlled trials assessing dosimetry, powered for both effectiveness and safety outcomes. Consideration should be given to the adoption of agreed clinical outcome measures and patient-based outcome measures for AMD.


Assuntos
Terapia com Luz de Baixa Intensidade/métodos , Degeneração Macular/radioterapia , Viés , Intervalos de Confiança , Sensibilidades de Contraste , Progressão da Doença , Humanos , Terapia com Luz de Baixa Intensidade/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde , Placebos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Acuidade Visual
11.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069993

RESUMO

Rett syndrome (RTT) is a rare neurodevelopmental disorder that is usually caused by mutations of the MECP2 gene. Patients with RTT suffer from severe deficits in motor, perceptual and cognitive domains. Electroencephalogram (EEG) has provided useful information to clinicians and scientists, from the very first descriptions of RTT, and yet no reliable neurophysiological biomarkers related to the pathophysiology of the disorder or symptom severity have been identified to date. To identify consistently observed and potentially informative EEG characteristics of RTT pathophysiology, and ascertain areas most worthy of further systematic investigation, here we review the literature for EEG abnormalities reported in patients with RTT and in its disease models. While pointing to some promising potential EEG biomarkers of RTT, our review identify areas of need to realize the potential of EEG including (1) quantitative investigation of promising clinical-EEG observations in RTT, e.g., shift of mu rhythm frequency and EEG during sleep; (2) closer alignment of approaches between patients with RTT and its animal models to strengthen the translational significance of the work (e.g., EEG measurements and behavioral states); (3) establishment of large-scale consortium research, to provide adequate Ns to investigate age and genotype effects.


Assuntos
Eletroencefalografia , Síndrome de Rett/diagnóstico , Síndrome de Rett/fisiopatologia , Animais , Biomarcadores , Modelos Animais de Doenças , Progressão da Doença , Fenômenos Eletrofisiológicos , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG/deficiência , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/fisiologia , Camundongos , Mutação , Fenótipo , Ratos , Síndrome de Rett/genética , Pesquisa Médica Translacional
12.
Nat Commun ; 12(1): 3430, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34078895

RESUMO

The limited availability of nasopharyngeal carcinoma-related progression biomarker array kits that offer physicians comprehensive information is disadvantageous for monitoring cancer progression. To develop a biomarker array kit, systematic identification and differentiation of a large number of distinct molecular surface-enhanced Raman scattering (SERS) reporters with high spectral temporal resolution is a major challenge. To address this unmet need, we use the chemistry of metal carbonyls to construct a series of unique SERS reporters with the potential to provide logical and highly multiplex information during testing. In this study, we report that geometric control over metal carbonyls on nanotags can produce 14 distinct barcodes that can be decoded unambiguously using commercial Raman spectroscopy. These metal carbonyl nanobarcodes are tested on human blood samples and show strong sensitivity (0.07 ng/mL limit of detection, average CV of 6.1% and >92% degree of recovery) and multiplexing capabilities for MMPs.


Assuntos
Técnicas Biossensoriais/métodos , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Análise Espectral Raman , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/química , Progressão da Doença , Metaloproteinases da Matriz/sangue , Metaloproteinases da Matriz/química , Nanopartículas Metálicas/química , Nanogéis/química , Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/patologia , Compostos Organometálicos/química , Sensibilidade e Especificidade , Propriedades de Superfície
13.
BMJ Open ; 11(6): e047007, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130961

RESUMO

OBJECTIVES: To investigate the risk factors contributing to severity on admission. Additionally, risk factors of worst severity and fatality were studied. Moreover, factors were compared based on three points: early severity, worst severity and fatality. DESIGN: An observational cohort study using data entered in a Japan nationwide COVID-19 inpatient registry, COVIREGI-JP. SETTING: As of 28 September 2020, 10480 cases from 802 facilities have been registered. Participating facilities cover a wide range of hospitals where patients with COVID-19 are admitted in Japan. PARTICIPANTS: Participants who had a positive test result on any applicable SARS-CoV-2 diagnostic tests were admitted to participating healthcare facilities. A total of 3829 cases were identified from 16 January to 31 May 2020, of which 3376 cases were included in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was severe or nonsevere on admission, determined by the requirement of mechanical ventilation or oxygen therapy, SpO2 or respiratory rate. Secondary outcome was the worst severity during hospitalisation, judged by the requirement of oxygen and/orinvasive mechanical ventilation/extracorporeal membrane oxygenation. RESULTS: Risk factors for severity on admission were older age, men, cardiovascular disease, chronic respiratory disease, diabetes, obesity and hypertension. Cerebrovascular disease, liver disease, renal disease or dialysis, solid tumour and hyperlipidaemia did not influence severity on admission; however, it influenced worst severity. Fatality rates for obesity, hypertension and hyperlipidaemia were relatively lower. CONCLUSIONS: This study segregated the comorbidities influencing severity and death. It is possible that risk factors for severity on admission, worst severity and fatality are not consistent and may be propelled by different factors. Specifically, while hypertension, hyperlipidaemia and obesity had major effect on worst severity, their impact was mild on fatality in the Japanese population. Some studies contradict our results; therefore, detailed analyses, considering in-hospital treatments, are needed for validation. TRIAL REGISTRATION NUMBER: UMIN000039873. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045453.


Assuntos
COVID-19 , Idoso , Estudos de Coortes , Progressão da Doença , Hospitalização , Humanos , Japão/epidemiologia , Masculino , Fatores de Risco , SARS-CoV-2 , Resultado do Tratamento
14.
Nat Commun ; 12(1): 3452, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103532

RESUMO

Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment.


Assuntos
Apraxias/diagnóstico por imagem , Apraxias/genética , Progressão da Doença , Neuroimagem , Fala , Idoso , Idoso de 80 Anos ou mais , Anisotropia , Apraxias/complicações , Apraxias/patologia , Disfunção Cognitiva/complicações , Imagem de Tensor de Difusão , Feminino , Fluordesoxiglucose F18/química , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neurobiologia , Neurônios/metabolismo , Neurônios/patologia , Patologia Molecular , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo
15.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066949

RESUMO

Neuroinflammation is one of the most significant factors involved in the initiation and progression of Parkinson's disease. PD is a neurodegenerative disorder with a motor disability linked with various complex and diversified risk factors. These factors trigger myriads of cellular and molecular processes, such as misfolding defective proteins, oxidative stress, mitochondrial dysfunction, and neurotoxic substances that induce selective neurodegeneration of dopamine neurons. This neuronal damage activates the neuronal immune system, including glial cells and inflammatory cytokines, to trigger neuroinflammation. The transition of acute to chronic neuroinflammation enhances the susceptibility of inflammation-induced dopaminergic neuron damage, forming a vicious cycle and prompting an individual to PD development. Epigenetic mechanisms recently have been at the forefront of the regulation of neuroinflammatory factors in PD, proposing a new dawn for breaking this vicious cycle. This review examined the core epigenetic mechanisms involved in the activation and phenotypic transformation of glial cells mediated neuroinflammation in PD. We found that epigenetic mechanisms do not work independently, despite being coordinated with each other to activate neuroinflammatory pathways. In this regard, we attempted to find the synergic correlation and contribution of these epigenetic modifications with various neuroinflammatory pathways to broaden the canvas of underlying pathological mechanisms involved in PD development. Moreover, this study highlighted the dual characteristics (neuroprotective/neurotoxic) of these epigenetic marks, which may counteract PD pathogenesis and make them potential candidates for devising future PD diagnosis and treatment.


Assuntos
Encéfalo/patologia , Epigênese Genética , Inflamação/genética , Inflamação/patologia , Doença de Parkinson/genética , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Progressão da Doença , Humanos
16.
BMC Infect Dis ; 21(1): 467, 2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34022827

RESUMO

BACKGROUND: Identifying and treating individuals with high risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease is critical for eliminating the disease. We aimed to conduct a systematic review and meta-regression analysis to quantify the dose-response relationship between interferon-gamma release assay (IGRA) levels and the risk of progression to active TB. METHODS: We searched PubMed and Embase from 1 January 2001 to 10 May 2020 for longitudinal studies that reported the risk of progression from latent to active TB as a function of baseline IGRA values. We used a novel Bayesian meta-regression method to pool effect sizes from included studies and generate a continuous dose-response risk curve. Our modeling framework enabled us to incorporate random effects across studies, and include data with different IGRA ranges across studies. The quality of included studies were assessed using the Newcastle-Ottawa scale (NOS). RESULTS: We included 34 studies representing 581,956 person-years of follow-up with a total of 788 incident cases of TB in the meta-regression analysis. Higher levels of interferon-gamma were associated with increased risk of progression to active tuberculosis. In the dose-response curve, the risk increased sharply between interferon-gamma levels 0 and 5 IU/ml, after which the risk continued to increase moderately but at a slower pace until reaching about 15 IU/ml where the risk levels off. Compared to 0 IU/ml, the relative risk of progression to active TB among those with interferon-gamma levels of 0.35, 1, 5, 10, 15, and 20 IU/ml were: 1.64 (1.28-2.08), 2.90 (2.02-3.88), 11.38 (6.64-16.38), 19.00 (13.08-26.90), 21.82 (14.65-32.57), and 22.31 (15.43-33.00), respectively. The dose-response relationship remains consistent when limiting the analysis to studies that scored highest in the NOS. CONCLUSION: The current practice of dichotomizing IGRA test results simplifies the TB infection disease continuum. Evaluating IGRA test results over a continuous scale could enable the identification of individuals at greatest risk of progression to active TB.


Assuntos
Progressão da Doença , Testes de Liberação de Interferon-gama/métodos , Interferon gama/sangue , Tuberculose Latente/sangue , Tuberculose Latente/epidemiologia , Mycobacterium tuberculosis/imunologia , Teorema de Bayes , Humanos , Tuberculose Latente/microbiologia , Tuberculose Latente/patologia , Estudos Longitudinais , Masculino , Análise de Regressão , Fatores de Risco , Teste Tuberculínico/métodos
17.
Crit Care ; 25(1): 175, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34034782

RESUMO

BACKGROUND: Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. METHODS: Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. RESULTS: Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). CONCLUSION: In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.


Assuntos
COVID-19/terapia , Estado Terminal/terapia , Terapia Respiratória/métodos , Terapia Respiratória/estatística & dados numéricos , Idoso , COVID-19/mortalidade , Estado Terminal/mortalidade , Progressão da Doença , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
18.
Eur J Endocrinol ; 185(1): 179-191, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33983135

RESUMO

Objective: Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translates these alterations into functional autonomy and potentially malignant behavior has not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs. Design and methods: MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact in vitro. Results: Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 2.35E-09) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests P = 7.96E-06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knockdown of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster. Conclusions: The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings.


Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Espectrometria de Massas/métodos , Metaboloma , Paraganglioma/patologia , Feocromocitoma/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Animais , Estudos de Coortes , Progressão da Doença , Feminino , Estudos de Associação Genética , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Metástase Neoplásica , Células PC12 , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/metabolismo , Prognóstico , Ratos , Análise Serial de Tecidos/métodos
19.
Front Immunol ; 12: 671013, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34046038

RESUMO

The impact of Covid-19 pneumonia caused by SARS-CoV-2 on transplanted populations under chronic immunosuppression seems to be greater than in normal population. Clinical management of the disease, particularly in those patients worsening after a cytokine storm, with or without allograft impairment and using available therapeutic approaches in the absence of specific drugs to fight against the virus, involves a major challenge for physicians. We herein provide evidence of the usefulness of high-dose intravenous immunoglobulin (IVIG) combined with steroid pulses to successfully treat a case of Covid-19 pneumonia in a single-kidney transplanted patient with mechanical ventilation and hemodialysis requirements in the setting of a cytokine storm. A rapid decrease in the serum level of inflammatory cytokines, particularly IL-6, IL-8, TNF-α, MCP-1 and IL-10, as well as of acute-phase reactants such as ferritin, D-dimer and C-reactive protein was observed after the IVIG infusion and methylprednisolone bolus administration with a parallel clinical improvement and progressive allograft function recovery, allowing the patient's final discharge 40 days after the treatment onset. The immunomodulatory effect of IVIG together with the anti-inflammatory and immunosuppressive potential of steroids could be an alternative strategy to treat severe cases of Covid-19 pneumonia associated with an uncontrolled inflammatory response in transplanted populations.


Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , Rejeição de Enxerto/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Falência Renal Crônica/terapia , Transplante de Rim , SARS-CoV-2/fisiologia , Esteroides/uso terapêutico , Transplantados , Doença Aguda , COVID-19/complicações , Progressão da Doença , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Diálise Renal , Respiração Artificial , Transplante Homólogo
20.
Surg Clin North Am ; 101(3): 381-389, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34048759

RESUMO

To care and treat patients with esophageal cancer, one must first understand the epidemiology of Barrett's esophagus (BE). BE is defined as the intestinal metaplasia occurring within the esophagus from normal squamous epithelium to abnormal specialized columnar epithelium. BE, while first described by Allison in 1948, was attributed to Norman Barrett in 1950, who reported a case of chronic peptic ulcer in the lower esophagus that was covered by columnar epithelium.


Assuntos
Adenocarcinoma/epidemiologia , Esôfago de Barrett/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Neoplasias Esofágicas/epidemiologia , Esôfago/patologia , Lesões Pré-Cancerosas/epidemiologia , Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Neoplasias Esofágicas/patologia , Humanos , Metaplasia , Lesões Pré-Cancerosas/patologia , Estados Unidos/epidemiologia
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