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1.
Health Sci Rep ; 5(3): e603, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35509386

RESUMO

Background: The waves of COVID-19 infections in Ontario, Canada, were marked by differences in patient characteristics and treatment. Our objectives were to (i) describe patient characteristics, treatment, and outcomes of hospitalized older adults with COVID-19 between waves 1, 2, and 3, (ii) determine if there was an improvement in in-hospital mortality in waves 2 and 3 after adjusting for covariates. Methods: This retrospective cohort study was done in five acute care hospitals in Toronto, Ontario. Consecutive hospitalized older adults aged ≥65 years with confirmed COVID-19 infection were included. Wave 1 extended from March 11 to July 31, 2020, wave 2 from August 1, 2020 to February 20, 2021, and wave 3 from February 21 to June 30, 2021. Patient characteristics and outcomes were abstracted from charts. A logistic regression model was used to determine the association between COVID-19 and in-hospital mortality in waves 2 and 3 compared with wave 1. Results: Of the 1671 patients admitted to acute care, 297 (17.8%) were admitted in wave 1, 751 (44.9%) in wave 2, and 623 (37.3%) in wave 3. The median age of our cohort was 77.0 years (interquartile range: 71.0-85.0) and 775 (46.4%) were female. The prevalence of frailty declined in progressive waves. The use of dexamethasone, remdesivir, and tocilizumab was significantly higher in waves 2 and 3 compared with wave 1. In the unadjusted analysis, in-hospital mortality was unchanged between waves 1 and 2, but it was lower in wave 3 (18.3% vs. 27.4% in wave 1). After adjustment, in-hospital mortality was unchanged in waves 2 and 3 compared with wave 1. Conclusion: In-hospital mortality in hospitalized older adults with COVID-19 was similar between waves 1 and 3. Further research should be done to determine if COVID-19 therapies have similar benefits for older adults compared with younger adults.

2.
Health Sci Rep ; 5(3): e608, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35509396

RESUMO

Background and Aims: Activity monitors, such as Fitbits®, are being used increasingly for research purposes and data have been validated in healthy community-dwelling older adults. Given the lack of research in older adults with neurocognitive disorders, we investigated the consistency of sleep data recorded from a wrist-worn activity monitor in this population. Methods: Fitbit® activity monitors were worn by hospitalized older adults as part of a parent study investigating sleep and step count in patients recovering from hip fracture surgery in a tertiary care academic hospital in Hamilton, Canada between March 2018 and June 2019. In this secondary analysis, we compared the proportion of missing sleep data between participants with and without a neurocognitive disorder and used a multivariable model to assess the association between neurocognitive disorder and missing sleep data. Results: Of 67 participants included in the analysis, 22 had a neurocognitive disorder (median age: 86.5 years). Sleep data were missing for 47% of the neurocognitive disorder group and 23% of the non-neurocognitive disorder group. The presence of a neurocognitive disorder was associated with an increased likelihood of missing sleep data using the Fitbit® activity monitors (adjusted odds ratio: 3.41; 95% confidence interval: 1.06-11.73, p = 0.04). Conclusion: The inconsistent nature of sleep data tracking in hospitalized older adults with neurocognitive disorders highlights the challenges of using interventions in patient populations who are often excluded from validation studies. As opportunities expand for activity monitoring in persons with neurocognitive disorders, novel technologies not previously studied in this group should be used with caution.

3.
Mol Ther ; 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35443935

RESUMO

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton's tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment.

4.
J Am Chem Soc ; 144(12): 5424-5434, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35302371

RESUMO

A new class of alkynylplatinum(II) bzimpy (bzimpy = bis(benzimidazol-2-yl)pyridine) double complex salts (DCSs) containing dialkoxynaphthalene or pyromellitic diimide moieties on the alkynyl ligand has been reported to display distinct morphological properties compared to their precursor alkynylplatinum(II) complexes, with the capability of being aligned by the directional Pt···Pt and/or π-π stacking interactions. The incorporation of donor and acceptor units on the alkynyl ligands has been found to significantly perturb the alignment of the oppositely charged complex ions in the DCSs to stack in a twisted head-to-head manner, attributed to the additional driving forces of electrostatic and donor-acceptor interactions. The modulation of the Pt···Pt distances and the extent of aggregate formation have been demonstrated by altering the charge matching between the platinum(II) bzimpy moieties and the donor or acceptor moieties on the alkynyl ligand.

5.
Phytother Res ; 36(4): 1748-1760, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35174914

RESUMO

Antitumor and antimetastatic effects of the medicinal herb Andrographis paniculata (AP) in esophageal cancer (EC) have been previously reported. In this study, we aimed to uncover the potential functional components and the underlying molecular mechanisms of AP in EC treatment using network pharmacology and experimental validation. Twenty-two potential active AP compounds against EC were revealed, including the antitumor/antiinflammatory compounds panicolin, moslosooflavone, and deoxyandrographiside. Epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), RAC-alpha serine/threonine-protein kinase (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), chemokine (C-X-C motif) ligand 8 (CXCL8), phosphatidylinositol 4,5-bisphosphate 3-kinase subunit alpha (PIK3CA), and toll-like receptor 4 (TLR4) were most highly ranked among the predicted targets of AP in EC treatment and may play important roles in the anti-EC effects of AP. KEGG pathway analysis revealed the enrichment of multiple cancer-related pathways and signaling pathways. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting validation showed that overnight treatment with 850.3 µg/ml of AP water extract significantly reduced the mRNA expressions of EGFR and AKT in human EC-109 cells. The presence of panicolin and moslosooflavone in the AP water extract samples were confirmed using LC-MS against reference standards. This study has comprehensively revealed for the first time the potential functional components of AP in EC and explored the underlying molecular mechanisms. Future studies should characterize the potential pharmacological properties of the other highly ranked yet understudied compounds in AP detected.


Assuntos
Andrographis , Neoplasias Esofágicas , Receptores ErbB , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Humanos , Água
6.
Avian Dis ; 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35191652

RESUMO

Runting stunting syndrome (RSS) in broiler chickens is characterized by altered intestinal morphology and gene expression and stunted growth. The objective of this study was to conduct a retrospective study of gene expression in stem and differentiated cells in the small intestine of RSS chicks. Two different models of RSS were analyzed: broiler chicks that were experimentally infected and broiler chicks that were naturally infected. Experimentally infected chicks were exposed to litter from infected flocks (RSS-litter chicks) or infected with astrovirus (RSS-astrovirus chicks). Intestinal samples from naturally infected chicks showing clinical signs of RSS were acquired from commercial farms in Georgia and were brought into a poultry diagnostic lab (RSS-clinical-GA) and from farms in Brazil that had a history of RSS (RSS-clinical-BR). The RSS-clinical-BR chicks were separated into those that were positive or negative for gallivirus based on DNA sequencing. Intestinal morphology and intestinal cell type were identified in archived formalin-fixed, paraffin-embedded tissues. In situ hybridization for cell-specific mRNA was used to identify intestinal stem cells expressing olfactomedin 4 (Olfm4), proliferating cells expressing Ki67, absorptive cells expressing sodium glucose cotransporter 1 (SGLT1) and peptide transporter 1 (PepT1), and goblet cells expressing mucin 2 (Muc2). RSS-litter and RSS-clinical-GA chicks showed 4% to 7.5% cystic crypts, while gallivirus-positive RSS-clinical-BR chicks showed 11.7% cystic crypts. RSS-astrovirus and gallivirus-negative RSS-clinical-BR chicks showed few cystic crypts. RSS-litter and gallivirus-positive RSS-clinical-BR chicks showed an increase in crypt depth compared to control or gallivirus-negative chicks, respectively. There was no expression of Olfm4 mRNA in the stem cells of RSS-litter and RSS-clinical-GA chicks, in contrast to the normal expression of Olfm4 mRNA in RSS-astrovirus and RSS-clinical-BR chicks. All chicks regardless of infection status showed normal expression of Ki67 mRNA in crypt cells, Muc2 mRNA in goblet cells, and SGLT1 or PepT1 mRNA in enterocytes. These results demonstrate that RSS, which can be induced by different etiologies, can show differences in the expression of the stem cell marker Olfm4.


El síndrome del enanismo infeccioso en pollos de engorde se asocia con alteración de la morfología de las células madre intestinales y la expresión de genes. El síndrome del enanismo infeccioso (con las siglas en inglés RSS) en pollos de engorde se caracteriza por alteraciones en la morfología intestinal y en la expresión de genes, además de retraso en el crecimiento. El objetivo de este estudio fue realizar un estudio retrospectivo de la expresión genética en células madre y células diferenciadas en el intestino delgado de pollitos con el síndrome del enanismo infeccioso. Se analizaron dos modelos diferentes del síndrome del enanismo infeccioso: en pollos de engorde que fueron infectados experimentalmente y en pollos de engorde infectados naturalmente. Los pollitos infectados experimentalmente se expusieron a la cama de parvadas infectadas (RSS-litter chicks), o infectados con astrovirus (RSS-astrovirus chicks). Se adquirieron muestras intestinales de pollitos infectados naturalmente que mostraban signos clínicos del síndrome del enanismo infeccioso de granjas comerciales en Georgia y se llevaron a un laboratorio de diagnóstico avícola (RSS-Clinical-GA) y de granjas en Brasil que tenían antecedentes del síndrome del enanismo infeccioso (RSS-Clinical-BR). Los pollitos de granjas de Brasil (RSS-Clinical-BR) se separaron en aquellos que fueron positivos o negativos para gallivirus de acuerdo con la secuenciación del ADN. Se identificaron la morfología intestinal y el tipo de células intestinales en tejidos archivados fijados con formalina e incluidos en parafina. La hibridación in situ para ARNm específico de células se utilizó para identificar células madre intestinales que expresan olfactomedina 4 (Olfm4), células en proliferación que expresaban Ki67, células absorbentes que expresan el cotransportador 1 de glucosa y sodio (SGLT1) y el transportador de péptidos 1 (PepT1), y células caliciformes que expresan mucina 2 (Muc2). Los pollos expuestos a cama infectada (RSS-litter) y los infectados naturalmente de Georgia (RSS-clinical-GA) mostraron entre un 4% y un 7.5% de criptas quísticas, mientras que los pollos infectados de granjas de Brasil (RSS-clinical-BR) que eran positivos para gallivirus mostraron un 11.7% de criptas quísticas. Los pollos infectados con astrovirus (RSS-astrovirus chicks) y los pollos de Brasil (RSS-clinical-BR) que eran negativos para gallivirus mostraron pocas criptas quísticas. Los pollos expuestos a cama infectada (RSS-litter chicks) y los pollos infectados de Brasil (RSS-clinical-BR) que eran positivos para gallivirus mostraron un aumento en la profundidad de las criptas en comparación con los pollos control o negativos para el gallivirus, respectivamente. No se observó expresión de ARNm de Olfm4 en las células madre de pollitos expuestos a cama infectada (RSS-litter chicks) ni en pollos infectados de Georgia (RSS-clinical-GA), en contraste con la expresión normal de ARNm de Olfm4 en pollitos infectados con astrovirus (RSS-astrovirus chicks) y en pollitos infectados de Brasil (RSS-clinical-BR). Todos los pollos, independientemente del estado de infección, mostraron una expresión normal de ARNm para Ki67 en las células de la cripta, de ARNm para Muc2 en las células caliciformes y ARNm de SGLT1 o PepT1 en los enterocitos. Estos resultados demuestran que el síndrome del enanismo infeccioso, que puede ser inducido por diferentes etiologías, puede mostrar diferencias en la expresión del marcador para células madre Olfm4.

7.
Anim Nutr ; 8(1): 91-101, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34977379

RESUMO

Nutritional stimulation of the developing small intestine of chick embryos can be conducted by in-ovo feeding (IOF). We hypothesized that IOF of glutamine and leucine can enhance small intestinal development by promoting proliferation and differentiation of multipotent small intestinal epithelial cells. Broiler embryos (n = 128) were subject to IOF of glutamine (IOF-Gln), leucine (IOF-Leu), NaCl (IOF-NaCl) or no injection (control) at embryonic d 17 (E 17). Multipotent, progenitor and differentiated cells were located and quantified in the small intestinal epithelium between E 17 and d 7 after hatch (D 7) in all treatment groups by immunofluorescence of SRY-box transcription factor 9 (Sox9) and proliferating cell nuclear antigen (PCNA), in-situ hybridization of leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) and peptide transporter 1 (PepT1) and histochemical goblet cell staining. The effects of IOF treatments at E 19 (48 h post-IOF), in comparison to control embryos, were as follows: total cell counts increased by 40%, 33% and 19%, and multipotent cell counts increased by 52%, 50% and 38%, in IOF-Gln, IOF-Leu and IOF-NaCl embryos, respectively. Only IOF-Gln embryos exhibited a significance, 36% increase in progenitor cell counts. All IOF treatments shifted Lgr5+ stem cell localizations to villus bottoms. The differentiated, PepT1+ region of the villi was 1.9 and 1.3-fold longer in IOF-Gln and IOF-Leu embryos, respectively, while goblet cell densities decreased by 20% in IOF-Gln embryos. Post-hatch, crypt and villi epithelial cell counts were significantly higher IOF-Gln chicks, compared to control chicks (P < 0.05). We conclude IOF of glutamine stimulates small intestinal maturation and functionality during the peri-hatch period by promoting multipotent cell proliferation and differentiation, resulting in enhanced compartmentalization of multipotent and differentiated cell niches and expansions of the absorptive surface area.

8.
Magn Reson Med ; 87(6): 2667-2684, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35061920

RESUMO

PURPOSE: Spatially selective arterial spin labeling (ASL) perfusion MRI is sensitive to arterial transit times (ATT) that can result in inaccurate perfusion quantification when ATTs are long. Velocity-selective ASL is robust to this effect because blood is labeled within the imaging region, allowing immediate label delivery. However, velocity-selective ASL cannot characterize ATTs, which can provide important clinical information. Here, we introduce a novel pulse sequence, called VESPA ASL, that combines velocity-selective and pseudo-continuous ASL to simultaneously label different pools of arterial blood for robust cerebral blood flow (CBF) and ATT measurement. METHODS: The VESPA ASL sequence is similar to velocity-selective ASL, but the velocity-selective labeling is made spatially selective, and pseudo-continuous ASL is added to fill the inflow time. The choice of inflow time and other sequence settings were explored. VESPA ASL was compared to multi-delay pseudo-continuous ASL and velocity-selective ASL through simulations and test-retest experiments in healthy volunteers. RESULTS: VESPA ASL is shown to accurately measure CBF in the presence of long ATTs, and ATTs < TI can also be measured. Measurements were similar to established ASL techniques when ATT was short. When ATT was long, VESPA ASL measured CBF more accurately than multi-delay pseudo-continuous ASL, which tended to underestimate CBF. CONCLUSION: VESPA ASL is a novel and robust approach to simultaneously measure CBF and ATT and offers important advantages over existing methods. It fills an important clinical need for noninvasive perfusion and transit time imaging in vascular diseases with delayed arterial transit.


Assuntos
Circulação Cerebrovascular , Imageamento por Ressonância Magnética , Artérias/diagnóstico por imagem , Velocidade do Fluxo Sanguíneo/fisiologia , Circulação Cerebrovascular/fisiologia , Humanos , Imageamento por Ressonância Magnética/métodos , Perfusão , Marcadores de Spin
9.
Child Abuse Negl ; 124: 105454, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34991013

RESUMO

BACKGROUND: Emotion regulation has been identified as an explanatory factor in the association between interpersonal childhood adversity and post-traumatic stress symptoms (PTSS). However, most studies focused on adults or older adolescents, neglecting youth from the community, especially gender and sexually diverse (GSD) adolescents, who have a higher risk for exposure to adverse events and psychological difficulties, compared to their heterosexual, cisgender (HC) peers. OBJECTIVE: The present cross-sectional study aimed to examine the mediating role of emotion regulation difficulties in the association between cumulative interpersonal childhood adversity and PTSS across HC and GSD adolescents. METHODS: A sample of 2904 ninth grade students (Mage = 14.53, SD = 0.61) completed a self-report survey. Multigroup path analyses were conducted to examine the proposed mediation model in all groups, and comparisons were made using chi-square difference tests. RESULTS: Greater difficulties in emotion regulation mediated the association between greater cumulative interpersonal childhood adversity (ß = 0.36, p < .001) and greater PTSS (ß = 0.35, p < .001) - regardless of HC or GSD status - although the direct association between cumulative interpersonal childhood adversity and PTSS was significantly stronger among GSD boys (ß = 0.36, p < .001) and GSD girls (ß = 0.35, p < .001) than among HC boys (ß = 0.21, p < .001) and HC girls (ß = 0.25, p < .001). CONCLUSIONS: Findings offer a modifiable target for prevention and/or intervention among middle adolescents, as emotion regulation difficulties may partially explain the presence of PTSS following cumulative interpersonal childhood adversity.


Assuntos
Experiências Adversas da Infância , Regulação Emocional , Transtornos de Estresse Pós-Traumáticos , Adolescente , Adulto , Estudos Transversais , Feminino , Heterossexualidade , Humanos , Masculino , Transtornos de Estresse Pós-Traumáticos/epidemiologia
10.
Haematologica ; 107(1): 178-186, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33375775

RESUMO

Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.


Assuntos
Leucemia Mielomonocítica Juvenil , Adulto , Criança , Humanos , Leucemia Mielomonocítica Juvenil/genética , Mutação , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-cbl/genética
11.
Blood ; 139(6): 894-906, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34582559

RESUMO

Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells. Menin-MLL1 inhibition upregulates markers of differentiation such as CD11b and downregulates expression of proleukemogenic transcription factors such as Meis1 in NUP98-fusion-transformed leukemia cells. We demonstrate that MLL1 and the NUP98 fusion protein itself are evicted from chromatin at a critical set of genes that are essential for the maintenance of the malignant phenotype. In addition to these in vitro studies, we established patient-derived xenograft (PDX) models of NUP98-fusion-driven AML to test the in vivo efficacy of menin-MLL1 inhibition. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias. Gene expression analysis revealed that menin-MLL1 inhibition simultaneously suppresses a proleukemogenic gene expression program, including downregulation of the HOXa cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas Proto-Oncogênicas/metabolismo , Animais , Linhagem Celular Tumoral , Regulação Leucêmica da Expressão Gênica , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Leucina Linfoide-Mieloide/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas/genética
12.
J Intern Med ; 291(5): 694-697, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34875129

RESUMO

Coronavirus disease-19 (COVID-19) has resulted in much acute morbidity and mortality worldwide. There is now a growing recognition of the post-acute sequela of COVID-19, termed long COVID. However, the risk factors contributing to this condition remain unclear. Here, we address the growing controversy in the literature of whether hospitalization is a risk factor for long COVID. We found that hospitalization is associated with worse pulmonary restriction and reduction in diffusion capacity at 3 months post-infection. However, the impact on mental health, functional and quality of life is equally severe in those who have and have not been hospitalized during the acute infection. These findings suggest that hospitalization is a risk factor for pulmonary complications of long COVID but not the overall severity of long COVID.


Assuntos
COVID-19 , COVID-19/complicações , Progressão da Doença , Hospitalização , Humanos , Qualidade de Vida , SARS-CoV-2
13.
Neural Comput ; 34(2): 415-436, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-34915556

RESUMO

The brain is thought to represent information in the form of activity in distributed groups of neurons known as attractors. We show here that in a randomly connected network of simulated spiking neurons, periodic stimulation of neurons with distributed phase offsets, along with standard spike-timing-dependent plasticity (STDP), efficiently creates distributed attractors. These attractors may have a consistent ordered firing pattern or become irregular, depending on the conditions. We also show that when two such attractors are stimulated in sequence, the same STDP mechanism can create a directed association between them, forming the basis of an associative network. We find that for an STDP time constant of 20 ms, the dependence of the efficiency of attractor creation on the driving frequency has a broad peak centered around 8 Hz. Upon restimulation, the attractors self-oscillate, but with an oscillation frequency that is higher than the driving frequency, ranging from 10 to 100 Hz.


Assuntos
Plasticidade Neuronal , Neurônios , Potenciais de Ação/fisiologia , Encéfalo/fisiologia , Modelos Neurológicos , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia
14.
Ann Surg ; 2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-34966066

RESUMO

OBJECTIVE: To quantify the absolute risks of adverse fetal outcomes and maternal mortality following non-obstetric abdominopelvic surgery in pregnancy. SUMMARY BACKGROUND DATA: Surgery is often necessary in pregnancy, but absolute measures of risk required to guide perioperative management are lacking. METHODS: We systematically searched MEDLINE, EMBASE, and Evidence-Based Medicine Reviews from January 1, 2000, to December 9, 2020, for observational studies and randomized trials of pregnant patients undergoing non-obstetric abdominopelvic surgery. We determined the pooled proportions of fetal loss, preterm birth, and maternal mortality using a generalized linear random/mixed effects model with a logit link. RESULTS: We identified 114 observational studies (52 [46%] appendectomy, 34 [30%] adnexal, 8 [7%] cholecystectomy, 20 [17%] mixed types) reporting on 67,111 pregnant patients. Overall pooled proportions of fetal loss, preterm birth, and maternal mortality were 2.8% (95% CI 2.2-3.6), 9.7% (95% CI 8.3-11.4), and 0.04% (95% CI 0.02-0.09; 4/10,000), respectively. Rates of fetal loss and preterm birth were higher for pelvic inflammatory conditions (e.g. appendectomy, adnexal torsion) than for abdominal or non-urgent conditions (e.g. cholecystectomy, adnexal mass). Surgery in the second and third trimester was associated with lower rates of fetal loss (0.1%) and higher rates of preterm birth (13.5%) than surgery in the first and second trimester (fetal loss 2.9%, preterm birth 5.6%). CONCLUSIONS: Absolute risks of adverse fetal outcomes after non-obstetric abdominopelvic surgery vary with gestational age, indication, and acuity. Pooled estimates derived here identify high-risk clinical scenarios, and can inform implementation of mitigation strategies and improve preoperative counselling.

15.
Front Immunol ; 12: 749094, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630428

RESUMO

Allogeneic stem cell transplantation (alloSCT) is utilised to cure haematological malignancies through a combination of conditioning regimen intensity and immunological disease control via the graft versus tumour (GVT) effect. Currently, conventional myeloablative chemotherapeutic or chemoradiation conditioning regimens are associated with significant side effects including graft versus host disease (GVHD), infection, and organ toxicity. Conversely, more tolerable reduced intensity conditioning (RIC) regimens are associated with unacceptably higher rates of disease relapse, partly through an excess incidence of mixed chimerism. Improvement in post-alloSCT outcomes therefore depends on promotion of the GVT effect whilst simultaneously reducing conditioning-related toxicity. We have previously shown that this could be achieved through BCL-2 inhibition, and in this study, we explored the modulation of JAK1/2 as a strategy to lower the barrier to donor engraftment in the setting of RIC. We investigated the impact of short-term treatment of BCL2 (venetoclax) or JAK1/2 (ruxolitinib) inhibition on recipient natural killer and T cell immunity and the subsequent effect on donor engraftment. We identified striking differences in mechanism of action of these two drugs on immune cell subsets in the bone marrow of recipients, and in the regulation of MHC class-II and interferon-inducible gene expression, leading to different rates of GVHD. This study demonstrates that the repurposed use of ruxolitinib or venetoclax can be utilised as pre-transplant immune-modulators to promote the efficacy of alloSCT, whilst reducing its toxicity.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Inibidores de Janus Quinases/uso terapêutico , Nitrilas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Condicionamento Pré-Transplante , Animais , Feminino , Genes MHC da Classe II , Interferons/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplantados , Transplante Homólogo
16.
Food Sci Technol Int ; : 10820132211050203, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34632838

RESUMO

Ultrasound is a useful alternative to thermal processing that can be applied to many food products and juices to aid with enzymes and microorganism inactivation and to improve the efficiency of unit operations generally applied in the food industry. The aim of this study was to evaluate the effect of a high-intensity sonication treatment (frequency 20 kHz; intensity 39.4 W/cm2) applied for treatment times from 0 to 105 min on the content of polyphenols, vitamin C, organic acids, and carotenoids, and on the hydrophilic and lipophilic antioxidant capacity and color of orange juice. Treatments were performed in triplicate and data was statistically analyzed. Sonication time did not have a significant effect (P > 0.05) on total polyphenols, total vitamin C, organic acid, and carotenoid contents, lipophilic antioxidant capacity, or juice color. The hydrophilic antioxidant activity and the lutein content increased significantly (P < 0.05) with increased sonication time. These results may be useful as a baseline for the development of sonication treatments that could be used in combination with other traditional and emerging processing approaches to protect the most important bioactive compounds and quality properties of orange juice.

17.
F1000Res ; 10: 87, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34631013

RESUMO

Background: Multiple long-term care (LTC) reports have issued similar recommendations for improvement across Canadian LTC homes. Our primary objective was to identify the most common recommendations made over the past 10 years. Our secondary objective was to estimate the total cost of studying LTC issues repeatedly from 1998 to 2020. Methods: The qualitative and cost analyses were conducted in Canada from July to October 2020. Using a list of reports, inquiries and commissions from The Royal Society of Canada Working Group on Long-Term Care, we coded recurrent recommendations in LTC reports. We contacted the sponsoring organizations for a cost estimate, including direct and indirect costs. All costs were adjusted to 2020 Canadian dollar values. Results: Of the 80 Canadian LTC reports spanning the years of 1998 to 2020, 24 (30%) were based on a national level and 56 (70%) were focused on provinces or municipalities. Report length ranged from 4 to 1491 pages and the median number of contributors was 14 (interquartile range, IQR, 5-26) per report. The most common recommendation was to increase funding to LTC to improve staffing, direct care and capacity (67% of reports). A median of 8 (IQR 3.25-18) recommendations were made per report. The total cost for all 80 reports was estimated to be $23,626,442.78. Conclusions: Problems in Canadian LTC homes and their solutions have been known for decades. Despite this, governments and non-governmental agencies continue to produce more reports at a monetary and societal cost to Canadians.


Assuntos
Assistência de Longa Duração , Canadá , Custos e Análise de Custo , Humanos , Recursos Humanos
18.
Phys Rev Lett ; 127(11): 117202, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34558931

RESUMO

Recently, antiferromagnets have received revived interest due to their significant potential for developing next-generation ultrafast magnetic storage. Here, we report dc spin pumping by the acoustic resonant mode in a canted easy-plane antiferromagnet α-Fe_{2}O_{3} enabled by the Dzyaloshinskii-Moriya interaction. Systematic angle and frequency-dependent measurements demonstrate that the observed spin-pumping signals arise from resonance-induced spin injection and inverse spin Hall effect in α-Fe_{2}O_{3}-metal heterostructures, mimicking the behavior of spin pumping in conventional ferromagnet-nonmagnet systems. The pure spin current nature is further corroborated by reversal of the polarity of spin-pumping signals when the spin detector is switched from platinum to tungsten which has an opposite sign of the spin Hall angle. Our results reveal the intriguing physics underlying the low-frequency spin dynamics and transport in canted easy-plane antiferromagnet-based heterostructures.

19.
J Occup Environ Med ; 63(9): 779-786, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34491965

RESUMO

OBJECTIVE: Determine effects on respiratory health of firefighters attending a catastrophic wildfire. METHODS: Within the Alberta Administrative Health Database, we identified five community-based controls for each firefighter in a cohort of 1234 deployed to the 2016 Fort McMurray fire. Spirometry records were identified and a stratified sample assessed clinically. We estimated PM2.5 particles exposure. RESULTS: Firefighters had an increased risk of asthma consultation post-fire (OR new onset asthma = 2.56; 95%CI 1.75 to 3.74). Spirometry showed decreased FEV1 and FVC with increasing exposure. In the clinical assessment, 20% had a positive MCT and 21% BWT. Those with ongoing fire-related symptoms had a higher concurrence of positive MCT and BWT (OR = 4.35; 95%CI 1.11 to 17.12). Lower diffusion capacity related to higher exposure. CONCLUSIONS: Massive exposures during a wildfire are associated with non-resolving airways damage.


Assuntos
Bombeiros , Incêndios , Exposição Ocupacional , Incêndios Florestais , Alberta/epidemiologia , Estudos de Coortes , Humanos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise
20.
Chest ; 160(2): e209-e215, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34366047

RESUMO

CASE PRESENTATION: A 34-year-old previously healthy man of Korean descent (height, 174 cm; weight, 47.4 kg) demonstrated dyspnea with cough and chest tightness. The patient had no relevant occupational exposures and no history of illicit drug or tobacco use. His medical history was notable for chronic sinus tachycardia of undetermined cause, hypertension, gout, glaucoma of the right eye, and a remote history of an intracranial malignancy 24 years prior treated with unspecified chemotherapy, craniotomy, and ventriculoperitoneal shunt placement. His active medications included diltiazem, candesartan, and colchicine as needed.


Assuntos
Fibrose Pulmonar Idiopática/diagnóstico , Doenças Pleurais/diagnóstico , Adulto , Diagnóstico Diferencial , Diagnóstico por Imagem , Dispneia , Humanos , Masculino , Pneumotórax
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