Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 134
Filtrar
1.
Pharmacol Res ; : 105919, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34601080

RESUMO

With the coming of the era of the aging population, hypertension has become a global health burden to be dealt with. Although there are multiple drugs and procedures to control the symptoms of hypertension, the management of it is still a long-term process, and the side effects of conventional drugs pose a burden on patients. Flavonoids, common compounds found in fruits and vegetables as secondary metabolites, are active components in Chinese Herbal Medicine. The flavonoids are proved to have cardiovascular benefits based on a plethora of animal experiments over the last decade. Thus, the flavonoids or flavonoid-rich plant extracts endowed with anti-hypertension activities and probable mechanisms were reviewed. It has been found that flavonoids may affect blood pressure in various ways. Moreover, despite the substantial evidence of the potential for flavonoids in the control of hypertension, it is not sufficient to support the clinical application of flavonoids as an adjuvant or core drug. So the synergistic effects of flavonoids with other drugs, pharmacokinetic studies, clinical trials and the safety of flavonoids are also incorporated in the discussion. It is believed that more breakthrough studies are needed. Overall, this review may shed some new light on the explicit recognition of the mechanisms of anti-hypertension actions of flavonoids, pointing out the limitations of relevant research at the current stage and the aspects that should be strengthened in future researches.

2.
Ann Neurol ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34617306

RESUMO

OBJECTIVE: Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationship - manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region-based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology. METHODS: Cortical thickness (N) and 18 F-Flortaucipir SUVR (T) were computed in 104 gray matter regions from a cohort of cognitively-impaired, amyloid-positive (A+) individuals. Region-specific residuals from a robust linear fit between SUVR and cortical thickness were computed as a surrogate for T-N mismatch. A summary T-N mismatch metric defined using residuals were correlated with demographic and imaging-based modulatory factors, and to partition the cohort into data-driven subgroups. RESULTS: The summary T-N mismatch metric correlated with underlying factors such as age and burden of white matter hyperintensity lesions. Data-driven subgroups based on clustering of residuals appear to represent different biologically relevant phenotypes, with groups showing distinct spatial patterns of higher or lower atrophy than expected. INTERPRETATION: These data support the notion that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may help identify possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials. ANN NEUROL 2021.

3.
Leuk Lymphoma ; : 1-8, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477034

RESUMO

Acute myelomagakaryocytic leukemia is a diagnostic and therapeutic challenge owing to its heterogeneity and overlapping features with other types of acute leukemia. In order to build a diagnostic profile, we analyzed the biological, clinical and hematologic characteristics of acute myelomagakaryocytic leukemia. We found that, in three patients diagnosed with acute myelomagakaryocytic leukemia, there were two types of leukemia cells. One type was myeloblastic with positive peroxidase (POX) stainig and the expression of antigens CD13 and CD33. The other type was megakaryoblastic with negative POX staining and the expression of antigens CD36, CD41, CD42a and CD61. Three patients displayed the same cytogenetic abnormality, a (9: 22) translocation. Among the three patients with RT-PCR, two patients displayed BCR-ABL fusion gene amplification and one patient showed a previously undescribed OTT-MAL fusion gene amplification.

4.
BMC Oral Health ; 21(1): 462, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556118

RESUMO

BACKGROUND: How to prevent pain after the extraction of impacted teeth is a serious challenge for all patients. The purpose of this clinical trial was to investigate whether pre-emptive low dose of etoricoxib can reduce postoperative pain in patients undergoing third molars surgery. METHODS: Patients were randomised to receive etoricoxib 60 mg or placebo 30 min before surgery. Post-operative pain was recorded using a visual analogue scale during 24 h within the post-operative period. The total dose of ibuprofen rescue intake was recorded. Kaplan-Meier curves and log-rank analyses were used to evaluate the proportion of patients without rescue analgesic. RESULTS: Scores for the post-operative pain in the etoricoxib group were significantly lower than those in the placebo group during first 12 h (p < 0.05). The number of patients without analgesic rescue medication was significantly lower in the etoricoxib group than in the placebo group. The average amount of rescue medication in the etoricoxib group (0.4 ± 0.9 dose) was lower than that in the placebo group (1.1 ± 0.9 doses, p = 0.004). Etoricoxib resulted in the long-term survival of patients without rescue analgesic (p < 0.001). CONCLUSIONS: This study revealed that etoricoxib has a substantial pre-emptive analgesic effect, resulting in the reduced use of analgesics after third molar removal. TRIAL REGISTRATION: Registered on ChiCTR1900024503. Date of Registration: 13/07/2019.


Assuntos
Dente Serotino , Dente Impactado , Método Duplo-Cego , Etoricoxib , Humanos , Dente Serotino/cirurgia , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Extração Dentária , Dente Impactado/cirurgia
5.
Nat Commun ; 12(1): 4902, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385461

RESUMO

Efficient and precise base editors (BEs) for C-to-G transversion are highly desirable. However, the sequence context affecting editing outcome largely remains unclear. Here we report engineered C-to-G BEs of high efficiency and fidelity, with the sequence context predictable via machine-learning methods. By changing the species origin and relative position of uracil-DNA glycosylase and deaminase, together with codon optimization, we obtain optimized C-to-G BEs (OPTI-CGBEs) for efficient C-to-G transversion. The motif preference of OPTI-CGBEs for editing 100 endogenous sites is determined in HEK293T cells. Using a sgRNA library comprising 41,388 sequences, we develop a deep-learning model that accurately predicts the OPTI-CGBE editing outcome for targeted sites with specific sequence context. These OPTI-CGBEs are further shown to be capable of efficient base editing in mouse embryos for generating Tyr-edited offspring. Thus, these engineered CGBEs are useful for efficient and precise base editing, with outcome predictable based on sequence context of targeted sites.


Assuntos
Sistemas CRISPR-Cas , Citidina Desaminase/metabolismo , Edição de Genes/métodos , Aprendizado de Máquina , Uracila-DNA Glicosidase/metabolismo , Animais , Sequência de Bases , Sítios de Ligação/genética , Caenorhabditis elegans/genética , Códon/genética , Citidina Desaminase/genética , Escherichia coli/genética , Feminino , Biblioteca Gênica , Células HEK293 , Humanos , Camundongos , Reprodutibilidade dos Testes , Uracila-DNA Glicosidase/genética
6.
Neuroimage Clin ; 31: 102769, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34333270

RESUMO

Delineation and quantification of normal and abnormal brain tissues on Magnetic Resonance Images is fundamental to the diagnosis and longitudinal assessment of neurological diseases. Here we sought to develop a convolutional neural network for automated multiclass tissue segmentation of brain MRIs that was robust at typical clinical resolutions and in the presence of a variety of lesions. We trained a 3D U-Net for full brain multiclass tissue segmentation from a prior atlas-based segmentation method on an internal dataset that consisted of 558 clinical T1-weighted brain MRIs (453/52/53; training/validation/test) of patients with one of 50 different diagnostic entities (n = 362) or with a normal brain MRI (n = 196). We then used transfer learning to refine our model on an external dataset that consisted of 7 patients with hand-labeled tissue types. We evaluated the tissue-wise and intra-lesion performance with different loss functions and spatial prior information in the validation set and applied the best performing model to the internal and external test sets. The network achieved an average overall Dice score of 0.87 and volume similarity of 0.97 in the internal test set. Further, the network achieved a median intra-lesion tissue segmentation accuracy of 0.85 inside lesions within white matter and 0.61 inside lesions within gray matter. After transfer learning, the network achieved an average overall Dice score of 0.77 and volume similarity of 0.96 in the external dataset compared to human raters. The network had equivalent or better performance than the original atlas-based method on which it was trained across all metrics and produced segmentations in a hundredth of the time. We anticipate that this pipeline will be a useful tool for clinical decision support and quantitative analysis of clinical brain MRIs in the presence of lesions.


Assuntos
Imageamento por Ressonância Magnética , Neuroimagem , Encéfalo/diagnóstico por imagem , Substância Cinzenta , Humanos , Redes Neurais de Computação
7.
Neuroimage ; 243: 118514, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34450261

RESUMO

Measures of change in hippocampal volume derived from longitudinal MRI are a well-studied biomarker of disease progression in Alzheimer's disease (AD) and are used in clinical trials to track therapeutic efficacy of disease-modifying treatments. However, longitudinal MRI change measures based on deformable registration can be confounded by MRI artifacts, resulting in over-estimation or underestimation of hippocampal atrophy. For example, the deformation-based-morphometry method ALOHA (Das et al., 2012) finds an increase in hippocampal volume in a substantial proportion of longitudinal scan pairs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, unexpected, given that the hippocampal gray matter is lost with age and disease progression. We propose an alternative approach to quantify disease progression in the hippocampal region: to train a deep learning network (called DeepAtrophy) to infer temporal information from longitudinal scan pairs. The underlying assumption is that by learning to derive time-related information from scan pairs, the network implicitly learns to detect progressive changes that are related to aging and disease progression. Our network is trained using two categorical loss functions: one that measures the network's ability to correctly order two scans from the same subject, input in arbitrary order; and another that measures the ability to correctly infer the ratio of inter-scan intervals between two pairs of same-subject input scans. When applied to longitudinal MRI scan pairs from subjects unseen during training, DeepAtrophy achieves greater accuracy in scan temporal ordering and interscan interval inference tasks than ALOHA (88.5% vs. 75.5% and 81.1% vs. 75.0%, respectively). A scalar measure of time-related change in a subject level derived from DeepAtrophy is then examined as a biomarker of disease progression in the context of AD clinical trials. We find that this measure performs on par with ALOHA in discriminating groups of individuals at different stages of the AD continuum. Overall, our results suggest that using deep learning to infer temporal information from longitudinal MRI of the hippocampal region has good potential as a biomarker of disease progression, and hints that combining this approach with conventional deformation-based morphometry algorithms may lead to improved biomarkers in the future.

8.
Phytother Res ; 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34342079

RESUMO

Bilobalide is a natural sesquiterpene trilactone from Ginkgo biloba leaves. It has good water solubility and is widely used in food and pharmaceutical fields. In the last decade, a plethora of studies on the pharmacological activities of bilobalide has been conducted and demonstrated that bilobalide possessed an extensive range of pharmacological activities such as neuroprotective, antioxidative, antiinflammatory, anti-ischemic, and cardiovascular protective activities. Pharmacokinetic studies indicated that bilobalide may have the characteristics of rapid absorption, good bioavailability, wide distribution, and slow elimination. This review aims to summarize the advances in pharmacological, pharmacokinetics, toxicity, and safety studies of bilobalide in the last decade with an emphasis on its neuroprotective and antiinflammatory activities, to provide researchers with the latest information and point out the limitations of relevant research at the current stage and the aspects that should be strengthened in future research.

9.
Acta Haematol ; : 1-7, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34375974

RESUMO

BACKGROUND: Adult chronic idiopathic thrombocytopenic purpura (ITP) is a chronic and usually lifelong hemorrhagic disorder in which enhanced platelet destruction and -weakened platelet production lead to thrombocytopenia. In this study, the p38 mitogen-activated protein kinase (p38-MAPK), early growth response 1 (EGR-1), p53, Bcl-xL, Bak, Bax, and reactive oxygen species (ROS) in platelets from adult patients with chronic ITP were investigated. METHODS: Platelets were isolated from blood samples collected from 20 adult patients with chronic ITP and 20 healthy volunteers. p38-MAPK, EGR-1, p53, Bcl-xL, Bak, Bax, and ROS were determined by flow cytometry, and the results were analyzed by EXPO32 ADC. RESULTS: Flow cytometry showed the expression levels of p38-MAPK (61.66 ± 19.38% vs. 27.52 ± 14.34%), EGR-1 (62.22 ± 20.48% vs. 9.05 ± 5.79%), p53 (56.82 ± 20.07% vs. 4.35 ± 2.04%), Bak (39.86 ± 11.45% vs. 20.82 ± 11.85%), Bax (36.85 ± 15.99% vs. 6.69 ± 5.01%), and ROS (19.98 ± 1.47% vs. 1.29 ± 0.10%) were all elevated (p < 0.05 compared with healthy volunteers). In addition, pro-survival Bcl-xL (5.38 ± 1.52% vs. 21.20 ± 6.04%) was decreased markedly in platelets from adult patients with chronic ITP (p < 0.05 compared with healthy volunteers). CONCLUSIONS: Our findings reveal that platelets in adults with chronic ITP display a proapoptotic gene expression phenotype, based on the enhanced expression of p38-MAPK, EGR-1, p53, Bak, Bax, and ROS, and attenuated expression of Bcl-xL, suggesting increased sensitivity toward apoptosis.

10.
Phytother Res ; 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34347307

RESUMO

Bergapten is a natural furocoumarin, also known as 5-methoxypsoralen, and its medicinal value has been paid more and more attention. By sorting out the pharmacological literature of bergapten, we found that bergapten has a wide range of pharmacological effects, including neuroprotection, organ protection, anticancer, antiinflammatory, antimicrobial, and antidiabetes effects. However,bergapten has complex impacts on the hepatic metabolic enzyme. Moreover, pharmacokinetic studies showed that bergapten has higher absolute bioavailability and can cross the blood-brain barrier and has a great potential for treating brain disease, but the mechanism needs further clarification to make greater use of its ability to treat brain diseases. Furthermore, the phototoxicity of bergapten combined with ultraviolet light has always been mentioned. In view of its wide range of pharmacological activities, bergapten is expected to be a potential drug candidate for the treatment of diabetes and diabetes-induced osteoporosis, epilepsy, Alzheimer's disease, depression, and cancer. However, further studies are needed to elucidate its molecular mechanisms and targets. The phototoxicity of bergapten as a side effect should be further avoided. On the other hand, the photoactivation of bergapten in the anticancer aspect can be better utilized.

11.
Brain ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34259858

RESUMO

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangle was measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden reveal significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we find similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu Ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

12.
Brain Res Bull ; 174: 281-295, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34216649

RESUMO

Rehmannia glutinosa, the fresh or dried root of Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & Mey., and Gardenia, the fruit of Gardenia jasminoides Ellis from Rubiaceae, both are famous traditional Chinese medicines that have been traditionally used in China. Catalpol and geniposide, as two kinds of iridoid glycosides with high activities, are the main bioactive components in Rehmannia glutinosa and Gardenia jasminoides Ellis, respectively. Over the past few decades, catalpol and geniposide have been widely studied for their therapeutic effects. The preclinical experiments demonstrated that they possessed significant neuroprotective activities against Alzheimer's disease, Parkinson's disease, stroke, and depression, etc. In this paper, the pharmacological effects and mechanisms of catalpol and geniposide on Alzheimer's disease and Parkinson's disease from 2005 to now were systematically summarized and comprehensively analyzed. At the same time, the pharmacokinetic characteristics of the analyzed compounds were also described, hoping to provide some enlightenment for the design, research, and development of iridoid glycosides.

13.
Arch Pharm Res ; 44(7): 633-654, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34269984

RESUMO

Atractylodes macrocephala Koidz is a widely used as a traditional Chinese medicine. Atractylenolides (-I, -II, and -III) are a class of lactone compounds derived from Atractylodes macrocephala Koidz. Research into atractylenolides over the past two decades has shown that atractylenolides have anti-cancer, anti-inflammatory, anti-platelet, anti-osteoporosis, and antibacterial activity; protect the nervous system; and regulate blood glucose and lipids. Because of structural differences, both atractylenolide-I and atractylenolide-II have remarkable anti-cancer activities, and atractylenolide-I and atractylenolide-III have remarkable anti-inflammatory and neuroprotective activities. We therefore recommend further clinical research on the anti-cancer, anti-inflammatory and neuroprotective effects of atractylenolides, determine their therapeutic effects, alone or in combination. To investigate their ability to regulate blood glucose and lipid, as well as their anti-platelet, anti-osteoporosis, and antibacterial activities, both in vitro and in vivo studies are necessary. Atractylenolides are rapidly absorbed but slowly metabolized; thus, solubilization studies may not be necessary. However, due to the inhibitory effects of atractylenolides on metabolic enzymes, it is necessary to pay attention to the possible side effects of combining atractylenolides with other drugs, in clinical application. In short, atractylenolides have considerable medicinal value and warrant further study.

14.
BMC Nephrol ; 22(1): 257, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238243

RESUMO

BACKGROUND: Few studies have evaluated the clinical presentation, management, and outcomes of patients with end-stage renal disease (ESRD) presenting with acute aortic dissection (AAD) in real-world clinical practice. Thus, this study investigated the clinical characteristics, management, and outcomes of AAD patients with ESRD. METHODS: A total of 217 patients were included. We evaluated the differences in the clinical features, management, and in-hospital outcomes of patients with and without a history of ESRD presenting with AAD. RESULTS: A history of ESRD was present in 71 of 217 patients. Patients with ESRD had atypical clinical manifestations (p < 0.001) and were more likely to be managed medically compared with patients without ESRD (p = 0.002). Hypertension and type B aortic dissection were significantly more common among patients with ESRD. Moreover, patients with ESRD had lower leucocyte and platelet counts than patients without ESRD in laboratory findings (p < 0.001). However, hospitalization days and in-hospital mortality were similar between the two groups (p > 0.05). Multivariate analysis identified Type A aortic dissection as an independent predictor of in-hospital mortality among patients without ESRD (OR, 13.68; 95% CI, 1.92 to 98.90; P = 0.006). CONCLUSIONS: This study highlights differences in the clinical characteristics, management, and outcomes of AAD patients with ESRD. These patients usually have atypical symptoms and more comorbid conditions and are managed more conservatively. However, these patients have no in-hospital survival disadvantage over those without ESRD. Further studies are needed to better understand and optimize care for patients with ESRD presenting with AAD.

15.
J Alzheimers Dis ; 82(3): 1123-1136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34151789

RESUMO

BACKGROUND: Sensitive measures of cognition are needed in preclinical and prodromal Alzheimer's disease (AD) to track cognitive change and evaluate potential interventions. Neurofibrillary tangle pathology in AD is first observed in Brodmann Area 35 (BA35), the medial portion of the perirhinal cortex. The importance of the perirhinal cortex for semantic memory may explain early impairments of semantics in preclinical AD. Additionally, our research has tied figurative language impairment to neurodegenerative disease. OBJECTIVE: We aim to identify tasks that are sensitive to cognitive impairment in individuals with mild cognitive impairment (MCI), and that are sensitive to atrophy in BA35. METHODS: Individuals with MCI and cognitively normal participants (CN) were tested on productive and receptive experimental measures of semantic memory and experimental tests of figurative language comprehension (including metaphor and verbal analogy). Performance was related to structural imaging and standard neuropsychological assessment. RESULTS: On the experimental tests of semantics and figurative language, people with MCI performed worse than CN participants. The experimental semantic memory tasks are sensitive and specific; performance on the experimental semantic memory tasks related to medial temporal lobe structural integrity, including BA35, while standard neuropsychological assessments of semantic memory did not, demonstrating the sensitivity of these experimental measures. A visuo-spatial analogy task did not differentiate groups, confirming the specificity of semantic and figurative language tasks. CONCLUSION: These experimental measures appear sensitive to cognitive change and neurodegeneration early in the AD trajectory and may prove useful in tracking cognitive change in clinical trials aimed at early intervention.


Assuntos
Cognição/fisiologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/psicologia , Testes de Estado Mental e Demência/normas , Sintomas Prodrômicos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento por Ressonância Magnética/normas , Masculino , Reprodutibilidade dos Testes
16.
J Digit Imaging ; 34(4): 1049-1058, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34131794

RESUMO

Automated quantitative and probabilistic medical image analysis has the potential to improve the accuracy and efficiency of the radiology workflow. We sought to determine whether AI systems for brain MRI diagnosis could be used as a clinical decision support tool to augment radiologist performance. We utilized previously developed AI systems that combine convolutional neural networks and expert-derived Bayesian networks to distinguish among 50 diagnostic entities on multimodal brain MRIs. We tested whether these systems could augment radiologist performance through an interactive clinical decision support tool known as Adaptive Radiology Interpretation and Education System (ARIES) in 194 test cases. Four radiology residents and three academic neuroradiologists viewed half of the cases unassisted and half with the results of the AI system displayed on ARIES. Diagnostic accuracy of radiologists for top diagnosis (TDx) and top three differential diagnosis (T3DDx) was compared with and without ARIES. Radiology resident performance was significantly better with ARIES for both TDx (55% vs 30%; P < .001) and T3DDx (79% vs 52%; P = 0.002), with the largest improvement for rare diseases (39% increase for T3DDx; P < 0.001). There was no significant difference between attending performance with and without ARIES for TDx (72% vs 69%; P = 0.48) or T3DDx (86% vs 89%; P = 0.39). These findings suggest that a hybrid deep learning and Bayesian inference clinical decision support system has the potential to augment diagnostic accuracy of non-specialists to approach the level of subspecialists for a large array of diseases on brain MRI.

17.
CNS Neurosci Ther ; 27(10): 1146-1156, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34109749

RESUMO

AIMS: CHD4 gene, encoding chromodomain helicase DNA-binding protein 4, is a vital gene for fetal development. In this study, we aimed to explore the association between CHD4 variants and idiopathic epilepsy. METHODS: Trios-based whole-exome sequencing was performed in a cohort of 482 patients with childhood idiopathic epilepsy. The Clinical Validity Framework of ClinGen and an evaluating method from five clinical-genetic aspects were used to determine the association between CHD4 variants and epilepsy. RESULTS: Four novel heterozygous missense mutations in CHD4, including two de novo mutations (c.1597A>G/p.K533E and c.4936G>A/p.E1646K) and two inherited mutations with co-segregation (c.856C>G/p.P286A and c.4977C>G/p.D1659E), were identified in four unrelated families with eight individuals affected. Seven affected individuals had sinus arrhythmia. From the molecular sub-regional point of view, the missense mutations located in the central regions from SNF2-like region to DUF1087 domain were associated with multisystem developmental disorders, while idiopathic epilepsy-related mutations were outside this region. Strong evidence from ClinGen Clinical Validity Framework and evidences from four of the five clinical-genetic aspects suggested an association between CHD4 variants and epilepsy. CONCLUSIONS: CHD4 was potentially a candidate pathogenic gene of childhood idiopathic epilepsy with arrhythmia. The molecular sub-regional effect of CHD4 mutations helped explaining the mechanisms underlying phenotypic variations.

18.
Neuroimage Clin ; 31: 102717, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34119903

RESUMO

Mild cognitive impairment (MCI) can be an early manifestation of Alzheimer's disease (AD) pathology, other pathologic entities [e.g., cerebrovascular disease, Lewy body disease, LATE (limbic-predominant age-related TDP-43 encephalopathy)], or mixed pathologies, with concomitant AD- and non-AD pathology being particularly common, albeit difficult to identify, in living MCI patients. The National Institute on Aging and Alzheimer's Association (NIA-AA) A/T/(N) [ß-Amyloid/Tau/(Neurodegeneration)] AD research framework, which classifies research participants according to three binary biomarkers [ß-amyloid (A+/A-), tau (T+/T-), and neurodegeneration (N+/N-)], provides an indirect means of identifying such cases. Individuals with A+T-(N+) MCI are thought to have both AD pathologic change, given the presence of ß-amyloid, and non-AD pathophysiology, given neurodegeneration without tau, because in typical AD it is tau accumulation that is most tightly linked to neuronal injury and cognitive decline. Thus, in A+T-(N+) MCI (hereafter referred to as "mismatch MCI" for the tau-neurodegeneration mismatch), non-AD pathology is hypothesized to drive neurodegeneration and symptoms, because ß-amyloid, in the absence of tau, likely reflects a preclinical stage of AD. We compared a group of individuals with mismatch MCI to groups with A+T+(N+) MCI (or "prodromal AD") and A-T-(N+) MCI (or "neurodegeneration-only MCI") on cross-sectional and longitudinal cognition and neuroimaging characteristics. ß-amyloid and tau status were determined by CSF assays, while neurodegeneration status was based on hippocampal volume on MRI. Overall, mismatch MCI was less "AD-like" than prodromal AD and generally, with some exceptions, more closely resembled the neurodegeneration-only group. At baseline, mismatch MCI had less episodic memory loss compared to prodromal AD. Longitudinally, mismatch MCI declined more slowly than prodromal AD across all included cognitive domains, while mismatch MCI and neurodegeneration-only MCI declined at comparable rates. Prodromal AD had smaller baseline posterior hippocampal volume than mismatch MCI, and whole brain analyses demonstrated cortical thinning that was widespread in prodromal AD but largely restricted to the medial temporal lobes (MTLs) for the mismatch and neurodegeneration-only MCI groups. Longitudinally, mismatch MCI had slower rates of volume loss than prodromal AD throughout the MTLs. Differences in cross-sectional and longitudinal cognitive and neuroimaging measures between mismatch MCI and prodromal AD may reflect disparate underlying pathologic processes, with the mismatch group potentially being driven by non-AD pathologies on a background of largely preclinical AD. These findings suggest that ß-amyloid status alone in MCI may not reveal the underlying driver of symptoms with important implications for enrollment in clinical trials and prognosis.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Peptídeos beta-Amiloides , Biomarcadores , Estudos Transversais , Progressão da Doença , Humanos , Irmãos , Proteínas tau
19.
Blood Coagul Fibrinolysis ; 32(7): 434-442, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102655

RESUMO

Adult chronic idiopathic thrombocytopenic purpura (cITP) is a chronic and usually life-long haemorrhagic disorder in which enhanced platelet destruction and weakened platelet production lead to thrombocytopenia. Platelets were isolated from blood samples collected from 40 adult patients with cITP and 40 healthy volunteers. Mitochondrial membrane potential (ΔΨm) and plasma membrane phosphatidylserine externalization were determined by flow cytometry, and activation of caspase-3 and expressions of Bax, Bak and Bcl-xL were analysed by western blotting. Flow cytometry showed increased mitochondrial depolarization and lower ΔΨm in platelets from adult patients with cITP. In addition, plasma membrane phosphatidylserine externalization was observed on platelets from adult patients with cITP, but rarely from healthy volunteers. Western blot analysis of platelet proteins revealed that, in adult cITP patients, caspase-3 was activated, which cleaved gelsolin and to release a 47-kDa fragment. Moreover, the expressions of Bax and Bak were elevated, and Bcl-xL was decreased markedly in platelets from adult patients with cITP. Our findings reveal, based on loss of mitochondrial membrane potential (Δψm), phosphatidylserine exposure, caspase-3 activation, enhanced expression of Bax and Bak, and attenuated expression of Bcl-xL, that platelet death in the pathogenesis of thrombocytopenia in chronic ITP in adults is apoptotic.

20.
Org Biomol Chem ; 19(20): 4537-4541, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-33949605

RESUMO

A practical and environment-friendly methodology for the construction of ß-keto sulfones through visible-light induced direct oxysulfonylation of alkenes with sulfonic acids at ambient temperature under open-air conditions was developed. Most importantly, the reaction proceeded smoothly without the addition of any photocatalyst or strong oxidant, ultimately minimizing the production of chemical waste.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...