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1.
Behav Brain Res ; 437: 114108, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36100010

RESUMO

BACKGROUND: Lifestyle factors such as physical activity and optimal sleep are associated with better cognition and lower levels of Alzheimer's disease (AD) biomarkers, including brain beta-amyloid (Aß) burden. OBJECTIVE: We utilised cross-sectional data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study to determine whether self-reported physical activity (measured via the International Physical Activity Questionnaire) moderates the relationship between self-reported sleep (measured via the Pittsburgh Sleep Quality Index), cognition, and brain Aß. METHODS: Participants were 349 community-dwelling cognitively normal older adults (75.3 ± 5.7 years), all of whom underwent comprehensive cognitive assessment. Data from a subset of participants (n = 201) were used for analyses with brain Aß burden (measured by positron emission tomography) as the outcome. RESULT: Physical activity moderated the relationship between sleep duration and episodic memory (ß = -0.10, SE =0.03, p = .005), and sleep efficiency and episodic memory (ß = -0.09, SE =0.04, p = .011), such that greater amounts of physical activity mitigated the impact of suboptimal sleep duration and efficiency on episodic memory. Physical activity also moderated the relationship between sleep duration and brain Aß (ß = -0.13, SE =0.06, p = .031), and overall sleep quality and brain Aß (ß = 0.13, SE =0.06, p = .027). CONCLUSION: Our findings suggest that physical activity may play an important role in the relationship between sleep and cognitive function, and brain Aß.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Encéfalo , Cognição , Exercício Físico , Sono , Idoso , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Austrália , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Cognição/fisiologia , Estudos Transversais , Exercício Físico/fisiologia , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Sono/fisiologia , Vida Independente
2.
Behav Brain Res ; 437: 114113, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36108777

RESUMO

Prepulse inhibition (PPI) allows assessing schizophrenia-like sensorimotor gating deficits in rodents. Previous studies indicate that PPI is modulated by the medial prefrontal cortex (mPFC), which is in agreement with our findings showing that PPI differences in the Roman rats are associated with divergences in mPFC activity. Here, we explore whether differences in PPI and mPFC activity in male Roman rats can be explained by (i) differences in the activation (c-Fos) of inhibitory neurons (parvalbumin (PV) interneurons); and/or (ii) reduced excitatory drive (PSD-95) to PV interneurons. Our data show that low PPI in the Roman high-avoidance (RHA) rats is associated with reduced activation of PV interneurons. Moreover, the RHA rats exhibit decreased density of both PV interneurons and PSD-95 puncta on active PV interneurons. These findings point to reduced cortical inhibition as a candidate to explain the schizophrenia-like features observed in RHA rats and support the role of impaired cortical inhibition in schizophrenia.


Assuntos
Interneurônios , Parvalbuminas , Córtex Pré-Frontal , Esquizofrenia , Filtro Sensorial , Animais , Masculino , Ratos , Proteína 4 Homóloga a Disks-Large/metabolismo , Interneurônios/fisiologia , Parvalbuminas/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos Endogâmicos , Esquizofrenia/fisiopatologia , Filtro Sensorial/fisiologia
3.
Physiol Rev ; 103(1): 391-432, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35953269

RESUMO

The heart is imbued with a vast lymphatic network that is responsible for fluid homeostasis and immune cell trafficking. Disturbances in the forces that regulate microvascular fluid movement can result in myocardial edema, which has profibrotic and proinflammatory consequences and contributes to cardiovascular dysfunction. This review explores the complex relationship between cardiac lymphatics, myocardial edema, and cardiac disease. It covers the revised paradigm of microvascular forces and fluid movement around the capillary as well as the arsenal of preclinical tools and animal models used to model myocardial edema and cardiac disease. Clinical studies of myocardial edema and their prognostic significance are examined in parallel to the recent elegant animal studies discerning the pathophysiological role and therapeutic potential of cardiac lymphatics in different cardiovascular disease models. This review highlights the outstanding questions of interest to both basic scientists and clinicians regarding the roles of cardiac lymphatics in health and disease.


Assuntos
Edema Cardíaco , Cardiopatias , Vasos Linfáticos , Animais , Modelos Animais de Doenças , Edema Cardíaco/fisiopatologia , Cardiopatias/fisiopatologia , Vasos Linfáticos/fisiopatologia
4.
Neurol India ; 70(Supplement): S117-S122, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36412357

RESUMO

Objective: To report a new patient friendly and convenient technique for phrenic nerve conduction with alternative sites of stimulation and recording. Methods: Phrenic nerve conduction was performed in forty volunteers and ten patients of peripheral neuropathy. Active recording electrode was placed in tenth intercostal space 2.5 cm away from para-spinal muscles (mid-scapular line), reference electrode in eighth intercostal space just medial to subcostal margin with ground between stimulating and recording electrode. Stimulation was done at the level of crico-thyroid space near or under the posterior margin of sternocleidomastoid muscle. This new method was compared with existing ones. Analysis: Data was analysed using SPSS 23 version. Correlation between height, weight, body mass index, age, and chest expansion was done using bi-variate correlation. Mean latency and amplitude of the study method were compared with other methods using MANNOVA test. Results: Total of forty subjects were studied. Thirty-seven were male subjects. Mean age was 28.03 ± 9.63 years, height 168.0 ± 9.60 cm and chest expansion 3.53 ± 0.64 cm. Right sided phrenic nerve mean latency was 5.99 ± 0.629 ms and amplitude 1.088 ± 0.178 mV. Left sided phrenic nerve conductions showed mean latency of 6.02 ± 1.82 ms, amplitude of 1.092 ± 0.2912 mV. These standard deviations were smaller than what were observed with other methods suggesting increased consistency of our results. There was no correlation between phrenic nerve conduction with age, height, gender or chest expansion. Conclusion: This study method gave a better as well as consistent morphology, higher amplitude and required lower amount of current strength. It was superior to previously reported methods in consistency of normative data.


Assuntos
Eletromiografia , Condução Nervosa , Doenças do Sistema Nervoso Periférico , Nervo Frênico , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Potenciais de Ação/fisiologia , Eletromiografia/métodos , Condução Nervosa/fisiologia , Exame Neurológico/métodos , Nervo Frênico/fisiologia , Nervo Frênico/fisiopatologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Eletrodos , Pescoço , Dorso
6.
Science ; 378(6621): 704-706, 2022 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-36395209
7.
Medicine (Baltimore) ; 101(45): e31529, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36397399

RESUMO

The diagnosis of endometriosis may delay for many years due to non-deterministic symptoms and avoiding surgical interventions. Kisspeptins are hormones that interact with endometrial tissue to limit invasions during placentation and various cancers and are suggested to be also associated with endometriosis. This study evaluated if serum kisspeptin levels are associated with the invasion depth in endometriosis. Forty patients between 18 and 45 years of age and admitted to a tertiary-care Obstetrics and Gynecology Department between 2020 and 2021 with a diagnosis of endometriosis, and 40 patients without endometrioma were included in the study. Demographic, obstetric, clinical, and biochemical characteristics were evaluated in patients with superficial (SE) and deep infiltrating (DIE) endometriosis and healthy controls. Twenty patients (50%) had SE, 14 (35%) had DIE, and 22 (55%) had endometrioma in the patient group. Fertility rates were higher among controls, but similar between patients with SE and DIE. CA125 levels were significantly higher in the DIE group. SE and DIE groups had similar kisspeptin values, significantly higher than controls. CA125 and kisspeptin levels were not correlated in study groups. Serum kisspeptin levels were significantly different between endometriosis patients and healthy controls. However, kisspeptin levels were unable to differentiate endometriosis severity. Our results suggest that kisspeptins might play a role in the pathogenesis of endometriosis, which needs further assessment in more comprehensive studies.


Assuntos
Endometriose , Kisspeptinas , Feminino , Humanos , Antígeno Ca-125/sangue , Endometriose/sangue , Endometriose/etiologia , Endometriose/patologia , Endometriose/fisiopatologia , Kisspeptinas/sangue , Ovário/patologia , Estudos Prospectivos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade
11.
Science ; 378(6619): 493-499, 2022 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-36327349

RESUMO

Can we construct a model of brain function that enables an understanding of whole-brain circuit mechanisms underlying neurological disease and use it to predict the outcome of therapeutic interventions? How are pathologies in neurological disease, some of which are observed to have spatial spreading mechanisms, associated with circuits and brain function? In this review, we discuss approaches that have been used to date and future directions that can be explored to answer these questions. By combining optogenetic functional magnetic resonance imaging (fMRI) with computational modeling, cell type-specific, large-scale brain circuit function and dysfunction are beginning to be quantitatively parameterized. We envision that these developments will pave the path for future therapeutics developments based on a systems engineering approach aimed at directly restoring brain function.


Assuntos
Encefalopatias , Encéfalo , Imageamento por Ressonância Magnética , Rede Nervosa , Optogenética , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Simulação por Computador , Imageamento por Ressonância Magnética/métodos , Optogenética/métodos , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia
12.
Nature ; 611(7936): 540-547, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36352232

RESUMO

A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord1-3 applied during neurorehabilitation4,5 (EESREHAB) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencing6-9 and spatial transcriptomics10,11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type12,13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.


Assuntos
Neurônios , Paralisia , Traumatismos da Medula Espinal , Medula Espinal , Caminhada , Animais , Humanos , Camundongos , Neurônios/fisiologia , Paralisia/genética , Paralisia/fisiopatologia , Paralisia/terapia , Medula Espinal/citologia , Medula Espinal/fisiologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Caminhada/fisiologia , Estimulação Elétrica , Região Lombossacral/inervação , Reabilitação Neurológica , Análise de Sequência de RNA , Perfilação da Expressão Gênica
13.
J Bras Pneumol ; 48(5): e20220098, 2022.
Artigo em Inglês, Português | MEDLINE | ID: mdl-36383779

RESUMO

OBJECTIVE: Patients with COPD are prone to cardiac remodeling; however, little is known about cardiac function in patients recovering from an acute exacerbation of COPD (AECOPD) and its association with exercise capacity. The aim of this study was to evaluate the cardiac function and structure and to compare their relationship with exercise capacity in patients with a recent AECOPD and patients with clinically stable COPD. METHODS: This was a cross-sectional study including 40 COPD patients equally divided into two groups: recent AECOPD group (AEG) and clinically stable COPD group (STG). Echocardiography was performed to assess cardiac function and chamber structure. The six-minute walk distance (6MWD) and the Duke Activity Status Index (estimated Vo2) were used in order to assess exercise capacity. RESULTS: No significant differences in cardiac function and structure were found between the groups. The 6MWD was associated with early/late diastolic mitral filling velocity ratio (r = 0.50; p < 0.01), left ventricular posterior wall thickness (r = -0.33; p = 0.03), and right atrium volume index (r = -0.34; p = 0.04), whereas Vo2 was associated with right atrium volume index (r = -0.40; p = 0.02). CONCLUSIONS: Regardless of the clinical condition (recent AECOPD vs. stable COPD), the cardiac function and structure were similar between the groups, and exercise capacity (determined by the 6MWD and Vo2) was associated with cardiac features.


Assuntos
Tolerância ao Exercício , Coração , Doença Pulmonar Obstrutiva Crônica , Humanos , Estudos Transversais , Ecocardiografia , Teste de Esforço , Tolerância ao Exercício/fisiologia , Ventrículos do Coração/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Cardíaca , Coração/diagnóstico por imagem , Coração/fisiologia
14.
Neurol India ; 70(Supplement): S326-S330, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36412391

RESUMO

Spinal dural arteriovenous fistulae (SDAVF) are most commonly idiopathic in origin but may occasionally be seen secondary to surgery, trauma, or inflammation. We report a case of 27-year-old male who came with features of a myelopathy. He was found to have an SDAVF associated with leptomeningeal spread (LMS) of a previously treated high-grade cerebral glioma. Hemorrhagic presentation of gliomas, as in this case, is due to upregulation of vascular endothelial growth factor, which has also been postulated to play a role in the development of SDAVFs. This may suggest a possible mechanism of induction of secondary SDAVFs associated with such tumors. While the coexistence of intracranial neoplasms with vascular malformations has been reported previously, this is the first case report of LMS of a high-grade glioma associated with an SDAVF.


Assuntos
Neoplasias Encefálicas , Malformações Vasculares do Sistema Nervoso Central , Glioma , Carcinomatose Meníngea , Doenças da Medula Espinal , Adulto , Humanos , Masculino , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Malformações Vasculares do Sistema Nervoso Central/etiologia , Malformações Vasculares do Sistema Nervoso Central/fisiopatologia , Glioma/complicações , Glioma/fisiopatologia , Glioma/secundário , Glioma/terapia , Imageamento por Ressonância Magnética , Carcinomatose Meníngea/complicações , Carcinomatose Meníngea/fisiopatologia , Carcinomatose Meníngea/secundário , Doenças da Medula Espinal/etiologia , Doenças da Medula Espinal/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/fisiologia
15.
Neurol India ; 70(Supplement): S282-S287, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36412382

RESUMO

Background: There is scant literature comparing high tidal volume ventilation (HTV) over low tidal volume (LTV) ventilation in acute traumatic cervical spinal cord injury (CSCI). Objective: The aim of this prospective randomized controlled parallel-group, single-blinded study was to compare the effect of two different tidal volumes (12-15 mL/kg and 6-8 mL/kg) in CSCI on days to achieve ventilator-free breathing (VFB), PaO2/FIO2 ratio, the incidence of complications, requirement of vasopressor drugs, total duration of hospital stay, and mortality. Materials and Methods: We enrolled patients with acute high traumatic CSCI admitted to the neurotrauma intensive care unit within 24 h of injury, requiring mechanical ventilation. Participants were randomized to receive either HTV, 12-15 mL/kg (group H) or LTV, 6-8 mL/kg (group L) tidal volume ventilation. Results and Conclusions: A total of 56 patients, 28 in each group were analyzed. Patient demographics and injury severity were comparable between the groups. VFB was achieved in 23 and 19 patients in groups H and L, respectively. The median number of days required to achieve VFB was 3 (2, 56) and 8 (2, 50) days, P = 0.33; PaO2: FIO2 ratio was 364.0 ± 64 and 321.0 ± 67.0, P = 0.01; the incidence of atelectasis was 25% and 46%, P = 0.16, respectively, in group H and group L. The hemodynamic parameters and the vasopressor requirement were comparable in both groups. There was no barotrauma. The duration of hospital stay (P = 0.2) and mortality (P = 0.2) was comparable in both groups. There was no significant difference in days to achieve ventilator-free breathing with HTV (12-15 mL/kg) ventilation compared to LTV (6-8 mL/kg) ventilation in acute CSCI. The PaO2:FiO2 ratio was higher with the use of 12-15 mL/kg. No difference in mortality and duration of hospital stay was seen in either group.


Assuntos
Vértebras Cervicais , Respiração Artificial , Traumatismos da Coluna Vertebral , Volume de Ventilação Pulmonar , Humanos , Lesões do Pescoço , Estudos Prospectivos , Respiração Artificial/efeitos adversos , Respiração Artificial/métodos , Traumatismos da Coluna Vertebral/etiologia , Traumatismos da Coluna Vertebral/fisiopatologia , Traumatismos da Coluna Vertebral/terapia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/terapia , Doença Aguda
16.
Neurol India ; 70(Supplement): S245-S250, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36412376

RESUMO

Background: Post spinal cord injury (SCI), sitting balance is considered a prerequisite for the effective performance of activities of daily living. Virtual Reality Training (VRT) may provide an interactive medium of rehabilitation, preventing a reduction in active participation of the patients while allowing for the training of sitting balance. Aim: The aim of this study was to evaluate the effect of the addition of VRT to conventional therapy in improving sitting balance in persons with SCI. Subjects and Methods: This was a single blinded randomized control trial conducted on 21 subjects with SCI (level of injury: D10 or below). They were randomly allocated into two groups; both groups received their routine exercise program. In addition, the intervention group, that is, Group B (n = 11) received 30 min of VRT in the seated position using Xbox-Kinect, while the conventional therapy group, that is, Group A (n = 10) received 30 min of additional conventional therapy to equalize the duration of the intervention (3 days/week, 4 weeks). The modified functional reach test and T-shirt test were measured at the beginning and at the end of 4 weeks. Results: MFRT changes for forward (Group A: 1.7 ± 1.09 cm; Group B: 4.83 ± 2.95 cm), right lateral (Group A: 2.43 ± 2.81 cm, Group B: 5.08 ± 1.85 cm), left lateral (Group A: 3.05 ± 4.65 cm, Group B: 6.19 ± 1.51 cm) were statistically significant for Group B (P < 0.05). No significant difference was observed between the two groups for T-shirt test (P > 0.05). Conclusion: VRT can be used as a part of a comprehensive rehabilitation program to improve sitting balance post-SCI.


Assuntos
Reabilitação Neurológica , Equilíbrio Postural , Traumatismos da Medula Espinal , Realidade Virtual , Humanos , Atividades Cotidianas , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/reabilitação , Traumatismos da Medula Espinal/terapia , Postura Sentada , Reabilitação Neurológica/métodos , Terapia por Exercício
17.
Neurol India ; 70(Supplement): S269-S275, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36412380

RESUMO

Background: Autonomic dysfunction, commonly seen in patients with cervical myelopathy, may lead to a decrease in blood pressure intraoperatively. Objective: The aim of our study is to determine if changes in Heart rate variability (HRV) could predict hypotension after induction of anesthesia in patients with cervical myelopathy undergoing spine surgery. Methods and Material: In this prospective observational study, 47 patients with cervical myelopathy were included. Five-minute resting ECG (5 lead) was recorded preoperatively and HRV of very low frequency (VLF), low frequency (LF), and high frequency (HF) spectra were calculated using frequency domain analysis. Incidence of hypotension (MAP <80 mmHg, lasting >5 min) and the number of interventions (40 mcg of phenylephrine or 5 mg of ephedrine) required to treat the hypotension during the period from induction to surgical incision were recorded. HRV indices were compared between the hypotension group and the stable group. Results: The incidence of hypotension after induction was 74.4% (35/47) and the median (IQR) interventions needed to treat hypotension was 2 (0.5-6). Patients who experienced hypotension had lower HF power and higher LF-HF ratios. A LF/HF >2.5 indicated postinduction hypotension likely. There was a correlation between increasing LF-HF ratio and the number of interventions that needs to maintain the MAP above 80 mmHg. Conclusion: HF power was lower and LF-HF ratio was higher in patients with cervical myelopathy who developed postinduction hypotension. Hence, preoperative HRV analysis can be useful to identify patients with cervical myelopathy who are at risk of post-induction hypotension.


Assuntos
Anestesia , Frequência Cardíaca , Hipotensão , Doenças da Medula Espinal , Humanos , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Hipotensão/diagnóstico , Hipotensão/etiologia , Estudos Prospectivos , Doenças da Medula Espinal/complicações , Doenças da Medula Espinal/fisiopatologia , Doenças da Medula Espinal/cirurgia , Cuidados Pré-Operatórios , Anestesia/efeitos adversos , Anestesia/métodos
18.
J Clin Invest ; 132(21)2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36317635

RESUMO

Sterile α motif domain-containing 9 (SAMD9) and SAMD9-like (SAMD9L) syndromes are inherited bone marrow failure syndromes known for their frequent development of myelodysplastic syndrome with monosomy 7. In this issue of the JCI, Abdelhamed, Thomas, et al. report a mouse model with a hematopoietic cell-specific heterozygous Samd9l mutation knockin. This mouse model resembles human disease in many ways, including bone marrow failure and the nonrandom loss of the mutant allele. Samd9l-mutant hematopoietic stem progenitor cells showed reduced fitness at baseline, which was further exacerbated by inflammation. TGF-ß hyperactivation was found to underlie reduced fitness, which was partially rescued by a TGF-ß inhibitor. These findings illustrate the potential role of TGF-ß inhibitors in the treatment of SAMD9/SAMD9L syndromes.


Assuntos
Medula Óssea , Proteínas Supressoras de Tumor , Animais , Humanos , Camundongos , Medula Óssea/fisiopatologia , Deleção Cromossômica , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Fator de Crescimento Transformador beta/genética , Proteínas Supressoras de Tumor/genética
19.
Acta Cir Bras ; 37(7): e370706, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36327405

RESUMO

PURPOSE: Abnormal activation of NOD-like receptor protein 3 (NLRP3) inflammasome can lead to the occurrence and progression of acute pancreatitis. This study investigated the protective effect of MCC950 on pancreatitis mice. METHODS: Eighteen mice were randomly divided into control group, severe acute pancreatitis (SAP) group and SAP+MCC950 group. Serum interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α) were measured by ELISA. Hematoxylin and eosin (HE) staining was used to evaluate the pathological damage. Western blotting was used to detect the expression of NLRP3 inflammasome and tight junction proteins in the small intestine and pancreas. RESULTS: MCC950 could reduce the levels of IL-6 and IL-1ß in SAP mice. After treatment with MCC950, the expression levels of NLRP3 inflammasome in the pancreas of SAP mice were significantly reduced and the pathological damage to the pancreas and intestine was alleviated. Compared with the control group, the expression of tight junction protein (ZO-1,occludin and claudin-4) in the intestinal mucosa of SAP mice was decreased, and the expression of claudin-4 and occludin were upregulated after MCC950 treatment. CONCLUSIONS: MCC950 can inhibit NLRP3 inflammasome activation and significantly reduce the inflammatory response and delay the process of pancreatitis. It has therapeutic potential in the treatment of acute pancreatitis.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pancreatite , Animais , Camundongos , Doença Aguda , Claudina-4/metabolismo , Inflamassomos/metabolismo , Interleucina-6 , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ocludina/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/fisiopatologia
20.
JACC Heart Fail ; 10(11): 860-870, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36328655

RESUMO

BACKGROUND: In patients with type 2 diabetes (T2D), risks of cardiovascular mortality and heart failure (HF) increase with decreasing kidney function (estimated glomerular filtration rate [eGFR]) and increasing albuminuria (urine albumin-to-creatinine ratio [UACR]). Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and T2D in FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis). OBJECTIVES: This study sought to evaluate the effects of finerenone on HF outcomes by eGFR and/or UACR categories. METHODS: FIDELITY included 13,026 patients with T2D and CKD (UACR 30-5,000 mg/g and eGFR ≥25 mL/min/1.73 m2) randomized to finerenone or placebo. Time-to-event outcomes were first hospitalization for heart failure (HHF), cardiovascular death or first HHF, recurrent HHF, and cardiovascular death or recurrent HHF, analyzed in subgroups by baseline eGFR (<60 and ≥60 mL/min/1.73 m2) and/or UACR (<300 and ≥300 mg/g). RESULTS: Compared with placebo, finerenone significantly reduced risk of first HHF (HR: 0.78 [95% CI: 0.66-0.92]; P = 0.003), cardiovascular death or first HHF (HR: 0.83 [95% CI: 0.74-0.93]; P = 0.002), recurrent HHF (HR: 0.79 [95% CI: 0.64-0.96]; P = 0.021), and cardiovascular death or recurrent HHF (HR: 0.82 [95% CI: 0.72-0.95]; P = 0.006). The risk of outcomes increased across baseline eGFR and UACR categories; lowest incidences were seen in patients with an eGFR ≥60 mL/min/1.73 m2 and a UACR <300 mg/g. Finerenone improved HF outcomes irrespective of baseline eGFR and/or UACR categories (all P interaction values >0.10). CONCLUSIONS: Compared with placebo, finerenone improved HF-related outcomes in patients with CKD and T2D, with consistent benefits across eGFR and/or UACR categories. (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], NCT02540993; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Chronic Kidney Disease [FIGARO-DKD], NCT02545049).


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Insuficiência Renal Crônica , Humanos , Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular/fisiologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Resultado do Tratamento
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