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2.
Medicine (Baltimore) ; 98(44): e17744, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689826

RESUMO

Congenital syphilis (CS) can cause serious impact on the fetus. However, congenital syphilis presenting as sepsis is a critical condition but hardly identified by the clinic for the first time. In this study, we aimed to identify the benefit of earlier and accurate diagnosis for the infants who suffer congenital syphilis presenting as sepsis.A retrospective study was performed with patients diagnosed of congenital syphilis presenting as sepsis who were the inpatients in the West China Second Hospital between 2011 and 2018. The control group was collected in the neonatal sepsis patients whose blood culture are positive.Fifty-eight patients were included in the study. In the congenital syphilis group, one patient died and 12 (41.3%) patients get worse to MODS (multiple organ dysfunction syndrome). Symptoms, signs, and lab examinations are found to be significantly different (P < .05) between two groups as below, including rash, palmoplantar desquamation, abdominal distension, splenomegaly, hepatomegaly, etc. And, at the aspect of Hb, PLT, WBC, CRP, ALT, AST, these differences occurred in the different groups. It is obvious that the prognosis of children with syphilis is worse. According to a comparison between the different outcomes in the CS, the worse outcome subgroup of patients is significantly younger and have more severely impaired liver function.Because of the high mortality of these infants, pediatricians should improve awareness of CS. Syphilis screening is recommended for pregnant women.


Assuntos
Sepse Neonatal/diagnóstico , Complicações Infecciosas na Gravidez/diagnóstico , Sepse/diagnóstico , Sífilis Congênita/diagnóstico , Sífilis/diagnóstico , Estudos de Casos e Controles , China , Diagnóstico Diferencial , Diagnóstico Precoce , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/microbiologia , Insuficiência de Múltiplos Órgãos/mortalidade , Sepse Neonatal/microbiologia , Sepse Neonatal/mortalidade , Gravidez , Complicações Infecciosas na Gravidez/microbiologia , Complicações Infecciosas na Gravidez/mortalidade , Estudos Retrospectivos , Sepse/microbiologia , Sepse/mortalidade , Sífilis/microbiologia , Sífilis/mortalidade , Sorodiagnóstico da Sífilis , Sífilis Congênita/mortalidade
3.
J Vis Exp ; (152)2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31633680

RESUMO

Isoproterenol (ISO), is a non-selective beta-adrenergic agonist, that is used widely to induce cardiac injury in mice. While the acute model mimics stress-induced cardiomyopathy, the chronic model, administered through an osmotic pump, mimics advanced heart failure in humans. The purpose of the described protocol is to create the chronic ISO-induced heart failure model in mice using an implanted mini-pump. This protocol has been used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation are described in detail and may be relevant to anyone interested in creating a heart failure model in mice. In addition, the weekly cardiac remodeling changes based on echocardiographic parameters for each strain and expected time to model development are presented. In summary, the method is simple and reproducible. Continuous ISO administered via the implanted mini-pump over 3 to 4 weeks is sufficient to induce cardiac remodeling. Finally, the success for ISO model creation may be assessed in vivo by serial echocardiography demonstrating hypertrophy, ventricular dilation, and dysfunction.

4.
Medicine (Baltimore) ; 98(31): e16665, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374040

RESUMO

BACKGROUND: The aim of this study was to summarize current evidence evaluating the association between antenatal infection and intraventricular hemorrhage (IVH) in preterm infants. MATERIALS AND METHODS: We searched for published articles on antenatal infection and IVH in 3 English (PubMed, the Cochrane Library, and EBSCO) and 3 Chinese (VEIPU, CNKI, and WANFANG) databases on May 19, 2019. In addition, the references of these articles were screened. The included studies had to meet all of the following criteria: preterm infants (<37 weeks); comparing antenatal infection with no infection; the outcomes included IVH (all grades), mild IVH, or sereve IVH; the type of study was randomized controlled trial or cohort study. RESULTS: A total of 23 cohort studies involving 13,605 preterm infants met our inclusion criteria. Antenatal infection increased the risk of IVH (odds ratios ([OR] 2.18, 95% confidence intervals [CI] 1.58-2.99), mild IVH (OR 1.95, 95% CI 1.09-3.49) and severe IVH (OR 2.65, 95% CI 1.52-4.61). For type of antenatal infection, the ORs and 95% CI were as follows: 2.21 (1.60-3.05) for chorioamnionitis, 2.26 (1.55-3.28) for histologic chorioamnionitis, 1.88 (1.22-2.92) for clinical chorioamnionitis, and 1.88 (1.14-3.10) for ureaplasma. CONCLUSIONS: Antenatal infection may increase the risk of developing IVH in the preterm infant. The evidence base is however of low quality and well-designed studies are needed.


Assuntos
Hemorragia Cerebral Intraventricular/epidemiologia , Recém-Nascido Prematuro , Infecção/epidemiologia , Resultado da Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Peso ao Nascer , Corioamnionite/epidemiologia , Feminino , Idade Gestacional , Humanos , Gravidez , Índice de Gravidade de Doença
5.
J Am Heart Assoc ; 8(11): e011625, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31433721

RESUMO

Background Branched-chain amino acid (BCAA) catabolic defect is an emerging metabolic hallmark in failing hearts in human and animal models. The therapeutic impact of targeting BCAA catabolic flux under pathological conditions remains understudied. Methods and Results BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a small-molecule inhibitor of branched-chain ketoacid dehydrogenase kinase, was used to enhance BCAA catabolism. After 2 weeks of transaortic constriction, mice with significant cardiac dysfunctions were treated with vehicle or BT2. Serial echocardiograms showed continuing pathological deterioration in left ventricle of the vehicle-treated mice, whereas the BT2-treated mice showed significantly preserved cardiac function and structure. Moreover, BT2 treatment improved systolic contractility and diastolic mechanics. These therapeutic benefits appeared to be independent of impacts on left ventricle hypertrophy but associated with increased gene expression involved in fatty acid utilization. The BT2 administration showed no signs of apparent toxicity. Conclusions Our data provide the first proof-of-concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure.

6.
Adv Mater ; 31(37): e1903277, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31348581

RESUMO

Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at-site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I-NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I-NM@siRNA nanomedicine demonstrates effective at-site siRNA release resulting from tumoral reactive oxygen species (ROS)-triggered sequential destabilization. Furthermore, the utility of 3I-NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I-NM@siRNA nanomedicine with angiopep-2 peptide is enhanced. The targeted Ang-3I-NM@siRNA exhibits superb blood-brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo-like kinase 1 and vascular endothelial growth factor receptor-2, Ang-3I-NM@siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple-interaction stabilization together with inbuilt self-destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases.

7.
World Neurosurg ; 129: e87-e96, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150848

RESUMO

BACKGROUND: For multilevel cervical fusion, anterior corpectomy and fusion (ACCF) induces more implant-related complications than anterior diskectomy and fusion (ACDF), which implies that the biomechanical stability of ACCF may be insufficient. The aim of this study was to assess whether the optimization of the cage profiles could improve the biomechanical performance of multilevel ACCF. METHODS: Three finite element models were constructed and compared, including 3-level ACDF, 2-level ACCF using a conventional cage for reconstruction, and 2-level ACCF using a new cage for reconstruction. The ends of the new cage possessed additional end rings and emulated the end plate geometries. The ranges of motion (ROMs) of the surgical segments and the stress peaks in the end plate, fixation system, and screw-bone interface were compared. RESULTS: Compared with preoperative status, ACDF and ACCF reduced the segmental ROMs by 96.1%-98.2%. The end plate stress peaks were the highest in ACCF using the conventional cage (10.1-18.6 MPa), followed by ACCF using the new cage (7.7-14.3 MPa) and ACDF (5.3-9.1 MPa). ACDF induced the highest stress peaks in the fixation system and screw-bone interface (32.5-39.3 MPa and 12.1-12.7 MPa, respectively), followed by ACCF using the conventional cage (20.4-31.7 MPa and 10.3-13.6 MPa, respectively) and ACCF using the new cage (18.6-25.7 MPa and 9.7-12.6 MPa, respectively). CONCLUSIONS: The application of the new cage decreased the risks of cage subsidence and instrument-related complications in multilevel ACCF. Under the condition where cage subsidence was prevented, ACCF was superior to ACDF in terms of construct stability and avoiding instrument-related complications.

8.
Diabetes ; 68(9): 1730-1746, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31167878

RESUMO

Recent studies implicate a strong association between elevated plasma branched-chain amino acids (BCAAs) and insulin resistance (IR). However, a causal relationship and whether interrupted BCAA homeostasis can serve as a therapeutic target for diabetes remain to be established experimentally. In this study, unbiased integrative pathway analyses identified a unique genetic link between obesity-associated IR and BCAA catabolic gene expression at the pathway level in human and mouse populations. In genetically obese (ob/ob) mice, rate-limiting branched-chain α-keto acid (BCKA) dehydrogenase deficiency (i.e., BCAA and BCKA accumulation), a metabolic feature, accompanied the systemic suppression of BCAA catabolic genes. Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKA dehydrogenase kinase (BCKDK) ( a suppressor of BCKA dehydrogenase) reduced the abundance of BCAA and BCKA and markedly attenuated IR in ob/ob mice. Similar outcomes were achieved by reducing protein (and thus BCAA) intake, whereas increasing BCAA intake did the opposite; this corroborates the pathogenic roles of BCAAs and BCKAs in IR in ob/ob mice. Like BCAAs, BCKAs also suppressed insulin signaling via activation of mammalian target of rapamycin complex 1. Finally, the small-molecule BCKDK inhibitor significantly attenuated IR in high-fat diet-induced obese mice. Collectively, these data demonstrate a pivotal causal role of a BCAA catabolic defect and elevated abundance of BCAAs and BCKAs in obesity-associated IR and provide proof-of-concept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.

9.
BMC Mol Cell Biol ; 20(1): 15, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31216990

RESUMO

BACKGROUND: To investigate the effects of serum amyloid A1 (SAA1) on lipopolysaccharide (LPS) -induced inflammation in vascular smooth muscle cells (VSMCs). SAA1 expression was detected in LPS induced VSMCs at different concentrations for different time by using Western blotting. After pre-incubation with recombinant SAA1 protein, VSMCs were treated with 1 µg/ml LPS for 24 h. The VSMCs were then divided into Control, SAA1 siRNA, Nox4 siRNA, LPS, LPS + SAA1 siRNA, LPS + Nox4 siRNA and LPS + SAA1 siRNA + Nox4 groups. MTT was performed to observe the toxicity of VSMCs. Lucigenin-enhanced chemiluminescence method was used to detect superoxide anion (O2-) production and NADPH oxidase activity. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine expressions of inflammatory factors. Western blotting was used to determine expressions of NOX-4 and p38MAPK/NF-κB pathway related proteins. RESULTS: LPS promoted SAA1 protein expression in a concentration-/time-dependent manner. Recombinant SAA1 protein could increase NOX4/ROS production and promote the release of inflammatory factors (IL-1ß, IL-6, IL-8, IL-17, TNF-α and MCP-1) in LPS (1 µg/ml) - induced VSMCs. Besides, both SAA1 siRNA and NOX-4 siRNA could not only enhance the O2- production and NADPH oxidase activity, but also up-regulate the protein expression of NOX4, the release of inflammatory factors, and the levels of p-p38 and p-NF-κB p65 in LPS-induced VSMCs. However, no significant differences in each index were observed between LPS group and LPS + SAA1 siRNA + Nox4 group. CONCLUSION: SAA1-mediated NOX4/ROS pathway could activate p38MAPK/NF-κB pathway, thereby contributing to the release of inflammatory factors in LPS-induced VSMCs.

10.
Brain Behav Immun ; 81: 228-246, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31207335

RESUMO

Traumatic brain injury (TBI) and ethanol intoxication (EI) frequently coincide, particularly in young subjects. However, the mechanisms of their interaction remain poorly understood. Among other pathogenic pathways, TBI induces glial activation and neuroinflammation in the hippocampus, resulting in acute and chronic hippocampal dysfunction. In this regard, we investigated the role of EI affecting these responses unfolding after TBI. We used a blunt, weight-drop approach to model TBI in mice. Male mice were pre-administered with ethanol or vehicle to simulate EI. The neuroinflammatory response in the hippocampus was assessed by monitoring the expression levels of >20 cytokines, the phosphorylation status of transcription factors and the phenotype of microglia and astrocytes. We used AS1517499, a brain-permeable STAT6 inhibitor, to elucidate the role of this pathway in the EI/TBI interaction. We showed that TBI causes the elevation of IL-33, IL-1ß, IL-38, TNF-α, IFN-α, IL-19 in the hippocampus at 3 h time point and concomitant EI results in the dose-dependent downregulation of IL-33, IL-1ß, IL-38, TNF-α and IL-19 (but not of IFN-α) and in the selective upregulation of IL-13 and IL-12. EI is associated with the phosphorylation of STAT6 and the transcription of STAT6-controlled genes. Moreover, ethanol-induced STAT6 phosphorylation and transcriptional activation can be recapitulated in vitro by concomitant exposure of neurons to ethanol, depolarization and inflammatory stimuli (simulating the acute trauma). Acute STAT6 inhibition prevents the effects of EI on IL-33 and TNF-α, but not on IL-13 and negates acute EI beneficial effects on TBI-associated neurological impairment. Additionally, EI is associated with reduced microglial activation and astrogliosis as well as preserved synaptic density and baseline neuronal activity 7 days after TBI and all these effects are prevented by acute administration of the STAT6 inhibitor concomitant to EI. EI concomitant to TBI exerts significant immunomodulatory effects on cytokine induction and microglial activation, largely through the activation of STAT6 pathway, ultimately with beneficial outcomes.

11.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(4): 409-414, 2019 Apr 30.
Artigo em Chinês | MEDLINE | ID: mdl-31068283

RESUMO

OBJECTIVE: To assess the geometrical matching of a new anatomical adaptive titanium mesh cage (AA-TMC) with the endplate and its effect on cervical segmental alignment reconstruction in single- and two-level anterior cervical corpectomy and fusion (ACCF) and compare the compressive load at the endplate between the AA-TMC and the conventional titanium mesh cage (TMC). METHODS: Twelve cervical cadaveric specimens were used to perform single- and two-level ACCF. The interbody angle (IBA), interbody height (IBH) and the interval between the AA-TMC and the endplate were evaluated by comparison of the pre- and postoperative X-ray images. The maximum load at the endplate was compared between the AA-TMC and TMC based on American Society for Testing and Materials (ASTM) F2267 standard. RESULTS: No significant differences were found between the preoperative and postoperative IBA and IBH in either single-level ACCF (11.62°±2.67° vs 12.13°±0.69° and 23.90±2.18 mm vs 24.23±1.13 mm, respectively; P > 0.05) or two-level ACCF (15.63°±5.06° vs 16.16°±1.05°and 42.93±3.51 mm vs 43.04±1.70 mm, respectively; P > 0.05). The mean interval between the AA-TMC and the endplate was 0.37 ± 0.3 mm. Compared to the conventional TMC, the use of AA-TMC significantly increased the maximum load at the endplate in both single-level ACCF (719.7±5.5 N vs 875.8±5.2 N, P < 0.05) and two-level ACCF (634.3±5.9 N vs 873±6.1 N, P < 0.05). CONCLUSIONS: The use of AA-TMC in single-level and two-level ACCF can significantly increase the maximum load at the endplate to lower the possibility of implant subsidence and allows effective reconstruction of the cervical alignment.


Assuntos
Vértebras Cervicais , Fusão Vertebral , Fenômenos Biomecânicos , Humanos , Próteses e Implantes , Telas Cirúrgicas , Titânio , Resultado do Tratamento
12.
Curr Opin Cardiol ; 34(3): 260-269, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30973397

RESUMO

PURPOSE OF REVIEW: Characterized by enlarged ventricle and loss of systolic function, dilated cardiomyopathy (DCM) has the highest morbidity among all the cardiomyopathies. Although it is well established that DCM is typically caused by mutations in a large number of genes, there is an emerging appreciation for the contribution of epigenetic alteration in the development of DCM. RECENT FINDINGS: We present some of the recent progress in the field of epigenetics in DCM by focusing on the four major epigenetic modifications, that is, DNA methylation, histone modification, chromatin remodeling as well as the noncoding RNAs. The major players involved in these DCM-related epigenetic reprogramming will be highlighted. Finally, the diagnostic and the therapeutic implications for DCM based on new knowledge of epigenetic regulation will also be discussed. SUMMARY: As a rapidly expanding field, epigenetic studies in DCM have the promise to yield both novel mechanistic insights as well as potential new avenues for more effective treatment of the disease.

13.
Am J Clin Nutr ; 109(6): 1569-1577, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31005973

RESUMO

BACKGROUND: Recent studies have shown that circulating branched-chain amino acids (BCAAs) are elevated in obese, insulin-resistant individuals. However, it is not known if supplementation of additional BCAAs will further impair glucose metabolism. OBJECTIVES: The aim of this pilot study was to determine the effects of BCAA supplementation on glucose metabolism in obese, prediabetic individuals. METHODS: This is a randomized crossover study involving 12 obese individuals with prediabetes. Participants were randomly assigned to receive a daily supplement containing either 20 g BCAA or protein low in BCAAs for 4 wk with a 2-wk washout in between. At each visit, an oral-glucose-tolerance test (OGTT) was performed. Collected blood samples were used to measure glucose, insulin, and insulin resistance-associated biomarkers. RESULTS: BCAA supplementation tended to decrease the plasma glucose area under the curve (AUC) measured by the OGTT (AUC percentage change from supplementation baseline, BCAA: -3.3% ± 3%; low-BCAA: 10.0% ± 6%; P = 0.08). However, BCAA supplementation did not affect plasma insulin during OGTT challenge (BCAA: -3.9% ± 8%; low-BCAA: 14.8% ± 10%; P = 0.28). The plasma concentrations of nerve growth factor (BCAA: 4.0 ± 1 pg/mL; low-BCAA: 5.7 ± 1 pg/mL; P = 0.01) and monocyte chemoattractant protein-1 (BCAA: -0.4% ± 9%; low-BCAA: 29.0% ± 18%; P = 0.02) were significantly lowered by BCAA supplementation compared to low-BCAA control. Plasma interleukin 1ß was significantly elevated by BCAA supplementation (BCAA: 231.4% ± 187%; low-BCAA: 20.6% ± 33%; P = 0.05). BCAA supplementation did not affect the circulating concentrations of the BCAAs leucine (BCAA: 9.0% ± 12%; low-BCAA: 9.2% ± 11%), valine (BCAA: 9.1% ± 11%; low-BCAA: 12.0% ± 13%), or isoleucine (BCAA: 2.5% ± 11%; low-BCAA: 7.3% ± 11%). CONCLUSIONS: Our data suggest that BCAA supplementation did not impair glucose metabolism in obese, prediabetic subjects. Further studies are needed to confirm the results seen in the present study. This study was registered at clinicaltrials.gov as NCT03715010.

14.
JCI Insight ; 52019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31021818

RESUMO

Right ventricular dysfunction is highly prevalent across cardiopulmonary diseases and independently predicts death in both heart failure (HF) and pulmonary hypertension (PH). Progression towards right ventricular failure (RVF) can occur in spite of optimal medical treatment of HF or PH, highlighting current insufficient understanding of RVF molecular pathophysiology. To identify molecular mechanisms that may distinctly underlie RVF, we investigated the cardiac ventricular transcriptome of advanced HF patients, with and without RVF. Using an integrated systems genomic and functional biology approach, we identified an RVF-specific gene module, for which WIPI1 served as a hub and HSPB6 and MAP4 as drivers, and confirmed the ventricular specificity of Wipi1, Hspb6, and Map4 transcriptional changes in adult murine models of pressure overload induced RV- versus LV- failure. We uncovered a shift towards non-canonical autophagy in the failing RV that correlated with RV-specific Wipi1 upregulation. In vitro siRNA silencing of Wipi1 in neonatal rat ventricular myocytes limited non-canonical autophagy and blunted aldosterone-induced mitochondrial superoxide levels. Our findings suggest that Wipi1 regulates mitochondrial oxidative signaling and non-canonical autophagy in cardiac myocytes. Together with our human transcriptomic analysis and corroborating studies in an RVF mouse model, these data render Wipi1 a potential target for RV-directed HF therapy.

15.
Proc Natl Acad Sci U S A ; 116(13): 6172-6180, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30867288

RESUMO

Heart performance relies on highly coordinated excitation-contraction (EC) coupling, and defects in this critical process may be exacerbated by additional genetic defects and/or environmental insults to cause eventual heart failure. Here we report a regulatory pathway consisting of the RNA binding protein RBFox2, a stress-induced microRNA miR-34a, and the essential EC coupler JPH2. In this pathway, initial cardiac defects diminish RBFox2 expression, which induces transcriptional repression of miR-34a, and elevated miR-34a targets Jph2 to impair EC coupling, which further manifests heart dysfunction, leading to progressive heart failure. The key contribution of miR-34a to this process is further established by administrating its mimic, which is sufficient to induce cardiac defects, and by using its antagomir to alleviate RBFox2 depletion-induced heart dysfunction. These findings elucidate a potential feed-forward mechanism to account for a critical transition to cardiac decompensation and suggest a potential therapeutic avenue against heart failure.


Assuntos
Insuficiência Cardíaca/metabolismo , Coração/fisiopatologia , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Proteínas Musculares/metabolismo , Fatores de Processamento de RNA/metabolismo , Animais , Regulação para Baixo , Insuficiência Cardíaca/fisiopatologia , Humanos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia
17.
J Mol Cell Cardiol ; 128: 198-211, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30742811

RESUMO

Heart failure is associated with hypertrophying of cardiomyocytes and changes in transcriptional activity. Studies from rapidly dividing cells in culture have suggested that transcription may be compartmentalized into factories within the nucleus, but this phenomenon has not been tested in vivo and the role of nuclear architecture in cardiac gene regulation is unknown. While alterations to transcription have been linked to disease, little is known about the regulation of the spatial organization of transcription and its properties in the pathological setting. In the present study, we investigate the structural features of endogenous transcription factories in the heart and determine the principles connecting chromatin structure to transcriptional regulation in vivo. Super-resolution imaging of endogenous RNA polymerase II clusters in neonatal and adult cardiomyocytes revealed distinct properties of transcription factories in response to pathological stress: neonatal nuclei demonstrated changes in number of clusters, with parallel increases in nuclear area, while the adult nuclei underwent changes in size and intensity of RNA polymerase II foci. Fluorescence in situ hybridization-based labeling of genes revealed locus-specific relationships between expression change and anatomical localization-with respect to nuclear periphery and heterochromatin regions, both sites associated with gene silencing-in the nuclei of cardiomyocytes in hearts (but not liver hepatocytes) of mice subjected to pathologic stimuli that induce heart failure. These findings demonstrate a role for chromatin organization and rearrangement of nuclear architecture for cell type-specific transcription in vivo during disease. RNA polymerase II ChIP and chromatin conformation capture studies in the same model system demonstrate formation and reorganization of distinct nuclear compartments regulating gene expression. These findings reveal locus-specific compartmentalization of stress-activated, housekeeping and silenced genes in the anatomical context of the endogenous nucleus, revealing basic principles of global chromatin structure and nuclear architecture in the regulation of gene expression in healthy and diseased conditions.

18.
Fetal Pediatr Pathol ; 38(1): 57-62, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30661433

RESUMO

INTRODUCTION: The main characteristics of absent pulmonary valve syndrome (APVS) include the absence or hypoplasia of the pulmonary valve, stenosis of the pulmonary valve annulus, and aneurysmal dilatation of the pulmonary trunk and its branches. In the more common type 1, the tetralogy of Fallot-like type, there is a ventricular septal defect, overriding aorta, pulmonary arterial dilatation, and absence of ductus arteriosus, The second type has an intact ventricular septum, less pulmonary artery dilatation, and a patent ductus arteriosus, with or without tricuspid atresia. CASE REPORT: This APVS had an intact ventricular septum with an absent ductus arteriosus. CONCLUSION: The APVS with intact ventricular septum with an absent ductus arteriosus may represent a third type of APVS.


Assuntos
Feto/anormalidades , Cardiopatias Congênitas/patologia , Valva Pulmonar/anormalidades , Humanos , Masculino
19.
Circ Res ; 124(1): 161-169, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30605412

RESUMO

On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present, and >40 scientists presented their latest work on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers, and physicians in the field of cardiovascular sciences met and discussed the most recent advances in their work and proposed future strategies for overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical, and mechanical cues to cells to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.


Assuntos
Disciplinas das Ciências Biológicas , Engenharia Biomédica , Pesquisa Biomédica , Insuficiência Cardíaca , Comunicação Interdisciplinar , Animais , Comportamento Cooperativo , Difusão de Inovações , Coração/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Miocárdio/metabolismo , Miocárdio/patologia , Recuperação de Função Fisiológica , Regeneração
20.
Med Sci Monit ; 25: 142-149, 2019 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-30612133

RESUMO

BACKGROUND This study aimed to verify the anti-subsidence ability of dome-shaped titanium mesh cage (TMC) used in anterior cervical corpectomy and fusion (ACCF). MATERIAL AND METHODS Thirty fresh human cervical vertebrae specimens were collected and randomly harvested into 2 groups: the traditional TMC group and the dome-shaped TMC group. The bone mineral density (BMD) of the specimens was recorded. Each group was biomechanically tested in axial compression with a cyclically loading range from 60 to 300 N at 0.5Hz for 10 000 cycles. The displacement data of the 2 groups were recorded every 10 cycles. RESULTS There was no significant difference in bone mineral density between the 2 groups of cervical specimens. The traditional TMC group stabilized at 535±35 cycles while the dome-shaped TMC group stabilized at 1203±57 cycles, which showed that the rate of subsidence of the dome-shaped TMC group was significantly slower than that of the traditional TMC group (p<0.05). After reaching stability, both groups had a more gradual and sustained growth. The peak displacement during fatigue testing was -2.064±0.150mm in the traditional TMC group and -0.934±0.086mm in the dome-shaped TMC group, which showed a significant difference (p<0.05). CONCLUSIONS The dome-shaped TMC showed a smaller subsidence displacement and a gentler subsidence tendency following the same cyclic loading (compared to the traditional TMC). From a biomechanical point of view, the dome-shaped TMC has stronger anti-subsidence ability due to its unique structural design that closely matches the vertebral endplate.


Assuntos
Vértebras Cervicais/fisiologia , Fusão Vertebral/métodos , Adulto , Fenômenos Biomecânicos , Densidade Óssea , Cadáver , Vértebras Cervicais/anatomia & histologia , Força Compressiva/fisiologia , Feminino , Humanos , Masculino , Pescoço/fisiologia , Próteses e Implantes , Telas Cirúrgicas , Titânio
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