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1.
Cell Metab ; 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32369736

RESUMO

Type 2 diabetes (T2D) is a major comorbidity of COVID-19. However, the impact of blood glucose (BG) control on the degree of required medical interventions and on mortality in patients with COVID-19 and T2D remains uncertain. Thus, we performed a retrospective, multi-centered study of 7,337 cases of COVID-19 in Hubei Province, China, among which 952 had pre-existing T2D. We found that subjects with T2D required more medical interventions and had a significantly higher mortality (7.8% versus 2.7%; adjusted hazard ratio [HR], 1.49) and multiple organ injury than the non-diabetic individuals. Further, we found that well-controlled BG (glycemic variability within 3.9 to 10.0 mmol/L) was associated with markedly lower mortality compared to individuals with poorly controlled BG (upper limit of glycemic variability exceeding 10.0 mmol/L) (adjusted HR, 0.14) during hospitalization. These findings provide clinical evidence correlating improved glycemic control with better outcomes in patients with COVID-19 and pre-existing T2D.

2.
J Am Heart Assoc ; 9(10): e015772, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32384006

RESUMO

Background Whether statin treatment can improve hemodynamic status of coronary atherosclerotic plaque remains unknown. It is of clinical interest to explore the hemodynamic change of coronary lesions after statin treatment. Methods and Results Consecutive patients with intermediate pre-test probability of coronary artery disease were prospectively enrolled and underwent baseline coronary computed tomography angiography (CCTA) as well as follow-up CCTA. The primary end point was to determine the lesion-specific change of △computed tomography-derived fractional flow reserve (△CT-FFR, defined as the change of CT-FFR value across each lesion) after rosuvastatin treatment. The secondary end point was to compare the change of other plaque characteristics according to serial CCTA findings. 152 patients (mean age: 67.1±9.7 years, 100 men, mean follow-up duration of 13.9±2.5 months) were finally included. In non-calcified plaque subgroup, △CT-FFR was significantly lower at follow-up compared with baseline (0.051±0.010 versus 0.035±0.012, P=0.013). All other parameters were not found to be significantly different between baseline and follow-up CCTA measurements. In calcified plaque and mixed plaque subgroups, all parameters showed no significant differences between baseline and follow-up CCTA groups (P>0.05 for all). According to multivariate regression analysis, non-calcified plaque was >2 times more likely than calcified plaque to observe the decrease of △CT-FFR (adjusted hazard ratio: 2.05 [1.03-4.09], P=0.042). Conclusions In patients with mild to intermediate coronary stenosis, rosuvastatin treatment resulted in a reduction in lesion-specific △CT-FFR at mid-term follow-up. This hemodynamic improvement was mainly observed for non-calcified lesions.

3.
Cell Mol Neurobiol ; 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32323150

RESUMO

Compound 511 (511) is specially developed for opioid addiction treatment based on the Ancient Chinese drug rehabilitation literature, and its composition has profound effects in the treatment of drug addiction in various clinical trials and animal experiments. The effect of 511 on the rewarding properties of morphine and craving responses and its potential mechanisms remain unclear. Here, we have applied a conditioned place preference (CPP) paradigm in mice to measure morphine-induced rewarding effects under the treatment of 511. Then we used the RNA sequencing strategy to screen its potential mechanisms. In our research, firstly, we found 511 could decrease CPP score, locomotor activity, self-administration, jumping behavior, weight loss, wet-dog shakes, and stereotyped behavior. Then the brain VTA region tissues were performed mRNA sequencing to detect potential mechanisms. We found the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) were downregulated in morphine-induced CPP, whereas the decreased BDNF and TrkB were reversed after 511 treatment. We retested the levels of BDNF and TrkB using qRT-PCR and Western blot and found the similar results to mRNA sequencing. It has been widely reported that BDNF-TrkB signaling in the VTA is involved in multiple facets of addiction, including reward and motivation, so we focused on the BDNF-TrkB signaling to investigate the anti-addiction mechanisms of 511 in morphine addiction mice. We studied the downstream pathway of BDNF-TrkB and the soma size of dopaminergic neurons. The results showed 511 could increase the phosphorylation levels of PI3K and AKT, which were decreased in morphine-induced CPP. Simultaneously, 511 could decrease the level of PLCγ1 and the phosphorylation levels of ERK and S6K, which were increased in morphine-induced CPP. In addition, 511 also enlarged the soma size of VTA dopaminergic neurons, which was reduced in morphine-induced CPP. Hence, our research indicated 511 maybe mediate the BDNF-TrkB signaling in VTA to improve morphine addiction behavior.

4.
Inflammation ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198725

RESUMO

The therapeutic effect of electroacupuncture (EA) on inflammatory pain has been well recognized clinically, but the mechanism is unclear. Interleukin-10 (IL-10), which is produced by regulatory T (Treg) cell, is a key anti-inflammatory cytokine for relieving inflammatory pain. Therefore, the aim of this study is to investigate whether EA could inhibit CFA-induced pain and attenuate inflammation progression by regulating the activation of immunocyte and inducing the expression of IL-10. In this study, mice were treated with EA (2/100 Hz, 2 mA) for five consecutive days after 1 day of CFA injection. The behavioral tests were measured and analyzed after the daily EA treatment; then, hind paw, spinal cord, and spleen tissues were prepared for assessment. The results showed that EA treatment significantly increased the mechanical threshold and thermal latency after CFA injection and boosted the expression of IL-10 in paw and spinal cord tissues. EA treatment promoted Treg cells; suppressed macrophage and neutrophils cells; reduced the expression of IL-1ß, NLRP3, and TNF-α; and ultimately relieved inflammatory pain. The findings suggested that the analgesic and anti-inflammatory effect of EA treatment could be partially associated with suppression of pro-inflammatory cytokines mediated by induction of IL-10.

5.
FASEB J ; 34(3): 4540-4556, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31999011

RESUMO

The mu-opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating an array of splice variants that are conserved from rodent to human. Both mouse and human OPRM1 have five exon 5-associated seven transmembrane full-length carboxyl terminal variants, MOR-1B1, MOR-1B2, MOR-1B3, MOR-1B4, and MOR-1B5, all of which are derived from alternative 3' splicing from exon 3 to alternative sites within exon 5. The functional relevance of these exon 5-associated MOR-1Bs has been demonstrated in mu agonist-induced G protein coupling, adenylyl cyclase activity, receptor internalization and desensitization, and post-endocytic sorting, as well as region-specific expression at the mRNA level. In the present study, we mapped a polyadenylation site for both mouse and human MOR-1Bs that defines the 3'-untranslated regions (3'-UTR) of MOR-1Bs and stabilizes mMOR-1Bs mRNAs. We identified a conserved miR378a-3p sequence in the 3'-UTR of both mouse and human MOR-1BS transcripts through which miR-378a-3p can regulate the expression of MOR-1Bs at the mRNA level. Chronic morphine treatment significantly increased the miR-378-3p level in Be(2)C cells and the brainstem of the morphine tolerant mice, contributing to the decreased expression of the mouse and human MOR-1B3 and MOR-1B4. Our study provides new insights into the role of miRNAs and Oprm1 splice variants in morphine tolerance.

6.
Circ Cardiovasc Imaging ; 13(1): e009775, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31910669

RESUMO

BACKGROUND: Dynamic computed tomography (CT) myocardial perfusion imaging (MPI) provides quantitative myocardial blood flow for the precise assessment of myocardial ischemia. However, compared with coronary CT angiography (CCTA), whether this functional imaging modality can reduce invasive coronary angiography without revascularization remains unknown. We aimed to determine the clinical outcomes of a dynamic CT-MPI+CCTA-guided versus CCTA-guided strategy in patients with suspected coronary artery disease. METHODS: Consecutive patients with intermediate pretest probability of coronary artery disease were prospectively enrolled and randomized to dynamic CT-MPI+CCTA-guided or CCTA-guided workup. The primary end point was the rate of invasive coronary angiography without revascularization within 3 months. The secondary end point was a composite of major adverse cardiac event at the 3-month, 6-month, and 1-year follow-up. RESULTS: A total of 240 patients (mean age, 69.01±11.2 years; 173 men) were included. The total radiation dose and contrast media usage within 90 days were higher in the CT-MPI+CCTA group than in the CCTA group (10.3 versus 7.1 mSv, P=0.031; 134.5±40.6 versus 108.1±48.2 mL, P<0.0001). Compared with the CCTA-guided group, the CT-MPI+CCTA-guided group had significantly lower rates of invasive coronary angiography within 90 days (48.3% [58/120] versus 30.8% [37/120], P=0.006) and invasive coronary angiography without revascularization (50.0% [29/58] versus 10.8% [4/37], P<0.0001). There were no significant differences regarding the frequency of major adverse cardiac event between the 2 groups at the 3-month, 6-month, and 1-year follow-up. CONCLUSIONS: In patients with intermediate pretest probability of coronary artery disease, CT-MPI+CCTA-guided patient management may be preferred over the CCTA-guided strategy as an approach to reduce unnecessary invasive procedures.

7.
Int J Cardiovasc Imaging ; 36(4): 723-730, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31907683

RESUMO

The present study aimed to investigate the association between perivascular fat attenuation index (FAI), high-risk plaque features and serum level of high sensitive C-reactive protein (hs-CRP). Consecutive patients with intermediate pre-test probability of CAD, who were referred for coronary CT angiography (CCTA), were included. High-risk plaque features were assessed by CCTA and included low attenuation plaque (LAP), positive remodeling (PR), napkin-ring sign (NRS) and spotty calcification. Lesion specific perivascular FAI was also measured for all plaques located on major epicardial vessels with diameter ≧ 2 mm. Laboratory test results, including hs-CRP, were recorded. 199 patients with 260 lesions were finally included. NRS and LAP were more commonly present in the group with elevated hs-CRP (35.9% vs. 19.4% and 14.1% vs. 2.6%, both p < 0.05) and more severe stenosis extent was also noted for this group. However, there was no significant difference between the elevated hs-CRP and normal hs-CRP group with respect to other CT parameters, such as lesion length, PR, spotty calcification and focal calcium score. Perivascular FAI failed to show significant difference between the two groups (- 69.8 ± 10.3HU vs. - 70.0 ± 12.0HU, p = 0.953) and there was poor correlation between perivascular FAI and hs-CRP measurements (r = - 0.04, p = 0.510). In conclusion, LAP and NRS are more commonly present in CAD patients with elevated level of hs-CRP. However, perivascular FAI failed to show such correlation with serum level of hs-CRP.

8.
Eur Radiol ; 30(2): 673-681, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31444596

RESUMO

OBJECTIVE: This study aimed to investigate the association between perivascular fat attenuation index (FAI) and hemodynamic significance of coronary lesions. METHODS: Patients with stable angina who underwent coronary computed tomography (CT) angiography and invasive fractional flow reserve (FFR) measurement within 2 weeks were retrospectively included. Lesion-based perivascular FAI, high-risk plaque features, total plaque volume (TPV), machine learning-based FFRCT, and other parameters were recorded. Lesions with invasive FFR ≤ 0.8 were considered functionally significant. RESULTS: This study included 167 patients with 219 lesions. Diameter stenosis (DS), lesion length, TPV, and perivascular FAI were significantly larger or longer in the group of hemodynamically significant lesions (FFR ≤ 0.8). In addition, smaller FFRCT value was associated with functionally significant lesions (0.720 ± 0.11 vs 0.846 ± 0.10, p < 0.001). No significant difference was found between the hemodynamically significant and insignificant subgroups with respect to CT-derived high-risk plaque features. According to multivariate analysis, DS, TPV, and perivascular FAI were significant predictors of lesion-specific ischemia. When integrating DS, TPV, and perivascular FAI, the area under the curve (AUC) of this combined method was 0.821, which was similar to that of FFRCT (AUC, 0.821 vs 0.850; p = 0.426). The diagnostic accuracy of FFRCT was higher than that of the combined approach, but the difference was statistically insignificant (79.0% vs 74.0%, p = 0.093). CONCLUSIONS: Perivascular FAI was significantly higher for flow-limiting lesions than for non-flow-limiting lesions. The combined use of FAI, TPV, and DS could predict ischemic coronary stenosis with high diagnostic accuracy. KEY POINTS: • Perivascular FAI was significantly higher for flow-limiting lesions than for non-flow-limiting lesions. • Combined use of FAI, plaque volume, and DS provided diagnostic performance comparable to that of machine learning-based FFR CTfor predicting ischemic coronary stenosis. • No significant difference was found between the hemodynamically significant and insignificant subgroups with respect to CT-derived high-risk plaque features.

9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(6): 1979-1985, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31839070

RESUMO

OBJECTIVE: To investigate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of malignant hematopathy and its influencing factors. METHODS: The clinical data of 300 cases received hematopoietic stem cell transplantation due to malignant hematological diseases in Zhu Jiang Hospital of Southern Medical University from January 2010 to June 2018 were analyzed retrospectively, and the factors affecting hematopoietic reconstruction, disease-free survival (DFS) and overall survival (OS) were compared between haploidentical HSCT and HLA matched HSCT. RESULTS: The hematopoietic reconstitution rate, incidence of GVHD, posttransplant recurrence rate and disease-free survival (DFS) were not statistically different between HLA-metched and haploidentical colorts. However, compared with HLA-matched HSCT group the time of platelet implantation was prolonged, the recurrence-related mortality was higher, and the overall survival (OS) rate was lower in the haploidentical HSCT group. Univariate analyses showed that non-remission before transplantation, and grade Ⅲ, Ⅳ aGVHD were the risk factors for OS in both groups (P<0.05). The age than 40 years old at the time of transplantation and unrelated donors were risk factors for OS in haploidentical HSCT group (P<0.05). Multivariate analysis showed that non-remission before transplantation and grade Ⅲ, Ⅳ aGVHD were independent prognostic indictor for OS with relative risk (RR) of 4.4 (95% CI,1.5-13.4), 9.3 (95% CI,2.3-37.0), 11.0 (95% CI,3.2-37.3) (P<0.05) in HLA-matched HSCT group. Unrelated donor, high-risk group, and gradeⅣaGVHD were independent prognostic indictors for OS with relative risk (RR) of 7.4 (95% CI,2.3-23.1), 2.4 (95% CI,1.3-4.5), 4.1(95% CI,1.6-10.5) (P<0.05) in haploidentical HSCT group. CONCLUSION: The comprehensive curative effect of HLA-matched HSCT is better than the haploidentical HSCT in hematological malignancies. In haploidentical HSCT the selecting related donor is better than unrelated donors, which required more platelet transfusion support.


Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Adulto , Neoplasias Hematológicas/terapia , Humanos , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos
10.
Circ Cardiovasc Qual Outcomes ; 12(11): e006073, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31707825

RESUMO

BACKGROUND: Recent court decisions have thrown into question the Food and Drug Administration's rules limiting manufacturer promotion of prescription drugs for unapproved uses. We assessed how providing pro forma disclosures or more descriptive evidence context about the data supporting an off-label claim affected physicians' beliefs about drug efficacy. METHODS AND RESULTS: In online and mailed surveys, we randomized national samples of board-certified, clinically active cardiologists, internists, and endocrinologists to receive 1 of 3 information scenarios about a hypothetical drug derived verbatim from excerpts on the website for Vascepa, a prescription fish oil for which Food and Drug Administration specially permitted off-label promotion after a manufacturer lawsuit. The scenarios presented information about the approved on-label indication (severe hypertriglyceridemia), off-label claim + pro forma disclaimers (suggestive but not conclusive evidence for use as an add-on to a statin for patients reaching low-density lipoprotein goal but with persistent moderate hypertriglyceridemia), and off-label claim + evidence context (eg, reports on 3 trials failing to demonstrate cardiovascular benefit of other triglyceride-lowering drugs for such patients). Among 686 respondents (48% response rate), 29% reported receiving off-label information about Vascepa (ie, use as an add-on to a statin) from the manufacturer, and 16% had prescribed it off-label for this purpose. Off-label prescribing was 5 times higher among physicians who received such off-label information (38% versus 7%, P<0.001). For the hypothetical drug, the proportion of physicians endorsing the unproven claim that the drug reduced cardiovascular risk was similar among those randomized to the on-label and off-label claim + pro forma disclaimers scenarios (35% versus 37% [95% CI, -6% to 11%]), but substantially lower among those randomized to the off-label claim + evidence context scenario (21% [95% CI, -24% to 7%]). CONCLUSIONS: Physicians who received company information about the unapproved use of Vascepa were more likely to report prescribing it off-label. Supplementing off-label claims with evidence context improved the prescribers' knowledge and reduced enthusiasm for the unproven, off-label indication of reducing cardiovascular risk.

11.
J Manag Care Spec Pharm ; 25(11): 1210-1224, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31663459

RESUMO

BACKGROUND: Step therapy policies that require prescribers to follow an ordered protocol for drug choices are widely used by public and private insurers to manage medication costs; however, the perceptions of prescribing physicians regarding these policies have not been studied. OBJECTIVE: To determine physician attitudes toward step therapy policies and the correlation of these beliefs with physician characteristics. METHODS: A sample of clinically active physicians specializing in internal medicine, cardiology, or endocrinology received a survey administered online or via mail. Five-point Likert scale questions assessed physicians' opinions of clinical, economic, and implementation elements of prior authorization policies; physician demographic characteristics; and the extent of their interactions with the pharmaceutical industry. RESULTS: 686 physicians (48%) responded to the survey, which was evenly divided among primary care physicians, endocrinologists, and cardiologists. Many respondents (70%) had interactions with industry, including receipt of meals or gifts and use of medication samples. Physicians reported that step therapy policies could improve the affordability of medication use (55% agree vs. 26% disagree) and its clinical appropriateness (59% agree vs. 19% disagree). By similar margins, however, physicians stated that step therapy policies were implemented inefficiently and inflexibly and often did not incorporate relevant patient-specific information. Physicians in subspecialties, especially endocrinology, and those who had interactions with the pharmaceutical industry were more likely to hold negative views of step therapy policies. CONCLUSIONS: Most physicians recognize the potential of step therapy to improve the quality and cost-effectiveness of prescribing, although interactions with industry may affect these opinions. Physician perception of ineffective implementation of these policies, however, undermines their acceptability. DISCLOSURES: The American Board of Internal Medicine (ABIM) funded the survey used in this study. The ABIM had no role in the design and conduct of the study or development and preparation of the manuscript. Survey honoraria was provided by the Consumers Union. Kesselheim and Avorn's work is funded by the Laura and John Arnold Foundation. Kesselheim is also supported by the Harvard-MIT Center for Regulatory Science, Arnold Ventures, and the Engelberg Foundation. Ross is employed by the ABIM. Fischer, Lu, and Tessema have nothing to disclose.

12.
Radiology ; 293(2): 305-314, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31549943

RESUMO

Background Direct intraindividual comparison of dynamic CT myocardial perfusion imaging (MPI) and machine learning (ML)-based CT fractional flow reserve (FFR) has not been explored for diagnosing hemodynamically significant coronary artery disease. Purpose To investigate the diagnostic performance of dynamic CT MPI and ML-based CT FFR for functional assessment of coronary stenosis. Materials and Methods Between January 2, 2017, and October 17, 2018, consecutive participants with stable angina were prospectively enrolled. All participants underwent dynamic CT MPI coronary CT angiography and invasive conventional coronary angiography (CCA) FFR within 2 weeks. Receiver operating characteristic (ROC) curve analysis was used to assess diagnostic performance. Results Eighty-six participants (mean age, 67 years ± 12 [standard deviation]; 67 men) with 157 target vessels were included for final analysis. The mean radiation doses for dynamic CT MPI and coronary CT angiography were 3.6 mSv ± 1.1 and 2.7 mSv ± 0.8, respectively. Myocardial blood flow (MBF) was lower in ischemic segments compared with nonischemic segments and reference segments (defined as the territory of vessels without stenosis) (75 mL/100 mL/min ± 20 vs 148 mL/100 mL/min ± 22 and 169 mL/100 mL/min ± 34, respectively, both P < .001). Similarly, CT FFR was also lower for hemodynamically significant lesions than for hemodynamically nonsignificant lesions (0.68 ± 0.1 vs 0.83 ± 0.1, respectively, P < .001). MBF had the largest area under the ROC curve (AUC) (using 99 mL/100 mL/min as a cutoff) among all parameters, outperforming ML-based CT FFR (AUC = 0.97 vs 0.85, P < .001). The vessel-based specificity and diagnostic accuracy of MBF were higher than those of ML-based CT FFR (93% vs 68%, P < .001 and 94% vs 78%, respectively, P = .04) whereas the sensitivity of both methods was similar (96% vs 88%, respectively, P = .11). Conclusion Dynamic CT myocardial perfusion imaging was able to help accurately evaluate the hemodynamic significance of coronary stenosis using a reduced amount of radiation. In addition, the myocardial blood flow derived from dynamic CT myocardial perfusion imaging outperformed machine learning-based CT fractional flow reserve for identifying lesions causing ischemia. © RSNA, 2019 Online supplemental material is available for this article.See also the editorial by Loewe in this issue.

13.
Front Genet ; 10: 796, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552097

RESUMO

Schistosomes are the only platyhelminths that have evolved separate sexes, and they exhibit a unique reproductive biology because the female's sexual maturation depends on a constant pairing contact with the male. In the female, pairing leads to gonad differentiation, which is associated with substantial morphological changes, and controls among others the expression of gonad-associated genes. In the male, no morphological changes have been observed after pairing, although first data indicated an effect of pairing on gene transcription. Comprehensive transcriptomic approaches have revealed an unexpected high number of genes that are differentially transcribed in the male after pairing. Their identities suggest roles for the male that are not restricted to feeding and enhanced muscular power to transport paired female and, as assumed before, to induce its sexual maturation by one "magic" factor. Instead, a more complex picture emerges in which both partners live in a reciprocal sender-recipient relationship that not only affects the gonads of both genders but may also involve tactile stimuli, transforming growth factor ß signaling, nutritional parts, and neuronal processes, including neuropeptides and G protein-coupled receptor signaling. This review provides a summary of transcriptomics including an overview of genes expressed in a pairing-dependent manner in schistosome males. This may stimulate further research in understanding the role of the male as the recipient of the female's signals upon pairing, the male's "capacitation," and its subsequent competence as a sender of information. The latter process finally transforms a sexually immature, autonomous female without completely developed gonads into a sexually mature, partially non-autonomous female with fully differentiated gonads and enormous egg production capacity.

14.
J Perinat Med ; 47(9): 979-985, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31562803

RESUMO

Background Hypercarbia increases cerebral blood flow secondary to cerebral vasodilatation, while hypocarbia can lead to vasoconstriction with a subsequent decrease in cerebral blood flow. The aim of this study was to examine CO2 cerebral vasoreactivity in a cohort of premature infants and to identify factors which influence this reactivity. Methods We prospectively studied a cohort of hemodynamically stable premature infants [birth weight (BW) <1500 g and gestational age (GA) ≤34 weeks]. Subjects underwent two studies, one in the first 72 h and the second after 1 week of life. Infants were continuously monitored via a physiology station that included transcutaneous CO2 (tcPCO2) monitor, near-infrared spectroscopy (NIRS), arterial pulse oximetry and heart rate. The total hemoglobin (Hb-T) signal of NIRS was used as an indicator of cerebral blood volume (CBV). Correlation between tcPCO2 and Hb-T was performed in each 1-h period using Pearson's correlation. Factors affecting the CO2 cerebrovascular reactivity were examined using bivariate and linear regression analyses. Results A total of 3847 1-h epochs were obtained from 140 studies of 72 premature infants. tcPCO2 correlated positively with Hb-T in 42% of epochs. In regression analysis, factors associated with increased percentage of positive correlation epochs were male sex and younger postmenstrual age (PMA; ß = 0.176, 0.169 and P-value = 0.036, 0.047 respectively). Factors associated with increased strength of positive correlation were mechanical ventilation and increased average tcPCO2 (ß = 0.198, 0.220 and P-value = 0.024, 0.011 respectively). Conclusion Increased prematurity, male sex, mechanical ventilation and hypercarbia are associated with stronger PCO2 cerebrovascular reactivity in premature infants. This association may explain their role in the pathogenesis of brain injury.

15.
J Law Med Ethics ; 47(3): 430-441, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31560634

RESUMO

Drug Safety Communications (DSCs) are used by the Food and Drug Administration (FDA) to inform health care providers, patients, caregivers, and the general public about safety issues related to FDA-approved drugs. To assess patient knowledge of the messaging contained in DSCs related to the sleep aids zolpidem and eszopiclone, we conducted a large, cross-sectional patient survey of 1,982 commercially insured patients selected by stratified random sampling from the Optum Research Database who had filled at least two prescriptions for either zolpidem or eszopiclone between July 1, 2012 and June 30, 2013. Among the 594 respondents (32.7% response rate), two-thirds reported hearing generally about drug safety information prior to starting a new drug, with the remaining one-third "rarely" or "never" hearing such information. Providers and pharmacists were primary sources of drug safety information. Two-thirds of zolpidem users and half of eszopiclone users reported having heard about the related DSC messages, ability to accurately identify the major factual messages was limited (overall median 2 correct out of 5, with men and those reporting higher educational level scoring higher [2/5 vs. 1/5, p=0.001]). Respondents reacted to new drug safety information about their sleep aids by reporting that they would want to learn about alternative ways to help them sleep (70%) and seek out more information about the safety of their specific sleeping pill (59-78%). Opportunities may exist for the FDA to work with providers and pharmacies to help ensure the DSC information is more widely received and is more fully understood by those taking the affected medications.

16.
Addict Biol ; : e12794, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31240833

RESUMO

Electroacupuncture (EA) has been developed on the basis of traditional Chinese acupuncture. EA can suppress craving in opioid addicts and opioid-seeking responses in rodents. However, the molecular mechanism of EA on the rewarding properties of morphine and craving responses is not known. Here, we have applied a conditioned place preference paradigm in mice to measure morphine-induced rewarding effects along with EA treatment. Circular RNAs (circRNAs) can function as micro RNA (miRNA) sponges to effectively regulate gene expression levels. CircRNA profiling within the nucleus accumbens (NAc) was performed in EA-treated and sham-treated mice. Following RNAseq, data were analyzed by gene ontology (GO) and Kyoto Encyclopedia Genes and Genomes (KEGG) tools. We identified 112 significantly differentially expressed circRNAs, including 51 that were up-regulated and 61 that were down-regulated. Our bioinformatics analyses show that these differentially expressed circRNAs map into pathways that are mainly involved with renin secretion and the cGMP-PKG signaling. We further constructed a circRNA-miRNA network that predicts the potential roles of the differentially expressed circRNAs and the interaction of circRNAs with miRNAs. Our secondary sequencing and bioinformatics analysis in the NAc after EA treatment on morphine-induced CPP provides putative novel targets on molecular mechanisms involved in morphine reinforcement and possibly craving.

17.
Front Pharmacol ; 10: 359, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068805

RESUMO

Background: Zanthoxylum nitidum (Roxb.) DC., also named Liang Mianzhen (LMZ), one kind of Chinese herb characterized with anti-inflammatory and relieving pain potency, which is widely used to treat injuries, rheumatism, arthralgia, stomach pain and so on in China. But its mechanism related to the anti-hyperalgesic has not been reported. The aim of this study was to investigate the analgesic activity of Liang Mianzhen on mice with Complete Freund adjuvant (CFA)-induced chronic inflammatory pain. Meanwhile, the peripheral and central mechanisms of analgesic effect of Liang Mianzhen were further examined via observing the effects of Liang Mianzhen on the signal pathway associated with inflammatory induced hyperalgesia. Methods: The inflammatory pain model was established by intraplantar injection of CFA in C57BL/6J mice. After 1 day of CFA injection, the mice were treated with LMZ (100 mg/kg) for seven consecutive days, and the behavioral tests were measured after the daily intragastric administration of LMZ. The morphological changes on inflamed paw sections were determined by hematoxylin eosin (HE) staining. Changes in the mRNA expression levels of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and nuclear factor κB p65 (NF-κBp65) were measured on day seven after CFA injection by using real-time quantitative PCR analysis and enzyme linked immunosorbent assay (ELISA) method, respectively. Moreover, immunohistochemistry and western blotting were used to detect extracellular regulated protein kinases 1/2 (ERK1/2) and NF-κB signal pathway activation. Results: The extract of LMZ (100 mg/kg) showed a significant anti-inflammatory and analgesic effect in the mice model. The paw edema volume was significantly reduced after the administration of LMZ compared to CFA group, as well as the paw tissues inflammatory damage was relived and the numbers of neutrophils in mice was reduced significantly. The CFA-induced mechanical threshold and thermal hyperalgesia value were significant improved with LMZ treatment at day three to day seven. We also found the mRNA levels of TNF-α, IL-1ß, IL-6 and NF-κBp65 were down-regulate after 7 days from the LMZ treatment compared to CFA group. Meanwhile, LMZ significantly suppressed over-expression of the phosphorylation of ERK1/2 and NF-κBp65 in peripheral and central. Conclusion: The present study suggests that the extract of LMZ attenuates CFA-induced inflammatory pain by suppressing the ERK1/2 and NF-κB signaling pathway at both peripheral and central level.

18.
Int J Parasitol ; 49(8): 615-624, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31136746

RESUMO

Facilitated by the Schistosoma mansoni genome project, multiple transcriptomic studies were performed over the last decade to elucidate gene expression patterns among different developmental stages of the complex schistosome life cycle. While these analyses enable the identification of candidate genes with key functions in schistosome biology, a diverse molecular tool set is needed that allows comprehensive functional characterization at the single gene level. This includes the availability of reliable reference genes to confirm changes in the transcription of genes of interest over different biological samples and experimental conditions. In particular, the investigation of one key aspect of schistosome biology, the pairing-dependent gene expression in females and males, requires knowledge on reference genes that are expressed independently of both pairing and of in vitro culture effects. Therefore, the present study focused on the identification of quantitative reverse transcription (qRT)-PCR reference genes suitable for the investigation of pairing-dependent gene expression in the S. mansoni male. The "pipeline" we present here is based on qRT-PCR analyses of high biological replication combined with three different statistical analysis tools, BestKeeper, geNorm, and NormFinder. Our approach resulted in a statistically robust ranking of 15 selected reference genes with respect to their transcription stability between pairing-unexperienced and -experienced males. We further tested the top seven candidate genes for their transcription stability during invitro culture of adult S. mansoni. Of these, the two most suitable reference genes were used to investigate the influence of the pairing contact on the transcription of genes of interest, comprising a tyrosine decarboxylase gene Smtdc1, an ebony ortholog Smebony, and the follistatin ortholog Smfst in S. mansoni males. Performing pairing, separation and re-pairing experiments with adult S. mansoni in vitro, our results indicate for the first time that pairing can act as a molecular on/off-switch of specific genes to strictly control their expression in schistosome males.

19.
PLoS One ; 14(5): e0216808, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31100080

RESUMO

Understanding oxidative stress and HTRA1 locus in abnormal angiogenesis resulting in wet AMD pathology is an important step in developing a novel therapeutic approach. Using subretinal injection of oxLDL into C57BL/6 mice, we observed a lesion resembling the features of choroidal neovascularization (CNV), including macrophage infiltration, increased VEGF expression, and neovascularization. However, incubating ARPE-19 cells with oxLDL-a carrier of oxidized phospholipids-resulted in increased expression of inflammatory cytokines and chemoattractant proteins that recruited monocytes, but no substantial increase in expression of VEGF. Furthermore, incubation of ARPE-19 with oxLDL induced higher expression of HTRA1, which we showed to synergize with oxLDL in elevating the expression of inflammatory cytokines and chemoattractant factors. To investigate the role of macrophage infiltration on these expression changes, we treated cultured J774 macrophages with oxLDL and applied the conditioned medium onto ARPE-19 cells. This treatment was found to greatly enhance the expression of VEGF in ARPE-19, indicating the necessity of macrophage secretory products to induce increased expression of VEGF in retinal pigment epithelium. Gene expression analysis revealed that oxLDL induced the expression of Wnt3A in macrophages, a key activator of canonical Wnt signaling pathways. In addition, western blot analysis showed that the macrophage conditioned media further enhanced the reduction of phosphorylated ß-catenin induced by oxLDL. Lastly, we investigated HTRA1 as a potential target for AMD therapeutics. We demonstrated the ability of anti-HTRA1 antibody in vitro to neutralize the protease activity of HTRA1 and reduce the inflammatory and angiogenic response to oxidative stress. Finally, we validated the neutralizing effect of anti-HTRA1 antibody in vivo by evaluating lesion size and protein expression in a laser-photocoagulation murine model of CNV. We found that the combination of oxLDL and HTRA1 enhanced CNV size, which was reversed by the addition of anti-HTRA1 antibody. This study not only provides preliminary evidence that HTRA1 may be a viable target for AMD therapeutics but also elucidates the biochemical mechanisms by which this therapeutic effect may be mediated.


Assuntos
Neovascularização de Coroide/metabolismo , Proteínas do Olho/metabolismo , Regulação da Expressão Gênica , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Macrófagos/metabolismo , Degeneração Macular/metabolismo , Fosfolipídeos/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Linhagem Celular , Neovascularização de Coroide/patologia , Inflamação/metabolismo , Inflamação/patologia , Lipoproteínas LDL/metabolismo , Macrófagos/patologia , Degeneração Macular/patologia , Camundongos , Oxirredução , Epitélio Pigmentado da Retina/patologia
20.
J Ethnopharmacol ; 239: 111885, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31009706

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kuntai capsule (KTC), a type of herb formulas, was first described in the book of Shang Han Za Bing Lun in the third century. KTC has been widely used for the clinical treatment of menopausal syndrome. Considering that premature ovarian failure is also known as premature menopause, this study was designed to investigate the effects and mechanisms of KTC on a mouse model of premature ovarian failure. MATERIALS AND METHODS: Forty-five female C57BL/6 mice were chosen for this study. Fifteen of the mice were separated into the Control group. The remaining thirty were used to establish the premature ovarian failure model by injecting intraperitoneally with 75 mg/kg cyclophosphamide and then by randomly dividing the mice into two groups. One group was considered the Model group, the other group treated with the Kuntai capsule intragastrically every day for one week called the KTC group. After treatment, mice were sacrificed for sampling. The ovaries morphology of mice was observed by hematoxylin and eosin (HE) staining, and all follicles were counted under microscope. Western blotting was used to detect the PI3K/AKT/mTOR pathway activation. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and anti-mullerian hormone (AMH)levels were measured by enzyme-linked immunosorbent assay (ELISA). The fertility was observed by giving treated mice 8 weeks for breeding. RESULTS: We found that primordial follicle counts were increased in the KTC group compared to the Model group. The phosphorylation of PI3K, AKT, mTOR, 4E-BP1 and S6K in the KTC group significantly reduced compared to Model group. Serum FSH and LH levels in the KTC group were decreased compared to the Model group, while, serum E2 and AMH levels in the KTC group were increased compared with the Model group. The litter size in the KTC group was improved compared to Model group. CONCLUSIONS: The KTC showed protective potentials of ovarian reserve and fertility to attenuate premature ovarian failure, which was relatively associated with activation of the PI3K/AKT/mTOR signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Feminino , Fertilidade/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Transdução de Sinais/efeitos dos fármacos
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