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1.
Methods Mol Biol ; 2191: 377-390, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32865755

RESUMO

Optogenetics is a new approach using light intensity to modulate the electrical activity of excitable cells by the interaction of light-sensitive proteins. This method has been widely and enthusiastically utilized in some fields over the last decade. Localizing a photosensitive protein to a specific place in the membrane of cardiomyocytes at a specific time is essential for most biological processes. In this case, vectors are injected into the circulation to allow them to spread throughout the whole heart. The aim of this protocol is to perform different illumination modes with blue laser to investigate optical control of Langendorff-perfused mice hearts which were systematically injected with adeno-associated virus (AAV) for ChR2(H134R) gene transfer. Electrograms (EGs) and epicardium monophasic action potential (MAP) showed that ChR2 expression in the heart can be flexibly controlled by blue light across different illumination sites with corresponding triggered ectopic rhythm. Illumination intensity, pulse duration, and impulse frequency were associated with the light capture rate. Flexible control of the cardiac rhythm with optogenetics provides an innovative approach to cardiac research and therapy.

2.
Eur J Pharmacol ; 889: 173571, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33031798

RESUMO

Chemotherapy drugs exerts beneficial antitumor activity before and after cancer surgery. Post-injury complications are a potential hazard after surgical tumor resection. Inflammation caused by surgical stress is known to promote the progression of post-injury complications. Recent studies have found that chemotherapy drugs can promote post-injury inflammatory response, leading to increased post-injury complications. Imidazole derivatives have effective anticancer activity. However, the impact of post-operative inflammation caused by imidazole derivatives is unclear. In this study, two novel phenanthroimidazole derivatives (L082 and L142) were synthesized and characterized. These compounds showed significant inhibitory effects on different tumor cells. The compound L082 also inhibited liver cancer in vivo. In addition, L082 played a significant role in inhibiting the accumulation of inflammatory cells and promoting the elimination of inflammatory cells at the incision, which may be related to inhibiting the production of ROS and NO in oxidative and nitric stress. These results suggest that L082 can be used as a bifunctional drug to suppress tumors and reduce post-injury inflammation complications.

3.
Ecotoxicology ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33068202

RESUMO

The fate and toxicity of silver nanoparticles (AgNPs) and ions in water bodies is largely determined by the natural organic matter (NOM)-mediated redox cycling. However, the process of NOM-mediated redox cycling in the day/night cycles remains elusive. In this study, the inter-transformation between AgNPs and Ag+ ion caused by humic acid (HA) was investigated under controlled light and dark conditions. It was shown that HA induced the reduction of Ag+ into AgNPs in simulated sunlight, and also oxidize AgNPs to release Ag+ in darkness. Kinetics data demonstrated that the rates of AgNPs formation and dissolution increased along with the increment of HA concentrations. Along with the pH increase, the reduction of Ag+ accelerated, but the oxidative dissolution of AgNPs was inhibited. In day-night cycles, the AgNPs and Ag+ concentrations exhibited similar wave-shaped change curves. The peaks of AgNPs and Ag+ ion appeared at 7 p.m. and 7 a.m., respectively. The toxicity of AgNPs/Ag+ to Escherichia coli was determined primarily by the concentration of dissolved Ag+, but also affected by the particle-specific toxicity. The dual role of HA implied that previous reports about the photo-reduction of Ag+ to AgNPs by NOM should be reconsidered, and the oxidizability of HA in darkness strongly affect the transformation and toxicity of AgNPs in water.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33068280

RESUMO

The relationship between vascular-specific epicardial adipose tissue (vEAT) volume and myocardial ischemia measured by fractional flow reserve (FFR) was not well investigated. Patients with typical and atypical chest pain undergoing coronary computed tomographic angiography scan followed by invasive coronary angiography in combination with FFR examination within one month were retrospectively included. EAT volume and CT attenuation was calculated. The patient with FFR ≤ 0.8 in at least one vessel was referred to as functional ischemia. The mean age of all patients was 61.7 ± 8.9 years and 66.7% of patients were male. There was a significant difference for left anterior descending branch (LAD) vEAT volume between patients with and without functional myocardial ischemia (28.7 ± 10.6 cm3 vs. 23.9 ± 8.7 cm3, p = 0.005). After adjusted by cardiac risk factors and CAD-RADS categories in multivariable logistic regression analysis, LAD-vEAT volume ≥ 24.6 cm3 (OR 3.355, 95% CI 1.546-7.281, p = 0.002) remained an independent predictor of functional ischemia. After adding LAD-vEAT volume ≥ 24.6 cm3 to a prediction model composed with cardiac risk factors and CAD-RADS categories, receiver operating characteristic curve analysis showed significantly improved areas under curve (AUC) for the new model (AUC: 0.795, p = 0.0319) compared with the previous ones. Moreover, the new model revealed significance in net reclassification improvement (NRI: 0.186, p = 0.037). In conclusion, LAD-vEAT volume measurements have incremental predictive performance beyond cardiac risk factors and CAD-RADS categories in identifying significant flow-limit ischemia detected by FFR.

5.
Chem Asian J ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33047472

RESUMO

A Rh(III)-catalyzed C-H arylation reaction of N-nitrosoanilines has  been developed in which arylboronic acids were used as arylation reagents.  It provides an efficient strategy for the synthesis of N-nitroso-[1,1'-biphenyl]-2-amine, which is an important starting material for the synthesis of N-hetero biaryl compounds, such as 2-amine-1,1'-biphenyl, carbazole, phenanthridone. This protocol can be applied to various N-alkyl substituted N-nitrosoanilines and N-nitrosoanilines with substituents on the phenyl ring. Arylboronic acids with both electron-donating and electron-withdrawing groups are tolerated.

6.
Anal Chem ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33047598

RESUMO

Despite huge promises, bioanalysis of protein biomarkers in formalin-fixed paraffin-embedded (FFPE) tissues by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for clinical applications is still very challenging. Here, we describe a sensitive and robust LC-MS/MS assay to quantify clinical protein biomarkers in FFPE tumor sections using automated antipeptide antibody immunocapture followed by in-sample calibration curve (ISCC) strategy with multiple isotopologue reaction monitoring (MIRM) technique. ISCC approach with MIRM of stable isotopically labeled (SIL) peptides eliminated the need for authentic matrices for external calibration curves, overcame the matrix effects, and validated the quantification range in each individual sample. Specifically, after deparaffinization, rehydration, antigen retrieval, and homogenization, the protein analytes in FFPE tumor tissues were spiked with a known concentration of one SIL peptide for each analyte, followed by trypsin digestion and antipeptide immunocapture enrichment prior to MIRM-ISCC-based LC-MS/MS analysis. This approach has been successfully used for sensitive quantification of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) in 15 representative FFPE tumor samples from lung, colorectal, and head and neck cancer patients. Except for one sample, PD-L1 and PD-1 in all samples were quantifiable using this assay with concentrations of 27.85-798.43 (amol/µg protein) for PD-L1 and 16.96-129.89 (amol/µg protein) for PD-1. These results were generally in agreement with the immunohistochemistry (IHC) data but with some exceptions. This approach demonstrated the feasibility to quantify low abundant protein biomarkers in FFPE tissues with improved sensitivity, specificity, and robustness and showed great potential as an orthogonal analytical approach to IHC for clinical applications.

7.
Org Lett ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33048560

RESUMO

This paper describes the case of a cross study between the C-N bond cleavage reaction field and the Catellani-Lautens reaction system. A series of highly functionalized C4-substituted indoles were synthesized using this strategy. By screening the alkyl groups of amines, the energy barrier of C-N bond cleavage reaction was reduced and the corresponding allenization products were avoided. Finally, the density functional theory calculation shows that the inert C-N bond activation reaction is not a concerted process; on the contrary, the coupling reaction first generates indole quaternary ammonium salt, and then C-N bond cleavage occurs via an SN2 process.

8.
Stat Med ; 2020 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-33012039

RESUMO

This article addresses the analysis of crossover designs with nonignorable dropout. We study nonreplicated crossover designs and replicated designs separately. With a primary objective of comparing the treatment mean effects, we jointly model the longitudinal measures and discrete time to dropout. We propose shared-parameter models and mixed-effects selection models. We adapt a linear-mixed effects model as the conditional model for the longitudinal outcomes. We invoke a discrete-time hazards model with a complementary log-log link function for the conditional distribution of time to dropout. We apply maximum likelihood for parameter estimation. We perform simulation studies to investigate the robustness of our proposed approaches under various missing data mechanisms. We then apply the approaches to two examples with a continuous outcome and one example with a binary outcome using existing software. We also implement the controlled multiple imputation methods as a sensitivity analysis of the missing data assumption.

9.
J Endourol ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33040587

RESUMO

PURPOSE: Male urethral injury,whether early or late treatment of urethral injuries is often multifactorial and controversial. The goal of this study is to determine whether early realignment can reduce post-surgical complications , evaluating the clinical feasibility of emergency endoscopic urethroplasty using single rigid ureteroscopy in the treatment of bulbar urethral severe injury. PATIENTS AND METHODS: Between September 2013 and March 2019, 15 male adult patients with severe bulbar urethral injury were enrolled into the current study. The patients mainly presented with dysuria or painful urination (15/15, 100%) and urethral bleeding (13/15, 86.7%). Urinary retention in 11 cases (11/15, 73.3%) .Six of them had swelling of perineum soft tissue or scrotal while 4 had testicular contusion. No pelvic fracture was found in all cases. The bulbar urethral at grade IV was confirmed completely rupture in all cases by endoscopy during operation.The modified endoscopic primary realignment were performed. RESULTS: This new urethral repair technique was successfully preformed in all patients and none converted to open operation. Mean operation time was 42.3±11.5 minutes (28-52 minutes) and the mean Foley catheter indwelling time was 34.5±6.9 days (28-42 days). During follow-up 41.3±22.8 months (12-64 months), mild urethral strictures (grade I) (19.7±9.5 weeks, 10-27 weeks post-surgery) developed in 8 patients (53.3%) and then were all improved 2.1±0.8 months (1.3 - 2.9) months after periodic dilatations of the urethra (4 to 10 times). Erectile dysfunction (ED) occurred in 3 patients (20%) after surgery and recovered from mild erectile dysfunction to normal by administration with oral sildenafil (100 mg, three times a week) for 12 weeks. The International Index of Erectile Function (IIEF-5) Score was significantly improved after surgery(25±3) compared to before (16.4±3.5) (p<0.05). CONCLUSIONS: Early endoscopic realignment via suprapubic puncture cystostomy by single rigid ureteroscopy provides an effective, feasible and safe procedure for severe bulbar urethral injury.

10.
Biosci Rep ; 40(10)2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33006362

RESUMO

Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer-related mortality globally. However, the mechanism underlying NSCLC is not fully understood. Here, we investigated the role of cancer-related regulator of actin dynamics (CRAD) in NSCLC. We showed that CRAD was up-regulated in human NSCLC tissues and lung cancer cell lines. Lentivirus-mediated knockdown of CRAD repressed the proliferation and colony growth of A549 and H1299 cells. Apoptosis was enhanced by CRAD silencing in both cells, implicating that CRAD might maintain the survival of lung cancer cells. Microarray and bioinformatic assay revealed that CRAD directly or indirectly regulated diverse genes, including those involved in cell cycle and DNA damage repair. qRT-PCR and Western blot results confirmed the dysregulated genes as shown in microarray analysis. Claudin 4 was up-regulated in CRAD silenced A549 cells. The knockdown of Claudin 4 blocked the effects of CRAD on the expression of cell cycle and apoptosis effectors and enhanced the viability of A549 cells with CRAD down-regulation. Taken together, our findings demonstrate that CRAD acts as an oncogene in NSCLC at least partly through repressing Claudin 4.

11.
J Appl Microbiol ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33034112

RESUMO

AIMS: The aim at this study was to determine the effects of unsaturated fatty acids on clinical plasmids. METHODS AND RESULTS: Two unsaturated fatty acids, linoleic acid (LA) and α-linolenic acid (ALA) at final concentration 0, 0.03, 0.3, and 3 mmol L-1 , respectively, were used to assess the effects on conjugative transfer of a mcr-1-harboring plasmid pCSZ4 (IncX4) in conjugation experiment. The inhibitory mechanisms were analyzed by molecular docking and the gene expression of virB11 was quantitated by qRT-PCR. Target plasmid diversity was carried out by TrwD/VirB11 homology protein sequence prediction analysis. Our results showed that LA and ALA inhibit plasmid pCSZ4 transfer by binding to the amino acid residues (Phe124 and Thr125) of VirB11 with dose-dependent effects. The expression levels of virB11 gene were also significantly inhibited by LA and ALA treatment. Protein homology analysis revealed a wide distribution of TrwD/VirB11-like genes among over 37 classes of plasmids originated from both Gram-negative and Gram-positive bacteria, CONCLUSIONS: This study demonstrates representing a diversity of plasmids that may be potentially inhibited by unsaturated fatty acids. SIGNIFICANCE AND IMPACT OF STUDY: Our work reported here provides additional support for application of curbing the spread of multiple plasmids by unsaturated fatty acids.

12.
J Neurooncol ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33034841

RESUMO

PURPOSES: Immunotherapies for solid tumor are gaining traction in the clinic, however, the immunological landscape of pituitary adenomas (PAs) is not well defined. In the present study, we used the RNA-seq data of PAs to investigate the impact of immunological landscape on clinical features of pituitary adenomas and aim to evaluate the potential immunotherapy for PAs. METHODS: We analyzed tumor-infiltrating immune cells in 115 PA samples using RNA-seq. Main immune cell types (B cells, CD8+ T cells, CD4+ T cells, macrophages and NK cells) were detected from the expression of genes. The association between immune cells abundance and immune checkpoint, as well as inflammatory factors were analyzed. 10 additional patients were enrolled for validation. RESULTS: In RNA sequencing data, landscape of PAs were identified. Our computationally inferred immune infiltrates significantly associate with patient clinical features. Growth hormone-secreting adenomas (GHomas) were found with higher B cells and CD8+ T cells infiltration. Moreover, GHomas showed relative different genetic background, significant invasive behavior and independently correlated with reduced progress-free time. Tumor progression was related to increased expression of PD-1/PD-L1 and was associated with higher immune infiltration. Analysis of cancer-testis antigen expression and CD8+ T-cell abundance suggested CTAG2 and TSPYL6 were potential immunotherapeutic targets in GHomas and non-functioning adenomas, respectively. CONCLUSIONS: Tumor-infiltrating immune cells confer important clinical and biological implications. Our results of immune-infiltrate levels in PAs may inform effective cancer vaccine and checkpoint blockade therapies and make it possible to take immunotherapy into invasive PAs.

13.
Toxicol Appl Pharmacol ; : 115273, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33035574

RESUMO

Given the poor prognosis of unresectable advanced gastric cancer (GC), novel therapeutic strategies are needed. The mitogen-activated protein kinase (MAPK) signaling cascade, the most frequently activated pathway in GC, plays an important role in tumorigenesis and metastasis. The MAPK/extracellular signal-regulated kinase (ERK) pathway is an attractive therapeutic target for GC. In this study, trametinib, a mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor, reduced the p-ERK level and significantly increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in GC cells, resulting in reduced sensitivity to trametinib. Physapubescin B (PB), a steroidal compound extracted from the plant Physalis pubescens L., inhibited the proliferation and induced the apoptosis of GC cells by suppressing STAT3 phosphorylation. The combination of PB and trametinib suppressed the STAT3 phosphorylation induced by trametinib, and synergistically suppressed gastric tumor growth in vitro and in vivo. Together, these results indicate that inhibition of both MEK and STAT3 may be effective for patients with MAPK/ERK pathway-addicted GC.

14.
Parkinsonism Relat Disord ; 81: 12-17, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-33035800

RESUMO

BACKGROUND: Brain iron disequilibrium and dopaminergic dysfunction are key pathophysiological features of Restless Legs Syndrome (RLS). Rep1 polymorphism in the promotor region of SNCA is associated with risk of Parkinson's disease, however its association with RLS and iron status is unclear. OBJECTIVE: To investigate SNCA-Rep1 polymorphism in RLS and its phenotypes. METHODS: We recruited RLS patients as well as age and gender matched healthy controls. Demographic information and clinical features of RLS were recorded. Laboratory examinations were performed to exclude possible secondary causes. RESULTS: 215 RLS patients and 369 healthy controls were included. We found that the Rep1 allele 0 homozygosity significantly decreased RLS risk (OR: 0.345; P < 0.0001, and remained significant after the Bonferroni correction). Phenotypic analysis demonstrated that longer Rep1 alleles were associated with increased susceptibility to iron deficiency (53.0% vs 36.1%, P = 0.017), however had no phenotypic significant effects on age, gender, onset age, duration, RLS family history, severity, laterality, extra body involvement and seasonal fluctuation. Multivariate logistic regression analyses confirmed long Rep1 allele was associated with higher risk of iron deficiency in RLS after adjusting for potential confounding factors. In detail, Rep1 allele 2 homozygosity was prone to a higher risk of peripheral iron deficiency in RLS (OR: 4.550, P = 0.006, remained significant after the Bonferroni correction). CONCLUSION: The SNCA-Rep1 variability modified RLS risk and influenced peripheral iron deficiency in this group of Chinese RLS patients. Rep1 allele 0 homozygosity decreased the risk of RLS, while homozygous allele 2 increased the risk of nonanemic iron deficiency in RLS.

15.
HPB (Oxford) ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33051141

RESUMO

BACKGROUND: The study aimed at establishing a nodal staging score (NSS) to quantify the likelihood that pathologic node-negative gallbladder cancer (GBC) patients are indeed free of lymph node (LN) metastasis. METHODS: Clinicopathological data of 1374 GBC patients with T1b-T2 stages were collected from the Surveillance, Epidemiology and End Result database (design cohort [DC], n = 1289) and the First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 85). NSS was derived from the count of examined LNs (ELNs) and T stage by using a beta-binomial model, and represented the probability that a node-negative patient is correctly staged. The prognostic value of NSS in node-negative GBC was evaluated by survival analysis. RESULTS: The probability of missing a nodal disease in node-negative GBC patients with T1b-T2 stages (pT1bN0 and pT2N0) decreased as the number of ELNs increased. NSS increased as the number of ELNs increased. For pT1bN0 and pT2N0 patients, examination of 5 and 27 lymph nodes could ensure an NSS of 90.0%, respectively. Multivariate analysis revealed that NSS was an independent predictor for overall survival in pT1bN0 and pT2N0 GBC patients (DC, HR:0.53, 95%CI: 0.42-0.66, p < 0.001; VC, HR: 0.33, 95%CI: 0.14-0.76, p = 0.009). CONCLUSION: NSS could evaluate the adequacy of nodal staging and predict the prognosis in pT1bN0 and pT2N0 GBC patients, and hence was helpful to guide their treatment strategies.

16.
Brief Bioinform ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33051665

RESUMO

Cholangiocarcinoma (CCA) is a type of cancer with limited treatment options and a poor prognosis. Although some important genes and pathways associated with CCA have been identified, the relationship between coexpression and phenotype in CCA at the systems level remains unclear. In this study, the relationships underlying the molecular and clinical characteristics of CCA were investigated by employing weighted gene coexpression network analysis (WGCNA). The gene expression profiles and clinical features of 36 patients with CCA were analyzed to identify differentially expressed genes (DEGs). Subsequently, the coexpression of DEGs was determined by using the WGCNA method to investigate the correlations between pairs of genes. Network modules that were significantly correlated with clinical traits were identified. In total, 1478 mRNAs were found to be aberrantly expressed in CCA. Seven coexpression modules that significantly correlated with clinical characteristics were identified and assigned representative colors. Among the 7 modules, the green and blue modules were significantly related to tumor differentiation. Seventy-eight hub genes that were correlated with tumor differentiation were found in the green and blue modules. Survival analysis showed that 17 hub genes were prognostic biomarkers for CCA patients. In addition, we found five new targets (ISM1, SULT1B1, KIFC1, AURKB and CCNB1) that have not been studied in the context of CCA and verified their differential expression in CCA through experiments. Our results not only promote our understanding of the relationship between the transcriptome and clinical data in CCA but will also guide the development of targeted molecular therapy for CCA.

17.
J Ethnopharmacol ; 265: 113324, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32890714

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Xueshuantong (FXST) is a traditional Chinese patent medicine composed of Panax notoginseng (Burkill) F.H.Chen (Araliaceae), Salvia miltiorrhiza Bunge (Lamiaceae), Astragalus propinquus Schischkin (Leguminosae), and Scrophularia ningpoensis Hemsl. (Scrophulariaceae). It has been widely used for the treatment of diabetic retinopathy (DR) and exerts a positive clinical therapeutic effect. AIM OF THE STUDY: The aim of this study was to observe the effect of FXST on diabetic rat retinas and investigate its pharmacological mechanism for improving DR. METHODS: The diabetic rat model was established by intraperitoneal injection of streptozotocin. The rats were divided into a normal group, diabetic group, and FXST group. The rats in the FXST group were treated with FXST by intragastric administration for 12 weeks while other rats were given the same volume of normal saline. The haemodynamic parameters of the central retinal artery in the rats were measured by ultrasound. Haematoxylin-eosin staining was utilised to observe the pathological structural changes in the retina. The apoptosis of retinal nerve cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling. RNA sequencing was used to screen the differentially expressed genes (DEGs), and enrichment analyses were performed. The DEGs were validated through real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The peak systolic velocity, end diastolic velocity, and mean velocity decreased while the resistance index and pulsatility index increased in the diabetic rat retinas. FXST also improved haemodynamics. In contrast with the diabetic group, FXST allayed the disorder and oedema of the retinal structure in addition to reversing the reductions in retinal thickness and retinal ganglion cell number. It also decreased the apoptosis index of retinal cells. A total of 1134 DEGs were identified by RNA sequencing in the FXST group compared to the diabetic group, including 814 upregulated genes and 320 downregulated genes. These genes were enriched in the complement and coagulation cascades as well as the peroxisome proliferator-activated receptor (PPAR) signalling pathway. Several DEGs, including PPAR gamma, perilipin 4, acyl-CoA dehydrogenase long chain, CD55 molecule, and plasminogen activator urokinase, were identified by qRT-PCR, and the results were consistent with the RNA sequencing data. CONCLUSIONS: FXST alleviates DR by improving the haemodynamics and morphological alterations of diabetic rat retinas, which are mediated by complement and coagulation cascades and the PPAR signalling pathway.

18.
J Parkinsons Dis ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32986682

RESUMO

BACKGROUND: Current drug treatments have little efficacy in advanced-to-end-stage Parkinson's disease (advPD), yet there are no reports of interventional trials in advPD. D1 dopamine agonists have the potential to provide benefit. OBJECTIVE: To determine the feasibility and safety of the selective D1/D5 dopamine partial agonist PF 06412562 in advPD. METHODS: A two-week, randomized, double blind, crossover phase Ib study in advPD patients compared standard-of-care (SoC) carbidopa/levodopa with PF 06412562. Each week, there was a Day 1 baseline evaluation with overnight levodopa washout, then treatment on Days 2 and 3 with either SoC or PF-06412562 (split dose 25 + 20 mg), followed by discharge on Day 4. Primary endpoints were safety and tolerability. Secondary endpoints were global clinical impression of change (GCI-C) rated by clinicians and caregivers. RESULTS: Eight advPD patients and their caregivers consented to participate and six were randomized (average disease duration: 22 y). None withdrew voluntarily. One participant with baseline Day 1 dehydration, pre-renal kidney injury, and autonomic dysfunction experienced symptomatic and serious hypotension after receiving PF-06412562 in Week 1 and was discontinued from the study. All other adverse events were rated mild (PF-06412562: n = 1, SoC: n = 0), moderate (PF-06412562: n = 1, SoC: n = 1), or severe but non-serious (PF-06412562: n = 3, SoC: n = 2). No clinically meaningful laboratory changes were observed. Among the five participants who completed the study, GCI-C favored PF-06412562 in two per clinicians' and four participants per caregivers' rating. CONCLUSION: PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs.

19.
Sci Rep ; 10(1): 14407, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873840

RESUMO

This research investigated the association between prolonged disposable diaper (DD) wearing in infancy and primary enuresis (PNE). As a case-control study, we collected data from 376 children with enuresis and 379 healthy children who were sex- and age-matched at three tertiary care institutions in mainland China from August 2017 to July 2018. The results of adjusted logistic regression showed the odds ratios (95% confidence intervals) for PNE across the categories of age of daytime DD use cessation were as follows: ≥ 25 months: 1.00, 18-24 months: 0.25 (0.17-0.37), and ≤ 17 months: 0.11 (0.06-0.20), independent of age, mother education, residence, toilet training approach, breastfeeding duration, UTI, constipation, anaphylactic disease and family history. After a similar multivariable adjustment, increased age of daytime DD use (per-month) had a positive correlation with PNE, OR = 1.17, 95% CI 1.13-1.20 and non-linear relationship was detected, whose point was 21 months (the effect sizes and the 95%CI on the left and right sides of inflection point were 1.04 (0.99-1.10), P = 0.131 and 1.25 (1.18-1.31), P < 0.001). Subgroup analysis found that the effect of duration of disposable diaper exposure for each additional month, those children had accepted assisted infant toilet training/elimination communication (AITT/EC) practice had a lower risk of PNE (OR = 1.08, 95% CI 1.04-1.12), compared with those without AITT/EC practice (OR = 1.20, 95% CI 1.14-1.27), P for interaction < 0.001. In conclusion, the children diagnosed with primary enuresis after age 5 stopped using disposable diapers at daytime later than the control group. Association between duration of DD exposure and the risk of childhood enuresis is modified by AITT/EC practice. Timely cessation use of disposable diaper and practice AITT/EC may shorten the time to nocturnal continence, and the prospective cohort studies are needed to verify the discoveries.

20.
Drug Dev Res ; 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32864754

RESUMO

BACKGROUND: The purpose of this study was to investigate the safety, tolerability and pharmacokinetics of tetramethylpyrazine nitrone (TBN) in healthy Chinese volunteers. METHODS: A single-ascending-dose (SAD) study where 68 subjects were randomized to a single dose of placebo or TBN (50, 100, 200, 400, 700, 1,000, 1,400, or 1,800 mg) through IV infusion over 30 min. A multiple-ascending-dose (MAD) study where 24 subjects received TBN twice daily (with 12 hr interval) for total 6.5 days at doses of either 700 or 1,400 mg. Adverse events were recorded and pharmacokinetic samples were collected during the whole study period. RESULTS: No serious adverse events were found in the study. All of the observed adverse events, including increased white blood cell (4.4% subjects) and neutrophil counts (4.4% subjects), and decreased hemoglobin levels (4.2% subjects), were laboratory test abnormalities. All the adverse events were mild and tolerable, and returned to normal without any intervention. In the SAD study, linear Cmax values were observed in the dose interval of 50-1,800 mg. In the MAD study, the average steady-state concentrations (Cavg.ss ) of TBN in the 700 and 1,400 mg dose group were 2,407 and 5,837 ng/ml, respectively. No drug accumulation was observed in this study. CONCLUSIONS: TBN is well tolerated in healthy volunteers. Linear Cmax values were observed in the interval of 50-1,800 mg, and target exposures of TBN were achieved without accumulation after twice daily administration to subjects. (This study has been registered at ChiCTR.org.cn. Identifier: ChiCTR1800016225 and ChiCTR1800019627.).

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