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Long-term continuous cropping affects the soil microecological community and leads to nutrient imbalances, which reduces crop yields, and crop rotation can increase soil productivity. To study the effects of the cultivation of tomato (Solanum lycopersicum) and corn (Zea mays) on the microbial community, physical and chemical factors and the structure of aggregates in cotton (Gossypium hirsutum) long-term continuous cropping soils were examined. Four cropping patterns were established, including one continuous cropping pattern and three crop rotation patterns, and the diversity of the soil microecological community was measured using high-throughput sequencing. The physical and chemical properties of different models of soil were measured, and the soil aggregate structure was determined by dry and wet sieving. Planting of aftercrop tomato and corn altered the bacterial community of the cotton continuous soil to a lesser extent and the fungal community to a greater extent. In addition, continuous cropping reduced the diversity and richness of the soil fungal community. Different aftercrop planting patterns showed that there were very high contents of soil organic carbon and organic matter in the cotton-maize rotation model, while the soil aggregate structure was the most stable in the corn-cotton rotation model. Planting tomato in continuous cropping cotton fields has a greater effect on the soil microbial community than planting maize. Therefore, according to the characteristics of different succeeding crop planting patterns, the damage of continuous cropping of cotton to the soil microenvironment can be alleviated directionally, which will enable the sustainable development of cotton production.
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In this study, Co3O4@MoS2 is prepared as anodic catalytic material for microbial fuel cells (MFCs). As the mass fraction of MoS2 is 20%, the best performance of Co3O4@MoS2 composite catalytic material is achieved, and the addition of MoS2 enhances both the electrical conductivity and catalytic performance of the composite catalyst. Through the structural characterization of Co3O4@MoS2 composite catalytic material, nanorod-like Co3O4 and lamellar MoS2 interweaved and stacked each other, and the agglomeration of Co3O4 is weakened. Among the four groups of single-chamber MFCs constructed, the Co3O4@MoS2-MFC shows the best power production performance with a maximum stable output voltage of to 539 mV and a maximum power density of up to 2221 mW/m2. Additionally, the ammonia nitrogen removal rate of the MFCs loaded with catalysts is enhanced by about 10% compared with the blank carbon cloth MFC. Overall, the findings suggest that Co3O4@MoS2 composite catalysts can significantly improve the performance of MFCs, making them more effective for both energy production and wastewater treatment.
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Fuentes de Energía Bioeléctrica , Molibdeno , Molibdeno/química , Catálisis , Disulfuros/química , Cobalto/química , Óxidos/química , ElectrodosRESUMEN
BACKGROUND: During city running or marathon races, shifts in level ground and up-and-down slopes are regularly encountered, resulting in changes in lower limb biomechanics. The longitudinal bending stiffness of the running shoe affects the running performance. PURPOSE: This research aimed to investigate the biomechanical changes in the lower limbs when transitioning from level ground to an uphill slope under different longitudinal bending stiffness (LBS) levels in running shoes. METHODS: Fifteen male amateur runners were recruited and tested while wearing three different LBS running shoes. The participants were asked to pass the force platform with their right foot at a speed of 3.3 m/s ± 0.2. Kinematics data and GRFs were collected synchronously. Each participant completed and recorded ten successful experiments per pair of shoes. RESULTS: The range of motion in the sagittal of the knee joint was reduced with the increase in the longitudinal bending stiffness. Positive work was increased in the sagittal plane of the ankle joint and reduced in the keen joint. The negative work of the knee joint increased in the sagittal plane. The positive work of the metatarsophalangeal joint in the sagittal plane increased. CONCLUSION: Transitioning from running on a level surface to running uphill, while wearing running shoes with high LBS, could lead to improved efficiency in lower limb function. However, the higher LBS of running shoes increases the energy absorption of the knee joint, potentially increasing the risk of knee injuries. Thus, amateurs should choose running shoes with optimal stiffness when running.
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Extremidad Inferior , Carrera , Zapatos , Humanos , Masculino , Fenómenos Biomecánicos/fisiología , Carrera/fisiología , Extremidad Inferior/fisiología , Adulto , Rango del Movimiento Articular/fisiología , Articulación del Tobillo/fisiología , Articulación de la Rodilla/fisiología , Adulto JovenRESUMEN
Background- Postoperative delirium is a common complication associated with the elderly, causing increased morbidity and prolonged hospital stay. However, its risk factors in chronic subdural hematoma patients have not been well studied. Methods- A total of 202 consecutive patients with chronic subdural hematoma at Peking University Third Hospital between January 2018 and January 2023 were enrolled. Various clinical indicators were analyzed to identify independent risk factors for postoperative delirium using univariate and multivariate regression analyses. Delirium risk prediction models were developed as a nomogram and a Markov chain. Results- Out of the 202 patients (age, 71 (IQR, 18); female-to-male ratio, 1:2.7) studied, 63 (31.2%) experienced postoperative delirium. Univariate analysis identified age (p < 0.001), gender (p = 0.014), restraint belt use (p < 0.001), electrolyte imbalance (p < 0.001), visual analog scale score (p < 0.001), hematoma thickness (p < 0.001), midline shift (p < 0.001), hematoma side (p = 0.013), hematoma location (p = 0.018), and urinal catheterization (p = 0.028) as significant factors. Multivariate regression analysis confirmed the significance of restraint belt use (B = 7.657, p < 0.001), electrolyte imbalance (B = -3.993, p = 0.001), visual analog scale score (B = 2.331, p = 0.016), and midline shift (B = 0.335, p = 0.007). Hematoma thickness and age had no significant impact. Conclusion- Increased midline shift and visual analog scale scores, alongside restraint belt use and electrolyte imbalance elevate delirium risk in chronic subdural hematoma surgery. Our prediction models may offer reference value in this context.
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Delirio del Despertar , Hematoma Subdural Crónico , Humanos , Masculino , Femenino , Anciano , Hematoma Subdural Crónico/complicaciones , Delirio del Despertar/complicaciones , Estudios Retrospectivos , Factores de Riesgo , Medición de Riesgo , ElectrólitosRESUMEN
BACKGROUND: In agricultural production, fungal diseases significantly impact the yield and quality of cotton (Gossypium spp.) with Verticillium wilt posing a particularly severe threat. RESULTS: This study is focused on investigating the effectiveness of endophytic microbial communities present in the seeds of disease-resistant cotton genotypes in the control of cotton Verticillium wilt. The technique of 16S ribosomal RNA (16S rRNA) amplicon sequencing identified a significant enrichment of the Bacillus genus in the resistant genotype Xinluzao 78, which differed from the endophytic bacterial community structure in the susceptible genotype Xinluzao 63. Specific enriched strains were isolated and screened from the seeds of Xinluzao 78 to further explore the biological functions of seed endophytes. A synthetic microbial community (SynCom) was constructed using the broken-rod model, and seeds of the susceptible genotype Xinluzao 63 in this community that had been soaked with the SynCom were found to significantly control the occurrence of Verticillium wilt and regulate the growth of cotton plants. Antibiotic screening techniques were used to preliminarily identify the colonization of strains in the community. These techniques revealed that the strains can colonize plant tissues and occupy ecological niches in cotton tissues through a priority effect, which prevents infection by pathogens. CONCLUSION: This study highlights the key role of seed endophytes in driving plant disease defense and provides a theoretical basis for the future application of SynComs in agriculture.
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Microbiota , Verticillium , Verticillium/fisiología , Gossypium/genética , Gossypium/microbiología , ARN Ribosómico 16S/genética , Bacterias/genética , Semillas/genética , Enfermedades de las Plantas/microbiología , Resistencia a la Enfermedad/genéticaRESUMEN
Staphylococcus aureus (S. aureus) is one of the important human pathogens and causes both superficial and systemic infections. More importantly, the formation of S. aureus biofilms, a main cause of its pathogenicity and drug resistance, has been a critical challenge in clinical treatment. Carvacrol, a plant-based natural product, has gained great interest for therapeutic purposes due to its effective biological activity with low cytotoxicity. The present study aimed to investigate the effect of carvacrol on anti-biofilm activity. Growth curve analysis showed that applying a sub-inhibitory concentration of carvacrol (4 µg mL-1) was not lethal to S. aureus SYN; however, the inhibition rate of biofilm formation was as high as 63.6%, and the clearance rate of mature biofilms was as high as 30.7%. In addition, carvacrol effectively reduced the production of biofilm-associated extracellular polysaccharides and showed no effect on eDNA release. Furthermore, qPCR analysis revealed that carvacrol significantly down-regulated the expression of icaA, icaB, icaC, agrA, and sarA (P < 0.05). The in vivo efficacy of carvacrol against biofilm infection was further verified with a biological model of G. mellonella larvae. The results showed that carvacrol was non-toxic to the larvae and can effectively increase the survival rate of the larvae infected with S. aureus strain SYN.
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The Y-Balance Test (YBT) is a reliable tool for assessing the dynamic balance of athletes' lower limbs. This study aimed to compare the effects of the YBT on lower limb biomechanics before and after fatigue. Sixteen adult male recreational athletes were recruited for the study, and motion capture in combination with a force plate was used to collect kinematic, dynamics, and center of pressure (COP) data of the dominant leg during YBT testing before and after fatigue. Based on the research findings, there were significant statistical differences in the distances reached during the YBT in three directions before and after fatigue. After fatigue, there is a significant decrease in the ROM of the hip and knee joints in all three directions. Also, there is a significant increase in hip joint torque in the anterior- and posterior-lateral directions, while a significant decrease in hip and ankle joint torque is observed in the posterior-medial direction. Moreover, there is an increasing trend in positive and negative joint work for the hip, knee, and ankle joints in all three directions after fatigue. The range of COP displacement also increases following fatigue. The decline in YBT scores demonstrates the detrimental impact of fatigue on the dynamic balance of the lower limbs of adult male amateur athletes. We hope that these results can provide information for athletes and coaches to better understand the effects of fatigue on the dynamic balance of lower limbs, so as to carry out targeted lower limb balance training and prevent sports injuries.
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Background: During competition and training, exercises involving the lungs may occur throughout the sport, and fatigue is a major injury risk factor in sport, before and after fatigue studies of changes in the lungs are relatively sparse. This study is to investigate into how fatigue affects the lower limb's biomechanics during a forward lunge. Methods: 15 healthy young men participate in this study before and after to exposed to a fatigue protocol then we tested the forward lunge to obtain kinematic, kinetic changing during the task, and to estimate the corresponding muscles' strength changes in the hip, knee, and ankle joints. The measurement data before and after the fatigue protocol were compared with paired samples t-test. Results: In the sagittal and horizontal planes of the hip and knee joints, in both, the peak angles and joint range of motion (ROM) increased, whereas the moments in the sagittal plane of the knee joint smaller. The ankle joint's maximum angle smaller after fatigue. Peak vertical ground reaction force (vGRF) and peak contact both significantly smaller after completing the fatigue protocol and the quadriceps mean and maximum muscular strength significantly increased. Conclusion: After completing a fatigue protocol during lunge the hip, knee, and ankle joints become less stable in both sagittal and horizontal planes, hip and knee range of motion becomes greater. The quadriceps muscles are more susceptible to fatigue and reduced muscle force. Trainers should focus more on the thigh muscle groups.
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Background: Staphylococcus haemolyticus is an opportunistic pathogen that belongs to coagulase-negative Staphylococci (CoNS). Increasing infection and multi-drug resistance cases caused by this strain have been reported and thus it poses a great health threat. Methods: The third-generation sequencing technology was performed on a S. haemolyticus SH-1 isolated from a clinical sample to analyze the drug resistance genes, which included vancomycin resistance related genes. In addition, antimicrobial susceptibility tests, transmission electron microscopy and Triton X-100 stimulated autolysis were conducted to understand its biological characteristics. Results: The study shows that this clinical isolate is a vancomycin intermediate-resistant strain. Genome comparison also revealed that WalK(N70K) and WalK(R280Q) mutations may contribute to the vancomycin resistant phenotype. Besides, S. haemolyticus SH-1 exhibit common features of thicker cell wall and decreased autolytic activity. Conclusion: S. haemolyticus SH-1 with WalKR mutations shows typical characteristics of vancomycin resistant strains. Combining the genome features and biological properties, our findings may provide important information for the understanding of the molecular mechanism of S. haemolyticus to vancomycin intermediate-resistance.
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BACKGROUND: This meta-analysis aimed to assess the rate of malignant transformation (MT) of oral leukoplakia (OL) and to study potential risk factors for the MT of OL into oral squamous cell carcinoma (OSCC). METHOD: We performed a bibliographic search on nine electronic databases, including PubMed, MEDLINE, and Wanfang Data, for data on the MT rate of OL. Possible risk factors were calculated using Comprehensive Meta-Analysis and Open Meta [Analyst] software. RESULTS: The pooled proportion of OL MT for the total population described in the 26 selected studies was 7.20% (95% confidence interval: 5.40-9.10%). Nonhomogeneous type lesions, higher grades of dysplasia, the location of the lesion (tongue and multifocal), and female sex had significant effects on the MT of OL. CONCLUSION: OL tended to develop into OSCC (7.2%), and those with significant MT risk factors should be subjected to regular follow-up and observation. However, we require large-scale prospective studies to validate these results, together with unified clinicopathological diagnostic criteria, standardized risk factor recording/assessment methods, and long-term follow-up guidelines.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Femenino , Neoplasias de la Boca/epidemiología , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/patología , Estudios Prospectivos , Leucoplasia Bucal/epidemiología , Leucoplasia Bucal/patología , Carcinoma de Células Escamosas de Cabeza y Cuello , Transformación Celular Neoplásica/patologíaRESUMEN
Introduction: Microbiome within plant tissues is pivotal for co-evolution with host plants. This microbiome can colonize the plant, with potential transmission via seeds between parents and offspring, affecting seedling growth and host plant adaptability to the environment. Methods: We employed 16S rRNA gene amplicon analysis to investigate the vertical distribution of core microbiome in cotton seeds across ecological niches [rhizosphere, root, stem, leaf, seed and seed-P (parental seed)] of the three cotton genotypes. Results: The findings demonstrated a significant decrease in microbiome diversity and network complexity from roots, stems, and leaves to seeds. The microenvironment exerted a more substantial influence on the microbiome structure of cotton than the genotypes. The core endophytic microorganisms in cotton seeds comprised 29 amplicon sequence variants (ASVs) affiliated with Acidimicrobiia, Alphaproteobacteria, Bacilli, Bacteroidia, Clostridia, Gammaproteobacteria, and unclassified_Proteobacteria. These vertically transmitted taxa are widely distributed in cotton plants. Through 16S rRNA gene-based function prediction analysis of the cotton microbiome, we preliminarily understood that there are potential differences in metabolic capabilities and phenotypic traits among microbiomes in different microhabitats. Discussion: In conclusion, this study demonstrated the crucial role of the microenvironment in influencing the cotton microbiome and offered insights into the structures and functions of the cotton seed microbiome, facilitating future crop yield enhancement through core seed microbiome regulation.
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The expression of the triggering receptor on myeloid cell-2 (TREM2) knockdown in microglia from the lateral habenula (LHb) reportedly induces depression-like behaviors in mice. However, the key molecular mechanism that mediates major depressive disorder (MDD) pathogenesis remains elusive. We herein show that Nrf2 regulates TREM2 transcription and effects TREM2 mRNA and protein expression. The activation of Nrf2 by sulforaphane (Nrf2 activator) increases the microglial arginase 1+ phenotype by initiating TREM2 transcription in the medial prefrontal cortex (mPFC) and ameliorates depression-like behavior in CSDS mice. The knockout of Nrf2 decreases TREM2 and the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice with depression-like behavior. Downregulating TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC, resulting in depression-like behavior in SFN-treated CSDS mice. Finally, the knockout of Nrf2 and downregulation of TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice and SFN-treated CSDS mice were associated with the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway. These data indicate that alterations in the interaction between Nrf2 and TREM2 may play a role in the pathophysiology of depression-like behavior in mice.
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Trastorno Depresivo Mayor , Microglía , Animales , Ratones , Microglía/metabolismo , Factor 2 Relacionado con NF-E2/genética , Arginasa/genética , Arginasa/metabolismo , Depresión/tratamiento farmacológico , Depresión/genética , Trastorno Depresivo Mayor/metabolismo , Fenotipo , Ratones Noqueados , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/genéticaRESUMEN
There are still few portable methods for monitoring lower limb joint coordination during the cutting movements (CM). This study aims to obtain the relevant motion biomechanical parameters of the lower limb joints at 90°, 135°, and 180° CM by collecting IMU data of the human lower limbs, and utilizing the Long Short-Term Memory (LSTM) deep neural-network framework to predict the coordination variability of selected lower extremity couplings at the three CM directions. There was a significant (p < 0.001) difference between the three couplings during the swing, especially at 90° vs the other directions. At 135° and 180°, t13-he coordination variability of couplings was significantly greater than at 90° (p < 0.001). It is important to note that the coordination variability of Hip rotation/Knee flexion-extension was significantly higher at 90° than at 180° (p < 0.001). By the LSTM, the CM coordination variability for 90° (CMC = 0.99063, RMSE = 0.02358), 135° (CMC = 0.99018, RMSE = 0.02465) and 180° (CMC = 0.99485, RMSE = 0.01771) were accurately predicted. The predictive model could be used as a reliable tool for predicting the coordination variability of different CM directions in patients or athletes and real-world open scenarios using inertial sensors.
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INTRODUCTION: Yoga therapy may have some potential in treating migraine, and thus this meta-analysis aims to explore the efficacy of yoga therapy for patients with migraine. METHODS: PubMed, EMbase, Web of science, EBSCO and Cochrane library databases have been systematically searched and we included the randomized controlled trials (RCTs) reporting the efficacy of yoga therapy for migraine patients. The outcomes included. RESULTS: This meta-analysis included six RCTs. The results revealed that compared with control group for migraine, yoga therapy was associated with remarkably decreased pain intensity (SMD = -1.21; 95% CI = -2.17 to -0.25; P = 0.01), headache frequency (SMD = -1.43; 95% CI = -2.23 to -0.64; P = 0.0004), headache duration (SMD = -1.03; 95% CI = -1.85 to -0.21; P = 0.01), HIT-6 score (SMD = -2.28; 95% CI = -3.81 to -0.75; P = 0.003) and MIDAS score (SMD = -0.52; 95% CI = -0.77 to -0.27; P < 0.0001). CONCLUSIONS: Yoga therapy may be effective to treat migraine patients, but it should be recommended with caution because of heterogeneity.
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Trastornos Migrañosos , Yoga , Cefalea , Humanos , Trastornos Migrañosos/terapia , Dimensión del Dolor , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Ureaplasma urealyticum (UU) is commonly present in human reproductive tract, which frequently leads to genital tract infection. Hence, there is an urgent need to develop a rapid detection method for UU. In our study, a real-time fluorescence loop-mediated isothermal amplification (LAMP) assay was developed and evaluated for the detection of UU. Two primers were specifically designed based on the highly conserved regions of ureaseB genes. The reaction was carried out for 60 min in a constant temperature system using Bst DNA polymerase, and the process was monitored by real-time fluorescence signal, while polymerase chain reaction (PCR) was performed simultaneously. In real-time fluorescence LAMP reaction system, positive result was only obtained for UU among 9 bacterial strains, with detection sensitivity of 42 pg/µL (4.2 × 105 CFU/mL), and all 16 clinical samples of UU could be detected. In conclusion, real-time fluorescence LAMP is a simple, sensitive, specific and effective method compared with conventional PCR, which shows great promise in the rapid detection of UU.
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OBJECTIVES: The aim of the present study was to compare the short-term outcomes between spontaneous ventilation video-assisted thoracic surgery (SV-VATS) and mechanical ventilation video-assisted thoracic surgery (MV-VATS) in the elderly. All patients included in the present study underwent lobectomy, segmentectomy, or wedge resection and lymph node dissection. DESIGN: A retrospective cohor. SETTING: The first affiliated hospital of Guangzhou Medical University, Guangzhou, China. PARTICIPANTS: The present study included 799 elderly patients diagnosed with non-small-cell lung cancer undergoing SV-VATS or MV-VATS. After propensity score matching, 80 patients in the SV-VATS group and 80 patients in the MV-VATS group were analyzed. INTERVENTIONS: Patients in the SV-VATS group received spontaneous-ventilation anesthesia, which was administered as follows: intravenous anesthesia + laryngeal mask airway + thoracic paravertebral block + visceral pleural surface anesthesia + thoracic vagus nerve block. Patients in the MV-VATS group received general endotracheal anesthesia. SV-VATS or MV-VATS was performed according to the preference of the patients. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in anesthesia time (226.3 ± 79.8 v 238.5 ± 66.2 min; p = 0.44), surgery time (166.2 ± 102.6 v 170.1 ± 83.4 min; p = 0.66), and number of dissected lymph nodes (5.3 ± 7.5 v 4.4 ± 7.4; p = 0.23) between the two groups. There were significant differences in intraoperative bleeding (61.5 ± 165.1 v 82.2 ± 116.9 mL; p < 0.001). After surgery, the two groups were statistically comparable in terms of hospitalization (17.6 ± 7.6 v 17.2 ± 6.9 days; p = 0.95) and incidence of complications (7.5% v 13.8%; p = 0.20), while there were significant differences in chest tube duration (6.1 ± 3.3 v 4.5 ± 1.2 days; p < 0.001). CONCLUSIONS: SV-VATS is feasible and as safe as MV-VATS, and it could be considered as an alternative treatment for the elderly.
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Anestesia de Conducción , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Humanos , Neoplasias Pulmonares/cirugía , Neumonectomía , Complicaciones Posoperatorias , Estudios Retrospectivos , Cirugía Torácica Asistida por VideoRESUMEN
Breyniahiemalis Huan C. Wang & Feng Yang (Phyllanthaceae), of sect. Cryptogynium (Müll.Arg.) Welzen & Pruesapan in subg. Breynia, is described from Yunnan, south-west China. It is known from only a single locality in the valley of the Yuanjiang River, and usually occurs in the understory of the savanna vegetation. It is characterized by its broadly elliptic to orbicular leaf blades, shallowly plate-like calyces of the staminate flowers, ovaries with clearly erose rim and urceolate capsules. Morphological comparisons with similar species are also presented.
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STUDY OBJECTIVES: The relationship of iron with cognitive and motor impairment in idiopathic rapid eye movement sleep behavior disorder (iRBD) remains unknown. METHODS: Twenty-nine (29) patients and 28 healthy controls (HCs) underwent susceptibility weighted imaging and susceptibility mapping. These images were used to evaluate the nigrosome-1 (N1) sign in the substantia nigra (SN), global and regional high-iron (RII) content, and volume of subcortical nuclei. RESULTS: The number of iRBD patients with N1 loss (12) was significantly higher than HCs (2) (p = 0.005). Compared with HCs, the iRBD patients had reduced volume of the right caudate nucleus (RCN) (p < 0.05, false discovery rate [FDR] correction) but no significant changes in global and RII iron of the subcortical nuclei (all p > 0.05, FDR correction). Multiple regression analysis revealed that: for cognitive function, the RII iron of the RCN was significantly correlated with visuospatial function and the global iron of the right dentate nucleus (RDN) was correlated with memory function; for motor function, the RII iron of the left DN (LDN) and global iron of the left CN correlated with the Alternate-Tap test (left, average), the global iron of the LDN correlated with the Alternate-Tap test (right), and the global iron of the left GP correlated with the 3-m Timed Up and Go test (all p < 0.05, FDR correction). CONCLUSIONS: Our exploratory analysis found that iRBD patients had a higher incidence of N1 loss and reduced RCN volume after FDR correction. Cognitive and motor impairment were associated with iron deposition in several cerebral nuclei after FDR correction.
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Trastorno de la Conducta del Sueño REM , Encéfalo , Humanos , Hierro , Equilibrio Postural , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Estudios de Tiempo y MovimientoRESUMEN
OBJECTIVE: A non-lipolysis nanoemulsion (NNE) was designed to reduce the first-pass metabolism of raloxifene (RAL) by intestinal UDP-glucuronosyltransferases (UGTs) for increasing the oral absorption of RAL, coupled with in vitro and in vivo studies. METHODS: In vitro stability of NNE was evaluated by lipolysis and the UGT metabolism system. The oral bioavailability of NNE was studied in rats and pigs. Finally, the absorption mechanisms of NNE were investigated by in situ single-pass intestinal perfusion (SPIP) in rats, Madin-Darby canine kidney (MDCK) cells model, and lymphatic blocking model. RESULTS: The pre-NNE consisted of isopropyl palmitate, linoleic acid, Cremophor RH40, and ethanol in a weight ratio of 3.33:1.67:3:2. Compared to lipolysis nanoemulsion of RAL (RAL-LNE), the RAL-NNE was more stable in in vitro gastrointestinal buffers, lipolysis, and UGT metabolism system (p < 0.05). The oral bioavailability was significantly improved by the NNE (203.30%) and the LNE (205.89%) relative to the suspension group in rats. However, 541.28% relative bioavailability was achieved in pigs after oral NNE intake compared to the suspension and had two-fold greater bioavailability than the LNE (p < 0.05). The RAL-NNE was mainly absorbed in the jejunum and had high permeability at the intestine of rats. The results of both SPIP and MDCK cell models demonstrated that the RAL-NNE was absorbed via endocytosis mediated by caveolin and clathrin. The other absorption route, the lymphatic transport (cycloheximide as blocking agent), was significantly improved by the NNE compared with the LNE (p < 0.05). CONCLUSION: A NNE was successfully developed to reduce the first-pass metabolism of RAL in the intestine and enhance its lymphatic transport, thereby improving the oral bioavailability. Altogether, NNE is a promising carrier for the oral delivery of drugs with significant first-pass metabolism.
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Absorción Fisicoquímica , Emulsiones/química , Lipólisis , Nanopartículas/química , Clorhidrato de Raloxifeno/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Transporte Biológico , Supervivencia Celular , Perros , Emulsiones/administración & dosificación , Femenino , Intestinos/fisiología , Linfa/metabolismo , Células de Riñón Canino Madin Darby , Masculino , Polietilenglicoles , Ratas Sprague-Dawley , Tensoactivos/química , PorcinosRESUMEN
PURPOSE: The objective of this study was to compare the in vitro Fick's first law, in vitro lipolysis, and in vivo rat assays for oral absorption of Biopharmaceutical Classification Systems Class II (BCS II) drugs in self-nanoemulsifying drug delivery system (SNEDDS), and studied drugs and oils properties effects on the absorption. METHODS: The transport abilities of griseofulvin (GRI), phenytoin (PHE), indomethacin (IND), and ketoprofen (KET) in saturated water solutions and SNEDDS were investigated using the in vitro Madin-Darby canine kidney cell model. GRI and cinnarizine (CIN) in medium-chain triglycerides (MCT)-SNEDDS and long-chain triglycerides (LCT)-SNEDDS were administered in the in vivo SD rat and in vitro lipolysis models to compare the oral absorption and the distribution behaviors in GIT and build an in vitro-in vivo correlation (IVIVC). RESULTS: In the cell model, the solubility of GRI, PHE, IND, and KET increased 6-8 fold by SNEDDS, but their permeability were only 18%, 4%, 8%, and 33% of those of their saturated water solutions, respectively. However, in vivo absorption of GRI-SNEDDS was twice that of the GRI suspension and those of CIN-SNEDDS were 15-21 fold those of the CIN suspension. In the lipolysis model, the GRI% in aqueous and pellet phases of MCT were similar to that in LCT. In contrast, the CIN% in the aqueous and pellet phases were decreased but that of the lipid phase increased. In addition, an IVIVC was found between the CIN% in the lipid phase and in vivo relative oral bioavailability (F r). CONCLUSION: The in vitro cell model was still a suitable tool to study drug properties effects on biofilm transport and SNEDDS absorption mechanisms. The in vitro lipolysis model provided superior oral absorption simulation of SNEDDS and helped to build correlation with in vivo rats. The oral drug absorption was affected by drug and oil properties in SNEDDS.