1. The exposed level of vitamin A in plasma might be exceeded due to the both inadvertent and clinical utilization. The adverse effects of vitamin A have been frequently reported, however, the ...mechanism remains unclear. The inhibition of vitamin A on the activity of UDP-glucuronosyltransferases (UGTs) was determined using in vitro incubation system to explain the adverse effects of vitamin A from a new perspective.
2. UGT supersomes catalyzed glucuronidation of 4-methylumbelliferone (4-MU), trifluoperazine (TFP), and cotinine was used as the probe reaction to evaluate the inhibition of vitamin A toward UGT isoforms, and 100 μM of vitamin A significantly inhibited the activity of all the tested UGT isoforms. Vitamin A exerted competitive inhibition on the activity of UGT1A1, 2B4, 2B7, and 2B15, and the inhibition kinetic parameters (K
i
) were calculated to be 31.1, 16.8, 2.2, and 11.6 μM for UGT1A1, 2B4, 2B7, and 2B15. In silico docking method was used to try to elucidate the inhibition mechanism of vitamin A toward UGT2B7. The results showed the significant contribution of hydrogen bonds and hydrophobic interaction on the UGT2B7 inhibition by vitamin A.
3. The present study provides a new perspective for the adverse effects of vitamin A through reporting the inhibition of vitamin A on the activity of important phase II drug-metabolizing enzymes UGTs, which benefits our deep understanding of mechanism of vitamin A's adverse effects when high exposure of vitamin A occurs.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Amyloid aggregation of pathological proteins is closely associated with a variety of neurodegenerative diseases, and α-synuclein (α-syn) deposition and Tau tangles are considered hallmarks of ...Parkinson's disease and Alzheimer's disease, respectively. Intriguingly, α-syn and Tau have been found to co-deposit in the brains of individuals with dementia and parkinsonism, suggesting a potential role of cross-talk between these two proteins in neurodegenerative pathologies. Here we show that monomeric α-syn and the two variants of Tau, Tau23 and K19, synergistically promote amyloid fibrillation, leading to their co-aggregation in vitro. NMR spectroscopy experiments revealed that α-syn uses its highly negatively charged C terminus to directly interact with Tau23 and K19. Deletion of the C terminus effectively abolished its binding to Tau23 and K19 as well as its synergistic effect on promoting their fibrillation. Moreover, an S129D substitution of α-syn, mimicking C-terminal phosphorylation of Ser
in α-syn, which is commonly observed in the brains of Parkinson's disease patients with elevated α-syn phosphorylation levels, significantly enhanced the activity of α-syn in facilitating Tau23 and K19 aggregation. These results reveal the molecular basis underlying the direct interaction between α-syn and Tau. We proposed that this interplay might contribute to pathological aggregation of α-syn and Tau in neurodegenerative diseases.
Various noninvasive respiratory support modalities are available in neonatal critical care in order to minimize invasive ventilation. Continuous positive airway pressure (CPAP) is the more commonly ...used but noninvasive positive pressure ventilation (NIPPV) seems more efficacious in the early post-extubation phase, although it is not clear if NIPPV may influence longterm outcomes. A recently introduced alternative is noninvasive high frequency oscillatory ventilation (NHFOV) which might be especially useful in babies needing high constant distending pressure. Preterm neonates may receive these respiratory supports for several weeks. Nonetheless, no data are available for the longterm use of NIPPV and NHFOV; few data exist on NHFOV and clinical outcomes, although its safety and suitability are reported in a number of preliminary short-term studies.
We designed an assessor-blinded, multicenter, three-arms, parallel, pragmatic, randomized, controlled trial with a superiority design, investigating the use of CPAP vs NIPPV vs NHFOV during the whole stay in neonatal intensive care units in China. Since safety data will also be analyzed it may be considered a phase II/III trial. Moreover, subgroup analyses will be performed on patients according to prespecified criteria based on physiopathology traits: these subgroup analyses should be considered preliminary. At least 1440 neonates are supposed to be enrolled. The trial has been designed with the collaboration of international colleagues expert in NHFOV, who will also perform an interim analysis at the about 50% of the enrolment.
The study is applying the best trial methodology to neonatal ventilation, a field where it is often difficult to do so for practical reasons. Nonetheless, ours is also a physiology-driven trial, since interventions are applied based on physiological perspective, in order to use ventilatory techniques at their best. The pragmatic design will increase generalizability of our results but subgroup analyses according to predefined physiopathological criteria are also previewed trying to have some advantages of an explanatory design. Since not all clinicians are well versed in all respiratory techniques, the training is pivotal. We intend to apply particular care to train the participating units: a specific 3-month period and several means have been dedicated to this end.
NCT03181958 (registered on June 9, 2017).
To satisfy the measuring demands for the micro components of the industry, micro/nano probing systems with various ball tips have been developed. However, most of them cannot be used to measure the ...real micro geometrical features high precisely because the parameters of the ball tips are not appropriate. The ball tips with a diameter of less than 100 µm, a sphericity and eccentricity of far less than 1 µm are required urgently. A review on the state-of-the-art of ball tips of micro/nano probing systems is presented. The material characteristics and geometric parameters of now available ball tips are introduced separately. The existing fabrication methods for the ball tips are demonstrated and summarized. The ball tips’ future trends, which are smaller diameter, better sphericity and smaller eccentricity, are proposed in view of the practical requirements of high-precision measurement for micro geometrical features. Some challenges have to be faced in future, such as the promotion and high-precision measurement for the small ball tip’s sphericity and eccentricity. Fusion method without the gravity effect when the molten ball tip solidifying is a more suitable way to fabricate a small diameter ball tip together with a shaft.
Introduction
Early onset sepsis (EOS) remains a potentially fatal newborn condition, especially in very preterm infants. Data on the pathogen distribution and antibiotic susceptibility patterns of ...EOS among very preterm infants are scarce but essential for the choice of empirical antibiotic administration. We sought to assess the epidemiologic characteristics and antibiotic susceptibility patterns of pathogens causing EOS among a cohort of very preterm infants in China.
Methods
This prospective, observational study included a cohort of infants born at a gestational age (GA) less than 32 weeks of 32 newborn intensive care units (NICUs) in China between January 1, 2018 and December 31, 2020. EOS was defined by isolation of pathogenic species from blood culture within 72 h of birth.
Results
A total of 108 EOS cases (18.4 per 1000 admissions) were identified among 5865 very preterm infants. Incidence of EOS increased with the decrease of GA and birthweight.
Escherichia coli
(
n
= 44, 40.7%) was the most common pathogen, followed by
Klebsiella
spp. (
n
= 10, 9.3%). The distribution and proportion of pathogenic bacteria varied significantly by GA.
E. coli
and
Klebsiella
spp. showed high resistance to ampicillin and third-generation cephalosporins, while they showed good susceptibility to carbapenem antibiotics and piperacillin–tazobactam.
Conclusion
Our data demonstrated that pathogens causing neonatal EOS showed high rates of resistance to ampicillin and third-generation cephalosporins. This raised questions about the best empirical antibiotic choice for preterm infants suspected of having EOS in low- and middle-income countries (LMICs).
The NASONE (Nasal Oscillation Post-Extubation) trial showed that noninvasive high-frequency oscillatory ventilation (NHFOV) slightly reduces the duration of invasive mechanical ventilation (IMV) in ...preterm infants, whereas NHFOV and noninvasive intermittent positive pressure ventilation (NIPPV) result in fewer reintubations than nasal continuous positive airway pressure (NCPAP). It is unknown whether NHFOV is similarly effective in extremely preterm neonates or in those with more severe respiratory failure (based on the duration of previous ventilation and CO2 levels).
To clarify whether NHFOV is better than NIPPV and NCPAP in reducing the duration of IMV in extremely preterm neonates or those with severe respiratory failure.
This study is a predefined secondary analyses of a multicenter randomized clinical trial that was performed at tertiary academic neonatal intensive care units (NICUs) in China. Participants included neonates enrolled in the NASONE trial between December 2017 and May 2021 and belonging to 3 predefined subgroups: (1) born at less than or equal to 28 weeks' (plus 6 days) gestation, (2) invasively ventilated for more than 1 week from birth, and (3) with CO2 greater than 50 mm Hg before or in the 24 hours after extubation. Data analysis was performed in August 2022.
NCPAP, NIPPV, or NHFOV since the first extubation and until NICU discharge, with airway pressure higher in NHFOV than in NIPPV and than in NCPAP.
The co-primary outcomes were total duration of IMV during the NICU stay, need for reintubation, and ventilator-free days calculated as per the original trial protocol. Outcomes were analyzed on an intention-to-treat basis as for the whole trial, and subgroup analyses followed the original statistical plan.
Among 1137 preterm infants, 455 (279 boys 61.3%) were born at 28 weeks' gestation or less, 375 (218 boys 58.1%) underwent IMV for more than 1 week from birth, and 307 (183 boys 59.6%) had CO2 greater than 50 mm Hg before or in the 24 hours after extubation. Both NIPPV and NHFOV were associated with significantly fewer reintubations (risk difference range, -28% 95% CI, -39% to -17% to -15% 95% CI, -25% to -4%; number needed to treat, 3-7 infants) and early reintubations (risk difference range, -24% 95% CI, -35% to -14% to -20% 95% CI, -30% to -10%) than NCPAP, and these reintubations were less frequently due to refractory hypoxemia. IMV was shorter in the NIPPV and NHFOV groups (mean difference range, -5.0 days 95% CI, -6.8 to -3.1 days to -2.3 days 95% CI, -4.1 to -0.4 days) than in the NCPAP group. Co-primary outcomes were not different between NIPPV and NHFOV; there was no significant interaction effect. Infants in the NHFOV group showed significantly less moderate-to-severe bronchopulmonary dysplasia than infants in the NCPAP group (range, -12% to -10%; number needed to treat, 8-9 infants) and better postextubation gas exchange in all subgroups. The 3 interventions were provided at different mean airway pressure and were equally safe.
The subgroup analyses of extremely preterm or more ill infants confirm the results obtained in the whole population: NIPPV and NHFOV appeared equally effective in reducing duration of IMV compared with NCPAP.
ClinicalTrials.gov Identifier: NCT03181958.
Objective
Cataplexy is a complicated and dynamic process in narcolepsy type 1 (NT1) patients. This study aimed to clarify the distinct stages during a cataplectic attack and identify the changes of ...the primary motor cortex (PMC) excitability during these stages.
Methods
Thirty‐five patients with NT1 and 29 healthy controls were recruited to this study. Cataplectic stages were distinguished from a cataplectic attack by video‐polysomnogram monitoring. Transcranial magnetic stimulation motor‐evoked potential (TMS‐MEP) was performed to measure the excitability of PMC during quiet wakefulness, laughter without cataplexy, and each cataplectic stage.
Results
Based on the video and electromyogram observations, a typical cataplectic attack (CA) process is divided into four stages: triggering (CA1), resisting (CA2), atonic (CA3), and recovering stages (CA4). Compared with healthy controls, NT1 patients showed significantly decreased intracortical facilitation during quiet wakefulness. During the laughter stage, both patients and controls showed increased MEP amplitude compared with quiet wakefulness. The MEP amplitude significantly increased even higher in CA1 and 2, and then dramatically decreased in CA3 accompanied with prolonged MEP latency compared with the laughter stage and quiet wakefulness. The MEP amplitude and latency gradually recovered during CA4.
Interpretation
This study identifies four stages during cataplectic attack and reveals the existence of a resisting stage that might change the process of cataplexy. The fluctuation of MEP amplitude and MEP latency shows a potential participation of PMC and motor control pathway during cataplexy, and the increased MEP amplitude during CA1 and 2 strongly implies a compensatory mechanism in motor control that may resist or avoid cataplectic attack.
Positron lifetime spectrum and electrical property measurements were performed on ZnO-based ceramics doped with different contents of TiO2. For ZnO-based ceramics with TiO2 content less than 1.8 ...mol%, the mean positron lifetime of the ZnO-based ceramic decreases with increasing in TiO2 content, and reaches a minimum value at 1.8 mol% TiO2. As the TiO2 content higher than 1.8 mol%, the mean positron lifetime increases with TiO2 content. The ZnO-based varistor with 1.8 mol% TiO2 exhibites an optimized varistor property; it has a relatively low leakage current IL, a relatively low breakdown voltage VB, and a relatively high nonlinear coefficient α. The effects of TiO2 doping on microdefects and electrical properties of ZnO-based varistors were discussed.
This study aimed to investigate the value of
technetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid (
Tc3PRGD
) imaging in diagnosis and staging of breast cancer compared with ...2-deoxy-2-
Ffluoro-D-glucose (
FFDG) imaging, and to explore the expression of integrin α
β
in tumor vascular endothelial cells.
Forty-two women with suspected breast cancer underwent both
Tc3PRGD
imaging and
FFDG imaging. Visual analysis was used to assess primary breast lesion, axillary lymph node, and distant metastasis. The tumor-blood (T/B) ratios from
Tc3PRGD
imaging and the maximum standardized uptake value (SUVmax) from
FFDG imaging were analyzed for breast lesions. Integrin α
β
was analyzed through immunohistochemistry.
Forty-five breast lesions were found (malignant, n = 38; benign, n = 7). The sensitivity, specificity, and accuracy of
Tc3PRGD
and
FFDG imaging in visual analysis for the breast lesion were 97.4, 87.5, and 95.6 % and 97.4, 71.4, and 93.3 %, respectively (P > 0.05). For semi-quantitative analysis, no significant difference of the area under the curves (AUC) was found in the imaging using the two radiopharmaceuticals (0.880 and 0.955; Z = 0.88, P > 0.05). The sensitivity, specificity, and accuracy for axillary lymph node metastasis with
Tc3PRGD
and
FFDG were 78.05, 99.36, and 94.92 % and 85.37, 98.72, and 95.64 %, respectively (P > 0.05). Nine patients with distant metastases were all detected with the two radiopharmaceuticals. The expression of integrin α
β
was correlated with
Tc3PRGD
uptake (r = 0.582, P = 0.001), which were significantly higher in the HER2-positive and stage III-IV patients (P < 0.05).
The prospective study demonstrated that
Tc3PRGD
imaging seems to be valuable for diagnosis of breast cancer and its staging. It may be less sensitive for detecting small lymph node metastatic lesions when compared with
FFDG imaging. Integrin α
β
in tumor microvessels was associated with the breast cancer subtype and its staging.
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