We present a simple, automated method for high-throughput formation of droplet interface bilayers (DIBs) in a microfluidic device. We can form complex DIB networks that are able to fill predefined ...three dimensional architectures. Moreover, we demonstrate the flexibility of the system by using a variety of lipids including 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC).
The self-assembly of Aβ to β-sheet-rich neurotoxic oligomers is a main pathological event leading to Alzheimer's disease (AD). Selective targeting of Aβ oligomers without affecting other functional ...proteins is therefore an attractive approach to prevent the disease and its progression. In this study, we report that photodynamic treatment of Aβ in the presence of catalytic amounts of chlorin e6 can selectively damage Aβ and inhibit its aggregation and toxicity. Chlorin e6 also reversed the amyloid aggregation process in the dark by binding its soluble and low molecular weight oligomers, as shown by thioflavin T (ThT) fluorescence and photoinduced cross-linking of unmodified protein (PICUP) methods. Using HSQC NMR spectroscopy, ThT assays, amino acid analysis, SDS/PAGE, and EPR spectroscopy, we show that catalytic amounts of photoexcited chlorin e6 selectively damage the Aβ histidine residues H6, H13, and H14, and induce Aβ cross-linking by generating singlet oxygen. In contrast, photoexcited chlorin e6 was unable to cross-link ubiquitin and α-synuclein, demonstrating its high selectivity for Aβ. By binding to the Aβ histidine residues, catalytic amounts of chlorin e6 can also inhibit the Cu
-induced aggregation and toxicity in darkness, while at stoichiometric amounts it acts as a chelator to reduce the amount of free Cu
. This study demonstrates the great potential of chlorin e6 as a multifunctional agent for treatment of AD, and shows that the three N-terminal Aβ histidine residues are a suitable target for Aβ-specific drugs.
Charge-carrier recombination within the photoactive and charge extraction layers is one of the major obstacles to achieve high performance perovskite solar cells. Here, we demonstrate an ultrathin ...layer of ZnOS in between SnO2 and halide perovskite film that can effectively passivate the defects, suppressing the nonradiative recombination loss. It also helps to moderate the perovskite layer with increasing surface potential, which facilitates transferring the carriers from the perovskite to the hole transport layer, consequently providing an understanding of the bottom-up interfacial passivation of perovskite films. An enhancement of V OC ∼ 100 mV mainly causes the efficiency improvement from 17.22 to 19.4% in the combined SnO2–ZnOS based solar cell. In addition, we have performed a device modeling and theoretical analysis of these perovskite solar cells with and without the passivation layer. Theoretical results for the electronic band structure indicate that ZnOS contains an intermediate band structure between SnO2 and perovskite resulting in a much better band bending for the SnO2–ZnOS based solar cells. It is observed that the numerical results are in good agreement with the experimental outcomes. The combined electron transport layer strategy provides a way for defect passivation for further efficiency enhancement of the perovskite solar cells through interface engineering.
To report on the safety of the first 5 cohorts of a gene therapy trial using recombinant equine infectious anemia virus expressing ABCA4 (EIAV-ABCA4) in adults with Stargardt dystrophy due to ...mutations in ABCA4.
Nonrandomized multicenter phase I/IIa clinical trial.
Patients received a subretinal injection of EIAVABCA4 in the worse-seeing eye at 3 dose levels and were followed for 3 years after treatment.
The primary end point was ocular and systemic adverse events. The secondary end points were best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, multifocal ERG, color fundus photography, short-wavelength fundus autofluorescence, and spectral domain optical coherence tomography.
The subretinal injections were well tolerated by all 22 patients across 3 dose levels. There was 1 case of a treatment-related ophthalmic serious adverse event in the form of chronic ocular hypertension. The most common adverse events were associated with the surgical procedure. In 1 patient treated with the highest dose, there was a significant decline in the number of macular flecks as compared with the untreated eye. However, in 6 patients, hypoautofluorescent changes were worse in the treated eye than in the untreated eye. Of these, 1 patient had retinal pigment epithelium atrophy that was characteristic of tissue damage likely associated with bleb induction. No patients had any clinically significant changes in best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, or multifocal ERG attributable to the treatment.
Subretinal treatment with EIAV-ABCA4 was well tolerated with only 1 case of ocular hypertension. No clinically significant changes in visual function tests were found to be attributable to the treatment. However, 27% of treated eyes showed exacerbation of retinal pigment epithelium atrophy on fundus autofluorescence. There was a significant reduction in macular flecks in 1 treated eye from the highest dose cohort. Additional follow-up and continued investigation in more patients will be required to fully characterize the safety and efficacy of EIAV-ABCA4.
Non-pharmacological behavioural adjuncts have been suggested as efficient safe means in reducing discomfort and adverse effects during medical procedures. We tested this assumption for patients ...undergoing percutaneous vascular and renal procedures in a prospective, randomised, singlecentre study.
241 patients were randomised to receive intraoperatively standard care (n=79), structured attention (n=80), or self-hypnotic relaxation (n=82). All had access to patient-controlled intravenous analgesia with fentanyl and midazolam. Patients rated their pain and anxiety on 0·10 scales before, every 15 min during and after the procedures.
Pain increased linearly with procedure time in the standard group (slope 0·09 in pain score/15 min, p<0·0001), and the attention group (slope 0·04/15 min; p=0·0425), but remained flat in the hypnosis group. Anxiety decreased over time in all three groups with slopes of −0·04 (standard), −0·07 (attention), and −0·11 (hypnosis). Drug use in the standard group (1·9 units) was significantly higher than in the attention and hypnosis groups (0·8 and 0·9 units, respectively). One hypnosis patient became haemodynamically unstable compared with ten attention patients (p=0·0041), and 12 standard patients (p=0·0009). Procedure times were significantly shorter in the hypnosis group (61 min) than in the standard group (78 min, p=0·0016) with procedure duration of the attention group in between (67 min).
Structured attention and self-hypnotic relaxation proved beneficial during invasive medical procedures. Hypnosis had more pronounced effects on pain and anxiety reduction, and is superior, in that it also improves haemodynamic stability.
Abstract Background Intraindividual blood pressure (BP) fluctuates dynamically over time. Previous studies suggested an adverse link between greater visit-to-visit variability in systolic blood ...pressure (SBP) and various outcomes. However, these studies have significant limitations, such as a small size, inclusion of selected populations, and restricted outcomes. Objectives This study investigated the association of increased visit-to-visit variability and all-cause mortality, cardiovascular events, and end-stage renal disease (ESRD) in a large cohort of U.S. veterans. Methods From among 3,285,684 U.S. veterans with and without hypertension and normal estimated glomerular filtration rates (eGFR) during 2005 and 2006, we identified 2,865,157 patients who had 8 or more outpatient BP measurements. Systolic blood pressure variability (SBPV) was measured using the SD of all SBP values (normally distributed) in 1 individual. Associations of SD quartiles (<10.3, 10.3 to 12.7, 12.7 to 15.6, and ≥15.6 mm Hg) with all-cause mortality, incident coronary heart disease (CHD), stroke, and ESRD was examined using Cox models adjusted for sociodemographic characteristics, baseline eGFR, comorbidities, body mass index, SBP, diastolic BP, and antihypertensive medication use. Results Several sociodemographic variables (older age, male sex, African-American race, divorced or widowed status) and clinical characteristics (lower baseline eGFR, higher SBP and diastolic BP), and comorbidities (presence of diabetes, hypertension, cardiovascular disease, and lung disease) were all associated with higher intraindividual SBPV. The multivariable adjusted hazard ratios and 95% confidence intervals for SD quartiles 2 through 4 (compared with the first quartile) associated with all-cause mortality, CHD, stroke, and ESRD were incrementally higher. Conclusions Higher SBPV in individuals with and without hypertension was associated with increased risks of all-cause mortality, CHD, stroke, and ESRD. Further studies are needed to determine interventions that can lower SBPV and their impact on adverse health outcomes.
Low dietary intake of vitamin E is a global public health issue. RRR-α-tocopherol (RRR-αT) is the only naturally occurring vitamin E stereoisomer, but the equimolecular mixture of all eight ...stereoisomers, synthetic vitamin E (S-αT), is commonly consumed. The objective of this study was to evaluate bioavailability and antioxidant activity of RRR-αT versus S-αT, in both mother and fetus, after maternal supplementation during pregnancy.
Female rats (7 weeks of age) received a modified AIN-93G diet supplemented with 75 IU/kg of RRR-αT (NVE, n = 20) or S-αT (SVE, n = 17). At delivery, the levels of αT, stereoisomer distribution, and antioxidant capacity were analyzed in maternal and fetal plasma.
NVE administration significantly increased the proportion of RRR-αT stereoisomer in maternal and fetal plasma. The percentage of RRR-αT increased from 32.76% to 88.33% in maternal plasma, and 35.25% to 97.94% in fetal plasma, in the NVE group compared to SVE. Fetal plasma from the NVE group was found to have higher total antioxidant capacity compared to SVE. Lastly, fetal plasma RRR-αT stereoisomer percentage was positively associated with expression levels of scavenger receptor class B type 1 (SR-B1) in the placenta.
Both natural and synthetic sources of vitamin E showed similar bioavailability. Still, NVE supplementation increased the proportion of RRR-αT and promoted higher antioxidant activity in fetal plasma at birth. Placental SR-B1 might be involved in the stereoselective transfer of RRR-αT stereoisomer across the placenta and may improve αT bioactivity in the fetus.
Inflammatory bowel disease-unclassified (IBD-U) is diagnosed in ∼10% of pediatric and adolescent onset IBD patients. The EUROKIDS registry (2004) initiated by the Porto IBD working group of ESPGHAN ...prospectively monitors diagnostic workup of newly diagnosed pediatric and adolescent onset IBD patients. We aimed to describe diagnostic workup, phenotype, and change of diagnosis over time in pediatric IBD-U patients.
Data were collected on children from 52 centers across 20 European countries and Israel, diagnosed with IBD from May 2005 through November 2013. Full endoscopy plus small bowel radiology was considered complete diagnostic workup. Participating centers reporting IBD-U patients were queried in 2014 for follow-up data.
IBD-U was the provisional first diagnosis in 265 of 3461 children (7.7%) (91/158 58% with pancolitis; 140 53% male), diagnosed more frequently under the age of 10 (median age 12.3 years, 89 34% under 10 years). Half (48%) had undergone complete diagnostic workup. Lack of small bowel radiology was the prevailing reason for incomplete workup. As a result of reinvestigations (endoscopy in 54%, radiology in 38%) during a median follow-up of 5.7 years (interquartile range, 2.5-7.8), a change in diagnosis from IBD-U to Crohn's disease (12%) or ulcerative colitis (20%) was reported.
Only half of patients reported as IBD-U in EUROKIDS had undergone complete diagnostic workup. Follow-up with reinvestigations resulted in a reduction of IBD-U rate to 5.6%. A diagnosis of IBD-U becomes less likely in case of complete diagnostic workup. Implementation of clear diagnostic criteria will further reduce the rate of IBD-U in the future.
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