Vaginal delivery of siRNA using a novel PEGylated lipoplex-entrapped alginate scaffold system

Sustained vaginal delivery of siRNA has been precluded by the mucosal barrier lining the vaginal tract. In contrast to prior reports, we showed that conventional lipoplexes administered intravaginally are unable to reach the vaginal epithelium under normal physiological conditions. Here we have developed a novel alginate scaffold system containing muco-inert PEGylated lipoplexes to provide a sustained vaginal presence of lipoplexes in vivo and to facilitate the delivery of siRNA/oligonucleotides into the vaginal epithelium. These PEGylated lipoplex-entrapped alginate scaffolds (PLAS) were fabricated using a freeze-drying method and the entrapment efficiency, release rate, and efficacy were characterized. We demonstrated that the PLAS system had an entrapment efficiency of ~ 50%, which released PEGylated lipoplexes gradually both in vitro and in vivo. While the presence of alginate diminished the cell uptake efficiency of PEGylated lipoplexes in vitro, as expected, we showed a six-fold increase their uptake into the vaginal epithelium compared to existing transfection systems following intravaginal administration in mice. A significant knockdown of Lamin A/C level was also observed in vaginal tissues using siLamin A/C-containing PLAS system in vivo. Overall, our results indicated the potential of the biodegradable PLAS system for the sustained delivery of siRNA/oligonucleotides to vaginal epithelium

Altered expression of protein tyrosine phosphatase, non-receptor type 22 isoforms in systemic lupus erythematosus

Introduction: A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human protein tyrosine phosphatase, non-receptor type 22 (PTPN22) complementary DNA (cDNA) is associated with an increased risk of systemic lupus erythematosus (SLE). How the overall activity of PTPN22 is regulated and how the expression of PTPN22 differs between healthy individuals and patients with lupus are poorly understood. Our objectives were to identify novel alternatively spliced forms of PTPN22 and to examine the expression of PTPN22 isoforms in healthy donors and patients with lupus. Methods: Various human PTPN22 isoforms were identified from the GenBank database or amplified directly from human T cells. The expression of these isoforms in primary T cells and macrophages was examined with real-time polymerase chain reaction. The function of the isoforms was determined with luciferase assays. Blood samples were collected from 49 subjects with SLE and 15 healthy controls. Correlation between the level of PTPN22 isoforms in peripheral blood and clinical features of SLE was examined with statistical analyses. Results: Human PTPN22 was expressed in several isoforms, which differed in their level of expression and subcellular localization. All isoforms except one were functionally interchangeable in regulating NFAT activity. SLE patients expressed higher levels of PTPN22 than healthy individuals and the levels of PTPN22 were negatively correlated with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC-DI). Conclusions: The overall activity of PTPN22 is determined by the functional balance among all isoforms. The levels of PTPN22 isoforms in peripheral blood could represent a useful biomarker of SLE

Optimal treatment protocol using dental implants for edentulous maxilla: a review of the literature

AIM: This systematic review analyzes the impact of factors affecting the rehabilitation of maxillary edentulous patients with implant-supported prosthesis. By identifying these variables we hope to establish standard treatment protocols for the edentulous maxilla. MATERIAL AND METHODS: The electronic data bases PubMed, Science Direct, and Embase were searched for clinical studies of complete maxillary implant supported removable and fixed dental prostheses. The analysis was confined to prospective studies with a mean follow-up of at least 1 year published prior to February 2017. RESULTS: A total of 158 publications were retrieved from the database searches. One additional article was included from manual searches. From these, 12 articles were included in this study for further analysis using PRISMA. The analysis of the selected articles revealed the following findings: 1. It is difficult to report a definite conclusion from the selected articles in the present review because they exhibit a great heterogeneity and differences in methodology. 2. High implant and implant supported fixed prosthesis survival rates can be achieved when five or more implants were placed in edentulous maxilla. 3. Whether implants were placed in healed bone sites or fresh extraction sockets did not significantly affect the implant survival rate. 4. Immediate loading of prosthesis did not show a difference in implant or prosthetic survival rate. 5. Continuing follow up is necessary because in fixed type of restoration fractured components of prostheses is very commonly seen

Association between use of non–vitamin k oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation

Importance:  Non–vitamin K oral anticoagulants (NOACs) are commonly prescribed with other medications that share metabolic pathways that may increase major bleeding risk. Objective:  To assess the association between use of NOACs with and without concurrent medications and risk of major bleeding in patients with nonvalvular atrial fibrillation. Design, Setting, and Participants:  Retrospective cohort study using data from the Taiwan National Health Insurance database and including 91 330 patients with nonvalvular atrial fibrillation who received at least 1 NOAC prescription of dabigatran, rivaroxaban, or apixaban from January 1, 2012, through December 31, 2016, with final follow-up on December 31, 2016. Exposures:  NOAC with or without concurrent use of atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; or phenytoin. Main Outcomes and Measures:  Major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding. Adjusted incidence rate differences between person-quarters (exposure time for each person during each quarter of the calendar year) of NOAC with or without concurrent medications were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. Results:  Among 91 330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years [SD, 10.8]; men, 55.8%; NOAC exposure: dabigatran, 45 347 patients; rivaroxaban, 54 006 patients; and apixaban, 12 886 patients), 4770 major bleeding events occurred during 447 037 person-quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person-quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone: 38.09 for NOAC use alone vs 52.04 for amiodarone (difference, 13.94 [99% CI, 9.76-18.13]); 102.77 for NOAC use alone vs 241.92 for fluconazole (difference, 138.46 [99% CI, 80.96-195.97]); 65.66 for NOAC use alone vs 103.14 for rifampin (difference, 36.90 [99% CI, 1.59-72.22); and 56.07 for NOAC use alone vs 108.52 for phenytoin (difference, 52.31 [99% CI, 32.18-72.44]; P < .01 for all comparisons). Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone. Conclusions and Relevance:  Among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with the use of NOACs alone, was associated with increased risk of major bleeding. Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs

Little Hierarchy, Little Higgses, and a Little Symmetry

Little Higgs theories are an attempt to address the little hierarchy problem, i.e., the tension between the naturalness of the electroweak scale and the precision measurements showing no evidence for new physics up to 5-10 TeV. In little Higgs theories, the Higgs mass-squareds are protected to the one-loop order from the quadratic divergence. This allows the cutoff to be raised up to \~10 TeV, beyond the scales probed by the precision data. However, strong constraints can still arise from the contributions of the new TeV scale particles and hence re-introduces the fine-tuning problem. In this paper we show that a new symmetry, denoted as T-parity, under which all heavy gauge bosons and scalar triplets are odd, can remove all the tree-level contributions to the electroweak observables and therefore makes the little Higgs theories completely natural. The T-parity can be manifestly implemented in a majority of little Higgs models by following the most general construction of the low energy effective theory a la Callan, Coleman, Wess and Zumino. In particular, we discuss in detail how to implement the T-parity in the littlest Higgs model based on SU(5)/SO(5). The symmetry breaking scale f can be even lower than 500 GeV if the contributions from the unknown UV physics at the cutoff are somewhat small. The existence of $T$-parity has drastic impacts on the phenomenology of the little Higgs theories. The T-odd particles need to be pair-produced and will cascade down to the lightest T-odd particle (LTP) which is stable. A neutral LTP gives rise to missing energy signals at the colliders which can mimic supersymmetry. It can also serve as a good dark matter candidate.Comment: 20 pages, 2 figures, RevTeX; v2: Yukawa sector in the SU(5)/SO(5) model slightly modified. Also added comments on the Dirac mass term for the fermionic doublet partner; v3: clarifying comments on the modified Yukawa sector. version to appear on JHE

Does open-plan office environment support creativity? The mediating role of activated positive mood

This study examines how perceived physical office environment features affect occupants’ creativity through positive moods. Based on a sample of 181 occupants in open-plan offices, we found that perceived spatial organization features had a positive relationship with occupants’ self-assessed creativity, and this relationship is mediated by positive moods. Although perceived architectonic details of the physical work environment do not have a direct effect on occupants’ creativity, there is also a mediating effect through positive moods. A further examination revealed that activated positive mood significantly mediates the relationship between both physical work environment features and occupants’ creativity, whereas deactivated positive mood was not significant as a mediator. When occupants perceived the physical work environment to be supportive in providing various workspaces and is well decorated, it is most likely to enhance creativity. Article in English. Ar atvirojo plano biurų aplinka palaiko kūrybiškumą? Poveikį darantis suaktyvintas pozityvus nusiteikimas Santrauka Šiame tyrime nagrinėjama, kaip suvokiamos fizinės biuro aplinkos ypatumai veikia darbuotojų kūrybiškumą, jiems esant pozityviai nusiteikusiems. Remdamiesi atvirojo plano biurų 181 darbuotojo pavyzdžiu nustatėme, kad suvokiamos erdvinės organizacijos ypatumams buvo būdingas pozityvus santykis su pačių darbuotojų savojo kūrybiškumo vertinimais, o šiam santykiui netiesioginę įtaką turi pozityvus nusiteikimas. Nors fizinės darbo aplinkos suvokiamos architektūrinės detalės neturi tiesioginio poveikio darbuotojų kūrybiškumui, vis dėlto pozityvus nusiteikimas daro netiesioginį poveikį. Tolesnis tyrimas atskleidė, kad suaktyvintas pozityvus nusiteikimas turi reikšmingą įtaką santykiui tiek tarp fizinės darbo aplinkos ypatumų, tiek tarp darbuotojų kūrybiškumo, o nesuaktyvintas pozityvus nusiteikimas neturėjo didelės reikšmės poveikio atžvilgiu. Darbuotojai suprato, kad fizinė darbo aplinka, kuri sudaro sąlygas kurti įvairias darbo erdves ir yra tinkamai apipavidalinta, labai tikėtina, jog ir sustiprina kūrybiškumą. Reikšminiai žodžiai: suaktyvintas pozityvus nusiteikimas, kūrybiškumas, nusiteikimas, fizinė darbo aplinka