α-Helical Peptides on Plasma-Treated Polymers Promote Ciliation of Airway Epithelial Cells

Airway respiratory epithelium forms a physical barrier through intercellular tight junctions, which prevents debris from passing through to the internal environment while ciliated epithelial cells expel particulate-trapping mucus up the airway. Polymeric solutions to loss of airway structure and integrity have been unable to fully restore functional epithelium. We hypothesized that plasma treatment of polymers would permit adsorption of α-helical peptides and that this would promote functional differentiation of airway epithelial cells. Five candidate plasma compositions are compared; Air, N2, H2, H2:N2 and Air:N2. X-ray photoelectron spectroscopy shows changes in at% N and C 1s peaks after plasma treatment while electron microscopy indicates successful adsorption of hydrogelating self-assembling fibres (hSAF) on all samples. Subsequently, adsorbed hSAFs support human nasal epithelial cell attachment and proliferation and induce differentiation at an air-liquid interface. Transepithelial measurements show that the cells form tight junctions and produce cilia beating at the normal expected frequency of 10-11 Hz after 28 days in culture. The synthetic peptide system described in this study offers potential superiority as an epithelial regeneration substrate over present “gold-standard” materials, such as collagen, as they are controllable and can be chemically functionalised to support a variety of in vivo environments. Using the hSAF peptides described here in combination with plasma-treated polymeric surfaces could offer a way of improving the functionality and integration of implantable polymers for aerodigestive tract reconstruction and regeneration

Psoralen-loaded lipid-polymer hybrid nanoparticles enhance doxorubicin efficacy in multidrug-resistant HepG2 cells

Background: Psoralen (PSO), a major active component of Psoralea corylifolia, has been shown to overcome multidrug resistance in cancer. A drug carrier comprising a lipid-monolayer shell and a biodegradable polymer core for sustained delivery and improved efficacy of drug have exhibited great potential in efficient treatment of cancers. Methods: The PSO-loaded lipid polymer hybrid nanoparticles were prepared and characterized. In vitro cytotoxicity assay, cellular uptake, cell cycle analysis, detection of ROS level and mitochondrial membrane potential (ΔΨm) and western blot were performed. Results: The P-LPNs enhanced the cytotoxicity of doxorubicin (DOX) 17-fold compared to free DOX in multidrug resistant HepG2/ADR cells. Moreover, P-LPNs displayed pro-apoptotic activity, increased levels of ROS and depolarization of ΔΨm. In addition, there were no significant effects on cellular uptake of DOX, cell cycle arrest, or the expression of P-glycoprotein. Mechanistic studies suggested that P-LPNs enhanced DOX cytotoxicity by increased release of cytochrome c and enhanced caspase3 cleavage, causing apoptosis in HepG2/ADR cells. Conclusion: The lipid-polymer hybrid nanoparticles can be considered a powerful and promising drug delivery system for effective cancer chemotherapy. Keywords: lipid-polymer hybrid nanoparticles, psoralen, drug delivery, HepG2, ADR cells, apoptosis.This work was supported by the National Natural Science Foundation of China (81273707), the Ministry of Education in the New Century Excellent Talents (NECT-12-0677), the Natural Science Foundation of Guangdong (S2013010012880, 2016A030311037), the Science and Technology Program of Guangzhou (2014J4500005, 201704030141), the Science Program of the Department of Education of Guangdong (2013KJCX0021, 2015KGJHZ012), the Science and Technology Program of Guangdong (2015A050502027), and the Special Project of International Scientific and Technological Cooperation in Guangzhou Development District (2017GH16)

A mixed methods approach to evaluating community drug distributor performance in the control of neglected tropical diseases

BACKGROUND: Trusted literate, or semi-literate, community drug distributors (CDDs) are the primary implementers in integrated preventive chemotherapy (IPC) programmes for Neglected Tropical Disease (NTD) control. The CDDs are responsible for safely distributing drugs and for galvanising communities to repeatedly, often over many years, receive annual treatment, create and update treatment registers, monitor for side-effects and compile treatment coverage reports. These individuals are 'volunteers' for the programmes and do not receive remuneration for their annual work commitment. METHODS: A mixed methods approach, which included pictorial diaries to prospectively record CDD use of time, structured interviews and focus group discussions, was used to triangulate data on how 58 CDDs allocated their time towards their routine family activities and to NTD Programme activities in Uganda. The opportunity costs of CDD time were valued, performance assessed by determining the relationship between time and programme coverage, and CDD motivation for participating in the programme was explored. RESULTS: Key findings showed approximately 2.5 working weeks (range 0.6-11.4 working weeks) were spent on NTD Programme activities per year. The amount of time on NTD control activities significantly increased between the one and three deliveries that were required within an IPC campaign. CDD time spent on NTD Programme activities significantly reduced time available for subsistence and income generating engagements. As CDDs took more time to complete NTD Programme activities, their treatment performance, in terms of validated coverage, significantly decreased. Motivation for the programme was reported as low and CDDs felt undervalued. CONCLUSIONS: CDDs contribute a considerable amount of opportunity cost to the overall economic cost of the NTD Programme in Uganda due to the commitment of their time. Nevertheless, programme coverage of at least 75 %, as required by the World Health Organisation, is not being achieved and vulnerable individuals may not have access to treatment as a consequence of sub-optimal performance by the CDDs due to workload and programmatic factors

Damages of the tibial post in constrained total knee prostheses in the early postoperative course – a scanning electron microscopic study of polyethylene inlays

<p>Abstract</p> <p>Background</p> <p>Investigation of the risk of fracture of the polyethylene (PE) inlay in constrained total knee prostheses.</p> <p>Methods</p> <p>Three unused and seven polyethylene inlays that had been implanted in a patient's knee for an average of 25.4 months (min 1.1 months, max 50.2 months) were investigated using scanning electron microscopy (SEM). All inlays were of the same type and size (Genesis II constrained, Smith & Nephew). The PE surface at the transition from the plateau to the post was analyzed.</p> <p>Results</p> <p>The unused inlays had fissure-free surfaces. All inlays that had been implanted in a patient's knee already had distinct fissures at the front and backside of the post.</p> <p>Conclusion</p> <p>The fissures of the transition from the plateau to the post indicated a loading-induced irreversible mechanical deformation and possibly cause the fracture of the inlay.</p

Radiolucent lines in low-contact-stress mobile-bearing total knee arthroplasty: a blinded and matched case control study

<p>Abstract</p> <p>Background</p> <p>Low-contact-stress (LCS) mobile-bearing total knee arthroplasty (TKA) (Johnson & Johnson, New Brunswick, NJ; previously: DePuy, Warsawa, USA) provides excellent functional results and wear rates in long-term follow-up analyses. Radiological analysis shows radiolucent lines (RLL) appearing immediately or two years after primary implantation, indicative of poor seat. Investigations proved RLL to be more frequent in uncemented TKA, resulting in a consensus to cement the tibial plateau, but their association with clinical findings and patients discomfort and knee pain is still unknown.</p> <p>Methods</p> <p>553 patients with 566 low-contact-stress (LCS) total knee prostheses were screened for continuous moderate knee pain. We compared tibial stress shielding classified by Ewald in patients suffering from pain with a matched, pain-free control group on blinded X-rays. We hypothesized a positive correlation between pain and radiolucency and higher frequency of such radiolucent lines in the most medial and most lateral zones of the tibial plateau.</p> <p>Results</p> <p>Twenty-eight patients suffered from knee pain in total. Radiolucencies were detected in 27 of these cases and in six out of 28 matched controls without knee pain. We could demonstrate a significant correlation of knee pain and radiolucencies, which appeared significantly more frequently in the outermost zones of the tibial plateau.</p> <p>Conclusion</p> <p>Our findings suggest that radiolucent lines, representing poor implant seat, about the tibial plateau are associated with knee pain in LCS patients. Radiolucencies are observed more often in noncemented LCS, and cementing the tibial plateau might improve implant seat and reduce both radiolucent lines and associated knee pain.</p

Interruptions of the FXN GAA Repeat Tract Delay the Age at Onset of Friedreich’s Ataxia in a Location Dependent Manner

Copyright: © 2021 by the authors. Friedreich’s ataxia (FRDA) is a comparatively rare autosomal recessive neurological disorder primarily caused by the homozygous expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene. The repeat expansion causes gene silencing that results in deficiency of the frataxin protein leading to mitochondrial dysfunction, oxidative stress and cell death. The GAA repeat tract in some cases may be impure with sequence variations called interruptions. It has previously been observed that large interruptions of the GAA repeat tract, determined by abnormal MboII digestion, are very rare. Here we have used triplet repeat primed PCR (TP PCR) assays to identify small interruptions at the 5′ and 3′ ends of the GAA repeat tract through alterations in the electropherogram trace signal. We found that contrary to large interruptions, small interruptions are more common, with 3′ interruptions being most frequent. Based on detection of interruptions by TP PCR assay, the patient cohort (n = 101) was stratified into four groups: 5′ interruption, 3′ interruption, both 5′ and 3′ interruptions or lacking interruption. Those patients with 3′ interruptions were associated with shorter GAA1 repeat tracts and later ages at disease onset. The age at disease onset was modelled by a group-specific exponential decay model. Based on this modelling, a 3′ interruption is predicted to delay disease onset by approximately 9 years relative to those lacking 5′ and 3′ interruptions. This highlights the key role of interruptions at the 3′ end of the GAA repeat tract in modulating the disease phenotype and its impact on prognosis for the patient.European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement number 242193/EFACTS; National Brain Appeal—Small Acorns Fund; The Wellcome Centre for Human Neuroimaging is supported by core funding from the Wellcome (203147/Z/16/Z); Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme; CRN; North Thames, National Institute for Health Research (NIHR). Medical Research Council (MR/N028767/1)

SEDLIN Forms Homodimers: Characterisation of SEDLIN Mutations and Their Interactions with Transcription Factors MBP1, PITX1 and SF1

BACKGROUND: SEDLIN, a 140 amino acid subunit of the Transport Protein Particle (TRAPP) complex, is ubiquitously expressed and interacts with the transcription factors c-myc promoter-binding protein 1 (MBP1), pituitary homeobox 1 (PITX1) and steroidogenic factor 1 (SF1). SEDLIN mutations cause X-linked spondyloepiphyseal dysplasia tarda (SEDT). METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effects of 4 missense (Asp47Tyr, Ser73Leu, Phe83Ser and Val130Asp) and the most C-terminal nonsense (Gln131Stop) SEDT-associated mutations on interactions with MBP1, PITX1 and SF1 by expression in COS7 cells. Wild-type SEDLIN was present in the cytoplasm and nucleus and interacted with MBP1, PITX1 and SF1; the SEDLIN mutations did not alter these subcellular localizations or the interactions. However, SEDLIN was found to homodimerize, and the formation of dimers between wild-type and mutant SEDLIN would mask a loss in these interactions. A mammalian SEDLIN null cell-line is not available, and the interactions between SEDLIN and the transcription factors were therefore investigated in yeast, which does not endogenously express SEDLIN. This revealed that all the SEDT mutations, except Asp47Tyr, lead to a loss of interaction with MBP1, PITX1 and SF1. Three-dimensional modelling studies of SEDLIN revealed that Asp47 resides on the surface whereas all the other mutant residues lie within the hydrophobic core of the protein, and hence are likely to affect the correct folding of SEDLIN and thereby disrupt protein-protein interactions. CONCLUSIONS/SIGNIFICANCE: Our studies demonstrate that SEDLIN is present in the nucleus, forms homodimers and that SEDT-associated mutations cause a loss of interaction with the transcription factors MBP1, PITX1 and SF1