Enhancement in corneal permeability of riboflavin using calcium sequestering compounds

Ethylenediaminetetraacetic acid, ethylenediamine-N,N′-disuccinic acid and ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid are polyaminocarboxylic acids that are able to sequester metal ions. Calcium is implicated in maintenance of intercellular matrix, zonula occludens (tight junctions) and zonula adherens of epithelium and endothelium cells. Corneal epithelium is impervious to many aqueous formulations due to it being lipophilic, whereby transcellular drug transit is resisted, whilst tight junctions restrict access via the paracellular route. Research has shown that integrity of tight junctions breaks down through loss of Ca2+ for endothelial and epithelial cells. This study investigates different Ca2+ sequestering compounds and their effect on corneal permeability of riboflavin at physiological pH. Riboflavin is a topically administered ocular drug applied during UV-induced corneal cross-linking for the treatment of keratoconus

From Quality-I to Quality-II: cultivating an error culture to support lean thinking and rework mitigation in infrastructure projects

While lean thinking may help tackle waste, rework remains an ongoing problem during the construction of infrastructure projects. Often too much emphasis is placed on applying lean tools rather than harnessing the human factor and establishing a culture to mitigate rework. Thus, this paper proposes the need for construction organisations to transition from the prevailing error prevention culture (i.e. Quality-I) that pervades practice to one based on error management (i.e. Quality-II) if rework is to be contained and reduced. Accordingly, this paper asks: What type of error culture is required to manage errors that result in rework and to support lean thinking during the construction of infrastructure projects? We draw on the case of a program alliance of 129 water infrastructure projects and make sense of how it enacted, in addition to lean thinking, a change initiative to transition from error prevention to an error management culture to address its rework problem. We observed that leadership, psychological safety and coaching were pivotal for cultivating a culture where there was an acceptance that ‘errors happen’ and effort was directed at mitigating their adverse consequences. The contributions of this paper are twofold as we provide: (1) a new theoretical underpinning to mitigate rework and support the use of lean thinking during the construction of infrastructure projects grounded in Quality-II; and (2) practical suggestions, based on actual experiences, which can be readily employed to monitor and anticipate rework at the coalface of construction

Ring-Like Structure in the Radio Lobe of MG0248+0641

We present radio and optical observations of MG0248+0641, which contains a kiloparsec-scale ring-like structure in one of its radio lobes. The radio observations show a typical core-double morphology: a central core between two lobes, each of which has a hotspot. The western radio lobe appears as a nearly continuous ring, with linear polarization electric field vectors which are oriented in a radial direction from the ring center. We consider several different interpretations for the nature of this ring, including gravitational lensing of a normal jet by a foreground galaxy. Even though simple lensing models can describe the ring morphology reasonably well, the high linear polarization seen around the ring cannot be easily explained. The chance interposition of a galactic supernova remnant, nova, planetary nebula, or H II region, has been ruled out. The highly polarized ring of MG0248+0641 is much like the prominent ring seen in 3C219, and the multiple ones in 3C310 and Hercules A, suggesting that similar physical processes are producing shell structures in these radio galaxies. The ring in MG0248+0641 may be caused by the formation of ``bubbles'', as a result of instabilities in the energy flow down the western radio jet. It may also be possible that the required instabilities are triggered by the infall of gas, via tidal interaction of the central source with a nearby galaxy. This scenario may be indicated by our marginal detection of an optical source close to the western hotspot.Comment: 21 pages. Submitted to AJ Aug 15, 1997; Accepted Sep 30, 1997. Minor changes in conten

Controlled in vitro delivery of voriconazole and diclofenac to the cornea using contact lenses for the treatment of Acanthamoeba keratitis

Acanthamoeba keratitis is caused by a protozoal infection of the cornea, with 80% of cases involving the improper use of contact lenses. The infection causes intense pain and is potentially blinding. However, early diagnosis improves treatment efficacy and the chances of healing. Despite the apparent accessibility of the cornea, patients do not always respond well to current eye drop treatments largely due to rapid dose loss due to blinking and nasolacrimal drainage. Here, the topical drug delivery of voriconazole alone and in combination with diclofenac via drug-loaded contact lenses, were investigated in vitro. The contact lenses were applied onto excised porcine eyeballs and maintained at 32°C under constant irrigation, with simulated tear fluid applied to mimic in vivo conditions. The drug delivered to the corneas was quantified by HPLC analysis. The system was further tested in terms of cytotoxicity and a scratch wound repopulation model, using corneal epithelial cells. Sustained drug delivery to the cornea was achieved and for voriconazole, the MIC against Acanthamoeba castellanii was attained alone and in combination with diclofenac. MTT and scratch wound data showed reasonable cell proliferation and wound repopulation at the drug doses used, supporting further development of the system to treat Acanthamoeba keratitis

Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response

Background: Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. Methodology/Principal Findings: This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Conclusions: Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value

Evaluation in Nonhuman Primates of Vaccines against Ebola Virus

Ebola virus (EBOV) causes acute hemorrhagic fever that is fatal in up to 90% of cases in both humans and nonhuman primates. No vaccines or treatments are available for human use. We evaluated the effects in nonhuman primates of vaccine strategies that had protected mice or guinea pigs from lethal EBOV infection. The following immunogens were used: RNA replicon particles derived from an attenuated strain of Venezuelan equine encephalitis virus (VEEV) expressing EBOV glycoprotein and nucleoprotein; recombinant Vaccinia virus expressing EBOV glycoprotein; liposomes containing lipid A and inactivated EBOV; and a concentrated, inactivated whole-virion preparation. None of these strategies successfully protected nonhuman primates from robust challenge with EBOV. The disease observed in primates differed from that in rodents, suggesting that rodent models of EBOV may not predict the efficacy of candidate vaccines in primates and that protection of primates may require different mechanisms

Common core assessments in follow-up studies of adults born preterm-Recommendation of the Adults Born Preterm International Collaboration

Of all newborns, 1%-2% are born very preterm (VP; <32 weeks) or with very low birthweight (VLBW; ≤1500 g). Advances in prenatal and neonatal care have substantially improved their survival, and the first generations who have benefited from these advances are now entering middle age. While most lead healthy lives, on average these adults are characterised by a number of adversities. These include cardiometabolic risk factors, airway obstruction, less physical activity, poorer visual function, lower cognitive performance, and a behavioural phenotype that includes inattention and internalising and socially withdrawn behaviour that may affect life chances and quality of life. Outcomes in later adulthood are largely unknown, and identifying trajectories of risk or resilience is essential in developing targeted interventions. Joint analyses of data and maintenance of follow-up of cohorts entering adulthood are essential. Such analyses are ongoing within the Adults Born Preterm International Collaboration (APIC; www.apic-preterm.org). Joint analyses require data harmonisation, highlighting the importance of consistent assessment methodologies. To present an expert recommendation on Common Core Assessments to be used in follow-up assessments of adults born preterm. Principles of Common Core Assessments were discussed at APIC meetings. Experts for each specific outcome domain wrote the first draft on assessments pertaining to that outcome. These drafts were combined and reviewed by all authors. Consensus was reached by discussion at APIC meetings. We present a recommendation by APIC experts on consistent measures to be used in adult follow-up assessments. The recommendation encompasses both "core" measures which we recommend to use in all assessments of adults born preterm that include the particular outcome. This will allow comparability between time and location. The recommendation also lists optional measures, focusing on current gaps in knowledge. It includes sections on study design, cardiometabolic and related biomarkers, biological samples, life style, respiratory, ophthalmic, cognitive, mental health, personality, quality of life, sociodemographics, social relationships, and reproduction. [Abstract copyright: © 2020 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.