MOF-Based Polymeric Nanocomposite Films as Potential Materials for Drug Delivery Devices in Ocular Therapeutics.

Novel MOF-based polymer nanocomposite films were successfully prepared using Zr-based UiO-67 as a metal-organic framework (MOF) and polyurethane (PU) as a polymeric matrix. Synchrotron X-ray powder diffraction (SXRPD) analysis confirms the improved stability of the UiO-67 embedded nanocrystals, and scanning electron microscopy images confirm their homogeneous distribution (average crystal size ∼100-200 nm) within the 50 µm thick film. Accessibility to the inner porous structure of the embedded MOFs was completely suppressed for N2 at cryogenic temperatures. However, ethylene adsorption measurements at 25 °C confirm that at least 45% of the MOF crystals are fully accessible for gas-phase adsorption of nonpolar molecules. Although this partial blockage limits the adsorption performance of the embedded MOFs for ocular drugs (e.g., brimonidine tartrate) compared to the pure MOF, an almost 60-fold improvement in the adsorption capacity was observed for the PU matrix after incorporation of the UiO-67 nanocrystals. The UiO-67@PU nanocomposite exhibits a prolonged release of brimonidine (up to 14 days were quantified). Finally, the combined use of SXRPD, thermogravimetric analysis (TGA), and Fourier transform infrared (FTIR) analyses confirmed the presence of the drug in the nanocomposite film, the stability of the MOF framework and the drug upon loading, and the presence of brimonidine in an amorphous phase once adsorbed. These results open the gate toward the application of these polymeric nanocomposite films for drug delivery in ocular therapeutics, either as a component of a contact lens, in the composition of lacrimal stoppers (e.g., punctal plugs), or in subtenon inserts.

Publisher Correction: Measuring the ionisation fraction in a jet from a massive protostar.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Measuring the ionisation fraction in a jet from a massive protostar.

It is important to determine if massive stars form via disc accretion, like their low-mass counterparts. Theory and observation indicate that protostellar jets are a natural consequence of accretion discs and are likely to be crucial for removing angular momentum during the collapse. However, massive protostars are typically rarer, more distant and more dust enshrouded, making observational studies of their jets more challenging. A fundamental question is whether the degree of ionisation in jets is similar across the mass spectrum. Here we determine an ionisation fraction of ~5-12% in the jet from the massive protostar G35.20-0.74N, based on spatially coincident infrared and radio emission. This is similar to the values found in jets from lower-mass young stars, implying a unified mechanism of shock ionisation applies in jets across most of the protostellar mass spectrum, up to at least ~10 solar masses.

GPR158 in the Visual System: Homeostatic Role in Regulation of Intraocular Pressure.

Purpose: GPR158 is a newly characterized family C G-protein-coupled receptor, previously identified in functional screens linked with biological stress, including one for susceptibility to ocular hypertension/glaucoma induced by glucocorticoid stress hormones. In this study, we investigated GPR158 function in the visual system. Methods: Gene expression and protein immunolocalization analyses were performed in mouse and human brain and eye to identify tissues where GPR158 might function. Gene expression was perturbed in mice, and in cultures of human trabecular meshwork cells of the aqueous outflow pathway, to investigate function and mechanism. Results:GPR158 is highly expressed in the brain, and in this study, we show prominent expression specifically in the visual center of the cerebral cortex. Expression was also observed in the eye, including photoreceptors, ganglion cells, and trabecular meshwork. Protein was also localized to the outer plexiform layer of the neural retina. Gpr158 deficiency in knockout (KO) mice conferred short-term protection against the intraocular pressure increase that occurred with aging, but this was reversed over time. Most strikingly, the pressure lowering effect of the acute stress hormone, epinephrine, was negated in KO mice. In contrast, no disruption of the electroretinogram was observed. Gene overexpression in cell cultures enhanced cAMP production in response to epinephrine, suggesting a mechanism for intraocular pressure regulation. Overexpression also increased survival of cells subjected to oxidative stress linked to ocular hypertension, associated with TP53 pathway activation. Conclusions: These findings implicate GPR158 as a homeostatic regulator of intraocular pressure and suggest GPR158 could be a pharmacological target for managing ocular hypertension.

[Analysis on factors related to spontaneous reduction in twin pregnancy following assisted reproductive technology].

Objective: To explorer factors related to spontaneous reduction in twin pregnancy following assisted reproductive technology. Methods: 2 848 twin pregnant women with treatment of vitro fertilization-embryo transfer (IVF-ET) or intra cytoplasmic sperm injection (ICSI) cycles were enrolled at Assisted Reproductive Centre of the First Affiliated Hospital of Nanjing Medical University, Nanjing Maternity Hospital and Shengjing Hospital of China Medical University from January 2013 to December 2016 respectively. Basic features of subjects, relevant clinical indicators, factors of assisted reproductive therapy and pregnancy outcome were collected from clinical assisted reproductive technology management system. According to the pregnancy outcome, the subjects with spontaneous reduction were classified as case group (n=686), and those with normal twin birth were classified as control group (n=2 162). The features of subjects in the two groups were compared. Non-conditional logistics regression model was used to analyze the related factors of the occurrence of spontaneous reduction. Results: The age of case group and control group were (30.6±4.3) and (30.2±4.0) years old respectively. After the adjustment of male sterile factor, compared to the subjects with luteinizing hormone level on the day of human chorionic gonadotropin administration (HCG) <1.43 IU/L, OR (95%CI) of the subjects with value at 2.59-5.10 IU/L was1.62 (1.08-2.42).Compared to the subjects with number of transferred embryo as 1, OR (95%CI) of the subjects with value as 3 was 0.23 (0.07-0.74). Compared to the subjects with stage of transferred embryo as cleavage stage, OR (95%CI) of the subjects with blastula stage was 0.42 (0.27-0.67). Conclusion: Luteinizing hormone level on day of HCG, number and stage of embryo transfer are related factors to spontaneous reduction in twin pregnancy following assisted reproductive technology.

Consensus conference on best practices in live kidney donation: recommendations to optimize education, access, and care.

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation.

Characterization of microRNA expression profiles in Leishmania-infected human phagocytes.

Leishmania are intracellular protozoa that influence host immune responses eliciting parasite species-specific pathologies. MicroRNAs (miRNAs) are short single-stranded ribonucleic acids that complement gene transcripts to block protein translation and have been shown to regulate immune system molecular mechanisms. Human monocyte-derived dendritic cells (DC) and macrophages (MP) were infected in vitro with Leishmania major or Leishmania donovani parasites. Small RNAs were isolated from total RNA and sequenced to identify mature miRNAs associated with leishmanial infections. Normalized sequence read count profiles revealed a global downregulation in miRNA expression among host cells following infection. Most identified miRNAs were expressed at higher levels in L. donovani-infected cells relative to L. major-infected cells. Pathway enrichments using in silico-predicted gene targets of differentially expressed miRNAs showed evidence of potentially universal MAP kinase signalling pathway effects. Whereas JAK-STAT and TGF-ß signalling pathways were more highly enriched using targets of miRNAs upregulated in L. donovani-infected cells, these data provide evidence in support of a selective influence on host cell miRNA expression and regulation in response to differential Leishmania infections.

Solid-organ transplantation in older adults: current status and future research.

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

Mechanosensitivity and the eye: cells coping with the pressure.

The cells of the various organ systems in humans are subject to mechanical forces to which they must respond. Here the authors review what is known of the ways in which the cells of animals, ranging from the prokaryotic to humans, sense and transduce mechanical forces to respond to such stimuli. In what way this pertains to the eye, especially with respect to axial myopia and the pressure related disease of glaucoma, is then surveyed.

Porous materials for thermal management under extreme conditions.

A brief analysis is presented of how heat transfer takes place in porous materials of various types. The emphasis is on materials able to withstand extremes of temperature, gas pressure, irradiation, etc. i.e. metals and ceramics, rather than polymers. A primary aim is commonly to maximize either the thermal resistance (i.e. provide insulation) or the rate of thermal equilibration between the material and a fluid passing through it (i.e. to facilitate heat exchange). The main structural characteristics concern porosity (void content), anisotropy, pore connectivity and scale. The effect of scale is complex, since the permeability decreases as the structure is refined, but the interfacial area for fluid-solid heat exchange is, thereby, raised. The durability of the pore structure may also be an issue, with a possible disadvantage of finer scale structures being poor microstructural stability under service conditions. Finally, good mechanical properties may be required, since the development of thermal gradients, high fluid fluxes, etc. can generate substantial levels of stress. There are, thus, some complex interplays between service conditions, pore architecture/scale, fluid permeation characteristics, convective heat flow, thermal conduction and radiative heat transfer. Such interplays are illustrated with reference to three examples: (i) a thermal barrier coating in a gas turbine engine; (ii) a Space Shuttle tile; and (iii) a Stirling engine heat exchanger. Highly porous, permeable materials are often made by bonding fibres together into a network structure and much of the analysis presented here is oriented towards such materials.

Variability across the optic nerve head in scanning laser tomography.

AIM: To characterise measurement variability in scanning laser tomography of the optic nerve head. METHODS: 21 normal and 21 glaucoma subjects underwent same and separate day test-retest Heidelberg retina tomograph imaging by the same and different operators. RESULTS: Rim area was most reproducible among parameters. Its variability tended to be highest temporally and increased (p<0.05) with testing involving different operators and visits. Nature of regional variability differed between glaucoma and normal eyes and between standard and 320 micro m reference planes. CONCLUSIONS: Rim area is reproducible and potentially useful as a marker of progression. Pattern of variability and the influence of different reference planes, disease, operators, and visits should be considered when evaluating progression.

Post-operative pain in needlescopic versus conventional laparoscopic cholecystectomy: a prospective randomised trial.

BACKGROUND: Needlescopic cholecystectomy (NC) utilises instruments and ports smaller than 3 mm in diameter compared with the 5 mm ones used in conventional laparoscopic cholecystectomy (LC). Post-operative pain control and recovery has been thought to be superior in NC, when compared with historical controls with LC, but has not been proven in a prospective fashion. PATIENTS AND METHODS: A prospective randomised trial of NC versus LC for patients with symptomatic gallstone disease, with standardisation of post-operative analgesia and daily assessment of post-operative pain, using a 5-point visual analogue scale. RESULTS: There were 64 eligible patients randomised into NC (28) and LC (36). Four patients who had NC were converted to LC due to technical problems. Another three and six patients from the NC and LC groups, respectively, had conversion to open surgery. Post-operative pain scores were low in both groups. Mean pain scores for those with successful NC and LC were: 1.24 versus 1.43 for the day of operation (P = 0.49), 0.86 versus 0.83 for the first day post-operatively (P = 0.92) and 0.75 versus 0.81 for the second post-operative day (P = 0.87). The mean number of intra-muscular analgesic injections required were 0.76 versus 0.83 after NC and LC, respectively (P = 0.93). There were no significant differences between the two groups in the time taken to return to feeding, eating a normal diet and discharge from hospital. CONCLUSION: There is no advantage of NC over LC in terms of post-operative pain or recovery. Nevertheless, NC can be performed safely and expediently and has an excellent cosmetic outcome and high patient acceptability.

The ability of the GDx nerve fibre analyser neural network to diagnose glaucoma.

PURPOSE: To evaluate the neural network used by the GDx in a group of normal subjects, patients with ocular hypertension (OHT) and patients with normal-pressure glaucoma (NPG). METHODS: The GDx neural network produces a "number" that indicates the likelihood that glaucoma is present. This number was compared in three groups representing different stages of health and disease, namely, normal controls (n = 101), OHT (n = 102) and NPG (105). The GDx number's ability to differentiate between normal and glaucoma individuals was then investigated. We also studied the relationship between the GDx number and retinal nerve fibre layer (RNFL) average thickness and visual field status to examine how well the GDx number reflects disease severity. RESULTS: The GDx number was significantly different among the groups (P < 0.01); it was highest in NPG and lowest in normal controls. The GDx number differentiated between glaucoma and normal with sensitivity of 92.3% and specificity of 96%. When combined with the parameter of RNFL average thickness, sensitivity and specificity were 88.5% and 100% respectively. In NPG a significant correlation was found between the GDx number and RNFL average thickness(rho = -0.88, P < 0.001) and visual field mean deviation (rho = -0.64, P < 0.001). CONCLUSION: The GDx number is able to differentiate between groups of normal, OHT and NPG subjects. Its close relationship with RNFL average thickness and visual field status in glaucoma indicates that it is able to reflect disease severity. Furthermore, its measured ability to distinguish between normal individuals and those with glaucoma demonstrates potential for use in glaucoma diagnosis.

Capsulotomy.

Research is continually seeking to better describe the relationship between pseudophakic capsular opacification and underlying cell biology, surgical technique, and intra-ocular lens biomaterial and design. Outcomes are reviewed from prospective, randomized studies that investigate the importance of capsulorhexis size, pharmacological treatment, and lens material in influencing capsular opacification and the need for capsulotomy. The results of several studies support the role of lens edge profile in inhibiting lens epithelial cell migration. A large post-mortem study also examines how lens type may affect anterior capsular opacification formation. Of particular interest is a histological report that sheds additional light on understanding cellular processes in posterior capsu-lar opacification.

Removal of a dinner fork from the stomach by double-snare endoscopic extraction.

Long and pointed foreign objects in the stomach are difficult to remove by endoscopy, and they can cause complications such as perforation and impaction. The endoscopic removal of long and pointed objects involves the following principles: (1) presenting the blunt end cephalad to prevent perforation or impaction during extraction; (2) orienting the long axis of the object in the line of extraction; and (3) applying traction to the foreign body without losing grip. Currently practised methods of extraction, which use a protector hood or an overtube, do not address these three principles. We report on a case in which an ingested metal dinner fork was removed from the stomach by using a double wire-loop snare technique. This method uses two snares to hold the object and allows the endoscopist to change the presentation, orient the axis, and maintain traction to allow the safe removal of long and pointed objects.