Steroid induced neuroprotection of damaged photoreceptor cells

Retinitis Pigmentosa (RP) is the name given to a group of hereditary diseases causing progressive and degenerative blindness. RP affects over 1 in 4000 individuals, making it the most prevalent inherited retinal disease worldwide, yet currently there is no cure. In 2011, our group released a paper detailing the protective effects of the synthetic progestin ‘Norgestrel’. A common component of the female oral contraceptive pill, Norgestrel was shown to protect against retinal cell death in two distinct mouse models of retinal degeneration: in the Balb/c light damage model and the Pde6brd10 (rd10) model. Little was known of the molecular workings of this compound however and thus this study aimed to elucidate the protective manner in which Norgestrel worked. To this aim, the 661W cone photoreceptor-like cell line and ex vivo retinal explanting was utilised. We found that Norgestrel induces a increase in neuroprotective basic fibroblast growth factor (bFGF) with subsequent downstream actions on the inhibition of glycogen synthase kinase 3β. Progesterone receptor expression was subsequently characterised in the C57 and rd10 retinas and in the 661W cell line. Norgestrel caused nuclear trafficking of progesterone receptor membrane complex one (PGRMC1) in 661W cells and thus Norgestrel was hypothesised to work primarily through the actions of PGRMC1. This trafficking was shown to be responsible for the critical upregulation of bFGF and PGRMC1- Norgestrel binding was proven to cause a neuroprotective bFGF-mediated increase in intracellular calcium. The protective properties of Norgestrel were further studied in the rd10 mouse model of retinitis pigmentosa. Using non-invasive diet supplementation (80mg/kg), we showed that Norgestrel gave significant retinal protection out to postnatal day 40 (P40). Overactive microglia have previously been shown to potentiate photoreceptor cell loss in the degenerating rd10 retina and thus we focussed on Norgestrel-mediated changes in photoreceptor-microglial crosstalk. Norgestrel acted to dampen pro-inflammatory microglial cell reactivity, decreasing chemokine (MCP1, MCP3, MIP-1α, MIP-1β) and subsequent damaging cytokine (TNFα, Il-1β) production. Critically, Norgestrel up-regulated photoreceptor-microglial, fractalkine-CX3CR1 signalling 1000-fold in the P20 rd10 mouse. Known to prevent microglial activation, we hypothesise that Norgestrel acts as a vital anti-inflammatory in the diseased retina, driving fractalkine-CX3CR1 signalling to delay retinal degeneration. This study stands to highlight some of the neuroprotective mechanisms utilised by Norgestrel in the prevention of photoreceptor cell death. We identify for the first time, not only a pro-survival pathway activated directly in photoreceptor cells, but also a Norgestreldriven mediation of an otherwise damaging microglial cell response. All taken, these results form the beginning of a case to bring Norgestrel to clinical trials, as a potential therapeutic for the treatment of RP.

UTFORMNING AV GÅNG-, CYKEL- OCH MOPED-NÄT ANPASSAT FÖR ELCYKEL

Purpose: An increase in the number of pedelecs on Swedish roads is according to studies soon reality. This creates a need to adapt the bmp-grid (bike-, moped- and pedestrian-grid) to pedelecs for them to experience good security, accessibility and comfort while using it. The guidelines Swedish municipalities follow are VGU(Design of Roads and Streets) and the GCM-manual(Bike-, moped-, and pedestrian-manual) which currently do not take society’s future increase of pedelecs into account. VGU and the GCM-manual are tools that are commonly used during planning and design of roads and streets. The aim of the thesis is to use current advice and recommendations on how to adapt the bmp-grid to the pedelec and with this complete current guidelines for bmp-infrastructure. Method: The document-analysis is made on current federal documents that have an impact on bmp-design. Scetch-suggestions were then developed from the author’s personal improvement suggestions and from advice and recommendations gathered during the document-analysis and the theoretical framework. Findings: It was discovered that if the bmp-grid’s design allow bikes traveling up to 30km/h and has a good standard for bicycles according to VGU, then the infrastructure generally fulfil the needs of the pedelec. Altough there are still areas in VGU that needs complements. This need to be done on the design-guidelines so they can aid the adaption of the infrastructure to the pedelec during the planning- and design process. Necessary steps according to the result is to give clearer notifications on bmp-design, issue guidelines for choosing DTS, motivate minimal widths on roads, categories bikers and pedestrians into separate groups, give out more detailed descriptions of when separation of bikers and pedestrians should be done and also to specify different types of bike-users. When taking needs and claim of the pedelec into consideration the result shows that: adaption of the whole bmp-grid to the pedelec is not possible, to simplify priorities the bmp-grid needs to be divided into different sections, space should be taken from the car-traffic, solutions with mixed-traffic and bike-fields for pedelecs can be used in low-speed areas, larger opportunities to connect towns to increase commuting with bicycles appeared with the pedelec. Implications: After examining current guidelines regarding the design of the bmp-grid and gathering opinions on this from interviews the conclusion is that several areas in VGU needs completion. The following are recommendations on how to take the pedelec into consideration during the design-process:• Connect towns and urban-areas with bmp-grids to make use of pedelecs capacity.• Where there is not enough space for both cars and separated pedelec- and bike lanes the speed for car-traffic can be lowered to 30km/h. This creates opportunities with mixed-traffic or bike-lanes.• The width of existing roads and streets are often greater than what’s described in VGU. They can be made smaller to free space on roads for bicycle-infrastructure.• To prioritize which parts of the bmp-grid that needs design to allow pedelecs the bmp-grid can be divided into main- and local grid. The main grid should be design with consideration to the needs and claim of the pedelecs. Limitations: The limitation of the study lies in that none of the interviews where done with employees in any of the bigger municipalities in Sweden. This gives the study a general application in small- to middle-sized cities but not in bigger cities.Keywords: elcykel, ebike, pedelec, utformning, cykel, infrastruktur, infrastructure, society, planering, utformning, säkerhet, fordonstyp

Role of microfinance to support agricultural climate change adaptations in Indonesia: Encouraging private sector participation in climate finance

The demands of mitigation and adaptation policies are important to understanding a country’s climate change preparation by providing microfinance in the agricultural sector. This could be seen as a strategy to fight against the challenges of future food security. In 2014, Indonesia established climate change adaptation policies. This legislation aims to pave the way for making actions on climate change adaptation mainstream in national and local development planning. Public and private finance have supported the implementation of the climate actions. However, most funding is still used for mitigation. Adaptation finance needs support, especially in agriculture. This research paper studies opportunities for microfinance to play a role together with existing resources in supporting climate change adaptation in Indonesia. The data was acquired and analysed through a literature review, analysis of case studies and interviews with stakeholders in the climate change-related financial sector. The central findings regarding the opportunity for microfinance to contribute to the existing schemes in Indonesian climate change adaptation finance for agriculture are worthy of the result. This study found that adaptation finance is mostly used for indirect activities. Meanwhile, local communities, and farmers in particular, need directly targeted measures to adapt to climate change. An alternative approach is providing microfinance, insurance and capacity development for farmers to produce high quality agricultural products. This would contribute to optimizing the agri-food value chain, which supports socio-economic development of stakeholders, especially farmers. Hence, microfinance appears to be one potential solution to support direct climate change adaptation actions for the agricultural sector. However, this may not be strong enough to finance the entire needs for agricultural climate actions. Adaptation is contextual, so it has to be grounded in the needs of local communities. Microfinance needs public sectors support as well as other resources from the private sector. In the case of rapid response to disasters, which often destroy the agricultural sector, microfinance should be advantageous in supporting adaptation. However, in reality, it does not work, as it is prevented by regulations. So, this can be an area the public sector can support as a risk-taker as well as by providing initial funds and resources for scaling up efforts.

Evidencia sobre la eficacia de cannabinoides en el dolor neuropático oncológico

Contexto: La eficacia de los cannabinoides en el dolor neuropático es desconocida. El control del dolor es determinante en los pacientes ya que genera un impacto negativo en la calidad de vida de los pacientes. Objetivo: El presente trabajo pretende demostrar la evidencia sobre la eficacia de los medicamentos cannabinoides en el control del dolor neuropático oncológico, mediante la evaluación de la literatura disponible. Metodología: Se realizó una revisión sistemática de literatura incluyendo estudios experimentales, observacionales y revisiones sistemáticas en un periodo de 15 años. Se incluyeron todos los estudios desde el años 2000 con evidencia IB según la escala de evidencia de Oxford. Resultados: Cuatro estudios cumplieron criterios para su inclusión, sin embargo la evidencia es baja y no permite recomendar o descartar los cannabinoides como terapia coadyuvante en control del dolor neuropático oncológico. La combinación de THC/CDB (Sativex®) parece ser un medicamento seguro pues no se reportaron muertes asociadas a su uso, sin embargo la presentación de eventos adversos a nivel gastrointestinal y neurológico podría aumentar el riesgo de interacciones medicamentosas y tener un impacto negativo en la calidad de vida de los pacientes oncológicos. Conclusiones: No hay suficiente literatura y la evidencia no es suficiente para recomendar o descartar el uso de los cannabinoides en dolor neuropático oncológico. Futuros estudios deben realizarse para analizar el beneficio de estos medicamentos. Aunque ética y socialmente hay resistencia para el uso de los cannabinoides, actualmente hay una gran discusión política en el mundo y en Colombia para su aceptación como terapia en el control del dolor.

Computational Models Development and Demand Response Application for Smart Grids

This paper focuses on computational models development and its applications on demand response, within smart grid scope. A prosumer model is presented and the corresponding economic dispatch problem solution is analyzed. The prosumer solar radiation production and energy consumption are forecasted by artificial neural networks. The existing demand response models are studied and a computational tool based on fuzzy clustering algorithm is developed and the results discussed. Consumer energy management applications within the InovGrid pilot project are presented. Computation systems are developed for the acquisition, monitoring, control and supervision of consumption data provided by smart meters, allowing the incorporation of consumer actions on their electrical energy management. An energy management system with integration of smart meters for energy consumers in a smart grid is developed.

The Hitchin map for one-nodal base curves of compact type

Studying moduli spaces of semistable Higgs bundles (E, \phi) of rank n on a smooth curve C, a key role is played by the spectral curve X (Hitchin), because an important result by Beauville-Narasimhan-Ramanan allows us to study isomorphism classes of such Higgs bundles in terms of isomorphism classes of rank-1 torsion-free sheaves on X. This way, the generic fibre of the Hitchin map, which associates to any semistable Higgs bundle the coefficients of the characteristic polynomial of \phi, is isomorphic to the Jacobian of X. Focusing on rank-2 Higgs data, this construction was extended by Barik to the case in which the curve C is reducible, one-nodal, having two smooth components. Such curve is called of compact type because its Picard group is compact. In this work, we describe and clarify the main points of the construction by Barik and we give examples, especially concerning generic fibres of the Hitchin map. Referring to Hausel-Pauly, we consider the case of SL(2,C)-Higgs bundles on a smooth base curve, which are such that the generic fibre of the Hitchin map is a subvariety of the Jacobian of X, the Prym variety. We recall the description of special loci, called endoscopic loci, such that the associated Prym variety is not connected. Then, letting G be an affine reductive group having underlying Lie algebra so(4,C), we consider G-Higgs bundles on a smooth base curve. Starting from the construction by Bradlow-Schaposnik, we discuss the associated endoscopic loci. By adapting these studies to a one-nodal base curve of compact type, we describe the fibre of the SL(2,C)-Hitchin map and of the G-Hitchin map, together with endoscopic loci. In the Appendix, we give an interpretation of generic spectral curves in terms of families of double covers.

Low temperature structural transitions in dipolar hard spheres: the influence on magnetic properties

We investigate the structural chain-to-ring transition at low temperature in a gas of dipolar hard spheres (DRS). Due to the weakening of entropic contribution, ring formation becomes noticeable when the effective dipole-dipole magnetic interaction increases, It results in the redistribution of particles from usually observed flexible chains into flexible rings. The concentration (rho) of DI-IS plays a crucial part in this transition: at a very low rho only chains and rings are observed, whereas even a slight increase of the volume fraction leads to the formation of branched or defect structures. As a result, the fraction of DHS aggregated in defect-free rings turns out to be a non-monotonic function of rho. The average ring size is found to be a slower increasing function of rho when compared Lo that of chains. Both theory and computer simulations confirm the dramatic influence of the ring formation on the rho-dependence of the initial magnetic susceptibility (chi) when the temperature decreases. The rings clue to their zero total dipole moment are irresponsive to a weak magnetic field and drive to the strong decrease of the initial magnetic susceptibility. (C) 2014 Elsevier B.V. All rights reserved.

Lithography-free micro- and nanostructuring based on conventional plasma etching

In now-a-days semiconductor and MEMS technologies the photolithography is the working horse for fabrication of functional devices. The conventional way (so called Top-Down approach) of microstructuring starts with photolithography, followed by patterning the structures using etching, especially dry etching. The requirements for smaller and hence faster devices lead to decrease of the feature size to the range of several nanometers. However, the production of devices in this scale range needs photolithography equipment, which must overcome the diffraction limit. Therefore, new photolithography techniques have been recently developed, but they are rather expensive and restricted to plane surfaces. Recently a new route has been presented - so-called Bottom-Up approach - where from a single atom or a molecule it is possible to obtain functional devices. This creates new field - Nanotechnology - where one speaks about structures with dimensions 1 - 100 nm, and which has the possibility to replace the conventional photolithography concerning its integral part - the self-assembly. However, this technique requires additional and special equipment and therefore is not yet widely applicable. This work presents a general scheme for the fabrication of silicon and silicon dioxide structures with lateral dimensions of less than 100 nm that avoids high-resolution photolithography processes. For the self-aligned formation of extremely small openings in silicon dioxide layers at in depth sharpened surface structures, the angle dependent etching rate distribution of silicon dioxide against plasma etching with a fluorocarbon gas (CHF3) was exploited. Subsequent anisotropic plasma etching of the silicon substrate material through the perforated silicon dioxide masking layer results in high aspect ratio trenches of approximately the same lateral dimensions. The latter can be reduced and precisely adjusted between 0 and 200 nm by thermal oxidation of the silicon structures owing to the volume expansion of silicon during the oxidation. On the basis of this a technology for the fabrication of SNOM calibration standards is presented. Additionally so-formed trenches were used as a template for CVD deposition of diamond resulting in high aspect ratio diamond knife. A lithography-free method for production of periodic and nonperiodic surface structures using the angular dependence of the etching rate is also presented. It combines the self-assembly of masking particles with the conventional plasma etching techniques known from microelectromechanical system technology. The method is generally applicable to bulk as well as layered materials. In this work, layers of glass spheres of different diameters were assembled on the sample surface forming a mask against plasma etching. Silicon surface structures with periodicity of 500 nm and feature dimensions of 20 nm were produced in this way. Thermal oxidation of the so structured silicon substrate offers the capability to vary the fill factor of the periodic structure owing to the volume expansion during oxidation but also to define silicon dioxide surface structures by selective plasma etching. Similar structures can be simply obtained by structuring silicon dioxide layers on silicon. The method offers a simple route for bridging the Nano- and Microtechnology and moreover, an uncomplicated way for photonic crystal fabrication.

On the undamped free vibration of a mass interacting with a Hertzian contact stiffness

Three methods are used to determine the natural frequency of undamped free vibration of a mass interacting with a Hertzian contact stiffness. The exact value is determined using the first integral of motion. The harmonic balance method is used on a transformed equation for an approximate solution, and the multiple scales method is used on an approximate equation. The maximum initial displacement avoiding contact loss is also determined, and the corresponding exact natural frequency is also obtained analytically. The methods are evaluated by studying the free vibration of an elastic sphere on a flat rigid surface. © 2011 Elsevier Ltd © 2011 Elsevier Ltd. All rights reserved.

On the long standing issue of an R phi(2) coupling between gravity and a massless free scalar field

Using 2-body trees on a flat space background, it is shown that the actions A[g, φ] = (Latin small letter esh) d4x√-g [(R/2K) + (1/2)(gμν ∂μφ∂νφ + λRφ2)] and Ā[ḡ, φ̄] = (Latin small letter esh) d4x√ - ḡ [(R̄/2k) + (1/2) ḡμν∂μφ̄∂ νφ] describe the same theory at the tree-level in this case. We also demonstrate the quantum equivalence (at one-loop) of the barred and unbarred systems for λ == -1/6 (conformal coupling).

The negative feedback actions of progesterone on gonadotropinreleasing hormone secretion are transduced by the classical progesterone receptor

Progesterone (P) powerfully inhibits gonadotropin-releasing hormone (GnRH) secretion in ewes, as in other species, but the neural mechanisms underlying this effect remain poorly understood. Using an estrogen (E)-free ovine model, we investigated the immediate GnRH and luteinizing hormone (LH) response to acute manipulations of circulating P concentrations and whether this response was mediated by the nuclear P receptor. Simultaneous hypophyseal portal and jugular blood samples were collected over 36 hr: 0–12 hr, in the presence of exogenous P (P treatment begun 8 days earlier); 12–24 hr, P implant removed; 24–36 hr, P implant reinserted. P removal caused a significant rapid increase in the GnRH pulse frequency, which was detectable within two pulses (175 min). P insertion suppressed the GnRH pulse frequency even faster: the effect detectable within one pulse (49 min). LH pulsatility was modulated identically. The next two experiments demonstrated that these effects of P are mediated by the nuclear P receptor since intracerebroventricularly infused P suppressed LH release but 3α-hydroxy-5α-pregnan-20-one, which operates through the type A γ-aminobutyric acid receptor, was without effect and pretreatment with the P-receptor antagonist RU486 blocked the ability of P to inhibit LH. Our final study showed that P exerts its acute suppression of GnRH through an E-dependent system because the effects of P on LH secretion, lost after long-term E deprivation, are restored after 2 weeks of E treatment. Thus we demonstrate that P acutely inhibits GnRH through an E-dependent nuclear P-receptor system.

Impact Of Drug Formulation And Free Platinum/cisplatin Ratio On Hypersensitivity Reactions To Cisplatin: Formulation Matters.

Use of cisplatin can induce type I hypersensitivity reactions that may also be linked to the quality of the drug utilized. We observed cases of hypersensitivity that appeared to be associated with the brand of cisplatin used. The aim of this study was to compare two different brands of cisplatin in relation to type I hypersensitivity reactions. Brand A was used in a tertiary care teaching hospital until 2012, and use of brand B started from January 2013, when the first hypersensitivity cases were observed. Patients were categorized based on symptom. Cisplatin of both brands was analysed by high-performance liquid chromatography (HPLC) and high-resolution electrospray ionization mass spectrometry (ESI-(+)-MS) and characterized according to US Pharmacopeia. There were no cases of hypersensitivity associated with the use of cisplatin brand A, whereas four of 127 outpatients that used cisplatin brand B were affected. The two brands were in accordance with the US Pharmacopeia parameters, and there was no significant difference in the total platinum levels between the two brands when analysed by HPLC. However, high-resolution ESI-(+)-MS analyses show that brand B contains approximately 2.7 times more hydrolysed cisplatin than brand A. The increase in the hydrolysed form of cisplatin found in brand B may be the cause of the hypersensitivity reaction observed in a subset of patients. We present the first study of the quality of drugs by high-resolution ESI-(+)-MS. Drug regulatory agencies and manufacturers should consider including measurement of hydrolysed cisplatin as a quality criterion for cisplatin formulations.

The effects of nitric oxide on the immune response during giardiasis

Nitric oxide (NO) is a free radical synthesized from L-arginine by different isoforms NO-synthases. NO possesses multiple and complex biological functions. NO is an important mediator of homeostasis, and changes in its generation or actions can contribute or not to pathological states. The knowledge of effects of NO has been not only important to our understanding of immune response, but also to new tools for research and treatment of various diseases. Knowing the importance of NO as inflammatory mediator in diverse infectious diseases, we decided to develop a revision that shows the participation/effect of this mediator in immune response induced against Giardia spp. Several studies already demonstrated the participation of NO with microbicidal and microbiostatic activity in giardiasis. On the other hand, some works report that Giardia spp. inhibit NO production by consuming the intermediate metabolite arginine. In fact, studies in vitro showed that G. lamblia infection of human intestinal epithelial cells had reduced NO production. This occurs due to limited offer of the crucial substrate arginine (essential aminoacid for NO production), consequently reducing NO production. Therefore, the balance between giardial arginine consumption and epithelial NO production could contribute to the variability of the duration and severity of infections by this ubiquitous parasite.

The Effects of Commercially Available Preservative-Free FDA-Approved Triamcinolone (Triesence (R)) on Retinal Cells in Culture

Purpose: To evaluate the effects of Triesence (R) (TRI), a new preservative-free triamcinolone approved by the U. S. Food and Drug Administration (FDA) for intraocular use, on human retina pigment epithelial (ARPE-19) and rat neurosensory (R28) cells in culture. Methods: ARPE-19 and R28 cell cultures were treated 24 h with 1,000, 500, 200, or 100 mu g/mL of crystalline (cTRI) or 1,000, 500, or 200 mu g/mL of solubilized (sTRI). TRI was solubilized by centrifuging the drug, discarding the supernatant containing the vehicle and then resuspending the drug pellet in an equivalent amount of Dimethyl sulfoxide to achieve the same concentration as the commercial preparation. Percentage of cell viability (CV) was evaluated by a trypan blue dye-exclusion assay. The mitochondrial membrane potential (Delta Psi m) was analyzed with the JC-1 assay. The caspase-3/7 activity was measured by a fluorochrome assay. Results: In the ARPE-19 cultures, the cTRI caused a decrease in CV at 1,000 mg/mL (13.03 +/- 6.51; P < 0.001), 500 mu g/mL (28.87 +/- 9.3; P < 0.001), 200 mu g/mL (54.93 +/- 5.61; P < 0.001), and 100 mu g/mL (82.53 +/- 0.65; P < 0.005) compared with the untreated controls (96.98 +/- 0.16). In R28 cultures, the cTRI treatment also reduced CV values significantly (P < 0.001) for the 1,000 mu g/mL (22.73 +/- 2.44), 500 mu g/mL (34.63 +/- 1.91), 200 mu g/mL (58.70 +/- 1.39), and 100 mu g/m (75.33 +/- 2.47) compared with the untreated controls (86.08 +/- 3.54). Once the TRI was solubilized (sTRI), the CV and Delta Psi m remained similar to the untreated controls for both ARPE-19 and R28 cells. The sTRI treatment with 1,000, 500, and 200 mu g/mL increased in caspase-3/7 activity in ARPE-19 cells (P < 0.01) and in R28 cells (P < 0.05) compared with dimethyl sulfoxide equivalent controls. Conclusion: The crystalline form of TRI (cTRI) can cause a significant decrease in CV to cultured retinal cells. Once the TRI is solubilized (sTRI), at the same concentrations, the cells remain viable with no decrease in CV or Delta Psi m. The sTRI can, however, increase caspase-3/7 activity, thus suggesting some degree of apoptosis.