New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration

: Retinitis pigmentosa (RP) is a form of retinal degeneration affecting a young population with an unmet medical need. Photoreceptor degeneration has been associated with increased guanosine 3',5'-cyclic monophosphate (cGMP), which reaches toxic levels for photoreceptors. Therefore, inhibitory cGMP analogues attract interest for RP treatments. Here we present the synthesis of dithio-CN03, a phosphorodithioate analogue of cGMP, prepared using the H-phosphonothioate route. Two crystal modifications were identified as a trihydrate and a tetrahydrofuran monosolvates. Dithio-CN03 featured a lower aqueous solubility than its RP-phosphorothioate counterpart CN03, a drug candidate, and this characteristic might be favorable for sustained-release formulations aimed at retinal delivery. Dithio-CN03 was tested in vitro for its neuroprotective effects in photoreceptor models of RP. The comparison of dithio-CN03 to CN03 and its diastereomer SP-CN03, and to their phosphate derivative oxo-CN03 identifies dithio-CN03 as the compound with the highest efficacy in neuroprotection and thus as a promising new candidate for the treatment of RP

FORMULATION OF THE HEAT CONDUCTION EQUATION FOR HETEROGENEOUS MEDIA WITH MULTIPLE SPATIAL SCALES USING REITERATED HOMOGENIZATION

Heterogeneous media with multiple spatial scales are finding increased importance in engineering. An example might be a large scale, otherwise homogeneous medium filled with dispersed small-scale particles that form aggregate structures at an intermediate scale. The objective in this paper is to formulate the strong-form Fourier heat conduction equation for such media using the method of reiterated homogenization. The phases are assumed to have a perfect thermal contact at the interface. The ratio of two successive length scales of the medium is a constant small parameter ε. The method is an up-scaling procedure that writes the temperature field as an asymptotic multiple-scale expansion in powers of the small parameter ε . The technique leads to two pairs of local and homogenized equations, linked by effective coefficients. In this manner the medium behavior at the smallest scales is seen to affect the macroscale behavior, which is the main interest in engineering. To facilitate the physical understanding of the formulation, an analytical solution is obtained for the heat conduction equation in a functionally graded material (FGM). The approach presented here may serve as a basis for future efforts to numerically compute effective properties of heterogeneous media with multiple spatial scales

Colchicine in acute heart failure: Rationale and design of a randomized double‐blind placebo‐controlled trial (COLICA)

Aims: Heart failure (HF) elicits a pro-inflammatory state, which is associated with impaired clinical outcomes, but no anti-inflammatory therapies have demonstrated a clinical benefit yet. Inflammatory pathways related with the interleukin-1 axis are overactivated during episodes of acute HF. Colchicine, an anti-inflammatory drug with proven benefits in acute pericarditis and ischaemic heart disease, may target this inflammatory response. This study aims to assess the efficacy of colchicine in acute HF patients. Methods: COLICA is a multicentre, randomized, double-blind, placebo-controlled trial enrolling 278 patients across 12 sites. Patients presenting with acute HF, clinical evidence of congestion requiring ≥40 mg of intravenous furosemide and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >900 pg/ml, are eligible for participation. Patients are enrolled irrespective of left ventricular ejection fraction, HF type (new-onset or not) and setting (hospital or outpatient clinic). Patients are randomized 1:1 within the first 24 h of presentation to either placebo or colchicine, with an initial loading dose of 2 mg followed by 0.5 mg every 12 h for 8 weeks (reduced dose if <70 kg, >75 years old, or glomerular filtration rate <50 ml/min/1.73 m2). The primary efficacy endpoint is the time-averaged proportional change in NT-proBNP concentrations from baseline to week 8. Key secondary and exploratory outcomes include symptoms, diuretic use, worsening HF episodes, related biomarkers of cardiac stress and inflammation, total and cardiovascular readmissions, mortality and safety events. Conclusion: COLICA will be the first randomized trial testing the efficacy and safety of colchicine for acute HF

The effect of changing the pre-slaughter handling on bovine cattle DFD meat

ABSTRACT Objective. To evaluate the effect that a series of changes in the handling techniques used throughout the pre and post slaughter periods and during the handling of cooled carcass have on the presence of DFD (Dark, firm and dry) meat. Materials and methods. Odds ratios (OR) and confidence intervals were estimated applying logistic regression models. Data from 18 visits to the slaughterhouse regarding: animal handling on arrival, slaughter period, and carcass storage was obtained through the use of a questionnaire. A total of 572 carcasses were analyzed to determine DFD meat using pH and color (L*, a*, b* and C*) measurements done on the Longissimus dorsi muscle. Results. Even after of the changes were made, the lairage period to slaughter continued to be a factor (p<0.05) associated to the presence of DFD meat (OR=1.13). Of the complementary variables, the amount of time that cattle spent on the resting pens was associated (p<0.05) to the presence of DFD meat (OR=1.003). Conclusions. Regardless of the changes made in the ante mortem handling, a high frequency of DFD was found (39%), suggesting a permanent audit program to detect other critical points in the supply chain. RESUMEN Objetivo. Para evaluar el efecto de una serie de modificaciones en las técnicas de manejo usadas en el periodo pre y post-sacrificio y manejo de las canales en refrigeración en relación con la presencia de carne DFD (dura, firme y seca). Materiales y métodos. Se obtuvieron razones de desigualdad e intervalos de confianza empleando modelos de regresión logística. En 18 visitas a la planta de sacrificio, se aplicó un cuestionario obteniendo información sobre manejo de los animales desde su llegada a la planta, etapa de sacrificio y almacenamiento de las canales. Se estimó la frecuencia de carne DFD de analizar un total de 572 canales, registrando en el Longissimus dorsi pH y color (L*, a* b*, C*). Results. De las modificaciones realizadas, el tiempo de permanencia al sacrificio sigue siendo fue un factor asociado (p<0.05) a la presencia de carne DFD (OR=1.13). De las variables complementarias, el tiempo de espera en los corrales de descanso resultó correlacionado (p<0.05) a la presencia de carne DFD (OR=1.003). Conclusiones. Independientemente de los cambios realizados en el manejo ante mortem, se encontró una alta frecuencia de carne DFD (39%), sugiriendo un programa de auditoría permanente para detectar otros puntos críticos de la cadena logística

Planck intermediate results. VIII. Filaments between interacting clusters

About half of the baryons of the Universe are expected to be in the form of filaments of hot and low density intergalactic medium. Most of these baryons remain undetected even by the most advanced X-ray observatories which are limited in sensitivity to the diffuse low density medium. The Planck satellite has provided hundreds of detections of the hot gas in clusters of galaxies via the thermal Sunyaev-Zel'dovich (tSZ) effect and is an ideal instrument for studying extended low density media through the tSZ effect. In this paper we use the Planck data to search for signatures of a fraction of these missing baryons between pairs of galaxy clusters. Cluster pairs are good candidates for searching for the hotter and denser phase of the intergalactic medium (which is more easily observed through the SZ effect). Using an X-ray catalogue of clusters and the Planck data, we select physical pairs of clusters as candidates. Using the Planck data we construct a local map of the tSZ effect centered on each pair of galaxy clusters. ROSAT data is used to construct X-ray maps of these pairs. After having modelled and subtracted the tSZ effect and X-ray emission for each cluster in the pair we study the residuals on both the SZ and X-ray maps. For the merging cluster pair A399-A401 we observe a significant tSZ effect signal in the intercluster region beyond the virial radii of the clusters. A joint X-ray SZ analysis allows us to constrain the temperature and density of this intercluster medium. We obtain a temperature of kT = 7.1 +- 0.9, keV (consistent with previous estimates) and a baryon density of (3.7 +- 0.2)x10^-4, cm^-3. The Planck satellite mission has provided the first SZ detection of the hot and diffuse intercluster gas.Comment: Accepted by A&