New tricks for old NODs

The mammalian NOD-like receptor NLRX1 appears to have a role as a regulator of antiviral response pathways

Incomplete Resolution of Deep Vein Thromboses during Rivaroxaban Therapy.

We present the case of a patient with a deep vein thrombosis (DVT) who failed rivaroxaban therapy. Our patient initially presented with left lower extremity edema, erythema, and pain. He was subsequently started on rivaroxaban therapy for a combined treatment period of 12 months, during and after which he persisted to have evidence of a DVT. The patient's prescribed drug regimen was changed from rivaroxaban to warfarin, which demonstrated a rapid resolution of the DVTs as determined by ultrasound assessment of our patient's lower extremity veins. Rivaroxaban, a factor Xa inhibitor, is a well-known oral anticoagulant that is used for a variety of indications and has become a mainstay in the treatment of deep vein thrombosis. With the introduction and emergence of this medication in the clinic, postmarketing reports of efficacy or lack thereof are important to review. In conclusion, we anticipate that it is likely that there are other patients with DVTs who may not respond to rivaroxaban and for whom alternative anticoagulation therapies should be explored

RESIK and RHESSI observations of the 20 September 2002 flare

Soft X-ray spectra 3.33 A - 6.15 A from the RESIK instrument on CORONAS-F constitute a unique database for the study of the physical conditions of solar flare plasmas, enabling the calculation of differential emission measures. The two RESIK channels for the shortest wavelengths overlap with the lower end of RHESSI spectral energy range, which is located around 3 keV, making it possible to compare both data sets. We aim to compare observations from RESIK and RHESSI spectrometers and cross-correlate these instruments. Observations are compared with synthetic spectra calculated based on the results of one-dimensional hydrodynamical (1D-HD) modelling. The analysis was performed for the flare on 20 September 2002. We estimated the geometry of the flaring loop, necessary for 1D-HD modelling, based on images from RHESSI and SOHO/EIT. The distribution of non-thermal electrons (NTEs) was determined from RHESSI spectra. The 1D-HD model assumes that non-thermal electrons with a power-law spectrum were injected at the apex of the flaring loop. The NTEs then heat and evaporate the chromosphere, filling the loop with hot and dense plasma radiating in soft X-rays. The total energy of electrons was constrained by comparing observed and calculated fluxes from GOES 1 - 8 A data. We determined the temperature and density at every point of the flaring loop throughout the evolution of the flare, calculating the resulting X-ray spectra. The synthetic spectra calculated based on the results of hydrodynamic modelling for the 20 September 2002 flare are consistent within a factor of two with the observed RESIK spectra during most of the duration of the flare. This discrepancy factor is probably related to the uncertainty on the cross-calibration between RESIK and RHESSI instruments

Structural abnormalities of the optic nerve and retina in Huntington’s disease pre-clinical and clinical settings

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related pathological remodelling has been reported in HD mouse models and HD carriers. In this study, we studied structural abnormalities in the optic nerve by employing Spectral Domain Optical Coherence Tomography (SD-OCT) in pre-symptomatic HD carriers of Caucasian origin. Transmission Electron Microscopy (TEM) was used to investigate ultrastructural changes in the optic nerve of the well-established R6/2 mouse model at the symptomatic stage of the disease. We found that pre-symptomatic HD carriers displayed a significant reduction in the retinal nerve fibre layer (RNFL) thickness, including specific quadrants: superior, inferior and temporal, but not nasal. There were no other significant irregularities in the GCC layer, at the macula level and in the optic disc morphology. The ultrastructural analysis of the optic nerve in R6/2 mice revealed a significant thinning of the myelin sheaths, with a lamellar separation of the myelin, and a presence of myelonoid bodies. We also found a significant reduction in the thickness of myelin sheaths in peripheral nerves within the choroids area. Those ultrastructural abnormalities were also observed in HD photoreceptor cells that contained severely damaged membrane disks, with evident vacuolisation and swelling. Moreover, the outer segment of retinal layers showed a progressive disintegration. Our study explored structural changes of the optic nerve in pre- and clinical settings and opens new avenues for the potential development of biomarkers that would be of great interest in HD gene therapies

Antioxidant status in the vitreous of eyes with rhegmatogenous retinal detachment with and without proliferative vitreoretinopathy, macular hole and epiretinal membrane

(1) Background: The aim of the study was to test the hypothesis that the antioxidant status in the vitreous body of eyes, which had been vitrectomized due to rhegmatogenous retinal detachment (RRD) with or without proliferative vitreoretinopathy (PVR), is higher than in eyes vitrectomized due to other retinal diseases. (2) Methods: four patient groups were analyzed: 22 eyes of patients with RRD without PVR, 27 eyes with RRD and PVR, 22 eyes with macular hole (MH) and 10 eyes with epiretinal membrane (ERM). Spectrophotometric methods were used to determine the total antioxidant status (TAS) values as well as superoxide dismutase (SOD) and glutathione reductase (GR) activities in the vitreous fluid samples. (3) Results: no significant differences in TAS values and antioxidant enzyme activities were observed among patient with RRD with and without PVR and with MH and ERM. The longer the duration of RRD leading to PVR and better postoperative visual acuity, the higher the TAS level. No significant differences were found between “macula on” and “macula off” subgroups within the RRD group and the RRD combined with PVR group. (4) Conclusions: The preliminary results do not support the thesis that the antioxidant status of vitrectomized eyes is different in patients with RRD with or without PVR in comparison to patients with MH and ERM. In patients with RRD, PVR presence and detached macula do not affect the values of TAS, SOD and GR in the vitreous fluid. The duration of the disease influences TAS in the vitreous in eyes with RRD complicated with PVR

Characterisation of solid particles emitted from diesel and petrol engines as a contribution to the determination of the origin of carbonaceous particles in urban aerosol

Solid particles emitted from diesel and petrol engines were studied using a scanning electron microscope fitted with an energy dispersive spectrometer. The soot emitted from different engines under different operating conditions differed in particle size, and the form and size of aggregates. Identification of the soot particles emitted from diesel or petrol engines in urban aerosol based on their size and morphology was found to be impossible

Urgent vitrectomy with vancomycin infusion, silicone oil endotamponade, and general antibiotic treatment in multiple cases of endophthalmitis from a single day of intravitreal injections—case series

The aim of this study was to report on the anatomical and functional results of surgical management of seven cases of endophthalmitis related to a single day of intravitreal aflibercept injections. Patients with signs of endophthalmitis who underwent aflibercept injections (seven eyes) performed on the same day were retrospectively evaluated. The data of visual acuity and optical coherence tomography (OCT) within nine months of the follow-up and the treatment and results of microbiological cultures are reported. Four of the total seven cases had a positive bacterial culture outcome (Streptococcus mitis). All patients underwent vitrectomy combined with phacoemulsification when the eyes were not pseudophakic, vancomycin infusion, and silicone oil tamponade within 24 h; additionally, systemic antibiotics were administered intravenously. The final best-corrected visual acuity (BCVA) after the treatment was finger counting or light perception in all cases, and all eyes were saved with disruption of the inner retinal layers and stabilization of the retina in regard to changes related to the wet age-related macular degeneration (AMD). Although the retinal anatomy was mostly preserved, most of the patients affected by Streptococcus mitis-induced endophthalmitis did not regain baseline vision after the therapy

A short splicing isoform of HBS1L links the cytoplasmic exosome and SKI complexes in humans.

The exosome complex is a major eukaryotic exoribonuclease that requires the SKI complex for its activity in the cytoplasm. In yeast, the Ski7 protein links both complexes, whereas a functional equivalent of the Ski7 has remained unknown in the human genome.Proteomic analysis revealed that a previously uncharacterized short splicing isoform of HBS1L (HBS1LV3) is the long-sought factor linking the exosome and SKI complexes in humans. In contrast, the canonical HBS1L variant, HBS1LV1, which acts as a ribosome dissociation factor, does not associate with the exosome and instead interacts with the mRNA surveillance factor PELOTA. Interestingly, both HBS1LV1 and HBS1LV3 interact with the SKI complex and HBS1LV1 seems to antagonize SKI/exosome supercomplex formation. HBS1LV3 contains a unique C-terminal region of unknown structure, with a conserved RxxxFxxxL motif responsible for exosome binding and may interact with the exosome core subunit RRP43 in a way that resembles the association between Rrp6 RNase and Rrp43 in yeast. HBS1LV3 or the SKI complex helicase (SKI2W) depletion similarly affected the transcriptome, deregulating multiple genes. Furthermore, half-lives of representative upregulated mRNAs were increased, supporting the involvement of HBS1LV3 and SKI2W in the same mRNA degradation pathway, essential for transcriptome homeostasis in the cytoplasm

Heterogeneous electrocatalysis in porous cathodes of solid oxide fuel cells

A general physics-based model is developed for heterogeneous electrocatalysis in porous electrodes and used to predict and interpret the impedance of solid oxide fuel cells. This model describes the coupled processes of oxygen gas dissociative adsorption and surface diffusion of the oxygen intermediate to the triple phase boundary, where charge transfer occurs. The model accurately captures the Gerischer-like frequency dependence and the oxygen partial pressure dependence of the impedance of symmetric cathode cells. Digital image analysis of the microstructure of the cathode functional layer in four different cells directly confirms the predicted connection between geometrical properties and the impedance response. As in classical catalysis, the electrocatalytic activity is controlled by an effective Thiele modulus, which is the ratio of the surface diffusion length (mean distance from an adsorption site to the triple phase boundary) to the surface boundary layer length (square root of surface diffusivity divided by the adsorption rate constant). The Thiele modulus must be larger than one in order to maintain high surface coverage of reaction intermediates, but care must be taken in order to guarantee a sufficient triple phase boundary density. The model also predicts the Sabatier volcano plot with the maximum catalytic activity corresponding to the proper equilibrium surface fraction of adsorbed oxygen adatoms. These results provide basic principles and simple analytical tools to optimize porous microstructures for efficient electrocatalysis

Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor

BACKGROUND: Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy. METHODS: Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60-100 mg twice daily (BID)) and docetaxel (75-100 mg m⁻²), or CP-868,596 (60 mg BID), docetaxel (75 mg m⁻²), and VEGFR inhibitor axitinib (5 mg BID). RESULTS: The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m⁻² docetaxel (maximum approved dose). Most treatment-emergent AEs were mild-moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3-16) cycles. CONCLUSIONS: The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs