Antibodies against oxidized LDL and atherosclerosis in rheumatoid arthritis patients treated with biological agents: a prospective controlled study.

OBJECTIVES: The aim of this study was to investigate the relation among atherosclerosis, antibodies against oxidized LDL (anti-oxLDL), and inflammation in rheumatoid arthritis (RA) patients treated with biological (b) disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Fifty-nine patients who were receiving conventional synthetic DMARDs and were eligible for treatment with a biological agent were included in the study. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and IgG antibodies against oxidized LDL (anti-oxLDL) as well as carotid intima-media thickness (cIMT) were determined before and after 6 months of treatment. Thirty-one healthy individuals were used as a control group. RESULTS: At baseline, RA patients had lower TC and HDL-C levels and increased cIMT compared to controls. After a 6-month follow-up, the re-evaluation of carotids revealed a statistically important decrease of cIMT values. This observation was accompanied by a statistically important elevation of HDL-C levels and a reduction of the titer of anti-oxLDL antibodies regardless of the bDMARD that was administered. No statistically significant association was found between the cIMT and anti-oxLDL, HDL-C, CRP, or DAS28 score neither before nor 6 months after treatment using linear regression analyses adjusted for age and gender. CONCLUSIONS: We provide evidence that atherogenic lipid profile and ongoing atherosclerosis which characterize RA patients appear to improve after biological therapy, and we also suggest a possible atherogenic effect of IgG anti-ox LDL antibodies.

The effects of biologic agents on cardiovascular risk factors and atherosclerosis in rheumatoid arthritis patients: a prospective observational study.

We aimed to evaluate the impact of biologic treatment on subclinical atherosclerosis and risk factors for cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA). Forty-nine biologic naïve RA patients, treated with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), who were eligible for treatment with a biologic agent, were included in the study. The serum levels of lipid parameters, as well as disease activity parameters were determined in RA patients before and after 3 and 6 months of therapy. Carotid artery intima-media thickness (cIMT) was measured before and after treatment. A comparison analysis of change of these parameters was also performed between anti-tumor necrosis factor (anti-TNF) and non-anti-TNF users. Furthermore, 31 non-smoking healthy volunteers, matched for age and gender, were used as a control group. At baseline, RA patients had a decrease in serum total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels compared with controls (209 ± 63 vs 233 ± 44 and 58 ± 15 vs 61 ± 14, p < 0.004), while cIMT was higher versus controls [0.9 (0.8-1) vs 0.6 (0.5-0.7), p < 0.001]. TC, HDL-C and apolipoprotein A1 levels were significantly increased 3 months after treatment (209 ± 63, 58 ± 15, 162 ± 32, vs 227 ± 45, 60 ± 15, 169 ± 29, respectively, p < 0.03) and this observation remained stable at a 6-month follow-up. After 6 months, there was also a statistically significant decrease in the cIMT [0.9 (0.8-1) vs 0.7 (0.6-0.8), p < 0.001]. Anti-TNF and non-anti-TNF users had comparable changes in cardiovascular risk parameters. The atherogenic lipid profile and subclinical atherosclerosis are features of RA, which appeared improved after biologic therapy initiation.

Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice.

Macular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3-/- mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.

Atomic force microscopy for the characterisation of pinning effects of seawater micro-droplets in n-decane on a calcite surface.

HYPOTHESIS: Roughness is an important parameter in applications where wetting needs to be characterized. Micro-computed tomography is commonly used to characterize wetting in porous media but the main limitation of this approach is the incapacity to identify nanoscale roughness. Atomic force microscopy, AFM, however, has been used to characterize the topography of surfaces down to the molecular scale. Here we investigate the potential of using AFM to characterize wetting behavior at the nanoscale. EXPERIMENTS: Droplets of water on cleaved calcite under decane were imaged using quantitative imaging QI atomic force microscopy where a force-distance curve is obtained at every pixel. FINDINGS: When the AFM tip passed through the water droplet surface, an attraction was observed due to capillary effects, such that the thickness of the water film was estimated and hence the profile of the droplet obtained. This enables parameters such as the contact angle and contact angle distribution to be obtained at a nanometer scale. The contact angles around the 3-phase contact line are found to be quasi-symmetrically distributed between 10-30°. A correlation between the height profile of the surface and contact angle distribution demonstrates a quasi-proportional relationship between roughness on the calcite surface and contact angle.

Outcome of refractory to conventional and/or biologic treatment adult Still's disease following canakinumab treatment: Countrywide data in 50 patients.

OBJECTIVE: To assess the efficacy and safety of the IL-1b inhibitor canakinumab in all adults with refractory Still's disease identified from the National Organization For Medicines for off-label drug use. METHODS: In a retrospective longitudinal multicenter cohort of 50 patients (median age 39 years) with active Still's disease despite treatment with corticosteroids (n = 11), conventional and synthetic (n = 34) and/or biologic disease modifying anti-rheumatic drugs (n = 30), we assessed the efficacy of canakinumab 150-300 mg administered every 4 (n = 47) or 8 weeks (n = 3) as combination therapy or monotherapy (n = 7) during a median follow-up of 27 (3-84) months. RESULTS: Α complete response was initially observed in 78% of patients within 3 months (median), irrespective of age at disease onset. A partial response was evident in 20%. One patient had resistant disease. Treatment de-escalation was attempted in 15 of 39 complete responders and a complete drug discontinuation in 21 patients for 8 months (median). Eleven patients (22%) relapsed during treatment, one during de-escalation process, and 11 after treatment discontinuation. Overall, 9 of 11 relapses were successfully treated with canakinumab treatment intensification or re-introduction. At last visit, 18% of patients were off treatment due to remission and 26% due to disease activity. Canakinumab had a significant corticosteroid sparing effect allowing weaning in 21 of 41 cases. Infections (20%, severe 4%) and leucopenia (6%) led to treatment cessation in one patient. CONCLUSION: High rates of sustained remission were observed in this, largest so far, real-life cohort of adult patients with refractory Still's disease treated with canakinumab.

Relationship between wetting and capillary pressure in a crude oil/brine/rock system: From nano-scale to core-scale.

HYPOTHESIS: The wetting behaviour is a key property of a porous medium that controls hydraulic conductivity in multiphase flow. While many porous materials, such as hydrocarbon reservoir rocks, are initially wetted by the aqueous phase, surface active components within the non-wetting phase can alter the wetting state of the solid. Close to the saturation endpoints wetting phase fluid films of nanometre thickness impact the wetting alteration process. The properties of these films depend on the chemical characteristics of the system. Here we demonstrate that surface texture can be equally important and introduce a novel workflow to characterize the wetting state of a porous medium. EXPERIMENTS: We investigated the formation of fluid films along a rock surface imaged with atomic force microscopy using ζ-potential measurements and a computational model for drainage. The results were compared to spontaneous imbibition test to link sub-pore-scale and core-scale wetting characteristics of the rock. FINDINGS: The results show a dependency between surface coverage by oil, which controls the wetting alteration, and the macroscopic wetting response. The surface-area coverage is dependent on the capillary pressure applied during primary drainage. Close to the saturation endpoint, where the change in saturation was minor, the oil-solid contact changed more than 80%.

Model-free classification of X-ray scattering signals applied to image segmentation.

In most cases, the analysis of small-angle and wide-angle X-ray scattering (SAXS and WAXS, respectively) requires a theoretical model to describe the sample's scattering, complicating the interpretation of the scattering resulting from complex heterogeneous samples. This is the reason why, in general, the analysis of a large number of scattering patterns, such as are generated by time-resolved and scanning methods, remains challenging. Here, a model-free classification method to separate SAXS/WAXS signals on the basis of their inflection points is introduced and demonstrated. This article focuses on the segmentation of scanning SAXS/WAXS maps for which each pixel corresponds to an azimuthally integrated scattering curve. In such a way, the sample composition distribution can be segmented through signal classification without applying a model or previous sample knowledge. Dimensionality reduction and clustering algorithms are employed to classify SAXS/WAXS signals according to their similarity. The number of clusters, i.e. the main sample regions detected by SAXS/WAXS signal similarity, is automatically estimated. From each cluster, a main representative SAXS/WAXS signal is extracted to uncover the spatial distribution of the mixtures of phases that form the sample. As examples of applications, a mudrock sample and two breast tissue lesions are segmented.

Correction: Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65.

The authors originally published this article under the incorrect license type; this has now been corrected and is published under the CC-BY license.

Donor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors.

Photoreceptor replacement by transplantation is proposed as a treatment for blindness. Transplantation of healthy photoreceptor precursor cells into diseased murine eyes leads to the presence of functional photoreceptors within host retinae that express an array of donor-specific proteins. The resulting improvement in visual function was understood to be due to donor cells integrating within host retinae. Here, however, we show that while integration occurs the majority of donor-reporter-labelled cells in the host arises as a result of material transfer between donor and host photoreceptors. Material transfer does not involve permanent donor-host nuclear or cell-cell fusion, or the uptake of free protein or nucleic acid from the extracellular environment. Instead, RNA and/or protein are exchanged between donor and host cells in vivo. These data require a re-evaluation of the mechanisms underlying rescue by photoreceptor transplantation and raise the possibility of material transfer as a strategy for the treatment of retinal disorders.

Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65.

Leber congenital amaurosis is a group of inherited retinal dystrophies that cause severe sight impairment in childhood; RPE65-deficiency causes impaired rod photoreceptor function from birth and progressive impairment of cone photoreceptor function associated with retinal degeneration. In animal models of RPE65 deficiency, subretinal injection of recombinant adeno-associated virus (AAV) 2/2 vectors carrying RPE65 cDNA improves rod photoreceptor function, and intervention at an early stage of disease provides sustained benefit by protecting cone photoreceptors against retinal degeneration. In affected humans, administration of these vectors has resulted to date in relatively modest improvements in photoreceptor function, even when retinal degeneration is comparatively mild, and the duration of benefit is limited by progressive retinal degeneration. We conclude that the demand for RPE65 in humans is not fully met by current vectors, and predict that a more powerful vector will provide more durable benefit. With this aim we have modified the original AAV2/2 vector to generate AAV2/5-OPTIRPE65. The new configuration consists of an AAV vector serotype 5 carrying an optimized hRPE65 promoter and a codon-optimized hRPE65 gene. In mice, AAV2/5-OPTIRPE65 is at least 300-fold more potent than our original AAV2/2 vector.

Sustainability assessment of tertiary wastewater treatment technologies: a multi-criteria analysis.

The multi-criteria analysis gives the opportunity to researchers, designers and decision-makers to examine decision options in a multi-dimensional fashion. On this basis, four tertiary wastewater treatment (WWT) technologies were assessed regarding their sustainability performance in producing recycled wastewater, considering a 'triple bottom line' approach (i.e. economic, environmental, and social). These are powdered activated carbon adsorption coupled with ultrafiltration membrane separation (PAC-UF), reverse osmosis, ozone/ultraviolet-light oxidation and heterogeneous photo-catalysis coupled with low-pressure membrane separation (photocatalytic membrane reactor, PMR). The participatory method called simple multi-attribute rating technique exploiting ranks was employed for assigning weights to selected sustainability indicators. This sustainability assessment approach resulted in the development of a composite index as a final metric, for each WWT technology evaluated. The PAC-UF technology appears to be the most appropriate technology, attaining the highest composite value regarding the sustainability performance. A scenario analysis confirmed the results of the original scenario in five out of seven cases. In parallel, the PMR was highlighted as the technology with the least variability in its performance. Nevertheless, additional actions and approaches are proposed to strengthen the objectivity of the final results.

Capillary saturation and desaturation.

Capillary desaturation experiments produce disconnected (trapped) ganglia of mesoscopic sizes intermediate between pore size and system size. Experimental evidence for interactions between these mesoscale clusters during desaturation is analyzed and discussed within the established microscopic and macroscopic laws of Newton, Young-Laplace, and Darcy. A theoretical expression for capillary number correlations is introduced that seems to have remained unnoticed. It expresses capillary desaturation curves in terms of stationary capillary pressures and relative permeabilities. The theoretical expression shows that the plateau saturation in capillary desaturation curves may in general differ from the residual nonwetting saturation defined through the saturation limit of the main hysteresis loop. Hysteresis effects as well as the difference between wetting and nonwetting fluids are introduced into the analysis of capillary desaturation experiments. The article examines experiments with different desaturation protocols and discusses the existence of a mesoscopic length scale intermediate between pore scale and sample scale. The theoretical expression is derived entirely within the existing traditional theory of two-phase flow in porous media and compared to a recent experiment.

Pore-scale micro-computed-tomography imaging: nonwetting-phase cluster-size distribution during drainage and imbibition.

We investigated the cluster-size distribution of the residual nonwetting phase in a sintered glass-bead porous medium at two-phase flow conditions, by means of micro-computed-tomography (µCT) imaging with pore-scale resolution. Cluster-size distribution functions and cluster volumes were obtained by image analysis for a range of injected pore volumes under both imbibition and drainage conditions; the field of view was larger than the porosity-based representative elementary volume (REV). We did not attempt to make a definition for a two-phase REV but used the nonwetting-phase cluster-size distribution as an indicator. Most of the nonwetting-phase total volume was found to be contained in clusters that were one to two orders of magnitude larger than the porosity-based REV. The largest observed clusters in fact ranged in volume from 65% to 99% of the entire nonwetting phase in the field of view. As a consequence, the largest clusters observed were statistically not represented and were found to be smaller than the estimated maximum cluster length. The results indicate that the two-phase REV is larger than the field of view attainable by µCT scanning, at a resolution which allows for the accurate determination of cluster connectivity.

Vanishing twins in diamniotic dichorionic in vitro fertilization gestation in mid-second trimester.

The authors report a diamniotic dichorionic twin pregnancy after in vitro fertilization (IVF) in mid-second trimester. The dead fetuses were delivered by cesarean section at the 20th week of gestation. The authors discuss management aspects and review of the literature.

Ultrasound diagnosis of recurring Jeune's syndrome: a case report.

Jeune's Syndrome or asphyxiating thoracic dystrophy (ATD) is a rare autosomal recessive skeletal dysplasia syndrome characterized by a small and narrow chest, short extremities, and often polydactyly associated with multiple organ manifestations. The severity of complications ranges from mild to lethal. This is a report of two cases of ATD diagnosed in successive pregnancies of a nonconsanguineous couple. The contribution of sonography in prenatal diagnosis of the syndrome is highlighted.

Assessment of platelet inhibition by point-of-care testing in neuroendovascular procedures.

Antiplatelet agents are an important component of the preventive strategies currently used in clinical practice to minimize the risk of thromboembolic events during and after endovascular procedures. Because of the variability in the response to antiplatelet agents, measuring the degree of platelet inhibition may help identify and properly treat poor responders. POC testing is defined as diagnostic testing at or near the site of patient care. Knowledge of the specifics of these devices among practicing neurointerventionalists is relatively limited. In this article, the different POC devices available are presented, and their clinical utility in relation to endovascular procedures is discussed.

The challenging trisomy 16: a case report.

BACKGROUND: Trisomy 16 is a very frequent autosomal anomaly accounting for about 2% of first trimester abortions. In most pregnancies the chromosomal genome found in the fetus is also present in the placenta. Confined placental mosaicism is frequently detected in the placental region along with a structurally normal fetus. CASE: We present the case of a 39-year-old primigravida with confined placental mosaicism diagnosed with chorionic villus sampling. Amniocentesis showed a normal karyotype (46, XX). Detailed scanning revealed no structural fetal anomalies, but severe oligohydramnios. CONCLUSION: Diagnosis of trisomy 16 does not necessarily mean that the newborn has anatomical abnormalities.

Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice.

Insertional mutagenesis following gene therapy with gammaretroviral vectors can cause the development of lymphoproliferation in children with X-linked severe combined immunodeficiency. In experimental studies, recombinant adeno-associated virus (rAAV) vectors have also been reported to increase susceptibility to carcinogenesis. The possibility of vector-induced transformation in quiescent ocular cells is probably significantly lower than in mitotically active cells, but given the increasing number of clinical applications of rAAV and lentiviral vectors for ocular disease, a specific assessment of their oncogenic potential in the eye is important. In this study, we investigated the effect of rAAV2/2 and integrating HIV-1 vectors upon the incidence of ocular neoplasia in p53 tumour-suppressor gene-knockout (p53(-/-)) mice, which are highly susceptible to intraocular malignant transformation. Subretinal injections of high titre rAAV2/2 or integrating HIV-1 vectors induced no tumours in p53(-/-) or p53(+/-) animals, nor significantly affected their natural longevity. We conclude that any insertional events arising from subretinal delivery of these vectors appear insufficient to cause intraocular malignancy, even in highly susceptible animals. These findings support the continued development of these vectors for ocular applications.

Point-of-care testing for anticoagulation monitoring in neuroendovascular procedures.

POC testing is defined as diagnostic testing at or near the site of patient care. Rapid measurement of the intensity of anticoagulation and, more recently, platelet inhibition allows dose titration of adjuvant medications such a heparin and antiplatelet agents during neuroendovascular procedures. However, knowledge among practicing physicians regarding the pathophysiologic basis of these measurements and variations in knowledge about the differences among devices is often limited. This review discusses the role of anticoagulation in endovascular procedures and the currently available POC tests for anticoagulation monitoring.