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It is unclear whether episodic memory is an appropriate descriptor of the cognitive continuum in mild cognitive impairment (MCI). Here, we investigated the ability of episodic memory to track cognitive changes in patients with MCI with biomarker evidence of Alzheimer's disease (AD). We examined 387 MCI amyloid-positive subjects, cognitively staged as "early" or "late" on the basis of episodic memory impairment. Cross-sectional and longitudinal comparisons between these 2 groups were performed for each amyloid, tau, and neurodegeneration (AT(N)) profile. Cross-sectional analyses indicate that "early" MCI represents a transitional phase between normal cognition and "late" MCI in the AD biomarker pathway. After adjusting by confounders and levels of A, T, and (N), "late" MCI progressed significantly faster than "early" MCI only in profiles with both abnormal amyloid and tau markers (A+T+(N)− p < 0.05, A+T+(N)+ p < 0.001). Episodic memory staging is useful for describing symptoms in prodromal AD and complements the AT(N) profiles. Our findings might have implications for the Numeric Clinical staging scheme of the National Institute on Aging and Alzheimer's Association research framework. • It is unclear whether episodic memory can track the prodromal cognitive continuum. • We studied episodic memory staging in patients with mild cognitive impairment with biomarker evidence of Alzheimer's disease. • This scheme tracks symptoms only in patients with mild cognitive impairment with abnormal amyloid and tau markers. • Episodic memory adds prognostic information to biomarker profiles in prodromal Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Coastal habitats, in particular sandy beaches, are becoming increasingly exposed to artificial light pollution at night (ALAN). Yet, only a few studies have this far assessed the effects of ALAN on the species inhabiting these ecosystems. In this study we assessed the effects of ALAN on Tylos spinulosus , a prominent wrack-consumer isopod living in sandy beaches of north-central Chile. This species burrows in the sand during daylight and emerges at night to migrate down-shore, so we argue it can be used as a model species for the study of ALAN effects on coastal nocturnal species. We assessed whether ALAN alters the distribution and locomotor activity of this isopod using a light system placed in upper shore sediments close to the edge of the dunes, mimicking light intensities measured near public lighting. The response of the isopods was compared to control transects located farther away and not exposed to artificial light. In parallel, we measured the isopods' locomotor activity in the laboratory using actographs that recorded their movement within mesocosms simulating the beach surface. Measurements in the field indicated a clear reduction in isopod abundance near the source of the light and a restriction of their tidal distribution range, as compared to control transects. Meanwhile, the laboratory experiments showed that in mesocosms exposed to ALAN, isopods exhibited reduced activity and a circadian rhythm that was altered and even lost after a few days. Such changes with respect to control mesocosms with a natural day/night cycle suggest that the changes observed in the field were directly related to a disruption in the locomotor activity of the isopods. All together these results provide causal evidence of negative ALAN effects on this species, and call for further research on other nocturnal sandy beach species that might become increasingly affected by ALAN. Image 1 • Artificial light pollution (ALAN) is a growing concern for coastal species. • We assessed ALAN effects on a marine isopod in the field and the laboratory. • ALAN disrupted the intertidal distribution of the isopod in the field. • ALAN disrupted the locomotor activity and circadian rhythm in the laboratory. Field and laboratory experiments showed that Artificial Light Pollution at Night (ALAN) disrupts the distribution and locomotor activity of a prominent costal isopod. [ABSTRACT FROM AUTHOR]

Deep learning-based models applied to digital pathology require large, curated datasets with high-quality (HQ) annotations to perform correctly. In many cases, recruiting expert pathologists to annotate large databases is not feasible, and it is necessary to collect additional labeled data with varying label qualities, e.g., pathologists-in-training (henceforth, non-expert annotators). Learning from datasets with noisy labels is more challenging in medical applications since medical imaging datasets tend to have instance-dependent noise and suffer from high inter/intra-observer variability. In this paper, we design an uncertainty-driven labeling strategy with which we generate soft labels from 10 non-expert annotators for multi-class skin cancer classification. Based on this soft annotation, we propose an uncertainty estimation-based framework to handle these noisy labels. This framework is based on a novel formulation using a dual-branch min–max entropy calibration to penalize inexact labels during the training. Comprehensive experiments demonstrate the promising performance of our labeling strategy. Results show a consistent improvement by using soft labels with standard cross-entropy loss during training (∼ 4. 0 % F1-score) and increases when calibrating the model with the proposed min–max entropy calibration (∼ 6. 6 % F1-score). These improvements are produced at negligible cost, both in terms of annotation and calculation. • Histological images are used to distinguish between seven spindle cell neoplasms. • An uncertainty-aware labeling strategy that quantifies the uncertainty is proposed. • We present an extensive study of soft label model calibration compared to the ground truth, labeled by an expert pathologist. • A novel formulation based on dual-branch entropy calibration (DBEC) is proposed to penalize overconfident outputs and uncertain soft labels. • Comprehensive experiments demonstrate the promising performance of our labeling strategy. [ABSTRACT FROM AUTHOR]

Purpose The aim of this work is to study the effect of physiological muscular uptake variations and statistical noise on tumor quantification in FDG-PET studies. Methods We designed a realistic framework based on simulated FDG-PET acquisitions from an anthropomorphic phantom that included different muscular uptake levels and three spherical lung lesions with diameters of 31, 21 and 9 mm. A distribution of muscular uptake levels was obtained from 136 patients remitted to our center for whole-body FDG-PET. Simulated FDG-PET acquisitions were obtained by using the Simulation System for Emission Tomography package (SimSET) Monte Carlo package. Simulated data was reconstructed by using an iterative Ordered Subset Expectation Maximization (OSEM) algorithm implemented in the Software for Tomographic Image Reconstruction (STIR) library. Tumor quantification was carried out by using estimations of SUV max , SUV 50 and SUV mean from different noise realizations, lung lesions and multiple muscular uptakes. Results Our analysis provided quantification variability values of 17–22% (SUV max ), 11–19% (SUV 50 ) and 8–10% (SUV mean ) when muscular uptake variations and statistical noise were included. Meanwhile, quantification variability due only to statistical noise was 7–8% (SUV max ), 3–7% (SUV 50 ) and 1–2% (SUV mean ) for large tumors (>20 mm) and 13% (SUV max ), 16% (SUV 50 ) and 8% (SUV mean ) for small tumors (<10 mm), thus showing that the variability in tumor quantification is mainly affected by muscular uptake variations when large enough tumors are considered. In addition, our results showed that quantification variability is strongly dominated by statistical noise when the injected dose decreases below 222 MBq. Conclusions Our study revealed that muscular uptake variations between patients who are totally relaxed should be considered as an uncertainty source of tumor quantification values. [ABSTRACT FROM AUTHOR]

Introduction Current guidelines for brain PET imaging advice against the injection of diazepam prior to brain FDG-PET examination in order to avoid possible interactions of benzodiazepines with the radiotracer uptake. Nevertheless, many patients undergoing PET studies are likely to be under chronic treatment with benzodiazepines, for example due to the use of different medications such as sleeping pills. Animal studies may provide an extensive and accurate estimation of the effect of benzodiazepines on brain metabolism in a well-defined and controlled framework. Aim This study aims at evaluating the impact of benzodiazepines on brain FDG uptake after single-dose administration and chronic treatment in rats. Methods Twelve Sprague–Dawley healthy rats were randomly divided into two groups, one treated with diazepam and the other used as control group. Both groups underwent PET/CT examinations after single-dose and chronic administration of diazepam (treated) or saline (controls) during twenty-eight days. Different atlas-based quantification methods were used to explore differences on the total uptake and uptake patterns of FDG between both groups. Results Our analysis revealed a significant reduction of global FDG uptake after acute (−16.2%) and chronic (−23.2%) administration of diazepam. Moreover, a strong trend pointing to differences between acute and chronic administrations (p < 0.08) was also observed. Uptake levels returned to normal after interrupting the administration of diazepam. On the other hand, patterns of FDG uptake were not affected by the administration of diazepam. Conclusions The administration of diazepam causes a progressive decrease of the FDG global uptake in the rat brain, but it does not change local patterns within the brain. Under these conditions, visual assessment and quantification methods based on regional differences such as asymmetry indexes or SPM statistical analysis would still be valid when administrating this medication. [ABSTRACT FROM AUTHOR]

[Display omitted] • The use of the vertical forest profile by wildlife has been largely overlooked. • Wildlife species differ in their use of the vertical profile of the forest. • Species that select the canopy can be underestimated in ground-based surveys. • In addition to the ground, studies on forest wildlife need to survey the canopy. Habitat use is how animals use the physical and biological components of the environment. Studies relating habitat and wildlife in forest ecosystems have typically been conducted from the ground, even though most wildlife use the three-dimensional space. The objective of our study was to understand how wildlife uses the whole vertical profile of the forest and to analyze possible associations between different species and vertical forest strata, using camera traps and occupancy models. We defined four strata (forest floor, understory, lower canopy, and upper canopy) that range from 0 to 32 m from the ground. We installed 16 camera-traps per stratum (n = 64), and we analyzed the use of each stratum by seven taxa using occupancy models. We detected 24 wildlife taxa, including 17 birds, six mammalian taxa and one reptile. Occupancy models showed that rodents and two bird species were associated either to the forest floor or to the lower strata (understory and ground), whereas one furnariid bird and one marsupial used the vertical profile more frequent than the forest floor. Finally, the lizard and a furnariid bird preferentially used the lower and upper canopy. For all but one of the species, activity patterns were similar between the upper and lower strata of the forest. Our study shows that wildlife species differ in the use of the vertical profile of the forest and suggests that occupancy of species that select the canopy can be largely underestimated from ground-based surveys affecting management decisions. [ABSTRACT FROM AUTHOR]

Introduction In preclinical research, the growing number of transgenic models has led to the need for renal-function studies in mice. Many efforts have been made to develop dedicated SPECT systems for rodents, but their availability is limited due to high capital costs. The aim of this work is to demonstrate the feasibility of mouse renal imaging by using an inexpensive alternative based on clinical gamma-cameras. Methods A healthy mouse was scanned 3 h after injection of 6 mCi of Dimercaptosuccinic acid (DMSA) labeled with 99mTc by using a single-head gamma-camera in conjunction with a dedicated pinhole collimator. List-mode data were binned to emulate multiple injections of 1 mCi, 0.1 mCi and 0.01 mCi of 99mTc-DMSA and 6-min ventral and dorsal planar images were acquired and SPECT imaging (60 projection images acquired over 60 min) was performed. An optimization of the protocols in terms of injected activity, time scan, renal cortex uniformity and cortex-to-pelvis contrast was carried out. Results The appropriate protocols were an injected activity of 0.6 mCi, combined with duration of scanning of 1 min for planar and 60 min for SPECT imaging. Our results were validated through the relative quantification of renal function, which showed that both kidneys contributed equally to the total function. They showed that functional structures of the mouse kidneys can be visually distinguished as easily as in human studies. Conclusions Our findings showed the feasibility of conducting quantitative DMSA SPECT studies of anesthetized mice on clinical gamma cameras. [ABSTRACT FROM AUTHOR]

Increasing demands on railway structures have led to a need for new cost-effective maintenance strategies in recent years. Current dynamic railway track monitoring systems are usually based on the analysis of axle-box accelerations to automatically detect track singularities and defects. These methods rely on hand-crafted feature extraction and classifiers for different tasks. However, the low performance shown in previous literature makes it necessary to complement these analyses with in-situ inspections. Very recent works have proposed the use of deep learning systems that allow extracting more generalizable features from time–frequency spectrograms. However, the lack of specific public domain datasets and the finite number of track singularities in a railway structure have limited the development of deep learning based systems. In this paper, we propose a method capable of outstanding in low-data scenarios. In particular, we explore the use of supervised contrastive learning to cluster class embeddings nearly in the encoder latent space, which is used during inference for prototypical distance-based class assignment. We provide comprehensive experiments demonstrating the performance of our method in comparison to previous literature for detecting worn-out crossings. • A deep learning system for worn railway crossings detection via axle-box accelerations. • A novel combination of prototypical inference and supervised contrastive learning. • Contrastive learning outperforms standard metric learning for few-shot learning. • The method outperforms by 8% prior methods for worn crossings classification. [ABSTRACT FROM AUTHOR]

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Abstract: Domestic dogs are the most abundant carnivores worldwide, primarily due to human support. Food and other subsidies to dogs do not necessarily prevent dog predation on wildlife, particularly where dogs are allowed to range freely. Dog impacts on wildlife are suspected to be significant, yet the nature of dog–wildlife interactions is not fully understood. We tested the hypothesis that the distribution of dogs can significantly influence the space use of potential prey, and that both lethal and non-lethal mechanisms may underlie this interaction. If this is true, then we predicted that (1) evidence of predation and harassment by dogs should be evident where prey and dog activities overlap and (2) potential prey should be less frequent in areas where the probability of dog presence is high. To test these predictions we conducted two related studies. (1) We interviewed dog owners to estimate the probability of dog attack on pudu (Pudu puda), a globally vulnerable deer, and the lethality of these attacks. (2) We conducted a camera-trap survey documenting the landscape-scale distribution of pudu and dogs. Interviews showed that both the probability of dog attack on pudu (>85%) and the lethality of such attacks was high (50%). In occupancy models applied to the camera-trap data, the variable that best explained the distribution of pudus was the probability of dog presence. We tested three alternative explanations for the negative association between pudus and dogs that were not supported. Our findings suggest that dogs are efficient at chasing pudu they detect and that both predation and non-lethal (avoidance) consequences of harassment may be shaping the distribution of pudu. This work brings into focus important mechanisms underlying the threats of domestic dogs to endangered prey. [Copyright &y& Elsevier]

• Segmentation of Gleason grades in prostate histology images using global Gleason score during training. • A weakly-supervised architecture that perform multi-class segmentation, including the background class. • Log-sum exponential pooling allows to adapt the weakly-supervised architecture to the extent of cancerous structures in the tissue. • Weakly-supervised CNNs perform at the same level as fully-supervised techniques for Gleason grading of tissue micro-arrays. Prostate cancer is one of the main diseases affecting men worldwide. The Gleason scoring system is the primary diagnostic tool for prostate cancer. This is obtained via the visual analysis of cancerous patterns in prostate biopsies performed by expert pathologists, and the aggregation of the main Gleason grades in a combined score. Computer-aided diagnosis systems allow to reduce the workload of pathologists and increase the objectivity. Nevertheless, those require a large number of labeled samples, with pixel-level annotations performed by expert pathologists, to be developed. Recently, efforts have been made in the literature to develop algorithms aiming the direct estimation of the global Gleason score at biopsy/core level with global labels. However, these algorithms do not cover the accurate localization of the Gleason patterns into the tissue. These location maps are the basis to provide a reliable computer-aided diagnosis system to the experts to be used in clinical practice by pathologists. In this work, we propose a deep-learning-based system able to detect local cancerous patterns in the prostate tissue using only the global-level Gleason score obtained from clinical records during training. The methodological core of this work is the proposed weakly-supervised-trained convolutional neural network, WeGleNet, based on a multi-class segmentation layer after the feature extraction module, a global-aggregation, and the slicing of the background class for the model loss estimation during training. Using a public dataset of prostate tissue-micro arrays, we obtained a Cohen's quadratic kappa (κ) of 0.67 for the pixel-level prediction of cancerous patterns in the validation cohort. We compared the model performance for semantic segmentation of Gleason grades with supervised state-of-the-art architectures in the test cohort. We obtained a pixel-level κ of 0.61 and a macro-averaged f1-score of 0.58 , at the same level as fully-supervised methods. Regarding the estimation of the core-level Gleason score, we obtained a κ of 0.76 and 0.67 between the model and two different pathologists. WeGleNet is capable of performing the semantic segmentation of Gleason grades similarly to fully-supervised methods without requiring pixel-level annotations. Moreover, the model reached a performance at the same level as inter-pathologist agreement for the global Gleason scoring of the cores. [ABSTRACT FROM AUTHOR]

If a mechanism of more efficient glycolysis depending on pyruvate is present in stallion spermatozoa, detrimental effects of higher glucose concentrations that are common in current commercial extenders could be counteracted. To test this hypothesis, spermatozoa were incubated in a 67 mM Glucose modified Tyrode's media in the presence of 1- or 10-mM pyruvate and in the Tyrode's basal media which contains 5 mM glucose. Spermatozoa incubated for 3 h at 37 °C in 67 mM Tyrode's media with 10 mM pyruvate showed increased motility in comparison with aliquots incubated in Tyrode's 5 mM glucose and Tyrode's 67 mM glucose (57.1 ± 3.5 and 58.1 ± 1.9 to 73.0 ± 1.1 %; P < 0.01). Spermatozoa incubated in Tyrode's with 67 mM glucose 10 mM pyruvate maintained the viability along the incubation (64.03 ± 15.4 vs 61.3 ± 10.2), while spermatozoa incubated in 67 mM Glucose-Tyrode's showed a decrease in viability (38.01 ± 11.2, P < 0.01). 40 mM oxamate, an inhibitor of the lactate dehydrogenase LDH, reduced sperm viability (P < 0.05, from 76 ± 5 in 67 mM Glucose/10 mM pyruvate to 68.0 ± 4.3 %, P < 0.05). Apoptotic markers increased in the presence of oxamate. (P < 0.01). UHPLC/MS/MS showed that 10 mM pyruvate increased pyruvate, lactate, ATP and NAD+ while phosphoenolpyruvate decreased. The mechanisms that explain the improvement of in presence of 10 mM pyruvate involve the conversion of lactate to pyruvate and increased NAD+ enhancing the efficiency of the glycolysis. • 10 mM pyruvate in a 67 mM Glucose-Tyrode's media maintains sperm functionality in comparison with a 67 mM glucose- Tyrode's. • Motility, linear motility, velocities membrane integrity, mitochondrial membrane potential and glutathione content were higher in the 10 mM pyruvate, 67 mM glucose media. • LACTATE and NAD+ content were higher in the spermatozoa incubated in the 10 mM pyruvate in a 67 mM Glucose-Tyrode's media. • The mechanism explaining the improvements may involve conversion of pyruvate to lactate and regeneration of NAD+. • The stallion spermatozoa may produce significant amounts of lactate under high Oxygen (Warburg effect). [ABSTRACT FROM AUTHOR]

Econazole is a feasible alternative treatment in the management of fungal keratitis. Nevertheless, its low water solubility is considered the main limitation to the incorporation into ophthalmic formulations. In this work, econazole nitrate is solubilized by using cyclodextrins to achieve an optimum therapeutic concentration. Phase solubility diagrams suggest α-cyclodextrin as the most effective cyclodextrin and later the inclusion complex formed with this one was characterized in solution by 1D, 2D-NMR, and molecular modeling. Econazole-α-cyclodextrin inclusion complex was included in 2 types of ocular hydrogels: a natural polysaccharides ion-sensitive hydrogel and a hyaluronic acid hydrogel. Both of them show no ocular irritation in the hen's egg test on chorioallantoic membrane assay and a controlled econazole release over time. Permeability studies suggest that hydrogels do not modify the econazole nitrate permeability through bovine cornea in comparison with an econazole-α-cyclodextrin inclusion complex solution. Finally, ocular biopermanence studies performed using positron emission tomography show these hydrogels present a high retention time on the eye. Results suggest the developed formulations have a high potential as vehicles for the econazole topical ocular administration as fungal keratitis treatment. [ABSTRACT FROM AUTHOR]

It is important to note that seasonality could affect ram reproductive parameters, and therefore, fertility results after artificial insemination. In this work, 1) we assessed fertility rates after cervical artificial insemination of 11,805 ewes at the beginning (June 21st to July 20th) and at the end (November 20th to December 21st) of the reproductive season in the Assaf breed for the last four years, and 2) we aimed to identify male factors influencing the different reproductive success obtained depending on the time at the mating season in which ovine artificial insemination was performed. For this purpose, we evaluated certain ram reproductive and ultrasonographical parameters as well as we performed a multiparametric and proteomic sperm analysis of 6–19 rams at two very distant points in the mating season (July as Early Breeding Season –EBS– and November as Late Breeding Season –LBS–). Rutinary assessments carried out in the ovine reproduction centers (testicular volume, libido, sperm production and mass motility) showed non-significant differences (P ≥ 0.05) between both studied times, as well as the ram ultrasonographic evaluation (Resistive and Pulsatility Index as Doppler parameters; and pixels mean gray level, and hypoechoic areas percentage and density as echotexture parameters). However, at level of sperm functionality, although sperm quality appeared non-significantly lower (P ≥ 0.05) in the EBS, we identified a significantly different (P < 0.05) sperm proteomic profile between the seasonality points. The following proteins were identified with the lowest abundance in the EBS with a fold change > 4, a P = 2.40e-07, and a q = 2.23e-06: Fibrous Sheath-Interacting Protein 2, Disintegrin and Metalloproteinase Domain-Containing Protein 20-like, Phosphoinositide-Specific Phospholipase C, Tektin 5, Armadillo Repeat-Containing Protein 12 Isoform X3, Solute Carrier Family 9B1, Radial Spoke Head Protein 3 Homolog, Pro-Interleukin-16, NADH Dehydrogenase [Ubiquinone] 1 Alpha Subcomplex Subunit 8, Testis, Prostate and Placenta-Expressed Protein, and Acyl Carrier Protein Mitochondrial. In conclusion, while our basic analyses on male and sperm quality showed similar results between the beginning and the end of the breeding season, on a proteomic level we detected a lower expression of sperm proteins linked to the energy metabolism, sperm-oocyte interactions, and flagellum structure in the EBS. Probably, this different protein expression could be related to the lower fertility rate of Assaf ewes after cervical artificial insemination at this time. More importantly, sperm proteins can be used as highly effective molecular markers in predicting sperm fertilization ability related to intraseasonal variations. • Fertility rate in Assaf breed is lower at the beginning of the breeding season. • Ram reproductive parameters are similar during the whole mating season. • Ram sperm proteomic profile changes through the breeding season. • Ram sperm proteins could be used as fertility biomarkers. [ABSTRACT FROM AUTHOR]

Seminal plasma plays an important role in sperm physiology. Seminal plasma proteins vehiculated in microvesicles, carry RNAs and proteins with a potential role in early embryo development. Additionally, proteins present in seminal plasma participate in redox regulation and energy metabolism. In view of these facts, we hypothesized that differences in protein composition of the seminal plasma among stallions may help to explain differences in freeze-ability seen among them. Three independent ejaculates from 10 different stallions of varying breeds were frozen using standard protocols in our laboratory. Aliquots of the ejaculate were separated and stored at −80 °C until further proteomic analysis. Semen analysis was performed using computer assisted sperm analysis and flow cytometry. Significant differences in proteome composition of seminal plasma were observed in the group of stallions showing better motility post thaw. 3116 proteins were identified, and of these, 34 were differentially expressed in stallions with better motility post thaw, 4 of them were also differentially expressed in stallions with different percentages of linearly motile sperm post thaw and 1 protein, Midasin, was expressed in stallions showing high circular velocity post thaw. Seminal plasma proteins may play a major role in sperm functionality; being vehiculated through extracellular vesicles and participating in sperm physiology. Bioinformatic analysis identifies discriminant proteins able to predict the outcome of cryopreservation, identifying potential new biomarkers to assess ejaculate quality. • Differences in seminal plasma proteins were present in stallions with better motility post thaw. • 34 proteins were differentially expressed in stallions with better motility post thaw. • Midasin was more abundant in stallions showing high circular velocity post thaw. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract, which two main types are Crohn’s disease and ulcerative colitis. It has multifactorial etiologies, being essential the use of animal models and disease activity measures to develop new therapies. With this aim, the use of animal models in combination with non-invasive molecular imaging can play an important role in the development of new treatments. In this study, IBD was induced in rats using 2,4,6-trinitrobenzenesulfonic acid (TNBS) and longitudinal [18F]FDG PET/CT scans were conducted to assess disease progression post-TNBS administration. Afterwards, [18F]FDG PET/CT scans were carried out after treatment with methylprednisolone to validate the model. In non-treated rats, SUV max (Standardized Uptake Value) rapidly increased after IBD induction, being particularly significant (p < 0.01) on days 7–13 after induction. There were no significant differences between non-treated and treated IBD rats from days 0–3. Nevertheless, treated IBD rats showed a significant decrease in SUV max between days 7–13 (p < 0.01). Histological examination showed descending and transverse colon as the most affected regions. There was a moderate (R2 = 0.61) and strong (R2 = 0.82) correlation of SUV max with Nancy grade (parameter for histological assessment of disease activity) and weight changes, respectively. In this study, we have performed the first longitudinal [18F]FDG PET/CT assessment of TNBS-induced IBD in rats, demonstrating the potential role of preclinical molecular imaging for the evaluation of new therapies in combination with IBD rat models. [ABSTRACT FROM AUTHOR]

Cystinosis is a rare autosomal recessive disorder in which cystine crystals accumulate within the lysosomes of various organs, including the cornea. Ocular treatment is based on the administration of cysteamine eye drops, requiring its instillation several times per day. We have introduced the cysteamine in two types of previously developed ocular hydrogels (ion sensitive hydrogel with the polymers gellan gum and kappa-carrageenan and another one composed of hyaluronic acid), aiming at increasing the ocular retention in order to extend the dosing interval. The biopermanence studies (direct measurements and PET/CT) show that these formulations present a high retention time on the ocular surface of rats. From the in vitro release study we determined that both hydrogels can control the release of cysteamine over time, showing a zero order kinetics during four hours. At the same time, these hydrogels could act as corneal absorption promoters, as they allow a higher permeation of cysteamine through bovine cornea compared to a solution. HET-CAM test and cytotoxicity assays show no irritation on the ocular surface. These results demonstrate that the developed formulations present a high potential as vehicles for the topical ocular administration of cysteamine. [ABSTRACT FROM AUTHOR]

[Display omitted] Adalimumab is an anti-TNFα drug approved for uveitis treatment by subcutaneous injection. This administration route exposes patients to systemic adverse effects and makes difficult to obtain therapeutic drug concentrations in the site of action due to the anatomical and physiological barriers of the eye. These inconveniences could be avoided by intravitreal injection. The aim of this study is to evaluate the pharmacokinetic profile and the biodistribution of the intravitreal administration of 89Zr-adalimumab in a uveitis rat model using PET imaging. Adalimumab was radiolabelled to 89Zr with a maximum specific activity of 10 MBq/mg. Four μL containing ≃1.74 MBq of 89Zr-labelled adalimumab were injected into the vitreous. A microPET acquisition was carried out immediately after the injection and at different time points through a 10-day study and blood samples were obtained through the tail vein. Radiolabelling was successfully performed with a radiochemical purity after ultrafiltration of 99.69 %. The antibody ocular pharmacokinetics followed a one-compartment model, showing an intraocular elimination half-life of 15.57 h for healthy rats and 33.64 h for rats with uveitis, implying that 89Zr-adalimumab remains around two times longer in rats with the disease compared to healthy ones. However, blood concentration half-life had similar values in both groups. In conclusion, this study shows for the first time the ocular and blood pharmacokinetic analysis of adalimumab in a uveitis model in rats. [ABSTRACT FROM AUTHOR]