Aniridia-related keratopathy relevant cell signaling pathways in human fetal corneas.

We aimed to study aniridia-related keratopathy (ARK) relevant cell signaling pathways [Notch1, Wnt/ß-catenin, Sonic hedgehog (SHH) and mTOR] in normal human fetal corneas compared with normal human adult corneas and ARK corneas. We found that fetal corneas at 20 weeks of gestation (wg) and normal adult corneas showed similar staining patterns for Notch1; however 10-11 wg fetal corneas showed increased presence of Notch1. Numb and Dlk1 had an enhanced presence in the fetal corneas compared with the adult corneas. Fetal corneas showed stronger immunolabeling with antibodies against ß-catenin, Wnt5a, Wnt7a, Gli1, Hes1, p-rpS6, and mTOR when compared with the adult corneas. Gene expression of Notch1, Wnt5A, Wnt7A, ß-catenin, Hes1, mTOR, and rps6 was higher in the 9-12 wg fetal corneas compared with adult corneas. The cell signaling pathway differences found between human fetal and adult corneas were similar to those previously found in ARK corneas with the exception of Notch1. Analogous profiles of cell signaling pathway activation between human fetal corneas and ARK corneas suggests that there is a less differentiated host milieu in ARK.

MDM2-Based Proteolysis-Targeting Chimeras (PROTACs): An Innovative Drug Strategy for Cancer Treatment.

Proteolysis-targeting chimeras (PROTACs) are molecules that selectively degrade a protein of interest (POI). The incorporation of ligands that recruit mouse double minute 2 (MDM2) into PROTACs, forming the so-called MDM2-based PROTACs, has shown promise in cancer treatment due to its dual mechanism of action: a PROTAC that recruits MDM2 prevents its binding to p53, resulting not only in the degradation of POI but also in the increase of intracellular levels of the p53 suppressor, with the activation of a whole set of biological processes, such as cell cycle arrest or apoptosis. In addition, these PROTACs, in certain cases, allow for the degradation of the target, with nanomolar potency, in a rapid and sustained manner over time, with less susceptibility to the development of resistance and tolerance, without causing changes in protein expression, and with selectivity to the target, including the respective isoforms or mutations, and to the cell type, overcoming some limitations associated with the use of inhibitors for the same therapeutic target. Therefore, the aim of this review is to analyze and discuss the characteristics of MDM2-based PROTACs developed for the degradation of oncogenic proteins and to understand what potential they have as future anticancer drugs.

Gene expression profile of extraocular muscles following resection strabismus surgery.

This paper aims to identify key biological processes triggered by resection surgery in the extraocular muscles (EOMs) of a rabbit model of strabismus surgery by studying changes in gene expression. Resection surgery was performed in the superior rectus of 16 rabbits and a group of non-operated rabbits served as control. Muscle samples were collected from groups of four animals 1, 2, 4 and 6 weeks after surgery and processed for RNA-sequencing and immunohistochemistry. We identified a total of 164; 136; 64 and 12 differentially expressed genes 1, 2, 4 and 6 weeks after surgery. Gene Ontology enrichment analysis revealed that differentially expressed genes were involved in biological pathways related to metabolism, response to stimulus mainly related with regulation of immune response, cell cycle and extracellular matrix. A complementary pathway analysis and network analysis performed with Ingenuity Pathway Analysis tool corroborated and completed these findings. Collagen I, fibronectin and versican, evaluated by immunofluorescence, showed that changes at the gene expression level resulted in variation at the protein level. Tenascin-C staining in resected muscles demonstrated the formation of new tendon and myotendinous junctions. These data provide new insights about the biological response of the EOMs to resection surgery and may form the basis for future strategies to improve the outcome of strabismus surgery.

CHOROIDAL THICKNESS IN DIABETIC PATIENTS WITHOUT DIABETIC RETINOPATHY.

PURPOSE: To compare choroidal thickness (CT) between diabetic patients without diabetic retinopathy and a nondiabetic group. To explore how CT relates to disease duration, mean arterial pressure, glycemia, glycosylated hemoglobin, intraocular pressure, and ocular pulse amplitude. METHODS: Choroidal thickness was assessed using a spectral-domain optical coherence tomography and enhanced depth mode at 13 locations (subfoveal and 3 measurements 500 µm apart in 4 directions-nasal, temporal, superior, and inferior). Linear regression models were used. RESULTS: One hundred seventy-five patients were recruited (125 diabetic patients without diabetic retinopathy and 50 nondiabetic patients). In diabetic patients, although without statistical significance, CT showed a trend to be thicker in all locations (6.16-24.27 µm). Choroidal thickness was negatively associated with age (P < 0.001) in both groups, but only in the diabetic group, it was positively associated to ocular pulse amplitude (with a mean increase between 8.5 µm and 11.6 µm for each millimeter of mercury increase in ocular pulse amplitude). Diabetic patients' CT seems to stabilize after 150 months of diabetes, increase with higher glycemia levels (>160 mg/dL) while showing no fluctuation with glycosylated hemoglobin and mean arterial pressure. CONCLUSION: There seems to be a thickening of the choroid in diabetic patients without diabetic retinopathy. Moreover, this tissue may be functionally different in diabetes, as the pattern of associations seems to differ between groups.

Open-Angle Glaucoma: Drug Development Pipeline during the Last 20 Years (1995-2015).

OBJECTIVES: To analyse drug development for open-angle glaucoma during the last 20 years. METHODS: Research was performed by referring to clinical trials registered at the International Clinical Trials Registry Platform (ICTRP). A search for the condition "open-angle glaucoma" with the intervention "drug" was performed. We included trials registered from 01/01/1995 to 01/01/2015, only involving studies in phases 1, 2, and 3. Only studies resorting to novel treatment strategies (either novel drugs or yet-untested fixed associations of approved medication) were considered. RESULTS: We recorded 158 studies for the condition of open-angle glaucoma with a drug-based intervention; 65 of the studies reported phase 2 trials and 74 reported phase 3 trials. Pharmaceutical companies were the primary sponsors of 95.3% of the trials. Most of the studies (66.5%, n = 105) involved a new drug, and the remainder (33.5%, n = 53) tested fixed drug associations. The bulk of the trials (n = 99, 62.7%) involved the use of prostaglandin analogues, either as a comparator or a study drug. In descending order of frequency, the studies conducted involved Rho-kinase inhibitors (n = 15), carbonic anhydrase inhibitors (n = 14), ß-blockers (n = 7), angiostatic steroids (n = 6), α2-adrenergic agonists (n = 4), 5-HT2A receptor agonists (n = 4), and NMDA receptor antagonists (n = 2). A cyclin-dependent kinase inhibitor, an LIM-domain kinase 2 inhibitor, an A1 adenosine receptor agonist, catechin, macrolide, saffron, and seawater were each tested in 1 clinical trial. CONCLUSION: Research into the medical treatment of glaucoma indicates the use of prostaglandin analogues. However, there are a significant number of trials testing other drug classes, particularly Rho-kinase inhibitors. This new focus could lead to a potential increase in the number of therapeutical options for the management of glaucoma in the future.

Diabetic choroidopathy: a review of the current literature.

Diabetic retinopathy is an increasingly prevalent disease, and a leading contributor to the burden of all-cause blindness worldwide. In addition to retinal changes, choroidal abnormalities are common in patients with diabetes. The first studies concerning this vascular structure were based on histologic, indocyanine angiography and laser Doppler flowmetry techniques, but the development of new optical coherence tomography (OCT) technologies and imaging software for enhanced depth imaging (EDI)-OCT in recent years has made it possible to provide more detailed images of the choroidal anatomy and topography.In diabetic patients, several choroidal changes have been described in the literature throughout the years; the recent focus is choroidal thickness, which is significantly different from that in healthy patients. However, understanding choroidal manifestations of diabetic eye disease remains a real challenge, and this gap is hindering efforts towards better defining choroidal evaluation as a predictive factor for disease evolution and treatment response.This review aims to summarize the recent literature concerning changes in choroidal structure in diabetic patients, the relationship to diabetic retinal disease progression, and finally, the current and potential application of the measurement of variations in choroidal thickness for patient management.

Macular Ganglion Cell Layer and Peripapillary Retinal Nerve Fibre Layer Thickness in Patients with Unilateral Posterior Cerebral Artery Ischaemic Lesion: An Optical Coherence Tomography Study.

The purpose of this study is to evaluate the macular ganglion cell layer (GCL) and peripapillary retinal nerve fibre layer (RNFL) thickness in patients with unilateral posterior cerebral artery (PCA) ischaemic lesions using spectral-domain optical coherence tomography (SD-OCT). A prospective, case-control study of patients with unilateral PCA lesion was conducted in the neuro-ophthalmology clinic of Centro Hospitalar Lisboa Central. Macular and peripapillary SD-OCT scans were performed in both eyes of each patient. Twelve patients with PCA lesions (stroke group) and 12 healthy normal controls were included in this study. Peripapillary RNFL comparison between both eyes of the same subject in the stroke group found a thinning in the superior-temporal (p = 0.008) and inferior-temporal (p = 0.023) sectors of the ipsilateral eye and nasal sector (p = 0.003) of the contralateral eye. Macular GCL thickness comparison showed a reduction temporally in the ipsilateral eye (p = 0.004) and nasally in the contralateral eye (p = 0.002). Peripapillary RNFL thickness was significantly reduced in both eyes of patients with PCA compared with controls, affecting all sectors in the contralateral eye and predominantly temporal sectors in the ipsilateral eye. A statistically significant decrease in macular GCL thickness was found in both hemiretinas of both eyes of stroke patients when compared with controls (p < 0.05). This study shows that TRD may play a role in the physiopathology of lesions of the posterior visual pathway.

Retinal Ganglion Cell Layer Analysis by Optical Coherence Tomography in Toxic and Nutritional Optic Neuropathy.

OBJECTIVE: To analyze the retinal ganglion cell layer (RGL) by optical coherence tomography (OCT) in toxic and nutritional optic neuropathy and to correlate its thickness and volume with functional damage. METHODS: We conducted an observational cross-sectional study in healthy subjects and in patients with toxic optic neuropathy observed in the Neuro-Ophthalmology Department of Central Lisbon Hospital Center. Complete ophthalmologic examination, OCT (Heidelberg Spectralis), and automated static perimetry were performed. Thickness and macular volume of RGL layer and inner plexiform layer were measured after manual segmentation. RESULTS: The study included 16 eyes of 12 healthy subjects and 16 eyes of 8 patients with toxic and nutritional optic neuropathy. Age and gender did not differ between the 2 groups. Ethambutol was the cause of toxic optic neuropathy in 4 patients and nutritional factors (tobacco-alcohol) in 4 patients. A statistically significant decrease in thickness and volume of RGL, in all quadrants at 2 and 3 mm, was detected in individuals with optic neuropathy compared with controls (P < 0.01). A positive correlation between RGL thickness and mean deviation (MD) and between RGL volume and MD was detected (P < 0.05). There was a negative correlation between MD and time of disease (r = 0.846 P = 0.001) and a positive correlation between MD and visual acuity in logMAR (r = 0.739 P = 0.006). A majority of the structural parameters also correlated negatively with time of disease (P < 0.05). CONCLUSIONS: Decreased RGL thickness and volume detected in this study support a mechanism of RGL toxicity. RGL analysis may contribute to the diagnosis and management of toxic and nutritional optic neuropathies.

The impact of multifocal intraocular lens in retinal imaging with optical coherence tomography.

Multifocal intraocular lenses (MF IOLs) have concentric optical zones with different dioptric power, enabling patients to have good visual acuity at multiple focal points. However, several optical limitations have been attributed to this particular design. The purpose of this study is to access the effect of MF IOLs design on the accuracy of retinal optical coherence tomography (OCT). Cross-sectional study conducted at the Refractive Surgery Department of Central Lisbon Hospital Center. Twenty-three eyes of 15 patients with a diffractive MF IOL and 27 eyes of 15 patients with an aspheric monofocal IOL were included in this study. All patients underwent OCT macular scans using Heidelberg Spectralis(®). Macular thickness and volume values and image quality (Q factor) were compared between the two groups. There were no statistically significant differences between both groups regarding macular thickness or volume measurements. Retinal OCT image quality was significantly lower in the MF IOL group (p < 0.01). MF IOLs are associated with a significant decrease in OCT image quality. However, this fact does not seem to compromise the accuracy of spectral domain OCT retinal measurements.

Choroidal Thickness in Nonarteritic Anterior Ischaemic Optic Neuropathy: A Study with Optical Coherence Tomography.

Nonarteritic anterior ischemic optic neuropathy (NA-AION) is the most common nonglaucomatous optic neuropathy in adults over 50 years of age. It is usually related to cardiovascular risk factors. The primary objective of this study was to evaluate choroidal thickness in patients with chronic NA-AION, and the secondary objective was to evaluate macular thickness in these patients. This cross-sectional study compared two groups: group 1 included 20 eyes of 20 patients with chronic NA-AION, and group 2 included 31 eyes of 31 healthy controls. In both groups, the choroidal thickness was measured using the enhanced depth imaging program of Heidelberg Spectralis® optical coherence tomography (Heidelberg Engineering, Heidelberg, Germany). The macular thickness was also measured using the automatic software of the same device. The mean follow-up time after NA-AION in group 1 was 57.17 ± 26.92 months. The mean choroidal thickness of the posterior pole was 244.38 ± 61.03 µm in group 1 and 214.18 ± 65.97 µm in group 2 (p = 0.004). The mean macular thickness was higher in group 2. Macular thickness is reduced in eyes that had an episode of NA-AION, whereas choroidal thickness is generally higher in these eyes when compared with normal eyes. The increase in choroidal thickness may be due to a local dysfunction in vascular autoregulatory mechanisms, which may predispose to ischemic phenomena.

PROteolysis-Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives.

Leukemia is a heterogeneous group of life-threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long-term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis-TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin-proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC-mediated degradation of leukemia-associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment.

Photoaged polystyrene nanoplastics exposure results in reproductive toxicity due to oxidative damage in Caenorhabditis elegans.

The increase of plastic production together with the incipient reuse/recycling system has resulted in massive discards into the environment. This has facilitated the formation of micro- and nanoplastics (MNPs) which poses major risk for environmental health. Although some studies have investigated the effects of pristine MNPs on reproductive health, the effects of weathered MNPs have been poorly investigated. Here we show in Caenorhabditis elegans that exposure to photoaged polystyrene nanoplastics (PSNP-UV) results in worse reproductive performance than pristine PSNP (i.e., embryonic/larval lethality plus a decrease in the brood size, accompanied by a high number of unfertilized eggs), besides it affects size and locomotion behavior. Those effects were potentially generated by reactive products formed during UV-irradiation, since we found higher levels of reactive oxygen species and increased expression of GST-4 in worms exposed to PSNP-UV. Those results are supported by physical-chemical characterization analyses which indicate significant formation of oxidative degradation products from PSNP under UV-C irradiation. Our study also demonstrates that PSNP accumulate predominantly in the gastrointestinal tract of C. elegans (with no accumulation in the gonads), being completely eliminated at 96 h post-exposure. We complemented the toxicological analysis of PSNP/PSNP-UV by showing that the activation of the stress response via DAF-16 is dependent of the nanoplastics accumulation. Our data suggest that exposure to the wild PSNP, i.e., polystyrene nanoplastics more similar to those actually found in the environment, results in more important reprotoxic effects. This is associated with the presence of degradation products formed during UV-C irradiation and their interaction with biological targets.

Proteolysis-Targeting Chimeras (PROTACs) targeting the BCR-ABL for the treatment of chronic myeloid leukemia - a patent review.

INTRODUCTION: PROteolysis-TArgeting Chimeras (PROTACs) allow the selective degradation of a protein of interest (POI) by the ubiquitin-proteasome system (UPS). With this unique mechanism of action, the research and development of PROTACs that target the Breakpoint Cluster Region Abelson (BCR-ABL) tyrosine kinase (TK) has been increasing dramatically, as they are promising molecules in the treatment of Chronic Myeloid Leukemia (CML), one of the main hematological malignancies, which results from an uncontrolled myeloproliferation due to the constitutive activation of BCR-ABL. AREAS COVERED: This review summarizes the patents/applications published in the online databases like Espacenet or World Intellectual Property Organization regarding PROTACs that promote BCR-ABL degradation. Patents will be described mostly in terms of chemical structure, biochemical/pharmacological activities, and potential clinical applications. EXPERT OPINION: The recent discovery of the enormous potential of PROTACs led to the creation of new compounds capable of degrading BCR-ABL for the treatment of CML. Although still in reduced numbers, and in the pre-clinical phase of development, some compounds have already been shown to overcome some of the difficulties presented by conventional BCR-ABL inhibitors, such as the well-known imatinib. Therefore, it is very likely that some of the present PROTACs will enter future CML therapy in the coming years.

Recent advances in oridonin derivatives with anticancer activity.

Cancer is a leading cause of mortality responsible for an estimated 10 million deaths worldwide in 2020, and its incidence has been rapidly growing over the last decades. Population growth and aging, as well as high systemic toxicity and chemoresistance associated with conventional anticancer therapies reflect these high levels of incidence and mortality. Thus, efforts have been made to search for novel anticancer drugs with fewer side effects and greater therapeutic effectiveness. Nature continues to be the main source of biologically active lead compounds, and diterpenoids are considered one of the most important families since many have been reported to possess anticancer properties. Oridonin is an ent-kaurane tetracyclic diterpenoid isolated from Rabdosia rubescens and has been a target of extensive research over the last few years. It displays a broad range of biological effects including neuroprotective, anti-inflammatory, and anticancer activity against a variety of tumor cells. Several structural modifications on the oridonin and biological evaluation of its derivatives have been performed, creating a library of compounds with improved pharmacological activities. This mini-review aims to highlight the recent advances in oridonin derivatives as potential anticancer drugs, while succinctly exploring their proposed mechanisms of action. To wind up, future research perspectives in this field are also disclosed.

Corneal transplantation in aniridia-related keratopathy with a two-year follow-up period, an uncommon disease with precarious course.

PURPOSE: The purpose of this study is to study the frequency, surgical transplantation technique and outcome in patients with aniridia-related keratopathy (ARK) with two-year follow-up period. METHODS: A retrospective registry-study including all ARK cases performed in Sweden and Denmark between 2001 and 2016 and registered in the Swedish Cornea Transplant Registry. RESULTS: A total of 36 eyes of 26 patients were subjected to corneal transplantation due to ARK during 2001 to 2016. Penetrating keratoplasty (PK) was the procedure of choice in 58.3% (n = 21) of the eyes, followed by a combination of PK and limbal stem cell transplantation in 13.9% (n = 5) and keratolimbal allograft in 13.9% (n = 5). Boston keratoprosthesis was used in 8.3% (n = 3), and anterior lamellar keratoplasty in 5.6% (n = 2). Thirteen of the procedures (36.1%) were retransplantations. Two years after surgery 26 cases were available to follow-up of which 16 of the grafts were functioning (61.5%). The median visual acuity showed a trend of improvement from hand motion to counting fingers. CONCLUSIONS: A majority of the ARK cases (61.5%) had a graft providing useful vision for the patient 2 years after corneal transplantation, but the visual gain was modest at best. Longer follow-up time is required to evaluate functional graft outcomes. Despite the introduction of limbal stem cell transplantation as a suitable treatment, PK was the most common surgical method in the present study.

Current clinical practice in corneal crosslinking for treatment of progressive keratoconus in four Nordic countries.

PURPOSE: To evaluate clinical practice in the diagnosis and treatment of progressive keratoconus with corneal crosslinking (CXL) in four Nordic countries. METHODS: A questionnaire was sent to all centres at which keratoconus patients are evaluated and CXL is performed in Sweden, Denmark, Norway and Iceland. Nineteen of 20 centres participated. RESULTS: CXL is performed approximately 1300 times per year in these four Nordic countries with a population of around 21.7 million (2019). In most cases, progression is evaluated using the Pentacam HR, and the maximum keratometry reading (Kmax ) is considered the most important parameter. The most frequently used treatment protocol in Scandinavia is the 9 mW/cm2 epi-off protocol, using hydroxylpropyl methylcellulose riboflavin (HPMC-riboflavin). The participants deemed the following areas to be in most need of improvement: adaptation of the CXL protocol to individual patients (5/19), the development of effective epi-on treatment protocols (4/19), optimal performance of CXL in thin corneas (4/19), improvement of the definition of progression (2/19), and diagnosis of the need for re-treatment (2/19). CONCLUSIONS: We concluded that the diagnosis of progressive keratoconus and the diagnostic equipment used are similar. Treatment strategies are also similar but are suitably different to provide an interesting basis for the comparison of treatment outcomes. The high degree of participation in this survey indicates the possibility of future scientific collaboration on CXL focusing on the areas deemed to need improvement. It would also be of interest to evaluate the possibility of creating a Nordic CXL Registry. The high number of CXL treatments performed ensures sufficient statistical power to solve many questions. Such a registry could be an important contribution to evidence-based care and would allow for longitudinal evaluation.

Dose Administration Aid Service in Community Pharmacies: Characterization and Impact Assessment.

Adherence to therapies is a primary determinant of treatment success. Lack of medication adherence is often associated with medical and psychosocial issues due to complications from underlying conditions and is an enormous waste of medical resources. Dose Administration Aid Service (DAAS) can be seen as part of the solution, allowing individual medicine doses to be organized according to the dosing schedule determined by the patient's prescriber. The most recent systematic reviews admit the possibility of a positive impact of this service. In line with this background, the study reported in this paper aimed to characterize DAAS implementation in Portugal and understand the perceptions of pharmacists and owners of community pharmacies regarding the impact of DAAS, preferred methodology types, and State contribution. The study was guided by qualitative description methodology and reported using the consolidated criteria for reporting qualitative research (COREQ) checklist. Data were collected through semi-structured interviews with 18 pharmacists and/or owners of community pharmacies. Using qualitative content analysis, we identified categories that revealed that automated weekly methodology is the preferred methodology, because of its easiness of use and lower cost of preparation. However, the investment cost was felt to be too high by the participants considering the number of potential users for implementation in practice. Participants were also unanimous in recognizing that DAAS has a very positive impact in terms of safety and medication adherence, and the majority agreed that it also helped reduce medication waste. Implications of these findings for medication adherence are discussed.

An inter-day assessment of the ABC parameters in the evaluation of progressive keratoconus.

The progression of keratoconus is commonly determined by comparing the results of corneal tomographic measurements on different occasions. However, investigations on the repeatability of measurements are commonly performed within the same day, thus not taking the inter-day variation into account. The effect of keratoconus disease severity on the measurement error is also seldom considered. In this post hoc investigation, the parameters A, B and C in the Belin ABCD Progression Display were evaluated in relation to disease severity in intra-day and inter-day measurements. Four consecutive measurements were performed on 61 patients with keratoconus on the same day (intra-day). In another cohort, four consecutive measurements were obtained and then repeated 3 days later in 25 patients with keratoconus and 25 healthy controls (inter-day). The results suggest that the diagnosis of disease progression would benefit from inter-day measurements, and the stratification of the parameters A and C according to disease severity. It is also recommended that tomographic systems such as the Pentacam HR be modified to allow the comparison of both single measurements and the mean of replicate measurements of the parameters used in the assessment of progression of keratoconus.

Gestar, parir e não se tornar mãe: recusas, impossibilidades e violações no contexto da Covid-19 / To gestate, give birth and not become a mother: refusals, impossibilities and violations in the context of the Covid-19 pandemic / Gestar, parir y no convertirse en madre: rechazos, imposibilidades y violaciones en el contexto de la Covid-19

Com o intuito de chegar aos motivos que levam pessoas à entrega voluntária, escolhemos a comarca do Rio de Janeiro, RJ - Brasil - como lócus privilegiado. O caminho metodológico utilizado para a presente pesquisa foi a análise documental sobre ações de destituição de poder familiar e extinção de poder familiar que tramitaram a partir da promulgação da Lei n. 13.509/17, com atenção especial ao contexto pandêmico. A partir de reflexões propostas por Ferreira e Lowenkron, a coleta e análise desses documentos foi realizada levando em conta que a produção, a escrita e a circulação dos autos são tecnologias de fabricação das realidades. A partir das multiplicidades de vozes sobre os motivos para a entrega voluntária, construímos três eixos de análise: (1) a impossibilidade do cuidado; (2) a recusa da maternidade, a resignação e a indiferença; e (3) a violência institucional.(AU)

This study sought to understand the reasons for "voluntary surrender" in the district of Rio de Janeiro, Brazil. We performed a document analysis of termination of parental rights actions and extinction of parental rights actions that took place after the promulgation of Law 13509/17, focusing on the context of the Covid-19 pandemic. Drawing on the reflections of Ferreira and Lowenkron, data collection and document analysis was performed bearing in mind that the production, writing and circulation of writs are reality manufacturing technologies. Based on the multiplicity of voices speaking about the motives, we defined three core themes of analysis: (1) the impossibility of care; (2) the refusal of motherhood, resignation and indifference; and (3) institutional violence.(AU)

Con el objetivo de llegar a los motivos que llevan a las personas a la "entrega voluntaria", elegimos la comarca de Río de Janeiro/RJ - Brasil como locus privilegiado. El camino metodológico fue el análisis documental sobre acciones de destitución de poder familiar y extinción de poder familiar que se tramitaron a partir de la promulgación de la Ley nº 13.509/17, con atención especial al contexto pandémico. A partir de reflexiones propuestas por Ferreira y Lowenkron, la colecta y análisis de esos documentos se realizó llevando en consideración que la producción, la redacción y la circulación de los autos son tecnologías de fabricación de las realidades. A partir de las multiplicidades de voces sobre los motivos, construimos tres ejes de análisis: (1) la imposibilidad del cuidado, (2) el rechazo de la maternidad, la resignación y la indiferencia y (3) la violencia institucional.(AU)

Altered Signaling Pathways in Aniridia-Related Keratopathy.

Purpose: To study the Notch1, Wnt/beta-catenin, sonic hedgehog (SHH), and mammalian target of rapamycin (mTOR) cell signaling pathways in naïve and surgically treated corneas of aniridia cases with advanced aniridia-related keratopathy (ARK). Methods: Two naïve corneal buttons from patients with advanced ARK submitted to penetrating keratoplasty for the first time, one corneal button from an ARK patient that had undergone a keratolimbal allograft (KLAL), two corneal buttons from ARK patients who had previously undergone centered or decentered transplantation, and two adult healthy control corneas were processed for immunohistochemistry in this descriptive study. Antibodies specific against elements of the Notch1 (Notch1; Dlk1; Numb), Wnt/beta-catenin (Wnt5a; Wnt7a; beta-catenin), SHH (glioma-associated oncogene homolog [Gli1]; Hes1), and mTOR (mTOR1; ribosomal protein S6 [rpS6]) signaling pathways were used as well as antibodies against PAX6 and keratin 13 (Krt13). Results: All ARK corneas presented signs of conjunctivalization and analogous signaling pathway changes in the subepithelial pannus and epithelium, with decreased detection of the Notch1 signaling pathway and an increased presence of the Notch1 inhibitors Numb and Dlk1. Increased detections of Wnt/beta-catenin (enhanced presence of Wnt5a, Wnt7a, and beta-catenin), SHH (detection of Gli1 and Hes1), and mTOR (identification of mTOR and rpS6) signaling pathways were found in the subepithelial pannus and epithelium of all ARK corneas, when compared with normal controls. Conclusions: The similarity in pathway alterations found in all ARK corneas, irrespective of limbal stem cell transplantation, further supports the discussion on the role of host-specific factors and limbal stem cell deficiency in ARK.