Assisted Community-Led Systematic Land Tenure Regularization

Systematic land cadastre is still an expensive and time-consuming endeavour in Mozambique. Government adopted the approach of systematic land cadastre, launching the "Terra Segura" Programme, to cover 4 thousand communities and 5 million rural parcels, out of an estimated total universe of circa 12 million parcels and plots. The initial exercises to attend this massive registration utilized traditional methods of land tenure regularization, resulting in being either too expensive or time-consuming initiatives, with serious problems of data quality. New approaches were designed and tested to create an effective sustainable cadastre, proposing an holistic approach to register the land. However, because strong evidence must be presented with regards to this holistic approach, there is a need to scale up the tests. The end goal of this scaling up exercise is to learn and disseminate lessons in local capacity development and improve the methodology and tools of the Terra Segura programme. Key Words

Surgical Management of Bilateral Limbal Stem Cell Deficiency

At the age of 43 years-old, a man was left with bilateral limbal stem cell deficiency after an ocular alkaline burn with lime, which resulted in corneal opacification. After multiple unsuccessful surgical attempts to restore vision, including penetrating keratoplasties and Boston keratoprosthesis, visual acuity was counting fingers in the left eye. At 73 years of age, the patient underwent another surgery in his left eye. Cauterization of neovessels and removal of the vascular pannus were followed by partial excision of Tenon’s capsule. Penetrating keratoplasty was followed by an intrastromal injection of anti-VEGF (vascular endothelial growth factor), and the ocular surface was covered with amniotic membrane. Postoperatively, the graft was clear with no signs of inflammation; vision improved to 20/50 and remained stable throughout the following two years. Herein we describe some adjunctive procedures that might have delayed failure and rejection of the corneal graft. This case demonstrates the difficulties in treating bilateral limbal stem cell deficiency in a tertiary eye care center with no capacity to perform stem cell therapy

Insights and future directions for the application of perinatal derivatives in eye diseases: A critical review of preclinical and clinical studies.

Perinatal derivatives (PnD) are gaining interest as a source for cell-based therapies. Since the eye is easily accessible to local administration, eye diseases may be excellent candidates to evaluate novel therapeutic approaches. With this work, we performed a systematic review of published preclinical and clinical studies addressing PnD in the treatment of ocular diseases. We have set two specific objectives: (i) to investigate the current level of standardization in applied technical procedures in preclinical studies and (ii) to assess clinical efficacy in clinical trials. Hereto, we selected studies that applied amniotic membrane (hAM) and mesenchymal stromal cells derived from amniotic membrane (hAMSC), placenta (hPMSC), umbilical cord (hUC-MSC) and Wharton's Jelly (hUC-WJ-MSC), excluding those where cells were not transplanted individually, following a systematic PubMed search for preclinical studies and consultation of clinical studies on https://clinicaltrials.gov and https://www.clinicaltrialsregister.eu/. Our bibliographic search retrieved 26 pre-clinical studies and 27 clinical trials. There was a considerable overlap regarding targeted ocular structures. Another common feature is the marked tendency towards (i) locally administered treatments and (ii) the PnD type. In the cornea/ocular surface, hAM was preferred and usually applied directly covering the ocular surface. For neuroretinal disorders, intra-ocular injection of umbilical or placental-derived cells was preferred. In general, basic research reported favourable outcomes. However, due to lack of standardization between different studies, until now there is no clear consensus regarding the fate of administered PnD or their mode of action. This might be accountable for the low index of clinical translation. Regarding clinical trials, only a minority provided results and a considerable proportion is in "unknown status". Nevertheless, from the limited clinical evidence available, hAM proved beneficial in the symptomatic relief of bullous keratopathy, treating dry eye disease and preventing glaucoma drainage device tube exposure. Regarding neuroretinal diseases, application of Wharton's Jelly MSC seems to become a promising future approach. In conclusion, PnD-based therapies seem to be beneficial in the treatment of several ocular diseases. However, much is yet to be done both in the pre-clinical and in the clinical setting before they can be included in the daily ophthalmic practice

Phase 2 randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis

Purpose: To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from impaired corneal innervation. Design: Phase 2 multicenter, randomized, double-masked, vehicle-controlled trial. Participants: Patients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye. Methods: The REPARO phase 2 study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study treatment, whereas efficacy was by intention to treat. Main Outcome Measures: Corneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining). Results: At week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) versus 54.9% receiving rhNGF 10 μg/ml (+35.3%; 97.06% confidence interval [CI], 15.88–54.71; P < 0.001) and 58.0% receiving rhNGF 20 μg/ml (+38.4%; 97.06% CI, 18.96–57.83; P < 0.001). At week 8 (key secondary end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 74.5% receiving rhNGF 10 μg/ml (+31.4%; 97.06% CI, 11.25–51.49; P = 0.001) and 74.0% receiving rhNGF 20 μg/ml (+30.9%; 97.06% CI, 10.60–51.13; P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled rhNGF treatment remained recurrence free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient. Conclusions: Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK

Phase I trial of recombinant human nerve growth factor for neurotrophic keratitis

Neurotrophic keratitis/keratopathy (NK), a rare degenerative corneal disease, lacks effective pharmacologic therapies.1 Because NK pathology involves trigeminal nerve damage and loss of corneal innervation, nerve growth factor (NGF) is surmised to promote healing of NK.2 Preliminary studies with murine NGF demonstrated efficacy for treating corneal neurotrophic ulcers;3 however, the complex tertiary structure of NGF has complicated the production of recombinant human NGF (rhNGF) suitable for clinical development. To this end, we developed an Escherichia coli–derived rhNGF formulation that demonstrated to be well tolerated and safe for topical ophthalmic use in a phase I study in healthy volunteers.4 We report phase I results of topical rhNGF for patients with moderate-to-severe NK

Urinary Mass Spectrometry Profiles in Age-Related Macular Degeneration

We and others have shown that patients with different severity stages of age-related macular degeneration (AMD) have distinct plasma metabolomic profiles compared to controls. Urine is a biofluid that can be obtained non-invasively and, in other fields, urine metabolomics has been proposed as a feasible alternative to plasma biomarkers. However, no studies have applied urinary mass spectrometry (MS) metabolomics to AMD. This study aimed to assess urinary metabolomic profiles of patients with different stages of AMD and a control group. We included two prospectively designed, multicenter, cross-sectional study cohorts: Boston, US (n = 185) and Coimbra, Portugal (n = 299). We collected fasting urine samples, which were used for metabolomic profiling (Ultrahigh Performance Liquid chromatography-Mass Spectrometry). Multivariable logistic and ordinal logistic regression models were used for analysis, accounting for gender, age, body mass index and use of AREDS supplementation. Results from both cohorts were then meta-analyzed. No significant differences in urine metabolites were seen when comparing patients with AMD and controls. When disease severity was considered as an outcome, six urinary metabolites differed significantly (p < 0.01). In particular, two of the metabolites identified have been previously shown by our group to also differ in the plasma of patients of AMD compared to controls and across severity stages. While there are fewer urinary metabolites associated with AMD than plasma metabolites, this study identified some differences across stages of disease that support previous work performed with plasma, thus highlighting the potential of these metabolites as future biomarkers for AMD

Caracterização do componente vascular da barreira hemato-retiniana: Estudos de microperfusão de arteríolas retinianas em coelhos normais e diabéticos

A Barreira Hemato-Retiniana (BHR) está localizada em 2 níveis - o epitélio pigmentado da retina e as células endoteliais dos vasos da retina, constituindo as chamadas Barreira Hemato-Retiniana Interna e Barreira Hemato-Retiniana Externa. Se bem que estas duas barreiras apresentem características comuns, os seus pormenores morfológicos, bioquímicos e, em suma, as suas funções são bem diferentes. Grande parte dos trabalhos estudando a permeabilidade e os mecanismos de transporte através da BHR referem-se, geralmente, à BHR como um todo, incluindo a externa e a interna, pouco se sabendo acerca da contribuição relativa de cada um dos seus componentes. Desenvolvemos um modelo experimental novo que nos permite estudar directamente in vitro a permeabilidade do componente vascular da Barreira Hemato-Retiniana quer em condições normais quer na diabetes experimental, através da utilização de técnicas de microperfusão adaptadas de estudos em túbulos renais, nas quais procedemos a ligeiras modificações. A aplicação desta metodologia à fisiologia vascular tem sido limitada em virtude, fundamentalmente, de problemas anatómicos relacionados com a dificuldade de isolamento de pequenos segmentos vasculares. Os vasos retinianos do coelho parecem ser particularmente apropriados para este tipo de estudo pois assentam directamente sobre a camada de fibras nervosas da retina, estando as suas paredes completamente livres de tecido glial em seu redor e em contacto directo com o vítreo, tornando possível a sua dissecção manual. Assim demonstrámos: 1 - A existência de um movimento uni-direccional de fluoresceína através dos vasos da retina, de fora para dentro do seu lúmen, aparentemente devido a um processo mais geral de transporte activo de aniões orgânicos; 2 - A existência de um fluxo de fluido de fora dos vasos para o seu lúmen; 3 - A dependência do fluxo de fluido em relação à fluoresceína e possivelmente em relação ao sistema mais geral de transporte de aniões orgânicos. Este fluxo de fluido também é dependente da temperatura; 4 - O transporte activo de fluoresceína aparece diminuído nas arteríolas de animais diabéticos, indicando uma alteração da permeabilidade nas suas paredes; 5 - A existência de um transporte de D-glicose do lúmen dos vasos retinianos para o banho, saturável e parcialmente inibido pela floretina; 6 - O fluxo de D-glicose, do lúmen dos vasos para o banho, encontra-se significativamente aumentado em arteríolas diabéticas e a floretina deixa de exercer uma acção inibitória. Este modelo experimental de microperfusão de segmentos vasculares da retina desenvolvido por nós, abre pois perspectivas extremamente interessantes na investigação da fisiologia e farmacologia dos vasos da retina, quer em situações normais quer em situações patológicas experimentais, bem como na manipulação farmacológica da retinopatia diabética