X-linked Adrenal Hypoplasia Congenita: report of two families and a new NR0B1 mutation

Background: X-linked Adrenal Hypoplasia Congenita (X-linked AHC) tipically manifests as adrenal insufficiency in a bimodal clinical presentation (5–60 days and 2–13 years) and, at pubertal age, hypogonadotropic hypogonadism (HH) in males. It is caused by mutations in NR0B1 (present in Xp21.2), a gene with a critical role in the development of adrenals and hypothalamic-pituitary-gonadal (HPG) axis. It represents ~1% of all causes of primary adrenal insufficiency under age 18. We present two kindreds with NR0B1 mutations, one with a previously unreported mutation. Clinical case - family A: The proband presented with adrenal crisis at day 18 of life. Family history was relevant for an uncle death as a newborn. Hormonal assays revealed elevated ACTH (34,5 pmol/L, reference: T, leading to a premature stop codon, p.Lys362*, in exon 1. His mother and sister were both asymptomatic carriers for this mutation. This mutation, not described previously, leads probably to a non-functional truncated protein. Clinical case - family B: Kindred B had two males who presented with adrenal crisis at the newborn age (proband: 14 days; brother: 16 days). At 6 months of age, the proband had elevated ACTH (193.2 pmol/L, reference: G; p.Tyr81*, in exon 1, present in the two affected males. His mother and one sister were also asymptomatic carriers. Conclusion: Our kindreds highlights the clinical aspects of the rare X-linked AHC and its challenging differential diagnosis. The diagnosis was based on …. Completar … and an apparently X-linked mode of inheritance. Molecular analysis of the NR0B1 gene allowed the identification of the molecular defect in both families. Two different nonsense mutation in exon 1 were identified, giving rise most probably to truncated non-functional proteins, confirming the disease severity or the clinical phenotype of the affected boys. Mutation identification was relevant for genetic counseling of the parents, as well as for the patient’s sisters

Impact of composition and morphology on the optical properties of Si-NC/P3HT thin films processed from solution

Blends of Si nanocrystals (Si-NCs) and organic semiconductors are promising materials for new optical and electronic devices processed from solutions. Here, we study how the optical properties of composite films containing Si-NCs and the organic semiconductor poly(3-hexylthiophene) (P3HT) are influenced by the composition and morphology resulting from different solution-processing parameters and different solvents used dichlorobenzene vs. chloroform). The optical spectra of the hybrid films are described using a simple phenomenological model, with which we can discern the contribution of each material in the films to the optical properties. From this analysis, we obtain quantitative information about the composition and morphology of the hybrid nanostructured films, which otherwise would be obtained from more demanding microscopy and spectroscopy techniques. For the case of the Si-NC/P3HT blend, we find that in films deposited from dichlorobenzene solutions the Si-NCs contribute sizably to light absorption.This work was funded by FCT/I3N via the HybridSolar project, by the DFG via Teilprojekt B2 and by the European Union and the Ministry of Innovation, Science and Research of the German State of North Rhine-Westphalia in the framework of an Objective 2 Programme (European Regional Development Fund, ERDF). Funding is also acknowledged from the Portuguese Foundation for Science and Technology (FCT) through the Projects Nos. PTDC/FIS/112885/2009 and PEst-C/CTM/LA0025/2011 and via the Strategic Project LA 25:2011-2012

Predicting pharmaceutical powder flow from microscopy images using deep learning

The powder flowability of active pharmaceutical ingredients and excipients is a key parameter in the manufacturing of solid dosage forms used to inform the choice of tabletting methods. Direct compression is the favoured tabletting method; however, it is only suitable for materials that do not show cohesive behaviour. For materials that are cohesive, processing methods before tabletting, such as granulation, are required. Flowability measurements require large quantities of materials, significant time and human investments and repeat testing due to a lack of reproducible results when taking experimental measurements. This process is particularly challenging during the early-stage development of a new formulation when the amount of material is limited. To overcome these challenges, we present the use of deep learning methods to predict powder flow from images of pharmaceutical materials. We achieve 98.9% validation accuracy using images which by eye are impossible to extract meaningful particle or flowability information from. Using this approach, the need for experimental powder flow characterization is reduced as our models rely on images which are routinely captured as part of the powder size and shape characterization process. Using the imaging method recorded in this work, images can be captured with only 500 mg of material in just 1 hour. This completely removes the additional 30 g of material and extra measurement time needed to carry out repeat testing for traditional flowability measurements. This data-driven approach can be better applied to early-stage drug development which is by nature a highly iterative process. By reducing the material demand and measurement times, new pharmaceutical products can be developed faster with less material, reducing the costs, limiting material waste and hence resulting in a more efficient, sustainable manufacturing process. This work aims to improve decision-making for manufacturing route selection, achieving the key goal for digital design of being able to better predict properties while minimizing the amount of material required and time to inform process selection during early-stage development

The Antioxidant Role of Xanthurenic Acid in the Aedes aegypti Midgut during Digestion of a Blood Meal

In the midgut of the mosquito Aedes aegypti, a vector of dengue and yellow fever, an intense release of heme and iron takes place during the digestion of a blood meal. Here, we demonstrated via chromatography, light absorption and mass spectrometry that xanthurenic acid (XA), a product of the oxidative metabolism of tryptophan, is produced in the digestive apparatus after the ingestion of a blood meal and reaches milimolar levels after 24 h, the period of maximal digestive activity. XA formation does not occur in the White Eye (WE) strain, which lacks kynurenine hydroxylase and accumulates kynurenic acid. The formation of XA can be diminished by feeding the insect with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl] benzenesulfonamide (Ro-61-8048), an inhibitor of XA biosynthesis. Moreover, XA inhibits the phospholipid oxidation induced by heme or iron. A major fraction of this antioxidant activity is due to the capacity of XA to bind both heme and iron, which occurs at a slightly alkaline pH (7.5-8.0), a condition found in the insect midgut. The midgut epithelial cells of the WE mosquito has a marked increase in occurrence of cell death, which is reversed to levels similar to the wild type mosquitoes by feeding the insects with blood supplemented with XA, confirming the protective role of this molecule. Collectively, these results suggest a new role for XA as a heme and iron chelator that provides protection as an antioxidant and may help these animals adapt to a blood feeding habit

Enxaqueca em 746 pacientes com esclerose múltipla

Enxaqueca piora o sofrimento do paciente que tem esclerose múltipla (EM). ID-migraine é uma ferramenta útil para seleção de pacientes com enxaqueca e Migraine Disability Assessment (MIDAS) é um questionário que avalia o impacto da doença. O objetivo do presente estudo foi avaliar a presença e impacto de enxaqueca em pacientes com EM. Métodos: Pacientes diagnosticados com EM e tratados em clínicas especializadas foram convidados a responder um questionário online se também apresentassem cefaleia. Resultados: O estudo incluiu 746 participantes com cefaleia e EM que preencheram completamente as respostas. Foram 625 mulheres e 121 homens, sendo 69% dos pacientes com idade entre 20 e 40 anos. Enxaqueca foi identificada em 404 pacientes (54,1%) e moderado a grave impacto da doença foi observado em 68,3% dos casos. Conclusão: Enxaqueca é uma cefaleia primária frequente e incapacitante relatada por pacientes com EM.Migraine adds to the burden of patients suffering from multiple sclerosis (MS). The ID-migraine is a useful tool for screening migraine, and the Migraine Disability Assessment questionnaire can evaluate disease burden. The aim of the present study was to assess the presence and burden of migraine in patients with MS. Methods: Patients diagnosed with MS attending specialized MS units were invited to answer an online survey if they also experienced headache. Results: The study included 746 complete responses from patients with MS and headache. There were 625 women and 121 men, and 69% of all the patients were aged between 20 and 40 years. Migraine was identified in 404 patients (54.1%) and a moderate-to-high burden of disease was observed in 68.3% of the patients. Conclusion: Migraine is a frequent and disabling type of primary headache reported by patients with MS