Paediatric cyclical Cushing's disease due to corticotroph cell hyperplasia

Background: Cushing's disease is very rare in the paediatric population. Although uncommon, corticotroph hyperplasia causing Cushing's syndrome has been described in the adult population, but appears to be extremely rare in children. Likewise, cyclical cortisol hypersecretion, while accounting for 15 % of adult cases of Cushing's disease, has only rarely been described in the paediatric population. Here, we describe a very rare case of a 13-year old boy with cyclical cortisol hypersecretion secondary to corticotroph cell hyperplasia. Case presentation: The case is that of a 13-year old boy, presenting with a long history of symptoms and signs suggestive of hypercortisolism, who was found to have cyclical ACTH-dependent hypercortisolism following dynamic pituitary testing and serial late-night salivary cortisol measurements. The patient underwent endoscopic transsphenoidal resection of the pituitary. Early surgical remission was confirmed by undetectable post-operative morning plasma cortisol levels. Histology and immunocytochemistry of the resected pituitary tissue showed extensive corticotroph cell hyperplasia. Conclusion: This report describes a rare case of cyclical Cushing's disease secondary to corticotroph hyperplasia in a paediatric patient. This highlights the challenging and varied nature of Cushing's disease and its diagnosis, and the need to keep a differential diagnosis in mind during the diagnostic process.</p

GDPR: an impediment to research?

Background: The recent introduction of the General Data Protection Regulation and Health Research Regulations has been an area of significant concern for those engaged in clinical research. These European regulations, following subsequent interpretation by Ireland's Department of Health, now place Ireland in a unique position which differs substantially from other European countries and may prove a significant impediment to Irish clinical research, depriving Irish patients of timely access to potentially life-saving treatments and making Ireland less attractive to pharmaceutical companies engaged in this area. At the very least, the regulations, as applied in Ireland, will place a significant extra burden of work on Ireland's clinical researchers and at their worst will force individuals and institutions out of the clinical research field, which will result in significant loss to the Irish knowledge economy and lead to the detriment of patient care.Aim: In this article, we explore what exactly is proposed by Europe's GDPR and by Ireland's Health Research Regulations. We look at the challenges presented to clinical researchers, and we highlight those areas, which need clarification by the Department of Health and by the Data Protection Commissioner.Conclusions: We propose five recommendations, which would ameliorate some of the more restrictive impositions of these regulations. This review was commissioned by the Irish Academy of Medical Science.</p

Lipofuscin accumulation and autophagy in glaucomatous human lamina cribrosa cells

Background: Disease associated alterations in the phenotype of lamina cribrosa (LC) cells are implicated in changes occurring at the optic nerve head (ONH) in glaucoma. Lipofuscin, the formation of which is driven by reactive oxygen species (ROS), is an intralysosomal, non-degradable, auto-fluorescent macromolecule which accumulates with age and can affect autophagy - the lysosomal degradation of a cell's constituents. We aimed to compare the content of lipofuscin-like material and markers of autophagy in LC cells from normal and glaucoma donor eyes. Methods: The number and size of peri-nuclear lysosomes were examined by transmission electron microscopy (TEM). Cellular auto-fluorescence was quantified by flow cytometry. Cathepsin K mRNA levels were assessed by PCR. Autophagy protein 5 (Atg5) mRNA and protein levels were analysed by PCR and Western blot. Protein levels of subunits of the microtubule associated proteins (MAP) 1A and 1B, light chain 3 (LC3) I and II were analysed by Western blot. Immunohistochemical staining of LC3-II in ONH sections from normal and glaucomatous donor eyes was performed. Results: A significant increase in the number of peri-nuclear lysosomes [4.1 × 10,000 per high power field (h.p.f.) ± 1.9 vs. 2.0 × 10,000 per h.p.f. ± 1.3, p = 0.002, n = 3] and whole cell auto-fluorescence (83.62 ± 45.1 v 41.01 ± 3.9, p = 0.02, n = 3) was found in glaucomatous LC cells relative to normal LC cells. Glaucomatous LC cells possessed significantly higher levels of Cathepsin K mRNA and Atg5 mRNA and protein. Enhanced levels of LC3-II were found in both LC cells and optic nerve head sections from glaucoma donors. Conclusions: Increased lipofuscin formation is characteristic of LC cells from donors with glaucoma. This finding confirms the importance of oxidative stress in glaucoma pathogenesis. Intracellular lipofuscin accumulation may have important effects on autophagy the modification of which could form the basis for future novel glaucoma treatments.</p

Fetal characteristics at the time of intervention at 124 days of gestation.

<p>Fetal characteristics at the time of intervention at 124 days of gestation.</p

Representative slices of whole-brain DTI colour maps of the thalamus (Th) for radial diffusivity (RD).

<p>Voxel diffusivity intensities falling below the low threshold are shown in red for RD measurements for all lamb brains. All low-diffusion maps are overlaid on diffusion images for a slice passing through the Th. All lambs in the unoperated control (Cont n = 6; A) group had no low RD values in the Th, but low RD values appeared in the Th of 4 lambs following sham surgery (Sham n = 5; B), 4 lambs following injurious ventilation (INJ n = 5; C), and 6 lambs following umbilical cord occlusion (INJ+UCO n = 7; D).</p

Absolute magnetic resonance spectroscopy (MRS) concentrations of metabolites in the preterm lamb brain.

<p>Individual absolute concentrations of lactate (Lac), creatine (Cr), choline (Cho), and N-acetylaspartate (NAA) using a single-voxel MRS encompassing supratentorial central white matter and deep grey matter in the unoperated control (Cont; blue open squares n = 6), sham surgery (Sham; blue closed squares n = 5), injurious ventilation (INJ; red open circles n = 5), and INJ + umbilical cord occlusion (INJ+UCO; red closed circles n = 7) groups. One way ANOVA comparisons tests relative to the Cont group were used with <i>P</i><0.05 was considered statistically significant. *<i>P</i><0.01, **<i>P</i><0.001 vs INJ+UCO.</p

Representative slices of whole-brain DTI colour maps of the thalamus (Th) for axial diffusivity (AD).

<p>Voxel diffusivity intensities falling below the low threshold are shown as red for AD measurements for all lamb brains. All low-diffusion maps are overlaid on diffusion images for a slice passing through the thalamus (Th). In the injurious ventilation (INJ n = 5; C) and umbilical cord occlusion (INJ+UCO n = 7; D) groups, red indicates lower values in the range of the threshold, while black indicates values below the threshold (see explanation in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188737#pone.0188737.s002" target="_blank">S2 Fig</a>). One sham surgery (Sham n = 5; B), one INJ, and three INJ+UCO lambs had widespread lower diffusivity values in the Th than unoperated control lambs (Cont n = 6; A).</p

Physiological parameters.

<p>(A) Fraction of inspired oxygen (FiO₂) in the unoperated control (Cont; blue open squares n = 6), sham surgery (Sham; blue closed squares n = 5), injurious ventilation (INJ; red open circles n = 5), and INJ + umbilical cord occlusion (INJ+UCO; red closed circles n = 7) groups. (B) pH. (C) Partial pressure of arterial oxygen (PaO₂) and (D) carbon dioxide (PaCO₂). *<i>P</i><0.01, **<i>P</i><0.001 vs INJ+UCO.</p