Clinical Practice: A Proposed Standardized Ophthalmological Assessment for Patients with Cystinosis

<p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>.</b> <a href="https://link.springer.com/article/10.1007/s40123-017-0089-3">https://link.springer.com/article/10.1007/s40123-017-0089-3</a></p><p></p><p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p

Catch–up growth in the first two years of life in Extremely Low Birth Weight (ELBW) infants is associated with lower body fat in young adolescence

<div><p>Aim</p><p>To investigate growth patterns and anthropometrics in former extremely low birth weight (ELBW, <1000 g) children and link these outcomes to neurocognition and body composition in childhood.</p><p>Methods</p><p>ELBW children were examined at birth (n = 140), at 9 and 24 months (n≥96) and at approximately 11 years within the framework of the PREMATCH (PREMATurity as predictor children’s of Cardiovascular and renal Health) case–control (n = 93–87) study. Regional growth charts were used to convert anthropometrics into Z–scores. Catch–up growth in the first two years of life was qualified as present if ΔZ–score >0.67 SDS. At 11 years, anthropometrics, neurocognitive performance, body composition, grip strength and puberty scores were assessed.</p><p>Results</p><p>ELBW neonates displayed extra–uterine growth restriction with mean Z–scores for height, weight and head circumference of –0.77, –0.93 and –0.46 at birth, –1.61, –1.67 and –0.72 at 9 months, –1.22, –1.61 and –0.84 at 24 months, and –0.42, –0.49 and –1.09 at 11 years. ELBW children performed consistently worse on neurocognitive testing with an average intelligence quotient equivalent at 11 years of 92.5 (SD 13.1). Catch–up growth was not associated with neurocognitive performance. Compared to controls, ELBW cases had lower grip strength (13.6 vs. 15.9 kg) and percentage lean body weight (75.1 vs. 80.5%), but higher body fat (24.6 vs. 19.2%) and advanced puberty scores at 11 years (all <i>P</i>≤0.025). Catch–up growth for weight and height in the first two years of life in cases was associated with a lower percentage body fat compared to cases without catch–up growth (16.8% catch-up growth for weight <i>vs</i>. 25.7%, <i>P</i><0.001; 20.9% catch-up for height <i>vs</i>. 25.8%, <i>P</i> = 0.049).</p><p>Conclusions</p><p>In young adolescence, former ELBW children still have difficulties to reach their target height. Compared to normal birth weight controls, ELBW adolescents show lower neurocognitive performance and grip strength and a higher percentage body fat, a potential risk factor for adverse health outcomes in adulthood. Our key finding is that catch–up growth in ELBW children in the first two years of life is associated with a lower percentage body fat and is therefore likely to be beneficial.</p></div

Difference in catch-up growth and no catch-up growth during childhood versus body fat in young adolescence in former ELBW children.

<p>Difference in catch-up growth and no catch-up growth during childhood versus body fat in young adolescence in former ELBW children.</p

The Functional Implications of Common Genetic Variation in <i>CYP3A5</i> and <i>ABCB1</i> in Human Proximal Tubule Cells

<i>Background:</i> Calcineurin inhibitors (CNIs) are the primary immunosuppressive drugs used in solid organ transplantation but are associated with the development of histological lesions leading to kidney failure. CNIs are metabolized by CYP3A and excreted by not only P-glycoprotein (P-gp) (<i>ABCB1</i>) in the gut and liver, but also by proximal tubule cells (PTCs) in the kidney. Multiple studies have demonstrated the importance of genetic variation in <i>CYP3A5</i> and <i>ABCB1</i> for CNI disposition and nephrotoxicity. The present study was designed to study the functional implication of variation in these two genes in human PTCs. <i>Methods</i>: A technique was developed to culture cells from renal tissue obtained from renal graft recipients by routine kidney biopsy. Primary cells were immortalized, subcloned, and then characterized for specific PTC markers (AQP1, CD13, brush border morphology) and donor <i>CYP3A5</i>(<i>rs776746</i>)/<i>ABCB1</i>(<i>rs1045642</i>) genotype. We then selected specific sets of confirmed conditionally immortalized PTCs (ciPTC) according to different combinations of the aforementioned genetic variants. Quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry were performed for studying <i>CYP3A5</i> and <i>ABCB1</i> expression. <i>CYP3A5</i> activity was assessed by differential midazolam (MDZ) hydroxylation and P-gp (<i>ABCB1</i> product) activity by a calcein efflux assay. Differential drug metabolism between cell lines was assessed by tacrolimus disappearance over 24 h. <i>Results:</i> Cell lines were generated from 27 out of 38 tissue samples. On the basis of genotype and PTC biomarkers, 11 subclones were selected. <i>In vitro</i> PTC morphology with brush border microvilli was confirmed. <i>CYP3A5*1</i> carriers had increased 1-OH/4-OH MDZ formation versus homozygous <i>*3</i> carriers (mean: 2.36 (95% CI:1.11–3.40) vs 0.88 (95% CI:0.48–1.27); <i>p</i> < 0.05). P-gp activity was confirmed by calcein accumulation (mean 38.6%; 95% CI:32.8–44.4%), which was higher in cell lines with the <i>ABCB1 3435TT</i> than the <i>3435CC</i>/<i>CT</i> genotype (46.2% vs 35.5%; 95% CI:28.7–42.2%). Tacrolimus disappearance was about two-fold higher in cell lines with the combined <i>CYP3A5*1</i>/<i>ABCB1 3435TT</i> genotype versus other genotype combinations. <i>Conclusion:</i> Biopsy-derived and immortalized human PTC cell lines demonstrate functional expression of genes involved in CNI metabolism. Differences in functional expression were detected according to common genetic variants in <i>CYP3A5</i> and <i>ABCB1</i>. The studied genetic variants had a significant impact on <i>in vitro</i> tacrolimus metabolism. In particular, ciPTC with the combined <i>CYP3A5*1/ABCB1 3435TT</i> genotype demonstrated higher tacrolimus disappearance versus ciPTCs with a different pharmacogenetic profile. This <i>in vitro</i> model stresses the importance of the incorporation of pharmacogenetic variation in studies involved in (renal) drug disposition

Mean Z–scores of height, weight and head circumference over time).

<p>Mean Z–scores of height, weight and head circumference over time).</p

Phenotype analysis, nephrin expression and evaluation of glomerular function in adriamycin exposed zebrafish.

<p>(A) Different categories of phenotype were defined in the adriamycin exposed embryos at 4 dpf: embryos with a normal phenotype, embryos with visible pericardial edema (white arrow) and dysmorphic or dead embryos. (B) 100 embryos per condition were live-screened at 4 dpf and assigned to a phenotype category. Increasing adriamycin concentrations in the culture medium were associated with an increasing percentage of embryos with pericardial edema. (C) qPCR was performed using total RNA from control and adriamycin exposed embryos at 4 dpf. A significantly decreased expression of nephrin (corrected for housekeeping gene <i>elfa</i>) was observed in the adriamycin exposed embryos compared to the control fish. The experiment was performed twice in triplicate. Bars represent means ± SD. * P<0.05 in comparison to condition without the addition of adriamycin. (D) Rhodamine-labeled 70 kDa dextran was injected in the cardiac venous sinus of 75 hpf old embryos. LEFT: A representative immunofluorescence picture of a control embryo immediately after injection shows the distribution of fluorescence through the vascular system of the zebrafish larva. A dose-dependent diminishing effect of adriamycin on fluorescence recorded in the fish eye 5 hours after injection was observed. Representative images of the eye from 0, 10 and 30 μM adriamycin treated embryos 5 hours after injection are shown. RIGHT: A diagrammatic representation shows the quantification of the mean fluorescence intensity ± SD recorded in the retinal vascular bed. * P < 0.05 in comparison to condition without the addition of adriamycin.</p

Flowchart of the Extremely Low Birth Weight (ELBW) cohort.

<p>Flowchart of the Extremely Low Birth Weight (ELBW) cohort.</p

Z–score trends in individual cases from birth till 11 years).

<p>(A) Z-scores for height, (B) Z-scores for weight, and (C) Z-scores for head circumference.</p

Characteristics in former ELBW children and controls.

<p>Characteristics in former ELBW children and controls.</p

Quantification of thrombocytes in nephrin depleted <i>Tg(cd41</i>:<i>EGFP)</i> transgenic zebrafish.

<p>(A) LEFT: GFP-labeled thrombocytes and thrombocyte precursors are formed in the zebrafish caudal hematopoietic tissue (CHT) region (white arrows) at 3 dpf. Representative pictures of the CHT region of a control and a nephrin depleted (100 μM nephrin morpholino) embryo at 3 dpf are shown. No obvious differences in thrombocyte numbers were observed. RIGHT: Pixel intensity was measured using ImageJ software. The graph represents means ± SD from measurements in three embryos per condition. (B) LEFT: Western blot for GFP and β-actin (loading control) was performed using total zebrafish lysates at 3 dpf. A representative blot is shown. RIGHT: Signal intensity was measured using ImageJ software. The graph represents means ± SD from measurements in two repeated experiments. (C) LEFT: Fluorescence-activated cell sorter (FACS) analysis of control zebrafish lysates for CD41 positive cells was performed at 3 dpf. MIDDLE: FACS analysis of morphant zebrafish lysates for CD41 positive cells was performed at 3 dpf. RIGHT: A diagrammatic representation of the number of GFP-positive cells per 100,000 counted cells. For each zebrafish lysate, 500,000 cells were counted and analyzed. Graphs represent means ± SD from three repeated experiments performed in duplicate. Mo, nephrin morpholino injected; Co, control morpholino injected; SCC, side scatter; GFP, green fluorescent protein.</p