Нарушение минерализации костей после аллогенной трансплантации гемопоэтических стволовых клеток у детей: одноцентровое когортное исследование

Bone mineral metabolism disorders are one of the most frequent late complications after allogeneic hematopoietic stem cell transplantation (HSCT) in children.The aim of the study was to detect the incidence and risk factors for bone mineral metabolism disorders in children who underwent allogeneic HSCT.Methods. We analyzed the data of medical charts of 294 children aged 0–17 y.o. who were hospitalized in 1994–2011, received  allogeneic HSCT, and survived for at least a year after intervention.  We determined the cumulative incidence and revealed risk factors for the development of osteopenia/osteoporosis and avascular necrosis.  Osteopenia/ osteoporosis was diagnosed after X-ray examination and annual computer X-ray osteodensitometry of the lumbar spine (during a 5-year period since 2003). The criteria for osteopenia is  bone density z-score 2.0, for osteoporosis — z-score 2.0 and  suffered fractures of the bones of the legs, compression fractures of  the spine and / or 2 fractures of the tubular bones of the hands (for both diagnoses). Avascular necrosis was diagnosed  radiographically and basing on magnetic resonance imaging results  (if there were complaints of pain or limb dysfunctions).Results. After the allogeneic HSCT during the median follow-up of 7.5 years bone mineral metabolism disorders developed in 48  patient (16%). Osteopenia / osteoporosis development was  associated with the following factors: the age 10 years (frequency  23.2% vs. 12% in children under 10 years, p = 0.014), acute graft- versus-host disease (GVHD) grade II–IV (24.2 vs 8.7% at GVHD  grade 0–I; p = 0.001), chronic GVHD (36.0% in extensive form vs.  14.5% in restricted form and 8.4% in the absence of chronic GVHD; p<0.001), immunosuppressive therapy >12 months (31.9 vs. 6.9% for therapy <3 months; p<0.001), glucocorticosteroid intake >3  months (93.8 vs 8.1% with GCs administration 3 months and 3.2% without GCs administration; p<0.001).Conclusion. Bone mineral metabolism disorders are revealed in 16% of cases in children who underwent HSCT. Determination of risk factors provides the possibility for timely diagnostics and improvement of therapy results.Нарушения костного минерального обмена являются поздними осложнениями аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) у детей.Цель исследования — определить частоту и факторы риска нарушений костного минерального обмена у детей после аллогенной ТГСК.Методы. Использовали данные, извлеченные из медицинской документации (истории  болезни, амбулаторные карты) детей (0–17 лет), госпитализированных в 1994–2011 гг. и  проживших минимум 1 год после аллогенной ТГСК. Определяли кумулятивную (до мая 2017  г.) частоту и факторы риска развития остеопении, остеопороза и аваскулярных некрозов.  Остеопению/остеопороз устанавливали рентгенологически (1994–2002 гг.) и по результатам ежегодной (на протяжении 5 лет начиная с 2003 г.) компьютерной рентгеновской  остеоденситометрии поясничного отдела позвоночника. Критерии остеопении — z-score  плотности костной ткани 2,0, остеопороза — z-score 2,0 и перенесенные переломы  костей ног, компрессионные переломы позвоночника и/или 2 переломов трубчатых костей  рук. Аваскулярные некрозы устанавливали (при наличии жалоб на боли или нарушения  функций конечностей) рентгенологически и по данным магнитно-резонансной томографии.Результаты. Нарушения костного минерального обмена в течение (медиана) 7,5 (6; 9) лет  развились у 48 (16%) из 294 детей, перенесших аллогенную ТГСК. С развитием остеопении/ остеопороза были ассоциированы возраст 10 лет (частота 23,2% против 12% у детей  младше 10 лет; р=0,014), острая реакция «трансплантат против хозяина» (РТПХ) II–IV  стадии (24,2 против 8,7% при РТПХ 0–I стадии; р=0,001), хроническая РТПХ (36,0% при  экстенсивной форме против 14,5% при ограниченной форме и 8,4% при отсутствии  хронической РТПХ; р<0,001), иммуносупрессивная терапия >12 мес (31,9 против 6,9% при  длительности <3 мес; р<0,001), прием глюкокортикостероидов >3 мес (93,8 против 8,1% при приеме 3 мес и 3,2% без терапии; р<0,001).Заключение. Нарушения костного минерального обмена встречаются в 16% случаев после  аллогенной ТГСК у детей, определение факторов риска их развития позволяет проводить своевременную диагностику и улучшать результаты терапии

Dual Mode of Mitochondrial ROS Action during Reprogramming to Pluripotency

Essential changes in cell metabolism and redox signaling occur during the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). In this paper, using genetic and pharmacological approaches, we have investigated the role of electron transport chain (ETC) complex-I (CI) of mitochondria in the process of cell reprogramming to pluripotency. Knockdown of NADH-ubiquinone oxidoreductase core subunits S1 (Ndufs1) or subunit B10 (Ndufb10) of the CI or inhibition of this complex with rotenone during mouse embryonic fibroblast (MEF) reprogramming resulted in a significantly decreased number of induced pluripotent stem cells (iPSCs). We have found that mitochondria and ROS levels due course of the reprogramming tightly correlate with each other, both reaching peak by day 3 and significantly declining by day 10 of the process. The transient augmentation of mitochondrial reactive oxygen species (ROS) could be attenuated by antioxidant treatment, which ameliorated overall reprogramming. However, ROS scavenging after day 3 or during the entire course of reprogramming was suppressive for iPSC formation. The ROS scavenging within the CI-deficient iPSC-precursors did not improve, but further suppressed the reprogramming. Our data therefore point to distinct modes of mitochondrial ROS action during the early versus mid and late stages of reprogramming. The data further substantiate the paradigm that balanced levels of oxidative phosphorylation have to be maintained on the route to pluripotency

Main concepts of the morphological analysis.

<p>a) morphological parameters calculated for each pore element, and b) examples of pores extracted from original soil images and their shape classifications (all five shape classes are shown in roundness (<i>4πA/P</i>^<i>2</i>)—isometry (<i>D/L</i>) coordinates).</p

Comparison of <i>C</i>_<i>2</i> cluster functions for original and reconstructed soil images for a) soil type I (best case), and b) soil type V (worst case).

<p>The legend is similar to that of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126515#pone.0126515.g004" target="_blank">Fig 4</a> for two-point probability and linear functions.</p

All original eight soil type images (left column) with their best performing reconstructions based on a cluster function analysis (middle column) or pore morphological analysis (right column) (if reconstruction performance for both analyses is identical, then only one image is shown).

<p>Size of thin section = 2.1×2.1 cm^<i>2</i>. Blue shaded areas highlight pore features that were poorly reconstructed: type II) vertical pore; III) complex elongated pores; V) one connected pore dominating entire image; VI) one connected fissure-like pore; VII) numerous horizontal cracks; VIII) horizontal features in the upper-right marked region.</p

Scatter plot of pore morphology classes using pore shape class 1–5 (Fig 3B) and orientation classes 6–8 (Fig 3B) for original and best reconstructed images for all soil types I-VIII.

<p>Scatter plot of pore morphology classes using pore shape class 1–5 (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126515#pone.0126515.g003" target="_blank">Fig 3B</a>) and orientation classes 6–8 (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126515#pone.0126515.g003" target="_blank">Fig 3B</a>) for original and best reconstructed images for all soil types I-VIII.</p

Soil thin-section information.

<p>*according to Russian soil classification [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126515#pone.0126515.ref083" target="_blank">83</a>]</p><p>Soil thin-section information.</p

Correlation functions for pores (solid and dashed lines) and solid phase (dash dot line).

<p><b><i>S</i></b>_{<b><i>2</i></b>}^{<b><i>(w)</i></b>}<b>and <i>L</i></b>_{<b><i>2</i></b>}^{<b><i>(w)</i></b>}<b>are, respectively, two-point probability and linear functions for pore phase; <i>L</i></b>_{<b><i>2</i></b>}^{<b><i>(b)</i></b>}<b>is a linear function for solid phase.</b> All correlation functions are evaluated in four principal directions according to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126515#pone.0126515.g001" target="_blank">Fig 1</a>. Example is for soil type I exhibiting the largest spatial correlation length of <i>L</i>_{<b><i>2</i></b>}^<i>(b)</i> across all soil types.</p

Overall scheme of the reconstruction procedure.

<p>Illustrations are provided for each stage using reconstruction of circles as example.</p

Schematic for correlation function computation in four principal directions (X, Y, X-diagonal and Y-diagonal) in a two-phase porous medium displaying pore (white areas) and solid (black areas) phase.

<p>Thick line segments represent examples providing correlation function’s local values of 1, while thin lines—0.</p