Этапные операции "damage control" при тяжелых повреждениях печени

Показана эффективность применения при тяжелых травмах печени этапных оперативных вмешательств "damage control", направленных на профилактику коагулопатии, полиорганной недостаточности, а также на уменьшение числа послеоперационных гнойно−септических осложнений и летальности.The efficacy of staged surgical procedures "damage control" aimed at prevention of coagulopathy, polyorgan insufficiency as well as the changes in the number of post−operative purulent septic complications and death is shown

Neonatal brain injury unravels transcriptional and signaling changes underlying the reactivation of cortical progenitors

Summary: Germinal activity persists throughout life within the ventricular-subventricular zone (V-SVZ) of the postnatal forebrain due to the presence of neural stem cells (NSCs). Accumulating evidence points to a recruitment for these cells following early brain injuries and suggests their amenability to manipulations. We used chronic hypoxia as a rodent model of early brain injury to investigate the reactivation of cortical progenitors at postnatal times. Our results reveal an increased proliferation and production of glutamatergic progenitors within the dorsal V-SVZ. Fate mapping of V-SVZ NSCs demonstrates their contribution to de novo cortical neurogenesis. Transcriptional analysis of glutamatergic progenitors shows parallel changes in methyltransferase 14 (Mettl14) and Wnt/β-catenin signaling. In agreement, manipulations through genetic and pharmacological activation of Mettl14 and the Wnt/β-catenin pathway, respectively, induce neurogenesis and promote newly-formed cell maturation. Finally, labeling of young adult NSCs demonstrates that pharmacological NSC activation has no adverse effects on the reservoir of V-SVZ NSCs and on their germinal activity

Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement.

Mesenchymal stem cell (MSC) administration via the intranasal route could become an effective therapy to treat neonatal hypoxic-ischemic (HI) brain damage. We analyzed long-term effects of intranasal MSC treatment on lesion size, sensorimotor and cognitive behavior, and determined the therapeutic window and dose response relationships. Furthermore, the appearance of MSCs at the lesion site in relation to the therapeutic window was examined. Nine-day-old mice were subjected to unilateral carotid artery occlusion and hypoxia. MSCs were administered intranasally at 3, 10 or 17 days after hypoxia-ischemia (HI). Motor, cognitive and histological outcome was investigated. PKH-26 labeled cells were used to localize MSCs in the brain. We identified 0.5 × 10(6) MSCs as the minimal effective dose with a therapeutic window of at least 10 days but less than 17 days post-HI. A single dose was sufficient for a marked beneficial effect. MSCs reach the lesion site within 24 h when given 3 or 10 days after injury. However, no MSCs were detected in the lesion when administered 17 days following HI. We also show for the first time that intranasal MSC treatment after HI improves cognitive function. Improvement of sensorimotor function and histological outcome was maintained until at least 9 weeks post-HI. The capacity of MSCs to reach the lesion site within 24 h after intranasal administration at 10 days but not at 17 days post-HI indicates a therapeutic window of at least 10 days. Our data strongly indicate that intranasal MSC treatment may become a promising non-invasive therapeutic tool to effectively reduce neonatal encephalopathy

Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity.

Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases

Transcriptional Dysregulation in Postnatal Glutamatergic Progenitors Contributes to Closure of the Cortical Neurogenic Period

Progenitors of cortical glutamatergic neurons (Glu progenitors) are usually thought to switch fate before birth to produce astrocytes. We used fate-mapping approaches to show that a large fraction of Glu progenitors persist in the postnatal forebrain after closure of the cortical neurogenesis period. Postnatal Glu progenitors do not accumulate during embryonal development but are produced by embryonal radial glial cells that persist after birth in the dorsal subventricular zone and continue to give rise to cortical neurons, although with low efficiency. Single-cell RNA sequencing reveals a dysregulation of transcriptional programs, which parallels changes in m6A methylation and correlates with the gradual decline in cortical neurogenesis observed in vivo. Rescuing experiments show that postnatal progenitors are partially permissive to genetic and pharmacological manipulations. Our study provides an in-depth characterization of postnatal Glu progenitors and identifies potential therapeutic targets for promoting brain repair.ISSN:2666-3864ISSN:2211-124

Intranasal Administration of Human MSC for Ischemic Brain Injury in the Mouse: <i>In Vitro</i> and <i>In Vivo</i> Neuroregenerative Functions

<div><p>Intranasal treatment with C57BL/6 MSCs reduces lesion volume and improves motor and cognitive behavior in the neonatal hypoxic-ischemic (HI) mouse model. In this study, we investigated the potential of human MSCs (hMSCs) to treat HI brain injury in the neonatal mouse. Assessing the regenerative capacity of hMSCs is crucial for translation of our knowledge to the clinic. We determined the neuroregenerative potential of hMSCs <i>in vitro</i> and <i>in vivo</i> by intranasal administration 10 d post-HI in neonatal mice. HI was induced in P9 mouse pups. 1×10⁶ or 2×10⁶ hMSCs were administered intranasally 10 d post-HI. Motor behavior and lesion volume were measured 28 d post-HI. The <i>in vitro</i> capacity of hMSCs to induce differentiation of mouse neural stem cell (mNSC) was determined using a transwell co-culture differentiation assay. To determine which chemotactic factors may play a role in mediating migration of MSCs to the lesion, we performed a PCR array on 84 chemotactic factors 10 days following sham-operation, and at 10 and 17 days post-HI. Our results show that 2×10⁶ hMSCs decrease lesion volume, improve motor behavior, and reduce scar formation and microglia activity. Moreover, we demonstrate that the differentiation assay reflects the neuroregenerative potential of hMSCs <i>in vivo</i>, as hMSCs induce mNSCs to differentiate into neurons <i>in vitro</i>. We also provide evidence that the chemotactic factor CXCL10 may play an important role in hMSC migration to the lesion site. This is suggested by our finding that CXCL10 is significantly upregulated at 10 days following HI, but not at 17 days after HI, a time when MSCs no longer reach the lesion when given intranasally. The results described in this work also tempt us to contemplate hMSCs not only as a potential treatment option for neonatal encephalopathy, but also for a plethora of degenerative and traumatic injuries of the nervous system.</p></div

Dose effect of hMSC on motor performance and lesion volume.

<p>Mice were treated intranasally with either 1×10⁶ or 2×10⁶ hMSCs or vehicle at 10 days after HI. (A) Preference to use the unimpaired forepaw in the cylinder rearing test (CRT) was assessed at 28 days after HI. Sham-operated littermates (Sham) were used as controls. (B–C) Quantification of ipsilateral MAP2 (B) and MBP (C) area loss measured as 1- (ipsi-/contralateral MAP2- or MBP-positive area) at 28 days after HI. Representative sections of MAP2 (D) and MBP (E) staining. Data represent mean ± SEM. **p<0.01; ***p<0.001 by ANOVA and Bonferroni post-hoc test. Sham n = 13; Vehicle n = 21; 1×10⁶ hMSC n = 11; 2×10⁶ hMSC n = 12. Data presented in this figure are results from pups pooled out of 11 different litters. Treatment groups were randomly distributed between litters.</p

<i>In vitro</i> proliferation of hMSCs.

<p>Proliferating capacity of hMSCs <i>in vitro</i>. 1000 hMSCs were plated (T0) and proliferation was assessed at 4(T0), 24(T24), 48(T48) and 96(T96) hours after plating the MSCs by adding ³H-thymidine to the culture and measuring ³H-thymidine uptake 16 hours later. Data represent mean ± SEM. ** p<0.01; *** p<0.001 by ANOVA and Bonferroni post-hoc test. (n = 10 wells for each condition).</p

hMSCs induce differentiation of mouse NSCs <i>in vitro</i>.

<p><i>In vitro</i> mNSC transwell differentiation assay in co-culture with hMSCs. mNSCs were fixed at 4(T0) and 96(T96) hours after co-culture with hMSCs and stained for (A) nestin (green), (B) Olig2 (red), (C) GFAP (green) and (D) βIII-Tubulin (red). Data represent mean ± SEM. *** p<0.001 by Unpaired two-tailed T-test. Scale bar  = 100 µm. (n = 4 wells per condition).</p