Conservative and disruptive modes of adolescent change in human brain functional connectivity

Adolescent changes in human brain function are not entirely understood. Here, we used multiecho functional MRI (fMRI) to measure developmental change in functional connectivity (FC) of resting-state oscillations between pairs of 330 cortical regions and 16 subcortical regions in 298 healthy adolescents scanned 520 times. Participants were aged 14 to 26 y and were scanned on 1 to 3 occasions at least 6 mo apart. We found 2 distinct modes of age-related change in FC: “conservative” and “disruptive.” Conservative development was characteristic of primary cortex, which was strongly connected at 14 y and became even more connected in the period from 14 to 26 y. Disruptive development was characteristic of association cortex and subcortical regions, where connectivity was remodeled: connections that were weak at 14 y became stronger during adolescence, and connections that were strong at 14 y became weaker. These modes of development were quantified using the maturational index (MI), estimated as Spearman’s correlation between edgewise baseline FC (at 14 y, FC14) and adolescent change in FC (ΔFC14−26), at each region. Disruptive systems (with negative MI) were activated by social cognition and autobiographical memory tasks in prior fMRI data and significantly colocated with prior maps of aerobic glycolysis (AG), AG-related gene expression, postnatal cortical surface expansion, and adolescent shrinkage of cortical thickness. The presence of these 2 modes of development was robust to numerous sensitivity analyses. We conclude that human brain organization is disrupted during adolescence by remodeling of FC between association cortical and subcortical areas

Versatility of nodal affiliation to communities

Graph theoretical analysis of the community structure of networks attempts to identify the communitites (or modules) to which each node affiliates. However, this is in most cases an ill-posed problem, as the affiliation of a node to a single community is often ambiguous. Previous solutions have attempted to identify all of the communities to which each node affiliates. Instead of taking this approach, we introduce versatility, V, as a novel metric of nodal affiliation: V = 0 means that a node is consistently assigned to a specific community; V > 0 means it is inconsistently assigned to different communities. Versatility works in conjunction with existing community detection algorithms and it satisfies many theoretically desirable properties in idealised networks designed to maximise ambiguity of modular decomposition. The local minima of global mean versatility identified the resolution parameters of a hierarchical community detection algorithm that least ambiguously decomposed the community structure of a social (karate club) network and the mouse brain connectome. Our results suggest that nodal versatility is useful in quantifying the inherent ambiguity of modular decomposition.Churchill Foundation NIH Oxford-Cambridge Scholars Foundation Gates Cambridge Trust NIHR Cambridge Biomedical Research Centr

Опыт использования расширенного транстрицепитального доступа при остеосинтезе сложных переломов дистального метаэпифиза плечевой кости

Background. The preferred treatment for intra-articular displaced fractures is open reduction and internal fixation. The need to obtain a better visualization of the fracture geometry made it necessary to develop a large number of new approaches and their modifications.Material and methods. The study included 186 patients with an intra-articular fracture of the distal humerus, who underwent plate osteosynthesis using the standard technique. The main group included 112 patients who were operated on using ETTA. The comparison group included 74 patients with a similar type of fracture, who were operated on using chevron olecranon osteotomy. The groups were comparable in terms of age, gender, mechanism of injury, and nature of the fracture. Long-term results were evaluated in 186 patients (minimum follow-up period – 12 months).Results. Comparative analysis revealed that the time of surgery was reduced by an average of 20 minutes (p=0.03) in the main group. The immediate and medium-term results were assessed according to the data of physical examinations, control radiography, dynamics of the increase in the amplitude of motion in the elbow joint. The results were comparable. When assessing complications, the migration of fixators was detected in 5.5% in the main group and 16% in the comparison group. In the comparison group, failure of union of the olecranon after osteotomy, migration of wires with skin perforation, and reactive bursitis were observed.Conclusion. 1. The extended transtriceps approach provides good visualization for fixing fractures of the distal humerus. 2. Evaluation of treatment results confirms that osteosynthesis using this access allows to reduce the time and trauma of the operation, to avoid complications associated with osteotomy of the olecranon, and to carry out successful postoperative rehabilitation, achieving good functional results. Актуальность. Предпочтительным методом лечения для внутрисуставных переломов со смещением является открытая репозиция и внутренняя фиксация. Необходимость получения лучшей визуализации геометрии перелома заставила предложить большое количество новых доступов и их модификаций.Цель. Разработка показаний для расширенного транстрицепитального доступа (РТТД) и определение функциональных результатов при фиксации переломов дистального отдела с использованием данного доступа.Материал и методы. В исследование включены 186 пациентов с внутрисуставным переломом дистального отдела плечевой кости, которым был выполнен остеосинтез пластинами по стандартной методике. В основную группу вошли 112 пациентов, которые были оперированы с использованием РТТД. В группу сравнения вошли 74 пациента с аналогичным типом перелома, которые были оперированы с применением шевронной остеотомии локтевого отростка. Группы были сопоставимы по возрасту, полу, механизму травмы и характеру перелома. Отдаленные результаты были оценены у 186 пациентов (минимальный срок наблюдения — 12 месяцев).Результаты. При сравнительном анализе было выявлено, что длительность оперативного вмешательства сократилось в среднем на 20 минут (р=0,03) в основной группе. Ближайшие и среднесрочные результаты оценивали по данным физикальных осмотров, контрольной рентгенографии, динамике прироста амплитуды движения в локтевом суставе. Результаты были сопоставимы. При оценке осложнений миграция фиксаторов выявлена в 5,5% у основной группы и 16% в группе сравнения. В группе сравнения к осложнениям добавились несращение локтевого отростка после остеотомии, миграция спиц с перфорацией кожи, реактивный бурсит.Выводы. 1. Расширенный транстриципитальный доступ обеспечивает хорошую визуализацию для фиксации переломов дистального отдела плечевой кости. 2. Оценка результатов лечения подтверждает, что остеосинтез с применением этого доступа позволяет сократить время и травматичность операции, избежать осложнений, связанных с остеотомией локтевого отростка, позволяет проводить успешную послеоперационную реабилитацию, достигая хороших функциональных результатов.

Quantification of Circulating Endothelial Progenitor Cells Using the Modified ISHAGE Protocol

Circulating endothelial progenitor cells (EPC), involved in endothelial regeneration, neovascularisation, and determination of prognosis in cardiovascular disease can be characterised with functional assays or using immunofluorescence and flow cytometry. Combinations of markers, including CD34+KDR+ or CD133+KDR+, are used. This approach, however may not consider all characteristics of EPC. The lack of a standardised protocol with regards to reagents and gating strategies may account for the widespread inter-laboratory variations in quantification of EPC. We, therefore developed a novel protocol adapted from the standardised so-called ISHAGE protocol for enumeration of haematopoietic stem cells to enable comparison of clinical and laboratory data.In 25 control subjects, 65 patients with coronary artery disease (CAD; 40 stable CAD, 25 acute coronary syndrome/acute myocardial infarction (ACS)), EPC were quantified using the following approach: Whole blood was incubated with CD45, KDR, and CD34. The ISHAGE sequential strategy was used, and finally, CD45(dim)CD34(+) cells were quantified for KDR. A minimum of 100 CD34(+) events were collected. For comparison, CD45(+)CD34(+) and CD45(-)CD34(+) were analysed simultaneously. The number of CD45(dim)CD34(+)KDR(+) cells only were significantly higher in healthy controls compared to patients with CAD or ACS (p = 0.005 each, p<0.001 for trend). An inverse correlation of CD45(dim)CD34(+)KDR(+) with disease activity (r = -0.475, p<0.001) was confirmed. Only CD45(dim)CD34(+)KDR(+) correlated inversely with the number of diseased coronaries (r = -0.344; p<0.005). In a second study, a 4-week de-novo treatment of atorvastatin in stable CAD evoked an increase only of CD45(dim)CD34(+)KDR(+) EPC (p<0.05). CD45(+)CD34(+)KDR(+) and CD45(-)CD34(+)KDR(+) were indifferent between the three groups.Our newly established protocol adopted from the standardised ISHAGE protocol achieved higher accuracy in EPC enumeration confirming previous findings with respect to the correlation of EPC with disease activity and the increase of EPC during statin therapy. The data of this study show the CD45(dim) fraction to harbour EPC

Understanding the errors of SHAPE-directed RNA structure modeling

Single-nucleotide-resolution chemical mapping for structured RNA is being rapidly advanced by new chemistries, faster readouts, and coupling to computational algorithms. Recent tests have shown that selective 2'-hydroxyl acylation by primer extension (SHAPE) can give near-zero error rates (0-2%) in modeling the helices of RNA secondary structure. Here, we benchmark the method using six molecules for which crystallographic data are available: tRNA(phe) and 5S rRNA from Escherichia coli, the P4-P6 domain of the Tetrahymena group I ribozyme, and ligand-bound domains from riboswitches for adenine, cyclic di-GMP, and glycine. SHAPE-directed modeling of these highly structured RNAs gave an overall false negative rate (FNR) of 17% and a false discovery rate (FDR) of 21%, with at least one helix prediction error in five of the six cases. Extensive variations of data processing, normalization, and modeling parameters did not significantly mitigate modeling errors. Only one varation, filtering out data collected with deoxyinosine triphosphate during primer extension, gave a modest improvement (FNR = 12%, and FDR = 14%). The residual structure modeling errors are explained by the insufficient information content of these RNAs' SHAPE data, as evaluated by a nonparametric bootstrapping analysis. Beyond these benchmark cases, bootstrapping suggests a low level of confidence (<50%) in the majority of helices in a previously proposed SHAPE-directed model for the HIV-1 RNA genome. Thus, SHAPE-directed RNA modeling is not always unambiguous, and helix-by-helix confidence estimates, as described herein, may be critical for interpreting results from this powerful methodology.Comment: Biochemistry, Article ASAP (Aug. 15, 2011

Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12–18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults

RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction

Thermodynamic folding algorithms and structure probing experiments are commonly used to determine the secondary structure of RNAs. Here we propose a formal framework to reconcile information from both prediction algorithms and probing experiments. The thermodynamic energy parameters are adjusted using ‘pseudo-energies’ to minimize the discrepancy between prediction and experiment. Our framework differs from related approaches that used pseudo-energies in several key aspects. (i) The energy model is only changed when necessary and no adjustments are made if prediction and experiment are consistent. (ii) Pseudo-energies remain biophysically interpretable and hold positional information where experiment and model disagree. (iii) The whole thermodynamic ensemble of structures is considered thus allowing to reconstruct mixtures of suboptimal structures from seemingly contradicting data. (iv) The noise of the energy model and the experimental data is explicitly modeled leading to an intuitive weighting factor through which the problem can be seen as folding with ‘soft’ constraints of different strength. We present an efficient algorithm to iteratively calculate pseudo-energies within this framework and demonstrate how this approach can be used in combination with SHAPE chemical probing data to improve secondary structure prediction. We further demonstrate that the pseudo-energies correlate with biophysical effects that are known to affect RNA folding such as chemical nucleotide modifications and protein binding.Austrian Science Fund. Erwin Schrodinger Fellowship (J2966-B12

Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells

Transplantation of vasculogenic progenitor cells (VPC) improves neovascularization after ischemia. However, patients with type 2 diabetes mellitus show a reduced VPC number and impaired functional activity. Previously, we demonstrated that p38 kinase inhibition prevents the negative effects of glucose on VPC number by increasing proliferation and differentiation towards the endothelial lineage in vitro. Moreover, the functional capacity of progenitor cells is reduced in a mouse model of metabolic syndrome including type 2 diabetes (Lepr(db)) in vivo.The aim of this study was to elucidate the underlying signalling mechanisms in vitro and in vivo. Therefore, we performed DNA-protein binding arrays in the bone marrow of mice with metabolic syndrome, in blood-derived progenitor cells of diabetic patients as well as in VPC ex vivo treated with high levels of glucose. The transcriptional activation of ETS transcription factors was increased in all samples analyzed. Downregulation of ETS1 expression by siRNA abrogated the reduction of VPC number induced by high-glucose treatment. In addition, we observed a concomitant suppression of the non-endothelial ETS-target genes matrix metalloproteinase 9 (MMP9) and CD115 upon short term lentiviral delivery of ETS-specific shRNAs. Long term inhibition of ETS expression by lentiviral infection increased the number of cells with the endothelial markers CD144 and CD105.These data demonstrate that diabetes leads to dysregulated activation of ETS, which blocks the functional activity of progenitor cells and their commitment towards the endothelial cell lineage

Pre-Procedural Atorvastatin Mobilizes Endothelial Progenitor Cells: Clues to the Salutary Effects of Statins on Healing of Stented Human Arteries

OBJECTIVES: Recent clinical trials suggest an LDL-independent superiority of intensive statin therapy in reducing target vessel revascularization and peri-procedural myocardial infarctions in patients who undergo percutaneous coronary interventions (PCI). While animal studies demonstrate that statins mobilize endothelial progenitor cells (EPCs) which can enhance arterial repair and attenuate neointimal formation, the precise explanation for the clinical PCI benefits of high dose statin therapy remain elusive. Thus we serially assessed patients undergoing PCI to test the hypothesis that high dose Atorvastatin therapy initiated prior to PCI mobilizes EPCs that may be capable of enhancing arterial repair. METHODS AND RESULTS: Statin naïve male patients undergoing angiography for stent placement were randomized to standard therapy without Atorvastatin (n = 10) or treatment with Atorvastatin 80 mg (n = 10) beginning three days prior to stent implantation. EPCs were defined by flow cytometry (e.g., surface marker profile of CD45dim/34+/133+/117+). As well, we also enumerated cultured angiogenic cells (CACs) by standard in vitro culture assay. While EPC levels did not fluctuate over time for the patients free of Atorvastatin, there was a 3.5-fold increase in EPC levels with high dose Atorvastatin beginning within 3 days of the first dose (and immediately pre-PCI) which persisted at 4 and 24 hours post-PCI (p<0.05). There was a similar rise in CAC levels as assessed by in vitro culture. CACs cultured in the presence of Atorvastatin failed to show augmented survival or VEGF secretion but displayed a 2-fold increase in adhesion to stent struts (p<0.05). CONCLUSIONS: High dose Atorvastatin therapy pre-PCI improves EPC number and CAC number and function in humans which may in part explain the benefit in clinical outcomes seen in patients undergoing coronary interventions