Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice

The present study aimed to determine the effect of thyroid hormone dysfunction on brown adipose tissue activity and white adipose tissue browning in mice. Twenty randomized female C57BL/6NTac mice per treatment group housed at room temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal 18F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivo14C-acetate loading assay and assessment of thermogenic gene and protein expression permitted analysis of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and hypothyroid mice. 18F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced 18F-FDG uptake. In white adipose tissue of both, hyper- and hypothyroid mice, we found a significant induction of thermogenic genes together with multilocular adipocytes expressing UCP1. Taken together, these results suggest that both the hyperthyroid and hypothyroid state stimulate WAT thermogenesis most likely as a consequence of enhanced adrenergic signaling or compensation for impaired BAT function, respectively

CT-Based Attenuation Correction in I-123-Ioflupane SPECT

Purpose Attenuation correction (AC) based on low-dose computed tomography (CT) could be more accurate in brain single-photon emission computed tomography (SPECT) than the widely used Chang method, and, therefore, has the potential to improve both semi-quantitative analysis and visual image interpretation. The present study evaluated CT-based AC for dopamine transporter SPECT with I-123-ioflupane. Materials and methods Sixty-two consecutive patients in whom I-123-ioflupane SPECT including low-dose CT had been performed were recruited retrospectively at 3 centres. For each patient, 3 different SPECT images were reconstructed: without AC, with Chang AC and with CT-based AC. Distribution volume ratio (DVR) images were obtained by scaling voxel intensities using the whole brain without striata as reference. For assessing the impact of AC on semi-quantitative analysis, specific-to-background ratios (SBR) in caudate and putamen were obtained by fully automated SPM8-based region of interest (ROI) analysis and tested for their diagnostic power using receiver-operator- characteristic (ROC) analysis. For assessing the impact of AC on visual image reading, screenshots of stereotactically normalized DVR images presented in randomized order were interpreted independently by two raters at each centre. Results CT-based AC resulted in intermediate SBRs about half way between no AC and Chang. Maximum area under the ROC curve was achieved by the putamen SBR, with negligible impact of AC (0.924, 0.935 and 0.938 for no, CT-based and Chang AC). Diagnostic accuracy of visual interpretation also did not depend on AC. Conclusions The impact of CT-based versus Chang AC on the interpretation of I-123-ioflupane SPECT is negligible. Therefore, CT-based AC cannot be recommended for routine use in clinical patient care, not least because of the additional radiation exposure

Evidence, Interpretation, and Qualification From Multiple Reports of Long- Term Outcomes in the Multimodal Treatment Study of Children With ADHD (MTA) Part II: Supporting Details

Objective: To review and provide details about the primary and secondary findings from the Multimodal Treatment study of ADHD (MTA) published during the past decade as three sets of articles. Method: In the second of a two part article, we provide additional background and detail required by the complexity of the MTA to address confusion and controversy about the findings outlined in part I (the Executive Summary). Results: We present details about the gold standard used to produce scientific evidence, the randomized clinical trial (RCT), which we applied to evaluate the long-term effects of two well-established unimodal treatments, Medication Management (MedMGT) and behavior therapy (Beh), the multimodal combination (Comb), and treatment “as usual” in the community (CC). For each of the first three assessment points defined by RCT methods and included in intent-to-treat analyses, we discuss our definition of evidence from the MTA, interpretation of the serial presentations of findings at each assessment point with a different definition of long-term varying from weeks to years, and qualification of the interim conclusions about long-term effects of treatments for ADHD based on many exploratory analyses described in additional published articles. Conclusions: Using a question and answer format, we discuss the possible clinical relevance of the MTA and present some practical suggestions based on current knowledge and uncertainties facing families, clinicians, and investigators regarding the long-term use of stimulant medication and behavioral therapy in the treatment of children with ADHD. (J. of Att. Dis. 2008; 12(1) 15-43

A comparison of five surface mixed layer models with a year of observations in the North Atlantic

Five upper ocean mixed layer models driven by ERA-Interim surface forcing are compared with a year of hydrographic observations of the upper 1000 m, taken at the Porcupine Abyssal Plain observatory site using profiling gliders. All the models reproduce sea surface temperature (SST) fairly well, with annual mean warm biases of 0.11  ° C (PWP model), 0.24  ° C (GLS), 0.31  ° C (TKE), 0.91  ° C (KPP) and 0.36  ° C (OSMOSIS). The main exception is that the KPP model has summer SSTs which are higher than the observations by nearly 3 ° . Mixed layer salinity (MLS) is not reproduced well by the models and the biases are large enough to produce a non-trivial density bias in the Eastern North Atlantic Central Water which forms in this region in winter. All the models develop mixed layers which are too deep in winter, with average winter mixed layer depth (MLD) biases between 160 and 228 m. The high variability in winter MLD is reproduced more successfully by model estimates of the depth of active mixing and/or boundary layer depth than by model MLD based on water column properties. After the spring restratification event, biases in MLD are small and do not appear to be related to the preceding winter biases. There is a very clear relationship between MLD and local wind stress in all models and in the observations during spring and summer, with increased wind speeds leading to deepening mixed layers, but this relationship is not present during autumn and winter. We hypothesize that the deepening of the MLD in autumn is so strongly driven by the annual cycle in surface heat flux that the winds are less significant in the autumn. The surface heat flux drives a diurnal cycle in MLD and SST from March onwards, though this effect is much more significant in the models than in the observations. We are unable to identify one model as definitely better than the others. The only clear differences between the models are KPP’s inability to accurately reproduce summer SSTs, and the OSMOSIS model’s more accurate reproduction of MLS

Cell Origin of Human Mesenchymal Stem Cells Determines a Different Healing Performance in Cardiac Regeneration

The possible different therapeutic efficacy of human mesenchymal stem cells (hMSC) derived from umbilical cord blood (CB), adipose tissue (AT) or bone marrow (BM) for the treatment of myocardial infarction (MI) remains unexplored. This study was to assess the regenerative potential of hMSC from different origins and to evaluate the role of CD105 in cardiac regeneration. Male SCID mice underwent LAD-ligation and received the respective cell type (400.000/per animal) intramyocardially. Six weeks post infarction, cardiac catheterization showed significant preservation of left ventricular functions in BM and CD105+-CB treated groups compared to CB and nontreated MI group (MI-C). Cell survival analyzed by quantitative real time PCR for human GAPDH and capillary density measured by immunostaining showed consistent results. Furthermore, cardiac remodeling can be significantly attenuated by BM-hMSC compared to MI-C. Under hypoxic conditions in vitro, remarkably increased extracellular acidification and apoptosis has been detected from CB-hMSC compared to BM and CD105 purified CB-derived hMSC. Our findings suggests that hMSC originating from different sources showed a different healing performance in cardiac regeneration and CD105+ hMSC exhibited a favorable survival pattern in infarcted hearts, which translates into a more robust preservation of cardiac function

Efficacy, Retention, and Tolerability of Brivaracetam in Patients With Epileptic Encephalopathies: A Multicenter Cohort Study From Germany

Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndrome

Heart Valve Tissue Engineering: Concepts, Approaches, Progress, and Challenges

Potential applications of tissue engineering in regenerative medicine range from structural tissues to organs with complex function. This review focuses on the engineering of heart valve tissue, a goal which involves a unique combination of biological, engineering, and technological hurdles. We emphasize basic concepts, approaches and methods, progress made, and remaining challenges. To provide a framework for understanding the enabling scientific principles, we first examine the elements and features of normal heart valve functional structure, biomechanics, development, maturation, remodeling, and response to injury. Following a discussion of the fundamental principles of tissue engineering applicable to heart valves, we examine three approaches to achieving the goal of an engineered tissue heart valve: (1) cell seeding of biodegradable synthetic scaffolds, (2) cell seeding of processed tissue scaffolds, and (3) in-vivo repopulation by circulating endogenous cells of implanted substrates without prior in-vitro cell seeding. Lastly, we analyze challenges to the field and suggest future directions for both preclinical and translational (clinical) studies that will be needed to address key regulatory issues for safety and efficacy of the application of tissue engineering and regenerative approaches to heart valves. Although modest progress has been made toward the goal of a clinically useful tissue engineered heart valve, further success and ultimate human benefit will be dependent upon advances in biodegradable polymers and other scaffolds, cellular manipulation, strategies for rebuilding the extracellular matrix, and techniques to characterize and potentially non-invasively assess the speed and quality of tissue healing and remodeling