Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

Arthro-IRM directe en traction axiale: technique et intérêt [Technique and value of direct MR arthrography applying articular distraction]

Direct MR arthrography has a better diagnostic accuracy than MR imaging alone. However, contrast material is not always homogeneously distributed in the articular space. Lesions of cartilage surfaces or intra-articular soft tissues can thus be misdiagnosed. Concomitant application of axial traction during MR arthrography leads to articular distraction. This enables better distribution of contrast material in the joint and better delineation of intra-articular structures. Therefore, this technique improves detection of cartilage lesions. Moreover, the axial stress applied on articular structures may reveal lesions invisible on MR images without traction. Based on our clinical experience, we believe that this relatively unknown technique is promising and should be further developed.

Information retention during competitive interactions : siblings need to constantly repeat vocal displays

Memory is essential to adjust behaviour according to past experience. In societies where animals interact on numerous occasions, memory of previous social interactions may help optimise investment in competition. How long information about the resource holding potential and motivation to compete of conspecifics is retained depends on how fast the value of this information fades, but also on the cost and benefit of retaining information. Information retention has never been investigated in the context of interactions prevailing within the family and more specifically sibling competition. In the absence of parents, barn owl (Tyto alba) nestlings vocally compete for priority of access to the next indivisible food item brought by a parent. The finding that owlets eavesdrop on vocal interactions between siblings to adjust investment in vocalization once competing with them suggests that they memorize siblings' vocal interactions. Playback experiments showed that owlets take into account the past siblings' vocal performance that signals hunger for at least 15 min, but only if the performance was witnessed during a sufficiently long period of time (30 min). Moreover, using natural vocal exchanges in another set of individuals, we showed that sibling signalling was no more taken into account after a few minutes. This suggests that young barn owls need to continuously display their motivation to trigger siblings' withdrawal from the current competition. Repeating a vocal display may ensure its honesty. Studying the extent to which individuals retain past information is important to understand how individuals adjust their competitive investment over resources.

Medical and pharmacological direct costs of a 9-week smoking cessation programme.

Background: Medical and pharmacological direct costs of cigarette smoking cessation programmes are not covered by health insurance in several countries despite documented cost-effectiveness. Design: prospective cost identification study of a 9-week programme in Switzerland. Methods: A total of 481 smokers were followed-up for 9 weeks. Socio-demographic characteristics, number of outpatient visits, dosage and frequency of use of nicotine replacement therapy (NRT) as well as date of relapse were prospectively collected. Individual cost of care until relapse or programme end as well as cost per week of follow-up were computed. Comparisons were carried out between the groups with or without relapse at the end of the programme. Results: Of the 209 men and 272 women included, 347 patients (72%) finished the programme. Among them, 240 patients (70%) succeeded in quitting and 107 patients (30%) relapsed. As compared with the group relapsing by the end of the programme, the group succeeding in quitting was more often living in a couple (68% vs. 55%, p = 0.029). Their mean weekly costs of visits were higher (CHF 81.2 ± 6.1 vs. 78.4 ± 7.6, p = 0.001), while their mean weekly costs for NRT were similar (CHF 24.2 ± 12.6 vs. 25.4 ± 15.9, p = 0.711). Mean total costs per week were similar (CHF 105.4 ± 15.4 vs. 103.8 ± 19.4, p = 0.252). More intensive NRT at week 4 increased the probability not to relapse at the end of the programme. Conclusions: Over 9 weeks, medical and pharmacological costs of stopping smoking are low. Good medical and social support as well as adequate NRT seem to play a role in successful quitting.

Anatomical exposure patterns of skin to sunlight: relative contributions of direct, diffuse and reflected ultraviolet radiation

Summary Background  The dose-response between ultraviolet (UV) exposure patterns and skin cancer occurrence is not fully understood. Sun-protection messages often focus on acute exposure, implicitly assuming that direct UV radiation is the key contributor to the overall UV exposure. However, little is known about the relative contribution of the direct, diffuse and reflected radiation components. Objective  To investigate solar UV exposure patterns at different body sites with respect to the relative contribution of the direct, diffuse and reflected radiation. Methods  A three-dimensional numerical model was used to assess exposure doses for various body parts and exposure scenarios of a standing individual (static and dynamic postures). The model was fed with erythemally weighted ground irradiance data for the year 2009 in Payerne, Switzerland. A year-round daily exposure (08:00-17:00 h) without protection was assumed. Results  For most anatomical sites, mean daily doses were high (typically 6·2-14·6 standard erythemal doses) and exceeded the recommended exposure values. Direct exposure was important during specific periods (e.g. midday during summer), but contributed moderately to the annual dose, ranging from 15% to 24% for vertical and horizontal body parts, respectively. Diffuse irradiation explained about 80% of the cumulative annual exposure dose. Acute diffuse exposures were also observed during cloudy summer days. Conclusions  The importance of diffuse UV radiation should not be underestimated when advocating preventive measures. Messages focused on avoiding acute direct exposures may be of limited efficiency to prevent skin cancers associated with chronic exposure.

Direct comparison of a radioiodinated intact chimeric anti-CEA MAb with its F(ab')2 fragment in nude mice bearing different human colon cancer xenografts.

Tumour localisation and tumour to normal tissue ratios of a chimeric anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb), in intact form and as an F(ab')2 fragment labelled with 125I and 131I, were compared in groups of nude mice bearing four different colon cancer xenografts, T380, Co112 or LoVo, of human origin, or a rat colon cancer transfected with human CEA cDNA, called '3G7'. For each tumour, three to four mice per time point were analysed 6, 12, 24, 48 and 96 h after MAb injection. In the different tumours, maximal localisation of intact MAb was obtained at 24 to 48 h, and of F(ab')2 fragment 12 to 24 h after injection. Among the different tumours, localisation was highest with colon cancer T380, with 64% of the injected dose per gram (% ID/g) for the intact MAb and 57% for its F(ab')2 fragment, while in the three other tumours, maximal localisation ranged from 14 to 22% ID g-1 for the intact MAb and was about 11% for the F(ab')2. Tumour to normal tissue ratios of intact MAb increased rapidly until 24 h after injection and remained stable or showed only a minor increase thereafter. In contrast, for the F(ab')2 fragment, the tumour to normal tissue ratios increased steadily up to 4 days after injection reaching markedly higher values than those obtained with intact MAb. For the four different xenografts, tumour to blood ratios of F(ab')2 were about 2, 3 and 5 to 16 times higher than those of intact antibodies at 12, 24 and 96 h after injection, respectively.

Direct mapping of 19F in 19FDG-6P in brain tissue at subcellular resolution using soft X-ray fluorescence

Low energy x-ray fluorescence (LEXRF) detection was optimized for imaging cerebral glucose metabolism by mapping the fluorine LEXRF signal of 19 F in 19 FDG, trapped as intracellular 19 F-deoxyglucose-6-phosphate ( 19 FDG-6P) at 1μm spatial resolution from 3μm thick brain slices. 19 FDG metabolism was evaluated in brain structures closely resembling the general cerebral cytoarchitecture following formalin fixation of brain slices and their inclusion in an epon matrix. 2-dimensional distribution maps of 19 FDG-6P were placed in a cytoarchitectural and morphological context by simultaneous LEXRF mapping of N and O, and scanning transmission x-ray (STXM) imaging. A disproportionately high uptake and metabolism of glucose was found in neuropil relative to intracellular domains of the cell body of hypothalamic neurons, showing directly that neurons, like glial cells, also metabolize glucose. As 19 F-deoxyglucose-6P is structurally identical to 18 F-deoxyglucose-6P, LEXRF of subcellular 19 F provides a link to in vivo 18 FDG PET, forming a novel basis for understanding the physiological mechanisms underlying the 18 FDG PET image, and the contribution of neurons and glia to the PET signal.

Respiratory failure in a mouse model of myotonic dystrophy does not correlate with the CTG repeat length.

Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control and transgenic mice carrying either 600 (DM600) or >1300 CTG repeats (DMSXL). The statistical analysis of respiratory parameters revealed that both DM1 transgenic mice sub-lines show respiratory impairment compared to control mice. In addition, there is no significant difference in breathing functions between the DM600 and DMSXL mice. In conclusion, these results indicate that respiratory impairment is present in both transgenic mice sub-lines, but the severity of respiratory failure is not related to the size of the (CTG)n expansion.

Outcome after proximal femoral fractures during primary total hip replacement by the direct anterior approach.

BACKGROUND: The literature suggests that intraoperative fractures of the greater trochanter and the metaphysis are increased with uncemented stems and the direct anterior approach. This study aims to determine the incidence and assess the functional and radiological outcome after such fractures. METHODS: 484 consecutive total hip replacements (THR) (64 ± 12 years) were analyzed. We treated trochanteric fractures conservatively without any further denuding, and secured metaphyseal fissures with cerclages. Postoperative X-rays and at the latest follow-up were compared to assess secondary fracture displacement and stem subsidence. Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores after 1 year were analyzed. For each patient sustaining a fracture, two patients without fractures were matched in terms of age, body mass index and gender. RESULTS: 13 (2.7 %, 5 male, 68 ± 9 years) patients with intraoperative fractures of the greater trochanter (n = 8) or the metaphysis (n = 5) were analyzed. Consolidation was observed in 7/8 patients sustaining a trochanteric fracture while secondary displacement of the fragment occurred in one case. Stem subsidence was observed in 2/5 cases (5 and 7 mm). Patients who sustained a fracture showed a trend towards poorer WOMAC scores at 1 year postoperatively, compared to patients without fractures. A significantly increased joint stiffness was also observed. CONCLUSION: The intraoperative fracture risk in this series of THR through a direct anterior approach was 2.7 %. Trochanteric fractures do heal without primary fixation. Metaphyseal fractures heal well if immediately stabilized with a cerclage.

The direct effects of tacrolimus and cyclosporin A on isolated human islets: A functional, survival and gene expression study.

The use of immunosuppressive drugs in transplanted patients is associated with the development of diabetes, possibly due to β-cell toxicity. To better understand the mechanisms leading to post-transplant diabetes, we investigated the actions of prolonged exposure of isolated human islets to therapeutical levels of tacrolimus (Tac) or cyclosporin A (CsA). Islets were isolated from the pancreas of multiorgan donors by enzymatic digestion and density gradient centrifugation. Functional, survival and molecular studies were then performed after 4 days of incubation with therapeutical concentrations of Tac or  CsA. Glucose-induced insulin secretion was significantly decreased in Tac, but not in CsA exposed islets, which was associated with a reduction of the amount of insulin granules as shown by electron microscopy. The percentage of apoptotic β-cells was higher in Tac than CsA exposed islets. Microarray experiments followed by Gene Set Enrichment Analysis revealed that gene expression was more markedly affected upon Tac treatment. In conclusion, Tac and CsA affect features of beta-cell differently, with several changes occurring at the molecular level.

Direct-on-line axial flux permanent magnet synchronous generator static and dynamic performance

In distributed energy production, permanent magnet synchronous generators (PMSG) are often connected to the grid via frequency converters, such as voltage source line converters. The price of the converter may constitute a large part of the costs of a generating set. Some of the permanent magnet synchronous generators with converters and traditional separately excited synchronous generators couldbe replaced by direct-on-line (DOL) non-controlled PMSGs. Small directly networkconnected generators are likely to have large markets in the area of distributed electric energy generation. Typical prime movers could be windmills, watermills and internal combustion engines. DOL PMSGs could also be applied in island networks, such as ships and oil platforms. Also various back-up power generating systems could be carried out with DOL PMSGs. The benefits would be a lower priceof the generating set and the robustness and easy use of the system. The performance of DOL PMSGs is analyzed. The electricity distribution companies have regulations that constrain the design of the generators being connected to the grid. The general guidelines and recommendations are applied in the analysis. By analyzing the results produced by the simulation model for the permanent magnet machine, the guidelines for efficient damper winding parameters for DOL PMSGs are presented. The simulation model is used to simulate grid connections and load transients. The damper winding parameters are calculated by the finite element method (FEM) and determined from experimental measurements. Three-dimensional finite element analysis (3D FEA) is carried out. The results from the simulation model and 3D FEA are compared with practical measurements from two prototype axial flux permanent magnet generators provided with damper windings. The dimensioning of the damper winding parameters is case specific. The damper winding should be dimensioned based on the moment of inertia of the generating set. It is shown that the damper winding has optimal values to reach synchronous operation in the shortest period of time after transient operation. With optimal dimensioning, interferenceon the grid is minimized.

Direct torque control of permanent magnet synchronous machines - analysis and implementation

Thedirect torque control (DTC) has become an accepted vector control method besidethe current vector control. The DTC was first applied to asynchronous machines,and has later been applied also to synchronous machines. This thesis analyses the application of the DTC to permanent magnet synchronous machines (PMSM). In order to take the full advantage of the DTC, the PMSM has to be properly dimensioned. Therefore the effect of the motor parameters is analysed taking the control principle into account. Based on the analysis, a parameter selection procedure is presented. The analysis and the selection procedure utilize nonlinear optimization methods. The key element of a direct torque controlled drive is the estimation of the stator flux linkage. Different estimation methods - a combination of current and voltage models and improved integration methods - are analysed. The effect of an incorrect measured rotor angle in the current model is analysed andan error detection and compensation method is presented. The dynamic performance of an earlier presented sensorless flux estimation method is made better by improving the dynamic performance of the low-pass filter used and by adapting the correction of the flux linkage to torque changes. A method for the estimation ofthe initial angle of the rotor is presented. The method is based on measuring the inductance of the machine in several directions and fitting the measurements into a model. The model is nonlinear with respect to the rotor angle and therefore a nonlinear least squares optimization method is needed in the procedure. A commonly used current vector control scheme is the minimum current control. In the DTC the stator flux linkage reference is usually kept constant. Achieving the minimum current requires the control of the reference. An on-line method to perform the minimization of the current by controlling the stator flux linkage reference is presented. Also, the control of the reference above the base speed is considered. A new estimation flux linkage is introduced for the estimation of the parameters of the machine model. In order to utilize the flux linkage estimates in off-line parameter estimation, the integration methods are improved. An adaptive correction is used in the same way as in the estimation of the controller stator flux linkage. The presented parameter estimation methods are then used in aself-commissioning scheme. The proposed methods are tested with a laboratory drive, which consists of a commercial inverter hardware with a modified software and several prototype PMSMs.

Personality and job stress: a comparison of direct effects on parenting

The impact of personality and job characteristics on parental rearing styles was compared in 353 employees. Hypotheses concerning the relationships between personality and job variables were formulated in accordance with findings in past research and the Belsky’s model (1984). Structural equation nested models showed that Aggression-hostility, Sociability and job Demand were predictive of Rejection and Emotional Warmth parenting styles, providing support for some of the hypothesized relationships. The findings suggest a well-balanced association of personality variables with both parenting styles: Aggression-Hostility was positively related to Rejection and negatively to Emotional Warmth, whereas Sociability was positively related to Emotional Warmth and negatively related to Rejection. Personality dimensions explained a higher amount of variance in observed parenting styles. However, a model that considered both, personality and job dimensions as antecedent variables of parenting was the best representation of observed data, as both systems play a role in the prediction of parenting behavior.