Impact of the Advisa MRI pacing system on the diagnostic quality of cardiac MR images and contraction patterns of cardiac muscle during scans: Advisa MRI randomized clinical multicenter study results.

BACKGROUND: The Advisa MRI system is designed to safely undergo magnetic resonance imaging (MRI). Its influence on image quality is not well known. OBJECTIVE: To evaluate cardiac magnetic resonance (CMR) image quality and to characterize myocardial contraction patterns by using the Advisa MRI system. METHODS: In this international trial with 35 participating centers, an Advisa MRI system was implanted in 263 patients. Of those, 177 were randomized to the MRI group and 150 underwent MRI scans at the 9-12-week visit. Left ventricular (LV) and right ventricular (RV) cine long-axis steady-state free precession MR images were graded for quality. Signal loss along the implantable pulse generator and leads was measured. The tagging CMR data quality was assessed as the percentage of trackable tagging points on complementary spatial modulation of magnetization acquisitions (n=16) and segmental circumferential fiber shortening was quantified. RESULTS: Of all cine long-axis steady-state free precession acquisitions, 95% of LV and 98% of RV acquisitions were of diagnostic quality, with 84% and 93%, respectively, being of good or excellent quality. Tagging points were trackable from systole into early diastole (360-648 ms after the R-wave) in all segments. During RV pacing, tagging demonstrated a dyssynchronous contraction pattern, which was not observed in nonpaced (n = 4) and right atrial-paced (n = 8) patients. CONCLUSIONS: In the Advisa MRI study, high-quality CMR images for the assessment of cardiac anatomy and function were obtained in most patients with an implantable pacing system. In addition, this study demonstrated the feasibility of acquiring tagging data to study the LV function during pacing.

Infirmier en psychiatrie de liaison : développement de la supervision en milieu somatique [Liaison psychiatry nurse: The development of supervision in somatic medicine].

BACKGROUND: Over the years, somatic care has become increasingly specialized. Furthermore, a rising number of patients requiring somatic care also present with a psychiatric comorbidity. As a consequence, the time and resources needed to care for these patients can interfere with the course of somatic treatment and influence the patient-caregiver relationship. In the light of these observations, the Liaison Psychiatry Unit at the University Hospital in Lausanne (CHUV) has educated its nursing staff in order to strengthen its action within the general care hospital. What has been developed is a reflexive approach through supervision of somatic staff, in order to improve the efficiency of liaison psychiatry interventions with the caregivers in charge of patients. The kind of supervision we have developed is the result of a real partnership with somatic staff. Besides, in order to better understand the complexity of interactions between the two systems involved, the patient's and the caregivers', we use several theoretical references in an integrative manner. PSYCHOANALYTICAL REFERENCE: The psychoanalytical model allows us to better understand the dynamics between the supervisor and the supervised group in order to contain and give meaning to the affects arising in the supervision space. "Containing function" and "transitional phenomena" refer to the experience in which emotions can find a space where they can be taken in and processed in a secure and supportive manner. These concepts, along with that of the "psychic envelope", were initially developed to explain the psychological development of the baby in its early interactions with its mother or its surrogate. In the field of supervision, they allow us to be aware of these complex phenomena and the diverse qualities to which a supervisor needs to resort, such as attention, support and incentive, in order to offer a secure environment. SYSTEMIC REFERENCE: A new perspective of the patient's complexity is revealed by the group's dynamics. The supervisor's attention is mainly focused on the work of affects. However, these are often buried under a defensive shell, serving as a temporary protection, which prevents the caregiver from recognizing his or her own emotions, thereby enhancing the difficulties in the relationship with the patient. Whenever the work of putting emotions into words fail, we use "sculpting", a technique derived from the systemic model. Through the use of this type of analogical language, affects can emerge without constraint or feelings of danger. Through "playing" in that "transitional space", new exchanges appear between group members and allow new behaviors to be conceived. In practice, we ask the supervisee who is presenting a complex situation, to design a spatial representation of his or her understanding of the situation, through the display of characters significant to the situation: the patient, somatic staff members, relatives of the patient, etc. In silence, the supervisee shapes the characters into postures and arranges them in the room. Each sculpted character is identified, named, and positioned, with his or her gaze being set in a specific direction. Finally the sculptor shapes him or herself in his or her own role. When the sculpture is complete and after a few moments of fixation, we ask participants to express themselves about their experience. By means of this physical representation, participants to the sculpture discover perceptions and feelings that were unknown up to then. Hence from this analogical representation a reflection and hypotheses of understanding can arise and be developed within the group. CONCLUSION: Through the use of the concepts of "containing function" and "transitional space" we position ourselves in the scope of the encounter and the dialog. Through the use of the systemic technique of "sculpting" we promote the process of understanding, rather than that of explaining, which would place us in the position of experts. The experience of these encounters has shown us that what we need to focus on is indeed what happens in this transitional space in terms of dynamics and process. The encounter and the sharing of competencies both allow a new understanding of the situation at hand, which has, of course, to be verified in the reality of the patient-caregiver relationship. It is often a source of adjustment for interpersonal skills to recover its containing function in order to enable caregiver to better respond to the patient's needs.

Image quality assessment in digital mammography: part II. NPWE as a validated alternative for contrast detail analysis.

Assessment of image quality for digital x-ray mammography systems used in European screening programs relies mainly on contrast-detail CDMAM phantom scoring and requires the acquisition and analysis of many images in order to reduce variability in threshold detectability. Part II of this study proposes an alternative method based on the detectability index (d') calculated for a non-prewhitened model observer with an eye filter (NPWE). The detectability index was calculated from the normalized noise power spectrum and image contrast, both measured from an image of a 5 cm poly(methyl methacrylate) phantom containing a 0.2 mm thick aluminium square, and the pre-sampling modulation transfer function. This was performed as a function of air kerma at the detector for 11 different digital mammography systems. These calculated d' values were compared against threshold gold thickness (T) results measured with the CDMAM test object and against derived theoretical relationships. A simple relationship was found between T and d', as a function of detector air kerma; a linear relationship was found between d' and contrast-to-noise ratio. The values of threshold thickness used to specify acceptable performance in the European Guidelines for 0.10 and 0.25 mm diameter discs were equivalent to threshold calculated detectability indices of 1.05 and 6.30, respectively. The NPWE method is a validated alternative to CDMAM scoring for use in the image quality specification, quality control and optimization of digital x-ray systems for screening mammography.

The long non-coding RNA NEAT1 is increased in IUGR placentas, leading to potential new hypotheses of IUGR origin/development.

INTRODUCTION: Intrauterine Growth Restriction (IUGR) is a multifactorial disease defined by an inability of the fetus to reach its growth potential. IUGR not only increases the risk of neonatal mortality/morbidity, but also the risk of metabolic syndrome during adulthood. Certain placental proteins have been shown to be implicated in IUGR development, such as proteins from the GH/IGF axis and angiogenesis/apoptosis processes. METHODS: Twelve patients with term IUGR pregnancy (birth weight < 10th percentile) and 12 CTRLs were included. mRNA was extracted from the fetal part of the placenta and submitted to a subtraction method (Clontech PCR-Select cDNA Subtraction). RESULTS: One candidate gene identified was the long non-coding RNA NEAT1 (nuclear paraspeckle assembly transcript 1). NEAT1 is the core component of a subnuclear structure called paraspeckle. This structure is responsible for the retention of hyperedited mRNAs in the nucleus. Overall, NEAT1 mRNA expression was 4.14 (±1.16)-fold increased in IUGR vs. CTRL placentas (P = 0.009). NEAT1 was exclusively localized in the nuclei of the villous trophoblasts and was expressed in more nuclei and with greater intensity in IUGR placentas than in CTRLs. PSPC1, one of the three main proteins of the paraspeckle, co-localized with NEAT1 in the villous trophoblasts. The expression of NEAT1_2 mRNA, the long isoform of NEAT1, was only modestly increased in IUGR vs. CTRL placentas. DISCUSSION/CONCLUSION: The increase in NEAT1 and its co-localization with PSPC1 suggests an increase in paraspeckles in IUGR villous trophoblasts. This could lead to an increased retention of important mRNAs in villous trophoblasts nuclei. Given that the villous trophoblasts are crucial for the barrier function of the placenta, this could in part explain placental dysfunction in idiopathic IUGR fetuses.

Sequencing of Lp-PLA2-encoding PLA2G7 gene in 2000 Europeans reveals several rare loss-of-function mutations.

Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.8±63.2 vs 204.6±41.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10,000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor.

Role of the transcription factor sox4 in schwann cell development

Previous studies demonstrated that both Schwann cell differentiation and de-differentiation (in the situation of a nerve injury or demyelinating disease) are regulated by cell-intrinsic regulators including several transcription factors. In particular, the de-differentiation of mature Schwann cells is driven by the activation of multiple negative regulators of myelination including c-Jun, Notch, Sox-2 and Pax-3, all usually expressed in the immature Schwann cells and suppressed at the onset of myelination. In order to identify new negative regulators of myelination involved in the development of the peripheral nervous system (PNS) we analyzed the data from a previously performed transcriptional analysis of myelinating Schwann cells. Based on its transcriptional expression profile during myelination, Sox4, a member of the Sox gene family, was identified as a potential candidate. Previous studies demonstrated that prolonged Sox4 expression in oligodendrocytes maintains these cells in a premyelinating state, further suggesting its role as a negative regulator of myelination. Concomitantly, we observed upregulation of Sox4 mRNA and protein expression levels in the PNS of three different models of demyelinating neuropathies (Pmp22, Lpin1, and Scap KOs). To better characterize the molecular function of Sox4, we used a viral vector allowing Sox4 overexpression in cultured Schwann cells and in neuron-Schwann cell co-cultures. In parallel, we generated two transgenic lines of mice in which the overexpression of Sox4 is driven specifically in Schwann cells by the Myelin Protein Zero gene promoter. The preliminary data from these in vitro and in vivo experiments show that overexpression of Sox4 in PNS causes a delay in progression of myelination thus indicating that Sox4 acts as a negative regulator of Schwann cell myelination.

Structure function relationships of ENaC and its role in sodium handling.

The epithelial sodium channel (ENaC) in the apical membrane of polarized epithelial cells is the rate-limiting step for Na entry into the cell; in series with the basolateral Na pump, it allows the vectorial transepithelial transport of Na ions. ENaC is expressed in different epithelia like the distal nephron or colon, and the airways epithelium. In the lung ENaC controls the composition and the amount of pulmonary fluid, whereas in the distal nephron ENaC under the control of aldosterone and vasopressin, is essential to adapt the amount of Na+ reabsorbed with the daily sodium intake. Activating mutations of ENaC cause severe disturbances of Na+ homeostasis leading to hypertension in human and in mouse models. Functional expression of ENaC in different cell systems allowed the identification of structural domains of the protein that are essential for channel function and/or modulation of channel activity. Site-directed mutations in specific domains of the channel protein lead to channel hyperactivity or channel loss of function. Knowledge about ENaC structure-function relationships opens new opportunities for development of pharmacological tools for controlling ENaC activity, such as channel activators of potential benefit in the treatment of pulmonary edema, or highly potent ENaC blockers with natriuretic effects.

Connexins: key mediators of endocrine function.

The appearance of multicellular organisms imposed the development of several mechanisms for cell-to-cell communication, whereby different types of cells coordinate their function. Some of these mechanisms depend on the intercellular diffusion of signal molecules in the extracellular spaces, whereas others require cell-to-cell contact. Among the latter mechanisms, those provided by the proteins of the connexin family are widespread in most tissues. Connexin signaling is achieved via direct exchanges of cytosolic molecules between adjacent cells at gap junctions, for cell-to-cell coupling, and possibly also involves the formation of membrane "hemi-channels," for the extracellular release of cytosolic signals, direct interactions between connexins and other cell proteins, and coordinated influence on the expression of multiple genes. Connexin signaling appears to be an obligatory attribute of all multicellular exocrine and endocrine glands. Specifically, the experimental evidence we review here points to a direct participation of the Cx36 isoform in the function of the insulin-producing β-cells of the endocrine pancreas, and of the Cx40 isoform in the function of the renin-producing juxtaglomerular epithelioid cells of the kidney cortex.

Changes of MAP2 phosphorylation during brain development.

The microtubule-associated protein MAP2 is essential for development of early neuronal morphology and maintenance of adult neuronal morphology. Several splice variants exist, MAP2a-d, with a lack of MAP2a in cat brain. MAP2 is widely used as a neuronal marker. In this study we compared five monoclonal antibodies (MAbs) against MAP2. They show differences in the immunocytochemical distribution of MAP2 isoforms during development of the visual cortex and cerebellum of the cat. Local and temporal differences were seen with MAb AP18, an antibody directed against a phosphorylation-dependent epitope near the N-terminal end. In large pyramidal dendrites in visual cortex, the AP18 epitope remained in parts immunoreactive after treatment with alkaline phosphatase. Three MAbs, AP14, MT-01, and MT-02, recognized the central region of the MAP2b molecule, which is not present in MAP2c and 2d, and reacted with phosphorylation-independent epitopes. During the first postnatal week the immunostaining in cerebellum differed between antibodies in that some cellular elements in external and internal granular layers and Purkinje cells were stained to various degrees, whereas at later stages staining patterns were similar. At early stages, antibody MT-02 stained cell bodies and dendrites in cerebral cortex and cerebellum. With progressing maturation, immunoreactivity became restricted to distal parts of apical dendrites of pyramidal cells and was absent from perikarya and finer proximal dendrites in cortex. MT-02 did not stain MAP2 in cerebellum of adult animals. This study demonstrates that the immunocytochemical detection of MAP2 depends on modifications such as phosphorylation and conformational changes of the molecule, and that MAP2 staining patterns differ between MAbs. Phosphorylation and specific conformations in the molecule may be essential for modulating function and molecular stability of MAP2, and monoclonal antibodies against such sites may provide tools for studying the functional role of modifications.

A high-resolution anatomical atlas of the transcriptome in the mouse embryo.

Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease.

Alteration of neuromuscular function in squash

The alteration in neuromuscular function of knee extensor muscles was characterised after a squash match in 10 trained players. Maximal voluntary contraction (MVC) and surface EMG activity of vastus lateralis (VL) and vastus medialis (VM) muscles were measured before and immediately after a 1-h squash match. M-wave and twitch contractile properties were analysed following single stimuli. MVC declined (280.5+/-46.8 vs. 233.6+/-35.4 Nm, -16%; P<0.001) after the exercise and this was accompanied by an impairment of central activation, as attested by decline in voluntary activation (76.7+/-10.4 vs. 71.3+/-9.6%, -7%; P<0.05) and raw EMG activity of the two vastii (-17%; P<0.05), whereas RMS/M decrease was lesser (VL: -5%; NS and VM: -12%; P=0.10). In the fatigued state, no significant changes in M-wave amplitude (VL: -9%; VM: -5%) or duration were observed. Following exercise, the single twitch was characterised by lower peak torque (-20%; P<0.001) as well as shorter half-relaxation time (-13%; P<0.001) and reduced maximal rate of twitch tension development (-23%; P<0.001) and relaxation (-17%; P<0.05). A 1-h squash match play caused peripheral fatigue by impairing excitation-contraction coupling, whereas sarcolemmal excitability seems well preserved. Our results also emphasise the role of central activation failure as a possible mechanism contributing to the torque loss observed in knee extensors. Physical conditioners should consider these effects when defining their training programs for squash players.

Use of anisotropic modelling in electrical impedance tomography: description of method and preliminary assessment of utility in imaging brain function in the adult human head.

Electrical Impedance Tomography (EIT) is an imaging method which enables a volume conductivity map of a subject to be produced from multiple impedance measurements. It has the potential to become a portable non-invasive imaging technique of particular use in imaging brain function. Accurate numerical forward models may be used to improve image reconstruction but, until now, have employed an assumption of isotropic tissue conductivity. This may be expected to introduce inaccuracy, as body tissues, especially those such as white matter and the skull in head imaging, are highly anisotropic. The purpose of this study was, for the first time, to develop a method for incorporating anisotropy in a forward numerical model for EIT of the head and assess the resulting improvement in image quality in the case of linear reconstruction of one example of the human head. A realistic Finite Element Model (FEM) of an adult human head with segments for the scalp, skull, CSF, and brain was produced from a structural MRI. Anisotropy of the brain was estimated from a diffusion tensor-MRI of the same subject and anisotropy of the skull was approximated from the structural information. A method for incorporation of anisotropy in the forward model and its use in image reconstruction was produced. The improvement in reconstructed image quality was assessed in computer simulation by producing forward data, and then linear reconstruction using a sensitivity matrix approach. The mean boundary data difference between anisotropic and isotropic forward models for a reference conductivity was 50%. Use of the correct anisotropic FEM in image reconstruction, as opposed to an isotropic one, corrected an error of 24 mm in imaging a 10% conductivity decrease located in the hippocampus, improved localisation for conductivity changes deep in the brain and due to epilepsy by 4-17 mm, and, overall, led to a substantial improvement on image quality. This suggests that incorporation of anisotropy in numerical models used for image reconstruction is likely to improve EIT image quality.

Canakinumab Relieves Symptoms of Acute Flares and Improves Health-Related Quality Of Life (HRQoL) in Difficult-To-Treat Gouty Arthritis Patients by Suppressing Inflammation: Results of a Randomized, Dose-Ranging Study

RATIONALE:We investigated the impact of canakinumab, a fully human anti-interleukin-1b monoclonal antibody on inflammation and HRQoL in gouty arthritis patients.METHODS: In this 8-week, single-blind, dose-ranging study, patients with acute gouty arthritis flares, unresponsive/intolerant or contraindicated to NSAIDs and/or colchicine were randomized to single subcutaneous canakinumab (10, 25, 50, 90, or 150mg, N5143) or single intramuscular triamcinolone acetonide (TA, 40mg, N557). Patients assessed pain (Likert scale), physicians assessed clinical signs of joint inflammation, and HRQoL was recorded using SF-36.RESULTS: At baseline, 98% patients had moderate-to-extreme pain, 85% had moderate/severe joint swelling, 64-79% had elevated inflammatory markers and HRQoL scores indicated impaired physical function. Percentage of patients with no/mild pain was numerically greater in most canakinumab groups vs. TA, 24-72h post-dose; difference significant for 150mg group at these time-points (P<0.05). Canakinumab 150mg was associated with significantly lower Likert scores for tenderness [OR, 3.2; 95% CI, 1.27-7.89; P50.014] and swelling (OR, 2.7; 95% CI, 1.09-6.50, P50.032) at 72h vs. TA; erythema was not different. Median CRP and SAA levels normalized by 7 days post-dose in most canakinumab groups, but remained elevated in TA. Physical function improved at 7 days postdose in all groups, highest improvement for canakinumab 150mg. SF-36 scores for physical functioning and bodily pain with canakinumab 150mg approached US general population scores by 7 days post-dose and exceeded normal values by 8 weeks post-dose.CONCLUSION: Canakinumab 150mg produced significantly greater and rapid pain-relief and improvements in HRQoL vs. TAin acute gouty arthritis patients.

Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation.

Although canonical Notch signaling regulates multiple hematopoietic lineage decisions including T cell and marginal zone B cell fate specification, the downstream molecular mediators of Notch function are largely unknown. We showed here that conditional inactivation of Hes1, a well-characterized Notch target gene, in adult murine bone marrow (BM) cells severely impaired T cell development without affecting other Notch-dependent hematopoietic lineages such as marginal zone B cells. Competitive mixed BM chimeras, intrathymic transfer experiments, and in vitro culture of BM progenitors on Delta-like-expressing stromal cells further demonstrated that Hes1 is required for T cell lineage commitment, but dispensable for Notch-dependent thymocyte maturation through and beyond the beta selection checkpoint. Furthermore, our data strongly suggest that Hes1 is essential for the development and maintenance of Notch-induced T cell acute lymphoblastic leukemia. Collectively, our studies identify Hes1 as a critical but context-dependent mediator of canonical Notch signaling in the hematopoietic system.

Robustness of Drosophila early embryo and wing imaginal disc development

Within a developing organism, cells require information on where they are in order to differentiate into the correct cell-type. Pattern formation is the process by which cells acquire and process positional cues and thus determine their fate. This can be achieved by the production and release of a diffusible signaling molecule, called a morphogen, which forms a concentration gradient: exposure to different morphogen levels leads to the activation of specific signaling pathways. Thus, in response to the morphogen gradient, cells start to express different sets of genes, forming domains characterized by a unique combination of differentially expressed genes. As a result, a pattern of cell fates and specification emerges.Though morphogens have been known for decades, it is not yet clear how these gradients form and are interpreted in order to yield highly robust patterns of gene expression. During my PhD thesis, I investigated the properties of Bicoid (Bcd) and Decapentaplegic (Dpp), two morphogens involved in the patterning of the anterior-posterior axis of Drosophila embryo and wing primordium, respectively. In particular, I have been interested in understanding how the pattern proportions are maintained across embryos of different sizes or within a growing tissue. This property is commonly referred to as scaling and is essential for yielding functional organs or organisms. In order to tackle these questions, I analysed fluorescence images showing the pattern of gene expression domains in the early embryo and wing imaginal disc. After characterizing the extent of these domains in a quantitative and systematic manner, I introduced and applied a new scaling measure in order to assess how well proportions are maintained. I found that scaling emerged as a universal property both in early embryos (at least far away from the Bcd source) and in wing imaginal discs (across different developmental stages). Since we were also interested in understanding the mechanisms underlying scaling and how it is transmitted from the morphogen to the target genes down in the signaling cascade, I also quantified scaling in mutant flies where this property could be disrupted. While scaling is largely conserved in embryos with altered bcd dosage, my modeling suggests that Bcd trapping by the nuclei as well as pre-steady state decoding of the morphogen gradient are essential to ensure precise and scaled patterning of the Bcd signaling cascade. In the wing imaginal disc, it appears that as the disc grows, the Dpp response expands and scales with the tissue size. Interestingly, scaling is not perfect at all positions in the field. The scaling of the target gene domains is best where they have a function; Spalt, for example, scales best at the position in the anterior compartment where it helps to form one of the anterior veins of the wing. Analysis of mutants for pentagone, a transcriptional target of Dpp that encodes a secreted feedback regulator of the pathway, indicates that Pentagone plays a key role in scaling the Dpp gradient activity.