Whole-heart coronary vein imaging: a comparison between non-contrast-agent- and contrast-agent-enhanced visualization of the coronary venous system.

The feasibility of three-dimensional (3D) whole-heart imaging of the coronary venous (CV) system was investigated. The hypothesis that coronary magnetic resonance venography (CMRV) can be improved by using an intravascular contrast agent (CA) was tested. A simplified model of the contrast in T(2)-prepared steady-state free precession (SSFP) imaging was applied to calculate optimal T(2)-preparation durations for the various deoxygenation levels expected in venous blood. Non-contrast-agent (nCA)- and CA-enhanced images were compared for the delineation of the coronary sinus (CS) and its main tributaries. A quantitative analysis of the resulting contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) in both approaches was performed. Precontrast visualization of the CV system was limited by the poor CNR between large portions of the venous blood and the surrounding tissue. Postcontrast, a significant increase in CNR between the venous blood and the myocardium (Myo) resulted in a clear delineation of the target vessels. The CNR improvement was 347% (P < 0.05) for the CS, 260% (P < 0.01) for the mid cardiac vein (MCV), and 430% (P < 0.05) for the great cardiac vein (GCV). The improvement in SNR was on average 155%, but was not statistically significant for the CS and the MCV. The signal of the Myo could be significantly reduced to about 25% (P < 0.001).

Functional analysis of the post-transcriptional regulator RsmA reveals a novel RNA-binding site.

The RsmA family of RNA-binding proteins are global post-transcriptional regulators that mediate extensive changes in gene expression in bacteria. They bind to, and affect the translation rate of target mRNAs, a function that is further modulated by one or more, small, untranslated competitive regulatory RNAs. To gain new insights into the nature of this protein/RNA interaction, we used X-ray crystallography to solve the structure of the Yersinia enterocolitica RsmA homologue. RsmA consists of a dimeric beta barrel from which two alpha helices are projected. From structure-based alignments of the RsmA protein family from diverse bacteria, we identified key amino acid residues likely to be involved in RNA-binding. Site-specific mutagenesis revealed that arginine at position 44, located at the N terminus of the alpha helix is essential for biological activity in vivo and RNA-binding in vitro. Mutation of this site affects swarming motility, exoenzyme and secondary metabolite production in the human pathogen Pseudomonas aeruginosa, carbon metabolism in Escherichia coli, and hydrogen cyanide production in the plant beneficial strain Pseudomonas fluorescens CHA0. R44A mutants are also unable to interact with the small untranslated RNA, RsmZ. Thus, although possessing a motif similar to the KH domain of some eukaryotic RNA-binding proteins, RsmA differs substantially and incorporates a novel class of RNA-binding site.

Comparison between computational alanine scanning and per-residue binding free energy decomposition for protein-protein association using MM-GBSA: application to the TCR-p-MHC complex.

Recognition by the T-cell receptor (TCR) of immunogenic peptides (p) presented by Class I major histocompatibility complexes (MHC) is the key event in the immune response against virus-infected cells or tumor cells. A study of the 2C TCR/SIYR/H-2K(b) system using a computational alanine scanning and a much faster binding free energy decomposition based on the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method is presented. The results show that the TCR-p-MHC binding free energy decomposition using this approach and including entropic terms provides a detailed and reliable description of the interactions between the molecules at an atomistic level. Comparison of the decomposition results with experimentally determined activity differences for alanine mutants yields a correlation of 0.67 when the entropy is neglected and 0.72 when the entropy is taken into account. Similarly, comparison of experimental activities with variations in binding free energies determined by computational alanine scanning yields correlations of 0.72 and 0.74 when the entropy is neglected or taken into account, respectively. Some key interactions for the TCR-p-MHC binding are analyzed and some possible side chains replacements are proposed in the context of TCR protein engineering. In addition, a comparison of the two theoretical approaches for estimating the role of each side chain in the complexation is given, and a new ad hoc approach to decompose the vibrational entropy term into atomic contributions, the linear decomposition of the vibrational entropy (LDVE), is introduced. The latter allows the rapid calculation of the entropic contribution of interesting side chains to the binding. This new method is based on the idea that the most important contributions to the vibrational entropy of a molecule originate from residues that contribute most to the vibrational amplitude of the normal modes. The LDVE approach is shown to provide results very similar to those of the exact but highly computationally demanding method.

DNA's golden jubilee.

Review of : 50 Years of DNA Foreword by Phil Campbell, edited by Julie Clayton and Carina Dennis Palgrave Macmillan

Polymédication et personne agée: ni trop ni trop peu [Polypharmacy and the elderly: neither too much nor too little].

Elderly persons are at high risk of polypharmacy. Polypharmacy has been associated with numerous adverse outcomes, such as poorer quality of life, higher morbidity and mortality. However, deciding to stop or to continue a treatment is a difficult task, which confronts the physician to complex clinical and ethical choices. Such a decision requires a geriatric multidimensional assessment of the patient, an estimation of his or her prognosis, the definition of the goals of care and a careful assessment of the time to benefit of each drug. Diverse methods and tools to support the physician in this process are discussed in this article. However these can not replace a reflexive approach of the physician that integrates the values and representations of the patient with regard to his or her health and end of life, as well as his or her needs, fears and choices.

The circadian clock modulates renal sodium handling.

The circadian clock contributes to the control of BP, but the underlying mechanisms remain unclear. We analyzed circadian rhythms in kidneys of wild-type mice and mice lacking the circadian transcriptional activator clock gene. Mice deficient in clock exhibited dramatic changes in the circadian rhythm of renal sodium excretion. In parallel, these mice lost the normal circadian rhythm of plasma aldosterone levels. Analysis of renal circadian transcriptomes demonstrated changes in multiple mechanisms involved in maintaining sodium balance. Pathway analysis revealed the strongest effect on the enzymatic system involved in the formation of 20-HETE, a powerful regulator of renal sodium excretion, renal vascular tone, and BP. This correlated with a significant decrease in the renal and urinary content of 20-HETE in clock-deficient mice. In summary, this study demonstrates that the circadian clock modulates renal function and identifies the 20-HETE synthesis pathway as one of its principal renal targets. It also suggests that the circadian clock affects BP, at least in part, by exerting dynamic control over renal sodium handling.

Endocarditis prophylaxis revisited: experimental evidence of efficacy and new Swiss recommendations. Swiss Working Group for Endocarditis Prophylaxis.

Because of its severity, it is agreed that infectious endocarditis should be prevented whenever possible. Determining adequate prophylactic measures involves establishing (a) the patients at risk, (b) the procedures that might provoke bacteraemia, (c) the most effective prophylactic regimen, and (d) a balance between the risks of side effects from prophylaxis and of developing infectious endocarditis. Patients at risk and procedures inducing bacteraemia have been identified by clinical studies. On the other hand, the efficacy of prophylactic antibiotics has been based on animal studies. Randomised, placebo-controlled studies do not exist in humans because they would require large patient numbers and would raise ethical issues due to the severity of the disease. Case-control studies have indicated that infectious endocarditis prophylaxis is effective, but prevents only a limited number of cases. Animal experiments have revealed several key issues for human application. First, antibiotics do not prevent the early stages of valve colonisation, but rather kill the microorganisms after their attachment to the cardiac lesions. Second, the duration of antibiotic presence in the serum is critical. Under experimental conditions, the drugs must remain above their minimal inhibitory concentration for the organisms for > or = 10 h, to allow time for bacterial clearance from the valves. Third, antibiotic-induced killing is not the only mechanism allowing bacterial clearance. Other factors, such as platelet microbicidal proteins, may act in concert with the drugs to sterilise the lesions. Recommendations for prophylaxis have recently been revised in Europe and the USA. New information has improved the definition of groups at risk. Since most cases of infectious endocarditis are not preceded by medical procedures, primary prevention of infectious endocarditis should target infected foci responsible for spontaneous bacteraemia (e.g. poor dental hygiene). The purpose of this article is to update the existing recommendations in Switzerland, under the perspective of changing epidemiology, the availability of new drugs, and harmonisation with recommendations in other countries.

Que faire d'un stagiaire dans votre consultation [Tips for hosting a medical student in a PC consultation].

Hosting a medical student in one's primary care consultation challenges the practitioner to be a clinical teacher as well as providing high-quality patient care. A few tips can make this double task easier. Before the consultation it is possible to define the student's learning objectives and to plan the consultation. During the consultation itself some teaching models exist (One minute preceptor, SNAPP) that facilitate the teaching by maximising the teaching moments for each student-patient encounter. And finally after the consultation a time of reflection where both student and clinical teacher can think about what went well and what could be done better.

Der Einfluss des Ernährungswissens auf Nahrungsmittelpräferenzen bei Kindern: Eine experimentelle Untersuchung

Adipöse Kinder zeigen stärkere Präferenzen für und einen größeren Konsum fetthaltiger Nahrungsmittel. Die aktuelle Studie untersucht, ob Ernährungswissen die Präferenz für Nahrungsmittel beeinflusst. 59 Kinder nahmen an der experimentellen Untersuchung teil, in der Comicfiguren als konditionierte Reize und Nahrungsmittelbilder als unkonditionierte Reize dienten. Relative Präferenzen für die Comicfiguren wurden vor und nach gepaarter Präsentation und das Ernährungswissen mittels Fragebogen erfasst. Das Ernährungswissen scheint die Veränderung der Präferenzen zu beeinflussen. Vor allem die Veränderung der Präferenz für die mit dem fettarmen Nahrungsmittel gepaarte Comicfigur kann dadurch vorhergesagt werden. Ernährungswissen scheint die Attraktivität des fettarmen Nahrungsmittels zu steigern und somit Präferenz für das Nahrungsmittel zu beeinflussen. Es ist daher von Relevanz, dass in Interventionen bei kindlicher Adipositas über gesunde Ernährung aufgeklärt wird. Zukünftige Forschung soll weitere potentielle Einflussvariablen untersuchen.

Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias.

Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.

Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.

Artifact-free coronary magnetic resonance angiography and coronary vessel wall imaging in the presence of a new, metallic, coronary magnetic resonance imaging stent.

BACKGROUND: Coronary in-stent restenosis cannot be directly assessed by magnetic resonance angiography (MRA) because of the local signal void of currently used stainless steel stents. The aim of this study was to investigate the potential of a new, dedicated, coronary MR imaging (MRI) stent for artifact-free, coronary MRA and in-stent lumen and vessel wall visualization. METHODS AND RESULTS: Fifteen prototype stents were deployed in coronary arteries of 15 healthy swine and investigated with a double-oblique, navigator-gated, free-breathing, T2-prepared, 3D cartesian gradient-echo sequence; a T2-prepared, 3D spiral gradient-echo sequence; and a T2-prepared, 3D steady-state, free-precession coronary MRA sequence. Furthermore, black-blood vessel wall imaging by a dual-inversion-recovery, turbo spin-echo sequence was performed. Artifacts of the stented vessel segment and signal intensities of the coronary vessel lumen inside and outside the stent were assessed. With all investigated sequences, the vessel lumen and wall could be visualized without artifacts, including the stented vessel segment. No signal intensity alterations inside the stent when compared with the vessel lumen outside the stent were found. CONCLUSIONS: The new, coronary MRI stent allows for completely artifact-free coronary MRA and vessel wall imaging.

Ultrasons osseux et dépistages de l'ostéoporose

Comme technique alternative à la densitométrie osseuse par rayons-X (DXA), l'ultrason quantitatif (USQ) prend un intérêt de plus en plus important, pour l'évaluation osseuse non invasive du risque fracturaire d'origine ostéoporotique. Bien que l'USQ soit reconnu sur le plan scientifique dans le management de l'ostéoporose par de nombreuses sociétés internationales, il devient urgent de définir une stratégie d'utilisation clinique pratique. Dans cet article, plusieurs approches ont été évoquées, soulignant les avantages et inconvénients de chacune d'entre elles. Cependant, le coeur de cette article porte sur des recommandations opérationnelles pour l'utilisation de 2 appareil USQ, vendus en Suisse, dans le management de l'ostéoporose. Cette approche prend en compte les recommandations de l'Association Suisse contre l'Ostéoporose en terme de facteurs de risques ainsi que les indications officielles pour l'examen DXA conventionnel. [Ed.]

Neuronal potential of cells in early postnatal rat sciatic nerve.

A population of undifferentiated cells with neuronal potentialities were revealed in rat sciatic nerve. Explant cultures of sciatic nerve were prepared from newborn or early postnatal rat. Cultures were growth in F14 medium supplemented with 10% of fetal calf serum, incubated in a humidified 3% CO2, 97% air atmosphere. Within 2 weeks, refractile cells exhibiting the morphology of neurons were observed in all examined cultures. These cells had ovoid or multipolar refractile cells bodies with extended cytoplasmic processes. The neuronal nature of these cells was confirmed by their immunostaining with specific neuronal markers: neurofilament triplets, neuron-specific enolase, peripherin, microtubule-associated proteins, and brain spectrin. This neuronal population displayed various phenotypes. The CO2 concentration in the incubator plays an important role, since the number of differentiated neurons was lower in cultures incubated in 5% CO2. Since the sciatic nerve is devoid of nerve cell bodies in vivo, we concluded that early postnatal sciatic nerve contains crest cells with neuronal potentialities differentiating into neurons in response to the culture's environmental cues.

Aberrant right hepatic artery with a prepancreatic course visualized prior to pancreaticoduodenectomy.

Liver vascularization is known to present with several different variations. Generally, a normal vascular anatomy is reported in up to 50-80 % of cases. For this reason, a precise preoperative mapping of the hepatic vascularization prior to pancreatic surgery is essential to avoid injuries and subsequent complications. We report here a case of a young patient scheduled for Whipple procedure, who presented an arterial pattern type Michels IV, variation reported in 0.6 to 3 % in the literature. Another interesting particularity of this case was the fact that the right hepatic artery had a prepancreatic course. We think that every surgeon performing hepatopancreatic surgery should have heard of this special and rare situation.