Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1.

All nuclear-encoded mRNAs contain a 5' cap structure (m7GpppN, where N is any nucleotide), which is recognized by the eukaryotic translation initiation factor 4E (eIF4E) subunit of the eIF4F complex. The eIF4E-binding proteins constitute a family of three polypeptides that reversibly repress cap-dependent translation by binding to eIF4E, thus preventing the formation of the eIF4F complex. We investigated the biological function of 4E-BP1 by disrupting its gene (Eif4ebp1) in the mouse. Eif4ebp1-/- mice manifest markedly smaller white fat pads than wild-type animals, and knockout males display an increase in metabolic rate. The males' white adipose tissue contains cells that exhibit the distinctive multilocular appearance of brown adipocytes, and expresses the uncoupling protein 1 (UCP1), a specific marker of brown fat. Consistent with these observations, translation of the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC1), a transcriptional co-activator implicated in mitochondrial biogenesis and adaptive thermogenesis, is increased in white adipose tissue of Eif4ebp1-/- mice. These findings demonstrate that 4E-BP1 is a novel regulator of adipogenesis and metabolism in mammals.

Permanent radiofrequency ventricular pacing for management of drug-resistant ventricular tachycardia.

Three patients with frequent episodes of symptomatic, sustained ventricular tachycardia that often required physician intervention were treated with a permanent patient-activated radiofrequency ventricular pacemaker for self-termination of ventricular tachycarida. Before pacemaker implantation, electrophysiologic testing revealed the tachycardia to be resistant to all approved and several investigational antiarrhythmic drugs. In all three patients, ventricular tachycardia was reliably and reproducibly terminated with brief bursts of rapid right ventricular apical pacing over several hundred trials. No patient had rapid ventricular pacing-induced acceleration of ventricular tachycardia or pacing-induced ventricular fibrillation. Since the implantation of a radiofrequency ventricular pacemaker an average of 13.7 months ago, all episodes of ventricular tachycardia (average 43/patient) have been terminated successfully by radiofrequency pacing, and no patient has required hospitalization for an arrhythmia-related problem.

When interventions harm. Peer groups and problem behavior.

This article explored developmental and intervention evidence relevant to iatrogenic effects in peer-group interventions. Longitudinal research revealed that "deviancy training" within adolescent friendships predicts increases in delinquency, substance use, violence, and adult maladjustment. Moreover, findings from 2 experimentally controlled intervention studies suggested that peer-group interventions increase adolescent problem behavior and negative life outcomes in adulthood, compared with control youth. The data from both experimental studies suggested that high-risk youth are particularly vulnerable to peer aggregations, compared with low-risk youth. We proposed that peer aggregation during early adolescence, under some circumstances, inadvertently reinforces problem behavior. Two developmental processes are discussed that might account for the powerful iatrogenic effects.

The role of proactive and reactive aggression in the formation and development of boys' friendships.

This study tested the hypothesis that friends are more similar in proactive aggression than in reactive aggression. Interpersonal processes that may account for this similarity (i.e., selection and mutual influence) were also examined. In the fall and spring of the school year, the friendships of 185 4th-, 5th-, and 6th-grade boys were identified. Proactive and reactive aggressive behavior were assessed with a teacher-rating instrument for each boy. The results support the general hypothesis and suggest that proactively aggressive boys tend to select proactively aggressive peers as friends; however, mutual influence between stable friends does not appear to account for similarity. These findings are discussed within the framework of G. R. Patterson, J. B. Reid, and T. J. Dishion's (1992) theory of antisocial behavior.

Reactive and proactive aggression: evidence of a two-factor model.

This article examines the construct validity of reactive and proactive aggression, as assessed by the teacher-rating scale developed by K. A. Dodge and J. D. Coie (1987). In Study 1 (n = 149 boys), confirmatory factor analyses revealed that a 2-factor model, in which a substantial correlation was observed between the 2 latent factors, presented a better fit than a single-factor model. Study 2 (n = 193 boys) examined the relations presented by the 2 forms of aggression with peer status, leadership, social withdrawal, and victimization by peer. Reactive and proactive aggressive behaviors presented distinct patterns of relations consistent with the theoretical definitions. The results of these studies suggest that the questionnaire measures 2 forms of aggressive behavior that, although being substantially related, have a unique discriminant dimension.

The cardiac pacemaker: functions, falterings, and fate.

No pacemaker problem is predictable enough to plan for, with the possible exception of battery failure, so follow-up surveillance is essential. Pacemaker malfunctions are generally either actual device malfunctions or adverse interactions between the pacer and the patient's body. Depletion of the power source is the most common event.

Biomechanical modeling of posterior instrumentation of the scoliotic spine.

Scoliosis is a three-dimensional deformation of the spine that can be treated by vertebral fusion using surgical instrumentation. However, the optimal configuration of instrumentation remains controversial. Simulating the surgical maneuvers with personalized biomechanical models may provide an analytical tool to determine instrumentation configuration during the pre-operative planning. Finite element models used in surgical simulations display convergence difficulties as a result of discontinuities and stiffness differences between elements. A kinetic model using flexible mechanisms has been developed to address this problem, and this study presents its use in the simulation of Cotrel-Dubousset Horizon surgical maneuvers. The model of the spine is composed of rigid bodies corresponding to the thoracic and lumbar vertebrae, and flexible elements representing the intervertebral structures. The model was personalized to the geometry of three scoliotic patients (with a thoracic Cobb angle of 45 degrees, 49 degrees and 39 degrees ). Binary joints and kinematic constraints were used to represent the rod-implant-vertebra joints. The correction procedure was simulated using three steps: (1) Translation of hooks and screws on the first rod; (2) 90 degrees rod rotation; (3) Hooks and screws look-up on the rod. After the simulation, slight differences of 0-6 degrees were found for the thoracic spine scoliosis and the kyphosis, and of 1-8 degrees for the axial rotation of the apical vertebra and for the orientation of the plane of maximum deformity, compared to the real post-operative shape of the patient. Reaction loads at the vertebra-implant link were mostly below 1000 N, while reaction loads at the boundary conditions (representing the overall action of the surgeon) were in the range 7-470 N and maximum torque applied to the rod was 1.8 Nm. This kinetic modeling approach using flexible mechanisms provided a realistic representation of the surgical maneuvers. It may offer a tool to predict spinal geometry correction and assist in the pre-operative planning of surgical instrumentation of the scoliotic spine.

[A biomechanical study of new orthotic treatment approaches for the 3D correction of scoliosis]. / Etude biomécanique de nouveaux concepts de traitement orthotique pour la correction 3D de la scoliose.

Scoliosis is a complex deformity of the spine and rib cage often treated by the Boston brace. The goal of this research is to study the simulation of two new treatment approaches and to compare their results to the Boston brace. A personalized biomechanical model has been used to simulate the treatment on 20 scoliotic teenagers with double curvature. On the first treatment, different forces were applied at the thoracic apex level and the posterior displacement of the rib hump was locked. For the second treatment, an oblique force oriented 45 degrees with respect to the frontal plane was added at the lumbar apex. Following each simulation, geometrical and clinical measurements were calculated and compared to the initial geometry and the Boston brace treatment. Overall, the two new treatment modalities correct the thoracic Cobb angle in the frontal plane while maintaining the normal physiological curvatures in the sagittal plane, move the thoracic plane of maximum deformity towards the sagittal plane and reduce axial rotation and rib hump. In comparison, the Boston brace reduces the Cobb angles in the frontal as well as in the sagittal planes, moves the planes of maximum deformities towards the coronal plane and has no effect on axial rotation and rib hump. This biomechanical study shows force patterns that correct scoliosis more efficiently than the Boston brace. These new treatment approaches must be personalized for each patient and still require clinical evaluation.

[Biomechanical modeling of instrumentation for the scoliotic spine using flexible elements: a feasibility study]. / Modélisation biomécanique de l'instrumentation du rachis scoliotique à l'aide de mécanismes flexibles: étude de faisabilité.

Surgical instrumentation of the scoliotic spine is a complex procedure with many parameters, such as the spinal segment to operate on, the number and position of the hooks and screws, etc. Biomechanical modeling is a tool which can be used to determine the influence of these parameters. However, technical difficulties due to the large stiffness range of involved components and the large deformations associated with surgical maneuvers are encountered when using the finite elements method. Thus, the objective of this study is to adapt a modeling approach using analysis of flexible mechanisms and evaluate its feasibility. The model combines rigid bodies for the vertebrae and flexible elements representing intervertebral structures. The mechanical properties were calculated from published data and the geometry was personalized with intraoperative measurements. Following the installation of the hooks and screws on the modeled spine, two steps were used to simulate the surgical maneuvers: 1) translation and attachment of the hooks/screws on the first rod; 2) rod rotation. The feasibility of this modeling approach was evaluated by simulating the surgical maneuvers on 2 cases: 1) a physical model; 2) a clinical case. The agreement between intraoperative measurements and simulation results (frontal curvatures are reproduced with over 80% accuracy) shows the feasibility of the modeling approach. This approach also reduces computational convergence problems because of its limited sensitivity to stiffness differences between elements, which demonstrates the advantage of flexible mechanism modeling relative to finite element modeling. Long term goals of subsequent refinements are the development of a tool for surgical correction predictions and for the design of more efficient instrumentation.

Contrasting mechanisms of regulating translation of specific Drosophila germline mRNAs at the level of 5'-cap structure binding.

Translational control is a key genetic regulatory mechanism underlying the initial establishment of the major spatial axes of the Drosophila embryo. Many translational control mechanisms target eIF4E (eukaryotic initiation factor 4E), an initiation factor that recognizes the 5'-cap structure of the mRNA. Cap recognition by eIF4E, in complex with eIF4G, is essential for recruitment of the mRNA to the small ribosomal subunit. One established mechanism for repressing translation involves eIF4E-binding proteins, which competitively inhibit the eIF4E-eIF4G interaction. Our group has uncovered a novel mechanism for repression in which an eIF4E cognate protein called d4EHP, which cannot bind eIF4G, binds to the 5'-cap structure of cad mRNA thus rendering it translationally inactive. These two related, but distinct, mechanisms are discussed and contrasted in this review.

4E-BP3, a new member of the eukaryotic initiation factor 4E-binding protein family.

Translation initiation in eukaryotes is mediated by the cap structure (m7GpppN, where N is any nucleotide) present at the 5' end of all cellular mRNAs, except organellar. The cap is recognized by eukaryotic initiation factor 4F (eIF4F), which consists of three polypeptides, including eIF4E, the cap-binding protein subunit. The interaction of the cap with eIF4E facilitates the binding of the ribosome to the mRNA. eIF4E activity is regulated in part by two translational repressors, 4E-BP1 and 4E-BP2, which bind to it and prevent its assembly into eIF4F. We report here the isolation of 4E-BP3, a new member of the 4E-BP family. 4E-BP3 is homologous to 4E-BP1 and 4E-BP2, exhibiting 57 and 59% identity, respectively. The homology is most striking in the middle region of the protein, which contains the eIF4E binding motif and residues that are phosphorylated in 4E-BP1. 4E-BP3 is a heat stable protein that binds to eIF4E in vitro as well as in vivo. Further, 4E-BP3 overexpression specifically reduces eIF4E-dependent translation. The overlapping function and expression of the different 4E-BP family members imply that there is redundancy in this translational control mechanism, underscoring its importance.

Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors.

Protease inhibitors are potent antiviral agents against human immunodeficiency virus type 1. As with reverse transcriptase inhibitors, however, resistance to protease inhibitors can develop and is attributed to the appearance of mutations in the protease gene. With the substrate analog protease inhibitors BILA 1906 BS and BILA 2185 BS, 350- to 1,500-fold-resistant variants have been selected in vitro and were found not only to contain mutations in the protease gene but also to contain mutations in Gag precursor p1/p6 and/or NC (p7)/p1 cleavage sites. Mutations in cleavage sites give rise to better peptide substrates for the protease in vitro and to improved processing of p15 precursors in drug-resistant clones. Importantly, removal of cleavage site mutations in resistant clones leads to a decrease or even an absence of viral growth, confirming their role in viral fitness. Therefore, these second-locus mutations indicate that cleavage of p15 is a rate-limiting step in polyprotein processing in highly resistant viruses. The functional constraint of p15 processing also suggests that additional selective pressure could further compromise viral fitness and maintain the benefits of antiviral therapies.

Cardiac-directed overexpression of wild-type alpha1B-adrenergic receptor induces dilated cardiomyopathy.

Using transgenesis as a paradigm, we show here that alpha1-adrenergic receptors (alpha1AR) play an important role in cardiac homeostasis. Cardiomyocyte-specific overexpression of the alpha(1B)AR subtype resulted in the development of dilated cardiomyopathy and death at ~9 mo of age with typical signs of heart failure. Histological analyses showed the enlargement of all four cardiac chambers and cardiomyocyte disarray in the failing hearts. Transgenic animals showed increased left ventricular areas, as assessed by echocardiography. In addition, a progressive decrease in left ventricular systolic function was revealed. The abundance and activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) were reduced, and the ratio of phospholamban to SERCA2 was increased. alpha-Myosin heavy chain (MHC) mRNA was less abundant in older transgenic ventricles, whereas beta-MHC was induced in the failing hearts. Titin mRNA abundance was decreased at 9 mo, whereas atrial natriuretic factor mRNA was elevated at all times. This model mimics structural and functional features of idiopathic dilated cardiomyopathy. The results of this study suggest that chronic alpha1AR activity is deleterious for cardiac function.