Neurexin mediates the assembly of presynaptic terminals

Neurexins are a large family of proteins that act as neuronal cell-surface receptors. The function and localization of the various neurexins, however, have not yet been clarified. Beta-neurexins are candidate receptors for neuroligin-1, a postsynaptic membrane protein that can trigger synapse formation at axon contacts. Here we report that neurexins are concentrated at synapses and that purified neuroligin is sufficient to cluster neurexin and to induce presynaptic differentiation. Oligomerization of neuroligin is required for its function, and we find that beta-neurexin clustering is sufficient to trigger the recruitment of synaptic vesicles through interactions that require the cytoplasmic domain of neurexin. We propose a two-step model in which postsynaptic neuroligin multimers initially cluster axonal neurexins. In response to this clustering, neurexins nucleate the assembly of a cytoplasmic scaffold to which the exocytotic apparatus is recruited.     

Prognostic value of global myocardial performance indices in acute myocardial infarction: comparison to measures of systolic and diastolic left ventricular function

STUDY OBJECTIVES: Assessment of global myocardial performance by a single index (ie, the myocardial performance index [MPI]) has been suggested as an appealing alternative to the individual assessment of systolic and diastolic left ventricular (LV) function We sought to test the prognostic value of MPI in comparison to clinical characteristics and echocardiographic parameters of LV filling and ejection in acute myocardial infarction (AMI). PATIENTS: Four hundred seventeen consecutive patients with AMI were examined within 24 h of hospital admission. INTERVENTIONS: Doppler echocardiographic measures of systolic, diastolic, and global myocardial performance were assessed within 24 h of hospital admission. In addition to MPI (ie, the sum of the isovolumic time intervals divided by ejection time), we determined the isovolumic/heterovolumic time ratio, which expresses the time "wasted" by the myocardium to generate and decrease LV pressure without moving blood. RESULTS: The end points of the study at 30 days were death (4.7%), congestive heart failure (23%), and recurrent infarction (4.8%), and occurred in 109 patients, who were compared as group B to 314 patients without an event (group A). Multivariate analysis identified only age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02 to 1.07), LV ejection fraction (LVEF) < or = 40% (OR, 3.82; 95% CI, 2.15 to 6.87), and E-wave deceleration time (EDT) of < or = 130 ms (OR, 2.29; 95% CI, 1.0 to 5.21) as independent predictors of adverse events. CONCLUSION: LVEF and EDT are powerful and independent echocardiographic predictors of poor outcome following AMI, and are superior to indexes of global LV performance. Both parameters should be taken into consideration when deciding about the management of these patients.     

Responsiveness to rapid atrial pacing of the specialized atrioventricular conduction system in children

Summary Responsiveness to rapid atrial pacing of the specialized atrioventricular (A-V) conduction system was studied in 25 patients aged 2 months to 18 years. Atrial pacing via a catheter placed at the right atrial superior vena cava junction was initiated at rates slightly greater than the sinus rate and gradually increased to rates as high as 600 stimuli per minute. His bundle electrograms were obtained in most patients. When the atrial pacing rate (x-axis) was plotted against the corresponding ventricular rate (y-axis), the curve was M-shaped. The initial ascending limb occurred during 1:1 A-V conduction with rates as high as 270 stimuli per minute. The first descending limb resulted from Wenckebach type A-V block occurring at rates of 160 to 300 stimuli per minute. The second ascending limb corresponded to periods of 2:1 A-V block observed at rates of 200 to 536 stimuli per minute, and the final descending limb was related to higher degrees of block at both the pacing site and the A-V node. The second descending limb was seen with pacing rates of 296 to 600 stimuli per minute. The rates required to produce Wenckebach type A-V block in this group of children were higher than those reported in adults. One patient with spontaneous first-degree A-V block developed 2:1 A-V block at a pacing rate of only 150 stimuli per minute.This technique for studying the response to rapid atrial pacing of the specialized A-V conduction system characterises its functional capacity. The technique can be applied rapidly and safely in selected patients.     

Oral Insulin: The Rationale for This Approach and Current Developments

Insulin remains the most effective and durable hypoglycemic agent for the treatment of diabetes. The addition of an effective oral insulin dosage form to the antidiabetes armamentarium may have significant benefits in terms of fostering compliance and adherence among patients, as well as physiologic advantages due to the fact that such a dosage form replicates the natural route of insulin secretion and absorption through the portal vein and targets the liver directly. Several companies have developed technological platforms that protect polypeptides and proteins from enzymatic hydrolysis, enable their transport across the epithelial lining, and promote their absorption from the gastrointestinal tract. A review of the potential physiological rationale and advantages, as well as of current pertinent technologies used specifically with insulin, is herewith provided.