Actinomycin D, C2 and VII, inhibitors of Grb2-SHC interaction produced by Streptomyces

Actinomycin D, C2 and VII, cyclic peptides, inhibited Grb2 SH2 domain association (IC50 5-7 microM) with a phosphotyrosine containing peptide derived from the Shc protein (pTyr317). Actinomycins are the first examples of nonphosphorylated natural ligands of SH2 domain.     

Prediction of mandibular autorotation

PURPOSE: The purpose of this investigation was to test the hypothesis that the mandible rotates around the same point during maxillary impaction surgery as during initial jaw opening. This point, called the center of mandibular autorotation (CAR), could then be used to predict mandibular position and to decide whether only maxillary impaction would be needed to correct the occlusion and the facial profile. PATIENTS AND METHODS: Preoperatively, two lateral cephalograms were obtained from a consecutive series of 20 patients who underwent maxillary impaction without concomitant mandibular ramus osteotomy. One cephalogram was taken with the mandible in centric relation using a wax bite wafer and another with a jaw opening of 10 mm using a fabricated acrylic bite block with the mandible manipulated to its most retruded position. The CAR was calculated before and after jaw opening using the Rouleaux method on the lower incisor and gonion point. A third lateral cephalogram was taken within 2 days postoperatively. The postoperative lower incisal point was then transferred to the first cephalogram using cranial base superimposition. RESULTS: When the preoperative and postoperative distances between CAR and incisal point were compared, there was no significant difference between these distances, proving the hypothesis. CONCLUSIONS: The method used is a practical and precise way to determine the center of mandibular autorotation on an individual basis. The center of rotation during initial jaw opening is the same as during impaction surgery.     

Stress-induced left ventricular outflow tract obstruction: a potential cause of dyspnea in the elderly

OBJECTIVES: We sought to identify the pattern of disturbed left ventricular physiology associated with symptom development in elderly patients with effort-induced breathlessness. BACKGROUND: Limitation of exercise tolerance by dyspnea is common in the elderly and has been ascribed to diastolic dysfunction when left ventricular cavity size and systolic function appear normal. METHODS: Dobutamine stress echocardiography was used in 30 patients (mean [+/-SD] age 70 +/- 12 years; 21 women, 9 men) with exertional dyspnea and negative exercise test results, and the values were compared with those in 15 control subjects. RESULTS: Before stress, left ventricular end-diastolic and end-systolic dimensions were reduced, fractional shortening was increased, and the basal septum was thickened (2.3 +/- 0.5 vs. 1.4 +/- 0.2 cm, p < 0.001, vs. control subjects) in the patients, but posterior wall thickness did not differ from that in control subjects. Left ventricular outflow tract diameter, measured as systolic mitral leaflet septal distance, was significantly reduced (13 +/- 4.5 vs. 18 +/- 2 mm, p < 0.001). Isovolumetric relaxation time was prolonged, and peak left ventricular minor axis lengthening rate was reduced (8.1 +/- 3.5 vs. 10.4 +/- 2.6 cm/s, p < 0.05), suggesting diastolic dysfunction. Transmitral velocities and the E/A ratio did not differ significantly. At peak stress, heart rate increased from 66 +/- 8 to 115 +/- 20 beats/min in the control subjects, but blood pressure did not change. Transmitral A wave velocity increased, but the E/A ratio did not change. Left ventricular outflow tract velocity increased from 0.8 +/- 0.1 to 2.0 +/- 0.2 m/s, and mitral leaflet septal distance decreased from 18 +/- 2 to 14 +/- 3 mm, p < 0.001. In the patients, heart rate rose from 80 +/- 12 to 132 +/- 26 beats/min and systolic blood pressure from 143 +/- 22 to 170 +/- 14 mm Hg (p < 0.001 for each), but left ventricular dimensions did not change. Peak left ventricular outflow tract velocity increased from 1.5 +/- 0.5 m/s (at rest) to 4.2 +/- 1.2 m/s; mitral leaflet septal distance fell from 13 +/- 4.5 to 2.2 +/- 1.9 mm (p < 0.001); and systolic anterior motion of mitral valve appeared in 24 patients (80%) but in none of the control subjects (p < 0.001). Measurements of diastolic function did not change. All patients developed dyspnea at peak stress, but none developed a new wall motion abnormality or mitral regurgitation. CONCLUSIONS: Although our patients fulfilled the criteria for "diastolic heart failure," diastolic dysfunction was not aggravated by pharmacologic stress. Instead, high velocities appeared in the left ventricular outflow tract and were associated with basal septal hypertrophy and systolic anterior motion of the mitral valve. Their appearance correlated closely with the development of symptoms, suggesting a potential causative link.