CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation

The activity of cyclin-dependent kinase 2 (CDK2) is essential for progression of cells from G1 to the S phase of the mammalian cell cycle. CVT-313 is a potent CDK2 inhibitor, which was identified from a purine analog library with an IC50 of 0.5 microM in vitro. Inhibition was competitive with respect to ATP (Ki = 95 nM), and selective CVT-313 had no effect on other, nonrelated ATP-dependent serine/threonine kinases. When added to CDK1 or CDK4, a 8.5- and 430-fold higher concentration of CVT-313 was required for half-maximal inhibition of the enzyme activity. In cells exposed to CVT-313, hyperphosphorylation of the retinoblastoma gene product was inhibited, and progression through the cell cycle was arrested at the G1/S boundary. The growth of mouse, rat, and human cells in culture was also inhibited by CVT-313 with the IC50 for growth arrest ranging from 1.25 to 20 microM. To evaluate the effects of CVT-313 in vivo, we tested this agent in a rat carotid artery model of restenosis. A brief intraluminal exposure of CVT-313 to a denuded rat carotid artery resulted in more than 80% inhibition of neointima formation. These observations suggest that CVT-313 is a promising candidate for evaluation in other disease models related to aberrant cell proliferation.     

Accuracy of 3D MR microscopy for trabecular bone assessment: a comparative study on calcaneus samples using 3D synchrotron radiation microtomography

Magnetic resonance (MR) imaging is attractive for a noninvasive and radiation-free assessment of in vivo trabecular bone architecture. However the quantitative evaluation of architectural parameters could be biased by the limited sensitivity of MR. The aim of this study was to determine the accuracy of trabecular bone architectural parameters obtained from 3D high-resolution MR images, by comparison to reference images obtained by high-resolution X-ray microtomography using synchrotron radiation, from 29 samples of human calcaneus. MR images were obtained with a 66 m×66 m×66 m voxel size, using a 8.5 T MR microscope. Microtomography images were acquired with a 10 m×10 m×10 m voxel size, from the same samples. 3D architectural parameters characterizing the morphometry, topology, anisotropy, and orientation were computed from both modalities and carefully compared. To avoid errors, an identical region of interest was selected in the two corresponding images, and the same algorithms were run at identical spatial resolution. Our results establish that network connectivity, orientation and anisotropy are reliable from the MR data. The bone volume fraction, and morphometric parameters measured from the MR data, were found to be biased with respect to their values from the microtomography data, although there was a significant correlation between the two modalities.An erratum to this article can be found at     

SLIGA Based underwater weapon safety and arming system

 The Naval Surface Warfare Center, Indian Head Division (NSWCIHD) is applying microelectromechanical system (MEMS) technology to underwater weapon Safety and Arming (S&A) system development. MEMS technology provides an opportunity to develop a miniaturized S&A system that is more sophisticated with improved safety and reliability at a lower cost compared to current systems. An S&A system prevents premature initiation of the weapon while reliably ensuring initiation at the appropriate time. An S&A system uses multiple sensors and devices. In comparison with other weapon S&A systems, a critical aspect of underwater weapon S&A systems is the mechanical interlock system utilizing actuators and mechanical sensors. This paper describes the design, development and fabrication of S&A SLIGA device prototypes and of a SLIGA based S&A system. NSWCIHD worked with members of the HI-MEMS Alliance during design, development and fabrication. Advancements achieved by the HI-MEMS Alliance and SLIGA S&A design issues are discussed. Received: 25 August 1997/Accepted: 10 September 1997     

LIGA micro-openings for coherence characterization of X-rays

Infinitely thin opaque screens serving for diaphragms as defined in the visible-light optics are not feasible for operation with X-ray beams due to their high penetrability. Micro-openings of predicted sidewall shape in a gold layer up to 140 μm thick which would provide low transparency, are proposed. The proposed micro-openings were made using the LIGA technique and tested successfully at photon energies of up to 25 keV. The micro-openings can be used as targets for coherence X-ray pattern or, if long interference tails are avoided by means of the advanced sidewall shape, as X-ray beam collimators.     

Comparison of alveolar ventilation, oxygenation, pressure support, and respiratory system resistance in response to noninvasive versus conventional mechanical ventilation in foals

OBJECTIVE: To compare the efficacy of positive pressure ventilation applied through a mask versus an endotracheal tube, using anesthetized/paralyzed foals as a model for foals with hypoventilation. ANIMALS: Six 1-month-old foals. PROCEDURE: A crossover design was used to compare the physiologic response of foals to 2 ventilatory techniques, noninvasive mask mechanical ventilation (NIMV) versus endotracheal mechanical ventilation (ETMV), during a single period of anesthesia and paralysis. Arterial pH, PaO2, PaCO2, oxygen saturation, end-tidal CO2 tension, airway pressures, total respiratory system resistance, resistance across the upper airways (proximal to the midtracheal region), and positive end-expiratory pressures (PEEP) were measured. Only tidal volume (VT; 10, 12.5, and 15 ml/kg of body weight) or PEEP (7 cm of H2O) varied. RESULTS: Compared with ETMV, use of NIMV at equivalent VT resulted in PaCO2 and pH values that were significantly higher, but PaO2 was only slightly lower. Between the 2 methods, peak airway pressure was similar, but peak expiratory flow was significantly lower and total respiratory resistance higher at each VT for NIMV. Delivery of PEEP (7 cm of H2O) was slightly better for ETMV (7.1 +/- 1.3 cm of H2O) than for NIMV (5.6 +/- 0.6 cm of H2O). CONCLUSION: These data suggest that use of NIMV induces similar physiologic effects as ETMV, but the nasal cavities and mask contribute greater dead space, manifesting in hypercapnia. Increasing the VT used on a per kilogram of body weight basis, or the use of pressure-cycled ventilation might reduce hypercapnia during NIMV. CLINICAL RELEVANCE: Use of NIMV might be applicable in selected foals, such as those with hypoventilation and minimal changes in lung compliance, during weaning from endotracheal mechanical ventilation, or for short-term ventilation in weak foals.     

Early surgery in patients with mitral regurgitation due to flail leaflets: a long-term outcome study

BACKGROUND: The optimal timing for surgery in patients with mitral regurgitation is disputed. Because of the frequency of left ventricular dysfunction, which is difficult to predict, early surgery has been recommended, but its potential benefits have not been demonstrated. METHODS AND RESULTS: The outcomes of 221 patients (mean age, 65 +/- 13 years; 71% males) with flail leaflets diagnosed with two-dimensional echocardiography between 1980 and 1989 who were eligible for operation were analyzed. Group I comprised 63 patients who had early mitral valve surgery (within 1 month after diagnosis). Group II comprised 158 patients initially treated conservatively (80 of whom were operated on later). Group I patients were younger (P=.009), had more symptoms (P<.0001), and were more frequently in atrial fibrillation (P=.023) than group II patients. There was no difference in ejection fraction between the groups. The early surgery strategy was followed by an improved overall survival rate (P=.028) and a lower incidence of cardiovascular deaths (P=.025), congestive heart failure (P=.046), and new chronic atrial fibrillation (P=.032), as confirmed by multivariate analysis (adjusted risk ratios of 0.31, 0.18, 0.38, and 0.05, respectively; all P<.02). CONCLUSIONS: In patients with mitral regurgitation due to flail leaflets, the strategy of early surgery versus conservative management is associated with an improved long-term survival rate, decreased cardiac mortality, and decreased morbidity after diagnosis. This outcome advantage suggests that early surgery is a reasonable treatment option to be considered in low-risk candidates with repairable valves and severe mitral regurgitation.