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.     

Value of serum inorganic phosphate in the diagnosis of ischemic bowel disease

To clarify the value of the serum inorganic phosphate concentration in the diagnosis of ischemic bowel disease, a retrospective study of 24 patients with various causes of intestinal ischemia was carried out. Only 25 percent of the patients had elevations of their serum phosphate concentrations. These patients had the combination of extensive bowel injury, acute renal insufficiency, and acidosis. Mortality was significantly increased in these patients. Thus, the serum phosphate concentration was not a sensitive indicator of ischemic bowel disease, but elevations did predict extensive injury and poor prognosis.     

Periodic and sequential preventive maintenance policies over a finite planning horizon with a dynamic failure law

The purpose of this study is to propose and model periodic and sequential preventive maintenance policies for a system that performs various missions over a finite planning horizon. Each mission can have different characteristics that depend on operational and environmental conditions. These proposed preventive maintenance policies are defined and modeled mathematically. The study of these two policies is based on a dynamic system failure law that takes into account the different missions performed. The first step is to determine the optimal business plan to achieve, i.e. the set of missions to perform in order to maximize the profit of missions minus maintenance costs. Thus, for each plan, we determine the maintenance planning considering two policies. The first preventive maintenance policy is periodic and the objective is to determine the optimal number of preventive maintenance to achieve. For the second policy, namely sequential, we calculate the optimal number of preventive maintenance intervals and the duration of these different intervals.     

Maintenance strategy for leased equipment

In case of leasing, the user rents equipment for a predetermined time. During this period, all maintenance actions are performed by the lessor. The aim of this research paper consists in determining an optimal maintenance policy for ensuring a minimum reliability, required by the customer. Two strategies are proposed: the first consists in performing preventive actions whenever the system reliability reaches a predefined reliability threshold. These actions are characterized by a reduction of the system age. The objective is therefore to determine the effectiveness factor of the optimal maintenance minimizing maintenance costs. For the second strategy, “improving” actions replace corrective actions during an interval to be determined to minimize maintenance costs. The first strategy will be solved using a numerical procedure and the second strategy uses an algorithm of discrete event simulation.     

Estimation and diagnosis using multi-models with application to a wastewater treatment plant

Process diagnosis is still considered a challenging engineering problem. Technological and also environmental systems have complex behaviors often involving nonlinear relationships. When confronted to such systems, there is a need to build systems that can operate over a wide range of operating conditions. For that it is very attractive to appeal to a decomposition of the system model into a number of simpler linear models. This paper mainly focuses on the use of multi-models for process diagnosis. It is shown how the traditional tools of the linear automatic can be wide and applied to multi-model structures. A proportional multi-integral observer is used for fault diagnosis using banks of observers to generate structured residuals. The performances of the proposed diagnosis method are highlighted through the application to a wastewater treatment plant model (WWTP), which is an uncertain nonlinear system affected by unknown inputs.     

Identification and characterization of a lysis module present in a large proportion of bacteriophages infecting Streptococcus thermophilus

A lysis module encoded by the temperate bacteriophage phiO1205 was identified. This lysis module contains a lysin gene, designated lyt51, and two putative holin-encoding genes, designated lyt49 and lyt50. lyt51 encodes a lytic enzyme specifically directed against streptococcal cell walls. Similar to other phage-encoded lysins, Lyt51 appears to have a modular design in which the N-terminal portion corresponds to its enzymatic activity while the C-terminal region is responsible for its substrate binding specificity. The two putative holin-encoding genes, lyt49 and lyt50, located immediately upstream of lyt51, were identified on the basis of their homology to other identified holin-encoding genes. Expression of lyt49 or lyt50 in Escherichia coli was shown to cause cell death and leakage of the intracellular enzyme isocitrate dehydrogenase into the growth medium without apparent lysis of the cells. Southern blotting experiments demonstrated that at least one of the three components of the identified lysis module is present in all members of a large collection of bacteriophages, indicating that components of this lysis module are widespread among bacteriophages infecting Streptococcus thermophilus.     

Spectrophotometric and atomic absorption spectrometric determination of ramipril and perindopril through ternary complex formation with eosin and Cu(II)

Two sensitive, spectrophotometric and atomic absorption spectrometric procedures are developed for the determination of ramipril and perindopril. Both methods are based on the formation of a ternary complex, extractable with chloroform, between copper(II), eosin and the two cited drugs. Spectrophotometrically under the optimum condition, the ternary complexes showed an absorption maximum at 535 nm, with apparent molar absorptivities of 6.55 and 4.00 x 10(3) mol(-1) x cm(-1) and Sandell's sensitivities of 5.80 x 10(-2) and 1.04 x 10(-1) microg x cm(-2) for perindopril and ramipril, respectively. The solution of ternary complex obeyed Beer's law in concentration ranges 10-60 and 20-100 microg x ml(-1) for perindopril and ramipril, respectively. The proposed method was applied to the determination of the two cited drugs in pharmaceutical tablets. The atomic absorption spectrometric method, directly through the quantitative determination of copper content of the organic extract of the complex, was also investigated for the purpose of enhancing the sensitivity of the determination. The spectrophotometric and atomic absorption spectrometric procedures hold their accuracy and precision well when applied to the determination of ramipril and perindopril dosage forms.     

A comparison of alternate immunization regimes for measles in vaccinated populations

Infants today lose maternal measles antibody sooner than in the past. This is related to demographic changes in maternal immunization. Data for rates of decay of maternal antibody and seroconversion after measles vaccination for infants born to naturally immune (Group 1) or vaccinated (Group 2) mothers have been used to evaluate two vaccination schedules: Regime 1, measles-mumps-rubella (MMR) at 1 year of age and Regime 2, monovalent measles at 6 months followed by MMR at 15 months of age. Regime 2 costs less because MMR can be administered at 15 months with the last pentavalent booster. Months of protection/1000 children aged 0-15 months (child-months of protection) were estimated for infant populations ranging from 0 to 100% Group 1 for Regimes 1 and 2. Regime 1 provides more child-months of protection only for 100% Group 1 populations. For the study population Regime 2 provided at least 17% more child-months of protection than Regime 1. Regime 2 provides increased medical and financial benefits in proportion to the number of Group 2 infants in the population and thus is ever more advantageous for today's increasingly vaccinated populations.