Further understanding of doorway states in elastic systems.

In a previous work an elastic bar with a groove or notch that presents a doorway state was studied when the system was excited with 20 cycles of harmonic signals. The strength function had a Lorentzian width Γd = 1/πτd, where τd is the decay time of the prompt response. In the present paper, the doorway-state phenomenon is analyzed again for the same harmonic signals but for a very large number of cycles. The strength-function phenomenon is once more obtained, but now with a Lorentzian width Γ' which is larger than Γd. A qualitative and numerical explanation of this fact is given, leading therefore to further understanding of doorway states in elastic systems. The numerical results show a very good agreement with the values measured in the laboratory.

Effect of bovine ABCG2 Y581S polymorphism on concentrations in milk of enrofloxacin and its active metabolite ciprofloxacin.

The ATP-binding cassette transporter G2 (ABCG2) is involved in the secretion of several drugs into milk. The bovine Y581S ABCG2 polymorphism increases the secretion into milk of the fluoroquinolone danofloxacin in Holstein cows. Danofloxacin and enrofloxacin are the fluoroquinolones most widely used in veterinary medicine. Both enrofloxacin (ENRO) and its active metabolite ciprofloxacin (CIPRO) reach milk at relatively high concentrations. The aim of this work was to study the effect of the bovine Y581S ABCG2 polymorphism on in vitro transport as well as on concentrations in plasma and in milk of ENRO and CIPRO. Experiments using cells overexpressing bovine ABCG2 showed the effects of ABCG2 on the transport of CIPRO, demonstrating more efficient in vitro transport of this antimicrobial by the S581 variant as compared with the Y581 variant. Animal studies administering 2.5mg/kg of ENRO subcutaneously to Y/Y 581 and Y/S 581 cows revealed that concentrations in plasma of ENRO and CIPRO were significantly lower in Y/S animals. Regardless of the genotype, the antimicrobial profile in milk after the administration of ENRO was predominantly of CIPRO. With respect to the genotype effects on the amounts of drugs present in milk, AUC0-24 values were more than 1.2 times higher in Y/S cows for ENRO and 2.2 times for CIPRO, indicating a greater capacity of Y581S to transfer these drugs into milk. These results emphasize the clinical relevance of this polymorphism as a factor affecting the concentrations in plasma and in milk of drugs of importance in veterinary medicine.

Effect of bovine ABCG2 polymorphism Y581S SNP on secretion into milk of enterolactone, riboflavin and uric acid.

The ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP) is an efflux protein involved in the bioavailability and milk secretion of endogenous and exogenous compounds, actively affecting milk composition. A limited number of physiological substrates have been identified. However, no studies have reported the specific effect of this polymorphism on the secretion into milk of compounds implicated in milk quality such as vitamins or endogenous compounds. The bovine ABCG2 Y581S polymorphism is described as a gain-of-function polymorphism that increases milk secretion and decreases plasma levels of its substrates. This work aims to study the impact of Y581S polymorphism on plasma disposition and milk secretion of compounds such as riboflavin (vitamin B2), enterolactone, a microbiota-derived metabolite from the dietary lignan secoisolariciresinol and uric acid. In vitro transport of these compounds was assessed in MDCK-II cells overexpressing the bovine ABCG2 (WT-bABCG2) and its Y581S variant (Y581S-bABCG2). Plasma and milk levels were obtained from Y/Y homozygous and Y/S heterozygous cows. The results show that riboflavin was more efficiently transported in vitro by the Y581S variant, although no differences were noted in vivo. Both uric acid and enterolactone were substrates in vitro of the bovine ABCG2 variants and were actively secreted into milk with a two-fold increase in the milk/plasma ratio for Y/S with respect to Y/Y cows. The in vitro ABCG2-mediated transport of the drug mitoxantrone, as a model substrate, was inhibited by enterolactone in both variants, suggesting the possible in vivo use of this enterolignan to reduce ABCG2-mediated milk drug transfer in cows. The Y581S variant was inhibited to a lesser extent probably due to its higher transport capacity. All these findings point to a significant role of the ABCG2 Y581S polymorphism in the milk disposition of enterolactone and the endogenous molecules riboflavin and uric acid, which could affect both milk quality and functionality.

New developments in the application of optimal control theory to therapeutic protocols.

Optimal control theory is one of the most important tools in the development of new therapeutic protocols for treating infections. In this work, we present an algorithm able to deal with high-dimensional problems with bounded controls. The optimal solution is obtained by minimizing a positive-definite treatment cost function. Our method, based on Pontryagin's Minimum Principle and the coordinate cyclic descent method, allows solving problems of varied nature. In this paper, and by way of example, therapeutic enhancement of the immune response to invasion by pathogenic attack is addressed as an optimal control problem. The generic mathematical model used describes the evolution of the disease by means of four non-linear, ordinary differential equations. The model is characterized by the concentration of pathogens, plasma cells, antibodies and a numerical value that indicates the relative characteristic of an organ damaged by disease. From a system theory point of view, drugs can be interpreted as control inputs. Therapies based on separate application of the agents are presented in previous studies. We shall present the more general problem in this paper, considering combined therapies and bounded controls. Finally, we present several numerical simulations.

Short communication: The gain-of-function Y581S polymorphism of the ABCG2 transporter increases secretion into milk of danofloxacin at the therapeutic dose for mastitis treatment.

The ATP-binding cassette transporter ABCG2 restricts the exposure of certain drugs and natural compounds in different tissues and organs. Its expression in the mammary gland is induced during lactation and is responsible for the active secretion of many compounds into milk, including antimicrobial agents. This particular function of ABCG2 may affect drug efficacy against mastitis and the potential presence of drug residues in the milk. Previous in vitro and in vivo studies showed increased transport of several compounds, including fluoroquinolones, by the bovine ABCG2 Y581S polymorphism. Our main purpose was to study the potential effect of this bovine ABCG2 polymorphism on the secretion into milk of the antimicrobial danofloxacin administered at the therapeutic dose of 6mg/kg used for mastitis treatment. In addition, the effect of this polymorphism on the relative mRNA and protein levels of ABCG2 by quantitative real-time PCR and Western blot were studied. Danofloxacin 18% (6mg/kg) was administered to 6 Y/Y homozygous and 5 Y/S heterozygous cows. Danofloxacin levels in milk and milk-to-plasma concentration ratios were almost 1.5- and 2-fold higher, respectively, in Y/S cows compared with the Y/Y cows, showing a higher capacity of this variant to transport danofloxacin into milk. Furthermore, the higher activity of this polymorphism is not linked to higher ABCG2 mRNA or protein levels. These results demonstrate the relevant effect of the Y581S polymorphism of the bovine ABCG2 transporter in the secretion into milk of danofloxacin after administration of 6mg/kg, with potentially important consequences for mastitis treatment and for milk residue handling.

The analgesic activity of Hedyosmum bonplandianum: flavonoid glycosides.

Kaempferol 3-O-[alpha-L-rhamnopyranosyl (1-->6)-beta-D-glucopyranoside] and kaempferol 3-O-[beta-D-glucopyranoside] were isolated from the leaves of Hedyosmum bonplandianum H.B.K. (Chloranthaceae), which is used in Colombian folk medicine as an analgesic. The n-butanol extract and the glycosyl flavonoids isolated exhibited significant analgesic activity in mice.

Liposarcomas. Analisis de 23 casos. / Liposarcomas. Analysis of 23 cases

Se evalua el resultado del tratamiento quirurgico en 23 pacientes portadores de liposarcomas. El mayor porcentaje corresponde al sexo masculino, 14 casos (60,8%); con incidencia mayor entre la 4a. y 6a. decadas de la vida. La localizacion mas frecuente fue en el miembro inferior, 12 casos (52,2%). La histologia revelo que la mayoria de los pacientes eran portadores de tumores indiferenciados (17 casos - 74%). El tratamiento efectuado en mayor porcentaje (16 casos - 69,5%), fue la cirugia locorregional ampliada seguida de radioterapia. La sobrevida de 5 anos es de 11 casos (47,9%), comprobandose que los pacientes portadores de neoplasia diferenciada tienen mejor pronostico. En cuanto a los sometidos a cirugia ultrarradical, evolucionaron desfavorablemente en corto plazo

Liposarcomas. Analisis de 23 casos. / Liposarcomas. Analysis of 23 cases

Se evalua el resultado del tratamiento quirurgico en 23 pacientes portadores de liposarcomas. El mayor porcentaje corresponde al sexo masculino, 14 casos (60,8%); con incidencia mayor entre la 4a. y 6a. decadas de la vida. La localizacion mas frecuente fue en el miembro inferior, 12 casos (52,2%). La histologia revelo que la mayoria de los pacientes eran portadores de tumores indiferenciados (17 casos - 74%). El tratamiento efectuado en mayor porcentaje (16 casos - 69,5%), fue la cirugia locorregional ampliada seguida de radioterapia. La sobrevida de 5 anos es de 11 casos (47,9%), comprobandose que los pacientes portadores de neoplasia diferenciada tienen mejor pronostico. En cuanto a los sometidos a cirugia ultrarradical, evolucionaron desfavorablemente en corto plazo