Cardiovascular drug interactions with tyrosine kinase inhibitors

Imatinib mesylate, a selective inhibitor of tyrosine kinases, has excellent efficacy in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST). Inducing durable responses and achieving prolonged survival, it has become the standard of care for the treatment of these diseases. It has opened the way to the development of additional tyrosine kinase inhibitors (TKIs), including sunitinib, nilotinib, dasatinib and sorafenib, all indicated for the treatment of various haematological malignancies and solid tumours. TKIs are prescribed for prolonged periods and are often taken by patients with - notably cardiovascular - comorbidities. Hence TKIs are regularly co-administered with cardiovascular drugs, with a considerable risk of potentially harmful drug-drug interactions due to the large number of agents used in combination. However, this aspect has received limited attention so far, and a comprehensive review of the published data on this important topic has been lacking. We review here the available data and pharmacological mechanisms of interactions between commonly prescribed cardiovascular drugs and the TKIs marketed at present. Regular updating of the literature on this topic will be mandatory, as will the prospective reporting of unexpected clinical observations, given the fact that these drugs have been only recently marketed.

Heterose sobre os pesos de bovinos Canchim e Aberdeen Angus e de seus cruzamentos recíprocos

O trabalho foi conduzido para estimar a heterose sobre os pesos ao nascimento (PNT), à desmama (P210) e ao ano (P365) e sobre os ganhos de pesos médios diários do nascimento à desmama (G210) e da desmama ao ano (G365) nas quatro primeiras gerações do sistema de cruzamentos alternados entre as raças Canchim (C) e Aberdeen Angus (A). Os dados de 1.147 bezerros nascidos de 1981 a 1998 foram analisados pelo método dos mínimos quadrados, ajustando-se um modelo linear que incluiu os efeitos linear e quadrático da idade da mãe do bezerro e os efeitos fixos de sexo, grupo genético, mês e ano de nascimento do bezerro. Estimativas de heterose e de outras diferenças genéticas foram estimadas por contrastes entre médias e testadas pelo teste t. O contraste "CA" foi positivo e significativo (P<0,001) para as cinco características. O contraste F1CAF1AC teve sinal negativo e foi altamente significativo (P<0,001) para P210 e G210 e significativo (P<0,05) para P365. A geração F1 exibiu heterose de 4,8% para P210 e de 4,9% para G210. A heterose materna foi de 3,7%, 5,8%, 6,3% e 20,4%, respectivamente, para P210, G210, P365 e G365. A heterose média das terceira e quarta gerações do cruzamento alternado entre C e A foi de 4,6% para P210, 5,3% para G210 e de 3,5% para P365.

Warrants for Rumble Strips on Rural Highways, HR-235, 1982

Research was undertaken, sponsored by the Iowa Department of Transportation, to identify specific locations where rumble strips could be expected to improve highway safety. The objective of the research was to recommend warrants for their use on rural highways. An inventory of rumble strip installations on the rural highway systems in the state was conducted in 1981. A total of 685 installations was reported on secondary roads and 147 on primary highways. Over 97 percent of these were in advance of stop signs at. intersections. Most of the other installations were in advance of railroad grade crossings. The accident experience with and without rumble strips was compared in two ways. A before-and-after comparison was made for the same location if accident records were available for at least one full year both preceding and following the installation of rumble strips. Accident records for this purpose were available from a statewide computerized record system covering the period from 1977 through 1980. The accident experience at locations having rumble strips installed before 1978 was compared with a sample of comparable locations not having rumble strips.

Plasminogen activator inhibitor-1 activity and 4G/5G polymorphism in hemodialysis

Introduction: Chronic insufficiency alters homeostasis, in part due to endothelial inflammation. Plasminogen activator inhibitor-1 (PAI-1) is increased in renal disease, contributing to vascular damage. We assessed PAI-1 activity and PAI-1 4G/5G polymorphism in hemodialysis (HD) subjects and any association between thrombotic vascular access (VA) events and PAI-1 polymorphism. Methods: Prospective, observational study in 36 HD patients: mean age: 66.6 +/- 12.5 yr, males n=26 (72%), time on HD: 28.71 +/- 22.45 months. Vascular accesses: 10 polytetrafluoroethylene grafts (PTFEG), 22 arteriovenous fistulae (AVF), four dual lumen catheters (CAT). Control group (CG): 40 subjects; mean age: 60.0 +/- 15 yrs, males n=30 (75%). Group A (GA): thrombotic events (n=12), and group B (GB): No events (n=24). Groups were no different according to age (69.2 +/- 9.12 vs. 65.3 +/- 14.5 yrs), gender (males: 7; 58.3% vs. 18; 81.8%), time on HD (26.1 +/- 14.7 vs. 30.1 +/- 38.7 months), causes of renal failure. Time to follow-up, for access thrombosis: 12 months. Results: PAI-1 levels in HD: 7.21 +/- 2.13 vs. CG: 0.42 +/- 0.27 U/ml (p < 0.000 1). PAI-1 4G/5G polymorphic variant distribution in HD: 5G/5G: 6 (17%),4G/5G: 23 (64%); 4G/4G: 7 (19%) and in CG: 5G/5G: 14 (35%); 4G/5G: 18 (45%); 4G/4G: 8 (20%). C-reactive protein (CRP) in HD: 24.5 +/- 15.2 mg/L vs. in CG 2.3 +/- 0.2 mg/L (p < 0.0001). PAI-1 4G/5G variants: GA: 5G/5G: 3; 4G/5G: 8; 4G/4G: 1; GB: 5G/5G: 3; 4G/5G: 15; 4G/4G: 6. Thrombosis occurred in 8/10 patients (80%) with PTFEG, 3/22 (9%) in AVF, and 1/4 (25%) in CAT. Among the eight PTFEG patients with thrombosis, seven were PAI 4G/5G. Conclusions: PAI-1 levels were elevated in HD patients, independent of their polymorphic variants, 4G/5G being the most prevalent variant. Our data suggest that in patients with PTFEG the 4G/5G variant might be associated with an increased thrombosis risk.

Effects of cognitive abilities on metapopulation connectivity

Connectivity among demes in a metapopulation depends on both the landscape's and the focal organism's properties (including its mobility and cognitive abilities). Using individual-based simulations, we contrast the consequences of three different cognitive strategies on several measures of metapopulation connectivity. Model animals search suitable habitat patches while dispersing through a model landscape made of cells varying in size, shape, attractiveness and friction. In the blind strategy, the next cell is chosen randomly among the adjacent ones. In the near-sighted strategy, the choice depends on the relative attractiveness of these adjacent cells. In the far-sighted strategy, animals may additionally target suitable patches that appear within their perceptual range. Simulations show that the blind strategy provides the best overall connectivity, and results in balanced dispersal. The near-sighted strategy traps animals into corridors that reduce the number of potential targets, thereby fragmenting metapopulations in several local clusters of demes, and inducing sink-source dynamics. This sort of local trapping is somewhat prevented in the far-sighted strategy. The colonization success of strategies depends highly on initial energy reserves: blind does best when energy is high, near-sighted wins at intermediate levels, and far-sighted outcompetes its rivals at low energy reserves. We also expect strong effects in terms of metapopulation genetics: the blind strategy generates a migrant-pool mode of dispersal that should erase local structures. By contrast, near- and far-sighted strategies generate a propagule-pool mode of dispersal and source-sink behavior that should boost structures (high genetic variance among- and low variance within local clusters of demes), particularly if metapopulation dynamics is also affected by extinction-colonization processes. Our results thus point to important effects of the cognitive ability of dispersers on the connectivity, dynamics and genetics of metapopulations.

Iowa Department of Transportation Major Items - Preliminary Quantity Report, December 16, 2014; With Addendums

Weekly letting report.

Cultivar de soja BRS 66

BRS 66, oriunda do cruzamento BR 83-147 x FT-Abyara, é indicada para cultivo no Rio Grande do Sul. Na média de 21 ambientes no RS, no período de 1993/94 a 1995/96, essa cultivar apresentou rendimento médio de grãos de 2.883 kg/ha. Apresenta resistência ao cancro-da-haste, à podridão-parda-da-haste, à mancha-olho-de-rã, à raça 1 de Phytophthora sojae, à pústula-bacteriana e ao oídio. Tem flor branca, pubescência marrom, tegumento da semente amarelo-fosco, hilo marrom e tipo de crescimento determinado. É de ciclo médio e apresenta estatura da planta de média a alta, com boa resistência ao acamamento.

Iowa Department of Transportation Major Items - Preliminary Quantity Report, February 17, 2015; With Addendums

Weekly letting report.

La motivació com estratègia psicològica en la interacció d'entrenadors i esportistes en iniciació esportiva

Un dels aspectes més importants en iniciació esportiva és la motivació. Si aconseguim que els nostres jugadors estiguin motivats per realitzar la pràctica esportiva obtindrem per part seva una major implicació per les tasques d’entrenament i evitarem l’abandonament prematur de la pràctica esportiva per falta de motivació. Els jugadors en les seves primeres etapes s’inicien en l’esport per motius intrínsecs i hem d’esbrinar que és el que vol el nostre grup al principi de temporada. El qüestionari de motius de pràctica esportiva ens servirà per saber que és el que volen els nostres jugadors i com hem de plantejar les tasques d’entrenament per adequar-les a les seves motivacions. La interacció entrenador – jugadors és l’altre punt a tractar en aquest treball ja que la motivació extrínseca produïda per l’entrenador durant els partits i els entrenaments tindrà una repercussió en la motivació intrínseca del nen. El CBAS és un mètode adequat per identificar les conductes de l’entrenador quan interactua amb els seus jugadors durant els partits i quins aspectes s’han de millorar. L’objectiu d’aquest treball és plantejar estratègies per conèixer i millorar la motivació dels jugadors incidint sobre la motivació intrínseca i extrínseca d’aquests mitjançant la interacció que tenen l’entrenador i els jugadors.