Peripheral perfusion index does not accurately reflect hypoperfusion in healthy dogs undergoing elective ovariohysterectomy.

This study evaluated the variability of the peripheral perfusion index (PI) in 22 anaesthetised female dogs undergoing elective ovariohysterectomy and examined the relationship between peripheral PI and heart rate, blood pressure, blood pH, end tidal CO2 (EtCO2), O2 saturation (SpO2), core-peripheral temperature gradient (ΔTc-p), partial pressure of CO2 (PCO2), and concentrations of glucose, cortisol, lactate and bicarbonate (HCO3-). Blood pH, lactate and glucose concentrations were determined 15, 30, 45min into the ovariohysterectomy procedure and after extubation. Cortisol concentrations were assessed before anaesthesia and after extubation. Other variables were recorded at every 5min throughout the ovariohysterectomy procedure. Hyperglycaemia was observed in 59% of bitches during surgery, but serum cortisol concentrations remained unchanged. Most measures of perfusion (ΔTc-p, pH, PCO2, EtCO2, SpO2) and heart rate remained unchanged throughout anaesthesia and did not correlate with peripheral PI. Mean arterial pressure increased during the ovariohysterectomy procedure, while peripheral PI decreased, resulting in negative correlations between these variables at 30 and 45min. Lactate concentrations decreased from baseline to the time of measurement post-extubation. Peripheral PI gradually decreased during the ovariohysterectomy procedure, probably reflecting vasoconstriction induced by nociceptive stimuli. Using lactate concentrations as the reference standard for peripheral perfusion, low peripheral PI in healthy bitches undergoing ovariohysterectomy might not represent peripheral hypoperfusion.

CHK1 overexpression in T-cell acute lymphoblastic leukemia is essential for proliferation and survival by preventing excessive replication stress.

Checkpoint kinase 1 (CHK1) is a key component of the ATR (ataxia telangiectasia-mutated and Rad3-related)-dependent DNA damage response pathway that protect cells from replication stress, a cell intrinsic phenomenon enhanced by oncogenic transformation. Here, we show that CHK1 is overexpressed and hyperactivated in T-cell acute lymphoblastic leukemia (T-ALL). CHEK1 mRNA is highly abundant in patients of the proliferative T-ALL subgroup and leukemia cells exhibit constitutively elevated levels of the replication stress marker phospho-RPA32 and the DNA damage marker γH2AX. Importantly, pharmacologic inhibition of CHK1 using PF-004777736 or CHK1 short hairpin RNA-mediated silencing impairs T-ALL cell proliferation and viability. CHK1 inactivation results in the accumulation of cells with incompletely replicated DNA, ensuing DNA damage, ATM/CHK2 activation and subsequent ATM- and caspase-3-dependent apoptosis. In contrast to normal thymocytes, primary T-ALL cells are sensitive to therapeutic doses of PF-004777736, even in the presence of stromal or interleukin-7 survival signals. Moreover, CHK1 inhibition significantly delays in vivo growth of xenotransplanted T-ALL tumors. We conclude that CHK1 is critical for T-ALL proliferation and viability by downmodulating replication stress and preventing ATM/caspase-3-dependent cell death. Pharmacologic inhibition of CHK1 may be a promising therapeutic alternative for T-ALL treatment.

Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling.

Constitutively active casein kinase 2 (CK2) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). CK2 phosphorylates PTEN (phosphatase and tensin homolog) tumor suppressor, resulting in PTEN stabilization and functional inactivation. Downregulation of PTEN activity has an impact on PI3K/Akt/mTOR signaling, which is of fundamental importance for T-ALL cell survival. These observations lend compelling weight to the application of CK2 inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of CX-4945-a novel, highly specific, orally available, ATP-competitive inhibitor of CK2α. We show that CX-4945 treatment induced apoptosis in T-ALL cell lines and patient T lymphoblasts. CX-4945 downregulated PI3K/Akt/mTOR signaling in leukemic cells. Notably, CX-4945 affected the unfolded protein response (UPR), as demonstrated by a significant decrease in the levels of the main UPR regulator GRP78/BIP, and led to apoptosis via upregulation of the ER stress/UPR cell death mediators IRE1α and CHOP. In vivo administration of CX-4945 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth. Our findings indicate that modulation of the ER stress/UPR signaling through CK2 inhibition could be exploited for inducing apoptosis in T-ALL cells and that CX-4945 may be an efficient treatment for those T-ALLs displaying upregulation of CK2α/PI3K/Akt/mTOR signaling.

Effect of meloxicam on pregnancy rate of recipient heifers following transfer of in vitro produced embryos.

The main objective of this study was to determine if administration of meloxicam, a cyclooxygenase (COX) two inhibitor, to heifers in which embryo transfer (ET) is more difficult and requires a greater manipulation of the tract, would be beneficial. Nulliparous recipient heifers were divided in two groups: CON (n = 102), in which animals received 10 ml of saline IM (the same volume of meloxicam) and MEL (n = 105) animals that were treated with meloxicam. According to the degree in passing the catheter, recipients from both groups were classified as Grade I, easy (< 60 s), and Grade II (more than 80 s), difficult. Immediately after embryo transfer, MEL recipients received an injection of 200 mg of meloxicam (10 ml).There was no difference in the pregnancy rates on Day 35 considering animals which presented Grade I cervix independently whether the treatment was performed or not (p = 0.22). There was a statistical difference in the pregnancy rates (p < 0.01) between both groups (49.0% and 66.7% for CON and MEL, respectively) when cervical grade was not considered, on Day 35. Considering the animals that presented Grade II cervix, the pregnancy rate was higher for MEL (21.15% and 78.84%, respectively) in both examinations (p < 0.01).The authors concluded that meloxicam had a positive influence on general pregnancy rate of treated heifers in comparison to non-treated heifers. It was also observed that pregnancy rate was not influenced by meloxicam administration in Grade I heifers. Treatment increased the pregnancy rate of Grade II heifers.

Novel agents for enzymatic and fungal hydrolysis of stevioside / Novos agentes para a hidrólise enzimática e fúngica do esteviosídeo

A comparative study on the potential of some biological agents to perform the hydrolysis of stevioside was carried out, aiming at establishing an alternative methodology to achieve the aglycon steviol or its rearranged derivative isosteviol, in high yields to be used in the preparation of novel bioactive compounds. Hydrolysis reactions were performed by using filamentous fungi (Aspergillus niger, Rhizopus stolonifer and Rhizopus arrhizus), a yeast (Saccharomyces cerevisiae) and enzymes (pancreatin and lipases PL250 and VFL 8000). Pancreatin showed the best hydrolytic activity, furnishing isosteviol at 93.9% of yield, at pH 4.0, using toluene as a co-solvent. Steviol was produced using both pancreatin at pH 7.0 (20.2% yield) and A. niger atpH 7 (20.8% yield).

Um estudo comparativo do potencial de alguns agentes biológicos capazes de hidrolisar o esteviosídeo foi realizado,objetivando-se estabelecer uma metodologia alternativa para a obtenção da aglicona esteviol ou seu produto de rearranjo, isoesteviol, em rendimentos elevados que permitam o uso destas agliconas para o preparo de novos compostos bioativos. As reações de hidrólise foram realizadas usando fungosfilamentosos (Aspergillus niger, Rhizopus stolonifer e Rhizopus arrhizus), uma levedura (Saccharomyces cerevisiae) e enzimas(pancreatina, lipase PL250 e lipase VFL 8000). A pancreatina mostrou a melhor atividade hidrolítica dentre os sistemastestados, fornecendo isoesteviol com rendimento de 93,9% em pH 4,0, usando tolueno como co-solvente. Esteviol foi produzido tanto usando pancreatina em pH 7,0 (20,2% derendimento) quanto usando A. niger em pH 7,0 (20,8% de rendimento).

Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications.

T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous disease with respect to phenotype, gene expression profile and activation of particular intracellular signaling pathways. Despite very significant improvements, current therapeutic regimens still fail to cure a portion of the patients and frequently implicate the use of aggressive protocols with long-term side effects. In this review, we focused on how deregulation of critical signaling pathways, in particular Notch, PI3K/Akt, MAPK, Jak/STAT and TGF-beta, may contribute to T-ALL. Identifying the alterations that affect intracellular pathways that regulate cell cycle and apoptosis is essential to understanding the biology of this malignancy, to define more effective markers for the correct stratification of patients into appropriate therapeutic regimens and to identify novel targets for the development of specific, less detrimental therapies for T-ALL.

Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications

T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous disease with respect to phenotype, gene expression profile and activation of particular intracellular signaling pathways. Despite very significant improvements, current therapeutic regimens still fail to cure a portion of the patients and frequently implicate the use of aggressive protocols with long-term side effects. In this review, we focused on how deregulation of critical signaling pathways, in particular Notch, PI3K/Akt, MAPK, Jak/STAT and TGF-ß, may contribute to T-ALL. Identifying the alterations that affect intracellular pathways that regulate cell cycle and apoptosis is essential to understanding the biology of this malignancy, to define more effective markers for the correct stratification of patients into appropriate therapeutic regimens and to identify novel targets for the development of specific, less detrimental therapies for T-ALL.

Lung inhalation scintigraphy: development of a new aerosol system.

A new technique for lung inhalation scintigraphy is reported, developing a new aerosol system, based on the original system of Taplin [1]. With two small compact polypropylene reservoirs, this 99Tcm DTPA technique allowed continuous breathing during the inhalation period. This system proved to be a useful alternative to that using radioactive gases and the system of Taplin, due to its low cost and the ease with which several projections may be obtained.

Cintigrafia de ventilacao pulmonar por aerossol em diversas patologias pulmonares. / Lung inhalation scintigraphy with radioactive aerosols in several pulmonary diseases

Salienta-se a importancia da cintigrafia de ventilacao pulmonar com acido dietileno-tetramino-pentacetico ligado ao tecnecio 99m atraves de um sistema produtor de aerossol, ao lado da classica cintigrafia de perfusao com macroagregado de albumina marcado com tecnecio 99m, como meio diagnostico em diversas patologias pulmonares.Sao apresentados os aspectos da cintigrafia de ventilacao-perfusao em 15 individuos sem doenca pulmonar, fumantes e nao-fumantes. As caracteristicas destas cintigrafias sao tambem discutidas em 34 pacientes com diversas patologias pulmonares cancer de pulmao, doenca pulmonar obstrutiva cronica. Conclui-se que devido a qualidade das imagens obtidas, facil procedimento, inocuidade, baixo custo, alem de acrescentar informacoes aos metodos convencionais, a associacao das cintigrafias pulmonares de ventilacao e de perfurasao representa meio diagnostico de valia em diversas patologias pulmonares

Fração de ejeção do ventrículo esquerdo obtida por angiocardiografia radioisotópica. Correlação com os valores fornecidos pela ventriculografia convencional / Ejection fraction of the left ventricle obtained by radioisotopic angiocardiography. Correlation with values provided by conventional ventriculography

Quarenta e dois pacientes com suspeita clinica de insuficiencia coronaria foram submetidos a estudo cinecoronariografico e radiosotopico, com a finalidade de analisar a correlacao entre os valores da fracao de ejecao do ventriculo esquerdo (FE) obtidos pelos dois metodos. Os valores da FE obtidos pela ventriculografia convencional variaram de 0,14 a 0,85 (x igual 0,566) e pela medicina nuclear de 0,22 a 0,89 (x igual 0,573). Nao houve diferencas estatisticamente significativas entre as medidas obtidas pelos dois metodos.A equacao de regressao da FE pela angiografia convencional (y) em relacao a FE pela angiocardiografia radioisotopica (x) foi y = 0,11 + 0,80 x e a da regressao de x em y foi x = 0,08 + 0,86 y. Conclui-se que os valores da FE pelos metodos ensaiados apresentam correlacao significativa (r = 0,833)

Cintigrafia do miocardio com talio-201 em pacientes com prolapso da valva mitral, com e sem coronariopatia. / Myocardial scintillography with thalium 201 in patients with mitral valve prolapse, with or without coronary disease

Trinta pacientes com dor precordial e prolapso da valva mitral a cineangiografia e ao ecocardiograma modo-M foram submetidos a cintigrafia do miocardio com Talio-201 (201Tl) associado ao teste ergometrico (TE). Os pacientes foram assim distribuidos: grupo I (GR I) - 18 pacientes portadores de prolapso da valva mitral com arterias coronarias normais, dos quais 10 apresentavam TE positivo (55,6%) e 8 negativos; a cintigrafia do miocardio com 201Tl foi normal em 14 pacientes (77,8%); 4 apresentaram isquemia transitoria (3 em parede inferior e 1 em parede lateral); grupo II (GR II) - constituido por 12 pacientes com prolapso da valva mitral de doenca obstrutiva coronariana grave (lesoes maior igual 60% em pelo menos um vaso principal da circulacao coronaria), dos quais 9 apresentavam TE positivo (75%) e 3 negativo. A cintigrafia do miocardio com 201Tl apresentou defeitos de captacao em 9 (75%), sendo 6 com isquemia transitoria e 3 definitiva; nos outros 3 pacientes o mapeamento foi normal. Baseados nestes achados, os autores concluem que a cintigrafia do miocardio com 201Tl foi mais sensivel para detectar presenca de doenca obstrutiva coronariana em portadoes de prolapso da valva mitral (PVM) que o TE, apesar de um pequeno numero (22,2%) de pacientes com PVM e coronarias normais exibir defeitos de captacao do radioindicador