Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells

Acute myeloid leukaemia (AML) cells interact and modulate components of their surrounding microenvironment into their own benefit. Stromal cells have been shown to support AML survival and progression through various mechanisms. Nonetheless, whether AML cells could establish beneficial metabolic interactions with stromal cells is underexplored. By using a combination of human AML cell lines and AML patient samples together with mouse stromal cells and a MLL-AF9 mouse model, here we identify a novel metabolic crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption to feed the tricarboxylic acid cycle (TCA) and lipid biosynthesis. By performing transcriptome analysis and tracer-based metabolic NMR analysis, we observe that stromal cells present a higher rate of glycolysis when co-cultured with AML cells. We also find that acetate in stromal cells is derived from pyruvate via chemical conversion under the influence of reactive oxygen species (ROS) following ROS transfer from AML to stromal cells via gap junctions. Overall, we present a unique metabolic communication between AML and stromal cells and propose two different molecular targets, ACSS2 and gap junctions, that could potentially be exploited for adjuvant therapy

Genetic Algorithms to Simplify Prognosis of Endocarditis

This ongoing interdisciplinary research is based on the application of genetic algorithms to simplify the process of predicting the mortality of a critical illness called endocarditis. The goal is to determine the most relevant features (symptoms) of patients (samples) observed by doctors to predict the possible mortality once the patient is in treatment of bacterial endocarditis. This can help doctors to prognose the illness in early stages; by helping them to identify in advance possible solutions in order to aid the patient recover faster. The results obtained using a real data set, show that using only the features selected by employing a genetic algorithm from each patient’s case can predict with a quite high accuracy the most probable evolution of the patient

Risk factors for thyroid dysfunction in pregnancy: an individual participant data meta-analysis

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction

Patellar luxation in dogs: a retrospective study

Submitted by Guilherme Lemeszenski ([email protected]) on 2013-08-22T18:56:14Z No. of bitstreams: 1 S0102-09352009000200035.pdf: 151214 bytes, checksum: 3a419a048a5508aecdde4c468a2e9d5f (MD5)Made available in DSpace on 2013-08-22T18:56:14Z (GMT). No. of bitstreams: 1 S0102-09352009000200035.pdf: 151214 bytes, checksum: 3a419a048a5508aecdde4c468a2e9d5f (MD5) Previous issue date: 2009-04-01Made available in DSpace on 2013-09-30T19:49:57Z (GMT). No. of bitstreams: 2 S0102-09352009000200035.pdf: 151214 bytes, checksum: 3a419a048a5508aecdde4c468a2e9d5f (MD5) S0102-09352009000200035.pdf.txt: 17158 bytes, checksum: 600eaaa16aa49e42de9ebec8926c8217 (MD5) Previous issue date: 2009-04-01Submitted by Vitor Silverio Rodrigues ([email protected]) on 2014-05-20T15:13:07Z No. of bitstreams: 2 S0102-09352009000200035.pdf: 151214 bytes, checksum: 3a419a048a5508aecdde4c468a2e9d5f (MD5) S0102-09352009000200035.pdf.txt: 17158 bytes, checksum: 600eaaa16aa49e42de9ebec8926c8217 (MD5)Made available in DSpace on 2014-05-20T15:13:07Z (GMT). No. of bitstreams: 2 S0102-09352009000200035.pdf: 151214 bytes, checksum: 3a419a048a5508aecdde4c468a2e9d5f (MD5) S0102-09352009000200035.pdf.txt: 17158 bytes, checksum: 600eaaa16aa49e42de9ebec8926c8217 (MD5) Previous issue date: 2009-04-01Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)UNESP Faculdade de Medicina Veterinária e ZootecniaUNESP Faculdade de Medicina Veterinária e Zootecni

Hemodynamic Effects Of The Acute Intoxication With Bupivacaine, Levobupivacaine And 50% Enantiomeric Excess Mixture. An Experimental Study In Pigs [efeitos Hemodinâmicos Da Intoxicação Aguda Com Bupivacaína, Levobupivacaína E Mistura Com Excesso Enantiomérico De 50%. Estudo Experimental Em Suínos]

BACKGROUND AND METHODS: Until recently, bupivacaine had been the anesthetic of choice for loco-regional blocks due to the quality and duration of the anesthesia. But its cardiovascular toxicity is a source of concern for anesthesiologists who seek new pharmacological options with a smaller degree of this problem. Its levorotatory isomer, levobupivacaine, that would be less cardiotoxic due a smaller affinity for the receptors of the sodium channels of the cardiac cell, is one of these options. In Brazil, a presentation containing 75% of the levorotatory isomer and 25% of the dextrorotatory isomer, called 50% enantiomeric excess mixture is available. The aim of this study was to evaluate the hemodynamic repercussions of the intravascular injection of a toxic dose of those three agents to determine which one has the least impact in the case of an accident. METHODS: Large White pigs were anesthetized with thiopental, intubated, and placed on mechanical ventilation. Hemodynamic monitoring was achieved with a Swan-Ganz catheter and invasive blood pressure. After a period of rest, the animals were randomly divided in three groups. The intoxication was performed, on a double-blind fashion, with 4 mg.kg-1 of one of the drugs. Hemodynamic parameters were evaluated during 30 minutes. Analytical tests were used to compare the results among the groups. RESULTS: The 50% enantiomeric excess mixture and levobupivacaine had greater hemodynamic repercussions than the racemic mixture, which were more pronounced with the first drug. These results go against those found in humans, especially regarding the pure levorotatory isomer, but are similar to recent results reported in animals. One should be careful when extrapolating the data obtained in pigs to humans and further studies are necessary. CONCLUSIONS: In pigs, the 50% enantiomeric excess mixture, in particular, and levobupivacaine were more toxic when administered intravenously than racemic bupivacaine. © Sociedade Brasileira de Anestesiologia, 2007.5716373Groban, L., Deal, D.D., Vernon, J.C., Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs (2001) Anesth Analg, 92, pp. 37-43Chang, D.H.-T., Ladd, L.A., Copeland, S., Direct cardiac effects of intracoronary bupivacaine, levobupivaciane and ropivacaine in the sheep (2001) Br J Pharmacol, 132, pp. 649-658Albright, G.A., Cardiac arrest following regional anesthesia with etidocaine or bupivacaine (1979) Anesthesiology, 51, pp. 285-287Ohmura, S., Kawada, M., Ohta, T., Systemic toxicity and resusciation in bupivacaine, levobupivacaine, or ropivacaine-infused rats (2001) Anesth Analg, 93, pp. 743-748Åberg G, Toxicological and local anaesthetic effects of optically active isomers of two local anaesthetic compounds. Acta Pharmacol Toxicol 1972;31:273-286Luduena, F.P., Bogado, E.F., Tullar, B.F., Optical isomers of mepivacaine and bupivacaine (1972) Arch Int Pharmacodyn, 200, pp. 359-369Foster, R.H., Markham, A., Levobupivacaine. A review of its pharmacology and use as a local anaesthetic (2000) Drugs, 59, pp. 551-579Lyons, G., Columb, M., Wilson, R.C., Extradural pain relief in labour:potencies of levobupivacaine and racemic bupivacaine (1998) Br J Anaesth, 81, pp. 899-901Héctor, J.L., Columb, M.O., The relative motor blocking potencies of bupivacaine and levobupivacaine in labour (2003) Anesth Analg, 97, pp. 1509-1513Bardsley, H., Gristwood, R., Baker, H., A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers (1998) Br Clin Pharmacol, 46, pp. 245-249Smith AC, Ehler WJ, Swindle MMl - Anesthesia and Analgesia in Swine, em: Kohn DF, Wixson SK, White WJ et al - Anesthesia and Analgesia in Laboratory Animals, 1st ed., New York, Academic Press,1997;313-336Ettinger, S.J., (1975) Textbook of Veterinary Internal Medicine, , 1st ed, Philadelphia, WB SaundersLefrant, J.Y., Muller, L., de La Coussaye, J.E., Hemodynamic and cardiac electrophysiologic effects of lidocaine-bupivacaine mixture in anesthetized and ventilated piglets (2003) Anesthesiology, 98, pp. 96-103Delfino, J., Vale NB do - Bupivacaína levógira a 0,5% pura versus mistura enantiomérica de bupivacaína (S75-R25) a 0,5% em anestesia peridural para cirurgia de varizes (2001) Rev Bras Anestesiol, 51, pp. 474-481Tanaka, P.P., Souza, R.O., Salvalaggio, M.F., Estudo comparativo entre bupivacaína a 0,5% e a mistura enantiomérica de bupivacaína (S75-R25) a 05% em anestesia peridural em pacientes submetidos a cirurgia ortopédica de membros inferiores (2003) Rev Bras Anestesiol, 53, pp. 331-337Gonçalves, R.F., Lauretti, G.R., Mattos, A., Estudo comparativo entre bupivacaína 0,5% e mistura enantiomérica de bupivacaína (S75-R25) em anestesia peridural (2003) Rev Bras Anestesiol, 53, pp. 169-176Lacassie, H.J., Columb, M.O., The relative motor blocking potencies of bupivacaine and levobupivacaine in labor (2003) Anesth analg, 97, pp. 1509-1513Valenzuela, C., Snyders, D.J., Bennett, P.B., Stereoselectivite block of cardiac sodium channels by bupivacaine in guinea pig ventricular myocytes (1995) Circulation, 92, pp. 3014-3024Royse, C.F., Royse, A.G., The myocardial and vascular effects of bupivacaine, levobupivacaine, and ropivacaine using pressure volume loops (2005) Anesth Analg, 101, pp. 679-687Masuda, R., Takeda, S., Yoshii, S., Levobupivacaine exerts the most detrimental effect on the cardiovascular system among enantiomers of bupivacaína in anesthetized dogs (2004) Anesthesiology, 101, pp. A652Jung, C.W., Lee, K.H., Choe, Y.S., Comparison of resuscitative effect of insulin between bupivacaine and levobupivacaine induced cardiovascular collapse in dogs (2004) Anesthesiology, 101, pp. A649Udelsmann, A., Munhoz, D.C., Silva, W.A., Comparação entre os efeitos hemodinâmicos da intoxicação aguda com bupivacaína racêmica e a mistura com excesso enatiomérico de 50% (S75-R25). Estudo experimental em cães (2006) Rev Bras Anestesiol, 56, pp. 391-401Cox, B., Durieux, M.E., Marcus, M.A., Toxicity of local anaesthetics (2003) Best Pract Res Clin Anaesthesiol, 17, pp. 111-13