Preliminary effects of pagoclone, a partial GABAA agonist, on neuropsychological performance

Pagoclone is a novel cyclopyrrolone that acts as a partial GABAA receptor agonist. Preclinical studies suggest that pagoclone may have clinical utility as an anxiolytic agent, as well as a reduced incidence of side-effects. The present study was conducted to determine whether pagoclone would affect healthy individuals’ performances on neuropsychological measures as a function of dose within the projected therapeutic range. Twelve healthy adult subjects were randomly assigned to dosage groups in a 3-way crossover study. Participants were administered neuropsychological measures six hours following dosing on Day 1 and Day 6 of administration of the drug. Dose effects were noted on measures of alertness, learning, and memory and movement time. Significant effects were also noted on measures of alertness, learning and memory, information processing and psychomotor speed. Overall, the results of this small, preliminary study do not support a finding of behavioral toxicity for these doses of pagoclone. Rather, a pattern was found of transient and mild negative effects on learning and memory scores at the highest dose administered, though these changes were small and no longer evident by the sixth day of use

Modular deconstruction reveals the dynamical and physical building blocks of a locomotion motor program

The neural substrates of motor programs are only well understood for small, dedicated circuits. Here we investigate how a motor program is constructed within a large network. We imaged populations of neurons in the Aplysia pedal ganglion during execution of a locomotion motor program. We found that the program was built from a very small number of dynamical building blocks, including both neural ensembles and low-dimensional rotational dynamics. These map onto physically discrete regions of the ganglion, so that the motor program has a corresponding modular organization in both dynamical and physical space. Using this dynamic map, we identify the population potentially implementing the rhythmic pattern generator and find that its activity physically traces a looped trajectory, recapitulating its low-dimensional rotational dynamics. Our results suggest that, even in simple invertebrates, neural motor programs are implemented by large, distributed networks containing multiple dynamical systems

Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56dim and CD16C NK cells, and a higher frequency of GrzBC cells in CD56dim, CD56bright, and CD16C NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon g (IFNg) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower “natural” cytotoxicity. A marked and prolonged therapy-induced reduction of both “natural” and CD16- dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56dim subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNg production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies

A rapid method for determining arachidonic:eicosapentaenoic acid ratios in whole blood lipids: correlation with erythrocyte membrane ratios and validation in a large Italian population of various ages and pathologies

BACKGROUND: Omega-3 and -6 polyunsaturated fatty acids (LCPUFA), are important for good health conditions. They are present in membrane phospholipids.The ratio of total n-6:n-3 LCPUFA and arachidonic acid:eicosapentaenoic acid (AA and EPA), should not exceed 5:1. Increased intake of n-6 and decreased consumption of n-3 has resulted in much higher, ca 10/15:1 ratio in RBC fatty acids with the possible appearance of a pathological "scenario". The determination of RBC phospholipid LCPUFA contents and ratios is the method of choice for assessing fatty acid status but it is labour intensive and time consuming. AIMS OF THE STUDY: [i] To describe and validate a rapid method, suitable for large scale population studies, for total blood fatty acid assay; [ii] to verify a possible correlation between total n-6:n-3 ratio and AA:EPA ratios in RBC phospholipids and in whole-blood total lipids, [iii] to assess usefulness of these ratio as biomarkers of LCPUFA status. METHODS: 1 Healthy volunteers and patients with various pathologies were recruited.2 Fatty acid analyses by GC of methyl esters from directly derivatized whole blood total lipids and from RBC phospholipids were performed on fasting blood samples from 1432 subjects categorised according to their age, sex and any existing pathologies.AA:EPA ratio and the total n-6:n-3 ratio were determined. RESULTS: AA:EPA ratio is a more sensitive and reliable index for determining changes in total blood fatty acid and it is correlated with the ratio derived from extracted RBC phospholipids. CONCLUSIONS: The described AA:EPA ratio is a simple, rapid and reliable method for determining n-3 fatty acid status

Effects of n-3 PUFAs on breast cancer cells through their incorporation in plasma membrane

<p>Abstract</p> <p>Background</p> <p>PUFAs are important molecules for membrane order and function; they can modify inflammation-inducible cytokines production, eicosanoid production, plasma triacylglycerol synthesis and gene expression. Recent studies suggest that n-3 PUFAs can be cancer chemopreventive, chemosuppressive and auxiliary agents for cancer therapy. N-3 PUFAs could alter cancer growth influencing cell replication, cell cycle, and cell death. The question that remains to be answered is how n-3 PUFAs can affect so many physiological processes. We hypothesize that n-3 PUFAs alter membrane stability, modifying cellular signalling in breast cancer cells.</p> <p>Methods</p> <p>Two lines of human breast cancer cells characterized by different expression of ER and EGFR receptors were treated with AA, EPA or DHA. We have used the MTT viability test and expression of apoptotic markers to evaluate the effect of PUFAs on cancer growth. Phospholipids were analysed by HPLC/GC, to assess n-3 incorporation into the cell membrane.</p> <p>Results</p> <p>We have observed that EPA and DHA induce cell apoptosis, a reduction of cell viability and the expression of Bcl2 and procaspase-8. Moreover, DHA slightly reduces the concentration of EGFR but EPA has no effect. Both EPA and DHA reduce the activation of EGFR.</p> <p>N-3 fatty acids are partially metabolized in both cell lines; AA is integrated without being further metabolized. We have analysed the fatty acid pattern in membrane phospholipids where they are incorporated with different degrees of specificity. N-3 PUFAs influence the n-6 content and vice versa.</p> <p>Conclusions</p> <p>Our results indicate that n-3 PUFA feeding might induce modifications of breast cancer membrane structure that increases the degree of fatty acid unsaturation. This paper underlines the importance of nutritional factors on health maintenance and on disease prevention.</p

Ingestão dietética de pacientes bariátricas femininas após gastroplastia anti-obesidade

PURPOSE: Roux-en-Y gastric bypass is a popular and successful operation for the treatment of morbid obesity. However, it greatly restricts ingestion and moderately interferes with absorption of food, thus potentially paving the way for undernutrition, especially during the first year before patients adapt to the new condition. Aiming to document actual dietary intake during this period, a prospective observational study was performed. METHODS: Forty consecutive patients were investigated using a 24-hour dietary recall technique every 3 months after surgery for 1 year. Females only were accepted for greater homogeneity of the sample. All received a vitamin and mineral supplement on a daily basis as a postoperative routine. A questionnaire was employed regarding general, nutritional, and gastrointestinal changes as well as consumption of medications. Dietary intake was analyzed after data processing using the Virtual Nutri software package (São Paulo, SP, Brazil). RESULTS: The surgical response was within the expected range, with about 67% excess weight loss at the end of the 1st year, and the same occurred with gastrointestinal symptoms and drug requirements. Daily energy intake on the 4 analyzed occasions was 529.4 &plusmn; 47.4, 710.9 &plusmn; 47.6, 833.2 &plusmn; 72.0, and 866.2 &plusmn; 95,1 kcal/day (mean &plusmn; SEM); protein intake was increased in the same proportion at 6 and 9 months, but reduced at 12 months. Thus, patients did not meet standard recommendations regarding calories and proteins, even at the end of the 1st year; iron and zinc intake were also inadequate, although deficiencies were probably staved off by the prescribed supplement preparation. CONCLUSIONS: 1) The risk for postoperative undernutrition was evidenced up to 1 year, while spontaneous improvement in food intake was slow and inefficient; 2) Specific protocols should be devised to improve nutrition and health during the postoperative phase until successful dietary adaptation is achieved.OBJETIVO: A gastroplastia com anastomose gastrojejunal em Y de Roux é uma operação popular e bem sucedida no tratamento da obesidade grave. Ela restringe seriamente a ingestão e moderadamente a absorção do alimento, potencialmente abrindo caminho para desnutrição especialmente no primeiro ano, antes que o paciente se adapte à nova condição. Com o propósito de documentar a real ingestão neste período, um estudo prospectivo observacional foi executado. MÉTODO: Quarenta pacientes consecutivos foram investigados por recordatório de 24 horas a cada três meses após a operação, até um ano. Apenas mulheres foram arroladas para maior homogeneidade da amostra. Todas receberam diariamente um suplemento vitamínico-mineral, como rotina pós-operatória. Um questionário foi empregado abordando alterações gerais, nutricionais e gastrointestinais assim como consumo de medicamentos. Os ganhos dietéticos foram analisados mediante o programa Virtual Nutri (São Paulo, SP, Brasil). RESULTADOS: A resposta cirúrgica situou-se dentro da faixa esperada, com perda de cerca de 67% do excesso de peso após um ano, e o mesmo ocorreu com sintomas gastrointestinais e necessidades medicamentosas. A quantidade de energia diária nas quatro ocasiões foi de 529,4&plusmn;47,5, 710,9&plusmn; 47,7, 833,2&plusmn; 72,0 e 866,2&plusmn; 95,1 kcal/dia (média &plusmn; erro padrão da média), e o aumento do consumo de proteína foi da mesma proporção nos 6 e 9 meses e com redução em 12 meses. Consequentemente mesmo após um ano as pacientes estavam abaixo das recomendações usuais de calorias e proteínas. A contribuição da dieta no tocante a ferro e zinco também mostrou-se inadequada, embora quadros deficitários tenham provavelmente sido abortados pelo suplemento utilizado. CONCLUSÕES: 1) O risco para desnutrição pos-operatória ficou demonstrado até um ano, e a melhora espontânea da ingestão de alimentos revelou-se lenta e ineficiente; 2) Protocolos específicos deveriam ser elaborados visando melhorar a nutrição e a saúde na fase pós-operatória, até que se verifique uma adaptação dietética satisfatória

Novel nickel nanoparticles stabilized by imidazolium-amidinate ligands for selective hydrogenation of alkynes

[EN] The main challenge in the hydrogenation of alkynes into (E)- or (Z)-alkenes is to control the selective formation of the alkene, avoiding the over-reduction to the corresponding alkane. In addition, the preparation of recoverable and reusable catalysts is of high interest. In this work, we report novel nickel nanoparticles (Ni NPs) stabilized by three different imidazolium-amidinate ligands (ICy center dot(NCN)-N-(Ar); L1: Ar = p-tol, L2: Ar = p-anisyl and L3: Ar = p-ClC6H4). The as-prepared Ni NPs were fully characterized by (HR)-TEM, XRD, WASX, XPS and VSM. The nanocatalysts are active in the hydrogenation of various substrates. They present a remarkable selectivity in the hydrogenation of alkynes towards (Z)-alkenes, particularly in the hydrogenation of 3-hexyne into (Z)-3-hexene under mild reaction conditions (room temperature, 3% mol Ni and 1 bar H-2). The catalytic behaviour of Ni NPs was influenced by the electron donor/acceptor groups (-Me, -OMe, -Cl) in the N-aryl substituents of the amidinate moiety of the ligands. Due to the magnetic character of the Ni NPs, recycling experiments were successfully performed after decantation in the presence of an external magnet, which allowed us to recover and reuse these catalysts at least 3 times preserving both activity and chemoselectivity.The authors thank CNRS, UPS-Toulouse, INSA, "IDEX/Chaires d'attractivite l'Universite Federale Toulouse Midi-Pyrenees", "Instituto de Tecnologia Quimica" (ITQ; UPV-CSIC), "Juan de la Cierva" programme (IJCI-2016-27966), "Primero Proyectos de Investigacion" (PAID-06-18), "Instituto de Investigaciones Quimicas" (IIQ; CSIC-US), "Ministerio de Ciencia, Innovacion y Universidades" (MCIU/AEI), FEDER funds of the European Union (PGC2018-095768-B-I00) and ERC Advanced Grant (MONACAT 2015-694159) for financial support. We also thank L. Datas for the TEM facilities (UMS Castaing) and S. Cayez for the HRTEM measurements.López-Vinasco, AM.; Martínez-Prieto, LM.; Asensio, JM.; Lecante, P.; Chaudret, B.; Cámpora, J.; Van Leeuwen, PWNM. (2020). Novel nickel nanoparticles stabilized by imidazolium-amidinate ligands for selective hydrogenation of alkynes. Catalysis Science & Technology. 10(2):342-350. https://doi.org/10.1039/c9cy02172hS342350102Swamy, K. C. K., Reddy, A. S., Sandeep, K., & Kalyani, A. (2018). Advances in chemoselective and/or stereoselective semihydrogenation of alkynes. Tetrahedron Letters, 59(5), 419-429. doi:10.1016/j.tetlet.2017.12.057Lei, J., Su, L., Zeng, K., Chen, T., Qiu, R., Zhou, Y., … Yin, S.-F. (2017). Recent advances of catalytic processes on the transformation of alkynes into functional compounds. Chemical Engineering Science, 171, 404-425. doi:10.1016/j.ces.2017.05.021J. G. de Vries and C. 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Arginase levels and their association with Th17-related cytokines, soluble adhesion molecules (sICAM-1 and sVCAM-1) and hemolysis markers among steady-state sickle cell anemia patients

Sickle cell anemia (SCA) is characterized by a marked endothelial dysfunction, owing to many factors. Arginine metabolism can be related to the inflammatory chronic state presented by patients, playing a key role in their clinical outcome and vascular endothelium. We investigated the serum arginase levels in 50 SCA patients (22 men and 28 women, mean age of 17 ± 10.5 years) and 28 healthy controls. Serum arginase levels were associated with biochemical hemolysis markers and cytokines involved in Th17 response, as well as levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1). Arginase concentrations were higher in SCA patients, compared with controls (p = 0.005), and were significantly and positively associated with total bilirubin (p = 0.004), indirect bilirubin (p = 0.04), and aspartate aminotransferase (AST; p = 0.039) in the SCA patient group. Moreover, arginase was significantly and positively associated with transforming growth factor-beta (TGF-beta; p = 0.008) among SCA patients. sICAM-1 was significantly and positively associated to reticulocytes (p = 0.014) and AST (p = 0.04). sVCAM-1 was likewise associated with lactate dehydrogenase (p = 0.03). These data suggest a new insight into arginase metabolism, as we show here a shift in arginine catabolism, where TGF-beta may induces the arginase pathway instead of the nitric oxide pathway and a possible involvement of the vascular activation and the serum arginase in chronic hemolysis among SCA patients. Additional studies should be carried out in order to investigate the mechanisms by which TGF-beta participates in the metabolism of arginase in SCA patients