Combining Charge Density Analysis with Machine Learning Tools To Investigate the Cruzain Inhibition Mechanism.

Trypanosoma cruzi, a flagellate protozoan parasite, is responsible for Chagas disease. The parasite major cysteine protease, cruzain (Cz), plays a vital role at every stage of its life cycle and the active-site region of the enzyme, similar to those of other members of the papain superfamily, is well characterized. Taking advantage of structural information available in public databases about Cz bound to known covalent inhibitors, along with their corresponding activity annotations, in this work, we performed a deep analysis of the molecular interactions at the Cz binding cleft, in order to investigate the enzyme inhibition mechanism. Our toolbox for performing this study consisted of the charge density topological analysis of the complexes to extract the molecular interactions and machine learning classification models to relate the interactions with biological activity. More precisely, such a combination was useful for the classification of molecular interactions as "active-like" or "inactive-like" according to whether they are prevalent in the most active or less active complexes, respectively. Further analysis of interactions with the help of unsupervised learning tools also allowed the understanding of how these interactions come into play together to trigger the enzyme into a particular conformational state. Most active inhibitors induce some conformational changes within the enzyme that lead to an overall better fit of the inhibitor into the binding cleft. Curiously, some of these conformational changes can be considered as a hallmark of the substrate recognition event, which means that most active inhibitors are likely recognized by the enzyme as if they were its own substrate so that the catalytic machinery is arranged as if it is about to break the substrate scissile bond. Overall, these results contribute to a better understanding of the enzyme inhibition mechanism. Moreover, the information about main interactions extracted through this work is already being used in our lab to guide docking solutions in ongoing prospective virtual screening campaigns to search for novel noncovalent cruzain inhibitors.

Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor.

A series of tetrahydroisoquinolines functionalized with carbamates is reported here as highly selective ligands on the dopamine D2 receptor. These compounds were selected by means of a molecular modeling study. The studies were carried out in three stages: first an exploratory study was carried out using combined docking techniques and molecular dynamics simulations. According to these results, the bioassays were performed; these experimental studies corroborated the results obtained by molecular modeling. In the last stage of our study, a QTAIM analysis was performed in order to determine the main molecular interactions that stabilize the different ligand-receptor complexes. Our results show that the adequate use of combined simple techniques is a very useful tool to predict the potential affinity of new ligands at dopamine D1 and D2 receptors. In turn the QTAIM studies show that they are very useful to evaluate in detail the molecular interactions that stabilize the different ligand-receptor complexes; such information is crucial for the design of new ligands.

Does pterygopalatine canal injection with local anaesthetic and adrenaline decrease bleeding during functional endoscopic sinus surgery?

OBJECTIVE: To determine the effect of pterygopalatine fossa injection with xylocaine and adrenaline on: surgical field bleeding and blood loss during functional endoscopic sinus surgery for chronic rhinosinusitis, and the duration of the procedure. METHODS: A prospective, single-blinded, controlled trial was performed in a tertiary care academic centre. A total of 45 patients undergoing functional endoscopic sinus surgery for chronic rhinosinusitis, whose disease was symmetrical based on computed tomography grading, were included. A unilateral pterygopalatine fossa injection with 1 per cent xylocaine and 1:100 000 adrenaline was performed after the induction of anaesthesia. The contralateral side served as the control. The operating surgeon, who was blinded to the injected side, assessed the surgical field using a validated six-item grading system. Blood loss, blood pressure, heart rate and end-tidal carbon dioxide were recorded every 15 minutes for each side separately, and duration of surgery was noted. RESULTS: There was no statistically significant difference in the surgical field grade between the injected and non-injected sides (p = 0.161). There were no differences in blood loss or duration of surgery. CONCLUSION: Pterygopalatine fossa injection prior to functional endoscopic sinus surgery did not decrease intra-operative surgical field bleeding, blood loss or duration of surgery.

Frecuencia y sensibilidad antimicrobiana de agentes etiológicos de dacriocistitis / Frequency and antimicrobial sensibility of etiological agents of dacriocystitis

La dacriocistitis representa la infección más frecuente del sistema lagrimal. El estudio microbiológico de las dacriocistitis es importante para la adecuada selección de los antibióticos. El objetivo del estudio es determinar la frecuencia y sensibilidad antimicrobiana de los agentes causantes de dacriocistitis en pacientes que acudieron a la Cátedra de Oftalmología del Hospital de Clínicas de mayo de 1998 a abril de 2007. Los pacientes no recibieron antibióticos por lo menos por una semana antes de la toma de muestra, que fueron tomadas por aspiración del contenido del saco lagrimal por el canalículo inferior o punción directa del saco lagrimal, y cultivadas en aerobiosis y anaerobiosis siguiendo métodos convencionales. De 41 pacientes (23 adultos y 18 niños), 30 (73,1%) presentaron cultivos positivos; 16 (53.4%) monomicrobianos y 14 (46,6%) polimicrobianos. Se aislaron 51 microorganismos, 37 en adultos y 14 en niños. El 54% de los microorganismos aislados en muestras de adultos correspondió a bacilos gramnegativos (enterobacterias, Haemophilus sp, anaerobios, y bacilos gramnegativos no fermentadores); 41% a cocos grampositivos (Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus viridans, y estafilococo coagulasa negativo); el 72% de los micro-organismos aislados en niños correspondió a cocos grampositivos (Staphylococcus aureus y Streptococcus pneumoniae), y en una muestra se aisló Candida sp. La sensibilidad del Streptococcus pneumoniae a la penicilina y la del Staphylococcus aureus a la meticilina fue de 100%. Los microorganismos aislados presentaron buena sensibilidad a los antimicrobianos, pero por la gran variedad de microorganismos y la naturaleza polimicrobiana de los cultivos se debería ampliar el esquema inicial de tratamiento y de la profilaxis de la dacriocistorrinostomía y otros procedimientos intraoculares. Una opción es el uso de aminopenicilinas con un inhibidor de betalactamasa; asociado con colirio de tobramicina en niños y ciprofloxacina en adultos.

Dacryocystitis is the most frequent infection of the lacrimal sac. The microbiological evaluation of dacryocystitis is important to make an adequate choice of antibiotics. The objective of this study is to determine the frequency and antibiotic susceptibility of the etiological agents of dacryocystitis in patients attending the Ophthalmology Department of the Teaching Hospital of the National University of Asunción, Paraguay from May 1998 to April 2007. All patients were antibiotic-free for at least one week prior to sampling. Samples were taken by aspiration of the lacrimal sac obtained via canalicular reflux or incision of the lacrimal sac and cultured aerobically and anaerobically following standard methods. Out of 41 patients (23 adults and 18 children), 30 (73.1%) showed positive cultures, 16 (53.4%) of them were pure and 14 (46.6%) mixed cultures, yielding 51 microorganisms. Of the 37 microorganisms 54% were isolated in adults and corresponded to gram negative rods (enterobacterias, Haemophilus sp, anaerobic and non fermenting gram negative rods) while 41% to gram positive cocci: (Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus viridans, coagulase negative Staphylococcus). In children, 72% of the micro-organisms isolated were gram positive cocci (Staphylococcus aureus and Streptococcus pneumoniae) and Candida sp was found in one sample. The susceptibility patterns of the Streptococcus pneumoniae to penicillin and Staphylococcus aureus to methicillin were 100%. All isolates showed high susceptibilities to the tested antibiotics. However, due to the great variety of species and the polymicrobial nature of the cultures, the initial scheme and prophylaxis of the dacryocystorhinostomy and other intraocular procedures should be expanded. One option is the use of aminopenicillins with a betalactamase inhibitor associated with tobramycin in children and ciprofloxacin in adults.

Impact of parity on anthropometric measures of obesity controlling by multiple confounders: a cross-sectional study in Chilean women.

AIM: To find out whether there is an association between parity and obesity, evaluated through body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) in Chilean women after controlling for sociodemographic characteristics, health risk and gynaeco-obstetric factors. DESIGN: Cross-sectional study, using baseline data of the San Francisco Project. SETTING: San Francisco de Mostazal, located in the central region of Chile, 6512 Chilean-Hispanic women (Spanish heritage with a variable indigenous component). METHODS: A weighted random sample of 508 women who had their first pregnancy inside the primary child-bearing ages. Data were collected between 1997 and 1999. Statistical associations between parity and different anthropometric measurements of adiposity in multiple linear (MLnR) and logistic regression models (MLtR) were evaluated. RESULTS: In MLnR a modest parity-related increment in BMI and practically null increment in WC, WHR and WHtR was observed. Covariates that showed a statistically significant association with anthropometric measures of adiposity were age, low education, marital status, employment, smoking, smoking cessation, hypertension, diabetes, dyslipidaemia, parent's obesity, menarche and fetal macrosomia. Crude odds ratio (OR) showed a strong association between parity and anthropometric markers of obesity. Nevertheless, after adjustments in MLtR models, the association remained only for BMI. All the measures of abdominal obesity related to parous women showed OR smaller than 1 (95% confidence intervals 0.57 to 0.96). CONCLUSIONS: Parity modestly influences BMI, but does not seem to be related to WC, WHR and WHtR after controlling by confounders. Parity can increase adiposity but not necessarily following an abdominal pattern.

Encuesta con paracoccidioidina en la Provincia del Chaco, Republica Argentina / Survey with paracoccidioidin in Chaco Province, Argentine Republic

Se exponen los índices infección obtenidos con paracoccidioidina y su correlación con distintas zonas climáticas de la Provincia del Chaco, República Argentina; se observaron los mayores porcentajes (21,3%) en la localidad de Juan José Castelli, del sector occidental, sub región semiárida de la provincia