Design of Two New Sulfur Derivatives of Perezone: In Silico Study Simulation Targeting PARP-1 and In Vitro Study Validation Using Cancer Cell Lines.

Poly-ADP-Ribose Polymerase (PARP-1) is an overexpressed enzyme in several carcinomas; consequently, the design of PARP-1 inhibitors has acquired special attention. Hence, in the present study, three compounds (8-10) were produced through a Michael addition protocol, using phenylmethanethiol, 5-fluoro-2-mercaptobenzyl alcohol, and 4-mercaptophenylacetic acid, respectively, as nucleophiles and perezone as the substrate, expecting them to be convenient candidates that inhibit PARP-1. It is convenient to note that in the first stage of the whole study, the molecular dynamics (MD) simulations and the quantum chemistry studies of four secondary metabolites, i.e., perezone (1), perezone angelate (2), hydroxyperezone (3), and hydroxyperezone monoangelate (4), were performed, to investigate their interactions in the active site of PARP-1. Complementarily, a docking study of a set of eleven sulfur derivatives of perezone (5-15) was projected to explore novel compounds, with remarkable affinity to PARP-1. The molecules 8-10 provided the most adequate results; therefore, they were evaluated in vitro to determine their activity towards PARP-1, with 9 having the best IC50 (0.317 µM) value. Additionally, theoretical calculations were carried out using the density functional theory (DFT) with the hybrid method B3LYP with a set of base functions 6-311++G(d,p), and the reactivity properties were compared between the natural derivatives of perezone and the three synthesized compounds, and the obtained results exhibited that 9 has the best properties to bind with PARP-1. Finally, it is important to mention that 9 displays significant inhibitory activity against MDA-MB-231 and MCF-7 cells, i.e., 145.01 and 83.17 µM, respectively.

Synthesis, Cytotoxic Activity and In Silico Study of Novel Dihydropyridine Carboxylic Acids Derivatives.

To aid the possible prevention of multidrug resistance in tumors and cause lower toxicity, a set of sixteen novel dihydropyridine carboxylic acids derivatives 3a-p were produced; thus, the activation of various ynones with triflic anhydride was performed, involving a nucleophilic addition of several bis(trimethylsilyl) ketene acetals, achieving good yields requiring easy workup. The target molecules were unequivocally characterized by common spectroscopic methods. In addition, two of the tested compounds (3a, and 3b) were selected to perform in silico studies due to the highest cytotoxic activity towards the HCT-15 cell line (7.94 ± 1.6 µM and 9.24 ± 0.9 µM, respectively). Employing theoretical calculations with density functional theory (DFT) using the B3LYP/6-311++G(d,p) showed that the molecular parameters correlate adequately with the experimental results. In contrast, predictions employing Osiris Property Explorer showed that compounds 3a and 3b present physicochemical characteristics that would likely make it an orally active drug. Moreover, the performance of Docking studies with proteins related to the apoptosis pathway allowed a proposal of which compounds could interact with PARP-1 protein. Pondering the obtained results (synthesis, in silico, and cytotoxic activity) of the target compounds, they can be judged as suitable antineoplastic agent candidates.

Thromboembolic and hemorrhagic complications in patients with prosthetic heart valves cared for in a tertiary care center. What have we learned?

BACKGROUND: Heart valve replacement surgery with mechanical or biological prostheses entails a risk of thromboembolism and bleeding complications. OBJECTIVE: To determine the complications related to complementary anticoagulation therapy and the probability of risk. METHODS: One-hundred and sixty-three patients who underwent heart valve replacement between 2002 and 2016 with either mechanical or biological prostheses, and who received vitamin K antagonists after hospital discharge, were studied. Anticoagulation therapy was categorized into optimal and non-optimal according to INR values prior to the development of complications. Patients with comorbidities and other risk factors for thrombosis and/or bleeding were excluded. RESULTS: In total, 68.7 % of patients received mechanical prostheses, and 31.3 %, biological prostheses (p ≤ 0.001); 25.2 % experienced the complications that motivated the study (p ≤ 0.001), which were hemorrhagic in 48.8 %, thromboembolic in 26.8 %, and of both types in 24.4 % (relative risk = 4.229). Among the patients with complications, 95.1 % received mechanical prostheses, and 4.9 %, biological (p = 0.005); non-optimal INR was identified in 49.7 % (p ≤ 0.001). CONCLUSIONS: Given the high risk of thromboembolic and hemorrhagic complications, valve prostheses must be carefully chosen, and care priorities should include prevention and follow-up, especially in those patients who require anticoagulation therapy.

ANTECEDENTES: El reemplazo valvular por prótesis mecánicas o biológicas implica riesgo de tromboembolismo y complicaciones hemorrágicas. OBJETIVO: Determinar las complicaciones relacionadas con la terapia de anticoagulación complementaria y la probabilidad de riesgo en pacientes portadores de prótesis valvulares del corazón. MÉTODOS: Se estudiaron 163 pacientes entre 2002 y 2016, portadores de prótesis mecánicas y biológicas, quienes recibieron antagonistas de la vitamina K posterior al egreso hospitalario. La terapia de anticoagulación se categorizó en óptima y no óptima conforme a los valores de INR previos a las complicaciones. Fueron excluidos los pacientes con comorbilidades y otros factores de riesgo de trombosis y/o sangrado. RESULTADOS: a 68.7 % de los pacientes se les colocó prótesis mecánica y a 31.3 %, biológica (p ≤ 0.001); 25.2 % presentó las complicaciones motivo de estudio (p ≤ 0.001), hemorrágicas en 48.8 %, tromboembólicas en 26.8 % y de ambos tipos en 24.4 % (riesgo relativo = 4.229); a 95.1 % de los pacientes con complicaciones se les colocó prótesis mecánica y a 4.9 %, biológica (p = 0.005); 49.7 % presentó INR no óptimo (p ≤ 0.001). CONCLUSIONES: Ante riesgo alto de complicaciones tromboembólicas y hemorrágicas, la elección de las prótesis valvulares, la prevención y el seguimiento son prioridades, principalmente en quienes requieren terapia de anticoagulación.

Complicaciones tromboembólicas y hemorrágicas en pacientes portadores de prótesis valvulares del corazón en un centro de tercer nivel. ¿Qué hemos aprendido? / Thromboembolic and hemorrhagic complications in patients with prosthetic heart valves at third level care center. What have we learned?

Resumen Antecedentes: El reemplazo valvular por prótesis mecánicas o biológicas implica riesgo de tromboembolismo y complicaciones hemorrágicas. Objetivo: Determinar las complicaciones relacionadas con la terapia de anticoagulación complementaria y la probabilidad de riesgo en pacientes portadores de prótesis valvulares del corazón. Métodos: Se estudiaron 163 pacientes entre 2002 y 2016, portadores de prótesis mecánicas y biológicas, quienes recibieron antagonistas de la vitamina K posterior al egreso hospitalario. La terapia de anticoagulación se categorizó en óptima y no óptima conforme a los valores de INR previos a las complicaciones. Fueron excluidos los pacientes con comorbilidades y otros factores de riesgo de trombosis y/o sangrado. Resultados: a 68.7 % de los pacientes se les colocó prótesis mecánica y a 31.3 %, biológica (p ≤ 0.001); 25.2 % presentó las complicaciones motivo de estudio (p ≤ 0.001), hemorrágicas en 48.8 %, tromboembólicas en 26.8 % y de ambos tipos en 24.4 % (riesgo relativo = 4.229); a 95.1 % de los pacientes con complicaciones se les colocó prótesis mecánica y a 4.9 %, biológica (p = 0.005); 49.7 % presentó INR no óptimo (p ≤ 0.001). Conclusiones: Ante riesgo alto de complicaciones tromboembólicas y hemorrágicas, la elección de las prótesis valvulares, la prevención y el seguimiento son prioridades, principalmente en quienes requieren terapia de anticoagulación.

Abstract Background: Heart valve replacement surgery with mechanical or biological prostheses entails a risk of thromboembolism and bleeding complications. Objective: To determine the complications related to complementary anticoagulation therapy and the probability of risk. Methods: One-hundred and sixty-three patients who underwent heart valve replacement between 2002 and 2016 with either mechanical or biological prostheses, and who received vitamin K antagonists after hospital discharge, were studied. Anticoagulation therapy was categorized into optimal and non-optimal according to INR values prior to the development of complications. Patients with comorbidities and other risk factors for thrombosis and/or bleeding were excluded. Results: In total, 68.7 % of patients received mechanical prostheses, and 31.3 %, biological prostheses (p ≤ 0.001); 25.2 % experienced the complications that motivated the study (p ≤ 0.001), which were hemorrhagic in 48.8 %, thromboembolic in 26.8 %, and of both types in 24.4 % (relative risk = 4.229). Among the patients with complications, 95.1 % received mechanical prostheses, and 4.9 %, biological (p = 0.005); non-optimal INR was identified in 49.7 % (p ≤ 0.001). Conclusions: Given the high risk of thromboembolic and hemorrhagic complications, valve prostheses must be carefully chosen, and care priorities should include prevention and follow-up, especially in those patients who require anticoagulation therapy.

Computational Studies of Aflatoxin B1 (AFB1): A Review.

Aflatoxin B1 (AFB1) exhibits the most potent mutagenic and carcinogenic activity among aflatoxins. For this reason, AFB1 is recognized as a human group 1 carcinogen by the International Agency of Research on Cancer. Consequently, it is essential to determine its properties and behavior in different chemical systems. The chemical properties of AFB1 can be explored using computational chemistry, which has been employed complementarily to experimental investigations. The present review includes in silico studies (semiempirical, Hartree-Fock, DFT, molecular docking, and molecular dynamics) conducted from the first computational study in 1974 to the present (2022). This work was performed, considering the following groups: (a) molecular properties of AFB1 (structural, energy, solvent effects, ground and the excited state, atomic charges, among others); (b) theoretical investigations of AFB1 (degradation, quantification, reactivity, among others); (c) molecular interactions with inorganic compounds (Ag+, Zn2+, and Mg2+); (d) molecular interactions with environmentally compounds (clays); and (e) molecular interactions with biological compounds (DNA, enzymes, cyclodextrins, glucans, among others). Accordingly, in this work, we provide to the stakeholder the knowledge of toxicity of types of AFB1-derivatives, the structure-activity relationships manifested by the bonds between AFB1 and DNA or proteins, and the types of strategies that have been employed to quantify, detect, and eliminate the AFB1 molecule.

The Ability of Chlorophyll to Trap Carcinogen Aflatoxin B1: A Theoretical Approach.

The coordination of one and two aflatoxin B1 (AFB1, a potent carcinogen) molecules with chlorophyll a (chl a) was studied at a theoretical level. Calculations were performed using the M06-2X method in conjunction with the 6-311G(d,p) basis set, in both gas and water phases. The molecular electrostatic potential map shows the chemical activity of various sites of the AFB1 and chl a molecules. The energy difference between molecular orbitals of AFB1 and chl a allowed for the establishment of an intermolecular interaction. A charge transfer from AFB1 to the central cation of chl a was shown. The energies of the optimized structures for chl a show two configurations, unfolded and folded, with a difference of 15.41 kcal/mol. Chl a appeared axially coordinated to the plane (α-down or ß-up) of the porphyrin moiety, either with the oxygen atom of the ketonic group, or with the oxygen atom of the lactone moiety of AFB1. The complexes of maximum stability were chl a 1-α-E-AFB1 and chl a 2-ß-E-AFB1, at -36.4 and -39.2 kcal/mol, respectively. Additionally, with two AFB1 molecules were chl a 1-D-2AFB1 and chl a 2-E-2AFB1, at -60.0 and -64.8 kcal/mol, respectively. Finally, biosorbents containing chlorophyll could improve AFB1 adsorption.

In Vitro and Computational Studies of Perezone and Perezone Angelate as Potential Anti-Glioblastoma Multiforme Agents.

Glioblastoma multiforme (GBM) represents the most malignant type of astrocytoma, with a life expectancy of two years. It has been shown that Poly (ADP-ribose) polymerase 1 (PARP-1) protein is over-expressed in GBM cells, while its expression in healthy tissue is low. In addition, perezone, a phyto-compound, is a PARP-1 inhibitor with anti-neoplastic activity. As a consequence, in the present study, both in vitro and computational evaluations of perezone and its chemically related compound, perezone angelate, as anti-GBM agents were performed. Hence, the anti-proliferative assay showed that perezone angelate induces higher cytotoxicity in the GBM cell line (U373 IC50 = 6.44 µM) than perezone (U373 IC50 = 51.20 µM) by induction of apoptosis. In addition, perezone angelate showed low cytotoxic activity in rat glial cells (IC50 = 173.66 µM). PARP-1 inhibitory activity (IC50 = 5.25 µM) and oxidative stress induction by perezone angelate were corroborated employing in vitro studies. In the other hand, the performed docking studies allowed explaining the PARP-1 inhibitory activity of perezone angelate, and ADMET studies showed its probability to permeate cell membranes and the blood-brain barrier, which is an essential characteristic of drugs to treat neurological diseases. Finally, it is essential to highlight that the results confirm perezone angelate as a potential anti-GBM agent.

Resveratrol Potently Counteracts Quercetin Starvation-Induced Autophagy and Sensitizes HepG2 Cancer Cells to Apoptosis.

SCOPE: Resveratrol (RSV) has been described as a potent antioxidant, antisteatotic, and antitumor compound, and it has also been identified as a potent autophagy inducer. On the other hand, quercetin (QCT) is a dietary flavonoid with known antitumor, anti-inflammatory, and antidiabetic effects. Additionally, QCT increases autophagy. To study the hypothetical synergistic effect of both compounds, we test the combined effect of QCT and RSV on the autophagy process in HepG2 cells. METHODS AND RESULTS: Autophagy is studied by western blotting, real-time RT-PCR, and cellular staining. Our results clearly indicate a bifunctional molecular effect of RSV. Both polyphenols are individually able to promote autophagy. Strikingly, when RSV is combined with QCT, it promotes a potent reduction of QCT-induced autophagy and influences proapoptotic signaling. CONCLUSION: RSV acts differentially on the autophagic process depending on the cellular energetic state. We further characterize the molecular mechanisms related to this effect, and we observe that AMP-activated protein kinase (AMPK) phosphorylation, heme oxygenase 1 (HO-1) downregulation, lysosomal membrane permeabilization (LMP), and Zinc (Zn2+ ) dynamics could be important modulators of such RSV-related effects and could globally represent a promising strategy to sensitize cancer cells to QCT treatment.

Analgesia multimodal para el dolor posoperatorio del paciente con apendicectomía de urgencia / Multimodal analgesia for postoperative pain in patients undergoing emergency appendectomy

El dolor agudo es frecuente en los pacientes con afecciones que requieren intervención quirúrgica de urgencia. Su tratamiento satisfactorio es uno de los retos más importantes, presentando ventajas la terapéutica multimodal del dolor posoperatorio al empleo de una sola droga analgésica. Objetivo: comparar el uso de la analgesia multimodal con la monoterapia analgésica en el manejo del dolor posoperatorio de pacientes con apendicectomía de urgencia. Métodos: se realizó un estudio comparativo en 40 pacientes que fueron distribuidos de forma aleatoria en dos grupos de 20 pacientes cada uno. Después de la inducción de la anestesia los pacientes del grupo I recibieron dipirona intravenosa y los del grupo II recibieron además tramadol y ketamina. Se estudió calidad de la analgesia, necesidad de analgesia de rescate, complicaciones y efectos adversos. Resultados: la intensidad del dolor fue menor en el grupo II. La analgesia de rescate solo fue necesaria en el grupo I. Los efectos adversos fueron náuseas, vómitos y mareos en el grupo I. No se registraron complicaciones en los grupos en estudio. Conclusiones: la analgesia multimodal resulta un método que proporciona mayor control del dolor posoperatorio que la monoterapia analgésica en pacientes con apendicectomía de urgencia...

Acute pain is common among patients with disorders requiring emergency surgery, and its relief is one of the greatest challenges in such circumstances. Multimodal postoperative pain relief therapy has proven to be more effective than the use of a single analgesic. Objective: compare the use of multimodal analgesia with analgesic monotherapy for the management of postoperative pain in patients undergoing emergency appendectomy. Methods: a comparative study was conducted of 40 patients randomly distributed into two groups, each composed of 20 patients. After the induction of analgesia, patients in Group I received intravenous dipyrone, and those in Group II additionally received tramadol and ketamine. The following parameters were observed: quality of analgesia, need of rescue analgesia, complications and adverse effects. Results: pain intensity was lower in Group II. Rescue analgesia was required only in Group I. The adverse effects were nausea, vomiting and dizziness in Group I. No complications occurred in the study groups. Conclusions: multimodal analgesia is more effective than analgesic monotherapy as a method to control postoperative pain in patients undergoing emergency appendectomy...

Tramadol frente a morfina en la analgesia peridural posoperatoria de pacientes con histerectomía abdominal / Tramadol versus morphine for postoperative peridural analgesia in patients with abdominal hysterectomy

Introducción: el tratamiento del dolor posoperatorio es necesario para evitar sus efectos desfavorables. Objetivo: comparar la analgesia posoperatoria con el uso de tramadol y morfina por vía peridural en pacientes con histerectomía abdominal. Métodos: se realizó un estudio observacional analítico, longitudinal prospectivo en 140 pacientes que se les efectuó histerectomía por vía abdominal en el Hospital Militar Central "Dr. Carlos J. Finlay". Se aplicó anestesia general orotraqueal y se utilizó el catéter epidural para el manejo del dolor posoperatorio. Se dividieron aleatoriamente en dos grupos, cada uno con 70 pacientes. Un grupo recibió analgesia con morfina, 4 mg, y el otro tramadol, 100 mg. Se estudiaron las variables: duración, calidad de la analgesia posoperatoria y presencia de reacciones adversas. Resultados: la duración de la analgesia posoperatoria fue mayor en el grupo en que se empleó morfina (16,7 ± 4,0 h) que en el de tramadol (13,6 ± 4,2 h). Los valores de la escala visual análoga resultaron más elevados en el grupo Tramadol y con menor cantidad de reacciones adversas (38,6 por ciento) comparado con el grupo Morfina (55,7 por ciento). Conclusiones: la duración y la calidad de la analgesia posoperatoria en las pacientes que se les efectuó histerectomía, resultó mayor con el empleo de morfina peridural, aunque la utilización del tramadol por igual vía, constituye una alternativa eficaz y con menor incidencia de efectos adversos

Introduction: the treatment of postoperative pain is necessary to prevent its unfavorable effects. Objective: compare the use of peridural tramadol versus morphine for postoperative analgesia in patients with abdominal hysterectomy. Methods: an observational analytical prospective longitudinal study was conducted with 140 patients who underwent abdominal hysterectomy at Dr. Carlos J. Finlay Central Military Hospital. General orotracheal anesthesia was administered and an epidural catheter used to manage postoperative pain. Patients were randomly distributed into two groups, each with 70 members. One group received analgesia with morphine 4 mg and the other tramadol 100 mg. The variables studied were duration, quality of postoperative analgesia and presence of adverse reactions. Results: duration of postoperative analgesia was longer in the morphine group (16.7 ± 4.0 h) versus the tramadol group (13.6 ± 4.2 h). Visual analog scale values were higher in the Tramadol group with fewer adverse reactions (38.6 percent) versus the Morphine group (55.7 percent). Conclusions: the duration and quality of postoperative analgesia in patients with hysterectomy were greater with the use of peridural morphine, though the use of peridural tramadol is an effective alternative with fewer adverse effects.

Plasma membrane subdomain partitioning of Lck in primary human T lymphocytes.

Uncovering the plasma membrane distribution of tyrosine kinase Lck is crucial to understanding T lymphocyte triggering. Several studies of Lck species partitioning have given contradictory results. We decided to re-address this point by using phospho-specific antibodies to characterize active and inactive Lck partitioning in raft and non-raft membranes from primary human peripheral blood T lymphocytes. We show that most inactive Lck was localized in rafts and was associated with nearly all CD4 coreceptors and its negative regulator Csk in resting cells, while T cell receptor (TCR) engagement promoted a sustained dephosphorylation of inactive Lck. In contrast, active Lck had a more discrete distribution interacting with only a small number of CD4 coreceptors, and the kinase showed a rapid and short phosphorylation after TCR triggering. The differences in distribution and kinetics may be related to T lymphocyte signalling threshold modulation by Lck species and suggest how TCR triggering is first initiated. This study furthers our knowledge of the TCR activation model in primary human T lymphocytes.

Individual and combined soy isoflavones exert differential effects on metastatic cancer progression.

To investigate the effects soy isoflavones in established cancers, the role of genistein, daidzein, and combined soy isoflavones was studied on progression of subcutaneous tumors in nude mice created from green fluorescent protein (GFP) tagged-MDA-MB-435 cells. Following tumor establishment, mice were gavaged with vehicle or genistein or daidzein at 10 mg/kg body weight (BW) or a combination of genistein (10 mg/kg BW), daidzein (9 mg/kg BW), and glycitein (1 mg/kg BW) three times per week. Tumor progression was quantified by whole body fluorescence image analysis followed by microscopic image analysis of excised organs for metastases. Results show that daidzein increased while genistein decreased mammary tumor growth by 38 and 33% respectively, compared to vehicle. Daidzein increased lung and heart metastases while genistein decreased bone and liver metastases. Combined soy isoflavones did not affect primary tumor growth but increased metastasis to all organs tested, which include lung, liver, heart, kidney, and bones. Phosphoinositide-3-kinase (PI3-K) pathway real time PCR array analysis and western blotting of excised tumors demonstrate that genistein significantly downregulated 10/84 genes, including the Rho GTPases RHOA, RAC1, and CDC42 and their effector PAK1. Daidzein significantly upregulated 9/84 genes that regulate proliferation and protein synthesis including EIF4G1, eIF4E, and survivin protein levels. Combined soy treatment significantly increased gene and protein levels of EIF4E and decreased TIRAP gene expression. Differential regulation of Rho GTPases, initiation factors, and survivin may account for the disparate responses of breast cancers to genistein and daidzein diets. This study indicates that consumption of soy foods may increase metastasis.

Empleo del neuroestimulador KWD 80811 para el bloqueo del plexo braquial por vía axilar

INTRODUCCIÓN: La anestesia del plexo braquial por vía axilar es un proceder frecuentemente empleado para la cirugía del miembro superior; disponer de un neuroestimulador para identificar las estructuras a bloquear ofrece múltiples ventajas. OBJETIVOS: Evaluar la efectividad del bloqueo por esta vía utilizando el neuroestimulador KWD 80811. MATERIAL Y MÉTODO: Se realizó un estudio descriptivo longitudinal y prospectivo en 100 pacientes adultos, de uno u otro sexo, ASA I-III, programados para cirugía de la mano, antebrazo y tercio inferior del brazo, en el Hospital Universitario¼ Dr. Carlos J. Finlay¼ en el período comprendido entre enero-septiembre de 2008. El neuroestimulador KWD 80811 fue empleado para la detección del plexo braquial, y la técnica utilizada para el bloqueo fue la perivascular de Burnham. Como anestésico local se empleó lidocaína al 1 %(7 mg por kg de peso) asociado con adrenalina 1:200 000. RESULTADOS: Se registró período de latencia media de 19.2 min., la calidad de la analgesia quirúrgica fue excelente en el 93 % de los casos y mala en 1 %. Reportamos una sola complicación sin interferencia con el proceder ni secuelas para el paciente. CONCLUSIONES: Esta técnica constituye una alternativa con elevada eficacia, confortable para el paciente y con muy bajo índice de complicaciones.

Introduction: Anesthesia of brachial plexus by axillary route is a frequent surgical procedure for upper extremity; availability of a neurostimulator to identify structures to be blockaded offer many advantages. Objectives: To assess the effectiveness of blockade by this route using the KWD90811 neurostimulator. Material and Methods: A prospective, longitudinal and descriptive study was conducted in 100 adult patients of both sexes, ASA I-III programmed for hand, forearm and inferior third of the arm surgery in "Dr. Carlos J. Finlay" University Hospital from January to September, 2008. Above mentioned neurostimulator was used to detect of brachial plexus and the technique used for blockade was the Burnham's perivascular one. As local anesthesia 1% lidocaine was used (7 mg /kg/bw) associated with adrenaline 1: 200.000. Results: There was an average latency period of 19.2 min; quality of surgical anesthesia was excellent in 93% of cases and poor in 1% with an only one complication without interference in the procedure and sequelae for patient. Conclusions: This technique is a high performance alternative suitable for patient and with a very low rate of complications.

Bupivacaína isobárica frente a hipobárica en anestesia subaracnoidea para cirugía de caderas: Use of Bupivacaine( isobaric versus hypobaric) in subarachnoid anesthesia / Hip surgery

Introducción: La anestesia subaracnoidea se practica sistemáticamente para los procedimientos quirúrgicos de caderas por las múltiples ventajas que ofrece. Objetivo: Comparar los efectos de la bupivacaína isobárica frente a hipobárica en anestesia subaracnoidea para osteosíntesis de caderas. Método: Se estudiaron 100 pacientes adultos de uno u otro sexo en el Hospital Militar "Dr. Carlos J. Finlay". A 50 pacientes (Grupo A) se les administró bupivacaína 0.5% 3 ml, y a los restantes (Grupo B), bupivacaína 0.25% 4 ml. Se analizaron las variables: nivel sensitivo, grado de bloqueo motor, duración y calidad de la analgesia. Resultados: En 77% de los pacientes se obtuvo un nivel sensitivo de T 10, con discreto predominio del nivel T 4 en los pacientes del grupo A. En todos se presentó bloqueo motor completo y analgesia quirúrgica buena. La duración de la analgesia fue 368.4 ± 52.8 min. en el grupo B y 276 ± 29.69 min. en el grupo A. Conclusiones: La Bupivacaína hipobárica superó a la isobárica, pues con ella se alcanzó un nivel sensitivo más bajo y mayor duración de la analgesia.

Subarachnoid anesthesia is systematically applied for surgical procedures of hips due to its multiple advantages. Objective: To compare the effects of isobaric Bupivacaine versus the hypobaric one in subarachnoid anesthesia for hip osteosynthesis. Method: A total of 100 patients of both sexes were studied in "Dr. Carlos J. Finlay" Hospital. Fifty patients (Group A) received Bupivacaine (0.5%-3ml), and remainder (Group B) received Bupivacaine (0.25%-4 ml). We analyzed the following variables: sensitivity level, motor blockade degree, length, and quality of analgesia. Results: In 77% of patients there was a T10 sensitivity level, with a discrete predominance of T4 level in patients of A group. In all of them there was a total motor blockade and a good surgical analgesia. Length of analgesia was of 368.4±52.8 min in B group, and 276 ±29.69 min in A group. Conclusions: Hypobaric Bupivacaine was better than the isobaric one, since its use allow us to reach a lower sensitivity level, and a greater length of analgesia.

Inhibition of mammary tumor growth and metastases to bone and liver by dietary grape polyphenols.

The cancer preventive properties of grape products such as red wine have been attributed to polyphenols enriched in red wine. However, much of the studies on cancer preventive mechanisms of grape polyphenols have been conducted with individual compounds at concentrations too high to be achieved via dietary consumption. We recently reported that combined grape polyphenols at physiologically relevant concentrations are more effective than individual compounds at inhibition of ERalpha(-), ERbeta(+) MDA-MB-231 breast cancer cell proliferation, cell cycle progression, and primary mammary tumor growth (Schlachterman et al., Transl Oncol 1:19-27, 2008). Herein, we show that combined grape polyphenols induce apoptosis and are more effective than individual resveratrol, quercetin, or catechin at inhibition of cell proliferation, cell cycle progression, and cell migration in the highly metastatic ER (-) MDA-MB-435 cell line. The combined effect of dietary grape polyphenols (5 mg/kg each resveratrol, quercetin, and catechin) was tested on progression of mammary tumors in nude mice created from green fluorescent protein-tagged MDA-MB-435 bone metastatic variant. Fluorescence image analysis of primary tumor growth demonstrated a statistically significant decrease in tumor area by dietary grape polyphenols. Molecular analysis of excised tumors demonstrated that reduced mammary tumor growth may be due to upregulation of FOXO1 (forkhead box O1) and NFKBIA (IkappaBalpha), thus activating apoptosis and potentially inhibiting NfkappaB (nuclear factor kappaB) activity. Image analysis of distant organs for metastases demonstrated that grape polyphenols reduced metastasis especially to liver and bone. Overall, these results indicate that combined dietary grape polyphenols are effective at inhibition of mammary tumor growth and site-specific metastasis.

Gene expression changes induced in the testis by transplacental exposure to high and low doses of 17{alpha}-ethynyl estradiol, genistein, or bisphenol A.

The purpose of this study was to determine (1) the transcriptional program elicited by exposure to three estrogen receptor (ER) agonists: 17 alpha-ethynyl estradiol (EE), genistein (Ges), and bisphenol A (BPA) during fetal development of the rat testis and epididymis; and (2) whether very low dosages of estrogens (evaluated over five orders of magnitude of dosage) produce unexpected changes in gene expression (i.e., a non-monotonic dose-response curve). In three independently conducted experiments, Sprague-Dawley rats were dosed (sc) with 0.001-10 microg EE/kg/day, 0.001-100 mg Ges/kg/day, or 0.002-400 mg BPA/kg/day. While morphological changes in the developing reproductive system were not observed, the gene expression profile of target tissues were modified in a dose-responsive manner. Independent dose-response analyses of the three studies identified 59 genes that are significantly modified by EE, 23 genes by Ges, and 15 genes by BPA (out of 8740), by at least 1.5 fold (up- or down-regulated). Even more genes were observed to be significantly changed when only the high dose is compared with all lower doses: 141, 46, and 67 genes, respectively. Global analyses aimed at detecting genes consistently modified by all of the chemicals identified 50 genes whose expression changed in the same direction across the three chemicals. The dose-response curve for gene expression changes was monotonic for each chemical, with both the number of genes significantly changed and the magnitude of change, for each gene, decreasing with decreasing dose. Using the available annotation of the gene expression changes induced by ER-agonist, our data suggest that a variety of cellular pathways are affected by estrogen exposure. These results indicate that gene expression data are diagnostic of mode of action and, if they are evaluated in the context of traditional toxicological end-points, can be used to elucidate dose-response characteristics.

Antiestrógenos: mecanismo de acción y aplicaciones clínicas / Antiestrogens: Mechanism of action and clinical applications

Los antiestrógenos son compuestos que antagonizan la acción de los estrógenos compitiendo por su receptor. Los estrógenos están implicados en la proliferación y diferenciación de las células blanco y se consideran entre los principales factores de riesgo para el desarrollo de cáncer de mama y útero. Algunos antiestrógenos, entre ellos el Tamoxifén, son utilizados como terapia coadyuvante en el tratamiento del cáncer de mama y se ha propuesto su inclusión en los programas de prevención, en mujeres con alto riesgo. Los antiestrógenos se clasifican en tipo I o parciales (agonista/antagonista), y tipo II o puros (antagonista puro), los cuales tienen mecanismos de acción diferentes. Debido al continuo avance en el desarrollo de nuevos compuestos con actividad antiestrogénica, y su importancia aplicativa en clínica. En este documento se presenta una revisión del estado actual del conocimiento de estos compuestos, su mecanismo de acción y su aplicación clínica. El texto completo en inglés de este artículo está disponible en: http://www.insp.mx/salud/index.html

Cirugía estereotáxica en cuatro casos de Parkinson / Stereotaxic surgery in four cases of parkinson

Objetivo. Determinar la eficacia terapéutica de la talamotomía estereotáxica en pacientes con enfermedad de Parkinson que no responden al tratamiento médico. Métodos. Se realizaron cuatro talamotomías estereotáxicas utilizando el sistema Leskell para la inactivación de los núcleos ventrolaterales talámicos. Resultados. El seguimiento clínico postquirúrgico de los pacientes fue de 5 a 58 meses. Se observó la desaparición del temblor, rigidez y dolor en forma permanente; en un caso apareció temblor fino en el lado contralateral tres meses después de la cirugía. Conclusión. La talamotomía estereotáxica en pacientes con Parkinson refractario a manejo médico es benéfica para el control del temblor, rigidez y dolor

Factor quimiotáctico para espermatozoides: una nueva función biológica de la progesterona / Chemiotactic factor for spermatozoa: a new biological function of progesterone

Nuestro grupo describió recientemente la existencia de un factor quimiotáctico para espermatozoides (FQE) conteniendo en el líquido de folículos maduros. Simultáneamente, fue posible desarrollar un nuevo método que permite valorar la capacidad quimiotáctica de los espermatozoides y que por su simplicidad hace posible el estudio sistemático de las características del FQE. En este estudio se abordó la caracterización molecular del FQE de líquido folicular (LF). Se estudiaron LF de mujeres dentro de un programa de fertilización asistida y que fueron calificados como maduros de acuerdo a diferentes criterios. Los LF fueron fraccionados con diferentes técnicas que permitieron separar una fracción activa con características fisicoquímicas de lípido. La cromatografía en capa fina reveló la presencia de diferentes esteroides, que fueron ensayados individualmente para actividad quimiotáctica. Solamente la progesterona mostró la actividad buscada y su efecto mostró una curva dosis-respuesta dentro de valores fisiológicos. Nuestro estudio permitió identificar a la progesterona como el FQE previamente descrito. Esta función del esteroide es completamente novedosa y su mecanismo de acción es objeto de estudio en nuestro laboratorio