Fragment-Based Drug Discovery against Mycobacteria: The Success and Challenges.

The emergence of drug-resistant mycobacteria, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTM), poses an increasing global threat that urgently demands the development of new potent anti-mycobacterial drugs. One of the approaches toward the identification of new drugs is fragment-based drug discovery (FBDD), which is the most ingenious among other drug discovery models, such as structure-based drug design (SBDD) and high-throughput screening. Specialized techniques, such as X-ray crystallography, nuclear magnetic resonance spectroscopy, and many others, are part of the drug discovery approach to combat the Mtb and NTM global menaces. Moreover, the primary drawbacks of traditional methods, such as the limited measurement of biomolecular toxicity and uncertain bioavailability evaluation, are successfully overcome by the FBDD approach. The current review focuses on the recognition of fragment-based drug discovery as a popular approach using virtual, computational, and biophysical methods to identify potent fragment molecules. FBDD focuses on designing optimal inhibitors against potential therapeutic targets of NTM and Mtb (PurC, ArgB, MmpL3, and TrmD). Additionally, we have elaborated on the challenges associated with the FBDD approach in the identification and development of novel compounds. Insights into the applications and overcoming the challenges of FBDD approaches will aid in the identification of potential therapeutic compounds to treat drug-sensitive and drug-resistant NTMs and Mtb infections.

Methamphetamine alters the TLR4 signaling pathway, NF-κB activation, and pro-inflammatory cytokine production in LPS-challenged NR-9460 microglia-like cells.

Methamphetamine (METH) is a major public health and safety problem worldwide. METH is psychostimulant that activates microglia via the toll-like receptor (TLR) 4/MD2 complex, modulating the abundant production of pro-inflammatory cytokines in the central nervous system (CNS). The TLR4/MD2 complex on the surface of microglia recognizes pathogen-associated molecular patterns such as lipopolysaccharide (LPS) resulting in brain tissue inflammation and neuronal damage. Since METH has been associated with microglia-induced neurotoxicity, we hypothesized that METH impairs the expression of TLR4 and activation of NF-κB in NR-9460 microglia-like cells after LPS challenge. We demonstrated that METH decreases the distribution and expression of TLR4 receptors on the surface of microglia-like cells after incubation with endotoxin. Moreover, METH impairs the TLR4/MD2 complex signaling pathways, compromises the activation of NF-κB, and reduces the production of pro-inflammatory mediators in microglia-like cells upon LPS stimulation. Interestingly, microglia-like cells treated with METH and challenged with LPS showed considerable cellular morphological changes including enlarged nuclei and ruffled surface. Our results suggest that METH may have a significant impact on microglial-induced neuroinflammation, neurotoxicity, and the CNS defense against infection. It also highlights the importance of studying the effects of METH on the molecular and cellular components of users' CNS immunity. Finally, animal studies exploring the role of METH on the effectors functions of microglia after antigenic exposure are necessary to understand drug-related inflammation and neural damage in users.

Preoperative Brimonidine Tartrate 0.2% Does not Prevent an Intraocular Pressure Rise During Prostatectomy in Steep Trendelenburg Position.

PURPOSE: This study evaluated the effect of preoperative brimonidine tartrate 0.2% on intraocular pressure (IOP) during robotic-assisted laparoscopic radical prostatectomy in steep Trendelenburg position (sTBURG). MATERIALS AND METHODS: In this prospective randomized controlled masked interventional trial, eligible patients scheduled for robotic-assisted laparoscopic radical prostatectomy in sTBURG at the Toronto General Hospital had one eye randomized to placebo (artificial tears) or drug (brimonidine tartrate 0.2%) preoperatively. Visual acuity (VA), tonometry, disc photography, visual field (VF), and retinal nerve fiber layer (RNFL) assessments were performed preoperatively and postoperatively. A standardized anesthetic protocol was followed intraoperatively. IOP was measured using Tono-Pen AVIA (Reichert Inc., New York, NY) as follows: preanesthesia supine, anesthetized supine, hourly in sTBURG and awake supine. The primary outcome was IOP in sTBURG in the drug group compared with the placebo group. Secondary outcomes were changes in VA, VF, RNFL thickness, mean arterial pressure, and ocular perfusion pressure. This study was approved by University Health Network Research Ethics Board. RESULTS: In total, 26 eligible patients, mean age 61.9±5.1 years, were randomized to brimonidine (11 patients) and placebo (15 patients). Baseline IOP was not significantly different between the drug and placebo groups (P=0.42). Significant and sustained IOP elevation of >1.5X baseline in the sTBURG was noted in both groups. The mean IOP 1 hour after sTBURG was 29.4±6.9 and 27.2±3.4 mm Hg in the drug and placebo groups, respectively (P=0.35). No significant changes were noted in VA, VF, or RNFL. CONCLUSIONS: Significant and sustained IOP increases occur during sTBURG. Preoperative brimonidine does not prevent IOP spikes in sTBURG.

Conducta sexual y anticonceptiva en estudiantes de medicina / Sexual and Contraceptive Behavior in Medical Students

Introducción: estudios previos y la percepción del personal que labora en el Servicio Médico de la Universidad del Valle sugieren un comportamiento sexual poco responsable por parte del estamento estudiantil. Objetivo: el presente estudio describe el comportamiento sexual y anticonceptivo en estudiantes de primer, tercer y último año del programa de Medicina. Resultados: al Programa de Medicina ingresan adolescentes tardíos con proporción creciente de mujeres y, en su mayoría, de estrato socioeconómico medio y alto; los estudiantes hombres inician sus relaciones coitales más precozmente que las mujeres (p<0,001), si bien estas últimas están iniciando cada vez más temprano, al punto de no encontrar diferencias entre los sexos en la cohorte del primer año. Se evidencia un comportamiento sexual similar en los dos sexos, con un pequeño porcentaje de ambos sexos que se mantiene virgen (alrededor del 5,3%). Los métodos anticonceptivos más utilizados son el condón y la píldora. La conducta sexual responsable (uso de anticonceptivo en todas las relaciones coitales) prácticamente no se modifica entre los semestres. Existe un incremento significativo en embarazos, abortos inducidos y enfermedades de transmisión sexual (ETS) entre los estudiantes de un nivel de formación y otro. Los argumentos expuestos para no utilizar siempre un contraceptivo son insensatos.

Introduction: Previous research and data arising from the “Universidad del Valle” medical school Health Service suggest that students exhibit irresponsible sexual behavior. Objective: This paper describes sexual behavior and contraceptive methods commonly used among first, third and last year students. Results: Students entering the program are frequently late adolescents, with a growing female proportion, coming from high and middle social and economic classes. Although male students begin coital contacts earlier than females (p<0.001), in recent years this is tending to balance, showing no differences in the freshmen cohorts. Both genders have similar sexual behavior, with a small percentage remaining virgin until internship. Condom and oral contraceptives are favored as contraceptive methods. Medical students exhibit a high degree of risk-taking behavior, therefore unwanted pregnancies, abortions and STDs are frequent and become more prevalent in upper levels. Reasons exposed to avoid the use of contraceptive methods seem invalid and irrelevant.

Marcadores tiroideos en comunidades indigenas y negras de Colombia / Thyroid markers in Colombian indian and black community

El sistema hipotálamo-hipófisis-tiroides forma un conjunto anatómico y funcional único en el organismo, fundamental para la vida y la continuidad de la especie. Los marcadores hormonales constituyen un parámetro esencial en la evaluación del sistema endocrino. Al igual que otros marcadores biológicos, estos están sujetos a variaciones en individuos diferentes que en la mayoría de los casos determinan la enfermedad. La evaluación de marcadores hormonales en poblaciones aisladas de Colombia surge como una necesidad contemporánea tanto para las comunidades implicadas como para el resto de la población en cuanto a que los valores autóctonos revelados deberán considerarse como los verdaderos valores de referencia en nuestro país. En el presente trabajo se determinaron los valores de los marcadores tiroideos: T3, T4 y TSH en comunidades indígenas y negras de Colombia. Se evaluaron 180 muestras de plasma, correspondientes a 5 grupos indígenas, 3 grupos negros y 1 grupo control de mestizos de Santafé de Bogotá, utilizando las técnicas de inmunoensayo por polarización de la fluorescencia (FPIA) para T4 y de inmunoensayo en micropartículas enzimáticas (MEIA) para T3 Y TSH. comunidad así como establecer valores de referencia para estos grupos étnicos