Adverse Events and Drug Resistance in Critically Ill Patients Treated with Colistimethate Sodium: A Review of the Literature.

The adverse events related to sodium colistimethate have had variability regarding the prevalence of nephrotoxicity, neurotoxicity, and less frequent respiratory depression. In recent years, its use has been relevant due to the increase of multidrug-resistant bacteria since it is considered the last-line drug, being its main adverse event and reason for discrepancies between authors' nephrotoxicity. The indiscriminate use of antibiotic therapy has generated multiple mechanisms of resistance, the most common being related to Colistin, the bactericidal escape effect. Based on the search criteria, no randomized clinical trials were identified showing safety and efficacy with the use of Colistin, inferring that the application of the appropriate dose is governed by expert opinion and retrospective and prospective observational studies, which confounding factors such as the severity of the patient and the predisposition to develop acute renal failure are constant. In this review, we focus on identifying the mechanism of nephrotoxicity and bacterial resistance, where much remains to be known.

Changes in the neutrophil to lymphocyte ratio as predictors of outcome in pediatric patients with central nervous system tumors undergoing surgical resection.

BACKGROUND: Changes in neutrophil to lymphocyte ratio (ΔNLR) have been used as a clinical tool for stratification and prognosis of patients with solid tumors, there is scarce evidence of their clinical relevance in patients with tumors of the central nervous system who have also undergone surgical resection. OBJECTIVE: Determine if (ΔNLR) are associated with poor response to treatment and worse prognosis in pediatric patients with central nervous system tumors (CNST) who underwent surgical resection. METHODS: We performed a retrospective cohort study; demographic, clinical, and hematological variables were evaluated, Kaplan-Meier survival curves and Cox proportional hazards regression model were performed to evaluate prognosis. RESULTS: The ΔNLR cutoff value obtained through the third interquartile range was 4.30; The probability of survival and complete response to treatment was different between patients with high ΔNLR when compared to patients with low ΔNLR (p= 0.013, p=≪ 0.001, respectively). A high ΔNLR behaved as an independent predictor of worse Overall Survival (HR 2,297; 95% CI: 1,075-4.908, p= 0.032). CONCLUSION: An elevated ΔNLR was a predictor of poor response to treatment and a prognostic factor for worse Overall Survival in pediatric patients with CNST undergoing surgical resection.

The rs776746 variant of CYP3A5 is associated with intravenous midazolam plasma levels and higher clearance in critically ill Mexican paediatric patients.

WHAT IS KNOWN AND OBJECTIVE: Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The presence of single-nucleotide polymorphisms (SNPs) in the genes encoding these enzymes, such as CYP3A4*1B which is associated with low enzyme expression and activity and CYP3A5*3, has been associated with decrease in enzymatic activity and reduced drug clearance, with potential effects on drug levels and/or toxicity. The present study was conducted to determine the frequencies of the allelic variants of the CYP3A4 (rs2740574) and CYP3A5 (rs776746) genes and their effects on the plasma levels and clearance of intravenous midazolam in critically ill Mexican paediatric patients. METHODS: Seventy-two DNA samples were genotyped by real-time PCR with TaqMan probes. Plasma midazolam levels were determined at 3 and 24 h post infusion by high-performance liquid chromatography. RESULTS AND DISCUSSION: The allelic variant rs776746 (CYP3A5*3) was associated with high midazolam plasma levels; the median concentration in patients with the normal genotype (CC) <0.01 ng/ml (Q25 0.01-Q75 196.09), whereas patients with the allelic variant (TT+TC) had a median midazolam concentration of 320.3 ng/ml (Q25 37.51-Q75 529.51), p = 0.001. The median pharmacokinetic clearance rates were 0.10 L/kg/h (Q25 0.01-Q75 0.34) in patients with the allelic variant (TT+TC) and 0.03 L/kg/h (Q25 0.002-Q75 0.13) in patients with the normal genotype (CC), p = 0.042. WHAT IS NEW AND CONCLUSION: This is the first study that reports the frequency of the rs776746 polymorphism in critically ill paediatric patients, which is relevant, since carriers of the *1 allele synthesizing a functional enzyme may need higher doses to achieve adequate sedation. Our results show that compared with carriers of the normal allele, patients with the CYP3A5*3 allelic variant (rs776746) had increased plasma midazolam levels at 3 h after infusion discontinuation (320.3 ng/ml) and greater clearance (0.10 L/kg/h) of the drug.

Expression profiles of the Wnt/ß-catenin signaling-related extracellular antagonists during proliferation and differentiation in human osteoblast-like cells.

Bone formation is a dynamic process directed by osteoblast activity. The transition from the proliferation to differentiation stage during osteoblast maturation involves the downregulation of the Wnt/ß-catenin signaling pathway, and extracellular antagonists are important for the regulation of Wnt signaling. However, the expression levels of Wnt antagonists in these stages of human osteoblast maturation have not been fully elucidated. Therefore, the aim of the present study was to investigate the expression levels of extracellular Wnt antagonists during proliferation and differentiation in osteoblast-like cell lines. The results demonstrated an overlap between the differential expression of secreted Frizzled-related protein (SFPR)2, SFRP3, SFRP4 and Dickkopf (DKK) 2 genes during the differentiation stage in the MG-63 and Saos-2 cells. Furthermore, high expression levels of DKK3 in MG-63 cells, Wnt inhibitory factor 1 (WIF1) in Saos-2 cells and DKK4 in hFOB 1.19 cells during the same stage (differentiation), were observed. The upregulated expression levels of Wnt antagonists were also correlated with the high expression of anxin 2 during the differentiation stage. These findings suggested that Wnt-related antagonists could modulate the Wnt/ß-catenin signaling pathway. By contrast, DKK1 was the only gene that was found to be upregulated during the proliferation stage in hFOB 1.19 and Saos-2 cells. To the best of our knowledge, the present study provides, for the first time, the expression profile of Wnt antagonists during the proliferation stage and the initial phases of differentiation in osteoblast-like cell lines. The current results offer a basis to investigate potential targets for bone-related Wnt-signaling modulation in bone metabolism research.

Heterozygous Genotype rs17580 AT (PiS) in SERPINA1 is Associated with COPD Secondary to Biomass-Burning and Tobacco Smoking: A Case-Control and Populational Study.

Purpose: The protease inhibitor S (PiS) and Z (PiZ) variants have been stated as the only genetic cause of chronic obstructive pulmonary disease (COPD) in Caucasians. However, its frequency in admixed populations is low. We aimed to identify genetic susceptibility between PiS (rs17580) and PiZ (rs28929474) polymorphisms with COPD related to tobacco smoking and biomass-burning smoke as well as to determine its frequencies in Mestizo and Amerindian populations from Mexico. Patients and Methods: One thousand and eight hundred seventy-eight subjects were included in two comparisons of cases and controls, (1) smokers with and without COPD (COPD-S, n=399; SWOC, n=1106); (2) Biomass-burning smoke-exposed subjects with and without COPD (COPD-BS, n=98; BBES, n=275). In addition, 2354 Mexican subjects identified as Mestizos (n=1952) and Amerindian (n=402) were included. The population structure was evaluated using 59 informative ancestry markers. Results: The AT genotype of rs17580 is associated with COPD in both comparisons (COPD-S vs SWOC p<0.001, OR=2.16; COPD-BS vs BBES p<0.0001, OR=11.50). The population of the Mexico-North has a greater Caucasian contribution (54.7%) compared to the center (46.9%) and southeast (42.7%). Conclusion: The rs17580, AT genotype, is associated with COPD in Mexican-Mestizo smokers and exposed to biomass-burning smoke. The rs17580 AT is more frequent in the Mexican-Mestizo population of the North of the country, which has a high Caucasian component.

Analysis of CYP450 gene allelic variants can predict ifosfamide toxicity in Mexican paediatric patients.

Context: Ifosfamide (IFA) is an effective antineoplastic for solid tumours in children, although it is associated with high levels of systemic toxicity and causes death in some cases. Objective: The aim of this study was to determine whether the presence of certain allelic variants of genes CYP2B6, CYP2C9, CYP3A4 and CYP3A5 increases the risk of toxicity in children with solid tumours treated with ifosfamide.Materials and methods: A total of 131 DNA samples were genotyped by real-time polymerase chain reaction (RT-PCR) using TaqMan probes. Toxicity was assessed using WHO criteria, and survival analysis was performed using Kaplan-Meier curves.Results: The rs3745274 allelic variant in CYP2B6 was associated with haematological toxicity, affecting neutrophils; CYP3A4 variant rs2740574 was also associated with toxicity, affecting both leukocytes and neutrophils. Additionally, the CYP3A5 gene variant rs776746 was found to affect haemoglobin.Conclusions: Our results show that allelic variants rs3745274 (CYP2B6), rs2740574 (CYP34) and rs776746 (CYP3A5) increase the risk for high haematological toxicity.Clinical trial registration: 068/2013.

Comorbidity Index as a Predictor of Mortality in Pediatric Patients With Solid Tumors.

Purpose: The objective of this study was to determine whether a comorbidity index could be used to predict mortality in pediatric patients with chemotherapy-treated solid tumors. Methods: Pediatric patients who underwent chemotherapy treatment for solid tumors were included, and demographic, clinical, and comorbidity data were obtained from patient electronic records. Results: A total of 196 pediatric patients with embryonic solid tumors were included. Metastatic tumors were the most frequently observed (n = 103, 52.6%). The most common comorbidities encountered for the Charlson comorbidity index (CCI) were cellulitis (n = 24, 12.2%) and acute renal failure (n = 15, 7.7%). For the Pediatric Comorbidity Index (PCI), the most frequent comorbidities were pneumonia and sepsis, with n = 64 (32.7%) for each. We evaluated established the prognostic values for both indexes using Kaplan-Meier curves, finding that the CCI and PCI could predict mortality with p < 0.0001. Conclusion: Using the PCI, we observed 100% survival in patients without comorbidities, 70% survival in patients with a low degree of comorbidity, and 20% survival in patients with a high degree of comorbidity. Greater discrimination of probability of survival could be achieved using degrees of comorbidity on the PCI than using degrees of comorbidity on the CCI. The application of the PCI for assessing the hospitalized pediatric population may be of importance for improving clinical evaluation.

[Factors involved in host-pathogen interaction for the risk of Hodgkin lymphoma induced by Epstein Barr virus]. / Factores que participan en la interacción huésped-agente patógeno en el riesgo de Linfoma de Hodgkin inducido por el virus Epstein Barr.

Hodgkin lymphoma (HL) is a neoplasm characterized by malignant cells called Reed Sternberg and Hodgkin's cells in the lymphatic system. Such cells comprise 1% of the tumor while the remainder is made up of lymphocytes, histiocytes, eosinophils and plasma non-neoplastic cells. The annual global incidence of HL is 3-10/100,000 inhabitants and is most commonly found in young adults. The mechanism by which cell transformation is accomplished is not entirely clear; however, some evidences suggest that oncogenic viruses like the Epstein Barr virus (EBV) may have a high impact on the pathogenesis of lymphoproliferation. Genetic and environmental factors could be involved, since it has been found a high incidence of HL among members of the same family. In Mexico, there have been studies to determine the prevalence of EBV in patients with HL and found the presence of this virus in up to 64.2% of the cases. EBV has been detected in the Reed Sternberg cells and Hodgkin cells in 50% of cases of classical HL. There is not a satisfactory explanation for this, but it has been proposed that geographic and immunological variabilities play a role in the positivity of EBV in HL. However, despite recent advances in the field, there is insufficient evidence to show a clear association between host factors, environment and pathogens, and the risk of lymphoproliferation leading to the development of HL. This review aims to give an overview about the risk factors that influence the interaction of host, pathogens and environment in the etiology of HL.

Factores que participan en la interacción huésped-agente patógeno en el riesgo de Linfoma de Hodgkin inducido por el virus Epstein Barr / Factors involved in host-pathogen interaction for the risk of Hodgkin lymphoma induced by Epstein Barr virus

El linfoma de Hodgkin (LH) es una neoplasia del sistema linfático. La incidencia mundial anual del LH es de 3-10/100,000 habitantes. El mecanismo mediante el cual se lleva a cabo la transformación celular no es completamente claro; sin embargo, algunas evidencias parecen indicar que ciertos virus oncogénicos como el virus Epstein Barr (VEB), pueden tener alto impacto en la patogénesis de la linfoproliferación. También algunos factores genéticos y ambientales pueden estar involucrados, pues se ha encontrado una alta incidencia de casos de LH entre individuos de una misma familia que comparten características genéticas y conviven en un mismo ambiente. En México se han realizado estudios encaminados a conocer la prevalencia del VEB en pacientes con LH y se ha encontrado la presencia de este virus hasta en el 64,2%. El VEB ha sido detectado en las Células Reed Sternberg (CRS) y en Células de Hodgkin (CH) en el 50% de los casos de LH clásico. No se ha dado hasta ahora una explicación satisfactoria, pero se ha propuesto que la variabilidad geográfica y la variabilidad inmunológica desempeñan un papel determinante en la positividad del VEB en LH. A pesar de los avances que hasta ahora se tienen, no existen suficientes evidencias que permitan establecer una clara asociación entre los factores del huésped, el medio ambiente y el agente patógeno en el riesgo de la linfoproliferación que conduce al desarrollo de LH. La presente revisión tiene como objetivo analizar algunos de los factores de riesgo que influyen durante la interacción huésped, agente patógeno y medio ambiente en la etiología del LH.

Hodgkin lymphoma (HL) is a neoplasm characterized by malignant cells called Reed Sternberg and Hodgkin’s cells in the lymphatic system. Such cells comprise 1% of the tumor while the remainder is made up of lymphocytes, histiocytes, eosinophils and plasma non-neoplastic cells. The annual global incidence of HL is 3-10/100,000 inhabitants and is most commonly found in young adults. The mechanism by which cell transformation is accomplished is not entirely clear; however, some evidences suggest that oncogenic viruses like the Epstein Barr virus (EBV) may have a high impact on the pathogenesis of lymphoproliferation. Genetic and environmental factors could be involved, since it has been found a high incidence of HL among members of the same family. In Mexico, there have been studies to determine the prevalence of EBV in patients with HL and found the presence of this virus in up to 64.2% of the cases. EBV has been detected in the Reed Sternberg cells and Hodgkin cells in 50% of cases of classical HL. There is not a satisfactory explanation for this, but it has been proposed that geographic and immunological variabilities play a role in the positivity of EBV in HL. However, despite recent advances in the field, there is insufficient evidence to show a clear association between host factors, environment and pathogens, and the risk of lymphoproliferation leading to the development of HL. This review aims to give an overview about the risk factors that influence the interaction of host, pathogens and environment in the etiology of HL.

[Clinical pathological study of craniopharyngioma. Fifteen years at the National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez"]. / Craneofaringioma, estudio clínico-patológico. Quince años del Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez".

BACKGROUND: Craniopharyngioma is a sellar region benign cyst It's frequency ranges from 1.2% to 4.6% of all brain tumors. OBJECTIVE: To carry out a clinical pathological correlation of craniopharyngioma among adults and describe the tumor's biological characteristics. METHODS: We included 115 craniopharyngiomas; 100 were adamantimomatous and 15 were papillary type. Patient's age range was 15-90 years (mean 52.5 yrs); 54 (47%) were males and 61 (53%) females. The most frequent location was the supraselar region in 49 (42.6%) of cases. Total exeresis was performed in 72 patients (62.6%) and partial exeresis in 43 (37.4%). RESULTS: We noted a recurrence among 50 patients (43%), of which 5/15 were papillary and 45/100 adamantinomatous. The mean patient age for recurrent tumors was 50.46+/-14.13yrs and 48.65+/-11.95 for non recurrent tumors. Thirteen patients died (11.3%). We observed a statistical correlation between recurrence, exeresis (p=0.014), and death (p=0.047). Follow-up was longer among females than males and in suprasellar tumor location, papillary type, external epithelium cysts and laxo stellate reticulum. CONCLUSIONS: However a good prognostic factor in craniopharyngiomas was observed in older female patients with complete exeresis, small tumors, external epithelium cysts, edematous stroma, inflammation, and absence of atypical cell and mitosis.

Respuesta al tratamiento antituberculosis en pacientes con historia de tratamientos previos en el Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas / Response to antituberculous therapy in patients previously treated for TB at the National Institue for Respiratory Diseases Ismael Cosío Villegas

Antecedentes y objetivos: El Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), como centro de referencia nacional de enfermedades respiratorias, recibe pacientes con tuberculosis pulmonar (TBp) que ya han recibido múltiples tratamientos. El objetivo de este estudio fue evaluar los resultados del tratamiento antituberculosis en pacientes previamente tratados que fueron supervisados por el INER durante un nuevo retratamiento. Métodos: Estudio retrospectivo con análisis de los expedientes clínicos mediante un cuestionario estandarizado de los pacientes con TBp con antecedente de tratamiento previo, y cuyo nuevo tratamiento fue supervisado en el INER de 1994-2001. La respuesta al tratamiento fue analizada de acuerdo al número de tratamientos previos, al antecedente de fracaso al tratamiento antes de ingresar al INER, y de acuerdo a la presencia o no de tuberculosis multifarma-corresistente (TB-MFR). Resultados: Se incluyeron a 147 pacientes diagnosticados con TBp que habían recibido tratamiento previo. Las tasas de curación en el INER para los pacientes con uno, dos y tres o más tratamientos previos fueron 68.2%, 40.4%, 8.8% (p = 0.009); de abandono 6.8%, 4.3%, 3.1% (p = 0.7) y de fracaso 18.2%, 27.7%, 25.0% (p = 0.6) para cada uno de los grupos, respectivamente. La proporción de TB-MFR fue de 64.4% 86.3% y 94.4% en cada grupo (x² de tendencia, p = 0.0004). El fracaso previo fue predictor independiente de fracaso actual [RM = 2.4 (IC95% 0.9-6.4) p = 0.04]. Las tasas de curación de acuerdo al patrón de resistencia fueron: monorresistencia 71.4%; multifarmaco-rresistencia 44.9% y polirresistencia 30.8%, (x² de tendencia, p = -03). Conclusiones: En pacientes con TBp con múltiples tratamientos previos y que recibieron un retratamiento supervisado por el INER, hubo bajas tasas de curación, una proporción persistente de fracasos al tratamiento y una alta tasa de TB-MFR.

Background: The National Institute of Respiratory Diseases Ismael Cosío Villegas (INER) is a national third level referral center for all respiratory diseases, including multitreaded pulmonary tuberculosis patients (PTb). The purpose of this study was to evaluate the results of supervised PTb retreatment at the INER in patients previously treated for PTb. Methods: Retrospective review of clinical charts by a standardized questionary of previous treated PTb patients and whose new treatment was given and supervised al the INER from 1994 to 2001. The response was analyzed according to the number of previous treatments, history of failure to previous treatments and presence or absence of MDR PTb. Results: One hundred and forty seven patients had previously received treatment for PTb. The cure rates for patients with one, two, three or more previous PTb treatments were 68.2%, 40.4%, and 8.8% (p = 0.009); desertion 6.8%, 4.3%, and 3.1% (p = 0.7); failure 18.2%, 27.7%, and 25 % (p = 0.6) for each one of the groups, respectively. The proportion of MDR- PTb was 64.4%, 86.3%, and 94.4% in each group (X² trend, p = 0.0004). A previous treatment failure was a predictor of failure of treatment at the INER [OR = 2.4 (CI95% 0.9-9.64), p = 0.04]. According to resistance, cure rates were 71.4% for one drug resistance, MDR 44.9% and poly resistance 30.8% (X² trend, p= -03). Conclusions: For patients with one or more failed previous treatments for PTb, receiving a new supervised treatment regime at the INER, there were low cure rates, a high proportion of treatment failures and a high rate of MDR-PTb.

Aspectos metodológicos y éticos de la farmacogenómica en los ensayos clínicos aleatorizados / Contributions of pharmacogenomics to enhance the efficiency of randomized clinical trials

One of the greatest advances of the modern medicine has been the report of the complete sequence of the human genome. This has brought as a consequence an evolution in the design of the clinical research, in special of the randomized clinical trials (RCTs). The pharmacogenomics, a powerful tool for the prediction of pharmacological effects based on the genotype of the studied subjects, promises to be very useful next years for the development of the pharmaceutical industry. With the present integration of the pharmacogenomical methods to the investigation and development of new medicines it may start a new era in the medical prescription producing more individualized therapies, reduction of adverse events in the patients and in addition a faster development of new medicines in a more cost-effective way. Nevertheless new methodological, ethical and social challenges appear that will have to be solved simultaneously, to allow a legal use of the vast information generated by the genetic information.

Uno de los mayores avances de la medicina moderna se ha dado con el reporte en borrador de la secuencia del genoma humano. Esto ha traído como consecuencia nuevas opciones en el diseño de la investigación clínica, en especial en los ensayos clínicos aleatorizados (ECAs). La farmacogenómica que ha emergido como una herramienta poderosa para la predicción de efectos farmacológicos basados en el genotipo de los sujetos estudiados, promete ser de gran utilidad en los próximos años para el desarrollo de la industria farmacéutica. Cabe destacar que la integración actual de los métodos de la farmacogenómica a la investigación y desarrollo (I&D) de nuevos medicamentos, ofrece la perspectiva de una nueva era en la prescripción médica, con terapias más individualizadas, disminución de eventos adversos en los pacientes y además un desarrollo más rápido y costo-efectivo de nuevos medicamentos. Sin embargo, la aplicación de la farmacogenómica a la investigación clínica representa nuevas interrogantes metodológicas, éticas y sociales que tendrán que desarrollarse de igual manera, para permitir un uso legal de la información generada por los ECAs que incorporan información genética.

Implicaciones de los polimorfismos de un solo nucleótido en Mycobacterium tuberculosis y humanos en el manejo clínico de la tuberculosis / Implication of single nucleotide polymorphisms in Mycobacterium tuberculosis and humans in the clinical management of tuberculosis

Se analizan estudios de los polimorfismos genéticos de Mycobacterium tuberculosis asociados a resistencia y transmisión, así como los polimorfismos genéticos en humanos con asociación a gravedad y formas clínicas de la enfermedad y toxicidad hepática al tratamiento antituberculosis, y su utilidad en el estudio de los pacientes con tuberculosis multifarmacorresistente. Los nuevos métodos que ofrece la medicina geómica para la investigación en tuberculosis permiten sugerir nuevos criterios de aplicación inmediata en el manejo clínico de los pacientes con tuberculosis, en la evaluación de la eficacia de la terapéutica y en la prevención de eventos adversos para el paciente. Por ello, es importante evaluar el costo-beneficio de esta herramienta para fortalecer los centros de atención a pacientes con tuberculosis en países en desarrollo donde existen elevadas tasas de la enfermedad.

We review studies of Mycobacterium tuberculosis genetic polymorphisms associated to resistance and transmission; also, the genetic polymorphisms associated to severity and clinical presentation of human tuberculosis (TB) and hepatic toxicity associated to antituberculosis treatment. We discuss its usefulness in studies of patients with multidrug resistant TB. The new methods of genomic medicine suggest new criteria for immediate application in TB management, the evaluation of treatment efficacy and the prevention of patient complications. It is important to appraise cost-benefit of this tool to improve TB medical care centers from developing countries with high rates of TB.