Population pharmacokinetics of levetiracetam in neonates with seizures.

WHAT IS KNOWN AND OBJECTIVE: This study developed a population pharmacokinetic (PK) model of levetiracetam (LEV) for treating neonatal seizures (NS) and determined the influence of clinically relevant covariates to explain the interindividual variability and residual error. METHODS: Twenty newborns admitted to the Neonatal Intensive Care Unit at the Hospital Central "Dr. Ignacio Morones Prieto" were included. LEV doses were administered by intermittent infusion. Blood samples were drawn 3 times post-infusion. Levetiracetam was quantified by a chromatographic technique. NONMEM software was used to determine the population PK model of LEV in neonates and the influence of clinical covariates on drug disposition. RESULTS AND DISCUSSION: The LEV PK in neonates is described by a one-compartment open model with first-order elimination. The influence of creatinine clearance (CRCL) and body weight (BW) on clearance (CL[L/h] = 0.47*CRCL), as well as the volume of the distribution (Vd[L] = 0.65*BW) of LEV, were confirmed, considering interindividual variabilities of 36% and 22%, respectively, and a residual error of 13%. WHAT IS NEW AND CONCLUSION: Based on the PK of LEV in neonates and the influence of the final PK model, a priori dosing guidelines are proposed considering CRCL, BW and LEV plasma concentrations between 6 and 20 mg/L for NS treatment.

Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia.

Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m(-2)) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ⩾ 3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 µmol l(-1), P<0.008), this could reflect an increased MTX uptake in mucosal cells of patients with mucositis. From 17 single-nucleotide polymorphisms in the MTX pathway, only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis (AA (39%) vs AG/GG (15%), P=0.016). We found no evidence that erythrocyte folate levels mediate in the association between the rs7317112 and mucositis.

The need for re-TUR of the bladder in non-muscle invasive bladder cancer: risk factors of tumor persistence in re-TUR specimens.

AIM: This study evaluated the need for re-TUR of the bladder in non-muscle invasive bladder cancer (NMIBC) with complete transurethral resection (TUR) and examined the risk factors for disease occurrence in re-TUR of the bladder. METHODS: A cohort of 211 patients diagnosed consecutively of NMIBC (July 2009 to October 2011) underwent re-TURB 4-6 weeks after the initial TURB. Association with tumor presence in re-TURB of the following parameters was analyzed: sex, primary/recurrent, number, size, stage, grade, association of carcinoma in situ, early instillation of Mitomycin C, and its classification according to the EORTC risk groups. RESULTS: Fifty-seven (27%) cases exhibited residual tumors in the re-TURB and understaging was observed in 3 (1.4%) patients. The EORTC classified 151 (71.6%) patients as high risk; 124 (58.7%) patients received postoperative instillations of Mitomycin C. 31.8% of high risk patients exhibited tumors in the re-TUR compared to 14% of the low/intermediate risk (P<0.05). A total of 19.4% of patients with early instillation of Mitomycin C had tumor in re-TURB compared to 38.4% of patients without it (P<0.05). Multivariate analysis showed that high-risk tumors behaved as an independent risk factor for the tumor presence in re-TURB (HR=12.65, P=0.008), but early postoperative instillation of Mitomycin C was a protective factor (HR=2.16, P=0.02). The limitations of the study are the absence of randomization and its unicentric character. CONCLUSION: Patients who were at a high risk of tumor recurrence and/or progression according to the EORTC classification exhibited a higher percentage of tumors in re-TURB. Therefore, these patients are optimal candidates for re-TURB.

A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia.

Methotrexate (MTX) is an important component of therapy used to treat childhood acute lymphoblastic leukemia (ALL). Two single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, affect MTHFR activity. A large body of studies has investigated the potential role of MTHFR SNPs in MTX toxicity in pediatric ALL. However, the results are controversial. In this review and meta-analysis, we critically evaluate the relationship between the C677T and A1298C polymorphisms of MTHFR and MTX toxicity in pediatric ALL. The majority of published reports do not find associations between MTHFR polymorphisms and toxicity in pediatric ALL. When associations are reported, often the results are contradictory to each other. The meta-analysis confirms a lack of association. In conclusion, MTHFR, C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity in pediatric ALL.

Individualised analgesia, sedation, delirium and comfort management strategies in the ICU: a narrative review.

This group is a product of the collaboration agreement signed by SOMIAMA (Sociedad de Medicina Intensiva de Madrid) and SAR MADRID (Sociedad de Anestesiología, Reanimación y Terapéutica del Dolor de Madrid) under which the organisations agreed to create joint working groups to improve critical patient care. Pain, discomfort, agitation, and delirium cause suffering, delay discharge, and can lead to serious complications in patients admitted to medical and surgical critical care units and post-anaesthesia care units. The main objectives in this type of unit include: Ensuring the comfort of patients suffering or recovering from a critical illness.Avoiding complications associated with the measures, particularly pharmacological, taken to ensure that comfort.

Impossible bladder catheter removal. What can we do?

OBJECTIVE: The inability to remove a bladder catheter due to impossible balloon removal is a situation with controversial management; there are no action guidelines and it is limited to individual experience in most cases. In this article, we review the techniques described for removing a urethral catheter and we share our experience with one case. METHODS: A 70-year-old male with permanent bladder catheter was referred to the emergency department due to an inability to deflate the self-retaining balloon during routine change in his health centre. RESULTS: After unsuccessfully trying to puncture the balloon through the inflation channel previously cut above the valve, we punctured it via the suprapubic route under ultrasound guidance with a biopsy needle. Using this technique, we managed to rupture the balloon without free fragments, enabling the catheter to be changed without incident. CONCLUSIONS: There are various techniques for approaching this situation, the knowledge of which enables the urologist to resolve the problem by adapting to patient's characteristics and available resources. Suprapubic puncture of the self-retaining balloon is an easily reproducible technique with minimal complications and a lower rate of free fragments.

[Prevalence of cardiometabolic risk in a national sample of Costa Rican youth using the waist-height anthropometric indicator]. / Prevalencia de riesgo cardiometabólico en una muestra nacional de jóvenes costarricenses utilizando el indicador antropométrico cintura-estatura.

Central obesity is known as an indicator of cardiometabolic risk, but better anthropometric measures than Body Mass Index (BMI) are needed to detect it. Waist-to-height ratio (WHtR) is an indicator of central adiposity and a strong predictor of cardiometabolic risk. OBJECTIVE: To determine the pre valence of cardiometabolic risk in a representative sample of Costa Rican children and adolescents. PATIENTS AND METHOD: Cross-sectional and descriptive study carried out with 2,684 students from 64 educational centers in Costa Rica. Validated questionnaires were applied to the students and their weight, height, and waist circumference were determined. Weight and body fat percentage of the students were determined with a Tanita model SC-331 S (without column). Height was measured with a SECA stadiometer model 217. The abdominal circumference was estimated using a tape mea sure. BMI and WHtR were calculated for each participant. The behavior of the indicator WHtR was analyzed with logistic regression models. All procedures were approved by the Ethics Committee of INCIENSA. RESULTS: There was a strong and positive correlation between waist circumference and BMI (r = 0.748, p < 0.001, 56% of shared variance), and a positive and moderate correlation between WHtR and BMI (r = 0.611, p < 0.01, 37% of shared variance). CONCLUSIONS: A third part of the stu dent population of elementary, middle, and high schools (31.8%) is at cardiovascular and metabolic risk.

Removal of methyl parathion in water, by Dugesia dorotocephala.

The aim of this study was to determine the efficiency of Dugesia dorotocephala on Methyl parathion removal. An initial concentration of 1.25 microg mL(-1) of MeP was used to evaluate the removal capacity of planarian. A first-order removal kinetics was obtained with a disappearance rate constant (k(r)) of 0.49 days(-1) and 69% efficiency on contaminant removal. This is significantly different (p < 0.5) from the degradation occurring in control systems, leading us to conclude that D. dorotocephala effectively removes MeP from contaminated water.

Conformal prediction of HDAC inhibitors.

The growing interest in epigenetic probes and drug discovery, as revealed by several epigenetic drugs in clinical use or in the lineup of the drug development pipeline, is boosting the generation of screening data. In order to maximize the use of structure-activity relationships there is a clear need to develop robust and accurate models to understand the underlying structure-activity relationship. Similarly, accurate models should be able to guide the rational screening of compound libraries. Herein we introduce a novel approach for epigenetic quantitative structure-activity relationship (QSAR) modelling using conformal prediction. As a case study, we discuss the development of models for 11 sets of inhibitors of histone deacetylases (HDACs), which are one of the major epigenetic target families that have been screened. It was found that all derived models, for every HDAC endpoint and all three significance levels, are valid with respect to predictions for the external test sets as well as the internal validation of the corresponding training sets. Furthermore, the efficiencies for the predictions are above 80% for most data sets and above 90% for four data sets at different significant levels. The findings of this work encourage prospective applications of conformal prediction for other epigenetic target data sets.

Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia.

The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 × 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 × 10-5, model with SNPs HR=1.31, P=0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.

Methyl parathion toxicity to and removal efficiency by Typha latifolia in water and artificial sediments.

Methyl parathion (MeP) is a very hazardous pesticide freely used in agriculture in Mexico. This pesticide and others, arriving through different processes, exert significant effects on water quality with serious consequences for environmental and human health. This study evaluates the removal efficiency of common cattail Typha latifolia L. on MeP in water and artificial sediments. The effects of the pesticide on this macrophyte after 10 days of exposure were determined using a concentration range of 0-200 mg l(-1), 198.1+/-1.79 g average biomass, pH 7.0, 18-22 degrees C temperature and natural daylight/darkness periods, using chlorophyll production as a biomarker. Removal kinetics were conducted under similar conditions on days 0, 3, 7, 9, 11 and 14 of exposure, using 6 mg l(-1) in each system. Pesticide concentration, chlorophyll content and glutathione S-transferase (GST) activity were quantified. Results show a high removal efficiency of cattails on MeP in water and sediments relative to controls. An increase in GST activity and a decline in chlorophyll content in the test systems were not significantly different relative to controls. Cattails may thus be a good candidate for development of a phytoremediation system for MeP-contaminated water and artificial sediments.

ENVIRONMENTAL AUDITING: Change in Fish Fauna as Indication of Aquatic Ecosystem Condition in Río Grande de Morelia-Lago de Cuitzeo Basin, Mexico.

/ The Río Grande de Morelia-Lago de Cuitzeo basin in west central Mexico has experienced major increases in water pollution from a rapidly growing human population. We examined changes in the long-term distribution of fishes in relation to water quality and quantity in order to assess the condition and health of aquatic ecosystems inthe basin. Sampling between 1985 and 1993 revealed that five (26%) of the 19 native fish species known from the basin had been extirpated. Two of these were endemics, Chirostoma charari and C. compressum, and they are presumed extinct. Twelve (63%) of the remaining species had declines in distribution. Sixteen (80%) of the 20 localities sampled had lost species. The greatest declines occurred in Lago de Cuitzeo proper and in the lower portion of the Río Grande de Morelia watershed. Species losses from the lake were attributable to drying and hypereutrophication of the lake because of substantial reductions in the amount and quality of tributary inputs, whereas losses from the Río Grande de Morelia watershed were the result of pollution from agricultural, municipal, and industrial sources, especially in the region around the city of Morelia. Three localities in the upper portion of the Río Grande de Morelia watershed-Cointzio reservoir, La Mintzita spring, and Insurgente Morelos stream-contained most of the remaining fish species diversity in the basin and deserve additional protection. Fish faunal changes indicated major declines in the health of aquatic ecosystems in the Morelia-Cuitzeo basin.KEY WORDS: Fish distribution; Río Lerma; Ecosystem health; Water quality; Chirostoma; Threatened and endangered specieshttp://link.springer-ny.com/link/service/journals/00267/bibs/24n1p133.html

[Toxic effect of DDT, chlordane and water from the Ignacio Ramírez dam (Mexico), on Daphnia magna (Crustacea: Daphnidae)]. / Efecto tóxico del DDT, clordano y agua de la presa Ignacio Ramírez (México), sobre Daphnia magna (Crustacea: Daphnidae).

Chlorodiphenylnitrichloroethane (DDT) and chlordane (CLO) are currently used in Mexico to control malaria and termites. From 1990 to 1996 a total of 27 ton of DDT and 508 of CLO were imported. We establish a methodology to determine their environmental impact in a Mexican dam (Ignacio Ramírez). The toxic effect of DDT and CLO were evaluated on the o-demethylase (OD) and acethycholinesterase activities (AchA) of the cladoceran Daphnia magna exposed to different concentrations of the insecticides solved in water from three sites. Their effect on the AchA and OD activities, and so the CL50 were used as exposure bioindicators to determine the more polluted sites. The physicochemical characteristics of water and the biodiversity of the dam test sites were considered. The station near the floodgate has toxicity potential because enzymatic activities were modified. We suggest the use of AchA and OD activities measure in the cladoceran to evaluate the toxicity of a water body polluted by organochlorate insecticides.

Gill and liver histopathology in Goodea atripinnis Jordan, related to oxidative stress in Yuriria Lake, Mexico / Histopatología en las branquias e hígado de Goodea atripinnis Jordan, relacionada con el estrés oxidativo en la Laguna Yuriria, México

In aquatic ecosystems, the complex mixture of pollutants may mediate the formation of free radicals and cause oxidative damage to the biota. Yuriria Lake (a Ramsar site in Central Mexico) receives input of wastewater from its tributaries, agricultural runoff, and municipal discharge. We studied the lipid peroxidation (LPO), antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and histopathology of gill and liver of the native fish Goodea atripinnis in Yuriria Lake. Results were compared to a control group of fish cultivated in the laboratory. LPO, SOD, and CAT showed no significant differences compared to controls, but GPx showed greater and significant differences in both tissues. Three class sizes were identified; organisms of classes I and II had slight vasocongestion in the liver as compared to controls. Hepatocytes of class III showed cytoplasmic vacuolization, cellular disorganization, and the liver showed marked fibrosis compared to controls. Gills of controls and classes I and II showed no damage in gill filaments. Tissue damage in class III included hypertrophy, loss of the typical morphology, and edema in the gill filaments. The longer exposure of older organisms to Yuriria Lake conditions may have resulted in their poorer health condition...

En los ecosistemas acuáticos, la mezcla compleja de contaminantes presente puede mediar la producción de radicales libres y causar daño por estrés oxidativo a la biota. La laguna de Yuriria (sitio RAMSAR en la parte central de México) recibe aguas residuales de sus afluentes, escorrentías agrícolas y descargas municipales. Se estudió la peroxidación lipídica (LPO), las enzimas antioxidantes superóxido dismutasa, (SOD), catalasa (CAT) y glutatión peroxidasa (GPx); y la histopatología de las branquias e hígado del pez nativo Goodea atripinnis en la Laguna de Yuriria. Los resultados obtenidos fueron comparados con un grupo control de peces cultivados en laboratorio. La LPO, SOD y CAT no mostraron diferencia significativa en comparación con los controles; pero la GPx mostró diferencias significativas para ambos tejidos. Se identificaron tres clases de talla; los organismos de la clase I y II tuvieron una ligera vasocongestión en el hígado en comparación con los controles. Los hepatocitos de la clase III mostraron vacuolización citoplásmica, desorganización celular y el hígado mostró una marcada fibrosis. Las branquias de los organismos control y de las clases I y II no mostraron daño en sus filamentos. El daño tisular en los organismos de la clase III incluyó hipertrofia, pérdida de la morfología típica y edema en los filamentos branquiales. La exposición prolongada a las condiciones de la Laguna de Yuriria pudo haber influido en el precario estado de salud de los organismos más longevos...

Response to clomiphene citrate in the polycystic ovarian syndrome according to different LH/FSH ratios.

Twenty-nine clomiphene tests were carried out, 19 on subjects with polycystic ovarian syndrome (PCO) who did not wish to conceive and 10 on women with correct ovarian function (control women). The intention was to determine if the response of the hypothalamic-pituitary-ovary axis varies according to different LH/FSH ratios. The results indicate that with repeated LH/FSH ratios of less than 3, the positive and negative feedback systems are preserved in most subjects, but when the ratio is higher than 3, both systems are significantly altered (P less than 0.01). In the control group, both systems were preserved in all subjects. In another group composed of 26 infertile patients with PCO, the rate of ovulation and pregnancy after administration of clomiphene citrate (CC) was correlated according to different LH/FSH ratios. A significant (P less than 0.0001) reduction in the rate of ovulation and a lesser reduction in pregnancy was found with increasing LH/FSH ratios. In conclusion we suggest that the LH/FSH ratio is a good marker of this syndrome, and can be used to give a prognosis on the severity of the syndrome, as well as the ovulatory capacity of the subject after administration of CC.

Hemoglobin concentration and acetylcholinesterase activity of oligochaetes in relation to lead concentration in spiked sediments from Ignacio Ramirez reservoir.

This paper presents toxicity and uptake data of Limnodrilus hoffmeisteri generated by lead in systems using natural sediments from Ignacio Ramírez reservoir. Lead uptake, hemoglobin concentration, and acetylcholinesterase activity were studied in L. hoffmeisteri exposed to spiked sediments. All assays of lead uptake were conducted using whole sediments. Sediment texture was also considered. Acetylcholinesterase activity and hemoglobin concentration decreased after treatment with lead. Acetylcholinesterase activity and hemoglobin concentration tests indicated a response to the concentration of lead. These results suggest the usefulness of a diversity of bioassays to evaluate the toxicity of sediments polluted with heavy metals.