Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial.

BACKGROUND: Treatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors. METHODS: We conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration. RESULTS: Overall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies. CONCLUSIONS: Intravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02028117.

Antibiotic selection in the treatment of acute invasive infections by Pseudomonas aeruginosa: Guidelines by the Spanish Society of Chemotherapy / Elección del tratamiento antibiótico en la infección invasiva aguda por Pseudomonas aeruginosa: Guía de la Sociedad Española de Quimioterapia

Pseudomonas aeruginosa is characterized by a notable intrinsic resistance to antibiotics, mainly mediated by the expression of inducible chromosomic β-lactamases and the production of constitutive or inducible efflux pumps. Apart from this intrinsic resistance, P. aeruginosa possess an extraordinary ability to develop resistance to nearly all available antimicrobials through selection of mutations. The progressive increase in resistance rates in P. aeruginosa has led to the emergence of strains which, based on their degree of resistance to common antibiotics, have been defined as multidrug resistant, extended-resistant and panresistant strains. These strains are increasingly disseminated worldwide, progressively complicating the treatment of P. aeruginosa infections. In this scenario, the objective of the present guidelines was to review and update published evidence for the treatment of patients with acute, invasive and severe infections caused by P. aeruginosa. To this end, mechanisms of intrinsic resistance, factors favoring development of resistance during antibiotic exposure, prevalence of resistance in Spain, classical and recently appeared new antibiotics active against P. aeruginosa, pharmacodynamic principles predicting efficacy, clinical experience with monotherapy and combination therapy, and principles for antibiotic treatment were reviewed to elaborate recommendations by the panel of experts for empirical and directed treatment of P. aeruginosa invasive infections (AU)

Pseudomonas aeruginosa se caracteriza por una notable resistencia intrínseca a los antibióticos mediada fundamentalmente por la expresión de β-lactamasas cromosómicas inducibles y la producción constitutiva o inducible de bombas de expulsión. Además de esta resistencia intrínseca, P. aeruginosa posee una extraordinaria capacidad para desarrollar resistencia a prácticamente todos los antimicrobianos disponibles a través de la selección de mutaciones. El aumento progresivo de la resistencia en P. aeruginosa ha llevado a la aparición de cepas que, de acuerdo con el grado de resistencia frente a los antibióticos habituales, se han definido como multirresistentes, extensamente resistentes y panresistentes. Estas cepas se están diseminando mundialmente, complicando progresivamente el tratamiento de las infecciones por P. aeruginosa. En este escenario, el objetivo de las presentes recomendaciones es la revisión y puesta al día de la evidencia publicada para el tratamiento de pacientes con infección aguda, invasiva y grave por P. aeruginosa. Con este fin, se han revisado los mecanismos de resistencia intrínseca, factores que favorecen el desarrollo de resistencia durante la exposición a antibióticos, prevalencia de la resistencia en España, antibióticos clásicos así como los de reciente introducción activos frente a P. aeruginosa, principios farmacodinámicos predictores de eficacia, experiencia clínica con tratamientos en monoterapia o terapia combinada y principios del tratamiento antibiótico para elaborar por un panel de xpertos recomendaciones para el tratamiento empírico o dirigido de infecciones invasivas por P. aeruginosa (AU)

Impact of the feedback provided by a gastric electrical stimulation system on eating behavior and physical activity levels.

OBJECTIVE: The closed-loop gastric electrical stimulation (CLGES) abiliti® system provides tailored gastric electrical stimulation activated by food entry into the stomach and sensor-based data to medical professionals. The aim of this study was to analyze behavior changes using sensor-based food intake and activity data in participants treated with the CLGES system. METHODS: Food intake and activity data (3D accelerometer) were downloaded at baseline and monthly/bimonthly for 12 months in a subset of patients with obesity (N = 45) participating in a multicenter trial with CLGES. Measured food intake parameters included the number of intakes during allowed and disallowed periods, nighttime intakes, and between-meal snacks (average/d). Activity parameters included time in different levels of physical activity (min/d), sleep/sedentary (h/d), and estimated energy expenditure (EE). RESULTS: Weight loss at 12 months averaged 15.7 ± 7.7% of the baseline body weight. Stable reduction in the number of disallowed meals and between-meal snacks (P < 0.05), an increase in all levels of physical activity (P < 0.001), and an increase in activity-based EE (303 ± 53 kcal/d on average, P < 0.001) were seen. CONCLUSIONS: Significant improvement in eating and activity was seen in participants. It is hypothesized that feedback of the sensor-based data induced behavioral changes and contributed to weight loss in patients treated with CLGES.

Visceral and somatic pain modalities reveal NaV 1.7-independent visceral nociceptive pathways.

KEY POINTS: Voltage-gated sodium channels play a fundamental role in determining neuronal excitability. Specifically, voltage-gated sodium channel subtype NaV 1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown. Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV 1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling. These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics. ABSTRACT: Voltage-gated sodium channel NaV 1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV 1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV 1.7 knockout mouse (NaV 1.7Nav1.8 ) and selective small-molecule NaV 1.7 antagonist PF-5198007. NaV 1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV 1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV 1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV 1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV 1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV 1.7 (in NaV 1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV 1.7 antagonist PF-5198007. Our data demonstrate that NaV 1.7 (in NaV 1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of NaV 1.7 alone in the viscera may be insufficient in targeting chronic visceral pain.

Pharmacokinetics and Dosing of Ceftobiprole Medocaril for the Treatment of Hospital- and Community-Acquired Pneumonia in Different Patient Populations.

Hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP) are among the most common infections treated in the hospital setting, and together they place a significant burden on healthcare systems. Successful management of HAP and CAP depends on rapid initiation of empirical antibiotic therapy with broad-spectrum antibiotics. Ceftobiprole is a new-generation, broad-spectrum cephalosporin antibiotic for the treatment of HAP (excluding ventilator-associated pneumonia) and CAP. It displays potent in vitro activity against a broad range of pathogens important in pneumonia. This review summarizes the pharmacokinetic profile of ceftobiprole, and considers the pharmacokinetic parameters and pharmacodynamics underlying the choice of dosing regimen. Ceftobiprole shows linear pharmacokinetics after single and multiple doses and is eliminated predominantly through the kidneys. Ceftobiprole is administered as a 500 mg intravenous infusion over 2 h every 8 h, and steady-state concentrations are reached on the first day of dosing. Dose adjustment is recommended for patients with moderate or severe renal impairment and for those with end-stage renal disease. Extending the infusion time of ceftobiprole to 4 h is recommended to optimize drug exposure in critically ill patients with augmented renal clearance. However, there is no need for dose adjustments based on age, sex or ethnicity, or for patients with severe obesity. Population pharmacokinetic modelling and Monte Carlo simulations were used to determine the optimal dosing regimen for ceftobiprole in special patient populations, including paediatric patients. Future studies of ceftobiprole in patients with HAP and CAP would be of interest.

Implantable gastric electric stimulator with automatic daily activity compliance reporting.

In order for any obesity therapy to be successful real behavior change by the individual is required. We present an implantable obesity therapy that combines gastric electrical stimulation for satiety with onboard sensors that provide self-monitoring for the patient and compliance reporting to the clinician. An algorithm for processing data from the onboard three axis accelerometer for use in physical activity monitoring was developed and validated. Four obese patients participated in a study where self-reported sleep and exercise was compared with the events detected by the implanted system, and two commercially available, wearable activity monitors.

Efectividad de la microonda, masoterapia y ejercicios de Williams en pacientes con dolor lumbar / Effectiveness of microwave, massotherapy and Williams exercises in patients suffering from lumbar pain

Fundamento: el dolor lumbar constituye un problema de salud a nivel mundial, su tratamiento constituye un reto en la práctica médica asistencial.Objetivo: evaluar la efectividad de la microonda, masoterapia y ejercicios de Williams en pacientes con dolor lumbar.Método: se realizó un estudio prospectivo experimental en una muestra de 60 pacientes con lumbalgia subaguda y crónica. Se asignaron dos esquemas de tratamiento: uno con microonda combinada con masoterapia y ejercicios de Williams (Grupo A), otro con medicamentos y reposo (Grupo B). Se aplicó la escala analógica visual y la escala de Oswestry en la consulta inicial y al culminar el tratamiento.Resultados: se obtuvieron mejores resultados en el grupo A (estudio) que en el grupo B (control), en cuanto a reducción del dolor e independencia para las actividades de la vida diaria.Conclusiones: el protocolo de tratamiento fisioterapéutico resultó ser beneficioso, pues la recuperación y el alivio del dolor resultaron ser más rápidos y permitió la sustitución de fármacos (AU)

Foundation: low back pain is a health problem all over the world; its treatment is a challenge in medical care practice.Objective: to evaluate the effectiveness of the microwave, massotherapy and Williams exercises in patients suffering from low back pain.Method: an experimental prospective study was carried out on a sample of 60 patients suffering from chronic and subacute low back pain. Two treatment protocols were assigned: one with microwave combined with massotherapy and Williams exercises (Group A) and the other one with medication and rest (Group B). The visual analogue scale and Oswestry scale were applied in the first appointment and at the end of the treatment.Results: group A (study) had better results than group B (control) in reducing pain and in independence for daily activities.Conclusions: the physiotherapy treatment protocol proved to be beneficial, since the recovery and pain relief were quicker and allowed the substitution of drugs (AU)

Increasing yield of nanocrystalline cellulose preparation process by a cellulase pretreatment.

In this work the introduction of a cellulase treatment prior to NCC isolation was assessed. NCC was produced using sulfuric acid at two different concentrations (62 and 64% wt.). The effect of pore size for filtration step was also assessed. The smaller acid dose leaded to yields up to 65-70% and average size up to 160 nm. It also produced crystals with reduced sulfur content (0.6-1%). Cellulase pretreatment influenced NCC characteristics, as it increased overall yield a 12%, increased average particle size around 35 nm and reduced NCC sulfur content up to a 0.8%. We found that different conditions of enzymatic treatments led to quantitative differences on their effects on NCC. Acetate buffer used for enzymatic treatments was found to counteract effects of acid. The evidence presented in this work suggested that pretreating fibers with this cellulase represents a very interesting option to partially replace chemicals on NCC isolation.

Preparation and use of carbonyl-decorated carbenes in the activation of white phosphorus.

Here we present a protocol for the synthesis of two distinct carbonyl-decorated carbenes. Both carbenes can be prepared using nearly identical procedures in multi-gram scale quantities. The goal of this manuscript is to clearly detail how to handle and prepare these unique carbenes such that a synthetic chemist of any skill level can work with them. The two carbenes described are a diamidocarbene (DAC, carbene 1) and a monoamidoaminocarbene (MAAC 2). These carbenes are highly electron-deficient and as such display reactivity profiles that are atypical of more traditional N-heterocyclic carbenes. Additionally, these two carbenes only differ in their electrophilic character and not their steric parameters, making them ideal for studying how carbene electronics influence reactivity. To demonstrate this phenomenon, we are also describing the activation of white phosphorus (P4) using these carbenes. Depending on the carbene used, two very different phosphorus-containing compounds can be isolated. When the DAC 1 is used, a tris(phosphaalkenyl)phosphane can be isolated as the exclusive product. Remarkably however, when MAAC 2 is added to P4 under identical reaction conditions, an unexpected carbene-supported P8 allotrope of phosphorus is isolated exclusively. Mechanistic studies demonstrate that this carbene-supported P8allotrope forms via a [2+2] cycloaddition dimerization of a transient diphosphene which has been trapped by treatment with 2,3-dimethyl-1,3-butadiene.

A phase II trial of first-line sorafenib in patients with metastatic renal cell carcinoma unwilling to receive or with early intolerance to immunotherapy: SOGUG Study 06-01.

AIMS: Our aim was to evaluate first-line treatment of metastatic renal cell carcinoma (mRCC) with sorafenib in patients unwilling to receive immunotherapy or with early intolerance to immunotherapy. PATIENTS AND METHODS: Patients had clear-cell mRCC with good or intermediate risk status, were unsuited to cytokine therapy due to preference or intolerance (based on <4 weeks prior immunotherapy) and had not received antiangiogenic agents. Patients received sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Twenty-six evaluable patients were enrolled at six centres between March and July 2006. The most common metastatic sites were lung and bone; nine patients had one or two metastatic lesions. Median PFS was 7.5 months (95% confidence interval [CI] 5.1-17.5) and overall survival (OS) 15.4 months (95% CI 12.9-17.4). Among 21 patients evaluable for response, 19 (90.5%) experienced disease control (including one complete response; four partial responses; 14 stable disease). The majority of adverse events were grade 1-2 (87.3%). The most common were asthenia (53.0%) and diarrhoea (50.0%). CONCLUSION: In patients with mRCC who were unwilling to receive or intolerant to immunotherapy, treatment with sorafenib led to a high rate of disease control with toxicities that were generally mild and manageable. The PFS achieved in this essentially treatment-naïve population compares favourably with that obtained in the randomised first-line phase II study.

Epigenetic down-regulation of BIM expression is associated with reduced optimal responses to imatinib treatment in chronic myeloid leukaemia.

BACKGROUND: Expression of the pro-apoptotic BCL-2-interacting mediator (BIM) has recently been implicated in imatinib-induced apoptosis of BCR-ABL1(+) cells. However, the mechanisms involved in the regulation of BIM in CML and its role in the clinical setting have not been established. DESIGN AND METHODS: We analysed the mRNA expression of BIM in 100 newly diagnosed patients with CML in chronic phase by Q-RT-PCR and the protein levels by Western blot analysis. Methylation status was analysed by bisulphite genomic sequencing and MSP. CML cell lines were treated with imatinib and 5-aza-2'-deoxycytidine, and were transfected with two different siRNAs against BIM and cell proliferation and apoptosis were analysed. RESULTS: We demonstrated that down-regulation of BIM expression was present in 36% of the patients and was significantly associated with a lack of optimal response to imatinib as indicated by the decrease in cytogenetic and molecular responses at 6, 12 and 18 months in comparison with patients with normal BIM expression (p<0.05). Expression of BIM was mediated by promoter hypermethylation as demonstrated by restoration of BIM expression after treatment of CML cells with 5-aza-2'-deoxycytidine. Using CML cell lines with low and normal expression of BIM we further demonstrated that the expression of BIM is required for imatinib-induced CML apoptosis. CONCLUSION: Our data indicate that down-regulation of BIM is epigenetically controlled by methylation in a percentage of CML patients and has an unfavourable prognostic impact, and that the combination of imatinib with a de-methylating agent may result in improved responses in patients with decreased expression of BIM.

Unusual late-onset Wernicke's encephalopathy following vertical banded gastroplasty.

Wernicke's encephalopathy (WE) related to bariatric surgery is the consequence of thiamine depletion occurring usually after restrictive surgical procedures with gastric outlet impairment causing frequent vomiting. We present a 35-year-old man with body mass index of 47.2 who developed a WE 7 years after a vertical banded gastroplasty. Late stenosis of the outlet due to gastric band inclusion was the precipitating mechanism. Poor compliance of dietary pattern and vitamin supplementation along with episodic vomiting both contributed to progressive symptoms of instable gait and mental changes. Magnetic resonance imaging confirmed the diagnosis of WE by showing hyperintense T2 signals at the mammillary bodies. Recovery of symptoms was possible after early thiamine therapy. Unusual late-onset symptoms and contributing factors to WE are discussed.

Hematopoietic activity of Smilax aristolochiaefolia (zarzaparrilla) in mice with aplastic anemia.

Smilax aristolochiaefolia (Liliaceae) has been used in Mexican traditional medicine for the treatment of tumors, leprosy, anemia and as a tonic for skin infections and anemia. Aplastic anemia (AA) was induced in CD1 mice 8-12 weeks old distributed 10 animals each in Groups VSC, AA, AASa and AAr. Groups AA, AASa and AAr received benzene (2 ml/kg diluted v/v with corn oil) subcutaneously every three days until 20 dosages had been administered. The vehicular solution control group (VSC) received corn oil and the HC group (healthy control) received saline solution. Two days after the last benzene inoculation, groups AA and HC were bled and sacrificed to count blood and bone marrow cells. Group AASa received an aqueous S. aristolochiaefolia (0.4 g/kg) solution orally on days 3, 5 and 7 after the last dosage of benzene, meanwhile group AAr received no treatment after induction of AA (self recovery). On day 9 these groups were bled and sacrificed to count blood and bone marrow cells. Mice with aplastic anemia treated with S. aristolochiaefolia extract, recovered normal platelet levels and nucleated bone marrow cells as compared with the control, but the counts of erythrocytes and leukocyte were lower than controls (p<0.005). The aqueous extract of S. aristolochiaefolia (zarzaparrilla) restores hematopoeisis in the bone marrow of mice with aplastic anemia.

Prurigo nodular tratado con UVB de banda estrecha / Prurigo nodularis treated with narrow band UVB

Paciente femenina de 32 años, con cuadro clínico de cinco años de pápulas y nódulos pruriginosos, desarrollados en la parte distal de las extremidades; las lesiones excoriadas estaban cubiertas por costras y descamación. Se hizo diagnóstico de prurigo nodular confirmado por biopsia. La respuesta a los tratamientos convencionales fue pobre. Se inició fototerapia UVB de banda estrecha con buenos resultados.

Estudio de declaraciones nutricionales y saludables en los alimentos / No disponible

Fundamentos: En el mercado han aparecido en los últimosaños gran número de productos a los que se atribuye unvalor añadido de salud. El objetivo de este trabajo es evaluarsi el etiquetado de declaraciones nutricionales o propiedadessaludables de alimentos presentes en el mercado seajustan a los principios del nuevo Reglamento europeo dedeclaraciones nutricionales.Material y método: Estudio transversal observacional. Endos grandes superficies de Teruel se seleccionaron al azar58 productos de distintas categorías de alimentos en loscuales aparece en su etiquetado al menos una declaraciónnutricional o de propiedades saludables. Se ha analizadoel contenido de las etiquetas atendiendo a la categoría a laque pertenece; alegación y categoría de alegación; nutrienterelacionado con la alegación e información nutricional enrelación con lo dispuesto en la Reglamentación.Resultados: La mayor parte de los productos analizadoscorrespondían a la categoría de lácteos. De las 98 declaracionesidentificadas, el 66,3% correspondían a declaracionesnutricionales y 33,6% a propiedades sobre salud.Las declaraciones nutricionales más frecuentes hacíanalusión a las grasas (18), fibra (10) o vitaminas (10). El21% de las declaraciones nutricionales no se ajustaban ala reglamentación. Las declaraciones sobre salud más frecuenteshacían referencia a las grasas, tránsito intestinal yel control de peso corporal. En la mayor parte de los casosno indican la cantidad que es necesario consumir para lograrel efecto deseado.Conclusiones: Las informaciones nutricionales y de saluden los alimentos funcionales en ocasiones no se ajustan ala reglamentación. Cualquier información debe estar basadaen la transparencia y veracidad de la misma y debe estarbasada en datos científicos contrastados(AU)

Background: A recent years a growing number of productswith a reported healthy plus added value have been placedin the market. The objective of this study is to evaluate ifthe information in the labels of such products regardingnutrition and health claims comply with the new EuropeanRegulations on nutrition claims.Methods: Cross-sectional observational study. A randomsample of 58 products from different food categories availablein two shopping centers in Teruel has been analysed.Labels of these products contained at least one nutritionor health claim. The content of the labels was analysedconsidering the food category of the product, claim andcategory of the claim, nutrient related to the claim andnutrition information according to Regulations.Results: Most of the foods analysed were dairy products.Among the 98 claims identified, 66,3% were nutrition claimsand 33,6% health claims. The most frequent nutritionclaims were related to the fat content (18), fibre (10) orvitamins (10). 21% of the nutrition claims did not complyto the regulations. The most frequent health claims wererelated to fats and health effects, bowel function or bodyweight control. In most cases, no information was providedregarding the amount of product required to achieve thedesired effect.Conclusions: Nutrition and health information in functionalfoods not always is displayed according to regulations.Any information in this product must be true, be based ontransparency and sound scientific evidence(AU)

Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia.

OBJECTIVE: To develop and a priori validate a methotrexate population pharmacokinetic model in children with acute lymphoblastic leukaemia (ALL), receiving high-dose methotrexate followed by folinic acid rescue, identifying the covariates that could explain part of the pharmacokinetic variability of methotrexate. METHODS: The study was carried out in 49 children (aged 6 months to 17 years) who received high-dose methotrexate (3 g/m(2) per course) in long-term treatment. In an index group (37 individuals; 1236 methotrexate plasma concentrations), a population pharmacokinetic model was developed using a nonlinear mixed-effects model. The remaining patients' data (12 individuals; 278 methotrexate plasma concentrations) were used for model validation. Age, sex, total bodyweight (TBW), height, body surface area, lowest urine pH during infusion, serum creatinine, ALT, AST, folinic acid dose and length of rescue were analysed as possible covariates. The final predictive performance of the pharmacokinetic model was tested using standardised mean prediction errors. RESULTS: The final population pharmacokinetic model (two-compartmental) included only age and total bodyweight as influencing clearance (CL) and volume of distribution of central compartment (V(1)). For children aged < or =10 years: CL (L/h) = 0.287 . TBW(0.876); V(1) (L) = 0.465 . TBW, and for children aged >10 years: CL (L/h) = 0.149 . TBW; V(1) (L) = 0.437 . TBW. From the base to the final model, the inter-individual variabilities for CL and V(1) were significantly reduced in both age groups (30-50%). The coefficients of variation of the pharmacokinetic parameters were <30%, while residual and inter-occasional coefficients maintained values close to 40%. Validation of the proposed model revealed the suitability of the model. CONCLUSION: A methotrexate population pharmacokinetic model has been developed for ALL children. The proposed model could be used in Bayesian algorithms with a limited sampling strategy to estimate the systemic exposure of individual patients to methotrexate and adapt both folinic acid rescue and methotrexate dosing accordingly.

La eliminación urinaria de productos de lipoperoxidación depende de un ritmo biológico anual / Annual rhythm of urinary excretion of lipoperoxidation products

Introducción: existen numerosos rasgos biológicos ligados a ritmos diarios, anuales o estacionales. Uno de estos rasgos podría ser la producción y eliminación urinaria de productos de lipoperoxidación (sustancias reactivas al ácido tiobarbitúrico [TBARS]) eliminados por orina que son modificados por la crenoterapia con diferentes aguas mineromedicinales. El objetivo del presente artículo es analizar si la eliminación urinaria de TBARS depende de la época del año en que se determina. Material y métodos: se han obtenido muestras de orina de 230 voluntarios del Programa de Termalismo Social del IMSERSO (edad 52-81 años), 115 varones y 115 mujeres que se adscribieron a 2 balnearios diferentes en 6 épocas distintas del año: 110 al primero y 120 al segundo. A la llegada al balneario se determinó la concentración de TBARS mediante espectrofotometría; paralelamente se realizó a los pacientes historia clínica que incluyó registros de la presión arterial. Resultados: la media de eliminación total de TBARS a la llegada al balneario en la población del primero fue de 0,418 ± 0,025 nmol/mg de creatinina; en la segunda fue de 0,368 ± 0,01 nmol/mg de creatinina. Una de las posibles razones de los diferentes valores de ambas poblaciones, con un máximo de excreción urinaria en julio y un mínimo en noviembre, fue el hecho de que las determinaciones se realizaron en diferentes meses del año en ambas poblaciones. Conclusión: este estudio muestra que las tasas de eliminación de productos de lipoperoxidación siguen un ritmo anual

Introduction: many biological features are linked to daily, annual, or seasonal rhythms. One of these features could be the production and urinary excretion of lipoperoxidation products (TBARS), which are modified by crenotherapy with different mineromedicinal waters. The objective of the present article was to analyse whether urinary excretion of TBARS depends on the time of the year in which it is determined. Material and methods: urinary samples were obtained from 230 volunteers from the Social Thermalism Program of the Institute for the Elderly and Social Services (Instituto de Mayores y Servicios Sociales [IMSERSO]). There were 115 men and 115 women (aged 52-81years) who where assigned to two different spas at six different times of the year: 110 were assigned to the first spa and 120 to the second. TBARS concentration was determined on arrival at the spa by means of spectrophotometry; a clinical history was also taken, including blood pressure measurement. Results: the mean total TBARS excretion on arrival was 0.418 ± 0.025 nmol/mg of creatinine for the population from the first spa and 0.368 ± 0.01 nmol/mg of creatinine for the second. One of the reasons why these values differed between the two populations was that they were determined in different months of the year, showing a maximum excretion in July and a minimum in November. Conclusion: this study shows that excretion rates of lipid peroxidation products follows an annual rhythm

A purL mutant of Sinorhizobium fredii HH103 is symbiotically defective and altered in its lipopolysaccharide.

The pleiotropic phenotype of an auxotrophic purL mutant (SVQ295) of Sinorhizobium fredii HH103 has been investigated. SVQ295 forms colonies that are translucent, produce more slime and absorb less Congo red than those of wild-type strain HH103. SVQ295 did not grow in minimal medium unless the culture was supplemented with thiamin and adenine or with thiamin and AICA-riboside (5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside), an intermediate of purine biosynthesis. Bacterial cultures supplemented with AICA-riboside or adenine reached the same culture density, although the doubling time of SVQ295 cultures containing AICA-riboside was clearly longer. S. fredii SVQ295 induced pseudonodules on Glycine max and failed to nodulate six different legumes. On Glycyrrhiza uralensis, however, nodules showing nitrogenase activity and containing infected plant cells were formed. SVQ295 showed auto-agglutination when grown in liquid TY medium and its lipopolysaccharide (LPS) electrophoretic profile differed from that of its parental strain HH103-1. In addition, four monoclonal antibodies that recognize the LPS of S. fredii HH103 failed to recognize the LPS produced by SVQ295. In contrast, (1)H-NMR spectra of K-antigen capsular polysaccharides (KPS) produced by SVQ295 and the wild-type strain HH103 were similar. Co-inoculation of soybean plants with SVQ295 and SVQ116 (a nodA mutant derivative of HH103) produced nitrogen-fixing nodules that were only occupied by SVQ116.