Reanálisis del estudio de Carlos J. Finlay acerca del mosquito como vector de la fiebre amarilla

Introducción: El primer registro de la asociación causal entre el mosquito Aedes aegypti, y la transmisión de la fiebre amarilla, lo constituyó la comunicación presentada por Carlos J. Finlay a la Academia de Ciencias de La Habana en 1881. El científico cubano mostró los resultados de la inoculación, por picadura de mosquito infectado, en cinco sujetos de un conjunto de 20 personas sanas. Objetivo: Reanalizar la evidencia mediante la aplicación de técnicas estadísticas aún no desarrolladas en tiempo del científico cubano, y evaluar la fortaleza de la evidencia causal. Métodos: Los resultados se analizaron mediante el test exacto de Fisher, el factor de Bayes y la diferencia de riesgos, el riesgo relativo y el odds ratio de la asociación. Se valoró la fortaleza de la evidencia de la asociación causal mediante criterio estadístico sin desconocer los criterios de causalidad más actualizados. Resultados: El test exacto de Fisher fue altamente significativo (p= 0,009), y el factor de Bayes (24,9) resultó compatible con una evidencia fuerte a favor de la asociación entre la inoculación y el desarrollo de la enfermedad. También apoyaron la asociación, la diferencia de riesgos (0,55; IC 95 %: 0,15-0,96), el riesgo relativo (18,7; IC 95 %: 1,12-3-10,3) y el odds ratio (43,4; IC 95 %: 1,68-11-19,7). Conclusiones: Los resultados de Finlay resultaron robustos, y se ajustaron a los criterios de causalidad para explicar la transmisión de la fiebre amarilla por el mosquito.

Introduction: The first record of the causal association between the Aedes aegypti mosquito and the transmission of yellow fever was the communication submitted by Carlos J. Finlay to the Havana Academy of Sciences in 1881. The Cuban scientist showed the results of inoculation, by infected mosquito bite, in five subjects from a group of 20 healthy people. Objective: To revise the evidence through the use of statistical techniques not yet developed at the time of the Cuban scientist and to evaluate the strength of the causal evidence. Methods: Results were analyzed using Fisher's exact test, Bayes factor, and risk difference, relative risk, and odds ratio of association. The strength of the evidence of the causal association was assessed using statistical criteria minding the most up-to-date causality criteria. Results: Fisher's exact test was highly significant (p = 0.009), and the Bayes factor (24.9) was compatible with strong evidence in favor of the association between inoculation and disease development. The association was also supported by the risk difference (0.55; 95% CI: 0.15-0.96), the relative risk (18.7; 95% CI: 1.12-310.3), and the odds ratio (43.4; 95% CI: 1.68-1119.7). Conclusions: Finlay's results were robust, and adjusted to the causality criteria to explain the transmission of yellow fever by mosquitoes.

lncRNA deregulation in childhood acute lymphoblastic leukemia: A systematic review.

Childhood acute lymphoblastic leukemia (ALL), the most common pediatric cancer, is a heterogeneous disease comprised of multiple molecular subtypes with distinct somatic genetic alterations, which results in different outcomes for the patients. Accurate patient risk stratification through genetic markers could increase survival rates, but the identification of reliable biomarkers is needed, as 20­30% of B­ALL patients cannot be classified in the clinic with routine techniques and some patients classified as low­risk and good­responders to treatment will eventually relapse. Long non­coding RNAs (lncRNAs) can represent novel candidates with diagnostic, classification, prognosis, and treatment response potential. However, regarding childhood ALL, there is inconsistency in the data reported due to the lack of a consensus nomenclature for lncRNA naming and the methodology and designing applied for their study. Therefore, the aim of the article is to clarify the potential of lncRNAs as biomarkers in childhood ALL through a systematic review. From a revision of 23 manuscripts, it was found that AWPPH overexpression could represent a novel marker for ALL diagnosis, including both B and T immunophenotypes, and 18 lncRNAs were specifically associated with B­cell ALL (B­ALL) patients. We identified subtype­specific signatures for ETV6­RUNX1, hyperdiploidy and KMT2A subtypes. These signatures hold promise as novel diagnostic markers and could refine the classification of patients.

Underlying dimensions of the EORTC QLQ-C30 in a Cuban population of patients with advanced non-small cell lung cancer.

BACKGROUND: Quality of Life Core Questionnaire of the European Organization for the Research and Treatment of Cancer (EORTC QLQ-C30) is one of the most used quality of life questionnaires in cancer studies. It provides scores for five functional scales, nine symptom scales, and two single items which assess overall health status and quality of life. However, high correlations among QLQ-C30 items suggest a reduced dimensionality for the scale. OBJECTIVE: To assess the dimensionality of the EORTC QLQ-C30 using item response theory (IRT) in a training sample and confirmatory factor analysis (CFA) in a test sample. METHODS: We analyzed responses to QLQ-C30 from 1,107 patients with advanced lung cancer who were included in five clinical trials of immunotherapy. We used non-parametric and parametric IRT models (Mokken, and Samejima's graded response) in a random training set (n = 332) for initial assessment of dimensions and item characteristics of the QLQ-C30. Finally, we used CFA in the test set (n = 775) to confirm the measurement domains. RESULTS: Mokken model showed that QLQ-C30 fits a unidimensional scale, whereas Samejima model showed that most QLQ-C30 items present adequate difficulty and discrimination. All items showed adequate scalability indexes with an overall scalability of 0.47 (medium scale). The QLQ-C30-reduced dimensionality was confirmed by CFA (comparative fit index = 0.98, root mean square error of approximation = 0.055) with all items presenting factorial loadings > 0.40. CONCLUSIONS: The EORTC QLQ-C30 fits a unidimensional latent construct identified with perceived quality of life in advanced lung cancer patients. TRIAL REGISTRATION: RPCEC00000161, RPCEC00000181 and RPCEC00000205.

Metodología y sistemas para meta-análisis de ensayos clínicos / Methodology and systems for meta-analysis of clinical trials

Introducción: Frecuentemente la información médica sobre determinado aspecto clínico, es tan poco clara y contradictoria, que en ocasiones el profesional de la salud no tiene el tiempo o la orientación para poder analizarla en su totalidad, y poder así aprovecharla en su real magnitud. Objetivo: Revisar la metodología y los sistemas que existen para realizar meta-análisis de ensayos clínico. Métodos: Se ha revisado el proceso de análisis de esos conocimientos, llamado meta-análisis; éste es un estudio sistemático, cualitativo y cuantitativo de un grupo de informes o artículos de investigación, generalmente enfocado al análisis de un aspecto clínico. Resultados: En este artículo de revisión, se muestra cómo se diseña, se ejecuta y reporta el meta-análisis, así como los pasos para la realización del meta-análisis. Discusión: Se resumen y se comparan los sistemas que más se utilizan para realizar meta-análisis. Conclusiones: Con este trabajo se conocen que los análisis de sensibilidad, acumulado y de sesgo de publicación no pueden faltar para un meta-análisis, así los sistemas donde poder realizar cada uno de estos análisis(AU)

Introduction: Frequently the medical information on a certain clinical aspect is so unclear and contradictory, that health professional does not have the time or guidance to be able to analyze it in its entirety, and thus be able to take advantage of it in its real magnitude. Objective: To review the existing methodology and systems to perform meta-analysis of clinical trials. Methods: The process of analyzing this knowledge, called meta-analysis, has been reviewed; this is a systematic, qualitative and quantitative study of a group of reports or research articles, generally focused on the analysis of a clinical aspect. Results: In this review article, we show how the meta-analysis is designed, executed and reported, as well as the steps to carry out the meta-analysis. Discussion: The systems most used to perform meta-analysis are summarized and compared. Conclusions: With this work we know that the analysis of sensitivity, accumulated and publication bias cannot be missing for a meta-analysis, as well as the systems where each of these analyzes can be performed(AU)

Suicidal ideation in patients with fibromyalgia: a cross-sectional study.

Chronic pain, sleep disturbances, and depression, which are relevant symptoms of fibromyalgia syndrome, have been demonstrated to be associated with an increased likelihood of suicidal behaviors. Mortality from suicide has been shown to be greater among patients with fibromyalgia. This study aimed to assess the prevalence of suicidal ideation among a sample of patients with fibromyalgia and to evaluate its relationship with the clinical symptomatology of fibromyalgia. Baseline data from fibromyalgia patients willing to participate in different clinical studies were collected. Outcome measures included the Fibromyalgia Impact Questionnaire, the Beck Depression Inventory, the Pittsburgh Sleep Quality Index, the Brief Pain Inventory, and the SF-12 Health Survey. The scores for these scales were compared between patients with and without suicidal ideation. The presence of suicidal ideation was assessed using the answer provided to item 9 of the Beck Depression Inventory. The results were adjusted by age, sex, total comorbidity, and time since diagnosis with multiple linear regression. The sample comprised 373 patients of whom one hundred and seventy-nine (48%) reported suicidal ideation: 148 (39.7%) reported passive suicidal ideation and 31 (8.3%) active suicidal ideation. Suicidal ideation was markedly associated with depression, anxiety, sleep quality, and global mental health, whereas only weak relationships were observed between suicidal ideation and both pain and general physical health.

Is there a subgroup of long-term evolution among patients with advanced lung cancer?: hints from the analysis of survival curves from cancer registry data.

BACKGROUND: Recently, with the access of low toxicity biological and targeted therapies, evidence of the existence of a long-term survival subpopulation of cancer patients is appearing. We have studied an unselected population with advanced lung cancer to look for evidence of multimodality in survival distribution, and estimate the proportion of long-term survivors. METHODS: We used survival data of 4944 patients with non-small-cell lung cancer (NSCLC) stages IIIb-IV at diagnostic, registered in the National Cancer Registry of Cuba (NCRC) between January 1998 and December 2006. We fitted one-component survival model and two-component mixture models to identify short- and long- term survivors. Bayesian information criterion was used for model selection. RESULTS: For all of the selected parametric distributions the two components model presented the best fit. The population with short-term survival (almost 4 months median survival) represented 64% of patients. The population of long-term survival included 35% of patients, and showed a median survival around 12 months. None of the patients of short-term survival was still alive at month 24, while 10% of the patients of long-term survival died afterwards. CONCLUSIONS: There is a subgroup showing long-term evolution among patients with advanced lung cancer. As survival rates continue to improve with the new generation of therapies, prognostic models considering short- and long-term survival subpopulations should be considered in clinical research.

Recent cocaine use is a significant risk factor for sudden cardiovascular death in 15-49-year-old subjects: a forensic case-control study.

AIMS: The aims of the present study were to: (i) evaluate the prevalence of recent cocaine use in adolescents and young adults who had died by sudden cardiovascular death (SCVD); (ii) assess if recent cocaine use was associated with an increased risk of SCVD; and (iii) determine the demographic, clinical-pathological and toxicological characteristics of SCVD related to recent cocaine use. DESIGN: This was a case-control autopsy-based observational retrospective study. SETTING/CASES: Cases were all SCVD in individuals aged between 15 and 49 years during the period ranging from 1 January 2003 to 31 December 2009, with autopsies performed in Biscay, Spain. Medico-legal sudden deaths not due to cardiovascular diseases (SnoCVD) were used as the control group. In all deaths a complete autopsy and toxicological and histopathological studies were carried out. Recent cocaine use was considered when cocaine and/or benzoylecgonine were detected in blood. MEASUREMENTS: The risk for SCVD according to demographic variables (sex and age), cardiovascular risk factors (obesity, hypertension, diabetes and smoking) and toxicological variables (opioids, benzodiazepines, amphetamines, cannabis and alcohol) was analysed using three logistic regression models. We also estimated the prevalence of recent cocaine use in the general population aged 15-49 years based on the projection of population surveys. FINDINGS: Recent cocaine use was significantly higher in the SCVD group (27 of 311 subjects, 9%) than in the SnoCVD group (three of 126 subjects, 2%). In a full logistic regression controlling for all recorded covariates, the main risk factor for SCVD was recent cocaine use (odds ratio 4.10; 95% confidence interval 1.12-15.0). Compared with the estimated data in the general population, the prevalence of recent cocaine use was 13-58 times higher in people with SCVD. CONCLUSIONS: Recent cocaine use is associated significantly with an increased risk for sudden cardiovascular death in people aged 15-49 years.

Microbiota of healthy corals are active against fungi in a light-dependent manner.

Coral reefs are intricate ecosystems that harbor diverse organisms, including 25% of all marine fish. Healthy corals exhibit a complex symbiosis between coral polyps, endosymbiotic alga, and an array of microorganisms, called the coral holobiont. Secretion of specialized metabolites by coral microbiota is thought to contribute to the defense of this sessile organism against harmful biotic and abiotic factors. While few causative agents of coral diseases have been unequivocally identified, fungi have been implicated in the massive destruction of some soft corals worldwide. Because corals are nocturnal feeders, they may be more vulnerable to fungal infection at night, and we hypothesized that the coral microbiota would have the capability to enhance their defenses against fungi in the dark. A Pseudoalteromonas sp. isolated from a healthy octocoral displayed light-dependent antifungal properties when grown adjacent to Penicillium citrinum (P. citrinum) isolated from a diseased Gorgonian octocoral. Microbial MALDI-imaging mass spectrometry (IMS) coupled with molecular network analyses revealed that Pseudoalteromonas produced higher levels of antifungal polyketide alteramides in the dark than in the light. The alteramides were inactivated by light through a photoinduced intramolecular cyclization. Further NMR studies led to a revision of the stereochemical structure of the alteramides. Alteramide A exhibited antifungal properties and elicited changes in fungal metabolite distributions of mycotoxin citrinin and citrinadins. These data support the hypothesis that coral microbiota use abiotic factors such as light to regulate the production of metabolites with specialized functions to combat opportunistic pathogens at night.

Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric acute lymphoblastic leukemia.

Despite the clinical success of acute lymphoblastic leukemia (ALL) therapy, toxicity is frequent. Therefore, it would be useful to identify predictors of adverse effects. In the last years, several studies have investigated the relationship between genetic variation and treatment-related toxicity. However, most of these studies are focused in coding regions. Nowadays, it is known that regions that do not codify proteins, such as microRNAs (miRNAs), may have an important regulatory function. MiRNAs can regulate the expression of genes affecting drug response. In fact, the expression of some of those miRNAs has been associated with drug response. Genetic variations affecting miRNAs can modify their function, which may lead to drug sensitivity. The aim of this study was to detect new toxicity markers in pediatric B-ALL, studying miRNA-related polymorphisms, which can affect miRNA levels and function. We analyzed 118 SNPs in pre-miRNAs and miRNA processing genes in association with toxicity in 152 pediatric B-ALL patients all treated with the same protocol (LAL/SHOP). Among the results found, we detected for the first time an association between rs639174 in DROSHA and vomits that remained statistically significant after FDR correction. DROSHA had been associated with alterations in miRNAs expression, which could affect genes involved in drug transport. This suggests that miRNA-related SNPs could be a useful tool for toxicity prediction in pediatric B-ALL.

Validation of a Spanish version of the Revised Fibromyalgia Impact Questionnaire (FIQR).

BACKGROUND: The Revised version of the Fibromyalgia Impact Questionnaire (FIQR) was published in 2009. The aim of this study was to prepare a Spanish version, and to assess its psychometric properties in a sample of patients with fibromyalgia. METHODS: The FIQR was translated into Spanish and administered, along with the FIQ, the Hospital Anxiety Depression Scale (HADS), the 36-Item Short-Form Health Survey (SF-36), and the Brief Pain Inventory (BPI), to 113 Spanish fibromyalgia patients. The administration of the Spanish FIQR was repeated a week later. RESULTS: The Spanish FIQR had high internal consistency (Cronbach's α was 0.91 and 0.95 at visits 1 and 2 respectively). The test-retest reliability was good for the FIQR total score and its function and symptoms domains (intraclass correlation coefficient (ICC > 0.70), but modest for the overall impact domain (ICC = 0.51). Statistically significant correlations (p < 0.05) were also found between the FIQR and the FIQ scores, as well as between the FIQR scores and the remaining scales' scores. CONCLUSIONS: The Spanish version of the FIQR has a good internal consistency and our findings support its validity for assessing fibromyalgia patients. It might be a valid instrument to apply in clinical and investigational grounds.

Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial.

BACKGROUND: The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. METHODS: A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. RESULTS: The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. CONCLUSIONS: In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation. TRIAL REGISTRATION: Cuban National Register for clinical trials (No. 1745) (http://registroclinico.sld.cu/ensayos).

MS/MS networking guided analysis of molecule and gene cluster families.

The ability to correlate the production of specialized metabolites to the genetic capacity of the organism that produces such molecules has become an invaluable tool in aiding the discovery of biotechnologically applicable molecules. Here, we accomplish this task by matching molecular families with gene cluster families, making these correlations to 60 microbes at one time instead of connecting one molecule to one organism at a time, such as how it is traditionally done. We can correlate these families through the use of nanospray desorption electrospray ionization MS/MS, an ambient pressure MS technique, in conjunction with MS/MS networking and peptidogenomics. We matched the molecular families of peptide natural products produced by 42 bacilli and 18 pseudomonads through the generation of amino acid sequence tags from MS/MS data of specific clusters found in the MS/MS network. These sequence tags were then linked to biosynthetic gene clusters in publicly accessible genomes, providing us with the ability to link particular molecules with the genes that produced them. As an example of its use, this approach was applied to two unsequenced Pseudoalteromonas species, leading to the discovery of the gene cluster for a molecular family, the bromoalterochromides, in the previously sequenced strain P. piscicida JCM 20779(T). The approach itself is not limited to 60 related strains, because spectral networking can be readily adopted to look at molecular family-gene cluster families of hundreds or more diverse organisms in one single MS/MS network.

Polymorphisms in the methotrexate transport pathway: a new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia.

OBJECTIVES: Methotrexate (MTX) is an important component of therapy for pediatric acute lymphoblastic leukemia (ALL). Treatment with MTX often causes toxicity, which can necessitate dose reduction or treatment cessation. Interindividual differences in adverse reactions can be due to different factors, including polymorphisms in key genes. Recently, we confirmed the association between SLCO1B1 rs11045879 polymorphism and toxicity previously proposed by Treviño and colleagues. As SLCO1B1 is a transporter involved in MTX elimination, other polymorphisms in genes from this pathway could also have a role in MTX toxicity. The aim of the present study was to analyze in depth the role of polymorphisms in the genes of the MTX transport pathway as putative toxicity predictors in pediatric ALL. METHODS: We analyzed 384 single nucleotide polymorphisms in 12 transporter genes (SLCO1B1, SLCO1B3, SLCO1A2, ABCB1, ABCG2, ABCC1, ABCC2, ABCC3, ABCC4, SLC19A1, SLC22A6 and SLC22A8) and their correlation with different toxicity parameters in 151 pediatric ALL patients treated using the LAL/SHOP protocol. RESULTS: A significant association with MTX plasma levels was found for 21 polymorphisms from seven genes and 15 haplotypes. After correction, rs9516519 in ABCC4, rs3740065 in ABCC2, and haplotype GCGGG in ABCC2 remained significantly associated. CONCLUSION: Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.

Congestive heart failure in a 77-year-old woman receiving adjuvant treatment with imatinib for a large gastric gastrointestinal stromal tumour.

We report on a 77-year-old patient complaining of abdominal pain who was diagnosed with a gastric mesenchymal tumour with a poor prognosis (high mitotic index, 25% Ki-67 proliferation index and c-kit positive). During surgery, there was instrument-related rupture of the tumour. Coadjuvant therapy with imatinib was initiated. Three weeks later, the patient developed symptoms of congestive heart failure and this led to the discontinuation of imatinib treatment; diuretic treatment was initiated, which led to an improvement in the symptoms. Echocardiography study showed a left ventricle ejection fraction of 55% with an alteration in the relaxation of the ventricle. In the follow-up, there has been no evidence of disease relapse or development of new symptoms.

Bcl-2 and BLIMP-1 expression predict worse prognosis in gastric diffuse large B cell lymphoma (DLCBL) while other markers for nodal DLBCL are not useful.

AIMS: Previous studies have identified clinicopathological and immunohistochemical differences among diffuse large B cell lymphomas (DLBCL) as a function of disease location. Nevertheless, there is a continuing tendency to generalize the prognostic value of various identified markers without taking into account tumour site. Accordingly, we analysed the prognostic value of several of the immunohistochemical markers that have been proposed for nodal DLBCL in a group of patients with gastric DLBCL. METHODS AND RESULTS: Using histochemical methods, CD10, Bcl-6, Gcet1, MUM-1, Bcl-2 and BLIMP-1 expression was investigated in 43 cases of gastric DBLCL. As in nodal DLBCLs, expression of BLIMP-1, and of Bcl-2 in non-germinal centre B cell-like (non-GCB) patients, was associated with a worse prognosis. However, unlike nodal DBLCL, there was no significant association of prognosis with expression of CD10, Bcl-6, Gcet1 or MUM-1, or with categorization according to Hans or Muris algorithms. CONCLUSIONS: Although most markers of prognosis in nodal DLBCL are not useful indicators for gastric DLBCL, Bcl-2 or BLIMP-1 expression does correlate with worse prognosis. These data support the notion that clinicopathological features in DLBCL vary according to the disease location.

Sexual functioning in women and men with fibromyalgia.

INTRODUCTION: Sexual dysfunction has been associated with several chronic pain conditions, including fibromyalgia. However, the literature on sexual functioning in patients with fibromyalgia is limited and restricted to female patients. AIM: The aim of our study was to evaluate sexual functioning in female and male patients with fibromyalgia compared with healthy controls. MAIN OUTCOME MEASURE: Sexual functioning was evaluated using the Spanish validated version of the Changes in Sexual Functioning Questionnaire (CSFQ). METHODS: We used baseline data from several studies performed in adult patients with fibromyalgia (American College of Rheumatology criteria) of both sexes in which sexual functioning was included in the clinical evaluation. As a control group, we selected an age-matched group of healthy subjects. We calculated the proportion of patients exhibiting sexual dysfunction (i.e., a CSFQ total score equal to or lower than 41 in females and 47 in males). CSFQ scores for patients and controls were compared, and the effect sizes for the difference of means were calculated. RESULTS: Our sample comprised 293 patients with fibromyalgia (276 females and 17 males) and 86 healthy controls (72 females and 14 males). The frequency of sexual dysfunction was significantly higher in patients with fibromyalgia than in controls for both females (86.9% vs. 23.6%; relative risk [RR] 3.7, 95% confidence interval [CI], 2.4-5.6) and males (76.5% vs. 6.7%; RR 11.5, 95% CI, 1.7-77.6). We found significantly worse sexual functioning for all dimensions in both female and male patients with fibromyalgia. Effect sizes for the difference in mean scores of the CSFQ were large overall and for all dimensions in both females and males. CONCLUSION: Our results show that sexual dysfunction is common in patients with fibromyalgia. The disease seems to deeply affect all dimensions of sexual functioning in both females and males.

Polymorphisms of the SLCO1B1 gene predict methotrexate-related toxicity in childhood acute lymphoblastic leukemia.

BACKGROUND: Methotrexate (MTX) is an important component of the therapy for childhood acute lymphoblastic leukemia. Treatment with high-dose MTX often causes toxicity, recommending a dose reduction and/or cessation of treatment. Polymorphisms in genes involved in the MTX metabolism have been associated with toxicity with controversial results. The discrepancies could be due to differences in treatment protocols among studies, small, or non-homogeneous populations or the use of different toxicity criteria. The aim of the present study was to analyze the possible correlation of polymorphisms of genes involved in the MTX metabolism with the toxicity during therapy with the well-established LAL/SHOP protocol. PROCEDURE: We analyzed 10 polymorphisms in seven genes (MTHFR, TS, SHMT1, RFC1, ABCB1, ABCG2, and SLCO1B1) from the MTX metabolism in 115 Spanish pediatric B-ALL patients, using MTX plasma concentration as an objective and quantifiable marker of toxicity. RESULTS: We confirmed the suitability of MTX plasma levels as a toxicity marker. We found a statistically significant association between MTX plasma concentration and the SLCO1B1 rs11045879 CC genotype (P = 0.030). The rs4149081 AA genotype, in the same gene, could also be an indicator for high-MTX plasma concentrations. We did not find any significant association in the other genetic polymorphisms analyzed. CONCLUSIONS: Identification of the rs4149081 and rs11045879 SLCO1B1 polymorphisms in children with ALL could be a useful tool for monitoring patients at risk of low-MTX clearance in order to avoid MTX-related toxicity.

Cognitive performance and smoking in first-episode psychosis: the self-medication hypothesis.

The self-medication hypothesis attempts to explain the extraordinary high levels of cigarette smoking in schizophrenia; patients may smoke in an attempt to reduce their cognitive deficits, symptoms, or the side effects of antipsychotics. In a previous report, we detected beneficial performance in attention and working memory in patients with first-episode psychosis who smoked compared to non-smoking patients soon after stabilization. In the present study, we examine differences in the course of those deficits 12 months after the initiation of antipsychotic treatment. We also explore the association between smoking and symptoms and side effects of medication. Neuropsychological assessments were performed at baseline, month 6 and month 12 using a computerized battery that included measures of sustained attention (Continuous Performance Test CPT-O), selective attention (Stroop interference task) and working memory (CPT-XO). Patients met the criterion of fitting in the same smoking category throughout the study: non-smoker (n = 15; 0 cigarettes/day) and smoker (n = 26; >15 cigarettes/day). The non-smoking patients showed significant cognitive improvements, whereas smoking patients lost their superior baseline performance, which was probably obtained through nicotinic stimulation, at the 6- and 12-month assessments due to a static course of deficits. Smokers did not obtain any cognitive benefit after instauration of treatment and worsen their symptoms over the first year. These results suggest that smoking may constitute a marker of a more severe illness. Smoking was not associated with fewer extrapyramidal side effects. Smoking might improve attention and working memory to a similarly modest extent as atypical antipsychotics and could reflect an effort to ameliorate these cognitive dysfunctions previous to treatment instauration.

Chromosome instability in lymphocytes of children with coeliac disease.

Undiagnosed individuals with celiac disease (CD) or those who do not comply with gluten-free diet (GFD) are at a higher risk of developing malignancies. A possible origin of chromosomal alteration in autoimmune reaction could be mistakes in the rearrangement of V(D)J of the IgH gene. Our aim was to verify whether higher genomic instability was found in coeliac individuals and whether GFD reduced it. As marker of genomic instability we analysed the frequency of 2 translocations, t(14;18) and t(11;14), in peripheral blood by nested PCR, in 37 patients with CD at diagnosis, 27 patients with CD after 2 years on GFD, and 36 control individuals. No significant differences were found.