Diagnostic reference levels and complexity indices in interventional radiology: a national programme.

OBJECTIVES: To propose national diagnostic reference levels (DRLs) for interventional radiology and to evaluate the impact of the procedural complexity on patient doses. METHODS: Eight interventional radiology units from Spanish hospitals were involved in this project. The participants agreed to undergo common quality control procedures for X-ray systems. Kerma area product (KAP) was collected from a sample of 1,649 procedures. A consensus document established the criteria to evaluate the complexity of seven types of procedures. DRLs were set as the 3rd quartile of KAP values. RESULTS: The KAP (3rd quartile) in Gy cm2 for the procedures included in the survey were: lower extremity arteriography (n = 784) 78; renal arteriography (n = 37) 107; transjugular hepatic biopsies (THB) (n = 30) 45; biliary drainage (BD) (n = 314) 30; uterine fibroid embolization (UFE) (n = 56) 214; colon endoprostheses (CE) (n = 31) 169; hepatic chemoembolization (HC) (n = 269) 303; femoropopliteal revascularization (FR) (n = 62) 119; and iliac stent (n = 66) 170. The complexity involved the increases in the following KAP factors from simple to complex procedures: THB x4; BD x13; UFE x3; CE x3; HC x5; FR x5 and IS x4. CONCLUSIONS: The evaluation of the procedure complexity in patient doses will allow the proper use of DRLs for the optimization of interventional radiology. KEY POINTS: • National DRLs for interventional procedures have been proposed given level of complexity • For clinical audits, the level of complexity should be taken into account. • An evaluation of the complexity levels of the procedure should be made.

Education modulates the association of the FTO rs9939609 polymorphism with body mass index and obesity risk in the Mediterranean population.

OBJECTIVE: To define whether the rs9939609 FTO (fat mass and obesity associated) single nucleotide polymorphism (SNP) is associated with anthropometric measurements and its modulation by educational level in a Mediterranean population. METHODS: We studied 3 independent adult samples: a random sample (n = 1580) from the general population (GP), obese hospital patients (OHP) (n = 203) and elderly subjects (n = 1027) with high cardiovascular risk (HCR). Weight and height were directly measured. Education and physical activity (PA) were measured using questionnaires. RESULTS: The rs9939609 presented heterogeneous associations with BMI. In the GP, the minor A-allele was significantly associated with greater BMI, following a co-dominant pattern (P = 0.009), whereas in the OHP this association was recessive (P = 0.004). Conversely, we did not find a significant association with BMI in the HCR group (P < 0.596). In the GP we found a significant interaction between the FTO SNP and education (P = 0.048). In the stratified analysis, no association of the FTO SNP with greater BMI in university subjects was detected (P = 0.786), whereas the association was observed in non-university subjects (P = 0.001). The FTO × education interaction (P = 0.020) was also observed in determining obesity risk in the GP. A-allele carriers had a greater risk of being obese only if they had no university education (OR: 1.56; 95%CI: 1.09-2.23 for TA and OR: 2.01; 95%CI: 1.27-3.26 for AA subjects). The interaction of the FTO with education remained significant even after adjustment for PA. CONCLUSIONS: The association of the FTO SNP with greater BMI and obesity risk in the GP was strongly modulated by education.

A universal dose-response curve for radiochromic films.

PURPOSE: This paper presents a model for dose-response curves of radiochromic films. It is based on a modified version of single-hit model to take into account the growth experienced by lithium salt of pentacosa-10,12-diynoic acid polymers after irradiation. METHODS: Polymer growth in radiochromic films is a critical phenomenon that can be properly described by means of percolation theory to provide an appropriate distribution function for polymer sizes. Resulting functional form is a power function featuring a critical exponent and two adjustable parameters. Moreover, these parameters act as scaling factors setting a natural scale for sensitometric curves where the dependence on channel sensitivity is removed. A unique reduced response curve is then obtained from all the color channels describing film behavior independently of film dosimetry system. RESULTS: Resulting functional form has been successfully tested in several sensitometric curves from different Gafchromic EBT models, providing excellent agreement with experimental data in a wide dose range up to about 40 Gy and low dose uncertainty. CONCLUSIONS: The model presented in this paper describes accurately the sensitometric curves of radiochromic films in wide dose ranges covering all typical ranges used in external radiotherapy. Resulting dose uncertainty is low enough to render a reasonably good performance in clinical applications. Due to cross-correlation, only one of the adjustable parameters is totally independent and characterizes film batches.

Screening antimutagenic and antiproliferative properties of extracts isolated from Jackfruit pulp (Artocarpus heterophyllus Lam).

The present focused on the study of the antimutagenic and antiproliferative potential of pulp Jackfruit (Artocarpus heterophyllus Lam) extract, using Salmonella typhimurium tester strains TA98 and TA100 with metabolic activation (S9) and a cancer cell line M12.C3.F6 (murine B-cell lymphoma), respectively. Jackfruit pulp extract was sequentially fractionated by chromatography (RP-HPLC) and each fraction was tested for antimutagenic and antiproliferative activities. The organic extracts obtained from Jackfruit pulp reduced the number of revertants caused by aflatoxin B1 (AFB1) and proliferation of cells M12.C3.F6; a dose-response relationship was showed. Sequential RP-HPLC fractionation of the active extracts produced both antimutagenic and/or antiproliferative fractions. These results suggested that the Jackfruit contained compounds with chemoprotective properties to reduce the mutagenicity of AFB1, also proliferation of a cancer cell line.

Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with plasma lipid levels in a healthy Spanish population.

Genetic variants at the cholesteryl ester transfer protein (CETP) locus have been associated with CETP activity and mass, as well as plasma high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels. We have examined allele frequencies and lipid associations for the common CETP TaqIB polymorphism in a sample of 514 healthy subjects (231 men, mean age 37.4 years, and 283 women, mean age 35.7 years) residing in Valencia (Spain). The frequency of the less common TaqIB2 allele (0.351; 95% CI: 0.322-0. 380) was significantly lower than those reported for Northern European populations. Consistent with previous studies, we found a significant association of the TaqIB polymorphism with HDL-C levels. Homozygotes for the B1 allele had lower HDL-C levels than subjects carrying the B2 allele (P trend<0.001 and 0.002, for men and women, respectively). No statistically significant genotype effects were observed for any of the other lipid measures. Multivariate models including TaqIB genotype, body mass index, smoking, alcohol, physical activity, marital status and education were fitted to predict HDL-C levels. The TaqIB polymorphism was consistently an independent predictor of HDL-C levels (P<0.001), and explained 5.8% of its variance. To evaluate gene-environmental interactions, first order interaction terms were tested into the multivariate model. No statistically significant interactions between the TaqIB genotypes and smoking, alcohol, physical activity or education were detected. In conclusion, we observed a significant association of the TaqIB polymorphism with HDL-C levels, which remained consistent across different levels of behavioral factors. Moreover, we found that the TaqIB2 allele frequency was lower in our sample than in other European populations, which could be a contributing factor to the unexpectedly high prevalence of coronary heart disease observed in the region of Valencia.

The safety of olanzapine compared with other antipsychotic drugs: results of an observational prospective study in patients with schizophrenia (EFESO Study). Pharmacoepidemiologic Study of Olanzapine in Schizophrenia.

INTRODUCTION: Results of controlled clinical trials should be confirmed through safety and effectiveness studies in nonselected patient cohorts treated according to routine clinical practice. METHOD: Outpatients with schizophrenia (ICD-10 criteria) entered this prospective, naturalistic study when they received a new prescription for an antipsychotic drug. Treatment assignment was based on purely clinical criteria, as the study did not include any experimental intervention. Safety was evaluated through the collection of spontaneous adverse events and a specific questionnaire for extrapyramidal symptoms. Global clinical status was measured through the Clinical Global Impressions-Severity (CGI-S) and the Global Assessment of Functioning (GAF) scales. RESULTS: From the 2967 patients included, 2128 patients were treated with olanzapine as monotherapy or combined with other drugs (olanzapine group), and 821 were treated with other antipsychotic drugs as monotherapy or combined with other drugs (control group). There were no statistical differences between treatment groups at baseline regarding age, gender, disease duration, or severity of symptoms. Olanzapine was well tolerated and effective in this study. Overall incidence of adverse events was significantly lower in the olanzapine group compared with the control group (p < .001). Somnolence and weight gain were significantly more frequent in the olanzapine group, and akathisia, dystonia, extrapyramidal syndrome, hypertonia, hypokinesia, and tremor were significantly higher in the control group. Clinical improvement at endpoint, measured through the mean change in the CGI-S and the GAF, was significantly higher in the olanzapine group compared with the control group (p = .004). CONCLUSION: These results show that olanzapine is safe and effective in nonselected schizophrenic outpatients and are consistent with the efficacy and safety profile that olanzapine has shown in previous controlled clinical trials.

Environmental factors modulate the effect of the APOE genetic polymorphism on plasma lipid concentrations: ecogenetic studies in a Mediterranean Spanish population.

To investigate APOE gene--environment interaction effects on plasma lipid concentrations, we conducted a cross-sectional study in a Mediterranean Spanish population consisting of 396 men and 513 women aged 18 to 66 years. The frequency of the epsilon 4 variant was 0.071 (95% confidence interval 0.059, 0.082), confirming the lower frequency of this allele in Southern Europe. In general, the carriers of the epsilon 2 variant had lower concentrations (P <.05) of total and low-density lipoprotein cholesterol (LDL-C), carriers of the epsilon 3 variant had intermediate concentrations, and carriers of the epsilon 4 variant had higher concentrations (P <.05) in both sexes, even after multivariate adjustment for age, body mass index, alcohol consumption, tobacco smoking, physical activity, marital status, and education. However, when the homogeneity of allelic effects according to environmental factors was tested, significant interaction terms were found. In women, an important interaction between alcohol consumption and the APOE polymorphism in determining LDL-C concentrations was found (P <.003). LDL-C concentrations in female drinkers with the epsilon 2 variant were significantly lower (P <.014) than in nondrinkers with the epsilon 2 variant. Likewise, in female drinkers with the epsilon 4 variant, LDL-C concentrations were also significantly (P <.010) lower than in nondrinkers with the epsilon 4 variant. Moreover, in female drinkers, LDL-C concentrations did not differ between carriers of the epsilon 4 and the epsilon 3 variants, and in nondrinkers, LDL-C concentrations did not differ between carriers of the epsilon 2 and the epsilon 3 variants. We also found a statistically significant interaction effect (P <.001) between the APOE polymorphism and physical activity in determining high-density lipoprotein cholesterol concentrations in men. Our results indicate that environmental factors are important modulators of the effect of the APOE polymorphism on plasma lipid concentrations.

[Apolipoprotein E gene polymorphism and risk of hypercholesterolemia: a case control study in a working population of Valencia]. / Polimorfismos en el gen de la apolipoproteína E y riesgo de hipercolesterolemia: un estudio de casos y controles en una población laboral de Valencia.

BACKGROUND: The apolipoprotein E (apoE) gene is polymorphic with three common alleles (epsilon 2, epsilon 3, epsilon 4) whose allelic frequency and association with lipid levels varies from population to population. The aim of this study was to estimate the association between these genetic variants and the risk of hypercholesterolemia in a Mediterranean Spanish population. PATIENTS AND METHODS: A case-control study in a working population from Valencia was carried out. A total of 330 cases (148 men and 182 women) with moderate hypercholesterolemia (total cholesterol > 200 mg/dl or with lipid lowering treatment) and age range 20 to 60 years, were identified. 330 normocholesterolemic controls matched by age and sex were selected. From all of them data of apoE genotype, body mass index, lipid and lipoprotein levels, socioeconomic and life-style variables were obtained. RESULTS: The epsilon 2 allele frequency was statistically lower in cases (0.033) than in controls (0.086). The epsilon 4 allele frequency was higher in cases (0.115) than in controls (0.039). In the crude logistic regression analysis, the apoE polymorphism was related (p < 0.001) to the risk of hypercholesterolemia. After adjustment by age, body mass index, educational level, tobacco smoking, alcohol consumption and physical activity the epsilon 2 allele was associated with a lower risk of hypercholesterolemia (odds ratio [OR] = 0.36; 95% confidence interval (CI): 0.20-0.64), and the epsilon 4 allele was associated with a higher risk (OR = 3.04; 95% CI: 1.82-5.06). CONCLUSIONS: The apoE genotype was significantly related to the risk of moderate hypercholesterolemia in the Mediterranean Spanish population.

[Genetic and molecular study of cystinuria in the Valencian community]. / Estudio genético y molecular de la cistinuria en la Comunidad Valenciana.

BACKGROUND: The aim of this study has been to know the prevalence of the four most common mutations reported in SLC3A1 gene involved in human cystinuria, and to estimate the association with different phenotypic manifestations of this disease in population of the Valencian Community, Spain. PATIENTS AND METHODS: We have carried out a cross-sectional study with a control group in 16 families with one or more members diagnosed as cystinuric patients. 149 subjects (38 cystinuric patients, 39 relatives and 72 controls) were studied. Genetic analyses were carried out using PCR (polymerase chain reaction), RFLPs (restriction fragment length polymorphisms) and sequencing of PCR products. Parametric and non parametric tests were applied in the statistical analyses. RESULTS: None of the four mutations studied were found in the control group. M467T mutation was the most prevalent in cystinuric patients as well as in relatives, showing and allelic frequency of 0.06 and 0.03 respectively. Regarding to the association analysis between genotype and phenotype, we found that, in cystinuric subjects, urinary excretion of some dibasic amino acid was higher in those who carried M467T mutation (p < 0.05). The formation of cystine crystals was also higher in cystinuric patients who carried this mutation (p < 0.05). CONCLUSIONS: Prevalences of recurrent mutations reported up to now in SLC3A1 gene are very low in cystinuric subjects of the Valencian Community, Spain. Only mutation M467T has been found, without differences between cystinuric and their relatives, although in the first ones was associated with a more accurate phenotype manifestation of the disease.

p27Kip1 represses transcription by direct interaction with p130/E2F4 at the promoters of target genes.

The cyclin-cdk (cyclin-dependent kinase) inhibitor p27Kip1 (p27) has a crucial negative role on cell cycle progression. In addition to its classical role as a cyclin-cdk inhibitor, it also performs cyclin-cdk-independent functions as the regulation of cytoskeleton rearrangements and cell motility. p27 deficiency has been associated with tumor aggressiveness and poor clinical outcome, although the mechanisms underlying this participation still remain elusive. We report here a new cellular function of p27 as a transcriptional regulator in association with p130/E2F4 complexes that could be relevant for tumorigenesis. We observed that p27 associates with specific promoters of genes involved in important cellular functions as processing and splicing of RNA, mitochondrial organization and respiration, translation and cell cycle. On these promoters p27 co-localizes with p130, E2F4 and co-repressors as histone deacetylases (HDACs) and mSIN3A. p27 co-immunoprecipitates with these proteins and by affinity chromatography, we demonstrated a direct interaction of p27 with p130 and E2F4 through its carboxyl-half. We have also shown that p130 recruits p27 on the promoters, and there p27 is needed for the subsequent recruitment of HDACs and mSIN3A. Expression microarrays and luciferase assays revealed that p27 behaves as transcriptional repressor of these p27-target genes (p27-TGs). Finally, in human tumors, we established a correlation with overexpression of p27-TGs and poor survival. Thus, this new function of p27 as a transcriptional repressor could have a role in the major aggressiveness of tumors with low levels of p27.

Scanning tunnelling spectroscopy study of paramagnetic superconducting ß''-ET(4)[(H(3)O)Fe(C(2)O(4))(3)]·C(6)H(5)Br crystals.

Scanning tunnelling spectroscopy (STS) and microscopy (STM) were performed on the paramagnetic molecular superconductor ß''-ET(4)[(H(3)O)Fe(C(2)O(4))(3)]·C(6)H(5)Br. Under ambient pressure, this compound is located near the boundary separating superconducting and insulating phases of the phase diagram. In spite of a strongly reduced critical temperature T(c) (T(c) = 4.0 K at the onset, zero resistance at T(c) = 0.5 K), the low temperature STS spectra taken in the superconducting regions show strong similarities with the higher T(c) ET κ-derivatives series. We exploited different models for the density of states (DOS), with conventional and unconventional order parameters to take into account the role played by possible magnetic and non-magnetic disorder in the superconducting order parameter. The values of the superconducting order parameter obtained by the fitting procedure are close to the ones obtained on more metallic and higher T(c) organic crystals and far above the BCS values, suggesting an intrinsic role of disorder in the superconductivity of organic superconductors and a further confirmation of the non-conventional superconductivity in such compounds.

[Time to first antibiotic dose in community-acquired pneumonia diagnosed in an emergency department]. / Tiempo hasta la administración de la primera dosis de antibiótico en las neumonías adquiridas en la comunidad en un Servicio de Urgencias Hospitalario.

BACKGROUND: Early antibiotic administration to patients diagnosed of community-acquired pneumonia (CAP) has been associated with a lower mortality. In the USA, its administration within four hours has been implanted as a quality standard. The objective of this work was to analyze, in a Spanish emergency department, the performance with patients with CAP, focusing on the administration of the first dose of antibiotic. PATIENTS AND METHOD: Clinics, welfare and organizational aspects have been analysed on 93 patients diagnosed of CAP in an emergency department in order to identify their influence on antibiotic administration within 4 hours. RESULTS: 46.2% of patients received antibiotics within 4 hours. The fact that patients were assisted in the higher complexity level showed a positive association with the antibiotic administration within 4 hours. On the contrary, presence of more than 10 patients waiting to be admitted showed a negative association. CONCLUSIONS: Early antibiotic administration in the CAP is possible. On order to guarantee a higher number of patients taking antibiotics within 4 hours we have to improve quality of care in both the emergency department (to guarantee correct classification according to the level of complexity) and in the hospital (management of beds to avoid delay in the admission of the patients).

Prevention and early detection of tuberculosis.

1,570 subjects with known TB contacts (active TB, old TB and primary infection) and individuals with no known contacts but belonging to 'defined TB risk groups' were screened at the Department of Tuberculosis Prevention at the La Fe Hospital in Valencia. The total infection rate was 40.13% and active TBC was diagnosed in 2.23% of the population screened. Infection and disease rates were significant in all the groups examined, showing the need for correct screening not only for active TB contacts but also for child primary infection contacts, old TB cases not previously screened and subjects with no known contacts but belonging to a 'TB risk group'.

Prevalence of the methylenetetrahydrofolate reductase 677C > T mutation in the Mediterranean Spanish population. Association with cardiovascular risk factors.

Methylenetetrahydrofolate reductase (MT-HFR) is a key enzyme involved in folate metabolism. A common cytosine (C) to a thymine (T) mutation at nucleotide 677 (677C > T) in the MTHFR gene which converts an alanine residue to a valine, has been related with several biochemical phenotypes and with cardiovascular risk, depending on the population studied. Our objective was to estimate the prevalence of the 677C > T mutation in a large and randomly selected sample (289 men and 427 women) from the Mediterranean Spanish population, and to test the association between this genetic variant and some cardiovascular risk factors. For both genders, the prevalence of CC, CT and TT subjects was 32.0, 52.2 and 15.8%, respectively. The frequency (95% confidence interval) of the 677T allele was 0.44 (0.40-0.48) in men and 0.40 (0.37-0.44) in women. This prevalence was significantly different from other European countries, and among the highest reported in the world for any healthy population. We found no association between the 677C > T gene variants and age, body mass index (BMI), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or diastolic blood pressure in men and women. However, in men, a statistically significant increase of systolic blood pressure with the number of mutant alleles was found (122.2 mmHg in CC, 125.1 mmHg in CT and 128.5 mmHg in TT subjects; p for trend = 0.030). This association remained significant (p = 0.047) even after adjustment for age, BMI, alcohol consumption, tobacco smoking, education and physical activity.

[Sensitivity, specificity and predictive value of the genetic analysis of SLC3A1 gene variants used for the diagnosis of cystinuria among the spanish population]. / Sensibilidad, especificidad y valor predictivo del análisis genético de variantes en el gen SLC3A1 aplicado al diagnóstico de cistinuria en población española.

OBJECTIVE: To test the clinical usefulness of the analysis of point mutations R452W, M467T, 114C > A, 231T > A, 1136 + 3delT and 1332 + 7T > C in the gene SLC3A1 as well as their possible haplotypes used for the diagnosis of cystinuria in the mediterranean spanish population. MATERIAL AND METHODS: A total of 48 patients with cystinuria, 44 relatives without cystinuria, and 81 healthy controls were studied. A genetic analysis was conducted in order to identify variants in the gene SLC3A1. The sensitivity, specificity, and predictive value for each genetic variant and for the possible haplotypes were calculated. RESULTS: The specificity of mutations M467T, R452W, and 231T > A used for the diagnosis of cystinuria in the general population or for the different subtypes of cystinuria in involved families, was higher than 90%; nevertheless, none of the analysed variants reached a sensitivity higher than 80%. In the study of haplotypes, the highest sensitivity was obtained with the haplotype CTTT (83.8%); however, its specificity and predictive value were low (20.6% and 53.4%, respectively). CONCLUSIONS: The studied genetic variants did not show enough clinical usefulness.

Gender specific associations of the Trp64Arg mutation in the beta3-adrenergic receptor gene with obesity-related phenotypes in a Mediterranean population: interaction with a common lipoprotein lipase gene variation.

OBJECTIVE: To investigate the association between the Trp64Arg beta3-adrenergic receptor (ADRB3) mutation and obesity-related phenotypes in a Mediterranean Spanish population considering the effect of other genetic and environmental factors. DESIGN AND SUBJECT: Cross-sectional study in 1063 (476 men and 587 women) randomly selected from this population (aged: 18-68 years). MEASUREMENTS: Anthropometric (weight, height and waist-to-hip ratio), blood pressure, biochemical (lipids, fasting glucose, and uric acid), life-style variables, and the Trp64Arg, HindIII-Lipoprotein lipase (LPL) and apolipoprotein E polymorphism. RESULTS: Frequency of the Arg64 allele was low (0.051; 95% CI: 0.042-0.060). We found gender-specific associations between the Trp64Arg mutation and obesity related phenotypes. In men, carriers of the Arg64 variant had higher body mass index (BMI) (27.63 +/- 3.81 vs. 26.34 +/- 3.57 kg m-2, P=0.049) and total cholesterol (5.85 +/- 1.45 vs. 5.28 +/- 1.06 mmol L-1; P=0.011) compared with wild-type individuals. Logistic regression analysis, revealed that the risk of overweight was two times higher in male carriers of the Arg64 allele. In women, the Arg64 variant was only associated with higher fasting glucose (P=0.031). These genotype effects persisted after adjustment for age, genetic and life-style variables. For the LPL polymorphism, the H-/H- genotype was associated with lower BMI and with lower risk of overweight (OR: 0.49; 95% CI: 0.30-0.81) in both men and women. However, after adjustment for covariates, these associations only remained statistically significant (P < 0.02) in women. Moreover, in women, a statistically significant interaction (P=0.026) between the LPL and the ADRB3 gene loci in determining BMI was found. Thus, the Arg64 allele was associated with a higher BMI only in H+/H+ women. CONCLUSIONS: The Trp64Arg mutation was associated with BMI and lipids in men. In women, an additional gene-gene interaction with the LPL-HindIII polymorphism may explain the results.