Sospecha clínica y estudios diagnósticos iniciales en enfermedades metabólicas hereditarias / Clinical suspicion and initial diagnostic studies in inherited metabolic diseases

Las enfermedades metabólicas hereditarias (EMH) constituyen un grupo diverso y complejo de trastornos genéticos que, aunque individualmente son poco frecuentes, en su conjunto representan una importante causa de morbilidad y mortalidad. Se lleva a cabo una revisión exhaustiva de la literatura con el objetivo de proporcionar información que oriente la sospecha clínica y el enfoque en los estudios diagnósticos iniciales, cuya clave reside en una anamnesis completa que abarque los antecedentes familiares y obstétricos, junto con una consideración cuidadosa de las manifestaciones clínicas del paciente. Es crucial tener en cuenta la naturaleza multisistémica de estas enfermedades que pueden manifestarse desde el periodo neonatal, generalmente como intoxicaciones agudas, hasta una presentación más insidiosa en adultos jóvenes. Si la evaluación clínica sugiere la posibilidad de una EMH, es fundamental llevar a cabo medidas de apoyo general y realizar investigaciones de laboratorio de manera simultánea. En neonatos, donde la presentación de una EMH puede representar una emergencia médica que requiere una respuesta inmediata, esta acción es especialmente crítica. El diagnóstico de las EMH representa un desafío debido a su variabilidad clínica y sintomatología heterogénea. Sin embargo, la identificación temprana de estas enfermedades es fundamental para iniciar un tratamiento oportuno y mejorar el pronóstico de los pacientes.(AU)

Inherited metabolic diseases (IMDs) constitute a diverse and complex group of genetic disorders that, although individually rare, collectively represent a significant cause of morbidity and mortality. A comprehensive literature review is carried out with the aim of providing information to guide clinical suspicion and the approach to initial diagnostic studies, the key of which lies in a complete medical history encompassing family and obstetric backgrounds, along with careful consideration of the patient’s clinical manifestations. It is crucial to consider the multisystemic nature of these diseases, which can manifest from the neonatal period, usually as acute intoxications, to a more insidious presentation in young adults. If clinical evaluation suggests the possibility of an IMD, it is essential to implement general supportive measures and simultaneously perform laboratory investigations. In neonates, where the presentation of an IMD can represent a medical emergency requiring an immediate response, this action is especially critical. The diagnosis of IMDs poses a challenge due to their clinical variability and heterogeneous symptomatology. However, early identification of these diseases is crucial for initiating timely treatment and improving patient prognosis.(AU)

INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.

Pérdida auditiva y exposición laboral a ruido en minería: una revisión sistemática / Occupational hearing loss and noise exposure in mining: a systematic review

Objetivo: Revisar y analizar la pérdida auditiva derivada de la exposición laboral a ruido en los trabajadores del sector de la minería. Método: Análisis crítico de los trabajos recuperados mediante revisión sistemática en MEDLINE (PubMed), EMBASE, Cochrane Library, Scopus, Web of Science, LILACS, MEDES y TESEO hasta noviembre de 2021. La ecuación de búsqueda se formuló́ mediante los descriptores «Mining», «Occupational noise» y «Occupational Hearing Loss», utilizando también los DeCs, Entry Terms, términos del Diccionario Embase relacionados y los filtros: «2006» y «English», «Spanish», «French» y «Portuguese». La calidad de los artículos se evaluó mediante el cuestionario STROBE y el nivel de evidencia y grado de recomendación mediante los criterios SIGN. Resultados: De las 703 referencias recuperadas (todas digitalmente) tras aplicar los criterios de inclusión y exclusión, se seleccionaron 13 artículos. La evaluación mediante STROBE dio una media de 14.90 y según los criterios SIGN se obtuvo un grado de evidencia 3 y recomendación D. La obsolescencia de las publicaciones fue moderada (semiperiodo de Burton-Kebler: 6.00; índice de Price: 23,08%). Conclusiones: Los trabajos revisados presentaron un índice de obsolescencia adecuado sin embargo, su grado de evidencia y recomendación impidieron asegurar por completo la validez y fiabilidad de las observaciones realizadas. Los resultados mostraron asociación entre la exposición laboral a ruido y la périda auditiva entre los trabajadores del sector minero (AU)

Objective: To systematically review and analyze the occupational noise induced hearing loss in the mining industry workers. Method: Critical analysis of studies retrieved by systematic review of MEDLINE (PubMed), EMBASE, Cochrane Library, Scopus, Web of Science, LILACS, MEDES and TESEO through November 2021. The search strategy was developed by means of the descriptors «Mining», «Occupational Noise» and «Occupational Hearing Loss», as well as by using related DeCs Terms, entry Terms, Embase’s diccionary and the filters «from 2006» and English», «Spanish», «French» y «Portuguese ». Study quality was assessed using the STROBE questionnaire, and the level of evidence and grade of recommendation via the SIGN criteria. Results: Out of 703 references identified (all digitally) and after applying the inclusion and exclusion criteria, 13 articles were selected. The STROBE evaluation yielded a mean score of 14.90, and the SIGN criteria a 3 level of evidence and a D grade of recommendation. Article obsolescence was moderate (Burton-Kebler half-life: 6.00; Price index: 23.08%). Conclusions: This systematic review revealed an adequate level of obsolescence but degrees of evidence and recommendation limit the validity and reliability of the observations. Results indicated an association between occupational noise exposure and hearing loss in workers from the mining industry (AU)

Assessment of neurocognitive decline in cancer patients, except brain cancer, under long-term treatment with bevacizumab.

PURPOSE: We performed a cross-sectional study of neurocognitive function in non-brain cancer patients treated with long-term bevacizumab. METHODS/PATIENTS: From 2015 to 2017, we included patients with different types of cancer treated with bevacizumab with or without chemotherapy (BEV; N = 20) or only chemotherapy (ChT; N = 19) for at least 34 weeks, patients who received non-brain radiotherapy (RxT; N = 19), and healthy controls (HC; N = 19) were assessed once at week 34 of treatment (BEV and ChT) or at completion of radiotherapy. Neurocognition was evaluated with the Hopkins Verbal Learning Test-Revised (HVLT-R) total and delayed recall, the Trail Making Test A and B, and the Controlled Oral Word Association Test in the four groups. Non-parametric tests were used to assess differences between groups. RESULTS: The BEV, ChT, and RxT groups scored significantly lower than the HC group on all tests and especially on the HVLT-R total recall. In no case were the mean scores of the BEV group significantly lower than those of the ChT or RxT groups. CONCLUSIONS: Neurocognitive impairment was seen even in patients treated with local non-brain radiotherapy. Treatment with bevacizumab for a long period of time does not seem to worsen neurocognitive function to a greater extent than chemotherapy.

Effectiveness of a chat-bot for the adult population to quit smoking: protocol of a pragmatic clinical trial in primary care (Dejal@).

BACKGROUND: The wide scale and severity of consequences of tobacco use, benefits derived from cessation, low rates of intervention by healthcare professionals, and new opportunities stemming from novel communications technologies are the main factors motivating this project. Thus, the purpose of this study is to assess the effectiveness of an intervention that helps people cease smoking and increase their nicotine abstinence rates in the long term via a chat-bot, compared to usual practice, utilizing a chemical validation at 6 months. METHODS: Design: Randomized, controlled, multicentric, pragmatic clinical trial, with a 6-month follow-up. SETTING: Healthcare centers in the public healthcare system of the Community of Madrid (Madrid Regional Health Service). PARTICIPANTS: Smokers > 18 years of age who attend a healthcare center and accept help to quit smoking in the following month. N = 460 smokers (230 per arm) who will be recruited prior to randomization. Intervention group: use of a chat-bot with evidence-based contents to help quit smoking. CONTROL GROUP: Usual treatment (according to the protocol for tobacco cessation by the Madrid Regional Health Service Main variable: Continuous nicotine withdrawal with chemical validation (carbon monoxide in exhaled air). Intention-to-treat analysis. Difference between groups in continuous abstinence rates at 6 months with their corresponding 95% confidence interval. A logistic regression model will be built to adjust for confounding factors. RESULTS: First expected results in January 2020. DISCUSSION: Providing science-based evidence on the effectiveness of clinical interventions via information technologies, without the physical presence of a professional, is essential. In addition to being more efficient, the characteristics of these interventions can improve effectiveness, accessibility, and adherence to treatment. From an ethics perspective, this new type of intervention must be backed by scientific evidence to circumvent pressures from the market or particular interests, improve patient safety, and follow the standards of correct practices for clinical interventions. TRIAL REGISTRATION: ClinicalTrials.gov, reference number NCT03445507.

Chemotherapy and PARP inhibitors in heavily pretreated BRCA1/2 mutation ovarian cancer (BMOC) patients.

OBJECTIVES: The hallmarks of germline(g) and/or somatic(s) BRCA1/2 mutation ovarian cancer (BMOC) patients are increased sensitivity to platinum-based chemotherapy (PCT) and PARP inhibitors (PARPi). There is little information on the effectiveness of chemotherapy in heavily pretreated (≥3 CT lines) g/sBMOC patients. METHODS: g/sBMOC patients who received CT from 2006 to 2016 at 4 cancer centers in Spain were selected. Overall survival (OS) and time to progression (TTP) were calculated with Kaplan Meier and Cox models. RESULTS: 135 g/sBMOC patients were identified (6% sBRCA1/2 mutations). The median number of chemotherapy lines was 2 (1-7). The 6-years OS rate was 69.4% and 71% in BRCA1 or BRCA2 mutation carriers (p = 0.98). A total of 57 (42%) patients had ≥3 CT lines (3-7), which encompassed a total of 155 treatments. The median overall TTP across all treatment lines beyond 2nd line was 10.2 months (CI 95% 8.4-11.9 months). In the platinum-sensitive setting, TTP was improved with PCT plus PARPi (17.1 m), PCT (12.6 m) or PARPi (12.4 m) versus non-PCT (4.9 m; p < 0.001 all comparisons). In the platinum-resistant setting, these differences in TTP were not statistically significant. A multivariate model confirmed that primary platinum-free interval (PFI) > 12 months and exposure to PCT and PARPi associated with improved outcomes. PARPi exposure did not compromise benefit of subsequent CT beyond 2nd relapse. CONCLUSIONS: Heavily pretreated g/sBMOC demonstrated CT sensitivity, including for non-PCT choices. Primary platinum-free interval (PFI) >12 months and exposure to both platinum-based chemotherapy and PARPi associate with improved prognosis in heavily pretreated g/sBMOC patients.

Long-term affected flat oyster (Ostrea edulis) haemocytes show differential gene expression profiles from naïve oysters in response to Bonamia ostreae.

European flat oyster (Ostrea edulis) production has suffered a severe decline due to bonamiosis. The responsible parasite enters in oyster haemocytes, causing an acute inflammatory response frequently leading to death. We used an immune-enriched oligo-microarray to understand the haemocyte response to Bonamia ostreae by comparing expression profiles between naïve (NS) and long-term affected (AS) populations along a time series (1 d, 30 d, 90 d). AS showed a much higher response just after challenge, which might be indicative of selection for resistance. No regulated genes were detected at 30 d in both populations while a notable reactivation was observed at 90 d, suggesting parasite latency during infection. Genes related to extracellular matrix and protease inhibitors, up-regulated in AS, and those related to histones, down-regulated in NS, might play an important role along the infection. Twenty-four candidate genes related to resistance should be further validated for selection programs aimed to control bonamiosis.

Performance and precision of double digestion RAD (ddRAD) genotyping in large multiplexed datasets of marine fish species.

The development of Genotyping-By-Sequencing (GBS) technologies enables cost-effective analysis of large numbers of Single Nucleotide Polymorphisms (SNPs), especially in "non-model" species. Nevertheless, as such technologies enter a mature phase, biases and errors inherent to GBS are becoming evident. Here, we evaluated the performance of double digest Restriction enzyme Associated DNA (ddRAD) sequencing in SNP genotyping studies including high number of samples. Datasets of sequence data were generated from three marine teleost species (>5500 samples, >2.5 × 1012 bases in total), using a standardized protocol. A common bioinformatics pipeline based on STACKS was established, with and without the use of a reference genome. We performed analyses throughout the production and analysis of ddRAD data in order to explore (i) the loss of information due to heterogeneous raw read number across samples; (ii) the discrepancy between expected and observed tag length and coverage; (iii) the performances of reference based vs. de novo approaches; (iv) the sources of potential genotyping errors of the library preparation/bioinformatics protocol, by comparing technical replicates. Our results showed use of a reference genome and a posteriori genotype correction improved genotyping precision. Individual read coverage was a key variable for reproducibility; variance in sequencing depth between loci in the same individual was also identified as an important factor and found to correlate to tag length. A comparison of downstream analysis carried out with ddRAD vs single SNP allele specific assay genotypes provided information about the levels of genotyping imprecision that can have a significant impact on allele frequency estimations and population assignment. The results and insights presented here will help to select and improve approaches to the analysis of large datasets based on RAD-like methodologies.

Spontaneous cerebrospinal fluid leaks in the anterior skull base: a surgical challenge.

OBJECTIVE: This retrospective study aimed to evaluate the effective closure rate for spontaneous cerebrospinal fluid leaks with functional endoscopic sinus surgery and identify patient characteristics that may be associated with a need for additional therapy. METHOD: A retrospective analysis of patients with spontaneous cerebrospinal fluid leaks was performed. Data on the nature of presentation, patient body mass index, defect location and size, intracranial pressure, clinical follow up, and complications were collected. RESULTS: Twenty-five patients had spontaneous cerebrospinal fluid leaks with evidence of idiopathic intracranial hypertension. The most common sites were the cribriform plate, followed by the ethmoid roof and sphenoid lateral pterygoid recess. All patients underwent endonasal endoscopic surgery to repair the defect. Post-operatively, all patients underwent lumbar drainage and acetazolamide therapy. CONCLUSION: Spontaneous cerebrospinal fluid leaks represent a surgical challenge because of their high recurrence rates. The most important factor for obtaining a successful repair in these patients is reducing their intracranial pressure through nutritional, medical or surgical means.

[Positron emission tomography/computed tomography for lung cancer staging]. / Rendimiento del Positron Emission Tomography/Computed Tomography (PET/CT) en etapificación de cáncer pulmonar.

BACKGROUND: PET/CT (Positron Emission Tomography/Computed Tomography) is widely used in nodal and metastatic staging of lung cancer patients. AIM: To analyze PET/CT detection of metastatic disease in patients with lung cancer. MATERIAL AND METHODS: We reviewed retrospectively F18Fluorodeoxyglucose PET/CT scans performed between December 2008 and December 2013. We selected 143 patients aged 30 to 92 years (63% males) with confirmed lung cancer referred for staging, with no previous treatment. We reviewed whole body PET/CT and brain magnetic resonance images. SUVmax (Standardized Uptake Value maximum) of primary pulmonary lesion, hilar/mediastinal nodes, and distant metastases were calculated. RESULTS: Histological types encountered were adenocarcinoma in 55%, squamous-cell in 15%, small-cell in 8%, large-cell in 6% and adeno-squamous in 2%. In 22 cases (15%) histology was not available. Nodal involvement was observed in 60% of patients (44% hilar and 48% mediastinal). Skip metastases (mediastinal involvement without hilum involvement) were encountered in 17% of cases, and were significantly more common among high uptake lung tumors (p < 0.01). Best SUVmax cut-off for node involvement was 4.4 for hilum and 4.0 for mediastinum (sensibility: 86.4%, specificity: 99.8%). Sixty six patients (46.2%) showed distant metastases on PET/CT. The most common metastases were osseous in 22%, adrenal in 16%, hepatic in14%, pulmonary in 14% and cerebral in 12%. PET/CT detected a second unexpected synchronic cancer in eight patients (6%). CONCLUSIONS: PET/CT is accurate for nodal staging using an uptake index as SUVmax. Distant metastases are common, especially in bone, adrenal glands and liver.

The regulation of neuronal mitochondrial metabolism by calcium.

Calcium signalling is fundamental to the function of the nervous system, in association with changes in ionic gradients across the membrane. Although restoring ionic gradients is energetically costly, a rise in intracellular Ca(2+) acts through multiple pathways to increase ATP synthesis, matching energy supply to demand. Increasing cytosolic Ca(2+) stimulates metabolite transfer across the inner mitochondrial membrane through activation of Ca(2+) -regulated mitochondrial carriers, whereas an increase in matrix Ca(2+) stimulates the citric acid cycle and ATP synthase. The aspartate-glutamate exchanger Aralar/AGC1 (Slc25a12), a component of the malate-aspartate shuttle (MAS), is stimulated by modest increases in cytosolic Ca(2+) and upregulates respiration in cortical neurons by enhancing pyruvate supply into mitochondria. Failure to increase respiration in response to small (carbachol) and moderate (K(+) -depolarization) workloads and blunted stimulation of respiration in response to high workloads (veratridine) in Aralar/AGC1 knockout neurons reflect impaired MAS activity and limited mitochondrial pyruvate supply. In response to large workloads (veratridine), acute stimulation of respiration occurs in the absence of MAS through Ca(2+) influx through the mitochondrial calcium uniporter (MCU) and a rise in matrix [Ca(2+) ]. Although the physiological importance of the MCU complex in work-induced stimulation of respiration of CNS neurons is not yet clarified, abnormal mitochondrial Ca(2+) signalling causes pathology. Indeed, loss of function mutations in MICU1, a regulator of MCU complex, are associated with neuromuscular disease. In patient-derived MICU1 deficient fibroblasts, resting matrix Ca(2+) is increased and mitochondria fragmented. Thus, the fine tuning of Ca(2+) signals plays a key role in shaping mitochondrial bioenergetics.

Oral immunostimulation of the oyster Ostrea edulis: Impacts on the parasite Bonamia ostreae.

Bioactive compounds were orally administered to the native European oyster Ostrea edulis to evaluate the immune response and the progression of infection of the protozoan parasite Bonamia ostreae. The immunostimulants lipopolysaccharide and zymosan directly administrated to the water column induced an increase in lysozyme activity and the percentage of granulocytes in naïve oysters over a period of 7 days. In another set of experiments, zymosan and curdlan were microencapsulated in alginate and also administered to the water column to naïve and B. ostreae infected O. edulis. Oyster mortality, prevalence and intensity of infection and several immune parameters were evaluated up to 28 days post-administration. Lysozyme activity, nitric oxide production and the expression of galectin, lysozyme and superoxide dismutase increased after 24 h in both infected and uninfected oysters. Zymosan immunostimulated oysters displayed a decrease in the prevalence of B. ostreae infection not attributed to mortalities but which could be associated to the enhanced ability of immunostimulants to evoke an enhanced immune response in the oysters and reduce infection.

Rendimiento del Positron Emission Tomography/Computed Tomography (PET/CT) en etapificación de cáncer pulmonar / Positron emission tomography/computed tomography for lung cancer staging

Background: PET/CT (Positron Emission Tomography/Computed Tomography) is widely used in nodal and metastatic staging of lung cancer patients. Aim: To analyze PET/CT detection of metastatic disease in patients with lung cancer. Material and Methods: We reviewed retrospectively F18Fluorodeoxyglucose PET/CT scans performed between December 2008 and December 2013. We selected 143 patients aged 30 to 92 years (63% males) with confirmed lung cancer referred for staging, with no previous treatment. We reviewed whole body PET/CT and brain magnetic resonance images. SUVmax (Standardized Uptake Value maximum) of primary pulmonary lesion, hilar/mediastinal nodes, and distant metastases were calculated. Results: Histological types encountered were adenocarcinoma in 55%, squamous-cell in 15%, small-cell in 8%, large-cell in 6% and adeno-squamous in 2%. In 22 cases (15%) histology was not available. Nodal involvement was observed in 60% of patients (44% hilar and 48% mediastinal). Skip metastases (mediastinal involvement without hilum involvement) were encountered in 17% of cases, and were significantly more common among high uptake lung tumors (p < 0.01). Best SUVmax cut-off for node involvement was 4.4 for hilum and 4.0 for mediastinum (sensibility: 86.4%, specificity: 99.8%). Sixty six patients (46.2%) showed distant metastases on PET/CT. The most common metastases were osseous in 22%, adrenal in 16%, hepatic in14%, pulmonary in 14% and cerebral in 12%. PET/CT detected a second unexpected synchronic cancer in eight patients (6%). Conclusions: PET/CT is accurate for nodal staging using an uptake index as SUVmax. Distant metastases are common, especially in bone, adrenal glands and liver.

Phase I study of weekly kahalalide F as prolonged infusion in patients with advanced solid tumors.

PURPOSE: Kahalalide F (KF) is a dehydroaminobutyric acid-containing peptide from marine origin with activity against several human malignant cell lines. This dose-escalating phase I clinical trial evaluated the maximum tolerated dose (MTD), and the recommended dose for further phase II studies (RD) of weekly KF given as a prolonged (3- to 24-h) intravenous (i.v.) infusion. METHODS: Eligible patients with advanced solid tumors and adequate performance status, hematologic, renal, and hepatic function were recruited into this study. RESULTS: A total of 106 patients were treated with KF at four different weekly schedules: 3-h (n = 40), 24-h (n = 59), and two transitional schedules [6-h (n = 4) and 12-h (n = 3)]. For the 3-h weekly schedule, the MTD was 1,200 µg/m² and the RD was 1,000 µg/m². For the 24-h weekly schedule, the MTD was reached (6,650 µg/m²), but the RD could not be confirmed. Asymptomatic and reversible grade 3/4 transaminase increase was the most common dose-limiting toxicity in both schedules. Fatigue, paresthesia, pruritus, nausea, vomiting, and rash were the most common KF-related adverse events. No major deviations from linearity were detected in the pharmacokinetic (PK) profiles of both schedules, which showed a narrow distribution and short body residence. Prolonged disease stabilization (≥3 months) occurred in eight patients: two with the 3-h schedule and six with the 24-h schedule. CONCLUSIONS: Administration of KF as prolonged weekly infusion appears feasible, with 3-h and 24-h infusion times having an acceptable safety profile.

Effectiveness of a health professional training program for treatment of tobacco addiction.

INTRODUCTION: Advice can have a small but clinically important effect in promoting smoking cessation. Where studied, the rate of delivery has been found to be low. Training has been found to increases this rates, but there is little research on effectiveness in terms of smoking cessation rates. This study aimed to assess the effectiveness and cost-effectiveness of an health professionals educational program to increase long-term rates of nicotine abstinence in smoking outpatients. METHODS: We conducted a pragmatic cluster-randomized, controlled trial in 35 primary health care centers in Spain. Participants were all 830 health professionals who attended 5,970 smokers during recruiting period. After that we measured continuous abstinence 6 months after the intervention and biochemically validated (saliva cotinine test) 1 year following intervention. Cost-effectiveness was measured in terms of cost per life year gained. RESULTS: After 6 months, the rate of continuous abstinence was significantly higher in the intervention group (2.1% vs. 0.3%, p > .0001) with an odds ratio of 6.5 (95% CI = 3.3-12.7). After 1 year, biochemical validation was performed on 31 of the 67 patients previously registered as abstinent. All of them were abstinent and belonged to intervention group. The incremental cost per life year gained after 6 months was €969. CONCLUSIONS: A primary care training program on smoking cessation based on scientific evidence, behavioral theory, and active learning methods increases long-term continuous nicotine abstinence rate among outpatients in a significant way. These may be relevant for planning training of professionals, clinical assistance, and public health programs.

Uncovering QTL for resistance and survival time to Philasterides dicentrarchi in turbot (Scophthalmus maximus).

Disease resistance-related traits have received increasing importance in aquaculture breeding programs worldwide. Currently, genomic information offers new possibilities in breeding to address the improvement of this kind of traits. The turbot is one of the most promising European aquaculture species, and Philasterides dicentrarchi is a scuticociliate parasite causing fatal disease in farmed turbot. An appealing approach to fight against disease is to achieve a more robust broodstock, which could prevent or diminish the devastating effects of scuticociliatosis on farmed individuals. In the present study, a genome scan for quantitative trait loci (QTL) affecting resistance and survival time to P. dicentrarchi in four turbot families was carried out. The objectives were to identify QTL using different statistical approaches [linear regression (LR) and maximum likelihood (ML)] and to locate significantly associated markers for their application in genetic breeding strategies. Several genomic regions controlling resistance and survival time to P. dicentrarchi were detected. When analyzing each family separately, significant QTL for resistance were identified by the LR method in two linkage groups (LG1 and LG9) and for survival time in LG1, while the ML methodology identified QTL for resistance in LG9 and LG23 and for survival time in LG6 and LG23. The analysis of the total data set identified an additional significant QTL for resistance and survival time in LG3 with the LR method. Significant association between disease resistance-related traits and genotypes was detected for several markers, a single one explaining up to 22% of the phenotypic variance. Obtained results will be essential to identify candidate genes for resistance and to apply them in marker-assisted selection programs to improve turbot production.

Exploitation of a turbot (Scophthalmus maximus L.) immune-related expressed sequence tag (EST) database for microsatellite screening and validation.

In this study, we identified and characterized 160 microsatellite loci from an expressed sequence tag (EST) database generated from immune-related organs of turbot (Scophthalmus maximus). A final set of 83 new polymorphic microsatellites were validated after the analysis of 40 individuals of Atlantic origin including both wild and farmed individuals. The allele number and the expected heterozygosity ranged from 2 to 18 and from 0.021 to 0.951, respectively. Evidences of null alleles at moderate-high frequencies were detected at six loci using population data. None of the analysed loci showed deviations from Mendelian segregation after the analysis of five full-sib families including approximately 92 individuals/family. The markers are used to consolidate the turbot genetic map, and because they are mostly EST-derived, they will be very useful for comparative genomic studies within flatfishes and with model fish species. Using an in silico approach, we detected significant homologies of microsatellite sequences with the EST databases of the flatfish species with highest genomic resources (Senegalese sole, Atlantic halibut, bastard halibut) in 31% of these turbot markers. The conservation of these microsatellites within Pleuronectiformes will pave the way for anchoring genetic maps of different species and identifying genomic regions related to productive traits.

Photoinduced phase transitions by time-resolved far-infrared spectroscopy in V2O3.

Using time-resolved far-infrared spectroscopy, we observe multiple routes for photoinduced phase transitions in V(2)O(3). This includes (i) a photothermal antiferromagnetic to paramagnetic transition and (ii) an incipient strain-generated paramagnetic metal to paramagnetic insulator transition, which manifests as coherent oscillations in the far-infrared conductivity. The ∼100 ps conductivity oscillation results from coherent acoustic phonon modulation of the bandwidth W. Our results indicate that poor metals are particularly amenable to coherent strain control of their electronic properties.

One year oral Toxicity of D-004, a lipid extract from Roystonea regia fruits, in Sprague Dawley rats.

D-004, a lipid extract of royal palm (Roystonea regia) fruits that contains a reproducible mixture of fatty acids, has been shown to prevent testosterone and phenylephrine-induced prostate hyperplasia in rodents. This study investigated the long-term oral toxicity of D-004 in rats. Rats from both sexes were randomized into four groups (20 rats sex/group): a control and three treated with D-004 (800, 1500 or 2000 mg/kg/day, respectively). At study completion, rats were sacrificed under anaesthesia. Determinations of blood biochemical and haematological parameters and organ weight were done. Also, necropsy and histopathological studies were performed. Four of 160 rats died before study completion. No clinical signs of toxicity were observed throughout the study. Food and water consumption, bodyweight, blood biochemical and haematological parameters, organ weight ratios and histopathological findings were similar in control and treated groups. The histological lesions found in treated animals are commonly present in this specie and strain according to literature and our historical data. In conclusion, long-term (12 months) oral treatment of rats with D-004 (800-2000 mg/kg/day) did not show evidences of D-004-related toxicity under our conditions. The highest dose tested (2000 mg/kg) was a no-observed adverse effect level in this study.