Dose and time effects of solar-simulated ultraviolet radiation on the in vivo human skin transcriptome.

BACKGROUND: Terrestrial ultraviolet (UV) radiation causes erythema, oxidative stress, DNA mutations and skin cancer. Skin can adapt to these adverse effects by DNA repair, apoptosis, keratinization and tanning. OBJECTIVES: To investigate the transcriptional response to fluorescent solar-simulated radiation (FSSR) in sun-sensitive human skin in vivo. METHODS: Seven healthy male volunteers were exposed to 0, 3 and 6 standard erythemal doses (SED). Skin biopsies were taken at 6 h and 24 h after exposure. Gene and microRNA expression were quantified with next generation sequencing. A set of candidate genes was validated by quantitative polymerase chain reaction (qPCR); and wavelength dependence was examined in other volunteers through microarrays. RESULTS: The number of differentially expressed genes increased with FSSR dose and decreased between 6 and 24 h. Six hours after 6 SED, 4071 genes were differentially expressed, but only 16 genes were affected at 24 h after 3 SED. Genes for apoptosis and keratinization were prominent at 6 h, whereas inflammation and immunoregulation genes were predominant at 24 h. Validation by qPCR confirmed the altered expression of nine genes detected under all conditions; genes related to DNA repair and apoptosis; immunity and inflammation; pigmentation; and vitamin D synthesis. In general, candidate genes also responded to UVA1 (340-400 nm) and/or UVB (300 nm), but with variations in wavelength dependence and peak expression time. Only four microRNAs were differentially expressed by FSSR. CONCLUSIONS: The UV radiation doses of this acute study are readily achieved daily during holidays in the sun, suggesting that the skin transcriptional profile of 'typical' holiday makers is markedly deregulated. What's already known about this topic? The skin's transcriptional profile underpins its adverse (i.e. inflammation) and adaptive molecular, cellular and clinical responses (i.e. tanning, hyperkeratosis) to solar ultraviolet radiation. Few studies have assessed microRNA and gene expression in vivo in humans, and there is a lack of information on dose, time and waveband effects. What does this study add? Acute doses of fluorescent solar-simulated radiation (FSSR), of similar magnitude to those received daily in holiday situations, markedly altered the skin's transcriptional profiles. The number of differentially expressed genes was FSSR-dose-dependent, reached a peak at 6 h and returned to baseline at 24 h. The initial transcriptional response involved apoptosis and keratinization, followed by inflammation and immune modulation. In these conditions, microRNA expression was less affected than gene expression.

Pilot study of a novel pain management strategy: evaluating the impact on patient outcomes.

BACKGROUND: Our objective was to evaluate the impact of a novel multimodal pain management strategy on intraoperative opioid requirements, postoperative pain, narcotic use, and length of stay. METHODS: Consecutive patients undergoing elective laparoscopic colorectal resection were managed with an experimental protocol. The protocol uses a post-induction, pre-incision bilateral TAP block and local peritoneal infiltration at port sites with long-acting liposomal bupivacaine (20 mL long-acting liposomal bupivacaine, 30 mL 0.25 % bupivacaine, 30 mL saline). Experimental patients were matched on age, body mass index, gender, comorbidity, diagnosis, and procedure to a control group that received no block or local wound infiltration. Both groups followed a standardized enhanced recovery pathway. Demographics, perioperative, and postoperative outcomes were evaluated. The main outcome measures were intraoperative opioids, postoperative pain, opioid use, and length of stay. RESULTS: Fifty patients were analyzed-25 experimental and 25 controls. Patients were well matched on all demographics. In both cohorts, the main diagnosis was colorectal cancer and primary procedure performed a segmental resection. Operative times were similar (p = 0.41). Experimental patients received significantly less intraoperative fentanyl (mean 158 mcg experimental vs. 299 mcg control; p < 0.01). The experimental group had significantly lower initial (p < 0.01) and final PACU pain scores (p = 0.04) and shorter LOS (3.0 vs. 4.1 days, p = 0.04) compared to controls. Experimental patients trended toward shorter PACU times and lower opioid use and daily pain scores throughout the hospital stay. Postoperative complication and readmission rates were similar across groups. There were no reoperations or mortality. CONCLUSIONS: Our multimodal pain management strategy reduced intraoperative opioid administration. Postoperatively, improvements in PACU time, postoperative pain and narcotic use, and lengths of stay were seen in the experimental cohort. With the favorable finding from the pilot study, further investigation is warranted to fully evaluate the impact of this pain management protocol on patient satisfaction, clinical and financial outcomes.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Temporomandibular joint dysfunction in various rheumatic diseases.

Temporomandibular disorder (TMD) is an inclusive term in which those conditions disturbing the masticatory function are embraced. It has been estimated that 33% of the population have signs of TMD, but less than 5% of the population will require treatment. The objective of this study was to measure the frequency of TMD in rheumatoid arthritis (RA), osteoarthrosis (OA), ankylosing spondylitis (AS) and systemic lupus erythematosus, and to define the limitations in everyday's life that patients perceive when present. A six-month survey of consecutive outpatients in a rheumatology clinic in a teaching hospital in Mexico was carried out. We defined TMD as: 1) the presence of pain; 2) difficulty on mouth opening, chewing or speaking; 3) the presence of non-harmonic movements of the temporomaxilar joints. All three characteristics had to be present. Z test was used to define differences between proportions. We present the results of 171 patients. Overall, 50 patients had TMD according to our operational definition (29.24%). Up to 76% of the sample had symptoms associated with the condition. TMD is more frequent in OA and in AS (29.24% vs 38% OA, P=0.009; 39% AS; P=0.005). We found no association between the severity of TMD and the request for specific attention for the discomfort produced by the condition. Only 8 of 50 (16%) patients with TMD had requested medical help for their symptoms, and they were not the most severe cases. TMD is more frequent in RA and OA. Although it may produce severe impairment, patients seem to adapt easily.

Influence of fetal glutathione S-transferase copy number variants on adverse reproductive outcomes.

A nested case-control association study was designed to investigate the influence of maternal and fetal copy number variants (CNVs) on reproductive outcomes. Genotypes of ten CNVs encompassing GST and CYP genes were assessed. Significant associations were only found for child CNV genotypes. In particular, the child GSTM1 insertion allele was associated with prematurity protection (odds ratio, 95% CI: 0.67, 0.51-0.89; P < 0.01), whereas the child GSTT2B insertion allele was associated with an increased risk of being small for gestational age (odds ratio, 95% CI: 1.33, 1.07-1.67; P = 0.01). The study highlights the role of the fetal genome in prenatal development and also the need to analyse CNVs in a systematic manner.

Plasmon-exciton interactions on single thermoresponsive platforms demonstrated by optical tweezers.

Optical and hydrodynamic-size studies on single bare thermo-responsive microspheres, and microspheres covered either with Au nanoparticles, CdSe/CdS quantum dots, or a combination of both have been performed by optical tweezers. The photothermal heating of water in the focal region boosts the shrinkage of the microspheres, an effect that is intensified in the presence of Au nanoparticles. In contrast, bigger microspheres are measured when they are covered with quantum dots. Plasmon-exciton interactions are observable in the trap in the combined Au and quantum dots hybrid systems.

[Valuation of automatized ASPECTS as an artificial intelligence tool in daily clinical]. / Valoración del ASPECTS automatizado como herramienta de inteligencia artificial en la práctica clínica diaria.

AIMS: To evaluate an automated ASPECTS (ASPECTS-a) software against two radiologists' reading of CT scans requested from the Emergency Department. Describe the most frequent failures of the ASPECTS-a. MATERIAL AND METHODS: All the cranial CT Scans requested by the Emergency Department in one month were collected. The following data were recorded: age, sex, the reason for requesting the study, and imaging findings. A program was used that provides an ASPECTS score automatically. Subsequently, 2 radiologists independently reviewed all of the studies and provided the visual ASPECTS (ASPECTS-v). In case of discrepancy, a new reading was made by consensus. RESULTS: A total of 295 brain CT scans (45.1% male) with a mean age of 65 ± 20.0 years were included. 91.8% were interpreted as ASPECTS-v 10 in both cerebral hemispheres by both readers. ASPECTS-a scored 45% with ASPECTS 10 in both cerebral hemispheres. In 152 (51.5%) the ASPECTS-a and the ASPECTS-v did not coincide. The causes of the discrepancy were mainly due to segmentation errors (usually due to asymmetric atrophies). Most of the segmentation errors were located in the head of the caudate nucleus, observed in 60 studies. CONCLUSIONS: ASPECTS-a is a powerful and helpful tool, but human supervision is always necessary, particularly in groups of patients with pre-existing brain changes.

TITLE: Valoración del ASPECTS automatizado como herramienta de inteligencia artificial en la práctica clínica diaria.Objetivos. Evaluar un software del Alberta Stroke Program Early CT Score (ASPECTS) automatizado (ASPECTS-a) frente a la lectura de dos radiólogos en las tomografías computarizadas (TC) solicitadas desde el servicio de urgencias. Describir los fallos más frecuentes del ASPECTS-a. Material y métodos. Se recogieron las TC cerebrales solicitadas por el servicio de urgencias en el período de un mes. Se registraron los siguientes datos: edad, sexo, motivo de solicitud del estudio y hallazgos en la prueba de imagen. Se utilizó un programa que proporciona una puntuación del ASPECTS automáticamente. Posteriormente, dos radiólogos examinaron de forma independiente todos los estudios y realizaron un ASPECTS visual (ASPECTS-v). En caso de discrepancia, se hizo una nueva lectura en consenso. Se compararon los resultados del ASPECTS-a con el ASPECTS-v. Resultados. Se realizaron un total de 295 TC cerebrales urgentes con una edad media de 65 ± 20 años. El 91,8% lo interpretaron los dos lectores como ASPECTS 10 en ambos hemisferios cerebrales. El ASPECTS-a puntuó el 45% con ASPECTS 10 en ambos hemisferios cerebrales. En 152 (51,5%), el ASPECTS-a y el ASPECTS-v no coincidieron. Las causas de la discrepancia fueron fundamentalmente por errores en la segmentación (generalmente por atrofias asimétricas). La mayor parte de los errores en la segmentación se localizaban en la cabeza del núcleo caudado, lo que se observó en 60 estudios. Conclusiones. El ASPECTS-a es una herramienta potente y de gran ayuda, pero siempre es necesaria una supervisión humana, particularmente en grupos de pacientes con cambios cerebrales preexistentes.

E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models.

The thymidine kinase/ganciclovir (TK/GCV) cancer gene therapy approach is based on inducing GCV metabolite cytotoxicity in tumor cells expressing the herpes simplex virus TK gene and exposed to GCV. A bystander effect, mediated by gap junctions, accounts for the transfer of toxic metabolites from TK-expressing cells to neighboring cells. It has been proposed that E-cadherin participates in the formation and function of such gap junctions. In this study we investigate the influence of E-cadherin on TK/GCV suicide therapy with a panel of cellular and in vivo models of pancreatic ductal adenocarcinoma. We observed a strong correlation of E-cadherin expression and the TK/GCV bystander effect, associated with the modulation of gap junction communication and connexin expression or localization. Importantly, the co-expression of TK and E-cadherin genes in the adenoviral vector AdTat8TKIE improved TK/GCV cytotoxicity and triggered a potent antitumoral effect, superior to standard AdTat8TK/GCV in MIAPaCa-2 xenografts. The increased expression of E-cadherin resulted in the reduction of the bcl-2 content. Interestingly, the knockdown of bcl-2 sensitized cells to TK/GCV. Thus, we propose that by restoring E-cadherin in pancreatic tumor cells we will improve TK/GCV therapy, both by enhancing the bystander effect and by facilitating the induction of apoptosis.

Analysis of direct, indirect, and intangible costs of epilepsy.

INTRODUCTION: A financial estimate has been made of the costs of epilepsy in adults. METHODS: A prospective, observational study, over a period of 6 months, on epileptic patients over 14 years-old. Patients with concomitant diseases that could influence the outcome of the epilepsy were excluded. The direct costs included: treatment received, number of visits to neurology, primary care, and emergencies, number of days admitted to hospital, number and type of diagnostic tests, use of transport to and from hospital, and psychopedagogic and social support due to the epilepsy. The indirect costs were analysed according to, loss of work productivity of the patients, taking into account families where the patient needed supervision due to epilepsy. The total costs were derived from the sum of the direct and indirect costs. The intangible costs were calculated according to QOLIE-10 questionnaire. RESULTS: The mean direct cost per patient was 1,055.2 €. The mean indirect financial costs came to 1,528.8 € per patient. The total cost associated to epilepsy was a mean of 2,584 € for each patient, mainly arising from loss of work days (p<.05). For intangible costs according to the QOLIE-10 scale a mean of 77.8 was obtained. CONCLUSIONS: The greatest percentage of costs associated to epilepsy is due to the work productivity loss by the patients. The costs of psychological and social suffering in epilepsy lead to a deterioration in the quality of life.

Progression of a series of patients with relapsing-remitting multiple sclerosis treated for 7 years with natalizumab using the "no evidence of disease activity" parameter.

INTRODUCTION: The safety and effectiveness of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in clinical trials. However, due to the limitations of these trials, it is important to know how the condition behaves under long-term clinical practice conditions. OBJECTIVE: To determine the long-term effectiveness of natalizumab in patients with RRMS by means of annual evaluation of the "no evidence of disease activity" (NEDA) parameter, which includes number of relapses, disability (measured with the Expanded Disability Status Scale), and brain MRI parameters. PATIENTS AND METHODS: We performed a retrospective study of patients with RRMS from 3 centres who were treated with one or more doses of natalizumab. Each year, we evaluated NEDA status and safety based on the percentage of patients who discontinued treatment with natalizumab and experienced adverse reactions. RESULTS: The study included 89 patients, most of whom received treatment for 2 to 4 years, with a follow-up period of up to 7 years. Natalizumab significantly reduces the radiological and clinical progression of the disease, as well as the annual rate of relapses. The NEDA parameter demonstrates the effectiveness of the drug, with values of 75.28% for year one and 66.67% for year 7. Twenty-five patients (28.1%) dropped out after a median of 4 years. Fourteen of these patients (56%) dropped out due to the appearance of anti-JC virus antibodies, either in isolation or associated with another cause. Four dropouts (16%) were due to treatment ineffectiveness, with one patient dying due to progressive multifocal leukoencephalopathy. CONCLUSIONS: Natalizumab is highly effective as measured by the NEDA long-term remission parameter.

Endourological treatment for lumbar ureteral stones. What are the benefits of flexible ureterorenoscopy?

INTRODUCTION AND OBJECTIVES: Currently, there are no established criteria regarding treatment for lumbar ureteral stones. The objective of this work is to present our results in the endourological treatment of this pathology, analyzing the variables associated with the use of the flexible ureterorenoscope. MATERIAL AND METHODS: Retrospective review of 103 patients who underwent retrograde URS with semi-rigid or flexible ureterorenoscope. Proximal location: L2-L3. Medial location: L4-L5. Semirigid URS was the initial treatment, with conversion to flexible URS when it was required to complete the procedure. Success was defined as absence of residual fragments (6 weeks). Demographic, surgical, immediate postoperative variables, and those related to the stone, were analyzed. Their correlation with the use of the flexible ureterorenoscope was evaluated. RESULTS: Mean age: 57.2 years (SD 15.6); there were 73 men (70.9%). Stone size: 8 mm (range 4-30; IQR 4.5). Proximal location: 58 (56.3%). Previous JJ: 44.7%. Previous nephrostomy: 10.7%. Semirigid URS with conversion to flexible URS: 51 (49.5%). Impacted stones: 28.2%. Intraoperative complications: 2 (1.9%). Postoperative JJ: 84.5%. Immediate postoperative complications: 23 (22.3%) (Clavien-Dindo I-II: 91.3%). Postoperative ureteral stricture: 5.8%. Success: 88.4%. Residual fragments: 12 (11.7%). Spontaneous passage: 6 (50%). Greater performance of flexible URS in proximal ureteral stones (p = 0.001) of more than 11 mm (p = 0.02) in univariate analysis, and in proximal stones [OR 3.5; 1.5-8.1; p = 0.004] in multivariate analysis. CONCLUSIONS: Endourological treatment obtained a high success rate in our sample. Size greater than 11 mm and proximal ureteral location in univariate and multivariate analysis, respectively, behaved as predictors of flexible URS.

Endourological treatment for lumbar ureteral stones. What are the benefits of flexible ureterorenoscopy? / Tratamiento endourológico de la litiasis ureteral lumbar. ¿Qué aporta la ureterorrenoscopia flexible?

INTRODUCTION AND OBJECTIVES: Currently, there are no established criteria regarding treatment for lumbar ureteral stones. The objective of this work is to present our results in the endourological treatment of this pathology, analyzing the variables associated with the use of the flexible ureterorenoscope. MATERIAL AND METHODS: Retrospective review of 103 patients who underwent retrograde URS with semi-rigid or flexible ureterorenoscope. Proximal location: L2-L3. Medial location: L4-L5. Semirigid URS was the initial treatment, with conversion to flexible URS when it was required to complete the procedure. Success was defined as absence of residual fragments (6 weeks). Demographic, surgical, immediate postoperative variables, and those related to the stone, were analyzed. Their correlation with the use of the flexible ureterorenoscope was evaluated. RESULTS: Mean age: 57.2 years (SD 15.6); there were 73 men (70.9%). Stone size: 8mm (range 4-30; IQR 4.5). Proximal location: 58 (56.3%). Previous JJ: 44.7%. Previous nephrostomy: 10.7%. Semirigid URS with conversion to flexible URS: 51 (49.5%). Impacted stones: 28.2%. Intraoperative complications: 2 (1.9%). Postoperative JJ: 84.5%. Immediate postoperative complications: 23 (22.3%) (Clavien-Dindo I-II: 91.3%). Postoperative ureteral stricture: 5.8%. Success: 88.4%. Residual fragments: 12 (11.7%). Spontaneous passage: 6 (50%). Greater performance of flexible URS in proximal ureteral stones (P=0.001) of more than 11mm (P=0.02) in univariate analysis, and in proximal stones [OR 3.5; 1.5-8.1; P=0.004] in multivariate analysis. CONCLUSIONS: Endourological treatment obtained a high success rate in our sample. Size greater than 11mm and proximal ureteral location in univariate and multivariate analysis, respectively, behaved as predictors of flexible URS.

The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis.

Genome-wide association studies (GWAS) have revealed that different diseases share susceptibility variants. Twelve single-nucleotide polymorphisms (SNPs) previously associated with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls. Three SNPs were found to be associated with MS: rs1678542 in KIF5A (P=0.001, odds ratio (OR)=1.13, 95% confidence interval (CI)=1.05-1.23); rs3184504 in SH2B3 (P=0.00001, OR=1.19, 95% CI=1.10-1.27) and rs763361 in CD226 (P=0.00007, OR=1.16, 95%CI=1.08-1.25). These variants have previously been associated with rheumatoid arthritis and type 1 diabetes. The SH2B3 polymorphism has additionally been associated with systemic lupus erythematosus. Our results, in addition to validating some of these loci as risk factors for MS, are consistent with shared genetic mechanisms underlying different immune-mediated diseases. These data may help to shape the contribution of each pathway to different disorders.

Positionally cloned genes and age-specific effects in asthma and atopy: an international population-based cohort study (ECRHS).

BACKGROUND: Several genes identified by positional cloning have been associated with asthma and atopy, but few findings have been replicated. Age at onset of asthma has been associated with different phenotypic characteristics, and with variants at chromosome 17q21 identified through genome-wide association. This study examined the associations and age-specific effects on asthma, atopy and bronchial hyper-responsiveness (BHR) of five candidate genes previously identified by positional cloning (ADAM33, PHF11, NPSR1, DPP10, SPINK5). METHODS: 51 polymorphisms from 2474 participants from 13 countries who took part in the European Community Respiratory Health Survey (1990-2000) were studied. Asthma and age at onset of asthma were assessed by questionnaire data, BHR by methacholine challenge and atopy by specific immunoglobulin E to four common allergens. RESULTS: Significant associations with asthma, atopy and particularly for asthma with atopy were observed for a large region of 47 kb in the NPSR1 gene, even after Bonferroni correction for multiple comparisons (p<0.001). The associations with NPSR1 were stronger in those reporting a first attack of asthma before the age of 15, with statistically significant interactions with age of onset found for three SNPs. The evidence for ADAM33 and BHR and for an age-specific effect of two SNPs in DPP10 and asthma was weaker. CONCLUSION: This study provides further evidence for an effect of NPSR1 on asthma, atopy and atopic asthma. In addition, this analysis suggests a role for NPSR1 in early-onset asthma driven by the strong effect of this gene on atopic asthma.

[2 + 2] Photocycloaddition of 2(5H)-furanone to unsaturated compounds. insights from first principles calculations and transient-absorption measurements.

The [2 + 2] photocycloaddition reaction of 2(5H)-furanone to ethylene and acetylene has been investigated by means of DFT and CASSCF methods. In both cases, the reaction involves the formation of a triplet 1,4-biradical intermediate that evolves to the cyclobutane product after spin inversion. For acetylene, the lowest energy path in the triplet surface occurs through the (3)(pi-pi*) state of the 2(5H)-furanone. However, in the reaction with ethylene the lowest energy path in the triplet surface involves the (3)(pi-pi*) state of the alkene. Although reaction through the triplet state of olefins is usually disregarded due to the short lifetime of these species, we have experimentally measured that sensitization of ethylene triplet state can occur at typical synthetic conditions and, thus, lead to photochemical addition to the lactone.

Early life environment, neurodevelopment and the interrelation with atopy.

Both neurological and immunological systems are vulnerable to early life exposures. Neurological disorders and atopy have been related in animals and humans. Our main objective was to assess whether multiple exposures to early life determinants remain associated with neurodevelopment after considering the potential intermediate role of atopy. A second objective was to assess whether genes associated with atopy may inform about the potential neurotoxical mechanisms. Children were members of the AMICS birth cohort in Menorca (n=418, 87% of the recruited). General cognition was measured with the McCarthy Scales at age 4 and atopy through specific IgE at age 4 and prick test at age 6; 85 single nucleotide polymorphisms (SNPs) in 16 atopy and detoxification genes were genotyped. Among the 27 risk factors assessed, lower maternal social class, maternal smoking during pregnancy, being first born, shorter breastfeeding, higher DDT levels in cord blood, and higher indoor levels of NO2 (among the non-detoxifiers by GSTP1 polymorphism) were independently associated with poorer cognition. These associations were apparently not mediated by the relation between atopy and general cognition. Among the candidate atopic genes, variants in NQ01 (a detoxification gene) and NPRS1 (related with affective disorders like anxiety and stress management) had a significant association with general cognition (p-value<0.001). However, adjustment for the corresponding SNPs did not change the association between the early life determinants and general cognition. Multiple environmental pre-natal exposures were associated with neurodevelopment independently of their role in the immunological system. Atopic genes related to neurodevelopment suggest some potential mechanisms.

Single centrosome manipulation reveals its electric charge and associated dynamic structure.

The centrosome is the major microtubule-organizing center in animal cells and consists of a pair of centrioles surrounded by a pericentriolar material. We demonstrate laser manipulation of individual early Drosophila embryo centrosomes in between two microelectrodes to reveal that it is a net negatively charged organelle with a very low isoelectric region (3.1 +/- 0.1). From this single-organelle electrophoresis, we infer an effective charge smaller than or on the order of 10(3) electrons, which corresponds to a surface-charge density significantly smaller than that of microtubules. We show, however, that the charge of the centrosome has a remarkable influence over its own structure. Specifically, we investigate the hydrodynamic behavior of the centrosome by measuring its size by both Stokes law and thermal-fluctuation spectral analysis of force. We find, on the one hand, that the hydrodynamic size of the centrosome is 60% larger than its electron microscopy diameter, and on the other hand, that this physiological expansion is produced by the electric field that drains to the centrosome, a self-effect that modulates its structural behavior via environmental pH. This methodology further proves useful for studying the action of different environmental conditions, such as the presence of Ca(2+), over the thermally induced dynamic structure of the centrosome.

Joint effect of obesity and TNFA variability on asthma: two international cohort studies.

Obesity is a risk factor for asthma. Adipose tissue expresses pro-inflammatory molecules including tumour necrosis factor (TNF), and levels of TNF are also related to polymorphisms in the TNF-alpha (TNFA) gene. The current authors examined the joint effect of obesity and TNFA variability on asthma in adults by combining two population-based studies. The European Community Respiratory Health Survey and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults used comparable protocols, questionnaires and measures of lung function and atopy. DNA samples from 9,167 participants were genotyped for TNFA -308 and lymphotoxin-alpha (LTA) +252 gene variants. Obesity and TNFA were associated with asthma when mutually adjusting for their independent effects (odds ratio (OR) for obesity 2.4, 95% confidence interval (CI) 1.7-3.2; OR for TNFA -308 polymorphism 1.3, 95% CI 1.1-1.6). The association of obesity with asthma was stronger for subjects carrying the G/A and A/A TNFA -308 genotypes compared with the more common G/G genotype, particularly among nonatopics (OR for G/A and A/A genotypes 6.1, 95% CI 2.5-14.4; OR for G/G genotype 1.7, 95% CI 0.8-3.3). The present findings provide, for the first time, evidence for a complex pattern of interaction between obesity, a pro-inflammatory genetic factor and asthma.

Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: involvement of phospholipaseCgamma activity and glutamate receptor expression.

The involvement of brain-derived neurotrophic factor (BDNF) in cognitive processes and the decrease in its expression in Huntington's disease suggest that this neurotrophin may play a role in learning impairment during the disease progression. We therefore analyzed the onset and severity of cognitive deficits in two different mouse models with the same mutant huntingtin but with different levels of BDNF (R6/1 and R6/1:BDNF+/- mice). We observed that BDNF modulates cognitive function in different learning tasks, even before the onset of motor symptoms. R6/1:BDNF+/- mice showed earlier and more accentuated cognitive impairment than R6/1 mice at 5 weeks of age in discrimination learning; at 5 weeks of age in procedural learning; and at 9 weeks of age in alternation learning. At the earliest age at which cognitive impairment was detected, electrophysiological analysis was performed in the hippocampus. All mutant genotypes showed reduced hippocampal long term potentiation (LTP) with respect to wild type but did not show differences between them. Thus, we evaluated the involvement of BDNF-trkB signaling and glutamate receptor expression in the hippocampus of these mice. We observed a decrease in phospholipaseCgamma activity, but not ERK, in R61, BDNF+/- and R6/1:BDNF+/- hippocampus at the age when LTP was altered. However, a specific decrease in the expression of glutamate receptors NR1, NR2A and GluR1 was detected only in R6/1:BDNF+/- hippocampus. Therefore, these results show that BDNF modulates the learning and memory alterations induced by mutant huntingtin. This interaction leads to intracellular changes, such as specific changes in glutamate receptors and in BDNF-trkB signaling through phospholipaseCgamma.

Linkage disequilibrium between four MTTP gene polymorphisms in a Mexican population.

BACKGROUND: The microsomal triglyceride transfer protein plays an important role in the folding, assembling and secretion of lipoproteins that contain apoprotein B. Different polymorphisms in the MTTP gene have been associated with risk factors for coronary heart disease and diabetes, the first and fourth most common causes of death in Mexico, respectively. AIM: The objective of this study was to assess allele, genotype and haplotype frequencies of six MTTP polymorphisms in an unselected Mexican population. SUBJECTS AND METHODS: Six polymorphisms were analysed by DNA sequencing of polymerase chain reaction products in 155 Mexican individuals and Hardy-Weinberg equilibrium, genetic variability, linkage disequilibrium and neutrality test were evaluated. RESULTS: The rare alleles of the six polymorphisms analysed had frequencies greater than 1% and their genotype distributions were in accordance with Hardy-Weinberg equilibrium. All three promoter and I/T 128 polymorphisms were in linkage disequilibrium. Twelve different haplotypes were observed; GATGGT (70.44%) and TTCGGC (13.91%) were the most common. Diversity patterns in this Mexican population deviate significantly from expectations of the standard neutral model for infinite allele. CONCLUSION: The -493 G/T, -400 A/T, -164 T/C and I/T 128 polymorphisms can be useful for association studies in this population.