Induction of p38, tumour necrosis factor-α and RANTES by mechanical stretching of keratinocytes expressing mutant keratin 10R156H.

Background : Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma), characterized by ichthyotic, rippled hyperkeratosis, erythroderma and skin blistering, is a rare autosomal dominant disease caused by mutations in keratin 1 or keratin 10 (K10) genes. A severe phenotype is caused by a missense mutation in a highly conserved arginine residue at position 156 (R156) in K10. Objectives: To analyse molecular pathomechanisms of hyperproliferation and hyperkeratosis, we investigated the defects in mechanosensation and mechanotransduction in keratinocytes carrying the K10R156H mutation. Methods: Differentiated primary human keratinocytes infected with lentiviral vectors carrying wild-type K10 (K10wt) or mutated K10R156H were subjected to 20% isoaxial stretch. Cellular fragility and mechanosensation were studied by analysis of mitogen-activated protein kinase activation and cytokine release. Results: Cultured keratinocytes expressing K10R156H showed keratin aggregate formation at the cell periphery, whereas the filament network in K10wt cells was normal. Under stretching conditions K10R156H keratinocytes exhibited about a twofold higher level of filament collapse compared with steady state. In stretched K10R156H cells, higher p38 activation, higher release of tumour necrosis factor-alpha and RANTES but reduced interleukin-1 beta secretion compared with K10wt cells was observed. Conclusions: These results demonstrate that the R156H mutation in K10 destabilizes the keratin intermediate filament network and affects stress signalling and inflammatory responses to mechanical stretch in differentiated cultured keratinocytes.

Dental service utilization by Europeans aged 50 plus.

OBJECTIVES: To describe variations in the utilization of dental services by persons aged 50+ from 14 European countries and to identify the extent to which such variations are attributable to differences in oral health need and in accessibility of dental care. METHODS: We use data from the Survey of Health, Ageing, and Retirement in Europe (SHARE Waves 2 and 3) and estimate a series of multivariate logistic regression models to analyze variations in dental service utilization (overall dental attendance, preventive treatment and/or operative treatment, dental attendance in early life years) RESULTS: Overall dental attendance and incidence of solely preventive treatment are comparatively high in the Netherlands, Sweden, Denmark, Germany, and Switzerland. In contrast, overall dental attendance is relatively low in Spain, Italy, France, Greece, Poland, and Ireland. Moreover, a high incidence of solely operative treatment is observed in Austria, Italy, and France, whereas in the Netherlands, Sweden, Denmark, Switzerland, and Ireland, the incidence of solely operative treatment is comparably low. By and large, these variations persist even when controlling for cross-country differences in oral health need and in accessibility of dental care. CONCLUSIONS: In comparison with other European regions, there is a tendency toward more frequent and preventive dental treatment of the elderly populations residing in Scandinavia and Western Europe. Such utilization patterns appear only partially attributable to differences in need for and accessibility of dental care.

Sensores de reflectância e fluorescência na avaliação de teores de nitrogênio, produção de biomassa e produtividade do algodoeiro

O objetivo deste trabalho foi avaliar o potencial de utilização dos sensores de reflectância e fluorescência na avaliação de teores de N‑NO3‑ no pecíolo, na produção de biomassa e na produtividade do algodoeiro. Utilizou-se o delineamento experimental de blocos ao acaso em arranjo fatorial 3x4, com quatro repetições. Os tratamentos consistiram de três variedades de algodão (ST‑4288‑B2RF, ST‑4498‑B2RF e DP-164‑B2RF) e quatro doses de N (0, 45, 90 e 135 kg ha‑1). Aos 120 dias após a semeadura, foram realizadas leituras com sensores ópticos de reflectância e fluorescência. Não houve correlação significativa dos teores de N‑NO3‑ no pecíolo com os índices de reflectância; porém, houve correlação destes com a produção de biomassa (0,39) e a produtividade (0,32 a 0,41). Os índices do sensor de fluorescência correlacionaram-se significativamente com teores de N‑NO3‑ no pecíolo (0,34 a 0,61), produção de biomassa (0,30 a 0,53) e produtividade (0,34). Em comparação com os índices de reflectância, os de fluorescência apresentam maior capacidade de avaliar os teores de N‑NO3‑ no pecíolo, capacidade semelhante em detectar variação na biomassa e menor capacidade de detectar variação da produtividade do algodoeiro, quando se aplicam doses crescentes de N.

Scripta varia

Fragment d'une chronique rédigée en partie d'après Sigebert, de 991 à 1099 ; -- F. 97, Collection de lettres du XIIe siècle dont plusieurs se rattachent à l'histoire de Saint-Victor ; -- F. 159, Sur Otton, évêque de Padoue ; -- F. 164, Sur les maires du Palais ; -- F. 165, Chronique des rois de France de 985 à 1437 ; -- F. 172, Lettres du XIIIe siècle dont beaucoup sont de Clément IV, avec des statuas synodaux ; -- F. 266, Liste des évêques ayant siégé au concile de Latran en 1179 ; -- F. 270, Raimundus arbor philosophie amoris ; -- F. 297, Epitome super cognitione sui auctore Petro Seguier ; -- F. 368, Chronique de Normandie. Copiés sur le ms. Latin 14663, f. 168v.F. 392, Fragment de la chronique de Girard de Frachet.

Commentary : beyond vague causal effect estimation of obesity on health outcomes

In the current issue of epidemiology, Danaei and colleagues elegantly estimated both the direct effect and the indirect effect-that is, the effect mediated by blood pressure, cholesterol, glucose, fibrinogen, and high-sensitivity C-reactive protein-of body mass index (BMI) on the risk of coronary heart disease (CHD). they analyzed data from 9 cohort studies including 58,322 patients and 9459 CHD events, with baseline measurements between 1954 and 2001. Using sophisticated and cutting-edge methods for direct and indirect effect estimations, the authors estimated that half of the risk of overweight and obesity would be mediated by blood pressure, cholesterol, and glucose. Few additional percentage points of the risk would be mediated by fibrinogen and hs-CRP. How should we understand these estimates? Can we say that if obese persons reduce their body weight and reach a normal body weight, their excess risk of CHD would be reduced by half through an improvement in these mediators and by half through the reduction in BmI itself? Is that also true if these individuals are prevented from becoming obese in the first place? Can we also conclude that if these mediators are well controlled in obese individuals through other means than a body weight reduction, their excess risk of CHD would be reduced by half? Let us confront these estimates with observations from studies evaluating 2 interventions to reduce body weight, that is, bariatric surgery in patients with severe obesity and intensive lifestyle intervention in overweight patients with diabetes

Molecular predictors of gemcitabine response in pancreatic cancer.

Gemcitabine is one of the most used anti-neoplastic drugs with documented activity in almost all major localizations of cancer. In pancreatic cancer treatment, gemcitabine occupies a prominent place as a first line chemotherapy, partly because of the paucity of other efficacious chemotherapy options. In fact, only a minority of pancreatic cancer patients display a response or even stability of disease with the drug. There are currently no clinically applicable means of predicting which patient will derive a clinical benefit from gemcitabine although several proposed markers have been studied. These markers are proteins involved in drug up-take, activation and catabolism or proteins that define the ability of the cell to undergo apoptosis in response to the drug. Several of these markers are reviewed in this paper. We also briefly discuss the possible role of stem cells in drug resistance to gemcitabine.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

P-wave velocities of samples from the Penninic of the western Alps along NFP20-west seismic-reflection profiles

Using the transit pulse method, we have determined compressional wave velocities of rocks from various geological units belonging to the Penninic zone along the NFP20-West profiles of the Swiss western Alps. The velocities have been measured at confining pressures up to 400 MPa, along three orthogonal axes defined by the macrostructure of the rocks. The samples analysed show a degree of metamorphism ranging from greenschist to eclogite facies. This collection includes schists, dolomites, gneisses and ophiolitic rocks. The mean velocities range from 5.9 km/s for a quartzitic calcschist to 7.9 km/s for an eclogitic metagabbro. The velocity anisotropy is as high as 20 %. The range of acoustic impedance is wide, from 15 to 27 10(6) kg/m2s. From these measurements, normal incident reflection coefficients for likely rock assemblages within and between geological units were estimated in order to interpret zone of the strong reflections recorded along the seismic profiles. Reflection coefficients as high as 0.17 could be determined.

Neural plasticity associated with recently versus often heard objects.

In natural settings the same sound source is often heard repeatedly, with variations in spectro-temporal and spatial characteristics. We investigated how such repetitions influence sound representations and in particular how auditory cortices keep track of recently vs. often heard objects. A set of 40 environmental sounds was presented twice, i.e. as prime and as repeat, while subjects categorized the corresponding sound sources as living vs. non-living. Electrical neuroimaging analyses were applied to auditory evoked potentials (AEPs) comparing primes vs. repeats (effect of presentation) and the four experimental sections. Dynamic analysis of distributed source estimations revealed i) a significant main effect of presentation within the left temporal convexity at 164-215ms post-stimulus onset; and ii) a significant main effect of section in the right temporo-parietal junction at 166-213ms. A 3-way repeated measures ANOVA (hemisphere×presentation×section) applied to neural activity of the above clusters during the common time window confirmed the specificity of the left hemisphere for the effect of presentation, but not that of the right hemisphere for the effect of section. In conclusion, spatio-temporal dynamics of neural activity encode the temporal history of exposure to sound objects. Rapidly occurring plastic changes within the semantic representations of the left hemisphere keep track of objects heard a few seconds before, independent of the more general sound exposure history. Progressively occurring and more long-lasting plastic changes occurring predominantly within right hemispheric networks, which are known to code for perceptual, semantic and spatial aspects of sound objects, keep track of multiple exposures.

Quantitative Ultrasound of the Heel and Fracture Risk Assessment: an Updated Meta-Analysis

Objectives: Quantitative ultrasound (QUS) is an attractive method for assessing fracture risk because it is portable, inexpensive, without ionizing radiation, and available in areas of the world where DXA is not readily accessible or affordable. However, the diversity of QUS scanners and variability of fracture outcomes measured in different studies is an important obstacle to widespread utilisation of QUS for fracture risk assessment. We aimed in this review to assess the predictive power of heel QUS for fractures considering different characteristics of the association (QUS parameters and fracture outcomes measured, QUS devices, study populations, and independence from DXA-measured bone density).Materials/Methods : We conducted an inverse-variance randomeffects meta-analysis of prospective studies with heel QUS measures at baseline and fracture outcomes in their follow-up. Relative risks (RR) per standard deviation (SD) of different QUS parameters (broadband ultrasound attenuation [BUA], speed of sound &SOS;, stiffness index &SI;, and quantitative ultrasound index [QUI]) for various fracture outcomes (hip, vertebral, any clinical, any osteoporotic, and major osteoporotic fractures) were reported based on study questions.Results : 21 studies including 55,164 women and 13,742 men were included with a total follow-up of 279,124 person-years. All four QUS parameters were associated with risk of different fractures. For instance, RR of hip fracture for 1 SD decrease of BUA was 1.69 (95% CI 1.43-2.00), SOS was 1.96 (95% CI 1.64-2.34), SI was 2.26 (95%CI 1.71-2.99), and QUI was 1.99 (95% CI 1.49-2.67). Validated devices from different manufacturers predicted fracture risks with a similar performance (meta-regression p-values>0.05 for difference of devices). There was no sign of publication bias among the studies. QUS measures predicted fracture with a similar performance in men and women. Meta-analysis of studies with QUS measures adjusted for hip DXA showed a significant and independent association with fracture risk (RR/SD for BUA =1.34 [95%CI 1.22-1.49]).Conclusions : This study confirms that QUS of the heel using validated devices predicts risk of different fracture outcomes in elderly men and women. Further research and international collaborations are needed for standardisation of QUS parameters across various manufacturers and inclusion of QUS in fracture risk assessment tools. Disclosure of Interest : None declared.

EFEITO DE INJÚRIAS MECÂNICAS NO PROCESSO RESPIRATÓRIO E NOS PARÂMETROS QUÍMICOS DE GOIABAS 'PALUMA' E 'PEDRO SATO'

O objetivo deste trabalho foi avaliar o efeito das injúrias mecânicas por impacto, compressão ou corte na atividade respiratória e na composição química de goiabas 'Paluma' e 'Pedro Sato' colhidas no estádio de maturação "de vez" e armazenadas a 23,4±1 °C e 62±6 % UR (condições de ambiente). Na injúria por impacto, os frutos foram deixados cair, por duas vezes e em queda livre, de uma altura de 1,20 m, sofrendo os impactos em lados opostos de sua porção equatorial. Na injúria por compressão, os frutos foram submetidos a um peso de 3 kg, por 15 minutos. Para a injúria por corte foram efetuados 2 cortes no sentido longitudinal dos frutos, de 30 mm de comprimento por 2 mm de profundidade. Os frutos injuriados foram colocados em bandejas de isopor e armazenados sob as condições de ambiente, com a atividade respiratória avaliada diariamente e seus conteúdos de sólidos solúveis totais, açúcares redutores, acidez total titulável e ácido ascórbico, determinados a cada 2 dias. Houve um incremento na evolução da atividade respiratória dos frutos em todos os tratamentos durante o armazenamento, com os injuriados produzindo maior quantidade de CO2 (184,12 mg de CO2.kg-1.h-1) que os do controle (164,23 mg de CO2.kg-1.h-1). Os frutos da 'Paluma' apresentaram essa atividade mais intensa (178,39 mg de CO2.kg-1.h-1) que os da 'Pedro Sato' (169,35 mg de CO2.kg-1.h-1), e não se detectou durante o período de armazenamento a ocorrência de pico respiratório. Os teores de sólidos solúveis totais (9,39 °Brix), açúcares redutores (2,24 g de glicose.100 g-1), acidez total titulável (706,25 mg de ácido cítrico.100 g-1) e ácido ascórbico (65,33 mg.100 g-1) dos frutos injuriados apresentaram-se com valores menores que os do controle, ao longo do período de armazenamento.

Estimating the contribution of occupational solar ultraviolet exposure to skin cancer

BACKGROUND: Exposure to solar ultraviolet (UV) light is the main causative factor for skin cancer. Outdoor workers are at particular risk because they spend long working hours outside, may have little shade available and be bound to take their lunch at their workplace. Despite epidemiological evidence of a doubling in risk of squamous cell carcinoma in outdoor workers, the recognition of skin cancer as an occupational disease remains scarce. OBJECTIVE: To assess occupational solar UV doses and its contribution to skin cancer risk. METHODS: A numerical model (SimUVEx) was used to assess occupational and lunch break exposures, characterize exposure patterns and anatomical distribution. Risk of squamous cell carcinoma (SCC) was estimated from an existing epidemiological model. RESULTS: Horizontal body locations received 2.0-2.5 times more UV than vertical locations. Dose associated to lunch outdoor every day was similar to outdoor work one day per week but only half of a seasonal worker. Outdoor workers are associated with an increased risk of SCC but also of frequent acute episodes. CONCLUSION: Occupational solar exposure contributes largely to the overall lifetime UV dose, resulting in an excess risk of SCC. The magnitude of the estimated excess in risk supports the recognition of SCC as an occupational disease.

Reconstitution of the strand invasion step of double-strand break repair using human Rad51 Rad52 and RPA proteins.

The human Rad51 recombinase is essential for the repair of double-strand breaks in DNA that occur in somatic cells after exposure to ionising irradiation, or in germ line cells undergoing meiotic recombination. The initiation of double-strand break repair is thought to involve resection of the double-strand break to produce 3'-ended single-stranded (ss) tails that invade homologous duplex DNA. Here, we have used purified proteins to set up a defined in vitro system for the initial strand invasion step of double-strand break repair. We show that (i) hRad51 binds to the ssDNA of tailed duplex DNA molecules, and (ii) hRad51 catalyses the invasion of tailed duplex DNA into homologous covalently closed DNA. Invasion is stimulated by the single-strand DNA binding protein RPA, and by the hRad52 protein. Strikingly, hRad51 forms terminal nucleoprotein filaments on either 3' or 5'-ssDNA tails and promotes strand invasion without regard for the polarity of the tail. Taken together, these results show that hRad51 is recruited to regions of ssDNA occurring at resected double-strand breaks, and that hRad51 shows no intrinsic polarity preference at the strand invasion step that initiates double-strand break repair.