Structure of the extracellular domains of human and Xenopus Fn14: implications in the evolution of TWEAK and Fn14 interactions.

TWEAK (TNF homologue with weak apoptosis-inducing activity) and Fn14 (fibroblast growth factor-inducible protein 14) are members of the tumor necrosis factor (TNF) ligand and receptor super-families. Having observed that Xenopus Fn14 cross-reacts with human TWEAK, despite its relatively low sequence homology to human Fn14, we examined the conservation in tertiary fold and binding interfaces between the two species. Our results, combining NMR solution structure determination, binding assays, extensive site-directed mutagenesis and molecular modeling, reveal that, in addition to the known and previously characterized β-hairpin motif, the helix-loop-helix motif makes an essential contribution to the receptor/ligand binding interface. We further discuss the insight provided by the structural analyses regarding how the cysteine-rich domains of the TNF receptor super-family may have evolved over time. DATABASE: Structural data are available in the Protein Data Bank/BioMagResBank databases under the accession codes 2KMZ, 2KN0 and 2KN1 and 17237, 17247 and 17252. STRUCTURED DIGITAL ABSTRACT: TWEAK binds to hFn14 by surface plasmon resonance (View interaction) xeFn14 binds to TWEAK by enzyme linked immunosorbent assay (View interaction) TWEAK binds to xeFn14 by surface plasmon resonance (View interaction) hFn14 binds to TWEAK by enzyme linked immunosorbent assay (View interaction).

A double role of sperm in scorpions: the mating plug of Euscorpius italicus (Scorpiones: Euscorpiidae) consists of sperm.

Mating plugs occluding the female gonopore after mating are a widespread phenomenon. In scorpions, two main types of mating plugs are found: sclerotized mating plugs being parts of the spermatophore that break off during mating, and gel-like mating plugs being gelatinous fluids that harden in the female genital tract. In this study, the gel-like mating plug of Euscorpius italicus was investigated with respect to its composition, fine structure, and changes over time. Sperm forms the major component of the mating plug, a phenomenon previously unknown in arachnids. Three parts of the mating plug can be distinguished. The part facing the outside of the female (outer part) contains sperm packages containing inactive spermatozoa. In this state, sperm is transferred. In the median part, the sperm packages get uncoiled to single spermatozoa. In the inner part, free sperm is embedded in a large amount of secretions. Fresh mating plugs are soft gelatinous, later they harden from outside toward inside. This process is completed after 3-5 days. Sperm from artificially triggered spermatophores could be activated by immersion in insect Ringer's solution indicating that the fluid condition in the females' genital tract or females' secretions causes sperm activation. Because of the male origin of the mating plug, it has likely evolved under sperm competition or sexual conflict. As females refused to remate irrespective of the presence or absence of a mating plug, females may have changed their mating behavior in the course of evolution from polyandry to monandry.

Towards a dynamic model of e-commerce: environmental, technological and organisational drivers of B2C along time

Despite the important benefits for firms of commercial initiatives on the Internet, e-commerce is still an emerging distribution channel, even in developed countries. Thus, more needs to be known about the mechanisms affecting its development. A large number of works have studied firms¿ e-commerce adoption from technological, intraorganizational, institutional, or other specific perspectives, but there is a need for adequately tested integrative frameworks. Hence, this work proposes and tests a model of firms¿ business-to-consumer (called B2C) e-commerce adoption that is founded on a holistic vision of the phenomenon. With this integrative approach, the authors analyze the joint influence of environmental, technological, and organizational factors; moreover, they evaluate this effect over time. Using various representative Spanish data sets covering the period 1996-2005, the findings demonstrate the suitability of the holistic framework. Likewise, some lessons are learned from the analysis of the key building blocks. In particular, the current study provides evidence for the debate about the effect of competitive pressure, since the findings show that competitive pressure disincentivizes e-commerce adoption in the long term. The results also show that the development or enrichment of the consumers¿ consumption patterns, the technological readiness of the market forces, the firm¿s global scope, and its competences in innovation continuously favor e-commerce adoption.

Premenopausal serum androgens and breast cancer risk: a nested case-control study.

ABSTRACT: INTRODUCTION: Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited. METHODS: A case-control study nested within the New York University Women's Health Study was conducted. A total of 356 cases (276 invasive and 80 in situ) and 683 individually-matched controls were included. Matching variables included age and date, phase, and day of menstrual cycle at blood donation. Testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) were measured using direct immunoassays. Free testosterone was calculated. RESULTS: Premenopausal serum testosterone and free testosterone concentrations were positively associated with breast cancer risk. In models adjusted for known risk factors of breast cancer, the odds ratios for increasing quintiles of testosterone were 1.0 (reference), 1.5 (95% confidence interval (CI), 0.9 to 2.3), 1.2 (95% CI, 0.7 to 1.9), 1.4 (95% CI, 0.9 to 2.3) and 1.8 (95% CI, 1.1 to 2.9; Ptrend = 0.04), and for free testosterone were 1.0 (reference), 1.2 (95% CI, 0.7 to 1.8), 1.5 (95% CI, 0.9 to 2.3), 1.5 (95% CI, 0.9 to 2.3), and 1.8 (95% CI, 1.1 to 2.8, Ptrend = 0.01). A marginally significant positive association was observed with androstenedione (P = 0.07), but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis. Intra-class correlation coefficients for samples collected from 0.8 to 5.3 years apart (median 2 years) in 138 cases and 268 controls were greater than 0.7 for all biomarkers except for androstenedione (0.57 in controls). CONCLUSIONS: Premenopausal concentrations of testosterone and free testosterone are associated with breast cancer risk. Testosterone and free testosterone measurements are also highly reliable (that is, a single measurement is reflective of a woman's average level over time). Results from other prospective studies are consistent with our results. The impact of including testosterone or free testosterone in breast cancer risk prediction models for women between the ages of 40 and 50 years should be assessed. Improving risk prediction models for this age group could help decision making regarding both screening and chemoprevention of breast cancer.

Personality traits, behavioral and psychological symptoms and cognitive decline in patients at an early stage of Alzheimer's disease

The aim of this doctoral thesis was to study personality characteristics of patients at an early stage of Alzheimer's disease (AD), and more specifically to describe personality and its changes over time, and to explore its possible links with psychological and symptoms (BPS) and cognitive level. The results were compared to those of a group of participants without cognitive disorder through three empirical studies. In the first study, the findings showed significant personality changes that follow a specific trend in the clinical group. The profil of personality changes showed an increase in Neuroticism and a decrease in Extraversion, Openess to experiences, and Conscientiousness over time. The second study highlighted that personality and BPS occur early in the cours of AD. Recognizing them as possible precoce signs of neurodegeneration may prove to be a key factor for early detection and intervention. In the third study, a significant association between personality changes and cognitive status was observed in the patients with incipient AD. Thus, changes in Neuroticism and Conscientiousness were linked with cognitive deterioration, whereas decreased Openness to experiences and Conscientiousness over time predicted loss of independence in daily functioning. Other well-known factors such as age, education level or civil status were taken into account to predict cognitive decline. The three studies suggested five important implications: (1) cost-effective screening should take into account premorbid and specific personality changes; (2) psycho-educative interventions should provide information on the possible personality changes and BPS that may occur at the beginning of the disease; (3) using personality traits alongside other variables in the future studies on prevention might help to better understand AD's etiology; (4) individual treatment plans (psychotherapeutic, social, and pharmacological) might be adapted to the specific changes in personality profiles; (5) more researches are needed to study the impact of social-cultural and lifestyle variables on the development of AD.

Dissemination of periodic mammography and patterns of use, by birth cohort, in Catalonia (Spain)

Background: In Catalonia (Spain) breast cancer mortality has declined since the beginning of the 1990s. The dissemination of early detection by mammography and the introduction of adjuvant treatments are among the possible causes of this decrease, and both were almost coincident in time. Thus, understanding how these procedures were incorporated into use in the general population and in women diagnosed with breast cancer is very important for assessing their contribution to the reduction in breast cancer mortality. In this work we have modeled the dissemination of periodic mammography and described repeat mammography behavior in Catalonia from 1975 to 2006. Methods: Cross-sectional data from three Catalan Health Surveys for the calendar years 1994, 2002 and 2006 was used. The dissemination of mammography by birth cohort was modeled using a mixed effects model and repeat mammography behavior was described by age and survey year. Results: For women born from 1938 to 1952, mammography clearly had a period effect, meaning that they started to have periodic mammograms at the same calendar years but at different ages. The age at which approximately 50% of the women were receiving periodic mammograms went from 57.8 years of age for women born in 1938–1942 to 37.3 years of age for women born in 1963–1967. Women in all age groups experienced an increase in periodic mammography use over time, although women in the 50–69 age group have experienced the highest increase. Currently, the target population of the Catalan Breast Cancer Screening Program, 50–69 years of age, is the group that self-reports the highest utilization of periodic mammograms, followed by the 40–49 age group. A higher proportion of women of all age groups have annual mammograms rather than biennial or irregular ones. Conclusion: Mammography in Catalonia became more widely implemented during the 1990s. We estimated when cohorts initiated periodic mammograms and how frequently women are receiving them. These two pieces of information will be entered into a cost-effectiveness model of early detection in Catalonia.

Evolución de la mortalidad por cáncer de mama y diseminación de la mamografía de cribado en Cataluña: un análisis por regiones sanitarias

Fundamento: El descenso de las tasas de mortalidad por cáncer de mama (CM) se ha atribuido a la implantación de programas de cribado y a avances terapéuticos. El objetivo de este trabajo es comparar la evolución de su mortalidad en las regiones sanitarias de Cataluña en el periodo 1993-2007. Paralelamente, se ha analizado la diseminación de la mamografía periódica en las regiones sanitarias. Métodos: Se analizaron los datos del registro de mortalidad y encuestas de salud. Se utilizaron regresiones de Poisson y «joinpoint» para comparar las tasas de mortalidad por CM y analizar su evolución temporal. Se utilizaron modelos de efectos mixtos para comparar el nivel y la evolución de la mortalidad por regiones. Resultados. La tasa de mortalidad por CM descendió un 3% anual en Cataluña. Entre 1993 y 2007, la tasa estandarizada varió de 34,8 a 23,3 por 100.000 mujeres. Barcelona ciutat presentó unas tasas de mortalidad más elevadas que las regiones Centre (ratio de tasas (RT)=0,87), Costa de Ponent (RT=0,89), Tarragona (RT=0,9) y Lleida (RT=0,915), pero estas diferencias tendieron a desaparecer. No se observaron cambios de tendencia en la evolución de la mortalidad de las regiones, excepto en la región Centre. Durante los años 1990 Barcelona ciutat presentó unos porcentajes de utilización de mamografía periódica del 36,1% de las mujeres de 40-74 años, en la encuesta de 1994, la región Centre (23,7%) y Costa de Ponent (25,2%). Conclusiones: La progresiva utilización de mamografía periódica y la disminución de la mortalidad por CM fueron similares en las regiones sanitarias de Cataluña.

Evolutionary perspective on the interplay between family life, and parent and offspring personality

Consistent inter-individual variation in behaviour over time and across contexts has been reported for a wide variety of animals, a phenomenon commonly referred to as personality. As behavioural patterns develop inside families, rearing conditions could have lasting effects on the expression of adult personality. In species with parental care, conflicts among family members impose selection on parental and offspring behaviour through co-adaptation. Here, we argue that the interplay between the evolution of personality traits (i.e. boldness, exploration, activity, aggressiveness and sociability) expressed outside the family context and the specialized behaviours expressed inside families (i.e. offspring begging behaviour and parental response to offspring solicitations) can have important evolutionary consequences. Personality differences among parents may relate to the typically observed variation in the way they respond to offspring demand, and dependent offspring may already express personality differences which may relate to the way they communicate with their parents and siblings. However, there has been little research on how personality relates to parental and offspring behaviours. Future research should thus focus on how and why personality may be related to the specialized parent and offspring behaviour that evolved as adaptations to family life.

Cost-effectiveness of early detection of breast cancer in Catalonia (Spain)

Background: Breast cancer (BC) causes more deaths than any other cancer among women in Catalonia. Early detection has contributed to the observed decline in BC mortality. However, there is debate on the optimal screening strategy. We performed an economic evaluation of 20 screening strategies taking into account the cost over time of screening and subsequent medical costs, including diagnostic confirmation, initial treatment, follow-up and advanced care. Methods: We used a probabilistic model to estimate the effect and costs over time of each scenario. The effect was measured as years of life (YL), quality-adjusted life years (QALY), and lives extended (LE). Costs of screening and treatment were obtained from the Early Detection Program and hospital databases of the IMAS-Hospital del Mar in Barcelona. The incremental cost-effectiveness ratio (ICER) was used to compare the relative costs and outcomes of different scenarios. Results: Strategies that start at ages 40 or 45 and end at 69 predominate when the effect is measured as YL or QALYs. Biennial strategies 50-69, 45-69 or annual 45-69, 40-69 and 40-74 were selected as cost-effective for both effect measures (YL or QALYs). The ICER increases considerably when moving from biennial to annual scenarios. Moving from no screening to biennial 50-69 years represented an ICER of 4,469€ per QALY. Conclusions: A reduced number of screening strategies have been selected for consideration by researchers, decision makers and policy planners. Mathematical models are useful to assess the impact and costs of BC screening in a specific geographical area.

End-tidal carbon dioxide monitoring using a naso-buccal sensor is not appropriate to monitor capnia during non-invasive ventilation.

BACKGROUND: In acute respiratory failure, arterial blood gas analysis (ABG) is used to diagnose hypercapnia. Once non-invasive ventilation (NIV) is initiated, ABG should at least be repeated within 1 h to assess PaCO2 response to treatment in order to help detect NIV failure. The main aim of this study was to assess whether measuring end-tidal CO2 (EtCO2) with a dedicated naso-buccal sensor during NIV could predict PaCO2 variation and/or PaCO2 absolute values. The additional aim was to assess whether active or passive prolonged expiratory maneuvers could improve the agreement between expiratory CO2 and PaCO2. METHODS: This is a prospective study in adult patients suffering from acute hypercapnic respiratory failure (PaCO2 ≥ 45 mmHg) treated with NIV. EtCO2 and expiratory CO2 values during active and passive expiratory maneuvers were measured using a dedicated naso-buccal sensor and compared to concomitant PaCO2 values. The agreement between two consecutive values of EtCO2 (delta EtCO2) and two consecutive values of PaCO2 (delta PaCO2) and between PaCO2 and concomitant expiratory CO2 values was assessed using the Bland and Altman method adjusted for the effects of repeated measurements. RESULTS: Fifty-four datasets from a population of 11 patients (8 COPD and 3 non-COPD patients), were included in the analysis. PaCO2 values ranged from 39 to 80 mmHg, and EtCO2 from 12 to 68 mmHg. In the observed agreement between delta EtCO2 and deltaPaCO2, bias was -0.3 mmHg, and limits of agreement were -17.8 and 17.2 mmHg. In agreement between PaCO2 and EtCO2, bias was 14.7 mmHg, and limits of agreement were -6.6 and 36.1 mmHg. Adding active and passive expiration maneuvers did not improve PaCO2 prediction. CONCLUSIONS: During NIV delivered for acute hypercapnic respiratory failure, measuring EtCO2 using a dedicating naso-buccal sensor was inaccurate to predict both PaCO2 and PaCO2 variations over time. Active and passive expiration maneuvers did not improve PaCO2 prediction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01489150.

Meckel-Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe.

Meckel-Gruber Syndrome is a rare autosomal recessive lethal ciliopathy characterized by the triad of cystic renal dysplasia, occipital encephalocele and postaxial polydactyly. We present the largest population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. The study population consisted of 191 cases of MKS identified between January 1990 and December 2011 in 34 European registries. The mean prevalence was 2.6 per 100 000 births in a subset of registries with good ascertainment. The prevalence was stable over time, but regional differences were observed. There were 145 (75.9%) terminations of pregnancy after prenatal diagnosis, 13 (6.8%) fetal deaths, 33 (17.3%) live births. In addition to cystic kidneys (97.7%), encephalocele (83.8%) and polydactyly (87.3%), frequent features include other central nervous system anomalies (51.4%), fibrotic/cystic changes of the liver (65.5% of cases with post mortem examination) and orofacial clefts (31.8%). Various other anomalies were present in 64 (37%) patients. As nowadays most patients are detected very early in pregnancy when liver or kidney changes may not yet be developed or may be difficult to assess, none of the anomalies should be considered obligatory for the diagnosis. Most cases (90.2%) are diagnosed prenatally at 14.3±2.6 (range 11-36) gestational weeks and pregnancies are mainly terminated, reducing the number of LB to one-fifth of the total prevalence rate. Early diagnosis is important for timely counseling of affected couples regarding the option of pregnancy termination and prenatal genetic testing in future pregnancies.

Tuberous sclerosis: literature review and case report

Tuberous sclerosis (TS) or Bourneville"s disease is a rare, multisystemic genetic disorder. It involves alterations to ectodermal and mesodermal cell differentiation and proliferation, causing benign hamartomatous tumors, neurofibromas and angiofibromas in the brain and other vital organs including the kidney, heart, eyes, lungs, skin and mucosa. It also affects the central nervous system and produces neurological dysfunctions such as seizures, mental retardation and behavior disorders. Tuberous (rootshaped) growths develop in the brain, and calcify over time, becoming hard and sclerotic, hence the name given to the disease. Although inheritance is autosomal dominant, 60-70% of cases occur through spontaneous mutations. The disease is related to some mutations or alterations in two genes, named TSC1 and TSC2. Discovered in 1997, TSC1 is located on chromosome 9q34 and produces a protein called hamartin. TSC2, discovered in 1993, is located on chromosome 16p13 and produces a protein called tuberin. The prevalence of the disease is 1/6000-10,000 live newborns, and it is estimated that there are 1-2 million sufferers worldwide. This paper presents a literature review and a family case report of a mother and two of her daughters with oral features of TS

Temporomandibular Disorders and Headache in Adolescents

13-16-vuotiaiden purentaelimistön toimintahäiriöt ja päänsärky Tutkimuksen tarkoituksena oli selvittää purentaelimistön toimintahäiriöihin (TMD) liittyvien oireiden ja kliinisten löydösten esiintyvyyttä ja muutosta kolmen vuoden seurannan aikana päänsärystä kärsivillä nuorilla ja heidän verrokeillaan, TMD-löydösten yhteyttä eri tyyppisiin päänsärkyihin ja päänsärkyyn liittyviin tekijöihin, TMD-löydöksiä ennustavia tekijöitä sekä perhetaustan osuutta TMD-löydösten esiintyvyyteen. Tutkimus perustui kahteen laajaan koululaismateriaaliin Turun seudulla. Ensimmäinen 13-vuotiaiden nuorten ryhmä (n = 311) osallistui myös 16-vuotiaana seuranta-tutkimukseen. Toisen 13-vuotiaiden nuorten ryhmän (n = 154) äidit (n = 154) osallistuivat myös tutkimukseen, jossa selvitettiin tapaus-verrokkiasetelmassa TMD-löydösten ja päänsärkyjen esiintyvyyttä kahdessa sukupolvessa. Nuoret jaettiin päänsärkyryhmiin ja terveisiin kontrolleihin IHS (1988) päänsärky-kriteerien mukaisesti kyselykaavakkeen ja lääkärin suorittaman haastattelun ja kliinisen tutkimuksen antamien tietojen perusteella. Lääkäri määritteli äitien päänsärkydiagnoosin kyselykaavakkeen tietojen perusteella. Kaikki nuoret ja heidän äitinsä haastateltiin ja heille tehtiin kliininen purentafysiologinen tutkimus sokkoutetusti. Tutkimuksen tulokset osoittivat, että tytöillä esiintyi TMD-löydöksiä selvästi enemmän kuin pojilla sekä ennen puberteettia että sen jälkeen. Tutkimuksessa havaittiin selkeä yhteys TMD-löydösten ja molempien päänsärkytyyppien, migreenin ja episodisen tensiotyyppisen päänsäryn, välillä. Kolmen vuoden seurannan aikana TMD-löydöksissä havaittiin runsasta muutosta ja iän myötä vähenemistä, mutta TMD-oireiden kohdalla ei vastaavaa muutosta todettu. TMD-löydösten ja niska-hartiaseudun lihaskipujen välillä havaittiin yhteys 13-vuotiailla nuorilla. Mikään päänsärkyyn liittyvistä tekijöistä 13-vuotiailla ei osoittautunut ennustavaksi taustatekijäksi myöhemmille TMD-löydöksille. TMD-löydösten suhteen ei todettu perheyhteyttä. Päänsäryistä kärsivillä nuorilla on enemmän myös muita kiputiloja, kuten purentaelimistön toimintahäiriöitä ja niska-hartiaseudun kipuja, kuin heidän terveillä verrokeillaan. 1316 vuoden iässä nämä löydökset ovat valtaosaltaan lieviä ja vaihtelevia.

Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy.

Mutations in GDAP1, which encodes protein located in the mitochondrial outer membrane, cause axonal recessive (AR-CMT2), axonal dominant (CMT2K) and demyelinating recessive (CMT4A) forms of Charcot-Marie-Tooth (CMT) neuropathy. Loss of function recessive mutations in GDAP1 are associated with decreased mitochondrial fission activity, while dominant mutations result in impairment of mitochondrial fusion with increased production of reactive oxygen species and susceptibility to apoptotic stimuli. GDAP1 silencing in vitro reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE) upon mobilization of endoplasmic reticulum (ER) Ca2+, likely in association with an abnormal distribution of the mitochondrial network. To investigate the functional consequences of lack of GDAP1 in vivo, we generated a Gdap1 knockout mouse. The affected animals presented abnormal motor behavior starting at the age of 3 months. Electrophysiological and biochemical studies confirmed the axonal nature of the neuropathy whereas histopathological studies over time showed progressive loss of motor neurons (MNs) in the anterior horn of the spinal cord and defects in neuromuscular junctions. Analyses of cultured embryonic MNs and adult dorsal root ganglia neurons from affected animals demonstrated large and defective mitochondria, changes in the ER cisternae, reduced acetylation of cytoskeletal α-tubulin and increased autophagy vesicles. Importantly, MNs showed reduced cytosolic calcium and SOCE response. The development and characterization of the GDAP1 neuropathy mice model thus revealed that some of the pathophysiological changes present in axonal recessive form of the GDAP1-related CMT might be the consequence of changes in the mitochondrial network biology and mitochondria-endoplasmic reticulum interaction leading to abnormalities in calcium homeostasis.

Growth, production and quality of pineapple in response to herbicide use

In pineapple fields, weed competition is exacerbated by the fact that the crop is small and has a very slow vegetative development. The objective of this study was to determine the effects of herbicides on growth, yield and quality of pineapple, cultivar 'Pérola'. The experimental design was in randomized blocks with four treatments and four replications. Treatments consisted of weeding by hoe and the herbicides diuron; fluazifop-p-butyl and atrazine + S-metolachlor applied in post-emergence. The characteristics evaluated monthly during the vegetative stage were stem diameter, D-leaf length, number of leaves, number of emitted leaves and percentage of natural floral induction. In the reproductive phase, evaluations were made of average fruit weight (g) with and without crown, fruits length and diameter, number of slip, slip-sucker and sucker type seedlings, determination of soluble solids and pH in the pulp. There was no effect of herbicide treatment on the vegetative growth characteristics. Stem diameter increased until 330 days after planting, showing a decrease after this period. The D-leaf grew over time in all treatments, although phytotoxicity symptoms were observed after the first application of herbicides. The traits evaluated on the reproductive phase showed no significant differences in response to treatments. Therefore, the use of diuron fluazifop-p-butyl and atrazine + S-metolachlor did not affect growth, yield and fruit quality of pineapple, cultivar 'Pérola'.