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Compressive sensing has been used to demonstrate scene reconstruction and source localization in a wide variety of devices. To date, optical compressive sensors have not been able to achieve significant volume reduction relative to conventional optics of equivalent angular resolution. Here, we adapt silicon-photonic optical phased array technology to demonstrate, to our knowledge, the first application of compressive imaging in a photonic-integrated device. Our novel sensor consists of an $8\times 8$ grid of grating couplers with a spacing of $100~\mu$m. Path-matched waveguides route to a single multimode interferometer (MMI), which mixes and randomizes the signals into 64 outputs to be used for compressed sensing. Our device is fully passive, having no need for phase shifters, as measurement matrix calibration makes the measurements robust to phase errors. For testing, we use an Amplified Spontaneous Emission (ASE) source with a bandwidth of 40 nm, centered at 1545 nm. We demonstrate simultaneous multi-point (2 sources demonstrated in this work) brightness recovery and localization with better than 10 arcsecond precision in a sub-millimeter thick form-factor. We achieve a single source recovery rate higher than 99.9\% using 10 of the 64 outputs, and a 90\% recovery rate with only 6 outputs, 10 times fewer than the 64 needed for conventional imaging. This planar optical phased array compressive sensor is well-suited for imaging sparse scenes in applications constrained by form factor, volume, or high-cost detectors, with the potential to revolutionize endoscopy, beam locators, and LIDAR., Comment: 10 pages, 6 figures, pre-print to be published in SPIE Optical Engineering and Applications

Tiivistelmä. Hermostopiena on selkärankaisten alkionkehityksen aikana esiintyvä monikykyisitä soluista muodostuva väliaikainen rakenne, jonka solut vaeltavat joka puolelle alkiota, lopulta erilaistuen moniksi eri rakenteiksi. Hermostopienan muodostumisella on ollut tärkeä rooli selkärankaisten evoluutiossa, sen solujen vaellus jakaa piirteitä syövän metastaasin kanssa ja monet ihmisillä esiintyvät syndroomat johtuvat sen kehityshäiriöistä. Näistä piirteistä johtuen hermostopienasta on tullut houkutteleva kohde kehitys- ja evoluutiobiologeille, sekä syöpäbiologeille ja patologeille. Hermostopiena indusoituu alkionkehityksen neurulaatiovaiheen aikana hermostolevyn sivureunoille. Neurulaation jälkeen hermostopienan solut alkavat käymään läpi epiteelimesenkyymi-transitiota, irtaantuen samalla neuroepiteelistä, kun soluja vahvasti yhteen sitovien kadheriinimolekyylien sijasta aletaan ekspressoimaan heikompia sidoksia muodostavia kadheriineja. Irtaannuttuaan neuroepiteelistä, solut lähtevät vaeltamaan tarkasti säädeltyinä virtoina kohti kohdealueitaan. Hermostopiena voidaan jakaa neljään alapopulaatioon solujen lähtöpaikan, kohdealueen ja niistä syntyvien johdannaisten mukaan. Kraniaalinen hermostopiena tuottaa pään alueen luita ja hermoja, vagaalinen hermostopiena sydämen lihaksia ja etusuolen hermostoa, vartalon hermostopiena ääreishermoston ja lisämunuaisten soluja ja sakraalinen hermostopiena enteerisen hermoston soluja. Soluja ympäröivät kudokset osallistuvat vaellusreittien rajaamiseen erittämällä solujen liikettä inhiboivia molekyylejä. Kudokset voivat myös ohjata solujen liikkumista toimimalla fyysisinä esteinä, rajaten täten solujen käytössä olevaa tilaa. Tilan oikeanlaisella rajaamisella voi myös vauhdittaa solujen liikettä haluttuun suuntaan. Solujenvälisillä vuorovaikutuksilla, kuten kontaktivälitteisellä inhibitiolla ja kemotaksialla, on myös osuus vaellusreittien säätelyssä. Kontaktivälitteisessä inhibitiossa toistensa kanssa kosketuksiin tulevat solut lähtevät liikkeelle päinvastaisiin suuntiin, mikä estää solujen päällekkäisen asettumisen. Kemotaksiassa solut kulkevat jonkin viestiaineen gradientin suuntaisesti. Erittämällä tällaisia viestiaineita itse, solut pysyvät tiiviinä ryhminä vaelluksen ajan. Hermostopienan kehityksen mekanismien selvittäminen on vaatinut vuosikymmenten työn, mutta paljon on vielä selvittämättä. Avoimiin kysymyksiin, kuten yhteyksistä syöpään, tullaan toivottavasti löytämään vastauksia kuvantamismenetelmien kehittymisen myötä.

The trend of outsourcing in industries has led to a situation in which various service providers are working at industrial sites. Managing such complex multi-employer worksites is a challenge. This study introduces a collaboration procedure for supplier audits in the context of integrated health, safety, environment, and quality management by large Finnish industrial buyers. A supplier-audit database is analyzed and supplemented by interviews with the buyers. Altogether, 456 audit observations are categorized in seven thematic areas to introduce what kinds of development areas suppliers have. With regard to the collaborative nature of the procedure, the benefits from the buyers’ side were identified from the interviews. Cluster collaboration has proven advantageous in financial savings, objective assessments, and supplier development.

Source at https://doi.org/10.18632/aging.101900. Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life. We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries. The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect. Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.

BACKGROUND: Social inequalities in the prevalence of childhood overweight and obesity are well-established, but less is known about when the social gradient first emerges and how it evolves across childhood and adolescence.OBJECTIVE: This study examines maternal education differentials in children's body mass trajectories in infancy, childhood and adolescence using data from four contemporary European child cohorts.METHODS: Prospective data on children's body mass index (BMI) were obtained from four cohort studies-Generation XXI (G21-Portugal), Growing Up in Ireland (GUI) infant and child cohorts, and the Millennium Cohort Study (MCS-UK)-involving a total sample of 41,399 children and 120,140 observations. Children's BMI trajectories were modelled by maternal education level using mixed-effect models.RESULTS: Maternal educational inequalities in children's BMI were evident as early as three years of age. Children from lower maternal educational backgrounds were characterised by accelerated BMI growth, and the extent of the disparity was such that boys from primary-educated backgrounds measured 0.42 kg/m2 (95% CI 0.24, 0.60) heavier at 7 years of age in G21, 0.90 kg/m2 (95% CI 0.60, 1.19) heavier at 13 years of age in GUI and 0.75 kg/m2 (95% CI 0.52, 0.97) heavier in MCS at 14 years of age. The corresponding figures for girls were 0.71 kg/m2 (95% CI 0.50, 0.91), 1.31 kg/m2 (95% CI 1.00, 1.62) and 0.76 kg/m2 (95% CI 0.53, 1.00) in G21, GUI and MCS, respectively.CONCLUSIONS: Maternal education is a strong predictor of BMI across European nations. Socio-economic differentials emerge early and widen across childhood, highlighting the need for early intervention.

Juha Laine,1 T Sakari Jokiranta,2,3 Kari K Eklund,4,5 Merja Väkeväinen,1 Kari Puolakka6 1Pfizer Oy, Helsinki, 2United Medix Laboratories Ltd, Espoo, 3Research Programs Unit, Immunobiology, 4Department of Rheumatology, University of Helsinki, 5Helsinki University Central Hospital, Helsinki, 6Department of Medicine, South Karelia, Finland Abstract: Monitoring of anti-drug antibodies (ADAbs) or serum concentrations of biologicals in treatment of rheumatoid arthritis could provide an explanation for a loss of efficacy and help in the choice of subsequent medication. Current clinical practices do not generally include such monitoring of tumor necrosis factor (TNF)-α blockers on a routine basis. The main aims of this study were to estimate the probabilities of optimal and nonoptimal treatment decisions if infliximab or adalimumab drug trough level (DL) and ADAbs are tested or not in rheumatoid arthritis, and to model cost-effectiveness of performing such monitoring on a routine basis. Data on DLs and ADAbs concentrations were obtained in Finland from clinically requested monitoring analyses of 486 and 1,137 samples from patients on adalimumab and infliximab, respectively. DL was within the target range in 42% of samples from adalimumab- and 50.4% of infliximab-treated patients. ADAbs were detected in approximately 20% and 13.5% of samples from adalimumab- and infliximab-treated patients, respectively. ADAbs were found in 52.3% and 41.3% of those with low adalimumab or infliximab DLs, respectively. The monitoring data were incorporated into probabilities for making the optimal treatment decision. Economic impact of clinical decision-making was modeled in a short-term (3–6 months) scenario with 100 hypothetical patients. In the model, the combined measurement of DLs and ADAbs was cost-saving compared to the nontesting scenario when the monitoring results affected the treatment decision in at least 2–5 of 100 patients, a proportion which is easily exceeded in real-life clinical practice. This study indicates that routine monitoring of drug level and ADAbs is cost-beneficial in clinical practice, thereby improving the decision-making process in using TNF-α blockers. Keywords: anti-TNF drugs, anti-drug antibodies, trough level measurement

Yritysten arvoverkoston kehittäminen on kasvavassa määrin yritysten ja tutkimusyhteisöiden kiinnostuksen kohteena. Yritysten keskittyminen pääliiketoimintoihinsa on johtanut tilaaja-toimittajasuhteiden monimuotoistumiseen. Monet yritysten perinteisesti itse suorittamat toiminnot on ulkoistettu ja toimittajat harjoittavat palveluliiketoimintaansa usein tilaajayrityksen tiloissa. Tehdasalueen muodostuessa tilaajan ja usean eri toimittajan yhteiseksi työpaikaksi syntyy tehdasalueelle riskitekijöitä, joita ei aiemmin ole havaittu. Tutkimus pohjautuu tutkimustaustaan, jota on tehty Oulun yliopistolla prosessiteollisuuden toimialalla jo 2000-luvun alusta lähtien. 18 vuoden aikana tehdyt tutkimushankkeet ovat johtaneet IMS-järjestelmän tavoitteluun ja lopulta luoneet pohjan HSEQ (Health, Safety, Environment and Quality) -arviointimenetelmälle. HSEQ-arviointimenettelyn tarkoituksena on kannustaa toimittajayrityksiä toimintamallien kehittämiseen sekä kehittää yrityksen johtamismalleja että työhyvinvointia. Diplomityön tarkoituksena on selvittää, mitä hyötyjä tilaajayrityksille on arviointitoiminnasta realisoitunut ja mitä kehityskohteita arviointitoiminnassa vielä on. Kirjallisuuskatsauksessa perehdyttiin toimittaja-arviointeihin liittyvään teoriaan ja esiteltiin hankintatoimeen keskeisesti liittyviä teorioita. Empiirinen osuus suoritettiin puolijäsenneltynä haastattelututkimuksena seitsemään tilaajayritykseen ja pääarvioijille. Haastatteluissa oli läsnä HSEQ-asiantuntija ja kohdeyrityksen hankintainsinööri. Näin pyrittiin saamaan haastattelusta keskusteleva tilaisuus, jossa ilmenee useita eri näkökulmia. Tulokset vastasivat onnistuneesti työn tutkimuskysymyksiin. Tilaajien toimittaja-arvioinneista koetut hyödyt olivat merkittäviä ja lähtökohdat jatkaa arviointitoimintaa nykyisellään ovat olemassa. Toimittaja-arvioinneista koetut hyödyt olivat linjassa aiheesta tehtyjen aiempien tutkimusten kanssa, joten voidaan todeta, että perusteiltaan toimittaja-arviointien hyödyt ovat säilyneet ennallaan. Hyötyjen listaamisen lisäksi tutkimuksen edetessä löydettiin useita kehityskohteita auditointitoiminnalle. Kaikki kehityskohteet esitettiin tutkimuksen lopuksi pääarvioijille. Osa kehityskohteista oli jo aiemmin toteutettuja ja pääosa kehityskohteista todettiin pääarvioijan toimesta mahdollisiksi toteuttaa. Tämän tutkimuksen pohjalta voidaan todeta, että turvallisuus on kehittynyt vuosien myötä tilaajayrityksissä. Tilaajayrityksissä tunnistettiin selvästi turvallisuuskulttuurin kehittäminen, mutta toimittaja-arviointien yhteyttä turvallisuuden kehittymiseen ei tunnistettu. Pääarvioijat olivat kuitenkin vahvasti sitä mieltä, että toimittaja-arvioinnit ovat kehittäneet huomattavasti turvallisuutta yhteisillä työpaikoilla. Tämän näkemyseron tutkiminen tarjoaa mahdollisuuksia myös tulevaisuuden jatkotutkimuksiin. HSEQ-tietokantaan syötettyjen arviointien tarkempi läpikäynti ja etenkin yritysten, jotka on arvioitu jo useampaan kertaan, lukujen arviointi voisi kirkastaa näkemystä turvallisuuden kehittymisestä. Tapaturmatilastojen kehittymistä voidaan verrata myös yleiseen turvallisuuden kehittymiseen ja näin selventää, mikä on toimittaja-arviointien rooli turvallisuuden kehittymisessä. Growth of the companie’s value chain is increasingly being promoted by companies and research communities. The concentration of companies in their main business has led to the diversification of principal-supplier relations. Many of the activities traditionally carried out by companies have been outsourced and suppliers often carry out their service business on the premises of a principal company. When a factory area becomes a joint workplace for a principal company and multiple suppliers, there are risk factors in the factory area that are not previously known. The research is based on the research background that has been made at the University of Oulu in the process industry since the early 2000s. Research projects conducted over the course of 18 years have led to the pursuit of the IMS system and ultimately created the basis for the HSEQ (Health, Safety, Environment and Quality) assessment methodology. The purpose of the HSEQ assessment procedure is to encourage vendor companies to provide template development and to develop corporate leadership and well-being at work. The purpose of the thesis is to find out what benefits the principal companies have gained from the evaluation activity and what development targets are still in the evaluation process. The literature review focused on the theory of supplier evaluations and introduced theories related to procurement. The empirical part was conducted as a semi-structured interview with 7 principal companies and main evaluators. Interviews were attended by a HSEQ expert and the buyer of the target company. In this way, it was easier to interviewers to express different point of views. The results responded successfully to the research questions of the work. The benefits from principal company ratings have been significant and the starting points for continuing evaluation activities are present. The benefits of the supplier reviews were in line with previous studies on the subject, so it can be concluded that the benefits of supplier evaluations have remained unchanged. In addition to the benefits of listing, several development targets for audit activity were found in research progress. All the development objects were presented to the main evaluators at the end of the study. Some development targets had already been implemented and most of the development targets were found to be possible by the main evaluator. Based on this study, it can be concluded that security has evolved over the years in principal companies. The development of a security culture was clearly identified in the principal companies, but the relationship between supplier evaluations and the development of safety was not identified. However, the main evaluators were strongly convinced that supplier evaluations have considerably improved security in common workplaces. Examining this difference of perspective will also provide opportunities for further research into the future. A more thorough review of the assessments submitted to the HSEQ database, and in particular those that have been evaluated several times, could help clarify the perception of safety development. The development of injury statistics can also be compared with the general development of safety and thus clarify the role of supplier evaluations in the development of safety.

Aims: It is theoretically predicted that, at low galaxy inclinations, boxy/peanut bar components have a barlens appearance of a round central component embedded in the narrow bar. We investigate barlenses in the Calar Alto Legacy Integral Field Area (CALIFA) survey galaxies, studying their morphologies, stellar populations, and metallicities. We show that, when present, barlenses account for a significant portion of light of photometric bulges, i.e., the excess light on top of the disks, which highlights the importance of bars in accumulating central galaxy mass concentrations in the cosmic timescale. Methods: We made multi-component decompositions for a sample of 46 barlens galaxies drawn from the CALIFA survey, where M⋆/M⊙ = 109.7 − 1011.4 and z = 0.005−0.03. Unsharp masks of the Sloan Digital Sky Survey (SDSS) r′-band mosaics were used to identify the boxy/peanut or X-shaped features. Barlenses are identified in the images using our simulation snapshots as an additional guide. Our decompositions with GALFIT include bulges, disks, and bars as well as barlenses as a separate component. For 26 of the decomposed galaxies the CALIFA DR2 V500 grating data cubes were used to explore stellar ages and metallicities at the regions of various structure components. Results: We find that 25 ± 2% of the 1064 galaxies in the whole CALIFA sample show either X-shaped or barlens features. In the decomposed galaxies with barlenses, on average 13% ± 2% of the total galaxy light belongs to this component, leaving less than 10% for possible separate bulge components. Most importantly, bars and barlenses are found to have similar cumulative stellar age and metallicity distributions. The metallicities in barlenses are on average near solar, but exhibit a large range. In some of the galaxies barlenses and X-shaped features appear simultaneously, in which case the bar origin of the barlens is unambiguous. Conclusions: This is the first time that a combined morphological and stellar population analysis is used to study barlenses. We show that their stars are accumulated in a prolonged time period concurrently with the evolution of the narrow bar.

Contains fulltext : 178384.pdf (Publisher’s version ) (Open Access) Based on an analysis of the leading Finnish newspaper, Helsingin Sanomat, this paper explores Finnish attitudes towards and understandings of Russia. It pays special attention to the so-called Karelia Question and the way it has shaped public discussion in Finland. The article seeks to investigate human signifying practices in the region’s specific social and cultural circumstances and explains meaning-making as a social practice. It evaluates how public opinion, as expressed in the letters page of the newspaper, has evolved and been affected by the broader changes that have occurred at the border. There are clear changes over time, both in a quantitative and qualitative sense. This may be summarised as representing a trend of general fading into history, but also as a more cyclical effect and as the interplay between bilateral relations and broader geopolitical changes. 15 p.

Contains fulltext : 170114_a.pdf (author's version ) (Open Access) Contains fulltext : 170114.pdf (Publisher’s version ) (Closed access)

The discs in galaxies are radially extended, rotationally supported, flattened systems. In the cosmological Lambda Cold Dark Matter model the formation of the discs is intimately connected with galaxy formation. Generally it is assumed that the discs have exponentially decreasing stellar surface brightness profiles, but completely satisfactory theoretical explanation for this has not been presented. Large number of studies in the past decade have challenged this view, and have found a change in the slope of the surface brightness profile in the outer regions of many galaxies discs: the surface brightness can decrease more, or less, steeply than in the inner regions. The transition between the two slopes is often called a disc break. Consequently, the discs are divided in three major categories: single exponential Type I, down-bending break Type II, and up-bending break Type III. Formation of these break features has been linked to the initial formation of the discs, internal evolution, and also with the interactions between galaxies. By studying the detailed properties of the disc break features, the evolutionary history of discs, and galaxies in general, can be better understood. The thesis work focuses on the structural analysis of the galaxies in the Spitzer Survey of Stellar Structure in Galaxies (S4G), which consists of 2352 galaxies observed in the 3.6 and 4.5 µm mid-infrared wavelengths with the Spitzer space telescope. Work has been carried out as a part of the data-analysis pipelines of the S4G survey, utilizing surface photometry. In addition, special emphasis has been put on the study of the disc and disc break properties in a wide range of galaxy morphological types and stellar masses. The thesis work attempts to at least partially understand how galaxy stellar mass and observed wavelength affect the properties of the discs and breaks, and how galaxy structural components are connected with the breaks. The data comprises mainly of the 3.6 µm infrared data, providing a view to the stellar mass distribution of galaxies. We find that the Type II breaks are the most common disc profile type, found in 45 ± 2% of the sample galaxies, consisting of 759 galaxies in the stellar mass range 8.5 ≲ log10(M*/M⊙) ≲ 11. Type I discs are found in 31 ± 2%, and the Type III breaks in 23 ± 2% of the sample. The fraction of the profile types also depends of the galaxy stellar mass: fractions of the Types II and III increase, while Type I fraction decreases, with increasing stellar mass. We attribute these changes with stellar mass to the increased frequency of bar resonance structures in higher mass galaxies, which are commonly associated with a Type II break, and to the increased fraction of Type III profiles in generally more massive early-type disc galaxies. In addition to the Type II breaks associated with bar resonance structures, we find that nearly half of these breaks relate to the visual spiral outer edge, confirming previous results of the Type II break connection with galaxy structure, and thus the internal evolution rather than initial formation of discs. Complementary data in optical wavelengths from the Sloan Digital Sky Survey shows a strong change in the properties of the discs inside the Type II breaks, indicating that the inner discs are evolving via star formation. In late-type spiral galaxies (T ≳ 4) with a Type II break, possible evidence of radial stellar migration is found in the outer disc: the slope of the surface brightness profile is shallower in the infrared compared to optical wavelengths, indicating that older stellar populations are more evenly spread throughout the disc. Formation of the Type I and III profiles remain poorly understood. However, indication that some of the Type III profiles are formed by environmentally driven processes is found, with a correlation between the properties of the local environment and the disc profile parameters. Furthermore, indication of star formation possibly causing the up-bends in spiral galaxies is found through a presence of young stellar population in the outer disc section.

Caspase-6 (CASP6) has emerged as an important player in Huntington disease (HD), Alzheimer disease (AD) and cerebral ischemia, where it is activated early in the disease process. CASP6 also plays a key role in axonal degeneration, further underscoring the importance of this protease in neurodegenerative pathways. As a protein's function is modulated by its protein-protein interactions we performed a high throughput yeast-2-hybrid (Y2H) screen against ∼17,000 human proteins to gain further insight into the function of CASP6. We identified a high confidence list of 87 potential CASP6 interactors. From this list, 61% are predicted to contain a CASP6 recognition site. Of nine candidate substrates assessed, six are cleaved by CASP6. Proteins that did not contain a predicted CASP6 recognition site were assessed using a LUMIER assay approach and 51% were further validated as interactors by this method. Of note, 54% of the high-confidence interactors identified show alterations in human HD brain at the mRNA level, and there is a significant enrichment for previously validated huntingtin (HTT) interactors. One protein of interest, STK3, a proapoptotic kinase, was validated biochemically to be a CASP6 substrate. Furthermore, our results demonstrate that in striatal cells expressing mutant huntingtin (mHTT) an increase in full length and fragment levels of STK3 are observed. We further show that caspase-3 is not essential for the endogenous cleavage of STK3. Characterization of the interaction network provides important new information regarding key pathways of interactors of CASP6 and highlights potential novel therapeutic targets for HD, AD and cerebral ischemia.

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Polymer adsorption on cellulose nanofibrils and the effect on nanofibril water binding capacity were studied using cellulose nanofibril films together with quartz crystal microbalance with dissipation (QCM-D) and surface plasmon resonance (SPR). The experiments were performed in the immersed state, and special attention was paid to the effect of polymer properties on the water content and viscoelastic properties of the polymer/fibril layer. The dry mass of the adsorbed polymers was determined using SPR. The type of the adsorbed polymer strongly affected the water content and viscoelastic properties of the nanofibril film. The adsorption of a highly charged flocculating polymer, PDADMAC, caused dehydration of the film, which was also detected as nanofibril film stiffening. The adsorption of xyloglucan introduced a dispersing effect to the nanofibril film, which was detected as a loosening and softening of the nanofibril/polymer layer. A dispersing effect was also achieved with carboxymethyl cellulose (CMC), but CMC did not adsorb irreversibly on the nanofibril surfaces. In addition to the nanofibril film studies, the effect of polymer adsorption on cellulose nanofibril suspension aggregation was demonstrated using confocal laser scanning microscopy (CLSM). Xyloglucan was shown to open the nanofibril aggregate structures and act as a dispersing agent, whereas the other polymers studied did not have as significant an effect on aggregation.

Emerging evidence suggests a role for cortisol in essential hypertension, and preliminary reports indicate that urinary free cortisol (UFC) may be an intermediate phenotype.The objectives of this study were: 1) confirm bimodality of UFC, 2) assess whether UFC variations aggregate in hypertensive families, and 3) compare low-mode and high-mode UFC groups for distinguishing features.Subjects included 390 hypertensives and 166 normotensives from the general community.Subjects had blood pressure and laboratory measurements on high- and low-salt diets. Familial aggregation was evaluated in 250 hypertensive siblings from 117 families.Hypertensives had higher UFC than normotensives (P0.001) and bimodal distribution of UFC (P0.0001). Analyses were controlled for gender and dietary sodium, which are confounding determinants of UFC. Mean low-mode UFC (33.8+/-10.6 microg per 24 h) was similar to that of normotensives. The high mode, comprising 31.3% of hypertensives, had less change in mean arterial pressure between diets than the low mode (P=0.01) without any other significant differences. Observed proportions of concordance and discordance for UFC mode differed significantly from that expected (P0.001). Observed concordance for the high mode was twice that expected, whereas for the low mode, it was similar to that expected by chance. Family membership explained a significant proportion of variance in UFC classification (P=0.027). UFC mode of one sibling was a significant predictor of the UFC mode of the other sibling [odds ratio 6.6, 95% confidence interval (2.4-18.0), P0.001].High-mode UFC is an intermediate phenotype of hypertension associated with salt resistance and a strong familial component supporting heritability.

Undergraduates given accurate instructions pressed keys for token points under either a variety of reinforcement schedules (variety training) or under a single schedule. Response rates on a fixed-interval (FI) test schedule then were assessed. Experiment 1 compared variety training inclusive of Fl-optimal rates (functional) to training excluding such rates (nonfunctional). Participants provided functional training showed low test rates relative to those provided nonfunctional and single-instruction training, implicating response- rate history as a determinant of subsequent Fl performance. Experiment 2 manipulated functional and nonfunctional variety training, and the correspondence of Fl test-phase point densities with those of high-, low-, or both high- and low-rate training components. Performances under Fl were affected by density correspondence, suggesting discriminative control of response rate by point density.

Background The administration of protamine to patients who received heparin during cardiopulmonary bypass (CPB) induces hypotension. Protamine inhibits the carboxypeptidase N-mediated degradation of bradykinin, a peptide that causes vasodilation and tissue-type plasminogen activator (t-PA) release. This study tests the primary hypothesis that blocking the bradykinin B2 receptor would attenuate protamine-related hypotension. Methods We conducted a prospective, double-blind, randomized study in 16 adult male patients undergoing elective cardiac surgery requiring CPB and taking an angiotensin-converting enzyme (ACE) inhibitor preoperatively, because ACE inhibition increases bradykinin concentrations during CPB. Subjects were randomized to receive either saline solution (N = 8) or the bradykinin B2 receptor antagonist HOE 140 (100 μg/kg, N = 8) before the administration of protamine. Mean arterial pressure (MAP) and t-PA activity were measured intraoperatively and before and after protamine administration. Results Protamine administration caused a significant increase in bradykinin concentrations in the saline solution group (from 6.0 ± 1.3 to 10.0 ± 1.6 fmol/mL, P: = .043), as well as the HOE 140 group (from 6.5 ± 1.8 to 14.3 ± 4.6 fmol/mL, P: = .042). Protamine significantly decreased MAP in the saline solution group (from 69.8 ± 4.4 mm Hg to a mean individual nadir of 56.1 ± 2.6 mm Hg, P: = .031), but bradykinin receptor antagonism blunted this effect (from 74.3 ± 3.7 mm Hg to a mean individual nadir of 69.6 ± 1.2 mm Hg in the HOE 140 group, P: = .545). Hence, during protamine infusion, MAP was significantly lower in the saline solution group compared with the HOE 140 group (P: = .002). t-PA activity decreased significantly during administration of HOE 140 (from 3.59 ± 0.31 to 1.67 ± 0.42 IU/mL, P: = .001) but not during saline solution (from 2.12 ± 0.48 to 1.44 ± 0.36 IU/mL, P: = .214). Similarly, t-PA activity decreased significantly during protamine administration in the HOE 140 group (from 1.67 ± 0.42 to 0.77 ± 0.26 IU/mL, P: = .038) but not in the saline solution group (from 1.44 ± 0.36 to 0.99 ± 0.26 IU/mL, P: = .132). Conclusion Increased bradykinin contributes to protamine-related hypotension through its B2 receptor in ACE inhibitor-treated patients. Clinical Pharmacology & Therapeutics (2005) 78, 477–485; doi: 10.1016/j.clpt.2005.08.010

Objective— Angiotensin-converting enzyme inhibition (ACEI) increases vascular tissue plasminogen activator (t-PA) release through endogenous bradykinin (BK). We tested the hypothesis that gender influences the effect of ACEI on t-PA release. Methods and Results— We measured the effect of intra-arterial enalaprilat (0.33 μg/min per 100 mL forearm volume) on forearm blood flow (FBF) and net t-PA release before and during BK (25 to 400 ng/min) and methacholine (3.2 to 12.8 μg/min) in premenopausal women, postmenopausal women not using hormone replacement, young men, and older men. Baseline net t-PA release was similar among groups. Enalaprilat increased basal t-PA release in premenopausal (from 0.9±1.0 to 5.1±1.7 ng/min per 100 mL, P =0.023) and postmenopausal women (from −3.9±2.2 to 3.9±1.1 ng/min per 100 mL, P =0.010) but not in young or older men ( P =0.028 men versus women). Enalaprilat potentiated the effect of exogenous BK on FBF similarly in all groups. However, during enalaprilat, BK-stimulated t-PA release was greatest in premenopausal women (339.9±86.4 ng/min per 100 mL at the 100 ng/min dose, P P Conclusion— ACEI enhances basal t-PA release in women, independent of menopausal status, but not in men. During ACEI, both gender and menopausal status affect BK stimulated t-PA release.

Background This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors potentiate activation of the kallikrein-kinin system during cardiopulmonary bypass (CPB). Methods The effects of CPB on concentrations of bradykinin and its metabolite bradykinin 1–5 (BK1–5) were determined in 31 patients taking an ACE inhibitor who were randomized to continue ACE inhibitors until coronary artery bypass surgery (ACE inhibitor group, N = 19) or to discontinue them 48 hours before surgery (no ACE inhibitor group, N = 12). Arterial and venous blood was sampled before CPB, at 30 minutes of CPB, at 60 minutes of CPB, after separation from CPB, and on postoperative day 1. Results Arterial bradykinin (P < .001 [from 22.4 ± 24.1 fmol/mL to 86.2 ± 98.7 fmol/mL in the no ACE inhibitor group]) and arterial (P < .001) and venous (P = .016) BK1–5 concentrations increased significantly during CPB. Arterial bradykinin concentrations were significantly higher (P = .017), whereas BK1–5 concentrations (P = .024) and the molar ratio of BK1–5/bradykinin (P = .008) were significantly lower in the ACE inhibitor group compared with the no ACE inhibitor group. In addition, arterial bradykinin concentrations were significantly increased in smokers compared with nonsmokers (P = .015), when we controlled for the ACE inhibitor group. There was no effect of smoking on ACE activity (P = .597 overall). There was a significant inverse correlation between arterial bradykinin and mean arterial pressure (r2 = 0.2137, P = .010) and a significant correlation between arterial bradykinin and tissue-type plasminogen activator antigen concentrations (r2 = 0.174, P = .022) during CPB. Tissue-type plasminogen activator antigen was significantly higher in the ACE inhibitor group than in the no ACE inhibitor group (18.0 ± 7.8 ng/mL versus 12.4 ± 4.5 ng/mL, P = .016) but not in smokers compared with nonsmokers (P = .451). Conclusion Preoperative ACE inhibitors and smoking potentiate the kinin response to CPB and may contribute to the hemodynamic and fibrinolytic response observed during CPB. Clinical Pharmacology & Therapeutics (2004) 76, 379–387; doi:10.1016/j.clpt.2004.06.004

Thrombin and protease-activated receptor 1 (PAR1) activation antagonists were prepared based upon the peptide RPPGF, the angiotensin-converting enzyme breakdown product of bradykinin. A library of 72 peptides consisting of d and/or synthetic amino acids was designed with various substitutions in positions 1 to 5 in Arg-Pro-Pro-Gly-Phe (RPPGF). Two compounds, rOicPGF (TH146) and betaAK2K-4(rOicPGF) (MAP4-TH146), were characterized further. TH146 or MAP4-TH146 completely inhibits threshold gamma-thrombin-induced platelet aggregation at a concentration of 142 +/- 0.05 or 19 +/- 0.06 microM, respectively. TH146 completely inhibits threshold alpha-thrombin-induced washed platelet aggregation at 444 +/- 0.04 microM. TH146 or MAP4-TH146 blocks 2 nM alpha-thrombin-induced fibroblast calcium mobilization with an IC(50) value of 110 or 18 microM, respectively. Furthermore, significant prolongation of the activated partial thromboplastin time, prothrombin time, or thrombin clotting time occurs at 31, 62, or 7.8 microM TH146 and 0.4, 6.25, or 1.56 microM MAP4-TH146, respectively. TH146 and MAP4-TH146 inhibit both alpha-thrombin with a K(i) value of 97 and 49 microM, respectively, and factor VIIa with a K(i) value of 44 and 5 microM, respectively. Both TH146 and MAP4-TH146 specifically bind to the exodomain of recombinant PAR1. MAP4-TH146 (200 microM) completely blocks thrombocytin, a PAR1-activating snake venom protease, without inhibiting the enzyme's active site. TH146 inhibits gamma-thrombin-induced aggregation of mouse platelets, prolongs mouse bleeding times, and delays the time to mouse carotid artery thrombosis. TH146 and MAP4-TH146 inhibit human and mouse platelet aggregation and mouse thrombosis. Analogs of RPPGF are model compounds to develop PAR1 activation antagonists as well as direct inhibitors to thrombin and factor VIIa.

We studied the effect of salt intake and hypertension on the systemic kallikrein-kinin system (KKS), as measured by bradykinin (BK) 1-5, a stable circulating bradykinin metabolite, and the tissue KKS, as measured by urinary kallikrein excretion. Venous BK 1-5, urinary kallikrein, and components of the renin-angiotensin-aldosterone system were measured in 35 normotensive and 19 hypertensive subjects who were maintained on a high (200 mmol/day) or low (10 mmol/day) salt diet. Salt restriction decreased mean arterial pressure (MAP) (P < 0.001 overall) and the plasma angiotensin-converting enzyme (P = 0.017) and increased plasma renin activity (P < 0.001) and serum aldosterone (P < 0.001). There was an interactive effect of salt intake and hypertension on plasma BK 1-5 (P = 0.043), with BK 1-5 significantly lower during low compared with high salt intake in normotensive (24.7 +/- 2.6 versus 34.9 +/- 5.6 fmol/ml, P = 0.002) but not hypertensive subjects (30.6 +/- 4.6 versus 27.5 +/- 2.8 fmol/ml, P = 0.335). In normotensives, the change in plasma BK 1-5 from high to low salt intake correlated with the change in MAP (r = 0.533, P = 0.004). Urinary kallikrein was higher during low compared with high salt intake (P < 0.001) in both groups. There was no effect of salt intake on urinary BK 1-5. In summary, the systemic and renal KKSs act in tandem to modulate the response to salt intake. The systemic system is activated during high salt intake and counterbalances increased vascular response to pressors. With sodium restriction, the renal system is activated and counterbalances the increased sodium-retaining state induced by activation of the renin-angiotensin-aldosterone system. With hypertension, these modulating effects are diminished or lost, supporting a role for both systems in the development/maintenance of hypertension.

Background— Increased plasminogen activator inhibitor-1 (PAI-1) concentrations after coronary artery bypass grafting (CABG) are associated with increased risk of vein graft occlusion. Because angiotensin II stimulates PAI-1 expression, we tested the hypothesis that preoperative angiotensin-converting enzyme (ACE) inhibition decreases PAI-1 expression after CABG. Methods and Results— We measured the effects of cardiopulmonary bypass (CPB) on PAI-1 antigen and tissue-type plasminogen activator (tPA) antigen and activity in 31 patients taking an ACE inhibitor (ACEI) who were randomized to continue ACEI until the morning of surgery (ACEI group, n=19) or to discontinue it 48 hours before surgery (No-ACEI group, n=12). Arterial blood samples were taken at baseline before CPB, twice during CPB, after separation from CPB, and on postoperative day 1 (POD1). CPB caused an early decrease in PAI-1 antigen, followed by an increase in PAI-1 antigen on POD1 ( P P =0.013) and the change in PAI-1 antigen from baseline to POD1 ( P =0.009) were higher in the No-ACEI group (from 17.0±5.0 to 48.7±8.8 ng/mL) versus the ACEI group (from 19.9±3.4 to 33.1±6.2 ng/mL). There was no significant difference between the 2 groups in intraoperative tPA activity ( P =0.259); however, the increase in tPA activity was significantly greater in the ACEI group than in the No-ACEI group ( P =0.030). Conclusions— Preoperative ACEI attenuates the increase in PAI-1 after CABG, suggesting a role for ACE inhibition in reducing the risk of acute graft thrombosis.

Previous authors (e.g., B. R. Sarason, Shearin, Pierce, & Sarason, 1987) have found that perceived social support can affect the emotional well-being of an individual. Consequently, the effective assessment of social supports is a key issue in both research and clinical practice. The Multidimensional Scale of Perceived Social Support (MSPSS; Zimet, Dahlem, Zimet, & Farley, 1988) divides perceived social support into 3 distinct constructs-that derived from Family members, from Friends, and from Significant Others. This study is the first to assess the MSPSS using confirmatory factor analysis in both a college student (N = 549) and psychiatric outpatient (N = 156) sample. Based on several goodness-of-fit indicators, a 3-factor model for the MSPSS was supported in both samples, as was a single, higher order domain of Global social support. The perceived social support factors of Family and Friends consistently had the strongest associations with symptomatology. These results support the use of the MSPSS as a brief instrument for assessing the hierarchical structure of perceived social support in a variety of samples.

Angiotensin (Ang) II induces oxidative stress in vitro and in animal models of hypertension. We tested the hypothesis that Ang II increases oxidative stress in human hypertension, as assessed by plasma F2-isoprostane concentrations. Plasma F2-isoprostanes, hemodynamic and endocrine parameters were measured at baseline and following a 55 min infusion of 3 ng/kg/min Ang II in 13 normotensive and 13 hypertensive volunteers ingesting a high- (200 mmol/d) or low- (10 mmol/d) sodium diet. Mean arterial pressure (MAP) and body mass index were higher in hypertensive subjects. Ang II infusion increased MAP (p.001) and plasma aldosterone concentrations (p.001) and decreased plasma renin activity (p.001) and renal plasma flow (p.001) to a similar extent in both groups. Plasma F2-isoprostane concentrations were similar at baseline. There was no effect of Ang II on F2-isoprostane concentrations during low-salt intake in either group (normotensive 51.7 +/- 7.1 to 53.7 +/- 6.5 pg/ml and hypertensive 52.2 +/- 8.2 to 56.2 +/- 10.0 pg/ml; mean +/- SE). During high-salt intake, Ang II increased F2-isoprostane concentrations in the hypertensive group (52.3 +/- 7.2 to 63.2 +/- 10.4 pg/ml, p=0.010) but not in the normotensive group (54.2 +/- 4.4 to 58.9 +/- 6.6 pg/ml, p=0.83). Acute Ang II infusion increases oxidative stress in vivo in hypertensive humans. The renin-angiotensin system may contribute to oxidative stress in human cardiovascular disease.

Bradykinin, through its B 2 receptor, stimulates endothelial release of a number of vasodilators, such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Angiotensin-converting enzyme (ACE) inhibitors enhance the effects of local bradykinin by decreasing its degradation and by increasing B 2 receptor sensitivity. Clinical and experimental studies demonstrate that blockade of the B 2 receptor attenuates the antihypertensive, antihypertrophic, and antiatherosclerotic effects of ACE inhibitors. Thus, the evidence strongly supports a role for bradykinin in mediating the cardiovascular benefits of ACE inhibitors.

Cyclopentenone prostaglandins (PGs), particularly those of the J-series, affect proliferation and differentiation in a number of cell lines. J-ring PGs have been shown to be ligands for the peroxisome proliferator-activated receptor (PPAR)-gamma and to modulate NF-kappaB-mediated gene transcription. We have previously reported that large quantities of eicosanoids, including PGJ(2), are produced by the human colorectal cancer cell line HCA-7 while lesser amounts of Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) are formed. In this and other cell lines, cyclopentenone PGs have been shown to increase cell proliferation, but factors that influence their formation and metabolism are poorly understood. Unlike other PGs, cyclopentenone PGs contain alpha,beta-unsaturated carbonyl groups that readily adduct various biomolecules such as glutathione (GSH) in vitro. We now report that in HCA-7 cells, PGJ(2) is largely metabolized by conjugation to GSH. Characterization of the adducts by liquid chromatography (LC)-mass spectrometry (MS) revealed two major metabolites consisting of (1) a novel GSH conjugate in which the carbonyl at C-11 of PGJ(2) is reduced and (2) intact PGJ(2) conjugated to GSH. Approximately 70% of the PGJ(2) added to HCA-7 cells was esterifed to GSH after 2 h of incubation, suggesting this pathway represents the major route of metabolic disposition of PGJ(2) in HCA-7 cells.

Free radical-initiated oxidant injury and lipid peroxidation have been implicated in a number of neural disorders. Docosahexaenoic acid is the most abundant unsaturated fatty acid in the central nervous system. We have shown previously that this 22-carbon fatty acid can yield, upon oxidation, isoprostane-like compounds termed neuroprostanes, with E/D-type prostane rings (E(4)/D(4)-neuroprostanes). Eicosanoids with E/D-type prostane rings are unstable and dehydrate to cyclopentenone-containing compounds possessing A-type and J-type prostane rings, respectively. We thus explored whether cyclopentenone neuroprostanes (A(4)/J(4)-neuroprostanes) are formed from the dehydration of E(4)/D(4)-neuroprostanes. Indeed, oxidation of docosahexaenoic acid in vitro increased levels of putative A(4)/J(4)-neuroprostanes 64-fold from 88 +/- 43 to 5463 +/- 2579 ng/mg docosahexaenoic acid. Chemical approaches and liquid chromatography/electrospray ionization tandem mass spectrometry definitively identified them as A(4)/J(4)-neuroprostanes. We subsequently showed these compounds are formed in significant amounts from a biological source, rat brain synaptosomes. A(4)/J(4)-neuroprostanes increased 13-fold, from a basal level of 89 +/- 72 ng/mg protein to 1187 +/- 217 ng/mg (n = 4), upon oxidation. We also detected these compounds in very large amounts in fresh brain tissue from rats at levels of 97 +/- 25 ng/g brain tissue (n = 3) and from humans at levels of 98 +/- 26 ng/g brain tissue (n = 5), quantities that are nearly an order of magnitude higher than other classes of neuroprostanes. Because of the fact that A(4)/J(4)-neuroprostanes contain highly reactive cyclopentenone ring structures, it would be predicted that they readily undergo Michael addition with glutathione and adduct covalently to proteins. Indeed, incubation of A(4)/J(4)-neuroprostanes in vitro with excess glutathione resulted in the formation of large amounts of adducts. Thus, these studies have identified novel, highly reactive A/J-ring isoprostane-like compounds that are derived from docosahexaenoic acid in vivo.

Abstract —Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with increased circulating PAI-1 antigen and increased risk of thrombotic cardiovascular events. A 4G/5G polymorphism located 675 bp upstream from the transcription start site of the PAI-1 gene affects PAI-1 antigen concentrations. To test the hypothesis that PAI-1 4G/5G genotype influences the effect of activation of the RAAS on PAI-1 expression, we measured morning PAI-1 antigen concentrations in 76 subjects with essential hypertension during low (10 mmol/d) and high (200 mmol/d) salt intake. Low salt intake was associated with activation of the RAAS as measured by plasma renin activity (2.3±0.2 versus 0.5±0.0 ng angiotensin I · mL −1 · h −1 , P P =0.017) and PAI-1 4G/5G genotype (F=7.6, P =0.001) on PAI-1 antigen. More importantly, there was a significant interactive effect (F=7.8, P =0.001) of salt intake and PAI-1 4G/5G genotype on PAI-1 antigen. PAI-1 4G/5G genotype influenced the relationship between serum triglycerides and PAI-1 antigen such that the relationship was significant only in 4G homozygotes during either high ( R 2 =0.31, P =0.014) or low ( R 2 =0.37, P =0.006) salt intake. This study identifies an important gene-by-environment interaction that may influence cardiovascular morbidity and the response to pharmacological therapies that interrupt the RAAS.

Bradykinin is a vasoactive nonapeptide involved in cardiorenal physiology and inflammatory states. It has been linked to the pathophysiology of hypertension and diabetes. Correlating levels of bradykinin with disease states has been hampered by its rapid degradation, artifactual production during blood sampling, and nonspecific radioimmunoassay techniques. We previously identified BK1-5 as the stable in vivo plasma metabolite of systemic bradykinin in humans. We now report a sensitive and specific assay method for BK1-5 in human blood utilizingliquid chromatography–tandem mass spectrometry(MS) with electrospray ionization. [ 13 C 2 , 15 N]Glycine was incorporated into chemically synthesized BK1-5 for use as an internal standard. Blood samples (5 ml) were collected into 15-ml chilled ethanol to prevent artifactual kinin production and degradation. BK1-5 in ethanolic plasma supernatant was purified on a polymeric solid phase extraction cartridge. MS analysis was in the selective reaction monitoring mode. Precision of the assay is ±7.5% and accuracy is 99%. Recovery of BK1-5 through sample preparation was 43% and the lower limit of detection is 4 fmol/ml blood. Concentrations of BK1-5 in 12 normal volunteers were 44.2 ± 7.1 fmol/ml blood (mean ± SE). During blood sampling, no artifactual production of BK1-5 was detected for up to 60 s prior to denaturing the sample. This assay provides the first accurate and precise method using MS to quantify BK1-5 in human blood as a marker for the production of systemic bradykinin in humans.

Background —Bradykinin stimulates dose-dependent tissue plasminogen activator (tPA) release from human endothelium. Although bradykinin is known to cause vasodilation through B 2 receptor–dependent effects on NO, prostacyclin, and endothelium-derived hyperpolarizing factor production, the mechanism(s) underlying tPA release is unknown. Methods and Results —We measured the effects of intra-arterial bradykinin (100, 200, and 400 ng/min), acetylcholine (15, 30, and 60 μg/min), and nitroprusside (0.8, 1.6, and 3.2 μg/min) on forearm vasodilation and tPA release in healthy volunteers in the presence and absence of (1) the B 2 receptor antagonist HOE 140 (100 μg/kg IV), (2) the NO synthase inhibitor l - N G -monomethyl- l -arginine (L-NMMA, 4 μmol/min intra-arterially), and (3) the cyclooxygenase inhibitor indomethacin (50 mg PO TID). B 2 receptor antagonism attenuated vasodilator ( P =0.004) and tPA ( P =0.043) responses to bradykinin, without attenuating the vasodilator response to nitroprusside ( P =0.36). L-NMMA decreased basal forearm blood flow (from 2.35±0.31 to 1.73±0.22 mL/min per 100 mL, P =0.01) and blunted the vasodilator response to acetylcholine ( P =0.013) and bradykinin ( P =0.07, P =0.038 for forearm vascular resistance) but not that to nitroprusside ( P =0.47). However, there was no effect of L-NMMA on basal ( P =0.7) or bradykinin-stimulated tPA release ( P =0.45). Indomethacin decreased urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin F 1α ( P =0.04). The vasodilator response to endothelium-dependent ( P =0.019 for bradykinin) and endothelium-independent ( P =0.019) vasodilators was enhanced during indomethacin administration. In contrast, there was no effect of indomethacin alone ( P =0.99) or indomethacin plus L-NMMA ( P =0.36) on bradykinin-stimulated tPA release. Conclusions —These data indicate that bradykinin stimulates tPA release from human endothelium through a B 2 receptor–dependent, NO synthase–independent, and cyclooxygenase-independent pathway. Bradykinin-stimulated tPA release may represent a marker for the endothelial effects of endothelium-derived hyperpolarizing factor.

Undergraduates pressed computer keys to move a cursor through a visual matrix under a multiple fixed ratio 18/differential-reinforcement-of-low-rate 6-s schedule. In Experiment 1, instructions to “Go Fast” or “Go Slow” produced schedule¬insensitive performances for the majority of participants. Subsequent manipulations designed to increase reinforcer magnitude and to place social contingencies on effective cursor movement failed to undermine instructed insensitivity. Such instructed insensitivity may be caused by operant blocking, that is, response-rate instructions prevented acquisition of control by stimulus features associated with the reinforcement schedule. In Experiment 2, participants showing original compliance with response-rate instructions were exposed to the schedule contingencies without instructions. Participants thus exposed to both reinforcer points and schedule-discriminative stimuli were unlikely to show insensitivity upon reintroduction of the instructions, consistent with an operant blocking interpretation of insensitivity. The importance of examining instructional effects in terms of basic principles of stimulus control was emphasized.

The morphology of galaxies can be quantified to some degree using a set of scale-invariant parameters. Concentration (C), Asymmetry (A), Smoothness (S), the Gini index (G), relative contribution of the brightest pixels to the second order moment of the flux (M20), ellipticity (E), and the Gini index of the second order moment (GM) have all been applied to morphologically classify galaxies at various wavelengths. Here we present a catalog of these parameters for the Spitzer Survey of Stellar Structure in Galaxies (S4G), a volume-limited near-infrared imaging survey of nearby galaxies using the 3.6 and 4.5 micron channels of the IRAC camera. Our goal is to provide a reference catalog of near-infrared quantified morphology for high-redshift studies and galaxy evolution models with enough detail to resolve stellar mass morphology. We explore where normal, non-interacting galaxies -those typically found on the Hubble tuning fork- lie in this parameter space and show that there is a tight relation between Concentration and M20 for normal galaxies. M20 can be used to classify galaxies into earlier and later types (e.g., to separate spirals from irregulars). Several criteria using these parameters exist to select systems with a disturbed morphology, i.e., those that appear to be undergoing a tidal interaction. We examine the applicability of these criteria to Spitzer near-infrared imaging. We find that four relations, based on the parameters A&S, G&M20, GM, and C&M20, respectively, select outliers in the morphological parameter space, but each selects different subsets of galaxies. Two criteria (GM > 0.6, G > -0.115 x M20 + 0.384) seem most appropriate to identify possible mergers and the merger fraction in near-infrared surveys. We find no strong relation between lopsidedness and most of these morphological parameters, except for a weak dependence of lopsidedness on Concentration and M20., 22 pages, 19 figures, 7 tables. Full catalogs available on request. Accepted by ApJ

The published literature describing clinical evidence used in treatment decisionmaking for the management of tooth loss continues to be characterized by a lack of consistent outcome measures reflecting not only clinical performance but a range of patient concerns. Recognizing this problem, an international group of clinicians, educators, and scientists with a focus on prosthodontics formed the Oral Rehabilitation Outcomes Network (ORONet) to promote strategies for improving health based on comprehensive, patient-centered evaluations of comparative effectiveness of therapies for oral rehabilitation. An initial goal of ORONet is to identify outcome measures for prosthodontic therapies that represent multiple domains with patient relevance, are amenable to utilization in both institutional and practice-based environments, and have established validity. Following a model used in rheumatology, the group assessed the prosthodontic literature, with an emphasis on implantbased therapies, for outcomes related to longevity and functional, psychologic, and economic domains. These systematic reviews highlight a need for further development of standardized outcomes that can be integrated across clinical and research environments. Int J Prosthodont 2013;26:XXX–XXX. doi: 10.11607/ijp.3400

Dilated cardiomyopathy (DCM) associates left ventricular (LV) dilatation and systolic dysfunction and is a major cause of heart failure and cardiac transplantation. LMNA gene encodes lamins A/C, proteins of the nuclear envelope. LMNA mutations cause DCM with conduction and/or rhythm defects. The pathomechanisms linking mutations to DCM remain to be elucidated. We investigated the phenotype and associated pathomechanisms of heterozygous Lmna(K32/) (Het) knock-in mice, which carry a human mutation. Het mice developed a cardiac-specific phenotype. Two phases, with two different pathomechanisms, could be observed that lead to the development of cardiac dysfunction, DCM and death between 35 and 70 weeks of age. In young Het hearts, there was a clear reduction in lamin A/C level, mainly due to the degradation of toxic K32-lamin. As a side effect, lamin A/C haploinsufficiency probably triggers the cardiac remodelling. In older hearts, when DCM has developed, the lamin A/C level was normalized and associated with increased toxic K32-lamin expression. Crossing our mice with the Ub(G76V)-GFP ubiquitin-proteasome system (UPS) reporter mice revealed a heart-specific UPS impairment in Het. While UPS impairment itself has a clear deleterious effect on engineered heart tissues force of contraction, it also leads to the nuclear aggregation of viral-mediated expression of K32-lamin. In conclusion, Het mice are the first knock-in Lmna model with cardiac-specific phenotype at the heterozygous state. Altogether, our data provide evidence that Het cardiomyocytes have to deal with major dilemma: mutant lamin A/C degradation or normalization of lamin level to fight the deleterious effect of lamin haploinsufficiency, both leading to DCM.

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Item does not contain fulltext 2012 Annual Conference of the Association for Borderlands Studies Houston, 13 april 2012

A stereospecific microassay for the simultaneous determination of morphine and active metabolites morphine-6-β-D-glucuronide, morphine-3-β-D-glucuronide and normorphine using reversed-phase high-performance liquid-chromatography with ultraviolet detection is described. Solid-phase extraction was followed by chromatography on an octadecylsilica column eluted by 16.5% acetonitrile in phosphate buffer, pH 2.1 with sodium dodecyl sulfate as an ion-pairing agent. Using an 80 μl sample size the limits of quantitation were 94 ng/ml for all drugs. Coefficients of variation ranged from 2.0% to 6.3%. The assay is specific and separates the stereoisomers morphine-6-α-D-glucuronide and morphine-6-β-D-glucuronide. This microassay has been applied to samples of guinea pig plasma, following subcutaneous injections of morphine, and to hepatic microsomal enzyme preparations from a pregnant guinea pig. Neonatal guinea pigs produce substantial amounts of morphine-3-glucuronide and morphine-6-glucuronide from morphi...

A method for simultaneous extraction of cocaine and metabolites benzoylnorecgonine, benzoylecgonine and norcocaine from meconium was developed. The procedure uses solid-phase extraction columns with both cation-exchange and hydrophobic properties after vortex-mixing meconium with methanol. Chromatography utilizes reversed-phase high-performance liquid chromatography with a C18 column and phosphate buffer-acetonitrile as mobile phase. The method is specific and sensitive to 50 ng/g meconium for all compounds. Standard curves are linear from 0.05 to 5.0 micrograms/g (r2or = 0.989). Intra-assay coefficients of variation wereor = 6.9%. Meconium from infants exposed to cocaine in utero contained varying combinations of the four drugs.

Item does not contain fulltext THE 2010 EUROPEAN CONFERENCE OF THE Association for Borderlands Studies Veroia, 25 september 2010 6 p.